CS258594B1 - Ethyl esters of (Z) -2-alkoxyimino-2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] acetic acid - Google Patents

Abstract

The invention relates to ethyl esters of [Z/-2- -alkoxyimino-2-C2- [4-acetamidobenzenesulfonamido]-4-thiazolyl] acetic acids of general formula I, new substances used as intermediates in the preparation of new beta-lactam antibiotics. These substances can be prepared, for example, by reacting 4-acetamidobenzenesulfonylthiourea or its salts with ethyl [Z/-2-alkoxyimino-4-halogeno-3- -oxobutanoates of general formula II or by reacting ethyl [Z/-2-alkoxyimino-2- [2- -amino-4-thiazolyl] acetates of general formula III with 4-acetamidobenzenesulfonyl chloride.

Description

The present invention relates to (Z) -2-alkoxyimino-2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] acetic acid ethyl esters of the formula I '

NHCOCH

NORWEGIAN

COOCH ₂ CH ₃ in which R represents an alkyl group having 1 to 2 carbon atoms.

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

(Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) ethyl acetate are important intermediates in the preparation of highly effective beta-lactam antiobiotics, third generation cephalosporins, known for their activity on Gram-positive and Gram-negative microorganisms / British Pat . No. 2,025,933 or Belgian Pat. No. 889,913]. Similarly, the esters of formula (I) are prepared in the preparation of a novel type of beta-lactam antibiotics.

The novel ethyl esters of formula X according to the invention can be prepared, for example, by the following preferred methods:

a) reaction of 4-acetamidobenzenesulfonylthiourea with ethyl Z-2-alkoxyimino-4-halo-3-oxobutanoates of the general formula II

NORWEGIAN

II

XCH ₂ COCCOOCH ₂ CH ₃ (11), wherein R is C 1 -C 2 alkyl and X is bromine or chlorine, in the presence of base-reacting agents, for example dimethylaniline or sodium acetate in a suitable solvent, for example C 1 -C 4 alkanol carbon or a mixture thereof with water in ratios of 1: 100 to 100: 1 or in a mixture of alkanol of 1 to 4 carbon atoms with tetrahydrofuran or dioxane in a ratio of 1: 100 to 100: 1 in the presence of up to 90% water at 0 to 70 ° C, preferably at a temperature of 10 to 40 ° C.

It is preferred to use an alkali metal salt of 4-acetamidobenzenesulfonylthiourea, in particular the sodium salt; it is then not necessary to add a basic reagent to the reaction mixture, the reaction being carried out in the abovementioned solvents or mixtures thereof in the indicated proportions at 0 to 70 ° C, preferably at 10 to 40 ° C;

b) reaction of (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) ethyl acetate of formula III h ₂ n

Γ ^'with COOCH ₂ CH _3/111 /, wherein R represents an alkyl group having 1-2 carbon atoms, 4-acetamidobenzensulfoohloridem: in the presence of a base, e.g. triethylamine, dimethylaniline, pyridine, etc., In a suitable solvent, e.g. in a chlorinated hydrocarbon with 1 to 2 carbon atoms and 1 to 4 chlorine atoms, or mixtures thereof with pyridine, optionally in pyridine alone at a temperature of -20 to 100 ° C.

Advantageously, the reaction may be carried out in water in the presence of a water-soluble base such as an alkali metal hydroxide, optionally in the presence of phase transfer catalysts such as tetrabutylammonium hydrogen sulfate and the like.

It goes without saying that in addition to the above methods other variations are possible, which are common to the skilled person and which therefore do not need to be explicitly named. The following examples illustrate some of the preparation methods.

Example 1

2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] - (Z) -2-methoxyiminoacetate ethyl (formula I, R = methyl)

To a suspension of 21.3 g (0.07 mol) of 4-acetamidobenzenesulfonylthiourea sodium salt in a mixture of 50 ml of ethanol and 50 ml of water is added with stirring at room temperature 21 g (85% content),

0.072 mol of ethyl 4-bromo- [Z] -2-methoxyimino-3-oxobutanoate. After stirring for 1 h, the reaction mixture is extracted with 50 ml and 10 ml of ethyl acetate, the solution is washed with 100 ml of saturated sodium chloride solution, filtered with charcoal and dried over magnesium sulfate. Evaporation in a vacuum rotary evaporator gave 29 g of an oily residue which crystallized after dissolution in 20 ml of isopropyl alcohol. The product was filtered off with suction, washing with isopropyl alcohol and petroleum ether to give 19 g (61.9%) of a yellowish product, m.p. 192 DEG-210 DEG C. (decomposition). The melting point of the analytical sample (dimethylformamide / isopropanol) is 227-229 ° C. The structure was confirmed by NMR and IR spectroscopy.

Example 2

2- [4- 2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] - (Z) -2-methoxyiminoacetate ethyl (Formula I, R = methyl)

Alternatively, the compound of Example 1 can be prepared as follows:

To a solution of 37 g (0.16 mol) 2- (2-amino-4-thiazolyl) - (Z) -2-methoxyiminoacetate ethyl acetate in 70 ml pyridine was added 38.5 g (0.16 mol) 4- acetamidobenzenesulfochlorid.

The reaction mixture was stirred at room temperature for 30 minutes. 185 ml of water and 185 ml of methylene chloride are then added and the pH of the reaction mixture is adjusted to 2.9 with dilute hydrochloric acid (1: 1). The precipitated product was filtered off with suction and washed with water and methylene chloride to give, after drying at 60 DEG C., 67.6 g (98.2%) of a yellow product, m.p. the melting point of the analytical sample (dimethylformamide / isopropanol) is 228-231 ° C. The structure was confirmed by NMR and IR spectra.

Example 3

2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] - (Z) -2-methoxyiminoacetate ethyl (Formula I, R = ethyl)

Following the procedure described in Example 2, an yellowish product was obtained from an equivalent amount of the corresponding ethoxy derivative and analogous treatment with a yield of 91.8%; mp 180-195 ° C; the melting point of the analytical sample (dimethylformamide / isopropanol) is 203-207 ° C. The structure was confirmed by NMR and IR spectra.

(Z) -2-Alkoxyimino-2- [2- (4-acetamidobenzenesulfonamido) -4-thiazolyl] acetic acid ethyl esters of formula (I)

Claims (1)

SUBJECT OF THE INVENTION NORWEGIAN II ^x COOCH ₂ CH ₃ (1) wherein R is C 1 -C 2 alkyl.