Note: Descriptions are shown in the official language in which they were submitted.
-1- '
INTERMEDIATES USEFUL FOR THE
PREPARATION OF PENEMS
This is a divisional application of Canadian Patent
Application Serial No. 612,260, filed September 21, 1989.
The present invention is directed to efficient
multistep processes for the preparation of compounds of the
formula (6) and (6'), as shown in Scheme 3 below; and to
certain of the intermediates, specified by the general
formulas (8) and (9) below, which find special value in these
multistep processes. The compounds of the formulas (6) and
(6') are useful as precursors of the various penem antibiotics
specified by the formula (7) and (7'), also shown in Scheme 3
below.
The subject matter. of this divisional application is
directed to the intermediate of general Formula (8), described
in more detail hereinunder. The subject matter of the parent
application was restricted to the processed discusses above
and to the intermediate of general formula (9). However, it
should be understood that the expression "the invention", or
the like, encompasses subject matter of both the present and
this divisional application.
Heretofore, a number of processes have been reported
for the preparation of penem antibiotics substituted at the 2-
position with an alkyl group or a thioether group, -SR2, as
found in the formulas (6), (6'), (7) and (7') below. For
-la-
thioether compounds (6) and (7)) two of the more general of
these processes are illustrated in Schemes 1 and 2. In Scheme
1, an
-Z-
alternative intermediate to the silver salt of the
mercaptan is the mercaptan itself, reportedly obtained
by Zn/H+ reduction of the tritylated thiol
(Girijavallabhan et al., J. Antibiotics 39, 1182
s -
(1986); U.S. Patent 4,584,I33). Menard et al., U.S.
Patent 4,272,437, has also described processes related
to those of Scheme 2, which were applied more generally
to the synthesis also of the compounds (6') and (7').
For example intermediates of the type (R) are reacted
with an acylating agent such as
RSR6CH-COCI
to form compounds structurally related to (L), which in
turn are heated to close the ring and thus form said
compounds (6') and (7'). See also published
application EP 199,446, where compounds of the type
(6') and (7') below in which RS and R6 are taken
together are similarly prepared.
30
-3-
Scheme 1
H H
Rd SC~3 Rd SC03
ICHZC02Re
NH ~ N
0 i Oi -1C02Re
(A) (B)
H
Rd ~ SAg
S
AgN03 ~H CICORf
N
0~ ~C02Re
is (c)
s
H II
Rd S~ ORf
~ ~//~H s trong
N -~ base
O ~ vC0 2Re
(D)
2s H
Rd % S
~H RgXa
N
O~ COZRe
(E)
H
d ~ S S Rg
R I I
0 ~ N C02Re
(F)
.~~~~~'79
_4_
References:
Girijavallabhan et al., J. Antibiotics 39, II82
(I98b); U.S. Patent 4,584,133, wherein
off
Rd - CH ~ , Re - -CH2CH=CH2 , Rf - beta-naphthyl,
H
Rg = C2H5 , CH2N~ , etc., Xa - leaving group.
1~ DiNinno et al., U.S. Patent 4,610,823 (1986);
Leanza et al., Tetrahedron 39, 2505 (1983), wherein
f
~-Si0
Rd - CH ~ , Re - -CH2CH=CH2 or -CH20N02, Rf - C6H~,
15 H
Rg = alkyl, aralkyl, etc., Xa - leaving group.
See also GirijavalZabhan et al., U.S. Patents
4,443,373 and 4,530,793 for an alternative synthesis of
the compounds (E), wherein Rd is CH3CHOH- and Re is
CH2CH=CH2 or CH2CH20Si(CH3)3, from the compound (A).
30
-5-
Scheane 2
H H
Ra , SC03 Ra ~ SC03
S ~~H CHOC02Rb ('H H
i
Oi NH 0 i N~C02Rb
(G) (H)
H
Ra ~ S03
S02C12 ~ 'H ~1 03P
N '
* 0 ~' ~C02Rb
13 (I)
H H
Ra , SCm3 Ra ~ SAg
r~H ~p~3 AgN03
' N
0~ ~C02Rb 0~ ~C02Rb
(J) (R)
S
H I I
Ra ~ S~SEt
C1CS2Et I//~H P~ CH3C6H5
N--~' 3 b heat
0 C02R
(L)
1 ~~.0~'~~
-s-
A $ o
Ra O S SEt Ra ' S SEt
C1~C03E
N N
0/ C02Rb 0 ~ C02Rb
(M) (N)
H
Ra ~ S SRc
LO
RcSH
N
O ~ C02Rb
(0)
Reference:
DiNinno et al., Tetrahedron Letters 23, 3S35
t1982), wherein:
4
+Si 0
Ra - CH ~ , Rb - -CH2CH=CH2, Rc - -CH(CH3)2'
H
-CH2CH20H, etc.
These steps assumed on the basis of the footnote
16 reference to U.R. 2,042,514.
See also Ganguly et al., J. Antimicrob. Chemo. 9,
Suppl. C1, (1982) using several similar steps in a
different sequence.
1
_7-
Ghosez et al., TetrahedronLetters 39, 2493 (1983)
have described the synthesis of 2-oxopenams from
penicillin G and the conversion of same to
2-alkoxypenem derivatives of penicillin G. Japanese
Rokai 84-115,788 CChem. Abst. 96:34979y, Dement Abst.
78700D) similarly describes conversion of hydroxy and
carboxy protected 6-(1-hydroxyethyl)-2-oxopenams to the
corresponding alkoxy analogs.
Additional, alternative methods for the synthesis
of penems include those described by Dextraze et al.,
U.S. Patent 4,769,451; Pirie et al., U.S. Patent
4,751,297; Volkmann et al., U.S. Patent 4,739,047;
erighty, U.S. Patent 4,69S,626; Hrighty et al., U.S.
Patent 4,782,145; Perrone et al., J. Org Chem., 5I,
3413 (1986); eatastini et al., U.S. Patent 4,631,150;
UR Patent application 2,187,448; Alpegiani et al., U.S.
Patent 4,S77,016; and Franceschi et al., J. Antibiotics
36, 938 (1983).
There have been numerous reports in the literature
concerning the conversion of 2-oxocarbapenams and
3-oxocephams to 2-(alkylthio)-2-carbapenems and
3-alkylthio-3-cephems via enolic esters:
0 ~ ~ N i ORi
d 0~
COORh COORh
(P) (Q)
RASH
SR3
N
~0
COORh
(R)
-8-
where Rh is a conventional carboxy protecting group, Rl
is, for example, diphenyl- or diethylphosphoryl, tosyl,
mesyl, or trifluoromethanesulfonyl. See for example
Sletzinger et al., Tetrahedron Letters 21, 4221 (1980);
s -
Andrus et al., J. Am. Chem. Sac. I06, 1808 (I984);
Evans et al., Tetrahedron Letters 26, 3787 (198S), and
27, 3119 (I986) and U.S. Patent 4,673,737; Ratcliffe et
al., 2I, 31 (1980); ibid. I979, 4947; Salzmann et al.,
ibid. 21, 1193 (I980); Melillo et al., ibid. 21. 2783
l0
(1980); Iimori et al., and J. Am. Chem. Soc. 105, 1659
(I983). However, the chemistry observed with these
carbapenem ketone groups has been generally
inapplicable to the thiolactone carbonyl group of
15 2-oxopenems. For example, the reaction of mesyl
chloride or mesyl anhydride with a compound of the type
(4) below produces a compound of the type
ORI H
20 '~ S ~~ 0
H
~ ~ S02CH3 ;
N
0~ C02R
(S)
while either tosyl chloride or triflyl chloride and a
compound of the type (4) produces a compound of the
type:
1
OR H
S ,0
H
r H ~1
N
O ~ C02R
(T)
_9_
More recently it was specifically reported in published
European patent application 257,419 that a compound of
the type (4) below was reacted with diphenylphosphoryl
chloride to form the diphenylphosphoryl ester in situ,
which was in turn reacted with a phenol to form a
compound of the type
/ \ a
CH3CH (OR1)~~~~ ~,~5 0 r OZ
N
0~~ COCR2
(U)
in very low yield. This application offers no specific
support for the asserted broader use of other potential
enol ester forming reagents such as triflyl chloride,
which is in fact a known chlorinating agent, not a
triflate ester forming reagent (vide s-upra; and
Hakimelahi et al., Tetrahedron Letters, 1979, pp.
3643-3644). '
2S
~3~~:a7
-IO-
We have now discovered an efficient multistep
process for the synthesis of penem antibiotics, as
summarized in Scheme 3. In particular, the present
s
invention is directed to the processes of combined
chemical steps:
( I ) ---~, ( 2 ) ---~ ( 3 ) ---.,~ ( 4 ) ;
( 1 ) ---~) ( 2 ) -----~ ( 3 ) ---~ ( 4 ) --.-i t 5 ) --1 ( 6 ) : and
(6')
t 4 ) ---.~ t 5 ) ----~, ( 6 ) .
(6' )
In Scheme 3, the various variable symbols are
defined as follows:
R is -CH2CX=CHZ, -CH2CH2Si(CH3)3, p-nitrobenzyl,
or a conventional radical forming an ester which is
hydrolyzed under physiological conditions;
X is H or C1;
R1 is a conventional silyl protecting group;
R2 is a pharmaceutically acceptable radical;
RS and R6 are taken separately, R5 is hydrogen or
(C~-C8~alkyl; R6 is hydrogen, methyl, (C1-C8)alkoxy or
OR ; R is a conventional hydroxy protecting group; and
R$ is hydrogen, (C1-C$)alkoxy or OH; or
RS and R6 are taken together and are
- (CH2) m0 tCH2) p-
where m and p are each zero or an integer from 1 to 5,
with the proviso that the sum of m and p is at least 3;
and
RS and R$ correspond to RS and R6, except that
when R$ is taken separately from R5, the value ORS is
replaced by OR.
1~~0~~7~
-11-
Scheme 3
OR1 OR1
H H
SC03 SAg
~H AgN03 g H
N
N~CO~R 0 ~ ~C02R
(I)
OR1
'\ S H 0
H S H ~/' C1C-O ~ ~ N02
~ ~ N---~ ba se
C028
(2)
OR1 0
I
SCO ~'~ -N42
H
H stronq
t __N~ base
C02R
(3)
OR1
~O
A
(F3CS02)20
30 H
N l base
~~~ C02R
(4)
_12_
Scheme 3 (Copt.)
OR1
H
S OS02CF3
H
I ~H I HSR2
N
0 ~ COZR
(5)
ORl
I H
S~ SR2
H
H
N
1$ 0 ~ COZR
(6)
OH
H
~ S~ SR2
H .i~~i
H ~ (or a correspopnding
ester hydrolyzed under
0~ N COON physiological conditions)
30
I .~~~J ~ 7~
-I3-
Scheme 3 (font. )
t5 ) (RSR6CH) ZC~.t (CN) n Lin+~
s
ORI
H
S CHRSR6
H r,,,
H
i
~ ~ C02R
( 6' )
OH
H
1$ S CHRS R$
H ~~~ ( (or a correspopnding
H ester hydrolyzed under
0 ~ ~ COOH Physiological conditions)
(7.)
25
1~~0 Q79
-14-
Conventional radicals which form esters which are
hydrolyzed under physiological conditions have become
as common in the beta-lactam art as pharmaceutically-
acceptable salts. As in the case of numerous other
s
beta-Iactam antibiotics, such "pro-drug" esters are
generally used orally to enhance gastrointestinal
absorption. Once absorbed, they are hydrolyzed in vivo
to form the corresponding penem acid. Preferred ester
l0 radicals are -CHR30COR4 or -CHR34C02R4, where R3 is
hydrogen or methyl and R4 is (C1-C8)alkyl, most partic-
ularly pivaloyloxymethyl and
1-(ethoxycarbonyloxy)ethyl.
Among the conventional silyl protecting groups are
1~ trimethylsilyl and dimethyl-t-butylsilyl. The latter
is most preferred for its ease of introduction and
removal, while at the same time possessing excellent
stability as a protecting group during the various
other process steps of the present invention.
20 Pharmaceutically acceptable radicals R2 have been
extensively defined in the prior art, as will be
evident from the following prior art references:
(a) Hamanaka, U.S. Patent 4,614,737;
(b) Girijavallabhan et al., U.S. Patent
2s 4,614,738;
(c) Hamanaka, U.S. Patent 4,619,924;
(d) Girijavallabhan et al., U.S. Patent
4,443,463;
(e) Girijavallabhan et al., U.S. Patent
30 4,530,793;
(f) Girijavallabhan et al., U.S. Patent
4,584,133;
(g) Ganguly et al., U.S. Patent 4,690,922;
-15-
(h) McCombie, European published application
6I,205;
(i) Hamanaka, European published application
132,10I;
3
(j) Hamanaka, European published application
138,539;
(k) Perrone et al., European published
application 199,490;
l0 (1) Takemura et al., European published applica-
tion 210,883;
(m) Kirkup et al., European published application
238,28S;
(n) Sunegawa et al., European published applica-
15 tion 243,686;
(o) McCombie et al., European published applica-
tion 257,602; and
(p) DiNinno et al., Tetrahedron Letters 3535
(1982) .
20 Preferred values of R2 found in the prior art (as
noted by lower case letter from the list of references
immediately above) are as follows:
(C1-C4)alkyl (b, e, h, p), (1,3-dioxacyclopent-4-
yI)methyl (a), (1,3-dioxacyclopent-2-yI)methyl (a),
25 (2-oxo-1,3-dioxacyclopent-4-yl)methyl (a), (1-methyl-
2-imidazolyl)methyl (i), piperidinomethyl (k),
2-hydroxyethyl (b, e, h), 2-(p-nitrobenzyloxycarbonyl-
amino)ethyl (e, h), 2-(piperidino)ethyl (b),
2- (pyrrolidino) ethyl (b) , 2- (morpholino) ethyl (b) ,
30 2- (4- (allyloxycarbonyl) piperazino) ethyl (b) ,
1-oxo-3-thiolanyl (cis and/or trans) (c),
1,I-dioxo-3-thiolanyl (c), I-oxo-3-thianyl (cis and/or
traps) (c), 1,1-dioxo-3-thianyl (c), 1-oxo-4-thianyl
(cis and/or traps) (c), 1,1-dioxo-4-thianyl
-16-
(c), 4-hydroxy-3-thiolanyl (m), 4-hydroxy-1-oxo-3-
thiolanyl (cis and/or traps) (m), 4-hydroxy-l,l-dioxo-
3-thiolanyl (m), 4-hydroxy-3-furyl (m), I,3-dioxacyclo-
hex-5-yl (a), 2-oxo-1,3-dioxacyclohex-5-yl (a),
s
1-(p-nitrobenzyloxycarbonyl)-3-pyrrolidinyi (e, f),
2-oxo-3-pyrrolidinyl (j, o), 1-methyl-5-(dimethylamino-
carbonyl)-3-pyrrolidinyl (n), 1-methyl-5-(2-(dimethyl-
aminocarbonyl)ethyl-3-pyrrolidinyl (n), and traps-4-
hYdroxy-1-(benzyloxycarbonyl)-3-pyrrolidinyl (m).
The most highly preferred values of R2 in the
present process are -C2H5, -CH2CH(CH3)2, -CH2CH20H,
Is (cis) ~_o , s~0 , SO .
I~ 2
and -CH CH NHCOCH - ~ ~ -NO (
NCO ~ ~ NO 2 2 I I 2 2
2 ~ 2 0
Preferred values of -CHRSRB, also found in the
prior art) are methyl, hydrox~~methyl, 2-tetrahydro-
furyl, 2-tetrahydropyranyl or methoxymethyl.
Frequently, the hydroxymethyl group is further reacted
to form, for example, a carbamate.
In addition to the processes noted above, the
present invention is also specifically directed to
novel intermediates of the formulas (3) and (5), shown
in combined form by the formula
OR1
H
_ S-Z
H ~~%s X1 _--(8)
N~X2
0 ~ ~ C02R
-I7-
wherein R and RI are as defined above; and
Z, XI and X2 are taken together and are
,)-O-S02CF3 ; or
Z, X1 and X2 are taken separately, X1 and X2 are
each hydrogen, and Z is p-nitrophenyloxycarbonyl;
and to certain novel intermediates of the formula
ORl
H
CH20R9
__
A -(9)
N
0~~ C02R
wherein R and R1 are as defined above; and
R9 is methoxymethyl, benzyloxymethyl or
2-tetrahydropyranyl. These compounds are also
encompassed by the broader formula (6') above.
30
-18-
The present invention, which is readily carried
out, provides an efficient process for penem
antibiotics having the formula (7) or (7').
In the first step of this process, a triphenyl-
methylthio compound of the formula (1), in the presence
of two or more molar equivalents of a weakly basic
amine such as pyridine and in the dark, is reacted with
silver nitrate (at least one molar equivalent, usually
LO
in excess, e.g., 1.5-2 molar equivalents) to produce
the silver salt of the corresponding mercaptan. This
reaction is generally carried out in a reaction inert
solvent, such as methanol. Temperature is not
critical, nut lower temperatures, e.g., -25~ to 25~ C.
are generally preferred, with 0-5~ C. particularly
convenient and satisfactory. Generally without
isolation the intermediate silver salt is converted
directly with excess hydrogen sulfide gas to the
mercaptan. Silver is recovered as the sulfide by
filtration and the mercaptan (2) recovered from the
mother liquor by conventional methods such as
extraction and solvent evaporation.
As used herein, the expression "reaction inert
solvent~ refers to a solvent which does not interact
with starting materials, reagents, intermediates or
products in a manner which adversely affects the yield
of the desired product.
In the second step, the mercaptan (2) is reacted
with substantially one molar equivalent of
4-nitrophenyl chloroformate to form the intermediate
compound of the formula (3). This step is carried out
in the presence of substantially one molar equivalent
of a tertiary amine, preferably diisopropylethylamine
i~~o~7~
-19-
and/or dimethylaminopyridine, usually in a reaction
inert solvent such as tetrahydrofuran, and is
preferably carried out at lower temperatures, e.g.,
-25~ to 25~ C., conveniently at 0-5~ C. If desired,
s
the intermediate (3) is isolated and characterized by
conventional methods. However, it is preferred to
simply employ the initially obtained solution of the
compound of formula (3) directly in the next step.
In the third step, the intermediate (3) is
cyclized in the presence of a strong base to form the
desired 2-oxopenem of the fornula (4), a known
compound, for example, when R is allyl. Preferably,
this step is carried out on a solution of the compound
1~ of the formula (3) in a reaction inert solvent such as
tetrahydrofuran. The preferred strong base is lithium
hexamethyldisilylamide in the same reaction inert
solvent, generally used in a large molar excess (e. g.,
3-5 molar equivalents). This base, conveniently
Purchased as a 1M solution in tetrahydrofuran, is
generally diluted (e. g., to about 0.1 to 0.2 M) with
tetrahydrofuran and cooled to low temperature (e. g.,
-50~ to -I00~ C., conveniently -78~ C., the temperature
of an acetone-dry ice bath. A solution of the compound
of the formula (3) in the same solvent is added
portionwise, maintaining the same low temperature. The
reaction, which is substantially complete upon
completion of the addition, is conveniently quenched
with excess acetic acid and the 2-oxopenem (4) isolated
bY conventional methods of concentration and
extraction.
In the next step the 2-oxopenem (4) is reacted
with freshly distilled triflic anhydride, generally in
slight molar excess, at reduced temperature (0~ to
i~'-~~'~'~~
-ZO-
-90~ C., conveniently -78~ C.) in a reaction inert
solvent such as methylene chloride in the presence of a
molar excess (generally 4-fi molar equivalents) of a
tertiary amine, preferably diisopropyiethylamine. Zf
s
desired, the resulting enolic triflate ester of the
formula (5) is isolated by chromatography of the
reaction mixture on silica gel and characterized.
However, this is unnecessary, the reaction solution
being well-suited for direct reaction with an
appropriate reagent in the next step.
In the fifth step of the present sequence, in one
of its preferred embodiments, a solution of the
appropriate mercaptan, R2SH, conveniently dissolved in
the same reaction inert solvent such as methylena
chloride, is added portionwise to the cold solution of
the triflate ester (5), generally allowing the
temperature to rise no more than about 10-40~ C. from
its initial value of about 0~ to -90~ C. Upon
completion of the reaction, the desired penem
Y
intermediate of the formula (6) is isolated by conven-
tional methods, as exemplified below.
In said fifth step, in another of its preferred
embodiments, a solution of the appropriate cuprous
salt:
(R5R6CH) 2Cu (CN) n Lin+1
wherein RS and R6 are as defined above and n is zero or
1, in the same or another reaction-inert solvent is
reacted with triflate (5) in like-manner to produce
penem intermediates of the formula (6'). However, when
R6 is a hydroxy protecting group, it is generally
preferred to use a cuprous salt wherein n is zero.
~3~0 ~~~
-2I-
When R is a conventional radical forming an ester
which is hydrolyzed under physiological conditions, and
absent an amino protecting group in the radical R2, or
a hydroxy protecting group in the radical RSR6CH, the
s
penem antibiotic is obtained by conventional removal of
the silyl protecting group, e.g., by methods
specifically exemplified below. When R is -CH2CX=CH2,
-CH2CH2Si(CH3)3 or p-nitrobenzyl, an additional
conventional chemical step is required to form the
l0
acidic penem antibiotic of the formula (7) or (7'), or
its pharmaceutically acceptable salt.
When R is -CH2Cx=CH2, the group is best removed by
the action of at least one molar equivalent of an
alkali metal salt of an acid such as 2-ethylhexanoic
acid in a reaction inert solvent such as ethyl acetate,
in the presence of catalytic amounts of triphenylphos-
phine and tetrakis(triphenylphosphine)palladium,
directly forming the alkali metal salt of the penem
antibiotic. '~Ihen RZ contains nitrogen protected by an
allyloxycarbonyl group, said group is removed by the
same method.
When R is -CHZCH2Si(CH3)3, the group is best con-
currently removed with the dimethyl-t-butylsilyl
25 Protecting group, preferably using a molar excess of
tetrabutylammonium fluoride in a reaction inert solvent
such as tetrahydrofuran.
When R is E-nitrobenzyl, the group is generally
removed by conventional hydrogenolysis over a noble
30 metal catalyst, preferably palladium, for example
palladium-on-carbon. When R2 contains a nitrogen
protecting group such as benzyloxycarbonyl, said group
is removed by the same method.
I344~~~
-22-
When the side chain contains a conventional
hydroxy protecting group R~, it is likewise removed by
conventional methods. The preferred groups of this
class are methoxymethyl, benzyloxymethyl and
tetrahydropyranyl, which are hydrolyzed by aqueous acid
and/or hydrogenation. -
The mercaptans required for the present reaction
sequence are generally known or available by conven-
tional methods. Preferred methods for the synthesis of
3S-mercaptothiolane 1R-oxide are specifically described
below.
The penem antibiotics of the formula (7), as well
as their pharmaceutically acceptable salts and esters,
are employed in medicine according to methods described
in references cited above.
It will be specifically noted that the compounds
the of the formula (6) wherein R2 is
(cis)
S-O
are used to prepare the corresponding product of
Hamanaka, U.S. 4,619,924, i.e., the compound of the
above formula (7), or an ester with R2 of the same
value. These products are a mixture of
diastereoisomers, one having R2 as 1R-oxo-3S-thiolanyl
and the other R2 as 1S-oxo-3R-thiolanyl. Of these, the
18,3S-isomer of the formula
HO H
- ~~ S S ~ ~ IO
H I ~~H I S _-_ (10)
N
O OH
i
O
13!0 ~'~3
-23-
and its pharmaceutically acceptable salts and esters
are preferred. This is not only because these
compounds, and their several iaanediate precursors, are
single, homogeneous compounds, such that the quality of
s
the final products is much better controlled relative
to the previously reported diastereomeric mixture (an
important factor in clinical use), but because they
show clinical advantages over Hamanaka's diastereomeric
mixture.
The pure diastereomeric, antibacterial compound of
the formula (10), its salts and its esters are tested,
formulated and used according to methods detailed in
above cited Hamanaka, U.S. Patent 4,619,924,
Within the human dosage
ranges there disclosed, the more preferred dosage range
for these compounds is about 10-80 mg/kg/day, both
orally and parenterally. These figures are
illustrative only, since in some circumstances the
attending physician will find it more beneficial to
employ dosages outside of these ranges. In vivo
hydrolyzable esters, particularly the pivaloyloxymethyl
and 1-(ethoxycarbonyloxy)ethyl esters, are preferred in
oral use, while the sodium or potassium salts are
particularly preferred for parenteral use.
The following examples are given by way of
illustration and are not to be construed as limitations
of this invention, many variations of which are
possible within the scope and spirit thereof.
-24-
c~~raunr p t
Allyl 2-[4R-Mercapto-3S-(IR-(dimethyl-t-butyl
silyloxy)ethyl)-2-azetidinon-1-ylJacetate
A solution of 20 g (33.2 mmol) of allyl
2-[4R-(triphenylmethylthio)-3S-(1R-(dimethyl-t-butylsi-
lyloxy)ethyl)-2-azetidinon-1-ylJacetate (Jeff et al.,
Tetrahedron, vol. 39, 2505-25I3, 1983; U.S. Patent
4,610,823) in b00 ml of methanol was cooled to 0~ C.
and was treated with 5.94 ml f73 mmol) of pyridine.
The following portion of the reaction sequence was
conducted with the reaction flask protected from light.
To the solution was added solid silver nitrate (10.2 g,
60 mmol) and the reaction mixture was allowed to stir
for 1.5 hours while maintained at 0~ C. Once this
reaction was complete, hydrogen sulfide gas was slowly
introduced with constant stirring. The dark mixture
was then filtered through celite with recovery of
silver sulfide and the filtrate was concentrated. The
organic residue was partitioned between ethyl acetate
and brine. The layers were separated and the aqueous
phase was reextracted with fresh ethyl acetate. The
combined organic layers were dried over sodium sulfate
and were then evaporated to yield title product which
was used directly in the next step.
EX.~MPLE 2
Allyl 2-[4R-(4-Nitrophenyloxycarbonylthio)
3S-(1R-(dimethyl-t-butylsilyloxy)ethyl)
2-azetidinon-1-ylJacetate
A solution of 4.06 g (33.2 mmol) of dimethylamino-
pyridine and 6.69 g (33.2 mmol) of 4-nitrophenylchloro-
formate was prepared in 700 mI of THF. The solution
~.~~Or~'~~
-25-
was cooled to 0~ C, and was treated simultaneously with
a solution of the entire batch of title product from
the preceding Example in 60 mI of TAF, and a separate
solution of 5.78 ml (33.2 mmol) of
s
diisopropylethylamine in 60 ml of THF. The addition
required 0.5 hours and formed a white precipitate.
After stirring the mixture for 5 minutes, the reaction
mixture was filtered with exclusion of atmospheric
moisture and the filtered solution of present title
product placed in a constant addition funnel and
immediately used in the next step.
A portion of this solution, following filtration
through a small gortion of silica gel using CDC13 as
eluant, was characterized by means of 1H-NMR (300 MHz)
which showed delta: 8.22 (2H, d, J=8 Hz), 7.29 (2H, d,
J=8 Hz), 5.74-5.89 (1H, ddd, J=18 Hz, 12 Hz, J=6 Hz),
5.46 (IH, d, J=2 Hz), 5.25 (1H, d, J=18 Hz), 5.17 (1H,
d, J=12 Hz), 4.57 (2H, d, J=6 Hz), 4.25 (1H, dq, J=6
0 Hz, J=5 Hz), 4.I0 (1H, d, J=19 Hz), 3.90 (1H, d, J=19
Hz), 3.27 (1H, dd, J=5 Hz, J=2 Hz), 1.26 (3H, d, J=6
Hz) , 0.84 (9H, s) , 0.06 (3H, s) , 0.04 (3H, s) .
L'Y3 MST L' Z
Allyl 5R,6S-2-Oxo-6-[1R-(dimethyl-t-butyl
silyloxy)ethvllpenam-3-carboxylate
The entire solution of the product of the
preceding Example was added to 133 ml (133 mmol) of
1.0M lithium hexamethyldisilylamide (in THF) which was
previously diluted with 1000 ml of THF and cooled to
-78~ C. The addition required 0.5 hours and the
30 solution turned bright yellow. Acetic acid (38 ml, 664
mmol) was added and the reaction mixture was stirred
~~'~~1.~~
-26-
for 10 minutes. Approximately I/2 of the solvent was
removed through concentration and the remainder was
diluted with diethyl ether to a volume of 2.7 liters.
The ether solution was washed with saturated
S
bicarbonate solution) saturated brine solution and then
dried over sodium sulfate. The organic phase was
concentrated and the residue was filtered through a pad
of silica gel eluting with 15% ethyl acetate in hexane.
There was obtained 6.98 g (56%) present title product
t0
as a waxy solid; m.p. 45-48~ C.; 1H-t~IMR(CDC13, 300
~.Hz)delta: 5.78-S.94 (1H, ddd, J=18 Hz, J=11 Hz, J=7
Hz), 5.51 (1H, d, J=2 Hz), 5.32 (1H, d, J=I8 Hz), 5.25
(IH, d, J=11 Hz), 5.00 (1H, s), 4.65 (2H, d, J=7 Hz),
15 4~32 (1H, dt, J=7 Hz, J=4 Hz), 3.54 (IH, dd, J=4 Hz,
J=2 Hz), 1.28 (3H, d, J=7 Hz), 0.86 (9H, s), 0.07 (3H,
s), 0.05 (3H, s); C13-NMR(CDC13, 75.43 MHz)delta:
199.0, 169.0, 163.4, 130.4, 1I9.6, 71.7, 67.1, 6f.1,
64.6, 62.4, 25.6, 22.5, 17.9, -4.2, -S.I; m/e
20 calculated for C13H18N05SSi[P-tBu]: 328.0675, found:
328.0615.
EXAMPLE 4
Allyl 5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethylJ-
2-(trifluoromethanesulfonyloxy)penem-3-carboxvlate
A solution of 100 mg (0.260 mmol) of title product of
2S
the preceding Example in 5 ml of methylene chloride was
treated with 0.180 ml (1.03 mmol) diisopropylethyl
amine. This clear solution was then cooled to -78~ C.
in a dry ice-acetone bath. Freshly distilled triflic
anhydride (0.045 ml, 0.270 mmol) was added and the
clear solution was stirred for 1 hour at -78~ C. to
form a cold solution of present title product, which
was used directly in the next step.
-27-
A small portion of this solution was purified by
chromatography on silica gel followed by low
temperature (-78~ C.) crystallization from pentane;
m.p. 40~ C.; 1H-NMR(CDC13, 300 MHz)delta: 5.84-5.98
3
(1H, ddd, J=18 Hz, J=12 Hz, J=6 Hz), 5.73 (1H, d, J=2
Hz), 5.37 (1H, dd, J=18 Hz, J=1 Hz), 5.25 (1H, dd, J=I2
Hz, J=1 Hz), 4.73 (2H, dd, J=6 Hz, J-1 Hz), 4.25 (1H,
dq, J=6 Hz, J=4 Hz), 3.86 (IH, dd, J=4 Hz, J=2 Hz),
1.24 (3H, d, J=6 Hz), 0.87 (9H, s), 0.08 (6H, s); m/e
calculated for CI4H17N07S2SiF3[P-tHuJ: 460,0I68,
found: 460.0246.
L'Y3l4tDT L' S
Ally1 SR,6S-6-[1R-(Dimethyl-t-butylsilyloxy)ethyl]-
2-((1R-oxo-3S-thiolanyl)thio]penem-3-carboxylate
A solution of 69 mg (0.388 mmol) of
3S-(acetylthio)thiolane-1R-oxide in S ml of methylene
chloride was treated with 5 m1 of water and was cooled
to 0~ C. The stirred mixture was charged with 0.78 ml
(1.56 mmol) of 2.0M sodium hydroxide and was allowed to
stand for 0.5 hours. The reaction mixture was quenched
with 0.089 ml (1.56 mmol) acetic acid and was extracted
with 5x 10 ml of methylene chloride. The organic phase
was dried with sodium sulfate, filtered and was then
treated with 0.135 ml (0.780 mmol) of diisopropylethyl
amine. This solution of 3S-mercaptthiolane-1R-oxide
was allowed to stand while the operation of the preced-
ing Example was completed. It was then added to the
entire cold solution of the preceding Example over 0.5
hour while maintaining the temperature below -65~ C. at
a11 times. After 18 hours at -78~ C. the reaction
mixture was treated with IO ml of water and was allowed
to warm to room temperature. The product was extracted
-28-
with methylene chloride and the organic phase was
washed with brine and then dried and evaporated. After
filtration through silica gel, there was obtained
129 mg (98%) of present title product; m.p.
s
131-134~ C.: 1H-NMR(CDC13, 30Q MHz)delta: 5.80-S.96
(1H, ddd, J=18 Hz, J=12 Hz, J=6 HZ), 5.62 (1H, d, J=2
Hz), 5.3S (1H, dq, J=18 Hz, J=2 Hz), 5.19 (1H, dq, J=12
Hz, J=2 Hz), 4.66 (2H, m), 4.21 (1H, dq, J=7 Hz, J=3
Hz), 3.93 (1H, dd, J=14, J=7 Hz), 3.67 (IH, dd, J=3,
J=2 Hz), 3.56-3.72 (IH, m), 3.09 (1H, m), 2.54-2.84
(4H, m), 1.23 (3H, d, J=7 Hz), 0.8S (9H, s), 0.05 (6H,
s); C13-NMR(CDC13, 75.43 MHz)delta: 171.9, 1S9.4,
I50.8, 131.7, 118.7, 118.5, 71.8, 6~.i, 65.2, 64.1,
1? 6I.?, S2.7, 46.7, 33.2, 25.i, 22.5, 17.9; m/e
calculated far C17H24N05S3Si(P-tBu]: 446.0587, found:
446.0597.
EXAMPLE 6
Allyl 5R,6S-6-(1R-Hydroxyethyl)-2-[(1R-oxo-
3S-thiolanyl)thio]penem-3-carboxylate
-
A solution of 100 mg (0.I98 mmol) of the title
product of the preceding Example in 2 ml of dry THF and
0.114 ml of acetic acid was treated with 0.S94 ml
(0.594 mmol) 1M tetrabutylammonium fluoride and the
2s solution was allowed to stir at room temperature for 18
hours. The reaction mixture was poured into a mixture
of 50 ml ethyl acetate and 10 ml of water. The
solution pH was adjusted to 6.4 by the addition of 20%
potassium acetate in water. The organic phase was
removed and the aqueous layer was cashed twice more
with 20 ml of ethyl acetate. The combined organic
layers were dried over sodium sulfate and then
evaporated. The residue was chromatographed on silica
-29-
gel (32-63 microns) with 15$ methanol in ethyl acetate.
There was obtained 70.6 mg (92$) of present title
product as a solid; m.p. 15I-155~ C.; 1H-NMR(DMSO-d-6,
300 MHz)delta: 5.96 (IH, m), 5.82 (1H, d, J=3 Hz),
S.45 (IH, dd, J=18 Hz, J=3 Hz), 5.3I (1H, s), S.29 (1H,
dd, J=12 Hz, J=3 Hz), 5.78 (1H, dd, J=18 Hz, J=6 Hz),
5.65 (1H, dd, J=18 Hz, J=6 Hz), 3.77-4.12 (4H, m), 3.08
(1H, m) , 2.67-2.98 (3H, m) , 2.49 (1H, m) , 1.23 (3H, d,
J=7 Hz); C13-NMR(DMSO-d-6, 75.43 MHz)delta: 173.S,
158.9, 153.6, 132.4, 117.6, II6.2, 71.3, 71.2, 64.6,
63.8, 60.4, 52.2, 46.3, 33.4, 21.4.
E:~AMPLE 7
Sodium 5R,6S-6-(IR-Hydroxyethyl)-2-[(1R-oxo-
3S-thiolanyl)thioJpenem-3-carboxylate
-
A solution of the title product of the preceding
Example (30 mg, 0.077 mmol) in 1 ml of methylene
chloride was treated with 0.058 ml (0.081 mmol) of
sodium ethylhexanoate in ethyl acetate solution (1.39
~ol/ml). The reaction mixture was treated with 6 mg
(0.0223 mmol) triphenylphosphine and 6 mg (0.005 mmol)
tetrakis(triphenylphosphine) palladium in 0.5 ml of
methylene chloride. The mixture was allowed to stir
for 1 hour at room temperature. Ethyl acetate (30 ml)
was added and the mixture filtered to yield crude
product. The latter was taken up in distilled water
and treated with a small amount of activated carbon,
filtered and the filtrate lyophilized to yield present
title product, 10.5 mg: 1H-NMR(DMSO-d-6, 300 MHz)delta:
5.52 (1H, d, J=3 Hz), 5.24 (1H, brs), 3.74-3.96 (2H,
m), 3.50-3.66 (2H, m), 2.88-2.98 (1H, m), 2.70-2.86
(1H, m), 2.44-2.60 (2H, obscured), 2.2-2.36 (1H, m),
1.14 (3H, d, J=7 H2).
-30-
EXAMPLE 8
A11y1 SR,6S-6-(IR-(Dimethyl-t-butyl-
silyloxy)ethyl]-2-((1,1-dioxo-3R- and
3S-thivlanyl)thio]penem-3-carbo3cylate
A solution of 50 mg (0.129 mmol) of the title
product of Example 3 at 0~ C. in 4 ml of methylene
chloride was treated with 0.089 ml (0.5I mmol) diiso-
propylethyl amine. This clear solution was then cooled
to -78~ C. in a dry ice-acetone bath. Freshly
l0 distilled trifluoromethanesulfonic anhydride (0.024 rnl,
0.142 mmol) was added and the clear solution that
resulted was stirred for 1 hour at -78~ C. The
resulting cold solution of Example 4 title product was
treated with a solution of 19.6 mg (0.129 mmol) of
1S racemic 3-mercaptothiolane-1,1-dioxide (Bezmenova et
al., Rhim. Geterotsikl. Soedin. 1975, 188, 2; Chem.
Abstr. 1975, I70558) and 0.022 ml (0.129 mmol)
diisopropylethyl amine in 1 ml of methylene chloride.
Addition required 0.5 minutes and the solution
20 temperature was kept below -70~ C. at a11 times. After
2 hours at -78~ C. the reaction mixture was allowed to
warm to room temperature and was stirred overnight.
The solution was then treated with 10 mI of water and
was extracted with ethyl acetate. The organic phase
25 was washed with brine and then dried and evaporated.
After filtration through silica gel (3:2 hexane: ethyl
acetate), there was obtained 66.7 mg (100%) present
title product as a mixture of diastereomers. These
diastereomers were separated by chromatography on
30 silica gel by eluting with a solution of 6:3:1
hexane: ethyl acetate: benzene. The more polar
diastereomer had the following properties: m.p.
-31-
180-181~ C., (alpha]D = +57.14~ (c=0.49 g/100 ml); HRMS
calculated for C17H24N06S3Si: 462.0536 (P-_tHu), found:
462.0473. The less polar diastereomer had the
following properties: m.p. 169-170~ C. [alpha]D =
s
+111.78~ (c=0.73 g/100 ml); HRMS calculated for
C17H24N06S3Si: 462.0536 (P-tBu), found: 462.0506.
The blocking groups are removed from these
compounds according to the methods of Examples 6 and 7
to yield the known products of Hamanaka, U.S. Patent
4,619,924.
~Y~MDT c 4
Allyl 5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)
ethyl]-2-(ethylthio)penem-3-carboxylate
Title product of Example 3 (100 mg, 0.262 mmol)
Was converted to a cold solution of title product of
Example 4 according to the method of Example 4. This
solution, at -78~ C., was treated with a solution of
0.096 ml (1.3 mmol) ethanethiol and 0.226 ml (1.3 mmol)
diisopropylethylamine in 1 ml of acetonitrile.
Addition required 0.5 minutes and the solution
temperature was kept below -70~ C. during this time.
After 5 minutes at -78~ C. the reaction mixture was
allowed to warm to 0~ C. and was stirred for 2 hours.
The solution was then treated with 10 mI of water and
Was extracted with ethyl acetate. The organic phase
was washed with brine and then dried and evaporated.
After filtration through silica gel (4:1 hexane: ethyl
acetate) there was obtained 110 mg of present title
product; m.p. 83-84~ C.; HRMS calculated for
C19H31N04S2Si: 429.1464, found: 429.1026; a compound
earlier reported in racemic form by Leanza et al.
Tetrahedron, vol. 39, 2505-2513 (1983).
34 05'9
-32-
Present title compound is deblocked according to
Examples 6 and 7 to form the corresponding known penem
antibiotic previously reported by Gangaly et al., _J.
Antimicrobiol. Chemotherapy, vol. 9, pp. C1-CS (1982).
s
EXAMPLE 10
Allyl 5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)
ethyl]-2-(isopropylthio)penem-3-carboxylate
By the methods of the preceding Example, title
product of Example 3 (105.3 mg, 0.274 mmol) and
LO isopropyl mercaptan t0.239 ml, 1.37 mmol) were
converted to present title product, purified by
chromatography on silica gel using Z9:1 hexane: ethyl
acetate as eluant, 60 mg, m.p. I04-106~ C.; previously
kno~n in racemic form, Leanza et al., loo. cit.;
is
deblocked by the methods of Examples 6 and 7 to yield
the corresponding, known penem antibiotic, Ganguly et
al., loo. cit.
EXAMPLE 11
Allyl 5R,6S-6-[1R-(Dimethyl-t-butylsilyloxy)-
ethyl-2-((hydroxvethyl)thin]penem-3-carboxylate
By the methods of Example 8, the title product of
Example 3 (61 mg, 0.158 mmol) and 2-mercaptoethanol
i0.012 ml, 0.I74 mmvl) were converted to present title
product, purified by chromatography on silica gel using
3:2 hexane:ethyl acetate as eluant, 60 mg; m.p. 80~ C.;
[alpha]D = +160.4~ (c=2.22 g/100 ml); HRMS calculated
for C19H31N~5S2Si: 445.1412, found: 445.1420.
-33-
EXAMPLE 12
Allyl SR,6S-6-[1R-(Dimethyl-t-butylsilyl
oxy)ethyl]-2-T2-(4-nitrobenzyloxy
carbonylamino)ethylthio]penem-3-carboxylate
By the methods of the preceding Example, the title
product of Example 3 (49.5 mg, 0.I29 mmol) and
2-[(4-nitrobenzyloxycarbonyl)amino]ethyl mercaptan
(33 mg, 0.129 mmol; Shinkai et al., Synthesis 1980,
924) were converted to present, chromatographed title
product, 71 mg; m.p. 103-105~ C.; [alpha]D = t88.34~
(c=3.26 g/100 ml?~ HRMS calculated for C23H28N3~8S2Si:
566.1088 (P-tBu), found: S66.1119.
EXAMPLE 13
Allyl 5R,6S-6-[1R-(Dimethyl-t-butylsilyl-
oxy)ethyl]-2-[1-(4-nitrobenzyloxycarbonyl)-
3S-pyrrolidinylthio]penem-3-carboxylate
By the methods of Example 8, the title product of
Example 3 (101.7 mg, 0.264 mmol) and 3S-mercapto-1-
(E-nitrobenzyloxycarbonyl)pyrrolidine (0.050 ml, 0.289
x0 mmoi; Sigimura et al., Heterocycles 24, I331, 1986)
were converted to present title .product which,
following extraction into ethyl acetate, was purified
by chromatography on silica gel using 2:I hexane: ethyl
acetate as eluant, 147 mg: m.p. 105-106~ C.; [alpha]D =
+260~ (c=0.84, CHC13) .
EXr~MPLE 14
2-(Trimethylsilyl)ethyl SR,6S-2-Oxo-6-[1R-(Di
methyl-t-butylsilyloxy)ethyl]penem-3-carboxylate
By the methods of Examples 1-3 above, 2-(tri-
methylsilylethyl 2-[4R-(triphenylmethylthio)-3S-(1S-
(dimethyl-t-butylsilyloxy)ethyl)-2-azetidinon-1-yl]-
acetate was converted to present title product;
1H-NMR(CDC13, 300 MHz)delta: S.52 (1H, d, J=3 Hz),
13~4~7~
-34-
4.96 (1H, s), 4.35 (1H, q, J=8 Hz, J=5 Hz), 4.26 (2H,
dt, J=12 Hz), 3.56 (1H, dd, J=5 Hz, J=3 Hz), 1.30 (3H,
d, J=8 Hz), 1.06 (2H, dt, J=12 Hz), 0.89 (9H, s), O.I
(3H, s) , 0.08 (3H, s) , 0.05 (9H, s) ; C13-NMR (CDC13,
62.89 MHz)delta: 199.3, I69.2, 163.9, 71.8, 66.4,
65.5, 64.7, 62.5, 25.7, 22.5, 17.9, 17.4, -I. S, -4.2,
-5.1; m/e calculated for C15H26N~5SSi2 [P-t-Bu]:
388.1179, found: 388.1125.
According to the sequential s~eps and methods of
Examples 4-6, the product is further converted, via key
inte ..ediate 2-(trimethylsilyl)ethyl 5R,6S-6-[1R-(di-
methyl-t-butylsilyloxy)ethyl]-2-(trifluoromethanesul-
fonyloxy)penem-3-carboxylate, to 2-(trimethylsilyl)-
1$ ethyl 5R,6S-6-[1R-(dimethyl-t-butylsilyloxy)ethyl]-
2-[(IR-oxo-3S-thiolanyl)thin]penem-3-carboxylate. The
dimethyl-t-butylsilyl and trimethylsilylethyl pro-
tecting groups are removed by the action of tetrabutyl-
ammonium fluoride in THF at room temperature according
to the method described in Example 8, above and
Girijavallabhan et al., U.S. Patent 4,443,373.
EXAMPLE I5
Pivaloyloxymethyl SR,6S-6-(IR-Hydroxyethyl)-2-
[(1R-oxo-3S-thiolanyl)thin]penem-3-carboxylate
2S Hy the sequential steps and methods of
Examples I-6, pivaloyloxymethyl 2-[4R-(triphenylmethyl-
thio)-3S-(1S-(dimethyl-t-butylsilyloxy)ethyl)-2-
azetidinon-I-yl]acetate is converted to present title
product. The corresponding 1-(ethoxycarbonyloxy)ethyl
30 ester is prepared in like manner.
l~~~l~'~~
-35-
EXAMPLE 16
Allyl SR,6S-2-[Methoxymethoxy)methyll-6-[1R-(dimethyl-
t-butylsilyloxy)ethyl]penem-3-carboxylate
Title product of Example 3 (49,8 mg, 0.I29 mmol)
was converted to a cold solution of triflate title
product of Example 4 according to the method of
Example 4. This solution was passed through a short
plug of silica geI and then an equal volume of 20$
ethyl acetate in hexane was used to elute the product
from the silica gel. The resulting solution was
evaporated in vacuo and then taken up in dry
tetrahydrofuran. In a separate flask 103 mg (0.284
mmol) methoxymethoxytri-n-butyl stannane [Johnson et
al~. J. Org. Chem., 53, 4131 (1986)] was dissolved in 3
ml of dry tetrahydrofuran, the resulting solution
cooled to -78~C, and 0.18S ml (0.297 mmol) 1.6M n-butyl
lithium in hexane added dropwise over one minute. The
resulting solution was allowed to stir for 10 minutes.
In a third flask was prepared a clear, colorless
solution of 29 mg (0.142 mmol) copper (I) bromide
dimethyl sulfide complex in 2 ml of 1:1 tetrahydro-
furan:diisopropyl sulfide [Hutchinson et al., J. Am.
Chem. Soc., 109, 4930 (1987)]. To the solution of the
copper (I) complex, cooled to -78~C, was added via a
cold steel cannula the solution of the lithium reagent
over a few seconds. To the resulting brown solution,
at -78~C, was added the above solution of triflate with
a syringe pump over 0.5 hour. After stirring for an
additional hour, the reaction mixture was quenched with
1 ml of pH 7 NH4C1/NH40H buffer, then diluted with
ethyl acetate and allowed to come to room temperature.
The organic phase was washed with brine, dried over
sodium sulfate and evaporated in vacuo. The residue
was chromatographed on silica gel (15$ ethyl
-36-
acetate in hexane) to yield present title product.
1H-NMR (CDC13, 300MHz) delta 5.9 (1H, ddd, J=178z,
J=128z, J=68z), 5.58 (1H, d, J=28z), 5.4 (1H, dd,
J=I7Hz, J=18z), 5.25 (IH, dd, J=128z, J=18z), 4.88 (IH,
d, J=178z), 4.7 (IH, d, J=178z), 4.7 (2H, s) 4.6-4.8
(2H, m), 4.23 (1H, dq, J=6.88z, J=4.38z), 3.7 (1H, dd,
J = 4.3, J = 28z), 3.4 (3H, s), 1.25 (3H, d, J=6.88z),
0.9(9H, s), 0.1 (6H, s); IR (CHC13) 1790, I710 cm 1.
W (dioxane) lamda 321 nm, 250 nm. HRMS calc. for
CI6H24N06SSi 386.1087 (p -tBu), found 386.1058.
EXr~.MPLE 17
Sodium SR,6S-2-Hydroxymethyl-6-(1R-1-
hvdroxyethyl)penem-3-carboxylate
By means of the combined hydrolitic methods of
Ex~ples 6 and 7, the title product of the preceding
Example is converted to present title product.
EXAMPLE I8
Allyl SR,6S-2-Methyl-6-[1R-(dimethyl-t-butyl-
silyloxy)ethvl]penem-3-carboxylate
By the method of Example 16, title product of
Example 3 (5I.4 mg, 0.I34 mmol) was converted to a
solution of the triflate title product of Example 4 in
tetrahydrofuran. In a separate flask was placed 16 mg
(0.179 mmol) cuprous cyanide and one ml of dry
tetrahydrofuran. The suspension was cooled to 0~C and
0.336 ml (0.471 mmol) of 1.4M methyl lithium in
tetrahydrofuran was added dropwise over 10 minutes.
The resulting clear solution was allowed to stir for
0.5 hours, then cooled to -78~C and the triflate
solution prepared above added over 0.5 hour with a
syringe pump. After stirring for an additional hour,
the cold reaction was quenched with one ml of
~~~.fls~9
-37-
pH 7 NH4C1 - NH40H buffer, then diluted with ethyl
acetate and allowed to come to room temperature. The
organic phase was washed with brine, dried over sodium
sulfate and evaporated in vacuo. The residue was
chromatographed on silica gel (10$ ethyl acetate in
hexane) to provide present title product; 1H-NMR
(CDC13, 300MHz) delta 5.91-5.79 (1H, ddd, J=17H2,
J=11H2, J=5.5H2), 5.47 (1H, d, J=1.5H2), 5.33 (1H, dd,
J=17H2, J=2H2), 5.16 (1H, dd, J=11H2, J=2H2), 4.71-4.53
(2H, m), 4.16 (1H, dq, J=6H2, J=5H2), 3.57 (1H, dd,
J=SHz, J=1.5H2) , 2.28 (3H, s) , 1.17 (3H, d, J=6H2) ,
0.81 (9H, s), 0.01 (6H, s); IR (CHC13) I785, 17I0 cm 1;
UV (dioxane) lamda 314nm, 262 nm.
1~ (alpha]DO - +65.63~ (c=1.34); HRMS calcd. fcr
C18H29N04SS:383.1586, found 383.1610.
25
~~~~~~s~~
-38-
PREPARATION 1
(R)-3-Thiolanyl P-Toluenesulfonate
(R) -4- (Diethylthio) 1, 2-butanediol (1 . 0 g, 7.35
mmol) and P-toluenesulfonyl chloride (3.0 g, 15.8 mmol)
were combined in 10 ml of pyridine at 0-5~ C., then
stirred at room temperature, at which time tlc (3:1
hexane: ethyl acetate) indicated no diol (Rf 0.1),
appreciable of the diol ditosylate (Rf 0.53), some
intermediate thiolanium salt (Rf 0.03) and a trace of
title product (Rf 0.72). The reaction mixture was then
heated at 60~ C. for 8 hcurs, at which time tlc (5:1
hexane: ethyl acetate) indicated an appreciable amount
of the desired title product (Rf 0.45), only a trace of
the ditosylate (Rf 0.22), some probable thiolanium salt
(Rf 0.0), and other, generally less polar impurities.
The cooled reaction mixture was diluted with an equal
volume of water and two volumes of ethyl acetate. The
organic layer was separated, washed with saturated
NaCl, dried (I~IgS04), stripped and the residue chromato-
graphed on silica gel using 10:1 hexane: ethyl acetate
as eluant to yield 0.1 g less polar impurities
(stench!) and 0.25 g of present, purified title
product; tlc Rf 0.55 (4:1 hexane: ethyl acetate);
(alpha]D = +15.87 (c=0.6, CH30H).
PREPARATION 2
3R-(E-Toluenesulfonyloxy)thiolane 1R-Oxide
A solution of 46.30 g (0.179 mol) title product of
the preceding Preparation in 600 ml acetone, under
nitrogen was cooled to 0~ C. In a separate flask
6I.73 g (0.100 mol) potassium peroxymonosulfate was
stirred in 500 ml distilled water until clear. This
-39-
was added to the acetone solution at 0~ C. and the
mixture allowed to warm to room temperature. After 25
minutes 75 ml of 10~ (wlv) aqueous sodium sulfite was
added, the acetone was evaporated, 300 ml ethyl acetate
added and the aqueous layer was extracted with ethyl
acetate (3 x 100 ml). The combined extracts were dried
(MgS04) and concentrated to dryness to yield 48.57 g of
crude product. The latter was purified by silica gel
chromatography using 10:10:1 ethyl acetate:CH2C12:CH30H
as eluant to afford purified title product, 34.67 g
(71$); [alpha]D = +4.26~ (c=3.0, CHC13).
PREPARATION 3
3S-(Acetylthio)thiolane 1R-Oxide
In a flame-dried flask under nitrogen, 31.67 g
(0.1156 mol) title product of the preceding Preparation
was dissolved in 300 ml acetone and 19.81 g (0.1734
mol) potassium thioacetate was added. The mixture was
heated at reflux for 3.5 hours and allowed to stir at
room temperature overnight. The mixture was filtered,
rinsed and washed with 500 ml acetone and the filtrate
and washings were evaporated in vacuo to obtain 23.96 g
of the desired product as an oil. The oil was purified
by flash chromatography on a 120 mm x 25 cm silica gel
column eluting with 19:1 ethyl. acetate: methanol
collecting 125 ml fractions. Fractions 42-64 were
combined and stripped to yield purified title product
as an oil which crystallized on standing, 16.46 g;
(80b); m.p. 51-52~ C.; [alpha]D = -83.41~ (c=0.86,
CHC13 ) .
l~~n~'~~
-40-
Analysis calculated for C6HlOS202:
C, 40.4; H, 5.6~.
Found: C, 40.I5; H, 5.53.
Present title product is alternatively prepared in
like manner from the title product of Preparation 7
below.
PREPARATION 4
(R)-4-Chlorobutane-1,3-diol
In flame dried glassware under nitrogen, methyl
(R)-4-chloro-3-hydroxybutyrate (1.00 g, 6.55 mmol was
dissolved in 6.5 mI of dry tetrahydrofuran. The
solution was cooled to 0~C and a solution of lithium
borohydride (178 mg, 8.19 mmol) in 4.1 ml of dry
tetrahydrofuran was added by syringe over a 30 minute
period, using 2 ml of tetrahydrofuran for rinse. The
ice bath was removed and the solution stirred at 23~C
for 6 hours, then cooled to 0~C, quenched with 40 ml of
methanol and acidified with 8 ml of saturated
methanolic HC1. The mixture was stripped of solvent in
vacuo and the residue treated with methanol and the
reaction azeotroped (3 x 5C m1) to remove methyl borate
and stripped to an oil (1.55 g). The latter was flash
chromatographed on an 8.5 cm diameter x 5 cm deep pad
of silica gel gradiently eluted with CH2C12, 1:1
CH2C12:ethyl acetate and ethyl acetate to yield 0.67 g
(820) of title product as an oil; [alphalD = +24.5~
(C=1.01, CH30H).
1~~~5'~~
-41-
PREPARATION 5
(R)-4-Chloro-3-(methanesulfonyloxy)butyl
Methanesulfonate
In a 500 ml 3-neck flask under nitrogen, title
S
product of preceding Preparation 5.0 g, 0.040 mol) was
dissolved in 150 ml of CH2C12. The solution was cooled
to -20~C. Triethylamine (8.12 g, 11.2 mls, 0.080 mol)
and dimethylaminopyridine (0.489 g, 0.004 mol) were
added followed by mesyl chloride (9.19 g, 6.21 ml,
0.080 mol). The solution was stirred at -20 to -15~C
for one hour and then poured over 1 liter of crushed
ice and stirred for ten minutes. The separated aQUeous
layer was extracted with methvlene chloride (1 x 300
ml). The ccmbined organic layers were washed with IN
HC1 (1 x 500 ml), saturated NaHC03 (1 x 500 ml) and
brine (1 x 500 ml), dried over MgS04, and stripped in
vacuo to afford 9.96 g (88~) of present title product;
[alpha]D = +32.74 (C=1.06, CHC13).
PREPARATION 6
(R)-3-Thiolanyl Methanesulfonate
Title product of the preceding Prepara~ion (3.5 g,
D.0125 mol) was dissolved in 60 ml of 1:6 H20:CH3CN
under N2. Sodium sulfide nonahydrate (3.90 g, 0.050
mol) was added. After heating at 50~C for 76 hours,
the reaction mixture was diluted with 250 ml CH2C12,
washed with H20 (1 x 100 ml) and then brine (1 x 100
ml), dried over MgS04, and stripped in vacuo to yield
present title product, which was chromatographed on
silica gel using CH2C12 followed by 9:1 CH2C12:ethyl
acetate as eluant to yield 1.30 g (57~) of present
title product; [alpha]D = +16.8~ (C=3.0, CHC13).
~3~~J ~7a
-42-
PREPARATION 7
3R-(Methanesulfonyloxy)thiolane 1R-Oxide
By the method of Example 3 of published
International patent application WO 88/08845, title
product of the preceding Example (I.17 g, 6.42 mmol)
and potassium peroxymonosulfate (Oxone; 2.2I g, 3.6
mmol) in I5 ml of acetone were converted to 0.96 g
(75%) of present title product as a white solid;
falpha)D = +2.04~ (C=2.94, CHC13).
20
30
