Note: Descriptions are shown in the official language in which they were submitted.
The present invention relates to certain novel
2-substituted and 2,6-disubstituted penem compounds which
possess potent antibiotic activity. ~lso provided are
various novel intermediates useful in preparing the bio-
logically active penem derivatives and various processes
for the producton of the intermediates and active compounds.
The penem ring system has the formula
', ~S~
O 7 1 ~ 2
'`,
and systematically can be designated as 7-oxo-4-thia-1-
azabicyclo[3.2.0]hept-2-ene. For the sake of
-1- ~
;
61
simplicity, it is named "2-penem" in the present
application and the numbering system used is as follows:
-~ ~ S
0 4 ~ 3
There is thus provided by the present invention
the novel penem compounds having the formula
~N /~
C02Z
wherein Z is hydrogen or an easily removable ester
protecting group; X is
(a) a radical of the formula
(i) ~ORa in which Ra is hydrogen;
(ii) -CORb in which Rb is hydrogen, hydroxy,
optionally substituted (lower) alkyl or
optionally ring-substituted phenyl or
heterocyclic, the substituents on the alkyl
group being one or more (preferably 1 or 2)
of halo, hydroxy, oxo, carboxy,
carb(lower)alkoxy, carbamoyl, (lower)alkoxy,
amino, (lower) alkylamino, di-
_ (lower)alkylamino, (lower)alkanoylamino or
optionally substituted phenyl or heterocyclic
and the substituents on the phenyl or
heterocyclic rings being one or more
(preferably 1 or 2) of hydroxy,
, .,~
.,,. ~
(lower)alkoxy, ha:lo, (lower) alkyl,
halo(lower) alkyl, methanesulfonyl, oxo,
(lower)alkylthio, amino, (lower)alkylamino,
di(lower)alkylamino, (lower)alkanoylamino,
(lower) alkanoyloxy, carboxy, carboxy (lower)
alkyl, sulfo or sulfo(lower) alkyl; or
(iii) -OCORC in which Rc is amino, (lower)-
alkylamino, di(lower)alkylamino or optionally
substituted (lower)alkyl in which the
lo substituents are as defined under (ii); or
(b) a substituted (lower)aliphatic, (lower)-
cycloaliphatic or (lower)cycloaliphatic(lower)-
aliphatic radical or a ring-substituted phenyl,
phenyl(lower)alkyl, heterocyclic, heterocyclic
(lower)alkyl or heterocyclicthio(lower)alkyl
radical, substituents for the above-mentioned
aliphatic, cycloaliphatic, phenyl or heterocyclic -
groups being
NR
Il
(i) -CNR2R3 or -N=C-NR2R3 in which Rl is
Rl
hydrogen, (lower)alkyl or phenyl and R2 and
R3 are each independently hydrogen,
(lower)alkyl, phenyl or benzyl;
(ii) -ORd in which Rd is amino, (lower)alkylamino,
di(lower)alkylamino, substituted
(lower)alkyl, (lower)alkenyl or optionally
ring-substituted phenyl, phenyl(lower)alkyl,
_ heterocyclic or heterocyclic (lower)alkyl,
the substituents
. ., ."
36~
on the alkyl, phenyl and heterocyclic groups
being as defined under (a) (ii);
(iii) -O(CH2)nORr in which n is an integer from 1
~- to 6 and Rr is optionally substituted
(lower)alkyl or optionally ring-substituted
phenyl or heterocyclic, the substituents on
~ the alkyl, pheny:l or heterocyclic groups
: being as defined under (a) (ii);
(iv) -OCORr' in which Rrl is amino, (lower)-
alkylamino, di(lower)alkylamino or Rr,with
the proviso that Rrl may not be unsubstituted
(lower)alkyl;
(v) -OS03H;
. o
(vi) -OP(OH)2;
(vii) -OS02Rr in which Rr is as defined under (b)
( i ii ) ;
O
(viii) -OP (ORe) (ORr) in which Re is (lower)alkyl
and Rr is as defined under (b) (iii);
(ix) -S(O)nRd in which n is 0, 1 or 2 and Rd is as
defined under (b)(ii) or is in the case where
NR
n=O -C-NR5R6 in which R4 is hydrogen or
(lower) alkyl and R5 and R6 are each
independently hydrogen or (lower)alkyl, with
the proviso that Rd may not be unsubstituted
phenyl;
_(x) -CORf in which Rf is amino(lower) alkyl,
(lower) alkylamino (lower)alkyl, di(lower)-
alkylamino(lower) alkyl, -NHNH2, -NR17NR18,
-- 4
666~
-NHR19~ -S-R17, ~0(CH2)n-A-Re or ~NReRg in
which R17, R18 and Re are (lower)alkyl~ R19
; is hydrogen or (lower)alkyl, A i5 O, S, NH or
-- NCH3 and n and Rg are as defined under (b)
(iii) and (b)(viii);
(xi) -PO(ORW)2 in which Rw i~ hydrogen or
(lower)alkyl;
(xii) -NHRh in which Rh is optionally substituted
~ phenyl, optionally substituted heterocyclic,
- 10 -CH=NH, -SO3H, -OH, (lower)alkoxy, amino,
(lower) alkylamino, di(lower)alkylamino, -
NHCOCH3, -CS2CH3~ -S02CH3' S2 ~
S S S
-SO2NH2, -CNH2, -CNHCH3, -C-NH
NH
-C-NR7R8 in which R7 and R8 are each
independently (lower) alkyl, phenyl or NH NH
NH
phenyl(lower)alkyl, -C-Rg in which Rg is
(lower)alkyl, phenyl or phenyl(lower)- alkyl,
O
or -C-Ri in which Ri is amino(lower)- alkyl,
-NH2, (lower)alkylamino, di(lower)-
alkylamino, -NH ~ , -NH-C-R1o
- in which R1o is (lower)alkyl or optionally
substituted phenyl or heterocyclic, the
phenyl and heterocyclic substituents being
NH
defined under (a)(ii), -NH-C-NH2,
(lower)alkoxy,
-- 5 --
....
~6~
-OCH2 ~ , -OCH2 ~ NO2 or -
o(CH2)2Si(CH3)3;
O
(xiii) -S-C-R11 in which R11 is (lower)alkyl
substituted by amino, (lower) alkylamino or
d~(lower) alkylamino;
(xiv) -NRjRk in which Rj is (lower)alkyl and Rk is
(lower)alkyl, (lower) alkoxy, heterocyclic,
O
amino, or -C-R1 in which Ri i8 a~ defined
under (b)(xii) or, when taken together with
the nitrogen, Rj and Rk represent
o
-N ~ , providing that
~ ~
when Rk is amino or -CH2CH2NH2, Rj is methyl
and also providing that Rj and Rk may not
both be (lower)alkyl;
(xv) -NRj'Rk' in which Rj' is (lower)alkoxy and
Rk' is (lower) alkyl, heterocyclic,
amino(lower) alkyl, (lower) alkylamino-
(lower)alkyl, di(lower)alkylamino(lower)-
O
; - alkyl or -C-Ri in which Ri i5 as defined
under (b)(xii) or, when taken together with
the nitrogen, Rj' and Rk' represent
O
_
O
. -- 6 --
. .
,
, - ,1
.
.,
., ,
,,
,,
~'
(xvi) -NRlRmRn in which Rl, Rm and Rn are each
independently (lower)alkyl or when taken
together with the nitrogen, represent
-N~;
(xvii) -N=CHXRx in which Rx is (lower) alkyl or
optionally ring-substituted phenyl or
heterocyclic, the substituents on the phenyl
or heterocyclic ring being as defined under
(a)(ii);
(xviii) -N=CRXRy in which Ry is (lower) alkyl or
optionally ring-substituted phenyl or
heterocyclic, the phenyl and heterocyclic
substituents being as defined under (a)(ii), .
and Rx is as defined under (b)(xvii);
(xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy,
amino, di(lower)alkylamino or
20 -NH ~ ; or
- NOH
(xx) C (CH2)nNR15Rl6 in which n is an integer
from 1 to 6 and R15 and Rl6 are each
independently hydrogen or (lower)alkyl; and
Y is hydrogen or a radical selected from the group
consisting of
(a) _optionally substituted (lower)aliphatic,
(lower)cyclo-aliphatic or (lower) cycloaliphatic
: (lower) aliphatic, the substituents being one or
: more of hydroxy, (lower)alkoxy, optionally
substituted phenyloxy, optionally substituted
: heterocyclicoxy, optionally substituted
(lower)alkylthio optionally substituted
~ phenylthio, optionally substituted
:'~
-- 7
~'~
.
:, .
:;
heterocyclicthio, mercapto, amino,
: tlower)alkylamino, di(lower)alkylamlno,
(lower)alkanoyloxy, (lower)alkanoylamlno,
~ptionally substituted phenyl, optionally
substituted heterocycllc, carboxy, carb
(lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl,
N,N-di(lower)alkylcarbamoyl, halo, cyano, oxo,
thioxo, -SO3H, -OSO3H, -SO2-(lower)alkyl,
O
(lower)alkylsulfinyl, nitro, phosphono or -OP
(ORe)(ORr) in which Re and Rr are as defined above
the substituents on the (lower)alkylthio group
being one or more of halo, hydroxy, (lower)alkoxy,
; 15 amino, (lower)alkanoylamino or optionally
substituted phenyl or heterocyclic and the phenyl
or heterocyclic substituents above being one or
more of hydroxy, (lower)alkoxy, halo,
(lower)alkyl, halo (lower)alkyl, methanesulfonyl,
(lower)alkylthio, amino, (lower)alkanoylamino,
(lower)alkanoyloxy, carboxy, carboxy(lower)alkyl,
sulfo or sulfo(lower)alkyl;
(b) -ORS in which Rs i8 optionally substituted
(lower)alkyl or (lower) alkanoyl or optionally
substituted phenyl or heterocyclic, the
substituents on the alkyl and alkanoyl being one
or more of halo, hydroxy, (lower)alkoxy,
(lower)alkylamino, di (lower)alkylamino, amino,
oxo, (lower)alkanoylamino or optionally
substituted phenyl or heterocyclic and the
substituents on the phenyl or heterocyclic being
one or more of hydroxy, (lower)alkoxy halo,
(lower) alkyl, halo (lower) alkyl,
methanesulfonyl, (lower)alkylthio,
(lower)alkylamino, di(lower)alkylamino, amino,
: (lower)alkanoylamino, (lower) alkanoyloxy,
carboxy, carboxy(lower)alkyl, sulfo or
sulfo(lower)alkyl;
8 --
' ',: .''-
:,
l,~f~
(c) S(O)nRs in which n is o, 1 or 2 and Rs is as
defined above;
(d) halo; and
(e) _optionally substituted phenyl or heterocyclic in
which the substituents are one or more of hydroxy,
(lower)alkoxy, halo, (lower)alkyl, halo
(lower)alkyl, methanesulfonyl, (lower)alkylthio,
amino, (lower)alkylamino, di(lower)alkylamino,
(lower)alkanoylamino, (lower)alkanoyloxy,
carboxy, carboxy(lower)alkyl, sulfo or
sulfo(lower)alkyl; or a pharmaceutically
acceptable salt thereof, with the proviso that
when Y is hydrogen, X may not be -CH20CH2CH20CH3.
The compounds of formula I wherein Z is
hydrogen (and their pharmaceutically acceptable salts and
physiologically hydrolyzed esters) are potent antibacterial
agents. The remaining compounds are useful intermediates
for preparation of the biologically active penems.
Substituent groups disclosed above for the 2- and
6-positions of the penem ring may be further defined as
follows:
(a) Halo includes chlorine, bromine, fluorine
and iodine. Preferred halo substituents are
chlorine and fluorine;
(b) (Lower)alkyl includes both straight and branched
chain saturated aliphatic hydrocarbon radicals
having from 1-6 carbon atoms inclusive, e.g.
methyl, ethyl, n-propyl, isopropyl, n-butyl,
_isobutyl, sec-butyl, tert-butyl, n-pentyl,
isopentyl, n-hexyl, etc. Preferred (lower)alkyl
substituents have from 1-4 carbons and most
preferably 1-2 carbons;
~'
_ g _
.. ~,
,A_,
'
'
~'
(c) (Lower)aliphatic is intended to include acyclic
straight and branched chain saturated and
-unsaturated hydocarbon radicals having from 1-6
carbon atoms inclusive. The unsaturated radicals
may contain one or more double or triple bonds,
but preferably contain either one double bond or
one triple bond. Examples of (lower) aliphatic
are methyl, ethyl, n-propyl, isopropyl, n-butyl,
t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, 1-
propenyl, 2-propenyl, isopropenyl, 2-methyl-2-
propenyl, ethynyl and 2-propenyl. The most
preferred aliphatic radicals are (lower)alkyl as
ln (b);
(d) (Lower)cycloaliphatic is intended to represent
alicyclic saturated and unsaturated hydrocarbon
radicals having from 3-8 ring carbon atoms,
preferably 3-6 carbon atoms. The unsaturated ring
may contain one or more (preferably one) double
bond. Examples of this group include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-
cyclohexadienyl and cyclohexienyl
(e) (Lower)cycloaliphatic (lower)aliphatic represents
cycloaliphatic-aliphatic radicals having 3-8
carbon atoms (preferably 3-6) in the cyclo-
aliphatic ring and 1-6 carbon atoms (preferably 1-
4 and most preferably 1-2) in the aliphatic
,
-- 10 --
~,i,~.',
;
,~
~6f~
portion. Examples include cyclopropylmenthyl,
cyclopropylethyl, cyclopropylpentyl, cyclo-
butylethyl, cyclopentylmethyl, cyclohexylmethyl,
_cyclopropenylmethyl, cyclopentenylethyl,
cyclopropylethenyl, cyclopropylethynyl, etc. The
most preferred radicals of this type are
cycloalkyl-alkyl in which the cycloalkyl portion
contains 3-6 carbons and the alkyl portion
contains 1-2 carbons;
(f) (Lower)alkoxy includes Cl-C6 alkoxy radicals, the
alkyl portion of which being defined as in (b).
Examples include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-
pentyloxy, etc. Preferred are Cl-C4 alkoxy and
most preferred are Cl-C2 alkoxy;
(g) (Lower)alkylthio includes Cl-C6 alkylthio
radicals in which the alkyl portion is as defined
under (b). Examples include methylthio, ethylthio
and n-butylthio;
(h) (Lower)alkylamino includes Cl-C6 alkylamino
radicals in which the alkyl portion is as under
(b). Examples are methylamino, ethylamino, n-
propylamino and n-butylamino;
(i) Di(lower)alkylamino represents di Cl-C6 alkylamino
in which each alkyl is as defined under (b).
Examples are dimethylamino and diethylamino;
(j) (Lower)alkanoyloxy represents radicals of the
O
_formula (lower)alkyl-C'-O- in which alkyl is as
defined under (b);
(k) (Lower)alkanoylamino includes radicals of the
O
formula (lower)alkyl-C-NH- in which alkyl is as
under (b);
o
(l) Carb(lower)alkoxy represents -C-(lower)alkoxy in
which (lower)alkoxy is as under (f);
(m) Halo(lower)alkyl represents alkyl radicals in
which one or more hydrogen atoms are replaced by a
halogen atom;
(n) Sulfo(lower)alkyl represents - (CH2)nSO3H in
which n is 1-6;
(o) Carboxy(lower)alkyl represents - (CH2)nCOOH in
which n is 1-6;
(p) Phenyl (lower)alkyl represents -(CH2)
in which n is 1-6;
(q) (Lower)alkylamino(lower)alkyl represents
-(CH2)nNH-(lower)alkyl in which n is 1-6 and
alkyl is as defined under (b);
(r) Di(lower)alkylamino(lower)alkyl represents
~ (lower)alkyl
- (CH2)nN in which n is 1-6
~ (lower) alkyl
_
~ 30 and each alkyl is as defined under (b);
o
(s) (Lower)alkanoyl represents (lower)alkyl-C-
in which alkyl is as under (b);
(t) N-(Lower)alkylcarbamoyl represents
O
(lower)alkyl-HN-C- in which alkyl is as under (b);
- 12 -
.
..... .
; l~f~~l
(u) N,N-Di(lower)carbamoyl represents
(lower)alkyl O
N-C- in which each alkyl is
llower)alkYl
as under (b);
(v) Amlno(lower)alkyl represents -(CH2)nNH2 in
which n is 1-6;
(w) Hydroxyamino (lower)alkyl represents - (CH2)nNHOH
in which n is 1-6;
o
(x) (Lower)alkylsulfinyl represents -S- (lower)alkyl
in which (lower)alkyl is as defined above under
(b); and
(y) (lower)alkenyl represents straight or branched
unsaturated aliphatic hydrocarbon radicals con-
taining one double bond and having from 2-6 carbon -
atoms inclusive, e.g. vinyl, allyl, isopropenyl,
2- or 3-methallyl or 3-butenyl.
The term "heterocyclic" as used herein is intended
to include heteromonocyclic and heterobicyclic residues of
aromatic character as well as appropriate partially or
wholly saturated residues, said heterocyclic residues con-
taining at least one heteroatom selected from oxygen, sulfur
and nitrogen and being bonded to the penem ring carbon atom
via a ring carbon atom. The preferred heterocyclic groups
are either S- or 6-membered monocyclic radicals or fused 6,6
or 5,6 bicyclic radicals. Illustrative of suitable
heterocyclic radicals are the following:
[~ ~;~ ~L N
~.
, ~,
12f~6~
¢~H ~ ~r~
~N ~ ~N~
~ N ~ N
H H
N _N
N ~ N_N
Nl N-1~ N I 11 ~NI
~N ~1 ~ S ~!J J~ O ~N N `S ~ ~N
~N ~ N ~N ~,N-
a n d
-- 1 4 --
12~6~
Similarly, the terms heterocyclic-(lower) alkyl,
heterocyclic-thio-(lower)alkyl, heterocyalicoxy and
heterocyclic-thio represent - (CH2)n-Heterocyclic,
(CH2)n-S-Heterocyclic, -O-Heterocyclic and -S-
Heterocyclic, respectively, in which n is 1-6
(preferably 1 or 2).
Since an asymmetric carbon atom is present in
the 2-substituted compounds of formula I, such
compounds may exist either in the form of
racemic mixtures (R, S form) or as the individual
dextrorotatory and levorotatory (R- and S- forms)
optical isomers. Preferred are the compounds in which
the configuration of the 5-carbon atom corresponds to
that of natural penicillin (5R-configuration). Sub-
stituents at the 5- and 6- positions of the 2,6-
disubstituted penems may be in the cis or trans
position in relation to one another. Where the penem
6-substituent contains an asymmetric carbon atom, the
resulting isomers are identified herein as isomers A,
B, C and D (see Example 58 for stereochemistry). The
preferred isomer in compounds of this type is isomer B.
Separation of the various optical and geometric isomers
may be carried out by conventional separation and
resolution procedures well-known to those skilled in
the art.
The present invention is intended to include the
compounds o-f formula I in the form of isomer mixtures and
also in the form of the individual separated and resolved
isomers.
The pharmaceutically acceptable salts referred to
above include the nontoxic carboxylic acid salts, e.g.
nontoxic metallic salts such as sodium, potassium, calcium,
aluminum and magnesium, the ammonium B alt and salts with
nontoxic amines such as trialkylamines (triethylamine),
- 15 -
,, . ,~1
~, ,,d~
procaine, dibenzylamine, N-benzyl-~-phenethylamine, 1-
ephenamine, N,N'-dibenzylethylenediamine, N-
alkylpiperidine and other amines which have been used to
form salt~ of penicillins and cephalosporins. When a basic
group is present, the present invention also includes the
pharmaceutically acceptable acid addition salts, e.g. salts
with mineral acids such as hydrochloric, hydrobromic,
hydroiodic, phosphoric, sulfuric or with suitable organic
carboxylic acids or sulfonic acids such as trifluoroacetic,
p-toluenesulfonic, maleic, acetic, citric, oxalic,
succinic, benzoic, tartaric, fumaric, mandelic, ascorbic and
malic. Compounds containing an acid group and a basic group
can also be in the form of inner salts, i.e. a zwitterion.
Preparation of the above-described salts may be carried out
according to conventional procedures for forming salts of ~-
lactam antibiotics such as penicillins and cephalosporins.
The term "easily removable ester protecting group''
is one which has acquired a definite meaning within the ~-
lactam and peptide art. Many such groups are known which
are used to protect the carboxyl group during subsequent
chemical reactions and which may later be removed by
standard methods to give the free carboxylic acid. Known
ester protecting groups include 2,2,2-trichloroethyl,
tertiary alkyl of from 4-6 carbon atoms, tertiary alkenyl of
from 5-7 carbon atoms, tertiary alkynyl of from 5-7 carbon
atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon
atoms, N-phthalimidomethyl, benzoylmethyl,
halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl,
benzhydry~, trityl, trimethylsilyl, triethylsilyl, ~-
trimethylsilylethyl, and the like.
- 16 -
~36~;~
Choice of an ester protecting group is dependent on the
subsequent reaction conditions the group must withstand and
the condi~ions desired for removing it. Selection of a
suitable group is well within the ability of one skilled in
the art. For use as a chemical intermediate the most pre-
ferred ester is the p-nitrobenzyl ester which can be readily
removed by catalytic hydrogenation. For preparation of
compounds containing functional groups reducible under such
removal conditions, a preferred alternative is the ~-
trimethylsilylethyl ester removable by treatment with
fluoride ions. Also included within the scope of easily
removable ester protecting groups are physiologically
cleavable esters, i.e. those esters known in the penicillin
and cephalosporin art to be easily cleaved within the body
to the parent acid. Examples of such physiologically
cleavable esters include indanyl, phthalidyl, t
methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl,
thienylglycyloxymethyl or acyloxymethyl of the formula
-CH2C-Y
in which Y' is Cl-C4 alkyl or phenyl. Particularly pre-
ferred esters of this type are methoxymethyl,
acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.
It will be appreciated that the compounds of
formula I may exist in various states of solvation and the
anhydrous as well as solvated (including hydrates) forms are
intended ~o be within the scope of the invention.
- 17 -
Ik ~,,
~36~61
With respect to the compounds of formula I,
the preferred compounds are those wherein Y is hydrogen
or tlower)alkyl optionally substituted (preferably at the
~-carbon) by hydroxy. More preferred compounds within the
above group are those wherein Y is hydroxy, ethyl or
~-hydroxyethyl. Still more preferred compounds of
formula I are those wherein Y is hydrogen or ~-hydroxyethyl.
The most preferred compounds are those wherein Y is
~-hydroxyethyl.
A preferred embodiment of the present invention
consists of the compounds of formula I wherein substituent
X is a substituted (lower)aliphatic, (lower)cycloaliphatic
or (lower)cycloaliphatic(lower)aliphatic radical or a ring-
substituted phenyl, phenyl(lower)alkyl, heterocyclic,
heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl
radical, the substituents for the above-named aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenyl-
alkyl, heterocyclic, heterocyclic-alkyl and heterocyclicthio-
alkyl radicals being
NRl
CNR2R3 or 1 2 3
Rl
Rl is hydrogen, (lower)alkyl or phenyl and R2 and R3 are
each independently hydrogen~ (lower)alkyl, phenyl or benzyl.
Within this class, the preferred compounds are those wherein
Y is hydrogen, ethyl or ~-hydroxyethyl, especially those
wherein Y is hydrogen or ~-hydroxyethyl and most especially
those wherein Y is ~-hydroxyethyl.
12~6~61
Another preferred embodiment of the present
invention consists of the compounds of formula I wherein
X is a substituted (lower)aliphatic, (lower)cycloaliphatic
or (lower)cycloaliphatic(lower)aliphatic radical or a ring-
substituted phenyl, phenyl(lower)alkyl, heterocyclic,
heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl
radical, the substituents on the above-mentioned aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenyl-
alkyl, heterocyclic, heterocyclic-alkyl or heterocyclicthio-
alkyl radicals being
-CORf
in which Rf is amino(lower)alkyl, (lower)alkylamino(lower)-
alkyl, di(lower)alkylamino(lower)alkyl, -NHNH2, -NR17NR18,
-NHOR19, -SR17, -O(CH2)n-A-R or ~NReRg in which R17, R18,
Re and Rg are (lower)alkyl, Rlg is hydrogen or (lower)alkyl,
A is O, S, NH or NCH3 and n is an integer from 1 to 6.
Within this class, the preferred compounds are those wherein
Y is hydrogen, ethyl or ~-hydroxyethyl, especially those
wherein Y is hydrogen or ~-hydroxyethyl and most especially
those wherein Y is ~-hydroxyethyl.
Still another preferred embodiment of the present
invention consists of the compounds of formula I wherein
X is
(a) -(CH2)n~ ~ in which n is an
an integer from 1 to 6, preferably 1 to 4;
(b) -(CH2)nNHOH in which n is an integer from 1
to 6, preferably 1 to 4;
--Iq--
~ 2~36~6~
(c) -(CH2)nPO(O-Cl-C6 alkyl)2 in which n is an
integer from 1 to 6, preferably 1 to 4 and
alkyl is prefe:rably methyl, ethyl or iso-
propyl; NH
Il
~ (d) -(CH2)nNH-C in which n is an
: Cl-C6 alkyl
integer from 1 to 6, preferably 1 to 4,
and alkyl is preferably methyl or ethyl;
NH2
( ) ( 2)n \ in which n is an integer from
1 to 6, preferably 1 to 4;
O
(f) -(CH2)nOC(CH2)mNRARB in which n and m are
each independently 1 or 2 and RA and RB
are each independently hydrogen or (lower)-
alkyl; or
(g) -(CH2)nNHCI-Rc in which n is an integer of
NH
1 to 6, preferably 1 to 4, and Rc is Cl-C4
alkyl (preferably methyl or ethyl), phenyl or
~ .
(CH2)m ~ n which m is 1 or 2.
Within this class of compounds, the preferred members are
those wherein Y is hydrogen, ethyl or ~-hydroxyethyl,
preferably those wherein Y is hydrogen or ~-hydroxyethyl
and most preferably those wherein Y is ~-hydroxyethyl.
,: ,
'
' .
12~fi~
Other preferred embodiments of the present invention
include the intermediates of the formulae:
(A) ~ _
C2R"
III
wherein Y is hydrogen or as defined above in regard to
compounds of formula I, Q is phenyl or (lower)alkyl, R"
is an easily removable ester protecting group, X is 1 or 2
and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I)
when x is l;
(B) Y ~ SHgCOOCH3
N ~ P(Q)3
CO2R" IIIa
in which Y, Q and R" are as defined above under (A); and
(C) y ~-T
N ~ P(Q)3
C2R "
IV
wherein Y is as defined above in regard to compounds of
formula I, Q is phenyl or (lower)alkyl,-R" is an easily
lX~36~
removable ester protecting group and T is
C H O
16 5 11
-C-C6H5 or -C-X wherein X is as defined above in
C6H5
regard to compounds of formula I.
In the intermediates of formulae III, IIIa and
IV, Q is preferably phenyl, R" is preferably p-nitrobenzyl
and X and Y are preferably those substituent groups mentioned
as being preferred in connection with the compounds of
formula I. ReactiVe functional groups such as
mercapto, amino and hydroxy in substituents Y and X may
be protected by conventional blocking- groups during con-
version of the intermediates to biologically active end-
products.
Compound I may be prepared by one ox
more of the reaction routes discussed below. The various
synthetic routes may be divided into three main processes
depending on the stage of incorporation of the 6-substituent,
i.e. Y. Thus, in Process I, the 6-substituent is incor-
porated in the basic starting material; Process II involves
incorporation of Y at the end of the synthesis and in
Process III substituent Y is incorporated in mid-synthesis.
Each of the three main processes in turn can vary in the
procedure for incorporating the desired 2-substituent, i.e,
X. In general, it is preferred to incorporate substituent
Y in mid-synthesis and to incorporate substituent X by
acylation of mercaptide intermediate III or IIIa shown
below since these procedures have been found to be the most
generally useful.
The steps of Process I may be seen from the
following scheme: ~
1~6~6~
Process I (Variation 1): Early incorporation of 2-substituent
O
Y-CH=CH-OAc CSI ~ ~ ~OAc XC-SNa >
N pH 7.5
O ~ H
O O
Y~SII-X ~ Y~,SC-X
,~ CHO ¦ SOC12
N~H 2R O ~ N ~ OH
C02R"
O
Y~SC-X p0 Y~ SIl_X
~ Cl base N ~ P03
C02R" C2R"
de-protect ~N
2 CO
O
Ac = CH3C-
0 = C 6H5 -
-13-
6~
Process I (Variation 2): Late incorporation of 2-substituent
~ OAc CH3e-SNa
Y-CH=C~-OAc CSI > ~ N~ H pH 7.5
Y ~ SAc ~ Y ~ SAc
CHO SOC12
N~ C2R" ON ~ OH
C02R
Y ~ SAc P03 ~ ~ SAc MA
N ~ Cl base N ~ P03 base
C2R" C2R"
, _ _
Y~ SM ~ SC-X
N~P03
C2R" C2R"
~ de-protect
X-C- ~ = acylating agent
MA = heavy metal salt
1~366~L
:; Process I (Variation 3): Late incorporation of 2-substituent
Y ~ ~OAc 03CSNa
Y-CH=CH-OAc CSI > ~ N~ pH 7.5
O H
CHO ~ sc03 SOC12
N~ 2 O N ~ OH
C2R"
3 ~ ~ SC03 MA
N ~ Cl base o ~ N ~ P03 base
C2R" C2R"
o
SM ~ I ~ Y ~ SC-X
, ,~N ~P 0 3
C2R" C2R"
de-protect
CO R" o
2 CO
-~5--
1~6~
In Process I a vinyl ester (Y = H or a radical as
defined in connection with compounds I) containing the
desired 6-substituent is converted to the optionally l-
substituted 4-acetoxy-2-azetidinone by a cycloaddition
reaction with chloro sulfonyl isocyanate (CSI) followed by
reduction with an organic reducing agent such as sodium
sulfite. The CSI reaction is conveniently carried out in an
inert organic solvent such as diethyl ether at a temperature
of OC or below. The reduction step may be conducted in an
aqueous or aqueous-organic reaction mixture at a temperature
of 0 or below and at a slightly basic pH.
Following formation of the
4-acetoxy-2-azetidinone, Process I may be separated into
three different paths. In one route (Variation 1), the
O
azetidinone is reacted with a thiolic acid X-C-SH wherein X
is as defined in connection with compounds I, or a salt
thereof, in a suitable solvent (e.g. aqueous or aqueous
organic). Displacement of the acetoxy group results in
incorporation of the desired 2-substituent in the
azetidinone at this stage. The displacement reaction is
; preferably carried out at room temperature or below and at a
slightly basic pH ( ~7.5). When Y ~ H, cis and trans isomers
of the resulting azetidinone are preferably separated (e.g.
by chromatography) at this point in the process. Variations
2 and 3 depicted above convert the 4-acetoxy-2-azetidinone
into the 4-acethylthio-2-azetidinone and 4-tritylthio-2-
azetidinone products, respectively, by nucleophic dis-
placement~with thioacetic acid or triphenylmethyl mercaptan
(or a salt thereof such as the sodium salt), respectively.
- 26 -
,j.....
~,
~2~36~
The 4-thio azetidinone iB next reacted with a
o
glyoxylate ester HC-CO2R" wherein R~' i6 an easily removable
ester protecting group such as p-nitrobenzyl or trimethyl-
silylethyl, or a reactive oxo derivative thereof such as ahydrate, in an inert organic solvent (e.g. benzene, toluene,
xylene, and the like) and preferably at an elevated
temperature (e.g. 50C. up to most preferably reflux
temperature). When a hydrate of the ester is employed,
resulting water may be removed azeotropically or with
molecular sieves. The hydroxy ester product is formed as a
mixture of epimers which can be optionally purified as by
chromatography or used directly in the next step.
Conversion of the hydroxy ester to the corresponding
chloro ester is achieved by reaction with a chlorinating re-
agent (e.g. SOC12, POCl3, PC15, and the like) in an inert :
organic solvent (e.g. tetrahydrofuran, diethyl ether,
methylene chloride, dioxane, and the like) in the presence
or absence of a base, preferably an aliphatic tertiary
amine (e.g. triethylamine) or a heterocyclic tertiary amine
(e.g. pyridine or collidine). The reaction is
advantageously run at from about -10C. to room temperature.
Chloro ester product is obtained as a mixture of epimers
which can optionally be purified before use in the next
step.
The phosphorane intermediate may be obtained by
reaction of the chloro ester with a suitable phosphine
(preferably triphenylphosphine or a tri(lower)alkyl
phosphine such as triethylphosphine or tri-n-butyl
phosphine)
,~.,
1~366~
in an inert organic solvent such as dlmethylformamide,
dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, dioxane
or an aliphatic, cycloaliphatic or aromatic hydrocarbon
(e.g. hexa~e, cyclohexane, benze;ne, toluene, and the like)
in the presence of a base, preferably an organlc tertlary
amine such as triethylamine, pyridine or 2,6-lutidine. The
reaction is advantageously carried out at temperatures from
room temperature to the reflux temperature of the solvent
system.
At this stage the process again diverges into two
routes. In Variation I (where the 2-substituent has already
been incorporated), the phosphorane intermediate is
converted to the desired penem by thermally cyclizing in an
inert organic solvent at a temperature of from just above
room temperature to the reflux temperature of the solvent
system. Most conveniently, the cyclization is carried out
under reflux conditions. Suitable inert organic solvents t
include aliphatic, cycloaliphatic or aromatic hydrocarbons
(e.g. benzene, toluene, hexane, cyclohexane), halogenated
hydrocarbons (e.g. methylene chloride, chloroform, carbon
tetrachloride), ethers (diethyl ether, dioxane,
tetrahydrofuran, dimethoxyethane), carboxylic acid amides
(e.g. dimethylformamide), di C1-C6 alkylsulfoxides (e.g.
dimethylsulfoxide) or a Cl-C6 alkanol (e.g. methanol,
ethanol, t-butanol), or a mixture thereof.
In variations 2 and 3 the phosphorane is converted to
a heavy metal mercaptide of the formula
- 28 -
~ 2~36661
~S- _
q~
C2R ~ X
III
or
/sHgcoocH3
n
N ~P ( Q ) 3
C2R "
IIIa
wherein Q is preferably phenyl or (lower)alkyl, x is 1 or 2
and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I) when
x is 1. Mercaptide formation is accomplished by reaction of
the phosphorane with a salt of Hg(II), Pb(II), Cu(II) or
Ag(I) or with (methoxycarbonyl)mercury(II) acetate in a
methanol-containing solvent and ln the presence of an
organic or inorganic base such as aniline, pyridine,
collidine, 2,6-lutidine, an alkali metal carbonate, and the
like. A p~eferred base is pyridine. The reaction may be
carried out at room temperature or, if desired, with
moderate cooling or heating. The anion (A) of the heavy
metal salt may be any anion which gives a soluble salt in
the selected solvent, e.g. N03 , CH3C00 , BF4 , F , C104 ,
N02-, CN0-, etc. The mercaptide intermediate is then
reacted with an acylating agent capable of introducing the
moiety X-C- wherein X is the desired penem
- 29 -
~6~;6~
2-substit~ent. The acylating agent (X-C-O) may be the acid
O
X-C-OH or a reactive functional derivative thereof such as
an acid halide (preferably acid chloride), acid azide, acid
anhydride, mixed acid anhydride, active ester, active
thioester, etc. Acylation is conducted in an inert solvent
(e.g. a halogenated hydrocarbon such as methylene chloride
or an ether such as dioxane, tetrahydrofuran or diethyl
ether) and, when an acid derivative is used, in the
presence of an acid acceptor such as a tri(lower)alkylamine
(e.g. triethylamine) or a tertiary organic base such as
pyridine, collidine or 2,6-lutidine. When the free acid is
employed, the acylation is conducted in the presence of a
suitable condensing agent, for example a carbodiimide such
as N,N'-dicyclohexylcarbodiimide. Acylation of the
mercaptide can be achieved over a wide temperature range,
but is preferably carried out from about -20 to +25C.
Following acylation, the resulting phosphorane is cyclized
as described above to give the desired penem ester.
Formation of the phosphorane via the mercaptide
intermediate (Variations 2 and 3) has been found to result
in product of much better purity than that obtained by the
more conventional route of Variation 1.
Once the carboxyl-protected penem is formed, the
protecting group may be removed by conventional deblocking
procedure~ (e.g. hydrolysis, hydrogenation or photolysis)
to give the de-blocked penem. Removal of the
p-nitrobenzyl ester, for example, may be achieved by
- 30 -
catalytic hydrogenation in the presence of a noble metal
catalyst such as palladium or rhodium, including derivatives
thereof such as oxides, hydroxides or halides, said catalyst
being optionally supported on a conventional carrier such
as carbon or diatomaceous earth. A non-reducible aqueous
or non-aqueous inert solvent such as water, ethanol,
methanol, ethyl acetate, tetrahydrofuran, diethyl ether or
dioxane is used. Hydrogenation may be conducted at
atmospheric or elevated pressure and is conveniently run
at room temperature for a period of from about 1-5 hours
depending on the solvent and catalyst used. If an equi--
valent weight of a base such as an alkali metal or alkaline
earth metal hydroxide or an amine is employed during the
hydrogenation, the product may be recovered in the form of
a carboxylic acid salt. Removal of the ~-trimethylsilyl-
ethyl ester, another useful protecting group, is conveniently
achieved by treatment with a source of fluoride ions. Other
ester protecting groups can be similarly removed by methods
well-known to those skilled in the art.
In a second main process (Process II), the
reaction sequence is as shown below:
~6'.i6~
Process II (Variation 1): Early incorporation of 2-substituent
o
~OAc XC-SNa
CH2=CH-OAc CSI ~ ~ pH 7.5
O O
Il 11
SC-X ~ ~SC-X >
CHO ¦ SOC12
N~ C2R" O - N ~ OH
CO 2
~rSC-X ' p0 ~S ll_X ,~
N ~ Cl base N ~ P03
C2R" C2R"
~N ~ bas > ~ f ~ .X
C 2 C2R"
Y~S
de-protect ~ N ~ X
CO
-3~-
12~6G6~
.
~ Process Il (Variation 2): Late incorporation of 2-substituent
.
CH2=cH-oAc CSI > ~ ~ pH 7.5 >
O H
~ SAc CHO ~ SAc SOC12
O ~H C2R o N ~ OH
CO2R
SAc ~ ~ ~ p03 base
C2R" C 2
SM ~ ~ SC-X
N ~ P03 ~
C2R" C2R"
.
~N ~ base > ~ ~ X
C2Rn o C2R"
~ S
- de-protect ~ ~
o
co2
--3 3--
~ Z ~3~
Process II (~Jariation 3): Late incorporation of 2-substituent
OAc03CSNa
CH2-CH-OAc CSI~ ~ N~ pH 7.5
O H
SC03 CHO ~ SC03 SOC12
N~ CO2R" ~
C2R"
SC0~ ~ ~ ~ p03 base
2 C 2
N ~ P03 ~ 5C-X
C2R" C2R"
~ base ~ cO2XR"
de-protect ~ N
co2
.
-3't-
~2~366~L
As can be seen Process II is substantially the
same as Process I (except that Y must be H) up through the
thermal cyclization step which produces the 2-substituted
penem. A 6-substituent, however, if desired, is now in-
corporated at this stage by reaction of the 2-penem with a
suitable electrophile in an inert solvent (e.g. tetrahydro-
furan, diethyl ether, dimethoxyethane, and the like) and in
the presence of a strong base. In this procedure the 2-
penem can be reacted in the form of the free acid (obtained
by de-blocking as described above) in the presence of about
two equivalents of base or, alternatively, a suitable 2-
penem ester may be used in the presence of about one equi-
valent of base. Any ester inert to anion chemistry (the
reaction involves anion formation with base followed by
reaction of the electrophile with the penem anion) may be
employed, e.g. (lower)alkyl such as methyl, ethyl, n-propyl
or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl
such as trimethylsilyl or t-butyldimethylsilyl, and the
like. Penem esters having activated methylene groups such
as p-nitrobenzyl are not suitable and, if the 2-penem ester
is of this type, it must be first de-blocked and either used
as the free acid or converted to a suitable ester. The
particular base used is not critical and the usual strong
bases such as sodium hydride, phenyl lithium or butyl
lithium are suitable. Most preferably, however, a lithium
disilylamide or a lithium dialkylamide such as lithium di-
cyclohexylamide (LDCA), lithium diethylamide, lithium di-
methylamide or lithium di-isopropylamide (LDA) is used.
--35-
The electrophile is selected so as to generate the desired
Y-substituent upon reaction with the anion and may be,
for example, a halogen (e.g. Br2, I2), an alkyl halide
(e.g. CH3I) or a similar halide such as an aliphatic,
cycloaliphatic, cycloaliphatic-aliphatic, phenyl-
(lower)alkyl, heterocyclic, heterocyclic-thio, heterocyclic-
thio-(lower)alkyl, or heterocyclic-(lower)alkyl, halide,
a tosylate or mesylate (e.g.
3 2 2 ~ CH3, CH3CH2S2CH3~ ~ SO2 ~ SO2
0CH2CH2CH20SO2CH3, etc.), an epoxide (e.g. ~ ), an
S
episulfide (e.g. ~ ), an aldehyde (e.g. CH3CHO, C6H5CH2CHO),
~o
a ketone (e.g. CH3COCH3, ~ ) or an ester (e.g.
CH3CH2COOCH3 or C6H5COOCH3). Representative examples of
other suitable electrophiles are shown below:
CH2=CH-CH2Br
1~` 1
Br CH3CCH=CH2
; ~ Br
Br CH3CH-CH3
Q
o Cl 0CH2Br
HCHO 0C-CCH2Br
0~o
CH2SCH2Cl
CH3SSO2CH3 00CH2C1
36~
0CH=CHCHO 0 ~
CH3CCH2C1 ~ ~ C-CH Cl.
S 11 2
A most preferred electrophile is acetaldehyde which gives
rise to the hydroxyethyl 6-substituent. Introduction of
the 6-substituent by this process is preferably carried out
with cooling (e.g. -80 to OC.) according to the general
procedure described in Canadian Journal of Chemistry, 50(19),
3196-3201 (1972).
After formation of the desired 2,6-penem, any
ester protecting group may be removed as discussed above
to give the de-protected product.
The third main reaction process (Process III)
can be understood from the following scheme:
Process III (Variations 1 and 2):
sc03 sc03
H O N~
Y ~ Y~SC03
base N~B
de-protect / \ MA/base
-3~--
~ ~6~61
~SC03~f M
N~ N\B
~ C~oH20R " ~ X- C ~
~Sc03 ~SC-X
o N~_OH ~N
C2R
\ / SOC12 / de-protect
o~Cl ~ SC-X
C2R"
~,~ b0se
f~o
\ / CO 2 R "
P03 Y~5~:X
C02R"
C2R"
~/base ,¦ SOC12
-3~-
lZr~66~;1
~_~ , SM S C - X
o~ ~Z 03 ~N~_ Cl
CO R"
2 C2R"
O
\ / X-C- ~3 ~ base
03~ ~r ~ p03
C2R" C2R"
Y
~X Yo~N ~x
C2R " CO 2R "
~ de-protect~ de-protect
Y
.X
CO ~ O
2 C0
_ _ .
B = blocking group for ring nitrogen
- 39-
~f3~661
The 4-tritylthio-2-azetidinone of Process III
is formed as described in Process II (Variation 3). The
ring nitrogen of the azetidinone is then protected by a
conventional easily removable blocking group such as
triorganosilyl (e.g. trimethylsilyl or t-butyldimethylsilyl),
methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, and
the like. Introduction of the desired Y-substituent at the
l-position of the azetidinone is then achieved by reaction
of an appropriate electrophile with the N-protected
azetidinone in the presence of a strong base (reaction con-
ditions as described above in connection with Process II).
At this point the process diverges into two routes depending
on the time of de-blocking the azetidinone.
In one route the N-protected intermediate is
de-blocked by conventional procedures (e,g. acid hydrolysis)
and then converted to the 2,6-penem via ester formation,
chlorination of the hydroxy ester, conversion of the chloro
ester to a phosphorane, conversion of the phosphorane to a
heavy metal mercaptide, acylation of the mercaptide with
X-C- ~ , thermal cyclization of the resulting phosphorane
to give the 2,6-penem ester and removal of the carboxyl-
protecting group. Reaction conditions for these steps are
as disclosed in connection with Process II (Variation 3).
An alternative route involves the steps of
converting the N-protected azetidinone to a heavy metal
mercaptide, acylating the mercaptide with the moiety
X-C- ~9 , removing the N-protecting group, reacting the
~S~~
12~
de-protected azetidinone with the glyoxylate ester,
chlorinating, reacting the chloro ester with the phosphine
to give the phosphorane, cyclizing the phosphorane to give
the penem ester and removing the carboxyl-protecting group
to give the 2,6-penem. Reaction conditions for these steps
are as disclosed previously.
In preparing the 2-penem or 2,6-penem compounds
according to the above processes, free functional groups in
substituents X or Y which do not participate in the reaction
may be temporarily protected in a manner which is itself
known, such as free amino groups by acylation, tritylation
or silylation, free hydroxyl groups, for example, by
etherification or esterification, mercapto groups by esteri-
fication, and free carboxyl or sulfo groups, for example, by
esterification, including silylation, After the reaction
has taken place, these groups can, if desired, be liberated,
individually or jointly, in a manner which is itself known.
Additionally, it is possible in compounds of
formula I to functionally modify the 2- and/or 2,6-
substituents during or at the conclusion of the reaction
procedures according to known processes to obtain other
substituents included within the scope of the present
invention. Thus, for example, carbonyl groups can be re-
duced to alcohol groups, unsaturated aliphatic groups can
be halogenated, amino groups can be alkylated or acylated,
nitro groups can be converted to hydroxyamino and amino
groups, hydroxyl groups can be etherified or esterified, etc.
The penem free acid compounds may be converted
to pharmaceutically acceptable salts thereof or to easily
12~ 6~
removable esters thereof (particularly physiologically
cleavable esters). Salts may be formed by reaction of the
free acid with a stoichiometric amount of a suitable non-
toxic acid or base in an inert solvent followed by recovery
of the desired salt as by lyophilization or precipitation.
Esters (in particular physiologically cleavable esters) may
be prepared in an analogous manner to preparation of the
corresponding esters of penicillins and cephalosporins.
Resulting mixtures of isomers can be separated into the
individual isomers according to known methods. Mixtures of
diastereomeric isomers, for example, can be separated by
fractional crystallization, adsorption chromatography
(column or thin-layer) or other suitable separation methods.
Resulting racemates can be resolved into the antipodes in
the customary manner, for example by forming a mixture of
diastereomeric salts with optically active salt-forming
reagents, separating the diasteromeric salts and converting
the salts into the free compounds, or by fractional crystal-
lization from optically active solvents.
Accordingly, the present invention also provides
for a process for the preparation of the compounds of
formula I which comprises cycli~ing a compound of the formula
y S--C -X
N ~ P(Q)3
C2R"
1~66~1
wherein Q is phenyl or (lower~alkyl, Rll is an easily remo~able
ester group and X and Y are as defined above in an inert organic
solvent at a temperature of from just above room temperature to
the reflux temperature of the solvent removing by methods known
per se the removable e~ter group and,optionally, other protecting
groups; and, if Y is hydrogen and when desired, converting the
product to any other desired product where Y is not hydrogen by
treating said product with a corresponding electrophile in an
inert solvent in the presence of a strong base.
The present invention also comprises those em-
bodiments according to which--compounds used as intermediate
products are used as starting materials and the remaining
process steps are carried out with these, or the process
is discontinued at any stage, Furthermore, starting materials
can be used in the form of derivatives or can be formed
during the reaciton.
The free acid penem compounds provided by the
present invention and pharmaceutically acceptable salts
.;,
-~13-
and physiologically cleavable esters of said acids have
been found to be potent broad-spectrum antibacterial agents
useful in the treatment of infectious diseases in animals,
including man, caused by both Gram-negative and Gram-positive
organisms. The compounds are also of value as nutritional
supplements in animal feeds and as agents for the treatment
of mastitis in cattle.
The 2-penem acids (and physiologically cleavable
esters and pharmaceutically acceptable salts thereof) pro-
vided according to the present invention (i.e. compounds
of general formula I wherein Y = H) possess antibacterial
activity per se and are also useful intermediates (preferably
in their carboxyl-protected form) for preparing the 2,6-
disubstituted penems I via anion formation and reaction with
an electrophile.
The active compounds provided by the present in~
vention may be formulated as pharmaceutical compositions
comprising, in addition to the active ingredient, a pharma-
ceutically acceptable carrier or diluent, The compounds
may be administered both orally and parenterally. The
pharmaceutical preparations may be in solid form such as
capsules, tablets or dragees, or in liquid form such as
solutions, suspensions or emulsions. In the treatment of
bacterial infections in man, the active compounds of this
~r~66~;~
invention may be administered orally or parenterally in
an amount of from about 5 to 200 mg./kg./day and preferably
about 5 to 20 mg./kg./day in divided dosage, e.g. three
or four times a day. They are administered in dosage units
containing, for example, 125, 250 or 500 mg. of active in-
gredient with suitable physiologically acceptable carriers
or diluents.
The present invention also provides a method of
combatting bacterial infections in animals, particularly
warm-blooded animals, which comprises administering an acid
of formula I or a physiologically cleavable ester
thereof or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition thereof, to an infected host
in an amount sufficient to com~at such infection,
Illustrative examples of the preparation of
starting materials and end-products of the present invention
follow. All temperatures are in degrees Centigrade. For
the sake of convenience, certain abbreviations are employed
in the examples, Definitions of the less obvious of these
abbreviations are as follows:
CSI chloro sulfonyl isocyanate
pet. ether petroleum ether
b.p. boiling point
n,m.r. nuclear magnetic resonance
h hour
ether diethyl ether (unless otherwise indicated)
~t5
~2~36~61
Celite Trademark of Johns-Manville Products
Corporation for diatomaceous earth
psi pounds per square inch
r.t. room temperature
PNB p-nitrobenzyl
m.p. melting point
LAH lithium aluminum hydride
n-BuLi n-butyl lithium
MIBK met~yl isobutyl ketone
Et C2H5-
Tr C( 6 5)3
Me CH3-
THF tetrahydrofuran
Ph phenyl
DMF dimethylformamide
TEA triethylamine
PNBG p-nitrobenzylglyoxylate
THP tetrahydropyranyl
TFA trifluoroacetic acid
HMPT (or HMPA) hexamethylphosphorus triamide
EtOAc ethyl acetate
DMSO dimethylsulfoxide
Ac CH3CO-
Ms CH3SO2-
DMAP 4-dimethylaminopyridine
Py pyridine
LDA lithium diisopropyl amide
q6-
3fi661
EXAMPLE ~
2'-(2'-Die~hyl~hos~hQno-~'-ethyl)~enem-3-carboxyl1c Acid
-
~S ~ 1l
(CH2)2P-(oEt)2
CO2H
Ol O
(EtO)2-P-(cH2)2co2cH3 ~ (EtO)2P-(cH2)2co2H
1 2
o O
Il 11
(EtO)2P-(CH2)2COC1 ) (Eto)2-p-cH2)2cosH
3 4
A mixture of 1 (11.2 g, 50 mmoles) and 5N NaOH (10 ml)
was stirred and cooled (ice-bath) for 15 min and at room
temperature for 15 min. The mixture was extracted with
ether and the extract discarded. The aqueous solution was
acidified with 5N HCl and extracted wht CH2Cl2 to give
after drying and evaporation of ~olvent 10.0 g (95%) of oil
2, nmr ~ (CDC13), 4.1 (4H, m), 1. 8 - 2. 9 (4H, m) 1. 2
(6H, t).
~ o a cooled (ice-bath) solution of ~ (2.26 g, 10.76
mmoles) was added dropwlse oxalyl chloride (2.74 g, 1.88
ml, 21.5 ~moles). ~he mixture was kept at room temperature
for 6 h and then it was
- 47 -
~2~3666~
evaporated to d~ness. The traces of (COCl)2 were removed azeo-
tropically with benzene to give 2.4 g (quantitative yield~ of
c-ude 3.IP. v C 1800; 1735 cm . n~r ~ 4.3 (4H, m!, 3.0 - '-7
(2H, m) 2.0 - 3.0 (2H, m), 1.4 (6H, m). This was treated
with H2S/TEA in a standard procedure to glve 1.9 g (80~.) of oil 4
estimated to be 80% pure. Nmr: ~ 4.1 (4H, q), 2.7 - 3.5
(2H, m), 1.7 - 2.5 ~2H, m) 1.33 (6H, t).
(EtO)2~-(c~2)2cs ~ (CH3)2~(OE )2
~ O
NH 4 o~ N
To 4 (1.9 g, 8.4 mmoles) was added under N2 lM
solution of NaHCO3 (10 ml), followed by addition of 5 (0.813 g,
6.3 mmoles) in H2O ~3 ml). The pH of the mixture W2S adjusted
to 7-8 by adding more NaHCO3. After standing for 4 h the
mixture was extracted with CHC13 to give after drying and con-
centration 1.05g (56.4~ based on 5) of solid 6, m.p. 64-67,
nmr ~ 7.7 (NH), 5.3 (lH q), 4.2 (4H,) 3.8 (lH q) 3.5 (lH, q),
2.6-3.2 (2H, m) 1.7-2.4 (2H, m), 1.3 (6H,)
(CH2)2~(OEt)2 S (cH2)2-P-(OEt)2
NH ~
C 2
6 7
A mixture of 6(260 mg, 0.88 mmole) and p-nitrobenzyl
glyoxalate (198 mg, 0.88 mmole) was refluxed in benzene (6 ml)
under a Dean Stark apparatus for 16 h to give after eva~oration
of benzene 453 mg of heavy oil 7, nmr ~ 8.3 (2H, d) 7.6 (2H, d)
5.3-5.7 (4H,) 4.9 (OH), 4.2 (4H,) 3.55 (lH g), 3.4 (lH, gj, 2.5-3.2
(2H, m) 1.7-2.5 (2H, m) 1.3 (6H)
5 ~ (CH2)2~O~t)2 ~ 5 ~ (CH2)2 -(~t~2
~N ~ H O N ~ Cl
o PNB
O2PNB 2
7 8
A crude 7 (504 mg, 0.88 mmole) was dissolved in LM
solution of pyridine in THF (0.9 ml). To this was added dropwise
with stirring and cooling (ice-bath) lM solution of SOC12 in THF (0.9 ml)
and the mixture was stirred in the cold for 15 min and at room
temperature for 40 min. To it was added benzene (10 ml), and the
solid was filtered off. The filtrate was concentrated in vacuo to
give 463 mg (quantitative yield) of crude 8, r~r ~ 8.3 (2H, d), 7.6
(2H, d), 6.1 (lH, s), 5.7 (lH, m), 5.3 (2H, d), 4.2 (4H), 1.8-3.6
(6H, m) 1.3 (6H).
(CH2)2~-(OEt)2 5 ~ (CH2)2-P-(OEt)2
N ~ 1 ~
C02PNB C02PNB
8 9
~119-
~36~
To a solution of crude 8 (463 mg, 0.88 mmole) in
THP (4 ml) was added triphenylphosplline (236 mg, 0.9 mmole)
and 2,6 lutidine (96 mg, 0.9 mmole) and the mixture was al-
lowed to stand at room temperature for 65 h. Then it was fil-
tered, the filtrate concentrated and the resiclual oil chromato-
graphed on a silica gel column with ethyl acetate-296 EtOH as
eluent, to give 203 mg (30.6%) of oil 9, which solidified on
standing, m.p. 126-128C.
F~s ~ (CH2)2$(OE-)2 ~~(CH2)2P(OEt)2
CO PNB
CO2PNB 2
A solution of 9 (470 my, 0.635 mmole) in toluene
(30 ml) was refluxed for 5 h followed by concentration and
chromatography on silica gel-ethyl acetate to give 167 mg
(569~) of 10 as oil, IR 1795, 1710 cm
nmr 0 8,3 (2H, d) 7.7 (2H, d) 5.7 (lH, m), 5.38 ~2H, d)
4.1 (4H) 1.8-3.8 (6H, 1.35 (6H).
(CH ) -~-(OEt) ~N-- ~ 2 ~ 2
C02PNB C02H
11
~366f~;3L
To a solution of 10 (59 mg, 0.126 mmole) in THF (3 ml)
and ether (1 ml) was added NaHC03 (9 mg, 0.107 mmole), water (1
ml) and 10% pd.celite (60 mg) and the mixture hydrogenated at 30
psi for 2 h. The product was isolated as usual to give 36 mg
(86%) of 11 as oil, IR (CHc13) 179g, 1730, 171~ cm~l, nmr ~ 9.0
(CO2H), 5.6 (lH, m) 4.4 (4H), 3.6 (lH, q), 3.15 (lH, q) 1.7-3.0
(4H, m), 1.3 (6H).
- 51 -
..~
i6~1
~Q~
6-Acetoxymethyl-2-methyl~e~m-3-C~ Q~ a9ia
~cO ~ ~ CH3
N 4~
C02H
. _ .. .. _
Preparation of 1,3-diacetoxypropene
(Ref. L.W. McTeer U.S. 2,866,813. CA 53 9063)
Ac20
CH2=CH-CHO ---~AcOCH2CH=CH-OAc + CH2=CH-CH(OAc)2
Preparation of catalyst: A solution of boric acid (6.2 g)
and oxalic acid (12.6 g) in water (44 ml) was evaporated to
dryness to give the solid catalyst.
Procedure: Acrolein (140 g; 2.5 mol) was mixed with acetlc
anhydride (256 g, 2.5 mol) at r.t. A 5 ml portion of this
mixture was transferred to a one-liter Erlenmeyer flask and
treated with a few drops of catalyst, prepared by
dissolving 1.0 g of solid catalyst in 5 ml acetic
anhydride. A vigorous exothermic reaction set in
~ - .
~6~i1
and the reaction mixture was kept at a temperature of 40 -
60 (controlled by cooling with ice-bath), and the rest of
the acroleinacetic anhydride mixture wa~ introduced into
the flask in portions of 10 to 15 ml followed by a few
drops of catalyst. The resulting mixture was distilled to
remove unreacted starting material B followed by
1,l-diacetoxy-propene. The product 51.6 g (13.06%) was
obtained next, b.p. 54 - 57C/ 1.2 mm. NMR: ~ (ppm, CDC13)
7.4 (H, d, J = 12), 5.3 - 5.8 (H, m), 4.5 (2H, d, J = 7)
2.16 (3H, s), 2.05 (3H, s). IR: vc=O 1770, 1750, vc=O 1680.
CS~ OAc ~ OAc
AcOCH2CH=CH-OAc ) AcO ~ AcO ~ NH
~ NH
1 0 2a 2b
PROCEDURE:
CSI (16.92 g; 0.12 mol) was added dropwise to cooled
(ice salt bath, -15C) 1 (18.96 g; 0.12 mol). The pale
yellow mixture was kept at 5 for 5 h whereby it changed to
deep yellow. This was diluted with ethyl acetate (20 ml) ,
cooled to -30C, and added in portions to a cooled (ice salt
bath) mixture of water (3.4 ml); ice (17.0 g) NaHC03 (0.3g)
and Na2 S03 (3.4 g). After addition, the resulting mixture
was stirred vigorously for 20 min and some additional NaHC03
was added to keep pH at 7-8. The layers were separated, and
aqueous layer was extracted with ethyl acetate (2 x 50 ml).
The combined organic phase was dried (Na2S04; NaHC03; 1:1).
It was filtered and evaporated to give 17.4 g of an oil.
This was distilled under high vacuum (0.01-0.05 mm) in a
hot air bath. (temp. 55 - 85) to remove 1. The undistilled
light brown oil was cooled, taken up in ether and filtered
over celite-charcoal to give,
- 53 -
~;
.li,l~
after evaporation to dryness 5.28 g (22%) of 4:1 mlxture of
2a and 2b (determined by nmr) as colourless oil. NMR: 7.25
(H, NH), 6.0 (0.25H, d, J = 4.3), 5.8 (0.75H, d, J = 15.),
4.5 (0.5H,- d, J = 6.5), 4.4 (1.5H, d, J = 4.5), 3.8
(0.25H, m), 3.5 (0.75H, m), 2.13 (3H, s), 2.1 (3H, 8).
IR: c=o 1780, 1740.
A c O~ 3
I
~ NH
0
2 AcO~ Ac~SAcAcS ~--`~OAc
o ,~ O ~ 0~
3a 3b 3c
PROCEDURE
Sodium thioacetate was prepared by addition of
thioacetic acid (2.22 ml, 2.363 g) to a solution of IM
NaHCO3 (31.0 ml) under nitrogen. This was added to a cooled
(ice bath) solution of 2 (5.2 g; 25.9 mmoles) in water (20
ml) and stirred for 4 h at room temperature. Some acetone
(20 ml) was added to render the reaction mixture
homogeneous. The mixture was concentrated in vacuo to remove
acetone and then extracted with methylene chloride. The
extract was dried and evaporated to give 5.6 g of
a mixture of isomers (83.14%) of 3a and 3b. The NMR
spectrum of the crude oil showed that there were one trans
and two cis compounds present in the mixture. A sample (550
mg) was chromatographed on silica gel (30 g, 10~ H20) and
eluted with benzene-ether-methanol to give 200 mg of a
mixture of 3a and 3b in the ratio 7:1, followed by 150 mg
of an unknown cis compound (~ 5.55, d, J = 4.3) to
- 54 -
,, v
`
which structure 3c was tentatively assigned. NMR: 6.78
(H,NH), 5.52 (0.17H, d, J = 4.3), 5.18 (0.83H, d, J = 1.5)
4.37 (2H, d, J = 4.5), 3.45 (H, m), 2.35 (3H, s), 2.05
(3H,s). I~: Vc=O 1765, 1740, 1600 cm.~1
AcO ~ 02N ~ OH2C02CH¢o~)~ ~ SAc
N O ~ N-CH-OH
3 4 C02PNB
PROCEDURE:
A mixture of crude 3 (2.17 g; 10 mmoles) and p-
nitrobenzyl glyoxylate (2.5 g; 11 mmoles) in benzene (200
ml) was refluxed 20 h under a Dean Stark water collector
followed by concentration in vacuo to give 3.4 g of crude 4
as oil. This was used as such without further purification.
NMR: ~ 7-5 - 8.5 (4H), 5.2 - 5.8 (4H), 3.4 - 5.1 (4H), 2 -
2.4 (6H). IR: VC=O 1665, 1740, 1740, 1730, 1700.
AcO ~ SOC12 AcO ~ SAc
N-CH-OH ~ N-7H-Cl
C02PNB C02PNB
PROCEDURE:
To a cooled (ice-bath) solution of crude 5 (3.3
g; 7.75 mmoles) and pyridine (0.67 g; 8.5 mmoles) in
benz~ne (20 ml) was added dropwise thionyl chloride
(1.01 g; 8.5 mmoles) in benzene (10 ml) and the mixture
stirred at the above temperature for 15 min and at
r.t. for 15 min. The benzene solution was decanted, and
the residual semi solid washed three
- 55 -
-r ~
~1
36~6~L
times with 15 ml portions of benzene. The combined benzene
solution was evaporated to give 1.90 g of crude 5 (55%).
NMR: ~ 7.5 - 8.5 (4H), 6.12 and 6.2 (lH), 5.66 (lH, m), 5.4
(2H, d, J_- 6), 4.3 - 4.7 (2H, m), 3.63 (H, m) 2.4 (3H, d),
2.1 (3H, s). IR: Vc=O 1765, 1740, 1730, 1700.
AcO ~ Ac 3 Aco~SAc
~ N-FHCl Dioxa~e ~ N -C=P(~)
10CO2?NE 2
PROCEDURE:
15 A mixture of crude 5 (1.90 G; 4.27 mmoles)
triphenylphosphine (1.572 g; 6 mmoles) and 2,6-lutidine
(0.642 g; 6 mmoles) in dioxane (20 ml) was heated at 55
for 18 h. It was cooled, filtered and evaporated to give
3.8 g of a crude dark oil. This was chromatographed on
silica gel to give 1.2 g (42%) of 6.
AcC~SAc AcO~--
~N--F=p(~p) 3 o~ ~
256 2 7 ~o2PNe
PROCEDURE:
A solution of crude 6 (1.20 g; 1.79 mmoles) in
toluene (15 ml) was refluxed for 5 h. it was cooled and
evaporated to give an oil which was chromatographed on SiO2
- 56 -
;, ,
.
.,
~36~à61
(30 g) and eluted with benzene to give 0.4 g of 7 (57%) .
Anal- Calc'd for C17H16N207S C 52.04; H 4.11; N 7.14.
Found: C 51.77; H 4.08; N 7.30.
Sepa~ation of the cis and trans isomers was achieved
through careful chromatography on silica gel (60 g) eluting
with benzene. cis-isomer: ~ (ppm, CDC13): 7.5-8.5 (4H,
aromatics), 5.67 (lH, d, J = 5, H-5), 5.28 (2H, AB quartet,
benzyl), 4.33 (2H, d, AcOCH2), 4.20 (lH, dt, H-6), 2.31
(3H, s, CH3), 2.0 (3H, s, CH3CO). VC=O 1770, 1740, 1730
10 cm~l.
trans isomer: ~ (ppm, CDC13): 7.5-8.5 (4H, aromatics), 5.53
(lH, d, J = 2, H-5), 5.30 (2H, AB quartet, benzyl), 4.32
(2H, d, AcoCH2), 4.27 (lH, dt, J = 5, J - 2, H - 6), 2.31
(3H, s, CH3), 2-0 (3H, s, CH3CO). VC=O 1770~ 1740~ 1730
cm~1.
~S t
Ac(~ ~CH AC~ CH
~ N _~ 3 NaHC03 C2Na
C02PNa
PROCEDURE:
To a solution of trans 7 (119 mg; 0.3 mmole) in
ethyl acetate (15 ml) and water (7 ml) was added NaHCO3
(25.2 mg, 0.3 mmole), and Pd/C (110 mg) and this was
hydrogenated 4.5 h at 30 psi. The mixture was filtered and
layers separated. The aqueous layer was washed with ether
and then lyophilized to give 40 mg of solid 8 (48~).
- 57 -
12~366~1 ~
V 1765, 1740, 1600 cm . ~ (ppm, D2O): 5.52 (lH, H-5~,
4.85 (2H, AcOCII2), 4.0 (lH, 1i-6), 2.65 (3H, CH3), 2.40 (3H,
CH3CO).
CH3 ~ ;3
C2Na C02H
PROCED~R~:
To a solution of crude trans 8 (100 mg) in cold water
(2 ml) was acidified with cold lN HCl and extracted with
CHC13. The extract was dried (Na2SO4) and evaporated to give 30 mg
of a pale yellow solid. M.P. 111-113 with decomposition. IR:
V 1780, 1750, 1680. (Neat). IR: (XBr): v 1775 (Strong),
1745, 1670.
Treatment of cis paranitrobenzyl 6-acetoxymethyl-
2-methyl-penem-3-carboxylate according to the above procedure
gives the cis sodium salt and free acid.
- 5~-
36~63~
ExamDle 3
Potassium 6-(2'-Hvdroxvisopropyl)-2-methylpenem-3-carboxylate
(anion process)
\y~OH
CH3
C02~C
. _ _
FNr~ 3 LDA HO~f ~
02H + C02K
1 4a
A solution of acid 1 (116 mg, 0.627 mmoles) in anhydrous
THF (4cc, freshly distilled over LAH) was added dropwise at -78C
to a THP (2cc) solution of LDA (from diisopropylamine, 70.7 mg,
98 ~1, 0.699 mmoles, and n BuLi 1.6 M, 0.440cc, 0.704 mmole stirred
at -78C for 30 min). The mixture was stirred for 5 min. followed
by successive addition of diisopropylamine (70.7 mg, 98 ~1, 0.699 mmole)
and 1.6 M n BuLi (0.440cc, 0.704 mmole) at -78. It was then stirred
for 10 min. at -78 and treated rapidly with acetone (5cc). The
mixture was allowed to react with acetone for 10 min. It was acidified
(pH=2) with 1~ HCl, diluted with ethyl acetate (40 cc) and washed with
brine (3 x 20 cc). It was dried over Na2SO4. Solvent evaporation
gave a crude residue (3a) which was taken up in CH2C12 (crude yield
90 mg). The crude acid was dissolved in cold MIBK (2 cc) and
treated dropwise with potassium 2-ethyl hexanoate. It gave two
batches of potassium salt (36.4 mg, 26%) as a cis and trans mixture,
the trans isomer being predominant.
-59-
~.~f~566~;
6) 60 ~1H~ d~ JS-6 cis = 4~H-5)~ 5.55 ~lH, d~
J 6 t = 2, H-5), 3-93 (lH~ d~ J6--5 cis 4' )'
~lH, d, J6-5 trans = 2, H-6), 3.50 ~b.s.,OH), 2.34 (3H~ s, CH3),
1.47, 1.40 (6H, 2s, 2CH3), 1.35, 1.32 (6H, 2s, 2CH3)
V (nujol mull) 1765, 1582, VOH 3600 - 3100
W ~EtOH) Amax 257 ~ = 3920), 300 ~E = 4020).
Example 4
Potassium 6-Hydroxybenzyl-2-meth-~lpenem-3-carboxylate (anion process)
~ H
HO X ~ 8~
C02K
-
~H
CH3 ~ HO ~ XH3
1 4b
A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous
THF (6 cc, distilled over LAH) was added dropwise to a cold (-78)
THF (2cc) solution of LDA made from diisopropylamine (84 ~1, 60.6 mg,
0.599 mmole) and 1.6 M n-BuLi (0.380 cc, 0.608 mmole). The mixture
was stirred for 5 min, followed by successive addition of diisopropyl
amine (84 ~1, 60.6 mg, 0.599 mmole) and 1.6 M n-BuLi (0.380 cc, 0.608
mmole). It W2S then stirred for 7 min at -78 and treated rapidly with benz-
aldehyde (300 yl). The mixture was allowed to react at -78
for 20 min. It was acidified with 1~ HC1 (pH-2), diluted with ethyl
acetate (40 cc), washed with 1:1 H2O-brine (3 x 20 cc) and brine (1 x 20cc)
It was dried over Na25O4. Solvent evaporation gave a residue which was
dissolved in MIBK (2cc). It was treated dropwise with potassium 2-ethvl
-6~ -
hexanoate. It gave 4b (35 my) in 20% yield as a
diastereoisomeria mixture. ~ : (ppm, DMSOd6) 7.95 (5H, s,
H-aromatic) 5.57 (d, J5-6 trans = 1.5, H-5), 5.45 (d, J
5-6 trans - 1.5, H-5) 5-35 (d, J5-6 cis = 4~ H 5)~ 5-0 ( ~
C-H hydroxybenzyl), 4-25 (dd, J6-5 cis = 4, J 6-C-H
hydroxy benzyl = 10, H-6), 3.90 (m, H-6), 3.65 (b.s., OH),
2.35 (3H, 2s, CH3) Vc=O ("NUJOL MULL")* 1760, 1590, vOH
3600 - 3100. UV (H2O) max 252 ( s = 5,100), 296 (~ =
3,300)-
Exam~le 5
Potassium Ç-Thiomethyl-2-methyl~e~em-3-carboxylate (anion
Drocess )
SMe
~ ~ CH3
N ~
2
S SMe S
3 2 3
C02H X C02K
1 4c
A solution of acid 1 (100 mg, 0.540 mmole) in
anhydrous THF (5cc, distilled over LAH) was added dropwise
to a cold (-78) THF (2cc) solution of LDA made from
diisopropylamine (84 1, 60.6 mg, 0.599, mmole) and 1.6 M
n-Butyl lithium, (0.380 cc, 0.608 mmole). The mixture was
stirred for 7 - 8 min, followed by successive addition of
diisopropylamine (84 ~l, 60.6 mg, 0.599 mmole) and 1.6 M
n-Butyl lithium (0.380 cc, 0.608 mmole). It was then
stirred for 7 min at -78 and treated rapidly, with methyl
thiomethylsulfonate (300 ~ l, excess). The mixture was
allowed to react at -78 for 5 min. It was acidified with 1%
HC1 (pH-2), diluted with ethyl acetate (40 cc) , washed with
1:1 H2O-brine (3 x 20 cc) and brine (20 cc).
*Trade Mark
- 61 -
., .
~ ~fi~l
The organic solution was dried over Na2SO4. Solvent
evaporation gave a residue which was dissolved in cold MIBK
(2cc). The cold solution wa~ treated dropwise with
potassium 2-ethylhexanoate. It gave ~ (40 mg)in 28% yield
as a 8:3 mixture of cis and trans isomers (decomp.) 115
120) ~ (ppm, DMSOd6 ) 5.85 tlH, d, J5-6 ci8 = 4, H 5) ,
5-57 (lH~ d~ J5-6 trang = 1-5, H-5), 4.87 (lH, d, J6-5 cis =
4, H-6), 4.72 (lH, d, J6-5 tran8 = 1.5, H-6), 3.42 (b.s.,
OH), 2.37 (s, SCH3), 2.33 (s, CH3), 2.25 (8, SCH3). Vc=O
("NUJOL MULL)* 1770, 1600, UV (H2O) ~max 252 ( ~= 4200),
297 ( F = 3700)
Example 6
l-(~-Nitrobenzvloxycarbonylmethvltriphenylphosphoranyl)-4-
tsilver me~captidyl)-2-aze~idinone
~ SAg
N ~P ~ 3
C02PNB
STr
OAc Na0Me ~ H
0 H o
A methanol (90cc) suspension of triphenylmethyl
mercaptan (13.8 g, 0.05 mmole) was degassed for 0 . 5
hour with a nitrogen stream. The mixture was cooled
down at O and sodium hydride (2.4 g, 0.05 mole, 50%
oil dispersion) was added portionwise. The resulting
solution was stirred for 5 min and 4-acetoxyazetidinone
(7.7 g, 0.059 mole) in water (55 cc) was added rapidly.
Precipitation of 4-triphenyl methyl mercaptoazetidinone
(2) occurred immediately. The
* Trade Mark
- 62 -
. .~ , ~
,. . ..
~6~
mixture was stirred for 4 h at room temperature. The solid
was filtered off, washed with water and di6solved in
methylene chloride. The methylene chloride solutlon was
washed with diluted HCl, water, aqueous sodium bicarbonate
water and brine and dried over MgSO4,
(89.8%, m.p.: 146.5 - 147.5C)
Anal. Calc'd for C22H19NOS: C, 76.49; H, 5.54; N, 4.05; S,
9.28
Found: C, 7.54; H, 5.60; N, 4.00; S, 9.36.
~ (ppm, CDC13) 7.60 - 7.10 (15H, m, H-trityl), 4.62 (lH,
bS, NH),
4-40 (lH~ dd~ J4-3 trans = 3 ~ J4-3 cis = 5~ H-4)~3-24 (lH~
ddd~ Jgem = 15~ J3_4 ci6 = 5, J3_NH = 1.8, H-3), 2.81 (lH,
~ gem 15~ J3_4 trans = 3-0, J3_NH = 1.2, H-3)
Vc=O (CHC13) 1760, VNH 3340
F' ? ~ ~S~ OH ~ S~
02PNB C02PNB
2 3
Hydrated p-nitrobenzyl glyoxylate t4.54 g, 0.02
mole) and azetidinone 2 (6.90, 0.02 mole) were refluxed in
benzene through a Dean Stark condenser filled with 3A
molecular ~ieves for 24 h. Further glyoxylate (2 x 454 mg,
2 mmoles) wa6 added with reflux period (18 h) after each
addition. The mixture was diluted with ether, washed with
5% aqueous HCl, water, aqueous 5% NaHCO3 water and brine. It
was dried over MgSO4 (12 g, quantitative) A small fraction
of the epimeric mixture was separated on a ~ilica gel plate
(CH2Cl2- ether 6:4)
Isomer A:
Rf = 0.87, m.p. = 170.5 - 171.5
- 63 -
~6~61
~ (ppm, CDC13) 8.07 (2H, d, J=9, Hm aromatic), 7.45 tpart
of d, Ho aromatic), 7.40-7.00 (15H, m, Trltyl), 5.25 (2H, s,
CH2-PNB), 4.75 (lH, s, H-C-O), 4-37 tlH, dd, J3_4 trans= 3
J3-4 cis ~-4, H-3), 2.83 (lH, dd, Jgem = 16, J4-3 CiB = 4~
H-4), 2.10 (lH, dd, Jgem = 16, J4-3 trans = 3~ H 4)~ 1-42
(b.s., OH).
c=o (CHCl3 1770, 1760 (shoulder), vNO2 1525, vOH 3475.
Isomer B:
10 Rf 0.75, m.p. = 152 - 153
~ (ppm, CDC13), 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (,2H,
d, J = 9, Ho aromatic), 7.40 - 7.00 (15H, M, trityl), 5.30
(3H, s, CH2-PNB, H-C-0), 4.45 (lH, t, J = 3.5, H-4), 2.90 -
15 2.70 (2H, AB part of ABX, H-4), 1.55 (b.s., OH).
vc=o(CHC13) 1767, 1755 (shoulder), vNO2 1525, CH
STr SOCl2 STr
~ pyridine ~
C02PNB C02PNB
3 4
A cold (-15) THF (150 cc, dried over molecular sieves)
solution ~f azetidinone 3 (12 g, 21.7 mmoles) was treated
with pyridine (1.9 g, 24.1 mmoles, 1.94 cc) and dropwise
with thionyl chloride (2.86 g, 24 mmoles, 1.88 cc) under a
nitrogen atmosphere. The mixture was stirred for 45 min at
-15. The precipitate was filtered off and washed with
benzene. Evaporation of solvent gave a residue which was
- 64 -
,"~ ~
,-~, . .
taken up in benzene and treated with activated charcoal
(11.7 g, 94%, crystallized out from chloroform).
~(ppm, CDCl3) 8.17 (2H, d, J = 8, Hm aromatic), 7.67 - 7.00
(17H, m, ~o aromatic, Tr-H), 5.80 (8, H-C-Cl), 5.37, 5.33
(2s, H-C-Cl, CH2-PNB), 4.81 (lH, m, H-4), 3.27 - 2.40 (2H,
m, H-3)
c=o (KBr film) 1785, 1770 vN0 1525.
STr
~ ~3P
C02PNB C02PNB
4 S
A THF (100 cc, distilled over LAH) solution of
chloroazetidinone 4 (11.6 g, 20.2 mmole~) was treated with
triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6-lutidine
(2.36 g, 2.56 ca, 22.0 mmoles). The mixture was refluxed for
72 h. The precipitate was filtered off and washed with
ether. The organic solution was washed with 2% aqueous HCl
and 5% aqueous bicarbonate and dried over MgSO4.
Evaporation of solvent gave a residue which was purified
through silica gel pad (200 g). The desired phosphorane was
eluted with 30,40 and 50% ether-benzene (11.4 g, 70.4%,
m.p.: 201-202).
Anal. Calc'd for C49H40N205SP: C, 73.57; H, 5.04; N, 3.50;
S, 4.01.
Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87.
Vc=O (CHCl3 1740, ~phosphorane (1620, 1610), VN0 1525.
- 65 -
3fi6~
T-
03 ,__~SAg
~3 pyridine ~ ~ 3
02PNB
C2 PNE3
4-Tritylmercapto azetidinone 5 (1.6 g, 2 mmoles) t
was dissolved in CH2Cl2 (20 cc) and the solvent was flushed
down at 55-60. Phosphorane 5 at 55 - 60 was dissolved in
preheated (55-60) methanol (32 cc). Immediately after the
obtention of a methanolic solution of 6 it was treated with
a preheated (55 - 60) mixture of methanolic 0.15 M silver
nitrate solution (16 cc, 1.2 eq) and pyridine (174 mg, 178
l, 2.2 mmoles, 1.1 eq). The warming bath was then
immediately removed. The mixture was stirred at room
temperature for 2 h and at OC for 1 h. The silver
mercaptide 6 was filtered off, washed twice with cold tO)
methanol and three times with ether. (1.12 g, 84.5%, m.p.:
130-135 dec-.).
Vc=O (CHCl3) 1795, 1725 (shoulder), v phosphorane (1620,
1605), vN02 1530.
- 66 -
6f~
Example 7
1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-
- ~silver mercaptidyl)-2-azetidinone)
SCOC~13 K2C03,AgNO3 SAg
1~' ~ 1~
o ~ - C=PPh3 MeOHO ~ N` C=PPh3
10COOPNB COOPN~
A solution of phosphorane 7 (1.796 g, 3.0 mmoles)
in chloroform, (3ml) was diluted with methanol (90 ml),
lS cooled at OC under nitrogen atmosphere and treated
successively with silver nitrate (0.51 g, 3.0 mmoles) and
potassium, carbonate (0.33 g, 2.4 mmoles). The reaction~
mixture (protected from light) was stirred at oc for 15
min., then the cooling bath was removed and stiring was
continued for 3 h. The reaction mixture was cooled down to
-10C, stirred for 1 h and filtered; the silver mercaptide
was successively washed with cold methanol and ether; 1.91
g, M.P.: 138 - 145C dec, 96~. I.R. ("NUJOL")* cm~1: 1748,
1620 and 1605. An analytical sample was obtained by,
preparative TLC (ethyl acetate); M.P.: 140 - 5C dec, calc'd
for C30H24N2O5SPAg: C, 54.31; H, 3.65; N, 4.22; S, 4.83.
Found: C, 54.11; H, 3.48; N, 3.92; S, 4.62.
Example 8
1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl-4-
(silver mercaptidyl~ -2-azetidinone
A. Use of aniline as base
. .
SCOCH3 Aniline, AgNO3SAg
1~' . ....... ~ r~
~ N MeOH ~ N ~
35 Cl PPh3 C=PPh3
COOPNB COOPN~
- 67 - 6
* Trademark
~r36~1
A solution of phosphorane 7 (1.8 g, 3.0 mmoles)
in chloroform (4 ml) was diluted with methanol (90 ml),
cooled to -15C under nitrogen atmosphere and treated
successively with silver nitrate (0.56 g, 3.3 mmoles) and
aniline (1.5 ml, 16.5 mmoles). The reaction mixture
(protected from light) was stirred at -15C for 0.5 h and
then the cooling bath was removed and stirring was
continued for 24 h. The reaction mixture was cooled to -10C
and stirred for 1 h before being filtered; the silver
mercaptide was successively washed with cold methanol and
ether; 1.55 g, M.P. 114-5C dec. 77.9%. IR ("NUJOL")*cm 1;
identical to compound of Example 7.
Silver-l-(Paranitrobenzyl 2'-~riphenyl~hosphoranylidene-2'-
ace~ate)-2-azetidinone-4-thiolate
B. Use of 4-dimethylamino~yridine (DMAP~ as base
SCOCH SAg
r~' 3 AgN3/DMAP I _,/
20 ~L N ~ C H 2 C 1 2 / C 3 3 3 ~-- N ~ ~1) 3
C02PNB C02PNB
A solution of the above S-acetyl phosphorane
(17.96 g, 30 mmol) in methanol and dichloromethane (1:2,
450 ml) was purged with nitrogen (5-10 min), cooled to 5C
and treated successively with silver nitrate (5.35 g, 31.5
mmol) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol). The
ice-bath was removed and the solution refluxed vigorously
for 2 h and then stirred at room temperature for 1 h. The
colored reaction mixture was treated with charcoal,
filtered and evaporated. The residue was redissolved in the
minimum amount of dichloromethane and added dropwise, with
stirring to cold methanol (300 ml). The precipitated silver
salt was collected by filtration, washed with ether and
35 dried; 18.1 g (91%); ir (CHC13) vmax: 1745 (C=O of
B-lactam) and 1607 cm~1 (C=O of ester).
* Trademark
- 68 -
.~
i66~
Silver~ a~Lnitrobenzyl 2'-trihenyh~b~9
-2"-aoeta~e)-2-
C. Use of di~zabicycloun~ecene (D~U~ a~ ba.~e
~COCH3
AgNo3 ~ SAg
DBU, MeOH ~
C02PNB C02PNB
The above S-acetylphosphorane (36. 0 g, O. 060 mol)
10 was dissolved in methylene chloride 120 ml. The solvent was
evaporated in order to obtain an oil. The resulting oily
residue was dis601ved in warm (35C) methanol (240 ml) and
treated rapidly with a methanolic (420 ml) solution of
silver nitrate (10-68 g. O. 0628 mol). The resulting solution
15 (or su6pension) was stirred at room temperature for 5 min,
cooled down (ice-bath) and a DBU (8. 96 ml, O. 060 mol):
solution in methanol (20 ml) was added over a 5 min period.-
~The mixture was stirred for 5 min. The solid was filtered,
washed once with cold (0C) methanol and ether and
20 dried under vacuum; 37. 0 g (93%); ir ("NUJOL NAILL")* vmax
(c=O) and 1600 cm 1 (phosphorane)
D. Use of pyrrolidine as base
Silver 1~ aranitrobenzyl 2'-trlphenylphosphora}
idenç-2"-aceta~e)-2-azetidinone-4-thiQlate
SCoCH
SAg
Pyrrolidine I
AgNO3 ~
~ - N ~ ~ N
O f=PPh ~-PPh3
COOPNB COOPNB
To a cold (0C) solution of 4-acetylthio -1-
(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)
-2-azetidinone(O. 60 g, 1. 0 mmol) in CH2C12 (2 ml) was
35 added MeOH (4 ml), a solution of AgN03 in MeOH (O. 14N, 7. 86
ml, 1. 1 mmol) and a solution:. of pyrrol-
*Trade Mark
-- 69 --
~ ,,.~,
idine tO.92 ml, 1.1 mmol) in MeOH (2 ml~. The cooling bath
was removed and the reaction mixture was stirred for 1.75 h,
cooled to -10C, stirred for 0.25 h and filtered. The solid
was washed~with cold MeOH and dried in vacuo; 0.548 g, m.p.
115C, 82.4%. ir ("NUJOL")* vmax: 1775 (C=O) and 1600 cm 1
(aromatics).
Exam~le
Mercuric
(II)-~2'-Triphenyl~hos~horanylidene-2'_-acetatel
-2-azetidinone-4-thiolate
STr
H g ( OA c ) 2
O~N \C
1 3
I C02PNB
S)2Hg
1 l
II C02PNB
A solution of I (2.4 g, 3 mmoles) in dichloromethane
(15 ml) was cooled to 5C and treated with a solution of
mercuric acetate (0.525 g, 1.65 mmole) dissolved in
methanol (15 ml). After stirring at 5 ~or 2 h, the solvent
was evaporated and the residue redissolved in
dichloromethane and washed with cold water. The organic
solution after being dried (MgS04) and treated with
charcoal, was evaporated to give a foam which crystalized
when triturated in ether. Yield: 1.73 g (91~) M.P. 123 -
127C, I.R. (CHC13) 1745 cm 1 (vc=O e lactam) 1608 cm l
(phenyl)
*Trade Mark
- 70 -
;6~
Ex~ampl~_10
2-Methyl~enem-3-~ni~Qk~nzyl~d~Q~Lg~Q
(from mercaptide ~;ermediate)
,
S ) 2 H g
~ SCOCH~
~ PPh 2CH3COCl ~/
N ~ p y r i d i n e ~ N ~ 3
CO2PNB
II III
A solution of II (262 mg, 0.2 mmole), acetyl chloride
(35 mg, 0.44 mmole) and 2 drops of pyridine in 10 ml of
dichloromethane was stirred at 5C for 1 h. The
precipitated mercuric chloride was then filtered off and
the filtrate waæhed successively with cold dilute
hydrochloric acid, sodium hydroxide and finally brine. The
organic solution was submitted to a stream of hydrogen
sulfide for 2 minutes at 5C and stirred at that temperature
for an additional 10 minutes in order to precipitate the
last traces of mercuric salts. Some charcoal was added to
the black mixture which was then filtered through a pad of
celite. Evaporation of the clear filtrate left 193 mg
(80.7%) of III as a foamy material.
I.R. (CHC13) 1755 (, Vc=O B-lactam) 1692 (v ) 1620
(phenyl). SCOCH3
- 71 -
SCOCH3 S
r r ~ CH3
C02PNB C02PNB
2 III 3 IV
Phosphorane 111 (75 mg, O. 126 mmole) in toluene
(10 cc) was refluxed over a 2. 5 h period under nitrogen
atmosphere. Solvent evaporation and purification of the
residue afforded a crystalline derivative (25 mg, 63%)
whose physical and spectral data were in complete agreement
with those of the title product.
Product IV may if desired be subjected to
catalytic hydrogenation (30% Pd on "CELITE")* to produce the
corresponding 3-carboxylic acid product.
*Trade Mark
- 72 -
~3666~L
Example 1
2-Aminome~hylpenem-3-carboxyli$ Acld
from me~Q~p~de~int~mediate)
f~ CH2NH2
COOH
1 0 ,_ _
SCOCH N
~SAg ClCOCH2N3 ~--f 2 3
~ N!
~N ~ C H 2 C 1 2 o ~C- P P h 3
f=PPh3
COOPNB COOPN8
A solution of silver mercaptide 1 (1.25 g, 1.99
mmole) in dichloromethane (15 ml) kept under nitrogen
atmosphere was cooled at 0C and treated dropwlse with a 2M
solution of azidoacetyl chloride in dichloromethane (1.13
ml, 2.26 mmoles). The reaction mixture was stirred at 0C
for lh; the cooling bath was removed and stirring was
continued for 5 h. The reaction mixture was filtered over a
"CELITE"* pad and the 601ids were wa6hed with
dichloromethane (35 ml). The filtrate and washings were
combined, washed with sodium bicarbonate solution and water,
dried over anhydrous sodium sulfate and concentrated in
vacuo to an orange syrup which was purified by column
chromatography (30 g of silica gel 60, eluate; ether-2%
ethyl acetate
*Trade Mark
- 73 -
. .
(200 ml), ether -6% ethyl acetate (200 ml) and ether-20%
ethyl acetate (500 ml), fraction slze: 10 ml). The
combination and evaporation of fractions 49-80 gave a yellow
powder; 0.13 g, M.P. 61-70, 60.8%.
SCOCH2N3 S
F~ To i ~ e n e ~N ~ C H 2 N 3
Cl=PPh3 COOPNB
COOPNB
2 3
A solution of phosphorane 2 (0.593 9, 0.93 mmole) in
toluene (20 ml) was heated at 105C for 1 h, cooled to 23C
and concentrated to a semi-crystalline compound which was
purified by column chromatography (12 g of silica gel 60,
Eluate: benzene (100 ml), benzene-2% ether (100 ml) and
benzene-4% ether; fraction size: 10 ml). The combination and
evaporation of fractions 18 - 26 gave a yellow syrup which
crystallized on standing; 0.18 g, M.P.: 127-8C, 53.7%. NMR
(CDC13, ~ 8.22 (2H, d, JHO, Hm = 8-8 Hz~ P
nitrobenzyl), 7-60 (2H, d, JHm, Ho = 8-8 Hz~ Hm of p
nitrobenzyl), 5.71 (lH, dd, J5,6 cis = 3-6 Hz~ J5,6 trans
= 2.1 Hz, H-5), 5.33 (2H, center of ABq, Ja b = 14.0 Hz,
CH2 of p-nitrobenzyl), 4.58 (2H, center of ABq, Ja b =
15.0 Hz, CH2on C-2) 3.88 (lH, dd, J6,s cis = 3-6 Hz~ Jgem =
16.5 Hz, H-6 cis) and 3-55 (lH, dd, J5,6 trans = 2-1 hz~
Jgem=16 5 Hz, H-6 trans)
I.R. ("NUJOL")* cm 1 2115 and 2090 (N3), 1780 (c=o of B-
lactam) and 1685 (c=o of p-nitrobenzyl ester).
An analytical sample was obtained by preparative T.L.C.;
M.P. 127-8C, calc'd for C14H11N5O5S: C, 46.54; H, 3.07; N,
19.37; S, 8.87. Found: C, 46.43; H, 3.08; N, 19.37; S, 8.90.
*Trade Mark
- 74 -
~, .~ I
,i ~, .,
lZr~
CH2N 30~ Pd/ "CE~,ITE'' r~~ ~ CH NH
3 THF, e th er, H 20 a~ N ~ 2 2
COOPNB COOH
3 4
To a solution of penem 3 (0.18 g, 0.5 mmole) in
tetrahydrofuran (6 ml) was successively added ether (6 ml),
water (6 ml) and 30% palladium on ~ CELITE" * (O. 18 g). The
reaction mixture was hydrogenated under 30 p.s.i. at 23C
for 2.5 h and filtered over "CELITE"* pad; the pad was
washed with water and the filtrate and washings were
combined, washed with ether-THF mixture and lyophilized to
give 30 mg, 30%, of compound 4. [Water and ether insoluble
compound were diss 01 ved in chloroform and the organic
solution was washed with water and dried over anhydrous
sodium sulfate. The evaporation of solvent under reduced
pressure gave 77 mg (42.8%) of starting material 3]. NMR
(DMSO d-6) ~:5.7 (dd, J5-6ci8 - 3-5 Hz~ J5-6trans = 1-5 Hz~
H-5)- I. R. ("NUJOL")* cm 1 1775 (c=o of B-lactam) and
1615, 1585. U.V. ~H20 m : (F=2320) and 307 (~=2685).
max
Title product 4 was also obtained from
intemediate 3 by the following route:
1 ~-- ~ CH2N3 H2,Pd/D-E~ ~ ~ CH2NH2
30 o~L_ ~ ~ THF, E~er, O~N ~
COOPNB 2 COOH
3 q
To a solution of penem 3 (2.4 g, 6.89 mmoles) in
tetrahydrofuran-ether-water mixture (1:1:1, 165 ml) was
added 30% palladium on diatomaceous earth (4.8 g). The
reaction mixture was hydrogenated under 45 p.s.i. at 23C
for 2.5 h and
*Trade Mark
- 75 -
6~
filtered over celite pad. The filtrate and washlngs were
combined, washed twice with ether, centrifugated and
filtered several times to give a clear solution which was
lyophilized; 0.622 g, 45%. The crystallization of the
compound was induced by the addition of water (0.8 ml); the
suspension was centrifuged and the water was removed
leaving an orange solid. This solid was washed twice with
water and a slightly yellow solid was obtained after
drying: 0.273 mg, 19.8%. UV~ 2 : 307 (~ =4318) and 257
max
(~ =2650). Some crude starting material (1.2 g, 50~) was
recovered. The compound (50 mg) can also be purified by
column chromatography ["SEPHADEX" *GIO, column size: 1.6 x
100 cm, flow rate: 10 ml/h, eluent: distilled water,
fraction volume: 1.5 ml, detector: refractive index3.
H20
UV~ : 307 (~=3597) and 255 (E=2424).
max
The stability of the compound in aqueous solution was
checked by:
UV: 6 h 307 (~=3545 and 255 (F =2773)
21 h 307 (~=3467) and 255 (~=2411)
28 h 307 ( =3337) and 254 (~=2398)
46 h 307 (F =3259) and 254 (~=2398)
70 h 307 (~=3076)
94 h 307 (~=2842)
170 307 (~=1900)
A sample of compound 4 was kept at 23C for 3 days
H 0
and the UV was taken: UV~ 2 :307 ( =3055) and ( =2008).
max
Compound 4 was converted as described below to two
additional 2-penem derivatives.
*Trade Mark
- 76 -
Ç3~
S\ ~ Nal~CO3, H 2O ~ ; ~ 2
~ I ~CH2NH3 CH C-OEt 5 C:)G91a(3
A suspension of compound 4 (50 mg, 0.25 mmole) in
distilled water (0.5 ml) was treated with one equivalent of
sodium bicarbonate (21 mg) followed by the addition of
ethyl acetimidate (21. 8 mg, 0. 024 ml). The reaction
mixture was stirred at 23C for 20 min and lyophilized
10 giving 52 mg of a yellow solid. NMR (D2O) ~: 5.7 (m, H-5)
and 2.23 (b.s., CH3 of amidine). I.R. (KBr)cm 1 1772 (c=o
of B-lactam). U.V. ~D20 m~ : 305 (~=3116) and 253
max
15 ( =2525). The compound 5 was applied on a column
("SEPHADEX")*G10, column size: 1.6 x 100 cm 1 Eluent: H2O,
detector: I.R. fraction size: 1.6 ml) and lyophilization of
appropriate fractions gave 23 mg 45% of slightly yellow
20 powder U.V.~ 2 m~: 303 (~=2960) and 248 (F=2885).
max
2 . ~ (~) NaHCO , H O S H
~cH2NH3 3 2 ~ ~ CH2N=C +6NaCI
O ~~ C ~ N ~ ~NH2
4 c~) H- -OEt 6 COO(~la(~)
A suspension of compound 4 (50 mg, 0.25 mmole) in
distilled water (0-5 ml) was treated with sodium
bicarbonate (21 mg, 0.25 mmole) and stirred for 1.5 min
before the addition (2 min) of a mixture of sodium
bicarbonate (126 mg, 1.5 mmole) and ethyl formimidate
hydrochloride (164 mg, 1.5 mmole). The reaction mixture was
stirred for 10 min at 23C and lyophilized giving an orange
powder. U.V. ~H2m~: 304 (~=2300).
*Trade Mark m a x
- 77 -
. .~
E x a m p 1 e 12
Sodium 2-Hydroxyaminopropylpenem-3-carboxylate
NHCH
N ~
CO Na
1 ) NaOH S ~
02N/--~02E~ 2) HCl conc 2 C02H
To a cold 5% aqueous solution of sodium hydroxide (320
ml) was added ester 1 (21.6 g, 0.134 mole). The resulting
mixture was stirred at room temperature for 2 h and then
concentrated to 250 ml and acidified wilh concentrated HC1.
The mixture was extracted with ethyl acetate (4 x 200 ml)
and the organic extracts were dried over sodium sulfate.
Concentration on rotary evaporator left an oil. Yield 13.2
g (75%).
- 78 -
,~,, . .1,"
,~, "
~f~6~
2 CO2H + SOCl2 2 COCl
A solution of acid 2 (13.2 g, 0.1 mole) in SOC12
t25 ml) was stirred for 2 h at 30C. After evaporation of
thionyl chloride, the residue was distilled under vacuum T =
76-78C (P=0.2 mm Hg). Yield 8.8g (58.3%) as a colourless
liquid: n.m.r. (CDCl3) ~ ppm:2.40 (2H,m,B-CH2); 3.15 (2H, t,
~ -CH2); 4.50 (2H, t, r-cH2) i.r. (neat): 1550 cm 1
(VN0 ); 1790 cm~1 (VC=O~ acid chloride).
S ~ N02
~ 1) H25/Et3N , f a
O. COCl ~Ac - _
2) NaHCO3/ ~ N
A solution of ~ (19.46 g, 0.128 mole) in methylene
chloride (200 ml) was added rapidly to a cold (0-10)
stirred solution of triethylamine (36 ml, 0.256 mole) in
methylene chloride (500 ml) which had been saturated at 0-51
with H2S. The mixture was stirred at -10 for 1 h and then
a stream of nitrogen was passed throuqh the solution to
eliminate the excess of H2S. The mixture was washed with
10% HC1, the organic extract was concentrated to about 150
ml and then sodium bicarbonate (10.9 g) and water (500 ml)
was added. The pH was adjusted to about 7.5 with NaHCO3 or
HC1. The resulting mixture was cooled to 0C and
4-acetoxy-2-azetidinone (16.8 g, 0.13 mole) in water (20 ml)
was added with vigourous stirring. After 4 h the mixture was
extracted with ethyl, acetate. ~he extracts were washed
- 79 -
with 10% HC1, sat. NaHC03, brine, dried (Na2SO4) and
evaporated. The residue was purif:Led by column
chromatography (SiO2 ; eluent: ether
then ether-ethyl acetate 5%) giving an oil which
crystallized in ethyl acetate-hexanes yielding 4 (3.5 g,
12.5%) as a white powder. (m.p. 45-47,C).
~H(
C02P~B
4 5
A mixture of azetidinone 4 (1.09 g, 5 mmoles) and
p-nitrobenzyl glyoxylate hydrate (1.2 g, 5.25 mmoles) in
benzene (100 ml) was heated at reflux with a Dean-Stark trap
o
filled with 4A molecular sieves for 18 h. Evaporation of
the solvent gave the glyoxylate adduct 5 (2.1 g) as an oil.
~ ~ 2 SOCl2 ~ ~ N02
25 O~ ~C0 ?Ns Y ~H -Cl
H 2 ~2PNB
Azetidinone glyoxylate 5 (2.1 g) was dissolved in
tetrahydrofuran (50 ml) and pyridine (0.57 ml, 7 mmoles)
was added to the solution. The mixture was cooled to OC and
SOCl2 (0.5 ml, 7 mmoles) was slowly added. The mixture was
stirred 1 h at OC and then filtered before evaporation to
dryness. Filtration of this material over a pad of silica
gel with CH2Cl2 gave a foam; yield 1.9 g (85%).
- 80 -
1~36~
a~ ~--~N 2 ¢) 3 ~ ~f ~--
N ~ C~~-Cl 2,6-lutidine C=P~
CO2PNa 12PNa
6 7
To a solution of chloroazetidinone (6.2 g, 14 mmoles)
in THF (300 ml) was added triphenyl phosphine (5.5 g, 0.02
mole) and 2,6-lutidine (2.4 ml, 0.02 mole). The mixture was
heated at 45C for 20 hours. Lutidine hydrochloride was
filtered off and washed with ether. The filtrate was then
evaporated. The residue was purified by chromatography
through a silica gel column and eluted with dichloromethane
and dichloromethane-ethylacetate (1:1). Evaporation of
eluent gave a white solid (2. 9 g, 30%.)
~ Toluene ~ ~ N0
~ ~3 C02PNs
C022~
7 8
Phosphorane l (2.0 g, 3 mmoles) in toluene
(150 ml) was refluxed for 2.5 h. Bvaporation of solvent
afforded an oil which was purified by chromatography
through a silica gel column and eluted with dichloromethane
and dichloromethane-ethylacetate (9: 1) - Evaporation of
the solvent gave a syrup which crystallized in
ethylacetate-hexanes as a white solid (0. 82 g, 40. 7%)
- 81 -
66~
~ --\NO 30% Pd/DE
J_N ~ 2 THF-E~ER-H20-NaHC0
CO 2 ~B
8 ~ ~/V\NHCH
C2Na
To a solution of ester 8 (50 mg, O. 127 mmole) in a
tetrahydrofuran-ether mixture (2:3, 25 ml) was added water
(10 ml), sodium biaarbonate (10 mg, O. 127 mmole) and 30%
palladium on diatomaceous earth (50 mg). The reaction
mlxture was hydrogenated under 50 p. s.i. for 3 h at 25C,
filtered over a celite pad and washed with ether. Aqueous
solution was lyophilized yielding a yellow powder (30 mg)
of hydroscopic compound.
- 82 -
~3~61
Example 13
6-EthYl-2-aminomethylpenem-3-carboxylic Acid (cis and
trans isomers)
10 C~N--~ ~112NU2 2
C02H
a. Silver cis and trans 3-ethyl-l-(p-nitrobenzvl-2'-
triphenylphosphoranylidene-2'-acetate)-2-azetldinone-
4-thiolates
A solution of cis and trans 3-ethyl-l-(p-nitrobenzyl-
2'-phosphoranylidene-2'acetate)-4-acetylthio-2-azetidinones
- 83 -
o
(1.88 ~., 3.0 mmoles; ~xample 1, structure 7) in chloroform
(4 ml.) was diluted with methanol (90 ml.), cooled to 0 and
treated successively with finely powdered silver nitrate
(0.51 g., 3.0 mmoles) and potassium carbonate (0.33 g.,
2.4 ~moles). The miiture was stirred vigorousl~ 15 ~in.
at 0, 3 h at room temperature and 1 h at -10C. The
precipitated silver mercaptide was collected by filtration,
washed with methanol and with ether and dried in a vacuum.
The title product was obtained as a grevish solid, m.p.
112-135 d. vC=O 1750, 1620, 1605.
b. Cis and trans 3-ethvl-1-~n-n trobenzvl-2'-~hosphoranvlidene-
. .
2'-acetate)-4-azidoacetvlthio-2-azetidinones
A solution of the above crude mercaptide (1.31 g, 2 mmoles)
in dichloromethane (15 ml) was cooled to 0 and treated,
under a nitrogen atmosphere, with a 2r1 solution of azidoacetyl
chloride in dichloromethane (1.13 ml, 2.26 mmoles). The mix-
ture was stirred at 0 for 1 h and at room temperature for
5 h. The insoluble silver salts were removed by filtration
over Celite and ~ashed with dichloromethane. Lhe combined
filtrates were washed with dilute sodium bicarbonate solution
and water, dried and concentrated. The oilv residue was
purified by chromatography over silica gel (35 g) eluting
with ether-ethyl acetate. The pertinent fractions were
concentrated to give a mi.~ture of cis and trans acylated
compounds as a semi-solid; 0.62 mg. v (CDC13): 2105, 1760, 1690,
1621 c~ .
c. Cis and trans ~-nitrobenzyl-2-azidor~ethYl-6-ethylpenem-3-
_ _
carboxylates
~-solution of the above crude phosphorane (0.60 g) in
o
~Z~36~6 ~
toluene (30 ml) was ~ept at 105 for 1 ;1, cooled and concentrated
to leave an oily residue which was purified by colwnn cnromato-
graphy over silica gel (20 g) eluting witn increasin~ pro~or-
tions of etner in benzene. T.~e pertinent fractions were
concentrated to give both the cis and trans isomers.
cis isomer: ~ (ppm, CDC13): 8.25 (2~1, d, J = 8.8, ~o of
paranitrobenzyl), 7.65 (2~, d, ~m), 5.93 (lH, d, J = 4.1, H-5),
5.38 (2H, AB quartet, J = 14.0, benzyl), 4.68 ~2H, AB quartet,
J = 15.0, CH2-.~3), 3.4 (lH, m, h-6), 2.0 (2H, m, CH2CH3), 1.1
(3H, t, J = 7.4, CH2CH3).
trans isomer: ~ (ppm, CDC13): 8.18 (2~, d, J = 8.8, Ho), 7.59
(2H, d, Hm), 5.52 (lH, d, J = 1.4, H-5), 5.33 (2H, AB ~uartet,
J = 14.0, benzyl), 4.58 (2~, A3 quartet, J = 15.0, CH2-i~3), 3.7
(lH, dt, J = 1.4, J = 7.4, ~-6), 1.9 (2H, m, CH2CH3), 1.1 (3H,
t, J = 7.4, CH2C~3).
d. Trans 2-Aminomethyl-6-ethylpenem-3-carboxylic Acid
A mixture of the above trans p-nitro benzyl ester
(0.20 g, 0.5 mmole), THF (6 ml), ether (6 ml), water (12
ml) and 30% palladium on celite (0.20 g) was reduced at 23
for 2.5 h at an initial hydrogen pressure of 30 psi. Tl~e
catalyst was removed by filtration over celite and washed with
water. The combined filtrates were washed with etAer-THF and
lyopnilized to give the crude trans acid (12 mg). Chromatography
over a column of Sephadex G-10 eluting witn water gave the pure
trans acid (6 mg) as a Aygroscopic powder. vC=O 1775, 1615 cm 1.
AmaX = 306 (f - 3465). ~ (ppm, D2O-DMSO): 5.40 (lH, d, J =
2.0, H-5), 2.0 (2H, m, CH2CH3), 1.1 (3h, t, J = 7.4, CI12CH3).
~g5~
e. cis 2-~minomethyl-6-ethylpenem-3-carboxvlic ~cid
Reduction of the cis-p-nitro~enzyl ester as descri~ed
above for the trans-ester ga~e thé cis-acid as a yellowish
hygroscopic power (13~) v~=O 1775, 1615 cm 1. ~ma~ 304
(~=3563). ~(ppm, DzO-DMSO): 5.75 (lH, d, J = 4. O, H-5), 2.0
(2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3).
/~t
Example ~X~
The following compounds may be prepared according
to tne yeneral procedure of Example ~
~ S
N ~
C02Z
Acylating Agent Y X Z
CH3COCl -c~3 -CH3 Na, H
Ac20 -CH3 -CH3 Na, H
3 2 2CH3 -c~3 -c~3 Na, H
2 5 1 -CH3 2 5 Na, H
0CH2COCl -CH3 -CH20 ~a, ~
00CH2cOcl -c~3 -C~200 Na, H
COCl -CH3 ~ Na, H
COCl -CH3 ~ Na~
(CF3CO~20 -CH3 -CF3 Na
2 5 2 OCl -c~3 -CO2Et Na
~COCl -C~3 ~ ~ Na, H
CH3 ~CH3
--~6 -
1'~3~
Acylating Aqent Y X Z
~ C~2COCl -C~3 ~5 Na, ~i
3( 2)2COCl -CH3 -(CH2)2NH2
N3(CH2)3COCl -CH3 -(CH2)3NH2 H
NC(CH2)2CoCl -CH3 -(CH2)3NH2 H
02N(CH2)3COCl -CH3 -(CH2)3NHOH Na, H
3(CH2)4COcl -CH3 -(CH2)4NH2 H
N3(CH2)20CH2COCl -CH3 -CH20(CH2)2NH2
3( 2)2 C 2 Cl -CH3 -CH2S(CH2)2NH2
AcNH(CH2)2C02C02Et -CH3 -(CH2)2NHAc Na, H
CH3COC1 2 5 -C~I3 Na, H
2 5C 2 5 2 5 Na, H
0CH2COCl -C2HS -CH2~ Na, H
00cH2COCl -C2H5 C 20 Na, H
COCl -C2H5 ~ Na, H
N3(CH2)2COCl C2H5 -(CH2)2N~2 H
N3(CH2)3COCl -C2H5 ( 2)3 2 H
2 ( 2)3 -C2HS -(CH2)3NHOH Na,
N3(CH2)4COCl -C2HS (CEI2)4~1H2
CH3COCl iso-C H7 -CH3 Na, H
C2 5COCl iso-C3H7 -C2H5 Na, H
COC1 iso-C3H7 ~ Na, H
COCl
iso-C3H7 ~ Na, H
~ COC1 iso-C3H7 ~ iNa, H
0CH2COCl iso-C3H7 -CH2~ ~ia, H
3 2 iso-C H 2 2
-~7 -
o
~f3~6~
N3(CH2)2COCl iso-C H (C~l2)2'~ 2
3(C~12)3COCl iso-C3H7 -(CH2)3NH2 H
2 ( 2) 3 Cl iso-C3H7 -(CH2)3NHOH Na, H.
Example ~
cis- and trans-6-Acetoxymethvl-2 aminomethvlpenem-3-carboxYlic
A _
C
C02H
a) 3-Acetoxymethyl-4-tritylthio-2-azetidinones (cis and trans
isomers)
A solution of a mixture of cis and trans 4-acetoxy-
3-acetoxymethyl-2-azetidinone (4.7 g, 25 mmoles) (Example 2,
structure 26) in water (200 ml) was added rapidly to a vigorously
stirred solution of sodium triphenylmethyl mercaptide (from
triphenylmethyl mercaptan, 55.2 g; and sodium hydride, 9.6 g,
in methanol, 300 ml). The mixture was stirred at room tempera-
ture for 4 h and the solids were collected by filtration,
washed with water, and dissolved in dichloromethane. The solu-
tion was washed with dilute hydrochloric acid, water, aqueous
sodium bicarbonate and water, dried and concentrated to leave
85% of a solid which was used as such in tne next experiment.
b) cis and trans 3-Acetoxymethyl-l-(p-nitrobenzyl-2'-hydroxy-
2'-acetate)-4-tritvlthio-2-azetidinones
A solution of the above azetidinone (8.0 g, 20 mmoles)
and p-nitrobenzyl glyoxylate (4.54 g, 20 mmoles) were refluxed
in benzene (100 ml) through a Dean-Star~ water separator filled
1~6~
with 3A molecular sieves. After 24 h a second quantity of p-
nitrobenzyl glyoxylate (4.54 g) was added and the reflux
continued for a further 24 h. The mixture was diluted with
ether, washed with 5% aqueous hydrochloric acid, water, aqueous
5% sodium bicarbonate and water. Drying and cbncentration left
100% of the crude isomeric mixture as an oil.
c) cis and trans 3-AcetoxvmethYl-l-p-nitrobenzyl-2'-chloro-
2'-acetate)-4-tritYlthio-2-azetidinones
A solution of azetidinones from part b(l2.2 g, 20
mmoles) and pyridine (1.9 g, 24 mmoles) in dried THF (150 ml) was
cooled to -15 and treated dropwise with thionyl chloride (2.86
g, 24 mmoles) under a nitrogen atmosphere. The mixture was
stirred 45 min at -15, the precipitate was removed by
filtration and washed with benzene, and the filtrates were
concentrated to leave a semi-solid (95%).
d) cis and trans 3-Acetoxymethyl-l-(p-nitrobenzYl-2'-tri~henYl-
Phosphoranvlidene-2'-acetate)-4-tritylthio-2-azetidinones
A mixture of azetidinones from step c (12.6 g, 20
mmoles), triphenylphosphine (7.8 g, 30 mmoles) and 2,6-lutidine
(2.6 cc, 22 mmoles) in THF (100 ml) was heated under reflux for
80 h. The insoluble material was removed by filtration and
washed with ether. The filtrates were washed with 2% aqueous
hydrochloric acid,` 5% aqueous sodium bicarbonate and water, dried
and concentrated. The residue was dissolved in benzene, filtered
slowly through a pad of silica gel (250 g) and the pad was eluted
with increasing proportions of ether in benzene. Concentration
of the pertinent fractions gave a mixture of the title compounds
(65%)- VC=O 1740, Vc=pO3 1620, 1610, vNO2 1525 cm~l.
- 89 -
.~
~2~366~
e) Silver cis and trans 3-Acetoxvmethvl-1-(-nitrobenzyl-2'-
triphenvl~hosphoranvlidene-2'-acetate~-2-azetidinone-4-
thiolates
The crude azetidinones from step d (8.5 g, lo mmoles)
were dissolved in hot methanol (55-60). A hot solution (55-60)
of silver nitrate (2.04 g; 12 mmoles) and pyridine (0.87 g, 11
mmolesj in methanol (80 ml) was added. The mixture was allowed
to cool down to room temperature in 2 h and stirred a further 1 h
at 0~. The silver mercaptide was collected by filtration, washed
with ice-cold methanol and then with ether (5.7 g, 82%, melts
with decomposition). vc=O 1745, 1740, 1625 cm~1.
f) cis and trans 3-AcetoxYmethvl-4-azidoacetYlthio-1-(p-
nitrobenzyl-2'-tri~henylphosphoranvloidene-2'-acetate)-2-
azetidinones
The above silver mercaptide tfrom step e; 1.4 g, 2
mmoles) in dichloromethane (15 ml) treated as described in
Example 28 with azidoacetylchloride (2.3 mmoles) gave 0.78 g of a
yellow powder.
g) cis and trans 6-Acetoxvmethyl-2-azidomethvl~enem-3-
carboxylic Acid p-Nitrobenzvl Esters
A solution of the above crude phosphorane (0.70 mg) in
toluene (35 ml~ was kept at 105 for 1 h, cooled and concentrated
to leave an oil which was purified by chromatography over silica
gel (25 g) eluting with increasing proportions of ether in
benzene. The pertinent fractions were concentrated to give the
cis and trans-isomers of the title compound.
-- 90 --
6~
cis isomer: ~ (ppm, CDC13): 8.5-7.5 (4H, aromatics), 5.67
(lH, d, J = 5, H-5), 5.31 (2H, AB quartet, Cli2-benzyl), 4.50
(2H, A~ quartet, CH2N3), 4.33 (2H, d, AcOCH2), 4.26 (lH, dt,
H-6), 2.0 (3H, s, CH3).
trans isomer: ~ (ppm, CDC13): 8.5-7.5 (4H, aromatics),
5.62 (lH, d, J = 2, H-S), 5.33 (2H, A3 quartet, CH2-benzyl),
4.40 (lH, dt, H-6), 4.50 (2H, A~ quartet, CH2~3), 4.27 (2H,
d, AcOCH2), 2.0 (3H, s, CH3).
h) trans 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic
A _
Hydrogenation of the above trans isomer by the
procedure described in Example 28 gave the title compound.
vc=O 1775, 1740, 1616 cm 1. ~max 304 (~ = 3192).
i) cis 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic
A _
Hydrogenation of the corresponding cis isomer
as described in Example 28 gave the title compound as an
unstable hygroscopic semi-solid.
_ q/_
~2~366~
Example ~
The following compounds may be prepared according
to the general procedure of Example ~ .
~N--~
CO2 z
Acylating Agent Y X Z
CH3COCl -C~20Ac -CH3 H
C~H5COCl C 2 -C2H5 H
COCl -CH2Ac ~ H
COCl -CH2Ac ~ H
~ OCl -CH2Ac ~ H
3( 2)2 2 -(CH2)2~H2 H
N3(CH2)3COCl C 2 -(CH2)3NH2 H
N3(CH2)4COCl C 2 -(CH2)4NH2 H
02N(C 2)3 C 2 -(CH2)3NHOH H
CH3COCl -(CH2)2OAC -CH3 H
COCl -(CH2)20Ac ~ H
3 2 -(CH2)20AC 2 2 H
3t 2)2C ( 2)2 -(CH2)2~H2 H
N3(CH2)3COCl -(CH2)20AC (C 2)3 2 H
ICH3
-3 -Cli-OAc -CH3 H
CIH3
3 2 -C~.-OAc ~2 2 li
_q,~,_
1~36~
Exam~le 17
_ cis an~ trans
6-(l'-Hydroxy-1'-ethyl)-2-meth~lpenem-3-carboxylic
Acld. Sodlum Salts
IH
(Y = -CH-CH3; X =-CH3)
To a solution of 2-methylpenem-3-carboxylic acid
(100 mg, 0.54 mmoles) in THF (8 ml) was added diisopropyl-
amine (0.08 ml, 0.57 mmoles) at 0 and n-butyl lithlum (0.75
ml, 1.20 mmoles) at -78. After stirring 2 min at -78,
~,~r~6fi~il
freshly distilled acetylaldehyde (0.5 ml) was added and
stirring was continued for 10 min. The reaction mixture was
quenched with a saturated ammonium chloride solution (10 ml)
and washed with ethyl acetate. The aqueous layer was
acidified with O.lN hydrochloric acid (18 ml) and extracted
with ethyl acetate (3 x 20 ml). Concentration of the dried
ethyl acetate phases left an oil (49 mg). The oil was
dissolved in methylisobutyl ketone and treated with an
excess of sodium methylhexanoate in the same solvent.
Addition of ether precipitated the title compounds as a
white amorphous solid (25 mg). ~ (ppm, D20): 5.6-5.83 (lH,
m, H-5, cis and trans), 2.27 (3H, s, CH3 ), 1.22 and 0.90
(3H, 2d, CH3).
Example 18
cis 6-(1'-HydroxY-l'-ethyl)-2-methylpenem-3-carboxylic Acid
Sodium Salt (isomer "D")
2-Methylpenem-3-carboxylic acid (100 mg) was treated
with LDCA and acetaldehyde as described in Example 17. The
residue (58 mg), obtained after concentration of the dried
ethyl acetate phases, was extracted with ether and the ether
solution concentrated to an oil (48 mg). This oil was con-
verted to a sodium salt with sodium methyl hexanoate as
described in Example 17. This yielded 29 mg of a white solid
which was identified as cis-6-(1'-hydroxy-1'-ethyl)-2-methyl
penem-3-carboxyllc acid, sodium salt, contaminated with a
little sodium 5-methyl-1,3-thiazole-4-carboxylate. ~ (ppm,
DMS0-d6): 5.5 (lH, d, J = 4.1, H-5), 2.22 (3H, s, CH3),
1.02 (3H, d, J = 5.5, CH3).
- 94 -
1~36~;61
ExamDle 19_
cis a~d traB~
6-t2'-Hydroxy-2'-p~o~yl)-2-e~lylpenem-3-carboxylic
5Acids. Potassium Salt~s
(Y = (CH3)2 C-; X = -C2H5)
OH
Substitution in the general procedure of Example 3 for
the 2-methylpenem-3-carboxylic acid used therein of an
equimolar amount of 2-ethylpenem-3-carboxylic acid gave a
mixture of potassium salts. ~ (ppm, DMSOd6 ): 5.60 and 5.56
(lH, 2d, J = 4 and J = 2, H-5), 3.92 and 3.60 (lH, 2d, J = 4
and J = 2, H -6), 2.88 and 2.86 (2H, 2q, CH2-CH3), 1.47,
1.41, 1.36 and 1.32 (6H, 4s, CH3), 1.2 and 1.4 (3H, 2t,
CH2CH3)- ~ max 257 (~ = 3705) and 302 ( F = 3815)
20Example 20
cis and trans 6-1'-Hydroxy-l
carbQxYlic Acid. Sodium Salts
To a solution of 2-methoxymethylpenem-3-carboxylic
acid (see Preparation 6; 116 mg, 0.55 mmoles) in THF (10 ml)
was added diisopropylamine (0.08 ml, 0.57 mmoles) at O and
n-butyl lithium (0.75 ml, 1.20 mmoles) at -78. After
stirring 2 min at -78 freshly distilled acetaldehyde (0.5
ml) was added and stirring was continued for 10 min. The
reaction mixture was quenched with a saturated ammonium
chloride solution (10 ml) and washed with ethyl acetate. The
aqueous layer was acidified with hydrochloric acid (0.lN,
18 ml) and extracted with ethyl acetate (3 x 20 ml).
Concentration of the dried ethyl acetate phases left an oil
(53 mg) which
_ 9s _
g~
36~
was converted to a mixture of the sodlum ~alt~ of the tltle
compounds as described in Example 17. White amorphous hydro-
scoplc powder (21 mg). ~ (ppm, D2O): 5.7-5.85 (lH, m, H-5,
cis and tran~) 3.38 (3H, 28, OCH3 1.22 and 0.92 (3H, 2d,
S CH3). vC=O 1770, 1600 cm 1
Example 21
cis and tran6 6-Acetyl-2-methvlpenem-3-carboxylic Acid.
Sodium Salts
15 (Y = -C-CH3; X = -CH3)
To a solution of 2-methylpenem-3-carboxylic acid
(100 mg, 0.54 mmoles) in THF (10 ml) was added
diisopropylamine (0.08 ml, 0.57 mmoles) at O and n-butyl
lithium (0.75 ml, 1.20 mmoles) at -78. After stirring for
2 min at -78, ethyl acetate (1 ml) was added and stirring
was continued for 10 min. The reaction mixture was quenched
with a saturated ammonium chloride solution (10 ml) and
washed with ethyl acetate. The aqueous layer was carefully
acidified at O with 0.lN hydrochloric acid and extracted
rapidly with ethyl acetate (3 x 20 ml). Concentration of the
dried extracts left an oil (36 mg) which was converted to
the title compounds as described in Example 17. ~ (ppm,
D2O): 5.90-6.10 (lH, 2d, J = 4, J = 2, H-5), 3.8 (lH, m,
H-6 cis and trans3, 2.34 and 2.27 (3H, 2s, CH3), 2.12 and
2.0 (3H, 2s, CH3).
- 96 -
,.~
~J~6
Example 22
The following compounds may be prepared according
to the ge~eral procedures of Examples 3-5 and 17-21.
S
/~ x
~__ N ~
CO2 z
X Y Z
-CH3 OH
-CH-C6H4-OCH3 K
-CH3 OH
-CH-nBu Na
-CH3 o
-C-0 Na
-CH3 -CH20H Na
-CH3 OH
-CHCF3 Na
2 5 -SCH3 K
2 5 OH
-C-CH3 Na
2 5 O
-C-CH3 Na
6 5 OH
-CH-CH3 Na
6 5 OH
-C(CH3)2 K
6 5 O
-C-CH3 Na
- 97 -
x y z
8H Na
-CH20CH3 OH
-C(CH3)2 K
-CH20CH3 OH
-C-0 K
-CH20CH3 0 s
-C-CH3 Na
-CH20CH3 0
-C-0 Na
2 3 OjH
-CHCH3 Na
3~ ~ OH
-CH -C ~ -C-(CH3)2 K
- 98 -
~ ;~J36~
Example 23
The following compounds may be prepared according
to the general procedure of Example 3.
~ /~x
N ~
CO2 z
:~ Y, Z
OH
~H -CHCH3 Na
_ 99 _
~'~r~fi~6~ ~' ' ' '
x y z
-
OH
-H -CH-~ K
0~
6 4 3 Na
OH
-H -CH-n-C El Na
OH
-H -CH-CF Na
-H -CH20H Na
1
-H -C-CH3 Na
o
-H -C-~ Na
-H -SCE13 K
OH
-CHCH3 Na
OH
-CEI-~ K
jo
-C-CH3 Na
OH
-CH-CH Na
OH
2 0 . -CH-CH ~a
0~
C 2~ -CH-~ X
OH
-CH200 -C}~(CH3)2
_loo--
O lzJ3666
~y
Example ~
2-(4'-Phthalimido-l'-butyl)oenem-3-carboxylic Acid
"N il--
C02H
TEA HzS ~ ~ H
To a solution of triethylamine hydrosulfide,
previously prepared by bubbling H2S gas through a methylene
chloride (200 ml) solution of triethylamine (8.8 ml, 63.7 mmoles),
was added dropwise a methylene chloride (75 ml) solution of 1
(Gabriel Ber. 41, 2010) (10.65 g, 40.2 mmoles), at 0C over
a 30 min period. The mixture was stirred at 0C for 15 min
and 2 h at room temperature. The Organic solution was diluted with
methylene chloride (125 ml) and washed with lN HCl (2 x lS ml),
water (2 x 15 ml) and brine. It was dried over MgS04 and the
solvent was flashed down to give 10.5 g (100%) of 2 as a white
solid. m.p.: 93-94C n.m.r. (CDC13) ~ 7.5 - 8 (4H, m), 4.47
(lH, broad s), 3.5 - 3.9 (2H, m), 2.5 - 2.9 (2H, m), 1.4 - 1.9
(4H, m). Anal. calc'd for C13H13NO3S: C, 59.29; H, 4.97; N, 5.32;
S, 121t. Found: C, 58.92; H, 4.91, N, 5.42; S, 12 31.
--tO~ ~
~ 2~36-~6~L
P.c ~~--s~
rNf
~ ~aHC03
3 F~ J---J
A suspension of 2 (3.04 g, 11.6 mmoles) in a
solution of IM sodium bicarbonate (11.6 ml) was stirred at
room temperature under nitrogen for 15 min. To it was added
3 (1.5 g, 11.6 mmoles) and the resulting mixture was stirred
at room temperature for 1.5 h. The reaction mixture was
diluted with water and extracted with methylene chloride.
The organic phase was dried and evaporated in vacuo to give
3.82 g of solid 4; m.p.: 95 - 96C; i.r. (CHC13) 1775, 1710
cm~1. n.m.r. ~ 7.8 (4H, d, J = 2Hz) 7.05 (]-H, broad s),
5.25 (lH, dd, Jcis = 5Hz, Jtrans = 3Hz), 3.5 - 3.0 (2H,
m) , 1.5 - 2.0 (4H, m) Anal. calc'd for: C16Hl6N204S: C,
57.62; H, 4.85; N, 8.43; S, 9.64. Found C, 57.43; H,
4.82; N, 8.44; S, 9.71.
- 102 -
~6~
C8_co2cH2~>N02
C02CH 2~No2
A benzene solution (30 ml) of 4 ~3.0 g, 9.04
mmoles~ and p-nitrobenzyl glyoxalate (2.22 g, 9.8 mmoles)
was refluxed under a Dean-Stark condenser filled with 3A mole-
cular sieves for 21 h. Evaporation of the solvent afforded
5.4 g of 5 as an oil (100%). i.r. (neat) 3200 - 3600,
1770, 1710, 1525 cm n.m.r. (CDC13) ~ 8.21 (2H, d J = 9Hz),
7.75 (4H, d J = 2Hz), 7.52 ~2H, d, J = 9Hz, 5.52 (lH, broad s),
5.32 (3H, 2s), 4.55 (lH, broad s), 3.5 - 3.7 (2H, m), 3.45 (lH,
gem cis SHz) 3.02 (lH, dd, J = 15Hz J
= 3Hz), 2.4 - 2.9 (2H, m), 1.4 - 2.0 (4H, m)
~ SOC12 ~f ~
C2CH 2~Ho2 C02CH 2~02
Azetidinone glyoxalate 5 (4.9 g, 9.05 mmoles)
was treated at 0C with thionyl chloride (15 ml) at 0C
for 0.5 h and at room temperature for 1 h. The excess of
thionyl chloride was codistilled with benzene in vacuo to
--Jo3--
12~3~i661
afford 6 as a yellow syrup ~5.0 g, 100~) n.m.r. (CDCL3)
~ 8.2 (2H, d, J = 9Hz), 7.72 (4H, broad 5), 7.60 (2H, d,
J = 9Hz), 6.1 ~lH, broad s), 5.50 - 5.85 (lH, m),
5-32 t2H, 2s), 3.4 - 4.0 (2H, m), 3.1 - 3.3 (lH, m), 2.8 -
3.05 (lH, m), 2.50 - 2.85 (2H, m), 1.5 - 1.9 (4H, m).
~3P
C02CH2~No2 C02CH2~No2
A solution of 6 (21.6 q, 38.8 mmoles) in
tetrahydrofuran (85 ml, distilled over ~AH) was treated
with triphenyl phosphine (10.2 g, 38.8 mmoles) and 2.6-
lutidine (5.0 ml, 42.9 mmoles) for 18 h at 40C. The
mixt~re was diluted with benzene-ether 1:1 (30 ml), washed
with water, lN HCl, saturated NaHC03, brine and dried over
MgSO4. Evaporation of the solvent afforded a dark brown oil.
It was passed through a silica gel (700 g) column (benzene-
ether) to give 16.0 g (53~) of 7 as a thick oil. NMR (CDC13)
~ 8.2 (2H, d, J = 9Hz), 7.8 (8H, d, J = 2Hz), 7.52 (16H, broad s),
5.2 (lH, broad s) 4.78 (lH, 2s), 4.30 - 4.52 (lH, m), 3.5 - 3.8
(2H, m), 2.8 - 3.5 (2H, m), 2.1 - 2.9 (4H, m), 1.5 - 1.9 (4H, m)
1~36661
5 F~ 3 ~ ~N
C2CH 2~No2 2 2 2
A solution of phosphorane 1 (5.0 g, 6.4 mmole6) in
toluene (35 ml) was refluxed for 3 h. Evaporation of the
solvent gave a residue which was passed through a silica gel
(100 g) column. Elution with benzene followed by ether gave
600 mg of the ester 8 as oil i.r. (neat 1790, 1710, 1520
cm 1 n.m.r. (CDC13) ~ 8.22 (2H, d, J = 9Hz), 7.82 (4H, d,
J = 2Hz), 7.65 (2H, d, J = 9Hz), 5.69 (lH, dd, Jci8 =
4Hz, Jtran8 2Hz), 5.35 (2H, 2s), 5.12 (lH, dd, Jgem = 16Hz,
Jci8 = 4Hz), 3.50 (lH, dd, Jgem = 16Hz~ Jtrans = 2Hz)~
3.1 - 3.8 (2H, m), 2.5 - 3.0 (2H, m), 1.4 - 2.0 (4H, m).
O o
~ ~0~)
C2CH No2 C02H
8 9
A two phase mixture made of ester 8 (196 mg, 0.
39 mmole) in ether (2 ml) , tetrahydrofuran (4 ml) and
sodium, bicarbonate (32 mg, 0.39 mmoles) in water (2 ml) was
hydrogenated on 30~ Palladium on Diatomaceous earth (190
mg) in a Parr shaker at 40 p. B. i. H2. After 4.5 h it was
filtered over "CELITE"* pad and the pad was washed with
water and tetrahydrofuran. The filtrate and washings were
combined and the organic phase was
*Trade Mark
- 105 -
~.
~2r~3666~ ~
separated. The aqueous solution was washed with ether, aci-
dified with lN hydrochloric acid (3 x 0.4 ml) and extracted
(after each acid portion added) with ethyl acetate ~4 x 2 ml).
The organic extracts were washed with brine, dried Gver MgS04 and
the solvent was removed by evaporation to afford the acid 9, 67 mg
(47%), as a yellow solid. i.r. ~nujol) 1775, 1705, 1690 cm 1.
n.m.r. (DMS0) ~ 7.92 (4H, s), 5.71 (lH, dd, J i ~ 4Hz, Jt
= 2Hz), 3.90 (lH, dd, J = 16 Rz, Jcis = 4Hz), 3.47 (lH, dd~
J = 16 Hz, J = 2Rz), 3.3 - 4.3 (3R, m), 2.7 - 3.05 2H, m),
gem trans
1.5 - 2.0 (4H, m).
--lo6--
~f~6~i6~L
Example 2
Sodlum 2~-(Aceton~ln~h~L-n~ ~nem-3-~1kQ8yLL~
o ~ H 3
C2Na
~
r--f~ 2 3 ~ sCOCH2--C--C~3
C02PNB C02PNB
Ketal 1 (2.0 g, 4.54 mmoles) was treated at 0 with
95% TFA (20 cc) for 15 min. The mixture was diluted with
brine and extracted with methylene chloride (4 x 30 cc).
The methylene chloride extracts were washed with,
water-brine (3 times) and brine, and dried over MgSO4 (1.44
g, 80%).
~ (ppm, CDC13) 8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H,
d, J = 9, Ho aromatic), 5.70 - 5.25 (m, CH2- PNB, H-C-O,
OC~ ~
H-4, _C=C ),
H OH
4.75 (lH, bs, OH), 3.76 (center of ABq, CH2-CO), 3.47 (part
of a dd~ J3_4 ci~ = 5~ H-3), 3.05 (2H, 2dd, Jgem = 15, J3_4
trans = 3, H-3), 2.30, 2.28 (1.67H, 2s, CH3), 1.98 (1.33 H,
s, CH3) VC=O (CHC13) 1780, 1755, v NO 1525.
N__OCH
0 l~ 3
Il ~SCOCH -C-CH
~ ScocH2ccH3 ~ 2 3
~ N~fpH ~ N~H
C02PNB ` co2P~a
- 107 -
- 3
~.~J~
A methylene chloride (50 cc) solution of ketone 2 tl.44
g, 3.63 mmoles) was treated at O under nitrogen atmosphere
with methoxyl amine hydrochlorlde (334 mg, 1.1 eq.).
Triet~yl amine (367 mg, 0. 51 cc, 1 eq.) was then
added dropwise to the mixture. It was then stirred at room
temperature for 18 h. The reaction mixture was diluted with
methylene chloride, washed with water-brine (2 times), brine
and dried over MGSO4 (1.52 g, 98%).
~ (ppm, CDC13) 8.12 (2H, d, J=8, Hm aromatic), 8.40 (2H, d,
J = 8 Ho aromatic), 5.50-5.05 (4H, m, CH2- PNB, H-4,
H-C-O), 3.80-3.60 (m, OCH3, part of H-3 cis, part of OH),
3.55-270 (m, part of H-3 cis, H-3 trans, CH2CO, part of OH),
1.97, 1.90, 1.88 (3H, 3s, CH3) VC=O (CHC13) 1770, 1750,
1690.
N~OCH3 N`~ OCH3
2 3 /S C O C H - C - C H
¦~' OH SOC12 ~ 2 3
a~N~ pyrLdlne ~ N~Cl
C02PNB C02PNB
3 4
A cold (-15C) THF (20 cc, distilled over LAH)
solution of azetidinone 3 (1.52 g, 3.57 mmoles) was treated
dropwise with pyridine (325 mg, 0.332 cc, 4.10 mmoles, 1.15
eq) and thionyl chloride (488 mg, 0.299 cc, 4.10 mmoles,
1.15 eq) under nitrogen atmosphere. The mixture was stirred
for 15 min at -15. The solid was filtered off and washed
with benzene. The resulting solution was evaporated down.
The residue was taken upon benzene and treated with charcoal
(1.2 g, 76%)
~ (ppm, CDC13) 8.23 (2H, d, Hm aromatic), 7.80 (2H, d, Ho
aromatic), 6. 12, 6.08 (lH, 2s, H-C-Cl) , 5.75 - 5.55 (lH,
m, H-4), 5.40,
- 108 -
........
~6~
5. 30 (2H, 2s, CH2- PNB) , 3.95 - 3.80 (3H, 3s, OCH3)
3.80 - 2.95 (4H, m, 2H-3, CH2-CO), 2.00 - 1.85 (3H, 4s,
CH3)
vc=O (CHC13) 1790, 1765 (shoulder), 1700, v NO 1530.
N~OCH3 N~OCH3
SCOCH -C-CH 2 3
~FN~C1 ~L N~P~3
0 pNa
2 2
~ 5
A THF (20 cc, distilled over LAH) solution of
chloroazetidinone 4 (1.2 g, 2.70 mmoles) was treated with
triphenyl phosphine (1.06 g, 4.05 mmoles 1.5 eq) and 2,6-
lutidine (318 mg, 0.346 cc, 2.97 mmoles, 1.1 eq). The
mixture was stirred for 4 days at room temperature under
nitrogen atmosphere. It was diluted with ethyl acetate,
washed with 2% aqueous HCl, H20, 2% aqueous NaHC03,
water and brine. The solution was then dried over MgS04 and
the solvent was evaporated. Crude 5 was purified on silica
gel (10 times by weight) column (ethyl acetate, 770 mg,
25 45%).
vc=o (CHCl3) 1755, 1695, v 1630 - 1610, ~ NO 1525.
N--OCH 3
S COCH - C - Cl~ ~ C H - C - C H
N~P3 Toluene O N ~
r co PNB
Co2PNB 2
- 109 -
.
:
J~
Phosphorane 5 (700 mg, 1.05 mmole) was refluxed
in toluene for 4.5 h. Toluene evaporation afforded a residue
which was passed through a silica gel (1:15 ratio) column
(4% ether-~enzene). It gave 6 as a crystalline material (251
mg, 62%, m.p. 116-125)
Anal. calc'd for C17H17N3O6S: C, 52-17;
Found: C, 51.15; H, 4.18; N, 10.33.
(ppm, CDC13) 7.70 (2H, d, Hm aromatic), 7.12 (2H, d, Ho
aromatic), 5.00 (2H, s, CH2PNB), 4.85 (lH, m, H-5),
3.75 - 2.70 (7H, m, CH30, CH2, H-6), 1.77, 1.72, 1.65 (3H,
s, CH3)-
v c=o (CHCl3) 1787, 1742, 1705, NO2 1530.
U.V. (EtOH) ~max 318 (E = 8420), 262 (~ = 12,539) .
OCH3 H ~ CH -C-CH
2 3 NaHC03 N~ 2 3
20 CO2PN~ C02Na
6 7
A mixture of ester 6 (151 mg, 0.386 mmole) in
THF (20 cc), ether (40 cc) and NaHCO3 (32 mg, 0.381 mmole)
in water (20 cc) was shaken ln a Parr hydrogenator for 3 h
at 35 p.s.i. H2, using 30% Pd on "CELITE"* (200 mg) as
catalyst. The catalyst was filtered off and washed with
water and ether. The resulting aqueous mixture was washed
with ether (3 x 60 cc) and lyophilized (32 mg, 30%).
~ (ppm, DMSO) 5.50 (m, H-5), 3.75 (s, OCH3), 0.77 (s, CH3).
Vc=O ("NUJOL MULL")* 1770, 1600, 1400.
U.V. (H2O) max 300 ( F = 2,800) , 255 ( F = 2,400).
*Trade Mark
- 110 -
12r3~61
Example ~P
The following 2-penem compounds may be prepared
by acylation of l-(p-nitrobenzyloxycarbonylmethyltriphenyl-
phosphoranyl)-4-(silver mercaptidyl)-2-azetidinone with
the appropriate acylating agent followed by cyclization
and deblocking steps. The general reaction scheme is
shown below:
O O
SAg or ~ SCOR
2. RCOCl ~
Co2pNB C02PNB
S\ H2/30% Pd/diatomaceous
~R earth >
C 2
r, S
¦ ~ R
~----N ~
CO2
for variation 1: use RCO2~ + iBuCOCl
for variation 2: use HCl + PC15 + RCO2H
12~3666~
Acvlatinq Agent ~ethod Product
NH-(c}l2)4-co2H 1 2-(4-Aminobutyl)penem-3-
carboxyllc acld
CIH3
0C~12OCONH-CH-co2~l 1 2-(1-Aminoethyl)penem-3-
(both D and L) carboxylic acid
CH2CH3
0CH2OCONH-CH-CO2H 1 2-(1-Aminopropyl)penem-3-
(both D and L) carboxylic acid
CIH3
CEI_cH3
0cH2ocoNH-cH-co2H 1 2-(1-Amino-2-methylpropyl)-
(both D and L) p~nem-3-carboxylic acid
0CH2OCONII-CH-CO2H 1 2-(1-Aminobenzyl)penem-3-
(both D and L) carboxylic acid
CH20
0CH2OCONH-CH-CO2H 1 2-(1-Amino-2-phenylethyl)-
(both D and L) penem-3-carboxylic acid
CH2OCH20-NO2-p
~CH20CONH-CH-C02H 1 2-(1-Amino-2-hydroxyethyl)-
(both D and L) penem-3-carboxylic acid
CH2C02CH20 N2 P
0CH2OCONH-CH-CO2H 1 2-(1-Amino-2-carboxyethyl)-
(both D and L) penem-3-carboxylic acid
CH2coNH
0CH2OCONH-CH-CO2H 1 2-(1-Amino-2-carbamoylethyl)-
(both D and L) penem-3-carboxylic acid
CH2CH2SCH
0CH OCONH-CH-CO2H 1 2-(1-Amino-3-methylthiopropyl)-
(both D and L) penem-3-carboxylic acid
(CH2) 4NHCo2CH2Ç5
0CH2OCONH-CH-CO2H 1 2-(1,5-Diaminopentyl)penem-
(both D and L) 3-carboxylic acid
ICH3
0cH2ocoNcH2co2H 1 2-[(Methylamino)methyllpenem-
3-carboxylic acid
CH
0cH2ocoNcH2cH2co2H 1 2-~2-(Methylamino)ethyll-
penem-3-carboxylic acia
~13~
Acylatinq Agent Method Product
CIH3
0CH20CONCH2CH2C1~2C02H 1 2-[3-(Methylamino)propyl]-
penem-3-carboxylic acid
C11~3
0cH2ocoNcH2cH2cH2cH2co2Ei 1 2-[4-(methylamino)butyl]-
penem-3-carboxylic acid
Cl 2H5
0CH20CONCH2Co2H 1 2-[(Ethylamino)methyl]penem-
3-carboxylic acid
f2H5
0cEl2ocoNcH2cH2co2H 1 2-[2-~Ethylamino)ethyl]penem-
3-carboxylic acid
f 2H 5
0CONCH2CH2c~2co2H 1 2-[3-(ethylamino)propyl]-
penem-3-carboxylic acid
IC2H5
0CH20CONCH2CH2CH2CH2C02H 1 2-[4-(Ethylamino)butyl]-
penem-3-carboxylic acid
0CH20CONCH2C02H 1 2-[(Phenylamino)methyl]-
penem-3-carboxylic acid
0cH2ocoNcH2cH2co2H 1 2-[2-(Phenylamino)ethyl]-
penem-3-carboxylic acid
0cH2ocoNcH2cH2cH2co2H 1 2-[3-(Phenylamino)propyl]-
penem-3-carboxylic acid
01
0cH2ocoNcH2cH2cH2cH2co2H 1 2-[4-(Phenylamino)butyl]-
penem-3-carboxylic acid
CH3CONHCEi2C02H 1 2-[(Acetylamino)methyl]-
penem-3-carboxylic acid
CH3CONHCHzCH2C02H 1 2-[2-(Acetylamino)ethyl]-
penem-3-carboxylic acid
CH3cON C 2C 2C 2C 2 1 2-~3-(Acetylamino)propyl]-
penem-3-carboxylic aci G
~1/3
.
~2~36C~
Acylatinq Aqent Method Product
-
CH3CONHCH2CH2CH2CH2C02H 1 2-[4-(Acetylamino)butyl]-
penem-3-carboxylic acid
C6H5CONHCH2C02H 1 2-[(Benzoylamino)methyl]-
penem-3-carboxylic acid
C6H5coNHcH2cH2co2H 1 2-[2-~Benzoylamino)ethyl]-
penem-3-carboxylic acid
6 5 2 2 2C02H 1 2-[3-(Benzoylamino)propyl]-
penem-3-carboxylic acid
C6H5coNHcH2cH2cH2cH2co2H 1 2-[4-Benzoylamino)butyl]-
penem-3-carboxylic acid
0cH2ocoNHcH2coNHcH2co2H 1 2-[(Glycinamido)methyl]-
penem-3-carboxylic acid
0cH2ocoNHcH2coNHcH2cH2co2H 1 2-[2-(Glycinamido)ethyl]-
penem-3-carboxylic acid
0cH2ocoNHcH2coNHcH2cH2cH2co2H 1 2-[3-(Glycinamido)propyl]-
penem-3-carboxylic acid
H2ocoNHcH2coNHcH2cH2cH2- 1 2-[4-(Glycinamido)butyl]-
CH2C02H penem-3-carboxylic acid
H2NcoNHcH2co2H 1 2-(Ureidomethyl)penem-3-
carboxylic acid
H2NcoNHcH2cH2co2H 1 2-(2-Ureidoethyl)penem-3-
carboxylic acid
2 2 2C 2C2H 1 2-(3-Ureidopropyl)penem-3-
carboxylic acid
H2NCONHCH2CH2C~2CH2C02H 1 2-(4-Ureidobutyl)penem-3-
carboxylic acid
1 Xf~ ~ 6 ~
Acvlatina AaentMethod Product
CH3~HCONHCH2C02H 1 2-~(Methylcarbamoylamlno)-
me~hyl~penem-3-c~rboxylic ~cid
CH3NHCONHCH2CH2C02H 1 2-[2-(.~ethylcarbamoylamino)-
methyl]penem-3-carboxylic acid
CH3NHCONHCH2CH2CH2C02~ 1 2-[3-~Methylcarbamoylamino)-
propyl]penem-3-carboxylic acid
CH3NHcoNHcH2cH2cH2c~2co2H 1 2-[4-(~lethylcarbamoylamino)-
butyl]penem-3-carboxylic acid
0tJHCONHCH2CO H 1 2-[(Phenylcarbamoylamino)-
mF_hyl]penem-3-carboxylic acid
0~HcoNHcH2cH2co2H 1 2-[2-Phe~.ylcarbamoylamino)-
ethyl]penem-3-carboxylic acid
0NHcoNHcH2cH2c~2co2H 1 2-[3-(Phenylcarbamoylamino)-
propyl]?enem-3-carboxylic acid
~NHcoNHcH2c~2c~2cH2co2H 1 2-[4-(Phenylcarbamoylamino)-
butyl]penem-3-carboxylic acid
CH3CONHCONHCH2C02H 1 2-[(Acetylcarbamoylamino)-
methyl]?enem-3-carboxylic acid
CH3CONH CONHCH2CH2C02H 1 2-[2-(Acetylcarbamoyla~ino)-
ethyl~penem-3-car~oxyl~c acid
CH3coNHcoNHcH2cH2c~2co2H 1 2-[3-(Acetylca-bamoylamino)-
propyl]penem-3-car~oxylic aci_
CH3C0 2 2 2 2 2 1 2-[4-~cetylca_bamoylamino)-
butyl]penem-3-carboxylic acid
0CONHCONHCH2C02H 1 2-[(Benzoylcarbamoylamino)-
metnyl3penem-3-carboxylic acid
-115-
~36~
Acylatinq Aqent Method Product
0CONHCONHCH2C~2CO2H 1 2-- [2- (Benzoylcarbamoylamino~-
ethyl]penem-3-carboxylic acid
0COI~HCONHCH2CH2CH2CO2~ 1 2- [3-~Benzoylcarbamoylamino)-
propyl]penem~3-carboxylic acid
0CONHCONHCH2CH2CH2CH2CO2H 1 2- [ 4-tBenzoylcarbamoylamino)-
butyl]-penem-3-carboxylic aci~
CH3OCONHCONHCH2CO2H 1 2- [ (Carbomethoxycarbamoyl-
amino)methyl]penem-3-
carboxylic acid
CH3OCONHCONHCH2CH2CO2H 1 2- [2-(Carbomethoxvcarbamoyl-
amino)ethyl]penem-3-
carboxylic acid
CH3ocoNHcoNHcH2c~l2cH2co2H 1 2-[3-(Carbomethoxycarbamoyl-
~mino)propyl]penem-3-
carboxylic acid
CH3ocoNHcoNHcH2cH2cH2cH2co2~ 1 2-[4-(Carbomethoxycarbamoyl-
amino)butyl]penem-3-
carboxylic acid
(cH3)3si(cH2)2ocoNHcoNHcH2co2H 1 2-[t2-trimethylsilylethyloxy-
carbonylcarbamoylamino)-
methyl]penem-3-carboxylic acid
3 3 2)20-ONHcoNHcH2- 1 2-[2-(2-trimethylsilylethyl-
CH2C02H oxycarbonylcarbamoylamino)-
ethyl]penem-3-carboxylic acid
3 3 2)2 CoNHcoNHcH2 1 2-~3-t2-trimethylsilylethyl-
2c~2co2H oxycarbonylcarbamoylamino)-
propyl]penem-3-carboxylic acic
-116-
fi~
Acylating Aqent Method Product
(CH3)3si(cH2)2ocoNHcoNHcH2- 1 2-[4-(2-Trimethylsilylethyl-
CH2CH~CH2C02H oxycarbonylcarbamoylamino)-
. butyl]penem-3-carboxylic acid
CH3S2CNHCH2C02H 1 2-[(Methylthiothiocarbonyl-
amino)methyl]penem-3-
carboxylic acid
CH3s2cNHcH2cH2co2H 1 2-[2-(~ethylthiothiocarbonyl-
amino)ethyl]penem-3-
carboxylic acid
CH3S2cNHcH2cH2c 2 2 1 2-[3-(~ethylthiothiocarbonyl-
amino)?ropyl]penem-3-
carboxylic acid
CH3s2cNHcH2cH2cH2cH2co2H 1 2-[4-(Methylthiothiocarbonyl-
amino)butyl]penem-3-
carboxylic acid
CH3S02NHCH2C02H 1 2-[(Methanesulfonylamino)-
methyl]penem-3-carboxylic
acid
CH3S02NHCH2CH2C02H 1 2-[2-(Methanesulfonylamino)-
ethyl]penem-3-carboxylic
acid
CH3S02NHCH2CH2CH2C02 1 2-[3-(Methanesulfonylamino)-
propyl]penem-3-carboxylic
acid
CH3SO2N~CH2CH2CH2CH2C02 1 2-[4-(1~ethanesulfonylamino)-
butyl]penem-3-carboxylic
acld
0S02NHCH2Co2H 1 2-[(Benzenesulfonylamino)-
methyl]penem-3-carboxylic
acid
-111-
AcYlatinq A~ent Method Product
~HcNHcH2cH2co2~ 1 2-[2-(N-~ethylthiocarbamoyl-
amino)ethyl]penem-3-
carboxylic acid
H3CNHCNHCH2C~2CH2C2H 1 2-[3-(N-Methylthiocarbamoyl-
amino)propyl]yenem-3-
carboxylic acid
H3cNHcNHcH2cH2cH2cH2co2H 1 2-[4-(N-Methylthiocarbamoyl-
amino)butyl]penem-3-
carboxylic acid
0NHcNHcH2co2H 1 2-[(N-Phenylthiocarbamoyl-
amino)methyl)penem-3-
carboxylic acid
0NHcNHcH2cH2co2H 1 2-[2-(N-Phenylthiocarbamoyl-
amino)ethyl]penem-3-
carboxylic aci~
0NHcN~cH2cH2cH2co2H 1 2-[3-(N-Phenylthiocarbamoyl-
amino)propyl~penem-3-
carboxylic acid
H2cH2cH2co2H 1 2-[4-(N-Pnenylthiocarbamoyl-
amino)butyl]penem-3-
carboxylic acid
1I NHCH2C2H 1 2-[(Guanylamino)methyl~-
~ penem-3-carboxylic acid
~ 1l 2 2 2 1 2-[2-(Guanylamino)ethyl]-
HO ~ ~ penem-3-carboxylic acid
NHCH CH CH C02H 1 2-[3-(Guanylamino)propyl]-
2 2 2 penem-3-carboxylic acid
~O~
HO
~11~~
~2)~366~l
Acylatinq Aqent Method Product
N 1l NHCH2CH2CH2CH2C02H 1 2-[4-(Guanylamino)butyl~-
~o~N penem-3-carboxylic acid
~ ~ 1 2-[(Acetimidoylamino)metnyl]-
H3CJI N-CH2C02H penem-3-carboxylic acid
" -CH2CH2C02H 1 2-[2-(Acetimidoylamino)ethyl]-
penem-3-carboxylic acid
CH2CH2cH2c 2 1 2-[3-(Acetimidoylamino)propyl]-
penem-3-carboxylic acid
-cH2cH2cH2cH2co2 1 2-[4-(Acetimidoylamino)butyl]-
penem-3-carboxylic acid
N ~ O
N CH2C 2 1 2-[(Formimidoylamino)methyl]-
penem-3-carboxylic acid
" -CH2CH2C02H 1 2-[2-(Formimidoylamino)ethyl]-
penem-3-carboxylic acid
CH2C 2 2 2 1 2-[3-(Formimidoylamino)propyl~-
penem-3-carboxylic acid
-CH2CH2C~l2cH2c02 1 2-[4-(Formimidoylamino)butyl]-
penem-3-carboxylic acid
02NCH2C02 1 2-[(Hydroxyamino)methyl]-
penem-3-carboxylic acid
02NCH2CH2C02H 1 2-[2-(Hydroxyamino)ethyl]-
penem-3-carboxylic acid
02NcH2cH2cH2cH2co2H 1 2-[4-(Hydroxyamino)butyl]-
penem-3-carboxylic acid
_//~
l~S~
Acvlatinq AqentMethod Product
IOCH3 2[(Methoxyamino)methyl]-
(cH3)3si(cH2)2ocoN-cH2oo2H * 1 penem,3-carboxylic acid
ICH3
(CH3)3SI(cH2)2000N-CH2CH2C02H * 1 2-[2-(Methoxyamlno)ethyl]-
penemr3-carboxylic acid
~CH3
(CH3)3Si(CH2)20a)NCH2CH2cH2c02H * 1 2-[3-(~5ethoxyamino)propyl]-
penem,3-carboxylic acid
ICH3
(cH3)3si(cH2)2oooNcH2cH2cH2cH2co2H * 1 2-[4-(methoxyamino)butyl]-
penem-3-carboxylic acid
lH2
(cH3)3si(cH2)2ocoNcH2co2H * 2 2-[(Hydrazino)methyl]penem-
3-carboxylic acid
~H2
(cH3)3si(cH2)2ocoNcH2cH2co2H * 2 2-[2-(Hydrazino)ethyl]penem-
3-carboxylic acid
NH2
(CH3)3SI(CH2)20C~ cH2cH2cH20o2H * 2 2-[3-(Hydrazino)propyl]penem-
3-carboxylic acid
NIH2
(cH3)3si(cH2)2oooNcH2cH2cH2cH2oo2H * 2 2-[4-(Hydrazino)butyl]penem-
3-carboxylic acid
Nl(CH3)2
(cH3)3si(cH2)2ocoNcH2oo2H * 2 2-[(2,2-Dimethylhydrazino)-
methyl]penem,3-carboxylic acid
I (CH3)2
(CH3)3Si(CH2)2OcONCH2CH2co2H * 2 2-[2-(2,2-Dimethylhydrazino)-
ethyl]penemr3-carboxylic acid
- 120 -
1~6~
I (CH3 ) 2
(CH3)3Si(CH2)20CONcH2cH2cH2oo2H * 2 2-[3-(2~2-Dimethylhydrazino)-
propyl]penem-3-carkoxylic acid
I (CH3)2
(cH3)3sI(cH2)2oco~cH2cH2cH2cH2oo2H * 2 2-[4-(2,2-Dimethylhydrazino)-
kutyl]penem-3-carboxylic acid
* use trimethylsilylethyl instead of F~3 in azetidinone
intermediate and deblock with r.
- 120(a) -
1~6~
Acylating Aqent Method Product
CH3coNHNHcH2co2H * 2 2-[t2-Acetylhydrazino)methyl]-
penem-3-carboxylic acid
CH3coNHNHcH2cH2co2H * 2 2-[2-(2-Acetylhydrazino)-
ethyl]penem-3-carboxylic acid
CH3CONHNHCH2c 2 2 2 * 2 2-[3-(2-Acetylhydrazino)-
propyl]penem-3-carboxylic acid
CH3coNHNHcH2cH2cH2cH2co2H * 2 2-[4-(2-Acetylhydrazino)-
butyl]penem-3-carboxylic acid
(cH3)2NcH2co2H 2 2-[(Dimethylamino)methyl]-
penem-3-carboxylic acid
H3)2NcH2cH2co2H 2 2-[2-(Dimethylamino)ethyl]-
penem-3-carboxylic acid
(CH3)2NC 2 2 2 2 2 2-[3-(Dimethylamino)propyl]-
penem-3-carboxylic acid
(CH3)2NCH2cH2cH2cH2co2~ 2 2-[4-(Dimethylamino)butyl]-
penem-3-carboxylic acid
ICH3
CH3coNcH2co2H 1 2-[(N-Methylacetamido)methyl]-
penem-3-carboxylic acid
CH
CH3CONCH2CH2C02H 1 2-[2-(N-Methylacetamido)ethyl]-
penem-3-carboxylic acid
CIH3
CH3coNcH2cH2cH2co2H 1 2-[3-(n-Methylacetamido)propyl]-
penem-3-carboxylic acid
CH
CH3CONCH2CH2CX2CH2C02H 1 2-[4-(N-Methylacetamido)butyl]-
penem-3-carboxylic acid
1~3666~l
Acylatinq Aqent Method Product
2 2 1 2-[(Phthalimido)methyl]penem-
3-carboxylic acid
-CH CH CO H 1 2-[2-(Phthalimido)ethyl]-
2 2 2 penem-3-carboxylic acid
1 2-[3-(Phthalimido)propyl]-
-CH CH CH CO H
2 2 2 2 penem-3-carboxylic acld
. 1 2-[4-(Phthalimido)butyl]-
~ -CH2CH2CH2CH2CO2H penem-3-carboxylic acid
0CH2OCONHCH2CH2OCH2co2H 1 2-[(2-Aminoetnoxy)methyl]-
penem-3-carboxylic acid
0cH2ocoNHcH2cH2scH2co2H 1 2-[(2-Aminoethylthio)methyl]-
penem-3-carboxylic acid
C~ 02CH20
0cH2ocoNHcH2c~2NcH2co2H 1 2-[(2-Aminoethylamino)methyl]-
penem-3-car~oxylic acid
CH3
0CH2OCONHCH2CH2NCH2co2H 2 2-[N-(2-Aminoethyl)-N-
methylamino]methylpenem-3-
carboxylic acid
0CH2OCONH ~ CH2CO2H 1 2-(p-Aminobenzyl)penem-3-
carboxylic acid
CH2co2H~
0CH2ocoNH ~ 1 2-(o-Aminobenzyl)penem-3-
carboxylic acid
0cH2ocoNH ~ CO2H 1 2-(p-Aminophenyl)penem-3-
carboxylic acid
~_~C02H
0CH2OCONH ~ 1 2-(m-Aminophenyl)perem-3-
carboxylic acid
- /:2 ;L-
~2~fi~
Acylatinq Aqent Method Product
C2H--
0CH20CONH ~ 1 2-(o-Aminophenyl)penem-3-
carboxylic acid
0CH20CONHCH2 ~ C02H 1 2-[p-(Aminomethyl)phenyl]-
penem-3-carboxylic acid
,_~C02H
0CH2ocoNHcH2 ~ ~ 1 2-[m-(~minomethyl)phenyl]-
penem-3-carboxylic acid
C2H ~
0CH20CONHCH2 ~ 1 2-[o-(Aminomethyl)phenyl]-
penem-3-carboxylic acid
-123-
~fi~
Example ~
The 2-penem products listed below as the triethylamine
salts are treated with (C~3)3N So3 in CH2C12 solution at 0.
Addition of sodium 2-ethylhexanoate in l-butanol to the re-
action solution results in precipitation of the indicated
products as disodium salts.
Starting Material Product
CH2)nNH2~1--~(C~2~n-NHS03Na
O O
C02N(C2H5)3 C2Na
Exp. A n = 1 A. n = 1
Exp. B n = 2 B. n = 2
Exp. C n = 3 C. n = 3
Exp. D n = 4 D. n = 4
2~
Example ~'
The following 2-penem products may be prepared
from the indicated starting materials by the procedure
S CH3I
~ ~ (CH2)nN(CH3)2 > N ~ 2 2
O C 2
C02PNR
~fi~
H2/Pd ~ ~(C~12)n ( 3 3
CO2
Starting Material Product
(C32)nN(CH3)2 ~ ~ (C~lz)n ( 3)3
C02PNB 2
Exp. A n = 1 A. n = 1
Exp. B n = 2 B. n = 2
Exp. C n = 3 C. n = 3
Exp. D n ~ 4 D. n = 4
29
Examp le ~r
The following 2-penem products may be prepared
from the indicated starting materials by the procedure
SAg Sco(cH2)
+ Cl(C~2)nCCl ~N ~ p~3
CO PNB
Co2PNB 2
~/~5-
~2~fi~
s ~3 s
(CH2)nCl ~ (CH2)n~~
Co2pNB Co2pNB
¦ deblocking ~deblocXing
(C~2 ) nC~( CH 2 ) n ~)
co2~ C2
Starting Material Product
tCH2) nC1 ~ (CH2) n~
C02PNB C2
Exp. ~ n = 1 A. n = 1
Exp. B n = 2 B. n = 2
Exp. C n = 3 C. n = 3
Exp. D n = 4 D. n = 4
5o
Example ~r
The following 2-penem products may be prepared
from the indicated starting materials by the procedure
. 2~3fi66~L
o o
o o ,o 11 11
~SC-(CH2)m-C R TFA ~ ~/SC ( 2)m
N`~OH ~/
CO Z
C2 z B 2
O N
H2NB SC (CH2)m
co2%
N 8
~ SC~ (CH2)m .C-R , 1- ~3P
SOC12 1 1 . >
,~ N C 1 2 .
'1/
C02Z
S ~B
~ ~ \ 11
L~ ~(CH2)m-C R
C02Z
OH
~(C~I2)m
N ~
CO2
m = 0-2 z = - (C~2~ 2Si (C~3~ 3
R = ~I, C~3 B = O (CH2) 2 ( 3 3
-/d 7 -
12~36661
Starting Material Product
l ~ ~) OH
SC- (CH2)m-C-R S~ N
L N~r OH ~ (CH2)m C R
C02H
C02PNB
EXP. A R = H m = 0 A. R = H m = 0
EXP. B R = H m = 1 B. R = H m = 1
EXP. C R = H m = 2 C. R = H m = 2
EXP. D R = CH3 m = 0 D. R = CH3 m = 0
EXP. E R CH3 E. R = CH3 m = 1
EXP. F R 3 F. R = CH3 m = 2.
Substitution in the above procedure of H2NOCH3
for t~e H2NO (CH2) 2Si (CU3)3 USed therein reSU1tS in fOrmatiOn
Of the fO11OWing ~roducts.
r ~ S~ llOCI~3
,Ll ~(CH2) m~C~R
CO 2H
EXP. A m = 0 R = H
EXP. B m = 1 R = H
EXP. C m = 2 R = H
EXP. D m = 0 R = CH3
EXP. E m = 1 R = C~I3
EXP. F m = 2 R = CH3
~ ~666~L
Substitution in the above procedure of (CH3)3Si-
(CH2)20CONHNH2 for the ~2NO(CH2)2Si(CH3)3used therein re-
sults in formation of the following products,
S NNH2
~(CH2 ) m~C~R
CO 2H
Exp. A m = O, R = H
~Exp. B m = 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3
Exp. E m = 1, R = CH3
Exp. F m = 2, R = CH3
Substitution in the above procedure of (CH3)2NNH2
for the H2No(CH2)2Si(CH3)3 used th~rein results in formation
of the following products:
~_~ S~ , NN(CH3)2
,~N ~ ( CH 2 ) m~C~ R
co2~
Exp. A m = O, R = H
Exp. B m - 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3
Exp. E m = 1, R = CH3
Exp. F m = 2, R = CH3 .
-J29-
~ 2~6~61
!
Substitution in the above procedure of
(CH~)3Sl(C~2)2OCOM-NH2 for the H2MO(CH2)2Si(CH3)3 used
therein results in formation of the following products:
S NNH0
~~ ~(CH2)m~C~R
N ~
C02H
Exp. A m = 9, R = H
Exp. B m = 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3
Exp. E m = 1, R = CH3
Exp. F m = 2, R = CH3.
_13O -
~:2r~6~6~L
Exam~le 31
~( ~ )2
CO 2H
~SAg 1~' 5 ~H 2C 1
~p + C lCOCH 2CH 2Cl ~
C02PNB co2pNa
II I ~ I c
A solution of I (1.1 g, 1.6 mmole) and II (0.16 ml, 1.6
mmole) in methylene chloride (30 ml) was cooled in an ice
bath and treated dropwise with lM solution of pyridine in
methylene chloride (1. 7 ml, 1. 7 mmole). The resulting
reaction mixture was stirred at room temperature for 1 h
and then filtered over celite* and washed with methylene
chloride. The filtrate and washings were combined and
washed successively with lN HCl (5 ml), water (5 ml), lM
NaHC03 (5 ml) and brine, and then dried (MgS04) and
evaporated in vacuo to give III 900 mg ( 87% ) as an
amorphous solid. It was used in the next step without
further purification. IR (CHC13) 1755, 1690 cm 1 NMR (CDC13)
~ 8. 22 (2H, d, J=9 Hz), 7. 55 (15H, m), 6. 72 (2H, d, J=9 Hz),
5. 7 (lH, m), 5. 0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4H, m).
*Trade Mark
- 131 -
12~6~
~ ~ ~ ~2Cl+ ~ ) p
C02PNB ~ 5 ~ ~(--<)2
III IV ~ ~ ~
1 0 C02PN~
A mixture of III (1.3 g, 2 mmoles) and LY (0.65 ml, 3
mmoles) wa6 heated at 80C for 4 h. The reaction
mixture was diluted with methylene chloride (10 ml) and
washed with water (2 x 5 ml). Organic layer was dried -~
(MgS04) and evaporated in vacuo to give y, 1.4 g (90%), as
an amorphous solid. lt was used in the next step without
further purification. IR (CHC13) 1755, 1690 cm 1 NMR
(CDC13) ~ 8.25 (2H, d, J=9 Hz), 7.55 (lS H, m), 6.8 (2H,
d, J=9 Hz), 5.7 (lH, m), 5.1 (2H, 2s), 4.72 (2H, dq J=12
Hz, J=6 Hz), 2.6 14H,m), 1.4 (6H, 8), 1.28 (6H, s).
25 ~ 5 ~ ~t ~ )2
~3
Co2pNB ~ ~( ~ )2
v
C02PN3
VI
A solution of y (1.6 g, 2.06 mmoles) in toluene
(60 ml) waæ heated under reflux for 5 h.
The solvent wa6 evaporated in vacuo and the
residual oil was chromatographed on silica gel column
- 132 -
l~r366~;1
(30 g). Elution with benzene followed by ether removed
first unpolar material and then ethyl acetate gave VI, 620
mg (62%) as a white solid, m.p.: 83-40C from ether,
IR (CHC13- r 1790, 1710 cm~1 NMR: (CDC13) ~ 8.2 (2H, d, J=9
S Hz) , 7.6 (2H, d, J=9 Hz) 7.5 (2H, 8) 5. 65 (lH, dd, Jtrans
= 4 Hz, Jcis = 2 Hz), 5.22 (2H, 2s), 4.75 (2H, dq J=12 Hz,
J=6 Hz) 3.85 (lH, dd, Jgem = 15 Hz, J trans = 4 Hz)~ 3-5
(lH~ dd~ Jgem = 15 Hz, JciB = 2 Hz), 2.8-3.3 (2H, m), 1.4
(6H, s), 1.28 (6H, s).
~ ~ ~(-<)2 ~ F~ ~ 2
C02~NE~ C02H
Vl VII
To a solution of VI (200 mg, 0.4 mmole) in
tetrahydrofuran (8 ml) and ether (4 ml) was added sodium
bicarbonate (34 mg, 0. 4 mmole) , water (4 ml) and 30% Pd/
"CELITE"* (200 mg) followed by hydrogenation 2h at 40 p.s.i.
The mixture was filtered and layers were separated. The
aqueous phase, after washing with methylene chloride (2 x 5
ml) , was cooled with ice, acidified with lN HCl (1 ml), and
extracted with chloroform (5 x 5 ml). Organic extracts
were dried (MgSO4) and evaporated in vacuo to give VII, 76
mg (52%) , as an oil. IR (CHC13) 1790, 1710 cm 1. NMR
(CDC13) ~ 9.5 (lH, ws) , 5-65 (lH, dd, Jtrans = 4Hz~ Jcis =
2 Hz), 4. 72 (2H, d~ J=12 Hz, J=6 Hz) 4.2- 5.1 (2H, m),
3.4-4.1 (2H, m), 2.7-3.4 (2H, m), 1.35 (6H, s), 1.25 (6H,
8).
*Trade Mark
- 133 -
. . --
~, ,~.
i6J~
Exam~l~ 32
~ ~ ~P(o
C02H
_
lo ~5 q + Clc~c~2)3R(oc2H5)2 - R
C2 PNB ~5 ~/( CH2) 3P (OC2H5 2
l l
1 5 1 2 ~ N ~P ~t~ 3
co2P~a
To a cooled (ice bath) mixture of 1 (1.324 g, 2
mmoles) and 2 (0,54 g, 2.2 mmoles, crude) in CH2C12 (15 ml)
was added dropwise 1 M solution pyridine /CH2C12 (2.2 ml,
2.2 mmoles). The mixture was stirred at r.t. for 1 h and
filtered over "CELITE"*. The filtrate was washed
successively wlth 0.5N HC1, H20, 0.5 M NaHC03 and brine. It
was driad (MgS04) and filtered over "CELITE"* charcoal to
give after evaporation to dryness 0.9 g of an oil. The oil
was chromatographed on SiO2 (10% H20) and eluted with
ethylacetate to give 0.5 g of 3. (32.8%). NMR
~ (ppm, CDC13) 7.0-8.4 (m, l9H), 4.8-5.8 (3H, m), 4.1 (4H,
~), 3.3-4.2,(2H, m) 2.7 (2H, m),1.9 (2H, m), 1.3 (6H, t).
*Trade Mark
- 134 -
1.28~
~S~@ (OEt)2
~P
- ~02PN3 ~ ~\~ (OLt)
~ 022~3
3 (0.4 g, 0.52 mmole) in toluene (35 ml) was
refluxed for 4 h and evaporated to dryness to give an oil
which contained 3, 4 and 3P=O. This was chromatographed
on sio2 (10% H2O) and eluted with EtOAc to give 0.1 g of
pure 4, followed by 0.15 g of 3 and 4. NMR ~ (ppm, CDC13),
8.3 (2H, d), 7.67 (2.H, d) , 5.7 (H, q) , 5.33 (2H, d) ,
4. 2 (4H, q) , 3.83 (H, q), 3.4 (H, q), 2.9 (2H, m), 1.9
(2H, m), 1.3 (6H, t). IR (neat) 1790 cm~l (~-lactam) 1710
cm~l (ester).
S ~ ~OEt)2
N ~
0 2PN ~ ( O- t )
CO 2H
A mixture of 4 (0. 1 g, 0. 207 mmole) , 30% Pd/
"CELITE"* (0.1 g) and NaHCO3 (17 mg, 0.207 mmole) in THF (10
ml), ether (5 ml) and water (5 ml) was hydrogenated at an
initial pressure of 40 psi for 2 h. It was filtered over
"CELITE"* and the layers separated. Basic aqueous layer was
washed well with ethylacetate and acidified with lNHCl. It
was extracted with CH2C12 and dried (MgSO4). The CH2C12
solution was evaporated to give 48 mg of 5 (66. 5%) .
11
IR spectrum ~ 1790 (~-lactam) ~ 1700 (-C-OH).
*Trade Mark
- 135 -
lX8666~
Exam~le 33
~ S~P (OMe) 2
C2 N~
0 o= + (~'~10~3~ F~S ~Oi~le)2
CO PNB 2 3
2 _ _ CO~P~B
A mixture of 1 (1.07 g, 1.66 mmole) and 2
(0.42 g, 3 mmoles) in CH2Cl2 (3 ml) was heated at 80 for 5
h. The crude oil was chromatographed on SiO2 (3% H2O) and
eluted with ether, ether-ethylacetate (1:1) and ethyl
acetate: 5% EtOH to give 1.0 g of 3 (82%). The oil
crystallized on standing, M.P. (ether) 138-40.
NMR ~ (ppm, CDC13) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-5.5(3H,
m), 3.8 (3H, s), 3.6 (3H, s), 1.5-3.5 (6H, m).
O ~ ~0 2(OM~ R IC~e)2
2 2
3 4
3 (0.5 g, 0.69 mmole) in toluene (30 ml) was
refluxed for 4 h. It was evaporated to dryness,
chromatographed on SiO2 (3% H2O) and eluted with Et2O:
EtOAc (1:1) followed by EtOAc: 10% EtOH to give 0.18 g of 4
(58%). NMR ~ (ppm, CDC13, 8.25 (2H, d), 7.6 (2H, d), 5.65
(H, ~), 5.3 (2H, d), 3.8 (3H, s) 3.6 (3H, s), 2.7-3.6 (2H,
m), 1.5-2.5 (4H, m).
- 136 -
~0
~86~6
Oc~s~ 30% Pd/ "(~ELITE"*
N ~ NaHC03
C2 P `'3
4 F~/R(O~e) 2
1 5 C2Na
A mixture of 4 (50 mg, 0.112 mmole), NaHCO3
(9.12S mg) and 30% Pd/"CELlTE"*(50 mg) in THF (5 ml), Et2O
(2.5 ml) and water (2.5 ml) was hydrogenated at an initial
pres~ure of 40 psi (for 2 h). It was filtered o~er
"CELITE"* and the layers separated. The basic aqueous layer
was washed well with EtOAc and lyophilized under high
vacuum to give 28 mg of ~. (75.9%) (hygroscopic). IR (KBr)
1770 cm~1 (B-lactam), 1610 cm~l (-COO~).
*Trademark
- 137 -
~X~6~i6~
Example 34
(l'R.5R.6R? and (l'S.5S.6S)
6-(1'-HydroxY-l'-ethyl)-2-methylpenem-3-carboxylic Acid (isomer Dl
(illustrates most preferred Process of introducinq 6-substituent
in mid-synthesis
OH
10o
co2Na~ K
A. Preparation of 4-Tritylthio-2-azetidinone Intermediates
151. 1-(Trimethylsilyl)-4-tritylthio-2-azetidinone
20- sc~3 sc~3
c L N ~ ~ ~ Si(Me)
A solution of 4-tritylthio-2-azetidinone (345 mg,
1 mmole), 1, 3, 3, 3, -hexamethyldisilazane (80 mg, 0. 5 mmole)
and chlorotrimethylsilane (55 mg, 0.5 mmole) in dichloromethane
(20 ml) was heated under reflux for 18 h. Concentration of the
reaction mixture left virtually pure title compound.
~ (ppm, CDC13): 7.32 (15H, m, aromatics), 4.22 (lH, dd, H-4),
2.67 (lH, dd, J = 4.1, J = 16, H-3), 2.22 (lH, dd, J = 2.2, J =
16, H-3), 0.3 (9H, s, CH3).
- 138 -
,,.,,i,
. . . .
~X86~6~
2. 1-tt-ButYldimethvlsilyl~-4-trity~hio-2-azetidinone
SC~3 ~ C~3
~N ~ O ~ N~Si/ cH3
C(CH3)3
Triethylamine (1.62 ml, 11.6 mmoles) was added dropwise
in 5 min to a cooled (O) and stirred solution of
4-tritylthio-2-azetidinone (3.5 g, 10.1 mmoles) and chloro-t-
butyldimethylsilane (1.68 g, 12.7 mmoles) in DMF (35 ml). The
reaction mixture was stirred at room temperature for 18 h, diluted
with water (250 ml) and ether (200 ml). The organic phase was
washed with water (3 x 50 ml), dried and concentrated to leave an
oil (4.33 g). Crystallization from pentane gave a total of 4.1
g(89%) of the title compound as a white solid, m.p. 113-4. ~
(ppm, CDC13 ): 7.45 (15H, m, aromatics), 4.2 (lH, dd, H-4), 2.63
(lH, dd, J = 4, J = 16, H-3), 2.13 (lH, dd, J = 2, J = 16, H-3),
1.0 (9H, s, t-Bu), 0.35 (6H, s, Me).
Vc=O 1735 cm 1 Anal. calc'd for C28H33, NOSSi-: C, 73.15; H, 7.24;
N, 3.05; S, 6.97%. Found: C, 73.27; H, 7.32; N, 2.97; S 6.94%.
- 139 -
l~&f~
3. 1-Methoxvmethyl-4-tritylthio-2-azetidinone
SC~3 ~ iC~3
~ H 0 C~2oC:~3
A solution of 4-tritylthio-2-azetidinone (1.38 g,
4.0 mmoles) in THF (lO ml) was added to a well stirred suspension
of sodium hydride (200mg of commercial 50%, 4.1 mmoles, washed
with pentane) in THF (10 ml) maintained at -15. Methanol (12
drops) was added and the mixture was stirred at -15 for 0.5 h.
Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the
mixture was stirred for 2h, diluted with ether, washed with water
and brine, dried and concentrated to leave an oil (1.72 g).
Crystallization from pentane gave a white solid (1.41 g) m.p
72-76 ~ (ppm, CDC13 ): 7.3 (15H, m, aromatics), 4.4 (3H, m, NCH2O
and H-4), 3.22 (3H, s, CH3 ), 2.76 (2H, m, H-3).
4. 1-(Methoxyethoxymethyl) -4-tritYlthio-2-azetidinone
sc~3 sc~3
~ _ ~ ~
N~ o~ N o
To a suspension of tetrabutylammonium bromide (322 mg, 1
mmole) and potassium hydroxide (85%, 70 mg, 1.1 mmole) in
dichloromethane (10 ml) cooled to 5 was added with vigorous
stirring 4-tritylthio-2-azetidinone (345 mg, 1 mmole) and
methoxyethoxymethyl chloride (187 mg, 1.5 mmole). The mixture was
stirred at room temperature for 2 h, the
- 140 -
",~
solvent was evaporated and the residue partitioned between water
and ethyl acetate. The dried organic phase was concentrated to
leave a viscous oil (415 mg). Purification by column
chromato~raphy on silica gel eluting with ether
(5%)-dichloromethane gave the title compound (206 mg, 48%) as an
oil. ~ (ppm, CDC13): 7.30 (15H, m, aromatics), 4.57 (2H, AB
quartet, N-CH20), 4.46 (lH, dd, H-4), 3.50 (4H, s, OCH2CH2O),
3.30 (3H, s, CH3), 2.75 (2H, m, H-3).
5. 1-(2'-Tetrahvdropvranyl)-4-tritylthio-2-azetidinone
SC~3 ~ c~3
~ , n
,~ N~ ~N~ t
n-Butyl lithium (1.6M, 1.6 ml, 2.56 mmoles) was added
dropwise to a solution of 4-tritylthio-2-azetidinone (863 mg, 2.5
mmoles) in THF maintained at -78. After stirring for 15 min,
2-chlorotetrahydropyran (560 mg, 4.7 mmoles) was added and the
reaction mixture was allowed to come to room temperature in 1.5
h. The reaction solution was diluted with ethylacetate, washed
with brine, dried and concentrated to leave an oil (635 mg).
Column chromatography on silica gel eluting with
dichloromethane-ether gave a mixture of the isomeric title
compounds contaminated with a little starting material. ~ (ppm,
CDCl3 ): 7.28 (15H, m, aromatics) , 4.4 (H, dd, H-4), 2.9-2.2
(2H, m, H-3) , 4.1-3.2 and 2.2-0.7 (tetrahydropyranyl).
- 141 -
1~8~6~
B. Prep~E~tion of 3-~l'-Hydroxy-1'-ethyl)
-l-m~thoxym~hyl-4-tri~ylthio-2- azstidinQ~L
H
~3
N ~(~ O
a) (1'S 3S.4R and l'R.3R 4S)i6Omer ~isomer C¦
A 6olution of lithium diisopropyl amide was prepared
in THF (5 ml) at -78C from n-butyl lithium (1.6M, 1.0 ml, 1.6
mmol) and diisopropylamine (0.25 ml, 1.84 mmol). After 30 min a
solution of 1-methoxymethyl-4-tritylthio-2-azetidinone (491 mg,
1.42 mmol) in THF (6 ml) was added dropwise and the solution was
stirred for 15 min. Acetaldehyde (3.0 ml) was added dropwise,
followed, after 20 min, by water (30 ml). The mixture was
acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5
x 20 ml). The combined organic phases were washed with brine,
dried and concentrated to leave an oil which crystallized upon
trituration with ether: 440 mg, 80%, mp 188.5-9C; 1 Hmr (CDC13)
25 ~:7.3- (15H, m, aromatics), 4.37 (2H, ABq, N-CH2O), 4.32 (lH, d,
J=2, H-4), 3.17 (3H, s, OCH3), 3.32-2.70 (2H, m, H-3 and H-5), and
1.12 ppm (3H, d, J=7, CH3); Anal. calcd for C26H27N03S: C 72.02, H
6.28, N 3.23, S 7.39; found: C 71.99, H 6.02, N 3.21, S 7.40%.
b) (~'_S, 3S. 4R and 1'R. 3R. 4S) and rl'R. 3S. 4R and
l'S. 3R. 4S) (isomers C and B).
A solution of lithium diisopropyl amide (0.482 mmol) i6
prepared at -78C in dry ether (3 ml) from butyl lithium 0.191 ml
of 2.52 M æolution in hexane, 0.482 mmol) and diisopropyl amine
- 142 -
..~
~8~
(0.067 ml, 0.482 mmol). After 20 mi.n, a solution of t4R and 4S)
1-methoxymethyl-4-tritylthio-2-azetidinone (0.171 g, 0.439 mmol)
in a mixture of dry ether (lml) ancl dry THF (1 ml) was added
dropwise a~d the resulting clear solution was stirred at -78C for
15 min. A solution of tetrabutyl ammonium fluoride l0.96 ml of a
0.5M solution in THF, O. 48 mmol) was then added. A precipitate was
formed with the generation of a slight pink colour. After 5 min at
-78C, the reaction mixture was quenched with freshly distilled
acetaldehyde (0.2 ml, excess), and the stirring continued for 15
more min. The work-up was done by adding to a saturated solution
of ammonium chloride and extracting with ethyl acetate (2 x 25
ml). The combined organic phases were washed with brine and dried
over anhydrous magnesium sulfate. Evaporation of the solvent under
vacuum gave an oil (0.228 g) which was chromatographed on 10 g of
silica gel A mixture of benzene and ethyl acetate (6:4)gave 0.106
g (62% recovery) of substrate and a mixture of the two isomer
alcohols which were separated by chromatography on thick laye~
plates (same solvent-system). The alcohol with the high Rf (0.033
g, 17 %) was identical to the above isomer (isomer C): mp
188.5-189C (Ether-dichloromethane); The alcohol with low Rf
(0.030 g, 16%) (isomer B), was obtained as an oil which
crystallized with difficulty from hexanes: mp 94-95C.
ir (CH2C12) ~max : 3600 (OH), 1760 cm~l (C=O); 1Hmr (CDC13)
~:6.9-7.5 (15H, m, aromatics), 4.2 (2H, center of ABq, J=11.5,
CH2- O-CH3), 4.28 (lH, d, J=2.0, 4-H), 3.65 (lH, center of a broad
sextet, H-l'), 3.3 (lH, dd, J3,4 trans= 2-5~ J3,1 = 5-5~ H3)~ 3-15
(3H, s, O-CH3), 1.55 (lH, broad s, OH-l'), 1.05 (3H, d, J=6.5,
H-2'); ~a~l- calcd for C26H27N03S: C 72.02, H 6.28, N 3.23, S
7.39; found: C 71.77, H 6.36, N 3.15, S 7.43%.
- 143 -
'
~28666~
C. Preparation o~
trans 3-Acetyl-l-methoxymethyl-4-tritylthio-2-azetidinone
EtOA ~ CH3 ~
Lithium diisopropylamide was prepared under a nitrogen
atmosphere at -78C in the usual manner from diisopropylamine
(0.34 ml, 2.4 mmol) and n-butyl lithium tl.l ml of a 2.2M solution
in hexane, 2.4 mmol) in THF (3 ml). A solution of l-methoxymethyl-
4-tritylthio-2-azetidinone (0.78 g, 2 mmol) in THF (3 ml) was added
dropwise and, after stirring at -78C for 20 min, ethylacetate
(0.53 g, 6 mmol) was added in one portion and stirring continued
for 0.75 h at -78C. The reaction mixture was diluted with ether
and washed with an ammonium chloride solution, water and brine, dried
and concentrated to give an oil (0.7 g). Purification was achieved
by chromatography over silica gel (20 g) eluting with increasing
amounts of ether in benzene. The pertinent fractions were concen-
trated to give the title material as a colorless oil (0.32 g, 37%);
IHmr (CDC13) ~:7.7-6.8 (15H, aromatics), 4.85 (lH, d, J=2, H-4),
4.5 (2H, s, N-CH2-0), 3.9 (lH, d, J=2, H-3), 3.22 (3H, s, CH3) and
2-0 ppm (3H, s, CH3); ir vmax: 1770, 1710 cm
128~i~i161
D. Preparation of
trans 3-Acetyl-l-(t-butyldimethylsilyl)-4-trltylthio-2-azetidinone
- ~ Si EtOAc ~ ~ Sl~
3 2 \(CH3)2
Diisopropyl lithium amide was prepared in the usual
manner from diisopropylamine (0.18 ml, 1.24 mmol) and n-butyl-
lithium (0.78 ml of a 1.6M solution in hexane, 1.24 mmol) in THF
(8 ml). A solution of l-(t-butyldimethylsilyl)-4-tritylthio-2-
azetidinone (0.46 g, 1 mmol) in THF (8 ml) was added dropwise
at -78C. After a 5 min stirring period,ethyl acetate (1 ml)
was added in one portion and the mixture was stirred 3 h at -78C.
The mixture was acidified with cold hydrochloric acid (0.5N) to
pH 6 and extracted with ethyl acetate (2 x 20 ml). The combined
organic phases were dried and concentrated to give an oil (0.5 g)
which crystallized from pentane: 200 mg total, 40%; mp 122-4C;
ir v : 1750, 1710 cm ; lHmr (CDCl ) ~: 8-7.1 (15H, m, aromatics),
max 3
4.83 (lH, d, J=2,H-4), 3.38 (lH, d, J=2, H=3), 1.80 (3H, s, CH3),
0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH3).
E. ~re~aration of
trans-l-(t-Butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone
o
SC~3 H~ ~3
~Si (CH3) 2 S\i(CH3)2
t-Bu t-Bu
To a cooled (-78C) solution of diisopropylamine (0.34 ml,
2.4 mmol) in tetrahydrofuran (5 ml) was added dropwise, under N2, a
_l~5~
1~6~Gl
solution of 1.5 M n-BuLi (1.6 ml, 2.4 mmol). After stirring for
30 min, a solution of 1-(t-butyldimethylsilyl)-4-tritylthio-2-azeti-
dinone (1.0 g, 2.18 mmol) in tetrahydrofuran (5 ml) was added dropwise
and stirring was maintained for 30 min. Ethyl formate tO.8 ml, 9.9 mmol)
was added and the cooled solution was stirred for 10 min. The reaction
mixture was washed successively with cold lN hydrochloric acid (5 ml),
lM sodium bicarbonate (6 ml), water (10 ml) and brine. The organic
layer was dried (MgSO4), evaporated and crystallized from pentane to
give 810 mg (76%) of formate as a white solid mp 132-3C; ir (CHC13)
: 1760, 1715 cm ; IHmr (CDC13) ~: 9.0 (lH, d, J=1.25 Hz), 7.30
(15H, m), 4.7 (lH, d, J=1.5Hz) and 3.5 ppm (lH, t, J=1.5 Hz).
NOTE: a) diisopropyl amine was distilled over CaH and stored on KOH
b) tetrahydrofuran was distilled over L.A.H. and stored on
molecular sieves 3A
c) ethyl formate was stirred at room temperature with K2CO3,
then distilled over P2O5
d) n-BuLi was titrated with lN hydrochloric acid
F. Preparation of
l-(t-Butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-
azetidinones. (4 isomers).
OH
~5i/ C~51~
(Me)2 \(Me)2
n-Butyllithium (1.6M, 3.4 ml, 5.44 mmol) was added in
5 min to a solution of diisopropylamine (0.847 ml, 6.23 mmol) in
THF (30 ml) maintained at -78C. After 0.5 h a solution of l-(t-
butyldimethylsilyl)4-tritylthio-2-azetidinone (2.0 g, 4.4 mmol)
in THF (20 ml) was added; after 15 min acetaldehyde (10 ml) was
~ C~
~2~
added in one portion; after another 15 min water tlOO ml) was added.
The mixture was acidified ~pH 5-6) with dilute hydrochloric acid and
extracted with ethyl acetate (3 x 30 ml). The organic phases were
washed wi~h brine, dried and concentrated to leave an oil which
was found to consist of a mixture of four isomers by tlc (labelled
isomers A,i3,C,D by decreasing order of polarity).
Crystallization of the oily residue in ethyl acetate-pentane
gave isomers i3 and C as a white solid and left A and D in the mother-
liquors. The four pure compounds were obtained by preparative chro-
matography (~aters, 500) of the above solid and mother-liquors. The
relative proportions were: A, 1796i B, 329~; C, 39%; D, 12%. In the above
reaction, when ether was substituted for THF and the re~ction quenched
after 1 min at -78C, the relative proportions of A,~3,C, and D were:
12.9, 30.5, 38.2 and 18.4%. In ether, when the reaction was allowed
to come to 20C in 2 h before quenching, the proportions were: 13.4,
24.6, 44, and 1896. When one molar equivalent of anhydrous magnesium
bromide was added to the reaction mixture, the proportions changed to:
19.2, 19.7, 30.1 and 31P6.
somer A: This isomer possesses a cis-stereochemistry at C -C . It
3 4
is a racemic mixture composed of the (l'S, 3R, 4R) and the (l'R, 3S,
4S ) enantiomers. Compounds later derived from compound A are referred
to as "Isomer A". They consist of an enantiomeric mixture and possess
the same configuration at Cl" C3 and C4. Compounds derived from
compound A, through a reaction that proceeds with inversion of
configuration, will be referred to as "Isomer D" if the inversion
takes place at Cl, and as "isomer C" for the inversion, at C3 mp 152-3C;
lHmr (CDC13) ~: 8.0-6.8 (15H, m, aromatics), 4.30 (lH, d, J=5.5, H-4),
3.78 (lH, m, H-l'), 3.10 (lH, dd, J=5.5, J=10, H-3), 1.22 (3H, d,
J=6.5, CH3), 0.95 ~9H, s, Bu), 0.27 (6H, 2s, CH3). _ nal. calcd for:
C 30H37NO25i: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71.28,
H 7.41, N 2.48, S 6.19%.
"~ 7
12~6~
Isomer B: This isomer posseses a trans-stereochemistry at C3-C4. It
is a racemic mixture composed of the (l'R,3S,4R) and the (l'S,3R,45)
enantiomers. Compounds with the same configuration at Cl" C3 and C4
are referred to as "Isomer B" ir (CHCl ) v : 1745 cm (C=O); mp
' 3 max
158-9C; lHmr (CDC13) ~: 7.60-7.10 (lSH, m, aromatics), 4.02 (lH, d,
J=0.8 H-4), 3.32 (lH, dd, J=3.0, J=0.8, H-3), 3.55-3.15 (lH, m, H-l'),
0.88 (12H, CH3, and t-Bu), 0.16 (6H, s, CH3);
Isomer C: This isomer possesses a trans-stereochemistry at C3-C4.
It is a racemate formed of the (l'S,3S,4R) and the (l'R,3R,4S)
enantiomers. Compounds with the same configuration at Cl" C3 and
C4 are referred to as "Isomer C". mp 134-6C; IHmr (CDC13) ~: 7.60-
7.10 (lSH, m, aromatics), 4.32 (lH, d, J=1.8, H-4), 3.02 (lH, dd,
J=2.7, J=1.8, H-3), 3.0-2.5 (lH, dq, J=2.7, J=6, H-l'), 1.02 (3H,
d, J=6, CH3), 0.95 (9H, s, t-Bu), 0.27 (6H, s, CH3); ir (CHC13)
V : 1735 cm 1 (C=0)
max
Isomer D: This isomer possesses a cis-stereochemistry at C3-C4.
It is a racemate composed of the (l'R,3R,4R) and the (l'S,3S,4S)
enantiomers. Compounds with the same configuration at Cl" C3 and
C4 are referred to as "Isomer D". mp 171-2Ci Hmr (CDC13) : 7.80-
6.90 (15H, m, aromatics), 4.70 (lH, d, J=4.5, H-4), 3.02 (lH, dd,
J=4.5, J=0.5, H-3), 2.39 (lH, dq, J=0.5, J=6.5, H-l'), 1.0 (3H, d,
J=6.5, CH3), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CH3). Anal. calcd
for C30H37NO2SSi: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71-27,
H 7.43, N 2.51, S 6.31%.
-J'f~
128~
O OH
b) ~ SC~3 4 ~ ~ SC~3
~ Si/ O ~ Si
\Me2 \Me2
2 trans isomers
A solution of trans 3-acetyl-1-(t-butyldimethyl-
silyl)-4-tritylthio-2-azetidinone (1.0 g, 2 mmoll in THF (30 ml)
was added dropwise, under a nitrogen atmosphere, to a cooled
(0) and stirred suspension of sodium borohydride (0.38 g,
10 mmol) in THF (120 ml). The ice bath was removed and the
mixture was stirred at room temperature for 4 h. It was poured
into ice-cold hydrochloric acid (lN, pH 6), stirred for 15 min
and extracted with ether (3X). The combined ether extracts were
dried and concentrated to give an oil (1.04 g) which was
crystallized in pentane to give the title compounds as a 70:30
mixture of the C and B isomers. mp 119-121C; 84%.
OH
c) ~ c~3 H. ~ SC~3
S\i(CH3)2~ S~i(CH3)2
t-Bu
Isomer B
A suspension of Cuprous iodide (4.78 g, 15 mmol) in ether
(50 ml) was cooled to 0C and treated under N2, with a 1.9 M
solution of methyl lithium (26 ml, 50 mmol). The brown solution
was stirred at O~C for 10 min and then cooled to -60C and treated
dropwise with the trans l-l(t-butyl dimethylsilyl)-3-formyl-4-
tritylthio-2-azetidinone (2.43 g, 5.0 mmol) in a mixture of tetra-
hydrofuran (10 ml)/ether (40 ml). Stirring was continued for 3 h.
The solution was warmed up to -40C and treated carefully with a lM
solution of ammonium chloride. The mixture was filtered over Celite
_l ,yq _
1~6~,61
and the organic phase was washed with a LM solution of ammonium
chloride (3 x 5 ml) and then brine and dried over sodium sulfate. Filtration
and evaporation gave alcohol, isomer B, which crystallized from
warm pentane to yield 1.6 g (65%), m~ 160-1C; ir (CHC13) V : 1730 cm ;.
Hmr (CDC13) ~: 7.32 (15H, m), .4.05 (lH~ s), 3.4 (lH, d, J=3HZ, 3.25-
3.55 (lH, m), 1.6 (lH, s), 0.9 (12H, s) and 0.1 ppm (6H, s).
NOTE: a) tetrahydrofuran and ether were distilled over L.A.H.
~) methyl lithium was titrated with lN hydrochloric acid
c) copper (I) iodide was purified by continuous extraction
with anhydrous tetrahydrofuran in a Soxhlet extractor for
18 h, then dried under vacuum in a dessicator (P205) for 18 h.
O OH
d) ~ SC~3 ~ CH ~ SC~3
O ~S i (~ ~ S i
`tBu ~tBu
Methylmagnesium iodide (0.1 ml, 0.1 mmol) was added
dropwise to a cooled (0C) and stirred solution of trans l-(t-butyl-
dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (25 mg, 0.05 mmol)
in THF (2 ml). The solution was stirred 1.5 h at 0C, poured onto
an ammonium chloride solution, acidified with a hydrochloric acid
solution (lN) and extracted with ether. Drying and concentration
of the organic extracts left an oil consisting of starting material
and a small amount of a mixture of the two trans title compounds with
isomer B predominating.
--~ 5~ -
~6~;61
F. PreParation Of
(l'S,3S,4R and l'R,3R,4S) l-(t-Butyldimethylsilyl)-3-(1'-trimethyl-
silyloxy-l ' -ethyl)-4-tritylthio-2-azetidinone (isomer C)
OH OS i -
~3 ~ ~ SC~3
O ~ ~ O ~si~
A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldime-
thylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone
(15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry
THF (6 ml) was stirred at room temperature until disappearance of the
starting material (15 min). Purification of the reaction mixture
by column chromatography (silica gel, CH2C12) gave the desired
compound as a white solid (128 mg, 74~) mp 144-46C. IHmr (CDC13) ~:
7.10-7.60 (15H, m, aromatics), 4.30 (lH, d, J=1.5, H-4), 2.25-2.89
(2H, m, H-3, H-l'), 0.82-1.07 (12H, m, t-Bu, H-2'), 0.27 (6H, s,
CH3), -0.10 (9H, s, -O-Si(CH3)3; ir (CHC13) V a : 1736 cm (C=O).
G. Preparation Of
(l'S,3R,4R and l'R,3S,4S) l'(t-Butyldimethylsilyl)-3-(1'-methoxymethoxy
ether-l'-ethyl)-4-tritylthio-2-azetidinone (isomer A).
2 3
~3 ~ ~ N ~ ~ (Me)2
N O Si
Si(Me)2 ~ t-Bu
t-Bu
n-Butyllithium (ca 12.5 ml of 1.6M solution in hexane,
20 mmol; just enough to obtain a permanent pink coloration) was
added dropwise to a solution of (l'S,3R,4R and l'R,3S,4S) l-(t-Butyl-
dimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone
(isomer A) (10.1 g, 20 mmol) in THF (100 ml) maintained at -78.
~l5l~
~6~;6~
After a 15 min stirring period a solution of bromomethoxymethyl
ether (2 ml, 2q mmol) in THF (30 ml) was added dropwise. The mixture was
stirred 1 h at -78 and 2 h at room temperature and poured into an
ammonium chloride solution (200 ml). Extraction with ethyl acetate
(3 x 200 ml), washing with brine, drying with sodium sulfate and
concentration gave the crude title compound which was purified by
chromatography on silica gel eluting with increasing amounts of
ether in benzene (10.4 g 95%). lHmr (CDC13) ~: 7.1-7.5 (15H, m,
aromatics), 4.47 (lH, d, H-4), 4.23 (2H, ABq, J=7, 0-CH2-0), 3.1-3.4
(2H, m, H-3 et H-l'), 3.23 (3H, s, 0-CH3), 1.37 (3H, d, J=6.5, CH3),
0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH3).
. Pre~aration of
(1`5,3S,4R and l'R,3R,4S) l-(t-;3utyldimethylsilyl)-3-(1'-formyloxy-1'-
ethyl)-4-tritylthio-2-azetidinone (isomer C)
~H 0,CHO
~3 ~ ~ c~3
\ S 1~ ~ i~
A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethyl-
silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer c)
(50 mg, 0.1 mmol), p-bromobenzenesulfonylchloride (100 mg, 0.4 mmol)
and dimethylaminopyridine (24 mg, 0.2 mmol) in DMF (3 ml) was stirred
at room temperature until disappearance of starting material (0.5 h).
Then the reaction mixture was diluted with water and extracted with
ether. The organic extracts were washed with brine, dried (MgS04)
and evaporated. The title compound was purified by column chromato-
graphy. IHmr (CDC13) ~: 7.80 (lH, s, CHO), 7.20-7.66 (15H, m, aromatics),
3.90-4.36 (lH, m, H-l'), 4.07 (lH, d, J=2, H-4), 3.22 (lH, broad s, H-3~,
1.18 (3H, d, J=6.5, H-2'), 1.0 (9H, s, t-Bu), 0.31 (6H, s, di-CH3).
~2866~1
I. Prepar~tion of
(l'R,3S,4R and l'S,3R,4S) l'(t-Butyldimethylsilyl)-3-1'-acetoxy-
l~-ethyl)-4-tritylthio-2-azetidinone (Isomer B)
OH OAc
2 ~
A solution of (l'R,3S,4S and l'S 3R 4S) l-(t-butyldi-
methylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone
(13.85 g, 27.5 mmol) in pyridine (75 ml) acetic anhydride
(50 ml) (prepared at 0) was stirred at room temperature for 40 h.
The reagents were evaporated off (the last traces being removed
azeotropically with toluene 3 times) leaving a nearly white solid.
Crude derivative was crystallized from an ether-petroleum
ether mixture to give pure title compound (97.5%). IHmr (CDC13 ~:
7.64-7.03 (15H, m, H aromatic), 4.60 (lH, m, J=6, H-l'), 3.92 (lH,
d, J=2, H-4), 3.55 (lH, dd, J=2, J=6, H-3), 1.79 (3H, s, CH3CO), 0.98
(3H, d, J=6,CH3), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH3); ir
(CHC13) V : 1775, 1740 cm (C=O)
J. Pre~aration of
l-(t-~utyldimethylsilyl)-3-(l'-Paranitrobenzyldioxvcarhonyl)
ethyl)-4-tritylthio-2-azetidinone. (4 isomers)
pH QCO PNB
C~3 ~ SC~3
~Si~ 2 ~ ~ Si~ 2
~tBu \tBu
"Isomer C" n-Butyllithium (8.8 ml of 1.6 M solution in hexane,
14 mmol; just enough to obtain a permanent pink coloration) was
-l53~
added dropwise to a solution of "Isomer C" of 1-~t-butyldime-
thylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone
(6.55 g, 13 mmol) in THF (70 ml) maintained at -78C. After
a 15 min stirring period a solution of paranitrobenzyl chloro-
formate (3.2 g, 14.8 mmol) in THF (30 ml) was added dropwise.
The mixture was stirred 1 h at -78C and poured into ~n a~monium
chloride solution (100 ml). Extraction with ethyl acetate
(3 x 100 ml) washing with brine, drying and concentration left
11 g of crude material. The pure title compound was obtained by
chromatography on silica gel (220 g) eluting with increasing
amounts of ether in ben~ene. 93%,mp 118-9C (ether); IHmr (CDC13)
~: 8.35-7 (19H, m, aromatics), 5.12 (2H, s, benzyl), 4.08 (lH, d,
J=1.8, H-4), 4-3.5 (lH, dq, J=6.5, J=2, H-l'), 3.10 (lH, dd, J=2,
J=1.8, H-3), 1.2 (3H, d, J=6.5, CH3), 1.0 (9H, s, Bu) and 0.30
ppm (6H, 2s, CH3); ir (CHC13) Vmax: 1745 cm (C=O)i Anal. calcd
for C38H42N2O6SiS: C 66.83, H 6.20, N 4.10, S 4.69: found: C 66.90,
H 6.26, N 4.11, S 4.59.
"Isomer B" The "Isomer B" of l-(t-butyldimethylsilyl)-3-(1'-
hydroxy-l'-ethyl(-4-tritylthio-2-azetidinone, treated as described
above gave pure "Isomer B" of l-(t-butyldimethylsilyl)-3-(1'-para-
nitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone as a
foam, 95%. IHmr (CDC13) ~: 8.32-6.90 (19H, m, aromatics), 5.1
(2H, s, benzyl), 4.65-4.20 (lH, m, H-l'), 3.97 (lH, d, J=1.5, H-4),
3.58 (lH, dd, J=1.5, J=5.8, H-3), 1.1 (3H, d, CH3), 0.7 (9H, s; Bu
and 0.2 ppm (6H, s, CH ); ir (film) v : 1755, 1740 cm C=O.
3 max
"Isomer A" The "Isomer A" of l-(t-butyldimethylsilyl-3-(1'-hydroxy-
l'-ethyl)-4-tritylthio-2-azetidinone, treated as described above
gave pure "Isomer A" of l-(t-butyldimethylsilyl-3-(1'-paranitro-
benzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone as an oil.
9S~ IHmr (CDC13) ~: 8.3-6.7 (19H,m, aromatics), 4.95 (2H, ABq, benzyl),
--1 5Y--
4.53 (lH, p, J=7.5, J=7.5, H~ , 4.31 (lH, d, J=6, H-4), 3.32 (lH,
dd, J=6, J=7.5, H-3), 1.44 (3H, d, J=6.5), 0.95 (9H, s, tBu) and
0.2 ppm (6H, 2s, CH3).
"Isomer D" Likewise "Isomer D" of l-(t-butyldimethylsilyl-3-(1'-
hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone, gave pure "Isomer D"
of l-(t-butyldimethylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-
ethyl)-4-tritylthio-2-azetidinone, 90%. 1Hmr (CDC13) ~: 8.3-6.7
(19H, m, aromatics), 5.20 (2H, ABq, benzyl), 4.72 (lH, d, J=5, H-4),
3.50 (lH, dq, J=6.5, J=0.5, H-l'), 2.85 (lH, dd, J=0.5, J=5, H-3),
1.03 (3H, d, J=6.5, CH3), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH3);
mp 130-2C. Anal. calcd for C 66.83, H 6.20, N 4.10, S 4.70; fou-.d:
C 66.56, H 6.28, N 3.96, S 4.89.
K. Pre~aration of
(l'S,3S,4R and l'R,3R,4S) l-(t-ButyldimethYlsilyl)-3-(1'-methane-
sulfonyloxy-~-ethyl)-4-tritylthio-2-azetidinone (Isomer C)
OH OMs
(CH3)2 ~ 3
A solution of ~l'S,3S,4R~andl'R,3R,4S)-l-(t-butyldimethyl-
silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C)
(2.0 g, 4 mmol) in dichloromethane (80 ml) was treated at 5C, with
methanesulfonyl chloride (0.99 g, 8.6 mmol) and triethylamine (0.87 g,
8.6 mmol). After stirring at that temperature for 1 h under N2, the
solution was washed with brine, dried (MgSO4) and evaporated to
dryness. ~fter crystallization from ether-pet-ether, 1.9 g (81.9%)
of mesylate was obtained. mp 120-22C; Hmr (CDC13) ~: 7.13-7.61
- I 5~ -
1~86~
(15H, m, aromatics), 4.50 (lH, d, J=2, H-4), 3.62 (lH, dq, J=6.5, 2,
H-l'), 2.96 (lH, dd, J=2, 2, H-3), 2.84 (3H, s, methanesulfonyl),
1.22 (3H, d, J=6.5, H-2'), 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6H,
s, Si (CH3)2); ir Vmax (CHC13): 1746 (C=O), 1343 and 1180 cm 1 (SO
L. Preparation of
(l'R,3S,4R and l'S,3R,4S) l-(t-Butyldimethylsilyl)-3-(1'-methane-
sulfonyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B)
OH ~sO
SC~3 ~ SC~3
S i ~
A solution of (l'R,3S,4R and l'S,3R,4S) l-(t-butyldimethyl-
silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B?
(5.03 g, 10 mmol), methanesulfonylchloride (2.52 g, 22.0 mmol) and
triethylamine (2.23 g, 22.0 mmol) in CH2C12 (200 ml) was stirred
at 5C for 1 h. Then the solution was washed with brine, dried
(MgSO4) and evaporated to leave a residue which crystallized as a
white solid when triturated in ether (5.40 g, 93%) mp 127-31C.
IHmr tCDC13) ~: 7.20-7.63 (15H, m, aromatics), 4.51 (lH, dq, J=5.0-6.2,
H-l'), 4.10 ~lH, d, J=2.0, H-4), 3.63 (lH, dd, J=5.0-2.0, H-3), 2.03
(3H, s, -CH3), 1.01 (3H, d, J=6.2, H-2'), 0.90 (9H, s, t-Bu), 0.12
(6H, s, -CH3); ir (CHC13) V ax 1745 cm (C=O).~
--156-
1286~61
M. Preparation of
(1'5,3S,4R and l'R,3R,4S) 3-(1'-p-Bromobenzenesulfonyloxy-l'-ethyl)-
l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C)
OH OSO ~Br
SC~3 ~ SC~3
S i~
A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethyl-
silyl)-3-(1'-hydroxy~ ethyl)-4-tritylthio-2-azetidinone (Isomer C)
(2.5 g, 5 mmol) in dry THF (100 ml) was cooled to -78C and treated
with 2.52M butyllithium/hexane (2.38 ml, 6 mmol). After 3-4 min
p-bromobenzenesulfonylchloride (1.53 g, 6 mmol) dissolved in THF
was added dropwise. The solution was stirred at -78C for 3 h and
then allowed to come to room temperature. Then the solvent was
evaporated and the desired product purified by column chromatography
(silica gel, CH2Cl2) (3.36 g, 94.6%) mp 142-44C; IHmr (CDC13) ~:
7.68 (4H, s, benzenefulsonyl), 7.28-7.60 (15H, m, aromatics), 4.59
(lH, d, J=1.8, H-4), 3.68 (lH, dq, J=6.2, H-l'), 2.99 (lH, dd, J=1.8,
2.0, H-3), 1.18 (3H, d, J=6.2, H-2'), 1.08 (9H, s, t-Bu), 0.40 and
0.38 (6H, 25, -CH3); ir (CHC13) Vmax: 1749 cm (C=O)-
1~.86~;6~
N. Preparation o~
(l'S,3R,4R and l'R,35,45) 3~ Methoxymethyl-l'-ethyl)-9-tritylthio-2-
azetidinone (isomer A).
CCH2OCH3 OCH2OCH3
C~3 ~ c~3
~ ~ S ' 2 N ~H
t-Bu
A cold (0C) HMPA-H2O (116 ml-13 ml) solution of
Isomer A of l-(t-butyldimethylsilyl)-3-(1'-methoxymethyl-1'-ethyl)-
4-tritylthio-2-azetidinone (11 g, 20 mmol) was treated with sodium
azide (2.7 g, 42 mmol). The cold bath was removed and the mixture
was stirred for 30 min. It was then poured into cold water (1.3 ~)
and dried. The title compound recrystallized from ethyl acetate-hexanes
(7.2 g, 83%) as a white solid mp 173-174C. IHmr (CDC13) ~: 7.10-7.
(lSH, m, aromatics), 4.85 (2H, ABq, J=7.4, O-CH2-O), 4.53 (lH, d,
J=5.2, H-4), 4.42 (lH, s, N-H), 4.15 (lH, m, H-l'), 3.5 (lH, m, H-3),
3.47 (3H, s, O-CH3), 1.5 (3H, d, J=6, CH3). ir (KBr) V : 3400-3500
(N-H) and 1760 cm (C=O).
O. Preparation of
(l'S,3S,4R and l'R,3R,4S) 3-(1'~ ethoxymethyloxy-1'-ethyl)-4-tritylthio-
2-azetidinone (Isomer C)
H OCH2OCH3 OCH2OCH3
J.,,~ ~ ' .~N/H
A cold (dry ice-acetone bath) solution of (l'S,3S,4R
and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-
tritylthio-2-azetidinone (5.03 q, 10 mmol) in THF (50 ml, distilled
over LAH) was treated dropwise with a 1.6M solution of n-butyl
lithium in hexane (13.0 ml) until a pink coloration persisted.
A THF (20 ml) solution of bromomethyl methylether (1.49 g, 0.97 ml,
1.19 mmol) was added dropwise. The mixture was stirred at -78C
for 30 min and for a 3 h period at 0C. It was poured in an ice cold
ammonium chloride solution and extracted with ether. The ether extracts
were combined, washed with water, dried (MgS04) and concentrated to give
crude (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(1'-methoxy-
methyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (5.83 g, 100%) which was
deprotected as described below:
A cold (ice bath) solution of the above derivative
(5.83 g, 10 mmol) in HMPA-H20 (90 ml-10 ml) was treated with sodium
azide (1.365 g, 21 mmol). The cooling bath was removed and the mixture
was stirred at room temperature for a 2 h period. It was then poured
slowly into ice cold water (900 ml) and stirred for 30 min. The precipi-
tate was collected by filtration and redissolved in methylene chloride.
The solution was washed with water and brine and dried (MgS04) to give
the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHC13)
v : 3400 (N-H) and 1760 cm (C=O);lHmr (CDC13~ ~: 7.67-7.12 (15H, m,
H aromatics), 4.63 (2H, center of ABq, J=6, 0-CH2-0), 4.49 (lH, s, N-H),
4.40 (lH, d, J=3, H-4~,4.25-3.80 (lH, m, H-l'), 3.35-3.15 and 3.26
(4H, s + m, CH3 and H-3) and 1.30 ppm (3H, d, J=6, CH3)
~ I !;q-
~2~6~
P, Preparat ion of
(l'R,3S,4R and l'S,3R,4S) 3-tl'-Formyloxy-l~-ethyl)-4-tritylthio-2-
azetidinone (Isomer B)
OSO2~Br OCHO
3 ~ ~ SC~3
~ ~Si/~ ~ H
A solution of (l'S,3S,4R and l'R,3R,4S) 3-~1'-p-bromo-
benzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-
2-azetidinone ~Isomer C) in DMF (3 ml) was heated at 50C for 48 h
and then at 100C for 4 h. The reaction mixture was then diluted
with H2O and extracted with ether. The ethereal extracts were
washed with ~rine, dried (MgSO4) and evaporated. The title compound
was obtained as white crystals after purification by column chro-
matography (silica gel, 5~ CH3CN-CH2C12) (2 mg, 4.8%) mp 131-32C
IHmr (CDC13) ~: 8.07 tlH, s, CHO), 7.24-7.56 (15H, m, aromatics),
5.23 (lH, dq, J=6.4, 7, H-l'), 4.38 (lH, dm J=2.4, H-4), 4.25 (lH, s,
NH), 3.20 (lH, dd, J=7, 2.4, H-3), 1.43 (3H, d, J=6.4, H-2'); ir
(CHC13) Vma : 3400 (NH), 1765 (C=O), 1725 cm (C=O).
Q. Preparation of
(l'R,3S,4R and l'S,3R,4S) 3-(1'-Acetoxy-l'-ethyl)-4-tritylthio-2-
azetidinone (isomer B)
OAc OAc
J STr NaN3 J- ~ STr
HMPT O ~ NH
tBDMS
Pure derivative (l'R,3S,4R and 1'5,3R,45) l-(t-~utyl-
dimethylsilyl)-3-(1'-acetoxy-1'-ethyl)-4-tritylthio-2-azetidinone
(5.77 g, 10.57 mmol) was dissolved in warm HMPT-water (60 ml, 10 ml).
/60-
The solution was cooled down at room temperature and NaN3 (1.2 g
was added in. It was stirred for 45 min (reaction progression was
followed by tlC) and poured slowly in stirred cold water (800 ml).
The mixture was stirred for 20 more min. The crystalline material
was collected and washed with water. It was redissolved in CH2C12,
washed with water (twice) and brine and dried over MgSO4. Solvent
evaporation left a foam which crystallized out from ether-petroleum
ether (4.90 g, 96.5%, mp 143-44.5C).
ir (CH2C12)~m~x: 3395 (N-E3), 1772, 1738 cm (C=0). IHmr (CDC13)
: 7.9-6.8 (15H, m, H aromatic), 5.12 (lH, center of dq, J=6.5, 7.5,
H-l'), 4.33 (lH, d, J=2.8, H-4), 4.20 (lH, bs, N-H), 3.17 (lH, ddd,
J3-1' 7 5~ J3_4=2.8~ J3_NH=l, H-3)~ 2-1 (3H, s, CH3Co), 1.35 (3H, d,
J-6.5, CH3).
R. Preparation o~
3-(1'-Hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone. Mixture of four
isomers) OH OAc
O ~ ~Si(CH~ ~ 3 2 ~ 3
i-Cl ~ c~3
3MF-N(Et)3 ~ Si~
A solution of lithium diisopropyl amidel(0.74 mmol) was
prepared at -78C in dry tetrahydrofuran (5 ml) from diisopropyl
amine (0.103 ml, 0.74 mmol) and BuLi (0.29 ml of a 2.52 M in hexane).
After 30 min at -78C, a solution of the (R and S) l-trimethylsilyl-4-
tritylthio-2-azetidinone (0.292 g, 6.99 mmol) in dry tetrahydrofurane
(2 ml) was added dropwise. After 5 min, excess of freshly distilled
acetaldehyde (0.2 ml) was added all at once. After 20 min at -78C, tlc
indicated complete disapp~arance of starting materials and the reaction
-l6/-
mixture was quenched by adding to a saturated solution of ammonium
chloride. Extraction with ethyl acetate (2 x 25 ml) followed by washing
of the combined organic phases with saturated NH4Cl, brine and drying
on anhydrous magnesium sulfate gave, after evaporation of the solvent,
a yellow oil. Filtration of this oil on silica gel (10 g, elution
C6H6:E~oAc~ 6:4) gave a mixture of alcoho~ (0.215 g, 80%). This
mixture (IHmr) cannot be separated either by hplc or by tlc.
a: Acetylation
Acetylation of an aliquot of the mixture (0.065 g) with
excess acetic anhydride (1.0 ml) and pyridine (1.4 ml) gave a mixture
of acetates. hplc Analysis indicated four components2: a) 34:6%; b) 17.4%;
c) 30.1%; d) 17.9%. Compound a) was identical to the isomer B by direct
comparison (hplc). 4
b: t-Butyldimetyl silyl derivatives
The mixture of alcohols (0.121 g, 0.34 mmol) was treated
with t-butyl dimethylchlorosilane (0.117 g, 0.776 mmol) and triethyl
amine (0.10 ml, 7.14 mmol) in dry dimethylformamide (1 ml) for 36 h
at room temperature. After dilution with ethyl acetate, the solution
was washed with saturated ammonium chloride and dried over anhydrous
magnesium sulfate. Evaporation gave an oil (0.716 g) which contains
4 components by HPLC. a = 3.7~; b = 60.6~i c = 31.1%i d = 4.6%
(the identity of each one has not been established)4
NOTE:
IButyl lithium and lithium hexamethyl disilazane were ineffective
2Order of increasing polarity
3Acetylation of the product derived from l-t-butyldimethylsilyl-4-
tritylthio-2-azetidinone gave the following ratio:
_ = 29.5%; c = 24.1%; b = 33.8%; a = 12.5%_
4Reaction of a mixture of alcohols derived from (R and S)
l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone gave the
following proportions: a = 5.2g; b = 41.3%; c = 48~; d = 4.6%
-/6 1-
1~86~
S . Preparat ion of
(l'R,3S,4R and l'S,3R,45) 3~ Benzoxy-1'-ethyl)-4-tritylthio-2-
azetidinone (Isomer B)
MsO OCO~
5C~3 ~ sc~3
A solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-methanesulfo-
nyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (035 mq,
2 mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H20-DMF (10 ml)
was heated at 90C for 7.5 h. Then the reaction mixture was
diluted with H2O and extracted with ethyl acetate. The organic
extracts were washed with brine, dried (MgSO4) and evaporated.
The residue, purified by column chromatography (silica gel, 5% CH3
CN-CH2C12) gave the title compound as a white solid (108 mg, 23.2%)
mp 158C~ lHmr (CDC13) ~: 7.03-8.25 (20H, m, aromatics), 5.32 (lH,
dq, J=6.1, 9, H-l'), 4.40 (lH, d, J=2.5, H-4), 4.30 (lH, s, N-H),
3.40 (lH, dd, J=9, 2.5, H-3), 1.50 (3H, d, J=6.1, H-2');ir (CHC13)
V : 3400 (N-H), 1765 (C-O), 1715 cm (C=O).
T. Preparation of
3-(1'-Paranitrobenzyldioxycarbonyl-l~-ethyl)-4-tritylthio-2-
azetidinone (4 isomers).
~CO PNB
SCb3
Si N ~ H
\tBu
"Isomer C"
a) A solution of "Isomer C" of l-(t-butyldimethyl-
silyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-trityl-
thio-2-azetidinone (1.3 g) in a mixture of TFA (5 ml), water
-l63-
~28666~L
(5 ml), dichloromethane (20 ml) and methanol (30 ml) was stirred
for 2 days at room temperature. The solution was diluted with
water and the aqueous phase extracted with dichloromethane. The
combined organic phases were washed with sodium bicarbonate and
water, dried and concentrated to leave an oil. Crystallization
from ether gave the pure title compound (902 mg), mp 78-80C;
'Hmr (CDCl3) : 8.25-6.75 (19H, m, aromatics), 5.21 (2H, s, benzyl),
5.05 (lH, m, H-l'), 4.40 (lH, s, N-H), 4.27 (lH, d, J=2.8, H-4),
3.37 (lH, dd, J=5.3, 2.8, H-3) and 1.37 ppm (3H, d, J=6.5, CH3);
ir (CHCl3) vm : 3390 (N-H), 1765 and 1745 (shoulder) (C=O, and 1525
cm (NO2).
b) A cold (0C) HMPT-H20 (90 ml - 19 ml) solution of
"Isomer C" of l-(t-butyldimethylsilyl)-~-(l'-paranitrobenzyldioxy-
carboxyl-l'-ethyl)-4-tritylthio-2-azetidinone (9.11 g, 13.3 mmol)
was treated with sodium azide (1.82 g, 27.9 mmol). The cold bath
was removed and the mixture was stirred for 30 min. It was then
poured into water (1 R) and extracted with ether (5 x 200 ml).
The ether fractions were combined and washed with water (5 x 200 ml),
brine and dried over MgSO4. ~lternatively since the title compound
precipitated out on water dilution, it was filtered off and
recrystallized from ether; 7.22 g, 89~, mp 78-80C.
"Isomer B"
__
"Isomer B" of 3-(1'-paranitrobenzyldioxycarbonyl-
l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described
above for the "Isomer C"; 92~; mp 155.5-6C (ether); IHmr (CDC13)
~: 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzyl), 4.95
(lH, m, H-l'), 4.35 (lH, d, J=2.9, H-4), 4.17 (lH, s, N-H), 3.20
(lH, dd, J=10.8, J=2.9, H-3) and 1.40 ppm (3H, d, J=7.5, CH3);
ir (CHC13) V : 3480, 3390 (N-H), 1772, 1750 (C=O), and 1525 cm
(NO2). Anal. calcd for C32H28N2O6S: C 67.59, H 4.96, N 4.93,
S 5.64; found: C 67.48, H 4.98, N 4.92, S 5.67.
~86~
"Isomer A"
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-
l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described
above for the "Isomer C"; mp 205-6C. IHmr (CDC13) ~: 8.2-6.7
(19H, m, aromatics), 5.22 (2H, ABq, benzyl), 5.57-4.85 (lH, m, H-1'),
4.65 (lH, N-H), 4.50 (lH, d, J=6.5, H-4), 3.65 (lH, dd, J=6.5, 12,
JN H=l~ H-3) and 1.52 ppm (3H, d, J=7.5).
"Isomer D"
"Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-
l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described
above for "Isomer C"; IHmr (CDC13) ~: 8.15-6.70 (19H, m, aromatics),
5.23 (2H, ABq, benzyl), 5.20 (lH, m, H-l'?, 4.75 (lH, NH), 4.52
(lH, d, J=5.5, H-4), 3.42 (lH, J=5.5, 3, H-3 and 1.5 ppm (3H,
d, J=6.5, CH3). (J value for H-3 taken after D20- exchange).
U. Pre~aration of
.
(l'R,3S,4R and l'S,3R,4S) 3-(1'-methanesulfonyloxy-1'-ethyl)-4-
tritylthio-2-azetidinone (isomer .3)
MsO MsO
~3
~Si ~ ~ N ~
A solution of (l'R,3S,4R and l'S,3R,4S) l-(t-butyldimethyl-
silyl) -3-(1'-methanesulfonyloxy-1'-ethyl)-4-trithylthio-2-azetidinone.
(Isomer B) (4.95 g, 8.5 mmol) and sodium azide (1.11 g, 17.0 mmol)
in 10~ H20-HMPA (50 ml) was stirred at room temperature for 30 min.
Then the solution was diluted with water (250 ml) and extracted
with ether. The organic extracts were washed with brine, dried
(MgS04) and evaporated. Crystallization of the residue (ether-pet-
ether) gave the title compound (3.33 g, 83.8~). mp 130-31C. lHmr
(CDC13) ~: 7.20-7.62 (15H, m, aromatics), 4.97 (lH, dq, J=6.4, 6.1,
H-l'), 4.56 (lH. d, J=2.8, H-4), 4.22 (lH, m, N-H), 3.27 (lH, dd,
J=6.1, 2.8, H-3), 3.0 (3H, s, -CH3), 1.63 (3H, d, J-6.4, H-2');
ir (nujol) Vmax: 3195 (n-H), 1768 cm (C=0).
~ 6 ~-
1286~i61
V. Preparation of
(l'S,3S,4R and l'R,3R,4S?3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-
2-azetidinone. (Isomer C)
. .
OMs ~Ms
SC~3 ~ c~3
~i(CH3)2 N ~ H
t-Bu
A solution of (l'S,3S,4R and l'R,3R,4S)l-(t-butyldimethyl-
silyl)-3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone
(isomer C) (2.85 g; 4.9 mmol) in 10% aqueous HMPA (25 ml) was treated
with sodium azide (0.65 g, 10 mmol) and stirred at 25C for 0.5 h. By
diluting the solution with water (250 ml), the reaction product was
forced to crystallize out. The crude mesylate was redissolved in
dichloromethane, washed with brine, dried (MgSO4) and evaporated.
Trituration in ether gave the title compound as white crystals mp 155-60C;
1.80 g; 78.6~; lHmr(CDC13) ~: 7.43 (15H, m, aromatic), 5.02 (lH, dq, J=6.9,
4.9, H-l'), 4.55 (lH, s, N-H), 4.95 (lH, d, J=3, H-4), 3.33 (lH, dd, J=4.9,
3, H-3), 1.51 (3H, d, J=6.9, H-2'); ir V : 3395 (N-H), 1768 cm (C=O);
Anal. calcd for C2~H25NO4S. C 64.22, H 5.39, N 3.00; found: C 63-93~ H 5.39,
N 3.24%.
W. Preparation Of
(l'S,3S,4R and l'R,3R,4S) 3-(1'-p-Bromobenzenesulfonyloxy-l'-ethyl)-
4-tritylthio-2-azetidinone (Isomer C)
2~ 2~
SC~3 ~C~3
\ N ~H
A solution of (l'S,3S,4R and 1' R, 3R, 45) 3-(1'-p-bromoben-
zenesulfoxyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-
azetidinone (Isomer C) (1.42 9, 2 mmol) and sodium benzoate (0.865 g,
1~8~
6 mmol) in 10% H20-HMPA (40 ml) was stirred at room temperature
for 1 h. Then the solution was diluted with H2O (100 ml) and
extracted with ether. The ether ext:racts were washed with brine,
dried (MgSO4) and evaporated. The c.rude crystalline title compound
was triturated in a small volume of ether and collected by filtration
(0.92 g, 77%) mp 125-26C. IHmr (CDC13) ~: 7.80 (4H, s, benzenesulfonyl),
7.30-7.65 (15H, m, aromatics), 5.13 (lH, dq, J=6.5, 4.0, H-l'), 4.50
(lH, d, J=2.9, H-4), 4.40 (lH, s, N-H), 3.40 (lH, dd, J=4.0, 2.9, H-3),
1.50 (3H, d, J=6.5, H-2');ir (CHC13) V : 3400 cm (N^H), 1770 cm
(C=O) .
X. Pre~aration Of
(l'R,3S,4R and l'S,3R,4S) 3-(1'-Hydroxy-l~-ethyl)-4-tritylthio-2-
azetidinone (Isomer B)
OSO ~Br OH
~3 ~ c~3
~ S i--t O ~
\
To a warm solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-p-
bromobenzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-trityl-
thio-2-azetidinone (Isomer C) in HMPA (5 ml) was added dropwise
l~ml of H20. The reaction mixture was kept at 90C for 20 h, then
diluted with ether and washed 4 times with brine. The organic
solution was dried (MgSO4), evaporated and the crude title compound
purified by column chromatography (silica gel, 15% CH3CN-CH2C12).
A white solid was obtained (122 mg, 44.5%) mp 187-189C which was
found to be identical to a sample of the title compound prepared by
another method.
-/6 ~~
~2~6~
Y. Preparation Of
3-(l'-HydroxY-ll-ethyl)-4-tritylthio-2-azetidinone
pH qH
SC~3 _ ~ SC~3
N ~ ~ O ~
Both isomers, (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy-
l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) and (l'R,3S,4R and
l'S,3R,4S) 3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone
(Isomer D) were prepared by the same method. For example, a
solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-
(l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (1.0 g,
2 mmol) and sodium benzoate (0.865 g, 6 mmol) in 10% H20 - DMF (40 ml)
was stirred at room temperature for 18 h. Then the reaction mixture
was diluted with H2O and extracted with ether. The organic extracts
were washed with brine, dried (MgSO4) and evaporated. The crude
title compound was crystallized from cold ether (0.47 g, 61%) mp
134-35C. IHmr (CDC13) ~: 7.12-7.56 (lSH, m, aromatics), 4.48
(lH, s, N-H), 4.28 (lH, d, J=2.8, H-4), 2.94 (lH, dq, J=6.5, 6.2,
H-l'), 3.06 (lH, dd, J=6.2, 2.8, H-3), 2.18 (lH, s, -OH), 1.30
(3H, d, J=6.5, H-2');ir (CHC13) V : 3400 ~n-H), 1760 cm (C=O).
Similarly (l'R,35,4R and 1'5,3R,45) 1-(t-butyldimethylsilyl)-3-
(l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B)
mp 190-92C. lHmr (CDC13) ~: 7.10-7.55 (lSH, m, aromatics),
4.45 (lH, d, J=2.5, H-4), 4.28 (lH, s, NH), 4.10 (lH, dq, J=6.4,
5.3, H-l'), 3.08 (lH, dd, J=5.3, 2.5, H-3), 1.50 (lH, s, -OH),
1.30 (3H, d, J=6.4, H-2');ir (CHC13) Vmax: 3400 (N-H), 1760 cm
(C=O )
-l6 ~-
lX86~6~
Z. Preparation o~
(l'S,3R,4R and l'R,3S,45) 3~ MethoxyTnethyl-l~-ethyl)-l-(paranitr
benzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones tIsomer A)
OCH20CH3 OCH2OCH3
C~
H ~ ~ OH
C02PNB
A mixture of Isomer A of 3-(1'-methoxymethyl-1'-ethyl)-4-
tritylthio-2-azetidinone (7.5 g, 17.3 mmol), paranitrobenzyl glyoxylate
hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) was heated under reflux
for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves.
The solution was cooled in ice and triethylamine (0.24 ml, 1.7 mmol)
was added dropwise. The mixture was stirred for 1 h, washed with
diluted hydrochloric acid, sodium bicarbonate and brine, dried and
concentrated to give the title compound as a foam (10.5 g, 94%). lHmr
(CDC13) ~: 8.25-6.84 (19H, m, aromatics), 5.24 (2H, s, benzyls), 4.67-
4.83 (3H, m, O-CH2 and H-4), 4.34-4.55 (lH, m, H-2"), 4.02 (lH, m, H-l'),
3.54 (lH, m, H-3), 3.40 (3H, s, O-CH3), 1.38 (3H, d, J=6.5, CH3);ir tKBr)
V : 3360 (OH), 1770 (C=O of ~-lactam), 1735 (C=O of ester) and 1605 cm
max
(aromatics).
AA. Pre~aration of
(l'S,35,4R and l'R,3R,4S) 3-(1'~ ethoxymethoxy l'-ethyl)-l-(paranitro-
benzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C)
OCH2OCH3 CHO OCH2OCH3
J..~ C02PNB ~
O2PNB
A solution of hydrated paranitrobenzyl glyoxylate (1.73 9,
7.11 mmol) was refluxed in toluene (90 ml) using a Dean Stark condenser
filled with 3A molecular sieves for a 2 h period. To the boiling
solution was added (1'5,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-
-/69-
;6~;1
ethyl)-4-tritylthio-2-azetidinone (3.0 g, 6.93 mmol) and the
mixture was refluxed for 2 h more. The mixture was cooled to room
temperature, triethyl amine (70 mg, 97 ~1, 0.69 mmol) was added
and it w ~ stirred for 2 h. The reaction mixture was diluted
with ether, washed with 1% aqueous HC1, water,1% aqueous NaHCO3
water and brine, dried (MgSo4 and concentrated to give the title
compound (4.60 g, 100%); ir (CHC13) vmax: 3530-3100 (0-H), 1765,
1750 (C=0) and 1525 cm 1 (NO2); 1Hmr (CDC13) ~: 8.22, 8.18 (2H,
2d, J=8, Hm aromatics), 7.67-7.0 (17H, m, H-aromatics), 5.3 (2H,
bs, CH2-PNB), 5.30-5.02 (m, ~-2'~), 4.89-4.52 (m, H-l' and O-H),
4.63, 4.59 (lH, 2d, J=2, H-4), 4.33, 4.30 (2H, 2 center of 2 ABq,
J=7, J=7, O-CH2-O), 4.1-3.67 (lH, m, H-l'), 3.2 (lH, H-3), 3.1,
3.6 (3H, 2s, CH3-O), and 1.15 ppm (3H, d, J=6.5, CH3).
BB. Prepara~ion of
(1'R.3S.4R and 1S.3R.4S) 3-ll'Acetoxy-1'-ethyl)-1-
(Daranitrobenzyl-2"-hydroxy - 2"-acetate) 4 - tritylthi~-2-
azeti~dinone
pAc
J" ~STr ~0 PNa ,~
"Isome B"
A solution of hydrated p-nitrobenzyl glyoxylate
(triturated with ether) (1.82 (g, 30 mol) was refluxed in benzene
o
through a Dean Stark condenser filled with 3A molecular sieves for
2 h . To that was added azetidinone (1'R,3S,4R and l'S,3R,4S)
3-(l'-acetoxy-1'-4-tritylthio- 2-azetidinone (10-88 g, 25.2 mmol)
and the mixture was refluxed for 1 h more. The solution was cooled
at room temperature and triethyl amine (0.35 ml, 2.5 mmol was
added. It was then stirred for 2 h; the reaction progression
being followed by tlc. *Solvent evaporation afforded a white
- 170 -
~2~666~L
foam in quantitative yield (100~., mixtl~re of epimers) *A1 .erllatively
the sol~tion can be acid and base s:zshed. ir (CH3C12) v : 3520 (OH),
1775, 1/q5 -m (C=O); 1Hmr (CDC13) ~: 8.2, 8.18 (2H, 2d, J=~, Ho
aromatic), 7.8C-6.~0 (l~H, m, I~-aro:natic), 5 28, 5.17 (2H, 24, CH2-PNB,
4.89 (0.67H, à, J=7 2, CHO), ~ 80 (center or m, H-l'), 4 38 (0 33 1~,
2d, J=8 8, CHO), 4.22 (D 33H, d, J4 3=2.5, H-4), ~.09 (0.67H, d, J4 3=
2 1 ~1-4) 3.65 (D.67H, dd, J3 1,=5 8, J3_4 2 1~ ?
dd, J3 1~=5-5 J3 4=2.5, l3-3), 3.33 (0 3311, d, J=8 8, 0~3), 3.23 (0.67H,
d, J=7.5, OH), 1.38, 1 86 (3H, 2s, CH3CD), 1.10, 1 06 (3H, 2d, J=5.8,
~.3, C~33)
CC Preparation of
3~ paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl
2"-hydroxy-2"-acetate)4-tritylthio-2-azetidinone (4 isomers).
OCO PNB OCO PNB
~S ~3 ~S_~
CO2PNB
"Isomer C"
A mixture of "Isomer C" of 3-(l'-paranitrobenzyl-
dioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (1.70 g,
0.3 mmol), paranitrobenzyl glyoxylate hydrate (815 mg, 3.6 mmol)
and toluene (50 ml) was heated under reflux 7 days in a Dean and
Stark apparatus filled with 3A molecular sieves. The cooled
solution was washed with dilute hydrochloric acid, sodium bicar-
bonate and brine, dried and concentrated to give the title compound
(2.l g) as an epimeric mixture at carbon-2". Purification was
effected by chromatography over silica gel. Alternatively the title
compound could be prepared by using a catalytic amount of triethyl
_~q / _
;6~
amine. Less polar epimer at 2": IHmr (CDC13) ~: 8.25-6.80 (23H, m,
aromatics), 5.30 and 3.12 (4H, 2s, benzyls), 4.65 (lH, d, J=9, H-2"),
4.45 (lH, d, J=2.5, H-4), 4.45-4.10 (lH, m, H-l'), 3.50 (lH, d, J=9,
2"-OH), 3.28 (lH, dd, J=2.5, J=2.5, H-3) and 1.23 ppm (3H, d, J=6.5,
CH3); ir (CHC13) Vmax: 3530 to 3200 (D-H), 1765, 1750 (C=O) and 1525 cm
(NO ). More polar isomer at C-2": Hmr (CDCl ) ~: 8.25-6.85 (23H, m,
2 3
aromatics), 5.25 and 5.08 (4H, 2s, benzyls), 5.05 (lH, d, J=7, H-2"),
4.35 (lH, d, J=2.5, H-4), 4.40-4.05 (lH, m, H-l'), 3.42 (lH, J=7, 2"-OH),
3.33 (lH, dd, J=2.5, 2.5, H-3), 1.23 (3H, d, J=6.5, CH3); ir (CHC13)
Vmax: 3520 to 3200 (O-H), 1755 (C=O) and 1525 cm (NO2).
"Isomer B"
A mixture of hydrated paranitrobenzylglyoxylate (1;74 g,
7.66 mmol) and (l'R,3S,4R and 1'5,3R,45) 3-(1'-paranitrobenæyldioxy-
carbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (3.63 g, 6.38 mmol)
was refluxed in toluene (70 ml) on a Dean Stark condenser filled with
3A molecular sieves for 3h. The solution was cooled down to room
temperature and triethyl amine (64.5 mg, 89 ml, 0.639 mmol) was
added. It was then stirred for 4 h, diluted with ether and washed
with 2% aqueous HCl, water, 2% aqueous NaHCO3, water and brine. It
was dried and concentrated to give pure title compound (5.02 g, 100%).
Separation of the 2 epimers was ef~ected on preparative silica gel
plate. Less polar epimer at 2": ir (CHC13) V : 3500 (O-H), 1772,
1750 (C=O) 1525 cm (NO2); lHmr (CDC13) ~:8.30-8.0 and 7.65-6.80,
(23H, m, aromatics), 5.27 and 5.13 (4H, 2s, benzyls), 4.71 (lH, m,
J=6.5, 6.5, H-l'), 4.28 (lH, d, J=2.2, H-4), 4.23 (lH, d, J=8.7, H-2"),
3.50 (lH, dd, J=2.2, 6.5, H-3), 3.28 (lH, d, J=8.7, O-H) and 1.18 ppm
(3H, d, J=6.5, CH3). More polar epimer: ir (CHC13) V 3480 (O-H)
1772, 1750 (C=O) and 1525 cm (NO2); IHmr (CDC13) ~: 8.35-6.90 (23H,
m, aromatics), 5.15 (4H, benzyls), 4.72 (lH, d, J=7.5, H-2"0),4.90-
~Z~3666~
4.50 (lH, m, J=6.5, 6.5, H-l'), 4.10 (lH, d, J=2, H-4), 3.68 (lH, dd,
J=2, 6.5, H-3), 3.28 (lH, d, J=6.5, O-H) and 1.15 ppm (3H, d, J=6.5,
3)
"Isomer A"
The "Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-
l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-
(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones.
IHmr (CDC13) ~: 8.3-6.7 (23H, m, aromatics), 5.17 (2H, benzyls),
5.0 (lH, m, H-l'), 4.9 and 4.8 (lH, 2d, J=6, H-4, two epimers),
4.32 and 3.96 (lH, 2s, H-2", two epimers), 3.68 (lH, dd, J=6, 6,
H-3( and 1.47 ppm (3H, 2d, J=6.5, CH3, two epimers).
"Isomer D"
The "Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-
l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of
"Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-
(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones.
IHmr (CDC13) ~: 8.30-6.60 (23H, m, aromatics), 5.20 (4H, m, benzyls),
4.83 (lH, 2d, J=5, H=4), 5.50-4.30 (2H, m, H-l' and H-2"), 3.48
(lH, m, H-3), 3.15 (lH, m, O-H), 1.37 and 1.30 ppm (3H, 2d, CH3).
DD. Preparation of
(l'S,3S,4R and l'R,3R,45)3-(l'~lethanesulfonyloxY-l'-ethyl)-l-(parani-
trobenzyl 2"-hydroxy-2"-acetate)~-tritylthio-2-azetidinone (isomer C)
(epimers at C2"~.
OMs OMs
5C~3 ~N OH
02PNB
A solution of paranitrobenzylglyoxylate hydrate (9.72 g;
42.6 mmol) in benzene (350 ml) was refluxed for 2 h, removing the water
azeotropically in a Dean-Stark trap. To that solution was added the
~ / 7 3
~'~8~
(1~S,35,4R and 1~R,3R,4S)3~ methanesulfonyloxy-l'-ethyl)
-4-tritylthio-2-azetidinone (16.62 g, 35.5 mmol) and the reflux
maintained for an additional 0.5 h. Then the reaction mixture was
cooled to-~room temperature, treated with triethylamine (0.5 ml;
3.5 mmol) and stirred for 3 h in order to complete the reaction.
Evaporation of the solvent left a white foam which was used as
such in the next step. 1Hmr (CDCl3) ~: 8.12 (2H, d, J=9, Hm
aromatic), 7.28 (17H, part of d,Ho aromatic, trityl), 5.28 (2H, s,
-CH2-PNB), 4.88 (0.5 H, s, H-l"), 4.62 (1.5H, m, H-2" and H-4),
4.00 (2H, m, H-l~, -OH), 3.15 (lH, m, H-3), 2.73 (3H, s, mesylate
and 1.30 ppm (3H, d, J=6 Hz, H-2~);ir max:3520 (O-H), 1775 (C=o)
and 1765 cm 1 (C=O).
EE. Preparation of
(1'S.3R.4R and 1'_R.3S 4~l
3-(l-Methoxymethyl-l'-ethyl)-l-rparanitrobenzyl
2"-chloro-2"-acetate)-4-trit~lthio-2-a~et;d;nonP (Isomer A~
OCH 2 OCH 3 OCH 2 OCH 3
20 ~SC;~3 ~SC~3
OH a~ ~C 1
2 C 2 D N~3
Pyridine (1.1 ml, 14.2 mmol) was added dropwise to
a solution of Isomer A of 3-(l'-methoxymethyl-1'-ethyl)
-l-(paranitrobenzyl-2"-hydroxy-2"-acetate)
-4-tritylthio-2-azetidinone (7 g, 10.9 mmol) in THF (350 ml)
cooled to -15C. Immediately after thionyl chloride (1.0 ml, 14.0
mmol) was added dropwise and the mixture was stirred at -150 for
0.5 h. The precipitate was removed by filtration and washed with
benzene. The combined filtrates were concentrated , the residue
dissolved in fresh benzene and the solution treated with
activated charcoal, filtered and concentrated to leave to title
compound as an oil (6.5 g, 90%), 1 Hmr (CDC13) ~ : 6.65-8.35
(19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH3) and
1.42 ppm (3H, d, J=6, CH3).
- 174 -
iÇi~
FF. Preparation of
(1'5,3S,4R and l'R,3R,45) 3~ ethoxymethyloxy-l'-ethyl)-l-(paranitro-
benzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C)
IOCH20CH3 0CH20CH3
STr SOC12 J ~ STr
N ~ OH ~ ~ Cl
C02PNB C02PNB
A cold (ice-MeOH bath) THF (60 ml, distilled over LAH)
solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-ethyl)-
l-paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone
(4 25 g, 6.62 mmol) was treated dropwise with pyridine (0.696 ml,
8.61 mmol) and thionyl chloride (0.530 ml, 8.61 mmol). The mixture
was stirred for 30 min at -15~C. The precipitate was collected by fil-
tration and washed with benzene. The THF-benzene solution was concentrated
and the residue was dissolved again in benzene. The resulting
solution was treated with charcoal. Removal of charcoal on a Ce~ite
pad and subsequent benzene evaporation afforded the title compound
(4.86 g, 100%); ir (CHC13) Vmax: 1770 (C=O) and 1525 cm (NO2); Hmr
tCDC13) ~: 8.15, 8.12 (2H, 2d, H-aromatics), 7.70-7.00 (17H, m, H-aromatics),
5.62, 5.02 (lH, 2s, H-2"), 5.27 (2H, s, CH2-PNB), 4.7 (lH, d, H-4), 4.7-3.7
(m, O-CH2-O, H-l'), 3.5-2.8 (m, H-3), 3.12, 3.08 (3H, 2s, O-CH3), and
1.30-0.96 ppm (3H, m, CH3).
~J7 ~ ~
~6~
GG. Preparation of
(l'R, 35,4R and l'S,3R,45) 3-(1'-Acetoxv-l'-ethYl~-l-(paranitrobenzYl
2"-chloro-2"acetate)-4-tritylthio-2-azetidinone
OAc pAc
STr SOCl J ~ STr
OH Pyridine O ~ ~ I C1
C02PNB C02PNB
"Isomer B"
A THF (distilled over LAH) solution of (l'R,35,4R and l'S,
3R,4S) 3-(1'-acetoxy-1'-ethyl)-1-(paranitrobenzyl-2"-hydroxy-2"-acetate)-
4-tritylthio-2-azetidinone (from 10.88 g of N-H) was treated at -15C
(ice-methanol bath) under nitrogen atmosphere with pyridine (2.19 g,
2.24 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol)
and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol). The mixture was
stirred for 20 min at -15. The salt was filtered off and washed
with benzene. Solvent (THF + benzene) evaporation afforded a residue
which was taken up in benzene (warm) and treated with charcoal. The
suspension was filtered through a celite pad and solvent evaporation
left a foam; ir (CH2C12) V : 1780, 1740 cm (C=O) lHmr (CDC13 ~:
8.17, 8.21 (2H, 2d, J=8, Ho aromatic) 7.76-6.88 (17H, m, H-aromatic),
5.31, 5~16, 5.12, 4.73 (3H, 4s, CH2-PN~3, CHCl), 5.12-4.55 (lH, m, H-1'),
4.35-4.25 (lH, m, H-4), 3.80-3.45 (lH, m, H-3) 1.90 (3H, s, CH3CO), 1.12
1.07 (3H, J=6.5, CH3).
-I 7~-
12~6~61
HH. 3~ Paranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-chloro-
2"-acetate)-4-tritylthio-2-azetidinones (mixture of epimers at C2").
2 2
SC~3
N ~ OH O ~ N ~ Cl
C02PNB 02PNB
"Isomer C"
Pyridine (58 ms, 0.73 mmol) was added dropwise to a
solution of "Isomer C" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-
l-(paranitrobenzyl 2"-hydroxy-2"-acetate)-3-tritylthio-2-azetidinones
(470 mg, 0.6 mmol; mixture of epimers at C-2") in THF (15 ml) cooled
to -15"C. Immediately after thionyl chloride (86.5 mg, 0.73 mmol)
was added dropwise and the mixture was stirred at -15C for 0.5 h.
The precipitate was removed by filtration and washed with benzene.
The combined filtrates were concentrated, the residue dissolved in
fresh benzene and the solution treated with acti~ated charcoal, ~iltered
and concentrated to leave the title compound as an oil. 530 mg; 100%.
Hmr (CDC13) ~: 8.7-6.8 (23H, m, aromatic), 5.53 (lH, s, H-2"), 5.30
and 5.17 (4H, 2s, benzyls), 4.52 (lH, d, J=2, H-4), 4.20-3.70 (lH, m,
H-l'), 3.31 (lH, dd, H-3), 1.27 and 1.21 ppm (3H, 2d, J=6.5); ir (CHC13)
V : 1780, 1750 (C=O) and 1525 cm (NO2).
"Isomer B"
"Isomer B" of 3-(1-paranitrobenzyldioxycarbonyl-1'-ethyl)-
l-(paranitrobenzyl 2"-chloro-2"-acetate)-~tritylthio-2-azetidinones
(mixture of C-2" epimers) was prepared as described above for the
"Isomer C" in quantitative yield. lHmr (CDC13) ~: 8.25-6.90 (23H, m,
aromatics), 5.40-5.0 (4H, m, benzyls), 5.40-4.45 (lH, m, H-l'), 4.82
and 4.57 (lH, 2s, H-2"), 4.36 and 4.31 (lH, 2d, J=2.5, H-4), 3.63 (lH,
m, J=2.5, J=6.5, H-3), 1.25 and 1.18 ppm (3H, 2d, J=6.5, CH3)i ir
(CHCl ) : 1780, 1750 (C=O), and 1525 cm (NO2).
3 max
~l77
~.2~366~1
"Isomer A"
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-
l'-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinones
(mixture of C-2" epimers). IHmr (CDC13) ~: 8.30-6.80 (23H, m, aromatics),
5.45-4.80 (lH, m, H-l'), 5.18 and 5.21 (4H, 2s, benzyls), 4.87 (lH, 2d,
H-4), 4.22 and 3.87 (lH, 2s, H-2"), 4.05-3.40 (lH, m, H-3), 1.57 and
1.50 ppm (3H, 2d, CH3).
"Isomer D"
"Isomer D" of 3-(1"-paranitrobenzyldioxycarbonyl-1'-ethyl-
l'-(paranitrobenzyl 2"-chloro-2"-acetate~-4-tritylthio-2-azetidinones
(mixture of C-2" epimers). IHmr (CDC13) ~: 8.30-6.70 (23H, m, aromatics),
5.32-5.10 (4H, m, benzyls), 5.48 and 5.30 (lH, 2s, H-2"), 4.82 (lH, d,
J=5, H-4), 5.30-5.20 (lH, m, H-1'), 3.15 (lH, m, H-3), 1.40 and 1.30
ppm (3H, 2d, J=6.5, CH3); ir CHC13) V : 1780, 1750 (C=O) and 1525 cm
(N02 )
II. Pre~aration of
(l'S,35,4R and l'R,3R,4S)3-(1'-M~thanesulfonyloxy-l'-ethyl)-l-(paranitro-
benzyl 2"-chloro-2"-acetate(-4-tritylthio-2-azetidinone (isomer C)
(epimers at C2").
OMs OMs
SC~3 ~ SC~3
NOH ~ N ~Cl
C02PNB 2
To a cold solution (5~C) of ~l'S,3S,4R and l'R,3R,4S)3-
(l'-methanesulfonyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate)-
4-tritylthio-2-azetidinone (24.0 g, 35.5 mmol) in dry tetrahydrofuran
(350 ml) was bdded pyridine (3.65 g, 46.2 mmol) and thionyl chloride
(5.5 g, 46.2 mmol) dropwise. After stirring for 45 min, ether (100 ml)
was added to precipitate the hydrochloride salt which was filtered off.
~ ~ '7 8' ~
~6663
The filtrate was evaporated and the residue redissolved in benzene (2C0 m
and treated with charcoal. Evaporation of the solvent left a nearly
white foam which was used as such in the next step. IHmr (CDC13) ~:
8.18 (2H, d, J=9, Hm aromatic), 7.72 (17H, m, part of d.Ho aromatic,
trityl), 5.57 and 5.12 (lH, s, H-2"), 5.28 (2H, s, -CH2PNB), 4.73
(lH, 2d, H-4), 3. 21 (lH, 2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21
ppm (3H, 2d, H-6H2; H-2'); ir Vmax 1779 cm (C=O)
JJ. Preparation Of
(l'S,3R,4R and l'R,3S,4S) 3-(1'-MethoxY~ethoxy-l'-ethYl)-l-(~aranitro-
benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone
(Isomer A)
OCH2OCH3 OCH2OcH 3
SC~3 ~C~3
O ~ ~ Cl N ~ p~
O2PNB 2
A mixture of Isomer A of 3-(1'-methoxymethoxY-l'-ethyl)-l-
(paranitrobenzyl-2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone
(6.6 g, 10 mmol), triphenylphosphine (3.3 g, 12.5 mmol), 2,6-luti-
dine (1.3 ml, 11 mmol) and dioxane (140 ml) was heated under reflux
for 2 days. The solution was diluted with ether, washed with dilute
acid (5% HCl), water, dilute sodium bicarbonate solution and brine,
dried and concentrated. The residue was purified by chromatography
on silica gel eluting with 10% ether in benzene. Concentration of the
pertinent fractions left the title compound as a foam (1.4 g, 13.7~)
ir (KBr) V : 1750 (C=O) and 1660-1650 cm (C=C, aromatics).
_/~q_
~.X~36~6~
KK. PreParation o~
(l'S,3S,4R and l'R,3R,45) 3~ Methoxymethyloxy-l'-ethyl)-l-(paranitro-
benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone
(Isomer C).
OCH2OCH
OCH2OCH3 I STr
J STr P~3 ~ ~
O PNB
CO2PNB 2
A dioxane (100 ml, distilled over LAH) solution of (l'S,
3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-l'-ethyl)-l-(paranitrobenzyl-
2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (4.86 g, 6.62 mmol),
triphenylphosphine (2.60 g, 9.93 mmol) and 2,6-lutidine (770 mg, 0.837 ml,
7.20 mmol) was heated under reflux for 4 h and kept in a hot bath (100C)
for 16 h. The mixture was diluted with ether, washed with l~ aqueous HCl,
water, 10% aqueous NaHCO3, water and brine and dried (MgSO4). The
solution was concentrated and the residue filtered through a silica gel
(65 g) column (5%, 10% and 20% ether-benzene) to give the title compound
(2.8 g, 48%). ir (CHCl3) Vmax: 1795 (C=O), 1620 and 1605 (phosphorane)
and 1515 cm (NO2).
LL. (l'R,3S,4R and l'S,3R,4S) 3-(1'-Acetoxy-l'-ethyl)-l-(paranitrobenzyl-
2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azeditinone
(Isomer B)
OAc OAc
J""" ~ STr ~3P J ~ STr
~ 2,6-lutidine O L N ~ ~3
02~NB C02~?NB
A dioxane (100 ml, freshly distilled over LAH) solution
of crude (l'R,3S,4R and l'S,3R,4S) 3-(l'-acetoxy-l'-ethyl)-l-(paranitro-
-/~0 -
lX~6~6~
benzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone was treated
with 2,6-lutidine (2.97 g, 3.23 ml, 27.72 mmol) and triphenyl phosphine
(9.91 g, 37.8 mmol). The mixture was refluxed (oil bath 130) for
18 h. The solvent was evaporated and the residue was redissolved
in methylene chloride. The resulting solution was successively
washed with diluted HCl, H20, diluted aqueous NaHC03,H20 and brine.
Drying and solvent evaporation left the title compound as a solid
which was triturated with ether and collected by filtration (14.6 g,
65-9~); ir (CH2C12) Vmax: 1750 (C=0) and 1620, 1610 cm (phosphorane).
MM. 3~ Paranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl-2"-
triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone.
2 NB 2
C~3 ~ SC~3
~L_ ~ Cl 0 ~ ~3
02PNB C02PNB
ISOMER B
A mixture of (l'R,3S,4R and l'S,3R,4S) 3-(1'-paranitro-
benzyl-dioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl-2"-chloro-2"-acetate)
-4-tritylthioazetidinone (isomer B) (4.96 g, 6.22 mmol, mixture of
epimers at C-2"), triphenyl phosphine (2.47 g, 9.42 mmol) and 2,6-
lutidine (740 mg, 0.80 ml, 6.91 mmol) was refluxed in dioxane (freshly
distilled over LAH) for 30 h. The solution was diluted with ether and
ethyl acetate, washed with 5% aqueous HCl, water, 10% aqueous NaHC03,
water and brine and dried (MgS04). Solvent evaporation afforded a
~1 8~( ~
~.286~
residue which was passed through a silica gel (10 times its weight)
column (10% ether-benzene, ether, and ethyl acetate). The title compound
was obtained as a crystalline solid (3.1 g, 49%), mp 189-190 (ether);
ir (CHC13~ v : 1750 (C=O), 1620, 1605 (phosphorane) and 1522 cm
2)
ISOMER C
Isomer C of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-
l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-
2-azetidinone was prepared as described above for isomer B. ir (CHC13)
v : 1750 (C=O), 1610, 1620 (phosphorane) and 1520 cm (N02); IHmr
tCDC13) ~: 8.6=6.7 (H, aromatics), 5.22 and 4.95 (benzyls), 4.70 (H-4),
2.6 (H-3), 1.19 and 1.07 ppm (CH3).
ISOMER D
A mixture of Isomer D of 3-(1'-p-nitrobenzyldioxycarbonyl-
l'-ethyl)-l-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azeti-
dinone (4.598 g, 4.45 mmol; purity 77%, mixture of epimers at C-2"),
triphenylphosphine (1.425 g, 5.44 mmol; Aldrich) and 2,6-lutidine
(0.63 ml, 580 mg, 5.40 mmol; Anachemia) in dioxane (65 ml; distilled
from LAH) was heated at gentle reflux under N2 for 41 h, monitoring
the reaction by tlc (benzene:ether=3:1). The dark reaction mixture
was cooled, diluted with EtOAc and washed successively with 0.1 NHCl,
water, 2% NaHC03 and then brine. Drying (Na2S04) and evaporation
of the solvents gave 4.18 y of a dark coloured oil which was purified
by column chromatography (SiO2, 88 g; eluent 10-25~ ether in benzene)~
yielding 1.108 g (1.08 mmole, yield 24.3%) of the title compound as
a yellowish foam: IHmr (CDC13) ~: 1.08 (d, J=6Hz, l'-CH3); ir (neat)
max 1745 cm 1 (s, C=O)
-/ '81-
~ ~36G~
NN. Preparation of
(l'S,3S,4R and l'R,3R,4S)3~ Methanesulfonvloxv-1'-ethvl)-1-(pananitro-
benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidi-
none (isomer C)
OMs - OMs
SC~3 ~ sc~3
N P~3
C02PNB C02PNB
A solution of (l'S,35,4R and l'R,3R,45)3-(1'-methanesul-
fonyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-
azetidinone (24.7 g, 35.5 mmol), triphenylphosphine (11.2 g, 42.7 mmol)
and 2.6-lutidine (4.2 g, 39.1 mmol) in dry dioxane (350 ml) was refluxed
under nitrogen for 19 h. The solvent was evaporated and the crude ~roduct
redissolved in ethyl acetate and washed successively with dilute HCl,
NaHC03 and brine. Purification was completed by chromatography on a
silica gel column (8.5 x 12 cm). Elution with 10% ether-dichloromethane
(1.5 ~J and then ether (1.5 ~) gave the purified phosphorane; 12.36 g (40~).
Hmr (CDC13) ~: 2.53 and 2.93 ppm (3H, 2s, mesylate)i ir v : 1749 and 1620
cm (C=O)
00. Pre~aration of
(l'R,3S,4R and l'S,3R!4S) 3-(1'-Hydroxv-l'-ethyl)-l-(Paranitrobenzvl-
2"-triphen~flphosphoranvlidene-2"-acetate) 4-tritylthio-2-azetidinone
(Isomer B).
OAc OH
~STr J........ Tr
I NaOH ~ ~
0~ _ N ~ p~ ~ - N P~3
C02PNB C02PNB
A solution of phosphorane (l'R,3S,4R and l'S,3R,4S) 3-
(1'-acetoxy-1'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranyl-
idene-2~-acetate)-4-tritylthio-2-azetidinone (4.43 g, 5.00 mmol)
1~36~;6~
in methanol (10 ml) THF (60 ml~was treated at room temperature
with 1% aqueous NaOH (1 eq, 200 mg in 20 ml H2O). The reaction
progression was followed by tlc*. The mixture was diluted with
ether-ethyl acetate and washed with HCl, H2O, aqueous NaHCO3,
H2O and brine. Solvent evaporation afforded a residue which was
crystallized fro~ benzene-ether (3.7 g, 87.7%) mp 169.5-170.5C.
ir (CH2C12) Vmax: 1745 (C=O) and 1620 cm (phosphorane)
*Heating the mixture increased the reaction rate.
PP. Preparation o~
(1'5,3R,4R and l'R,3S,4S) Silver 3-(1'-methoxymethyl-1'-ethyl)-1-(para-
nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-
thiolate (Isomer A)
C~i20C~3 OCH20CH3
SAg
~ P~3 O ~ p~3
CO 2PNB
Silver 3-(1'-methoxymethyl-1'-ethyl)-1-(paranitrobenzyl
-2"-triphenylphosphoranylidene-2"-acetate)-3-tritylthio-2-azetidinone
(isomer A), was prepared as described elsewhere for the isomer C of
the paranitrobenzyldioxy carbonyl derivative. Yield 50%. ir (neat
V x 1745 cm (C=O),
_/ g~LJ _
36~61
QQ, Preparation of
l'S,3S,4R and l'R,3R,4S) Silver 2-(l' methoxymethyloxy~ ethyl)-l-
(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-
4-thiolate (Isomer C).
.
- 2 CH3 OCH2OCH3
0 ~ ~ P~3 AgNO3 o ~N ~ ~3
C02PNB C02PNB
(1'5,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-ethyl)-1-(para-
nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-
azetidinone (887 mg, l.0 mmol) was first dissolved in hot ( 40C)
methanol (30 ml), treated with pyridine (103 mg, 0.105 ml, 1.3 mmol)
and, after cooling, was -treated with a 0.15 l~ methanol solution of
silver nitrate (8.7 ml, 1.3 mmol). The mixture was stirred for 1 h
at 23C, cooled (ice bath) and stirred for 20 min. The salt was
filtered and washed successively with cold methanol and ether (3 times,
671 mg, 87~). ir (CHC13) Vmax: 1745 (C=O), 1605 (phosphorane) and 1520
cm (NO2).
RR. Preparation of
Silver 3-(l'-paranitrobenzyldioxycarbonyl-1'-ethYl)-l-(paranitrobenzyl
2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate.
SAg
N ~ p~3 O N~G~P~
O2PNB
"Isomer B"
(l'R,3S,4R and l'S,3R,45) 3-(l'-paranitrobenzylcarbonyl-
dioxy-l'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-
acetate)-4-trithio-2-azetidinone (1.02 g, 1 mmol) was first dissolved in
1~3666~
CH2C12 (3 ml) and diluted with hot (55C) MeOH (20 ml). The hot
solution was treated first wlth pyridine (120 ml, 117 mg, 1.48
mmol) and a hot (55C) 0.15M methanolic solution of silver nitrate
(8 ml, 1.2~mmol). The mixture was stirred at room temperature for
15 min, then at 0C for 2 h. It was then concentrated to a 10%
solution on the rotary evaporator (no bath). The mercaptide was
filtered and washed twice with cold (-15C) methanol and three
times with ether. (917 mg, 100%), :Lr ("NUJOL MULL")* vmax: 1745
(C=O), 1600 (phosphorane) and 1517 cm~1 (N02).
"Isomer C"
Silver 3-(l'-Paranitrobenzyldioxycarbonyl-l'-ethyl)
-1-(paranitrobenzyl
2"-triphenylphosphoranylidene-2"-triphenylphosphora-
nylidene-2~-acetate3-2-azetidinone-4-thiolate, "Isomer C", was
prepared as described above for the ~Isomer B"; ir(llNUJOL")* ,Vmax:
1745 (C=O) and 1600 cm~1 (phosphorane).
"Isomer D"
A solution of Isomer D of 3-(l'-p-nitrobenzylcarbonyl-
dioxy-l'-ethyl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-
acetate)-4-tritylthio-2-azetidinone (145 mg, 0.142 mmol) was
prepared by first dissolving it in CH2C12 (5 ml), removing the
CH2Cl2 at 55- 60 and adding hot MeOH (4 ml). To the above
solution was added a hot solution of AgN03 in MeOH (0.15 M, 1.14
ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 ~l, 0.17 mmol,
1.2 eq). The silver mercaptide started to precipitate immediately.
The mixture was stirred 2 h at room temperature and 1 h at 0. The
mercantide was collected by filtration and washed with ice-cold
MeOH and ether, yielding 99 mg (O. 11 mmol, 78%) of the title
compound as a brownish solid: ir ("NUJOL") vmax: 1750 cm 1 (s,
c=o) -
*Trade Mark
',.
SS. Preparation of
(l'R,3S,4R and l'S,3R,4S) Silver 3-(1'-hydroxy-1'-ethyl)-1-)paranitro-
benzyl-2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-
thiolate (Isomer B)
OH OH
J ~ STr g 3 ~ ~ SAg
N ~ P~3 C5H5N ~ P~3
C02PNB C02PNB
A solution* of (l'R,3S,4R and l'S,3R,45) 3-(1'-
hydroxy-l'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-
acetate)-4-tritylthio-2-azetidinone (lg, 1.19 mmol) in MeOH (10 ml),
was treated with pyridine (124 ~1, 121.3 mg, 1,53 mmol) and at 10C
with a 0.15M solution of silver nitrate in MeOH (15 ml, 2.25 mmol -
or until no more precipitation of the silver mercaptide occurred). The
mixture was stirred for 1 h and concentrated on the rotary evaporator
(no bath) to approximatively 10% concentration. The solvent was
filtered off. The cake was washed once with MeOH and 3 times with
ether, and pumped under high vacuum (954 mg, 100~). ir (Nujol mull)
V : 3500-3400 (O-H), 1752 (C=O) 1595 (phosphorane) and 1525 cm (NO2)
max
*The crystalline material was first dissolved in CH2C12.
T~, Preparation o~
(l'R,3R,4R and l'S,3S,45) 4-Acetylthio-3-(1'-p-nitrobenzyldioxycarbonyl-
l'-ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-
azetidinone (Isomer D)
OCO PNB OCO2PNB
SAg CH3cocl-pyr ~SAc
~ CH 2C 12 N ~P ~ 3
CO PNB
CO2PNB 2
To a stirred solution of silver 3-(1'-paranitrohenzyl
2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate
- ! ~7 -
~6~i61
(isomer D) (85 mg, 0.095 mmol) in CH2C12 (5 ml) containing pyridine
(30 ~ 0.37 mmol; Fisher) was added at 0-5C CH3COCl (20 ~1, 0.28
mmol) and the mixture was stirred at 0-5~C for 30 min. The precipitate ~hich
formed was filtered and washed with CH2C12. The filtrate and washings
were combined, washed successively with brine, diluted HCl, saturated
NaHCO3 and then brine, dried (Na2SO4) and evaporated yielding 75 mg
(0.091 mmol, crude yield 95%) of the title compound as a syrup: lHmr
(CDC13) ~: 2.33 (s, -SOCOCH3); ir (neat) Vmax: 1750 (~-lactam, ester),
1695 (thioester), 1520 and 1350 cm (-NO2).
W . Preparation of
(l'R,5R,6R and l'S,SS,6S) cis p-Nitroben~yl 2-methyl-6-(1'-p-nitrobenzvl-
diox carbonylmeth 1- enem-3-carboxylate (Isomer D)
Y Y P
OCO PNB OC02PNB
toluene ~ ~ ro PNB
CO2PNB 2
A solution of the above acetylthioazetidinone ~74 mg,
0.09 mmol) in toluene (30 ml) was heated at reflux under N2 atmosphere
for 7 h. After evaporation of the solvent, the residue was purified
by hplc (SiO2; eluent, benzene:ether=3:1) yielding 24 mg (0.044 mmol,
yield 49%) of the penem ester as a syrup. (Note: this oil could be
crystallized from THF-ether or CH2C12-ether: lHmr (CDC13) ~: 1.40
(3H, d, J=6.5 Hz, l'-CH3), 2.38 (3H, s, 2-CH3), 4.07 (lH, dd, J5 6=4Hz,
J6 1=9Hz, 6-H), 5.05-5.30-5.34-5.59 (2H, AB type, 3-CO2CH2-Ar), 5.30
(2H, s, l'-OC02-CH2-Ar), 5.1-5.6 (lH, m, l'-H), 5.68 (lH, d, J5 6=4Hz,
5-H), 7.49-7.64-8.18-8.33 (4H, A2'B2', l'-aromatic Hs), 7.53-7.68-8.18-
8.33 (4H, A2lB2', 3-aromatic Hs); ir (neat) v a : 1780 (~-lactam),
1750 (-OCO2-), 1710 (ester), 1520 and 1350 cm (-NO2).
~36~
W , Preparation of
- (l'R,SR,6R and l'S,5S,6S) Potassium and sodium 6~ hydroxyethyl)-
2-methylpenem-3-carboxylate (isomer D).
OCO PNB OH
S H2/Pd-Celite ~
2 TN~-eth9r-N2o ~ I ~ 33
A solution of the above penem ester (24 mg, 0.044 mmol)
in THF (5 ml) was mixed with ether(l0 ml), H20 t5 ml), phosphate buffer
(1.00 ml, 0.05 molar pH 7.00: Fisher) and 30~ Pd-Celite (50 mq, Engelhard).
This mixture was hydrogenated at 35 psi for 21.5 h at room temperature.
After removal of the catalyst (over Celite), the aqueous layer was
separated, washed with ether and lyophilized yielding 12 mg
of the title mixture o~ sodium and potassium salts
as a white powder: lHmr (D20) ~: 1.23 (3H, d, J=6Hz, l'-CH3), 2.27 (3H, s,
2-CH3), 3.85 (lH, dd, J5 6=4HZ~ J6 1=9Hz, 6-H), 4.3 (lH, m, l'-H) and
5-65 ppm (lH, d, J5 6=4Hz, S-H); ir (Nujol) vmax: 1755 ( -lactam) and
1570 cm (-C02~ i uv (H20)~ : 297 (~ 2300, calcd as K-salt), 258
(~ 1900, calcd as K-salt). This material was identical to a
sample of title compound prepared by an aldol condensation of acetal-
dehyde with the dianion of 2-methylpenem-3-carboxylic acid.(IHmr, ir,uv)
/~ -
~X8~
Example ~
(l'S,5R,6S and l'R,5S,6R) 6~ Hydroxy-l'-ethyl)-2-methylpenem-3-carboxylic Acid
(isomer C)
OH
~`
C02H
Method A:
OC02PNB 2 1 2 O~l
SAc ~ S ~ ~ S ~ H
N ~ p~3 ~ N ~ P~3 O N ~ O N ~
2 C02PNB CO2PNB CO2H
Method B:
2 ~ 2 2 2
SAc ~SAC
~Si~-~ 0 ~ ~Sl~ O ~ Si~+ ~ N
2 NB I 2
SAc ~ Ac
l l ~ ~
O - N ~ P~3
C02PNB 02PNB
_ /qo -
~.2~36~;61
METHOD A
1) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(1'-paranitrobenzyldioxy-
carbonyl-l'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene-
2"-acetate)-2-azetidinone (isomer C).
J 2 N3SAg J 2
., ~ CH3COCl ' ~
~ C5H5N ~ N ~ P~3.
C02PNB C02PNB
A cold (ice-MeOH bath) solution of l'S,3S,4R and l'R,3R,4S)
silver 3-(1'-paranitrobenzyl-dioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl
2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate
~isomer C) (1.14 g, 1.30 mmol) in CH2C12 (60 ml) was treated with
pyridine (0.6 ml, 0.74 mmol) and dropwise with acetyl chloride (236 mg,
0.213 ml, 3.00 mmol). The reaction mixture was stirred for 1 h at
-15C. The precipitate was filtered and washed with ether. The
filtrate was washed with 2% aqueous HCl, water, 2~ aqueous NaHC03,
water and brine and dried (MgSO4). The residue upon solvent evaporation
was triturated in ether (895 mg, 83.7~, mp 184-5C dec); ir (CHC13)
v : 1755, 1695 (C=O), 1620 and 1605 cm (phosphorane). Anal. calcd
max
for C42H36N3011SSi: C 61.38, H 4.42, N 5.11, 5 3.90; found: C 61.26,
H 4.49, N 4.8B, S 4.26.
_l 9l--
~X~
2) (l'S,5R,6S and l'R,5S,6R) Paranitrobenzyl 2-methYl-6-(l'-Paranitr
benzyldioxycarbonyl-l'-ethyl)-penem-3-carboxylate (isomer C?
2 J 2
P~3 O ~`_
C02PNB C02PNB
A solution of (l'S,3S,4R and l'R,3R,4S) 4-acetylthio-
3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-
triphenylphosphoranylidene-2"-acetate)-2-azetidinone (isomer C)
(855 mg, 1.04 mmol) in toluene (60 ml) was heated under reflux for
4.5 h. The residue upon concentration of the solution was passed
through a silica gel (10 g) column (1% ether in benzene) to give
the pure title compound (393 mg, 69.6%), mp 157-158C (CHC13-ether);
ir (CHC13) V : 1785, 1745, 1710 (C=O) and 1525 cm (NO2); IHmr
(CDC13) ~: 8.30-7.2 (8H, m, H-aromatics) 5.46 (lH, d, J=1.8, H-5),
5.40-5.0 (5H, m, z CH2-PNB and H-l'), 3.95 (lH, dd, J=1.8, J=5.4,
H-6), 2.35 (3H, s, CH3) and 1.43 ppm (3H, d, J=5.4, CH3); Anal. calcd
for C24H21N3OloS: C 53.04, H 3.89, N 7.73i found C 52.76, H 3.86,
N 7.69.
3) (l'S,5R,6S and l'R,5S,6R) 6-(1'-Hydroxy-l'-ethyl)-2-methyl penem-3-
carboxylic acid (isomer C)
1 2 JOH
H2
02PNB C02H
A mixture made of (l'S,5R,6S and l'R,5S,6R) parani-
trobenzyl 2-methyl-6-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-
penem-3-carboxylate (206 mg, 0.379 mmol), TXF-ether-H20 (30 ml, 40 ml,
20 ml), a 0.05 M pH 7 buffer solution (7.64 ml, 0.382 mmol) and 30%
Pd on Celite (500 mg) was hydrogenated at 42 psi H2 on a Parr shaker
12~36661
for 16 h. The catalyst was filtered and washed with water. The
aqueous phase was washed with ether (3 times), acidified portionwise
with cold 1% aqueous HC1 to pH 2.5 and extracted with ethyl acetate
(15 x 20 ml) between each HCl addition. The ethyl acetate extracts
were combined and washed with brine (3 x 30 ml). Evaporation of
the solvent and trituration of the residue with ether gave the title
compound (57 mg, 65.6%), ir (KBr) V : 3580-3300 (O-H), 1755 and
1660 cm (C=O); uv (EtOH) ~ 311 (~ 6538), 262 (~ 3672); IHmr
(DMSO-d6) ~: 5.57 (lH, d, J=1.7, H-5), 4.02 (lH, m, H-l'), 3.75
(lH, dd, J=1.7, J=3.5, H-6), 2.23 (3H, s, CH3) and 1.23 ppm (3H, d,
CH3).
METHOD B
1) Silver (1'5,3S,4R and l'R,3R,45) 1-(t-Butyldimethylsilyl)-3-(1'-para-
nitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone-4-thiolate (isomer C)
2 B 2
~3 ~ S~g
o~LN~S~Me2 '' O ~s
~tBu ~ Bu
Isomer C of l'-(t-butyldimethylsil~ 3-
(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-aze-
tidinone (1 g, 143 mmol) was dissolved by stirring in hot (40C)
methanol (12 ml). A solution of silver nitrate (0.59 g) in
methanol (12 ml) was added followed by pyridine (0.13 ml). The
mixture was stirred vigorously 1 h at room temperature and 2 h
at 0. The solid silver mercaptide was collected by filtration
and washed with ether, 352 mg (46%). ir V : 1735 cm ~C=O).
-/~3~
6~
2) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-l-(t-but~ldimethylsilyl-3-
(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone (isomer C)
OC02PNB OC02PNB
SAg ~ SAc
~si `si
tBu ~ tBu
To a solution of isomer C of silver l-(t-butyldi-
methylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-2-azeti-
dinone-4-thiolate (880 mg) in dichloromethane (40 ml) stirred at
0C was added pyridine (0.57 ml) followed, dropwise, by acetyl
chloride (0.49 ml). The mixture was stirred 0.5 h at 0, the
solids removed by filtration and the filtrates diluted with
ether, washed with aqueous hydrochloric acid (2%), water, sodium
bicarbonate (2~) and brine, dried and concentrated to leave
the title material as an oil. (610 mg). IHmr (CDC13) ~: 8.2
and 7.48 (4H, 2d, aromatics), 5.40 (lH, d, J=2.2, H-4), 5.2
(2H, s, benzyl), 5.3-4.9 (lH, m, H-l'), 3.42 (lH, dd, J=2, H-3),
2.32 (3H, s, CH3), 1.40 (3H, d, J=6.5, CH3), 0.95 (9H, s, t-Bu)
and 0.2 ppm (6H, CH3).
3) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(l'-paranitrobenzyldioxy-
carbonyl-l'-ethyl)-2-azetidinone. (isomer C)
OCO PNB ~OC02PNB
SAc ~ S~c
Si ~ N
tBu
Isomer C of the above S-acetyl N-t-butyl-
methyl-silyl-azetidinone derivative (1.4 g) was dissolved in a
mixture of TFA (0.5 ml), water (0.5 ml), methanol (3 ml) and
dichloromethane (2 ml) and stirred at room temperature for 48 h.
The solution was diluted with water (lO0 ml) and extracted with
dichloromethane (4 x 20 ml). The combined organic extracts were
-/qY-
~36~61
washed with sodium bicarbonate t2%) and brine, dried and concen-
trated to leave the crude title compound as an oil. Purification
was done by chromatography over silica gel (30 g) eluting with 5
ether in benzene; (650 mg). Crystallization from benzene gave a
white solid. ~Hmr (CDC13) ~: 8.15 and 7.45 (4H, 2d, aromatics),
6.18 (lH, N-H), 5.19 (2H, s, benzyl), 5.05 (2H, m, H-4 and H-l'),
3.35 (lH, dd, J=2.5, 4.5, H-3), 2.34 (3H, s, CH3) and 1.42 ppm
(3H~ d~ J=6.5~ CH3); ir vmax 1780~ 1750~ 1695 cm (C=O).
4) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(1'-paranitrobenzyldioxycar-
bonyl-l'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)-2-azetidinones
(epimers at C-2"). (isomer C)
OCO PNB OCO2PNB
~SAC J~SAC
O ~ N~ H O N ~ H
0 2PNB
A mixture of isomer C of 4-acetylthio-3-(1'-paranitro-
benzyldioxycarbonyl-l'-ethyl)-2-azetidinone (750 mg), paranitrobenzyl-
glyoxylate hydrate (525 mg) and benzene (50 ml) was heated under
reflux for 3 days over a Dean and Stark apparatus filled with 3A
molecular sieves. A second portion of glyoxylate (52 mg) was added
and reflux was continued for 2 more days. The mixture was diluted
with ether, washed with hydrochloric acid (2%), water, sodium
bicarbonate (2~) and water, dried and concentrated to leave an
oily residue (975 mg). Chromatography on silica gel, eluting
with benzene-ether (85=15) gave the pure title compounds. IHmr
(CDC13) ~: 8.25-6.75 (8H, m, aromatics), 5.30 and 5.12 (4H, 2s,
benzyls), 5.05-4.70 (lH, H-2"), 4.45-4.35 (lH, 2d, H-4), 4.50-4.10
(lH, m, H-l'), 3.30 (lH, m, H-2 and 1.25 ppm (3H, 2d, CH3).
1~666~L
5) (1'S 3S 4R ~and 1'~.3R,4Sl
4-aoetylthio-3~ paranitrobenzyl~ioxy-
carbonvl-l'-ethy~L=l-~Paranitrobenzyl
2"-triphen~l~hosphoranylidene-2"-aaetate)2-azetidinone (i~s~o Qr C~
2 B 2 j)C 2 P ME~
10~ SC12 ~/ 3 ~ 3
~2PN8 02PN8 CO,P`JB
Isomer C of 4-acetylthio-3-(l'-paranitrobenzyl-
dioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate)
-2-azetidinone (577 mg, 1 mmol) was dissolved in anhydrous THF
(10 ml) and Pyridine (95 mg, 1.2 mmol) was added to the solution.
The solution was cooled to 0' and thionyl chloride (143 mg, 1.2
mmol) was added slowly. The mixture was stirred 30 min at O,
diluted with a little ether and the insoluble salts removed by
filtration and washed with ether. The comblned filtrates were
concentrated to give the crude mixture of epimers of the C-2"
chloro compound. It was dissolved in THF (20 ml),
triphenylphosphine (314 mg, 1.2 mmol) and 2,6-lutidine (129 mg,
1.2 mmol) were added and the solution was stlrred at 45C for 4
days. The solids were removed by filtration, washed with benzene
and the combined filtrates were concentrated to leave an oil
whose spectral characteristics and tlc behaviour were identical to
a sample of the title compound prepared by acylation of the
corresponding silver thiolate.
The desired penem product may be produced by reacting the
the title compound according to the method of steps 2 and 3 of
Example 35 (Method A).
- 196 -
36~
Example 36
(i'R,5R,6C and 1'5,~5,6R) 6~ Hydroxy-l'-ethyl)-~-methylPcnem-3-c~rbox/llc Acl~
(iso~er B~
OH
CH3
C02H
METHOD A
OCO2PNB 10C02PN3 2 OH
~SAg ~Ac 11 ~ `~CH ~ S~--CH
~02PNB C02PNB CO 2P NB CO 2 H
METHOD B
OH OH pH OH
~SAg 1 ) TMS/TEA ~SAc ~ ~CH3 ~ 5 ~ CH3
~ 3 pyr d ne ~ ~ 3 CO2PNB ~ C02H
METHOD A
1) (l'R,35,4R and 1'5,3R,45) 4-Acethylthio-3-(1'-paranitrobenzyl-dioxv-
carbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-
acetate)-2-azetidinone, (isomer B)
OCO2PNB ~CO2PNB
O ~ ~ 3 AcCl J ~ ~ cp~3
C02PNB C02PNB
A solution of ~l'R,35,4R and 1'5,3R,45) silver 3-~1'-
paranitrobenzyldioxycarbonyl-l'-ethyl) l'-paranitrobenzyl 2"-triphenyl-
phosphoranylidene-2"-acetate)-2-azetidinone-4-thiolste (isomer B)
(917 mg, 1.03 mmol) in CH2C12 (20 ml) was treated at -15C (ice-MeOH
bath) with pyridine ~242 ~1, 247 mg, 3.13 mmol) and dropwise with
acetyl chloride (142 ~1, 157 mg, 2.0 mmol). ~e mixture uas stirred
-197-
lZ~661
for 15 min at -15C and the solid was filtered and washed with ether.
The organic solution was washed with 2% aqueous HCl, water, 2% aqueous
NaHC03, water and brine and dried over MgS04. The residue upon solvent
evaporation crystallized from ether (710 mg, 80%, mp 183-185C; ir (CHC13)
V : 1755, 1695 (C=0), 1620, 1605 ~phosphorane) and 1625 cm (N2~;
2) (l'R,5R,6S and 1'5,5R,6R) Paranitrobenzyl 2-methyl-6-(1'-paranitro-
benzyld:oxycarbonyl-l'-ethyl)-enem-3-carboxylate. (isomer B)
J 2 SA ~,. S
~ ~ ~ ~ CH3
o~__N ~ p~3 ~ ~ N ~
2 2
A solution of (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-3-
(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-ltparanitrobenzyl 2"-triphe-
nylphosphoranylidene-2"-acetate)-2-azetidinone (650 mg, 0.791 mmol) was
refluxed in toluene for 7 h. The concentrated solution upon solvent
evaporation was passed through a silica gel column (10 times its weight)
and the title compound (0.5% ether-benzene to 2~ ether-benzene) was
obtained as a white solid; 329 mg, 77%, mp 134-135C, (CH2C12-ether); ir
(CHC13) V : 1785, 1745, 1705 (C=0) and 1525 cm (N02); IHmr (CDC13) ~:
8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (lH, d, J=1.5,
H-s), 5.5-4.75 (5H, m, 2CH2-PNB, H-l'), 3.86 (lH, dd, J=7.8, J=1.5, H-6),
2.38 (3H, s, CH3) and 1.50 ppm (3H, d, J=6.3, CH3); Anal. calcd for
C24H21W301oS: C 53.04, H 3.89, N 7.73, S 5.90i found: C 53.05, H 3.98,
N 7.63, S 6.02.
--J98~ -
6~i1
3) (l'R,5R,6S and 1'5,5S,6R) 6~ Hydroxy~ ethyl)-2-methyl penem
-3-carboxylic acid (isomer B)
C2PNB ~ H
3 H2 ~N ~ 3
2 O2H
A mixture of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl
2-methyl-6-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-penem-3-carboxy-
late (isomer B) (65 mg, 0.12 mmol), 0.05 M pH 7 buffer solution
(1.06 eq), H2O-~HF-ether (10 ml, 10 ml, 25 ml) was shaken on a Parr
hydrogenator using 30% Pd on Celite (200 mg) for 16 h at 50 psi H2.
The catalyst was filtered and washed with small volumes of water. The
aqueous layer was washed with ether (3 times), acidiied portionwise
with 1% cold aqueous HCl, extracted with ethyl acetate between each
addition of HCl, and saturated with brine and extracted throughly
with ethyl acetate. The ethyl acetate extracts were combined, washed
with brine (5 times) and dried (MgSO4). Solvent evaporation afforded
a solid residue which was triturated with methylene chloride (19.4 mg,
71~). ir (nujol) Vmax: 3500 (O-H), 1785, 1672 cm (C=O)i uv (EtOH)
~ a : 260 ( 3450), 309 ( 6400); ~Hmr (DMSO d6) ~: 5.54 (lH, d,
J=1.5, H-5), 3.88 (lH, m, H-l'), 4.2-3.5 (2H, bs, O-H), 3.65 (lH, dd,
J=6.5, J=1.5, H-6), 2.28 (3H, s, CH3) and 1.15 ppm (3H, d, J=6, CH3).
-19q -
666~
METHOD B
1) (l'R 35.4R and l'S.3R.4S)
4-Acet~lthio~3-(l'-trimethylsilyloxy-l'-
ethyl)-l-~pa~anitrobenzyl
2"-triphenvlphosphoranylidene-2"-ace~Aa~e~
-2-azetidinone tlsomer Bl
~)H OTMS
J.", ~f Ag TMSCl AcCl J ~SAc
o~ ~p~ 3 TEA j 5 O'~-- ~P~ 3
C02PNB C02?~n3
A suspen6ion of (l'R,3S,4R and l'S,3R,4S) silver
3-(l'hydroxy-l'-ethyl)-l(paranitrobenzyl
2"-triphenylphosphoranylidene-2"-
acetate)-2-azetidinone-4-thiolate (505 mg, 0.715 mmol) in
THF (25 ml) was cooled to -15C (ice-MeOH bath), treated
dropwise with triethyl amine (289 mg, 398 ~1, 2.86 mmol),
trimethyl chlorosilane (310 mg, 362 ~1, 2.85 mmol) and
finally with imidazole (50 mg, 0.734 mmol), stirred for 3 h
at -15-C and at room temperature for 16 h. (ir of an aliquot
showed absence of hydroxyl group,). The mixture was cooled
to -15-C, diluted with CH2C12 (20 ml), treated with
pyridine (226 mg, 231 ~1, 2.86 mmol) and acetylchloride
(168 mg, 152 ~l, 2.14 mmol), stirred for 0.5 h, diluted
with ether, washed with dilute aqueous HCl, water 5% aqueous
NaHCO 3 water and brine and dried. The 5 olvent was removed
on the rotary evaporator and the residue purified by
filtration through a silica gel column (1:10 ratio, 3% to
10% ether in benzene) to give the title compound (360 mg,
84.2%) mixed with a little of the desilylated derivative
(30 mg, 7.8%). ir (liquid film) vmax : 1750, 1790 (C=O),
1620 (phosphorane) and 1518 cm 1 (NO2)
- 200 -
., ~
1~86~63
2) (l'R,35,4R and l'S,3R,45) 4-Acetylthio-3-(ll-hydroxy-ll-ethyl)-l-
(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azeti-
dinone (isomer B)
OTMS OH
J SAc H3 ~ ~ SAc
~ Cj61_ N~P~3
C02PNB 02PNB
A solution of (l'R,35,4R and l'S,3R,45) 4-acetylthio-3-
l'-trimethylsilyloxy-l'-ethyl)-l(paranitrobenzyl 2"-triphenylphospho-
ranylidene-2"-acetate)-2-azetidinone (360 mg, 0.504 mmol) was treated
with TFA (3 drops) and stirred at room temperature for 18 h. The
mixture was diluted with ethyl acetate, washed with water, dilute
aqueous NaHC03, water and brine and dried (MgSO4). Solvent
evaporation afforded the title compound (334 mg, 100~); ir (CHC13)
v : 1755, 1690 (C=O), 1620, 1605 (phosphorane and 1520 cm (NO2).
max
3) (l'R,5R,65 and l'S,5S,6R) Paranitrobenzyl 2-methyl-6-(1'-hydroxy-1'-
ethyl)-penem-3-carboxylate (isomer B)
OH OH
~ ~ SAc a J"'~H3
~02PNB C02PNB
A solution of (l'R,35,4R and l'S,3R,45) 4-acetylthio-
3-(1'-hydroxy-1'-ethyl)-l(paranitrobenzyl 2"-triphenylphosphoranyl-
idene-2"-acetate)-2-azetidinone (410 mg, 0.638 mmol) in toluene
(40 ml) was refluxed for a 7 h period. Toluene was partially
evaporated. The residue was passed through a silica gel (1 to
12 ratio) column (3%, 4% and 5% ether in benzene) to give the
title compound (151 mg, 65%) as a white solid mp 161-161.5C;
ir (CDCl ) V : 3600, 3500-3400 (OH), 1780, 1608 (c=O) and 1525 cm
3 max
(N02); IHmr ~CDC13) ~: 8.20 (2H, d, J=7, Ho aromatic), 7.60 (2H, d
aromatic), 5.57 (lH, d, J=2, H-5), 5.29 (2H, center of A~q, J=15,
CH2-PNB), 4.2 (lH, dq, J=7, J=6, H-l'), 3.67 (lH, dd, J=7, J=2, H-6),
~01 ~
2.33 (3H, s, CH3) and 1.33 ppm (3H, d, J=6, CH3); ~n31-
calcd for C16H16N265: C 52.74, H 4.43, N 7.69, S 8.80;
found: C 52.67, H 4.41, N 7.71, s 8.96.
4) (1'R.9R.6S and l'S.5S,6R) 6-(1'-Hydroxy~ ethyl)-
52-methyl ~enem -3-carboxylic acid lisomer B)
o ~N _~C 3 2 .~ ~OH
2 CO2i~
10 A mixture of (1', S~, 6S and l'S,5S,6R)
paranitrobenzyl 6-(l'-hydroxy-1'-ethyl)
-2-methylpenem-3-carboxylate (89 mg, 0.244 mmol),
THF-H2O-ether (15 ml, 10 ml, 30 ml), a 0,OS M pH 7 buffer
solution (5.06 ml, 0.253 mmol) and 30% Pd on "CELITE"* (250
mg) was shaken on a Parr hydrogenator for 3.5 h at 45 psi
H2. A work-up identical to the one previously described
gave title compound (32 mg, 57%).
Example 37
(1'S.5R.6R and 1'Rl55.6S) 6-(1'-Hydroxy-1'-ethyl)
-2-methyl~enem-3-carboxy~ic Acid (iso~ç~)
~f~s
o~
CO2H
1) (1'S.3R.4R and l'R.3S,~S) 4-Ac~ylthio-~-(l'-
methoxymethoxy-l'-ethy~)-l(paranitrobenzyl
2"-t
-2"-aç~o~o~LL,L~
(iso~ A)
~Ag p ~35A
N ~ 3
C02PNB C02PNB
*TradeMark
- 202 -
~ ~36661
Isomer A of 4-acetylthio-3-(1'-methoxymethoxy-1'-ethyl)
-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-2-azeti-
dinone was prepared as described elsewhere for isomer C of the paranitra-
benzyl dioxycarbonyl derivative, yield 85%. ir (neat) V : 1750 and
1690 cm (C=O).
2) (l'S,3R,4S and l'R,3S,4S) 4-AcetYlthio-3-(1'-hYdroxy-l'-ethyl)-l-(para-
nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone,
(isomer A)
~CH20cH3 OH
~AC ~I~AC
O ~ ~3 0 ~ ~3
02PNB C02PNB
Isomer A of 4-acetylthio-3-(1'-methoxymethoxy-1'-ethyl)-
l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate~-2-azetidi-
none (500 mg, 0.68 mmol) was added to a cooled solution (0C) of tri-
fluoroacetic acid (50 ml) and water (10 ml) and stirred for 15 min
in ice and 3 h at room temperature. The reaction mixture was concen-
trated, dichloromethane was added and the solution was washed with
sodium bicarbonate, water, and brine, dried and concentrated to give
the title compound (450 mg, 96%);ir (neat) ~max 3400 (OH), 1745
and 1690 cm (C=O).
12~3666~
3) (l'S.5R.6R and 1'R.5S,~L Pa~anitxobenzyl 6-l1'-hyd~oxy
-1'-ethyl)-2-methyl penem-3-carboxyl~te (isom~ A
OH OH
3 /~N--~ 3
02PNB 02PNB
Prepared as described fox isomer C of the
paranitrobenzyl dioxycarbonyl derivative, yield 45%,
1Hmr (CDC13) ~: 7.93
(4H, ABq, aromatics), 5.68 (lH, d, J=4.0, H-5), 5.33
(2H, Asq, ben~yl), 4.3 (lH, m, H-l~), 3.8 (lH, dd,
J=4.0, H-6), 2.41 (3H, s, CH3), 2.31 (lH, s, OH), and
1.42 ppm (3H, d, J=6, CH3 ); ir (CHC13) Vmax: 3100--
3600 (OH), 1780 and 1710 cm 1(C=o).
4) (l'S.5R.6R and l'R.5S.6Sl 6-(1'-Hydroxy-1'-ethvl)
-2-methyl penem-3-carboxylic acid (isomer A)
OH OH
CH , ~;~--CH 3
C02PNB C02H
A mixture of isomer A of paranitrobenzyl
6-(l'-hydroxy- 1'-ethyl)-2-methyl penem-3-carboxylate (82
mg, 0.2 mmol), palladium on Celite t30%, 400 mg), THF (10
ml), ether (25 ml), water (10 ml) and buffer (0.05 M, pH=7,
Fisher #SO-B-108) (4 ml) was hydrogenated on a Parr shaker
at an initial hydrogen pressure of 45 psi for 4 h. The
catalyst was removed by filtration on "CELITE"* and washed
with water. The filtrates were washed with ether and the
aqueous layer was acidified in the cold hydrochloric acid
(0.25 M) and extracted with ethyl acetate (5 x 10 ml). The
combined organic extracted were washed with brine, dried
and concentrated. The foamy solid was
*TradeMark
- 204 -
~Z~6~
triturated in ether to give a white solld (2 mg, 44%). ir
(''NUJOL'')*V max: 3500 (OH), 1765 and 1665 cm 1 (C=O) ; uv (EtOH)
max: 301 ( ~5922), 260 (~ 4280).
- Exam~le 38
(l'R 5R.6S and 1'5.5~.6R)2-Aminomethy1-6- (l'-hydroxy-l'-ethy
-~enem-3-carboxylic Acid (isomeL ~1
Ho~",~ S ~
~ N ,~/ CH 2 NH2
C02H
(1'R 3S.4R and l'S.3R.4S) 4-azidoacetylthio-3-(1'-hYdroxy-l'-
ethyl)~ aranitrobenzyl 2"-tri~henylphogphoranylidene-2"-
acetatel-2-azetidinone (isomer 3)
OH
OH SAg TMSCl ClCOCH2~l3 ,~3 JF~cccH2N3
N~P~3 T~ ~3
C02PNB 2
A cold (ice-MeOH bath) suspension of (1'R,3S,4R and
1'S,3R,4S) silver 3-(1'-hydroxy-1'-ethyl)-1- (paranitrobenzyl 2"-
triphenyl phosphoranylidene -2"-acetate) -2-
azetidinone-4-thiolate (970 mg, 1.37 mmol, from 1 g of the
corresponding trityl) in THF (40 ml) was treated dropwise with
trimethylchlorosilane (0.695 ml, 595 mg, 5.48 mmol), trlethyl
amine (0.765 ml, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734
mmol). The mixture was stirred under N2 for 17 h, then cooled to
-15C (ice-MeOH bath) and azidoacetyl chloride (406 mg, 3.40
mmol) was added in. It was stirred for 30 min (the reaction
progression being followed by tlc). The solid was filtered and
washed with ether. The filtrate was diluted with more ether,
washed with 1% aqueous HC1, water, 1% aqueous NaHCO3 , water and
brine and dried (MgSO4l. The residue
*Trade Mark
- 205 -
~ X~36~6~
upon solvent evaporation was taken up ln moist CH2C12 (50 ml) and
treated with TFA (3 drops, cleavage of TMS-ether being followed
by tlc). The methylene chloride solution was then washed with 1%
aqueous NaHCO3, water and brine and dried (MgSO4). The residue
was passed through a silica gel (B times its weight) column
(benzeneether 1:1, ether and ethylacetate-ether 1:1) to give the
title compound (565 mg, 69.8%); ir tfilm) vmax : 3500-3200
(0-H),
2100 (N3), 1755, 1609 (C=O), 1620-1605 (phosphorane) and
1518 cm 1 (NO2).
(l~R 5R.6S and l~S 5S 6R~ paranitrobenzYl 2-azidomethvl-6-
(1'-hydroxy-1'-ethyl)-penem-3-carboxylate (isomer B)
OH OH
j ~ ScoC~2N3 ~oluene J
o ~ 1 ~3 ~ 2~3
~O2PN~3 2
A solution of (l'R,3S,4R and l'S,3R,4S) 4-azido-
acetylthio-3-(l'-hydroxy-l'-ethyl)-l-(paranitrobenzyl
2"-triphenyl-phosphoranylidene-2"-acetate)-2-azetidinone (500 mg,
0.731 mmol) in toluene 100 ml was refluxed under N2 for 30 min.
The solution was concentrated under vacuum and the residue was
passed through a silica gel (5 g) column (3.5-4% ether-benzene)
and yielded the title compound (193 mg, 65.1%) as a yellowish
solid 1Hmr (CDCl3) ~ 8.13 (2H, d, Ho aromatic), 7.52 (2H, d, Hm
aromatic), 5.59 (lH, d, J=1.8, H-5), 5.27 (2H, center of ABq,
J=13.5, CH2-PNB), 4.50 (2H, center of ABq, J=16, CH2-N3), 4.15
(lH, m, H-1'), 3.73 (lH, dd, J=6.3, J=1.8, H-6), 1.92 (lH, d,
J=4, O-H) and 1.33 ppm t3H, d, J=6.3 CH3); ir (CHC13) vmax :
2110 (N3), 1785, 1705 (C=O) and 1520 cm 1 (NO2).
- 206 -
~3666~L
(l'R,5R,6S and l'S,5S,6R) 2-aminomethyl-6-(l'-hydroxy-1'-ethyl)-
penem-3-carobxylic acid (isomer B)
~ H2 F~
C02PNB C02H
A solution of (l'R,5R,6S and l'S,5S,6R) paranitro-
benzyl 2-azidomethyl-6-(l'-hydroxy-l'-ethyl)-penem-3-car~oxylate
(25 mg, 0.062 mmol) in THF-ether-water (6 ml, 6 ml, 15 ml) was
shaken on a Parr hydrogenator for 2.5 h at ~0 psi H2 using 10% Pd
on carbon (100 mg). The catalyst was filtered and washed with
small volumes of water. The aqueous layer was washed with ether
(3 times) and lyophilized to give the title compound (11 mg, 73%).
IHmr (D20) ~: 5.75 (lH, d, J=2, H-5), 4.30 (lH, center of m, J=6.5,
H-l'), 4.02 (lH, dd, J=6.5, J=2, H-6) and 1.37 ppm (3H, d, J=6.5,
CH3); ir (nujol mull) ~max 3550-2450 (0-H, N-H), 1765 (C=0) and
1600 cm 1 (C02~ ; uv (H20), ~ : 309 ( 3650), 255 (~ 2815).
.:Lo~ -
1~36661
Example 39
(1'R SR 6S and l'S 55.6R)-2-(4-Amlnobuty~)-6-(l'-hydrPXY-ethyl~-
-pçnem-~ rboxylic Acid (isomer BL
OH
oj~ ( 2~ 4NH2
COOH
(l'R 3S.5R and l'S,3R 4S) 4-(~-azidobu~anoylthio)-3-
(l'-hydroxyethyl)-1-(paranitrobenzyl
2"-triphenyl~hosph~ranylidene -2"-açç~ate)-2azetidinone
JOH THSCl N3 (CH2) 4COCl H ~Ç,,,,~f -C (C~2) 4N3
O~C TEA, Im. C5H5N H2 ~C=PPh3
COOPN~ OOPN~
A solution of (l'R,3S,4R and l'S,3R,4S) silver 3-
(1'-hydroxyethyl)-1-(paranitrobenzyl
2"-triphenylphosphoranylidene 2"-acetate)-2-azetidinone
-4-thiolate t3.03 g, 4.28 mmol) in dry THF (S5 ml) kept under a
nitrogen atmosphere was cooled to -25C and successively treated
30 with triethylamine (2.39 ml, 17.12 mmol) trimethylchlorosilane
(2.18 ml, 17.12 mmol) and imidazole (0.10 g, 1.47 mmol). The
reaction mixture was stirred at -25C for 0.25 h, the cooling
bath was
- 208 -
~366Ç;~L
removed, and the stirring was continued ~or 16 h. The reaction
mixture was cooled to 0C and diluted with CH2Cl2 (55 ml); it was
then treated successively with pyri.dine (0.73 ml, 9.0 mmol) and
with a solution o~ 4-aminobutanoyl chloride (1.36 g, 8.56 mmol)
in CH2Cl2(10 ml). The reaction mixture was stirred at 0C for 1
h and filtered through a "CELITE"* pad. The pad was washed with
CH2Cl2 (25 ml); the filtrate and washings were combined and
diluted with EtOAc (300 ml) . ~he organic solution was washed
with lN HCl solution, H2O, saturated NaHCO3 solution and H2O,
dried over anhydrous MgSO4 and concentrated on a rotary
evaporator to an orange syrup (3.83 g). The syrup was disso~ved
in CH2C12 (75 ml) and water (4 ml) and TFA (O. 2 ml) were added;
the reaction mixture was stirred at 23C for 1.5 h, washed with
NaHCO3 and H2O, dried over anhydrous Na2SO4 and concentrated to
an orange syrup (3.4 g). Purification of the syrup was achieved
by a column chromatography (silica gel G 60, 80 g; eluent: EtOAc
in CH2Cl2 10% ~ 75%). Evaporation of the appropriate fractions
gave an oil; 2.14 g, 67.7%. Anal. calcd for C37H36N5O7SP: C
61.23, H 5.00, N 9.65, S 4.42; found: C 61.17, H 5.10, N 10.02, S
3.71.
(1'R.5R,6S and 1'S.5S 6R) ~aranitrobenzyl 2-(~-azidobutyl)-6
-fl'-hydroxye~hyl~-penem-3-carboxylate
OH R o~
J""~ ~ SC (C-~2) 4N3 ~ J" S
oL N \ Toluene o~N ~(CH2) N3
f 3 OOPN3
COOPNB
A solution of (l'R,3S,4R and l'S,3R,4S) 4-( -azido-
butanoylthio)-3-(l'-hydroxy-l'-ethyl)-l-(paranitrobenzyl-2"-tri-
phenylphosphoranylidene-2~-acetate)-2-azetidinone (2.04 g, 2.81
mmol) in a toluene-CH2Cl2 mixture (30:1, 310 ml) was refluxed for
9 h under a
*Trade Mark
- 209 -
l~Ç~6661
nitrogen atmosphere (The CH2C12 was removed at the beginnlng of
reflux). The reaction mixture was cooled to 23C and the toluene
was removed in vacuo leaving an orange residue which was purlfied
by colum~ chromatography (silica gel 60, 45 g; eluent, ether in
pet. ether, 1:1 9:1). The appropriate fractions were combined
and concentrated to a syrup which was crystallized from an
ether-pet.ether mixtuxe, 0.443 g, mp 85C, 35.2%. Anal. calcd for
C19H21N506S: C 51.00, H 4.73, N 15.65, S 7.17; found: C 51.05, H
4.86, N 15.86, S 7.19. The fractions corresponding to unreacted
starting material were cyclized as described
above to give an additional quantity (0.276 mg, 21.9%) of title
compound. vmax : 2100 (N3), 1770 (C=O, B-lactam,) and 1705cm 1
(C=0, PNB ester); ~v(H20 23C) ~max :268 (~ 13757), 316
(~ 69826). 1Hmr (CDC13):~ 1-36 (d~JH-2''-H-1''= 6-3 Hz~ 3H~
methyl), 1.52-1.77 (m, 4H, H-2', H-3'), 2.57-3.00 (m, 2H, H-4'),
3.00-3.42 (m, 2H, H-l'), 3-72 (dd, JH-6-H-5 = 1-6 Hz~
JH_6_H_1"=6.4 Hz, H-6), 4.02-4.42 (m, lH, H-l"), 5.32 (ABq, J.
a-b= 13.6 Hz, 2H, CH2 of PNB ester), 5-60 (d, JH-5-H-6 = 1-6 Hz~
lH,H-5), 7.61 (d, JHm_HO =8.8 Hz, 2H, Hm of PNB ester) and 8.21
ppm (d~ JHo-Hm= 8-8 Hz, 2H, Ho of PNB ester).
(1'R.5R.6S and l'_L,L5.5~ In~h~ ~-6
-(l'-hydroxyethyl~-penem-3-carboxylic acid
OH
OH S 109~ Pd/C S
--~OOPNP DME:: E t 2 ' ~ 2 O~ ( CH 2 ) 4 ~IH
To a solution of (1'R, 5R, 6S and l'S,5S,6R)
paranitro-benzyl 2-( -azidobutyl)-6-(1'-hydroxyethyl)
-penem-3-carboxylate (0.54 g, 1.21 mmol) in dimethexyethane (50
ml) was added ether (50 ml), water (50 ml) and 10% Pallaaium on
charcoal (0.54 g). The reaction mixture was hydrogenated under 45
psi of hydrogen at 23C for 3 h. The reaction
- 210 -
, ~ ~,
12~6661
mixture was filtered over a l'CELITE''*pad and the filtrate was
diluted with ether. The aqueous phase was separated, washed with
ether and lyophylized. The crude title compound was purified by
hplc. ir (-KBr) vmax: 1760 (C=O, B-lactam) and 1565 cm 1 (C-O,
carboxylate); 1Hmr (D2O) ~: 1. 32 (d, JCH3-H-l''=6. 4 Hz, 3H, CH3),
1. 45-1. 85 (m, 4H, H-l', H-3~ ), 2. 50-3. 20 (m, 4H, H-l', H-4~ ), 3. 84
(dd~ JH-6-H-l"= 6- 1 Hz, J H-6-H-s =1. 4 Hz, 1-H, H-6), 4. 00-4. 45
(m, lH, H-l"- and 5. 62 ppm (d, J H-5-H-6 =1. 4 Hz, lH~ H );
(H20) max: 260 ( 4240), 302 (~: 5480).
Example 40
(l" R.5R.6S and
1' S 5S 6R)-2-(trans-3' -~mino-l~ -çYclobutyl)-6-(l"-hydroxy -l"
ethyl)pe~em-3-çarboxylic Acid (isomer B)
OH
~ O""UH2
COOH
(1"R.3S.4R and l"S.3R 4S) 4-ttrans-~' -azidocyclobutanoylthio)-3-
-hydroxy-l~-ethyl)-l-~E2ara~nltroben~YL
20 2"' -triDhenyl~ho6phoranylidene-2"' -acstate)-2-azetidinone
~C ~ ~ C-~h ~ r ~ 3
COOPNB COOPN3
A solution of (1' R, 3S, 4R and l' S,3R,4S) silver 3-(l' -
hydroxyethyl)-l-(paranitrobenzyl
2"-triphenylphosphoranylidene -2"acetate)-2-azetidinone
-4-thiolate (1. 01 g, 1. 43 mmol) in dry THF (25 ml), kept under a
30 nitrogen atmosphere, was cooled to -40C and successively treated
with triethylamine (0. 80 ml, 5. 74 mmol) trimethylchlorosilane
(0. 726 ml, 5. 72 mmol) and imidazole (0. 10 g, 1. 47 mmol). The
reaction mixture was warmed to -15C, stirred for 3 h, the
cooling bath was removed and the stirring was continued for 18 h.
35 The reaction mixture was cooled to -15C and diluted with CH2C12
(25 ml); it was
*TradeMark
- 211 -
1~3666~
then treated with pyridine (0.15 ml, 1.85 mmol) and
trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The
cooling bath was removed and the solution was stlrred for 1 h and
treated wiIh pyridine (0.15 ml, 1.~5 mmol) and
trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The
reaction mixture was stirred at 23C for 1 h and filtered
through a "CELITE"*pad. The filtrate was diluted with EtoAc (100
ml) and washed with lN HCl, H2O, saturated NaHCO3 solution and
H2O, dried over anhydrous MgSO4 ancl concentrated on a rotary
evaporator to an orange syrup (1.47 g). To a solution of the
syrup in CH2C12 (50 ml) was added H2O (2 ml) and TFA (0.2 ml).
The reaction mixture was stirred at 23C for 2 h, washed with
saturated NaHCO3 solution and H2O, dried over anhydrous Na2SO4
and concentrated to an orange syrup (1.1 g). Purification of the
syrup was achieved by column chromatography (silica gel 60, 20 g;
eluent EtOAc-ether 35% + 70%) . Evaporation of the appropriate
fractions gave the title compound as an oil; 0.77 g, 74.4% ir
(neat) vmax: 3440 (OH), 2100 (N3), 1755 (C=O B-lactam), 1735
(C=O), 1680 (C=O) and 1625 cm~1 (aromatics).
(l"R.5R.6S and l"S SS 6Rl paranitrobenzyl 2-(trans-3'-
azidocyclobutyll-6-(1"-hydroxy-1"-ethyl)penem-3-carboxylate
~ N3 ~oluene ~ ~.............................. , N3
COOPN~ COOPN3
A solution of (1"R,3S,4R and l"S,3R,4S) 4-(trans-
3'-azidocyclobutanoylthio)-3-(1"-hydroxy-1"-ethyl)-1-(paran-
itrobenzyl-2"'-triphenylphosphoranylidene-2"' -acetate)-2-
azetidinone (2.27 g, 3.14 mmol) in CHC13 (40 ml) was diluted
with toluene (300 ml) and refluxed under a nitrogen atmosphere
for 6 h. The first 60 ml of solution (CHC13 + toluene) were
removed with a Dean-Stark trapp. The reaction mixture was cooled
to 23C and the solvent was evaporated
*Trade Mark
- 212 -
~A . -'
61
under a reduced pressure leaving an orange syrup which was
purified by a silica gel column (silica gel 60, 35 g, eluent,
ether-benzene, 0 6%). Evaporation of the appropriate fractions
gave the title compound, 0.38 g, Mp 134-5C, 27.3%. Anal calcd
for C1gH1gN506S: C 51.24, H 4.30, N 15.73, S 7.20; found: C
50.98, H 4.20, N 15.83, S 7.10; ir (KBr) vmax : 2110 (N3), 1765
C=O B-lactam), 1690 (C=O PNB ester), 1510 (NO2 ) and 1355 cm 1
(NO2); Hmr (CDCl3) ~: 1-36 (d, JCH3-H-1=6 3 Hz~ 3H~ CH3 )~
2.0-2.75 (m, 4H, H-2', H-4'), 3.67 (dd, JH_6_H_5"1.5 Hz,
JH_6_H_l"= 6.5 Hz, lH, H-6), 3.8-4.55 (m, 3H, H-l', H-3' and
~ 5-30 (ABq~ Ja-b =13-6 Hz, 2H, CH2-Ph-NO2), 5.60 (d,
JH 5 H 6=1 5 Hz, lH, H-5), 7-59 (d, JHo-Hm=8 3 Hæ~ 2 ~
PNB) and 8.20 (d,JHm_Ho=8.8 Hz, 2H, H-0 of PNB). uv (CHCl3,
23C) Amax : 266 ( E 13050) and 322 ppm ( 10008). The
lS unreacted phosphorane was recovered mixed with Ph3P-0 and
cyclized as described before to give an additional quantity of
title compound: 0.145 g, 10.4% for a total yield of 37.7%.
t1"R 5R 6S and l"S,5S.6R)-2-(~ans-3'-amino-l'-
cYclobutyl(-6-(l"-hydroxyethyl)penem-3-carboxylic acid
~ 3 DME,et~e-, H20 J ~ ~ ~ ""NH2
OOPNs coo~
To a solution of (l"R,5R,6S and 1"S,5S,6R) paranitrobenzyl
2-(trans-3'-azidocyclobutyl)-6- (l"-hydroxyethyl)-penem-3-
carboxylate (0. 33 g, 0. 74 mmol) in dimethoxyethane (40 ml)
added ether (40 ml and 10% Palladium on charcoal (0.33 g). The
reaction mixture was hydrogenated under 45 psi of H2 for 3 h and
filtered over a Celite pad. The pad was washed with water and the
filtrate and washings were combined and diluted with ether. The
aqueous phase was separated, washed with ether and lyophylized,
0.20 g, 95%, uv (H20, 23C) AmaX 258 (E 2725) and 306 ( 3613).
The crude material was triturated
- 213 -
1~6~i6~
with water and the white solid was filtered and dried overP205 under high vacuum for 5 h, 84 mg, 40%; 1Hmr (D20) ~:
1-34 (d~ JH-2"-H-1"=6-3 Hz, 3H, H-2"-, 2.3-2.7 (m, 4H,
H-2', H-4'), 3.90 (dd, J H_6_H_5=1.5 Hz, J H-6-H-1" =6-1
Hz, lH, H-6) and 5.68 (d, JH_5_H_6=1.5 Hz, lH, H-5); uv
(H2O, 23C) Amax : 258 (E 4738) and 306 (E 6318). The
filtrate was purified by hplc, 58 mg; uv (H2O, 23C) Amax:
257 ( E3580) and 306 (E 5033).
- 214 -
,, ~.
~t
Example ~
~ ollowing the general procedure of Example ~ , the
following 2,6-disubstituted penem compounds may be prepared using the
indicated electrophiles.
~lectrophile Product
R ~_~S
O
C02H
3 CH3-
CH3CH20502~CH3 CH3CH2-
CH3CH2CH205o2 ~ CH3 3 2 2
CH =CH-CH -Br CH2=CHCH2-
HC--C-CH Br HC-CCH2
Br
l~r~6G61
Electrophile R =
2 0CH2_
CH
~ Br CH3
0CH2CH2CH2S2 ~ 3 0
0CH=CHCH2Br
0C-CCH2Br 0C_CCH2-
Br
Br
CH CH-CH ~
CH30CH2Cl CH30CH2-
CH35CH2Cl CH3SCH2- ~)
~ Cl ~O ~
CH30CH2CH2Cl CH30CH2CH2-
3 2 2 3 2 2
HCHO HOCH2-
O O
may be oxidized to produce CH3SCH2- and CH3SCH2-
O O
may be oxidized to produce CH3SCH2CH2- and CH3SO2CH CH -
OH protected via -C-OPNB
~ 2~3666~
Electrophile R =
OH
CH3CH2CHO CH3CH2CH-
2 2
OH
~S CH CH-CH -
2 2
SH
/ ~/ CH3CH-CH2-~a) 0
~ O ~ OH
0OC82C1 0OCH2-
0CH20CH2C1 0CH20CH2-
00CH2CH2C1 0 2 2
0CH20CH2CH2C1 0CH20CH2CH2-
0SCH2C1 0SCH2- q
0CH2SCH2C1 0CH25CH2-
0SCH2CH2C1 05CH2CH2-
0CH25CH2CH2C1 0CH25cH2cH2- ~)
o OH
0~ 0~ ~
o
~9SH protected -C-O-PNB
may be oxidized to produce HO35CH2CH2-
0 may be oxidized to produce CH3CH-CH2-
O 5O38
may be oxidized to produce 0 CH2 and 0S02CH2-
may be oxidized to produce 0C82SCH2- and 0CH25O2CH2-
@) may be oxidized to produce 0SCH2CH - and 0502CH2CH2-
0 may be oxidized to produce 0CH2SCH2CH2- and 0CH2SO2CH2CH2-
~ ~/ q ~
~2~6~
Electrophile R =
~ . .
~<IS
(~) (~3
SH
0CH2CHO 0 ~ OH
0CH=CH-CHO 0~
3 2 2 3 CH3CH2C-
C1
s o
Il u
CH3C-SC2H5 /
Cl 0
O
0 ~ ~ `Cl
O O
J~/,
~/ O
0 0
0CO2CH3 0
~ay be oxidized to produce 0
5O3H
6G6~
Electrophile R
o
2 3
Cl
~S ~ Cl ~ ~ D
0CH=CHC02CH3 0~\
OH
0C-C-CHO 0C_C-CH-
O
0C_C-C02CH3 0C--C-C-
SH
0CHS 0 ~
OH
CHO
~C02CH3
C1
Br
Br
_~, 19 -
~r~6G~l
Electrophile R =
~3 , Br ~/\
~Br ~
C~\Br CN
~;~Br C~i
3_ ~ Br [~N
\> ~Br C~\Y~
~ Br
C2H50C-Cl C 2H 50C-
C2H50CCH2Br C2H50C /\
N - C-CH 2 C 1 NC ~\
_~1
~r3~
Electrt ph i 1 e R =
FCH2CH2C2CH3 F~
02N-CH2Cl HONH
3 OCH 2 c 1 sl ~ o~\
- o
(PNB-O) 2P 2 3P~\
NH2
C H 3 CHO /~\
OH OMS ~ 3
~S~
NHCO 2 PNB
NH2
J~ Ct~3 as i 58Example /~
CIH3
NH2 ~HCH3 N-CO2PNB
Also, J~
or ~ CH3
-- co2~
~36~6~
NH2 N(CH3)2 N(CH3)2
~C02H
or
NH2 NHCOCH3 NHCOCH3
4C--0 2H
or
NHCONHR
NH2 NHCONHR
> 3
R = H, CH3,
or CH3CO-
NH2 NHC2C2H5 2 2 5
CO H
~ Z~366~1
Also,
OCOCH3 OCOCH3
OH
o Si~
OH OCONHCH3 OCONHCH3
STr ~ ~ 2HH3
N --N
OH OMS CH3,~s ; SH
G~ ~ 5'/ ~ 5 / ~ N ~
S I CH3
S ~ N ,N
CH3
_~ ~3- Co2H
~36661
Electrophile R =
NRR' R, R' = H, CH3
~)CH 2CHO
`r'~ R, R ' = H, CH 3
RR ' N
CH 0-
CH30Cl
~6~i61
ExamDle 42
(1'S,5R 6S ~nd 1'R.SS,6R) B-Trimethvlsi1yle~hyl-6(1'-açQ~Q~y-1'
ethy~ methyl~enem-3-~car~oxylat~ Qmer C)
OAc
/~ ~Me
C02~ 51--
3-(1'-hydrQxy-l~-ethy~ -trim~hyl~ilylethyl-2"-t~iphenyl-
~hos~horanylidene-2~-acetate!-4-tritylthio-2-azetidinone
STr ~OH
~ 1) LDA ~ Me ~Tr
2 2) CH3C~0 ~N PPh3 SiMe3
To a solution of diisopropylamine (185 mg, 1.84 mmol) in
tetrahydrofuran (5 ml) at -78 C was added n-butyl lithium (1.3
ml, 2.0 mmol) with stirring. After 5 min, a solution of 1-tB-
trimethylsilylethyl 2'- triphenylphosphoranylidene -2'-acetate)-
-4-tritylthio-2-azetidinone (1.27 g, 1.67 mmol) in
25 tetrahydrofuran (15 ml) wa6 added dropwise over 20 min with
stirring. After 2 min, freshly distilled acetaldehyde (1 ml) was
added and the solution was stirred for 5 min. Hydrochloric acid
(12.6 ml of 0.3M) was added and the mixture was allowed to warm
to 23 C. Nater and ethyl acetate (20 ml each) were added, shaken,
and separated. The organic phase was washed with water and
saturated sodium chloride (20 ml each), dried and the solvent was
evaporated in vacuo to give crude product, 1.37 g. The product
was absorbed from methylene chloride onto 7 g of silica gel and
placed (dry) on a 28 g silica gel column. The column was eluted
with ether (100 ml) and then with ether/ethyl acetate 1:1 (50
ml). The first 20 ml of column fractions were discarded. The
rest were combined and the solvent was
- 225 -
. f l i
12~36661
evaporated in vacuo to give a product, 1.03 g. This product was
absorbed from ether onto a 50 g silica gel column (wet). The column was
eluted with ether (680 ml) and then with ethyl acetate (200 ml). Later fractions
were combined (major low Rf spot on tlc) and the solvent was evaporated
in vacuo to give partially purified title compound, 440 mg (33~);
ir V : 3400 ~OH) and 1750 cm ~-lactam and ester); IHmr ~CHC13) ~:
too poorly resolved to make peak assignments other than aromatics
and trimethylsilyl.
Silver 3-(1'-hydroxy-1'-ethyl)-1-(~-trimethylsilylethyl 2"-triphenyl-
phosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate.
OH OH
Me ~ STr AgNo3/pyridine ~ Me ~ Ag
iMe3 C2 SiMe3
A solution of silver nitrate (425 mg, 2.5 mmol).
pyridine ~79 mg, 1.0 mmol) and water ~10 ml) was added to a
solution of the above compound ~403 mg, 0.50 mmol) in ether ~10 ml).
The mixture was stirred vigorously for 1 h. The precipitate was
collected by filtration and washed with water and ether to give
the title mercaptide 267 mg (80~). ir V : 3400 (OH) and 1750 cm
(~-lactam and ester).
1~6~61
4-Acetylthio-3-(l'-acetoxy-l'-ethyl)-l-(~-trimethYlsilylet-
hyl 2~-tri-p~nYlphosphoranylidene-2l~-acetate ! - 2-azetidinone
OH OAc
PY ne ~ Me~ ~3
A solution of acetyl chloride (70 mg, 0.88 mmol) in
methylene chloride (1 ml) was addecl dropwise to a solution
of the above silver mercaptide (267 mg, 0.40 mmol) and
pyridine (70 mg, 0.88 mmol) in methylene chloride (5 ml) at
0C. The mixture was stirred at 0C for 1.5 h and then at
23C for 15 min. The precipitate was filtered off and the
solution was washed with 0.1 M hydrochloric acid and 0.1 M
sodium bicarbonate (10 ml each). The solvent was evaporated
in vacuo to give the title compound, 153 mg (59%); ir vmax:
3450 (OH), 1750 (~-lactam and ester) and 1690 cm~1
(thioester); 1Hmr (CDC13) ~: 7.5-8.2 (m, 15H, Ph), 5.85
(br, lH, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH2, H-3),
2.0-2.6 (3 singlets; 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH3,
CH2Si) and 0.20 ppm (s, 9H, SiMe3).
(l'S 5R 6S and l'R.SS.6R) ~-trimethylsilylethyl
6-~l'-acetoxy-l'-ethyl)_2-methyl~enem-3-carboxylate
(isomer C).
OAc
OAc ¦ H H
Me~SAc Me~ ~--Me
N~PPh3 ~ --~2~ SiMe3
A solution of the above phosphorane (150 mg, 0.23 mmol)
in toluene (15 ml) was heated under reflux for 2 h. The
solution
- 227 -
., ."
,r.
~J~
was mixed with 1 g of silica gel and the solvent was
evaporated in vacuo. The silica was placed on a 4 g silica
gel column (dry) and eluted with ether. The first 5 ml
fraction tsingle high Rf spot on tlc), on evaporation of the
solvent, gave the title compound, 65 mg (76~) as a waxy
solid. ir vmax: 1790 (~-lactam), 1740 (ester) and 1700
cm~l (OAc); lHmr (CDC13) ~: (d, J=2Hz, lH, H-5), 5.4 (m, lH,
H-l'), 4.3 (m, 2H, OCH2), 3.90 (q, J=2Hz, 4Hz, lH, H-7),
2.37 (s, 3H,2-CH3), 2.11 (s, 3H, OAc), 1.42 (d, J=6.5, Hz,
3H, 2'-CH3), 1.1 (m, 2H,CH2Si) and 0.05 ppm (s, 9H, SiMe3).
The product was found to be a single isomer.
Example 43
(l'R 5R 6S and l'S.5S 6R)
6-1'-Amino-l'-ethyl)-?-methvlpenem-3-carboxyllc Acid
02H
Procedure A
~l'R.3S 4R and
l'S 3R 4S)3-(1'-azido-1'-ethyl)-1-(paranitrobenzyl 2"-
triphonvlphosphoranylidene-2"-acetate)-4-tritylthio
-2-azetidinone lisomer B)
SC~ ~ c~3
N P~3 N ~ 3
C02PNB C02PNB
A solution of (l'S,3S,4R and l'R,3R,4S)3-(1-methane-
sulfonyloxy-l'-ethyl)-l-(paranitrobenzyl
2"-triphenylphosphoranylidene-
2"-acetate)-4-tritylthio-2-azetidinone (isomer C) (12.36 g,
13.4 mmol) in 10~ H2O-HMPA (135 ml) was heated at 85C for
35 7 h in the presence of sodium azide (1.75 g 27.0 mmol). The
solution was then poured into
- 228 -
lX~il
cold water (1 Q ) and the reaction product which
crystallized out was collected by filtration. Redissolution
in dichloromethane, washing with brine and drying (MgSO4)
gave the azido phosphorane as a yellow foam after
evaporation of the solvent: 11.5 g (98.9%). It was used as
such for the next step. ir Vmax (CHC13): 2100 (N3), 1740
and 1610 cm~1 (C=O).
(l'R 3S 4R and l'S 3R 4S)4-acetylthio-3-(l'-azido-l'-ethyl)
-l-(paranitrobenzyl 2"-triphenvlphosphoranylidene
-2"-acetate) -2-azetidinone (isomer B)
3 j~S) 2H5 ~ SCOCH3
o N ~1 3 N ~P~ 3 N~P~ 3
C02PNB C022NB C02PN~
A cooled solution (5C) of (l'R,3S,4R and l'S,3R,4S)3-
(1'-azido-l'-ethyl)-l-(paranitrobenzyl
2"-triphenylphosphoranylidine-2"-acetate)-4-tritylthio-
2-azetidinone (8.9 g, 10.25 mmol) in dichloromethane (30 ml)
was treated with a solution of mercuric acetate (2.12 g,
6.66 mmol) in methanol (30 ml). After stirring at 5C for
0.5 h and room temperature for 1.5 h, the solvent was
evaporated and the crude mercuric salt redissolved in
dichloromethane and washed with dilute NaHCO3 and brine.
After drying (MgSO4) the solution was cooled to 5C and
treated directly with pyridine (1.66 g, 21 mmol) and
dropwise with acetyl chloride (1.65 g, 21 mmol). The
reaction mixture was stirred at 5C for 1 h. The
precipitated mercuric chloride was filtered off and the
filtrate washed successively with dilute HC1, NaHC03 and
brine. Then the organic solution was saturated at 5C with
hydrogen sulfide in order to precipitate the remaining
mercuric impurities as mercuric sulfide. The crude thioester
obtained after evaporation of the solvent was purified on a
silica gel column (8.5 x 9 cm), eluting with dichloromethane
(500 ml)
- 229 -
~ .~
~36~
and 15% acetonitrile-dichloromethane: 5.1 g (74.6~ Hmr
(CDC13) ~: 3.70 (lH, m, H-l'), 2.98 (lH, m, H-3), 2.33 and 2.20
(3H, 2s, acetyl), 1.28 (3H, d, J=6.2 Ha, H-2'); ir vmax
(CHC13): 2115 (N3) 1758, 1693 and 1620 cm 1 (C=0)
(1'R.5R.6S and 1~S,5S,6R) paranitrobenzyl 6-(l'azido-1'-ethyl)
-2-methylpenem-3-carboxylate (isomer B)
N3 N3
D-- ~ 3 ~PNB
C02PN~ 2
A solution of (l'R,5R,6S and l'S,5S,6R)4-aeetylthio-2-
(1'-azido-l'-ethyl)-l-paranitrobenzyl
2"-triphenylphosphoranylidene-2~-acetate)-2-azetidinone (5.lg,
13.1 mmol) in toluene (100 ml) was refluxed for 2 h under
nitrogen. The solvent was evapoxated and the reaction mixture
purified by chromatography on a silica gel column (7 x 5 cm). The
azido penem was eluted with dichloromethane (further elution with
10% ether-dichloromethane allowed to recover 1.82 g of unreacted
phosphorane):1.21 g (40.6%) mp 132-34C; 1Hmr (CDC13) ~: 8.21
(2H, d, Hm aromatie), 7.60 (2H, d, Ho aromatic), 5.51 (lH, d,
J=1.6 Hz, H-5), 5.33 (2H, ABq, H-benzyl), 3.92 (lH, dq, J=8, 6.4
Hz, H-l'), 3.67 (lH, dd, J=1.6, 8 Hz, H-6), 2.37 (3H, s, CH3),
1.46 (3H, d, J=6.4 Hz, H-2'); ir vmax (CDC13): 2123 (N3), 1788
and 1712 em 1 (C=O).
- 230 -
1~36~
(l'R 5R.65 and l'S 5S,6R)6-(l'amino-1'-ethyl)-2-methvl
penem-3-c~rboxylic acid ~isomer BL
~ 3 NH2
~ ~ H3 ~ ~ CH3
C02PNB . C02H
A solution of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl
6-(l'azido-1'-ethyl)-2-methyl penem-3-carboxylate (440 mg,
1.13 mmol) in THF-ether-water (1:1:1) (120 ml) was
hydrogenated at 50 psi for 1 h in the presence of 10% Pd-C
(440 mg). The catalyst was filtered off, the filtrate
extracted with ether and the aqueous phase lyophilized. The
crude amino acid (100 mg) was purified by hplc: 19.5 mg 1Hmr
(D20) ~: 5.69 (lH, d, J=o.s Hz, H-5), 3.94 (2H, m, H-6,
H-l'), 2.28 (3H, s, CH3), 1.50 (3H, d, J=6.4 Ha, H-2'); ir
v max ("NUJOL")*: 1767, 1576 cm~l (C=O); uv (H20) ~max
300 m~ ( 5326).
Procedure
(l'R.3S,4S and l'S 3R 4S)
3-(1'-azido-1'-ethyl)-4-tritylthio-2azetidinone (Isomer B)
pMs ~3
~ C~3 ~ SC~3
S~i~CH3)2 ~ N
t-Bu
A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldime-
thylsilyl)-3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-
2-azetidinone (Isomer C) (1.75 g, 3 mmol) and sodium azide
(0.39 g, 6 mmol) in 10% H20:HMPA (15 ml) was heated under N2
at 75-80C for 3 h. Then the reaction mixture was diluted
with ethyl acetate and washed several times with brine. The
organic phase was dried (MgS04 ) and evaporated to leave an
oil which crystallized spontaneously.
*Trade Mark
- 231 -
.,,,,~,~
.,,., ,.~..
36~;6~
5.35 (2H, ABq, benzyl ester), 5.20 (2H, 8, benzyl carbamate),
4.90 (lH, broad N-H), 4.20 (lH, dq, J=6, 8, H-11), 3.80 (lH, dd,
J=1.2, 8.0, ~-6), 2.40 (3H, B, (CH3 ), 1.40 (3H, d, J=6, CH3 );
ir vmax : 3435 (n-H), 1777 and 1717 cm 1 (C=O).
The p-nitrobenzyl ester may bs subjected to catalytic
hydrogenation as by the procedure of example 43 (Procedure A) to
provide the corresponding carboxylic acid.
Exam~le 44
6-Dimethylaminomethyl-2-methylpenem-3-carboxylic Acid
~ N ~ ~ CH
02H
l-(t-~uty1~_methylsilyl)-3-JaLm~h~1lmL~ome~hyl-4-tritylthio-2-
aæetidinone tcis ~g~ trans).
C~l 2 ~ c ~ ~ SC~3
O ~ ~ S~ 2 3 ~si
\t-8U \ t- BU
To a solution of dlmethylamine (18.5 ml of a 2N solution in
methanol, 36.9 mmoles) in methanol (80 ml) was added a solution
of hydrochloric acid in methanol (2.5 ml) of a 5N solution in
methanol) followed by trans l-(t-butyl-
dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (3.0 g, 6.16
mmoles) and by sodium cyanoborohydride (0.27 g, 4.31 mmoles) The
mixture was stirred at room temperature for 3.5 h, poured onto
ice-hydrochloric acid (pH=2) and made basic with sodium
- 234 -
~Z~3666~
hydroxide (lN NaOH, pH =9) The mix~ure was extracted with ether
and the ether phrase was washed with brine, dried and evaporated
to give the title compound as a crude oil (3.0g).
cis and trans 3-dimethylaminomethyl-4-tritYlthio-2-azetidinone
SC~3 NaN3 ~N ~SC~3
1 O O ~ 5 L/ 2 Me ~ N ~H
\t-3u
A solution of the above crude compound (3.0 g, 6 mmoles) in
hexamethylphosphorous triamide (HMPT, 16 ml) containing water
(10%) was cooled (50) and treated with sodium azide (0.78 g, 12
mmol). The mixture was stirred 1.5 h at room temperature, poured
onto ice-water and extracted with ether (5 x 30 ml). The organic
phases were extracted with hydrochloric acid (lN) and the acidic
extracts washed well with ether to remove the HMPT. The acidic
phase was made basic (lN, NaOH) and extracted with
dichloromethane. The organic layer was washed with brine, dried
and concentrated to give the title compounds as an amorphous
white solid (1.5 g, 62.5% overall). The mixture of isomers was
separated on a Waters Prep 500*, eluting with methanol (5%),
ammonia (0.2%), ethyl acetate (95%). Trans isomer: 1.0 g, m.p.
129-131C (Pentane); ~ (ppm, CDC13 ): 6.8-7.8 (lSH, m,
aromatics), 4.5 (lH, N-H), 4.28 (lH, d, J=2.5, H-4), 3.35 (lH, m,
H-3), 2.75-2.1 (2H, m, H-l'), 2.3 (6H, s, CH3 ).
Cis isomer: 0.5 g, m.p. 132-3 C (ether-pentane); ~ (ppm, CDC13):
7.7-6.7 (15H, m, aromatics), 4.72 (lH, N-H), 4.5 (lH, d, J=5.3,
H-4), 3.5 (lH, n:, H-3), 2.85-2.35 (2H, m, H-l'), 2.31 (6H, s,
CH3 ). The cis to trans ratio can be varied by changes in
conditions.
* Trade Mark
- 235 -
6~61
cis and trans
6-dimethylaminomethvl-2-methylpenem-3-carboxylic acid
The title compound was prepared from cis and trans
3-dimethylaminomethyl-4-tritylthio-2-azetidinone by the
procedure of Example 58.
(ppm, CDC13): 5.5 (lH, d, J=1.3), 3.7 (lH, dt, J=1.3, J=8),
2.8 (2H, d, J=8), 2.35 (6H, s), 2~3 (3H, s).
- 236 -
Example 45
2-Amininoacetoxymethvl-penem-3-carboxylic-Acid (via
mercaptide intermediate
~ H 2 OCCH 2NH 2
C02H
4-Azidoacetoxyacetylthio-l-(paranitrobenzyl
2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone
S~OH ClCOCH2N3 S~3
d~--N~f~P~3 C6H5N o~--M~P~I13
CO 2 PNB CO 2 PNB
A cold (ice-MeOH bath) solution of 4-hydroxyacetylthio
-l-(paranitrobenzyl 2'-triphenylphosphoranylidene
-2'-acetate) -2-azetidinone (586 mg, 0.954 mmol) in
methylene chloride (15 ml) was treated successively with
azido acetyl chloride 240 mg, 2.01 mmol) and dropwise with
- 237 -
~36~61
Trituration in ether and filtration gave g51 mg (76.5~) of the
azido compound as a white solid mp 185-90C, dec. lHMR (CDC13) ~:
7.23-7.78 (15H, m, aromatics), 4.43 (lH, d, J=3, H-4), 4.37 (lH, s,
N-H), 3.89 (lH, dq, J=7, 6.5, H-l'), 3.16 (lH, dd, J=7, 3, H-3), 1.50
3H, d, J-6.5, H-2'); ir V (CHCl ): 3410 (n-H), 2123 (N ) and
max 3 3
765 cm 1 (C=O).
(l'R,3S,4R and l'S,3R,4S) 3-(1'-amino-1'-ethyl)-4-tritylthio-2-
azetidinone (Isomer B).
.
~H ~ C~3
A suspension of (l'R,3S,4R and l'S,3R,4S) 3-(1'-azido-
l'- thyl)-4-tritylthio-2-azetidinone (Isomer B) (1.0 g, 2.41 mmol)
and platinum oxide (100 mg) in ethyl acetate (100 ml) was hydroge-
nated for 1 h at a pressure of 50 psi. Since the reaction was incomplete,
200 mg of platinum oxide was added and the mixture hydrogenated for one
additional hour. Finally, 200 mg of platinum oxide was again added
and the reaction continued for 2.5 h. Total catalyst: 500 mg. Total
time: 4.5 h. Then the catalyst was filtered off and the solvent
evaporated. The crude amine crystallized from ether: 700 mg (80~).
mp 128-30C. IHmr (CDC13) ~: 7.13-7.63 (lSH, m, aromatics), 4.40
(lH, d, J=2.5, H-4), 4.30 (lH, broad, H-l), 3.30 (lH, dq, J=5.1, 6.3,
H-l'), 3.03 (lH, dd, J=5.1, 2.5, H-3), 1.20 (3H, d, J=6.3, H-2') and
1.0-1.80 ppm (2H, broad, NH2).
-~3
666~
(l'R,3S,4R and 1'5,3R,45) 3=(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)-
4-tritylthio-2-azetidinone (Isomer B)
~ . = . . .
NH HNC02PNB
SC~3 ~ c~3
N ~ H N ~ H
A solution of (l'R,3S,4R and l'S,3R,4S) 3-(1'-amino-1'-
ethyl)-4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 2.57 mmol) in
dichloromethane (100 ml) was cooled to 5C and treated with p-nitro-
benzylchloroformate (0.61 g, 2.83 mmol) and pyridine (0.22 g, 2.83
mmol). After stirring at 5C for 45 min and at room temperature
for 2.25 h, the reaction mixture was washed with dilute HCl, brine,
dried (MgS04) and finally evaporated to dryness. The crude carbamate
was crystallized from ether: 1.03 g (70.5~). mp 147-50C. IHmr (CDC13) ~:
7.10-8.33 (19H, m, aromatics), 5.23 (2H, s, benzyl), 5.08 (lH, N-H),
4.40 (lH, s, N-H), 4.29 tlH, d, J=2.2, H-4), 4.10 (lH, dq, J=8, 6, H-l'),
.18 (lH, dd, J=2.2, 8, H-3) and 1.23 ppm (3H, d, J=6, H-2'); ir V
max
CHC13): 3395 (N-H), 1765 and 1724 cm (C=0).
(l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 2-methyl 6-(1'-p-nitrobenzyl-
oxycarbonylamino-l'-ethyl) penem-3-carboxylate (Isomer B)
2 2
3 ~ ~
C02PNB
The title product was prepared from (l'R,5R,65 and
l'S,55,6R) 3-(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)-4-tritylthio-
2-azetidinone (isomer B) by the standard procedure; mp 108-110C. IHmr
(CDC13) ~: 7.50-8.40 ~8H, m, aromatics), 5,58 (lH, d, J=1.20, H-5),
_L33-
1~t3666~
pyridine ~226 mg, 231 ml, 3.0 mmol) in methylene chloride ~10 ml);
At the end of the addition tlc showed disappearance of starting material
The mixture was diluted with ether, washed successively with dilute
HCl, water, dilute aqueous sodium bicarbonate, water and brine. It was
dried over sodium sulfate. Purification of the residue was performed
on a silica gel (10 g) column, eluting with 20~ ether in benzene,
ether, and 30% ethyl acetate in ether. Concentration of the pertinent
fraction gave the title compound as a foam; 533 mg, 80.1%; ir v
(CHC13): 1763, 1702 (C=0), 1625 (C=P~3), 1522 (N02) and 2110 cm (N3).
paranitrobenzyl 2-azidoacetoxymethylpenem-3-carboxylate
~ 5 ~ ~ 3 r ~
02PNB C02PNB
A solution of phosphorane (533 mg, 0.764 mmol) was
heated under reflux in toluene (90 ml) for 0.5 h using a catalytic
amount of hydroquinone. The solvent was concentrated on the
evaporator and the concentrated solution was passed through a silica
gel (10 g) column. (benzene: ether, 48:2). It gave the tltle
compound (236 mg, 73.7~) as an oil. This oil was found to be unstable
at room temperature. It was kept at -78C until needed. lHmr (CDC13) ~:
8.21 (2H, d, Hm aromatic), 7.57 (2H, d, Ho aromatic), 5.68 (lH, dd,
J . =4, J =2, H-5), 5.43 (2H, center of ABq, J=16, CH2-PNB),
5-6 ClS 5-6 trans
5.39 (2H, CH20), 3.93 (2H, s, CH2-N3), 3.72 (part of dd, J6 5 i =4~ H-6),
and 3.50 ppm (lH, dd, J =17, J =2, H-6); ir v (CHCl ): 1795,
gem 6-5 trans max 3
1755, 1710 (C=0), 1525 (N02), 2110 cm (N3).
-7t~-
36661
2-Aminoacetoxymethylpenem-3-carboxvlic acid
,0, o
2 ~ ~ ~ NH2
02PNEI C02H
A mixture of above ester (219 mg, 0.522 mmol) in THF
(16 ml)-ether (30 ml) and water (16 ml) was shaken on a Parr
hydrogenator for 2.25 h at 50 psi of H2 using 10% pd/C (240 mg)
as catalyst. The catalyst was filtered off and washed with water
and ether. The aqueous phase was washed with ether (3 x 30 ml)
and lyophilized. The crude powder was purified on a reversed
phase hplc column and gave the title compound (8 mg, 6.7~) as a
white powder. lHmr (D2O) ~:5.72 (lH, dd, J5-6 cis=3 5~ J5-
6trans=2, H-5), 5.37 (2H, center of ABq, J-13.5, CH2-O), 3.96
(2H, s, CH2-NH2), 3.87 (lH, dd, Jgem=16-5, J6-5 cis=3 5~ H 6) and
3-49 Nmr (lH~ dd Jgem=16-5, J6-5 tranS=2, H-6); ir vmax (nujol
1775, 1755 and 1600 cm~l (C=O); uv (H2O) ~max 306 (~4900), 256
(~3000)-
- 239 -
~ ~6~.16~
Example 46
Silver l-(B-Trimethylsilylethyl-2'-triphenvl~hosphoranYlidene-2'-
acetate)-2-azetidinone-4-thiolate
~ SAg
o N ~ P~3 ~CH3
C02CH2CH25i~ CH3
di-~-trimethylsilylethyl fumarate
Cl ~ H0~-~-~ 3)3 ~ ~ Si(cH
o pyridine 3 3Si
To a cold (-10C) ether (20 ml) solution of 2-
trimethyl-silyl ethanol (4.73 g, 0.04 mmol) ~H. Gerlach Helv.
Chim. Acta 60, 3039 t1977)] and pyridine (5.66 ml, 0.07 mol),
under nitrogen, was added dropwise (15 min) fumaryl chloride
(3.78 ml., 0.035 mol) dissolved in ether (10 ml). The black
mixture was stirred five minutes at -10C and ten at room
temperature. Charcoal was added and the reaction mixture
filtered on a Celite pad. The filtrate was washed with sodium
bicarbonate 1% - brine (1:1, 150 ml). The aqueous phase was back
extracted with ether (30 ml). The ether solutions were combined,
washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure to give
- 240 -
~3G~i61
a brown solid. This compound was purified on a silica gel pad (30 g,
4 x 5 cm) with benzene (300 ml) as eluent to give an oil (4.855 g,
77%) which solidified on standing: mp 33-34C. Anal. calcd for
C14H28O4Si2: C 53.12, H 8.91i found: C 53.35, H 8.91. IHmr (CDC13) ~:
6.78 (2H, s, C=CH), 4.26 (4H, m, CH2-0~, 1.03 (4H, m, CH2-Si) and
3)3Si); ir (CHC13) vmax: 1710 (C=O of ester)
1643 (C=C), 1267, 12S8, 862 and 840 cm (Si-C).
Trimethylsilyle-thyl glyoxylate hydrate
(CH3~3Si = 2) (CH3)25 CO2 ~ i(CH3)3
A solution of di-~-trimethylsilylethyl fumarate
(37 g, 0.117 mmol) in methylene chloride (1.1 ~) was ozonized at
-78C until a blue color persisted. The excess ozone was purged
with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) was added.
The solution was allowed to gradually warm to 23C. The reaction
mixture was diluted with carbon tetrachloride to 2 liters and washed
with 1~ aqueous solution of sodium carbonate (500 ml). The organic
phase was dried over sodium sulfate, filtered on Celite and evapo-
rated (~ 25C) to dryness to give 43.9 g of the titl~e compound (97%)i
ir (neat) v : 3450 (-OH), 1740 (ester, 1255, 860 and 840 cm (Si-C).
l-(~-trimethylsilylethyl_2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone
o6~ CIH (OH) z ~
Trimethylsilylethyl glyoxylate hydrate (4.000 g,
11.6 mmol) and the 4-tritylthio-2-azetidinone (4.8 g, 24.96 mmol)
were refluxed in benzene (25 ml) through a Dean Stark condenser,
under nitrogen for 24 h. The solvent was evaporated under a
vacuum. The product was chromatographed on a silica gel column
(450 g, 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene
_2y~-
1~36661
chloride (1:19) until the title compound started to come out
(- 1.5 ~) and then with ethylacetate: methylene chloride (1:9,
2 ~). The fractions containing the title compound were combined
and evaporated to dryness to give 5.415 g (89%) of the title
compound. IHmr (CDC13) ~: 7.80 to 6.70 tl5H, m, trityl), 5.23
and 4.90 (lH, 2s, H-C-O), 4.50 to 4.10 (3H, m, H-3 and O-CH2),
2.60 (2H, m, H-2), 0.95 (2H, m, CH2-Si and 0.1 ppm (9H, s, Si-CH3);
ir (CHC13) vmax: 3520 (-OH), 1765 (C=O of ~-lactam), 1740 (C=O of
ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm (C-Si)
1-(3-trimethylsilylethyl 2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone
STr SOC12 ~ STr
N ~ "~= Si(CH3)3 pyridine ~ ~ ~ Si(CH3)3
A solution of thionyl chloride (0.74 ml, 10.37 mmol) in
dry THF (9 ml) was added dropwise with stirring to a solution of
l-(~-trimethylsilylethyl 2'-hydroxy-2'-acetate)-4-tritylthio-2-
azetidinone (4.9 g, 9.37 mmol), pyridine (0.84 ml, 10.38 mmol) and
dry THF (40 ml) at -15C under a nitrogen atmosphere. The mixture
was stirred at -15C for 2 h. The precipitate was removed by
filtration on a Celite pad and washed with benzene (50 ml). The
filtrate was evaporated in vacuo at 30C. The residue was dissolved
in benzene (100 ml), treated with charcoal and filtered through
a Celite pad. Evaporation of the solvent gave a residue which was
purified through a silica gel pad (100 g, 4.7 x 11 cm): hexane-
benzene (1:1, 400 ml), ether-benzene (1:19, 1 ~). Evaporation of
the pertinent fractions gave 4.64 g of the title compound (92%).
Hmr (CDC13) ~: 7.30 (15H, m, aromatic H), 5.77 and 5.43 (lH, 2s,
CH-Cl), 4.7 to 4.2 (3H, m, H-4 and CH2-O), 2.85 to 2.50 (2H, m,
H-3), 1.15 (2H, m, CH2-Si) and 0.06 ppm (9H, s, Si-CH3); ir (neat)
v : 1760 (C=O), 860 and 840 cm (C-Si).
max
_ 2~
l~S36~61
~ -trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate)-4-
tritylthio-2-azetidinone
Tr ~ p STr
Cl 2~6-lutiaine ~ p~
2 Si(CH3)3 2 Si(CH3)3
A dioxane (20 ml) solution of the above chloroazeti-
dinone (4.12 g, 7.568) was treated with triphenylphosphine (2.209 g,
8,424 mmol) and 2,6-lutidine (0.98 ml, 8.424 mmol). The mixture
was refluxed for 3.5 h. The cooled solution was filtered and
the white solid washed with THF. The filtrate was evaporated to
dryness. The residue was purified on a silica gel column (200 g,
4 x 31 cm) using ethylacetate-hexane (3:7, 1 ~; 7:3, 1 ~) to give
the title phosphorane (4.836 g, 83~). ir (film) v : 1755 (C=O),
max
1615 (phosphorane), 850 and 830 cm (Si-C). Anal. calcd for
C47H46NO3PSSi: C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08,
N 1.83
Silver l-(~-trimethylsilylethyl 2'-triphenylphosphoranylidene-2'-
acetate)-2-azetidinone-4-thiolate
STr SAg
+ AgNo3 + (nBu)3N + CF3C2 ether/H20 ~ P~3
2i(CH3)3 ~ Si(CH3)3
l-(~-trimethylsilylethyl 2'-triphenyl phosphoranylidene-2'-azetate)
-2-azetidinone (7.64 g, lO mmol) was dissolved in ether (60 ml).
An aqueous solution of silver nitrate (0.5M, 80 ml, 40 mmol) was
added followed by a rapid addition ( 1 min) of a solution of
tributylamine (3 ml, 12.58 mmol) and trifluoroacetic acid (0.154 ml,
-2~3 ~
36~
successively with cold lN hydrochloric acid, lM sodium bicarbonate
and brine, dried (MgS04) and evaporated in vacuo. The residue (mixture
of hydroxy and mesylate cpd) was treated a second time as before, to
give the mesylate (90 g, 97%) as an amorphous solid. It was used as
such in the next step without further purification. The analytical
sample was recrystallized from methylene chloride mp 167-168C; ir (neat)
v : 1755 cm ; lHmr (CDC13) ~: 7.3 (15H, m), 4.4 (lH, d, J=2Hz),
3.9 (lH, dd, J=8Hz, 4Hz), 3.2 ~2H, bs), 2.8 (3H, s), 0.95 (9H, s) and
0.3 ppm (6H, s).
trans 3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone and trans-
3-azidomethyl)-4-tritylthio-2-azetidinone
M 0 ~"~ ~ SC~
Si(CH3)2 H 0 H
t-Bu
A solution of trans -l-(t-butyldimethylsilyl)-3-methane-
sulfonylmethyl-4-tritylthio-2-azetidinone (21.0 g, 37.0 mmol) in H~A
(90 ml) was cooled in an ice bath and treated with sodium azide (2.7 g,
41.2 mmol) in H20 (10 ml). The reaction mixture was stirred at room
temperature for 1 h, diluted with ethyl acetate, washed with H20
(5 x 100 ml), dried (MgS04) and evaporated in vacuo. The trans-3-
methanesulfonyloxymethyl-4-tritylthio-2-azetidinone was diluted with
HMPA (90 ml), treated at roam temperature with sodium azide (2.7 g,
41.2 mmol) in H20 (10 ml), heated at 60C for 2 h and triturated
with cold water. The crude azide was diluted with benzene-ether
(5:1) and washed with water (S x 20 ml). Evaporation of the solvent
followed by crystallization from ether gave 18.0 g (77%) of azide as
a white solid. The analytical sample was recrystallized from CH2C12/
ether mp 174-5C; Anal. calcd for C23H20N405: C 68.97, H 5.03, N 13.99;
' Z~
~36~i61
found C 68.78, H 5.00, N 14.16; ir (nujol) v : 2100, 1765 cm : IHmr
(CDC13) ~: 7.35 (15H, m), 4.75 (lH, bs), 4.4 (lH, d J=2Hz), and 3.1-3.7 ppm
(3H, m).
trans-3-aminomethyl-4-tritylthio-2-azetidinone
H H SC~ H H
H2N~ ~ ~3
H NH
To a solution of trans 3-azidomethyl-4-tritylthio-2-
azetidinone (10.0 g, 47.5 mmol) in dry methanol (500 ml) was added
ammonium chloride (19.0 g) and zinc powder ~1.0 g) and the suspension
was stirred at room temperature for 5 h. The reaction mixture was
filtered and evaporated. The residue was partitioned between lN
hydrochloric acid and benzene. The aqueous layer was basified
with lM sodium bicarbonate and extracted with methylene chloride.
The extracts were washed with brine, dried (MgSO4) and evaporated
in vacuo. The crude amine crystallized from ether, 14.05 g (79~);
mp 139-9Ci Anal. calcd for C23H22N20Cl l/4 CH2C12: C 70.56, H 5.73,
N 7.08; Found: C 70.68, H 5.94, N 7.27; ir (CHC13) v : 3400 and
1760 cm ; lHmr (CDC13) ~: 7.35 (15H, m), 5.15 (lH, m), 4.3 (lH, bs),
2.7-3.5 (3H, m) and 1.3 ppm (2H, m).
--2~6 ~
~ ~6~;61
trans 3-phthalimidomethyl-4-tritylthi.o-2-azetidinone
H2N ~ 3 ~ N ~ ~ SC~3
A solution of trans 3-aminomethyl-4-tritylthio-2-
azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide
(8.3 g, 37.9 mmol) in benzene (200 ml) was heated under reflux
for lS h. The solvent was evaporated in vacuo and the residue
crystallized from ether to give 17.4 g (93%) of the title compound;
mp 172-3Ci Anal. calcd for C31H24N2035: C 73.78, H 4.79, N 5.55,
found: C 73.92, H 4.87, N 5.49; ir (CHCl ) ~ : 1770 and 1715 cm
3 max
IHmr ~CDC13) ~: 7.8 (4H, m), 7.3 (15H, m), 4.45 (lH, d, J=2Hz), 3.3-
4.1 (3H, m) and 3.3-4~6 ppm (lH, m).
trans 3-phthalimidomethyl-1-~paranitro~enzyl 2'-hydroxy-2'-acetate)-
4-tritylthio-2-azetidinone
" ~ C~3
02PNB
A mixture of trans-3-phthalimidomethyl-4-tritylthio-2-
azetidinone (17.4 g, 34.52 mmol), paranitrobenzylglyoxylate hydrate
(9.4 g, 41.4 mmol) and triethylamine (4.8 ml, 34.5 mmol) in tetra-
hydrofuran (250 ml) was stirred at room temperature for 20 h. The
reaction mixture was evaporated in vacuo and the residue was treated
with charcoal in benzene. Evaporation of the solvent yielded the
crude hydroxyglyoxylate (25 g, quantitative) as an amorphous solid.
~ Z~7~
12~36~
It was used in the next step without further purification. ir ~CHC13)
V : 1770 and 1715 cm ; IHmr (CDCl ) ~: 8.1 (2H, d, J=9Hz), 7.55
max 3
(3H, d, J=9Ha), 7.3 (19H, m), 5.0-5.4 (2H, bs), 4.3-5.0 (2H, m)
and 2.8-3.8 ppm (4H, m).
trans-3~phthalimidomethyl-1-(paranitrobenzyl-2'-chloro-2'-acetate)-
4-tritylthio-2-azetidinone
OH ~ ~ ~ Cl
2 NB 2
To a cooled (ice bath, 0C) solution of trans-3-phthal-
imidomethyl-l-(paranitrobenzyl-2'-hydroxy-2'-acetate)-4-tritylthio-
2-azetidinone (25 g, 35 mmol) in tetrahydrofuran (150 ml) was added
dropwise a lM solution of thionyl chloride in tetrahydrofuran (46 ml,
46 mmol) followed by a lM solution of pyridine in tetrahydrofuran
(46 ml, 46 mmol). The reaction mixture was stirred at room tempe-
rature for 20 min, diluted with pet-ether (50 ml) and filtered over
a Celite/charcoal bed. The solvent was evaporated in vacuo to give
the chloro azetidinone (26 g, quantitative) as an amorphous solid.
It was used in the next step without further purification. ir (CHC13)
V : 1775 and 1720 cm . ~Hmr (CDC13) ~: 3.12 (2H, d, J=9Hz), 7.60
(2H, d, J=9Hz), 7.3 (19H, m), 5.25 (2H, m), 4.7-5.4 (lH, m), 4.55
(lH, bs) and 3.3-4.0 ppm (3H, m).
-2 ~ ~~
~2~ i6~
trans-3-phthalimidomethyl-1-(paranitrobenzyl-2'-triphenylphosphora-
nylidene-2'-acetate)-4-tritylthio-2-azetidinone
~ ~ ~ Cl
C02PNB C02PNB
A mixture of trans-3-phthalimidomethyl-1-(paranitro-
benzyl-2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone (26 g,
35.5 mmol), triphenylphosphine (10.25 g, 39.1 mmol) and 2.6 lutidine
(4.6 ml, 39.1 mmol) in dioxane (200 ml) was heated at 100C for 20 h.
The reaction mixture was filtered over Celite and evaporated. The
residue was chromatographed on a silica gel column (350 g) eluting
with benzene to benzene/ether (1:1) to yield the phosphorane
(21 g, 62%) as a white solid. ir (CHC13) vmax: 1750 and 1710 cm
Hmr (CDC13) ~: 7.4 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, m) and 3.7 ppm
(lH bs).
trans-3-phthalamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphora-
nylidene-2'-acetate)-4-tritylthio-2-azetidinone
N ~ p~3 C2H ~ 3
CO~PNB C02PNB
A cooled (ice bath) suspension of trans-3-phthalimido-
methyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-
4-tritylthio-2-azetidinone (18.02 g, 18.83 mmol) in tetrahydrofuran
(30 ml), water (30 ml) and acetone (30 ml) was treated dropwise
with sodium sulfide (4.97 g, 20.7 mmol) in acetone/water 1:1 (30 ml)
and heated to reflux for 8 h. The reaction mixture was diluted with
water, acidified with lN hydrochloric acid and extracted with dichlo-
- 2V9-
~666~1
romethane. The organic extracts were washed with brine and evaporated
in vacuo to give 17.1 g (88%) of the title compound as an amorphous
light yellow solid. It was used in the next step without further
purification. ir (neat) V : 3150-3600, 1750 and 1700 cm i ~mr
(CDC13) ~: 7.4 (38H, m) and 3.3-5.5 ppm (8H, m).
trans-3-phthalisoimidomethyl-1-(paranitrobenzyl-2'-triphenylphos-
phoranylidene-2'-acetate)-4-tritylthio-2-azetidinone
~N~""~ 3 ~ H H SC~
C2H N ~ ~3 N P~3
C02PNB 02PNB
A solution of trans-3-phthalimidomethyl-1-(paranitrobenzyl-
2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone
(17.1 g, 17.54 mmol) in dichloromethane (125 ml) was treated dropwise
at room temperature with N,N'-dicyclohexylcarbodiimide (3.62 g,
17.54 mmol) in dichloromethane (30 ml). The solution was filtered
over Celite and evaporated to give the title compound (18.23 g,
quantitative) as an oil. It was used in the next step without further
purification. ir (neat) V : 2110, 1755 and 1710 cm i IHmr (CDCl ) ~:
max 3
7.5 (38H, m), 4.6-5.3 (4H, m) and 3.9 ppm (2H, bs).
6~
trans-3-aminomethyl-1-(paranitrobenzyl-2'-triphenyl~hosphoranylidene-
2'-acetate)-4-tritylthio-2-azetidino _
o~N ~ _ H2N~ 'P3
N ~ P~3 N ~ p~
C02PNB C02PNB
A solution of trans-3-phthalisoimidomethyl)-1-(parani-
trobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-
azetidinone (5.9 g, 6.16 mmol) in tetrahydrofuran (40 ml), cooled to
-20C, was treated dropwise under N2 with hydrazine (0.2 ml, 6.16
mmol) and stirring was maintained for 30 min. The reaction mixture
was acidified with lN hydrochloric acid and washed with ether; the
aqueous phase was basified with lM sodium bicarbonate and extracted
with methylene chloride. The organic extracts were washed with
brine, dried (MgS04) and evaporated. The residue was purified on
a silica gel column (60 g) eluting with ether to ethyl acetate to
give 3.38 g (66~) of the amino phosphorane as an amorphous solid.
ir (CHC13) v : 1730, 1710 cm ; IHmr (CDC13) ~: 6.5-8.1 (34H, m),
3.8-5.3 (6H, m) and 0.9-1.9 ppm (2H, m).
trans 3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphora-
nylidene-2'-acetate)-4-tritylthio-2-azetidinone
SC~ ~ H ~ SC~3
N ~ P~3 N ~ ~3
C02PNB 02PNB
To a cooled (ice bath) solution of trans 3-(aminomethyl-
l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-
tritylthio-2-azetidinone (5.0 g, 6.04 mmol) in dichloromethane
(S0 ml) was added dropwise under N2 a solution of acetic formic
anhydride (600 mg, 6.8 mmol) in dichloromethane (5 ml) followed by
2 ~-
~f~
a solution of triethylamine (1 ml, 7 ~mol) in dichloromethane (2 ml).Stirring was continued for 30 min. The solution was washed
successively with lN hydrochloric acid, water, lM sodium bicar~onate
and brine. The organic layer was dried (MgSO4), evaporated and
the residue was chromatographed on a silica gel column (50 g). ~lution
with ether to ethyl acetate yielded 2.0 g (39~) of the formamide as an
amorphous solid. ir (CHC13) v : 1740, 1685 and 1620 cm ; IHmr
(CDC13) ~: 6.6-8.2 (35H, m), and 2.5-5.3 ppm (7H, m).
trans silver 3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphos-
phoranylidene-2'-acetate)-2-azetidinone-4-thiolate
H~N ~-~SC~3 o~
N ~ p~3 N ~ p~3
02PNB C02PNB
A solution of trans 3-formamidomethyl-1-(paranitro-
benzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-
azetidinone (550 mg, 0.64 mmol) in dichloromethane (10 ml) was
evaporated to dryness and diluted with hot methanol (20 ml). The
solution was stirred at 60C and treated with a pre-heated (60C)
solution of 0.15 M silver nitrate in methanol (5.7 ml, 0.86 mmol)
followed by a solution of 1.5 M pyridine in methanol (0.57 ml,
0.86 mmol). The creamy solution was stirred at room temperature
for 30 min, then in an ice bath for 2 h. The solid was filtered
washed with cold methanol and ether, and dried to give 300 mg (65%)
of the silver salt as a beige solid. It was used in the next step
without further purification.
_~ ~ z _
~L~,S~6~
trans 4-acetylthio-3-formamidomethyl 1-(paranitrobenzyl-2'-
triphenylphosphoranylidene-2'-acetate)-2-azetidinone
HCRN / L j--~` R
C02PNB C02PNB
To a cooled (ice bath) solution of trans silver 3-
formamidomethyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-
2'-acetate)-2-azetidinone-4-thiolate (800 mg, 1 11 mmol) in
dichloromethane (10 ml) was added dropwise under N2 a solution
of lM acetylchloride in dichloromethane (1.33 ml, 1.33 mmol)
followed by a solution of lM pyridine in dichloromethane (1.33 ml,
1.33 mmol). The solution was stirred in a cold bath for 1 h, and
was then ~iltered over Celite. The filtrate was washed
successively with lN hydrochloric acid, water, lM sodium bicarbonate
and brine and the organic layer was dried (MgS04) and evaporated.
The residue was purified on a silica gel column (5.0 g) and eluted
with ethyl acetate to 10% methanol in ethyl acetate to give 450 mg
(62~) of the title compound: ir (CHC13) Vmax: 1755, 1685 and 1620 cm
Hmr (CDC13) ~: 8.18 (2H, d, J=9Hz), 7.0-8.0 (20H, m), 6.75 (2H, d,
J=9 Hz), 6.3 (lH, m), 5.5 (lH, m), 5.2 (2H, bs), 4.9 (lH, bs), 3.6
(lH, m), 3.0 (lH, m) and 2.2 ppm (3H, two s).
' ~3-
L
paranitrobenæyl 6-formamidomethyl-2-methylpenem-3-carboxylate
& ~- ~ P~3 ~ H ~ ~ CH3
02PNB
C02PNB
A solution of trans 4-acetylthio-3-formamidomethyl-1-
(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-
azetidinone (450 mg, 0.686 mmol) in toluene (10 ml) was heated
under reflux for 12 h. Concentration and purification on a silica
gel column eluting with ether to 10~ methanol in ether gave 100 mg
(39%) of the penem as an amorphous solid. ir (CHC13) Vma : 1780
and 1690 cm ; IHmr (C~C13) ~: 8.2 (2H, d, J=9Hz), 8.2 (lH, s),
7.6 (2H, d, J=9Hz), 6.9 (lH, m), 5.55 (lH, s), 5.35 (2H, 2s), 3.3-
4.1 (3H, m) and 2.33 ppm (3H, s).
6-formamidomethyl-2-methylpenem-3-carboxylic acid sodium and
potassium salts
~.""~H ,o, ~""~ s
a~
C02PNB 2~ and
A mixture of paranitrobenzyl 6-formidomethyl-2-methyl-
penem-3-carboxylate (80 mg, 0.21 mmol), palladium on Celite (30~,
100 mg), tetrahydrofuran (10 ml), ether (25 ml) and 0.05 M buffer
solution pH 7 (4.46 ml, 0.223 mmol) was hydrogenated on a Parr
shaker at an initial hydrogen pressure of 45 psi for 3 h. The
catalyst was removed by filtration on Celite and washed with water.
The filtrate and washings were combined and the phases separated.
The aqueous phase was washed with ether (3 x 15 ml) and lyophylized.
--~S~ ~
~6~
0.2 mmol) in ether (20 ml). The mlxture was meohaniaally stlrred
for 19 min. The precipitate waa flltered, rinaed with ether (200
ml), triturated in water (70 ml), fi.ltered again and rinsed with
ether (100 ml). The light brown solid waa dried under vacuum
(water aspirator 10 min and pump 65 min) to give the title
compound (6.52 g). IR (CHC13 ) v max :1862 (C=0),1630
(phosphorane), 860 and 840 cm~1 (Si-C).
- 243a -
1~6661
Example 47
6-Formamidomethyl-2-methylpenem-3-carboxylic acid,
sodium and potassium salts
lD ~ ~"' ~ c ~ a~ a~d :~
trans 1-(t-butyldimethylsilyl)
-3-methanesulfonyloxymethyl-4-tritylthio
-2-azetidlnone
OH H H
HJ~ 3 ~' ~ C~3
C~ ~5~ (CH3) 2 Si (CH3) 2
t-au
A solution of trans-l-(t-butyldimethylsilyl)-3-hydroxy-
methyl.-4-tritylthio-2-azetidinone (8.0 g, 16.36 mmol) in
dichloromethane (50 ml) was treated at 5C with
methanesulfonyl chloride (1.4 ml, 18 mmol) in
dichloromethane (10 ml) and triethylamine (2.5 ml, 18 mmol).
Stirring was maintained for 1 h under N2. Then the solution
was washed
- 244 -
~.~ ,- ~
The crude solid was purified by hplc to glve 18 mg of a mixture
of the sodium and potassium salts.
uv (H2O) max: 299 (~ 4933), 259 (~ 4094) ; ir ("NUJOL")*
max: 3100-3650 and 1755 cm 1; 1Hmr (D2O)~ : 8.15 (lH, s), 5.53
(lH, d, J=1.4H~), 4.0 (lH, m), 3.74 (2H, d, J=5Hz), 3.25-4.25
(lH, m) and 2.27 ppm (3H, 8).
Exam~le 48
(1'S 5R.6S. and 1'R.5S.6R) 6-_(l'-Hx~roxy-1'-propyl)-2-
methyl~enem-3-carboxylic acid. sodi~um salt ~isomer C)
Et ,~
>5.~ ~
co2Na
trans_1-t-Bu~yldimethylsilyl-3-pro~ionyl-4-tritylthio
-2-a~Q~idinones
+ 2 ~ \SlMe2
PROCE~URE:
n-BuLi (37.50 ml, 1. 6M/hexane, 60 =mmol) was added
dropwise under N2 to a cooled (dry ice-acetone bath) and stirred
solution of diisopropylamine (8.50 ml, 60 mmol) in dry THF (200
ml). The mixture was stirred in the cold and 1-t-butyldimethyl-
silyl-4-tritylthio-2-azetidinone (22.9 g, 50 mmol) in dry THF
30 (100 ml) was added. After 15 min, methyl propionate (40 ml,
excess) was added and the reaction mixture was kept at -78 for 4
h. Then the cooling bath was removed and the internal temperature
was allowed to come to OC (-40 min). It was poured over ice-HCl
(pH - 6) and extracted with ether. The layers were separated and
the aqueous layer was extracted with ether. The combined ether
solution was washed with water and brine and dried
*Trade Mark
- 255 -
~'3~;~;63l
(Na2SO4). It was evaporated in vacuo to give an oil in
quantitative yield. This contained a mixture of starting
material and title compound. It was used as such and
1l
purified in the next step. ir (Neat) vmax : 1710 (-C-), 1750
cm 1 (B-lactam).
1-t-Buty~dim~hylsilyl-3-(l'-hydro~xy-l'-p~,g~ syl~hio-2-
az~idi nonçs
OH
O ~ 5~Me ~ ~ 5 r
PROCEDURE:
A solution of 1-t-butyldimethylsilyl-3-propionyl-
4-tritylthio-2-azetidinone (26 g, 50 mmol) and sodium
borohydride (7.6 g, 200 mmol) in THF (400 ml) was stirred at,
room temperature for 18 h. It was poured onto ice-HCl (lN) (pH 6)
and extracted with ether. The acidic phase was extracted several
times with ether and the combined ether solution was washed with
brine, dried (Na2SO4) and evaporated to give an amorphous solid,
25.0 g. This crude product was chromatographed on SiO2 (ACT. 1,
400 g) and eluted first with CH2C12 to give 10.8 g of
1-t-butyldimethylsilyl-4-tritylthio-2-azetidinone. Elution with
20% ether in CH2Cl2 gave 10.3 g of the title compound as a
mixture of two isomeric trans alcohols. This was separated by
hplc (Water Associates, System 500*), and using 10% EtoAc in
CH2C12 as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether)
134-36C. 1Hmr (CDC13)~ : 7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1
(H, dd), 2.5 (H, m), 0.7-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm
(6H, s). Anal. calcd for C31H39NO2SSi: C 71.91, H 7.59, N 2.71;
found: C 71.51, H 7.60, N 2.96. isomer B, white solid, 5.4 g; mp
(pentane-pet. ether) 97-99C. 1Hmr (CDC13) ~ : 7.1-7.8 (15H, m,
STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 (5H, m), 0.85
(9H, s) and 0.1 ppm (6H, s).
*Trade Mark
- 256 -
97-99C. 1Hmr (CDC13 ) ~: 7.1-7.8 (15H, m, STr), 4.15 (H,
d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 (5,H, m), 0.85 (9H, s)
and 0.1 ppm (6H, s). Total yield of these two alcohols
(based on recovered starting material was 67.5%.
(l'S 3S,~R and l'R~3R!4S~
l-t-butvldimethylsilyl-3-rl'-paranitrobenzyldioxycarbonyl-
l'-propyl)-4-tritylthio-2-azetidinone (isomer C).
OH ST ~Co22~B
n~ 2 ~ ~STr
d--~ S i.`~!e 2 O ~ S iMe 2
PROCEDURE:
To a cooled (dry ice-acetone bath) solution of (l'S,3S,
4R and l'R,3R,4S)
1-t-butyldimethylsilyl-3-(1'-hydroxy-1'-propyl)-
4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry
THF (20 ml) was added dropwise under N2 a solution of 1.6M
n-BuLi/hexane (4.88 ml, 7.8 mmol) stirred at -78C for 25
min Paranitrobenzyl chloroformate (1.56 g, 7.2 mmol) in dry
THF (10 ml) was then added dropwise and the resulting
mixture was stirred at -78C for 4 h. It was diluted with
ether and washed with NH4C1 solution brine. The organic
phase was dried (Na2SO4 ) and evaporated to dryness to give
4.2 g of title compound (Quantative yield). 1Hmr (CDC13) ~:
8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s), 4.05 (H, d),
3.75 (H, dt), 3.25 (dd), 0.55-1.8 (5H, m), 0.9 (9H, s) and
0.25 ppm (6H, d).
- 257 -
~,
~ 2~36~i61
~1'S 3S.4R and l'R 3R 4S) 3~
~aranitrobenzyldioxycarbonyl-l'-propyl)
-4-tritylthio-2-azetidinone (isomer C)
OC02PNB OCO2P~,3
,_~ S Tr ~J,. STr
oL~ ` + ~MPT + NaN3
SiMe2 (10% ~120) o~N~
PROCEDURE:
To a cooled (ice bath) solution of (l'S,3S,4R and
l'R,3R,4S) 1-t-butyldimethylsilyl-3-(1'-
paranitrobenzyldioxy-carbonyl-l'propyl)-4-tritylthio
-2-azetidinone (isomer C) (4.2 g, 6 mmol) in HMPT (40 ml)
containing 10% H2O was added sodium azide (0.78 g, 12
mmol). The mixture was stirred at room temperature for 1 h.
It was diluted with water (100 ml) and extracted with
benzene: pet. ether (1:1) (4 x 15 ml). The organic phase was
washed several times with water (6 x 30 ml) and brine It
was dried (Na2SO4 ) and evaporated to dryness to give 3.5 g
of a solid (quantitative yield). It was treated with
pentane and filtered to give 3.4 g of a pale yellow solid.
mp 84-86C; lHmr (CDC13) ~: 8.2 (2H, d), 7-7.7 (17H, n),
5.2 (2H, s), 4.95 (H, dt), 4.4 (NH), 4.25 (H, d), 3.4 (H,
dd), 1.7 (2H, m) and 0.95 ppm (3H, t).
- 258 -
~ ¢
,,1, ,._
~2~fi661
(1'5,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-1'-
propyl)-l-(paranltrobenzyl 2"-hydroxy-2"-hydroxy-2"-acetate)-4-
tritylthio-2-azetidinone (isomer C).
QC02PNB PC2P~JB
. ~ STr THF ~ " ~ STr
O ~ N PNB glyoxalate TEA ~ N ~ H
PROCEDURE:
To a solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitro-
benzyldioxycar~onyl-l'-propyl)-4-tritylthio-2-azetidinone (isomer C)
(3.2 g, 5.5 mmol) and paranitrobenzyl glyoxylate hydrate (1.362 g,
6 mmol) in dry THF (50 ml) was added a catalytic amount of TEA
(4 drops) and Na2504 (to absorb H20 formed). The resulting
mixture was stirred at room temperature for 6 h. It was filtered
and evaporated to dryness to give 4.35 g of an amorphous solid (quan-
titative yield). lHmr (CDC13) ~: 8.25 (4H, dd), 7-7.g (19H, m),
5.28 (2H, s), 5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt),
3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t),
(l'S,3S!4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-1'-
propyl)-l-(paranitrob~;L_____ hloro-2"-acetate(-4-tritylthio-2-
azetidinone (isomer C)
~OC02PaB Py/THF J 2
N ~ H SOC12/THF O N ~ Cl
02PNB
C02PNB
PROCEDURE:
To a cooled (ice salt bath) solution of the above glyoxylate
(4.35 g, 5.5 mmol) in dry THF (30 ml) was added lM py/THF (7 ml, 7
mmol) followed by dropwise addition of lM SOC12/THF (7 ml, 7 mmol). The re-
-259-
~Z~36~
sulting mixture was stirred at the above-indicated temperature for 1 h.
It was diluted with benzene (30 ml), stirred in the cold (ice water
bath) for 30 m-n and filtered over Celite-charcoal. The filtrate
was evaporated to dryness to give 3.8 g of an amorphous solid
(85.3~); IHmr (CDC13) ~: 8.15 (4H, d), 6.75-7.7 (19H, m), 5.65
(H, s), 5.2 (2H, s), 5.1 (2H, s), 4.5 (H, m), 3.85 (H, m), 3.4
(H, m), 1.25~2.0 (2H, m) and O.g ppm (3H, t).
(l'S,35,4R and l'R,3R,45) 3-(1'-paranitrobenzvldioxycarbonyl-1'-
propyl)-l-~paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)
-4-tritylthio-2-azetidinone (isomer C)
OCO PNB OCO2PNB
2 STr ~ ." ~ STr
N Cl lutidine O ~ ~ ~3
02PNB - 02PNB
PROCEDURE:
To a solution of the above chloro compound ~3.7 g,
4.568 mmol) in dioxane (35 ml) was added ~3P (1.197 g, 5 mmol)
and lutidine (0.54 g, 5 mmol). The mixture was heated in an
oil bath at 100 C for 3 days. It was cooled, diluted with
ether and washed successively with lN HCl, IM NaHC03 and brine.
It was dried (Na25O4) and filtered over Celite-charcoal. The
filtrate was evaporated to dryness to give 3.6 g of an oil.
This was chromatographed on SiO2 (120 g) and eluted with
benzene, benzene-ether to give 1.45 g of title compound as
an amorphous solid (31~); ir (neat) vmax: 1750 cm (broad).
- L~
(l'S 3S.4R and l'R.3R.4S)
4-acetYlthio-3-(l'Paranitrobenzvldioxycarbonyl-
l'-propyl)-l-(Paranitrobenzyl 2"-triphenylphosphoranylidene
-2"-acetate)-2-azetidinone (isomer C)
2 ~C022Ng 2
~J ~ STr AgN03~J" ~ SAg C~i3~Cl ~J ~ SAc
o~N~P~3 Py/MeOH O ~P~3 Py/MeOH ~ o~N~P~3
2 2 G2PN3
PROCEDURE:
To a hot solution (60C) of the above phosphorane (1.4
g, 1.35 mmol) in MeOH (40 ml) was added with stirring a hot
solution of AgNO3 (0.3 g, 1.76 mmol) in MeOH (10 ml)
followed by pyridine (0.107 g, 0.11 ml, 1.76 mmol). The
silver mercaptide began to precipitate immediately. The
mixture was stirred at room temperature for 15 min and at
OC for 2 h. It was filtered, and the solid washed well with
cold MeOH and ether, 1.2 g (quantitative yield); mp
113-115C (d); ir("NUJOL")*. vmax : 1740-1760 cm~l (broad).
This solid was used as such. To a cooled (ice bath)
solution of the above mercaptide (1.2 g, 1.35 mmol) in
CH2C12 (15 ml) was added acetyl chloride (0.118 g, 0.107
ml, 1.5 mmol) in CH2C12 (2 ml) followed by pyridine
(0.119 g, 0.122 ml, 1.5 mmol) in CH2Cl2 (2 ml). The mixture
was stirred at 0C for 30 min. It was filtered over
"CELITE"* to remove silver salt and the filtrate was washed
successively with HCl (0.5N), H2O, NaHCO3 (0.5 M) and brine.
The CH2Cl2 solution was dried (MgSO4) and evaporated to
dryness to give 0.94 g of title compound as an amorphous
solid. (83.4%) ir (neat) vmax: 1750 cm~l (broad).
*Trade Mark
- 261 -
....-
.
~ 2r36~
(l'S,5R,6S and l'R,5S,6R) paranitrobenzyl 6~ paranitrobenzyldioxy-
carbonyl-l'-propyl)-2-methylpenem-3-carboxylate (isomer C)
2 NB OIC02PNB
J~ ~sTr ~f ~
02PNB CO PNB
PROCEDVRE:
A solution of the above phosphorane (0.4 g, 1.077 mmol)
in toluene (35 ml) was heated to reflux and 5 ml of toluene was
distilled off. The yellow solution was refluxed for 7.5 h. It
was evaporated to dryness to give 0.76 q of a thick oil. This was
chromatographed on SiO2 (ACT 1.30 g) and eluted wlth benzene and
benzene-ether to give the title compound as a solid, 0.32 g (53.4%);
mp (pentane) 160-162C; Hmr (CDC13) ~: 7.3-8.4 (8H, m, aromatic),
5.4 (H,d), 5.3 (4H, benzyls, m), 5.0 (H, dt), 4.0 (H, dd), 2.35 (6H, s),
0.8 (2H, dq) and 1.0 ppm (3H, t).
(l'S,5R,6S and l'R,5S,6R) 6-(1'-hydroxy-1'-propyl)-2-methylpenem-3-
carboxylic acid (isomer C), sodium salt.
CH3 H2/Pd-Celite HO ~ ~ CH3
N ~ phosphate O N ~
PROCEDURE: \CH3 buffer \ - +
A mixture of the above ester (48 mg, 0.086 mmol) and
30% Pd-Celite (100 mg) in TH~ (10 ml), Et2O (20 ml), H2O (10 ml)
and phosphate buffer (pH7, 2 ml) was hydrogenated at an initial
pressure of 50 psi for 23 h It was filtered over Celite and
the layers separated. The organic layer was washed with H2O (2 x 5 ml)
and the combined water layer was washed with EtOAc (2 x 10 ml). The
aqueous layer was then lyophilized to give the title campound as
a white salt, 30 mg; ir (KBr) v : 1750 (~-lactam), and 1600 -
1650 cm (broad, -CO2 ); uv ~ : 258 (~ 1105) and 305 (~ 1244).
~ C ~--
Example 49
(l'R 5R.6S and l'S 5S 6R) 6-(l'-HydLQ~y-1'-~opyl ~2-methylpenem
-3-carboxylic acid sodium and pQ~a~ium s~lts_(isomer B~
H~ ,H
~R ,,~ ~ CH 3
CO 2H
(l'R.3S.4R apd l'S.3Rl4Sl 1-t'-Butyldi~thY19~1~1:3b~ 9~-YlXY
-1'-propyl)-4-tritylthio2-azetidinone ~isomer B)
OH HCO ~ t N OCHO
~J. ~ ~ STr 2 3 ~J ~STr
~SiMe2 C~2C12 o Si.~e2
4-Dimethylaminopyridine (DMAP) was prepared according to a)
H.C. Brown et al. Org. Synth. Collect Vol. 5, 977 (1973) and b)
Helmet Vorbruggen et al. Angew. Chem. Int. Ed., 17, 569, (1978).
PROCEDURE:
To a cooled (OC) solution of (1'R,3S,4R and l'S,3R,4S)
1-t-butyldimethylsilyl-3(1'-hydroxy-1'-propyl)-4-trityl-
thio-2-azetidinone (isomer B) (3.612 g, 7 mmol) in CH2C12 (50
ml) was added Et3N ( 4.48 ml, 35 mmol) HCO2H (0.63 ml, 16 8
mmol) and DMAP (0.854 g, 7 mmol) followed by dropwise addition of
acetic anhydride (7.14 g, 7 mmol) The yellow solution was
stirred at -40C and milky mixture. It was poured onto ice-lN
HCl (pH 6) and the layers were separated. The CH2C12 solution
was washed with lM NaHCO3 and brine. It was dried (Na2SO4 ) and
evaporated to dryness to give 3.8 g of a solid residue. This was
treated with pentane and filtered to glve 3.7 g of a white solid
O
(96.8%); mp 125-27C; ir (neat) vmax: 1720 (H-C) and 1750 cm~
(B-lactam); 1Hmr (CDC13) ~: 7.1 (H, s, H -C-) 6.8-7.7 (15H, m),
4.8 (H, m), 4.05 (H, d, J=1.5), 3.7 (H, m, J=1.5, J=7), 1.4 (2H,
35 m), 0.95 (9H, s), 0.8 (3H, t) and 0.1 ppm (6H, s); Anal. calcd
for C32H39NO3SSi:C 70.42; H 7.20; N 2.57; found: C 70.20; H
7.33, N 2.73.
- 263 -
~2~6~;61
(l'R,3S,4R and l'S,3R,4S) 3-(1'-formyloxy-1'-propyl)-4-tritylthio-2-
azetidlnone (isomer B)
OCHO OCHO
S~r ~ NaN HMPT ~ ~ Tr
~ SiMe2 10% H2O N~H
PROCEDURE:
To a cooled tice bath) solution of t3.7 g, 6.77 mmol)
in HMPT t40 ml) Containing 10~ H20 was added NaN3 tO.91 g, 14 mmol).
The mixture was stirred at room temperature for 1.5 h. It was poured
onto ice water (200 ml) and extracted with ether (4 x 40 ml). The
ether solution was diluted with pet-ether and washed extensively
with water and brine to remove HMPT. It was dried (Na2S04) and
evaporated to dryness to give 2.92 g of a thick colorless oil. (quan-
titative yield). IHmr (CDC13) ~: 8.1 (H, H-C-,S), 7.1-7.7 (15H~ m,
-STr), 5.23 (H, m, J=7), 4.38 (H, d, J=2.5), 4.3 tH, -NH), 3.35 tH, dd,
J=2.5, J=7), 1.75 t2H, m) and 1.0 ppm t3H, t).
tl'R,3S,4R and l'S,3R,4S) 3-tl'-formyloxy-1'-ethyl)-1-tparanitrobenzyl
2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone tisomer B)
OCHO ~ STr OCHO STr
-- PNB GLYOXYLATE ~
H Et3N/THF
CO 2PNB
PROCEDURE:
A mixture of 3-~1'-formyloxy-1'-propyl)-4-tritylthio-2-
azetidinone tisomer B), t2.9 g, 6.77 mmol), PNB glyoxylate tl-59 g,
7 mmol), Et3N t5 drops) and Na2S04 tanhydrous, 5.0 g) in T8F t50 ml)
was stirred at room temperature for 18 h. It was filtered and
evaporated to dryness to give an amorphous solid in quantitative
yield (4.33 g); IHmr tCDC13) ~: 8.2 t2H, d), 7.1-7.8 tl8H, m), 5.2
--26 1~-
l~r~6~;61
(2H, d), 4.9 (H, m), 4.65 and 4.3 [H, 4.65 (1/2 H,s) 4.3
(1/2 H, s)], 4.2-4.3 (H, d, 1/2 H at 4.2, 1/2 H at 4.3),
3.65 (H, m), 1.4 (2H, m) and 0.8 ppm (3H, t).
tl'R 3S 4R and l'S 3R 4S)
3-fl'-formyloxy-1'-propyl)-1-(paranitrobenzyl
2"-chloro-2"-aceta~e)-4-tritylthio-2-azetidinone (isomer B)
oc~o oc~o
J~ "~sTr ~J,., ~ STr
a~ N y OH SOC 1 2/THF O~ N ~f C 1
C32PNB co2~s
PROCEDURE:
To a cooled (ice salt bath) solution of the above
glyoxylate (4.3 g, 6.77 mmol) and lM Py/THF (8 ml, 8 mmol)
in dry THF (30 ml) was added dropwise lM SOC12 /py (8 ml, 8
mmol). The resulting solid mixture was stirred at the above
temperature for 1 h. It was diluted with benzene (30 ml) and
stirring was continued for 20 min. It was filtered over
"CELITE"*- charcoal and the filtrate was evaporated to
dryness to give 4.1 g of an amorphous solid (92%). ir (neat)
O o
max : 1720 (H-C-), 1750 (-C-OPNB) and 1780 cm~1
(~-lactam); lHmr (CDC12 ~: 8.25 (2H, d), 7.8 (H, s, H-C-),
7-7.75 (17H, m), 5.25 (2H, d), 5.0 (H, m), 4.6 -(H, s), 4.4
(H, d), 3.7 (H, m), 1.6 (2H, m) and 0.9 ppm (3H, t).
*Trade Mark
- 265 -
lZ~36~;61
(l'R,3S,4R and l'S,3R,4S) 3~ formyloxY-l~-prop~l)-l-(paranitrobenæ
2"-triphenylphosphoranylidene-2"-acetate~-4-tritylthio-2-azetidinone
(isomer B)
OCHO OCHO
STr ~ ......... STr
l 03P dioxane ' ~
O ~ ~ Cl lutidineo ~ ~ ~3
C02PNB C02PNB
PROCEDURE:
A mixture of the above chloro compound (4.0 g, 6.07 mmol)
~3P (1.834 g, 7 mmol) and lutidine (0.749 g, 7 mmol) in dioxane (40 ml)
was heated at 100C (oil bath) for 2 days. It was cooled, diluted
with ether and washed successively with cold solution of lN HCl,
lM NaHCO3 and brine. The organic solution was dried (Na25O4) and
filtered over Celite-charcoal. It was evaporated to dryness to give
an oil which was chromatographed on SiO2 (Act. 1, 200 g) and eluted
with benzene and benzene-ether to give 2.60 g of the title compound
as an amorphous solid (48.45~); ir (neat) V : 1720 (H-C-O-), and
1750-1760 cm (-CO2PNB and ~-lactam).
(l'R,35,4R and 1'5,3R,4S) 4-acetylthio-3-(1'-formyloxy-1'-propyl)-1-
(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone
(isomer B).
OCHO OCHO OCHO
" ~ STr O ~ ~ ~3~N ~ P~3
2CO2PNB
PROCEDURE:
A warm solution (60C) of 0.15 M AgNo3-cH3o~ (8.7 ml,
1.3 mmol) was added to a mixture of the above phosphorane (0.88 g,
1 mmol) and pyridine (0.103 g, 1.3 mmol) in MeOH (5 ml) warmed
-~ ~6-
6~
to 60C. The mixture was stirred at room temperature for 15 min
and at OC for 2 h. It was filtered and washed with cold MeOH to
give 0.53 g of the silver mercaptide as a yellow solid (71%)
which was used as such. To a cooled (ice bath) mixture of the
above mercaptide (0.53 g, 0.71 mmol) and pyridine (0.079 g, 1
mmol) in CH2Cl2 (10 ml) was added dropwise CH3COC1 (0.079 g, 1
mmol) in CH2Cl2 (5 ml). After stirring at 0C for 1 h, it was
filtered. The filtrate was washed well with a cold solution of
0.5M HC1, 0.5M NaHCO3 and brine. It was dried (Na2SO4) and
evaporated to dryness to give 0.43 g of an oil. (63%); ir (neat)
max:
1700-1760 cm 1 (broad -C and B-lactam).
(l~R,3S.4R and l'S.3R.4S) and acetylthio-3-(1'-hydrox~ -
l'-propyl-l-(~aranitrobenzyl 2"-tr1~henvl~hoa~horanylide
-2"-acetate)-2-azetidinone ~isQme~-~3)
oc~o pH
n~SAC ~3Cl/MeOH , ~ SAc
od--N~ P~3 ~
2 2
PROCEDURE:
The above formate (1 0 g, 1 45 mmol) in THF (10 ml) was
treated at room temperature with HC1/MeOH (10 ml, prepared from 2
ml concentrated HCl and diluted with MeOH to a volume of 24 ml)
The mixture was kept at room temperature for 0.5 h. It was
basified with lM NaHCO3, extracted with EtOAc solution, washed
with brine and dried (Na2SO4 ) It was evaporated to give 0.9 g
of crude title compound. This was chromatographed on SiO2 and
eluted with ether and ether: EtOAc (1:1) to give 0.6 g of pure
title compound as an amorphous solid (62.5%); 1Hmr (CDC13)~ :
8 25 (2H, d), 7 3-8.1 (17H, m, aromatic), 5.6 (H, m), 5.2 (2H),
4 9 (H), 4 4 (H, m), 2 3 (3H, SAc), 1.5 (2H, m) and 0.9 ppm (3H,
t).
- 267 -
-
~ ~6~6~
(l'R,5R,6S and l'S,SS,6R) paranitrobenzyl 6-(1'-hydroxy-1'-~ropyl)-2-
methylpenem-3-carboxylate (isomer B).
OH
~ ~ 3 ~H3
02PNB - 02PNB
PROCEDURE:
The above phosphorane (0.2 g, 0.3 mmol) in toluene
(45 ml) was heated to reflux and 5 ml of toluene was distilled off.
The resulting solution was refluxed for 6 h. It was cooled and
evaporated to dryness to give 0.2 g of an oil. This was chroma-
tographed on SiO2 and eluted with ether to give 0.1 g of title
compound as a white solid. (87%); mp (pentane) 133-135C; IHmr (CDC13)
~: 8.3 (2H, d), 7.6 (2H, d), 5.6 (H, d), 5.35 (2H, d), 4.15 (H, m),
3.8 (H, m), 2.4 (3H, s, CH3), 2.2 (H, OH), 1.7 (2H, m) and 1.05
ppm (3H, t).
(l'R,5R,6S and l'S,5S,6R) 6-1'-hydroxy-1'-propyl)-2-methylpenem-3-
carboxylic ac id (isomer B), mixed K and Na salts
OH OH
F~ 3
CO2PNB 2 (lla+K)
PROC~DURE:
A mixture of the above ester (0.07 g, 0.185 mmol), 30
Pd-Celite (150 mg) and buffer solution (pH 7, 4 ml) in THF (15 ml,
Et2O (25 ml) and deionized water (15 ml was hydrogenated at an
initial pressure of 48 psi for 4 h. It was filtered over Celite
and the layers were separated. The aqueous layer was washed with
ethylacetate and then lyophilized to give 91 mg of a solidi
r (KBr) v : 1780 (~-lactam) and 1650 cm (broad, -CO ); uv
max 2
H O ~ : 255 (~ 983) and 300 (~ 1092).
2 max
lX~6~
Exam~le ~
(l'R,5R,6S ~nd l'S,5S,6R) 6-(1'-Hydroxy-2'-~henylethyl)-2-methylpenem-
3-carboxylic acid (isomer B)
H, .~H
CH3
C02H
trans l-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2-
azetidinone
~Tr + LDA + ~CH CO Et ~ ~STr
N -SiMe2 2 2 N -~lMe2
l-t-Butyldimethylsilyl-4-tritylthio-2-azetidinone
tl8.32 g, 40 mmol) in dry THF (100 ml) was added dropwise
under N2 to a cooled (-78C) LDA solution [prepared under N2,
at -78C from dropwise addition of 1.6 M n-8uLi (101.25 ml,
162 mmol) to diisopropyl amine (22.95 ml, 162 mmol) in dry
THF (150 ml) and stirred at -78C for 30 min]. The mixture was
stirred at -78"C for 30 min and ethyl phenylacetate (15.66 g, 15.12 ml
15.12 ml, 93.6 mmol) in dry TH~ (50 ml) was added and the reaction
mixture was stirred at -78C for 2 h. It was poured onto ice-
lN HCl (pH S-6) and extracted with ether several times. The
ether solution was washed with brine and dried (Na2SO4). It was
evaporated to dryness to give 33.7 g of a crude solid. This was
dissolved in ether (10 ml) and triturated with pentane (200 ml).
The solid was filtered and washed several times with pentane
to give 18.3 g of a white solid (79.6~) mp 141-143. IHmr (CDC13 ~:
7.0 - 7.6 (20H, m), 4.8 (H, d), 3.7 (H, d), 3.53 (H, s), 3.43
(H, s) 1.5 (9H, s) and 0.3 ppm (6H, s).
--L6q_
6~
l-~t-butyldimethylsilyl-3-(1'-hydroxy-?'-phen~lethyl)
OH
5 ~ STr (P ~J~f Tr
O N ~iMe2 N ~~iMe2
trans 1-~t-butyldimethylsilyl)-3-phenylacetyl
-4-tritylthio2-azetidinone (28.8 g, 50 mmol) and NaBH4 (0.5
g, 0.25 mole) in THF (200 ml) were stirred at room
temperature for 18 h. The mixture was poured onto ice-lN HCl
and extracted with CH2C12. The CH2C12 solution was washed
with brine and dried (Na2S04 ). It was evaporated to give an
amorphous solid (27.7 g). A portion of the solid (23.0 g)
was chromatographed on sio2 and eluted with hexane: ether to
give off-white solid (14.4 g) which was found to be a
mixture of (l'R,3S,4R and l'S,3R,4S) and (l'S,3S,4R and
l'R,3R,4S) isomers in the ratio o~ 1:1 (60~). lHmr (CDC13)
~: 7-7.7 (20H, m), 4.37 (1/2H, d), 4.18 (1/2H, d), 3.3-3.8
(H, m), 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, m), 0.87
(9H, d) and 0.25 ppm (6H, s).
l-(t-butyldimethylsily~L-3-(~ o~mylQ~y-2~--p-hen-ylethylL
-~its~L~;hiQ-2-a~
¢`~", Tr ~p H, ~C STr ~ ST-
09C~ 2 o~1--+i.~1e 2 o~N--,~LMe
isomer B i somer C
To a cooled (-40C) solution of the above mixture of
alcohols (14.4 g, 24.9 mmol) in CH2C12 (250 ml) was added
Et3N (15.93 ml, 125 mmol), HC02H (2.24 ml, 59.76 mmol) and
DMAP (3.04 g,
- 270 -
24.9 mmol) . After stirring for 5 min acetic anhydride (2.
35 ml, 249 mmol) was added dropwise. The clear solution was
stirred at -40C for 15 min whereby it turned into a white
cloudy mixture. It was kept at -40C for another 45 min
(total time 1 h). It was poured onto ice-lN HCl, and the
layers separated. The CH2Cl2 solution was washed well with
cold lN HCl,H2O, lM NaHCO3 and brine. It was dried (MgSO4 )
and evaporated to give 14.0 g of an amorphous solid. This
was separated by hplc (Water Associates, System 500*) to
lo give: "Isomer B" 6.0 g, mp 172-73C and "Isomer C" 6.0 g mp
188-89C. Total yield of pure compound 12.0 g (73.2~).
Isomer C: lHmr (CDC13) ~: 6.8-7.7 (21H, m), 5.05 (H, dt),
4.05 (CH, d) 3.65 and 3.75 tH, two doublets), 2.7-2.9 (2H,
d), 0.88 (9H, s) and 0.2 ppm (6H, s). Isomer B: 1Hmr (CDCI3)
~: 7.75 (H, s), 6.9-7.5 (20H, m), 4.3 (H, dt), 3.95 (H, d),
3.37 (H, dd), 2.95 (H, s), 2.85 (H, s), 0.9 (9H, s) and 0.2
ppm (6H, s).
3-(l'-formyloxy-2'-phenylethyl)-4-tritylthio-2-azetidinone
tl'Rr3S,4R and l'S,3R,4S enantiomers)
~OC'10 S~R ~ STr
N--S i,Ye 2 N
I somer B
To a cooled (ice bath) solution of the above formate
(5.9 g, 9.375 mmol) in HMPT containing 10~ water (50 ml) was
30 added NaN3 (1.3 g, 20 mmol). The mixture was stirred at room
temperature for 1.5 h. It was poured onto ice water (300 ml)
and extracted with ether (3 x 100 ml). The ether solution
was washed well with water and brine. It was dried (Na2S04 )
and evaporated to give a solid residue. This was treated
with
*Trade Mark
- 271 -
. .. .
petroleum ether and filtered to give 4.4 g of a white solid
(92%) mp 169-71C. Anal. calcd for C31H27NO3S: C 75.
N 2.84; found: C 7504, H 5.64 N 2.78. 1Hmr(CDC13)~ : 7.9 (H, 8),
7.1-7.6 (20H, m), 5.4 (H, m), 4.6 (H, NH), 4.2 (H, d), 3.3 (H,
dd), 3.15 (H, s) and 3.0 (H, 5).
3-(1'-formyloxy-2'-phenylethyl)-l-(par.anitrobenzyl
2"-hYdroxy-2"acetate)4-tritylthio-2-azetidinone (1'R.3S,4R and
l'S.3R.4S enantiomers)
o,~STr '~ ~,F~STr
o ~H N ~OH
C02P~3
A suspension of PNB glyoxylate (2.37 g, 10.16 mmol) in dry
benzene (100 ml) was refluxed under a Dean Stark
apparatus (packed with moleoular sieve 3~) for 2 h. Then the
above N-H compound (4.2 g, 8.537 mmol) was added and refluxing
continued for 1 more h. It was cooled to room temperature Et3N
(0.12 ml, 0.85 mmol) was added and the mixture was stirred at
room temperature for 1.5 h. It was evaporated to dryness to give
the title compound in quantitative yield as a mixture of two
isomeric alcohols. 1Hmr (CDC13)6 : 8.0-8.3 (2H, two doublets),
7.5 and 7.6 (H, two singlets), 7.0-7.4 (20H, m), 5.25 (2H, d),
4.9 (H, OH), 4.25 and 4.35 (H, two doublets), 3.5-4.5 (H, m,
broad), 3.1- 3. 3 (H, m) and 2.9 ppm (2H, m).
- 272 -
. . .
~36~61
3-(l'-formyloxy-2~-phenYlethyll-1-(~aranitrobenzyl 2"-chloro-2"-
acetate)-4-tritylthio-2-azetidinone (l~R 3S.4R and l'S.3R 4S
enantiomers)
~!~9T~ ¢Oc~
C02PNB C022NB
To a cold (ice salt bath) solution of the above glyoxylate
(6.0 g, 8.537 mmol) in dry THF (30 ml) was added a lM solution of
pyridine in THF (10 ml, 10 mmol) followed by the dropwise
addition of a lM solution of thionyl chloride in THF (10 ml, 10
mmol). After 1 h at the above temperature was diluted with
benzene (30 ml) and stirring was continued in the cold for 30
min. It was filtered over "CELITE"*-charcoal and evaporated to
dryness to give 6.0 g of an amorphous solid (98%): 1Hmr (CDC13)
: 8.2 (2H, m), 7-7.7 (23H, m), 5.8 (H, s), 5.25 (2H, s), 4.35
(H, d), 3.5-4.0 (H, m), 3.3 (H, m) and 2.9 ppm (2H, d).
3-(l'-f~ormYloxy-2'-phenylethyl)-1-(Daranitrobenzyl
2"-triphenylphosphoranylidene-2"-acet~a~e~ -tritylthio
-2-azetidinone (l'R 3S.4R and lS.3R 4S enantiomers).
H OCHO ST--
N~f.Cl N ~ ~
C02PNB C02PNB
A mixture of the above chloro compound (6.0 g 8.333 mmol), ~3P
(2.489 g, 0.5 mmol) and lutidine (1.0165 g, 1.1 ml, 9.5 mmol)
*Trade Mark
- 273 -
~,
~666~
in dioxane (50 ml) was heated at 110C (bath temp) for 18 h.
It was cooled and filtered over Celite. The filtrate was
diluted with ethyl acetate and washed with cold lN HCl, H2O, lM
NaHCO3 and brine. It was dried (Na2SO4) and evaporated to give
8.0 g of a crude product. This was chromatographed on SiO2 and
eluted with ether: hexane (1:1) and ether to give 4.0 g of the
title compound. mp (needless from ether) 235-37C (d). (51~);
ir (film) V a : 1720, 1750 cm
4-acetYlthio-3-(l~-formyloxy-2~-phenylethyl)-l-(paranitrobenzyl
2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (l'R,3S,4R
and l'S,3R,4S enantiomers)
. ~ OCHO ~ OCHO SA
O ~ ~ ~3 o~N ~ ~3 ~ N ~ P~3
C02PNB 02PNB C02PNB
To a refluxing solution of the above phosphorane (3.6 g,
3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in CH2C12 (30 ml) and MeOH
(30 ml) was added dropwise a 0.15M AgNO3/MeOH solution (28 ml, 4.2 mmol).
The mixture was stirred at room temperature for 2.15 h. It was
concentrated to a small volume ( 10 ml), cooled and filtered to give
the silver mercaptide as a yellow solid (2.3 g, 77%). This mercaptide
and pyridine (0.277 g, 3.5 mmol) in ice-cold (CH2Cl2 (20 ml) was
treated dropwise with CH3COCl (0.27 g, 3.5 mmol) in CH2C12 (5 ml).
The mixture was stirred at room temperature for 3 h. It was filtered
over Celite and the filtrate was washed with cold lN HCl, H20, IM
NaHCO3 and brine. It was dried (MgSO4) and evaporated to dryness
to give 1.0 g of an amorphous solid (89.8~ Hmr (CDC13) ~: 8.2
(2H, d), 7.0-8.0 (23H, m), 4.5-5.7 (4H, m), 2.6-3.3 (3H, m), and 2.3 ppm
(2H, d, SAc).
_ Z 7V-
S~66~1
4-acetylthio-3-(l'-hydroxy-2'-phenylethyl)-l-(paranitrobenzyl 2"-
triphenylphosphoranylidene 2"-acetate)-2-azetidinone tl'R,3S,4R
and 1'5,3R,45 enantiomers).
OCHO 5 H ~
~N ~ P~3 ~ N ~ P~3
O PNB
CO2PNB 2
A solution of the above phosphorane (1.8 g, 2.416 mmol)
in THF (10 ml) was treated with lN HCl/MeOH (l0 ml) and the mixture
was stirred at room temperature for 4h. It was concentrated to
remove methanol, diluted with cold water, basified with lM NaHCO3
and extracted with CHCl3. The CHC13 solution was dried (MgSO4)
and evaporated to give 1.65 g of an amorphous solid. This was chro-
matographed on SiO2 and eluted with ether: ethyl acetate to give
1.30 g of the title compound (75~ Hmr (CDC13) ~: 8.2 (2H, d),
6.7-8.0 (22H, m), 4.0-6.0 (5H, m), 2.5-3.5 (3H, m) and 2.2 ppm
(3H, SAc).
paranitrobenzyl 6-(l'-hydroxy-2'-phenylethyl)-2-methylpenem-3-
carboxylate (l'R,SR,6S and 1'5,5S,6R enantiomers)
H OH
C02PNB
A solution of the above phosphorane (1,2 g, 1.67 mmol)
in toluene (80 ml) was heated to reflux (10 ml was distilled off
to remove moisture and low boiling point solvent present) for 6 h.
It was evaporated to dryness and the crude product was chromato-
graphed on SiO2. The title compound was obtained by eluting the
column with ether to give 0.65 g of amorphous solid (89%). IHmr
--2 ?5-
~2.r~6G61.
(CDC13) ~: 8.2 (2H, d), 7.6 (2H, d), 5.4 (H, d), 5.2-5.4 (2H, d),
4.0-4.5 (H, m), 3.7-4.0 (H, dd), 3.0 (2H, d) and 2.3 ppm (3H, S).
6- (1'-hYdroxy-2'-Phenylethyl)-2-methylpenem-3-carboxylic acid
(l'R,5R,6S and l'S,5S, 6R enantiomers)
3 ~ ~ CH3
C02PNB C02H
A mixture of the paranitrobenzyl ester (0.33 g,
0.75 mmol), 0.05 M Buffer solution (pH 7, 17.4 ml), THF (30 ml),
Et2O (30 ml), distilled H20 (60 ml), and 30~ Pd/Celite (0.69 g)
was hydrogenated at an initial pressure of 50 psi for 24 h. It
was filtered over Celite and the organic layer washed with water,
The combined water layer was washed several times with EtOAc and
it was lyophilized for 18 h to give the title compound as a yellow
solid salt. This was treated with a small amount of water, acidified
with cold lN HCl and extracted well with CHC13. The CHC13 solution
was dried (MgSO4) and evaporated to give a solid residue. This
was treated with ether and filtered to give 30 mg of a white solid
(13.2%), mp 165-167C; ir (nujol) V : 3580 (OH, Sharp), 1660 and
1760 cm ; uv ~MeOH) ~ x 310 (~ 5490) and 254 (~ 4880).
-27~-
Exam~le 51
4'R 5R.6S and 4'S.5S.6R) 6-(2',2'-Dim~thyl-1', 3'-dioxolan
-4~-v1)-2 methvl~enem-3-carboxvlic Acid (isomer C)
~ Q
~."~s
o~L N ~ 3
CO 2H
A. PREPARATION OF
~
/ ~ ~ ST.
(4'R,3S,4R and 4'S,3R,4S) and (4'S,3S,4R and 4'R,3R,4S)
1-(t-Butyldimethylsilyl)-3-(2',2'-dimethyl-1'-,3'-dioxolan-
4'-yl)-4-tritylthio-2-azetidinone ("Isomer C" and "Isomer B")
- 277 -
Ethyl _-(2-methoxy-2-propyl)glycolate )
POC13 ~ Et
To a solution of ethyl glycolate (15.6 g, 0.150 mol;
freshly distilled) and 2-methoxypropene (16.4 g, 0.216 mol; 95~
pure) ) in CH2C12 (150 ml) was added at 0-5 phosphorus oxychloride
(3 drops, 35 mg, 0.23 mmol) and the mixture was stirred at 0-5
for 15 min and at room temperature for 1.5 h. This was then
quenched with pyridine (30 drops), stirred 45 min and the solvent
evaporated. The residue diluted with pentane (150 ml) was dried over
K2CO3. After filtration, the solvent was evaporated yielding 27.89 g
(0.158 mol, 100%; 94.9~ pure) of the title compound as a colourless oil:
lHmr (CC14) ~: 1.25 (3H, t, J=7Hz -CH2CH3), 1.28 (6H, s, Me2), 3.12
(3H, s, -OCH3), 3.88 (2H, s, -OCH2CO-), 4.10 (2H, q, J=7Hz, -CH2CH3);
ir (neat) Vm x 1760 and 1735 cm (ester).
1) J. Meinwald Q* o~., Tet. Lett., 4327 (1978)
2) M.S. Newman and M.C. Vander Zwan, J. Org. Chem.,38, 2910 (1973).
(3S,4R and 3R,4S) l-(t-8utyldimethylsilyl)-3-(1'-keto-2'-(2"-methoxy-
2"-isopropyloxy)-1'-ethyl)-4-tritylthio-2-azetidinone
STr 1) LDA/THF ~ X ~ ~ STr
Si 2) ~ Et OCH3 ~Si
OMe
To a stirred solution of diisopropylamine (18.5 ml,
0.134 mol) in THF (400 ml; freshly distilled from LAH1 at -78C
was added n-butyllithium (1.6M in hexane, 90 ml, 0.144 mol) under
--11 9"--
6~;61
N2 atmosphere. After 30 min, a solution of l-(t-butyldimethylsilyl)
4-tritylthio-2-azetidinone (50.0 g, 0.109 mol) in THF (100 ml) was
added dropwise over 10 min and the mixture was stirred for 5 min.
To this pink solution was added ethyl 0-(2-methoxy-2-propyl)glycolate
(23.94 g, 0.136 mol) and the mixture was stirred for 1 h. After
removing the dry-ice bath saturated NH4Cl solution (200 ml) was
added followed by brine (100 ml). The aqueous phase was extracted
with Et2O (3 x 100 ml). The combined organic extracts were washed
with brine, dried (Na2SO4) and evaporated yielding 60.95 g (0.103 mol,
crude yield 94.6%) of the title compound as a crude orange oil. This
crude material was used in the next reaction. A pure sample was
obtained by column chromatography (SiO2, eluent: 2% St2O in benzene);
IHmr (CDC13) ~: 0.30 (6H, s, Si-CH3), 0.95 (9H, s, t-Bu), 1.12 (3H, s,
CH3), l.lS (3H, s, CH3), 3.15 (3H, s, OCH3), 3.57 (lH, A of AB, J
17Hz), 3.77 (lH, d, J=1.6Hz, H-3), 3.97 (lH, B of AB, J =17Hz), 4.83
lH, d, J=1.6Hz, H-4), 7.1-7.6 (lSH, m, aromatic Hs); ir (neat) v
max
1750, 1725, 1710 cm (C=O); tlc, Rf 0.53 (benzene; Et2O=4:1),
Rf 0.61 (hexane: EtOAc = 2sl).
(3S,4R and 3R,4S) l-(t-Butyldimethylsilyl)-3-(1'-hydroxy-2'-methoxy-
isopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of epimers
at C-l')
O QH
STr NaBH ~ Sl ~
A solution of crude l-(t-butyldimethylsilyl)-3-(1'-keto-2'
(2"-methoxy-2"-isopropyloxy)-1'-ethyl)-4-tritylthio-2-azetidinone
(60.95 g, 0.103 mol) in THF (100 ml) was diluted with abs.EtOH
(350 ml) and to this solution was added at 0C NaBH4 (4.88 g, 0.156
mol). The mixture was stirred at room temperature for 2 h and
_? tq~
~3~
quenched by slow addition of brine (280 ml). The mixture was
extracted with Et2O (3 x 150 ml) and the extracts were washed with
brine, dried (Na2SO4) and evaporated to yield a yellow residue
which was redissolved in CH2C12 (500 ml). This was dried (Na2SO4)
again and evaporated yielding 57.1 g (0.0966 mol, crude yield 93.8%)
of the title compound as a crude yellow foam: Hmr (CDC14) ~: 0.17
(s, SiCH3), 0.80, 0.87 (2s, Si-tBu), 1.22, 1.25 (2s, CH3), 3.03 (s, OCH3),
4.32 (d, J=2Hz, H-4), 7.0-7.7 (m, aromatic Hs); ir (neat) V 3460 (OH),
1745 (C=O), 1595 (aromatics): Rf 0.47 and 0.42 (hexanes: EtOAc=2:1).
This crude material was used in the next step without purification.
(4'R,3S,4R and 4'S,3R,4S) and (4'S,3S,4R and 4'R,3R,45) l-(t-Butyldimethyl-
silyl)-3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone.
(Isomer C and Isomer B)
QH _L_~
STr p-TsOH H2o ~ ~ ~ Tr
~ ~ Si/ X OMe / ~
A solution of (3S,4R and 4R,4S) l-(t-butyldimethylsilyl)-
3-(1'-hydroxy-2'-methoxyisopropyloxyethyl)-4-tritylthio-2-azetidinone
(mixture of diastereomers at C-l' (57.1 g, 0.0966 mol; crude) in
CH2C12 (500 ml) was treated at room temperature with p-toluenesulfonic
acid monohydrate (200 mg) and 2,2-dimethoxypropane (20 ml) and then
stirred for 1 h. It was washed with sat. NaHCO3 and then brine, dried
(Na2SO4) and evaporated yielding 49.64 g (0.0888 mol, crude yield 91.9%)
of a mixture of the title compounds (Isomer B and Isomer C) as yellowish
foam. This was purified by H~LC (Waters 500 Silicagel; eluent, hexane:
EtOAc=9:1) and by crystallization yielding 14.28 g (25.5 mmol, 26.4~)
of the title compound (Isomer C) as white crystalsi mp 146-7C (pentane);
Hmr (CC14) ~: 0.27 (6H, s, Si-CH3), 0.95 (9H, s, Si-tBu), 1.15 (6H, s,
--ZS?o--
i6~
di-Me), 2.5-2.9 (lH, m, H-4'), 2.97 (lH, t, J=1.8 Hz, H-3), 3.25-3.9
(2H, m, H-5'), 4.27 (lH, d, J=1.8Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs);
ir (nujol) V : 1750 (C=O) and 1595 cm (aromatics); Rf 0.45 (hexanes:
EtOAc-4:1) and 14.50 g (25.9 mmol, yield 25.9~) of the title compound
(Isomer B) as white crystals: mp lg4-5C (Et20-pentane); IHmr (CC14) ~:
0.02 (6H, s, SiMe), 0.833 (9H, s, Si-tBu), 1.13, 1.18 (6H, 2s, diMe),
2.5-2.8 (lH, m, H-4'), 3.3-4.1 (2H, m, H-5'), 3.48 (lH, dd, J3 4=1.5Hz,
J3 4,=5.0Hz, H-3), 3.93 (lH, d, J4_3=1.5Hz, H-4), 7.1-7.7 (15H, m,
aromatic Hs); ir (nujol) v : 1650 (C=O) and 1595 cm (aromatics);
Rf 0.37 (hexanes: EtOAc=4:1). Anal calcd for C33H41N0355i: C 70.80,
H 7.38, N 2.50, 5 5.73; found: (Isomer C) C 70.23, H 7.30, H 7.3-;
N 2.41, S 5.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05.
_ Z~ _
~2~36~61
B. Preparation of the Penem Product (Isomer C)
(4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
4-tritylthio-2-azetidinone (Isomer C)
~STr NaN3 ~ ~ STr
Si ~ HMPT-H O N ~H
To a stirred solution of (4'R,3S,4R and 4's,3R,4S) l-(t-
butyl-dimethylsilyl)-3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-4-trityl-
thio-2-azetidinone (Isomer C) )14.3 g, 25.6 mmol) in hexamethylphos-
phoric triamide(230,4 ml) was added slowly ( in 20 min) at 0-5C a
solution of sodium azide (2.50 g, 38.4 mmoli 1.5 eq) in H2O (25.6 ml).
The mixture was stirred at room temperature for 2 h and poured into
cold water (2.5 2). The white precipitate formed was collected,
washed with H2O and dried yielding 11.26 g (25.3 mmol, crude yield
98.8%) of the title compound as a white solid. A pure material was
obtained by crystallization from CH2C12-Et2O: mp 192-3C (dec.)i IHmr
(CDC13)~:1.33, 1.37 (6H, 2s, di-Me), 3.27 (lH, t, J=3Hz, H-3), 3.8-4.4
(3H, m, H-4' and H-S'), 4.40 (lH, d, J=3Hz, H-4), 4.47 (lH, br, NH,
D2O exchanged) and 7.1-7.7 ppm (15H, m, aromatic Hs); ir (nujol) V
3220 (NH), 1760 (C=O) and 1950 cm (aromatics); Rf 0.31 (hexanes:
EtOAc = 3:2).
6ti~il
(4'R,35,4R and 4'S,3R,4S) 3-t2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
l-(~-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone
(mixture of epimers_ at_C-2") (Isomer C)
STr ~O2PNB ~ ~ Tr
N~ Et3N/THF N ~ OH
C02PNB
A suspension of p-nitrobenzyl glyoxylate hydrate
(6.57 g, 28.95 mmol; 1.15 eq) in benzene (500 ml) was heated at
reflux with Dean-Stark trap for 2 h. Evaporation of the solvent
gave p-nitrobenzyl glyoxylate as an oil. A mixture of thls oil
and (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1'-3'-dioxolan-
4'-yl)-4-tritylthio-2-azetidinone (Isomer C) (11.2 g, 25.2 mmol)
in THF (350 ml, distilled from LAH) was treated with triethylamine
(289 mg, 2.86 mmol) at room temperature under N2 for 18 h (overnight).
After evaporation of the solvent, the residue diluted with CH2C12
(200 ml) was washed successively with brine containing lN HCl (2.9 ml)
sat. NaHCO3 and brine, dried (Na2SO4) and evaporated after addition
of Et2O (30 ml) to give 17.2 g (26.3 mmol, crude yield 100%i purity 95.8~)
of the title compound as a white foam: Rf 0.40 and 0.30 (benzene: Et2O=3:2).
Each isomer was separated by hplc (SiO2, eluent, benzene: Et2O=3:2) and
purified by crystallization from CH2C12-Et2O. Isomer I: Rf 0.40 (benzene:
Et20=3:2); mp 153-4C; lHmr (CDC13) ~: 1.20 (6H, s, di-Me), 3.1 (2H, m,
H-3 and OH), 3.5-4.2 (3H, m, H-4' and H-5'), 4.55 (lH, d, J=2Hz, H-4),
5.12 (lH, br, H-2"), 5.30 (2H, s, OCH2Ar) and 7.1-8.3 ppm (19H, m,
-2.~'3 ~
6~i6~L
aromatic Hs); ir (nujol) Vmax: 3370 (OH), 1775 (3-lactam) and 1745 cm
(ester); Anal. calcd for C36H34N2O8S: C 66.04, H 5.23, N 4.28, found:
C 65.85, H 5.64, N 4.11. Isomer II: Rf 0.30 (benzene: Et2O=3:2);
mp 164-5C; 1Hmr (CDC13) ~: 1.17 (6H, s, di-Me), ~3.2 (2H, m, H-3 and OH),
3.4-4.0 (3H, m, H-4' and H-5'), 4.57 (lH, d, J=2Hz, H-4), 5.23 (lH, br,
-2"), 5.27 (2H, s, -OCH2Ar), and 7.1-8.3 ppm (19H, m, aromatic Hs);
ir (nujol) V : 3340 (OH), 1765 (~-lactam) and 1740 cm (ester);
Anal- calcd for C36H34N2O8S: C 66.04, H 5.23, N 4.28, S 4.90, found:
C 66.01, H 5.34, N 4.28, S 4.75.
(a'R ~C,aR 3 L~l ~',C,~,R,,4,C.) 3-(2'.2'-DimethY1-1',3~-dioxolan-4'-Yl)-l-
(P-nitrobenzvl 2"-chloro-2"-acetate)-4-tritvlthio-2-azetidinone
(mixture of epimers at C-2") (Isomer C)
Tr SOC12-Pyr ~ ~ STr
y H THF O N ~ C1
C02PNB C02PNB
To a stirred solution of (3'R,3S,4R and 4'S,3R,4S)
3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-hydroxy-
2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) (17.13 g, 25.07 mmol;
mixture of epimers at C-2") in THF (250 ml) was added at -15C under
N2 pyridine (2.84 ml, 35.1 mmol) and then immediately afterwards
thionyl chloride (2.20 ml, 30.1 mmol; Anachemia). The mixture was
stirred for 20 min at -15 and then the white precipitate was filtered
off. After washing with benzene, the filtrates and washings were
combined and concentrated. The residue dissolved in benzene (250 ml)
was treated with activated charcoal, filtered and evaporated, yielding
17.94 g (26.65 mmol, crude yield 100%; purity 94.1%) of the crude
title compound as white foam: Rf 0.76 .(benzene: Et2O=3:2); 1Hmr (CDC13) ~:
~ 2 ~ ~
6661
1.20 (6H, s, diMe), 3.17 tlH, m, H-3), 3.4-3.9 (3H, m, H-4' and H-5'),
4.67, 4.72 (lH, 2d, J=2.5 Hz, H-4), 5.30 (2H, s, OCH2Ar), 5.83 (s, H-2")
and 7.1-8.3 ppm (19 H, m, aromatic Hs)i i:r (neat) Vmax: 1770 cm (~-lactam
and ester). This material was used in the next step without purification.
(4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-1-
(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-
2-azetidinone (Isomer C)
.. STr 3 ~ STr
~N ~ Cl diox. ~ ~ P~3
C02PNB C02PNB
A mixture of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-
1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-
2-azetidinone (Isomer C) (17.87 g, 25.0 mmol; purity 94.1~ mixture of
epimers at C-2"), triphenylphosphine (7.27 g, 27.5 mmol) and 2,6-lutidine
(3.19 ml, 27.5 mmol) in dioxane (350 ml; distilled from LAH) was heated at
reflux under N2 for 40 h. Evaporation of the solvent in vacuo gave 29.5 g
of dark oil which was purified by column chromatography (SiO2 330 g; eluent
20-50% Et2O in benzene), yielding 10.5 g of yellowish solid. This solid
was rinsed with Et20 to give 7.49 g (8.33 mmol, yield 33.3~) of the
title compound as slightly yellow crystals: lHmr(CDC13) ~: 1.07 (s, di-Me)
and 7.1-8.2 ppm (m, aromatic Hs); ir (nujol) V : 1760 cm (C=O). An
analytical sample was obtained by crystallization from CH2C12-Et2O:
mp 231-2C; Anal. calcd for C54H47N2O7PS: C 72.14, H 5.27, N 3.12, S 3.57i
found: C 72.18, H 5.43, N 2.98, S 3.41; Rf 0.17 (benzene: Et20=1:1).
- 2 ~ 5 -
12S~6~
(4'R,35,4R and 4'S,3R,4S) Silver_3-(2',2'-dimethyl-1',3'-dioxolan-
4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-
azetidinone-4-thiolate (Isomer C)
. STr ~ SAg
, ~ AgNO3-Pyr
N ~ P~3 MeOH C~ ~
CO PNB
CO2PNB 2
A solution of (4'R,35,4R and 4'5,3R,45) 3-(2',2'-dimethyl-
1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene--2"-
acetate)-4-tritylthio-2-azetidinone (Isomer C) (319 mg, 0.355 mmol) in
CH2C12 (10 ml) was evaporated to yield an oily residue which was
redissolved in hot methanol (~3 ml; 60). To this solution was added
at 60 a hot solution of AgNO3 in MeOH (0.lSM, 4.0 ml, 0.60 mmol)
and then pyridine (29 ~1, 0.36 mmol). The mixture was stirred at
room temperature for 5 h and at 0C for 1 h. The precipitate was
collected and washed with ice-cold methanol and then cold Et2O, yielding
255 mg (0.334 mmol, yield 94.1~) of the title compound as a brownish
solid: ir (nujol) v : 1750 cm (s, C=O).
(4'R,35,4R and 4'5,3R/4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetyl-
thio-2-azetidinone (Isomer C)
O~ "~ SAg cH3cocl/pyr ~ ~ SAc
~N ~ P~3 CH2C12 O ~ ~3
2 O2PNB
To a solution of (4'R,35,4R and 4'5,3R,45) silver
3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-
triphenylphosphoranylidene-2"-acetate-2-azetidinone-4-thiolate
(Isomer C) (254 mg, 0.333 mmol) in CH2C12 (15 ml) containing
~~ ~6 -
~L~J3~
pyridine (100 ~1, 1.24 mmol; 3.72 eq) was added at 0-5C acetyl
chloride (71 ~1, 1.0 mmol; 3.0 eq). The mixture was stirred at
0-5C for 40 min. After filtration of the precipitate over Celite
the filtrate was washed successively with brine containing lN HCl
(1.25 ml), sat. NaHCO3 and then brine, dried (Na2504) and evaporated,
yielding 200 mg of an oil which was crystallized from Et20 to give
155 mg (0.222 mmol, yield 66.7%) of the title compound as white
crystals: lHmr (CDC13) ~: 1.23 (s, di-Me), 2.20, 2.33 (2s,-SAc) and
.2-8.3 ppm (m, aromatic Hs): ir (nujol) V : 1750 (3-lactam and
max
ester) and 1690 cm (thioester). An analytical sample was obtained
by crystallization from CH2C12-Et20: mp 177-8C; Anal. calcd for
C37H35N2O8PS: C 63.60, H 5.05, N 4.01, S 4.59; found: C 63.34, H 5.32,
N 3.83, S 4.31; Rf 0.62 OEtOAc)
(4'R,5R,65 and 4'S,4S,6R) p-Nitrobenzyl 6-(2',2'-dimethyl-1',3'-
dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer C)
7'g ~
\~; ~ SAc toluene ~ ~ ' ~ ~ H3
~02PNB 02PNB
A suspension of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-
dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphospho-
ranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (443 mg,
0.634 mmol) in toluene (70 ml) was heated at reflux under N2 for 6 h.
Evaporation of the solvent gave white solid which was purified by
column chromatography (SiO2 10 g; eluent 10% Et20 in benzene)
yielding 247 mg (0.587 mmol, yield 92.7%) of the title compound
as white solid: lHmr (CDC13) ~: 1.42 (6H, s, di-Me), 2.38 (3H, s, ?-CH3),
3.8-4.5 (4H, m, H-6, H-4' and H-5'), 5.02-5.25-5.33-5 57 (2H, AB type,
_~ ~7~
12~3666~
-OCH2Ar), 5.57 (lH, d, J=1.8 Hz, H-5) and 7.52-7.67-8.12-8.27 ppm
(4H, A2'B2', aromatic Hs); ir (nujol) v x 1760 (3-lactam) and
1700 cm (ester). An analytical sample was obtained by crystallization
from CH2Cl2-Et2O: mp 167-8C; uv (EtOH) ~ a : 265 ( 14,000) and 314 m~
(~ 10,000); Anal. calcd for C19H20N2O75: C 54.28, H 4.79, N 6.66, 5 7.63;
found: C 54.15, H 4.78, N 6.54, S 7.64; Rf 0.62 (benzene-Et2O=l:l).
(4'R,5R,6S and 4'5,5S,6R) 6-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)
-2-methylpenem-3-carboxylic acid (Isomer C)
~ CH3 2/ C
C 0 2PNB o 2H
A solution of (4'R,5R,6S and 4'S,5S,6R) p-nitrobenzyl
6-(2',2'-dimethyl-1',3'-dioxolan-4-yl)-2-methylpenem-3-carboxylate
(Isomer C) (195 mg, 0.464 mmol) in THF (20 ml) was mixed with Et2O
(20 ml), H2O (20 ml), NaHCO3 (39 mg, 0.46 mmol) and 10% Pd-C (200 mg,
Engelhard). This mixture was hydrogenated at 35 psi for 4 h at
room temperature. After removal of the catalyst (over Celite), the
aqueous layer was washed with EtOAc (x2), saturated with NaCl, acidified
with lN HCl (0.47 ml) and immediately extracted with EtOAc (20 ml x 3).
The extracts washed with brine were dried (Na2SO4) and evaporated
yielding 94 mg of yellowish solid which was rinsed with pentane
to give 89 mg (0.31 mmol, yield 67%) of the title compound as yellowish
solid: mp 132-3C; Rf 0.60 (Acetone: HOAc=5: 0.7); IHmr (CDCl3) ~:
1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH3), 3.9-4.6 (4H, m, H-6,
H-4' and H-5') and 5.59 ppm (lH, d, J=1.7 Hz, H-5); ir (nujol) V : _
1760 (~-lactam) and 1660 cm (CO2H); uv (EtOH) ~ : 309 (E 6300) and
263 m~ (~ 3800).
- 2 9'~-
6~i6'1
Example ~
(4'S,5R,6S and 4'R,5S,6R) 6-(2'~2'-Dimethyl-1',3'-dioxolan-4'-yl)-2-
methyl~enem-3-carboxylic Acid (Isomer B)
7~
~""~S\
02H
(4'5,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
4-tritylthio-2-azetidinone (Isomer B)
o ~N ~ / NaN~ O ~ Tr
/ ~<
~(
The title compound was prepared as described in Example~t~5
for the "Iso~er C" from t4ls~3s~4R and 4'R,3R,4S) l-(t-butyl-
dimethylsilyl)-3-(2',2'-dimethyl-1',3'-dioxolan-3'-yl)-4-trityl-
thio-2-azetidinone tIsomer B) (14.4 g, 25.8 mmol): yield 10.8 g,
24-3 mmol, 94.1%; mp 15SC (CH2C12-Et2O); Rf 0.24 (hexanes:
EtOAc=2:1); Hmr (CDC13) : 1.37, 1.40 (6H, 2s, di-Me), 3.23
(lH, dd, J3-4=2.5 Hz, J3 4,=5Hz, H-3), 3.7-4.5 (4H, m, H-4',H-5',N-H),
4.50 (lH, d, J=2.5Hz, H-4) and 7.1-7.6 ppm (lSH, m, aromatic Hs);
ir (nujol) 3170 (NH) and 1745 cm (C=O); Anal. calcd for C27H27NO3S:
C 72.78, H 6.11, N 3.14, S 7.20; found: C 72.16, H 6.11, N 3.14, S 7.17.
-2~9 -
~36~
(4'S,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
l-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone
(mixture of epimers at C-2") (Isomer B)
CIHO O
N ~H Et3N/THF
02PNB
The title compound was prepared as described in Example 103
for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-
1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer B) (10.8 g,
24.3 mmol): yield 15.8 g, 24.1 mmol, 99.3%); yellowish foam; Rf
0.29 and 0.22 (benzene: Et2O+l:l); IHmr (CDC13) ~: 1.28, 1.34
(2s, di-Me), 3.4-4.4 (m, H-3, H-4',H-5', H-2",0H), 4.39, 4.53
(2d, J=2Hz, H-4), 5.15, 5.25 (2s, OCH2Ar) and 7.1-8.3 ppm (m,
aromatic Hs); ir (neat) V : 3440 (br, OH), 1760 (C=O), 1520, 1350
cm (NO2).
(4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
l-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone
(mixture of epimers at C-2") (Isomer B)
~ STr SOC12-pyr ~ ~ STr
~ THF
CO 2PNB CO 2PNB
The title compound was prepared as described in Example 103
for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1',3'-
1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-
tritylthio-2-azetidinone (Isomer B) ~14.9 g, 22.8 mmol; mixture of
qO ~
~ 2~6~i6~l
epimers at C-2"); yield 14.1 g, 20.9 mmol, 91.9%; yellowish foam;
Rf 0.52 (benzene: Et20=3:2); IHmr (CDC13) ~: 1.30, 1.38 (6H, 2s,
di-Me), 3.4-4.5 (4H, m, H-3, H-4',H-5'), 4.57 (lH, d, J=3Hz, H-4),
5.13 (s, H-2"), 5.27 (s, OCH2Ar) and 7.1-8.3 ppm (19H, m, aromatic Hs);
ir (neat) v x 1780 cm (3-lactam, ester).
(4'S,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-
yl)-l-(p-nitrobenzyl 2"-triphenylphosphoranilidene-2"-acetate)-4-
tritylthio-2-azetidinone (Isomer B)
ST~ dlox. ~N ~Sf~3
C02PNB C02PNB
The title compound was prepared as described in Example 103
for the "Isomer C" from (4'5,35,4R and 3'R,3R,45) 3-(2',2'-dimethyl-
1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-
tritylthio-2-azetidinone (Isomer ~) (14.0 g, 20.8 mmol; mixture of
epimers at C-2"): yield 4.64 g, 5.16 mmol, 24.89s; mp 190-95C (dec.,
CH2C12-Et20); IHmr (CDC13) 0: 1.12, 1.20, 1.27, 1.35 (4s, di-Me)
and 7.0-8.1 ppm (m, aromatic Hs); ir (CH2C12) vmax: 1750 cm (~-lactam
ester); Anal. calcd for C54H47N2O7PS: C 72.14, H 5.27, N 3.12, S 3.57
found: C 71.90, H 5.57, N 3.07, S 3.56; Rf 0.21 (benzene: Et2O=l:l).
_2,ql ~
i~36~;61
l4' S 3S 4R and 4'_R.3S.4R) Silver 3-~2' 2' -dimethyl~ ' -dioxol~n
-4' -yl)-l-(p-nitrobenzyl 2"-triDhenyl~hosl~hQranyli~,ene
-2"-acetate)2-azetidinone-4-thiolate (Isomer B)
STr AgNOl-pyr 7~g ~Ag
O N ~P~3 MeOH o ~ 3
Co2PNE3 2
The title compound was prepared a6 de6cribed in Example 51
15 for the "Isomer C" from (4' S, 3S,4R and 4' R, 3S,4R) 3-
(2', 2' -dimethyl-1',3' -dioxolan-4' -yl)-l-(p-nitrobenzyl
2"-triphenyl-phosphoranylidene-2"-acetate)
-4-tritylthio-2-azetidinone (Isomer B) (1. 00 g, 1. 12 mmol):
yield 580 mg, O. 760 mmol, 67. 8%; mp 129-135C (dec); ir (nujol)
20 Vmax: 1745 cm~1 (B-lactam, ester).
(4' S.3S.4R and~ R.3R.4S) 3-~2'.2' -Dimç~hyl-1' 3' -dioxolan
-4' -yll-1-(p-nitrobenzyl 2"-tri~henyl;~hQ~pht ranylidene-2"
-aceta~)-4-acetylthio-2-azetidinone (Isome~
0~ ~3 3 ~ ~
C02PNB 02P~8
The title compound was prepared as described in Example 51
for the "Isomer C" from (4' S, 3S, 4R and 4' R, 3R, 4S) silver
3-(2', 2' -dimethyl-l', 3' -dioxolan-4~ -yl)-1-(p-nitrobenzyl
35 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone
-4-thiolate (Isomer B) (2. 46 g, 3 22 mmol): yield after
purification by column chromatography (SiO2
- 292 -
'~
~.2~6~i6~
32 g, eluent lO~-50~ EtOAc in CH2Cl2=l:l); IHmr (CDC13) ~: 1.23, 1.27,
1.30 (3s, di-Me), 2.22, 2.33 (2s, SAc) and 7.3-8.3 ppm (m, aromatic Hs);
ir (neat) V a 1755 (~-lactam, ester) and 1695 cm (thioester).
(4'S,5R,65 and 4'R,55,6R) p-Nitrobenzyl 6-(2',2'-dimethyl-1',3'-
dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer B)
3 0 ~ ~
O PNB
2 2
The title compound was prepared as described in Example 103
for the "Isomer C" from (4'S,35,4R and 4'R,3R,45) 3-(2',2'-dimethyl-1',
3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-
acetate)-4-acetylthio-2-azetidinone (Isomer B) (200 mg, 0.286 mmol):
yield 64 mg, 0.15 mmol, 53~; mp 151-2C (CH2C12/Et20); Rf 0.67 (benzene:
Et20=1:1); IHmr (CDC13) ~: 1.29, 1.38 (6H, 2s, di-Me), 2.30 (3H, s,
2-CH3), 3.6-4.4 (4H, m, H-6, H-4',H-5'), 5.00-5.18-5.28-5.46 (4H, ABq,
-OCH2Ar), 5.47 (lH, d, J=l.SHz, H-5) and 7.42-7.55-8.05-8.15 ppm (4H,
A2'B2', aromatic Hs); ir (neat) V : 1785 cm (~-lactam) and 1710 cm
(ester); uv (EtOH) ~ a : 266 (~ 13,300) and 314 m~ (~ 9,700); Anal. calcd
ClgH20N2075: C 54.28, H 4.79, N 6.66, S 7.63; found: C 54.00, H 4.75,
N 6.68, S 7.61.
~ ~ ~ 3 ~
6~i6~
(4'5,5R,6S and 4'R,5S,6R) 6-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-
2-methylpenem-3-carboxylic acid (Isomer B)
~ ~ ~ H2/Pd-C ~ ~ H3
C02PNB C02H
The title compound was prepared as described in Example 103
for the "Isomer C: from (4'S,5R,65 and 4'R,55,6R) p-nitrobenzyl 6-
(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-carboxylate
(Isomer B) (79 mg, 0.19 mmol): yield a~ter recrystallization from
CH2C12-pentane 9 mg, 0.032 mmol, 17~; Rf 0.54 (Acetone: HCAc=5:0.5);
lHmr (CDC13) o: 1.35, 1.44 (6H, 2s, di-Me), 2.37 (3H, s, 2-CH3), 3.6-4.5
(4H, m, H-6, H-4',H-5') and 5.56 ppm (lH, brs, H-5); ir (neat) V
1785 cm (3-lactam); uv (EtOH) ~ a : 307 (~ 4300) and 262 m~ (~ 3700).
~3
Example ~
(l'R,5R,6S and l'S,5S~6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2-
ethyl)-2-methylpenem-3-carboxylic acid (Isomer C)
OH
0 ""~ 5
N ~ 3
(l'R,35,4R and 1'5,3R,4S) 3-(1',2'-dihydroxyethyl)-1-(p-nitrobenzyl
2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone
(Isomer C)
Ac H ~ ' SAc
\~ - ~ TFA-H2O ~
O ~ ~
C02PNB C02PNB
A solution of (4'R,3S,4R and 4'S,3R,45) 3-(2',2'-
dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphos-
-2 9~`
~X~36~61~
phoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C)
(472 mg, 0.676 mmol) in trifluoroacetic acid (1.0 ml) and H2O (0.1 ml)
was left at room temperature for 30 min. The mixture was added
dropwise to a cold solution of NaHCO3 (2.5 g) in H2O (50 ml) and
extracted with CH2C12 (20 ml x 3). The extracts washed with sat.
NaHCO3 and then brine were dried (Na2SO4) and evaporated yielding
458 mg (0.695 mmol, crude yield 100%; purity 97.3%) of the crude
title compound as yellowish foam: IHmr (CDC13) ~: 2.20, 2.32 (2s, SAc)
and 7.2-8.3 ppm (m, aromatic Hs); ir (neat) v : 3420 (OH), 1745
(~-lactam, ester) and 1690 cm 1 (thioester); Rf 0.16 OEtOAc).
(l'R,35,4R and l'S,3R,4S) 3-(1'-Hydroxy-2'-methoxymethoxy-1'-ethyl)-
l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetyl-
thio-2-azetidinone (Isomer C)
OH
OH
HO J ~", ~ SAc BrCH20CH3-dimethylaniline ~ ~"--~ SAc
N ~ P~3 CH2C12 o N ~ P~3
7 CO2PNB
To a solution of (l'R,3S,4R and l'S,3R,4S) 3-(1',2'-
dihydroxyethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-
acetate)-4-acetylthio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol;
purity 97.3%) and bromomethylmethylether (55.2 mg, 0.442 mmol; 4 drops)
in CH2C12 (8 ml) was added at 0C, N,N'-dimethylaniline (58.8 mg, 0.483 mmol;
5 drops) and the mixture was stirred at room temperature for 20 h. Addi-
tional bromomethylmethylether (2 drops) and N,N'-dimethylaniline (2 drops)
were added and it was stirred for another 4 h. The mixture diluted with
CH2C12 was washed successively with lN HCl, sat. NaHCO3 and brine, dried
(Na2SO4) and evaporated. The crude residue was purified by hplC (SiO2,
eluent EtOAc) collecting (31 mg, 0.186 mmol, yield 42.2%) of the title
compound as an oil: Rf 0.24 (EtOAc); IHmr (CDC13) ~: 2.20, 2.32 (2s, SAc),
3.30 (s, OCH3), 4.52 (s,-OCH2O-) and 7.4-8.3 ppm (m, aromatic Hs); ir
(neat) v : 3420 (OH), 1755 (br, ~-lactam and ester) and 1690 cm
(thioester).
-295 -
36~6~
l'R,5R,6S and l'S,5S,6R) p-Nitrobenzyl 6-(1'-hydroxy-2'-methoxy-
methoxy-2'-ethyl)-2-methylpenem-3-carboxylate
OH
PH SAc /o~o~ ~ S
toluene ~ 2
C02PNB
A solution of (l'R,3S,4R and l'S,3R,45) 3-(1'-hydroxy-
2'-methoxymethoxy-1'-ethyl)-1-(p-nitrobenzyl 2"-triphenylphosphora-
nylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (167 mg,
0.238 mmol) in toluene (30 ml) was heated at reflux under N2 for 8 h.
Evaporation of the solvent in vacuo gave oily residue which was purified
by hplc (SiO2, eluent EtOAc) to give 68 mg (0.16 mmol, yield 67~) of
the title compound as an oil: Rf 0.61 OEtOAc), 0.15 (benzene: Et2O=l:l);
lHmr (CDC13) ~: 2.38 (3H, s, 2-CH3), 3.35 (lH, br, OH), 3.40 (3H, s, OCH3),
3 6-3.8 (2H, m, H-2'), 3.90 (lH, dd, J6_5=2Hz, J6-1' 4Hz, H 6),
(lH, m, H-l'), 4.67 (2H, s, -OCH20-), 5.03-5.27-5.38-5.62 (ZH, ABq, OCH2Ar),
5.65 (lH, d, J=2Hz, H-5) and 7.55-7.70-8.15-8.30 ppm (4H, A2'B2', aromatic
Hs)i ir (neat) V : 3450 (OH), 1785 (~-lactam), 1710 (ester) and 1520 cm
(NO2); uv (EtOH) ~ : 266 (~ 13000) and 313 m~ (~ 9100)i Anal. calcd for
C18H20N2O8S: C 50.94, H 4.75, N 6.60; found: C 51.13, H 4.77, N 6.36.
_2.96, ~
~ ~r:3~:i66~
(l'R,5R,6S and l'S,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-
2-meth 1 enem-3-carbox lic acid (Isomer C)
Y P Y
OH OH
~ CH3
02PNB CO2H
A solution of (l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl
6-(1'-hydroxy-2'-methoxymethoxy-2'-ethyl)-2-methylpenem-3-carboxylate
(Isomer C) (51 mg, 0.12 mmol) in THF (10 ml) was mixed with Et2O
(10 ml), H2O (10 ml), NaHCO3 (10 mg, 0.12 mmol) and 10% Pd-C (50 mg;
Engelhard). It was hydrogenated at room temperature at 32 psi for
3 h. After filtration of the catalyst over Celite, the aqueous
layer separated was washed with Et2O (x 3) and saturated with NaCl.
The aqueous phase acidified at 0C with 0.lN HC1 (1.2 ml) was
immediately extracted with EtOAc (15ml x 3). The extracts were washed
with brine, dried (Na2SO4) and evaporated yielding 22 mg of yellowish
solid which was rinsed with a small amount of Et2O to give 20 mg
(0.069 mmol, yield 58%) of the title compound as slightly yellow solid:
1Hmr (DMSO-d6) ~: 2.28 (3H, s, 2-CH3), 3.27 (3H, s, OCH3), 3.49(2H, d,
J=6 2HZ, 2~-H), 3.87 (lH, dd~ J6-5 1-7Hz~ 6-1~
(2H, s, -OCH2O-) and 5.55 ppm (lH, d, J=1.7 Hz, 5-H); ir (KBr) ~ :
3410 (OH), 1755 (~-lactam) and 1655 cm (CO2H); uv (EtOH) ~ :
308 (~ 6800) and 262 m~ (~ 4200), mp 137-8C (dec.).
--2q7-
36~
Exam~le 54
1'S 5R 6S and l'R.5S~6R) 6-(l'-Hydr~ 2'-methoxymQthQxY
-2'-ethyl)-2-methylpenem-3-carboxylic acid (Isomer B!
,OH
~O~ .,~S~
1 0 ~
02H
(l'S 3S.4R and l'R.3R.4S) 3-(l'.2'-dihydroxyethyl)
-l-(p-nitrobenzyl 2"-triphenyl~ho6~hQra~ylidene-2"-
acetate)-4-acetylthio-2-azetidinone _(ISQmer Bl
OH
(V r_fAc HF-H;~O ~J~SAC
o~ N ~p~3 N ~p~3
02PN9 C02PN9
The title compound was prepared as described in Example 53
for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S)
3-(2',2'-dimethyl-l',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl
2"-triphenylphosphoranylldene-2"acetate)-4-acetylthio
-2-azetidinone (Isomer B) (1.03 g, 1.47 mmol): yield 970 mg, 1.47
mmol, 100%; yellowish foam: 1Hmr (CDC13) ~: 2.20, 2.32 (2s, -SAc)
and 7.3-8.2 ppm (m, aromatic Hs); ir (neat) v max: 3410 (OH),
1750 (B-lactam, ester) and 1690 cm~1 (thioester): Rf 0.16
(EtOAc).
- 298 -
... ...
~....~
, , ~
~!36~
(l'S,35,4R and l'R,3R,45) 3~ HvdroxY-2~-methoxymethoxy-l~-ethyl)-
1-(p-nitrobenzYl 2"-triPhenylphosphoranylidene-2"-acetate)-4-acetYl-
thio-2-azetidinone (Isomer,B)
OH OH
~ ~........ SAc ~ O ~ "" J SAc
" ~ BrCH2OCH3/dimethylaniline l l
O~ - N ~ P~3 CH2C12 ~ N ~ p~3
C02PNB 02PNB
The title compound was prepared as described la Exa~.~d~
for the "Isomer C" from (1's,3S,4R and l'R,3R,4S) 3-(1',2'-dihydroxy-
ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-
acetylthio-2-azetidinone (Isomer B) (485 mg, 0.736 mmol): yield
205 mg, 0.292 mmol, 39.6~; oil: IHmr (CDC13) ~: 2.22, 2.33 (2s,
SAc), 3.32 (s, OCH3), 4.57 (s,-OCH2O-) and 7.2-8.3 ppm (m, aromatic H~
ir (neat) ~ : 3420 (OH), 1755 (~-lactam, ester) and 1690 (thioester)
Rf 0.32 (EtO~c ) .
(l'S,5R,6S and l'R,5S,6R) p-Nitrobenzyl 6-(l'-hydroxY-l~-meth
methoxy-2'-ethyl)-2-methylpenem-3-carboxylate
OH QH
O ~ ." ~ SAC ~O ~
toluene-HR ~ ~ ~ CH3
~02PNB O2PNB
The title compound was prepared as described in Ex~3p`c
for the "Isomer C" from (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy-2'-
methoxymethoxy-l'-ethyl~-l-(p-nitrobenzyl 2"-triphenylphosphoranyl-
idene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (205 ms,
0.292 mmol) and hydroquinone (10 mg, 0.09 mmol): yield 38 mg, 0.090
mmol, 31~; 152-4C; Rf 0.23 (benzene: Et20=1:1); ~Hmr (C~C13) ~:
2.37 (3H, s, 2-CH3), 3.40 (3H, s, OCH3), 3.4-3.9 (3H, m, H-6, H-2"),
-299-
1~36~6~L
~.15 (lH, M, H-l'), 4.67 (2H, 8, -OCH20-), 5. 10-5. 27-5.39-5.56
(2H, ABq, -OCH2Ar), 5.67 (lH, d, J=l.S Hz, H-S) and
5.55-5.16-8.15-8.27 ppm (4H, A2'B2', aromatic H3); ir (CH2C12
mull) vmax : 3370 (OH), 1785 (B-lactam) and 1700 cm~1 (ester);
uv (THF-EtOH=1:1) Amax: 265 (~ 10400) and 314 m~ (~ 7800).
(l'S.SR,6S and 1'R.5S.6R) 6-(l'-Hydroxy-2'-methoxymethoxy-2'-
ethyl)-2-methylpenem-3-carboxylic acid (Isomer B)
OH OH
J'C~ CH H 2/Pd-C ~ ~J=
02P~B co2
The title compound was prepared as described in Example 53
for the "Isomer C" from (1'S,5R,6S and l'R,5S,6R) p-nitrobenzyl
6-(1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylpenem
-3-carboxylate (Isomer B) (36 mg, 0.085 mmol): yield 7.5 mg,
0.026 mmol, 30%; yellowish crystals; lHmr (CDC13) ~ : 2.36
(3H, s, 2-CH3), 3.39 (3H, 3, OCH3), 3.6-3.9 (3H, m, H-6, H-2'),
4.15 (lH, m, H-l'), 4.66 (2H, s, OCH20) and 5.67 ppm (lH, d,
J=1.4 Hz, H-5); ir tCH2C12)VmaX: 1785 (B-lactam) and 1675 cm 1
(CO2H); uv (EtOH) max: 308 (~ 2900) and 263 m~ (F 2900)
- 300 -
~,~
~t~6
5~
Example ~
2-Benzimidoylaminomethylpenem-3-carboxylic ACid
CH2 -NH- C- CH
COOH
A. ~ 2 ~ H2C02Na + (COC1)2 2 2 > ~ 2 ~ H2COC-
(I) (II)
To a suspension of 0.38 g (0.0015 mole) of sodium 3-benzyl-1,2,~-oxadiazol-5-one-
4-aCetate (I)l in 10 ml of methyl chloride, containing 2 drops of DMF~ was addedat room temperature 0.13 ml (0.0015 mole) of oxalyl chloride, causing the mixture
to effervesce. The reaction mixture was stirred at room temperature for 1 hour.The NaCl that had formed was removed by filtration and the filter cake was washed
with several small portions Of methylene chloride. The solution of acid chloride
(II), was used directly.
1. K. Takacs and K. Harsanyi, Ber. 103~ 2330 (1970).
B. (II) ~ ~ 03 pyridine 0~ ~ ~ ~ ~ 2
02PNB 02PNB
(III) (IV)
A solution of 1.0 g ~0.0015 mole) of (III) and 0.12 ml (0.015 mole) of pyridine
in 10 ml of methylene chloride under a nitrogen atmosphere was cooled to ~. The
acid chloride (II) solution was added all at once to the solution of (III) and
the reaCtion mixture was stirred at ~ for 5 minutes~ then at room temperature
for 1.5 hrs. A thick precipitate formed in the reaction mixture. The mixture
was filtered and the filtrate diluted with methylene chloride to a volume to 70-90 ml . The organic phase was then washed successively with 70 ml of O.lN hydro-chloric acid, 80 ml of 1% sodium bicarbonate and 80 ml of water. The methylene
chloride phase was dried over magnesium sulfate. The solvent was removed at
--301--
~ Xr~6~
reduced pressure and the residual oil chromatographed on
Mallinckrodt "SILIC AR CC-7"*silica gel using chloroform as the
eluant, giving 0.4 g (30.5%) of (IV) as an oil. The infrared and
nuclear magnetic resonance spectra were consistent for (IV).
toluene ~ ~ ~ ~ CH
2~
(V)
A solution of 0.4 g (0.00045 mole) of IV in 50 ml of toluene was
lQ heated at reflux for 4 hrs. The solvent was removed at reduced
pressure and the residue chromatographed on Mallinckrodt~SILICAR
CC-7'~* silica gel, using 5% ethyl acetate in methylene chloride
as eluant, affording 0.15 g (66.6%) of V as an oil which
solidified. The infrared and nuclear magnetic resonance spectra
were consistent for V.
Anal. Calcd for C23 H 18N407S: C, 55-86; H, 3.67; N, 11.33.
Found: C, 56.17; H, 3.76; N, 11.23.
loZ Pd/C ~ ~ 2
2~
A solution of 0.135 g (0.00027 mole) of V in 40 ml of
tetrahydrofuran and 40 ml of anhydrous diethyl ether was added to
a slurry of 10% palladium on carbon catalyst in 40 ml of water
under a nitrogen atmosphere. The resultant mixture was
hydrogenated in a Parr hydrogenation apparatus at room
temperature at an initial hydrogen pressure of 52 psi for 3.5
hrs. Hydrogen uptake was 4.5 psi. The catalyst was removed by
filtration, washing the filter pad well with water. Additional
diethyl ether was added to the filtrate and the phases were
separated. The aqueous phase was extracted 3x with diethyl ether.
The aqueous phase was then concentrated to dryness at reduced
pressure. The residue was chromatographed, using the high
pressure liquid chromatography technique, to afford 0.050 g (58%)
of the title penem acid; decomp 156-173. The infrared and
nuclear
*Trade Mark
- 302 -
~f~
magnetic resonance spectra were consistent for the desired
product.
Anal. Calcd for C15H15N303S~1.5H20: C, 52.31; H, 5.27; N,
12.20.
Found: C, 51-64; H, 4.95; N, 12.31.
Example 56
2-Phenylimidoylaminomethylpenem-3-carboxylic Acid
~ CH2-NH-C
COOH
Following the procedure of Example 55 but using an
equimolar amount of sodium 3-phenyl-1,2,4-oxadiazol-5--
one-4-acetate as the starting material in place of the
sodium 3-benzyl-1,2,4-oxadiazol-5-one-4-acetate used
therein, there was produced the title product.
Bioloaical Data
Representative compounds of the present invention were
subjected to in vitro antibiotic screening against a variety
of microorganisms. Samples of the indicated compounds after
solution in water and dilution with Nutrient Broth were
found to exhibit the following Minimum Inhibitory
Concentration (MIC) in mcg./ml. versus the indicated
microorganisms as determined by overnight incubation at
37C. by the tube dilution method.
- 303 -
6~61
M.I.C. in mcg/ml
Compoun~d L~x~m~lQ N~-L
Orqanism
Streptococcus pneumoniae 125
5 A9585
Streptococcus pyogenes >125
A9604
Staphylococcus aureus
A9537
10 Staph aureus +50% 8
Serum A9537
Staphylococcus aureus 32
A9606
Staphylococcus aureus 4
15A15097
Streptococcus faecalis 125
A20688
Escherichia coli 8
A15119
20 Escherichia coli 2
A20341-1
Klebsiella pneumoniae 125
A15130
Klebsiella species 4
25A20468
Proteus mirabilis 8
A9900
Proteus mirabilis 63
A9716
30 Proteus morganii 63
A15153
Proteus rettgeri 32
A21203
Serratia marcescens 63
35A20019
Enterobacter cloacae 16
A9659
Enterobacter cloacae 16
A9656
40 Pseudomonas aeruginosa 125
A9843A
Pseudomonas aeruginosa >125
A21213
Hemophilus influenzae
45A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 304 -
. . .
~ ~r~6~61
M.I.C. in mcg/m1
ComDound (ExamDle No.
5Organism 2 3
Streptococcus pneumoniae
A9585
Streptococcus pyogenes 2 4
A9604
10 Staphylococcus aureus 8 2
A9537
Stapn aureus +50% >63 >63
Serum A9537
Staphylococcus aureus 4 4
15A9606
Staphylococcus aureus 8 32
A15097
Streptococcus faecalis 63 125
A20688
20 Escherichia coli 32 63
A15119
Bscherichia coli 32 63
A20341-1
Klebsiella pneumoniae 63 125
25A15130
Klebsiella species >125 >125
A20468
Proteus mirabilis 63 63
A9900
30 Proteus vulgaris 63 32
A9716
Proteus morganii 63 125
A15153
Providencia stuartii 32 63
A21205
Serratia marcescens 125 63
A20019
Enterobacter cloacae 125 125
A9659
40 Enterobacter cloacae >125 125
A9656
Pseudomonas aeruginosa >125 >125
A9843A
Pseudomonas aeruginosa >125 >125
A21213
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 305 -
~! r
~36~1
M.I.C. in mcq/ml
Com~ound (Exam~le No.)
5Organism 4 5
Streptococcus pneumoniae 1 .5
A9585
Streptococcus pyogenes 4 4
A9604
10 Staphylococcus aureus 8 4
A9537
Staph aureus +50% >63 >63
Serum A9537
Staphylococcus aureus 4 9
15A9606
Staphylococcus aureus 125 63
A15097
Streptococcus faecalis 125 125
A20688
20Escherichia coli >126 63
A15119
Escherichia coli >125 125
A20341-1
Klebsiella pneumoniae >125 63
25A15130
Xlebsiella species >125 >125
A20468
Proteus mirabilis 63 63
A9900
30 Proteus vulgaris 63 32
A9716
Proteus morganii 125 125
A15153
Providencia stuartii 125 32
A21205
Serratia marcescens >125 63
A20019
Enterobacter cloacae >125 125
A9659
40 Enterobacter cloacae >125 125
A9656
Pseudomonas aeruginosa - >125
A9843A
Pseudomonas aeruginosa - >125
A21213
Hemophilus influenzae
A5833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 306 -
M l.C. in mc~/ml
ComPound (Example No.)
Or~anism 11(5) 11(6)
Streptococcus pneumoniae
A9585 1 2
Streptococcus pyogenes
P~9604 2 4
Staphylococcus aureus
A9537 4 4
Staph aureus +50~
Serum A9537 32 63
Staphylococcus aureus
A9606 32 125
Staphylococcus aureus
A15097 63 63
StreptococCus faecalis
A20688 >63 125
Escherichia coli
AlSll9 16 16
Escherichia coli
A20341 - 1 >63 125
Klebsiella pneumoniae
A15130 63 125
Xle~siella species
A20468 > 63 > 125
Proteus mirabilis
A9900 8 16
Proteus vulgaris
A21559 63 32
Proteus morganii
A15153 16 32
Proteus rettgeri
A21203 32 32
Serratia marcescens
A20019 32 63
Enterobacter cloacae
A965g 63 63
Enterobacter cloacae
A9656 63 63
A9843A 16 32
Pseuaomonas aeruginosa
~21213 32 > ~2 5
Hemophilus influenzae
A9833
Haemop~ilus influenzae
~21522
Bacteroides fragilis
A 20931
Bacteroides fragilis
A20929
^37~
lXJ~6~61
M.I.C. in mcg/ml
CompQund (Example No.)
Organism 12
Streptococcus pneumoniae .016
A9585
Sreptococcus pyogenes .06
A9604
10 Staphylococcus aureus .13
A9537
Staph aureus +50% 4
Serum A9537
Staphylococcus aureus 8
A9606
Staphylococcus aureus 125
A15097
Streptococcus faecalis 63
A20688
20 Escherichia coli .5
A15119
Escherichia coli 63
A20341-1
Klebsiella pneumoniae 8
A15130
Klebsiella species >125
A20468
Proteus mirabilis
A9900
Proteus vulgaris
A9716
Proteus morganii
A15153
Proteus rettgeri 2
A21203
Serratia marcescens
A20019
Enterobacter cloacae 2
A9659
Enterobacter cloacae
A9656
Pseudomonas aeruginosa
A9843A
Pseudomonas aeruginosa 125
A21213
Haemophilus influenzae 125
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 308 -
6~1
M.I.C, in rncq/ml
Compound (Example No.)
Orqanism 32 18 24
Streptococcus pneumoniae .25 .25 .016
A9585
Streptococcus pyogenes 8 2 .25
A9604
Staphylococcus aureus 8 4 .03
A9537
Staph aureus +50~ 32 63 63
Serum A9537
Staphylococcus aureus 16 4 16
A9606
Staphylococcus aureus 63 16 >125
A15097
Streptococcus faecalis~i25 125 16
A20688
Escherichia coli 63 4 63
A15119
Escherichia coli >125 16 >125
A20341-1
~lebsiella pneumoniae125 32 >125
A15130
Klebsiella species >125 125 >125
A20468
Proteus mirabilis 63 16 32
A9900
Proteus vulgaris 125 16
A9555
Proteus morganii 125 32 32
A15153
Proteus rettgeri 63 32
A21203
Serratia marcescens 63 32 16
A20019
Enterobacter cloacae 125 32 >125
A9659
Enterobacter cloacae 125 63 125
A9656
Pseudomonas aeruginosa125 125 ~125
A9843A
Pseudomonas aeruginosa125 125 >125
A21213
Hemophilus influenzae - - -
A9833
Haemophilus influenzae
A21522
Bacteroides fragi lis - - -
A20931
Bacteroides fragilis
A20929
_3O~ -
661
M I.C. in mcg/ml
Compound ~Examole No.)
Organism
Pseudomonas aeruginosa - - _
A20599
Pseudomonas aeruginosa - _ _
A9925
Pseudomonas aeruginosa
A20229
Proteus species
A20543
Proteus mirabilis - _ 16
A9716
Providencia stuartii - - 63
A21205
lX~6~61
M.I.C. in meg/ml
Compou~d (Exam~
5Organism 25
Streptocoeeus pnsumoniae 2
A9585
Streptocoeeus pyogenes 16
A9604
10 Staphylococcus aureus 32
A9537
Staph aureus +50% >63
Serum A9537
Staphyloeoccus aureus >125
15A9606
Staphylococcus aureus >125
A15097
Streptococcus faecalis 125
A20688
20 Escherichia coli 63
A15119
Escheriehia coli >125
A20341-1
Klebsiella pneumoniae >125
25A15130
Klebsiella species >125
A20468
Proteus mirabilis 63
A9900
Proteus vulgaris
A9716
Proteus morganii 125
A15153
Proteus rettgeri 125
35A21203
Serratia mareeseens >125
A20019
Enterobaeter eloaeae >125
A9659
40 Enterobaeter eloaeae >125
A9656
Pseudomonas aeruginosa 125
A9843A
Pseudomonas aeruginosa 125
45A21213
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Baeteroides fragilis
A20931
Baeteroides fragilis
A20929
- 311 -
M.I.C. in mca/ml
Compound (Example No.)
organism 25
Pseudomonas aeruginosa
A20599
PseudoNonas aeruginosa
A9925
Pseudomonas aeruginosa
A20229
Proteus species
A20543
Proteus mirabilis 63
A9716
Proteus mirabilis
A9555
- 312 -
M.I.C. in m~s~ml
Compound (Example No.)
5Organism 31
Sreptococcus pneumoniae 63
A9585
Streptococcus pyogenes 125
A9604
10 Staphylococcus aureus 32
A9537
Staph aureus +50% 32
Serum A9537
Staphylococcus aureus >125
15A9606
Staphylococcus aureus 63
A15097
Streptococcus faecalis 63
A20688
20 Escherichia coli 63
A15119
Escherichia coli 32
A20341-1
Klebsiella pneumoniae >125
25A15130
Klebsiella species 63
A20468
Proteus mirabilis 125
A9900
30 Proteus vulgaris >125
A9555
Proteus morganii 125
A15153
Proteus rettgeri 125
35A21203
Serratia marcescens 125
A20019
Enterobacter cloacae 125
A9659
40 Enterobacter cloacae 32
A9656
Pseudomonas aeruginosa 125
A9843A
Pseudomonas aeruginosa 125
45A21213
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 313 -
:
6~
M.I.C. in mcq/ml
Compound (Example No.)
5Organism 33 34
Streptococcus pneumoniae .06 .25
A9585
Streptococcus pyogenes .13 2
A9604
10 Staphylococcus aureus 1 4
A9537
Staph aureus +50~ 16 63
Serum A9537
Staphylococcus aureus 125 4
15A9606
Staphylococcus aureus >125 16
A15097
Streptococcus faecalis 125 125
A20688
20 Escherichia coli 16 4
A15119
Escherichia coli >125 16
A20341-1
Klebsiella pneumoniae 125 32
25A15130
Klebsiella species >125 125
A20468
Proteus mirabilis 8 16
A9900
30 Proteus vulgaris 63 16
A9555
Proteus morganii 32 32
A15153
Proteus rettgeri 16 32
35A21203
Serratia marcescens 63 32
A20019
Enterobacter cloacae 125 32
A9659
40 Enterobacter cloacae 63 63
A9656
Pseudomonas aeruginosa 125 125
A9843A
Pseudomonas aeruginosa 125 125
45A21213
Hemophilus influenzae - -
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 314 -
6~
M.I.C. in mcg/ml
Compound (Example No.)
5 ~ Organi 5 m _35_ 36. 40
Streptococcus pneumoniae 32 .25 .004
A9585 32 .25 .008
Streptococcus pyogenes125 1 .004
A9604 125 1 .004
10 Staphylococcus aureus - - .008
A9537 >125 2 .008
Staph aureus +50% - - .06
Serum A9537 >63 8 .06
Staphylococcus aureus - - .06
A9606 >125 4 .06
Staphylococcus aureus - - .06
A15097 >125 8 .25
Streptococcus faecalis>125 63 .5
A20688 >125 63 .5
20 Escherichia coli >125 16 .13
A15119 >125 16 .25
Escherichia coli >125 16 <.25
A20341-1 >125 16 .13
Klebsiella pneumoniae>125 16 <.25
A15130 >125 16 .5
Klebsiella species >125 16 .5
A20468 >125 16 .5
Proteus mirabilis >125 32 <.25
A9900 >125 16 .25
30 Proteus vulgaris >125 16 <.25
A21559 >125 16 .25
Proteus morganii >125 32
A15153 >125 16
Proteus rettgeri >125 16 <.25
A21203 >125 16 .5
Serratia marcescens >125 16 .5
A20019 >125 16 .5
Enterobacter cloacae>125 32 4
A9659 >125 - 2
40 Enterobacter cloacae>125 16 .5
A9656 >125 - .5
Pseudomonas aeruginosa>125 >125 16
A9843A >125 - 16
Pseudomonas aeruginosa>125 >125 125
A21213 >125 - 63
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 315 -
P,~
~36~
M.I.C. in mcg/ml
ComPound lExample No.)
Orqanism 37 38 39
Streptococcus pneumoniae
A9585 03 03 .016
Streptococcus pyogenes .06 .5 .03
Staphylococcus aureus
A9537 .5 .03 .06
Staph aureus +50%
Serum A9537 4 .25 .13
A9606 1 .25 .13
Staphylococcus aureus 2 .5 .25
Streptococcus faecalis 2 32 4
Escherichia coli
AlSll9 2 8
A20341-1 8 8 2
Klebsiella pneumoniae 8 16 4
Xlebsiella species
A20468 63 32 4
Proteus mirabilis
A9900 2 2 4
Proteus vulgaris 4 2 2
Prote~s morganii
A15153 8 2
A21203 2 2 4
Serratia marcescens 8 16 4
Enterobacter cloacae
A9659 8 32 4
A9656 32 1 16
A9843A 63 2 16
Pseudomonas aeruginosa
A21213
He~ophilus influenzae
~833
~ae~ophilus influenzae
A21522
Bacteroides fragilis
~20931
Bacteroiacs fragilis
A20929 _3~L-
~ ~6'~6~L
M.I.C. in mcq/ml
Compound (Example No.)
5organi6m 43
Sreptococcus pneumoniae >63
A9585
Streptococcus pyogenes >63
A9604
10 Staphylococcus aureus >63
A9537
Staph aureus +50% >32
Serum A9537
Staphylococcus aureus >63
15A9606
Staphylococcus aureus >63
A15097
Streptococcus faecalis >63
A20688
20 Escherichia coli >63
A15119
Escherichia coli >63
A20341-1
Klebsiella pneumoniae >63
25A15130
Klebsiella species >63
A20468
Proteus mirabilis >63
A9900
30 Proteus vulgaris >63
A21559
Proteus morganii >63
A15153
Proteus rettgeri >63
35A21203
Serratia marcescens >63
A20019
Enterobacter cloacae >63
A9659
40 Enterobacter cloacae >63
A9656
Pseuaomonas aeruginosa >63
A9843A
Pseudomonas aeruginosa >63
45A21213
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 317 -
:: $
~6~i61
M.I.C. in mcq~ml
Compound ~Example No.
5Oraanism 45
Streptococcus pneumoniae 2
A9585
Streptococcus pyogenes 16
A9604
10 Staphylococcus aureus 32
A9537
Staph aureus +50% >32
Serum A9537
Staphylococcus aureus 2
15A9606
Staphylococcus aureus 8
A15097
Streptococcus faecalis 63
A20688
20 Escherichia coli 2
A15119
Escherichia coli 32
A20341-1
Klebsiella pneumoniae 8
25A15130
Klebsiella species >63
A20468
Proteus mirabilis 4
A9900
30 Proteus vulgaris 16
A21559
Proteus morganii 8
A15153
Proteus rettgeri 8
35A21203
Serratia marcescens 8
A20019
Enterobacter cloacae 8
A9659
40 Enterobacter cloacae 8
A9656
Pseuaomonas aeruginosa 63
A9843A
Pseudomonas aeruginosa >63
45A21213
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 318 -
,~., ~.
~
M.I.C. in mcg/m~
Compound ~Example No~L
5Orq~nism 47
Streptococcus pneumoniae .S
A9585
Streptococcus pyogenes .5
A9604
10 Staphylococcus aureus 8
A9537
Staph aureus +50% 32
Serum A9537
Staphylococcus aureus 16
15A9606
Staphylococcus aureus 32
A15097
Streptococcus faecalis >63
A20688
20 Escherichia coli 32
A15119
Escherichia coli 32
A20341-1
Klebsiella pneumoniae 63
25A15130
Klebsiella species 63
A20468
Proteus mirabilis 32
A9900
30 Proteus vulgaris 32
A21559
Proteus morganii 63
A15153
Proteus rettgeri 32
35A21203
Serratia marcescens 63
A20019
Enterobacter cloacae 63
A9659
40 Enterobacter cloacae 63
A96S6
Pseuaomonas aeruginosa >63
A9843A
Pseudomonas aeruginosa >63
45A21213
Hemophilus influenzae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929
- 319 -
.~
~ ,~r;~6661
M.I.C. in mc~/ml
ComPound ~Example No.)
Organism 4.8 49 50
streptocc~ccus pneumoniae>125 1 32
Strept cc~ccus pyogenes>125 16 32
Staphyloc~ccus aureus >125 32 125
A9537
Staph aureus +509c. >63 >63 >63
Serum A9537
Staphyl coccus aureus >125 32 >125
A 1509 7 > 125 > 125 > 125
A 206 88 > 125 > 125 > 125
A 15 119 > 125 > 125 > 125
A 20 341 - 1 > 125 > 125 > 125
A 15 130 > 125 > 125 > 125
A 2046 8 > 125 > 125 > 125
A9900 > 125 > 125 > 125
Proteus vulgaris >125 >125 >125
A15 15 3 > 125 > 125 > 125
Proteus rettgeri >125 >125 >125
A21203
Serratia marcescens >125 >125 >125
Enterobacter cloacae >125 ~125 >125
A9 659
Enterobacter cloacae ~125 >125 >125
A9 65 6
Pseudomonas aeruginosa>125 >125 >125
A9 84 3A
Pse domonas aeruginosa>125 >125 >125
He~ophilus influenzae
A9 8 33
Haemophilus influenzae
A2 1522
Bacteroides fragilis
A20931
Bacteroi~cs fragilis
A20929 _ 3,~o_
1~6661
ComPound (Example No.)
Orqanism 51 52 53 ~_
Streptococcus pneumonlae 63 16 4 32
Streptococcus pyogenes 63 32 4 32
Staphylococcus aureus >63 63 >8 - 63
staph aureus +50~ >32 >32 >32 >32
Staphylococcus aureus >63 63 63 >63
StaphylocoCcus aureus >63 63 >63 >63
Streptococcus faecalis >63 63 >63 >63
A20688
A15119 >63 >63 63 63
A20341-1 ~63 >63 63 63
A15130 >63 >63 63 >63
Klebsiella species >63 >63 >63 >63
A20468
A9900 63 >63 ~63 63
ProteUs vulgaris >63 >63 >63 >63
A15153 >63 >63 >63 >63
A21203 >63 63 32 63
Serratia marcescens >63 . >63 >63 63
A9659 >63 >63 63 >63
Enterobacter cloacae >63 >63 63 63
Pseudomonas aeruginosa 63 63 63 63
A9843A
Pse domonas aeruginosa 63 63 63 63
Hemophilus influen~ae
A9833
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroi~es fragilis
A20929 -32l-
12~36661
M I.C. in mc~/ml
Compound ~Exa~ple No.)
Orqanism 55 56
Streptococcus pneumoniae
A9585 .5 . 2 5
Streptococcus pyogenes
A9604 .5 .25
Staphylococcus aureus
A9537 .5 .25
Staph aureus ~509u
Serum A9537 16 16
Staphylococcus aureus
A9606 32 16
Staphylococcus aureus
A15097 >63 >125
Streptococcus faecalis
A20688 >63 125
Escherichia coli
AlSll9 63 63
Escheri chia coli
A20341-1 >63 >125
Klebsiella pneumoniae
A15130 >63 125
Klebsiella species
A20468 >63 >125
Proteus mirabilis
A9900 63 63
Proteus vulaaris
A21559 63 125
Proteus morganii
A15153 63 63
Proteus rettgeri
A21203 63 63
Serrati a marcescens
A20019 63 125
Enterobacter cloacae
A9659 >63 125
Enterobacter cloacae
A9656 63 125
Pseudomonas aeruginosa
A9843A 63 63
Pseudomonas aeruginosa
A21213 63 125
He3nophilus influenzae
A98 33
Haemophilus influenzae
A21522
Bacteroides fragilis
A20931
Bacteroides fragilis
A20929 - -
~3Z~^
1~36~1
Representative compounds of the present invention were
also tested in vivo in mice and their PD50 (dose of compound
in mg/kg required to protect 50% of the treated mice against
an otherwise lethal infection of a microorganism) values
determined with respect to the test organisms shown below.
- 323 -
'i.,~
6~
S. aureus A9537
# of infecting
organisms of
S. aureus # of Treatment PD50
Compoun_ a 9537 _ _ treatments route
(m ~kg/treatment
Compound
of Ex.65 7.8 x 105 2 IM 0.12
Compound
of Ex.36 6.6 x 105 2 IM 7.7
- 324 -
1~.36~
S. aureus A9537
# of infecting
organisms of
S. aureus # of Treatment PD50
Compound a 9537 treatments route
(maJka/treatment
Compound
10 of Ex.62 8.6 x 105 2 IM 1.0
Compound
of Ex.56 8 x 105 2 IM >5
Compound
of Ex.39 8 x 105 2 IM 0.04
- 325 -
12r`3~i6~
Mouse blood levels after intramuscular administration
of representative compounds of the present invention were
determined and are reported in the table below.
*Mouse Blood Levels in mcg/ml After
intramuscular Administration of
40 mq/kq Body Weiqht
Compound Minutes After Administration
10 20 30 45 60 90 120
_
Compound of Ex. 4044.7 34.4 23.7 17.6 9.8 3.6
*Average of 6 mice
, .~,~
. .
-326-
