CS253749B2 - Process for preparing 3-substituted 2-oxo-4,4-dimethyl-1-azetidinysulphates - Google Patents

Description

The invention relates to a process for the preparation of 3-substituted 2-oxo-4,4-dimethyl-1-azetidinyl sulfates.

U.S. Pat. No. 4,337,197, issued June 29, 1982, discloses O-sulfated beta-lactam-hydroxamic acids having antibacterial activity. According to this patent, preferred compounds correspond to the general formula

Rf = NH

3i

CH • Ra

N_o —SO ₃ ® M® in which R a

R ₃ and R ₄ represent an acyl group, whether they are the same or different and each represent a hydrogen atom or an alkyl group and represents hydrogen or a cation.

Several processes for the production of the above compounds are described, including a process using "an intermediate of formula"

in which

A 'represents a nitrogen protecting group and

- Y 'represents a benzyl or pivaloyl group.

As described in the above cited patent, the hydroxyl group in this intermediate is converted to a leaving group using, for example, a conventional reagent such as methanesulfonyl chloride. The resulting fully protected compound corresponds to the general formula

A — NH.

OL ’

CH — —R 'r //

NH-O-Y 'in which

L 'is a leaving group, and can be cyclized by treatment with a base such as potassium carbonate to form a compound of formula

A'-NH-CH-CH-R1

. N — O — Y ¹

As an alternative, the aforementioned patent describes a one-step cyclization process consisting in the reaction of an intermediate of the formula

A-NH

OH

IN

Λ

-NH-O-Y 'with triphenylphosphine and ethyl azodicarboxylate.

It has now been found that the pharmaceutically acceptable salt of [3S (Z)] -2- [f [1- (2-amino-4-thiazolyl) -2 - [[2,2-dimethyl-4-oxo-1- (sulfooxy)] (3-azetidinyl) amino] -2-oxoethylidene-amino] oxy] acetic acid, a compound of formula (I)

(AND)

O CH, n l

C - C - NH - CH - C - CH 2

I, cNO-SO3H of cr 1 ch ₂ -cooh is an excellent antibacterial agent.

For the preparation of [3S (Z)] -2 - [[[2- (2-amino-4-thiazolyl) -2-L [2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl] amino]] It was desirable to improve the process described in U.S. Pat. No. 4,337,197.

In our related Czechoslovak Patent Specification No. 253,740, a preferred process for the preparation of compounds of formula IV is described

A-NH

CH 1 CH ₂ (IV) CN-OR 'R ^J wherein A is benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, o-nitrophenylsulfenyl or triphenylmethyl, R are identical or different and are each alkyl C1 to 4 carbon atoms;

R ₃ represents benzyl, p-nitrobenzyl, benzyloxymethyl, 2-methoxy-2-propyl, 2-ethoxy-2-propyl, tetrahydropyran-2-yl, 2-trimethylsilylethyl, tert-butyldimethylsilyl or tert-butyl a butyldiphenylsilyl group.

This preferred process for the production of the above intermediates is followed by the process of the invention.

Accordingly, the present invention provides a process for the preparation of 3-substituted 2-oxo-4,4-dimethyl-1-azetidinyl sulfates of formula I '

RHN ch ₃ ch- ₃

d)

N-O-SO3H in which

R represents a hydrogen atom or a radical of formula

O

A compound of formula (VII ₎ and pharmaceutically acceptable salts thereof

A-NH? ^H 3 \ h CH-CH,

I, C-N-OH (VII) wherein

A represents a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butyloxycarbonyl group, an o-nitrophenylsulfenyl group or a triphenylmethyl group;

H, N

CH C-CH

The β-N-O-SO 3 H (I) is optionally acylated with a carboxylic acid of formula XI

(XI) wherein R 'represents a carboxyl function protecting group, after which the carboxyl function protecting group is cleaved from the product, and / or the resulting compound is optionally converted to its pharmaceutically acceptable salt.

Sulfonation of the compound of formula VII gives the corresponding compound of formula VIII

A-NH ₃

CHI, C -

-C — CH, (VIII)

-no-sat ₃ h or a basic salt thereof. This sulfonation may be accomplished using sulfur trioxide complex with pyridine, dimethylformamide or 2,6-lutidine.

Cleavage of the amino function at the 3-position (residue A) from the compound of formula VIII then provides the compound of formula I.

The procedure used to cleave the protecting group will depend on the nature of the respective group.

and

Optional acylation of a compound of formula (I) is a conventional procedure and can be accomplished using either the carboxylic acid (XI) itself. or an acid halide, anhydride, or activated ester thereof.

The starting hydroxamic acids of general formula VII may be prepared by deprotecting the intermediates of formula IV vyrobených.způsobem in our above-cited Czechoslovak patent in which R and R ₂ are methyl groups.

Pharmaceutically useful salts of the compounds of formula I 'include salts formed with inorganic or organic cations. These include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts derived from organic bases such as dicyclohexylamine, benzathine, hydrabamide and N-methyl-D- glucamine. The compounds of formulas I 'and I are depicted as acids. However, these substances may also exist in the form of zwitterions (inner salts). Such salts also fall within the designation of pharmaceutically acceptable salts and are part of the invention.

Pharmaceutically usable salts of [3S (Z)] -2-Z / 1- (2-amino-4-thiazolyl) -2- [2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl] amino-2-oxoethylidene-amino-iodoacetic acids are unexpectedly superior antibacterial agents compared to other O-sulphated beta-lactam-hydroxamic acids. More specifically, these salts of the invention are excellent in adsorption when administered orally to a mammal, have improved stability to beta-lactamasane that breaks beta-lactam rings, and also have improved chemical stability.

The above-mentioned pharmaceutically acceptable salts of β S (Z) -2-β-1- (2-amino-4-thiazolyl) -2 - [[2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl] -amino] The 2-oxoethylidene-amino-oxyacetic acid can be used to combat infections caused by gram-negative bacteria in mammals such as pets (e.g., dogs, cats, horses, etc.) and humans. These salts are particularly suitable for oral administration, but all other routes of administration that have hitherto been used to provide penicillins and cephalosporins to the site of infection are also contemplated.

A pharmaceutically acceptable salt of [3S (Z)] -2 - ([{1- (2-amino-4-thiazolyl) -2- [1,2,2-dimethyl-4-oxo] -) may be used to combat infections caused by gram-negative bacteria in mammals. 1- (sulfooxy) -3-azetidinyl] amino-2-oxoethylidene] amino-oxy] acetic acid administered to a mammal in need of such treatment in an amount of from about 1 mg / kg / day to about 350 mg / kg / day, preferably from about 10 mg / kg / day. kg / day to 100 mg / kg / day.

For oral administration, the pharmaceutically acceptable salt may be used in a suitable dosage form, such as a tablet, capsule, or solution or suspension in an aqueous vehicle.

High antimicrobial activity of the disodium salt of [3S (Z)] -2-f [[1- (2-amino-4-thiazolyl) -2 - [[2,2-dimethyl-4-oxo-1- (sulfooxy) -3] The azetidinyl] amino-2-oxoethylidene amino oxoacetic acid is shown by the following minimum inhibitory concentration (MIC) values found in the potency test of the above compound against various microorganisms.

MIC (pg / ml)

Staph. aureus> 100

Staph. aureus> 100

E. coli 0.8

E. coli 0.2

K. aerogenes 0.4

Prot. mirabilis <0.05

Prot. vulgaris <0.05

Ent. cloacae 0,4

Continuation table

Organism

Ser. marcescens Ps. aeruginosa Ps. aeruginosa

MIC (µg / ml)

0.2

1.6

The invention is illustrated by the following non-limiting examples. The method of the invention is used to prepare [3S (Z)] - 2- (η 1 - (2-amino-5-thiazolyl) -2 - [[2,2-dimethyl-4-oxo-1- (sulfooxy) -3] -azetidinyl] -amino] -2-oxoethylidene] -amino oxyacetic acid as a chiral material and as a component of a racemic mixture.

Example 1

(3 - [(Z)] -2-trans- (2-amino-4-thiazolyl) -2-if-2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl] -amino disodium salt -2-oxoethylidene] amino-iodoacetic acid

A) (3-) -3-J '(tert-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone

8.07 g (25 mmol) of (3 -) - 3 - [(tert-butyloxycarbonyl) amino] -4,4-dimethyl-1- (phenylmethoxy) -2-azetidinone in 40 ml of methanol in the presence of 0.6 g 10% palladium on carbon catalyst was hydrogenated at room temperature at atmospheric pressure for 2 hours. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. Acetonitrile was added to the residue and the mixture was evaporated, repeated twice. 5.78 g of the foamed title compound are obtained.

B) (3 -) - 3 - [(tert-Butyloxycarbonyl) amino] -2-oxo-4,4-dimethyl-L-azetidinyl sulphate potassium salt

To a solution of 5.78 g (25 mmol) of (3 -) - 3 - ((tert-butyloxycarbonyl) amino) -1-hydroxy-4,4-dimethyl-2-azetidinone in 120 mL of dry pyridine was added under argon at 0 ° The pyridine-sulfur trioxide complex (8.02 g, 50 mmol) was added in portions, and the reaction mixture was stirred at room temperature for 2.5 hours, then concentrated in vacuo. M aqueous buffer based on potassium monohydrogen phosphate (pH 7) and adjusted to pH 5.2 with 1N potassium hydroxide, is chromatographed on 270 ml of Dowex-50 (K ⁺ > ion exchange resin) using 10% aqueous acetone as eluent. The combined and concentrated in vacuo to give 13.6 g of crude product, which was further purified by chromatography on 680 ml of HP-20 adsorbent, eluting first with 200 ml of water and then with 10% aqueous acetone. to give 7.13 g of the title compound, m.p. M.p. 3-170 ° C.

C) (3 +) - 3-Amino-2-oxo-4,4-dimethyl-1-azetidinyl sulfate

5.48 g (15 mmol) of (3 +) - 3 - ((tert-butyloxycarbonyl) amino) -4,4-dimethyl-1-azetidinylsulphate potassium salt are suspended under argon at -10 ° C in 20 ml of dry dichloromethane, 6 ml of anisole was added to the suspension, followed by 26 ml of trifluoroacetic acid over 2 minutes, the reaction mixture was stirred at -10 ° C for 20 minutes, concentrated in vacuo, triturated with ether three times and dried in vacuo. is the crude title compound as a white solid.

D) [3+ (Z)] -2 - [[[1- (2-Amino-4-thiazolyl) -2 - [[2,2-dimethyl-4-oxo-1- (sulfooxy)] - diphenylmethyl ester sodium salt 3-azetidinyl] amino] -2-oxoethylidene-amino] oxyacetic acid.

6.52 g (16 mmol) of (Z) - (2-amino-4-thiazolyl) - [[(2-diphenylmethoxy) -2-oxoethoxy] imine acetic acid and 2.5 ml (18 mmol) of triethylamine were added under argon at temperature Dissolve -30 ° C in 60 mL of dimethylformamide, add dropwise 3.5 mL (17 mmol) of diphenyl chlorophosphate and stir the reaction mixture at -30 ° C for 1.5 h.

To the above crude (3 +) - 3-amino-2-oxo-4,4-dimethyl-1-azetidinyl sulphate, dissolved at 0 ° C in 10 ml of dimethylformamide, was added 6.6 ml of triethylamine, and this solution was at -30 ° C dropwise to the above mixed anhydride. The reaction mixture was stirred at -30 ° C to -20 ° C for 3.5 hours, then allowed to warm to room temperature. The insolubles were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in 60 mL of 20% acetone in 0.5 M sodium monohydrogen phosphate buffer (pH 7) and adjusted to pH 6.0 with 2N sodium hydroxide. The mixture is then chromatographed on 300 ml of Dowex 50 (Na ⁺ ) ion exchanger using 20% aqueous acetone as eluent. Appropriate fractions were combined and lyophilized to dryness. The crude product was dissolved in 200 ml of wet acetonitrile and the insoluble inorganic salts were filtered off. Concentration of the filtrate in vacuo afforded 19.32 g of the title compound contaminated with the starting acid.

E) disodium β 3 + (Z) J -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[2,2-dimethyl-4-oxo-1- (sulfooxy) -3] 2-Oxoethylidene-amino-iodoacetic acid

19.3 g of crude [3+ (Z)] -2- [[1- (2-amino-4-thiazolyl)] - 2 - [[2,2-dimethyl-4-oxo-1 - ( sulfooxy) -3-azetidinyl-amino-2-oxoethylidene-amino-oxy-acetic acid was suspended in 50 ml of dichloromethane and 6 ml of anisole under argon at -10 ° C.

After addition of 90 ml of trifluoroacetic acid, the reaction mixture was stirred for 1 hour, then concentrated in vacuo and the residue triturated three times with ether. The crude product was dissolved in 40 ml of 0.5 M sodium hydrogenphosphate buffer, pH 7.0, and the pH of the solution was adjusted to 6.8 with 2N sodium hydroxide. The resulting solution was chromatographed on 900 ml of HP-20 ion exchanger using water as eluent. The respective fractions are divided into two parts. The less pure fraction is re-chromatographed on 500 ml of HP-20 ion exchanger. Appropriate fractions were combined with the fractions from the first chromatography and lyophilized. There were obtained 3.8 g of the title compound, melting at 195-210 ° C with decomposition.

For C ^ 2H ^H NN ^N ^ ^ ^ ^N ^ ^{O Na} : C, 27.46; H, 3.41; N, 13.35; S, 12.22.

found 27.46% C, 3.48% H, 13.06% N, 12.04% P. _f ·

Example 2

[3S (Z)] -2 - [[[1- (2-amino-4-thiazolyl) -2- [1,2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl]] - amino-2-oxoethylidene-amino-oxy-acetic acid

A) (3S) -3 - [(tert-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone

The title compound is obtained by repeating the procedure described in Example IA except substituting (3 +) - 3 - [(tert-butyloxydarbonyl) amino] -4,4-dimethyl-1- (phenylmethyoxy) -2- azetidinone uses (3S) -3 - [(tert-butyloxycarbonyl) amino] -4,4-dimethyl-1- (phenylmethoxy) 2-azetidinone.

B) (3S) -3 - [(tert-Butyloxycarbonyl) -amino-2-oxo-4,4-dimethyl-1-azetidinyl sulfate potassium salt

The title compound is obtained by repeating the procedure described in Example IB except that (3 +) - 3 - [(tert-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone is used ( 3S) -3 - [(tert-butyloxycarbonyl) amino] -1-hydroxy-4,4-dimethyl-2-azetidinone.

After evaporation of the volatiles, the crude residue was dissolved in a 10% acetone solution in 0.5 M potassium monohydrogen phosphate buffer (pH 7.2) and the pH was adjusted to 3N with potassium hydroxide.

5.0. The resulting solution was then subjected to Dowex (K ⁺ ) ion exchange chromatography followed by purification by HP-20 ion exchange chromatography.

C) Sodium salt of diphenylmethyl [3S (Z) j-2- _one and [1- (2-Amino-4-thiazolyl) -2-j / 2,2-dimethyl-4-oxo-l- (sulfooxy) -3 -azetidinyl-amino-2-oxoethylidene-1-amino-oxy-acetic acid

To 1.152 g (2.81 mmol) of (Z) - (2-amino-4-thiazolyl) - N 2 -diphenylmethoxy) -2-oxoethoxy / imino-acetic acid in 9.4 ml of dimethylformamide was added 0.54 ml (3). (09 mmol) of diisopropylethylamine, the mixture is cooled to -20 ° C, 0.59 mL (2.81 mmol) of diphenylchlorophosphate is added and the resulting mixture is stirred for 1 hour to give the mixed anhydride,

0.98 g (2.81 mmol) of (3S) -3- (tert-butyloxycarbonyl) amino-2-oxo-4,4-dimethyl-1-azetidinyl sulfate potassium salt is suspended in 7.5 ml of dichloromethane, The reaction mixture was cooled to -10 ° C and 2.13 ml of anisole was added, followed by 9.4 ml of trifluoroacetic acid. The resulting mixture was stirred at -10 ° C for 1 hour, then about 5 mL of toluene was added and the volatiles were evaporated. The residue was triturated with hexane and anhydrous ether and dried in vacuo to give (3S) amino-2-oxo-4,4-dimethyl-1-azetidinyl sulfate as a white powder.

The residue is cooled to -20 ° C, dissolved in 9.4 ml of dimethylformamide, and 1.47 ml (8.34 mmol) of diisopropylethylamine are added first, followed immediately by the mixed anhydride prepared above. The reaction mixture was stirred at -20 ° C for 3 hours, then the volatiles were removed in vacuo, the residue was dissolved at 0 ° C in 20% aqueous acetone, and the pH adjusted to 6.5 with aqueous sodium bicarbonate.

The resulting mixture was purified first by column chromatography on a Dovex 50x2-400 (Na ⁺ ) ion exchanger using 20% aqueous acetone as eluent, followed by subsequent chromatography on HP-20 adsorbent. Gradual elution of the column with water, 5% aqueous acetone, 10% aqueous acetone, 20% aqueous acetone, 30% aqueous acetone and 40% aqueous acetone gave the title compound.

D) 3S (Z) J-2- [f] 1- (2-Amino-4-thiazolyl) -2- [1,2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl] amino] disodium salt -2-oxoethylidene-amino-oxoacetic acid

[3S (Z) J-2-J] -1- (2-Amino-4-thiazolyl) -2- [1,2,2-dimethyl-4-oxo-1- (sulfooxy) -3-azetidinyl] amino] -2- (2-amino-4-thiazolyl) sodium salt The oxoethylidene-amino-iodoacetic acid is suspended in 11.2 ml of dichloromethane at -10 ° C. Anisole (1.12 ml) was added first and then 18.7 ml trifluoroacetic acid was added dropwise. The reaction mixture was stirred at 0 ° C for 40 min. Toluene was added and the volatiles were evaporated. The residue was triturated with anhydrous ether and dried in vacuo to give a white solid. This residue was dissolved in water (pH 2.75) and purified by chromatography on HP-20 adsorbent. Gradual elution of the column with water, 5% aqueous acetone, 10% aqueous acetone and 20% aqueous acetone and lyophilization of the eluate gave 640 mg of the title compound as the inner salt (zwitterionic). This zwitterion is dissolved in water and two equivalents (244 mg, 2.9 mmol) of sodium bicarbonate (pH 5.75) are added. Chromatography of this solution on HP-20 adsorbent (water elution) afforded 572 mg of the title compound after lyophilization of the appropriate fractions, melting at 140-145 ° C with decomposition.

Analysis: for ^C 13 ^{H H} i2 5 ° 9 ^S 2 ^Na 2 ^{'1' 56H} 2 ° Calculated 28.31% C, 3.10% H, 13.64% N;

Found: C, 28.31; H, 3.19; N, 13.76.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 3-substituted 2-oxo-4,4-dimethyl-1-azetidinyl sulfates of the formula I RHN = ^H3 CH-CH — CH, I I d> C-N-O-SO 3 H in which R represents a hydrogen atom or a radical of formula O CH ₂ COOH and pharmaceutically acceptable salts thereof, characterized in that the compound of formula VII is sulfonated A — NH | ^H 3 CH-CH-CH, I I C-N-OH (VII) wherein A represents a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butyloxycarbonyl group, an o-nitrophenylsulfenyl group or a triphenylmethyl group, the A-protecting group is cleaved from the product and the compound of formula I obtained H ₂ N, CH C — CH, II cno-so ₃ h (I &gt;) is optionally acylated with a carboxylic acid of formula XI H ₂ N / - C-COOH XI (XI) II I 'I o ch ₂ -coor 'in which R 'represents a carboxyl function protecting group, after which the carboxyl function protecting group is cleaved from the product, and / or the resulting compound is optionally converted to its pharmaceutically acceptable salt.