CA1221357A - Process for the production of penem compounds - Google Patents

Abstract

A B S T R A C T

Penems of the formula I

I
in which R i5 N-methylcarbamoylethyl or glycylaminoethyl, G is hydroxyloweralkyl and X is hydrogen, a pharmaceutically acceptable salt forming group or a metabolisable ester group, or a protecting group are disclosed.

One process for their preparation involves reacting a compound II

II

in which R1 and R2 are protected carboxy groups and Met is a thiophilic metal with a thiocarbonyl III

S=C(Y)2 III

in which Y is a leaving group, followed by removal of one of R1 and R2(to give a compound of formula I in which R is H together with its thione tautomer). The organic groups R can be introduced into the so-obtained compound by known methods.
Three other processes for the production of the compounds of formula I are disclosed.

Description

35i7 PROCESS FOR THE PRODUCTION OF PENES COMPOUNDS

This invention relates to processes for preparing 6-hydroxy~lkyl-2-substituted thio-penem-3-carboxylic acids, and their salts and esters (referred to heroin .
as penes) to certain novel penes and pharmaceutical compositions containing them.

Penes, a recent addition to the family of synthetic ~-lactams, possess potent anti-bacterial activity.
They have, hitherto been prepare by laborious, time consuming, multi step processes which result in low yields and are thus uneconomical.

3~7 According to one aspect of the present invention we provide a process for the preparation of penes compounds of formula I

G So SO

O OX

wherein R is N-methylcarbamoylethyl of qlycylaminoethyl and G is hydroxy-loweralkyl, X is hydrogen, a pharmaceutically accept-able salt forming group e.g. an alkali metal cation, a pharmaceutically acceptable ester group or a car boxy protecting group 7 a) characterized in that, a tautomer~c compound of formula a),(Vb)]

G H G I I

( Ye) ( Vb) is subjected to an alkylation reaction introducing the group R;

I

b) reacting a compound of formula VII

G S R ' Al I

POOH

Jo in which R' is an organic group different from the desired group R with a they'll of formula VIII ' or reactive derivate thereof R SO VIII ' in which R is as defined above c) reacting a compound of formula IX

G , So SO
I s ON IX
\
Ç~

with a trivalent organophosphorous compound, wherein in the processes (a) to (e) above, any lung-tonal groups on the reactants may be protected by protecting groups, which are removed at any appropriate stave of the process, and a so-obtained compound of formula I, if desired, is subjected to deprotection of a protected carboxyl group R2 (if present) and is isolated as the free acid, as a pharmaceutically acceptable salt or pharmaceutically acceptable ester 3~i7 Among the methods used in process (a) for transforming a tautomeric compound of formula [(Via), (Vb)] into a compound of formula I, it is preferred to use one or other of the following:

(i) reaction with a compound of the formula RZ

in which R is as defined above and Z is a leaving group. Typical leaving groups Z are halides, e.g. chlorine, bromide and iodine, hydroxyl and trichloromethylsulfonyl;

(ii) olefine addition, for example using an appropriate 1,2-unsaturated substituted C2-C6 alkaline;

The tautomeric compound [(Via), (Vb)~ is preferably produced by (i) reacting a compound of formula II
;

S eta G I/

. \ /
/ \ 2 R

I
- pa -with a compound of formula III
SKYE III

5 in which Y is a leaving group, to produce a compound of f or mu 1 a I V

G SO
1~R1 IV
. . , lot 1 owed by removal of the protected car boxy group Al whereby the cautomeric compound r (Via), (Vb)] is obtained, (b) a compound of formula VI

SKYE Y
G

\ VI
C~2 - R2 wherein R2 and Y are as defined above, is subjected to intramolecular cyclisation whereby a tautomeric compound [(Y avow b)] is obtained. ¦

I
_ 6 b -Group G may for example be hydroxymethyl, l-hydroxy-ethyl or 2-hydroxyprop-2-yl. Preferably G is 1-hydroxyeihyl; and for convenience the invention is illustrated in the following description with reference to compounds in which G is l-hydroxyethyl, it being understood that other hydroxyalkyl groups can be used instead of said 1-hydroxyethyl group.

I

Compounds of formula I are useful as antibiotics, being active against both gram positive and gram Vega-live organisms such as Staphylococcus Ayers, Escherlchia golf and Pseudomonas aeruginosa.

., .
For instance compounds of the formula when tested in standardized microbiological assays, are found to be active against such gram-positive organists as Staphylococcus epidermis and Bacillus subtilis and such gram-neyativ~ organisms as E. golf and Salmonella at test levels of 0.1 to 2.0 micrograms/ml. Additionally they show activity against organisms which produce beta-lactamases, e.g. penicillins and cephalosporinase, indicating a resistance against these enzymes.

Thus a further aspect of the present invention come proses a pharmaceutical composition comprising an anti bacterially effective amount of a penes of formula I
together with a compatible, pharmaceutically acceptable carrier or excipient.

The dosage administered of the novel penes of this invention is dependent upon the age and weight of the animal species being treated, the mode of ad minis-traction, and the type and severity of bacterial in-fection being prevented or reduced. Typically, the dosage administered will be in the range of 1 to 250 mg/kg, with 5 to 20 mg/kg in divided dosages being preferred.

he penes of this invention may be administered either orally or parenterally. Preferably, the come pounds are administered orally.

Fox oral administration, the antibacterial compounds of this invention may be formulated in the form of tablets, capsules, elixirs or the like. Likewise, they may be admixed with animal feed. They may also be applied topically in the form of ointments, both hydrophilic and hydrophobic, in the form of lotions which may be aqueous, non-aqueous or of the emulsion type, in the form of creams, or by mechanical delivery systems, e.g. transdermal.

The compounds of formula I may also be utilized in liquid Norm such as solutions, suspensions and the like for optic no optic use and may also be administered parentarally via intramuscular injection.

As used herein "pharmaceutically acceptable salts"
means alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium, magnesium and aluminum salts; amine salts formed from suitable organic amine, i.e., aliphatic, cycloalipha~`
tic (cycloaliphatic)aliphatic or araliphatic primary, secondary or tertiary moo-, dip or polyamides, or heterocyclic bases, e.g., salts derived from triethyl-amine, 2~hydroxyethylamine, di-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, 4-am~nobenzoic acid-2~die~
thylaminoethyl ester, l-ethylpiperidine, bicyclohexyl-amine, N,N'-dibenzylethylenediamine, pardon, collie dine, quinoline, procaine, dibenzylamine, l-ephenamine and N-alkylpiperidine~ Acid addition salts formed from mineral acids such as hydr~chlbric, hydrobromic, hydra-ionic, phosphoric or sulfuric acids, or formed from organic carboxylic or sulf~nic acids such as trifler-acetic, para-t~luene sulf~nic, m~leicJacetic, citric oxalic, succinic, benzoic, tartar tic, fumaric, mandelic, ascorbic and mafia acids.
.

Suitable pharmaceutically acceptable ester groups are those known in the penicillin, cephalosporin and penes arts to be cleavable from the parent compound, within the body, to give the corresponding acid.

Examples of such esters are indanyl,phthalidyl, my-thoxymethyl, glycycloxymethil, phen~lslycy loxymethyl, thin glycyloxymethy.l, acetoxymethyl and pivaloyloxy-- methyl.

Suitable carboxyl protecting groups are those which can be removed under conventional conditions without react tying with other functional groups present on the ~-lactam, for example allylic9 cyanoloweralkyl, lower-alkylsilylloweralkyl, cellophane esters, p-nitrobenzyl and in chloroethyl. For instance the preferred protect tying group in R2 is allele and in Al and R2, in compound Tithe preferred protecting groups are preferably respect very 1 oriole Kyle so lye 1 oweral~yl and ally.

:.

~L2~L3~7 Unless otherwise stated, the term "loweralkyl" includes branched- and straight-chain alkyd groups of from 1 to :
6, preferably 1 to 4, carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl, ponytail and Huxley.

The term "removable hydroxy protecting group" means any such group conventionally used for this purpose, with the only requirement being computability with the hydroxy substituent on the penes and ~-lactam inter- .
mediates and removability utilizing elemental zinc or any other conventional agent for this purpose which will not adversely affect the penes or ~-lactam inter-mediates structure. The preferred hydroxy protecting groups include trichloroethoxycarbonyl~ dimethyltri-butylsilyl, trimethylsilyloxvcarbonyl and trim ethyl-sill.

The process of this invention can be used to produce penes of any desired stereochemistry The most pro-furred stereochemistry of the final penes compounds issuer), less preferred is (5R,6R,8S). Final penes of desired stereochemistry can be obtained by selection of starting material of appropriate stereochemistry.

In process (i): the conversion of metal salt II unto Tony IV is typo icily conducted, in a suitable solvent. When metal salt II is obtained according to reactive scheme 1, step Bras described below it may be used directly, i.e.
without isolation from thy reaction mixture in which it it formed. Thus the same solvent may be used in this step as in the preceding step.

Temp~ratllre will usually be if. the range from about 10C to about 45C; about 25C is preferred. Leaving I` group Y in the thiocarbonyl reagent III is typically sheller, bxomo, loo, or imidazolyl. l,l-thiocarbonyl-dimidazole is preferred as reagent III because of its crystalline nature and ease of use.

The removal of one of the protected car boxy protecting groups at position 3 of the throne IV to afford the tautomer a)? ( Vb)~ is typically conducted in a suitable organic solvent such as t~trahydrofuran, ethyl-ether or Dixon at a temperature in the range of from about 10C to about 45C, about 25C being preferred. The removal is usually effected by the I

addition of one functional equivalent of fluoride ion so thaw only a single protected car boxy group is removed.

In one embodiment of the invention R2 is allylicoxy-carbonyl, preferably -C - OCH2CH=CH2 and Al is -C-OCH2CH2Rl wherein Al is a loweralkylsi1yl group, especially in-methylsilyl, t-butyldiphenylsilyl or an equivalently functioning group. In such cases particularly when R2 R

is -C-OCH2CH=CH2 and Al is trimethylsilylethoxycarbonyl it will be ensured that it is Al which is removed by treatment with fluoride Jon.

Typically, tetrabuty]ammoniumfluoride (TBAF) is used as the fluoride ion source, although any other suitable source of fluoride ion may similarly be used to provide one functional equivalent of fluoride ion, e.g. SHOWOFF or OF.

For instance a stoichiometric excess of the fluoride ion source may be used provided this gives rise to the presence of only no functional equivalent in the no-action mixture. This is true particularly for TBAF.
Moreover, because TBAF dissociates slowly in these solutions and as removal of the ally protecting group (preferred for R2) is Mach slower than removal of the trimethylsilyl protected car boxy group (preferred for Al), an excess ego. 2 equivalents) of TBAE results in only one functional equivalent of fluoride ion being employed in this reaction step.

The tautomeric compound of formula V may be isolated ~22135 at this stage for synthesis of other penes, as described in more detail below.
In process ( it .thecyclization of the compound of formula into the tautomeric compound V is typically carried out in an an hydrous inert organic solvent for example, twitter-hydrofuran, and a non-neuclophilic strong base, for example lithium diisopropyl aside (LEA) and lithium di-(trimethyl-silyl)amine added to the system to effect cycl;zation.
Usually cyclization will be carried out at from about lo -50C to Luke and preferably a aback and will generally be complete within about 5 minutes to 24 hours.
Usually an essentially equimolar amount of the strong base will be used The transformation of a tautomeric compound V into aye compound of formula I ( by the process (a) of the`inYenti.on is typically carried out in an an hydrous inert organic solvent for example, tetrahydrofuran, ethyl ether or Dixon it temperatures ranging from about -10C to about 45C e.g. Luke to 45C with room tempt - 20 erasure (about 25C) being preferred.

In the case of this transformation being carried out on a tautomeric compound V` obtained via process (a) or (ii)it will be noted that deprotection of the 8-position hydroxy group may previously be conducted, using suit-able reagents, as discussed below, in such solvents an din a similar temperature range. Thus the transformation may be conducted as a continuation of such preceding deprotection step namely without isolation of the taut Homeric compound V. Thus the same solvents will be used in both steps and it will also be usual to carry out reactions at about the same temperature, or at yeast ~22~3~i7 in the same above mentioned temperature range in both steps. If the tautomer is, first, isolated, different solvent and temperature can be used in this step come pared with the preceding step but, nevertheless, these will preferably be the same.

Transformation using a compound RZ is generally carried out in the preset e of a base or acid acceptor. Such bases and acid acceptors known in the art for this reaction can be used e.g. inorganic bases such as lo alkali metal carbonates or bicarbonates, or organic bases such as ~riethylamine. Where tetrabutylammonium fluoride has previously been used (to remove Al in process (i) ) and remains in the reaction solution this also will function as a base in this reaction.

The alkylation step can, for example, be carried out, in one embodiment, by the reaction of a compound X
of formula / Rio . CHIHUAHUAS I
... Roll X

in which Rio and Roll are as defined above, with the on tautomeric compound of formula Y . This particular reaction will typically be carried out in a suitable organic solvent, for example tetrahydrofuranO An Essex-tidally equimolar amount of an acid acceptor, or example an inorganic carbonate, facilitates the reaction.
Typical reaction temperatures are on the range from about -5C to about 30C, and the reaction is generally complete within l to 24 hours.
.. . . .
... ...

~2~35~7 - 15 _ Olefin addition is generally carried out using a radical initiator for example AEN[2,2'-azobis(2-methylpropio-neutral.

The removal of the protecting group from the protected corbel group R2 can be carried out by conventional procedures selected according to the identity of the protecting group. The preferred protecting group is allylic, preferably ally, and its removal can, in general be effected under catalytic conditions in the 10 presence of a base, preferably by utilizing procedures described in our European Patent Application Public-lion No. 0013663. Thus the allylic groups are prefer-ably removed by utilizing a suitable aprotic solvent, such as tetrahydrofuran, deathly ether ox ethylene 15 chloride, with an alkali petal alkylcar~oxylate, pro-fireball potassium or sodium ethyl xanoate two give the alkali metal penes salt, preferably the sodium or potassium penes salt directly or carboxylic acid, pro-20 fireball 2-ethylhexanoio acid (to give the penes. free-acid) and a mixture of a palladium compound and in-phenol phosphine as a catalyst. Most preferably this step proceeds with the removal of the allylic protecting group and the formation of the alkali metal salt of the 25 penes in situ.

As the product is generally obtained as a zwitterion deprotection of the allylic group requires only the catalyst and any mild neucleophile (ego HO or alcohol).

In another, though lets preferred embodiment protected car boxy groups Al and R2 are both of the structure -C-OCH2CH2R"2 in which both R2s may be the same or different and chosen from cyan, loweralkylsilyl, eye. in-methylsilyl or t-butyldiphenylsilyl, or cellophane ester of the formula -S02Rx (wherein Axis an aureole group), or an equivalently functioning (electron withdrawing) group.
Preferably both R"2 groups are chosen from trim ethyl-sill, t-butyldlphenylsilyl with the former most prefer-lo red.

When carrying out the above procedure in which both Al and R2 have the structure -C-QCH2CH2R"2 the removal of one car boxy group from the position 3 in the tautomeric compound of formula Y is conveniently effected according to toe procedure described above which uses one unyoke-tonal equivalent of fluoride ion preferably TBAF. Sub-sequent deplot2cti~n of the r2mai--ing car boxy protecting group R2 can then be carried out wafter the transformation reaction by using reaction conditions and reagents identical to those used in the previous removal of the protected car boxy group. Preferably, the deprotection is carried out using tetrahydrofuran as solvent, at about 25C with TBAF as the fluoride ion source.

This procedure will usually yield thy free acid of the I penes product. The formation of alkali metal salts and metabDlisable esters can be carried out by treating the free acid according to conventional procedures. For example, the free acid can be reacted with a slot-cliometric amount of a suitable non-toxic base in an ... . . , .. . .. .... .. . , . . . . . . . . . . . ,.. .. . ...

.

inert solvent followed by recovery of the desired salt by lyophilization or precipitation. Or a metabolisable ester can be formed by reaction of an alkali metal salt of a penes with a reactive derivate of the d sired ester function; for example, the phthalidyl or pivaloy-loxymethyl esters are prepayable by reaction of the corresponding alkali metal penes salts with sheller-phthalide or pivaloyloxymethylchloride i n a sol vent such as dimethylformamide, preferably with the addition of a lo catalytic amount of sodium iodide.

The intermediates of formula II are prepayable, for example, by the reaction scheme I shown in the accom-paying flow chart and in the procedures of this reaction scheme, as described below, it will be under-stood that any functional groups in any of the inter-mediates will be protected if necessary, or desired.

_ 3~i'7 OH H20 + O = C /
-H3--C~SR" \ / 2 ), - N C
Ox/ \ HO/ OR

XX (XIXa, XIXb) OH r SCHICK I or H ¦ ¦ . ZOO
ox N\ / OH

R/ \ R

OH ION
Chef r or '' SHEA clue XVI \ C/ 1 C\

H/ \R2 Al I
ED

OH
SHEA I rrSMet II own\ OR

I
-- 19 _ In the above reaction scheme intermediate XVIII is ox-twined in step A by reacting an azetidinone XX in which R" is a Selfware protecting group, with the mixes ester (XIXa, -XIXbr , in which Al and R2 are as defined above.

In this step A the reaction is ty~icallv conducted in a suitable organic solvent at about room temperature Preferably the solvent is polar organic such as do methylformamide; other solvents are for example twitter-hvdrofuran, acetonitrile and dimethylsulfoxide.

The mixed ester preferably has the formula O O
If 11 C OUCH 2 _______~ OH\ /c-ocH2cH=cH2 H20~0=C~ C

C-OCH2CH2R~ OH 11 ~C~2CH2 o in which Rj is preferably chosen from trimethylsilyl, t-butyldi~henylsilyl. or other equivalently functioning loweralkylsil~l groups. Preferred are trimethylsilyl and t-butyldiphenylsilyl groups with the former most referred for reason of ready availability and ease of use.

Thus, rerun to the above formulae, I and R2 ore-fireball have the identities _I_OCH2CH2Rj and O
-COUCH OH -OX respectively the Selfware protecting group Al in the azetidinone XX is preferably triphenylmethyl, 2-~yranyl or a loweralkyl-.. . . . . .. .
carbonyl.

- 20 _ Step B, the chlorination of compound XVIII, is typically conducted in a suitable organic solvent (which may be the same solvent as that used in the preceding step) at temperatures of about -15C to about 10C in the presence of an acid acceptor. If the solvent is itself, or comprises, an acid acceptor, e-g- py~idine no ad-ditional acid acceptor is necessary. Alternatively, an organic solvent which is not an acid acceptor, for ox-ample, ethylene chloride, chloroform, dim ethyl formamide or acetonitrile ma be utilized, and in such case a separate acid acceptor, organic or inorganic will be added to the reaction mixture. Typical ox the suitable acid acceptors are organic bases, for example, pardon or triethylamine and inorganic bases, for example, sodium or potassium carbonate. The chlorinating agent may be one conventionally used for the conversion of alcohols to chlorides for example, thinly chloride, ; oxalyl chloride, phosphorous pentachloride, phosphorous trichloride or ~hosphorvus oxychloride. Thinly chloride is the most pro erred.

The chlorination reaction may ye carried out directly on the product of step A without isolation vows the solvent can be the same as in the preceding step).

Step C, the dechlorination of compound XVII, can be carried out in any suitable organic solvent, fox example, tetrahydrofuran, ethylene chloride or dimethylformamide, and it may be carried out in the same solvent as is used for the preceding step, thus it may be carried out directly on the product of Step B, without isolation.

Water, or any proton source, adjusted by the addition of a mild acid, can be included to enhance the activity of the zinc. Typical reaction temperatures are in the rang -15C to about 25C : 0C is ore-furred.

In this step a protected 5-hydroxy group can be de-protected concomitantly with dechlorination if, as is preferred, the protecting group is one which is no-movable by elemental zinc.

If a hydroxy protecting group is present (at the 5 position) which is not so removable by zinc) a sepal rate removal step is conducted to remove it. Such removal steps are well known in the ~lactam art.
This removal step, if required, can be carried out at lo any time after step C.

Step D can be carried out in a polar solvent, lot ox-ample, methanol, ethanol, dimethylformamide, twitter--- hydrofuran or water. Suitable reactive salts of thiopholic metals are, for example, any reactive salts of copper, mercury, silver, lead, nickel and thallium in which the anion does not interfere in the reaction It is preferred to use Queue), silver (I) and Hg(II)/
with sliver (I) as most preferred. The salts may be salts or organic or inorganic acids, and suitable salts _ . _ .. . . . . . _ . .................... . _ _ .. . . . . .... ..
are, for example, silver nitrate, silver fluoborate, and silver acetate. Silver nitrate is the preferred salt. Typical copper salts are Cooper) acetate, . . _.. . .. . . .. . . .. .. . . . .. . . . .. _ . . .. .. _ .. . . . . .. ... ... . . . . . . . . . . .. . . .. .. .... .. .. . .. .... . . . .. _ . ._ . .
. .. .. . . . . . . .. .. . . . . . . . .. ... . . .. . . . . . . .. _.. . .. . . . . .. . .. . . . . .~.. .
. . _.. _ .. . _. . ._.

Lo and Cooper) nitrate. A typical suitable mercury salt is mercuric acetate. In the case of lead salts it it observed that these give much slower reaction rates.

Silver salts are most preferred due to their ease of recovery and relative non-~oxicity.

The reaction is facilitated by using an acid acceptor, e.g. pardon or triethylamine. Preferably the no-action is carried out under an inert, e.g. nitrogen, atmosphere.

It Lo highly preferred, when carrying out the above procedures, that the ~-lactam intermediates produced in each step are not isolated but remain in the no-action vessel and are treated according to the next reaction step. This facilitates the process to a very ; great extent as several steps can be carried out in the same solvent without regard to the separation of the desired product.
.... ;
For instance, in a preferred embodiment of the process including the procedures of reaction scheme 1 the ester of formula (XIXa, XIXb) is added to the azetidinone of formula XX to form the intermediate of formula XVIII. This intermediate is then directly treated with the chlorinating agent, preferably thinly chloride to form the chloride intermediate of formula VOW. This intermediate, again without isolation, is treated directly with elemental zinc to remove the chlorine atom and possibly concomitantly, if present, a hydroxy protecting group on the 5-substituent so as to afford the intermediate of formula XVI.

I
_ 23 -Thus the first steps A, B, C, and subsequent repro-section of the 5 position hydroxv group are conduct able in the same reaction vessel, in the same solvent and this enables west caused by isolation of inter-mediate compounds to be mitigated.

In a highly preferred embodiment a compound of formula in which the 5 position hydroxy group is not pro.
tooted may be treated directly, without isolation from the reaction mixture in which it it formed, to protect 10 the said hydroxy group then without isolation the protected product may be subjected to to cyclization reaction with the thiocarbonyl compound of formula III, and thereafter, without isolation, the tautomeric pro-duct is treated to remove the position hydroxy pro-15 tooting group. Alternatively the aforesaid hydroxyprotection arc deprotection can be dispensed with and the compound of formula II used directly, without is-lotion, in the cyclization reaction with thiocarbonyl of formula III~

It is likewise preferred to dispense with the isolation of the tautomeric product (Y a, Y b) when working up or preparing other compounds of formula I; thus the various transformation procedures can be carried out directly without separation of the tautomer from the reaction I mixture in which it was prepared, and the resulting compound of formula I can be subjected to removal of the car boxy protecting group in R2, likewise, directly with-out isolation from the reaction mixture in which it was formed.

3~7 _ 24 --I OWE
SHEA SO' OH` SO

2 2 H SHEA R2 XX XXIII XXI
B' I H
SCHICK-- Suet I

Ox ON\
SUE

XXI
OH I/

C:~3--¢~
_. . N

IT

_ 25 -The intermediates of formula VI can be made, for example, by following the reaction scheme 2 as shown in the accompanying flow chart. As in the case of reaction scheme l describe d above, it will be understood that any functional groups in any of the intermediates will be protected if necessary, or desired.

Step Al The reaction of azetidinone XX with the a-substituted acetate XXIII is preferably carried out in the presence lo of an acid acceptor, preferably at a temperature in the range from about 15C to about 30C.

W is a leaving group preferably tussle, Mazola sheller broom, idea or trifluoromethyls~l~onyl, most.
preferably idea or broom.

lo R2 in the acetate XXIJI is preferably allylic-oxv-carbonyl most preferably allyloxycarbonyl.

If the solvent is also an acid acceptor, e.g. pardon, no additional acid acceptor is required. Alternatively, an organic solvent which is not an acid acceptor, e.g.
acetonitrile may be employed. In these cases, a sepal rate acid acceptor, organic or inorganic must be used.
Preferably the reaction is conducted in acetonitrile using sesame carbonate or tetraalkylammonium hydroxide as the acid acceptor.

3~i7 Sty can be carried out by following the procedures described above in connection with step D of reaction scheme 1.

SUE can be carried out by following the procedures described above in connection with the conversion of metal salt II with the thiocarbonyl compound of formula . III into thin IVY. In this case however, the cyclization (which occurs in reaction scheme 1 with using the malonate divester) does not occur and the : . -thiocarbonyl azetidone intermediate VI is obtained.

Usually the metal salt intermediate of formula XXI we e treated to protect the 5 position hydroxy group (if it is not already protected) before step C' is carried out.
The resulting protected group can be deprotected, if desired, after the cyclization of the compound of formula VI i.e. the deprotection being carried out for example, on the compound of formula V . Conventional hydroxy protection and deprotection procedures can be used as discussed below.

In the preferred form of this process the intermediate of formula XXII is utilized directly in the reaction of step B', without separation from the reaction mixture in which it is formed yin step A') and the compound of formula XXI so formed likewise treated, directly, without isolation from the reaction mixture in the procedure of step C'.

If the intermediate of formula XXII formed in step B is treated to protect the 5 position hydroxy group before Lo _ 27 --it it treated in stew C' the protecting procedure can likewise be carried out directly on the intermediate of formula XXI without separating it from the reaction mixture in which it is formed. And likewise the pro-5 acted intermediate so formed can be treated in step Without separation from the reaction mixture.

Similarly the cyclization of intermediate of formula YIP
and the removal of any 8 position hydroxy protecting group from the resulting compound can be carried out sequentially on intermediates without separating the cyclized pro-duct from the reaction mixtures in which they are formed, where the 8-hydroxy group in the resulting penes is protected this will then be removed by conventional procedures. Subsequent deprotection of the 3 position carboxyl group and formation of a free acid, salt or metabolisable ester can be carried out using the pro-seeders discussed above.

Suitable hydroxv protecting grouts are well known in the penes art and methods for their attachment to hydroxy groups are likewise well known. A particularly preferred protecting procedure for instance, for the protection of the 5-hydroxy group in the compounds of formula II and XXI comprises reacting the appropriate intermediate, (e.g. of formula IT having an unprotected hydroxy group, with bis-~ilylacetamide which readily farms the trimethylsilyl protecting group at the apt proprlate hydroxy moiety. The protection of the 5- -hydroxy moiety in the azetidinone intermediates in the processes discussed above can ye carried out with--out isolation of the intermediate involved. Thus the inert solvent used may be the same as the one used in -the preceding step erg. DMF. Other solvents for ox-ample, chloroform and ethylene chloride may also be used. Temperatures for the hydroxy protection pro-seedier are typically from about C to about 30C.

Methods for the removal of a group protecting 5 or 8-hydroxy group are well known in the penes art. Prefer-ably, when the hydroxy protecting group is trimethylsilyl, addition of a mild aqueous acid solution, such as asset acid, to the solution in which the intermediate to be Doria-tooted is prepared effects removal. Thus, for example, Theresa no need to isolate a protected derivative of the compound of formula IV before proceeding to de-protect the 8-hydroxy group.

., ~2~3~7 Process (b? involving sulfoxide replacement, is usually carried out in an inert solvent, for example dichloro-methane or tetxahydrofuran. The reaction temperature is usually in the range 0C to -70C.

when the they'll compound Voyeurs itself used the reaction is generally carried out in the presence of a base, e.g. an organic base such as diisopropylethylamine or triethylarnine, or an inorganic bass, for example potassium hydroxide or sodium methoxide.

Alternatively a reactive derivative, for example an alkali metal salt preferably sodium or potassium may be used. The sufoxides of formula VII can be obtained by e.g. treating a compound of formula I, buy in which R
may be any organic group with a mild oxidizing agent, for example m-chloroperoxybenzoic acid in an inert solvent, for example dichloromethane at between -30C
and 20C, e.g. OKAY to 5C.
Such compound of formula I can be prepared, for ox-_ ample by the other methods disclosed herein, or by methods disclosed in our European Patent Specification Publication No. 13662.

Process I involving cyclization of the compound of formula IX, is usually carried out analogously to the process described in our European Patent Application, Publication No. 58317.

Thus it is usually carried out in an inert solvent, for example an aromatic hydrocarbon e g . lot gene .

". ,.,~.. _ ........ . .....

I
_ 30 -Bunsen, aliphatic ethers e.g. diethylether and dip .
propylether, cyclic ethers eta. Dixon and tetrahydro- :
Furman, and halogenated hydrocarbons e.g. ethylene chloride and chloroform.

In general the cyclization reaction is conducted at temperatures in the range from 20C to 80C, usually from 40C to 60C for a period of from 6 to 24 hours Suitable trivalent organophosphorous compounds are cyclic and/or cyclic trialkylphosphites, triarylphosphites and mixed aureole alkylphosphites or phosphoramides. The preferred trivalent organophosphorous compound is a trialkylphosphite; most preferred is triethylphosphite.

The compounds of formula IX can be obtained by the reaction of a compound of the formula .... ., :
OH:

SHEA-- C - S C-S-R
_ . H I s . NH

in which R is as defined above with a reactive derivative erg chloride, of an acid of the formula o C

in which R2 is as defined above. This reaction is usually carried out under normal assaulting conditions, namely in an inert solvent and in the presence of an organic base, preferably a tertiary amine.

.

Lo Typical representatives of compounds which can be pro-duped by the methods described above are:

(5R,6S,8R)-2-[2-(aminoacet.~lamino)ethylthio~-I hydroxyethyl) penes 3~carboxylic acid, and (SR,6S,8R)--2~ methylcarbamoylethylthio)-6-(l-hydroxyethyl)-penem-3-car~oxylic acid and the alkali metal salts (particularly sodium and potassium salts) and metabolisable esters thereof (particularly pivaloyloxymethyl and phthalidyl esters), corresponding 5R,6R,8S stereo isomers, and duster-metric mixtures and enantiomeric mixtures comprising the foregoing, and other stereo isomers and sterPoisomeric mixtures of the same chemical compounds.

The following preparations, examples and illustrations describe in detail the processes of the present invention, methods for the preparation of the starting material and illustrations of the use of the inter-mediates produced by the instant process. Throughout lo these preparations, examples and illustrations, "NOR"
denotes nuclear magnetic resonance spectra; "rotation"
denotes optical rotation of the companionways in a suitably solvent; "MS" denotes mass spectra; W denotes ultra-violet spectra; "IT" denotes infrared spectra:
20 . Chromatography is performed on silica gel unless otherwise noted. The term "room temperature" refers to about 18C to about 25C.

PREPARATION OF STARTING MATERIALS
PREPARATION A

(US 9 4R,5R)-3~ Trichlorethoxycarbonyloxyethyl)-4-~tri .
phenylmethylthio~azetid;n-2-one To a 250m1 flask add 7.8 grams (0.0223M~ of 3-(1-trichloroethoxycarbonyloxyethyl)-4-acetoxyazeetidin-one, 220ml acetonitrile, 2.6 grams (0.252M) Suzanne carbon Nate and 5 2 grams (0 . 0l88M) triphenylmethanethiol ~trj.~yl-trio}). After stirring for 5 hours, add an additional 1.0 gram (3 . 0036M) tri.phenylmethanethiol end stir the mixt~rP
for another one-hQlf her. After overnight refrigeration filter to remove the solids and remove the solvents under reduced pressure to yield a crude reaction product. Cry matograph this cr~de-prod~ct on coarse silica gel elating 15 with ethylene chloride changing to 10~ and 20% ethyl ace-tate/methylene chloride to afford 7.89 grams (35,4R,5R)-3 tl-trichloroethoxycarbonyloxyethyl)-4-ttxiphenylmeethylth a2etidin-2-one with spectra as follows:
.
NOR = 7.7-7.1,16H; 5.05,1H,m; 4.~5,2H,q (J=18Hz), 4 . 45 llH,d Jo OH 3 I .
lo, dud tJ=l 5, essay); 1 . 5 0 OH Ed (J=9Hz~ .

3L3~

Preparation B

DO (TRIME'I~SII,~?L)KETOMAI~NP.TE

(a) In loom of ethylene sheller de dissolve 22. 50 grams 2-tr~methylsilylethanol. To this mixture odd 5 20000 grams triethylamine. Cool to about -20C., and add a solution of 15 grins of freshly distilled millennial dichlo-ride in loom ethylene chloride slowly o'er a period of one and one-half hullers. After the addition is completed, allow the reaction mixtllre to warm Jo room temperate and then wash twice with 5û0ml portions of water, followed by washings with 596 sodium bicarbonate solution Until the pi is greater than 9. Dry the solution over anhydrolls magnet sin sulfate and remove the solvents by evaporation to yield 30 . 22 grams of the trime~hylsilyl dozier of Masonic acid .
(b) Dissolve divester prepared as described in paragraph t a in 300ml Bunsen. Add to this . solution 140mg benzoic acid, 1 7ml benz~ldeh~de arid s~ffieien'. oiperldine to afford a pi of about 9. Reflex the solution, using a Dean Stark tube, for 8 hours and when remove the solvents 20 winder reduced prosier to afford, as the product, do ('cry-.
methylsilylethyl) benzylidlnemalonate.

(c) Dissolve the do (trimethylsilylethyl ) ensoul done malonate prepared as described in paragraph (b) in 500ml ethylene chloride and cool to about 0C0 Bubble 25 bone into the solution lmtil a distinct by eye to bl~e-green actor persists. D~scontin~le the admission of the ozone and allow the solllticn to stand fcJr five to ten mimltes. Pass nitrogen through the reaction vessel mail the excess ozone is completely removed . Add 7 5 milliliters s: f d~met~yl so five and allow the reaction mixtllre to cone to room empe-retooler. Evaporate the solvent and place the resulting oil ., in an open dish to allow any excess benzaldehyde to ox-doze. After standing overnight, dissolve the semi crystal-line mass in ethylene chloride and wash it, first with saturated sodium bicarbonate solution, and then with water.
Dry the washed ethylene chloride solution over an hydrous magnesium sulfate and remove the solvents. The resulting oil/crystaltine mass is recrystallized from petroleum ether to afford di(trimethylsilylethyl)ketomalonate.

PRE~R~TI~N
I_ ..

10 Preparatio~_of Ally trlmet~ylsily_e~lX~malonate Add to a 50~ml flask 25gm ketomalonic acid 1-1/2 H20, 250mg Tulane ~ulfonic acid, 58gm ally alcohol, and 20~m1 Bunsen. Refl~x.~sing a Dean Stark tube for 6-1/2 hours. Remove excess ally alcohol and Bunsen by 15 evapo~aticn under vacuum. Wash the residue with HO, then dustily at 2mmHg and collect Delilah ketomalonate as a vet-low oil, by 89-g~ C, yield 25gm.
odd the thus produced 25~m diallylke~onate to 14.9qm of (SUE
SiCH2CH2OH, then add 1/2ml of 1,5-diazabicyclo-[4.3.0~non-20 ennui (DUN). After 24 hours, wash the resultant mixture with cold 10% phosphoric acid, then with water. Dry the resultant product and distill at 0.4mm Hug to obtain ally trimethylsilylethylket~ malonate, by 91-100C., yield lam I : . NOR 05., (US).. lo (2H,T,J=9 Ho);

4.35, (2H,T,9HZ); 4,70, I D, J=6Hz); 5.25, (OH, M); 5.80, lo Ho ..................... ......................... ............. ... ...

Lo lo PREPARATION D

ALLY!-t5R,6S,8R,2'RS)-(ETHANECULFINYL)-6~ HYDROXY
ETHYL)PENEM-3-CARBOXYLATE

Stir a solution of allyl-(5R,6S,8R,2'RS)-2-(ethylthio)-6-hydroxyethyl)penem-3-carboxylate (31.59) in ethyl acetate (200 ml) and dichloromethane (100 ml) at 0-5C.
Add a solution of m-chloroperoxybenzoic acid (80-85%;
229) in ethyl acetate (120 ml) over 0.5 hour. After a further 0.5 hour, add the solution to a stirred mixture of ethyl acetate (150 ml), water ~125 ml) and sodium - bicarbonate ~15 g) and stir rapidly for 15 minutes. Dry the organic phase over McCoy, evaporate and chromatography rapidly on silica gel, eating with 1:1 hexane-ethyl acetate then pure ethyl acetate Evaporate the product fractions and pump the residue at high vacuum to give . .

__ , __ ._ ... , .. , .. .__.. .. _._.... .

I
- 36 _ the title compound as a thick yellow oil.

PMR~CDC13): 1.2-1.6 (m,6H) 9 3.0-3.35 (m,2H), 3.38 (bras, lo, etch by D20), 3.83 (m, lo), 4.18 (m, lo), 4.75 (bred, J=6.5 Ho), 5.2-5.6 (m, OH), 5.73 and 5.89 (both do Jc1.5 Ho, total lo) and 5.8-6.2 (m, lo).

The compound obtained is a mixture of isomers duster-isometric at the oxidized sulfur. The mixture was used in the following examples as both isomers react.

PROPORTION
2-(N-ALLYLOXYCARBONYLGLYCLAMINO)-ETHANETHIOL

Add pivaloyl chloride (2.4 ml) in SCHICK (10 ml) to a cooled (0-5C.) and stirred solution of N-allyloxy-oarbonylglycine (3.18 9) and triethylamine (2.8 ml) in dry SCHICK !50 ml). Stir the mixture at 0-5C. for 15 miss. and then add a solution of 2-amincethznethiol _ hydrochloride (2.4 9) and triethylamine (2.8 ml) in ethanol (15 ml) and SCHICK (40 ml). Stir at room tempt erasure for 1 hour, wash the mixture with aqueous 2N-H2S04 end aqueous Nikko, dry and evaporate.
Triturate the resulting solid with ether, filter and dry to give the title compound.

PER (CDC13): 1.42 (t, Jo Ho, etch. by D20 lo), 2.61 (m, OH), 3.50 I Jo Ho, OH), 3.88 (d, J=7Hz, OH), 4.57 (m, OH), 5.1-5.5 (m, OH), 5.6-6.2 (m, OH; lo etch. by D20) and 7~0 (by. S, lo, exch.by D20) ___ j . _ _ . .... ..... .. .

3~7 REPARATION F
. _ ~5R,6$,8R)-2-EïHYLTHIO-6-(1-HY~ROXYETHYL)-PENEM-3--CAR BOXY-LIT ACID
-A. Dissolve 3.0 grams (3S,4R,5R)-3-[1-(2,~,2-trichloroethoxycarbonyloxyethyl)]-4-(triphenylmethhealth)-azetidin-2-one (prepared as described in Preparation A) in 6ml dimethylformamide. To this solution add 200 grams di(trimethylsilylethyl) ketomalonate (prepared as described in Preparation B) and molecular sieves. After standing for two days at room temperature, perdition the reaction mixture between water and Mullen chloride. Separate the organic layer and remove the solvents by rotary evapora-lion. Purify the crude reaction product so obtained by column chromatography on silica gel eluding with ethylene chloride changing to I ethyl acetate/methylene chloride, to yield 4.26 grams (3S,4R,5R)~ l-hydroxy-l,l-di(tri-methylsilylethoxycarbonyl)methyl~-3-[1-(2,2,2-tricsheller-ethoxycarbonyloxy)ethyl]-4-triphenylmethylthio~azeetidin-one ha no spectra as follows:
NOR: B 7.5-7.1,1~H; 5.05,1H,m; 4.65,2~, s; 4.5,1H,d(J=1.5Hz); 4.2,4H,m;
3.~5,1H,dd(J=1.5,?Hz), 1.05,3H,d (J=7Hz); 0.9,4H,m; 0.05,18H.

B. To a solution of loll ethylene chloride, 2ml pardon and 1.0 gram coulomb caxbonate.add 4.26 gram US
4R,5R)~ hydroxy~ di(tr~methylsilylethoxycarbonyl) methyl]-3-[1-~2,2,2-trichlororethoxycarbQnyloxy)ettheology-triphenylmethylthio)-azetidin~2-one. After placing the mix-tore in an ice bath add slowly thereto 1.5ml of thinly .
...
:

I
_ 38 -chloride After nullify hour, the reaction is complete.
Wash the reaction mixture with swim bicarb~nake solution of pi less than 8 and remove the solvent under reduced pros-sure. Chromatography on silica gel using ethylene chloride

5 as elan to obtain 3.48 grams of the product, (3S,4R,5R) l-[l-chloro-l,l-di(tri~methylsilyleth~xyca~bonyloxxy)methyl~-' 3~1-(2,2,2-t~i-chl~roethoxycarbonyloxyethyl~-4-(trriphenyl-methyl~hio)a~etidin-2~one.

C. Dissolve 3.48 grams of (3S,4R,5R)~ sheller-101,~-di-(trimethylsilylethoxycarbonyl)methyl]-3-ll--( 2 r 2 r 2 tri-chloroethoxycarbonyloxyethyl]-4-triphe~yl-methhealth) azetidin-2-one in 50ml tetrahydr~f~ran. To this solution add 15ml water and 8 grams zinc dust. Place the mixture in an ice bath and add 16 grams of ammonia chloride in port 15 lions over a period of one Herr After a period of two hours, add 4ml of 100% acetic acid, and then prunes, an ad~iti~nai 6 Greece of zinc dust After a further period of one holly, filter the reaction mixture and remove the sol-vents under reduced Pressure. Partition the crude product 20 between water and ethylene chloride. Purify using column chromatography on silica gel using as eluant, 1% ethyl ace-tate/methylene chloride changing to 25~ ethyl acetate/methy-tone chloride to afford 1.644 yams of the desired product, ~3S,4R,SR)-l-[l,l-di(trimethylsilylethoxycarbonyl)methyl]-, . ... . . . . . .. .
I hydroxyethyl)-4-(triphenylmethylthio~azet;din-2-onno having spectra as follows:
NOR : = 7.5-7,15H; 4.15,5H; 3.9,1H,s;
3.4,1H,dd(J=105,6Hz); 1.05,3H,d (J=6Hz); 0.95,4H,m, 0.5,18H.

. . .. . .. _ .. _ .. ... .. . _ _ _ ,,, ...... ... . , ..... _ . .. ..

ii7 - 39 _ D. To a 25 ml flask having a nitrogen atoms-phone add 1 ml methanol and 200 my (0.000~89 moles) (3S,4R,5R)-l-[l,l-di(trimethylsilylethoxycarbonyl)methyl]-Ihydroxyethyl)-4-(triphenylmethylthio)azetidin-2-onno.
Cool the solution to about 0C, and add 0.025 ml (25 my, OKAY moles) pardon and 54 my (0.000317 moles) silver nitrate in 1 ml methanol. Allow the mixture to warm to room temperature, with stirring. After two hours, remove the methanol under high vacuum to afford silver (3S,4R,5R)-3-(1-hydroxyethyl)-1-[di(~-trimethylsilylethyl)-2--malonate]-azetidin-2-one-4-thiolate.

E. Dissolve silver (35,4R95R)-3-(l-hydroxy-ethyl di(~-trimethylsilylethyl)-2-malonate]-azetidin-2-one-4-thiolate in 2 ml ethylene chloride and to this solution added 68 my of l,l-th;ocarbonyldiim;dazole. Stir for another 1.5 hour and then directly apply the reaction mixture to a chromatography column of silica gel. flute : with ethylene chloride to afford the desired product, (~R,6~,8R)-2-th;one-3,3-di(trimethylsilylethoxycarrbonyl)-

6-(1-hydroxyethyl~-penem, hazing spectra as follows:

NOR: = 5.7,1H,d (J=lHz); 4.2,5H,m; 3.65 lR,dd lJ=l, 8Hz); 1. 3,~H,d ~J-8Hz);
O.95,4H,m; 0.05,18H~

35~
_ 40 -F. 61 milligrams of (5R,65,~R)-2-thione-3, Ed (trimethylsilylethoxycarbonyl~-6 (l-hydroxyethyl)penam is dissolved in 5ml t~trahydrof~ran and 2 equivalents of let-rabutylamm~nium fluxed in loll tetrahydrof~ran is slowly wadded at room emperor. Thin layer chromatography (so-lice, 10% ethyl ace~ate/methylene chloride) showed the immediate presence of the decarboxylated compound Tracy, 8R)-2-thione-3-(trimethylsilylethoxycarbonyl)-6-(ll~hydroxy-ethyl)-penam, which exists in equilibrium with (SR,6S,~R)-2-thiol-3-(trimethylsilylethoxycarbonyl)-Ç-(l-hydrroxyethyl)-penes.

G. To the solution of (5R,65,8R)-2-thione-3-(trime~hylsilylethoxycarbonyl)-6~ hydroxyethyl)penam and(5R,6S,8R)-2-thiol-3-(trimethylsilylethoxycarbonyllo-6-(1-hydroxyethyl~enem produced in the above step F add 2 ml of ethyl iodide, Stir at room temperature for about 15 minutes the partition between water and ethyl acetate.
opera the organic layer and remove the solvents by rotary evaporation to yield the desired product, (5R,6S,8R)-~-{tri-20 methylsilyl)ethyl-2-ethylthio-6-(1-hydroxyethyl)peenwomb-carboxylat~, having spectra as follows: ;

NOR: = 5.7,1H,d(J=1.5Hz~; 4.2,5H,m;
f 3.7,1H,dd(J=1.5,7Hz); 3,2H,m;
1.4-0.9,8H; 0.05,9~.

H. Dissolve 40 milligrams of (5R,6S,8R~-~-(tri-methyl-silyl)ethyl-2-ethylthio-6-(1-hydroxyethyl)ppenem-3-carboxy.late in my tetrahydrof~ran and to this slowly add one e~iYalent of tetrab~tylammoni~m flurried in my to-hydrof~ran at room temperature, After 15 minutes, the reaction is complete as shown by thin layer chromatography, .. . .. . . ..

Acidify with phosphoric acid to a pi not below 2, and thereafter purify to afford the desired product, (5R,6S,8R)-2-ethylthio I hydroxyethyl)-penem-3-carboxylic acid, identifiable by spectra and bioautogram with authentic (5R,6S,8R) 2-ethylthio-6~ hydroxyethyl) penem-3-czrboxylic acid.

PREPARATION G

Preparation of Ally (5R,6S,8R)-2-ethylt~i -6--(1-hydroxy-ethyl)penem-3-carboxylate A) Preparation of (-3S,4R,5R)-l-El-~ydroxy-l-al-l~-loxy-carbonyl-l-trimethylsilylethoxycarbonyl-methyl]-3--[1-(2,2,2~trichloroethox'y'carbonyloxyethyl)~-4-(tripfoe methylthio)azetidin-2-one Add 100mg of (3S,4R,5R)-3-[1-(2,2,2-trichloro-ethoxycarbonyloxyethyl -4-(triphenylmethylthio)-azetidin-2-one (prepared as described in Preparation A) and 0.2ml of dimethylformamide to a dry vial. Add 45mg of ally in-methylsilylethylketomalonate prepared as described in Preparation C), 0.0014ml of pardon and 0.0014ml of in-ethyl amine to the system. After standing at room tempera-tore for 50 minutes, remove the solvent by stripping to give the title product.

I

B) Preparation of (3S,4R,5R)~ l-allyloxycarbonyl-l-ohloro-l-trimethylsilylethoxycarbonylmethyl]-3-[1--(2,2,2-trichloroethoxycarbonyloxy)ethyl]-4-(triphenylmethhealth)-azetidin-2-one Add 4.26 my of (3S,4R,5R)-l-[l-hydroxy-l-allyloxy-carbonyl-l-trimethylsilylethoxycarbonyl-methyl~-3--[1-(2,2,2-trichloroethoxycarbonyloxy)ethyl]-4-ttripheenyl-methylthio)-azetidin-2-one to a solution of 10 ml of ethylene chloride, 2ml pardon and lam of calcium car-borate. Cool the system to 0-5C., by placing the system in an ice bath After cooling, slowly add 1.5ml of thinly chloride. After 25 minutes, the reaction is complete. Wash the reaction mixture with sodium bicarb-ovate solution of pi less than 8 and remove the solvent by stripping. Chromatography the residue on silica gel using ethylene chloride as the eluant to afford 3.48gm of the title compound.

C) Preparation of (3S,4R,5R)~ allyloxycarbonyl-l-.
trimethylsllylethoxycarbonyl-methyl]-3-(1-hydroxyeethyl)-4-(tri~henylmethylthio)-azetidin-2-one Dissolve 3.48gm of (3S,4R,5R)-l-[l-allyloxycar-bonyl-l-chloro-l-trimethylsilylethoxycarbonyl-methHoyle-~1-(2,2,2-trichloroethoxycarbonyloxy~ethyl]-4-(triiphenyl-methylthio)-azetidin-2-one in 50ml of tetrahydrofuran.
To the system add 15ml of water and 8gm of zinc dust.
Place the system in an ice bath and add 16gm of ammonium chloride in portions over 1 hour. Stir the solution at OPAQUE., for an additional 2 hours and then add 4ml of glacial acetic acid and, portions, an additional 6gms of zinc dust. Continue the reaction for an additional 1 hour, filter and remove the solvent by stripping.

~2~L~35'7 Dissolve the crude product in ethylene chloride and wash the organic solution with water. Purify the crude product by chromatography on silica gel using as eluant 1% ethyl-acetate (ethylene chloride changing to 25% ethyl acetate) to afford 1.64gm of title compound.

NOR: = .05, (5, OH); 1.05, (m, OH); 1.15, (D, OH, Jo 2.2, (5, lo); 3.38, (DUD, lo); 3.7, (m); 4.2, (m); 4.5, (m); 5.2, (m, OH); 5.8, (m, lo).

D) Preparation of Silver-(3S,4R,5R)-3-(1-hydroxyethyl)-l-allyloxycarbonyl-l-trimethylsilylsthoxycarbonyl--methyl-azetidin-2-one-4-thiolate To a 50 ml flask having a no Trojan atoms-phone add 5 ml of methanol and 1 gym (0.00158 moles) of (3S,4R,5R)-l-[l-allyloxycarbon~ trimethylsilylethoxy-carbonylmethyl]-3~1-hydroxyethyl)-4-triphenylmethyylthio-azetidin-2-one. Cool the solution to about 0C and then add ~.14,ml of pardon and 1.74 ml of methanol eon.-twining 294 my (0.00173 moles) of silver nitrate. Stir , the system at about 0C for 1 hour and then allow the system to warm to room temperature. After 2 hours of stirring at room tenlperature, add an additional 0.2 ml ox methanol containing 34 my of silver nitrate (0.0002 moles) to the system and continue the reaction for an additional hour. Stop the reaction and remove the ', methanol by stripping. Dissolve the residue in methyl tone chloride and wash the organic solution twice with water, then with brine. Dry the organic solution over an hydrous sodium sulfate, filter and remove the Matthew ylene chloride by stripping to give the title compound.

__ . _ _ "_ . __ . . , ... _ _ . _ . _ .. . .... _ .. _._.. . _ .... ,. _ .. ............... .. .. .

D') Repeat the procedure set forth in step D but replacing the silver nitrate with an equivalent quantity of 1) phallic nitrate, and 2) cupric nitrate to obtain respectively thallium (3S,4R,5R)-3-(1-hydroxyethyl)-1-allyloxycarbonyl-l-trimethylsilylethoxycarbonyl-methyl-azetidin-2-oone-thiolate;
and copper (35,4R,5R)-3-(l-hydroxyethyl)-1-allyloxycarbonyl-10 1-trimethylsilylethoxycarbonyl-methyl-azetidin-2-oone-4-thiolate.

PREPARATION D"
-D"), OH OH
Schick SKYE H 9 TV I Six (I) Eli) Chary a 50 ml flask, under nitrogen, with 3.98 9 15 (0.00631 M) compound I, in 10 ml methanol, cool to 0C.
Rand add a solution of 2.16 9 (0.0631 M) Hg(N03J~.H20 and 0.545 9 ~0.0069 My pardon in methanol. Stir for 3 hours at room temperature and remove methanol under reduced pressure Dissolve the residue in ethylene chloride and wash the organic solution twice with water, then with brine. Dry the organic solution over an hydrous . .

2~3~

sodium sulfate, filter and remove the ethylene under reduced pressure to give the compound II.

E) Preparation of Silver_ (3S,4R,5R)-3-(1-trimethyl-silyloxyethyl)-l~allyloxycarbonyl-l-trimethylsilyll-ethoxycarbonyl-methyl azetidin-2 one-4-thiolate Dissolve the entire amount of silver (3S,4R,5R3-3~ hydroxyethyl)-1-allyloxycarbonyl-1-tri-methylsilylethoxycarbonyl~methyl-azetiain-2-one-4--thiolate obtained from step (D) above in 10 ml of 10 an hydrous ethylene chloride Add 0.783 ml (0.00316 moles ) of bis-trimethylsilyl acetamide to the system.
Stir the system at room temperature for I minutes to yield the title compound.

E') Repeat the procedure rep E but replacing the silver salt by the thallium copper and mercury asset-dyne salts obtained in steps D' and D" to obtain respectively thallium (3S,4R,5R)-3-~1-trimethylsilyl-ox~ethyli-~-allyloxycarbonyl-l-trimethyls;lylethoxmy-carbonyl-methyl-azetidin-2-one-4-thiolate, copper (3S,4R,SR)-3-(1-trimethylsilyloxye$hyl)-1-allyl-oxycarbonyl-l-trimethylsilylethoxycarbonyl-methyl--azetidin-2-one-4 thiolate and mercury (35,4R,5R)-3-(1-trimethylsilyloxyethyl)-1-allyloxycarbonyl-l-trimethylsilylethoxycar~onyl-meethyl-azetidin-2-one-4-thiolate.

%~3~7 F) PreParatlon_of (5R!6S,8R)-2-thione-3-allyloxy-carbonyl-3-trimethylsilylethoxycarbonyl-6-11-trimeethyl-Slav After the completion of step (E) and to the same solution, add 619 my (0.00316 moles of 90%
thiocarbonyl-diimidazole to the system. Stir the system at room temperature for I hours and then filter the solution. Remove the ethylene chloride by stripping. Chromatography the crude product on silica gel eluding with 30% cyclohexan-: / ethylene chloride changing to ethylene chloride to afford 704 my of the title compound , F') Repeat step F but using the reaction solutions obtained in step E', to afford the title compound.

NOR: = 6.2-5.6, m, lo; 5~65, d ~J=1.5 Hal lo; 5.5-5.1, (m), OH; 4.7, d IJ=5.5HZ), OH; 4.5-401, m, OH; 3.62, dud (J=1.5, ', 4Hz), lo; 1.28, d (J=6Hz), OH; 1.2-0.85, m, OH; 0.2-0, m, 18H.

G) Preparation of (5R,6S,8R)-2- thione-3-allyloxy-carbonyl-3-tri~e~hylsllylethoxycarbonyl-6~(1-hydrooxyethyl) penal To a 25ml flask add loom of (5R,6S,8R)-2-thione -3-allyloxycarbonyl-3 trimethylsilylethoxy-carbonyl-6 (1-trimethylsilyloxyethyl~penam, lml of tetrahydrof~ran 0.05ml of water and 0.05ml of acetic acid. Stir the system at room temperature for 12 hours. Add ethyl acetate to the solution and wash the organic phase with sodium b carbonate JO solution, water and then brine. wry the organic phase over an hydrous sodium sulfate, filler and remove the solvent by stropping give the title compound.

NOR; = 6.15-5.6, m, lo; 5.69, d(J-2Hz), I 5.55-5.12, m, OH; 4.8-4.6, M, OH;
4.5-4.0, m, 3 H; 3.67, d, d(J=2, 7Hz~
lo; 2.8-2.3, m, lo; 1.37, d(J=6.Hz), OH; 1.2-0.8, m, OH; 0.3-0, m, OH.

- H) Preparation of (5R,6S,8R)Allyl-2-thiol-6~(1-hydroxy-ethyl)penem~3-carboxylate To 7.7mg of (5R,6S,8R)-2-thione-3-allyl-oxycar-bonyl-3-trimethylsilylethoxycarbonyl-6-(1-hydroxyeethyl) penal in lml of tetrahydrof~ran slowly add at room tempo-nature 2 equivalents of tetrabutylammoni~m-fluoride in 40ml of tetrahydrofuran~ Thin layer chromatography silica gel, 10% ethylacetate/methylene chloride shows the immediate presence of the decarboxyl axed compound (5R,6S,8R)allyl-2-thiol-6-(1-hydroxyethyl)penem-3--kirks late, which exists in equilibrium with (5R,6S,8R)-allyl-2-thione-6-(1-hydroxyethyl)penam-3-carboxylate.

_ ___ ._.... _._ ., .._ ... ., .., ...., ,.., ..., __..., .. .. ,._....._..........................................................
............ . ._ , , .......... ............ . _ Lo NOR- - d 5.85, d (J=lHz), lo; 5.8, m, lo; 5, lo; 5.4-5.1, m, OH; 4.7, OH; 4.25, M, let; 3.65, d, d Jo Liz), lo; 2.1, lo; 1.35, d (J=7Hz) OH.

5 I) Preparation of Allyl-(5R,5S,8R)-2-eth~lthio-6 (l-hydroxyethyl)penem-3-carboxylate To the solution of a (5R,6S,8R) allyl-2-thiol-6-(l-h~vxyethyl~penem-3-carboxylate (5R,6S,8R) : allyl-2-thione-;-6-tl-h~xyethyl)pen Charlotte ~librium mixture produced in step (~) above add 0.016ml of ethyl i ye and 16mg so-dim bicarbonate in 0.5ml water. Stir the system at room temperature for 15 minutes then add 25ml of ethyl acetate.
Wash the organic solution with water, dry the organic phase with an hydrous sodium sulfate, filter and remove the sol-vent by stripping to yield the title compounder PREPARATION H

Preparation of Allyl-(~R,6S,8R)-2-thiol-5~ hydroxy-ethyl) nem-3-carboxylate and Ally (5R,6S,8R)-2-~hione 6-(1-hydroxyeth~l)penam-3-carboxylate A) Preparation of (3~,4R,5R)-l-allyloxycarbony'lmethyl)-3-(l-hydroxyethyl)-4~(t'riphenYlmet~ylt~-io)azetidinn-2-one Add 3gm of (3S,4R,5R)-3-(1-hydroxyethyl)-4-(tri-phenylmethylthio)azetidin-2-one to loll of acetonitrile containing 0.286gm of sesame carbonate. Add 0.2gm of Audi ally acetate to the system. Stir the system at room tempo-writer for 16 hollers. Dilute with ether (50ml), filter and wash the ether layer with 1% aqueous phosphoric acid, lot-lowed by water. After drying over sodium sulfate remove solvent to give a foamy solid.

3~7 - 49 _ NOR: = 8.4, lo, s; 7.65, lo, d(J=lHz);

7.05, lo d(J=lHz); 5.95, lo, d (J=2Hz); 5.87 I m; 5.45 5.1, OH, m; 4.3, lo, m; 4.1, OH, Q(J=16Hz);
3.5, d d(J=2,6); 1.35; OH, d(J=6Hæ).

B) Preparation of Silver (35,4R,5R)-3~ ydroxyethyl)-l-allyl~xycarbonylmethyl-azetidln-2-~ne~4-thio-late To a 50ml flask having a nitrogen atmosphere add loll of methanol and 460mg OX (3S,4R,5R)-l-(allyloxycar-Bunnell hydroxyethyl)-4-ltriphenylmethylthlo)azetidin 2-one. To this system add 160mg silver nitrate and 0.15ml of pardon. Stir the system at 20C for 1 hour. Stop the reaction and remove the methanol by stripping to give the title ccmpo~nd~

B') Repeat the procedure of step B but replacing the silver nitrate with an equivalent quantity of -1) phallic nitrate, 2) cupric nitrate and 3) HgtN03)2.H20 to obtain respectively thallium (3S,4R,5R)-3-(1-hydroxy-ethyl)-l-allyloxycarbonylmethyl-azetidin-2-one-4-tthiolate~

copper (3S,4R,5R)-3-(1-hydroxyethyl)-1-allyloxycarbonyl-methyl-azetidin-2-one-4-thiolate, and mercury (3S,4R,5R)-3-(1-hydroxyethyl)-1-allyloxycarbonyl-methyl-azetidin-2-one-4-thiolate.

I

C) Pro aeration of Silver (3S,4R,5R)-3 ~l-trime~h lsil lox -_ _ P _ _ _ _ ._ Y Y . Y
ethyl)-l-allyloxycaxbonylmeth~l-azetidin-2-one-4-tthiolate Add the entire amount of silver (3S,4R,5R)-3-(l-hydroxyethyl)~l-allyloxycarbonyl-methylazetidinn-2-one-4-thiolate produced in step (B) above to 25ml of Mullen chloride. To this system add l.lml of bis-silylacet-aside. Stir the system at room temperature for 15 mutes to give the title compound.

C') Repeat the procedure of step C but replacing the silver salt with the respective thallium, copper and mercury salts obtained in step B' to afford respectively thallium (3S,4R,5R)-3-(1-trimethylsilyloxyethyl)-1-allyloxycarbonylmethyl-azetidin-2-one-4-thiolate9 copper (3S,4R,5R)-3-(1-trimethylsilyloxyethyl)-1-allyl-to oxycarbonylmethyl-azetidin-2-one-4-thiolate~ and mercury(3S,4R,5R)-3-6~-trimet.hylsilyloxyethyl~-1-allyl-..
oxycarbonylmethyl-azetidin-2-one-4-thiolate.

.
D) Preparation of (3S,4R,5R)-l-(allYloxycarbonylm'e'thyl) _ -tl-'trimethylsilyloxymethyl)-4~ it zolylthiocarbonyl-thio)azetidin-2-one After completion of step (C) above and to the same solution add 350mg of thiocarbonyldiimidazole. Stir the soys-them at room temperature for 3 hours. Filter the sol1ltion and wash the precipitate with ethylene chloride. Collect the filtrate and remove the ethylene chloride by strip-ping. Chromatography the residue on silica gel eating with 20g ethyl acetate/methylene chloride to yield 335mg of the title compound.

L3~7 _ 51 -D') Repeat the procedure of step D but using the respective thallium, copper and mercury salts pro-duped in step C' to afford in each case the title compound.

E) Preparation of '(5~,6S,8R) allyl-'2-thiol-6~ 'trime'thy~-silyloxymethyl)~nem-3-carboxylate and (5R,6S,8R) allele-2-thione-6-(l~rim~lsilyloxymethyl)pQl~m equilibrium Myra Add 170mg of (3S,4R,5R~-l-(allyloxycarbonylmethyl) I trimethylsilyloxymethyl) I imidazolyl-thiocarbo-nylthio)azetidin-2~one to 40ml of an hydrous tetrahydrof~ran under a nitrogen atmosphere. Cool the system to -78 C. and then add 0.6ml of 1 M lithium di-(trimethylsilyl) amine in hexane drops to the system. Stir the system at -78 C.
for 5 mounts. Add 0.2ml of acetic acid to the system.
Dilute the system to 200m~ with ethylene chloride. Wash the organic solution with water, aqueous sodium bicarbonate so-lotion and again with water Purify the product by chrome-tography by rapidly elating the sample through silica gel with 5% ethyl acetate/methylene chloride to afford 125mg of the desired products and the desilylated products.

F) Preparation of (5R,6S,8R) Allyl-2-thiol'-6-'(1-hydroxy-ethyl)penem-3 carboxylate and (5R,6S,8R) Allyl-2-~hione_ 6-~1-hydroxyethyl)~enam equilibrium mixture To a 25ml flask add the entire mixture produced in step (E) along with 5ml of tetrahydrof~ran, lml of we-ton and lml of acetic acid. Stir the system at room them-portray for 2 hours. Add ethyl acetate to the solution and wash the organic phase with sodium bicarbonate solution, we-ton and then brine. Dry the organic phase over anhydro~s sodium sulfate,' filter and remove the solvent by stripping to give the title compound.

Lo Thereafter the product of step F can be treated, if desired the ~rcceduxe descry Lo step I of the Example 7 to yield ally (5R,6S,8R)-2~ethylthio-6~ hydroxyethyl)penem 3 car-boxy late.

(5R,6S,8R)-6~ Hydroxyethyl)-2-(2-glycylaminoethylthio)-penem-3-carboxylic acid A. Allyl-(5R,6S,8R)-6-(1-hydroxyethyl)-2-(2-N-[allyloxycarbonylglycylamino]ethylthio)-penem-3-carboxylate Stir a solution of the product of Reparation 3 (0.50 9) and the product of preparation E (0.58 9) at 0-5C in dichloromethane and add thereto diisopropylethylamine (0.2 9). After 5 muons wash the solution with 10%
aqueous tartaric acid, dry and evaporate and purify the residue by preparative TLC (eluding with EtOAc; product Of 0.4) to obtain the title compound as a pale yellow foam.

. .. . .. _ .. . . _ _ . .. ...... .. . . . . __ _ _ ~%~

PER (CdC13): 1.35 (d, Jo Liz, OH), 3.16 (m, OH), 3 4-4.0 (m, OH), 4.24 (m, lo), 4.60 (d, J=7.5 Ho, OH), 4.63 (m, OH), 5.2-5.6 (m, OH), 5.75 (d, J=1.5 Ho, lo), 5.7-6.2 (m, OH) and 7.20 (bra t, Jo Ho).

B.
Stir a mixture of the product of preparation C (0.225 g), 2-ethylhexanoic acid (0.20 g) and triphenylphosphine (0.05 g) at 30-35C. in C~2C12 (20 ml) under nitrogen and add thereto tetrakis(triphenylphosphine)palladium (0.03 g). After 1.5 hour, collect the precipitate by centrifugation after adding ether (15 ml), wash with 3 x 10 ml of 4:1 ether:CH2C12 and dry under nitrogen to give the title compound as a cream powder.

IT (Nujol*)~ 3400, 1770, 1650 and 1590 cm * Trademark t!
Jo 35i~7 EXAMPLE

A.

Jo / squeak or 1 owe H C02--~V~, To a solution of 0.20 g of an equilibrium mixture of allele ~5R,55,8R~-6-(~-hydroxyethyll-2-thione-penam-3-carboxylate and Allah (~R,65,8R)-6-(1-hydr~xy-ethyl)-2-thiol-penem-3-carboxylate and diisopropyl-ethyl amine (0.15 9) in dry acetonitrile (4 ml ) add 1-idea, 2-(N-a~1yloxycarbonylglycylamino)-e~hane ~0.23 9).
-After 1 hour at room temperature dilute with aqueous tartaric acid and dry over magnesium sulfate. Evaporate end isolate the Russ from ~ichloromethane to give ally (SR,6S,8R)~6-(1-hydroxyethyl)-2-( 2[N-allyloxy-- carbonylglycylamino3ethylthio)-penem-3-carboxylatee, as a pale yellow foam.

8. Treat the product from step A by following exactly the procedure described in Example 1 , step B, to obtain (5R,6S,8R)-6-(1-hydroxyethyl)-2-(glycylamino-ethylthio)-penem-3-carboxyl;c acid.

(5R,6S,8R) 6-(l^Hydroxyethyl)~2-[2-glycylamino)ethylthio]
-penem-3-carboxylic acid A. (3S~4R,5R)-3-(1-trichloroethoxycarbonyloxy _ _ .
ethyl 1 ~2-allyloxyca bonylglycylamino-ethylthio)carbonothioylthio]-azetidin-2-one To a solution of ethanol (50 ml) containing l-N sodium hydroxide (20 ml) and 2-(N-allyloxycarbonyl^
glycylamino)-ethane they'll (5.0 I add carbon dis~lfide ill (4 ml) drops. Stir for 10 minutes, thin add drop-wise to a solution of (3594R,5R)-[1-~2-methoxy-1,2-dio-xoethyl)-3-(1-trichloroethoxycarbonyloxyethyl)-4-chloroazetidin-2-one (4.1 9) in ethanol. Stir the reaction mixture until TLC analysis indicates no starting material is present layout 4 hours) then dilute with ethyl acetate, wash the solution with saturated sodium chloride dry the solution over magnesium sulfate, evaporate, and chromatography the resulting residue on silica gel (40 9) elutlng with 30h ether-hexane. Combine the like equates as determined by the TLC and evaporate to a residue -which is the title compound of this step.

B. Allyl-(5R,6S,8R)-6-(1-trichloroethoxycarbonyl-.
oxyethyl)-2~ N-allyloxycarbonylglycylamino)-ethylthio]-penem-3-carboxylic acid ~25 To a solution of (3S,4R,5R)-3-~trichloro-,ethoxycarbonyl-4-L2-(N-allyloxycarbonylglycylaminoo)-ethytthio]carbonothioylthio]-azetidin-2-one (0.85 go in ethylene chloride (6 ml) cooled to about 10C, add, with st~rr;ngr calcium carbonate (0.6 93 followed by allyloxa-lylchloride (0.263 9, I en.) in ethylene chloride (1 ml), over 5 minutes while maintaining the temperature ~22~3~7 in the range 10-15~C. After TLC indicates starting compound is no longer present, transfer the mixture to a separating funnel using ethanol-free chloroform. Wash twice with ice/water, filter to remove excess calcium carbonate, dry over an hydrous sodium sulfate, and trays for to a 100 ml 3-neck flask. Adjust the volume of thy solution to about 50 ml with chloroform and heat at reflex temperature while adding a solution of triethyl-phosphate (0.6 ml, 2 en.) in chloroform t20 ml3 over 3 10 hours. Reflex the mixture for an additional 18 hours, evaporate and chromatography on 14 9 silica gel, eluding with 25% ether-hexane, and evaporate the combined like equates to obtain a residue comprising the title compound.
Purify by crystallization from ether-hexane to obtain the title compound.

C. Ally -(5R,6S,8R)-6-(1-hydroxyethyl)-2-[(2-N-_ allyloxyglycylamino)ethylthio3-penem-3-carboxylic acid Dissolve out 1.8 g ox the product obtained 20 from step B, in 15 ml tetrahydrofuran, 1.5 ml of water and 1.5 ml acetic acid at 0-5C with stirring.

Add 2.0 9 of zinc dust and stir until thin layer chromatography indicates only a trace of starting material. Filter the reaction mixture wash solids with ethyl acetate, combine the organic solvents and wash successively with 10% aqueous tartaric acid, water and with aqueous sodium bicarbonate solution. Dry the solvent phase over magnesium sulfate and concentrate to a residue. Isolate the residue from ether-hexane to obtain the title compound.

3~;7 D. Treat 0.225 9 of the compound obtained from step C by the procedure described in Example 17, step B, to obtain the title compound of this Example as a cream powder.

Sodium-(5R,6S,8R)-6-(1-hydroxyethyl)-2-(2-methylcaarbamoyl-ethylthio)-penem-3-carboxylate A. Allyl-~SR,6S,8R)-6-~1-hydroxyethyl)-2-(2-methylcarbamoylethylthio)-penem-3-carboxylate I Stir a solution of the penes ally ester sulfoxide (2.55 9) prepared in Preparation D in SCHICK ~40 ml) with 3-mercapto-N-methylpropionamide (1.92 g) and cool to -10C. Add diisopropylethylamine (0.6 ml) and continue stirring at -10C. for 0.5 hour. Add ether ~50 ml) and collect the precipitate and wash with ether. Stir the resulting solid with SCHICK (20 ml) for 0.5 hour at 0C., collect and dry to give the title compound as a white -powder. mop. 176-178C.
IR(nujol suspension): Max 3400, 3300, 1775~16q5?
1635, 1560 and 1510 cm 1.

! B. Sodi~-(5R,65~8R)-6-(1-hydr_xyethyl)-2-(2-[methylcarbamoyl]-ethylthio)-penem-3-carboxy-late -Stir a suspension/solution of the compound obtained in pa preparation A (0.66 I in dry THY (50 ml) containing sodium 2-ethyl-hexanoate (0.30 5 9 ) and triphenylphosphine (0.12 9) at 25C. under No and add Pod (PPh3)4 (0.08 9).
After 1.5 hour, add hexane (50 ml) and collect the crude L35~

product by centrifuge, wash with 2 x 20 ml ethyl acetate and partition with H20 (50 ml) - ethyl acetate (50 ml).
Treat the aqueous phase with No to remove dissolved organic then filter through 5 9 of reverse phase C-18 silica gel, washing with H20. Treat the filtrate with 5 9 of DEREK active carbon, stir 0.5 hour filter, wash with H20 and loopholes to give the title compound as a buff powder.
PER ~D20): 1.30 (d, Jo Ho; OH), 2.63 (m, OH), 2.72 (s, OH 3,14 (m, OH), 3.91 (dud, J=1.5 and 8 Ho, lo), 4.25 (pentet, Jo Ho, lo) and 5.69 (d, J=1.5 Ho, lo).

. . .
Sodium-(5R,65,8R)-6~ hydroxyethyl)-2-(2-methylcarba-. .
I moylethylthio) penem-3-carboxylate A. (3S,4R,5R)-3-(1-trichloroethoxycarbonyloxy-ethyl)-4-~(2-methylcarbamoylethy-lthio) carbonothioylthio]-azetidin-2-one .
To a solution of ethanol (50 ml) containing l-N sodium hydroxide (20 ml) and 3-mercapto-N-methyl-propionamide (2.6 g) add carbon disulfide (4 ml) drops. Stir for 10 minutes, then add drops to a solution of (3S,4R, 5~)-[1-(2-methoxy-192-dioxoethyl)-3-(l-trichloroe~foxy-carbonyloxyethy1)-4-chloroazetidin-2-one (4.1 9) in ethanol. Stir the reaction mixture until TLC analysis indicates no starting material is present (about 4 hours) then dilute with ethyl acetate, wash the solution with saturated sodium chloride, dry the solution over manges-I'm sulfate, evaporate the solvent and chromatography the resulting residue on silica gel (40 9) eluding with I
-- 59 _ 30~ ether-hexane. Combine like fractions as determined by TLC and evaporate to obtain the title compound of this step.

B. Allyl-(5R,6S,8R)-6-(l-trichloroethoxycarbonyl-oxyethyl)-2-(2-methylcarbamoylethylthio)-penem-3-carboxylate To a solution of the azetidinone obtained in step A
lo g) in ethylene chloride (6 ml) cooled to about 10C, add, with stirring, calcium carbonate (0.6 9) followed lo by allyloxalylchloride (0.263 9, 1.2 en.) in ethylene chloride (l ml), over 5 minutes, while maintaining the temperature in the range 10 to 15~. After TLC India gates starting compound is no longer present transfer the mixture to a separating funnel using ethanol-free chloroform. Wash twice with ice/water, filter to remove excess calcium carbonate, dry over an hydrous sodium sulfate, and transfer to a lo ml 3-neck flask.

Adjust the volume of the solution to about 50 ml with chloroform and heat at reflex temperature while adding a solution of triethylphosphite (0.6 ml 9 2 en.) in sheller-form (20 ml) over 3 hours. Reflex the mixture for an additional 18 hours, evaporate and chromatography on 14 9 silica gel, eluding with 25% ether-hexane and evaporate the combined like equates to obtain a residue comprising the title compound. Purify by crossly-station from ethylene chloride to give the title compound.

~2~L35~
_ 60 -C. Allyl-(5R,6S,8R)-6~ hydroxyethyl)-2-(2-methyl-carbamoylethylthio)-2-penem-3-carboxylate .. ..... .
Dissolve about 1.6 g of the product prepared according to the process of step B, in 15 ml of twitter-hydrofuran, 1.5 ml of water and 1.5 ml of acetic acid await 5C. with stirring. Add 2.0 9 of zinc dust and stir until thin layer chromatography indicates only a trace of starting material. Filter the reaction mixture, wash solids with ethyl acetate combine the organic solvents and wash successively with 10% aqueous tartaric acid, water and with aqueous sodium bicarbonate solution. Dry the solvent phase over magnesium sulfate and concentrate to a residue. Crystallize the residue from ether-hexane.

D. Sodium-(5R,6S,8R)-6~ hydroxyethyl-2-(2-~methylcarbamoyl~-ethylthio)-penem-3-carboxy-late.

.... .
Treat 0.~6 of the compound obtained in prepardtionO
by the procedure described in Example 4 , step B to -- obtain the title compound as a buff powder.

L35~7 Example 6 Allyl-(5R,&S,8R)-6-(1-hydroxyethyl)-2-[2-methylcarbra-moyl)ethylthio -penem-3-carboxylate I' COY/ Owlish To a solution of 0.20 9 of an equilibrium mixture of ally (5R,6S,8R)-6~ hydroxyethyl)-2-th;one-penem-3-earboxylate and ally ~5R,6Ss8R)-6-(1-hydroxyethyl)-2-thiol-penem-3-carboxylate, and diisopropylethylamine (0.15 9) in dry acetonitri1e (4 ml) add N-methyl-3-iodopropionamide (0.2 9).
fur 1 hour at 25'C., dilute with ethyl acetate (25 ml), wash with aqueous tartaric acid and dry (McCoy). Evaporate -- and crystallize the residue from dichloromethane to give the title compound, I

The (5R,6R,8S) isomers corresponding to the (5R96S,8R) compounds obtained in the above Examples can be obtained by following similar procedures to those described in the Examples but using appropriate stereo specific start-in material namely (3R,4R,5S)-3 (l-trichlorocarboxy-loxyethyl)-4-(triphenylmethyl t h i o ) - azetidin-2-one.

The (5R,6S,8R)-allyl-2-substituted thio-6-~1-hydroxy-ethyl)-penem-3-carboxylates may readily be converted to their corresponding alkali metal salts by the prove-dune described in our European Patent Application Publication No. 0013663. In this procedure the ally group can be removed by utilizing a suitable aprotic solvent such as tetrahydrofuran, deathly ether or ethylene chloride, with potassium or sodium 2-ethylhexanoate and a mixture of a palladium compound and triphenyl pros-phony as the catalyst to afford the corresponding penemsodium or potassium salt directly.
. . .

gL:22~L35~
- 63 _ A study of on vitro activity of the novel penes of this invention against gram Eve and - gram Eve bacteria, is given in the Table below. The study was carried out by microlitre using Mutter Hilton Ajar. The number of organisms of each group is indicated in brackets in the left-hand column. The figures given are the geometric mean Miss based on, the various values obtained for the individual strains of each group.

Compound 1. (5R,6S,8R) 6-(1-hydroxyethyl~-2-[2-(amino-acetylamino)-ethylthio]-penem-3-carboxylic acid.

2. (5R,6S,8R)-6-(1-hydroxyethyl)-2-~2-.(N-methyl-carbamoyl)ethylthio]-penem-3-carboxylic acid.

_ 64 --. _ . ... _ .. _ GEOMETRIC MEAN Miss mcg/ml 24 Hours ._. _ Gram Eve B Subtilis (1) Sarcina lute (1) Staphvl COCCUS l18~ 0.47 0.41 ~~Çp~5mysç I
total 22 strains _ Gram -Ye E. Coil ~11) Enterobacter I
..
Klebsiella (10) .
Morgan Ella/
Providencici (6) 2.1 1.0 Salmonella (3) Syria (4) total 37 strains . . _ _ _ - I -The compounds listed above, whether as free acid, salt or metabolisable ester exhibit low protein binding, good stability in human serum, and their metabolizes have little or no unpleasant odor.

FORMULATIONS

In the following Examples the term "drug" indicates _ . . ., .. ..... , ., .. _ . . ............................. ..
(5R,65,8R)-6-(1-hydroxyethyl)-2-(2-glycylaminoethyylthio)-penem-3-carboxylic acid, or (5R,6S,8R)-2-~N-methylcarbamoylethylth;o)-6-(1-hydproxy-ethyl)-penem-3-carboxylic acid, or a pharmaceutically-effectiYe equivalent amount ox any of their pharmaceutically acceptable salts, especially sodium or potassium salts 01 metabolisable esters.

I
- 66 _ Capsules No. Ingredient mg/capsule mg/capsule 1. Active ingredient 250 500 I Lactose US 100 50 3. Corn Starch, Food Grade 50 43.5 4. Microcrystalline Cellulose NO 95 50 5. Magnesium Stewart NO 5 6.5 Total 500 550 Method of Manufacture Mix Items nos. 1, 2, 3 and 4 in a suitable mixer for 10 -15 minutes. Add Item No. 5 and mix for 1 - 3 minutes.
Fill the mixture into suitable two-piece hard gelatin capsules using an encapsulating machine.

Tablet Formulation - Item No. Ingredient mg/tablet mg/tablet 1. Drug 250 500 2. Lactose, US 106 112 3. Corn Starch, Food Guide as 10% paste in water 20 40 I Corn Starch, Food Guide 20 40 5. Magnesium Stewart 4 8 400 my ~00 my ~2;~35~

.

Method of Manufacture .
Mix Items Nos. 1 and 2 in a suitable mixer for 10 - 15 minutes. Granulate the mixture with item No. 3. Pass the wet granulation through a coarse screen (1/4"). Dry the wet granules for 8 - 12 hours at 40-50~C. Using a suitable mill, pass the dried granules through a medium screen (No 12 to No. 16). Add Item No. 4 and mix for 10 - 15 minutes. Add Item No. 5 and mix further for 1-3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.

10 Injectable Suspension Formulation mg/ml Sterile drug 250.0 Bouncily Alcohol 9.0 Methylparaben 1.8 Propylparaben 0.2 15 Sodium Carboxymethylcellulose 5.0 Polyethylene Glycol 4000 10.0 Povidone 5.0 Sodium Citrate 15.0 Disodium Edetate 0.1 20 Water for injection q.5.
To make 1.0 ml Method of Manufacture -Dissolve parabens in a portion of the water for injection by heating it to 65-70~C. Cool to 25-35C~ Charge 25. and dissolve bouncily alcohol, sodium citrate, disodium edetate, PEG 4000, povidone and sodium carboxymethyl-cellulose. Filter the solution and sterilize by auto-cloven. Make a slurry of the sterile active and pass it through a killed mill. Mix it well with solution from Step 3 and pass it through the mill. Bring the suspension to the final volume/weight and fill into sterile containers.

Claims (7)

The embodiments of the invention in which an exclusive property or privilege are claimed are defined as follows:

1. A process for the preparation of compounds of the formula I

I

wherein R is N-methylcarbamoylethyl or glycylamino-ethyl, G is hydroxyloweralkyl, X is hydrogen, a pharmaceutically acceptable salt forming group, a pharmaceutically acceptable ester group or a carboxy protecting group, characterized in that (a) a tautomeric compound of formula [(Va), (Vb)]

wherein R2 is a protected carboxy group, is subjected to an alkylation reaction introducing the group R;

(b) reacting a compound of formula VII

VII

in which R' is an organic group different from the desired group R with a thiol of formula VIII' or reactive derivate thereof VIII' in which R is as defined above;

(c) for the production of a compound of formula I in which R is as defined above, reacting a compound of formula IX

IX

with a trivalent organophosphorous compound, wherein in the processes (a) to (c) above, any functional groups in the reactants may be protected by protecting groups followed if necessary or desired by removal of any protecting groups and isolation of a free acid, a pharmaceutically acceptable salt or pharmaceutically acceptable ester.

2. A process according to claim 1(a) characterized in that R2 is the group wherein R'1 is trimethylsilyl or t-butyldiphenylsilyl, or R2 is allyloxycarbonyl.

3. A process according to claim 1(a) characteri-zed in that R2 is allyloxycarbonyl.

4. A process according to claim 1(a) characteri-zed in that the tautomer is transformed into a compound of formula I by:
(i) reaction with a compound of formula RZ

in which R is as defined in claim 1 and Z is a leaving group;
(ii) olefin addition using an olefin of the formula CH2=CHR wherein R is as previously defined.

5. A process according to claims 1, 2 or 3, characterized in that in the starting materials G is 1-hydroxyethyl or protected 1-hydroxyethyl and the compounds of formula (Va), (Vb), or VII have the stereo configuration (5R,6S,8R) or(5R,6R,8S) or the compound of formula IX has the stereo configuration (4R,3S,5R) or (4R,3R,5S) and that in the compound of formula I produced G is 1-hydroxyethyl and the stereo configuration is (5R,6S,8R) or (5R,6R,8S).

6. A process according to claim 4 characterized in that in the starting materials G is 1-hydroxyethyl or protected 1-hydroxyethyl and the compound of formulae (Va) and (Vb) has the stereo configuration (5R,6S,8R) or (5R,6R,8S) and that in the compound of formula I
produced G is 1-hydroxyethyl and the stereo configura-tion (5R,6S,8R) or (5R,6R,8S).

7. A process according to claim 1 characterized in that in the starting materials G is 1-hydroxyethyl or protected 1-hydroxyethyl and the compounds of formulae (Va), (Vb) or VII have the stereo confiruga-tion (5R,6S,8R) or the compound of formula IX has the stereo configuration (4R,3S,5R) and that the compound of formula I produced is (5R,6S,8R)-2-[N-methylcarbamoyl-ethylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid, or (5R,6S,8R)-2-[2-(aminoacetylamino)ethylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid, or a sodium or potassium salt thereof or a pivaloyloxymethyl or phthalidyl ester thereof.