FI80702B - Process for the preparation of antibactrial thio-penem-3- carboxylic acids - Google Patents

Description

1 80702

The present invention relates to a process for the preparation of an anti-bacterial thio-penem-3-carboxylic acid and to an anti-bacterial thio-penem-3-carboxylic acid.

° H H H

H "" c '4-Vs N— SR

= <r_x r N \ coox o where R is -CH2-R11 where R11 is 2-amino-4-thiazolyl, 1-methyl-2-imidazolyl, aminoacetylaminomethyl, N-methylcarbamoylmethyl, dihydroxy lower alkyl,

-C = NH

NR15R16 where

R 15 and R 16 are independently hydrogen or lower alkyl, X is hydrogen, a pharmaceutically acceptable salt-forming group or a carboxy protecting group.

Penems, a recent addition to the genus of synthetic β-lactams, have potent anti-bacterial activity. To date, they have been prepared in laboratories, using time-consuming, multi-step methods with low yields and are thus uneconomical.

2 80702

Penem compounds are known in principle. For example, DE 31 09 086 and US 4,260,618 describe a large number of penem compounds, which, however, have only been shown to have acceptable antibacterial properties. In contrast, the compounds of the invention, which form a well-defined group of penem compounds, have highly advantageous and effective antibacterial properties, as will be apparent from the description below.

The process of the invention is characterized in that (a) a tautomeric compound [(Va), Vb)], wherein R is hydrogen (i.e. a compound of formula Va is in equilibrium with its tautomer)

With Vb)

10H s SH, ° H S S

r Y = 'LW_V

- N-L * R 2 / - N-kR, O O 2 (Va) (Vb) wherein R 2 is a protected carboxy group is subjected to a reaction in which a group R is attached: (i) by reaction of formula

RZ

wherein R is an organic radical as defined above and Z is a leaving group; (ii) (for the preparation of a compound of formula I wherein R is a C 2 -C 6 alkyl group having a hydroxy group attached to another 3 80702 carbon atoms from sulfur and optionally containing one or more other substituents), by reaction-substituted or unsubstituted 1,2-epoxy -C2-Ce with an alkane, (b) a compound of formula VII

O

OH *

I S T

^ -f V- s-R '(VII)

or N 2 COOH

wherein R 'is an organic group other than the desired group R, is reacted with a thiol of formula VIII' or a reactive derivative thereof R - SH (VIII ') wherein R is as defined above; (c) a compound of formula IX

OH

A_ I '% <ix> J-Vc / R2 is reacted with a trivalent organophosphorus compound, in any of the above methods (a) to (c), any functional groups of the reactants may be protected by 4 80702 protecting groups which are removed at any suitable stage in the process , and the compound of formula I thus obtained, if desired, deprotecting the protected carboxyl group R2 (if present) and isolating it as the free acid or a pharmaceutically acceptable ester.

To carry out process (a), a compound of formula (Va) or (Vb) according to process alternatives (a) (i) or (a) (ii) is prepared as follows: (a) (i) a compound of formula II .S Met G - - {

/ V

wherein R 1 and R 2 are protected carboxy groups which may be the same or different and the Met thiophilic metal atom is reacted with a compound of formula III S = C (-Y) 2 (III) wherein Y is a leaving group to give a compound of formula IV compound

/ S

r — 1-r \ IV

) N r ”1 5 80702 followed by removal of the protected carboxy group R1 to give a tautomeric compound where R is hydrogen (i.e. the compound of formula Va is in equilibrium with its tautomer Vb) c, _ / {, - *" - ^ 2 j ”" R 2 (Va) (Vh) wherein R 2 is as defined above, and that, if desired, such tautomeric compound is converted to a compound of formula I wherein R is an organic radical by the addition of such R by conventional methods; (a) (ii) a compound of formula VI

S

B

^ _j, - S - C-Y VI

J-XCH 2 -R 2 wherein R 2 and Y are as defined above are cyclized intramolecularly to give a tautomeric compound [(Va, (Vb)] as defined above in method (a) followed, if desired, by conversion to a compound of formula I. , wherein R is an organic radical as in process (a) above.

6 80702

As a method used in process (a) to convert a tautomeric compound of formula [(Va), (Vb)] to another compound of formula I, it is preferable to use one of the following: (i) by reacting the compound

R - Z

with wherein R is an organic group as defined in methods (a), (b) and (c) and Z is a leaving group. Typical leaving groups Z include halides, e.g. chlorine, bromine and iodine, hydroxyl and trichloromethylsulfonyl; (ii) reacting with a substituted or unsubstituted 1,2-epoxy C2-C6 alkane to give a compound of formula I wherein R is a C2-C6 alkyl group having a hydroxy group attached to another carbon atom based on the sulfur atom and optionally containing one or more other substituents.

Reactions of this type can thus be used, for example, in the preparation of compounds of the formula I in which R is e.g.

B

-CH2 - C - R13 I

OH

wherein R 1a is hydroxy-lower alkyl or carboxy-lower alkyl, wherein the carboxy group may be esterified or salted. Using a glycide, a compound of formula I wherein R is 2,3-dihydroxypropyl: glycidic acid and time metal glycidates can be obtained to give compounds of formula 7 80702 wherein R is 2-hydroxy-3-carboxylpropyl or an alkali metal salt of 2-hydroxy-3-carboxylpropyl in this order.

For convenience, the tautomeric compound [(Va, (Vb)] is simply referred to below as compound V.

The compounds of formula I are useful as antibiotics which are effective against gram-positive and gram-negative organisms such as Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.

For example, compounds of formula I have been shown in standard microbiological tests to be active against gram-positive organisms such as Staphylococcus epidermis and Bacillus subtilis and against gram-negative organisms such as E. coli and Salmonella at experimental concentrations of 0.1 to 2.0 pg. / ml. In addition, they show activity against β-lactamase-producing organisms, e.g. penicillamase and cephalosporinase, which shows resistance to these enzymes.

The dosage of the penems of this invention depends on the age and weight of the animal species to be treated, the mode of administration, the type of bacterial infection to be controlled or alleviated, and the severity. Typically, the dosage to be administered is between 1 and 250 mg / kg, preferably divided into doses of 5 to 10 mg / kg.

The novel penems of this invention may be administered either orally or parenterally. Preferably, the compounds are administered orally.

For oral administration, the antibacterial compounds of this invention may be formulated into tablets, capsules, β 80702 liquids, or the like. In addition, they can be mixed with animal food. They can also be applied topically in the form of hydrophobic and hydrophilic ointments, in the form of foam, or by means of mechanical pressure pipe systems, e.g. through the skin.

The compounds of formula I may also be used in the form of liquids such as solutions, suspensions and the like for use in the ears and eyes and may also be administered parenterally by intramuscular injection.

As used herein, the term "pharmaceutically acceptable salts" means alkali metal salts such as sodium and potassium salts; temporal earth metal salts such as calcium, magnesium and aluminum salts; amine salts formed from suitable organic amines, e.g. aliphatic cycloaliphatic, (cycloaliphatic) aliphatic or araliphatic primary, secondary or tertiary mono-, di- or polyamines, such as mono-, di- or polyamines, or heterocyclic hydroxyethylamine, di- (2-hydroxyethyl) amine, tri- (2-hydroxyethylamine), 4-aminobenzoic acid 2-diethylaminoethyl ester, 1-ethylpiperidine, bicyclohexylamine, N, N'-dibenzylethylenediamine, quinidine, pyridine, pyridine procaine, diioenzylamine, 1-efenamine and N-alkylpiperidine, The acid addition salts are preferably formed from mineral acids, for example hydrochloric acid, chlorobromoacetic acid, sulphonic acid, chloroiodic acid or organic acid, phosphoric or sulfuric acid, carboxylic acid or carboxylic acid, or are formed from -toluenesulfonic acid, maleic acid, acetic acid, citric acid , oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid.

, 80702

Suitable pharmaceutically acceptable ester groups are those known in the art of penicillin, cephalosporin and penem compounds which can be cleaved from the actual compounds within the body to form the corresponding acid.

Examples of such esters are indanyl, phthalidyl, methoxymethyl, glycyclooxymethyl, phenylglycyclooxymethyl, thienylglycyclooxymethyl, acetoxymethyl and pivaloyloxymethyl.

Suitable carboxyl protecting groups are those which can be removed under conventional conditions without reaction with other functional groups present in the β-lactam, for example allyl, cyano-lower alkyl, lower alkylsilyl-lower alkyl, sulfonic esters, p-nitrobenzyl and trichloroethyl. For example, a preferred protecting group on R2 is allyl; and in R 1 and R 2, in Compound II, preferred protecting groups are preferably lower alkylsilyl-lower alkyl and allyl, respectively.

Unless otherwise indicated, the term "lower alkyl" embraces branched and straight chain alkyl groups having 1 to 6, preferably 1 to 4, carbon atoms and includes, e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl and hexyl.

The term "removable hydroxy protecting group" means any group conventionally used for this purpose, with the sole requirement of compatibility with hydroxy substituents on penems and β-lactam intermediates and removability using elemental zinc or any other conventional agent used for this purpose that does not adversely affect the pen. -actam to the structure of intermediates. Preferred hydroxy protecting groups include trichloroethoxycarbonyl, dimethyltributylsilyl, trimethylsilyloxycarbonyl and trimethylsilyl.

In process (a) (i): the conversion of metal salt II to thion IV is carried out conventionally in a suitable solvent. Once the metal salt II is obtained according to Reaction Scheme 1, Step B, as described below, can be used immediately, e.g., without isolation from the reaction mixture in which it is formed. Thus, the same solvent as in the previous step can be used in this step. The temperature is usually between about 10 ° C and about 45 ° C, preferably about 25 ° C. The leaving group Y in thiocarbonyl in Reagent III is typically chlorine, bromine, iodine or imidazolyl. 1-1-Thiocarbonyldiimidazole is preferred as Reagent III because of its crystalline nature and ease of use.

Removal of one of the thio IV protected carboxy protecting groups at position 3 to give the tautomer [(Va), (Vb)] is carried out in a conventional manner in a suitable organic solvent such as tetrahydrofuran, ethyl ether or dioxane at a temperature between about 10 ° C and about 45 ° C. ° C, preferably at about 25 ° C. Removal is usually accomplished by adding an equivalent amount of fluoride ion so that only one protected carboxy group is removed.

In one embodiment of the method, R 2 is allyl oxycarbo-

0 O

I · Il,. ..

nyl, preferably -C-OCH 2 CH = CH 2 Da R 1 is -C-OCH 2 CH 2 R 1 wherein

R 1 * is a lower alkylsilyl group, especially trimethylsilyl, t-butyldiphenylsilyl or an equivalent functional group. In such cases, especially when R2 is

O

II

-C-OCH 2 CH = CH 2 and R 1 is trimethylsilylethoxycarbonyl, it is certain that it is R 1 which is removed by treatment with fluoride ion.

11 80702

Typically, tetrabutylammonium fluoride (TBAF) is used as the fluoride ion source, although any other suitable fluoride ion source can be similarly used to provide an equivalent amount of fluoride ion, e.g., c * F or KF.

For example, a stoichiometric excess of fluoride ion source may be used provided that it provides only an equivalent amount in the reaction mixture. This is especially true of TBAF. Moreover, because TBAF dissociates slowly in these solutions and when removal of the allyl protecting group (preferred meaning of R2) is much slower than removal of the trimethylsilyl-protected carboxy group (preferred meaning of R1), excess TBAF (e.g., 2 equivalents) only follows that an equivalent amount of fluoride ion is used at this stage.

The tautomeric compound of formula V can be isolated at this stage for the synthesis of other penems, as described in more detail below.

In process (a) (ii): The cyclization of a compound of formula VI to an tautomeric compound V is carried out in a conventional manner in an anhydrous inert organic solvent, for example tetrahydrofuran, and a non-nucleophilic strong base, for example, lithium diisopropylamide (LDA) and lithium di- ( trimethylsilyl) amine is added to the mixture to effect cyclization. Usually the cyclization is carried out at about -50 ° C to -100 ° C, and preferably at about -70 ° C, and is usually complete within about 5 minutes to 24 hours. Usually a substantially equimolar amount of strong base is used.

The conversion of tautomeric compound V to another compound of formula I is carried out in the usual way in an anhydrous inert organic solvent, for example tetrahydrofuran, and a non-nucleophilic strong base, for example lithium diisopropylamide (LDA) and lithium di (trimethylsilyl) amine is added to the mixture. Usually the cyclization is carried out at about -50 ° C to -100 ° C, and preferably at about -70 ° C, and is usually complete within about 5 minutes to 24 hours, usually using a substantially equimolar amount of strong base.

The conversion of tautomeric compound V to another compound of formula I is carried out in a conventional manner in an anhydrous inert organic solvent, for example tetrahydrofuran, ethyl ether or dioxane, at a temperature between about -10 ° C and about 45 ° C, preferably at room temperature (about 25 ° C).

In the case where this conversion is carried out for tautomeric compound V, it should be noted that deprotection of the hydroxy group in the 8-position may have been done previously using suitable reagents, as described later, in similar solvents and with a similar temperature range. Thus, the conversion can be carried out as a follow-up to such a deprotection step, namely without isolating the tautomeric compound V.

Thus, the same solvents can be used in both steps, and it is also common to carry out the reactions in both steps at approximately the same temperature or at least in the same temperature range mentioned above. If the tautomer is first isolated, a different solvent and temperature can be used in this step than in the previous step, however, they are preferably the same.

The conversion using RZ is usually carried out in the presence of i3 80702 base or acid acceptor. Bases or acid acceptors known for such a reaction may be used, for example, inorganic bases such as alkali metal carbonates or bicarbonates, or organic bases such as triethylamine. Where tetrabutylammonium fluoride has been previously used (removal of R 1 in process (a) and where it remains in the reaction solution, it also serves as a base in this reaction.

For example, the alkylation step may be carried out in one embodiment by reacting a compound of formula X with R 10 CH 3 / SO 3 CH (X) R n wherein R 10 and R 11 are as defined above with a tautomeric compound of formula V. This particular reaction is carried out in the usual manner in a suitable organic solvent, for example, tetrahydrofuran. A substantially equimolar amount of an acid acceptor, for example an inorganic carbonate, facilitates the reaction. Typical reaction temperatures range from about -5 ° C to about 30 ° C, and the reaction is usually complete within 1-24 hours.

The addition of olefin is usually carried out using a radical initiator, for example AB [2,2'-azobis (2-methylpropionitrile)].

Deprotection of the protected carboxyl group R2 can be carried out by conventional methods selected according to the nature of the protecting group. The preferred protecting group is an allyl group, preferably allyl, and its removal can generally be accomplished under catalytic conditions in the presence of a base, preferably using the methods described in our EP Application No. 0 013 663. Thus, allyl groups are preferably removed using a suitable aprotic solvent such as tetrahydrofuran. , diethyl ether or methylene chloride, alkali metal alkyl carboxylate, preferably potassium or sodium 2-ethylhexanoate (to give penem alkali metal salt, preferably penem sodium or potassium salt directly) or carboxylic acid preferably 2-ethyl-caproic acid (to give penem free acid and catalyst) and pally free acid with a mixture of trimethylphosphine).

Most preferably, this step proceeds by removing the allyl protecting group and forming the alkali metal salt of the penem in situ.

If the reaction product is an amphoteric ion, the removal of the allyl group requires only a catalyst and any weak nucleophile (e.g., H2O or alcohol).

In another, albeit less preferred embodiment, the protected carboxy groups R 1 and R 2 are both of the formula

O

II

-C OCH2CH2RU

wherein both R 3 may be the same or different and selected from cyano, lower alkylsilyl, e.g. trimethylsilyl or t-butyldiphenylsilyl, or a sulfonic ester of formula -SO 2 R X (where R * is an aryl group), or an equiva-1 residual functional (electron withdrawing) group. Preferably, both R 2 groups are rimethylsilyl or t-butyldiphenylsilyl, with the former being more preferred.

In carrying out the above method, wherein both the Grate and R2t have the structure is 80702 o

-C 0CH2CH2RS

removal of the carboxyl group at position 2 of one tautomeric compound of formula V is conveniently accomplished by the method described above using an equivalent amount of fluoride ion, preferably TBAF. Subsequent deprotection of the remaining carboxy protecting group R2 can then be accomplished (after the conversion reaction) using reaction ratios and reagents identical to those used to remove the previously protected carboxy group. Preferably, the removal is performed using tetrahydrofuran as a solvent, at about 25 ° C as a source of TBAF fluoride ion. This method usually produces the free acid of the penem product. The formation of the alkali metal salt and the metabolizable ester can be accomplished by treating the free acid by conventional methods. For example, the free acid can be reacted with a stoichiometric amount of the appropriate non-toxic base in an inert solvent, followed by isolation of the desired salt by lyophilization or precipitation. Or the metabolizable ester can be formed by the reaction of an alkali metal salt of penem with a reactive derivative of the desired ester group; for example, phthalidyl ester or pivaloyloxymethyl ester can be prepared by reacting the corresponding finer alkali metal salts with chlorithalide or pivaloyloxymethyl chloride in a solvent such as dimethylformamide, preferably with a catalytic amount of sodium iodide.

Intermediates of formula II can be prepared, e.g., according to Reaction Scheme 1 and using the methods set forth in this Scheme, as described below, it will be appreciated that any functional groups in any of the intermediates may be protected if necessary or desirable.

80702 BC

Reaction formula 1 / R2 '' OH H-O + O * c 'CH3- «j-η - SR“ Rx H + HO ^ R2

1-N

* \ h I ho / N, XX (XlXa, XlXb)

A

OH 'CH. C —T - [- SR "

I XVIII

J- \ / OH

c R / \ R B 1 2 OH 9a 'ch ^ -c —- t-sr "CH3 y ~ T-rSRB"

H ^ - £ - H XVII

o * '- \ Λ} -' VC1 h / \ r2 Rl / SsR2

D

OH

CH, C-r-SMet

J I H

XI J-Hv / h s \ 17 80702

In the above reaction scheme, intermediate XVIII is obtained in Step A by reacting an azide ion XX wherein H * 'is a sulfur protecting group with a mixed ester (X1Xa, XlXb1, wherein R1 and R2 are as defined above).

In step A, the reaction is carried out in the usual manner in a suitable organic solvent at about room temperature. The solvent is preferably a polar organic solvent such as dimethylformamide; other solvents include, for example, tetrahydrofuran, acetonitrile and dimethyl sulfoxide.

Preferably with a mixture ester

O O

Il II

^ C-OCH2CH * CH2 ^ 0HV ^ c-och2ch * ch2 h2o + o »c ^ ^ X c C-OCH2CH2Rf ^ OH ^ ^ C-OCH2CH2Rj ·

0 O

wherein R 1 'is preferably trimethylsilyl, t-butyldiphenylsilyl or another equivalent lower alkylsilyl group. Trimethylsilyl and t-butyldiphenylsilyl groups are preferred, with the former being more readily available and easy to use.

Thus, with reference to the above formulas, R 1 and R 2 preferably have -C-OCH, CH 0 R 'and -C-OCH 2 CH 2 = CH 2 and 2 2 i 11 * * 10 o respectively.

Sulfur protecting group R | the azide ion XX is preferably triphenylmethyl, 2-pyranyl or lower alkylcarbonyl.

Step chlorination of compound XVIII is carried out in the usual manner in a suitable organic solvent (which may be the same solvent as the solvent used in the previous step) at temperatures of about -15 ° C to about 10 ° C in the presence of an acid acceptor. If the solution is 80702 itself is or contains an acid acceptor, e.g. pyridine, an additional acid acceptor is not necessary. Alternatively, an organic solvent other than an acid acceptor, for example, methylene chloride, chloroform, dimethylformamide or acetonitrile may be used, in which case a separate acid acceptor, organic or inorganic, should be added to the reaction mixture. Typical suitable acid acceptors are organic bases, for example pyridine or triethylamine, and inorganic bases, for example sodium or potassium carbonate.

The chlorinating agent may be one conventionally used in the conversion of alcohols to chlorides, for example thionyl chloride, oxylyl chloride, phosphorus pentachloride, phosphorus trichloride or phosphorus oxychloride. Thionyl chloride is most preferred.

The chlorination reaction can be carried out directly on the product of step A> without isolation (the solvent can be the same as in the previous step).

Step C, the removal of chlorine from compound XVII can be carried out in any suitable organic solvent, for example tetrahydrofuran, methylene chloride or dimethylformamide, and can be carried out in the same solvent as in the previous step. Thus, it can be carried out directly on the product of step B without isolation.

Water or any proton source to which dilute acid has been added can be used to increase zinc activity. Typical reaction temperatures range from about -15 ° C to about 25 ° C; 0 ° C is preferred.

At this point, the protected 5-hydroxy group can be deprotected simultaneously with chlorine if, as is preferred, the protecting group is removable with the element zinc.

If a hydroxy-protecting group is present (in position 5) which is not thus removable (by zinc), a separate removal step i9 80702 is carried out to remove it. Such removal steps are well known in connection with β-lactams. This removal, if necessary, can be carried out at any time in step C. after.

Step D can be performed in a polar solvent, for example methanol, ethanol, dimethylformamide, tetrahydrofuran or water. Suitable reactive salts of thiopholic metals include, for example, any reactive salts of copper, mercury, silver, lead, nickel and thallium in which the reaction is not affected by the anion. It is preferred to use Cu (II), silver (I) and mercury (II), silver (I). being the most advantageous. The salts may be salts of organic or inorganic acids, and suitable salts include, for example, silver nitrate, silver fluoroborate and silver acetate. Silver nitrate is the preferred salt. Typical copper salts, a, are copper (II) acetate and copper (II) nitrate. A typical suitable mercury salt is mercury acetate. In the case of lead salts, it has been found that they give much slower reaction rates.

Silver salts are the most preferred, due to their readiness for re-use and their relatively non-toxic nature.

The reactions are facilitated by the use of an acid acceptor, e.g. pyridine or triethylamine. Preferably the reaction is carried out in an inert atmosphere, e.g. nitrogen.

It is highly preferred that in carrying out the above reactions, the β-lactam intermediates prepared in each step are not isolated but left in the reaction vessel and treated according to the next reaction step. This greatly facilitates the process because several steps can be performed in the same solvent regardless of the separation of the desired product.

For example, in a preferred embodiment comprising the reactions of Scheme 1, an ester of formula (XlXa, XlXb) is added to an azitidinone of formula XX to prepare an intermediate of formula XVIII. This intermediate is then treated immediately with a chlorinating agent, preferably thionyl chloride, to prepare the chloride intermediate of formula XVII. This intermediate, again without isolation, is immediately treated with the element zinc to remove the chlorine atom and possibly simultaneously, if present, to remove the hydroxy protecting group from the 5-substituent to give the intermediate of formula XVI.

Thus, the first steps A, B, C and the subsequent deprotection of the hydroxy group in the 5-position can be performed in the same reaction vessel, in the same solvent, and as a result, the material losses caused by the isolation of the intermediates are reduced.

In a highly preferred embodiment, a compound of formula II in which the hydroxy group in the 5-position is unprotected is treated immediately, without isolating it from the reaction mixture where it is formed, to protect said hydroxy group; then, without isolation, the protected product can be cyclized with a thiocarbonyl compound of formula III, and then, without isolation, the tautomeric compound is treated to remove the 8-position hydroxy protecting group. Alternatively, prior to protection and deprotection of said hydroxy, the compound of formula II may be used immediately, without isolation, in a cyclization reaction with a thiocarbonyl of formula III.

Similarly, it is preferable to dispense with the tautomeric product (Va,

Vb) isolation in the processing or preparation of other compounds of formula I; thus, various conversion methods can be carried out immediately without isolating the tautomer from the reaction mixture where it is prepared, and the resulting compound of formula I can be deprotected in the same manner without immediately isolating it from the reaction mixture where it is formed.

2i 80702

Reaction formula 2

OH OH

CH, -C —-r-SR 'CH.-6 -, - j — SR'

3 I A '3 I

H + WCH-R- —-- ► H

0 ^ - \ \ CH R

K 2R2 XX XXIII XXI2 B '

<j) H V

CH, C —-— SMet

3 I

B

/ & \ y '0 nch2r2 y xxi OH * ch3 — ί—— 3 ^ Γ fi 0 ^ CH2R2

VI

22 8 0 7 0 2

The intermediates of formula VI can be prepared, for example, according to the following reaction, step 2. As in the process of reaction scheme 1 described above, it is clear that any functional group in any intermediate can be protected if necessary or desirable.

False A1

The reaction of azitidone XX with α-substituted acetate XXIII is preferably performed in the presence of an acid acceptor, preferably at a temperature in the range of about 15 ° C to about 30 ° C.

W is a leaving group preferably tosyl, mesyl, chlorine, bromine, iodine or trifluoromethylsulfonyl, most preferably iodine or bromine.

Acetate XXIII 1 * 2 preferably has allyl oxycarbonyl, most preferably allyloxycarbonyl,

If the solvent is also an acid acceptor, e.g. pyridine, no Iisa acid acceptor is required. Alternatively, an organic solvent other than an acid acceptor, e.g. acetonitrile, may be used. In these cases, a separate acid acceptor, organic or inorganic, must be used. Preferably, the reaction is performed in acetonitrile using cesium carbonate or tetraalkylammonium hydroxide as the acid acceptor.

Step B1 can be performed according to the methods described above in connection with Step D of Reaction Scheme 1.

Step C can be carried out according to the methods described above for the conversion of metal salt II with a compound of formula III to thione LV. In this case, however, cyclization (which occurs in reaction scheme 1 using a malonate ester). does not occur and thiocarbonyl azitidone intermediate VI is obtained.

Usually, the metal salt intermediate of formula XXI is treated to protect the hydroxy group on the 23 80702 5-gun (if not already protected) before step C 'is performed. The resulting protected group can be deprotected, if desired after cyclization of the product of formula VI, deprotection can be carried out, for example, on a compound of formula V. Conventional hydroxy protection methods and deprotection methods can be used, as described below.

In a preferred form of this process, the intermediate of formula XII is used immediately in the reaction of step B * without isolating it from the reaction mixture where it is formed (in step A ') and the compound of formula XXI thus formed is treated directly in step C without isolating it from the reaction step.

If the 5-hydroxy group in the intermediate of formula XXII formed in step B is protected before step C, the protection can be carried out at the same time; directly to the intermediate of formula XXI without isolating it from the reaction mixture where it is formed. And similarly, the intermediate thus formed can be treated in step C 'without isolating it from the reaction mixture.

Similarly, cyclization of an intermediate of formula VI and removal of the 8-position hydroxy protecting group from the resulting compound can be performed sequentially without separating the cyclized product from the reaction vessel where they are formed. In the resulting penem compound, the 8-hydroxy group is protected, which is then removed by conventional methods. Subsequent removal of the carboxyl protecting group at the 3-position and. the formation of the free acid, salt or metabolizable ester can be performed using the methods described above.

Suitable hydroxy protecting groups are well known in the context of penem compounds and methods for attaching them to hydroxy groups are also well known. A particularly preferred method of protection, for example to protect a 5-hydroxy group in compounds of formulas IX and XXI, comprises a suitable intermediate (e.g. formula II) having an unprotected hydroxy group.

24 80702 with bis-silylacetamide, which immediately forms a trimethylsilyl protecting group on the desired hydroxy group. Protection of the 5-hydroxy group as an intermediate of azitidione in the methods discussed above can be accomplished without isolating the intermediate.

The inert solvent thus used may be the same as, for example, DMF used in the previous step. Other solvents, such as chloroform and methylene chloride, may also be used. Temperatures in hydroxy protection processes are typically from about 0 ° C to about 30 ° C.

Methods for deprotecting a 5- or 8-hydroxy group are well known in the context of penem compounds. Preferably, when the hydroxy protecting group is trimethylsilyl, the addition of a dilute aqueous solution of the acid, such as acetic acid, to the solution in which the deprotected intermediate is prepared causes removal. Thus, for example, it is not necessary to isolate a protected derivative of a compound of formula IV before deprotection of the 8-hydroxy group.

Process (b) comprising sulfoxide replacement is usually carried out in an inert solvent, for example chloromethane or tetrahydrofuran. The reaction temperature is usually 0 ° C to -70 ° C.

When a thiol compound VIII 'is used, the reaction is generally carried out in the presence of a base, e.g. an organic base such as diisopropylethylamine or triethylamine, or an inorganic base, for example potassium hydroxide or sodium ethoxide.

Alternatively, a reactive derivative, for example an alkali metal salt, preferably a sodium or potassium salt, may be used. Sulfoxides of formula VII can be obtained, for example, by treating a compound of formula I with a weak oxidizing agent, for example m-chloroperoxybenzoic acid in an inert solvent, for example dichloromethane between -30 ° C and 20 ° C, e.g. 0 ° C - 5 ° C.

Such a compound of formula I may be prepared, for example, by the methods disclosed herein, or by the methods disclosed in our EP patent publication no. 13662.

Process (c), which comprises cyclization of a compound of formula IX, is usually carried out uniformly in our EP application publication no. 58317.

Thus it is usually carried out in an inert solvent, for example an aromatic hydrocarbon, e.g. toluene, benzene, aliphatic ethers, e.g. diethyl ether, and dipropyl ether, cyclic ethers, e.g. dioxane, tetrahydrofuran, and a halogenated hydrocarbon, e.g.

In general, the cyclization reaction is carried out at temperatures between 20 ° C and 80 ° C, usually 40 ° C to 60 ° C, for 6 to 24 hours.

Suitable trivalent organophosphorus compounds include cyclic and / or acyclic trialkyl phosphites, triaryl phosphites, and arylalkyl phosphites or phosphoramides. The preferred trivalent organophosphorus compound is a trialkyl phosphite; most preferred is triethyl phosphite.

Compounds of formula IX may be obtained from formula

OH

I c

CH -C - "S ^ C-S-R

3 I II

H S

</ - NH

26 80702 wherein R is as defined above by reaction of a compound of formula with an acid of formula

O

II

C

R2 ^ ^ OH

wherein R 2 is as defined above, with a reactive derivative, e.g. chloride. This reaction is usually carried out under normal acylating conditions, namely in an inert solvent and in the presence of an organic base, preferably a tertiary amine.

The following examples illustrate in detail the methods of the present invention, methods for preparing the starting material, and the use of intermediates prepared by a direct process. In these examples, "NMR" means nuclear magnetic resonance spectrum, "rotation" means the optical rotation of a compound in a suitable liquid; "MS" means mass spectrum; UV stands for ultraviolet spectrum; and "IR" means infrared spectrum; chromatography was performed on silica gel unless otherwise noted. The term at room temperature refers to about 18 ° C to about 25 ° C.

27 80702

Preparation of starting materials Preparation example A

(3S, 4R, 5R1-3- (1-Trichloroethoxycarbonyloxyethyl) -4- (triphenylmethylthio azetidin-2-one

To a 250 mL flask add 7.8 g (0.0223 mL of 3- (1-trichloroethoxycarbonyloxyethyl) -4-acetoxyazetidin-2-one, 220 mL of acetonitrile, 2.6 g (0.252 M) of cesium carbonate, and 5, After stirring for 2 hours (2 g, 0.0188 M) triphenylmethanethiol, add an additional 1.0 g (0.0036 M} of triphenylmethanethiol and stir the mixture for another half hour. Store overnight in the refrigerator, then remove the solids by filtration and solvents under reduced pressure to give the crude reaction product Chromatograph this crude product on crude silica gel eluting with methylene chloride to 10% and 20% ethyl acetate / methylene chloride to give 7.89 g (3S, 4R, 5R) -3- (1-Trichloro-ethoxycarbonyloxy-ethyl-4- (triphenylmethylthio) -azetidine-2'-oneone having the following spectrum? NMR = 7.7-7.1, 16H, 5.05, 1H, m; , 85, 2H, q (J = 18Hz), 4.45, 1H, d (J = 1.5Hz), 3.3, 1H, dd (J = 1.5, 9Hz, 1.5.3H, d ( J = 9Hz).

Preparation Example B di (trimethylsilyl) ketomalonate (a) Dissolve 22.50 g of 2-trimethylsilylethanol in 100 ml of methylene chloride. To this mixture add 20.00 g of triethylamine. Cool to about -20 ° C and slowly add a solution of 15 g of freshly distilled malonyl dichloride in 100 ml of methylene chloride over 1.5 hours. After the addition is complete, allow the reaction mixture to warm to room temperature and then wash twice with 500 ml of water, then wash with 5% sodium bicarbonate solution until the pH is greater than 9. Dry the solution over anhydrous magnesium sulfate and remove the solvents by evaporation to give 30.22 g of trimethylsilyl diester of malonic acid.

28 80702 (b) Dissolve the diester prepared as described in (ai) in 3 ml of benzene. Add to this solution 140 mg of benzoic acid, 17 ml of benzaldehyde and sufficient piperidine to give a pH of about 9. Reflux the solution using Dean-Stark tube, 8 hours, and then remove the solvents under reduced pressure to give di (trimethylsilylethyl) benzylidene malonate.

(c) Dissolve the di (trimethylsilylethyl) benzylidenemalonate prepared as described in (b) in 500 mL of methylene chloride and cool to about Q ° C. Add ozone to the solution until a clearly distinguishable blue - blue - green color remains. Stop the ozone supply and allow the solution to stand for 5-10 minutes. Feed nitrogen through the reaction vessel until the excess ozone is completely removed, add 75 mL of dimethyl sulfide and allow the reaction mixture to warm to room temperature. Evaporate the solvent and place the remaining oil in an open container and allow any excess benzaldehyde to oxidize. After standing overnight, dissolve the semicrystalline mass in methylene chloride and wash it, first with saturated sodium carbonate solution, and then with water. Dry the washed methylene chloride solution over anhydrous magnesium sulfate and remove the solvents. The resulting oily / crystalline material is recrystallized from Petro-ether to give di (trimethylsilylethyl) ketomalonate.

Preparation Example C

preparation of allyltrimethylsilylethyl ketomalonate

To a 500 mL flask add 25 g of ketomalonic acid 1-1 / 2 H 2 O, 250 mg of p-toluenesulfonic acid, 58 gm of allyl alcohol, and 200 ml of Bentene. Reflux using a Dean-Stark tube for 6-1 / 2 hours. parasite excess allyl alcohol and benzene by evaporation in vacuo. Wash the residue with water, then distill at 2 mmHg and collect the diallyl ketomalonate as a yellow oil, b.p. 89-92 ° C, yield ----- 25 gm.

Add 25 g of the diallyl ketomalonate thus obtained to 14.9 gm of (CH 2) 2 SiCH 2 CH 2 OH, then add 1/2 ml of 1,5-diazabicyclo [4.3.1] 29,80702 non-5-ene (DHN). After 24 hours, wash the resulting mixture with cold 10% phosphoric acid and then water. Dry the resulting product and distill at 0.4 mmHg to give allyl trimethylsilylethyl ketomalonate, b.p. 91-100 ° C, yield 12 gm.

N. MR} = 0.05, (9H, SI; (2H, T, J = 9 Hz); 4.35, (2H, T, 9Hz); 4.70, (2H, D, J = 6Hz); ); 5.25, (2H, M); 5.80, (1H, M)

Preparation Example D

l-methyl-2-chloromethyl-imidazole

Place 10 g of 1-methylimidazole and 100 ml of 37% aqueous formaldehyde in a 150 ml Farr bomb and heat to 125 ° C in an oil bath, remove the water and evaporate the residue to a gel. Extract the gel in solution with methanol. Remove the methanol. Isolate the product, 1-methyl-2-hydroxymethylimidazole, on a coarse silica gel column and crystallize from CCl 3. Mix 4.4 g of 1-methyl-2-hydroxymethylimidate, 5.7 ml with SOCl 2 in 50 in CHCl 3 in a reaction flask. Stir for 18 hours and remove the solvent and excess SOCl 2 in vacuo. Evaporate to dryness to give the product 1-methyl-2-chloromethylimidazole.

Manufacturing mark E

Allyl (5R, 6S, 8R, 2'RS) - (ethanesulfinyl) -6- (1-hydroxyethyl) penem-3-carboxylate

Stir a solution of allyl (5R, 6S, 8R, 2 'RS) -2- (ethylthio) -6- (1-hydroxyethylpenem-3-carboxylate (31.5 g) in ethyl acetate (200 mL) and dichloromethane (100 mL). At 0 DEG--5 DEG C. Add a solution of m-chloroperoxybenzoic acid (80-85%; 22 g) in ethyl acetate (120 ml) over 0.5 hours, 0.5 hours after the addition add a solution of ethyl acetate (150 ml). , a mixture of water (125 ml) and sodium bicarbonate (15 g) and stir rapidly for 15 minutes. Dry the organic phase over MgSO 4, evaporate rapidly and chromatograph on silica gel eluting with 1: 1 hexane-ethyl acetate, then with pure ethyl acetate. Evaporate the product fraction. treat the residue under high vacuum to give the title product as a thick yellow oil.

80702 PMR (CDCl 3; d 1.2-1.6 (m, 6H), 3.0-3.35 (m, 2H), 3.38 (br.s, 1H, D 2 O; na), 3 .38 (m, 1H), 4.18 (m, 1H), 4.75 (br.d, J = 6.5 Hz), 5.2-5.6 (m, 2H1, 5.73 and 5.89 (both d, J = 1.5 Hz, total 1HJ. And 5.8 ^ 6.2 (m, 1H).

The product is obtained as a mixture of diastereoisomers from oxidized sulfur. The mixture was used in the following examples because both isomers reacted.

Preparation Example F

2- (N-Allyloxycarbonylglycylamino) -ethanethiol

Add pivaloyl chloride (2.4 mL) in CH 2 Cl 2 (10 mL) cooled (0 ° -5 ° C). to a stirred solution of N-allyloxycarbonylglycine (3.18 g) and triethylamine (2.8 ml) in dry CH 2 Cl 2 (50 ml). Stir the mixture at 0 ° -5 ° C for 15 minutes and then add 2-aminoethanethiol hydrochloride (2, 4 g) and a solution of triethylamine (2.8 ml) in ethanol (15 ml) and CH 2 Cl 2 (40 ml), Stir at room temperature for 1 hour, wash the mixture with aqueous 2M-H 2 SO 4 and aqueous NaHCO 3, dry and evaporate . Grind the resulting solid with ether to dust, filter and dry to give the title product.

FMR (CDCl 3): δ 1.42 (t, J = 8 Hz, ih as D 2 O), 2.61 (m, 2HJL, 3.5a (q, J = 7 Hz, 2H)., 3.88 ( d, J = 7 Hz, 2H.), 4.57 (m, 2H) 1.5: 5.5-5.5: (m, 2H.J., 5.6-: 6.2 (m, 2H> 1H) D 2 O * na and 7.0 (br, S, 1H, D 2 Oinal <3i 80702

Example 1 A. (3S, 4R, 5R) -1- [1-Hydroxy-1-allyloxycarbonyl-1-trimethylsilylethoxycarbonylmethyl] -3- [1- (2,2,2-trichloroethoxycarbonyloxyethyl) )] -4- (triphenylmethylthio) etidin-2-one.

Add 100 mg of (3S, 4R, 5R) -3- [1- (2,2,2-trichloroethoxycarbonyl-oxyethyl-4- (triphenylmethylthio) -azetidin-2-one (prepared as described in Preparative Example A) and 0.2 ml of dimethylformamide in a dry flask Add 45 mg of allyl trimethylsilylethyl ketomalonate (prepared as described in Preparative Example C), 0.0014 ml of pyridine and 0.0014 ml of triethylamine to the mixture, and after standing at room temperature for 50 minutes, remove the solvent by stripping to give the title product. .

B. (3S, 4R, 5R) -1- [1-Allyloxycarbonyl-1-chloro-1-trimethylsilylethoxycarbonylmethyl] -3- [1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4- ( preparation of triphenylmethylthio) -azetidin-2-one.

Add 4.26 mg of (3S, 4R, 5R) -1- [1-hydroxy-1-allyloxycarbonyl-1-trimethylsilylethoxycarbonylmethyl] -3- [1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -. 4- (triphenylmethylthio) -azetidin-2-one in a solution of 10 ml of methylene chloride, 2 ml of pyridine and 1 mg of calcium carbonate. Cool the mixture to 0-5 ° C by placing it in an ice bath. After cooling, slowly add 1.5 ml of thionyl chloride. After 25 minutes, the reaction is complete. Wash the reaction mixture with sodium bicarbonate solution having a pH of less than 8 and remove the solvent by stripping. Chromatograph the residue on silica gel using methylene chloride as eluent to give 3.48 mg of the title product.

32 80702 C. (3S, 4R, 5R) -1- [allyloxycarbonyl-1-trimethylsilyl-ethoxycarbonylmethyl] -3- (1-hydroxyethyl) -4- (triphenylmethylthio) -azetidine-2 -on manufacture.

Dissolve 3.48 g of (3S, 4R, 5R) -1- [1-allyloxycarbonyl-1-chloro-1-trimethylsilylethoxycarbonylmethyl] -3- [1- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4- (triphenylmethylthio) -azetidin-2-one in 50 ml of tetrahydrofuran. Add 15 ml of water and 8 g of zinc dust to the mixture. Place the mixture in an ice bath and gradually add 16 g of ammonium chloride over an hour. Stir the solution at 0-5 ° C for the next 2 hours and then add 4 ml of glacial acetic acid and gradually another 6 g of zinc dust. Continue the reaction for another hour, filter and remove the solvent by stripping. Dissolve the crude product in methylene chloride and wash the organic solvent with water. Purify the crude product by chromatography on silica gel using 1% ethyl acetate as eluent (finally increasing the proportion of ethyl acetate to 25% in methylene chloride to give 1.64 g of the title product.

NMR = 0.05 (5.9 H) '; 1.05 (m, 2 H), 1.15 (D, 3 H, J = 6); 2.2 (5, 1 H); 3.38 (DD, 1 H); 3.7 (m); 4.2 (mj; 4.5 (m); 5.2 (m, 2H); 5.8 (m, 1H).

D. Preparation of Silver (3S, 4R, 5R) -3- (1-hydroxyethyl) -1-allyloxycarbonyl -1-trimethylsilylethoxycarbonylmethyl azetidin-2-one 4-thiolate.

To a 50 mL flask with a nitrogen atmosphere, add 5 mL of methanol and 1 g (0.00158 moles) of (3S, 4R, 5R) -3- [1-hydroxyethyl) -4-triphenylmethylthioazetidin-2-one . Cool the solution to about 0 ° C and then add 0.14 mL of pyridine and 1.74 mL of methanol containing 294 mg (0.00173 moles) of silver nitrate. Stir the mixture at about 0 ° C for one hour and then allow the mixture to warm to room temperature. After stirring at room temperature for 2 hours, add a further 0.2 ml of methanol containing 34 mg of silver nitrate (0.002 mol) and continue the reaction for another hour. Stop the reaction and remove the methanol by stripping. Dissolve the residue in methylene chloride and wash the organic solution twice with water, then brine. Dry the organic solution over anhydrous sodium sulfate, filter and remove the methylene chloride by stripping to give the title product.

E. Preparation of Silver (3S, 4R, 5R) -3- (1-trimethylsilyloxyethyl) -1-allyloxycarbonyl-1-trimethylsilylethoxycarbonylmethylazetidin-2-one 4-thiolate.

Dissolve all the silver (3S, 4R, 5R) -3- (1-hydroxyethyl) -1-allyloxycarbonyl-1-trimethylsilylethoxycarbonylmethyl azetidin-2-one thiolate obtained in step (D) above in 10 ml of anhydrous methylene chloride. Add 0.783 mL (0.00316 (bol)) of bistrimethylsilylacetamide to the mixture and stir at room temperature for 15 minutes to give the title product.

F. Preparation of (5R, 6S, 8R) -2-thione-3-allyloxycarbonyl-3-trimethylsilylethoxycarbonyl-6- (1-trimethylsilyloxyethyl) penamine.

After completion of step (E) and in the same solution, 619 mg (0.00316 mol) of 90% thiocarbonyldiimidazole are added. Stir the mixture at room temperature for 20 hours and then filter the solution. Remove the methylene chloride by stripping. Chromatograph the crude product on silica gel eluting with 30% cyclohexane / methylene chloride to methylene chloride to give 704 mg of the title product.

34 80702 F '. Repeat step F, but use the reaction solution obtained in step E, but in which the silver salt is replaced by the thallium, copper, and mercuric azetidine salts to give the title product.

NMR = 6.2 - 5.6, m, 1H; 5.65, d (J-1.5Hz) 1H; 5.5-5.1 (m) 2H; 4.7: d (J = 5.5 Hz); 2H; 4.5 - 4.1: unres .: 3H; 3.62, d, d (J = 1.5, 4Hz), 1H; 1.28, d (J = 6Hz), 3H; 1.2 - 0.85 m, 2 H; 0.2 - 0.18H.

G. Preparation of (5R, 6S, 8R) -2-thione-3-allyloxycarbonyl-3-trimethylsilylethoxycarbonyl-6- (1-hydroxyethyl) penam.

To a 25 mL flask add 100 mg of (5R, 6S, 8R) -2-thione-3-allyloxycarbonyl-3-trimethylsilylethoxycarbonyl-6- (1-trimethylsilyloxyethyl) penam, 1 mL of tetrahydrofuran, 0.05 ml of water and 0.05 ml of acetic acid. Stir the mixture at room temperature for 12 hours. Add ethyl acetate to the solution and wash the organic phase with sodium bicarbonate solution, water and then brine. Dry the organic phase over anhydrous sodium sulfate, filter, and strip the solvent to give the title product.

NMR = 6.15 - 5.6, m, 1H, 5.69 + d (J-2Hz), 1H; 5.55 - 5.12: m: 2H; 4.8-4.6: M: 2H; 4.5 - 4.0: unres .: 3H; 3.67, d, d (J = 2.7 Hz), 1H; 2.8 - 2.3: m: 1H; 1.37, d, (J = 6Hz), 3H, 1.2-0.8, m, 2H; 0.3-0.0 M 9H.

H. Preparation of (5R, 6S, 8R) -allyl-2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate.

Slowly add 7.7 mg of (5R, 6S, 8R) -2-3570702 thione-3-ylyloxycarbonyl-3-trimethylsilylethoxycarbonyl-6- (1-hydroxyethyl) penem in 1 ml of tetrahydrofuran to 2 equivalents of tetrabutylammonium at room temperature. fluoride in 40 ml of tetrahydrofuran. Thin layer chromatography (silica gel, 10% ethyl acetate / methylene chloride) immediately shows the equilibrium of the decarboxylated product (5R, 6S, 8R) -allyl-2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate. With (5R, 6S, 8R) -allyl-2-thiol-6- (1-hydroxyethyl) penam-3-carboxylate, in the presence of.

NMR = d 5.85, d (J = 1 Hz), 1H; 5.8: m: 1H; 5, 1 H; 5.4 - 5.1: m: 2H; 4.7: 2H; 4.25, M, 1 H; 3.65, d, d (J = 1.1 Hz), 1H; 2.1, 1 H; 1.35, d (J = 7Hz) 3H.

Example 2

Allyl (5R, 6S, 8R) -2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate and allyl (5R, 6S, 8R) -2-thione-6- (1- preparation of hydroxyethyl) -penem-3-carboxylate.

A. Preparation of (3S, 4R, 5R) -1-allyloxycarbonylmethyl) -3- (1-hydroxyethyl) -4- (t-phenylmethylthio) azetidin-2-one.

Add 3 g of (3S, 4R, 5R) -3- (1-hydroxyethyl) -4- (triphenylmethylthio) azetidin-2-one to 10 ml of acetonitrile containing 0.286 g of cesium carbonate. Add 0.2 g of α-iodoallyl acetate to the mixture. Stir the mixture at room temperature for 16 hours. Dilute with ether (50 mL), filter and wash the ether layer with 1% aqueous phosphoric acid, then water. After drying over sodium sulfate, remove the solvent to give a foamy solid.

NMR = 8.4, 1H, s; 7.65, 1H, d (J = 1 Hz); 7.05, 1H d (J = 1 Hz); 5.95, 1H, d (J = 2Hz); 5.8: 1 H, m; 5.45 - 5.1, 1 H, m; Δ 80702 36 4.3, 1H, m; 4.1, 2H, Q (J = 16Hz); 3.5, d d (J = 2.6); 1.35; 3H, d (J = 6Hz).

B. Preparation of Silver (3S, 4R, 5R) -2- (1-hydroxyethyl) -1-allyloxycarbonylmethyl-azetidin-2-one 4-thiolate.

To a 50 mL flask with a nitrogen atmosphere, add 10 mL of methanol and 460 mg of (3S, 4R, 5R) -1- (allyloxycarbonyl) -3- (1-hydroxyethyl) -4- (triphenylmethylthio) azetidine. 2-one. To this mixture add 160 mg of silver nitrate and 0.15 ml of pyridine. Stir the mixture at 20 ° C for one hour. Stop the reaction and remove the methanol by stripping to give the title product.

C. Preparation of Silver (3S, 4R, 5R) -3- (1-trimethylsilyloxyethyl) -1-allyloxycarbonylmethyl azetidin-2-one 4-thiolate

Add all the silver (3S, 4R, 5R) -3- (1-hydroxyethyl) -1-allyloxycarbonylmethylazetidin-2-one β-thiolate obtained in step (B) above to 25 mL of methylene chloride.

To this mixture add 1.1 ml of bis-silylacetamide. Stir the mixture at room temperature for 15 minutes to give the title product.

D. Preparation of (3S, 4R, 5R) -1- (allyloxycarbonylmethyl) -3- (1-trimethylsilyloxymethyl) -4- (1'-imidazolylthiocarbonylthio) -azetidin-2-one.

After completion of step C above, add 350 mg of thiocarbonyldiimidazole to the same solution. Stir the mixture at room temperature for 3 hours. Filter the solution, wash the precipitate with methylene chloride. Collect the filtrate and remove the methylene chloride by stripping. Chromatograph the residue on silica gel eluting with 37 8 0 7 0 2 20% ethyl acetate / methylene chloride to give 335 mg of the title product.

E. (5R, 6S, 8R) -allyl-2-thiol-6- (1-trimethylsilyloxymethyl) penem-3-carboxylate and (5R, 6S, 8R) -allyl-2-thione-6- (1- preparation of an equilibrium mixture of trimethylsilyloxymethyl) penem.

Add 170 mg of (3S, 4R, 5R) -1- (allyloxycarbonylmethyl) -3- (1-trimethylsilyloxymethyl) -4- (1'-imidazolylthiocarbonylthio) azetidin-2-one in 40 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. Cool the mixture to -78 ° C and then dropwise add 0.6 mL of 1 M lithium di- (trimethylsilyl) amine in hexane. Stir the mixture at -78 ° C for 5 minutes. Add 0.2 ml of acetic acid to the mixture. Dilute the mixture to 200 mL with methylene chloride. Wash the organic solution with water, aqueous sodium bicarbonate solution and then water. Purify the product rapidly by chromatography eluting the sample through silica gel with 5% ethyl acetate / methylene chloride to give 125 mg of the desired product and the desilylated product.

F. (5R, 6S, 8R) -allyl-2-thiol-6- (1-hydroxyethyl) penem-3-carboxylate and (5R, 6S, 8R) -allyl-2-thione-6- (1-hydroxy) -ethyl) penam preparation of an equilibrium mixture.

Add 25 ml of the mixture obtained in step (E) in its entirety together with 5 ml of tetrahydrofuran, 1 ml of water and 1 ml of acetic acid. Stir the mixture at room temperature for 2 hours. Add ethyl acetate to the solution and wash the organic phase with sodium bicarbonate solution, water and then brine. Dry the organic phase over anhydrous sodium sulfate, filter, and strip the solvent to give the title product.

38 8 0 7 0 2

Example 3

Sodium (5R, 6S, 8R1-2- (2,3-dihydroxy-1-propylthio) -6- (1-hydroxyethyl) penem-3-carboxylate

OH u OH H OH

HjC — C //,.-VS* Ns-S H ^ C — C ^ ^ —S

A -► il HO

<] L "(I) (II)

To a 100 ml flask add 400 mg (0.000696 M) of an equilibrium mixture of thion I and the corresponding thiol tautomer (e.g. 7, step H), 10 ml of distilled tetrahydrofuran, 154 mg (0.00008 M) (3 eq.) Of glycide and 25 mg of potassium carbonate. Stir until a thin layer chromatograph shows no starting material. Acidify to pH 7 with 10% phosphoric acid, remove tetrahydrofuran by rotary evaporation and chromatograph the residue on a coarse silica gel column with 100% ethyl acetate, yield after isolation 160 mg of product II (yield 61%).

B. Add to a 50 ml flask, under a nitrogen atmosphere, a solution of 160 mg of the product II obtained in step II in 2 ml of ethyl acetate, 73 mg (0.0004 4 2 M) of sodium ethyl 2-hexanoate, in 10 mg of tri -phenylphosphine and at 5 mgr Pd (Fhj) P 2. Stir the reaction mixture for 3 hours, refrigerate overnight, add water and extract the product on an HPLC column with 100% water, yield after isolation is 32 mg of the title product as a white amorphous solid.

Example 4 N Atrium (5R, 6S, 8R) -2- (2,3-dihydroxy-1-propylthio) -6- (1-hydroxyethyl) penem-3-carboxylate A (3R, 4R, 5R) - 3- (1-Trichloroethoxycarbonyloxyethyl) -4 - {[(2,3-39,80702 dihydroxy-1-propylthiolecarbonylthioylthio] -azetidin-2-one,

To a solution of ethanol (50 ml), 1-K sodium hydroxide (20 ml and 2,3-dihydroxypropanethiol (2 g), carbon disulphide (4 ml), add dropwise, stir for 10 minutes, then add dropwise to a solution of (3S, 4R, 5R) -4- [1- (2-methoxy-1,2-dioxyethyl)] - 3- (1-trichloroethoxycarbonyloxyethyl) -4-chloroazetidin-2-one (4.1 g in ethanol) Stir the reaction mixture. until tlc analysis shows no starting material (about 4 hours) then dilute with ethyl acetate, wash the solution with saturated sodium chloride, dry the solution over magnesium sulfate, evaporate and chromatograph the resulting residue on silica gel (40 g) eluting with 30% ether-hexane. determined by tlc), evaporate the solvent to give the title product.

I.R. = 5.65 y; HMR; 5.5ppm (1H, d, J = 2 cps) 3.4ppm (1H, q, J = 8 and 2 cps) B. Allyl- (5R, 6S, 8R) -6- (1-trichloroethoxycarbonyloxyethyl) -li) -2- (2,3-dihydroxy-l ^ propylthio) -penem-3-carboxylate.

Add with stirring to a solution of (3S, 4R, 5R) -3- (trichloroethoxycarbonyloxyethyl) -4- (carbonothioylthio] -acetidin-2-one (0.7 g) in methylene chloride (6 mL) cooled to 10 ° C. ° C, calcium carbonate (0.6 g) followed by allyloxalyl chloride (0.263 g, 1.2 eq.). Add dropwise a solution of diisopropylethylamine (0.32 mL, 1.2 eq.) In methylene chloride (1 mL) over 5 minutes maintaining the temperature at 10 ° to 15 ° C. After TLC shows no starting material (15 minutes) at 15 ° C, transfer the mixture to a separatory funnel using ethanol-free chloroform, twice with ice water, filter to remove excess calcium carbonate. dry over anhydrous sodium sulfate and transfer to a 3-necked 10 mL flask. Set the volume of the solution in chloroform to approximately 50 ml and heat at reflux while adding a solution of triethyl phosphite (0.6 ml, 2 eq.) In chloroform (20 ml) for 3 hours, reflux the mixture for a further 18 hours, evaporate and chromatograph at 14 g. silica gel 40 80702 eluting with 25% ether-hexane, and combine similar eluates and evaporate to give a residue (450 mg) containing the title product, purified by crystallization from ether-hexane to give the title product in crystalline form, C, Allyl- (5R, 6S, 8R1- 6- (1-hydroxyethyl) -2- (2,3-dihydroxy-1-propylthiol-2-penem-3-carboxylate,

Dissolve about 1.6 g of the product prepared according to the procedure of Step B in 15 mL of tetrahydrofuran, 1.5 mL of water, and 1.5 mL of acetic acid at Q ° -5 ° C with stirring. Add 2.0 g of zinc dust and stir until the thin layer chromatograph shows only traces of starting material. Filter the reaction mixture, wash the solids with ethyl acetate, combine the organic solvents and wash sequentially with 10% aqueous tartaric acid, water and aqueous sodium bicarbonate. Dry the solvent phase over magnesium sulfate and evaporate the solvent. Crystallize the residue from ether-hexane.

D. Sodium (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2,3-dihydroxy-1-propylthio) penem-3-carboxylate.

Dissolve about 6.4 g of the product prepared in steps A-C in 190 mL of methylene chloride and add 5.32 g of sodium 2-ethylhexanoate in 190 mL of ethyl acetate. Add a mixture of 0.46 g of triphenylphosphine and Q, 46 g of tetrakis (triphenylphosphine) palladium. Stir for 1.5 hours and centrifuge. Precipitate the precipitate with ethyl acetate and dry under high vacuum to give the title product as a white amorphous solid.

Example 5 N-sodium (5R, 6S, 8R1-2- (2,3-dihydroxypropylthio) .- 6- (1-hydroxyethyl] penem-3-carboxylate, A, To a solution of 20 g of allyl ( An equilibrium mixture of 5R, 6S, 8r) -6-hydroxyethyl-2-thione and allyl (5R, 6S, 8RI-6- (1-hydroxyethyl) -2-thiolpenem-3-carboxylate and diisopropylethyl - 4i 80702 amine (0.15 g) in dry acetonitrile (4 ml), 2,3-dihydroxy-1-bromopropane (0.2 g) After about 1 hour at 25 ° C, dilute with aqueous tartaric acid and dry over magnesium sulphate. Evaporate and partition the residue from dichloromethane to give allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2,3-dihydroxypropylthio) penem-3-carboxylate.

B. Treat 160 mg of the reaction compound of Step A in exactly the same manner as in Example 3 B to give 32 g of the title product after isolation.

Example 6 (5R, 6S, 8R) -2- (1-Methyl-2-imidazolylmethyl) -6- (1-hydroxyethyl) -penem-3-carboxylic acid.

A. (5R, 6S, 8R) -allyl 2- (1-methyl-2-imidazolylmethylthio) -6- (1-hydroxyethyl) -penem-3-carboxylate.

In a 250 ml flask under a nitrogen atmosphere, place 1.38 g of an equilibrium mixture of the thionithiol of step H of Example 1, 50 ml of tetrahydrofuran (THF) and 1.2 g of 1-methyl-2-chloromethylimidazole (Preparation Example D). ° C. Add dropwise over 3 minutes 1.15 g of NaHCO 3 as a 10% aqueous solution. Stir for 45 minutes and allow to stand for one hour at 0 ° C. Remove the THP solvent and, after purification on silica gel columns, give the title product.

NMR - (CDCl 3, S = 6.95, 1H, s; 6.86, 1H, s; 5.9, 1H, m; 5.73, 1H, d; 5.32, 2H, m; 4.7, 2H, m 4.3, 2H, s, 4.2, 1H, m, 3.7, 1H, dd (J = 1.5, 6Hz), 3.68, 3H, s, 3H, d (J = 6 Hz).

<80702 B. Dissolve 1.05 g of the reaction product of Step A in 40 mL of ethyl acetate. React at room temperature with about 200 mg of Pd ° reagent, 200 mg of triphenylphosphine and 1.5 ml of caproic acid. Extract the title compound with water. Increase the yield by dissolving the unreacted starting materials in 15 mL of CH2Dl2, 1 mL of hexanoic acid, 0.3 mL of pyridine, 1.50 mg of triphenylphosphine, and about 100 mg of Pd ° for 1/2 hour. Extract the obtained title product with water and combine with the extract previously - the product has NMR - (D 2 O) = 7.3, 1H, s; 7.27, 1 H, s; 5.6, 1H, d (J = 1.6 Hz); 4.4: 1H: m; 3.85, 1H, dd (J = 1.5, 6Hz); 3.81, 3 H, s; 1.24, 3H d (J = 6 Hz).

Example 7 (5R, 6S, 8R) -6- (1-Hydroxyethyl) -2- (1-methyl-2-imidazolylmethylthio) penem-3-carboxylic acid.

A. (3S, 4R, 5R) -3- (1-Trichloro-ethoxycarbonyloxy-ethyl) -4 - [(1-methyl-2-imidazo-1-ylmethyl) -carbonothioylthio] -azetidine -2-one

To a solution of ethanol (50 ml), 1N sodium hydroxide (· 20 ml) and 2-methylthio N-methylimidazole (2.5 g), add carbon disulphide (4 ml) dropwise, stir for 10 minutes, then add it. dropwise to a solution of (3S, 4R, 5R) -4- [1- (2-methoxy-1,2-dioxyethyl)] - 3- (1-trichloroethoxycarbonyloxyethyl) -4-chloroazetidin-2-one (4.1 g) in ethanol . Stir the reaction mixture until TLC analysis shows no starting material (about 4 hours) then dilute with ethyl acetate, wash the solution with saturated sodium chloride, dry the solution over magnesium sulfate, evaporate and chromatograph the resulting residue on silica gel (40 g) eluting with 30% ether. Combine the eluents determined to be similar by 43 80702 TLC and evaporate the solvents to give the title product. I.R. = 5.65 μ.

NMR: 5.5ppm (1H, d, J = 2 cps) 3.4ppm (1H, 1, J = 8 and 2cps) B. Allyl- (5R, 6S, 8R) -6- (1-trichloroethoxycarbonyloxyethyl) -2- (l-methyl-2-imidazolyl methylthio) -penem-3-carboxylate.

To a solution of (3S, 4R, 5R) -3- (trichloroethoxycarbonyloxyethyl) -4 - [(1-methyl-2-imidazolylmethylthio) -carbonothioylthio] -azetidin-2-one (0.73 g) was added. and methylene chloride (6 mL) cooled to 10 ° C with stirring of calcium carbonate (0.6 g) followed by allyloxalyl chloride (0.263 g, 1.2 eq). Add dropwise a solution of diisopropylethylamine (0.32 mL, 1.2 eq.) In methylene chloride (1 mL) over 5 minutes while maintaining the temperature at 10-15 ° C. After TLC shows no starting material (15 minutes) at 15 ° C, change the mixture to a separatory funnel using ethanol-free chloroform. Wash twice with ice water, filter to remove excess calcium carbonate, dry over anhydrous sodium sulfate and transfer to a 3-necked 100 mL flask. Adjust the volume of the solution to approximately 50 mL with chloroform and heat to reflux while adding a solution of triethyl phosphite (0.6 mL, 2 eq.) In chloroform (20 mL) over 3 hours. Reflux the mixture for a further 18 hours, evaporate and chromatograph on 14 g of silica gel, eluting with 25% ether-hexane, and combine the similar eluates and evaporate to give a residue containing the title product. Purify by crystallization from ether-hexane to give the title product in crystalline form.

C. Allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (1-methyl-2-imidazolylmethylthio) -2-penem-3-carboxylate.

44 80702

Dissolve about 1.6 g of the reaction product prepared according to the method of Step B in 15 ml of tetrahydrofuran, 1.5 ml of water and 1.5 ml of acetic acid at 0-5 ° C with stirring. Add 2.0 g of zinc dust and stir until thin layer chromatography shows only traces of starting material. Filter the reaction mixture, wash the solids with ethyl acetate, combine the organic solvents and wash sequentially with 10% aqueous tartaric acid, water and aqueous sodium bicarbonate. Dry the solvent phase over magnesium sulfate and evaporate the solvent. Crystallize the residue from ether-hexane.

D. (5R, 6S, 8S) -6- (1-hydroxyethyl) -2- (1-methyl-2-imidazolylmethylthio) penem-3-carboxylic acid.

Treat the reaction product of Step C as described in Example 6B to give the title product.

Example 8 (5R, 6S, 8R) -6- (1-Hydroxyethyl) -2- (2-glycylaminoethylthio) -penem-3-carboxylic acid A. Allyl- (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-N [allyl-oksikarbonyyliglysyyliamino] ethylthio) -penem-3-carboxylate

Stir a solution of the reaction product of Preparation Example E (0.50 g) and the reaction product of Preparation Example P (0.58 g) at 0-5 ° C in dichloromethane and add diisopropylamine (0.2 g).

After 5 minutes, wash the solution with 10% aqueous tartaric acid, dry and evaporate and purify the residue by preparative TLC (eluting with EtOAc; reaction product Rf 0.4) to give the title product as a pale yellow foam.

PMR (CHCl 3): 1.35 (d, J = 7 Hz, 3H), 3.16 (m, 2H), 3.4-4.0 (m, 6H), 4.24 (m, 1H), 4.60 (d, 45 8 0 7 0 2 J = 7.5 Hz, 2H), 4.63 (m, 2H), 5.2-5.6 (m, 4H), 5.75 (d, J = 1.5 Hz, 1H), 5.7-6.2 (m, 3H) and 7.20 (br. T, J = 7 Hz).

B. Stir the reaction product of Preparation Example C (0.225 g), 2-ethylcaproic acid (0.20 g) and triphenylphosphine (0.05 g) at 30-35 ° C in CH 2 Cl 2 (20 mL) under nitrogen and add tetractis (triphenylphosphite). ) palladium (0.03 g). After 1.5 h, collect the precipitate by centrifugation after addition of ether (15 mL), wash with 3 x 10 mL of 4: 1 ether: CH 2 Cl 2 and dry under nitrogen to give the title product as a cream powder.

I.R. (nujoi): 3400, 1770, 1650 and 1590 cm-1.

Example 9 (5R, 6S, 8R) -6- (1-hydroxyethyl) -2 - [(2-glycylamino) ethylthio] penem-3-carboxylic acid.

A. (3S, 4R, 5R) -3- (1-Trichloro-ethoxycarbonyloxy-ethyl) -4 - [(2-allyloxycarbonyl-glycylamino-amino-ethyl) -carbonothioyl-ethyl] -azetidin-2-one sodium hydroxide (20 ml) and 2 - (N-allyloxycarbonyl-glycylamino) -ethanethiol (5.0 g), carbon disulphide (4 ml) dropwise. Stir for 10 minutes, then dropwise add (3S, 4R, 5R) -1- (2-methoxy-1,2-dioxyethyl) -3- (1-trichloroethoxycarbonyl-oxyethyl) -4-chloroazetidin-2-one (4.1 g) a solution in ethanol. Stir the reaction mixture until TLC analysis shows no starting material (about 4 hours), then dilute with ethyl acetate, wash the solution with saturated sodium chloride, dry the solution over magnesium sulfate, evaporate and chromatograph the resulting residue on silica gel (40 g) eluting with 30% ether-hexane. . Combine the 46 80702 eluates determined to be similar by TLC and evaporate the solvent to give the title product of this step.

B. Allyl- (5R, 6S, 8R) -6- (1-trichloro-ethoxycarbonyloxy-ethyl) -2 - [(2-N-allyloxycarbonyl-glycylamino) -ethylthio] -penem-3-carboxylic acid.

Add (3S, 4R, 5R) -3- (trichloroethoxycarbonyl-4- [2- (N-allyloxycarbonylglycylamino) ethylthio] carbonothioylthioazetidin-2-one (0.85 g) cooled to 10 ° C. to a solution in methylene chloride (6 mL) with stirring of calcium carbonate (0.6 g) followed by allyloxalyl chloride (0.263 g, 1.2 eq.) in methylene chloride (1 mL) over 5 minutes maintaining the temperature between 10 and 15 ° C. TLC shows that the starting material is no longer present, change the mixture to a separatory funnel using chloroform without ethanol, wash twice with ice water, filter to remove excess calcium carbonate, dry over anhydrous sodium sulfate, and transfer to a 3-necked 100 mL flask. chloroform and heat at reflux while adding a solution of triethyl phosphite (0.6 mL, 2 eq.) in chloroform (20 mL) over 3 h .. Reflux the mixture for an additional 18 h, evaporate and chromatograph on 14 g of silica gel, eluting with with 25% ether-hexane, combine similar eluates and evaporate to give a residue containing the title product. Purify by crystallization from ether-hexane to give the title product.

C. Allyl- (5R, 6S, 8R) -6- (1-hydroxyethyl) -2 - [(2-N-allyloxyglycylamino) ethylthio] -penem-3-carboxylic acid.

Dissolve 1.8 g of the product obtained in step B in 15 ml of tetrahydrofuran, 1.5 ml of water and 1.5 ml of acetic acid at 0-5 ° C with stirring.

47 80702

Add 2.0 g of zinc dust and stir until the thin layer chromatograph shows only traces of starting material. Filter the reaction mixture, wash the solids with ethyl acetate, combine the organic solvents and wash sequentially with 10% aqueous tartaric acid, water and aqueous sodium bicarbonate. Dry the solvent phase over magnesium sulfate and evaporate the solvent. Isolate the residue from ether-hexane to give the title product.

D. Treat 0.225 g of the product from Step C according to the procedure described in Example 8, Step B to give the title product of this example as a cream powder.

Example 10

Sodium (5R, 6S, 8R) - (1-hydroxyethyl) -2- (2-methylcarbamoyl-ethylthio) -penem-3-carboxylate.

A. Allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-methylcarbamoylthio) penem-3-carboxylate.

Mix a solution of the penemal l'lyl sulfoxide (2.55 g) prepared in Preparation Example E in CH 2 Cl 2 (40 mL) with 3-mercapto-N-methylpropionamide (1.92 g) and cool to -10 ° C. Add diisopropylethylamine (0.6 mL) and continue stirring at -10 ° C for 0.5 h. Add ether (50 mL) and collect the precipitate and wash with ether. Stir the resulting solid with CH 2 Cl 2 for 0.5 h at 0 ° C, collect and dry to give the title product as a white powder.

Sp. 176-178 ° C.

IR (nujol suspension): max 3400, 3300, 1775, 1695, 1635, 1560 and 1510 cm-1.

B. Sodium (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- [2- (methylcarbamoyl) ethylthio] penem-3-carboxylate.

49 80702

Stir a suspension / solution of the product from quenching example A (0.66 g) in dry THF containing sodium 2-ethylhexanoate (0.305 g) and triphenylphosphine (0.12 g) at 25 ° C under nitrogen and add Pd (PPh 3 ) 4 (0.08 g).

After 1.5 hours, add hexane (50 mL) and collect the crude product by centrifugation. Wash with 2 x 2 mL of ethyl acetate and partition with H2O (50 mL) -ethyl acetate (250 mL). Treat the aqueous phase with N »to remove dissolved organic matter. Then filter through 5 g of reverse phase C-18 silica gel and wash with water. Treat the filtrate with 5 g of DARCO activated carbon, stir for 0.5 hours, filter, wash with water and lyophilize to give the title product as a tan powder.

PMR (D 2 O): 1.30 (d, J = 7 Hz; 3H), 2.63 (m, 2H), 2.72 (s, 3H), 3.14 (m, 2H), 3.91 ( dd, J = 1.5 and 8 Hz), 4.25 (petent, J = 8, Hz, 1H) and 5.69 (d, J = 1.5 Hz, 1H).

Example 11

Sodium (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-metyylikarbamo-yylietyylitio) -penem-3-carboxylate.

A. (3S, 4R, 5R) -3- (1-Trichloro-ethoxycarbonyloxy-ethyl) -4 - [(2-methyl-carbamoylethyl-thio) -carbonothioyl-thio] -azetidin-2-one.

To a solution of 1N sodium hydroxide (20 mL) and 3-mercapto-N-methylpropionamide (2.6 g) in ethanol (50 mL) was added dropwise carbon disulphide (4 mL). Stir for 10 minutes, then dropwise add (3S, 4R, 5R) - [1- (2-methoxy-1,2-dioxoethyl) -3- (1-trichloroethoxycarbonyloxyethyl) -4-chloroazetidin-2-one ( 4.1 g) in ethanol. Stir the reaction mixture until TLC analysis shows no starting material (about 4 hours) then dilute with ethyl acetate, wash the solution with saturated sodium chloride, dry the solution over magnesium sulfate, evaporate the solvent and chromatograph the resulting residue on silica gel (40 g) eluting with 30% ether. hex-sequencing. Combine the eluates determined to be similar by TLC and evaporate to give the title product of this step.

B. Allyl (5R, 6S, 8R) -6- (1-trichloroethoxycarbonyloxyethyl) -2- (2-methylcarbamoylethylthio) penem-3-carboxylate.

To a stirred solution of azetidone (1.1 g) in step A in methylene chloride (6 mL) cooled to 10 ° C was added calcium carbonate (0.6 g) followed by allyloxalyl chloride (0.263 g, 1.2 eq.) In methylene chloride. (1 ml) over five minutes while maintaining the temperature between 10 and 15 ° C. After TLC shows that the starting material is no longer present, transfer the mixture to a separatory funnel using ethanol-free chloroform. Wash twice with ice water, filter to remove excess calcium carbonate, dry over anhydrous sodium sulfate, and transfer to a 3-necked 100 mL flask.

Adjust the volume of the solution to about 50 mL with chloroform and heat at reflux while adding a solution of triethyl phosphite (0.6 mL, 2 eq.) In chloroform (20 mL) over three hours. Reflux the mixture for a further 18 hours, evaporate and chromatograph on 14 g of silica gel, eluting with 25% ether-hexane. Combine similar eluates and evaporate to give the title product. Purify by crystallization from methylene chloride to give the title product.

C. Allyl (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2-methylcarbamoylethylthio) -2-penem-3-carboxylate.

Dissolve about 1.6 g of the product of step 80702 prepared according to the method of step B in 15 ml of tetrahydrofuran, 1.5 ml of water and 1.5 ml of acetic acid at 0-5 ° C with stirring. Add 2.0 g of zinc dust and stir until thin layer chromatography shows only traces of starting material. Filter the reaction mixture, wash the solids with ethyl acetate, combine the organic solvents and wash sequentially with 10% aqueous tartaric acid, water and aqueous sodium bicarbonate. Dry the solvent phase over magnesium sulfate and evaporate the solvent. Crystallize the residue from ether-hexane.

D. Sodium (5R, 6S, 8R) -6- (1-hydroxyethyl 2- [2- (methylcarbamoyl) ethylthio] penem-3-carboxylate.

Treat 0.66 g of the product obtained in Preparative Example C by the method described in Example 10, Step 8 to give the title product as a tan powder.

(5R, 6S, 8R) -allyl-2-substituted thio-6- (1-hydroxyethyl) -penem-3-carboxylate can be readily converted to their corresponding alkali metal salts in our EP application no. 0013663. In this method, the allyl group can be removed using a suitable aprotic solvent such as tetrahydrofuran, diethyl ether or methylene chloride, potassium or sodium 2-ethyl hexanoate as a catalyst, a mixture of palladium and triphenylphosphine to give the corresponding penem sodium or potassium salt directly.

By following the experimental methods published above using the appropriate starting materials, the following compounds can be prepared.

Γ

CH, -C-η-p ^ -SR

3 I

H m_L

/ \

0 CO2M

si 80702 M = hydrogen or alkali metal salt (preferably potassium or sodium salt).

The data for the CH - / ~ 0 ~ NH free acid of the (5R, 6S, 8R) isomer are as follows: 2 H, NMR (D2O) δ = 6.52, 1H, S; 5.52, 1H, d (J = 1.5 Hz); 4.28 - 4.04, 1H, m; 4.0 - 3.87, 2H ', m; 1.19, 3H, d (J = 6Hz).

13 The information for the sodium salt of the (5R, 6S, 8R) isomer of the -CH- C-N (CH3) g is as follows: 11 90 mHz NMR D2 O

^ 1.25 ppm, D J = 6Hz, 3H

3.17 ppm, s, 3H 3.30 ppm, s, 3H

3.8-4.3 ppm: m: 2h

5.70 ppm, D J = 1 Hz, H

A study of the in vitro activity of several representative novel penems of this invention against gram + Ve and cframma-ve bacteria is given in the table below. Study the performance of microlitral la using Muller Hinton Agar. The number of organisms in each group is indicated in parentheses in the left-hand column. The figures given are geometric means (MICs) based on several different values obtained for the individual strains in each group.

Compound 1. (5R, 6S, 8R) -6- (1-Hydroxyethyl) -2- [2- (aminoacetylamino) ethylthio] penem-3-carboxylic acid.

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

52 80702 3. (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (2,3-dihydroxypropylthio) -penem-3-carboxylic acid.

4. (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (1-methyl-2-imidazolylmethylthio) -3-carboxylic acid.

5. (5R, 6S, 8R) -6- (1-hydroxyethyl) -2- (N, N-dimethylcarbamido) -ylmethylthio) -penem-3-carboxylic acid.

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Claims (2)

A process for preparing an anti-bacterial penem compound of formula I ° HHHI - s H1 + c / ([- = / SR c <ί I f N \ coox o where R is -ch 2 -Ri where Rn is '2-Amino-4-thiazolyl, 1-methyl-2-imidazolyl, aminoacetylaminomethyl, N-methylcarbamoylmethyl, dihydroxy lower alkoxy, -C = NH' * 15 * 16 - where R15 and Rig are independently white or lower alkyl, X is a vate, pharmaceutically acceptable group forming group or a carboxy protecting group characterized by: (a) a tautomeric compound [(Vai), (Vb) J, where R is hydrogen (i.e., a compound of the formula Va) in equilibrium with its. tautomer Vb) OH c "OH I ς S * 1 SS -h-ry" Y-r γ <7 N - * - R2 J- Nk * - OO '2 (Va) (Vb) see 80702 where R2 is a protected carboxy group and is subjected to a reaction which introduces the group R: (i) by reaction with a compound of formula RZ where R is a previously defined organic radical and Z is an leaving group; (ii) (to produce a compound of formula I, where R is a C 2 -C 8 alkyl group having a hydroxy group attached to the second carbon atom from the sulfur atom and optionally containing one or more other substituents), by reaction with substituted or * unsubstituted 1,2-epoxy-C 2 -C 8 alkane (b) a compound of the formula VIIOH to A_ 'I (VII) J_n_LL COOH wherein R' is an organic group other than the desired group R is reacted with a thiol of formula VIII 'or with its reactive derivative R - SH (VIII ') where R is defined above; (C) a compound of formula IX OH Λ_ / 8 ^ 88 I s <»> o> - R2 is reacted with a trivalent organophosphorus compound, wherein in the above processes (a) - (c) which as heist functional groups in the reactants may be protected by protecting groups which are removed at any convenient stage of the process, and from the thus obtained compound of formula I the protection of the protected carboxyl group R2 (if present) is removed and isolated as acid or pharmaceutically acceptable ester. Process according to Claim 1, characterized in that the compounds: (5R, 6S, 8R) -2- [N, N-dimethylcarbamimidolyl) methylthio] -6- (1-hydroxy-ethyl) -penem-3-carboxylic acid, ( 5R, 6S, 8R) -2- (2,3-dihydroxy-1-propylthio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid, (5R, 6S, 8R) -2- [2- (aminoacetylamino) ) ethylthio] -6- (1-hydroxyethyl) -penem-3-carboxylic acid, (5R, 6S, 8R) -2- (1-methyl-2-imidazolylmethylthio) -6- (1-hydroxyethyl) -penem-3 carboxylic acid, (5R, 6S, 8R) -2- (N-methylcarbamoylethylthio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid, or their pharmaceutically acceptable acid or ester.