CS258595B1 - (z)-2-alkoxyimino-2-(2-/4-aminobenzensulfonamido/-4-thiazolyl)acetic acids and their n-acetyl derivatives - Google Patents

Abstract

The solution relates to acids / Z / -2-alkoxyimino- -2- [2- (4-aminobenzenesulfonamido) -4-thiazolyl] - acetic acid and their N-acetyl derivatives of formula I, new substances useful as key new synthesis intermediates beta-lactam antibiotics. These new substances are accessible to alkaline ester hydrolysis / Z / -2-alkoxyimino-2- -T2- / 4-acetamidobenzenesulfonamido / -4- thiazolyl] acetic acids.

Description

The invention relates to (Z) -2-alkoxyimino-2- [2- (4-aminobenzenesulfonamido) -4-thiazolyl] acetic acids and their N-acetylderivatives of the general formula I

NHX

wherein R is C 1 -C 2 alkyl and X is hydrogen or acetyl.

These novel, yet undescribed substances are intermediates in the synthesis of a novel class of beta-lactam antibiotics of the aminothiazole type with 4-aminobenzenesulfonamido in the branch chain.

As is well known, [Z] -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetic acids are a key intermediate in the synthesis of most 3-generation oephalosporins, very potent beta-lactam antibiotics used against both gram-negative and gram-positive microorganisms U.S. Pat. No. 2 025 933 or German publication No. 2 834 097 /. The same is true of the acids of the formula (I) in the preparation of a novel type of beta-lactam antibiotics.

The acids of the formula (I) are prepared, for example, by alkaline hydrolysis of the corresponding ethyl esters (Z) -2-alkoxyimino-2- [2- (4-azetamidobenzenesulfonamido) -4-thiazolyl] acetic acids of the formula (II).

wherein R is C 1 -C 2 alkyl, in a 0.1 to 50% aqueous solution of an alkali metal hydroxide, preferably a 5 to 10% solution, in a 1: 100 mixture of a C 1 -C 3 alkanol with this solution to 100: 5, optionally in a mixture of said alkanols with tetrahydrofuran or dioxane in a ratio of 1: 100 to 100: 1, containing 5 to 99% of said alkali metal hydroxide solution, at a temperature of 40 to 110 ° C, preferably at a temperature of 80 to 100 Deň: 32 ° C.

Hydrolysis can also be carried out in a two-stage process, wherein in the first stage, under less severe hydrolysis conditions, a 0.01 to 4% alkali metal hydroxide solution in any of the above. of solvents, temperature 0 to 40 ° C), only the ester is hydrolyzed to give (Z) -2-alkoxyimino-2-Q 2 - (4-acetamidobenzenesulfonamido) 4-thiazolyl] acetic acid of the general formula I wherein X is an ethyl group and R is as above this meaning.

In a second step, alkaline hydrolysis of the acid under the above conditions yields an acid of formula I wherein X is hydrogen and R is as defined above.

It is not critical for the reaction if the acid of formula I, wherein X is acetyl group and R is as defined above, is free or in the form of a salt, for example with an alkali metal.

Further details of the preparation process are given in the following examples.

It goes without saying that, in addition to the above processes, other alternatives leading to the desired compounds of formula (I) are possible, which are common to the person skilled in the art and therefore need not be explicitly named.

He did

2-p- (4-Aminobenzenesulfonamido) 4-thiazolyl] - (Z) -2-methoxyiminoacetic acid (Formula I),

R = methyl, X = hydrogen)

Suspension of 41 g (0.096 mol) of 2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] - (Z) -2-methoxyiminoacetate in a solution of 11.5 g of sodium hydroxide (0.29 mol) in 150 ml of water is heated to boiling for 100 minutes. The solution obtained is filtered with charcoal, cooled to 5 ° C and acidified with dilute hydrochloric acid (1: 1) to pH 3, and after stirring at 5 ° C for half an hour, the solution is acidified to pH 1.7. The product is filtered off with suction, washed with water and dried at 40 ° C. There was obtained 30.7 g (89 V) of a yellow crystalline product having a melting point of 148-153 ° C and a water content of 4.97%. The melting point of the analytical sample (dimethylformamide / water mixture) was 150-152 ° C.

The water content of the product is reduced by dissolving 10 g of the product in 40 ml of anhydrous ethanol, adding 30 g of calcined molecular sieves and refluxing for two hours with a chloro-calcium cap. Filtration of the molecular sieve by evaporation to dryness yielded 7.7 g of an amorphous product with a melting point of 120-130 ° C and a water content of 2.16%. The structure of the substance was proved by elemental analysis and NMR spectrum.

Example 2

2- [2- (4-Aminobenzenesulfonamido) -4-thiazolyl] - (Z) -2-ethoxyiminoacetic acid (Formula I, R = ethyl, X = hydrogen)

In analogy to Example 1, the title acid is obtained in the form of a yellowish product with a yield of 85%, m.p. 143-150 ° C and a water content of 4.86%. The melting point of the analytical sample (ethanol) is 170-172 ° C. Drying with a molecular sieve gives a product with a water content of 1.50%. The structure was confirmed by NMR and IR spectra.

Example 3

2- [2- (4-acetamido-benzenesulfonamido) -4-thiazolyl] - (Z) -2-methoxyiminoacetic acid (Formula I, R = methyl, X = acetyl)

A solution of 3.7 g (0.009 mol) of 2- (2-) - (4-acetamidobenzenesulfonamido) -4-thiazolyl-3- (Z) -2-methoxyiminoacetate in a mixture of 15 ml of methanol and 15 ml of 2N sodium hydroxide solution (0.03 mol) is allowed to stand for 5 hours at room temperature. The reaction mixture was then rotary evaporated at room temperature to half volume. Addition of 25 ml of water, adjusting the pH to 2.7 with dilute hydrochloric acid (1: 1), aspirating, washing with water and drying the precipitated product gave 2 g (57.9%) of the product, m.p. 172-180 ° C. The melting point of the analytical sample (dimethylformamide / isopropanol) is 241-242 ° C. The structure was confirmed by NMR and IR spectra.

Claims (1)

(Z) -2-Alkoxyimino-2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] acetic acids and their N-acetylderivatives of formula (I) wherein R is C 1 -C 2 alkyl and X is hydrogen or acetyl .