Note: Descriptions are shown in the official language in which they were submitted.
1~54~3~1
1 -
1 -
This application is a divisional of Canadian
Patent Application 442,383 filed December 1, 1983.
DESCRIPTION
The invention relates to a new process for
the preparation of (5R) penem compounds, of the. general
formula I and their pharmaceutically and/or veterin-
arily acceptable salts.
R1 s
~ ~Y
I
N
p OORZ
In the general formula I, Rl represents a
hydrogen atom or an organic group; R2 represents a
hydrogen atom or a carboxy protecting ~3roup; and Y
represents a hydrogen or halogen atom or an organic
group.
Organic groups which R1 may represent include
optionally substituted aliphatic or cy~:loaliphatic~
20groups.. The aliphatic groups are preferably alkyl
groups having from l to 12 carbon atom. and the op-
tional substitue~nts may be one or more hydroxy, amino,
cyano and/or mercapto groups. The hydroxx, amino and
.mercapto groups may be free or protected. Particularly
preferred alkyl groups are methyl and, ethyl, especially
the latter, and a preferred sustituent for such.a group
is a hydroxy group,
~~,~
o'~o
()
1~:~4~3;~1
- 2 -
which may be free or protected. the 1-hydroxyethyl group
in 6S, BR or 6R, BS configuration is most preferred. The
cycloaliphatic groups are preferably monocycloalkyl groups
having from 4 to 7 carbon atoms. Cyclopentyl and
cyclohexyl groups are especially perferred. Optional
substituents are preferably chosen from alkyl groups
having from 1 to 6 carbon atoms, for example methyl or
ethyl groups, hydroxy, amino and mercapto groups, the
hydroxy, amino and mercapto groups being free or protected.
the carboxy protecting group R2 may be any group which,
together with the -C00-moiety, forms an esterified
carboxy group, Examples of carboxy protecting groups R2
are, in particular, alkyl groups having from 1 to 6
carbon atoms, for instance methyl, ethyl or t-butyl;
halo-substituted alkyl groups having from 1 to 6 carton
atoms, for example 2,2,2-trichloroethyl; alkenyl groups
having from 2 to 4 carbon atoms for example allyl;
optionally substituted aryl groups, for example phen~rl and
~-vitro-phenyl; aryl substituted alkyl groups, the alkyl
2p part whereof has from 1 to 6 carbon atoms and the ar:~l
part whereof is optionally substituted, for example,
benzyl, p.-vitro-benzyl and p-methoxy-benzyl; aryloxy
substituted alkyl groups, the alkyl part whereof has from
1 to 6 carbon atoms, for example phenoxy-methyl; or
groups such as benzhydryl, o-vitro-benzhydryl, acetonyl,
trimethylsilyl, Biphenyl-t-butyl-silyl, and dimethyl-t-
butyl-silyl. the definition of R2 as a carboxy protecting
1;~54~~1
.c
- 3 -
group also includes any residue, such as acetoxymet.hyl,
pivaloyloxymethyl or phthalidyl, leading to an ester group
which is known to be hydrolyzed "in vivo" and to have
favourably pharmacokinetic properties.
When Y represents a halogen atom, it is preferably a
fluorine, chlorine or bromine atom.
When Y represents an organic group, it is preferably
a) a free or protected hydroxy,group;
b) a formyloxy group or an acyloxy group having from 2 to
6 carbon atoms, optionally substituted by a halog~:n
atom, by an acyl group having from 2 to 6 carbon .atoms,
or by an amino, hydroxy or mercapto group, the amino,
hydroxy or mercapto group optionally being in a
protected form;
~) an unsubstituted or N-alkyl substituted carbamoyloxy
group;
d) an alkoxy group having from 1 to 12 carbon atoms or an
alkylthio group having from 1 to 12 carbon atoms, either
of which is optionally substituted by one or more
halogen atoms, formyl groups, acyl groups having from
2 to 6 carbon atoms, and/or amino, hydroxy or merr_apto
groups, the amino, hydroxy or mercapto group optionally
being in a protected form;
e) a 1-pyridinium group, unsubstituted or substituted in
the.meta or para position with the group -CONH2;
f) a heterocyclylthio group -S-Het wherein Het, denoting
~~J4~~~
- 4 -
a saturated or unsaturated heterocyclic ring containing at
least one oxygen, sulphur and/or nitrogen heteroatom,
is preferably:
A) a pentatomic or hexatomic heteromonocyclic ring,
containing at least one double bond and at least one
oxygen, sulphur and/or nitrogen heteroatom,
unsubstituted or substituted by one or more
a') alkoxy groups having from 1 to 6 carbon atoms,
aliphatic acyl groups having from 2 to 6 carbon atoms,
hydroxy groups and/or halogen atoms;
b') alkyl groups having from 1 to 6 carbon atoms,
unsubstituted or substitu~_ed by one or more hydroxy
groups and/or halogen atoms;
c') alkenyl groups having from 2 to 6 carbon atoms,
unsubstituted or substitu~~ed by one or more hydroxy
groups and/or halogen atoms;
d') groups of the general formula -S-R3 wherein R3
represents a hydrogen atom or an alkyl group having
from 1 to 6 carbon atoms, or groups of the general
formula -S-CH2-COOR4 ~her~in R4 represents a hydrogen
atom, an alkyl group having from 1 to 6 carbon atoms
or a carboxy-protecting group;
e') groups of the general formula -(CH2)m-COOR4 or
-CH=CH-COOR4 or -(CHZ)m-CN or -(CH2)m-CONH2 or -(CH2 m_
-S03H Therein m is zero, 1, 2 or 3 and R4 is as
defined above; R
6
f') groups of the general formula -(CHZ)m-NCR Therein
m is es defined above, and each of R5 and R6,5which
y
C,
1~~~~~~
- 5 -
may be the same or different, represents a hydrogen atom,
an alkyl group having from 1 to 6 carbon atoms or an
aliphatic acyl group or when one of R5 and R6 is
hydrogen, the other may be also an amino protecting
group; or
B) a heterobicyclic ring, containing at least two double
bonds wherein each of the condensed heteromonocyclic
rings, being the same or different, is a pentatomic
or hexatomic heteromonocyclic ring containing at least
one oxygen, sulphur or nitrogen heteroatom, said
heterobicyclic ring being unsubstituted or substituted
by one or more substituents selected form a'), b'), c'),
e') and f') as defined above.
In the above definitions A) and B) preferred halogens are
chlorine, bromine and iodine; preferred alkyl groups are
methyl and ethyl; a preferred alkenyl group is allyl; a
preferred aliphatic acyl group is acetyl; a carboxy
pro'.ecting group may be any of the groups previously
indicated for the R2 substituent; and the free sulpho and
carboxy groups possibly present~may be salified, e.g. as
sod.um or potassium salts. A heteromonocyclic ring
of i:he above class A) may be,
1%~~48~1
- 6 -
for example, an optionally substituted thiazolyl, triazolyl,
thiadiazolyl, tetrazolyl or triazinyl ring. Preferred
substituents on such rings are, for example, one or more
substitutents chosen from amino, hydroxy, oxo end a Cl-C6-
alkyl group preferably methyl or ethyl, urherein the C1-C6-
alkyl group may be optionally substituted by a substituent
chosen from carboxy, sulpho, cyano, carbamoyl, amino,
methylamino or dimethylamino. A heterobicyclic ring of
the above class ~) may be for example, a
tetrazolopyridazinyl radical optionally substituted by
amino or carboxy.
In the above formula I the amino, hydroxy or mercapto
protecting groups possibly present may be those usually
employed in the chemistry of penicillins and cephalosporins
for these functions. They may be, for instance optionally
sut~stituted, especially halo-substituted, acyl groups,
e.51. acetyl, monochloroacetyl, dichloroacetyl,
trifluoroacetyl, benzoyl or p.-bromophenacyl;
triarylmethyl groups, in particular triphenylmethyl; silyl
groups, in particular trimethylsilyl, dimethyl-t-butyl-
silyl, Biphenyl-t-butyl silyl- or also groups such as
t-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-
trichloroethoxyc,arbonyl, benzyl, pyranyl and vitro. When,
in particular, the R1 substituent in formula (I) is a
hydroxyalkyl group, preferred protecting groups for the
hydroxy function are p-vitro-benzyloxycarbonyl; dimethyl-
t-butyl-silyl-; Biphenyl-t-butylsilyl; trimethylsilyl;
c
' ~~;ij4~3;~1
2,2,2-trichloroethoxycarbonyl; benzyl; p-bromo-phenacyl;
triphenylmethyl and pyranyl. All the alkyl and alkenyl
groups, including the aliphatic hydrocarbon moiety of the
alkoxy, alkyl thio and acyloxy groups, may be branched or
straight.
The pharmaceutically and/or veterinarily acceptable salts
may be both salts with acids, either inorganic acids such
as hydrochloric or sulphuric acid, or organic acids such
as citric, tartaric, fumaric or methanesulphonic acid,
and salts with bases, either inorganic bases such as
alkali metal or alkaline-earth metal hydroxides, in
particular sodium and potassium hydroxid~:s, or organic
bases such as triethylamine, pyridine, b~:nzylarnirre or
collidine. Preferred salts are the salts of the compounds
of formula I wherein R2 represents a hydrogen atom with
one of the bases hereabove specified in particular with
sodium hydroxide or potassium hydroxide.
The compounds of the general formula I obtainable by the
process of the invention are known compounds, described
and claimed in our British Patent Specifications Nos.
2043639A and 8210410. They are potent, broad-spectrum
antimicrobial agents, and are therefore useful in the
treatment of bacterial infections in warm-blooded
animals, especially in humans, by enteral or parenteral
administration.
1
3.~~4~~1
-e-
Desulphurative ring contraction of 2-thiacephem of the
general formula II
Rl S ~
6 25
' 3
N a~ Y
0 ~ II
- COOR2
~uherein Rl, R2 and Y are as above defined is a kno~un
rocess for the
p preparation of penems, but it suffers from
poor or adverse stereoselectivity. Although the carbon
atom in position 6 has the R configuration, the
desulphurization usually gives (5S)-penems ~uhich are
biologically inactive (H.R. Pfaendler et el., J. Am.
Chem. Soc., 101, 1979, 6306) or a mixture of (SS)-ar;d
(SR)-penems (A. Henderson et al., J. Chem. Soc. Commun.,
1962, 809). We have found and descr~bed-in Tetrahedron
Letter's, 24, pag. 3283 (1983) that (5R)-penems
can be obtained from such desulphurative ring contractions
if the substituE~nts Rl, RZ and Y and the solvent for
2p the process are suitably selected. A more general
stereoselective process, operable over the full range of
values of the substituents Rl, R2 and Y is, ho~uever,
clearly desirable, as it u~ould obviate the losses involved
in the formation of the undesired (SS)-isomers and their
separation from the desired (5R)-isomers.
The invention provides a process for the preparation of a f;SR)
penem having the general formula I as above defined,
1~;;~~~3~~
- 9 -
the process comprising oxidising a 2-thiacephem having
the general formula II as above defined and wherein the
carbon at position 6 has the R configuration to give a
sulphone having the general formula III
,0
R //~1
S.
S
1
Y Ill
0
COOR2
wherein Rl, R2 and Y are as above.defined, and ring
contracting the sulphone by extrusion of sulphur dioxide;
and, if desired, converting the resultant (5R) penem c~f the
general formula I into another compound of the general.
formula I; and/or, if desired, converting the resultant
compound of the general formula I into a salt thereof; and/
or, if desired, obtaining a free compound of the general
formula I from a salt thereof.
The oxidation may be carried out using oxidizing agents
usually used to convert an organic sulphide into the
corresponding sulphone. Preferred oxidizing agents are
peracids such as m-chloroperbenzoic,acid or peracetic
acid. The reaction is generally performed in an inert
solvent at a temperature of from 0 to 60°C, preferably
from 4 to 30°C.
The ring contraction of the sulphone, urith loss of
sulphur dioxide, may be effected simply by heating it in
1~,~~-~~3:~~
- to -
an inert organic solvent such as chloroform or benzene.
The ring contraction may, in some cases, even occur
spontaneously at room temperature. The.R configuration
of the carbon atom in position 6 in the 2-thiacephem II
is retained throughout the process, so that (5R)-penems
are obtained exclusively. It is noteworthy that, although
loss of sulphur dioxide from thiosulphonates has
occasionally been reported. (see, for example, W.L.F.
Armarego and E.E. Turner, ~. Chem. Soc. 1956, 1665;
A. Padwa and R. Gruber, ~. Org. Chem. 35, 1970, 1781),
this reaction has hardly any precedent as yields and
mildness of operative conditions are concerned and
for the first time it has been applied in the synthesis of
S-lactam compounds. The present invention also provides
routes to obtain the required compounds of formula II
possessing the (5R) configuration.
~2:~4~3;~1
- m -
According to the invention, the compounds of the general
formula II are prepared by either of the routes shown in
the following reaction scheme wherein:
Rl, R2 and Y are as defined above,
Z represents
i) a group of the formula SRS wherein R~ represents
an alkyl group having from 1 to 8 carbon atoms,
a phenyl or tolyl group, or, preferably, a hetero-
cyclic group, especially a 2-benzothiazolylthio
or 1-methyl-tetrazol-5-yl-thio group,
i:i) a group of the formula SCORB wherein R8 represents
an optionally substituted lower alkyl group,
preferably a methyl group,
ii:i) a group of the formula -NyOR9' wherein R9 and R10
15 independently represent lower alkyl or aryl
groups, or together with the dicarboxyamino gxoup
form a heterocvclic zing, preferably a succinimido
or phthalimido group, or
i~,r) a group of the formula -S~-R~, wherein R~ represents
20 an optionally substituted lower alkyl or aryl
group, preferably a methyl, phenyl or p-tolyl
group; and
L represents a halogen atom, an alkane sulphonyloxy
group or an arene sulphonyloxy group, preferably a
25 methanesulphonyloxy group.
1~S48~1
- 12 -
R
SZ
H2
IV
N
~ CH3 .
H ,~ C02R2
Z~SR~
R~ SZ V R VI
yH2 1 ~ SZ
~ OH
!N Y I
O V N
G ~ CH3
. CC~2R2 . .
C02R2
R1 SZ VII R1 SZ VIII
OH
N ' / Y ~
pi ~ v ~~ / ~ CH3
C02R2 ~ _ C02R2
R1 SZ I, IX ZI tY=H)
N ~'' '
O
0282
II
.,
iWD~~:~1
1 - 13a -
In one of its aspects the present invention,
provides a process for the preparation of a 2-thiace-
phem.derivative of the general formula II:
R1 S\ S .
w
N j .Y II~ - .
COOR2
Z0 wherein Rl represents a~ hydrogen atom,~an alkyl group
having 1 to 12 carbon atoms, or a cycloakyl group hav- '
ing 4 to 7 carbon atoms, said alkyl and cycloalky groups
woptionally substituted by hydroxy, protected hydroxy,
amino, protected amino, mercapto, prcte~cted mercapto or
cyano;
R2 represents a hydrogen atom.~or a carboxy
protecting group and Y represetns a hydrogen atom, ~a
halogen atom, a hydroxy, formyloxy, acetoxy, carbamoy-
loxy, N-(tricnloroacetyl) carbamoylozy or l-pyridin.ium
2p group, or a 1-pyridinium group substituted in the mesa
. or para posit.ion~with a -CO-NH2 grouF., comprising a
process selected from:
(a) a process for the pre~~aration of a
. 2-thiacephem derivative of the general
, formula II above wherein R1 and R2 are .
v as defined above and Y represents a
halogen,atom characterized 'in that a
compound of general formula IV:
~'1 C
1~,.)4~;j.~
1 - 13b -
R1
SZ
CH2
N
CH3 IV
0
.~
H C02R2
wherein R1, R2 are as above defined and Z represents:
(i ) a group of the formula SR.~ wherein R?
represents an alkyl group having from 1 to
8 carbon atoms, a phenyl or tolyl group, or
a 2-benzothiazolylthio or 1-methyl-tetrazol-
5-yl-thio group, -
(ii) a group of the formula SCORB wherein
R8 represents a lower alkyl group,
~OR g
(iii) a group of the formula -N~ ,
COR10
wherein R9~and R10 independently represE:nt
lower alkyl or aryl groups, or together with
the dicarboxyamino group form a succinimido
or phthalimido group, or
0
~~
(iv) a group of the formula -S-R~, whe~.vein
0
R~ represents a lower alkyl ar_ aryl group;
is first halogenated to obtain the compound of general
formula V:
1 - 13c -
R1 SZ
CH2
V
N .Y
0
'CO2R2
wherein R1, R2, and Z are as above defined and Y is a
halogen atom, and subsequently ozonolyzed to give a
compound of general formula VII:
R1 SZ
OH
I VII
N Y
~,/
0
C02R2
wherein R1, R2, and Z are as defined above and Y is a
halogen atom, transforming the hydroxy group into a
L group, wherein.L represents a halogen atom, an alkane
sulphonyloxy group or an arenesulphonyloxy group, so
to obtain a compound of ~leneral formula IX:
R1 SZ
L
IX
N Y
0
C02R2
2.5
wherein R1, R2, Z and L are as defined above and Y is
a halgen atom which is subsequently cyclized to give
the desired compound;
l;~;i4~3:~3~
1 - 13d -
(b) a process for preparing a 2-thiacephem
deriviative of the general formula II above
wherein R1 and R2 are as defined above and Y
represents a hydrogen atom charaterized in
that a compound of general formula IV:
R1 SZ
CH2
N IV
'~CH3
0
H ~C02R2
wherein R1, R2,~:and Z are as defined above is first
azonolyzed to give a compound of the general formula VI:
R1 SZ
OH
N VI
' ~CH3
0
C02R2
wherein R1, R2, and Z are as defined above, converting
';.he hydroxy group into a L group, wherein L is as de-
:pined above, to obtain the compound of general formula
'JIII:
R1 SZ
L
i
N VIII
CH3
C02R2
~.~::~4~~~.
1 - 13e -
wherein Rl, R2, Z and L are as defined above, which is
subsequently cyclized by treatment with a salt of H2S
with an organic or inorganic base to the desired compound;
5
(c) a process for the preparation of a 2-
thiacephem derivative of general formula II
above wherein R1 and R2 are as defined above
and Y is a halogen comprising process (b)
above wherein the resultant product of pro-
10
cess (b) is halogenated to give the des:i.red
compound;
(d) a process for the preparation of a 2-
thiacephem derivative of the general formula
15 II above wherein Rl and R2 are as defined
above and Y is a hydroxy group, comprising
either process (a) or process (c) above
wherein the resultant product therefrom,dis-
solved in an acetone-water mixture (2:1 v/v)
20 is reacted for 15 mintues at a temperature
of 0°C with a salt of a strong inorganic acid
thus obtaining a labile ester of said inor-
ganic acid which subsequently hydrolyzes in
the same reaction medium to the desired com-
25 pound;
1;~;~ ~ x:31
1 - 13f
(e) a process for the preparation of a 2--
thiacephem derivative of the general formula
II above wherein Rl and R2 are as defined
above and Y is a formyloxy or acetoxy group,
comprising either process (a) or process (c)
above wherein the resultant product therefrom,
dissolved in dichloromethane is treated. at
a i:emperature of 5°C and at daily intervals
for. 3 days with a suitable salt of the cor~
re:~ponding carboxylic acid to ..give the de-
si;~ed compound ;
(f) a process for the preparation of a 2-
thiacephs~n derivative of the general formula
II above wherein R1 and R2 are as defined
abave and Y is a carbamoyloxy group, compris-
25
ink process (d) above whexei.n the resultant
product therefrom, dissol~~ed in dichlorome-
thane, is treated, at a temperature of =40'C,
with a tr~chloroacetylisocyanate, raising the
reaction mixture it, room i:emperature and sub-
sequently isolating the desired 2-thiacephem
derivative of formula II, wherein R1, R2 are
as above defined and Y is a N-trichloroacetyl
carbamoyloxy group which, if desired, is sub-
mitted to the deprotection of the trichlora-
acetyl moiety of the first formed urethane
t
1~5~~;31
1 - 13g -
adduct by stirring for 20 hours its methanolic
solution with silica gel, so to obtain the
2-thiacephem deriviative of formula II, where-
in Rl, R2 axe as above defined and Y is a car-
bamoyloxy group; and
(g) a process for the preparation of a 2-
thiacephem derivative of the general formula
II above wherein R1 and R2 are as defined
above and Y is a 1-pyridinium or a 1-pyrid-
inium group substituted in t:he meta or para
position with a .-CO-NH2 group, comprising
process (a) or process (c) above wherein the
resultant product therefrom, is reacted at
room temperature with pyridine, nicotinamide
or isonicotinamide to give, respectively,
after purification by silica gel chromato-
graphy, the desired 2-thiacephem compounds
product of forrt~ula II, wherE:in R1, R2 are as
above defined and Y is a 1-pyridinium group
or a 1-pyridinium group substituted in meta
or para position by a -CO-NH2 group.
- 14 -
The group Y in the compounds of the.general formulae V,
III, IX and II may, if it represents a halogen atom,
be optionally transformed into any of the other groups
which Y may represent except a hydrogen atom. According
to a preferred feature of the invention, this
transformation is preferably carried out on the compounds
of the general formula zI.
The transformation into a group L of the hydroxy group
in the enol 'VI or VITI, which may be in equilibrium
with the corresponding keto-tautomer, is preferably
a mesylation. We have surprisingly found that, when this
reaction is carried out in tetrahydrofuran instead of
the ubiquitously used halogenated hydrocarbons, mesylates
IX or 'VTII having Z alkene geometry, which are the most
suitable ones for the subsequent cyclization, are almost
exclusively obtained (similar transformation perfoxned
in dichloromethane usually affords a 1:1 mixture of E,
Z isomers: see T.W. Doyle, et al. 'Can. J. Chem. 1977,
55, 2873; N:.J. Pearson, J. Chem. Soc., Chem. Comm. 1981,
9~7% P-C. Cherry et al. J. Chem. Soc., Chem. Comm. 1979
663). Cyclisation of VIII or ZX may be carried out in
a single step, by reaction with a sulphide or hydro-
sulphide, such as Na2S, NaHS, Bu9NHS, or with H2S in the
presence of a base such as triethylamine or pyridine.
The cyclisation of IX or VIII wherein Z represents a group
other than SR7 offers the clear advantage of releasing
~~.~4~~~
_ 15 _
easily separable, usually water soluble by-products 2H
(e.g. phenylsulphinic acid, succinimide), instead of by
products R3SH (e. g. mercaptobenzthiazole) which usually
require chromatographic separation or precipitation as
heavy metal salts (Age, Pb2~).
Against any reasonable expectation, which would rule out
the possibility of ha.logenating the 3-methyl group of
the compounds Ii (Y=H) owing to the presence of. the
disulphide moiety, we have found a method to effect:
such transformation in high yield. We can thus obi:ain
the compounds II (Y=halogen), which are invaluable
intermediates for the synthesis of highly active pc~nem
antibiotics i. A preferred halogenating reagent f~~r
such transformation is h-bromosuccinimide, which i;a
best used in the presence of a radical initiator, such
'as azobisisobutyronitrile or benzoyl peroxide in the
presence of acid scavengers, such as epoxides(e.g.
propylene oxide), alkaline-earth oxides,(e.g. calcium
oxide), or molecular sieves, in solvents such as
benzene or carbon tetrachloride, ethyl formate at
xemperature ranging from 20°C to 130°C.
The compounds II (Y=halogen)can be converted into
compounds IT (Y= an organic group) by reactions known
e~ r-se; e.g.
1) a compound II (Y=Br or C1)can be converted
into a compound II (Y=free or protected OH) by mild
~~548~1
- 16 -
alkaline hydrolysis, or by reaction with .cupxous
oxide/dimethylsulphoxide/water or by xeaction
with a salt of a strong inorganic acid, e.g.
a nitrate or a perchlorate, thus obtaining a
labile ester with the said inorganic acid, which
estex may be hydrolyzed, subsequently or in the
.same reaction medium, to the desired parent
alcohoJ_. Preferred salts of this type are
AgN03, A.gC109, NaNO3;
2) a compound IT (Y=Br or C1)can be converted into
a compound II (.Y= an unsubstituted or N-alkyl
substii:uted carbamoyloxy group) by conversion
into a compound of II CY=OH) as described abpve
followed by reaction with a suitable isocyanate;
for ex~unple, tr3chloroacetyl isocyanate is a
preferred reagent for obtaining compounds II
CY=OCO1JH2) , following deprotection ~of the
trichloroacetyl moiety on the first foamed
urethane adduct;
3) a compound II (Y=Br or C1)can be converted
into a compound II (,Y= acyloxy) by reaction
with a suitable salt of the corresponding
carboxylic acid in a suitable solvent ox under
phase-transfer catalysis; or by conversion into
a compound IZ (Y=OH) followed by conventional
acylation;
9) a compound II (Y= Br or C1) can be converted
1~54~~1
_ 17 _
into a compound II ~Y-S-Het) by reaction with
the corresponding HS-Het in the presence of a
base, or with a preformed salt of HS-Het with a
base, in a suitable solvent, such as tetrahydro-
furan, acetone, acetonitxile or dimethylformamide.
suitable base is txiethylamine; a suitable
preforrned salt is a sodium salt, e.g. sodium
1-methyl-1,2,3,4-tetrazol-5-yl-mercaptide.
Owing to the pronounced propensity of 3-hydroxvmethyl-2-
-~iacephem-4-~~axboxylates to lactonize, it is preferable
that in the process 1) described above R2 represents a
somewhat bulky group, forming with the linked carboxy
moiety an ester possessing a relative inextness to«ards
nucleophilic ~ittack by the neighbouring hydroxy group,
e.g. a tert-bui:yl ester. Alternatively, it may be
convenient to deprotect the hydroxy group from a
protected form thereof after the ring-contraction step
to the corresponding penem I, since 2-hydroxymethylpenem-
carboxylates do not lactonize easily. For ex~snple, a
2p compound II (Y=-Bx) may be converted into a compound II
(Y=ON02), which may eas.~ly be isolated, purified if
necessary, desulphurized to the corresponding penem I
whose reductive hydrolysis (e. g. Zn/CH3COOH) affords
without problems the free hydroxy derivative.
Owing to the different stability of the penem and 2-
1~,5~~3;~1
- 1a -
thiacephem nucleus towards the conditions required for
-COOR2 ester hydrolysis, a distinct advantage of the
invention is that ester hydrolyses not compatible with a
penem can be performed on the 2-thiacephem precursor, and
the ring contraction may be performed on the free acid,
or on a salt with an organic or inorganic base, or on a
different labile ester, which can be prepared in situ,
if desired; e.g. a trimethylsilyl, t-butyldimethylsilyl,
or t-butyldiphenylsilyl ester.
The following Examples illustrate the invention. The
abbreviations Me, But, Ph, Ms, pNB, THF, EtOAc, DMSO,
MeCN, stand respectively far methyl, t-butyl, phenyl,
methansulphonyl, p-nitrobenzyl, tetrahydrofuran, ethyl
acetate, dimethylsulphoxide and acetonitrile. NMR spectra
were taken either on a Hitachi-Perkin Elmer 60 MHz
apparatus, or on a Brucker 90 MHz; separation of inner
lines of AB quartets are referred to spectra taken on
the latter.
r
1~;~~~891
1 Example 1
Diphenylmethyl ~6,6-dibromopenicillanate ,
- ti
6r . --~ 6r~ .
~~(.oZH '~ N ~ ~?~H~Z
6,6-Dibromopenici7.lanic acid (90 g) in acetonitrile (450 ml)
was treated with ~~ solution of diphenyldiazomethane (49 g) in
the same solvent (150 ml). After 1 hour at 20°C the formed solid
was collected by filtration and washed with small portions of col~
ethyl ether, thus obtaining 116 g of title product. A second crop
(9 g) was obtained by evaporation of the mother liquors and
trituration with ethyl ether; yield 95%.
An analytical sample was obtained by crystallization from chloro-
form; mp 15?-158a ~ (CHCl film) 1800, 1750 cm 1;
max 3 _ ~ (CDC13)
1.24 and 1.58 (eac:h 3H, s, CMe2), 4.61 (1H, s, N.CH.CO), 5.80
(1H, S, N.CH.S), Ei.91 (1H, s, OCH), and ?.30 ppm (1,OH, s, Ar).
'Found: C, 47.80; H, 3.63; N, 2.64; S, 5.95; Br, 30.49°x.
C21H19Br2N035 requires C, 48.02; H, 3.64; N, 2.67; S, 6.10;
Br, 30.43ro.
1~:i4~3~1
- 20 -
1 Example 2
Tert-butyl 6,6-dibromopenicillanate
~r
Br
Br "'~ , ~ 8r S '..
o t
~' X02 f~! ° N '' ~Bu
Method A)
6,6-Dibromopenici~llanic acid (100 g) in ethyl ether (1 1)
at 0°C was sequentially treated with triethylamine (3? ml)
and PC15 (56 g). After~l hour stirring, the reaction mixture
was evaporated un3er vacuum (dry benzene added and removed)
and the crude acyl chloride dissolved in dichloromethane
- 10 (200 ml) and stirred for 24 hours with tert-butanol (500 ml)
in the presence of CaC03 ( 50 g ) . -rne suspemucu ~n~ .-~ ...-~ .-
then filtered off and the solution was washed with aqueous
NaHC03 (some unreacted-starting material could be recovered
by back-extracticn of the acidified aqueous washings), decolori-
15 zed with charcoal and evaporated to afford the title product,
which was then crystallized from diisopropyl ether, 69 g (60%);
mp 120-121°C, ~/ (CHC13 film) 1800 and 1140 cm 1; C~ (CDC13)
m ax
1.98 (15H, s, But and CH3), 2.05 (3H, s, CH3), 4.38 (1H, s,
N.CH.CO), and 5.70 (1H, s, N.CH.S) ppm.
. 1;~;~4~~1
- 21 -
Method B)
6,6-Dibromopenicillanic acid (15 g) in dichloromethane
(300 ml) was stirred overnight with 0-tert-butyl-N,N-
diisopropyl-isourea (25 g). The reaction mixture was
filtered and the solution washed with aqueous NaHC03.
Crystallization of the product from diisopropyl ether
gave the title compound, 8 g (47p).
v 12;i4~;~1
- 22 -
1 Example 3
Diphenylmethyl 6d-bromo-6(~-~1(R)-hydroxyethyl,~-penicillanate
Oy
~r
B~ ~ ~ : S
N
coZCNp~z o'-N -.c~a~cHP~~
Diphenylmethyl 6,6-dibromopenicillanate (120 g) in dry distilled
THF (900 ml) under nitrogen at -75°C was treated with a solut-
ion of ethylmagnesium bromide in ethyl ether (1 molar equivalent
After 20 min at -75°C, acetaldehyde (25.. ml) was added
and the mixture further stirred for 20 min at -?5°C. After
quenching with saturated aqueous NH4C1 (1E00 ml), partition
between water and ethyl ether, followed by removal of the
solvent, left the crude product which wa;~ fractionated by
silica gel chromatography (benzene-gthyl acetate) to afford
the'title compound, 67 g (60~), as a foan, crystallizable(diiso-
propyl ether) to a solid, mp 65-70~ ~ m~~ (film) 3450, 1?85
and 1740 cm 1; ~ (CDC13) 1.22 and 1.60 (each 3H, s, CMe2),
1.29 (3H, d, J= 6Hz, CH3.CH), 2.90 (1H, d, OH), 4.17 (1H, m,
CH3.CH.OH), 4.58 (1H, s, N.CH.CO), 5.49 ~;lti, s, N.CH.S),
6.90 (1H, s, OCHPh2), and 7.3 (lOH, s, Ar) ppm.
By using a similar procedure, and starting from tert-butyl
6,6-dibromopenicillanate, there was obtained tert-butyl 6at-
bromo-6(~-~1(R)-hydroxyethylJ-penicillanate in 65b yield after
1~5~~~1
- 23 -
crystallization from diisopropylether/hexane; mp 93-95°C (dec);
(CDC13) 1.28 (3H, d, J= 6Hz, CH3.CH), 1.54 (12H, s, But
and CH3), 1.65 (3H, s, CH3), 2.65 (1H, s, CH.OH), 4.25 (1H, m,
CH3.CH(OH).CH), 4.40 (1H, s, N=CH.CO), and 5.51 ppm (1H, s,
N.CH.Sj.
1~:~4~~1
- 24 -
1 Example 4
Diphenylmethyl 6c~-~1(R)-hydroxyethylJ-eenicillanate-1-oxide
off O
S
. '
,'G~CHP~'Z ~~N ~~~2~~~2
Diphenylmethyl 6a(-bromo-6~-(1(R)-hydroxyethyl"/-penicillanate
(52 g) in 95°~ ethanol (400 ml) was hydrogenated at 30 Psi in
the presence of 10°~ Pd/CaC03 (25 g) and CaC03 (11 g). The
reaction mixture was filtered and evaporated to afford a
residue which was partitioned between brine and dichloro-
methane. Removal of~the solvent left crude diphenylmethyl
6d li(R)-hydroxyethyl~-penicillanate, which was oxidize d
with 85°~ MCPBA (17 g) in 500 ml of chloroform at O-5°C for
1 hour. The filtered solution was then washed with aqueous
NaHC03 and the solvent removed to leave the crude title product
as a foam, 40 g (88~), which can be used as such or purified
. by silica gel chromatography; ~m~ (CHC13 film) 1790 and
1?50 cm 1; ~ (CDC13) 0.94 and 1.67 (each 3H, s, CMe2), 1.3?
(3H, d, J= 6Hz), 3.55 (iH, dd, J= 2 and 6.5Hz, CH. CH.CH),
4.25 (1H, m, CH3.CH(OH).CH), 4.64 (1H, s, N.CH.CO), 4.98
(iH, d, J= 2Hz, C~1.CH.S), 6.98 (1H, s, OCHPh2), and 7.30
(lOH, s, Ar) ppm.
By using a similar procedure, and starting from tert-butyl
6o~-bromo-6~-~(R)-hydroxyethy ~-penicillanate, there was
obtained (75~) tert-butyl 6 -~1(R)-hydroxyethyl,~-penicilla-
pate-1-oxide; (film) 3440, 1?85 and 1?40 cm 1.
Ymax '
1~:i4~~1
- 25 -
1 Example 5
Diphenylmethyl 6d- -~(R)-tent-butyldimethylsilyloxyethyl~-
penicillanate-1-oxide '
OH ~ O.~l'~28~
r~ H S ~~~ .S
,_, ~
o N '~ CO~CNP~2
Crude diphenylmethyl 6d-~(R)-hydroxyethylJ-penicillanate
-1-oxide, as obtained in Example 4 (40 g), was dissolved
in DMF (350 ml) and stirred for 3 hours a.t 50-55°C in the
presence of imidazole (18.5 g) and tert-butyldimethylsilyl-
chloride (27 g). The reaction mixture was. partitioned between
ethyl ether and brine and the organic layer washed several
timeswith water. Evaporation of the solvent and silica gel
chromatography afforded the title product:, 22. g; ~ m~ (CHC13
film) 1790 and 1755 cm 1; ~ (CDC13) 0.06 .(6H, s, SiMe2),
0.88 (13H, s, But and CH3), 1.3 (3H, d, ;I= 6Hz, CH3.CH),
1.7 (3H, s, CH3), 3.4- (1H, dd, J= 2 and ~~..SHz., CH. CH.CH),
4.40 (1H, m, CH3._CH.CH), 4.55 (1H, s, N.(:H.CO), 4.88 (1H, d,
J= 2, CH. CH. S), -6.9 (1H, s, OCHPh2), and 7.25 ppm (lOH,.s, Ar).
By using a similar procedure and starting from tert-butyl
6o(-I1(R)-hydroxyethy ~-penicillanate-1-oxide, there was obtained
1~;~4~~1
' - 26 -
1 tert-butyl 6 -~1(R)-tert-butyldimethylsilyloxyethyl"~-penicilla
nate-1-oxide in overall 55~ from the E~-bromo precursor;
_ m ax
(CHC13 film) 1785 and 1750 cm l; ~,,~ (CDC13) 0.06 (6H, s, SiMe2),
t
0.88 (9H, s, SiBu ), 1.25 and 1.66 (each 3H, s, CMe2), 1.28
t
(3H, d, J= 6Hz, CH3.CH), 1.45 (9H, s, OBu ), 3.5 (1H, dd,
J= 2 and SHz, CH.CH.CH), 4.4 (iH, s, N.CH.CO), 4.5 1H, m,
CH3.CH.CH), and 4.9 ppm (1H, d, J= 2Hz, CH. CH. S)
~;~~4~3~1
_ 27 _
1 Example 6
Diphen~lmethyl 6o~-~R ) -p-n i t rob enzyl oxycarbonyl oxyethyl~-
penicillanate-1-oxide
OH o ~COt pNB o
S ~,' H T
H .-= '~'~ 5 .
, ~.
o~" -wCOZCNP~z o ''~~NP~Z
Diphenylmethyl 6d-~(R)-hydroxyethy~ penicillanate-1-oxide
was acylated with p-nitrobenzylchlorocart>onate by using
N,N-dimethylaminopyridine as a base and ethanol-free dichloro-
methane as solvent, according to a general method, thus .
obtaining the title product as a foam; ~ (CDC13) 0.96 and
1.70 (each 3H, s, CMe2), 1..52 (3H, d, J= 6Hz, CH3.CH), 3_83
(1H,'dd, J= 2 and 6Hz, CH. CH.CH), 4.66 (:LH, s, N.CH.CO),
4.99 (1H, d, J= 2Hz, CH. CH. S), 5.28 (2H, s, OCH2Fh), 5.35
(1H, m, CH3.CH.CH), 7.01 (1H, s, OCHPh2)t 7.40 (lOH, m, Ar),
7.55 and 8.26 ppm (each 2H, d, J= BHz, A.r).
By following the same experimental procedure, there was
obtained tent-butyl 6o~-~(R)-p-nitrobenzyloxycarbonyloxy-
ethyl~-penicillanate-1-oxide
1~:i4~;~~
- 28 -
1 By following similar experimental procedures, and using
trichloroethylchlorocarbonate instead of p-nitrobenzylchloro-
carbonate, these were also obtained:
tert-butyl 6~(-/1(R)-p-nitrobenzyloxycarbonyloxyethylT-
penicillanate-1-oxide
diphenylmethyl 60(-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-
penicillanate-1-oxide
1;~54~~1
- 29 -
1 Example ?
3(S)-~(R)-h~drox~ethylJ-4(R)-benzthiazolyldithio-1-(1-
methoxycarbonyl-2-methyl-1-prop-2-eriyl)-azetidin-2-one
ON o
S_SJS~ C.~
I s .., -.t . I
N o ~-a
D ''
~,oz G~3 H 'coz c.~t3
A mixture of methyl 60(-~1(R)-hydroxyethyl7-penicillanate
-1-oxide (5 g) and 2-mercaptobenzthiazole (3.04 g) was
refluxed for 2 h in dry toluene. The solvent was removed
in vacuo and the crude product used as such for the next
step.
By using a similar procedure, there were obtained:
3(S)- 1(R)-tent-butyldimethylsilyloxyethyl>-4(R)-benz-
thiazolyl-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-
azetidin-2-one, starting from methyl 60(-~1(R)-tert-butyl-
dimethylsilyloxyethyl,~-penicillanate-1-oxide, and prolong-
ing the reaction time up to 6 h; y m~ (CHC13 film) 1?70
and 1?44 cm 1; ~ (CDC13) 0.02 and 0.04 (each 3H, s, SiMe2)
0.84 (9H, s, SiBut), 1.23 (3H, d, J= 6Hz, CH3.CH), 1.91
(3H, s, =C.CH3), 3.38 (1H, dd, J= 2 and 3.5Hz, CH. CH.CH),
3.69 (3H, s, OCH3), 4.23 (1H, m, CH3.CH.CH), 4.82 (1H, s,
N.CH.CO), 5.0? (2H, m, CH2=C), 5.42 (1H, d, J= 2Hz, CH. CH. S),
and ?.2-7.9 ppm (4H, m, Ar);
1;~54~~1
- 30 -
1 3(S)-~l(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-(1-
diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin
-2-one, starting from diphenylmethyl 6~-L1(R)-hydroxy-
ethyl/-penicillanate-1-oxide; ym~ (CHC13 film) 3400,
1?65 and 1740 cm 1; ~ (CDC13) 1.22 (3H, d, J= 6Hz, CH3.CH),
1.60 (3H, s, =C.CH3), 2.78 (iH, br s, OH), 3.42 (1H, dd,
J= 2 and 6Hz, CH. CH.CH), 4.18 (1H, m, CH3.CHOH.CH), 4.93
(1H, s, N.CH.CO), 4.90-5.10 (2H, m, CH2=C), 5.38 (1H, d,
J= 2Hz, CH.CH.S), 6.89 (1H, s, OCHPh2), and 7.15-7.90 ppm
(14H, m, Ar);
3(S)-/1(R)-tert-butyldimethylsilyloxyethvl%-4(R~-benz-
t_hiazolyldithio-1-(1-tert-butoxycarbonyl--2-methyl-1-prop-
2-enyl)-azetidin-2-one, starting from test-butyl 6u(-/1(R)-
tert-butyldimethylsilyloxyethyl/-penicillanate-1-oxide;
reaction time 6 h; ~ (CDC13) 0.06 (6H, s, SiMe2), 0.9
(9H, s, SiBut), 1.26 (3H, d, J= 6Hz, CH3.CH), 1.48 (9H, .
s, OBut), 1.95 (3H, s, =C.CH3), 3.40 (1H, dd, J= 2 and
4Hz,.CH.CH.CH), 4.20 (1H, m, CH3.CH.CH), 4.?1.(1H, s,
N.CH.CO), 5.1 (2H, br s, CH2=C), 5.42 (1H, d, J= 2Hz,
CH. CH. S), and ?.2-?.9 ppm (4H, m, Ar);
3(S)-/1(R)-tent-butyldimethylsilyloxyeth;,rl/-4(R?-benzthia-
zolycldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-
-1
enyl)-azetidin-2-one, y m~ (film) 1??2 and 1743 cm ;
t
(CDC13) 0.05 (6H, s, SiMe2), 0.80 (9H, s, SiBu ), 1.29
(3H, d, J= 6Hz, CH3.CH), 1.95 (3H, s, =C.CH3), 3.45 (1H,
dd, J= 2 and 4Hz, CH. CH.CH), 4.26 (1H, m, CH3.CH.CH), 4.95
(1H, s, N.CH.CO), 5.08 (2H, ABq, separation of inner lines
5Hz, CH2=C), 5.55 (1H, d, J= 2Hz, CH.CH.S), 6.93 (iH, s,
OCHPh2), and 7.1-8.0 ppm (14H, m, Ar);
1254~~1
- 31 -
1 3(S)-~1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin
-2- -one, starting from methyl 6~-/1(R)-trichloroethoxycarbonyl-
oxyethyl/-penicillanate-1-oxide; ym~ (CHC13) 1775 and
1745 cm 1; ~ (CDC13) 1.48 (3H, d, J= 6Hz, CH3.CH), 1.91
(3H; s, =C.CH3), 3.69 (3H, s, OCH3), 3.70 (1H, dd, CH. CH. CH)
4.68 (s, 2H, OCH2), 4.?6 (1H, s, N.CH.CO), 5.03-5.30 (2H, m,
CH2=C), 5.23 (1H, m, CH3.CH.CH), 5.32 (1H, d, J= 2Hz,
CH. CH. S), and ?.10-?.96 ppm (4H, m, Ar);
and, in a likenise>. fashion, starting from the corresponding
tert-butyl and diphenylmethyl penicillanates,
3(S)-~(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-(1-tent-butoxycarbonyl-2-methyl-1-prop-2-enyl)-aze-
t; ri; n-7-cane
3(S)-L1(R)-trichlo roethoxycarbonyloxyethyl%-4(R)-benzthiazolyl-
dithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-
azetidin-2-one;
and, starting from methyl 6~-/1(R)-tert-butyldimethylsilyloxy-
ethyl/-penicillan.ate-1-oxide,
3(R)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-
~tithio-1-(1-metho:Kycarbonyl-2-methyl-1-prop-2-enyl)-azetidin
-2-one.
1;54891
- 32 -
1 Example 8
3(S)-L1(R)-hydroxyethylJ-4(R)-benzthiazolyldithio-1-(1-
methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one
OH ~ DI-I
o ~~ s_s --~~~ ~
s ~~
~s
--.
O~-r~ N (z
GH
~°1~~3 coZcH3
The crude 3(S)-~1(R)-hydroxyethyl~-4(R)-benzthiazolyl-
dithio-1-~1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin
-2-one as obtained in Example 6 was diss~~lved in dry dichloro-
methane (300 ml) and treated with a stre.3m of ozone at -70°C
until TLC showed that all the starting material had reacted.
The solution was purged with nitrogen an~j then sodium meta-
bisulphite (10 ~) was added at -30°C. Th°_ mixture was let
rise to room temperature under vigorous stirring, then
filtered. The solution was washed with a~3ueous 4°~ NaHC03,
dried over Na2S04 and evaporated. The re~~idue was taken up
in ethyl ether, the undissolved matter filtered off and the
solution was evaporated to give the crud= title product.
An aliquot was purified by flash chrornat~~graphy over silica
gel (ethyl acetate-cyclohexane mixture a~~ eluants);
c5 (CDC13) 1.35 (3H, d, J=~7Hz, CH3.CH), 2.11 (3H, s, CH3),
2.75 (1H, br s, OH), 3.44 (1H, dd, J= 2.0 and S.OHz, CH. CH.CH),
3.79 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.29 (1H, d,
J= 2.OHz, CH. CH. S), and 7.25-?.95 ppm (4H, m, Ar).
12~~~91
- 33 -
1 By using a similar procedure, there was obtained:
3(S)-~l(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyl-
dithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin
-2-one, starting from crude 3(S)-~1(R)-tert-butyldimethyl-
silyloxyethyl7-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl
-2-methyl-1-prop-2-enyl)-azetidin-2-one; ,~ (film) 3350,
_ max
1770 and 1660 cm 1; ~ (CDC13) 0.05 and 0.07 (6H, each s,
SiMe2), 0.87 (9H, s, S:But), 1.27 (3H, d, J= 6.5Hz, CH3.CH),
2.0? (3H, s, =C.CH3). 3.33 (1H, dd, J= 2.2 and 4.2Hz, CH. CH.CH),
3.74 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.36 (1H, d,
J= 2.2Hz, CH. CH. S), 7.2-?.9 (4H, m, Ar), and 12.37 ppm (1H,
br s, OH);
3(R)-,(1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthia-
zolyl~3ithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-
azeti3in-2-one, starting from 3(R)-11(R)-tert-butyldimethyl-
silyloxyethyl7-4(R)-benzthiazolyldithio-1-(1-methoxycarbonyl
-2-methyl-1-prop-2-enyl)=azetidin-2-one; J (film) 3200,
_ max
1773, 1710, 1665 and 1620 cm 1; C5(CDC13) 0.20 (6H, s,.SiMe2),
0.94 (9H, s, SiBut), 1.52 (3H, d, J= 6Hz,-CH3.CH), 2.17
(3H, 'Sr s, =C.CH3), 3.6-3.7 (4H, s+dd, OCH3 and CH. CH.CH),
4.4 (1H, m, CH3.CH.CH), 5.25 (1H, d, CH.CH.S), and 7.3-7.9 ppm
(4H; m, Ar);
3(S)-/1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-(1-
diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin
-2-one, starting from crude 3(S)-L1(R)-hydroxyethyl/-4(R)-
benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl
-1-prop-2-enyl)-azetidin-2-one; ~max (CHC13 film) 3400,
-1
1770, 1730 and,1650 cm ;
~.;~.',;a~~~1
- 34 -
1 3(S)-/1(R)-tent-butyldimethylsilyloxyethyl/-4(R)-benz-
thiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-
prop-1-enyl)-azetidin-2-one, starting from crude 3(S)-/1(R)
tent-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio
-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-
azetidin-2-one; ym~ (CHC13 film) 3400, 1775, 1735, 1700 sh,
1655, and 1610 cm 1; ~ (CDC13) 0.06 (6H, s, SiMe2), 0.82
(9H, s, But), 1.26 (3H, d, J= 6Hz, CH3.CH), 2.08 (3H, s,
=C.CH3), 3.33 (1H, dd, J= 2 and 5.5Hz, CH. CH.CH), 4.18
(1H, rn, CH3.CH.CH), 5.22 (1H, d, J= 2Hz, CH. CH. S), 6.86
(1H, s~, OCHPh2), and 7.2-7.9 ppm (14H, m, Ar);
3(S)-~'1(R)-trichloroethoxycarbonyloxyethyl%-4(R)-benz-
thiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-
enyl)-~azetidin-2-one; (f (CDC13) 1.50 (3H, d, J= 6Hz,
CH3.CN), 2.14 (3H, s, =C.CH3), 3.67 (1H, dd, J= 2.2 and
5.5Hz, CH.CH.CH), 3.82 (3H,.s, OCH3), 4.62 (2H, ABq, J= 12 Hz,
separ~.tion of inner lines 2Hz, OCH2), 5.10-5.40 (2H, m,
CH3.Cr:.CH and CH.CH.S), 7.20-8.00 (4H, m, Ar), and 12.40 ppm
(1H, br s, OH);
and in a likewise fashion, starting from the corresponding
tert-butyl and diphenylmethylester,
3(S)-~1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-(1-tert-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-
azetidin-2-one;
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-
azetidin-2-one;
~':~ ~ ~;~ 1
- 35 -
1 3(S)-~1(R)-tert-butyldimethylsilyloxyethyl%-4(R)-benzthiazolyl-
dithio-1-(1-tent-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-
azetidin-2-one.
12;~4~i:~1
- 36 -
1 Example 9
3(S)-/1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio 1 (1
methoxycarbonyl-2-methylsulphonyloxy 1 prop 1 enyl)
azetidin-2-one
ON
CH
H
~ --
~~N ~'~OH D ~ OMs
cO2 CH3
A solution of 3(S)-~(R)-hydroxyethy~-4(R)-benzthiazolyl-
dithi-o-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azeti-
din-2-one (130 mg, 0.3 mmol) in anhydrous dichloromethane
(8 ml) was sequentially tre.3ted at -40°C with triethylamine
(0.043 ml, 0.3 mmol) and me-~hanesulphonyl chloride {0.024 ml,
0.31 mmol). The reaction wa~~ quenched after 5 minutes with
cold aqueous 2% NaHC03. Removal of the solvent from the
organic layer gave the crudE~ title product (quantitative
yield), which was used as such for the next step.
By following the same experimental procedure, there was
obtained:
3(S)-'1(R)-tert-butyldimethylsilyloxyethy~-4(R)-benzthiazolil-
dithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-
enyl)-azetidin-2-one, starting from 3(S) ~(R)-tert-butyl-
dimethylsilyloxyethy~-4(R)-benzthiazolyldithio-1-(1-methoxy-
carbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; an. aliquot
of this product was purified by flash chromatography (silica
gel; ethyl acetate-cyclohexane mixtures as eluant) to afford
~. ~c:,~ ~~ ~~ 1
- 37 -
1 the pure title compound as a 1:1 mixture of E and _Z isomers;
j~ m~ (film) 1885, 1730, 1363, and 1165 cm 1; ~ (CDC13)
0.05 and 0.10 (each 3H, s, SiMe2), 0.88 (9H, s, SiBut),
1.29 (3H, d, J= 6.5 Hz, CH3.CH), 2.20 and 2.53 (3H, each s,
=C.CH3), 3.18 and 3.29 (3H, each s, S02CH3), 3.42 (1H, m,
CH.CH.CH), 3.71 and 3.?8 (3H, each s, OCH3), 4.30 (1H, m,
CH3.CH.CH), 5.59 and 5.64 (1H, each d, J= 2Hz, CH._CH.S),
and ?.12-7.96,ppm (4H, m, Ar).
When tetrahydrofuran was used instead of dichloromethane
as a solvent, the formation of the undesired E isomer was
almost suppressied,and the pure _Z isomer thus collected;
(CDC13) 0.05 (6H, s, SiMe2), 0.88 (9H, s, SiBut), 1.29
(3H, d, J= 6.5Hz, CH3.OH), 2.53 (3H, s, =C.CH3), 3.29 (3H,
s, S02CH3), 3.42 (1H, dd, J= 2 and 5Hz, CH. CH.CH), 3.71
(3H, s, OCH3), 4.30 (1H, m, CH3.CH.Ct1), 5.59 (iH, d, J= 2Hz,
CH. CH. S), and 7.12-7.95 ppm ;4H, m, Ar).
By following this last procedure (tetrahydrofuran as a
solvent in the mesylation step), there were obtained:
3(R)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-/1-methoxycarbonyl-c-methylsulphonyloxy-1-prop-1-
(Z)-enyl%-azetidin-2-one, starting from 3(R)-/1(R)-tert-
butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-
methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one;
y m~ (CHC13 film) 1?75, 1735, 1365 and 1165 cm 1; Cj (CDC1
3
0.18 (6H, s, SiMe2), 0.88 (.9H, s, SiBut), 1.42 (3H, d,
J= 6.5Hz, CH3.CH), 2.33 (3H, s, =C.CH3), 3.05 (3H, s, S02CH3),
3.45 (3H, s, OCH3), 3.62 (1H, dd, CH.CH.CH), 4.3 (iH, m,
CH3.CH.CH), 5.40 (1H, d, J= 5Hz, CH.CH.S), and 7.15-7.85 ppm
(4H, m, Ar);
125 3~1
- 38 -
1 3(S)-(1(R)-hydroxyethyl/-4(R)-benzthiazolyldithio-1-L1-
diphenylmethoxycarbonyl-2-methylsulphonyloxy-I-prop-1-(Z)-
enyl/-azetidin-2-one, starting from 3(S)-/1(R)-hydroxyethyl/
-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-
hydroxy-1-prop-1-enyl)-azetidin-2-one; y (film) 3400,
max
1?75, 1730, 1365 and 1170 cm 1; ~ (CDC13) 1.22 (3H, d,
J= 6.5Hz, CH3.CH), 2.43 (3H, s, =C.CH3), 3.13 (3H, s, S02CH3),
3.35 (1H, dd, J= 2.5 and 4Hz, CH. CH.CH), 4.1 (1H, m, CH3.CH.CH),
5.40 (1H, d, J= 2.5Hz, CH.CH.S), 6.85 (1H, s, OCHPh2) and
7.1-7.9 ppm (14H, m, Ar);
3(S)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-(1-diphenylmethoxycar:~onyl-2-(Z)-methylsulphonyloxy
-1-prop-1-enyl)-azetidin-2-one, starting from 3(S)-/1(R)-tert-
butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-
diphenylmethoxycarbonyl-2-hydr~xy-1-prop-1-enyl)-azetidin-2-
-1
one; ~~ (CHC13 film) 177, 1725, 1370, and 1175 cm ;
(CDC13) 0.1 (6H, s, SiMe2), 0.9 (SH, s, SiBut), 1.28 (3H,
d, J= 6Hz, CH3.CH), 2.5 (3H, s, =C.CH3), 3.25 (3H, s, S02CH3),
3.35 (1H, dd, J= 2.5 and SHz, CH. CH.CH), 4.20 (1H, m, CH3.CH.CH),
5.50 (1H, d, J= 2.5Hz, CH.CH.S), 6.9 (1H, s, OCHPh2), and
?.1-7.9 ppm (14H, m, Ar);
3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-(1-tert-butoxycarbonyl-2-(Z)-methylsulphonyloxy-1~-
prop-1-enyl)-azetidin-2-one, starting from 3(S)-L1(R)-tert-
butyldimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-
tert-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one;
1254~3;~1
- 39 -
1 i~m~ (film) 17?3, 1710, 1370 and 1165 cm 1; ~ (CDC13)
0.06 (6H, s, SiMe2), 0.87 (9H, s, SiBut),~1.25 (3H, d,
t
J= 6Hz, CH3.CH), 1.49 (9H, si, OBu ), 2.45 (3H, s, =C.CH3),
3.25 (3H, s, S02CH3), 3.35 (1H, dd, J= 2.5 and SHz), 4.3
(1H, m, CH3.CH.CH), 5.60 (1H, d, J= 2.5Hz, CH.CH.S), and
7.1-?.9 ppm (4H, m, Ar);
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyl-
dithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-
enyl/-azetidin-2-one, starting from 3(S)-(1(R)-trichloro-
1() ethoxycarbonyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-methoxy-
carbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; Y
max -1
(CHC13 film) 1780, 1755 sh, 1730, 1380, 1250 and 1167 cm ;
(CDC13) 1.48 (3H, d, J= 6Hz, CH3.CH), 2.52 (3H, s, =C.CH3),
3.25 (3H, s, S02CH3), 3.72 (4H, s+dd, OCH3 and CH. CH.CH),
1-''~ 4.68 (2H, s, OCH2), 5.2 (1H, m, CH3.CH.CH), 5.47 (1H, d,
J= 2.5Hz, CH. CH. S), and 7.1-7.9 ppm (4H, m, Ar);
and likewise, starting from the corresponding tert-butyl and
diphenylmethyl esters, there was obtained:
3(S)-ll(R)-trichloroethoxy.carbonyloxyethylT-4(R)-benzthiazolyl-
2C dithio-1-~1-tert-butoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)~
enyl7 azetidin-2-one;
3(S)-~1(R)-trichloroethoxycarbonyloxyethyl%-4(R)-benzthiazolyl-
dithio-1-L1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-
1(Z)-enyl/-azetidin-2-one.
1;~~48;~1
_~,o-
1 Example 10
3(S)-L1(R)-methylsulphonyloxyethyl,J-4(R)-benzthiazolyl
dithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-
enyl)-azetidin-2-one
OH N OSo2~
H
S_S'.1C ~~ H S_5~. ~l
S ~ 5
i ~.~,
~~ ~/ o- " A~ Ut
i~oN ~ 3
Co2GH3 CotcH3
When in the reaction described in Example 8 the starting
materia~ywas exposed to an excess (2 molar equivalents) of
methanesulphonylchloride / triethylamine, the title product
was obtained as a foam in quantitative yield as a mixture of
1« E (20°x) 2.nd _Z (80i ) isomers;- ~m~ (film) 1780, 1733, 1360
and '1170 cm 1; ~ (CDC13) 1.58 (3H, d, J= 6Hz, CH3.CH),
2.22 and 2.56 (3H, each s, =C.CH3 of E and Z isomers), 3.00
(3H, s, CH3S02 on the hydroxyethyl chain), 3.20 (1H, dd,
J= 2.2 and 4.5Hz, CH. CH.CH), 3.28 (3H, s, CH3S02 on 'the
crotonic appendage), 3.76 (3H, s, OCH3), 5.11 (1H, m,
CH3.CH.CH), 5.52 (1H, d, J=~ 2.2Hz, CH.CH.S), and 7.3~~-7.95 ppm
(4H, m, Ar).
By following the same procedure, but using THF as a solvent,
3(S)-L1(R)-methylsulphonyloxyethy~.%-4(R)-benzthiazolyldithio-
-1-~l-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1-(Z)
enyl7-azetidin-2-one was prepared and displayed the following
1~s4~~i
- 41 -
-1
1 spectral data: ~~ ~ (film) 1777, 1728, 1360 and 1170 cm ;
(CDC13) 1.50 (3H, d, J= 6Hz, CH3.CH), 2.52 (3H, s, =C.CH3),
2.9 (3H, s, CH3S02 on the hydroxyethyl chain), 3.23 (3H, s,
CH3S02 on the crotonic appendage), 3.62 (1H, dd, J= 2.5 and
5.5Hz, CH.CH.CH), 5.05 (1H, m, CH3.CH.CH), 5.45 (1H, d,
J= 2.5Hz, CH.CH.S), 6.95 (1H, s, OCHPh2), and 7.10-7.95 ppm
(14H, m, Ar).
1254891
- 42 -
1 Example il
3(S)-/1(R)-tent-butyldimethylsilyloxyethylJ-4(R)-benzthiazolyl-
dithio-1-(1-methoxycarbonyl-2-trifluoromethylsulphonyloxy-1-
Erop-1-enyl)-azetidin-2-one
OS;HejBut
OS~Me2~u~
$-S- ~S ~ H $ S-~~~I
~ ~N~/~c~H O~Y/~ZOSpZCF3
~'.oZMe.
Crude 3(S)-/1(R)-t.ert-butyldimethylsilyloxyethyl7-4(R)-benz-
thiazolyldithio-1-~(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-
azetidin-2-one (3U0 mg) in THF (5 ml) at -40°C was sequentially
treated with triei.hylamine (170 ul) and trifluoromethansulphonic
anhydride (180 ul). Work-up and chromatography gave the two
separate geometrical isomers of the title product, as foams:
. -1
E isomer: ym~ (C:HC13) 1778, 1730, 1420, 1215, and 1135 cm ;
t
(CDC13) 0.08 (f~H, s, SiMe2), 0.86 (9H,.s, SiBu ), 1.26
(3H, d, J= 6Hz, Ctl3.CH), 2.05 (3H, s, =C.CH3), 3.46 (1H, dd,
2.2 and 4Hz, CH.CtI.CH), 3.81 (3H, s, OCH3), 4.28 (1H, m,
CH3.CH.CH), 5.?6 I1H, d, J= 2.2Hz, CH. CH. S), and 7.25-7.90
(4H, m, Ar); Z isomer (inter alia) ~ (CDC13) 2.45 (3H, s,
=C.CH3), 3.40 (1H, dd, J= 2 and 4Hz, CH.CH.CH), 3.64 (3H, s,
OCH3), 4.30 (1H, m, CH3.CH.CH), and 5.65 ppm (1H, d, J= 2Hz,
CH. CH. S).
- 43 - Z~J~~:~1.
1 Example 12
Methyl (?S,6R)-?-~1(R)-tent-butyldimethylsilyloxyethyl/-3-
methyl-2-thiacephem-4-carboxylate
~S~ Het dug ~ Si HetBu
s_5 ;/ 101 ~ s.s
s~
~-N ~ S w./
0 0
~ ~~3
CoZ cH3
A solution of triethylamine (0.5 ml) in dichloromethane
(10 ml) was saturated at -50°C with hydrogen sulphide.
After purging with nitrogen, 0.34 cc. of this solution was
added to a cold (-50°C) solution of 3(S)-/1(R)-tert-butyl-
dimethylsilyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-methoxy-
carbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one
(?5 mg, 0.121 mmol). ,
The mixture was allowed to warm up to room temperature and
then washed with water, dried (Na2S04) and evaporated.
Separation of the new compound from the formed 2-mercapto-
. benzthiazole and minor impurities was achieved by silica gel
chromatography (ethyl acetate-cyclohexane as eluants), thus
obtaining the title compound 2.s white crystals (19 mg, 200),
mp 85-87°C, ~ m~ (EtOH') 223 (~ = 4,773), 2?7 (6,335), and
326 (2,922) nm, ~m~ (CHC13 film) 1?85 and 1730 cm 1;
t
C~ (CDC13) 0.08 (6H, s, SiMe2), 0.88 (9H, s, SiBu ), 1.25
(3H, d, J= 6H2, CH3.CH), 2.22 (3H, s, CH3), 3.07 (1H, dd,
J= 2.2 and 3.5 Hz, CH. CH.CH), 3.8 (3H, s, OMe), 4.36 (iH,
m, CH3.CH.CH), and 4.62 ppm (1H, d, J= 2.2Hz, CH. CH. S).
124891
- 44 -
1 Found: C, 49.08; H, 6.96; N, 3.52; S, 15.16. C16H27N04SiS2
requires C, 49.32; H, 6.99; N, 3.60; S, 16.46.
When, instead of H2S/NEt3, a solution of NaSH (0.9 mol
equiv.) in DMF was used, and quenching (partition between
H20 and EtOAc) followed within 1 minute at O°C, the isolated
yield of the pure title product raised to 40-45°x.
When the above process was performed on the geometrical Z
isomer of the starting material, the yield was further
enhanced (up to 60-65°~).On the contrary, the _E isomer afforded
only a very low amount of the title product.
By following the same experimental procedure,
methyl (7R,6R)-7-~1(R)-tent-butyldimethylsilyloxyethyl>-
3-methyl-2-thiacephem-~1-carboxylate was obtained starting
from 3(R)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-benz-
thiazolyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-
-1-prop-1-enyl)-azetidin-2-one; (film) 1785 and 1725 cm 1;
max
~~(CD3COCD3) 0.03 and 0.05 (each 3H, s, SiMe2), 0.84 (9H, s,
SiBu.), 1.19 (3H, d, 6.5Hz, CH3.C1-i), 2.08 (3H, s, CH3), 3.72
(3H, s, OCH3), 4.11 (1H, dd, J= 5.5 and B.OHz, CH. CH.CH),
4.20 (1H, m, CH3.C'~I.CH), and 5.01 ppm (1H, d, J= 5.5Hz,
CH. CH. S).
1~~4~391
- 45 -
1 Example 13
Methyl (7S,6R)-7-L1(R)-hydroxyethy~-3-methyl-2-thiacephem
-4-carboxylate
OH off
N S_5~~~ ~~~ S~S
N
o'-~ ~OSUZUt3 O
CDICH~
(92c.u3
The crude 3(S)-/1(R)-hydroxyethyl%-4(R)-benzthiazolyldithio-
-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-
azetidin-2-one (145 mg, 0.287 mmol), as obtained in Example 9,
was dissolved in anhydrous dimethylformamide (2 mi) and
treated at +20°C with a freshly prepared solution of NaHS
(16 mg, 0.28? mmol) in the same solvent(1.6 ml). The mixture
was stirred for 2 minutes and then partitioned between ethyl
acetate and water.
After repeated washings with water, the solvent was removed
leaving a residue which was purified by pressure chromatography
on silica gel (ethyl acetate-cyclohexane as eluants) to give
the pure title product in 45°~ yield as a white powder;
-1
ym~ (nujol) 3400, 1170 and 1720 cm ; ~ (CDC13) 1.37 (3H,
d, J= 7Hz, CH3.CH), 2.22 (3H, s, CH3), 2.40 (1H, br s, OH),
3.12 (1H, dd, J= 2.0 and 4.5Hz, CH. CH.CH), 3.86 (3H, s, OCH3),
4.35 (1H, m, CH3.CH.CH), and 4.65 ppm (1H, d, J= 2.OHz,
CH. CH. S).
~t grade mufk
1~~4~91
- 46 -
1 By following a similar experimental procedure, there were
obtained:
Diphenylmethyl (7S,6R)-?-/1(R)-hydroxyethyl/-3-methyl-2-
thiacephem-4-carboxylate, starting from 3(S)-~(R)-hydroxy-
ethyl/-4(R)-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl
-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one;
max
(EtOH) 281 ( ~ = 5,900) and 326 (3,670) nm; y m~ (KBr)
3550-3250, 3080, 3060, 3020, 2960, 2920, 2840, 1775, 1720,
1660 and 1490 cm 1; ~ (CDC13) 1.36 (3H, d, J= 6.5Hz, CH3.CH),
2.17 (3H, s, CH3), 3.12 (1H, dd, J= 2.0 and SHz, CH. CH.CH),
4.36 !1H, m, CH3.CH.CH), 4.76 (1H, d, J= 2.OHz, CH. CH. S),
6.97 ;1H, s, OCH2Ph), and 7.30 (lOH, m, Ar);
Diphenylmethyl (7.S,6S)-7-~(R)-tert-butyldimethylsilyloxy-
ethyl7-3-methyl-2-thiacephem-4-carboxylate, starting from
3(S)-~'1(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyl-
dithic>-1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-
prop-:.-enyl)-azetidin-2-one; ~ (CDC13) 0.06 (6H, s, SiMe2),
0.83.i;9H, s, SiBut), 1.27 (3H, d, J= 6.5Hz, CH3.CH), 2.05
(3H, ~~, CH3), 3.08 (1H, dd, J= 3.O and 5.OHz, CH.C-H.CH),
4.32 I1H, m, CH3.CH.CH), 4.60 (1H, d, J= 3.OHz, CH. CH. S),
7.02 L1H, s, OCHPh2), and 7.30 ppm (lOH, s, Ar);
Tert-t~utyl (7S,6R)-7-~1(R)-tert-butyldimethylsilyloxyethyl/-
-3-mei:hyl-2-thiacephem-4-carboxylate, starting from 3(S)-/1(R)-
tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyldithio-1-
(1-tert-butoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-
azetidin-2-one; ~m~ (CHC13) 278 ( F= 6,300) and 327 nm
2, 560); ~m~ (CHC13 film) 1780 and 1720 cm 1; ~ (CDC13)
- 47 - ~~J'~~:~~
t
1 0.12 (6H, s, SiMe2), 0.88 (9t3, s, SiBu ), 1.25 (3H, d,
J= 6Hz, CH3.CH), 1.52 (9H, s, OBut), 2.10 (3H, s, CH3),
3.02 (1H, dd, J= 2.5 and SHz, CH.CH.CH), 4.28 (1H, m,
CH3.CH.CH), and 4.53 ppm (1H, d, J= 2.5Hz, CH. CH. S);
Methyl (7S,6R)-7-/1(R)-methylsulphonyloxyethyl%-3-methyl
-2-thiacephem-4-carboxylate, starting from 3(S)-/1(R)-
methylsulphonyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-
methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-
azetidin-2-one; ym~ 1?80, 1725, 1360 and 1175 cm 1; ~ (CDC13)
1.60 (3H, d, J= 6.5Hz, CH3.CH), 2.25 (3H, s, CH3), 3.0?
(3H, s, CH3S02), 3.27 (1H, dd, J= 2.2 and,5Hz, CH. CH.CH),
3.83 (3H, s, OCH3), 4.70 (1H, d, J= 2.2H, CH.CH.S) and
5.24 ;ppm (1H, m, CH3.CH.CH). ..
Diphenylmethyl (7S,6R)-7-/1(R)-methylsulphonyloxyethyl%-3-
me, thyl-2-thiacephem-4-carboxylate, starting from 3(S)-/1(R)-
methylsulphonyloxyethyl/-4(R)-benzthiazolyldithio-1-(1-
diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-aze-
tidin-2-one ~m~(CHC13) 282 ( ~= 7,080) and 330 (3,96b) nm;
(CDC1 )
ymax (CHC13 film) 1778, 1720, 1255 and 1170 cm 1; 3
1.53 (3H, d, J= 6Hz, CH3.CH), 2.10 (3H, s, CH3), 2.71 (3H, s,
CH3S02), 3.22 (1H, dd, J= 2.5 and 5.5Hz, CH. CH.CH), 4.67 (1H,
. d, J= 2.5Hz, CH. CH. S), 5.05 (1H, m, CH3.CH.CH); 6.90 (1H,
s, OCNPh2), and 7.25 (lOH, s, Ar);
Methyl (7~,6R)-7-/1(R)-trichloroethoxycarbonyloxyethyl/-3-
methyl-2-thiaceph-em-4-carboxylate, starting from 3(S)-/1(R)-
trichloroethoxycarbonyloxyethyl/-4(R)-benzthiazolyldithio-1-
' 1,54891
- 48 -
1 (1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-
azetidin-2-one; Amax (f.ilm) 1787, 1760 sh, 1725 and 1250 cm 1;
d(CDC13) 1.54 (3H, d, J= 5.5Hz, CH3.CH), 2.23 (3H, s, CH3)
3.30 (1H, dd, J= 2 and 7.5Hz, CH. CH.CH), 3.84 (3H, s, OCH3),
4,68 (1H, d, J-_ 2Hz, CH.CH.S), 4,78 (2H, s, OCH2), and
5,37 ppm (1H, m, CH3.CH.CH);
Diphenylmeth 1 (7S,6R)-7-[1(R)-p_nitrobenzyloxycarbonyloxyethyl]-
-3-methyl-2-thiacephem 4 carboxylate, starting from (3S)-
[1(R)-p-nitrobenzyloxycarbonyloxyethyl].(4R)-benzthiazolylditio-
-1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1-
-enyl)-azetidin-2-one; vmax 1787, 1745, 1720 sh cm 1; d(CLC13)
1.53 (3H, d, CH3-CH), 2.17 (3H, s, CH3), 3.28 (1H, dd, J= 2
and 6.5 Hz, CH-CH-CH), 4.65 (1H, d, J= 2Hz, CH. CH.S),,5.15
(2H, ;~, OCH2), 5.28 (1H, m, CH2.CH.CH), 6.97 (1H, s, O_CHPh2),
7.2-7,5 (12H, m, Ar) and 8.17 ppm (2H d J-_ 9Hz, Ar);
> >
and, __ikewise, there were obtained:
tert-butyl (7S,6R)-7 -[1(R)-trichloroethox carbon lox ethil]-
-3-met-hyl-2-thiacephem-4-carboxylate;
diphen~rlmethyl (7S,6R)-7-[1(R)-trichloroethoxycarbonyloxvethv7l
-3-metal-2-thiacephem-4-carbox late;
trichloroeth 1 (7S 6R)-7-[1(R)-trichloroethox carbon lox eth 1]-
-3-methyl-2-thiacephem-4-carboxylate;
trichloroethyl (7S,6R)-7-[1(R)-tert-butyldimethylsilvloxvet_h_v1_~-
-3-methyl-2 -thiace~hem-4-carboxylate;
acetoxymethvl (7S 6R)-7-[1(R)-trichloroethox carbon lox eth 1]-
1;~~4~3~1
_ 49 -
-3-methyl-2-thiacephem-4-carboxylate;
acetoxymeth yl (7S,6R)-7-[1(R)-tert-butyldimethylsilyloxyethylJ-
-3-methyl-2-thiacephem-4-carboxylate;
acetoxymethyl (7S,6R)-7-(1(R)-trimethylsilyloxyethyl]-3-methyl-
-2-thiacephem-carboxylate.
1;~~~~:31
- 50 -
1 Example 14
3(S)-~(R)-tent-butyldimethylsilyloxyeth~7.7-4(R)-succinimido-
thio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-envl)-azetidin-2-
one
OS;Yfe~ Bu
o OS;MezB~~ o
5-NJ1
J N ~ _--~ ~ o
o' .~ZCH3 0
~°t«3
Methyl 6~(-/1(R)-tert-butyldimethylsilyloxyethyl%-penicillanate
-1-oxide (2.32 g) dissolved in dimethylacetamide (35 ml) was
treated with acetic acid (0.15 ml), purged with nitro;~en, and
heated for 3 1/2 hours at 105°C in the presence of N-trimethyl-
5ilylsuccinimide (5 g). After cooling to room temperature,
the reaction mixture was partitioned between ethyl acetate
and cold water. Fractionation of the material.obtaine3 from
the organic layer (silica gel chromatography, ethyl acetate-
cyclohexane) afforded the title product as a white foam,
1.2 g (430); Lm~ (CHC13 film) 1770, 1735, 1710 sh, and
t
1680 cm 1; ~ (CDC13) 0.08 (6H, s, SiMe2), 0.87 (9H, s, SiHu ),
1.32 (3H, d, J= 6.5Hz, CH3.CH), 1.84 (3H, s, =C.CH3); 2.85
(4H, s, CO.CH2.CH2.C0), 3.29 (1H, dd, J= 3 and 4.5Hz, CH. CH.CH),
3.73 (3H, s, Ohle), 4.24 (iH, m, CH3.CH.CH), 4.66 (1H, s,
N.CH.CO), 4.85 (1H, d, J= 2.5Hz, CH.CH.S), and 5.00 ppm
(2H, br s, CH2=C).
7.;~ 'J'~~3;~1
- 51 -
1 By follovring a similar experimental procedure, there were
also obtained:
3-(S)-,~1(R)-tent-butyldimethylsilyloxyethyl/-4(R)-succinimido-
thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-
azetidin-2-one, and
3-(S)-/1(R)-tent-butyldimetY~ylsilyloxyethyl~-4(R)-phthalimido-
thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-
azetic~in-2-one, both isolated as crude materials and used as
such in the following steps.
125481
_ 52 _
1 Example 15
3(S)-L1(R)-tent-butyldimethylsilyloxyethvl>-4(R)-phthalimido-
thio-1-~1-methoxycarbonyl-2-methylsulphcnyloxy-1-prop-1-(Z)-
enyl%-azetidin-2-one
0 5: MeZBu OS;~ezsu o
" 5 SJS ~ N S-NJ D
1~~~
~'N OMS ---r I
o ~ ~ o ~--NW
cni cN3 ~oZ cu3
A solution of 3(S)-/1(R)-tert--butyldimethylsilyloxyethyl/-4(R)-
benzothiazolyldithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy-
-1-prop-1-(2)-enylJ-azetidin-~.'-one (lOC mg) in acetone (9 cc)
was treated with AgN03 (34 mg;~, soon followed by an ethanolic
slurry of potassium phthalimic~e (30 mg). After 30 min. stirring
at room temperature, the prec:~pitate was collected~partitioned
between water and EtOAc, and purified by short silica gel
chromatography to afford the -:itle product (55°x); ~m~ (film)
1 ~ CDC13) 0.1 (6H, s, SiMe2), 0.89
1?80, 1?45, and 1?25 cm ;
(9H, s, But), 1.4 (3H, d, CH3.CH), 2.2 (3H, s, =C.CH3), 3.05
(3H, s, S02.CH3), 3.4 (iH, m, CH. CH.CH), 3.6 (3H, s, OCH3),
4.2 (1H, m, CH3.CH.CH), 5.45 (1H, d, J= 2Hz, CH.CH.S); and
?.8 ppm (4H, m, Ar).
1~'S4891
- 53 -
1 Example 16
3(S)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-succinimido-
thio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin
-2-one
OS~Mela~ o OS;Ne28u o
5_N H S_nl
s _~ .-j. ~ o
0
0 ~--N ~~ o.- N ~- o N
H
cot f1e cozMe
The title product was obtained by ozonolysis of 3(S)-/1(R)-
tert-butyldimethylsilyloxyethyl~-4(R)-succinimidothia-1-(1-
methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one in
dichloromethane according to the procedure described in
Example 8, and used as such for further reactions. A sample
gas characterized as its dimethylketal (MeOH/dry HC11:
1- ~ (CDC13) 0.04 and 0.09
1770, 1730 and 1715 sh cm ,
m ax
(each 3H, s, SiMe2), 0.90 (9H, s, SiBut), 1.31 (3H, ~i, J= 5Hz,
:3.CH), 1.49 (3H, s, CH3), 2.84 (4H, s, COCH2.CH2C0), 3.21
and 3.26 (each 3H, s, ketal OCH3), 3.24 (1H, dd, J= 2.5 and
3.73 (3H, s, ester OCH3), 4.20 (1H, m, CH3.CH.CH),
4.43 (1H, s,~I~.CH.CO), and 4.94 ppm (1H, d, J= 2.5Hz).
Likewise, 3(S)-/1(R)-tert-butyldimethvlsilyloxyethyl%-4(R)-
hthalimidothio-1-(1-di henylmethyoxycarbonvl-2-hydroxy-1-
Prop-1-enyl)-azetidin-2-one, was obtained starting from
3( -S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phthalimido-
thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-
azetidin-2-one.
:~;~ 5 4 ~3;~ 1
- 54 -
1 Example 17
Methyl (7S,6R) 7 L1(R)-tent-butyldimethylsilyloxyeth~l/-3-
methyl-2-thiacephem-4-carboxylate
t f
pS;McIBu o~~ OS;MeIBv
'~ S lr~ ~~ ~H S ~ S
0
OSo2CN3 0
COZC H3
~t~ Hj
A solution of 3(S)-~1(R)-tent-butyldimethylsilyloxyethyl%
-4(R)-phthalimidothio-1-~1-methoxycarbonyl-2-methylsulphonyloxy-
-1-prop-1-(Z)-enylJ azetidin-2-one (400 mg) in dimethylformamide
(4 ml) was treated with finely ground NaSH (50 mg) unc.er
vigorous stirring. As soon as the last reagent was dissolved,
1(I the reaction was quenched by partition between ethyl ether and
water. Work-up gave the title compound, identical with the
sample described in Ex. 12.
_ 55 - Ii~J4
1 Example 18
Methyl (7S,6R)-?-L1(R)-tent-butyldimethylsilyloxyethy~/-3-
methyl-2-thiacephem-4-carboxylate
OS;MeIg~ o OS~M~18~~
N S_N~~ ~ N 5.5
~--N 0 I
O
N . Go?C~I3
~1C N3
3(S)-/1(R)-tent-bttyldimethylsilyloxyethyl%-4(R)-succinimido-
thio-1-(1-methoxycarbonyl-1-prop-2-enyl)-azetidin-2-one (0.8 g)
in dichloromethane~ was ozonized at -?O°C until tlc showed
complete conversion. Excess ozone was purged with-nitrogen
and dimethylsulphide (1 ml) was added. After 1 hour at room
temperature, any volatile material was removed in vacuo and
the residue reacted with equimolecular amounts of triethyl-
amine and mesyl chloride (CH2 I2,-20°to O°C) until conversion
of the enol into the mesylates was judged complete by tlc.
The mixture was concentracted in vacuo and partitioned between
ethyl acetate and gold, aqueous NaHC03. The organic layer
was evaporated to .afford the crude mixture of E,Z mesylates
which without purification was treated with NaHS in DMF
according to the p~ocedure described in Example 13. Purification.
of the resulting product by silica gel chromatography afforded
the title compound, identical with the material obtained
according to Example 12.
- 56 - ~IG ~J4~:~~
1 By a similar procedure,
Diphenylmethyl (7S,6R)-7-/1(R)-tert-butyldimethylsilyloxy-
ethyl/-3-methyl-2-thiacephem-4-carboxylate was obtained,
starting from 3(S)-~(R)-tert-butyldimethylsilyloxyethyl/-4(R)
-phthalimidothio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-
prop-2-enyl)-azetidin-2-one, and showed the same spectral
properties of the material previously described (Example 13).
~~54891
_ 5? _
1 Exampl a 19
Methyl (7S,6R)-?-C1(R)-tert-butyldimethylsilyloxyethy~/-3-
(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-2-thiacephem-4-
carboxvlate
OS~~'le2B~ N-N OS;MeZB~
H S_S ~N N -~ ~~N 5~5 N_.N
c', N3 l~!-N ~ S .J) N
D ~~ ~ 5 ~ ~ o ~-rv ~.,/
N
H cOzCH3 GH3 LOZcN~ CH3
3(S)-/1(R)-tent-butyldimethylsilyloxyethy:l/-4(R)-(1-methyl-
-1,2,3,4-tetrazol-5-yl)-dithio-1-/1-methoaycarbonyl-2-(1-
methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-~1-prop--2-enyl/-
azetidin-2-one (120 mg) in dichloromethan~°_ was subjected to
the same reaction sequence reported in Example 17 (ozonolysis,
mesylation, reaction with NaHS). The crud~° product was parritior~
between ethyl acetate and aqueous NaHC03, thus removing the
liberated mercaptotetrazole; the organic layer was washed
several time with water, evaporated and t;~e residue fractionated
by silica gel chromatography to afford the title product,
-1
i7 mg (17~); ym~ (film) 1787, 1725, 1587, 1360 and 1250 cm ;
t
(CDC13) 0.10 (6H, s, SiMe2), 0.89 (9H, s, SiBu ), 1.26
(3H, d, J= 6Hz, CH3-CH), 3.15 (1H, dd, J= 2.2 and 3.5Hz,
CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, NMe), 4.38 (1N, m,
CH3.CH.CH), 4.46 (2H, ABq, J= l4Hz, separation of inner lines
1-1Hz) and 4.68 ppm (1H, d, J= ~2.2Hz, CH. CH. S).
- 5s - 1;~~4L~~~
1 Exampl a 20
3(S)-~1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-
sulphonVlthio-1 fl-methoxycarbonyl-2-methyl-1-prop-2-enyl~-
azetidin-2-one
t
05; M~ZB~ ~ oS~ MP~B~ o
H . S_S ~S~ H 5_5 _P~
----~ o
0
o'
CD C H
2 3 H
3(S)-~1(R)-tert-butyldimethylsilyloxyethyl~-4(R)-benzthiazolyl-
dithic-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-
-2-one (2.6 g) in acetone (160 ml) and water (18 ml) was
treated under vigorous stirring with silver nitrate (0.98 g),
immediately followed by sodium benzenesulphinate (0.79 g) in
water (60 mlj. After 1 hour at ropm temperature the white
precipitate was filtered off, and the filtrate concentrated
in vacuo and then partitioned between water and ethyl acetate.
Removal of the solvent from the organic layer left the title
product as a yellowish powder (2.43 g, 98~), recrystallizable
from cyclohexane (white leaflets, mp 105-106°C); it (KBr)
3080, 3020, 2960, 2930, 2900, 2860, 170, 1750, 1330 and
1145 cm 1; d (CDC13) 0.05 (6H, s, Si~le~), 0.98 (12H, s+d,
SiBut and CH3.CH), 1.84 (3H, s, =C.CH3), 3.22 (1H, dd, J= 2 and
2.5Hz, CH. CH.CH), 3.75 (3H, s, OMe), 4.19 (1H, m, CH3.CH.CH),
4.58 (1H, s, N.CH.CO), 5.00 (2H, m, C=CH2), 5.37 (1H, d,
J= 2Hz, CH. CH. S), 7.60 and ?.96 ppm (3 and 2H, each m, Ar).
1~~~~~1
- 59 -
1 Found: C, 53.69; H, 6.99; N, 2.?O; S, 12.42ro. C23H35N06SiS2
requires C, 53.77; H, 6.87; N, 2.?4; S, 12.480.
By following the same procedure, there were also obtained:
3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-
sulphonylthio-1-(1-tent-butoxycarbonyl-2-methyl-1-prop-2-
enyl)-azetidin-2-one;
3(S) /1(R) tent-butyldimethylsilyloxyethyl/-4(R)-phenylsulphonyl
thio-1-(1-diphenylmethoxycarbonyl-2-methvl-1-prop-2-enyl)-
azetidin-2-one;
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-phenylsulphonyl
thio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin
-2-one;
_3(S)-/1(R)-trichloroethoxycarbonyloxyethyl)-4(R)-phenylsul-
Ehonylthio-1-(1-trichloroethoxycarbcnvl-2-methyl-1-prop-2-
enyl)-azetidin-2-one.
3~;~~4891
- 60 -
1 Example 21
3(S)-L1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-
sulphonylthio-1-L1-methoxycarbonyl-2-methylsulphonyloxy-
-1-~ro~-1(Z)-enyl/-azetidin-2-one
OSi Me2gu
A~ " S _ sot P~
1
D ~--N
t
C,aZCH3 ~ DSiMetB~
S-502~~
oso2CN3
O~J~'te28u p
g N S-S-C ~ O
S ~ (!J2 CNj
O~
~pZCN3
Procedure A)
The material from Example 20 (1 g) in dry dichloromethane
was ozonized at -?O°C. After purging with nitrogen, dimethyl-
sulphide (3.5 ml) was added and the mixture stirred f~~r 3 hours
zt room temperature. After removal of any volatile material
~n vacuo, the residue was partitioned between ethyl acetate
and water. Evaporation of the solvent left the intermediate
3(S)-/1(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-
sulphonylthio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-
azetidin-2-one; ~l 3450, 1?78, 1658 and 1620 cm 1; ~ (CDC13)
m a~:
0.08 (6H, s, SiMe2), 0.90 (9H, s, SiBut), 1.13 (3H, d,
J= 6Hz, CH3.CH), 1.90 (3H, s, =C.CH3), 3.12 (1H, dd, J= 2.5
- 6' - 1~;~~8~1
1 and 4Hz, CH. CH.CH), 3.73 (3H, s, OMe), 4.2 (1H, m, CH3.CH.CH),
5.52 (1H, d, J= 2.5Hz, CH.CH.S), ?.4-8.0 (5H, m, Ar), and
13 ppm (1H, s, OH).
This material was mesylated with triethylamine (272 ~1) and
mesyl chloride (151 ~1) in dry THF (10 ml) according to the
general procedure - see Example 10 -thus obtaining the title
product as a foam, 550 mg after silica gel chromatography;
(CDC13)
it (film) 1780, 1730, 1640, 13?O and 1145 cm 1;
0.05 (6H, s, SiMe2), 0.80 (9H, s, SiBut), 0.97 (3H, d, J= 6Hz,
1() CH3.CH), 2.50 (3H, s, =C.CH3), 3.15 (4H, m, S02CH3 and
CH.CH.CH), 3.76 (3H, s, OCH3), 4.13 (1H, m, CH3.CH.CH), 5.7
(1H, d, J= 2.8Hz, CH. CH. S), and ?.6-8.0 ppm (5H, m, Ar).
Procedure B)
3(S) 11(R)-tert-butyldimethylsilyloxyethyl7-4(R)-benzthiazolyl-
1!i dithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-
enyl/-azetidin-2-one (100 mg) in acetone-water 9:1 (10 ml)
was sequentially treated under stirring with silver nitrate
(34:3 mg) and an aqueous solution of sodium benzenesulphinate
(26.6 mg in 4 ml). After 15 min stirring at room temperature
2U the precipitated silver benzthiazolmercaptide was removed
by filtration and the solution partitioned between CH2C1~ and
water. Removal of the solvent left the title product as a
syrup (quantitative yield), sharing the same spectral properties
with the sample from procedure A).
~z~~891
- 62 -
1 According to the same methodology, there were obtained:
3(S)-~(R)-tert-butyldimethylsilyloxyethyl/-4(R)-phenyl-
sulphonylthio-1-/1-tert-butoxycarbonyl-2-methylsulphonyloxy-
-1-prop-1(Z)-enyl/-azetidin-2-one;
3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-4(R)-phenyl-
sulphonylthio-1-/1-trichloroethoxycarbonyl-2-methylsulphonyl-
oxy-1-prop-1(Z)-enyl/-azetidin-2-one.
:~254~91
- 63 -
1 Example 22
Methyl (?S,6R)-7-~1(R)-tert-butyldimethylsilylox~ethyl/-3-
methyl-2-thiacephem-4-carboxylate
OS. Met Bu OS;N~ZB~
VN S_SOZ~~ ~ H S~S
OSD LH
0 ~ N s 3 o f-- N
CDZCH3 . ~ICN3
3(S)-/1(R)-tent-butyldimethylsilyloxyethy:_/-4(R)-phenylsulphonyl-
thio-1-/1-methoxycarbonyl-2-methylsulphon~rlo~;y-1-prop-1(Z)-
enyl%-azetidin-2-one was allowed to react with NaHS in DMF
following the procedure described in Example 13 thereby obtain-
ing the title product, identical with the material previously
described. This preparation_allows for a ~~impler purification
o.f the product, since the by-product, sodium benzenesulphinate,
is soluble in water and does not need chromatographic separat-
ion or fractional crystallization to be removed (different
from, e.g., mercaptobenzthiazole).
According to the same methodologies, there were obtained:
Tert-butyl (?S,6R)-7-%1(R)-tent-butyldimethylsilyloayethyl/-
-3-methyl-2-thiacephem-4-carbox~~late;
Trichloroethyl (?5,6R)-?-/1(R)-trichloroethoxycarbonvloxy-
ethyl/-3-methyl-2-thiacephem-4-carboxylate.
- 64 - ~~~48~1
1 Example 23
3(S)-rl(R)-trichloroethoxycarbonyloxyethylJ-4(R)-acetyldithio-
1-L1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-envlJ
azetidin-2-one
OGOZ(,HZ~CQj
~\tptcH~~c~3
S ~ S-s GoUlg
~ 50 U( --'
~ ~N Z 3 ~ QSO1C.!!3
GO Z c.~3 CD 1 U13
A solution of 3(S)-~1(R)-trichloroethoxycarbonyloxyethyl7-
4(R)-benzothiazolyldithio-1-/1-methoxycar~bonyl-2-methyl-
sulphonyloxy-1-prop-1(Z)-enyl%azetidin-2-one (340 mg) in
THF (5 ml) was treated with thioacetic acid (43 ~1).
Five minutes later the mixture was evaporated and the crude
reaction product freed from 2-mercaptobenzothiazole by chroma-
tography to obtain the pure title compound as a colourless
syrup, 280 mg (96°x); ~m~ (film) 1??5, 1760 sh, 1730 br cm l;
(CDC13) 1.50 (3H, d, CH3.CH), 2.48 (3F1, s, =C.CH3), 2.62
(3H, s, COCH3), 3.29 (3H, s, S02CH3), 3.~r4 (1H, dd, CH. CH.CH),
3.83 (3H, s, OMe), 4.77 (2H, ABq, J= 11.'~Hz, separation of
inner lines 2Hz), 5.24 (1H, d, CH. CH. S), 5.25 (1H, m, CH3.CH.CH)
- 65 -
~.ic: 'J~ t~~..~'' ~.
1 Example 24
Methyl (7S,6R)-7-~(R)-trichloroethoxycarbonvloxyethylJ-3-
methyl-2-thiacephem-4-carboxylate
OLO~~i~CCp~
S
~S
. oSaz UI3 ---a
o'-N p i-N w
(p2LH3 L,OzC.N3
A solL:.tion of 3(S)-/1(R)-trichloroethoxycarbonyloxyethyl/-
4(R)-acetyldithio-1-/1-methoxycarbonyl-2-methylsulphonyloxy-
-1-prcp-1(Z)-enyl/azetidin-2-one (140 mg) in THF (10 ml) was
treated at O°C with a solution of tetrabutylammonium hydrogen
sulphide (65 mg) in the same solvent.
Work-up and chromatography afforded the title product: ~1
m ax
(EtOH) 280 (~ 4,974) and 327 nm (2,262); Y m~ (film) 1787,
1760 sh, 1725 cm 1; O (CDC13) 1.54 (3H, d, CH3.CH), 2.23
(3H, s, CH3), 3.30 (1H, dd, 2 and 7.5 Hz, CH. CH.CH), 3.84
(3H, s, Ohle), 4.68 (1H, d, CH. CH. S), 4.78 (2H, s, OCH2CC13),
and 5.3H ppm (1H, m, CH3.CH.CH), followed by some recovered
starting material.
1;~,;:i ~ ~:~ 1
- 66 -
1 Example 25
MethVl (?5,6R)-7-L1(R)-tent-butyldimethylsilyloxyethyl_/-
3-bromometh yl-2-thiacephem-4-carboxylate
OS:Mei6~~ OS~HetCiu
N
--~. --~ S ~5
J
p'!N ~ o ~ ~ Br
UJ2CH3 (,p2CH~
Methyl (7S,6R)-7-/1(R)-tert-butyldimethylsilyloxyethyl/-
3-methyl-2-thiacephem-4-carbo:Kylate (0.52 g)~propylene
oxide (0.95 ml) and N-bromosuccinimide (0.52 g) and azobis-
isobutyronitrile (0.05 g) in ~~arbon tetrachloride (40 ml) were
refluxed for six hours.
The reaction mixture was cooled to room temperature and
filtered. The filtrate was evaporated in vacuo and the residue
was.purified by silica gel column eluting with ethyl acetate -
exane mixtures, thus obtaining the title product as a yellowish
oil (80ro); ~ m~ (CHC13) 282 and 336 nm; Y m~ (CHC13 film)
1785, 1730 cm-1; ~ (CDC13) 0.10 (6H, s, SiMe2), 0.89 (9H, s,
SiBut), 1.28 (3H, d, CH3.CH.OSi), 3.23 (1H, dd, J= 2.0 and
3.5Hz, CH. CH.CH), 3.87 (3H, s, OCH3), 4.65 (2N, center ABq,
s.i.l. 4Hz, J= 11.5Hz, CH2Br), 4.30 (1H, m, CH3.CH.CH), 4.76
(1H, d, J= 2.OHz, CH.CH.s) ppm
Found: C, 41.1; H, 5.64; N, 3.01; S, 13.55; Br, 17.20;
C16H26BrN704Si52 requires C, 41.02; H, 5.59; N, 2.99; 5, 13.69;
Br, 1.06.
_ 67 _ 1;~548~1
1 By following a similar procedure, there were obtained:
tert-butyl (7S,6R)-7-[1(R)-tert-butyldimethylsilyloxyethil]-
-3-bromomethyl-2-thiacephem-4-carboxylate;
Amax (CHC13) 283 and 332 nm; vmax (film) 1787 and 1720 cm 1;
8 (CDC13) 0.9 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.28
(3H, d, CH3.CH), 1.55 (9H, s, OBut), 3.18 (1H, dd, J= 2.5
and 4.5Hz, CH.CH.CH), 4,35 (3H, m, CH2Br and CH3.CH.CH), and
4,71 ppm (1H, d, J= 2.5Hz, CH. CH. S);
p-nitrobenzyl (7S,6R)-7-(1(R)-p-nitrobenzyloxycarbonyloxyethyl]-
-3-bromomethyl-2-thiacephem-4-carboxylate; d(CDC13) 1.45 (3H,
d, CH3.CH), 3.43 (1H, dd, J= 2.5 and 6 Hz, CH. CH.CH), 4.45
(2H, ABq, J= l2Hz, CH2Br), 4.80 (1H, d, J= 2.5 EIz, CH. CH. S),
5.2, 5.5 (5H, m, two OCI-I2Ar and C~3.CH.CH); 7.47 and 7.60 (each
2H, d, J= 8.5Hz, Ar), and 8.20 ppm (4H, d, J= 8.5Hz, Ar);
1~ diphenylmethyl (7S,6R)-7-(1(R)-p-nitrobenzyloxycarbonylox~ethyl~ -
-3-bromomethyl-2-thiacephem-4-carboxylate; d(CDC13) 1.45
(3H, d, Cf~3.CH), 3.32 (1H, dd, J= 3 and 6Hz, CH. CH.CH), 4.18
(2H, ABq, J-_ ll.Hz, CIi2Br), 4.70 (1H, d, J= 3Hz, CH. CH. S), 5.20
(2H, s, OCH2Ar), 5.30 (1H, m, CH3.CH.CH), 6.97 (1H, s, OCHPh2),
7,10 - 7.40 (10H, br s, Ar), 7.45 and 8.15 ppm (each 2H, d, J=
9Hz, Ar);
diphenylmethyl (7S,6R)-7-C1(R)-tert-butyldimethylsilyloxyethyl)-
-3-bromomethyl-2-thiacephem-4-carboxylate; vmax(film) 1790
and 1730 cm-1; d(CDC13) 0.05 (6H, s, SiMe2), 0.8 (9H, s, SiBut),
1.22 (3H, d, J= 6.5 Hz, CH3.CH), 3.10 (1H, dd, J= 2.7 and 4.5 Hz,
~1;~~4891
- 68 -
1 CH. CH.CH), 4.05 (2H, s, CH2Br), 4.2 (1H, m, CH3.CH.CH),
4.63 (1H, d, J= 2.7 Hz, CH.CH.S), 6.92 (1H, s, OCHPh2), and
7.05-7.40 ppm (10H, m, Ar); amax (CHC13) 283 (e= 7.867) and
336 nm (e - 3.533); and, likewise:
trichloroethyl (7S,6R)-7-[1(R)-tert-butyldimethylsilyloxy-
ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate;
trichloroethyl (7S,6R)-7-(1(R)-trichloroethox~carbonyloxy~
ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate.
lzs4~~~
_ 69 _
1 Example 26
MethrLl (?S,6R)-7-~1(R)-tent-butyldimethylsilyloxyethylJ-
-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-
-4-carboxylate
a S; ale t t~~' GS;~1z28~'
H
S ,,5 ~~ H 5 .S N~N
S
N ~ B r U ~'-i~ .~/~ N
Uf
~~ Me. CGZfnz
A THF solution of crude methyl (7S,6R)-?-/1(R)-tert-butyl-
dimethylsilyloxyetryl%-3-bromomethyl-2-thiacephem-4-carboxy-
late was kept overnight in the presence of sodium 1-methyl-
1,2,3,4-tetrazol-5-thiolate bihydrate (3 mol equiv.).
Work-up and chromatography afforded the title product as an
oil in 85p yield; ~ (EtOH) 281 and 333 nm; y m~ (film)
_ max
1 ~ (CDC13) 0.10 (6H, s, Sihle2), 0.89 (9H,
1790~and 1725 cm ;
s, But), 1.26 (3H, d, CH3.CH), 3.15 (1H, dd, J= 2.2 and
3.5Hz, CH. CH.CH), a.88 (3H, s, OMe), 3.92 (3H, s, N.CH3),
4.38 (1H, m, CH3.Cri.CH), 4.46 (2H, ABq, sep. of inner lines
l4Hz, J= l4Hz), 4.t>8 (1H, d, CH.CH.S, J= 2.2Hz)
1~5489~1
- 70 -
1 By following a similar procedure, there was obtained:
tent-butyl (?S,6R)-?-~1(R)-tert-butyldimethylsilyloxyethyl/-
-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-2-thiacephem
-4-carboxylate, starting from tert-butyl (7S,6R)-?-/1(R)-
tent-butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephem
-4-carboxylate;
diphenylmethyl (?5,6R)-?-~(R)-tert-butyldimethylsilyloxyethylJ-
-3-(8-aminotetrazolo~l,5-b~pyridazin-6-yl)thiomethyl-2-thiace-
phem-4-carboxylate
szs4~~1
1 Example 27
(5aR,6S)-6-L1(R)-tert-butyldimethylsilyloxyethyl~-5a,6-
dihydro-3H,7H-azetoL2,1-cJ furoj~3,4-e_~-1,2,4-dithiazine-1,7-
dione
Osvl''h' j Bud O~il~eZ$vt
H S.5 H S~S
o ~-N ~~ 8 z o J r~ ~~
WZ~H3
Procedure A): A solution of methyl (?S,6R)-?-/1(R)-tert-
butyld:imethylsilyloxyethyl/-3-bromomethyl-2-thiacephem-4-
carbox:~late (15 mg) in DMSO (2 ml) and water (1.5 ml) was
stirred with Cu20 (50 mg) at 50°C for 2.5 hours.
The re;3ction mixture was partitioned between water and ethyl
acetate. Evaporation and chromatography of the organic extracts
afforded the title product as a white powder; Y (CHC1
max 3
film) 1800-1760 br cm 1; ~(CDC13) 0.06 (3H, s, SiCH3), 0.11
~.3H, s, SiCH3), 0.90 (9H, s, But),'1.33 (3H, d, CH3.CH), 3.33
'1H, dpi, J= 2.5 and 4.5Hz, CH. CH.CH), 4.44 (1H, m, CH3.CH.CH),
4.62 (LH, d, J= 2.5Hz, CH. CH. S), and 4.98 (2H, s, CH20)
Procedure B): The 2-bromomethyl precursor (250 mg) in 2:1
acetone-water (35 ml) was stirred for 15 min at O°C with
AgC104 (753 mg). The reaction mixture was partitioned between
H20/EtOAc and the organic layer evaporated to leave a residue.
Silica gel chromatography afforded the title product, identical
with the sample~described above under A).
1254891
- 72 -
1 Example 28
tert-Butyl (75,6R)-?-/1(R)-tent-butyldimethylsilyloxyethyl/-
3-hydroxymethyl-2-thiacephem-4-carboxylate
OS~M~ zg~t OS; M~ZBut
,5 ~ ~ S.s
o w ~~ B Z o
~.o ~ ut c
Z
5 tert-Butyl (?5,6R)-7-/1(R)-tent-butyldimethylsilyloxyethyl/-3-
bromomethyl-2-thiacephem-4-carboxylate (300 mg) in 2:1 acetone-
water (10 ml) was stirred for' 15 min at O°C with AgC104 (150 mg)
Removal of the solvent, followed by H20/EtOAc partition and
work-up of the organic layer, gave 250 mg (96~) of the title
product; 1 m~ (CHC13) 281 ar~d .335 nm; y (film) 3450,
m ax
1?85 and 112 cm 1; ~ (CDC13) O.1 (6H, s, SiMe2), 0.86 (9H, s,
SiBut), 1.25 (3H, d, CH3CH), 1.50 (9H, s, OBtit), 3.13 (1H, dd,
J= 2.5 and 4.5Hz, CH. CH.CH), 4.25 (centre of ABq, J= l3Hz,
CH20H), 4.3? (1H, m, CH3.CH.C:H), and 4.60 ppm (1H, d, J= 2.5Hz,
CH. CH. S).
- 73 - ~2548~~.
1 Example 29
tert-Butyl (7S,6R)-7-~1-(R)-tert-butyldimethylsilyloxyethyl/-
-3-(N-trichloroacetyl)carbamoyloxymethyl-2-thiacephem-4-carbo-
xylate
OS.He2~~
OStH eZ~a
H H
'S'S S~S
OOH -' o ~ ~ OCONN COtCt3
COz B,~ (,oz Bsi
tert-Butyl (7S,6R)-7-~1(R)-teat-butyldimethylsilyloxyethyl/-3-
hydroxymethyl-2-thiacephem-4-c;3rboxylate (250 mg) in ethanol-free
dichloromethane (2.5 ml) was treated at -40°C with trichloro-
acetylisocyanate(80 ~1). The mixture was let rise to room
temperature and then sequentially washed with aqueous 2~ NaHC03
and brine. Evaporation of the solvent from the organic layer
gave'the title product in quantitative yield;' 1 (EtOH)
m ax
max ~ ( CD3CN ), O . 1
275 and 329 nm; iJ 1795 and 1725 br cm-1;
(6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.3 (3H, d, CH3.CH) 1.5
(9H, s, OBut), 3.40 (1N, dd, J= 3 and 4Hz, CH. CH.CH), 4.35
(1H, m, CH3.CH.CH), 4.80 (1H, d, J= 3Hz, CH.CH.S), and 5.0 ppm
(centre of ABq, CH20C0).
- 1;54891
1 Example 30
tent-Butyl (7S,6R)-7-/1(R)-tert-butYldimethylsilyloxyethyl/-
-3-carbamoyloxvmethyl-2-thiacephem-4-carboxylate
OSs M~2Bv OSJ'1eZ 6v
S,S ~ S.S
' , ocor~H co cc~~ o ~ ~ ocoiuHy
o'~"
C028ut ~28~
5- A methanolic solution of tert-butyl (?S,6R)-7-~1(R)-tert-
butyldimethylsily'__oxyethyl/-3-(N-trichloroacetyl)carbamoyloxy-
methyl-2-thiacephc:m-4-carboxylate was stirred with silica gel
for 20 hours. The slurry was then charged onto a silica gel
column and the product eluted with ethyl acetate; ~ (CDC13)
O.1 (6H, s, SiMe2l, 0.9 (9H, s, SiBut), 1.35 (3H, d, CH3.CH),
1.60 (9H, s, OButl, 3.1 (1H, dd, CH. CH.CH), 4.3 (1H, m, CH3.C~.C'.
4.75 (1H, d, J= 31~z, CH. CH. S), and 5.0 ppm (centre of ABq,
OCH2C0).
125481.
_ 75 _
1 Example 31
Methyl (7S,6R)-7-L1(R)-tent-butyldimethylsilyloxyethylJ-3-
nitrooxymethyl-2-thiacephem-4-carboxylate
~si/''~et gu
H S'S N S
'S
-- ,I BZ ~ oHaz
o N ~ o
CD2CH3
2 3
A solution of methyl (7S,6R)-?-/1(R)-tert-butyldimeth_ylsilyl-
oxyethyl/-3-bromonethyl-2-thiacephem-4-carboxylate (200 mg) in
acetone (20 ml) was stirred for 20 min in the presence of
AgN03 (100 mg). The filtered reaction mixture was fractionated
by silica gel chromatography to obtain the title product,
120 mg; ~lm~ (CHC13) 280 and 337 nm; ~ (film) 1790, 1730,
m ax
1640 and 1280 cm 1; C~(CDC13) 0.08 (6H, s, SiMe2), 0.87 (9H,
s, SiBut), 1.38 (3H, d, CH3.CH), 3.18 (1H, dd, J= 2.5 and S.SHz,
CH._CH.CH), 3.85 (3H, s, OMe), 4.38 (1H, m, CH3.CH.CH), 4.73
(1H, d, J= 2.SHz, CH. CH. S), and 5.36 ppm (2H, ABq, J= 13.5Hz,
, s.i.l. 29.5Hz, CH20N02); further elution then afforded some
of the lactone described in Example 27.
X254891
- 76 -
1 Example 32
Methyl (7S,6R)-7-L1(R)-tert-butyldimethylsilyloxyethylJ-3-
formyloxymeth~l-2-thiacephem-4-carboxylate
Os~l' 2 ~ a
OSi M~~ ~ a
S~S oG~to
Bz I
O
COZCN3 Coz~H3
Methyl (7S,6R)-7-~1(R)-tent-butyldimethylsilyloxyethyl/-3-
bromomethyl-2-thiacephem-4-carboxylate (200 mg) in CH2C12
was treated at daily intervals with tetrabutylammonium
formiate (3 x 600 mg). After 3 days at 5°C tlc showed 80°k
conversion in the product (ethyl acetate/light petroleum 1:2).
Elution through a short silica gel column gave the title
t
material; ~ (CDC13) O.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu ),
1.35 (3H, d, CH3.CH), 3.20 (1H, dd, 2.5 and 7Hz, CH. CH.CH),
3.9 (3H, s, OMe), 4.5 (1H, m, CH3.CH.CH), 4.74 (1H, d, 2.5Hz,
CH. CH. S), 5.13 (center of ABq, CH20).
In a similar way, starting from the corresponding tert-butyl
and diphenylmethyl esters, there were obtained:
tert-butyl (7S,6R)-?-rl(Rl-tert-butyldimethylsilyloxyethy~/-
3-formyloxymethyl-2-thiacephem-4-carboxylate;
- ~,~548~1
1 diphenylmethyl (7S,6R)-?-/1(R)-tert-butyldimethylsilyloxy-
ethyl_/-3-formyloxymethyl-2-thiacephem-4-carboxylate
and, in a likewise fashion, the corresponding acetates were
obtained:
methyl (7S,6R)-7-ll(R)-tert-butyldimethylsilyloxyethyl./-3-
acetoxymethyl-2-thiacephem-4-carboxylate;
tert-outyl (7S,6R)-7-/1(R)-tent-but~ldimethylsilvloxyethyl_%-
-3-acetoxymethyl-2-thiacephem-4-carboxylate;
d_iphenylmethvl (7S,6R)-7-~1(R)-tent-butyldimethylsilyloxyethvl/-
ZO -3-acetox5~methyl-2-thiacephem-4-carboxylate;
trichloroethvl (7S,6R)-7-ll(R)-trichloroethoxycarbonyloxyethylJ-
-3-acetoxymethyl-2-thiacephem-4-carboxylate
~.254~~~
1 Example 33
Methyl (?S,6R)-?-L1(R)-hydroxyethy~/-3-methyl-2-thiacephem-
-4-carboxylate
OS;Melgu CN
H SOS H S .S
--:
O ,,.-N ~ O
GOZC H3 _ Zt~3
Methyl (?S,6R)-?-/1(R)-tert-butyldimethylsilyloxyethy~.%-3-
methyl-2-thiacephem-4-carboxylate (0.75 g) was added i:o a
solution of tetrabutylammonium fluoride trihydrate (2.03 g)
in acetic acid (1.23 ml) and THF (10 ml).
Work-up after 20 hours gave the tile compound (virtua:lly
quantitative yield), showing the spectral properties described
for the sample obtained in'Example 13.
By following a similar experimental procedure, there ,Here
obtained:
Methyl (7S,6R)-7-/1(R)-hydroxyethyl~-3-bromomethyl-2-thiacepherri
-4-carboxylate, starting from methyl (?S,6R)-?-/1(R)-tert-
butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephe;n-4-
carboxylate; y (film) 1??5, 1?30 cm 1; ~ (CDC13) 1.35
m ax
(3H, d, CH3.CH'), 3.38 (1H, dd, CH. CH.CH), 3.60 (1H, br s, OH),
3.9? (3H, s, OMe), 4.33 (1H, m, CH3.CH.CH), 4.46 (2H, centre
of ABq, J= llHz, sep. of inner lines 4Hz, CH2Br), and 4.88 ppm
(1H, d, J= 2.2Hz, CH. CH. S);
- ~9 - lzs~S91
1 Methyl (7S,6R)-7-/1(R)-hydroxyethyl/-3-(1-methyl-1,2,3,4-
tetrazol-5-yl)thiomethyl-2-thiacephem-4-carboxylate, starting
from methyl (7S,6R)-7-L1(R)-tent-butyldimethylsilyloxyethyl/-
-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-4-
5' carboxylate; (KBr) 1765 and 1707 cm 1; ~ (CD3COCD3) 1.30
Ymax
(3H, d, CH3.CH), 3.39 (1H, dd, CH. CH.CH), 3.79 (3H, s, NCH3),
3.97 (3H, s, OCH3), 4.0 (1H, m, CH3.CH.CH), 4.38 (2H, centre
of ABq, J= l6Hz, separation of inner lines l3Hz, CH2.S), 4.77
(1H, d, J= 2.2Hz, CH. CH. S) and 5.0 ppm (1H, br s, OH);
and, analogously, the corresponding tert-butyl, diphenylmethyl
and trichloroethyl esters were also prepared.
- so - 12~48~1
1 Example 34
(?S,6R)-7-L1(R)-methylsulphonyloxyethyl/-3-methyl-2-thia-
~hem-4-carboxylic acid
0 S~Z~H3 0 S~ZCH3
SOS N S.S
D ~-N ~ O i-_ N ~L.
~oZC H P~ ~ CazH
5~ Diphenylmethyl (7S,6R)-7-/1(R)-methylsulphonyloxyethyl/-3-
methyl-2-thiacephem-4-carboxylate was dissolved in cold
trifluoroacetic acid (0°C, neat). After 15' stirring at
the same temperature, carbon tetrachloride was added and the
solution thoroughly evaporated under vacuum without external
heating. The residue was triturated in CC14 and collected,
thus obtaining the title product; ~1 (CHC1 ) 281 and 326 nm;
max 3
~ (CHC13) 3000-.2300, 2970, 2930, 2850, I775, 1710, 1530
and 1170 cm 1; ~ (CD3COCD3) 1.58 (3H, d, CH3.CH), 2.23 (3H,
s, Me), 3.16 (3H, s, S02Me), 3.66 (1H, dd, J= 2 and 6Hz,
CH. CH.CH), 4.85 (1H, d, J= 2Hz, CH. CH. S), and 5.30 ppm (1H,
m, CH3.CH.CH).
The same material was obtained by TFA-hydrolysis of the
corresponding t-butyl ester, but prolonging the reaction
time to about 1 hour.
Similarly hydrolysis of the t-butyl or diphenylmethyl
precursors gave the following products:
i~548~1
' , - 81 -
1 (?S,6R)-7-L1(R)-tert-butyldimethylsilyloxyethyl/-3-methyl
-2-thiacephem-4-carboxylic acid;
(?S,6R)-?-L1(R)-hydroxyethyl/-3-methyl-2-thiacephem-4-
carboxylic acid;
(?S,6R)-?-l1(R)-hydroxyethylJ-3-acetoxymethyl-2-thiacephem-
-4-carboxylic acid;
(7S,6R)-?-!1(R)-hydroxyethyl%-3-carbamoyloxymethyl-2-thia-
cephem-4-carboxylic acid;
(?S,6R)-?-~1(R)-hydroxyeth~l~-3-(1-methyl-1,2,3,4-tetrazol-
-5-_~thiomethyl-2-thiacephem-4-carboxylic acid
1254891
- 82 -
1 Example 35
(7S,6R)-7-(1(R)-tort-butyldimethylsilyloxyethul)-3-methyl-
4-methoxycarbonyl-2-thiacephem-1,1-dioxide
~5~ /PLC Z sut ~5;~ Z gut
H ~ ,o
S
--N --~ ~ .S
0
caZCH3
Precedure a)
A solution of 117 mg of (7S, 6R)-7-/I(R)-t-butyldimethylsilY
loxyethyl;-3-methyl-4-met.,hoxycarbonyl-2-thiacephem in
5 ml of chloroform was treated with. 220 mg of
m-chloroperbenzoic acid at 0oC under stirring. After 3D
minutes the reaction mixture was partitioned between
dichloromethane and a 2o by weight aqueous sodium
bicarbonate solution. The organic layer was dried over
anhydrous sodium sulphate and the solvent was evaporated
off. The residue was purified by ~.hort-path
chromatography to afford the title product {89 mg) as
a syrup; Y max (CH2C12 film) 1800, 1735 cm l;
d(CDC13) 0.10 (6H,s, Me2Si), 0.90 (9H,s, ButSi), 1.27
(3H,d, CH3-CH), 2.18 (3H,s,CH3), 3.81-3.83 (lH,dd,+3H,s,
CH-CH-CH and OCH3), 4.35 (lH,m, CH3-CH-CH),5.05 (lH,d,
J=2.0 Hz, CH-CH-S) ppm; Amax (hexane) 276 (E=5.084)
and 297 (sh, E=3.745) nm.
~zs~s~s
- 83 -
1 Procedure b)
'A solution of 500 mg of (7S,6R)-7-/1(R)-t-butyldimethy-
-lsilyloxyethyi; -3-methyl-4-methoxycarbonyl-2-
thiacephem in 25 ml of chloroform was treated with 276 mg
of 80°o m-chloroperbenzoic acid at 20°C. The temperature
was allowed to rise to + 20°C within 30 minutes and
then, 4o by weight aqueous sodium bicarbonate solution
was added.
The organic layer was dried over anhydrous sodium
sulphate, and the solvent was evaporated off. The
125491
- 84 -
residue was separated by silica gel chromatography to
afford in the following order:
the 1,1 - dioxide, syrupy 35 mg; NMR and IR date as above;
- the 2-oxide, syrup, 60 mg; v max (CH2C12 film) 1795, 1740
5 cm 1; d (CDC13) 0.10 (6H,s, Me2Si); 0.90 (9H,s, 8utSi),
1:24 (3H,d, CH3-CH), 2.35 (3H,S,CH3); 2.85-3.90 (lH,dd,
+ 3H, s, CH-CH-CH and OCH3), 4.35 (1H, m, CH3-CH-CH),
5.27 (1H, d, J=2.5 Hz, CH-CH-S) ppm; Amax (hexane)
276 (E =5.092)nm;
10 - the 1-oxide, white powder, m.p. 90-93°C, 330mg; Ymax
(CH2C12 film) 1790, 1730 cm l; 40.10 (6H,s, Me2Si),
0.90 (9H,S,ButSi) 1.28 (3H,d,CH3-CH), 2.24 (3H,s, CH3),
3.60 (lH,dd, J=2.0 and 4.OHz, CH-CH-CH), 3.87 (3H,s, OCH3),
4.35 (lH,m, CH3-CH-CH), 4.67 (lH,d, J=2.OHz CH-CH-S) ppm;
15 Amax (hexane) 273 (e=4.862), 309 (sh,e=2,721) nm.
The solution of 300 mg of the 1-oxide in 30 ml of
chloroform was stirred for 1 hour at room temperature
in the presence of 160 mg of m-chloroperbenzoic acid.
The reaction mixture was washed with aqueous sodium
20 bicarbonate solution concentrated and purified by
flash-chromatography (silica gel, cyclohexane:ethyl
acetate as eluent) thus obtaining a further 280 mc~ of
the title product.
1z~4~~1
_ g5 _
1 Example 36
Hethyl (6S,SR)-6-~1(R)-tert-butyldimethylsilyloxyethyl/-?-
methylpenem-3-carboxylate
OSiMe2w
OS~Me~Bu
H o,S~v H S
w
a tolcH3
~°z~ ~3
A solution of 300 mg of (7S,6R)-7-~'1(R)-t-butyldimethylsi
lyloxyethyl~-3-methyl-4-methoxycarbonyl-2-thiacephem-
l,l-.dioxide in chloroform Was heated at 50oC for 5 hours.
Removal of the solvent afforded the title compound, free
of stereoisomers, in nearly quantitative yield (250 mg);
Amax (CHC13) 1795, 1715 cm l; d(CDC13) 0.08 (6H,s, Me2Si),
0.89 (9H,s, ButSi), 1.23 (3H,d,CH3-CH; 2.33 (3H,s, CH3),
3.61 (lH,dd, J=1.B and 5.0 Hz, CH-EH-CH), 3.75 (3,s, OCH3),
4.21 (lH,m, CH3-CI-i-CH), 5.50 (lH,d, J=1.SHZ, CH-CH-S);
Amax (EtOH) 257, 314 nm.
The above reaction occurred even at room temperature; e.g.
after 16 hours standing in chloroform NMR analysis
revealed a mixture 1:2 of the title product and the
starting material.
- 1;54891
1 EXAMPLE 3~
(7S,6R)-7-/~I(R)-hydroxyethyl~~ 3-methyl-4-methoxycarbonyl-
2-thiacephem-1,1-dioxide
~H off
os~o
'I
o N
U~tCN3 c~cN3
A solution of 40 mg of (7S,6R)-7-/ 1(R)-hydroxyethyl/-3-
methyl-4-methoxycarbonyl-2-ghiacephem in 1 ml of
chloroform was stirred at 0°C for 15 minutes in the
presence of 60 mg of m-chloroperbenzoic acid.
Partition between ethyl acetate and an acqueous solution
of sodium bicarbonate and removal of the solvent left
the title compount~, which vas further purified by
silica gel chromatography; d (CDC13) 1.36 (3H,d, 0=6.4Hz,
G H-
CH3-CH), 2.21 (3H,s., CH3), 3.80-3.88 (4H,m;CH-CH and
OCH3), 4.40 (lH,m,CH3-CH-CH), 5.08 (lH,d, ~=l.6Hz,
CH-CH-S).
~iG~~~~~~
- 87 -
1 FXANIPLE 38
Methyl (6S,5R)-6-/I(R)-hydroxyethyl ~ 2 methvlnP.,Pm 3
carboxylate
OH
S,~
~S
a J N'
Cozctt3 ~~~3
When a solution of the compound prepared in Example 3~-
in an inert solvent (e. g. chloroform or benzene) eras
alloured to stand for a fear days, or briefly heated at
50-80°C, the title compound uras formed, free of
diastereomers, in virtually quantitative yield.
b(CDC13) 1.34 (3H,d, J=6.4Hz, CH3-CH) 2.35 (3H,s, CH3),
3.68 (lH,dd, J=6.6 and l.SHz, CH-CH-CH), 3.80 (3H,s, OCH3),
4.40 (lH,m, CH3-CH-Cli), 5.56 (lH,d, J=l.SHz, CH-CN-S).
~.~?548~~.
_88_
1 Example 39
hiethyl (6S, 5R)-6-1 1(R)-tert-butyldimethylsilyloxyethyl/-2-
(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethylpenem-3-carboxylate
OS I'~et Gut OS i Me Z But
N _
S 'S S -11 iv '-----~. ~ S S _ N-N
0
o,-N ~ v. ..~" I
CoiCH3 3 ~z~H3
A solution of methyl (7S, 6R)-7-/1(R)-tert-butyldimethylsilyloxy-
etht~l%-3-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl-2-thiacephem-
-4-carboxylate in chloroform was stirred at 0°C with m-cloroperbenzoic
acid (2.5 molar equivalent) for 30 minutes, and then washed with
aqueous PJaHC03. The dried organic layer was refluxed for a few
hours (t.l.c. monitoring).
Evaporation of the sol~~ent and silica gel chromatography afforded
the title product; d(CI)C13) 0.07 (6H,s, SiMe2), 0.82 (9H, s, Sit3ut),
1.20 (3H,d, CH3-CH), 3.68 (1H, dd, 1.8 and 4Hz, CH. CH.CH), 3.80
(3H, s, PJ-Me), 3.81 (3li, s, OMe), 4.22 (1H, m, CH3-CH-CH), 4.69
(2H, centre of AE3q, ~= 14 Hz, separation of inner lines 11.5 Hz,
CH2S), and 5.54 ppm (iii, d, ~= 1.8 Hz, CH-CH-S).
1254891
- 89 -
1 Example 40
p-Nitrobenzyl (7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-
-3-methyl-2-thiacephem-4-carboxylate
ou~2 pHB OroZ~Ke
H
S~5
O ~--N J G~ -~ o ~ ~ut3
3
~z ~pNB
GOZ GH f'j, 2
A solution of diphenylmethyl (7S,6R)-7-/1(R)-p-nitrobenzyloxy-
carbonyloxyethyl/-3-methyl-2-thiacephem-4-carboxylate (200 mg)
in dichloromethane (25 ml) was treated for 30 min at 0°C with
trifluoroacetic acid (0.4 ml). Evaporation under vacuum in the
cold left the crude 2-thiacephem-4-carboxylic acid, which was
dissolved in acetonitrile-dimethylformamide (2:1, 10 ml) and
treated with triethylamine (0.050 ml) and p-nitrobenzylbromide
(100 mg). After 1 hour at 25°C, the mixture was partitioned
between ethyl acetate and aq. NaHC03.
The dried (MgS04) organic layer was concentrated and the residue
passed through a short colum of Si02 (ethyl acetate - light
petrol as eluants) to afford the pure title product, 150 mg
(79~); d (CDC13) 1.45 (3H, d, CH,3.CH), 3.43 (1H, dd, ~= 2.5
and 6 Hz, CH-CH-CH), 4.45 (2H, ABq, ~= 12 Hz, CH2Br), 4.80
(1H, d, ~= 2.5 Hz, CH-CH-S), 5.2 - 5.5 (5H, m), 7.47 and
7.60 (each 2H, d, Ar), and 8.20 ppm (4H, d, Ar).
1~.'~9~8~1.
- 90 -
' 1 Example 41
(7S,6R)-7-/1(R)-tert-butyldimethylsilyloxyethyl/-4-diphenyl-
methoxycarbonyl-2-thiacephem-3-(~yridinium)methyl bromide
~S~ M.e? Su* OS i 4l2 ~ ~3u~
N H
s~.s J
'-
co~c~ P~, Z CyctdP~~
A solution of diphenylmethyl (7S, 6R)-7-/ 1(R)-tert-
butyldimethylsilyloxyethyl/-3-bromomethyl-2-thiacephem-4-
-carboxilate (310 mg) in dry acetone (15m1) was treated with
pyridine (0.4 m1). After 20 hours at room temperature the
solvent was distilled off and the residue purified by silica
gel chromatography. The product-containing fractions (eluted
with CH2C12-HOAc-MeOH 70:15:15) were collected and freed from
the solvents to leave the title compound as a syrup; v
max
(CHC13 film) 1790, 1715 cm 1; d(CDC13~ (inter alia) 1.32
(3H, d, ~= 6.5 Hz), 3.33 (1H, dd), 4.45 (1H, m), 5.0 (1H, d,
0 < 2Hz), 7.11 (1H, s); Amax (CHC13) 283 and 337 nm (e = 4.060).
In a likewise manner, and starting from p-nitrobenzyl (7S,6R)-
-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-3-bromomethyl-2-
-thiacephem-4-carboxylate, there was obtained:
(75,6 ~)-7-/ 1(R)-p-nitrobenzyloxycarbonyloxyethyl/-4-p-
-nitrobenzyloxycarbonyl-2-thiacephem-3-(pyridinium) methyl
bromide.
12548~~.
- 91 -
1 Example 42
(7S,6R)-7-/ 1(R)-tert-butyldimethylsilyloxyethyl/-4-carboxy-
-2-thiacephem-3-(pyridinium) methyl trifluoroacetate
s~
O5~ Hez p5;
H
S.s
~,r-N r~ N
~Z(NPI~Z $ ~ Coz~l cF3coZo
A solution of the d.iphenylmethyl ester (obtained in Example
41) in dichlorometh,ine (10 ml) was treated with trifluoroacetic
acid (2 ml) at 0°C vor 15 min.
After evaporation in vacuo, the residue was taken up in a
small amount of chloroform. Ethyl ether was added under
stirring and then d~:canted off, to leave the crude title
product; vmax (CHC1:; film) 3420, 1785, 1715 and 1635 br cm 1 ;
d(CDC13) (inter alia) 1.30 (3H,d, ~= 6.5 Hz), 3.23 (1H, dd),
4.38 (1H, m), 4.76 ~;1H, d) ppm; Amax (CHC13) 262 and 334 nm.
i;~~4~9~1
- 92 -
1 Example 43
(7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-4-p-vitro
benz~loxycarbonyl-2-thiacephem-3- (3-carbamoylpyridinium)
methil bromide
ocoZ fnlB ocoiP~B
H
s
s j ~ \~ ~ o
A ~-'N ~ ~ r o. ~--nr ~~~ N~ ~r
colPNg ~ . ~~ corvNZ
2~
A solution of p-nitrobenzyl (7S,6R)-7-/ 1(R)-p-nitrobenzyloxy-
carbonyloxyethyl/-3-bromomethyl-2-thiacephem-4-carboxylate
(460 mg) in DMF (5 ml) was stirred overnight in the dark in
the presence of nicotinamide (200 mg). Most of the solvent
was distilled off z.nd the residue taken up in tetrahydrofuran
(150 ml). This solution was repeatedly washed with a solution
of NaCl in 0.1 N HC'1 (2x50 ml), with brine (2x50 ml)dried
(Na2S04) and evaporated. The residue was charged on the top
a column packed with silanised silica gel (Merck, Art. 7719).
Excess nicotinamide: and impurities were eluted with EtOAc,
then the product w<<s collected by eluting with EtOAc-HOAc
(9:1). Evaporation in vacuo left the title product; v
max
(CHC13) 1800, 1725, 1695 cm l; d (deuteroacetone; 200 MHz)
1.67 (3H,d,~= 6.4 Hz, CH3-CH), 4.14 (1H, dd, ~= 2.5 and
4.7 Hz, CH-CH-CH), 5.30 (1H, d, ~= 2.5 Hz, CH-CH-S), 5.4-
5.7 (7H,m, 2xCH20Ar, CH2N+, and CH3-CH,-CH), 7.7-8.4 (BH,m,
Ar), and 8.0, 8.7, 9.5 and 9.7 ppm (each 1H, br s, pyridinium).
12~4~~
- 93 -
Analogously, by using isonicotinamide instead of nicotinamide,
there was obtained
(7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxyethyl/-4-p-
nitrobenzyloxycarbonyl-2-thioacephem-3-(4-carbamoylpyridi-
nium)methyl bromide.
1;54891
- 94 -
1 Example 44
(6S,5R)-6-/1(R)-hydroxyethyl/-2-(piridinium)methyl penem-3-
-carboxylate
O~sPNB
~H
S~S ~ H S
l"_'N
c~3coz ° ~o
~P
_ A solution of (7S,6R)-7-/1(R)-p-nitrobenzyloxycarbonyloxy-
ethyl/-4-p-nitrobenzyloxycarbonyl-3-(pyridinium)methyl-2-
thiacephem acetate (prepared from the corresponding bromite
by conventional treatment SYl.th silver acetate or an ion-
exchange resin) in chloroform was treated with peracetic
acid (2 mol. equivalent) at 0°C. Work-up and gentle heating,
according to the general procedure described in Examples
37-39, gave (6S,5R)-6-/1(R)-p-nitrobenzyloxy~~arbonyloxyethyl/
-3-p-nitrobenzyloxycarbonyl-2-(pyridinium)methylpenem acetate;
v (KBr) 1795, 1740, 1705 cm l; 8(CDC13 + ~ieuteroacetone)
max
1.4 (3H,d, 3= 6.5 Hz, CH3-CH), 4.10 (1H, dd, 3= 1.7 and 8 Hz,
CH-CH-CH), 5.20 and 5.31 (each 2H, s, OCH2Ar), 5.2 (lH,m,
CH3-CH-CH), 5.77 (1H, d, ~= 1.7 Hz, CH-CH-S), 6.05 (2H,
ABq, 3= 15 Hz, CH2N), 7.4-8.3 (11H, m, Ar) and 9.15 ppm
(2H, d, ~= 6 Hz, o-Pyr).
This material (300 mg) in tetrahydrofuran-water (1:1, 40 ml)
was treated with ammonium chloride (5 g) under stirring to
1;~J~8~1
- 95 -
obtain a clear solution.
After cooling to about 10°C, iron powder (2.5 g) was
added under vigorous stirring; the reaction could be
monitored by TLC (H20-MeOH-NaCl 9:1:1) by following the
development of the product as a faster running spot. After
about one hour, celite~(3 g) was added and the whole
filtered through a glass septum, washing with demineralised
water. Removal of the organic solvent, followed by washing'
with ethyl ether, left an aqueous solution of the title
product and inorganic salts.
The former was obtained pure after reverse-F~hase chromatography
and freeze-drying; d (D20, 200 MHz) 1.27 (3f1, d, g=6.5 Hz,
CH3CH), 3.98 (1H, dd, 0=1.4 and 5.8 Hz, CH-(:H-CH), 4.24
(1H, m, CH3-CH-CH), 5.69 (1H, d, 0= 1.4 Hz (:H-CH-S), 5.94
(2H, ABq, 0= 14.9 Hz, CH2N), 8.10 (2H, t, 0=: 6.6Hz, pyridinium
m-H), 8.61 (1H, bd, ~= 7.7 Hz, pyridinium p-.H), 8.95 (2H, d,
= 6.6 Hz, pyridinium o-H) ppm.
In a likewise manner, starting from the comE~ounds described
in Example 43, there was obtained:
(6S,5R)-6-/1(R)-hydroxyethyl/-2-(3-carbamoyl_pyridinium)
methylpenem-3-carboxylate;
(6S,5R)-6-/1(R)-hydroxyethyl/-2-(4-carbamoylpyridinium)methyl-
penem-3-carboxylate
"'(' cad e. '(''n a r k
1~:;i~8~1
- 96 -
1 Example 45
(6S,5R)-6-/1(R)-hydroxyethyl/-2-(1-methyl-1,2,3,4-tetrazol-
-5-yl) thiomethylpenem-3-carboxylic acid, sodium salt
B
N wN
,_ s~s _~ ~' ~:
N S .N,N
N ~'~'13
totPN6 ~3 Co2lJ~
A solution of p-nitrobenzyl (7S,6R)-7-/1(R)-p-nitrobenzyloxy-
earbonyloxyethyl/-3-(1-methyl-1,2,3,4-tetrazal-5-yl)thiomethyl-
-2-thiacephem-4-carboxy,late in chloroform was oxidized with
m-chloropebenzoic acid, as described in Example 37, to give
the corresponding sulphone. lYithout purification, this material
was heated at 60°C in dry distilled tetrahydrofuran under a
stream of nitrogen until extrusion of S02 was complete.
Removal of the solvent and silica gel chromatography gave
p-nitrobenzyl (6S,5R)-6-/1(R)-p-nitrobenzylorycarbonyloxyethyl/-
-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyJ.penem-3-carboxylate;
d (COC13) 1.48 (3H, d, 3=7 Hz. CE13-CH) 3.84 L1H, dd, 3=2 and
5.5 Hz, CH-CH-CH), 3.96 (3H, s, NCH3), 4.69 (2H, ABq, J=
14 Hz, CH2S), 5.20 (1H, m, CH3-CH-CH), 5.24 (2H, s, OCH2Ar),
5.27 (2H, ABq, 3= 13 Hz, OCH2Ar), 5.61 (1H, d, 3= 2 Hz),
7.51 and 7.82 (each 2H,d,~= BHz, Ar), 8.02 ppm (4H, d, ~= 8 Hz,
Ar). Reaction of the above material with Fe/NH4C1, according
to the procedure described in Example 44, afforded the title
1;~',i~~391
- 97 -
1 product; d (D20) 1.28 (3H, d, 3=6.5 Hz), 3.87
(1H, dd, ~=1.4 and 6.3 Hz, CH-CH-CH), 4.10 (3H, s, NCH3),
4.19 (1H, m, CH3-CH-CH), 4.40 (2H, ABq, 3= 16 Hz, CH2S),
5.59 ppm (1H, d, 3= 1.4 Hz, CH-CH-S); Amax (H20) 315 nm.
12S4~3~1
- 98 -
1 Example 46
Methyl (6S,SR)-6-/ 1(R)-tert-butyldimethylsilyloxyethyl/-
-2-nitrooxymethylpenem-3-carboxylate
DSi1'~Z gut OSi I~ B
t
H
---~S ~ oN r7 2
o''~' ~N ~2 ,...
v
co2c~~ ~°x~3
A solui:ion of methyl (7S,6R)-7-/1(R)-tert-butyldimethylsily-
loxyethyl/-3-nitrooxymethyl-2-thiacephem-4-carboxylate (prepared
as described in Example 31) in chloroform was treated with
m-chloroperbenzoic acid (2 molar equiv, 0°C) to give the
1-sulphone. Aqueous hydrogen carbonate was added to extract
m-chlorobenzoic acid, and then the dried organic solution was
gently refluxed (t.l.c. monitoring), to give a solution of
the title penem compound; d(CDC13) (inter alia) 5.64 (1H, d,
3= 2 H~:, CH-CH-S) and 5.65 ppm (2H, ABq, 3= 15 Hz, sep. of
inner line 46 Hz, CH20N02); vmax (CHC13) 1790 and 1710 cm 1.
In a likewise manner, starting from trichloroethyl (7S,6R)-
-7-/1(F;)-trichloroethoxycarbonyloxyethyl/-3-nitrooxymethyl-
-2-thiacephem-4-carboxylate, there was obtained:
Trichloroethyl (6S,SR)-6-L1(R)-trichloroethoxycarbonyloxyethyl/-
-2-nitrooxymethylpenem-3-carboxylate
1;~~4~~i
- 99 -
1 Example 47
Plethyl (6S,5R)-6-/1(R)-tert-butyldimethylsilyloxyethyl/-2-
-hydroxymethylpenem-3-carboxylate
OS~Melgu~ ~Sil~(QZ$u
H
H
~S oNOt ~ 5 /~ Ol-l
p~N
CO1CN3 0 (pl
A solution of crude methyl (6S,5R)-6-/1(R)-tert-butyldimethyl-
silyloa:yethyl/-2-nitrooxymethylpenem-3-carboxylate (obtained
from 4'~ mg of the corresponding 3-bromomethyl-2-thiacephem
precur:,or, according to Examples 31 and 46) in dichloromethane
(2 ml) was stirred for 5 min at U°C with zinc dust (0.1 g)
and acetic acid (0.1 ml). The reaction mixture was filtered
and the solution was evaporated to give the crude title
product, which was purified by silica gel chromatography
(ethyl acetate - light petrol, from 1:4 to 1:1); vmax (CHC13
film) 1785, 1710 cm l; d(CDC13) 0.07 (6H, s, Sitle2), 0.88
t
(9H, s, SiBu ), 1.23 (3H, d, CH3-CH), 3.70 (1H, dd, ~= 1.8
and 4.5 Hz, CH-CH-CH), 4.25 (1H, m, CH3-CH-CH), 4.59 (2H, s,
CH20H) and 5.57 ppm (1H, d, ~= 1.8 Hz, CH-CH-S).
~254~~1
- ioo -
1 By operating in an analogous way on trichloroethyl (6S,5R)-
-6-/1(R)-trichloroethoxycarbonyloxyethyl/-2-nitrooxymethyl-
penem-3-carboxylate, complete deblocking of the protecting
groups was achieved, thus obtaining after aq. NaHC03 work up
and reverse phase chromatography (water as eluant);
(6S,5R)-6-/1(R)-hydroxyethyl/-2-hydroxymethylpenem-3-
carboxylic acid, sodium salt; d(D20) 1.30 (3fa, d, CH3-CH),
3.88 (1H, dd, ~= 1 and 6.3 Hz, CH-CH-CH), 4.~3 (1H, m, CH3-CH-CH),
4.63 (2H, ABq, 3= 14.5 Hz, separation of inner lines 4 Hz,
CH20H), and 5.62 ppm (1H, d, ~= lHz, CH-CH-Si; vmax tKBr) 1765
and 1610-1590 cm 1.
- 101 -
~;~~4~~1
1 Example 48
(6S,5R)-6-/1(R)-hydroxyethyl/-2-carbamoyloxyemethylpenem-
-3-carboxylic acid, sodium salt
0 Go~,C~, C(y
OH
~'5 ~ 5 oGoNffZ
~OCpNH2
° ~ ~ o ~ cozN a
(.c~cK2~ce3
~~h chloroform solution of trichloroethyl (7S,6R)-7-/1(R)-
trichl.oroethoxycarbonyloxyethyl/-3-carbamoyloxyethyl-2-
thiacE:phem-4-carboxylate was treated with m-chloroperbenzoic
acid according to the general procedure of Example 37. After
work-up, brief heating of the resulting 1-sulphone in an
inert solvent (benzene) gave trichloroethyl (6S,5R)-6-/1(R)-
-tricliloroethaxycarbonyloxyethyl/-2-carbamoyloxymethylpenem-
-3-carboxylatc; 8(CDC13) 1.5 (3H,d, CH3-CH),3.94 (1H, dd,
J= 2 and 8 Hz, CH-CH-CH), 4.73 and 4.82 (each 2H, s, OCH2CC13),
E
E
4.8 (:lH, m, CH3-CH-CH) 5.25 (2H, ABq, J= lOHz, CH20CONH2),
5.62 ;1H, d, J= 2Hz, CH-CH-S).
A THF solution of this material was treated with Zn dust
(approx. 6 parts by weight) and 1M aq. NaH2P04 under stirring.
After 3 hours stirring at 25°C, another portion of Zn was
added and the mixture kept stirring for 3 hours. Work-up
and reverse-phase chromatography afforded the title product;
8 (D20) 1.31 (3H, d, J= 6.5 Hz, CH3-CH), 3.91 (1H, dd,J= 1.5
and 6Hz, CH-CH-CH), 4.25 (1H, m, CH3-CH-CH), 5.19 (2H,
ABq, J= 14.5 Hz., CH20C0) and 5.66 ppm (1H, d, J= 1.5 Hz, CH-CH-S).
