HU190507B - Process for production of azetidinil sulpfon acids and analogic substances - Google Patents

Abstract

The invention relates to a process for the preparation of b-lactams having a substituent of the formula I in which R 1, R 2, R 3, R 4, R 5 and R 6 have the meaning given in the invention, and pharmaceutically acceptable salts thereof. These compounds have antibacterial activity against a number of Gram-positive and Gram-negative bacteria.

Description

This invention relates to novel 3-substituted azetidinylsulfonic acid derivatives and their salts, and to pharmaceutical compositions containing the novel compounds.

It has been found that the β-lactam nucleus can be biologically activated by the substituent (a) attached to the nitrogen atom in the ring (or a salt thereof).

β-Lactam antibiotics are disclosed, inter alia, in German Patent Publication No. 2716677, No. 4,971,778;

U.S. Patent Nos. 172,199 and 4,152,432.

The β-lactams containing the substituent (a) at position 1 (or a pharmaceutically acceptable salt thereof) and the acylamino substituent at position 34 are active against a number of gram-negative and gram-positive bacteria.

The novel β-lactam antibiotics of the present invention are represented by formula (I).

Throughout Formula I, and throughout this specification, symbols have the following meanings:

R 1 -aminothiazolyl-α - [- carboxy (C 1 -C 4)

-yl) oxyimino] acetyl, (amino-thiazolyl) -α (C 1-4 alkoxy) iminoacetyl, α- [4- (C 1-4 alkyl) -2,3-dioxy -1-piperazinyl] carbonylamino-phenylacetate, benzyloxycarbonyl or tert-butoxycarbonyl, and

R _{is C} 1-4 alkyl or carbamoyl.

The salts of the novel compounds may be salts with inorganic or organic bases. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts which are preferred, and alkaline earth metal salts such as calcium and magnesium salts with organic bases such as dicyclohexylamine, N 4 -dibenzylethylenediamine, N-methyl-D Salts formed with N, N-bis (dehydroabiethyl) ethylenediamine, salts with amino acids such as arginine, lysine, and the like. Non-toxic pharmaceutically acceptable salts are preferred, although other salts may be used, for example in product isolation or purification.

Salts are conventionally formed by reacting the free acid form of the product with one or more equivalents of the appropriate base to provide the desired cation in a solvent or medium in which the salt is insoluble or in water and freeze-drying the water. The salt is neutralized with an insoluble acid such as a cation exchange resin in hydrogen form (e.g. polystyrene sulfonic acid resin such as Dowex 50) or an aqueous acid and extracted with an organic solvent such as ethyl acetate, dichloromethane or the like. the free acid form is available and, if desired, other salts can be formed.

The β-lactams containing the substituent (a) in position 1 (or a salt thereof) and the amino or acylamino substituent in position 3 have at least one chiral center - the carbon atom (ac / S-lactam core 3). The present invention is directed to the preparation of the β-lactams described above in which the stereochemical configuration of the chiral center at the 3-position of the β-lactam nucleus is the same as that of naturally occurring penicillins (e.g., 6-penicillin). With the configuration of the carbon at its 6-position and with the carbon at the 7-position of naturally occurring cefamycins (e.g., cefamycin C).

In view of the preferred β-lactams of Formula I, the structural formulas are illustrated to show stereochemistry at the 3-position chiral center.

The present invention also encompasses racemic mixtures containing the β-lactams described above.

The β-lactams containing a substituent (a) at the 1-position of the β-lactam core (or a salt thereof) and an acylamino substituent at the 3-position of the β-lactam core are active against a number of Gram-negative and Gram-positive organisms. The substituent (a) (or a salt thereof) is essential for the efficacy of the compounds of the present invention.

The compounds of the present invention are useful in combating bacterial infections (including urinary tract infections and respiratory tract infections) in mammalian species such as domestic animals (dogs, cats, cows, horses and the like) and humans.

In order to combat bacterial infections in mammals, a compound of the present invention may require from about 1.4 mg / kg / day to about 350 mg / kg / day, preferably from about 14 mg / kg / day to about 100 mg / kg / day, in a mammal. up to. Any route of administration hitherto used to deliver penicillins and cephalosporins to the site of infection may also be used in connection with a new family of β-lactams of the present invention. Such modes of administration include oral, intravenous, intramuscular, and suppository administration.

The β-lactams of the present invention can be prepared from amino acids II. The amino group is first protected with a classical protecting group (tert-butoxycarbonyl, benzyloxycarbonyl) to give a compound of formula III. In III. In the general formula and throughout the description, the term " Ai " denotes any of the above nitrogen protecting groups.

The carboxyl group of a protected amino acid ΠΪ is then reacted with an amine of formula IV. The reaction is carried out in the presence of a coupling agent such as 3- [3- (dimethylamino) propyl] -1-ethylcarbodiimide or dicyclohexylcarbodiimide to give a salt of a compound of formula (V). The hydroxyl group of the compound of formula V (or a salt thereof) is converted to a leaving group using a classical reagent such as methanesulfonyl chloride (the methanesulfonyl group is hereinafter referred to as "Ms").

The fully protected compound of formula VI or a salt thereof is cyclized by treatment with a base such as potassium carbonate. The reaction is preferably carried out under reflux in an organic solvent, such as acetone, to give a compound of formula VIII or a salt thereof.

Alternatively, the cyclization of a compound of Formula V may be accomplished without prior conversion of the hydroxy group to any leaving group. A compound of Formula V (or vala-21)

190 507) with triphenylphosphine and diethyl azodicarbonate or carbon tetrahydrochloride and triethylamine to give a compound of formula VII.

The protecting group for the 3-position amino substituent of a compound of formula VII may be removed using conventional techniques in the art. For example, if the protecting group is tert-butoxycarbonyl, trifluoroacetic acid may be used to liberate the amino group. If the protecting group is a benzyloxycarbonyl group, catalytic hydrogenation (e.g., palladium on carbon) may be employed. When the o-nitrophenylsulfenyl group is the protecting group, p-toluenesulfonic acid can be used in combination with p-thiocresol. Deprotection affords a compound of Formula VIII or a salt thereof and are key to the preparation of the compounds of the present invention.

Well-known acylation techniques can be used to convert a compound of formula VHI to the corresponding compound of formula IX or a salt thereof. An example of such methods is the reaction with a carboxylic acid of the formula R 1 -OH or the corresponding carboxylic acid halide or carboxylic acid anhydride. Reactions with carboxylic acids are most conveniently performed in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, and a reactive intermediate capable of forming in situ, such as N-hydroxybenzothiazole or 4- (dimethylamino) pyridine. In cases where the acyl group R 1 contains reactive functional groups (e.g., amino or carboxyl groups), these functional groups must first be protected, followed by the acylation reaction, and finally deprotected from the resulting product.

The starting materials of formula II can be readily prepared using methods known in the art, see, for example, Synthesis, p. (1979) and J. Org. Chem., 44, 3967 (1979).

The following examples are specific embodiments of the present invention.

Example 1

3S- [3a (Z), 4/3] 2 - [[1 <2-Amino-4-thiazolyl) -2 [4-methyl] -2-oxo-1- (sulfomethoxy) -3-azetidinyl] dipotassium salt of amino-2-oxoethylidene] aminoamino-2-methylpropionic acid.

A) Aminoxymethanesulfonic acid

Acetone oxime (1.46 g, 20 mmol) was added to a suspension of 0.8 g (20 mmol) of a 60% sodium hydride in mineral oil solution in 16 mL of anhydrous dimethyl sulfoxide. 3.94 g (20 mmol) of the sodium salt of bromomethanesulfonic acid are added slowly. The reaction mixture was heated at 90-95 ° C for 4 hours under nitrogen, then cooled and washed with diethyl ether (2 x 250 mL). The solidified product was washed with dichloromethane (100 mL), filtered and dried over phosphorus pentoxide to give 15.3 g of crude product. This was dissolved in 20 mL of water and 7.5 g (22 mmol) of (tetrabutylammonium) hydrogen sulfate was added. The resulting ion-pair product was extracted with dichloromethane (2 x 200 mL). The dichloromethane solution was dried over sodium sulfate and concentrated in vacuo. The hydrolysis of acetone oxime was carried out by heating in 130 ml of 2N hydrochloric acid solution at 130 ° C for 4 hours. The solution was concentrated in vacuo twice from water and once from acetonitrile. The product solidified on addition of dichloromethane and dried in vacuo to give 2.5 g of the title compound.

B) Potassium salt of N- [N-α-tert-butoxycarbonyl-L-threonyl] -O-sulfomethylhydroxylamine.

1.14 g (8.9 mmol) of aminoxymethanesulfonic acid is added at 0 ° C to a solution of 1.96 g (8.9 mmol) of N-α-tert-butoxycarbonyl-L-threonine in 16 mL of water and 4 mL of tetrahydrofuran. The solution was adjusted to pH 4.5 with 1 N potassium hydroxide solution and added dropwise to 3- [3- (dimethylamino) propyl] -1-ethyl (1.87 g, 9.7 mmol). carbodiimide in 8 ml of water. The reaction mixture is stirred at room temperature for 2 hours, during which time the pH is maintained between 4 and 4.5 by careful addition of 1 N sulfuric acid. The product was treated with 3.05 g (8 mmol) of (tetrabutylammonium) hydrogen sulfate at pH 2.8 to form an ion pair and extracted with 4x100 mL of dichloromethane. The dichloromethane solution was dried over sodium sulfate and concentrated in vacuo to give 4.5 g of product as the tetrabutylammonium salt. This was converted to the potassium salt by ion exchange with 150 ml of Dowex 50 X potassium cycle resin (0.7 meq K / ml) to give 2.63 g of the title compound after lyophilization.

C) N- [N-ar (tert-Butoxycarbonyl) -O-ethanesulfonyl-L-threonyl] -O- (sulfomethyl) hydroxylamine (tetrabutylammonium) salt.

To a partial solution of 2.37 g (6.5 mmol) of N- [N-Or (tert-butoxycarbonyl) -L-trconyl] O- (sulfonethyl) hydroxy] amine potassium salt in 50 ml of anhydrous pyridine. 0.8 mL (excess) of methanesulfonyl chloride is added dropwise at 0-5 ° C under nitrogen. The reaction mixture was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was dissolved in water (10 mL) and tetrabutylammonium hydrogen sulfate (2.0 g, 6 mmol) was added at pH 2.8. The ion pair is extracted with chloroform. The chloroform was dried and concentrated in vacuo to give 2.6 g of crude product.

D) [3S- (3a / 4/3)] - 3 - [(tert-Butoxycarbonyl) amino] -4-methyl-2-oxy-1- (sulfomethoxy) azetidine potassium salt

Dissolve 2.6 g (4.0 mmol) of N- [N-after-butoxycarbonyl) -0-methylsulfonyl-L-threonyl] -O- (sulfomethyl) hydroxylamine (tetrabutylammonium) salt. In acetone (5 mL) and added dropwise to a refluxing suspension of potassium carbonate (2.2 g) and acetone (65 mL). After refluxing for 3.5 hours, the reaction mixture was cooled, filtered and concentrated in vacuo. The residue was dissolved in 10 mL of 0.5 M potassium hydrogen phosphate pH 5.5 and adjusted to pH 2.8. The product was extracted with dichloromethane (3 x 100 mL), the combined extracts dried and evaporated in vacuo to give crude β-lactam (tetrabutylammonium) salt (1.52 g). The potassium salt was prepared by ion exchange on Dowex 50 X resin (0.7 meq K / ml) in a 50 ml potassium cycle to give 0.53 g of crude product after lyophilization which was further chromatographed with 100 ml of ΗΡ-20-οη water. purified. The appropriate fractions were combined to give 0.245 g of product after lyophilization.

The results of elemental analysis are C _lo Hi ₇ N _a O ₇ SK.

1.2 Hj for 0 calculated:

190,507

C, 32.46; H, 5.28; N, 7.57; S, 8.66.

C, 32.52; H, 4.76; N, 7.43; S, 8.30.

E) [3S- (3a, 4/3) -P-Amino-4-methyl-2-oxy-1- (sulfomethoxy) -1-acetaldine.

0.245 g (0.68 mmol) of [3 S - (3a, 4/3)] - 3 - [(tert-butoxylcarbonyl) anino] -4-methyl-2-oxo-1- (sulfomethoxy) - The azetidine potassium salt is suspended in a mixture of 0.5 ml of dichloromethane and 0.5 ml of anisole. The reaction mixture was cooled to 0 ° C and trifluoroacetic acid (1.0 mL) was added under nitrogen. After stirring for 1 hour, the reaction mixture was concentrated in vacuo and the residue was concentrated twice more with benzene. This residue was triturated with diethyl ether and the diethyl ether decanted to give the desired product as a white solid.

F) {$ 3 - (3α (Ζ), 4β}) -2-H [1- (2-Amino-4-thiazolyl)

-2 - {[4-methyl-2-oxo-1 (sulfomethoxy) -3-azetidinyl] amino] -2-oxoethylidene] -amino-oxy-2-methylpropionic acid (7-diphenylmethyl) - ester, potassium salt.

0.30 g (0.68 mmol) of (Z) - (2-amino-4-thiazolyl) -O- [2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] - acetic acid and 0.10 g (0.68 mmol) of 1-hydroxybenzo-triazole hydrate were dissolved in 4 ml of anhydrous dimethylformamide under nitrogen. The solution was cooled to 9 ° C, 14, (-dicyclohexylcarbodiimide (0.14 g, 0.68 mmol) was added slowly. After the addition was complete, the reaction mixture was stirred at 0 ° C for 1 hour. To the reaction mixture was added at 0 ° C the above crude (about 0.68 mmol) 3-amino-1- (sulfomethoxy) azetidine in 10 mL of dimethylformamide; and 0.5 ml of Ν, Ν-diisopropylethylamine. The mixture was stirred at room temperature for 1 hour and then overnight at 0 C ^e. The solution was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and washed with water (2 mL). After distillation of dichloromethane, 0.372 g of crude product is obtained. This was dissolved in water and passed through 30 ml of Dowex 50 potassium cycle resin (0.7 meq K / ml) to give, after lyophilization, 0.211 g of crude product contaminated with 1-hydroxybenzotriazole.

G) [3S-13a (Z), 40] -2 - [{[1- (2-Amino-4-thiazolyl) -2- [4-methyl-2-oxo-1- (sulfomethoxy) -3-azetidine] yl] amino 3 2-oxoethylidene] aminoamino] -2-methylpropionic acid dipotassium salt.

0.211 g of 3S- [30o (Z), 40 = 3 -2 - [[l-2-amino-4-thiazolyl) -2 - {[4-methyl-2-oxo-1- (sulfomethoxy) -3-azetidinyl] Diphenylmethyl ester potassium salt of -N amino-J-2-oxyethylidene] -amyl-N-oxy] -2-methylpropionic acid was dissolved in dichloromethane (1.8 ml), anisole (0.5 ml) and ml of trifluoroacetic ecetsöv mixture of ^e and 0 C is stirred for 2 hours under nitrogen. The reaction mixture was concentrated in vacuo and then evaporated to dryness twice more with benzene. The residue was washed with diethyl ether: ethyl acetate (1: 1) and diethyl ether: acetonitrile (1: 1) to give a white solid. It is spun in 1.0 ml of a 0.5 molar solution of potassium dihydrogen phosphate pH 5.5, adjusted to 6.5 with 1 N potassium hydroxide solution and chromatographed with 40 ml of ΗΡ-20-οη water. Yield: 53 mg (m.p. 200 ° C (dec)).

Elemental analysis calculated for € ₁₄ Η _{) 7} Ν ₅ Ο ₉ -SjK2.2,75 H, 0:

C, 28.44; H, 3.84; N, 11.85; S, 10.84.

C% 2832, H% 336. N, 11.90; S, 10.37.

EXAMPLE 2 [2S] - [2a], 30 (Z / N - [3- (2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-methyl-4-oxo-1-azetidinyl] oxy | methanesulfonic acid

Following the procedure of Example E and using an equimolar amount of (ZX2-amino-4-thiazolyl) (methoxyl-lmino) -acetic acid instead of the thiazole acetic acid derivative used in Example 1 (F), the title compound was obtained as a hygroscopic solid monopotassium salt and distilling the acetonithyl in vacuo.

Infrared data: SQ '(1030 cm -1), β-lactam (1778 cm ^-1 ).

Elemental analysis results are C _n H, ₄ N _s O ₇ S j K. For 0.1 CH ₃ CN: calculated:

C, 38.11; H, 4.82; N, 15.92; S, 12.56.

C, 37.94; H, 5.36; N, 15.92; S, 12.56.

Example 2 {2S- [20 >) (3 R)] - [3 - [[(4-Ethyl-2,3-dioxl-1-piperazinyl) carbonyl] -aminophenyl-acetyl] -amino] -2-methyl- 4-oxo-1-azelidinyl] oxy-methanesulfonic acid '

Following the procedure of Example 1, and using the thiazole acetic acid derivative used in Example 1 Part F, the title compound is replaced by the title compound (O) [(4-ethyl-2,3-dioxo-1-plperazinyl) carbonyl] amino] -phenylacetic acid. compounds are obtained as a monopotassium salt in the form of a hygroscopic solid.

Infrared Spectrum: SOJ (1038 cm ^-1), β-lactam (1775 cm ^-1).

The results of elemental analysis are C ₂ oHj «N ₅ 0 ₉ SK.

1,6 H ₂ O calculated:

C, 41.53; H, 4.74; N, 12.11; S, 5.54.

C, 41.53; H, 4.46; N, 11.13; S, 5.61.

Example 4 (S) -3 - [(Benzyloxycarbonyl) amino] -4-methyl-2-oxo-sulfomethoxy-azetidine.

Following the procedure of Example 1, Parts A) to D), but substituting N- (tert-butoxycarbonyl) -L-threonine for Part B) with No (benzyloxycarbonyl) -L-serine, the title compound is obtained. potassium salt.

Infrared data: SC (1025 cm ^-1 ) / lactam (1775 cm ^-1 ).

Example 5 (2a, 3a) -3 - [(tert-Butoxycarbonyl) amino] -2-carbamoyl-4-oxy-1- (sulfomethoxy) azetidine.

a) Erythro-3-Hydroxy-D1-aspartic acid.

Erythro-3-hydroxy-DL-aspartic acid is prepared from trans-epoxysuccinic acid as described in C.W. Jones et al., Can. J. Chem. 47, 4363 (1969)]. Trans-epoxy succinic acid is prepared from fumaric acid as described in G. B. Payne et al. Org. Chem., 24, 54 (1959)].

b) methyl ester of erythro-3-hydroxy-DL-aspartic acid.

To a suspension of erythro-3-hydroxy-DL-aspartic acid (5.0 g, 33.5 mmol) in dry methanol (50 mL) was added concentrated hydrochloric acid (6 mL). The mixture was refluxed for 3 hours, then cooled to room temperature and vacuum

190 507 was evaporated. The residue was dissolved in 95% ethanol and the pH adjusted to 8.0 with pyridine. The white solid was filtered off and dried, yielding 5.2 g of the desired methyl ester (95% yield), m.p. 21 ° C.

c) erythro-3-hydroxy-LD-asparagine.

0 g (24.5 mmol) of erythro-3-hydroxy-DL-aspartic acid p-methyl ester are dissolved in 40 ml of concentrated ammonium hydroxide solution and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the resulting solid was dissolved in spinning water. The pH of the solution was adjusted to 5.0 with 6N hydrochloric acid solution, and the solution was concentrated in vacuo to about 20 ml and then allowed to stand overnight at 5 ° C. The white crystalline mass was filtered off and dried, yielding 3.4 g (95% yield) of the desired product, m.p. 233 ° C.

d) Potassium salt of N-cu (tert-butoxycarbonyl) -etritro-3-hydroxy-DL-asparagln.

7.0 g (47 mmol) of ethyl o-3-hydroxy-DL-asparagine are suspended in 50 ml of water and added to a solution by the addition of 3 N potassium hydroxide solution. The pH of the solution was adjusted to 10.0 and maintained at this pH while a solution of di-tert-butyl dicarbonate (15.5 g, 71 mmol) in tert-butanol (20 mL) was added dropwise. The reaction mixture was stirred at pH 10.0 overnight at room temperature. The tert-butanol is distilled off in vacuo and the aqueous residue is adjusted to pH 5.0 with 6N hydrochloric acid. The solution was concentrated in vacuo to a small volume and then adjusted to pH 3.0 with 6N hydrochloric acid. The solvent was evaporated in vacuo to give 20 g of a solid which contained the desired product in free acid form together with inorganic salts. (Yield is almost quantitative). 2.9 g of the solid are dissolved in water and dilute potassium hydroxide solution at pH 6.5 and chromatographed on 100 ml of HP-2 resin with water followed by acetone: water (1: 9). 1.8 g of the desired potassium salt are obtained.

e) Anynoxymethanesulfonic acid (tetrabutylammonium) salt.

1.02 g (3 mmol) of (tetrabutylammonium) hydrogen sulfate are added to a solution of 0.635 g (5 mmol) of aminoxymethanesulfonic acid in 2 mL of water and the pH is adjusted to 10.0 with dilute potassium hydroxide solution. The water was evaporated in vacuo and the residue was triturated with dichloromethane. After filtration, the filtrate was dried over sodium sulfate and evaporated to give 1.06 g (2.88 mmol) of the desired product.

t) Potassium salt of N- [N-? - (tert-butoxycarbonyl) -erythro-3-hydroxy-DL-asparagine] -O- (sulfo-methyl) -hydroxylamine.

0.792 g (2.77 mmol) of N-o (tert-butoxycarbonyl) -erythro-3-hydroxy-DL-asparagine potassium salt are dissolved in 3 mL of v 'and the pH of the solution is adjusted to 2.4 with dilute sulfuric acid. The solution is evaporated in vacuo, the residue is twice concentrated in water and then twice again from benzene. This residue was dissolved in 4 ml of anhydrous acetonitrile and 8 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. To this solution, while mixing, 0.424 g (2.77 mmol)

1-Hydroxybenzyl monohydrate was added followed by N, N-dicyclohexylcarbodiimide (0.572 g, 2.77 mmol). The mixture is stirred at 9 ° C for 2 hours and then a solution of 1.06 g (2.88 mmol) of the amino-methanesulfonic acid (tetrabutylammonium) salt in 5 ml of acetonitrile is added dropwise. After the addition was complete, the reaction mixture was stirred at 0 ° C for 4 hours. The reaction mixture was collected and concentrated in vacuo. Water (40 mL) was added and (triturated at -C until solidified. The solid was filtered off and the aqueous filtrate was concentrated to about 3 mL. The pH was adjusted to 4.0 and 80 mL of Dowex potassium Chromatography on 5-ion exchange resin The appropriate fractions were combined and concentrated to a small volume, adjusted to pH 3.4 and chromatographed on HP-2 resin to give 502 mg (46% yield) of the desired product after lyophilization. mp 145 ° C (dec.).

The results of elemental analysis are Ci _O H _ie N ₃ O ₉ SK.

For the formula 0.71 H ₂ O:

date:

C, 29.42; H, 4.80; N, 10.29; S, 7.85.

C, 29.42; H, 4.73; N, 20.04; S, 7.45.

g) N- [N-o (t-Butoxycarbonyl) -erythro-3-hydroxy-DL-asparaginyl] -O-sulfomethyl-hydroxylamine (tetrabutylammonium) salt.

To a solution of 104 mg (0.263 mmol) of the potassium salt of asparagine hydroxylamine numerase salt prepared in (f) in 1 mL of water was added 2.63 mL of 0.1 M (tetrabutylammonium) hydrogen sulfate solution in 0.5 M Dissolved in potassium dihydrogen phosphate pH pH. The solution was evaporated to dryness and the residue was triturated with dichloromethane. After filtration and distillation of dichloromethane, 156 mg (0.26 mmol) of the desired product is left.

h) (2a, 3a) -3 - [(tert-Butoxycarbonyl) amino] -2-carbamoyl-4-oxo-1- (sulfomethoxy) azetidine potassium salt. 140 mg (0.234 mmol) of the (tetrabutylammonium) salt obtained in (g) above are dissolved in 1.6 ml of anhydrous dichloromethane and stirred overnight with 1 g of dried 0.3 nm (3A) pore size sieve. The solution was aspirated with a syringe and diluted with 0.8 mL of anhydrous dichloromethane. To this solution was added 0.12 ml (0.85 mmol) of triethylamine under argon gas at -50 ° C under stirring, followed by the dropwise addition of trifluoromethanesulfonic anhydride (0.08 ml (0.42 mmol)). The reaction mixture was allowed to warm to -30 ° C over 1 hour and then triethylamine (0.06 mL) was added. After 5 minutes, the reaction mixture was concentrated in vacuo and the residue was dissolved in 2 mL of acetone. The solution was cooled to 0 ^E C and added in 1 ml of acetone was -szulfonsavkáliumsó 79 mg (perfluorobutane). Diethyl ether was then added and the solid was settled by centrifugation. This solid was mixed with water (2 mL) Dowex 50 potassium cycle ion exchange resin, filtered, and the water removed in vacuo. This gives the desired potassium salt as a crude product which does not contain amines. This crude salt was chromatographed on HP-20 resin eluting with water to give, after lyophilization, the desired potassium salt (15 mg, 20%), m.p. 149 ° C (dec).

Infrared data (KBr): 1786 cm- ¹ (β-lactam carbonyl) and 1696 cm- ¹ (band, amide and carbonate carbonate).

Claims (2)

PATENT CLAIMS A process for the preparation of the azetidinylsulfonic acid derivatives of the formula I, wherein: Rt-famnothiazolyl) -α- (1-carboxy (C14-alk-1-yl) -oxyimino] -acetyl, (aminothiazolyl) -C14 -alkoxy) -imino] -acetyl, a- (C4-C4 alkyl) -2 ₎ 3-dioxo-1-piperazine { ^/ -carbonylaminophenylacetyl, benzyloxycarbonyl or tert-butoxycarbonyl; and R ₁₄ alkyl or carbamoyl and salts with bases, salts thereof, characterized in that a V compound - leaving _R2 may have the above meanings and A benzyloxycarbonyl or t-butoxycarbonyl group, and the hydroxy substituted group , preferably converted to the methanesulfonyl group, or its salt by cyclization, the resulting compound VTI is optionally deprotected and then reacted with a carboxylic acid R 1 -OH R 1 as defined above or a reactive derivative thereof, if desired with its base. A process for the preparation of a pharmaceutical composition comprising a compound of formula I or a salt thereof, R 1 and R ₂ , as active ingredient, wherein the active ingredient obtained by the process of claim 1 is processed into a pharmaceutical composition together with the usual excipients.