CS257471B1

CS257471B1 - Process for preparing aminothiazole derivatives

Info

Publication number: CS257471B1
Application number: CS863308A
Authority: CS
Inventors: Miroslav Veverka; Tomas Motacek; Frantisek Povazanec; Jozef Stuchlik; Rudolf Pek
Original assignee: Miroslav Veverka; Tomas Motacek; Frantisek Povazanec; Jozef Stuchlik; Rudolf Pek
Priority date: 1986-05-07
Filing date: 1986-05-07
Publication date: 1988-05-16
Also published as: CS330886A1

Abstract

Riešenie sa týká spósobu přípravy aminotiazolových derivátov vzorca I h2n C CO2R^ N \>r2 (I), v ktorom Ri znamená metyl alebo etyl a R2 znamená vodík alebo metyl, používaných ako medziprodukt pri príprave tzv. aminotiazolových beta-laktámových antibiotik. Zlučeniny sa pripravujú reákciou tiomočoviny s estermi kyseliny 4~halogen-2-alkoxyimino-3-oxobutánovej vo vodě za přítomnosti tenzidov.The solution relates to a method for preparing aminothiazole derivatives of the formula I h2n C CO2R^ N \>r2 (I), in which Ri means methyl or ethyl and R2 means hydrogen or methyl, used as an intermediate in the preparation of so-called aminothiazole beta-lactam antibiotics. The compounds are prepared by the reaction of thiourea with esters of 4-halogen-2-alkoxyimino-3-oxobutanoic acid in water in the presence of surfactants.

Description

257471 2

Invention

relates to a process for the preparation of aminothiazole derivatives of formula I

(i) where

R 1 is hydrogen or methyl and R 4 is methyl or ethyl, as well as their hydrobromic acid and hydrochloric acid addition salts. Compounds having the Z-configuration of the oxiimino group are used as intermediates for the preparation of the so-called aminothiazole beta-lactam antibiotics.

Compounds of formula (I) wherein R 1 and R 3 are as defined above are prepared by reaction of thiourea with 4-chloro-2-methoxyimino-3-oxobutanoic acid ethyl ester in aqueous sodium acetate to effect sodium acetate in 69% yield (Brit. 2 025 933).

French Patent No. 1,581,184 discloses the preparation of a compound of formula I wherein R 1 is ethyl and R 1 methyl by reacting thiourea with ethyl 4-chloro-2-methoxyimino-3-oxobutanoic acid in anhydrous ethanol in a 24% yield, similar to as German Patent Specification. 2,728,766. M. Ochiai et al. (German Pat. No. 2,715,385 and 280,565) disclose thiourea with 4-bromo-2-methoxyimino-3-oxobutanoic acid methyl or ethyl ester for the preparation of the title compounds of formula I in diethylformamide, ethanol or a water-organic solvent isolated by extraction followed by separation of geometric isomers. M. Ochaia spol. (J. Antibiotics 33, 1 022, 1980) have found that the reaction of 4-chloro-2-hydroxyimino-3-oxobutanoic acid ethyl ester with thiourea, depending on the aqueous or organic environment, provides mixtures of the geometric E and Z-isomers of Formula I wherein R 2 is hydrogen and R 1 is ethyl and additionally indicate the need for neutralizing agents in the reaction.

A disadvantage of the prior art is that they lead to a mixture of geometric isomers with complex reaction mixture processing in the isolation of the product, or the use of economically disadvantageous organic solvents necessary to dissolve the compound of formula II in water.

The above-mentioned drawbacks are overcome by the method of the invention relating to the preparation of aminothiazole derivatives of the general formula I

H, N N-η 7 - C 7 -C 3 R 5.

II

N x'or 2 where 1 * 2 is hydrogen or methyl and R 6 is methyl or ethyl, and also hydrochloric acid addition salts thereof;

wherein the molar moiety of the compound of formula (II) XCI (COCC-C0.5R2) 2N (II), R < 2 > wherein X is bromine or chlorine and R < 3 > with 0.8 to 1.5 molar portions of thiourea at a pH of 1.2 to 6.5 of the reaction mixture, for 3 257471 the presence of 0.1 to 15% by weight of the compound of formula II - cationic or nonionic surfactants or their surfactants blends characterized by a hydrophilic lipophilic balance (HLB) of 8, 17.5, and the ability to reduce the size of the compound of formula (II) in the aqueous emulsion at -5 to 60 ° C and the carbon chain length in the molecule as in Formula II, wherein at a final pH of 4.5 to 6.5, a compound of Formula I is prepared and at a final pH of 1.2 to 3.5 its hydrochloric acid or hydrobromic acid addition salt thereof. An advantage of the process of the present invention is the selective synthesis of the Z-isomer of the desired derivative and avoiding separation operations with simplified reaction mixture processing, replacement of organic solvents, and increased product yield compared to prior art processes.

The process of the invention is carried out by adding 0.1 to 15% by weight, based on the compound of formula II, of a surfactant, selected from the group of cationic or nonionic surfactants or their synergistic mixtures, to 1 molar portion of the compound of formula II. The mixing of said components takes place at a temperature of -5 to 60 ° C preferably at a temperature of 15 to 25 ° C. Subsequently, water is gradually added in such a volume that in a subsequent emulsion or microemulsion characterized by the disappearance of the Tyndall effect, the concentration of the compound of formula II is from 5 to 25% by weight. Alternatively, the mixture of formula IIa can be introduced into water. The use of surfactants to form aqueous emulsions used in place of true solutions and methods to reduce the size of the micelles in the aqueous emulsion by the use of physicochemical effects without the need for mechanical equipment is described in, e.g. in Blazej, A. Tenzides Alfa, 1977 (Bratislava), or U.S. Patent No. 3,813,345.

Applied surfactants can be classified as cationic, anionic, or nonionic. It is preferred to use nonionic surfactants in combination with an anionic surfactant. Examples of cationic surfactants according to the invention include tertiary and quaternary water-soluble amines, stearyl dimethyl benzyl ammonium chloride, amidoalkyl amine oxides, alkyl pyridinium salts. They are known, for example, under the trade names Slovamin S-7 or S-20 (CHZWP-Novaky n.?.) Examples of anionic surfactants that can be used according to the invention are known under the Triton trademarks, e.g., Triton X-152 (Rohm, Haas CO) Hostapon (Hoechst) or Neokal (Society). In general, the use of nonionic surfactants, preferably in a synergistic ionic combination, is preferred. Examples of nonionic surfactants that can be used in the present invention include polyoxyethylene sorbitan esters of fatty acid mixtures under the tradename Atlox (AtlasChem. Ind.) Or polyoxyethylene (20) sorbitan monooleat under the trade name Tween 80 (Atlas Chem. Ind.), Alkylpolyglycoleters under the trade name Slovasol 0 (CHZWP-Novaky np), nonionic surfactants based on propylene oxide under the trade name Slovanik M-640 (CHZWP-Novakyn. p.) or surfactants based on higher fatty acids such as Emulgate.RTM. 45 (CHZWP-Novakyn. p.). As a synergistic mixture of nonionic surfactants, Slovapon N (CHZWP-Novak np) or a mixture of a nonionic surfactant with an ionic surfactant under the trade name Slovasol PLS (CHZWP-No-Vacuum np) can be used. 0.8 to 1.5 moles of thiourea are added to the formed emulsion or microemulsion in water in an aqueous solution or preferably in solid form at a temperature of -5 to 60 ° C, preferably 15 to 30 ° C. The reaction mixture may have a pH of 1.2 to 6.5, which may be achieved by the subsequent addition of reagents such as inorganic salts such as sodium bicarbonate or organic acids such as sodium acetate. For reaction, a period of 0, 2 to 3 hours is required, characterized by teaching the crystalline product from the reaction medium.

The compound of formula (I) may be isolated in sufficient purity such that the pH of the reaction mixture is adjusted to 4.5 to 6.5. The pH can be adjusted by using any suitable 257471 reagent, e.g., a strong base salt and a weak acid, or by addition of alkali hydroxide or ammonium hydroxide. The compound of formula 1 can be isolated from the reaction mixture by centrifugation. Another possibility of preparing the compound of formula I is to carry out the reaction at a pH of 1.2 to 3.5 followed by isolation of the compound of formula (I) precipitated from the reaction solution in the form of its hydrochloric or hydrobromic acid addition salts. In Salsh, the invention is described in the Examples. These examples illustrate the invention without limiting the scope of the invention in any way. Přikladl

Ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate

To 20 ml of water at room temperature, a mixture of 2.5 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate and 0.075 g of Slovasol O is added with stirring. 0.76 g of thiourea is added. The pH is adjusted to 5 by the addition of saturated potassium carbonate solution, the product is filtered off with suction, washed with water and dried. The dried product was suspended in 20 mL of 5: 1 hexanes / dichloromethane. The suspension is filtered off with suction and dried. 2.03 g of ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate are obtained, i.e. 89% with mp 158-163 ° C. Example 2

Ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate

The procedure as in Example 1 using Slovasol A and the crude product was suspended in 20 ml of diethyl ether.

Example3 to 24

The following aminothiazole derivatives were prepared analogously to Example 1 using the surfactants listed in Table 1.

n-IR-C11H-CO-H, on2

Table 1 Example R ~ R ·. Tenz id tt Extract No. 2 1 (° C) (%) 3 CH3 C2H5 Slovasol PLS "157-162 79 4 CH3 CH3 Slovapon CT 160-165 83 5 CH3 CH3 Slovasol 0 161-164 94 6H C2H5 Slovanik M-640 200-202 86 7 CH3 C2 5 Slovasol EL 158-161 85 8 H C2H5 Slovasol EL 200-202 82 9 CH3 CH Slovasol 24 30 160-363 89 10 CH3 C2 Tween 80 159-162 92 11 H ^ 5 Tween 80 202-205 90 12 CH3 C2H5 Tween 85 158-161 88 13 H cA Tween 85 200-203 81 14 H c af Slovafol 910 202-204 7 8 15 CR3 ch3 Slovamin SM 20 159-165 83 5 257471

Table 1 - continued Example No. R2 R1 Surfactant tt <° C) Yield (%) 16 CH3 C2H5 Slovapon N 157-162 83 17 H C2H5 Slovapon N 200-202 87 18 H ch3 Slovapon N 187-188 81 19 CH3 C2H5 Slovanik M 640 157-161 82 20 C2 C2 5 Slovasol 205 200-202 78 21 CH3 C2 «5 Slovasol 205 159-162 81 22 CH3 'C2« 5 Slovamin S-7 160-162 89 23 H 7 185-187 87 24 CH3 C2H5 Slovamin S-20 158-162 84 Example 25

Ethyl (2-aminothiazol-4-yl) - (2) -2-methoxyiminoacetate hydrobromide

A mixture of 2.5 g of ethyl 2-methoxyimino-3-oxo-4 "bromobutyrate and 0.075 g of Slovasol 0 was added to 20 ml of water at 25-30 ° C with stirring. To the formed emulsion was added 0.76 g of urea. After the pH of the reaction mixture stabilized at 1.8-1.4, the reaction mixture was stirred for a further 1 hour. 2.9 g of ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate hydrobromide are obtained, i.e. 94%. Example 26

Methyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate Add a mixture of 2.5 g of methyl 2-methoxyimino-3-oxo-4-chlorobutyrate and 0.25 g of Slovasol EL at a temperature of 35 to 37 ° C in succession of 20 ml of water and 0.98 g of thiourea was added to the resulting solution. The procedure of Example 1 is followed. 2.4 g of methyl (2-amino-thiazol-4-yl) - (Z) -2-methoxyiminoacetate are obtained, i.e. 86% with mp 159-165 ° C. Example 27

Ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate

To a mixture of 2.5 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate and 0.2 g of Slovasol O was added 20 ml of water. To the resulting emulsion was added 0.76 g of thiourea. The pH is adjusted to 5 by addition of saturated potassium carbonate solution, the product is filtered off with suction, washed with water and dried. The dried product is suspended in 20 ml of toluene, filtered off with suction and dried. 2 g of ethyl (2-amino-thiazol-4-yl) - (Z) -2-methoxyiminoacetate are obtained, i.e. 87% with mp 157-162 ° C. Example 28

Methyl (2-aminothiazol-4-yl) - (Z) 2 -hydroxyiminoacetate To a mixture of 2.5 g of methyl 2-hydroxyimino-3-oxo-4-chlorobutyrate was added 0.5 g of Slovasol EL at 30 ° C and after dissolution at this temperature, 10 ml of water is added in three portions. Thinurea (1.06 g) was added in one portion to the resulting solution. After stirring for 0.5 hour, the pH of the reaction mixture was adjusted to 5.2 by the addition of 10% sodium hydroxide. The precipitate was filtered off and washed with 15 ml of gasoline. 2.3 g of methyl (2-aminothiazol-4-yl) - (Z) -2-hydroxyiminoacetate are obtained, i.e. 82%.

Claims

EXAMPLE 29 Procedure as in Example 1 except that Slovasol 3520 was used and the crude product was washed with 20 mL of benzene-dichloromethane (5: 1). EXAMPLE 30 to 34 * The following aminothiazole derivatives were prepared analogously to Example 26 except that the surfactants listed in Table 2 were used. Table 2 Example No. R2 R1 Surfactant m.p. (° C) Yield (%> 30 CH3 c H Slovanik T-610 157-161 82 31 CH3 c2h5 Slovanik M 340 158-162 87 32 CH3 ^ 2R5 Slovanik PV-370 160-162 81 33 ch3 C2H5 Slovanik 310 159-161 89 34 H C2H5 Slovanik T-610 200-202 91 OBJECT OF THE INVENTION

A process for the preparation of aminothiazole derivatives of the general formula I H2N

R 2 is hydrogen or methyl and R 6 is methyl or ethyl, and also hydrochloric or hydrobromic acid addition salts thereof, characterized in that 1 molar moiety of the compound of formula (II) is reacted in water XCH 2 COC-C 0 R 1

Wherein X represents a bromine or chlorine atom and R 1 ' and having the above meanings with 0.8 to 1.5 molar parts of thiourea at a pH of 1.2 to 6.5 of the reaction mixture, in the presence of 0.1 to 15% by weight, calculated by combining II - cationic, anionic or nonionic surfactants or mixtures thereof characterized by a hydrophilic-lipophilic balance of from 8 to 17.5 and the ability to reduce the size of the compound of formula (II) by an aqueous emulsion at a temperature of -5 to 60 ° C with a carbon chain length in the molecular chain as the compound of formula (II) at a final pH of 4 From 5 to 6.5, a compound of formula I is prepared and at a final pH value of 1.2 to 3.5 is a hydrochloric or hydrobromic acid salt.