DD258610A5 - PROCESS FOR THE PREPARATION OF 5R, 6S-6- (1R-1-HYDROXYETHYL) -2- (OXO-3-THIOLANYLTHIO) -2-PENEM-3-CARBONSAEURES - Google Patents

Abstract

The invention relates to processes for the preparation of 5R, 6S-6- (1R-1-hydroxyethyl) -2- (1-oxo-3-thiolanylthio) -2-penem-3-carboxylic acids, which are useful as antibacterial agents. The object of the invention is to provide novel compounds which have antibacterial activity. According to the invention, the object is achieved by preparing compounds of the formula (I) by reacting compounds of the formula (IIId), where the substituent has the meaning given in the description, with a fluorine fluoride of the formula FCCOR3 OOworin the substituent which is described in US Pat Description acylated in a reaction-inert solvent at 0C to 80C in the presence of a tertiary amine, then cychisiert and then activated the ester function. Formula (I) and (IIId)

Description

-Si-C (CH ₃ )

4. The method according to any one of claims 1-3, characterized in that R ³

, -C _O

Cl '

5. The method according to any one of claims 1-3, characterized in that R ^{3 is} -CH ₂ -CH = CH ₂ .

Field of application of the invention

The present process relates to an improved process and intermediates for the preparation of SR ^ S-e-IIR-i-hydroxyethyl O-O-oxo-S-thiolanylthio) -penic-S-carboxylic acids having the formula

(I)

HO

or a pharmaceutically acceptable, cationic salt or the pivaloyloxymethyl ester thereof, in particular a salt or ester, which approximately consists of a 1: 1 mixture of diastereomers in which the penem substituent in the 2-position (cis-i-oxo-3) thiolanylthio), ie the thiolane ring substituents are located in cis position to each other.

Characteristic of the known technical solutions

These compounds were described for the first time in European Patent Application 130025, which also discloses the method of using these compounds as antibacterial agents.

Object of the invention

The synthetic method disclosed in EP 130025 is extremely versatile and therefore permits the convenient synthesis of a wide variety of analogs. However, for individual compounds, particularly the cis compound mentioned above as preferred and its pivaloyloxymethyl ester, more direct synthesis involving fewer chemical steps is highly desirable.

Explanation of the essence of the invention

An attractive precursor for the above compounds of formula (I) is 3R, 4R-acetoxy- [1R-1- (dimethyl-t-butylsilyloxy) ethyl] -2-azetidinone of the formula

.OCOCH.

"B

.NH

a compound which can be obtained in good yield e.g. Tetrahedron, Vol. 39, pp. 2505-2513 (1983) from 6-amino-penicillanic acid according to the method of Leanza et al. As a first step in a proposed vi synthesis, azetidinone was reported by Leanza et al. in the new connection with the formula

transformed. However, this compound lacked usefulness for the subsequent intended reaction with an acid chloride since the latter reagent preferentially reacted with the thiolane-sulfoxide group thereby forming worthless products. Unexpectedly, however, substitution of the acid chloride with an acid fluoride resulted in selective acylation on the nitrogen to form previously inaccessible compounds of the formula (HIb) (see below), thereby forming the intermediate compounds of the formula (IIIa) (see below) Recycling were supplied and, by further reactions, additional valuable intermediates having the formula (II) were provided. Although the above-mentioned dimethyl-t-butylsilylhydroxy-protective group is preferred, it may be replaced by other silylhydroxy-protective groups, of course

 Accordingly, the present invention relates to compounds having the formulas

F-C-C-OR 3 O O K ι N // O 3 * · λ * X wherein st and X is hydrogen or chlorine, δ.

or -CH - 0-C-C (CH,)

(II)

-0-R "

wherein R ^{3 is} as defined above and R ^{2 is} hydrogen or a conventional silylhydroxy protecting group (preferably dimethyl-t-butylsilyl), provided that R ^{2 is} not hydrogen when R ^{3 is} pivaloyloxymethyl, and

wherein R ^{1 is} a common silylhydroxy protecting group (preferably dimethyl-t-butylsilyl) and R is hydrogen or -CCOR ³

m «ι

0 0.

wherein R ^{3 is} as defined above.

Also included in the present invention is a process for preparing a compound of the formula

wherein R ¹ and R ^{3 are} as defined above which comprises acylating a compound of the formula

with an acid fluoride of the formula FCC-OR ³

ti

O O

in the presence of a tertiary amine in a reaction-inert solvent at ⁰ ° C to -80 ⁰ C. Low temperatures, eg. B.

-2O ⁰ C to -70 ° C, are preferred. The method further includes the usual methods for converting the product (III) via the compounds of the formula (II) into the compounds of the above formula (I).

Finally, when R ^{3 is} pivaloyloxymethyl, the invention relates to a process for the conversion of the corresponding acid chloride using potassium fluorosulfinate as a reagent into the acid fluoride (IV).

The term "reaction-inert solvent" defines a solvent which does not interact with the reagents, intermediates or products in such a way as to adversely affect the yield of the desired product.

The present invention further includes a process for the conversion of a compound having the above-mentioned formula (II), wherein R ^{2 is} hydrogen and R ^{3 is} a group other than pivaloyloxymethyl, into a compound having the above-mentioned formula (I) or into a compound of their pharmaceutically acceptable cationic salts.

It will be apparent to those skilled in the art that the above-exemplified allyl or 2-chloroallyl esters are exemplified by benzyl or p-nitrobenzyl esters.

could be replaced, the last deprotection now using conventional hydrogenolysis process

would be made.

In the first step of the present synthesis, racemic cis or trans-3- (acetylthio) thiolane 1-oxide is obtained by the action of an alkali metal alcoholate, e.g. As of sodium, under strictly adhered to anhydrous conditions in a reaction-inert solvent such. B. converted into isopropyl alcohol in the mercaptide salt,

CH ₃ -CS

UaOCH.

S-X)

(B)

preferably at reduced temperatures (eg. B. -5 ⁰ C to -45 ⁰ C), most preferably at -20 ° C to -30 ° C. While maintaining the same anhydrous conditions and the reduced temperature, the mercaptide salt (C) with

, -j r- 1

(D)

S-S-O

forms, which then with an azetidinone such as that with the above-shown formula (A), is reacted, and generally at somewhat higher temperatures (for example 20 ⁰ C to 20 ⁰ C), preferably at -5 ° C to + 5 ⁰ C, to represent the compound of formula (III a) (see above). Each of the resulting cis and trans products is composed of a pair of diastereomers in approximately equal amounts.

Subsequently, the compound of the formula (IIIa) is allowed to react with the acid fluoride of the formula (IV) under the conditions generally described and summarized above. The initial temperature most preferred covers the range from -45 ⁰ C to -60 ⁰ C, which is eventually raised to -15 ⁰ C to -25 ° C. An ideal reaction-inert solvent is methylene chloride. An ideal tertiary amine is Ν, Ν-diisopropylethylamine.

In the next step of the synthesis, the compound of formula (II) wherein R ^{2 is} a silyl protecting group and which now contains the complete penem ring system is formed by the action of a trialkyl phosphite (e.g., triethyl phosphite) on a compound with the formula (III b) in a reaction-inert solvent (eg in ethanol-free chloroform). The temperature is not critical, but will generally be above ambient, e.g. B. 40 ⁰ C to 80 ° C, conveniently be the boiling point when chloroform is the solvent.

At the last or penultimate stage, the silyl protecting group is removed by standard procedures, e.g. Example, in the case of dimethyl-t-butylsilyl, by the action of acetic acid and tetrabutylammonium fluoride in anhydrous tetrahydrofuran, wherein the compound of formula (I) in the form of their Pivaloyloxymethylesters or those of the formula (II) wherein R ^{2 is} hydrogen , is formed.

Lastly, when R ^{3 is} allyl or 2-chloroallyl, the ester is hydrolyzed to the desired penem of formula (I) (above), in the form of the acid or its pharmaceutically acceptable cationic salt. Anhydrous conditions are generally used to avoid decomposition of the beta-lactam. Preferred conditions include the use of 1 to 1.1 molar equivalents of an alkali metal salt of a lipophilic carboxylic acid (eg, sodium 2-hexanoate) in an anhydrous, reaction-inert solvent (eg, methylene chloride and / or ethyl acetate) in the presence of catalytic amounts of triphenylphosphine and tetrakis (triphenylphosphine) palladium (eg, about 0.15 molar equivalents of the former and about 0.075 molar equivalents of the latter). Although the temperature is not essential, the reaction is conveniently carried out at ambient temperature.

The required acid fluorides (IV) are prepared from the corresponding acid chlorides using reagents previously used for this purpose, either anhydrous cesium fluoride (usually at or near ambient temperature, with the reagents first being combined at lower temperatures, e.g. 0 ° C to -30 ⁰ C)

or Kaliumfluorsulfinat (FSO2K, usually at higher temperatures, for. example, 45-85 ⁰ C). Surprisingly, only the latter reagent provides satisfactory acid fluoride yield under the conditions specified therein when R ^{3 is} pivaloyloxymethyl.

With respect to the starting materials needed for the process of the present invention, 3R, 4R-4-acetoxy-3- [1R-1- (silyloxy) ethyl] -2-azetidinones are prepared according to the method of Leanza et al., Ref. s. above, easily accessible; the racemic cis- and trans-3- (acetylthio) -thiolane-1-oxides are each obtainable by the process of the above cited European patent application; Oxalyl chloride 2-allyl ester is prepared by the method of Alfonso et al., J. Am. Chem. Soc., Vol. 104, pp. 6138-6139,

(1982) available oxalic acid chloride 2- (2-chloroallyl) ester is obtained from 2-chloroallyl alcohol and oxalic acid chloride according to the procedure detailed below and oxalic acid 2-pivaloyloxymethylester is prepared by a step sequence of the benzyl half ester of oxalic acid and pivalo chloromethyl ester, as will also be explained in more detail below.

The following examples are given for the purpose of illustration and should not be construed as limitations of this invention in which many modifications are possible that are within its scope and spirit.

embodiments

Example 1 SS ^ RS-tiR-i-1-Dimethyl-t-butylsilyloxyethynyl-1-cis-i-oxo-S-thiolanylthiotethiocarbonyldithiol-azetidinone A three-necked flask equipped with a mechanical stirrer, dropping funnel and cryogenic thermometer was placed under N ₂ Atmosphere with racemic cis-S-IAcetylthioJthiolan-i-oxide (4.26g, 23.9mmol) and 90ml isopropyl alcohol filled. The reaction mixture was cooled to an internal temperature of -20 ° C and sodium methoxide (1.18 g, 21.9 mmol) was added all at once. The reaction mixture was stirred for 90 minutes at -2O ⁰ C to -25 ° C and then allowed to warm to -10 ⁰ C. The reaction mixture was again cooled to -30 ⁰ C and a solution of carbon disulfide (7.94 g, 104mmol) in 30ml of isopropyl alcohol was added over a period of 30min dropwise. The reaction mixture was stirred for 40 min at -25 ⁰ C to -30 ⁰ C. Over a period of thirty minutes, a solution of 3R, 4R-4-acetoxy-3- [1 R-1 - (dimethyl-t-butylsilyloxy) ethyl] -2-azetidinone (6g, 20.9 mmol, Leanza et al. , Tetrahedron 39, pp. 2505-2513 [1983]) in 54 ml of isopropyl alcohol. The reaction mixture was stirred at -20X for thirty minutes, then allowed to warm to 0 ⁰ C and stirred for ninety minutes at ⁰ ° C to 1 ⁰ C. The Rea.ktion was quenched with 150 ml of saturated ammonium chloride solution and then added 200ml of ethyl acetate. The mixture was transferred to a separatory funnel and treated with 150 ml of saline. The organic phase was separated and the aqueous phase was extracted with a further 200 ml of ethyl acetate. The combined ethyl acetate extracts were washed twice with 100 ml brine each. The organic phase was cooled to 5 ⁰ C and dried over MgSO 4; then it was filtered and concentrated in vacuo to a viscous oil. The oil was azeotroped four times with 50 mL each of methylene chloride and exposed to a high vacuum to give 8.32 g (90.5%) of a yellow foam containing a mixture of two diastereomers of the title compound.

An analytically pure sample was prepared by stirring a sample of the foam described above with isopropyl ether for two hours. The yellow solid was filtered and dried, mp. 85-89 ⁰ C (dec.). Analysis calculated for C ₁₆ H ₂₉ O ₃ NS ₄ Si:

C 43.69 H 6.65 N 3.19% Found C 43.41 H 6.38 N 3.06% IR (KBr) cm -1 ¹ 1770.

¹ H-NMR (CDCl ₃ ) delta (ppm): 0.072 (s, 3H, CH ₃ Si), 0.07-7 (s, 3H, CH ₃ Si), 0.877 (s, 9H, t -butyl), 1.21 (d, J = 6.1 Hz, 3H, CH _3), 2.74 to 3.24 (m, 6H, 3CH _2), 3.78 (m, 1 H, CHS), 4.29 (dd, J = 6.1, 3.7Hz, 1H, CH), 4.55 (m, 1H, CHO), 5.65 (m, 1H, CHS), 6.65 (bs, 1 H, NH).

Example 2 SS ^ R-N-EiZ-Chlorallyioxyloxalyll ^ -liR-i-ldimethyl-t-butylsilyloxylethyll ^ -tcis-i-oxo-S-thiolanylthiolthiocarbonyDthioi-a-

azetidinone

A three necked flask, equipped with a dropping funnel and a cryogenic thermometer, was filled under N ₂ with the product of the previous example (52.2 g, 118.7 mmol) and 975 ml of dry methylene chloride (run through neutral alumina). The reaction mixture was cooled to an internal temperature of -50 ° C to -55 ⁰ C and oxalic acid fluoride-2- (2-chloroallyl) ester (24.7 g, 148,4mmol) was added dropwise within a period of twenty minutes and the reaction mixture was further stirred at -50 to -55 ° C for ten minutes. 16.1 g (124.6 mmol) of N, N-diisopropylethylamine was added dropwise over sixty-five minutes. The reaction mixture was stirred for 75min at -50 ⁰ C to -55T. The mixture to -20 ⁰ C was allowed to warm and brought the reaction by slowly adding 900 ml of water to a standstill. The organic phase was separated and washed with a further 900 ml of water and 900 ml of brine. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo to 65.6 g (94%) of a mixture of two diastereomers in the form of a beige foam.

¹ H-NMR (CDCI ₃₎ delta (ppm): .033 (s, 3H, _CH3 Si), .095 (s, 3H, CH ₃ Si), 0.86 (s, 9H, t-butyl), 1.24 (d, J = 6.4Hz, 3H, CH _3), 2.75 to 3.77 (m, 7H, thiolane), 4.43 (m, 1 H, CH), 4.66 (m , 1 H, CHO), 4.84 (s, 2H, CH _2), 5.47 (d, 1 H, vinyl CH), 5.56 (d, 1 H, vinyl CH), 6.7 and 6 , 74 (2d, J = 3.7Hz, 1H, NCHS)

IR (KBr) cm " ¹ 1820, 1762, 1708.

Example 3 5-R, 6S-6- [1R-1- (dimethyl-t-butylsilyloxy) ethyl] -2- (cis-1-oxo-3-thiolanylthio) -2-penem-3-carboxylic acid (2 Chloroallyl ester A heated three-necked flask equipped with a reflux condenser and an equilibratable addition funnel was charged under an N ₂ atmosphere with the product of the preceding example (15.6 g, 26.6 mmol) and 800 ml of ethanol-free chloroform. The reaction mixture was heated to a weak boil and triethylphosphite (9.3 g, 56 mmol) in 70 ml of ethanol-free chloroform was added dropwise over a period of eight hours. The reaction mixture was heated to a gentle boil for a further eight hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was stirred with cold isopropyl ether, filtered and dried an off-white solid 6,23g (43%) which was obtained as mixture of two diastereomers, mp. 138-140 ⁰ C.

Analysis calculated for C _2i H ₃₂ O ₅ NS ₃ CISi:

C 46.86 H 5.99 N 2.60 S 17.87% Found C46 / 71 H 5.94 N 2.49 S 17.73%

¹ H-NMR (CDCl ₃ ) delta (ppm): 0.064 (s, 6H, 2CH ₃ Si), 0.87 (s, 9H, t -butyl), 1.24 (d, J = 6.4Hz, 3H , CH ₃ ), 2.70-4.05 (m, 8H, CHCO, thiolane), 4.25 (m, 1H, CH), 4.74 (q, J _AB = 14.1 Hz, 2H, CH ₂ ), 5.38 (d, J = 0.5Hz, 1H, CRS), 5.66 (m, 2H, vinyl CH ₂ ). IR (KBr) OrT ¹ 1784.

Example 4 5R, 6S-6- (1R-1-hydroxyethyl) -2- (cis-1-oxo-3-thiolanothio) -2-penem-3-carboxylic acid (2-chloro) allyl ester A heated three-necked flask, equipped with a thermometer and two addition funnels, was charged under an N ₂ atmosphere with the product of the preceding example (22.7 g, 42 mmol) and 65 ml of dry tetrahydrofuran.

The reaction mixture was cooled to an internal temperature of 5 ⁰ C, and 25.2 g (420mmol) of glacial acetic acid were added dropwise over a period of fifteen minute period, keeping the internal temperature was maintained at 5 ° C.

Tetrabutylammonium fluoride in tetrahydrofuran (1M, 126ml) was added dropwise while maintaining the internal temperature of 5 ° C over one hour. The reaction mixture was allowed to warm slowly to room temperature and stirred at room temperature for a further sixteen hours. The reaction mixture was poured into 2000 ml of ice-water and extracted with 3 × 1000 ml of ethyl acetate. The combined organic extracts were washed with 3 × 650 ml of water, 2 × 650 ml saturated NaHCO ₃ and 2 × 650 ml brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield 14.14 g (79%) of a yellow solid, which came as a mixture of two diastereomers. An analytical sample was prepared by stirring a portion of the sample in ethyl acetate, m.p. 145-149 ° C (dec.).

¹ H-NMR (DMSO-d ₆₎ delta (ppm): 1.17 (d, J = 6.8 Hz, 3H, CH _3), 2.38 to 4.04 (m, 9H, CHCO, CHO, thiolane ), 4.78 (q, J _AB = 14.1 Hz, 2Ή, CH ₂ ), 5.25 (d, J = 4.4Hz, 1H, OH), 5.48 (s, 1H, CHS ), 5.76 (d, 2H, vinyl CH ₂ ).

IR (KBr) cm " ¹ 1769.

Analysis calculated for C ₁₅ H ₁₈ O ₅ NS ₃ Cl:

C 42.49 H 4.28 N 3.31% Found C 42.79 H 4.39 N 3.28%

Example 5 Sodium SR ^ Se-fiR-i-hydroxyethyl-Z-cis-i-oxo-S-thiolanylthio) ^ -penem-a-carboxylate A baked, aluminum foil wrapped flask was charged with the product of the above under an argon atmosphere Example (18.2g, 43mmol) in 400ml degassed CHjCl ₂ , triphenylphosphine (1.69g, 6.5mmol), sodium 2-ethylhexanoate (60.1ml of an O, 82M solution in ethyl acetate, 49mmol) and tetrakis (triphenylphosphine) palladium ( 3.69 g, 3.2 mmol). The reaction mixture was stirred at room temperature for seventy minutes, a further 350 mg

Tetrakis (triphenylphosphine) palladium was added and the reaction mixture was stirred at room temperature for a further twenty-five minutes. Degassed ethyl acetate (275 ml) was added to the reaction mixture over six minutes. The reaction mixture was stirred at room temperature for thirty minutes, filtered and the solid was briefly air-dried, then slurried with 180 mL acetone for thirty minutes, filtered and dried to give the 15.3 g (97%) product as a yellow solid, which was obtained as a mixture of two diastereomers, corresponding to the cis-1-oxo-3-thiolanyl isomer of Example 2, page 20 of European Patent Application 130,025. Following the same procedure, the product from Example 9 below is converted into the same title product in similar yield.

Example 6 SR.eS-e-IIR-i-Hydroxyethyll-a-cis-i-oxo-thiolanylthioJ-a-penem-a-carboxylic acid The sodium salt of the preceding Example (1g) was dissolved in 10 ml H ₂ O and treated with 3 χ 3 ml of butanol and then extracted with 2 χ 3 ml of ethyl acetate. The aqueous phase was stirred forty-five minutes at 0-5 ⁰ C and 750 mkg activated charcoal and then filtered. The filtrate was extracted three times with 3 ml of butanol and then with 2 × 3 ml of ethyl acetate. The aqueous phase was stirred for ninety minutes at 0-5 ⁰ C with 750 mg of activated charcoal, then filtered and freeze-dried to give 696 mg of a pale tan solid. This was dissolved in 1.2 ml H ₂ O, cooled to 0-5 ° C, acidified with 1 N HCI to pH 2.6, forty five minutes, stirred at 0-5 ⁰ C, filtered, washed with a small amount of H ₂ O and dried to give 374 mg of a white solid, a mixture of two diastereomers, m.p. 178-181 ⁰ C (dec.). IR (KBr) cm "" ¹ 1778.1745

¹ H-NMR (DMSO-d ₆₎ delta (ppm): 1.16 (d, J = 5.6 Hz, 3H, CH _3), 2.38 to 4.00 (m, 9H, CHCO, CHO, thiolane ), 5.25 (bs, 1H, OH), 5.72 (s,

1H, CHS)

Analysis calculated for C ₁₂ H ₁₅ O ₅ NS ₃ :

C 41.24 H 4.33 N 4.01% Found C41.32 H 4.24 N 2.82%.

Example 7 aS ^ RN ^ Allyoxy-oxo-O-S-IIR-i-t-dimethyl-t-butylsilyloxy-1-yl-1-cis-i-oxo-S-thiolanylthiofthiocarbonyo-thiol-a-azetidinone Except that the reaction mixture was stirred at -50 for 3.5 hours ⁰ C maintained and was not heated before terminating the reaction to-20 ⁰ C, the procedure of example 2 was followed, the title product of example 1 (1.00 g, 0.00227 mol) with oxalic acid fluoride-2-allyl ester (0 , 37 g, 0.00283 mol) to the title compound of this example in the form of a viscous yellow oil, 1.19 g.

¹ H-NMR (CDCl ₃ ) 300MHz delta (ppm): 0.04 (s, 3H), 0.10 (s, 3H), 0.86 (s, 9H), 1.24 (d, 3H, J = 6.3Hz), 2.74 (m, 3H), 2.84 (m, 1H), 3.17 (m, 1H), 3.58 (m, 1H), 3.79 (dd, 1H, J = 8.8, 14.7 Hz), 4.40 (m, 1H), 4.79 (d, 2H, J = 5.9Hz), 5.32 (dd, 1H, J = 1 , 10.5Hz), 5.40 (dd, 1H, J = 1.17.2Hz), 5.94 (ddt, 1H, J = 5.9, 10, 5, 17.2Hz), 6.70 and 6.72 (2d, 1H, J = 3.5Hz).

Example 8 Allyl SR.sub.S-e-tiR-i-dimethyl-t-butylsilyloxyethyll-cis-i-oxo-S-thiolanylthiol-a-penem-a-carboxylic acid

Following the procedure of Example 3, the product of the preceding example (1.19 g, 0.00216 mol) was converted to the title product of this example, the latter being stirred, with pentane rather than isopropyl ether (yield 0.73 g), and further by silica gel chromatography purified with ethyl acetate as eluent, 0.415g, TLC Rf 0.3 (ethyl acetate). ¹ H NMR (CDCl ₃ ) 300MHz delta (ppm): 0.08 (s, 6H), 0.88 (s, 9H), 1.25 (d, 3H, J = 6.3Hz), 2.6- 2.9Hz), 2.6-2.9 (m, 4H), 3.13 (m, 1H), 3.64 (m, 1H), 3.70 and 3.72 (2 dd, 1 H, J = 1.5.4.7 Hz), 3.84 and 3.97 (2 dd, 1 H, J = 8.4, 14.2 Hz), 4.24 (m, 1 H), 4.70 (m, 2H), 5.24 (dd, 1H, J = 1.3, 10.5 Hz), 5.40 (dd, 1H, J = 1.3, 17.1 Hz), 5, 63 and 5.65 (2 d, 1 H, J = 1.5 Hz), 5.93 (ddt, 1 H, J = 5.6, 10.5, 7.1, 1 Hz).

Example 9 allyl 5R _> 6S-6- (1R-1-hydroxyethyl) -2- (cis-1-oxo-3-thiolanyl-thio) -2-penem-3-carboxylate The product of the preceding Example (200 mg, 0.397 mmol ) was reacted by the method of Example 4 to give the title compound of this example, which was purified by chromatography on silica gel with 1:19 CH ₃ OH: ethyl acetate as eluant, 133 mg.

¹ H-NMR (CDCl ₃ ) 300MHzdelta (ppm): 1.36 (d, 3H, J = 6.2Hz), 2.46 and 2.51 (2brd, 1H), 2.6-2.9 (m , 4H), 3.14 (m, 1H), 3.6-3.8 (m, 2H), 3.81 and 3.93 (2dd, 1H, J = 8.14Hz), 4.23 (m , 1 H), 4.66 (dd, 1 H, J = 5.6, 13 Hz), 4.77 (dd, 1 H, J = 5.6, 13 Hz), 5.25 (d, 1 H, J = 10.5Hz), 5.41 (d, 1H, J = 17.1Hz), 5.67 and 5.70 (2s, 1H), 5.94 (ddt, 1H, J = 5) , 6,10,5,17,1). IR (KBr) cm " ¹ 3233, 1767, 1681, 495, 1316, 1201, 1224.

Example 10

SS ^ R-N-tPivaloyloxymethyloxyoxalyO-S-LIR-i-tdimethyl-t-butylsilyloxylethyll ^ -lcis-i-oxo-S-thiolanylthiotthiocarbonyOthio] -2-azetidinone

The product of Example 1 (4,65g, 0,0106mol) was dissolved in 21,1ml dried CH ₂ CI ₂ and cooled to -30 ⁰ C. Oxalic acid fluoride-2-pivaloyloxymethyl ester (4,36g, 0.0211 mol) was added and the mixture was cooled to -5o C ^0. Ν, Ν-diisopropylethylamine (1.63 g, 2.21 ml, 0.0127 mol) was added by syringe within 5 minutes, whereby the mixture warmed to -35 ⁰ C. After 35 Minuteri at -35 ° C to -50 ⁰ C the mixture with 125 ml of dry CH ₂ CI ₂ and then diluted with 185 ml H ₂ O was. The CH ₂ Cl ₂ phase was separated, washed once with 185 mL of fresh H ₂ O, dried over Na ₂ SO ₄ , and the solvent removed to give the title product, 7.06 g, contaminated with acid fluoride but of sufficient purity for the next Step, TLC Rf 0.3 (ethyl acetate).

¹ H-NMR (CDCl ₃ 90 MHz) delta (ppm): 0.04 (s, 3H), 0.10 (s, 3H), 0.88 (s, 9H), 1.21 and 1.2-1 , 6 (s, and m, 12H), 2.6-3.4 (m, 5H), 3.6-4 (m, 2H), 4.4- ^, 8 (m, 2H), 5, 85 (s, 2H), 7.2 (m, 1H).

Example 11 SR.eS-e-fiR-i-Idimethyl-t-butylisilyloxy-ethyl-a-lcis-i-oxo-S-thiolanylthiol-a-peneno-a-carboxylic acid pivaloyloxymethyl ester Following the procedure of Example 3, the product of the above Example (6.98g crude product corrected to 6.52g, 0.0104mol) was converted to the crude title product of this example (11.8g), which was taken without titration by taking up in 480ml hexane and 90ml CH ₂ Cl ₂ , washing four times 300 ml of H ₂ O, drying over Na ₂ SO ₄ and concentration to a golden oil (8.71 g) was further purified while still adhering to the smell of triethyl phosphite.

Crystallization of this product from ethyl acetate (12 mL was used to dissolve) and hexane (165 mL to cloud point, 300 mL moreover during 3 hours digestion) provided purified title product, 2.50 g, DCRf 0.15 (ethyl acetate). ¹ H-NMR (CDCl ₃ ) delta (ppm): 0.1 (s, 6H), 0.9 (s, 9H), 1.2 (m, 12H), 2.4-4.5 (m, 9H), 5.7 (dd, 1H), 5.9 (q, 2H).

EXAMPLE 12 Pivaloyloxymethyl SR ^ Se-liR-i-hydroxyethyO-cis-i-oxo-S-thiolanylthiol ^ -penem-S-carboxylic acid ester Following the procedure of Example 4, the product of the preceding example (1.88g, 3, 25mmol) was converted to the title product of this example, which was first isolated by diluting the reaction mixture with 500ml of ethyl acetate, washing with 3 x 150ml brine, drying over Na ₂ SO _4, and concentration. The resulting residue was redissolved in 200 ml of ethyl acetate, washed with 2 × 150 ml of H ₂ O, each time adding enough saline to destroy the emulsion, and the combined extracts were shaken out again with ethyl acetate and the ethyl acetate was extracted with the first organic Phase united. The latter mixture was dried over Na ₂ SO ₄ and concentrated again to a foam, 1.66 g, which was crystallized from ethyl acetate and ether to give the purified title product, 1.34 g. IR (KBr) 2,96,5,60, 5,69, 5,91,6,75 micrometers.

¹ H-NMR (250MHz CDCI ₃₎ delta (ppm): (1.23 (s, 9H), 1.35 (d, 3H), 2.5 (bc, 1 H), 2.6-2.9 c, 4H), 3.16 (m, 1H), 3.62-4.0 (c, 3H), 4.25 (m, 1H), 5.7 and 5.72 (2d, 1H ), 5.88 (q, 2H).

Preparation Example 1 Oxalic acid fluoride-2- (2-chloroallyl) ester [(2-chloroallyloxy) oxalyl fluoride] CH ₂ = CCICh ₂ O (CO) COF

In baked glassware and dry nitrogen, cesium fluoride (167 g, 1.1 mol) was placed in a 1 liter one-necked flask, gently heated under high vacuum with the Bunsen burner until the solid was free-flowing, and then cooled to room temperature. Over CaH _2, distilled acetonitrile (183 ml) was added and the mixture was cooled to an internal temperature of -20 ⁰ C.

Oxalic acid chloride 2- (2-chloroallyl (ester (183g, 1.0 mol) was added dropwise over 30 minutes and the mixture warmed slowly to room temperature, stirred at this temperature for 16 hours, and the by-produced cesium chloride was passed through Filtration and washing with acetonitrile were isolated, the filtrate and wash were combined and concentrated, and the residue was distilled at reduced temperature to give 129 g (77%) of the desired product, bp 62-64 ° C / 22mm.

IR (CHCl ₃₎ cm ^"1 1770.1870

¹ H-NMR (CDCl ₃ ) delta (ppm) 4.80 (s, 2H), 5.4-5.6 (m, 2H).

Production Example 2

Oxalic acid fluoro-2-ailyl ester, [allyloxyalyl fluoride] CH ₂ = CHCH ₂ O (CO) COF

Following the procedure of the previous Preparation Example, oxalic acid chloride 2-allyl ester (252.5 g, 1.70 mol) and cesium fluoride (284 g, 1.87 mol) were reacted to the second distilled title product, bp 48-50 ° C / 35mm, 124-126 ° C (atmospheric pressure).

¹ H-NMR (CDCl ₃ ) 250 MHz delta: 4.76 (d, 2H, J = 6Hz), 5.28 (dd, 1H, J = 1.7Hz), 5.37 (dd, 1H, J = 1.17 Hz), 5.90 (ddt, 1H, J = 6.11, 17Hz).

¹³ C-NMR (CDCl ₃ ) 63MHz, delta: 68.5 (t), 120.4 (t), 129.7 (d), 146.3 (d, J _C - _F = 375Hz), 153.0 (d, Jc-cf = 87Hz).

IR (neat) 1860 (C = O), 1770 (C = O), 1120cm ' ¹ .

Production Example 3 Oxalic acid chloride 2- (2-chloroallyl) ester

[(2-chloroallyloxy) of oxalyl chloride]

Oxalic acid dichloride (130 ml, 1.49 mol) was placed under N ₂ in a dry three-necked flask and cooled to ⁰ ° C. With stirring was added dropwise 2-chloro-allyl alcohol (138g, 1,49mmol) to in such a manner that the temperature was maintained at 0-2 ⁰ C and remained the vigorous evolution of HCl under control, then the mixture was allowed to reach room temperature, kept it at this temperature for 16 hours and distilled to yield the title product, 214g, bp 82-84 ° C / 23mm.

Production Example 4 Oxalic acid chloride-2-benzyl ester

[(Benzyloxy) oxalyl chloride]

Under nitrogen, oxalic acid dichloride (262 ml) was dissolved in 1 liter of anhydrous ether and heated to reflux, at which temperature benzyl alcohol (207 ml) was added over 70 minutes. After refluxing for an additional 16 hours, the ether was removed and the residue was distilled under reduced pressure to give 372 g (94%) of the title product, b.p. 0.7 mm: 85 ^° C.

Production Example 5 Oxalic acid monobenzyl ester

The title product of the preceding Preparation Example (180g, 0.91 mol) was cooled in 800 ml of ether in an acetone-dry ice bath. After the mixture to 0 ⁰ C had been allowed to warm up, was added aqueous NH ₄ OH (2M, 906ml, 0.91 mol)

added in portions. Then, the mixture was warmed to room temperature, stirred for 1 hour, and the pH was adjusted to 8.5 with 95 ml of 2 M NH ₄ OH. The aqueous phase was separated, extracted with 2 × 400 ml of ether, covered with 500 ml of fresh ether, cooled to 10 ⁰ C and the pH was adjusted to 1.5 with 2 M HCl. The phases were separated, the aqueous phase was extracted with 2 x 400 ml of ether and the three acidic organic phases were combined, washed with 500 ml of brine, dried over Na ₂ SO ₄ and concentrated to give the title product as a white solid, 163g. ¹ H-NMR (CDCl ₃ ) delta (ppm): 5.2 (s, 1H), 6.95 (s, 2H), 7.3 (s, 5H).

Production Example 6 Oxalic acid-1-benzyl-2- (pivaloyloxy methyl ester

The product of the previous Preparation Example (163 g, 0.91 mol) was dissolved in 1 liter of CHCl 3 and carefully (foamed!) Neutralized with NaHCO ₃ (76.2 g, 0.91 mol). Separately, tetrabutylammonium hydrogen sulfate (308 g, 0.91 mol) in 1.5 liters of H ₂ O was carefully neutralized with the same amount of NaHCO ₃ . The former slurry was added slowly to the latter solution, the mixture was stirred vigorously for 20 minutes, the aqueous phase was separated and washed with 500 ml of fresh CHCl 3. The organics were combined, dried over Na ₂ SO ₄ , and concentrated to give 478 g of mono (tetrabutylammonium) oxalate 2-benzyl ester. This was taken up in 400 ml of acetone. Chloromethyl pivaloate (118 ml, 0.82 mol) was added and the mixture was stirred under N _{2 for} 16 hours at ambient temperature. The acetone was removed and the residue was taken up in 1 liter of ethyl acetate, washed with 4 × 500 ml H ₂ O and 1 × 500 ml brine, dried over Na ₂ SO ₄ and concentrated to the title product as an oil, 201 g DC R _f 0, 60 (2: 3 ethylacetaf.hexane)

¹ H-NMR (CDCl ₃ , 90 MHz) delta (ppm): 1.21 (s, 9H), 5.2 (s, 2H), 5.8 (s, 2Hh 7.3 (s, 5H).

Preparation 7 Oxalic acid (pivaloyloxymethyl) ester

The title product of the preceding Preparation Example (27.3 g, 0.093 mol) and 2.8 g of 10% Pd / C were combined in 150 mL of ethyl acetate and hydrogenated in a pair hydrogenator at four times atmospheric pressure and ambient temperature for 1.5 hours. The catalyst was filtered off through filtration through silica and the filtrate was freed from the solvent to give the title product as an oil, 19.3 g

¹ H-NMR (CDCl ₃ , 90 MHz) delta (ppm): 1.21 (s, 9H), 5.96 (s, 2H), 10.31 (s, 1H).

Production Example 8 Oxalyl chloride-2-pivaloyloxymethyl ester

The title product of the preceding Preparation Example (19.2 g, 0.094 mol) was dissolved in 20 mL of benzene and added portionwise over 20 minutes to oxalic acid dichloride (47.7 g, 33 mL, 0.376 mol) in 100 mL of benzene. After 30 minutes, the mixture was concentrated and the residue (19.2g) was distilled to give the title product, 16.4g bp. 83 ° C / 0.4mm.

Preparative Example 9 Oxalic acid fluoride-2-pivaloyloxymethyl ester [pivaloyloxymethyloxalyl fluoride] (CH ₃ J ₃ C (CO) COF

Kaliumfluorsulfinat (2.40 g, of 80% KSO ₂ F, corrected = 1.92 g pure substance, 0,016mol) was added to oxalyl chloride (3,50g, 0,016mol) and the mixture was heated in an oil bath gradually to 6O ⁰ C , where from this temperature began strong gas evolution. The bathroom was removed. Dais the reaction subsided, the oil bath was brought back again to its place, the mixture was heated to 80 ° C and 15 minutes so setting, cooled to 6O ⁰ C and distilled from a 6O ⁰ C hot bath to give the title product, 1, 19g, bp 52-54 ° C / 0.4mm, which solidified on storage at -50X and melts at ambient temperature.

¹³ C-NMR: 176.6, 152.6 and 151.5, 148.1 and 140, 28, 81, 8, 8, 8 and 26.6 with splitting of the oxalate carbonyls at 89 Hz and 252.6 Hz (coupling constant).

Claims (3)

claims: 1. A process for the preparation of 5R, 6S-6- (1R-1-hydroxyethyl) -2- (1-oxo-3-thiolanylthio) -2-penem-3-carboxylic acids of the formula (D OH or a pharmaceutically acceptable cationic salt thereof, characterized in that a compound of the formula R ¹ O (purple) wherein R ^{1 is} a commonly used Silylhydroxyschutzgruppe, with an acid fluoride of the formula % I Il 11 0 0 wherein R ^{3 is} -CH ₂ -C = CH ₂ and X is hydrogen or chlorine, in a reaction-inert solvent at ⁰ ° C to -80 ⁰ C in the presence of a tertiary amine acylated to produce a compound of the formula (IIIb) this then to a compound of the formula S> 0 (Ma) followed by hydrolyzing the Sylylethergruppe in the compound of formula (Ma) to a compound of the formula .N- (Lib) and then the ester function in the formula (II b) is activated to form a compound of the formula I and optionally converted into a salt. 2. The method according to claim 1, characterized in that the groups bound to the thiolane ring relative to each other have cis-stereochemistry. 3. The method according to any one of claims 1 or 2, characterized in that R ¹