CS243578B1 - Process for preparing 4-bromo-2- (methoxyimino) -3-oxo-butanoic acid ethyl ester - Google Patents

Abstract

The method for preparing ethyl ester of 4-bromo-2-(methoxyimino)-3-oxobutanoic acid is carried out by reacting 1 mol of ethyl ester of 2-(methoxyimino)-3-oxobutanoic acid with 0.8 to 1.5 mol of bromine (optionally catalyzed by proton acids, Lewis acids or complex compounds of Lewis acids). The ethyl ester obtained is a preferred intermediate in the preparation of aminothiazole β-lactam antibiotics.

Description

The process for the preparation of 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester is carried out by reacting 1 mole of 2- (methoxyimino) -3-oxobutanoic acid ethyl ester with 0.8 to 1.5 moles of bromine, where appropriate, proton acid catalysis, Lewis acids or Lewis acid complex compounds.

The ethyl ester obtained is a preferred intermediate in the preparation of amino thiazole / β-lactam antibiotics.

The present invention relates to a process for the preparation of 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester of the formula

Br-CH2-CO-CCO2C2H5

II

NOCH3

The substance is used as an intermediate in the preparation of so-called. aminothiazole β-lactam antibiotics.

It is known to prepare from 1 mole of 2- (methoxyimino) -3-oxobutanoic acid ethyl ester by reaction with 1.05 mole of bromine in dichloromethane to catalyze p-toluenesulfonic acid (US Pat. No. 4,196,205) or by reaction with 1 mole of bromine without Catalyst a (DOS No. 2,715,385).

The product obtained is characterized as an oil, characterized by NMR and IR spectra.

In German Patent Specification (DOS No. 2,715,385), 4.16 ppm (3H, s, OCH 3) and 4.36 ppm (2H, s, BrCH 2 CO) are reported for the NMR spectrum in the CDCl 3.

In the reproduction of both procedures, the inventors confirmed the known data, but in addition, a proton signal of 7.06 ppm (1H, s, BnCHCO) was observed in the NMR spectrum measured in CD3COCD3, possibly superseded by the signal (DOS No. 2,715,385). spectral solvent.

Similar thin layer chromatography (SiO 2 in gasoline system 87%, chloroform 4%, ethyl acetate 9% confirmed the presence of two substances).

This mixture is used without purification in the next step and, for example, reacts with thiourea to give 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid ethyl ester in a yield of 55% only (US Pat. No. 4,196,205). Thus, the 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester thus obtained is not optimal for the preparation of the desired aminothiazole derivatives.

It was fooled that the pure monobromo derivative, i. ]. ethyl 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester can be obtained easily and in high yield by the process according to the invention, which comprises reacting 1 mole of ethyl 2- (methoxyimino) -3 ester -obutanoic acid with 0.8 to 1.5 moles of bromine with optional catalysis of proton acids, Lewis acids or Lewisoy acid complex compounds.

The pure ethyl ester of 4-bromo-2- (methoxyimino) -3-oxobutanoic acid obtained, unlike the known mixture (oil), crystallizes in the form of cubes, which melts at 35-36.5 ° C.

The structure of the pure bromo derivative was confirmed by elemental analysis, NMR and IC spectra.

The following examples illustrate the invention but do not limit it in any way.

Example 1

To 8.65 g of ethyl 2-methoxyimino-2-oxobutanoate was added 20 ml of dichloromethane and 1 ml of conc. hydrobromic acid and the reaction mixture is heated to reflux. A solution of 7.2 g of bromine in 60 ml of dichloromethane is then added dropwise.

After the addition is complete, the reaction mixture is heated to reflux until decolorization occurs. After cooling, the reaction mixture was washed with 100 ml of saturated sodium bicarbonate solution and twice with 50 ml of water, respectively. The aqueous solutions were extracted once more with 30 ml of dichloromethane. The combined extracts were dried and concentrated. Crystallization from ethanol gave 11.28 g of white solid, 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester crystallizing in the shape of cubes, m.p. t. 35-36.5 ° C.

NMR Spectrum (100 MHz, CDs / CO)

4.38 ppm (2H, s, BrCH 3 -),

4.34 ppm (2H, q, CH 2 CH 3),

4.14 ppm (3H, s, OCH 3),

1.33 ppm (3H, t, CH 2 CH 3).

Elemental analysis for CzHioNCHBr: calculated:

H, 4.00; N, 5.56.

31.70% Br;

found:

32.24% C, 3.97% H, 5.67 _0/0 n.

31.58% Br.

IR (nujol):

v max (C = O) = 1720 cm ^-1 , 1755 cm ^-1 . Example 2

To 8.65 g of 2-methoxyimino-3-oxobutanoic acid ethyl ester was added dropwise 6.7 g of bromine at 40 ° C at such a rate that the reaction mixture remained viable. After the addition is complete, the reaction mixture is heated to decolorization.

After cooling, 50 ml of dichloromethane are added and treatment as in Example 1 yields 10.57 g of a syrupy substance. Crystallization from ethanol affords 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester of the indicated properties.

Example 3

To 8.65 g of 2-methoxyiminof-3-oxobutanoic acid ethyl ester was added 20 ml of dichloroethane and 0.4 g of aluminum bromide and the reaction mixture was heated to 83 ° C. A solution of 7.2 g of bromine in 60 ml of dichloroethane is then added dropwise. After the addition was complete, the reaction mixture was heated to decolorization. By processing as

In Example 1, 10.26 g of 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester of the indicated properties is obtained.

Example 1 4

To 2.5 g of 2-methoxyimino-3-oxobutanoic acid ethyl ester was added 1.82 ml of concentrated hydrobromic acid and hydrogen peroxide was added dropwise at 50 ° C to discolor the reaction mixture.

Working up as in Example 1 gave 2.71 g of 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester of the indicated properties.

Example 5

2- (2-Amino-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid ethyl ester g 4-Bromo-2- (meto (xyimino) -3-oxobutanoic acid ethyl ester) was dissolved in 50 ml ethanol and 50 ml added water

Thiourea and a solution of 2.69 g of potassium carbonate in 20 ml of water are added with stirring. The reaction mixture is stirred until crystalline material is formed.

After separation, the product obtained is washed with water and dried. 7.93 g of a slightly yellowish substance are obtained (87% m.p. 161-163 ° C).

NMR Spectrum (100 MHz, CD3 / 2CO):

6.90 ppm (lH, s, 5H thiazole),

4.27 ppm (2H, q, CH 2 CH 3),

3.86 ppm (3H, s, OCH3),

1.26 ppm (2H, t, CH 2 CH 3).

Elemental analysis for C 8 H 11 N 3 O 3 S: calculated:

% C, 41.91;% H, 4.84;% N, 18.33;

13.99% S;

found:

H, 4.89; N, 18.22.

14.08% S.

Claims (2)

SUBJECT Process for preparing 4-bromo-2- (methoxyimino) -3-oxobutanoic acid ethyl ester, characterized in that 1 mole of ethyl 2- (methoxyimino) -3-oxobutanoate is reacted with 0.8 to 1.5 moles of ethyl ester. bromine with optional catalysis of prolonic acids, LeYNALEZ wis acids or complex compounds of Lewis acids. 2. The process according to claim 1, wherein the reaction is carried out in an organic solvent and / or water environment.