CS257471B1 - Method of aminothiazole derivatives preparation - Google Patents

Abstract

The present invention relates to a process for preparing aminothiazole derivatives of formula I H2N C CO2 R6 N \> R2 (I), wherein R 1 is methyl or ethyl and R 2 is hydrogen or methyl used as intermediate in the preparation of so-called. aminothiazole beta-lactam antibiotics. Compound are prepared by the reaction of thiourea with esters of 4-halo-2-alkoxyimino-3-oxobutanoic acid in water in the presence of surfactants.

Description

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

(i) where

R 1 denotes hydrogen or methyl;

R 2 is methyl or ethyl, as well as their addition salts with hydrobromic acid and hydrochloric acid. Compounds having the Z-configuration of the oxiimino group are used as intermediates for the preparation of the so-called oxiimino group. aminothiazole beta-lactam antibiotics.

Compounds of formula I wherein R 1 and R 1 are as defined above are prepared by reacting thiourea with ethyl 4-chloro-2-methoxyimino-3-oxobutanoate in aqueous methanol with a neutralizing effect of sodium acetate in 69% yield (Brit. U.S. Pat. No. 2,025,933).

French patent no. 1,581,184 provides for the preparation of a compound of formula I wherein R ₃ is ethyl and R ₂ methyl, by reaction of thiourea with ethyl 4-chloro-2-methoxyimino-3-oxobutanoate in anhydrous ethanol at 24 ϊ-nominal yield, similar to German patent file no. No. 2,728,766. M. Ochiai et al. (German Pat. Nos. 2,715,385 and 280,565) discloses, for the preparation of the title compounds of formula I, the reaction of thiourea with 4-bromo-2-methoxyimino-3-oxobutanoic acid methyl or ethyl ester in diraethylformanide, ethanol or an aqueous organic solvent isolated extraction followed by separation of geometric isomers. M. Ochai et al. (J. Antibiotics 33, 1022, 1980) found that the reaction of ethyl 4-chloro-2-hydroxyimino-3-oxobutanoate with thiourea, depending on the aqueous or organic reaction medium, yields mixtures of geometric E and Z isomers of the derivative of Formula I wherein R ₂ is hydrogen and R 1 is ethyl and additionally indicate the need to use neutralizing agents in the reaction.

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

These drawbacks are overcome by the process according to the invention relating to the preparation of aminothiazole derivatives of the general formula I

H, N

N-ηΛ7

C-CO 3 R.

II

N ^x 'or ₂ where

1 * 2 denotes hydrogen or methyl and

R ^ is methyl or ethyl, as well as their addition salts with hydrochloric or hydrobromic acid, characterized in that 1 molar part of the compound of formula II is reacted in water

XCII ^ COC-CO ^ R.

Z J 2 1

N (II), i

° ^R 2 where

X represents a bromine or chlorine atom;

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 on the compound of formula II - cationic or nonionic surfactants or mixtures thereof, characterized by hydrophilic-lipophilic equilibrium (HLB) 8 to 17.5 and the ability to reduce the micelle size of the compound of formula II in an aqueous emulsion at a temperature of -5 to 60 ° C and a carbon chain length in the vacum molecule as the compound of formula II, with 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 hydrochloride or hydrobromic acid addition salts.

The advantage of the process according to the invention is the selective synthesis of the Z-isomer of the desired derivative and the avoidance of separation operations with simplified processing of the reaction mixture, substitution of organic solvents, and an increased product yield compared to the known processes.

The process according to the invention is carried out by adding 0.1 to 15% by weight, based on the compound of the formula II, of a surfactant selected from the group of cationic or nonionic surfactants or their synergistic mixtures to 1 mole of the compound of the 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 added successively in such a volume that in the 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, a mixture of the compound of formula II and surfactant can be introduced into water. The use of surfactants to form aqueous emulsions used instead of true solutions and a method to reduce micelle size in an aqueous emulsion by utilizing physicochemical effects without requiring the use of mechanical devices is described e.g. in the book Blažej, A. et al., Surfactants Alfa, 1977 (Bratislava) or U.S. Pat. 3,813,345.

The surfactants applied can be classified as cationic, anionic or nonionic. Preferred is the use of nonionic surfactants in combination with an anionic surfactant. Examples of cationic surfactants of the invention include tertiary and quaternary water-soluble amines, stearyl dimethyl benzyl ammonium chloride, amidoalkyl amine oxides, alkylpyridinium salts. They are known e.g. under the trademarks Slovamin S-7 or S-20 (CHZWP-Novaky n.?.). Examples of anionic surfactants which can be used according to the invention are known under the trade marks Triton, e.g. Triton X-152 (Rohm, Haas CO), Hostapon (Hoechst) or Neokal (Association).

It is generally preferred to use nonionic surfactants, preferably in synergistic combination with ionic surfactants. Examples of nonionic surfactants which may be used according to the invention include polyoxyethylene sorbitan fatty acid esters under the trade name Atlox (Atlas Chem. Ind.) Or polyoxyethylene (20) sorbitan monooleat under the trade name Tween 80 (Atlas Chem. Ind.) , alkylpolyglycol ethers under the trade name Slovasol 0 (CHZWP-Novaky np), non-ionic propylene oxide-based surfactants under the trade name Slovanik M-640 (CHZWP-Novaky

n. p.) or surfactants made on the basis of higher fatty acids than Emulsifier 45 (CHZWP-Novaky n. p.). As a synergistic mixture of nonionic surfactants, Slovapon N (CHZWP-Novaky n. P.) Or a mixture of a nonionic surfactant with an ionic surfactant under the trade name Slovasol PLS (CHZWP-Novaky n. P.) Can be used.

The formed emulsion or microemulsion in water is added 0.8 to 1.5 mol of thiourea in aqueous solution, or preferably in solid form at a temperature of -5 to 60 ° C, preferably at 15 to 30 ^D C. The reaction mixture may be a pH of 1.2 to 6.5, which can be achieved by the subsequent addition of agents such as inorganic salts, e.g. sodium bicarbonate or organic acid salts such as sodium acetate. A reaction time of 0.2 to 2-3 hours is required, characterized by recovery of the crystalline product from the reaction medium.

The compound of formula I can be isolated in sufficient purity by adjusting the pH in the reaction mixture to a value of 4.5 to 6.5. The pH can be adjusted using any suitable reagent, e.g. salts of strong base and weak acid or by addition of alkali metal or ammonium hydroxide. The compound of formula 1 can be isolated from the reaction mixture by centrifugation by filtration. A further 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, excluded from the reaction solution in the form of its addition salts with hydrochloric or hydrobromic acid.

More specifically, the invention is described in the examples. These examples describe the invention in more detail without limiting the scope of the invention in any way.

EXAMPLE

Ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyimino acetate

A mixture of 2.5 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate and 0.075 g of Slovasol O is added to 20 ml of water at room temperature with stirring. 0.76 g of thiourea is added to the resulting emulsions. 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 was suspended in 20 ml of hexane dichloromethane (5: 1). The suspension is filtered off with suction and dried. 2.03 g of ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate, i. 89% m.p. Mp 158-163 ° C.

Example 2

Ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyimino acetate

Procedure as in Example 1, using Slovasol A and suspending the crude product in 20 mL diethyl ether.

Priklad3až24

The following aminothiazole derivatives were prepared analogously to Example 1 except that the surfactants listed in Table 2 were used. First

n-ir-c J II

C-CO 3 H, he ₂

Table no. 1

Example R @ R Tenz i.d mp yield no. 2 1 (° C) (%) 3 ^CH 3 ^C 2 ^H 5 Slovasol PLS 157-162 79 4 CH ₃ ^CH 3 Slovapon CT 160-165 83 5 ^CH 3 ^CH 3 Slovasol 0 161-164 94 6 H ^C 2 ^H 5 Slovanik M-640 200-202 86 7 CH ₃ ^C 2 «5 Slovasol EL 158-161 85 8 H ^C 2 ^H 5 Slovasol EL 200-202 82 9 ^CH 3 _C ^H Slovasol 24 30 160-163 89 10 ^CH 3 ^C 2 «5 Tween 80 159-162 92 11 H ^ 5 Tween 80 202-205 90 12 CH ₃ ^C 2 ^H 5 Tween 85 158-161 88 13 H c _A Tween 85 200-203 81 14 H ^c Ή Slovafol 910 202-204 7 8 15 ^Cřl 3 ch ₃ Slovamin SM 20 159-165 83

Table no. 1 - continued

Example no. R ₂ ^R 1 surfactants mp <C) Yield (%) 16 ^CH 3 ^C 2 ^H 5 Slovapon N 157-162 83 17 H ^C 2 ^H 5 Slovapon N 200-202 87 18 H ch ₃ Slovapon N 187-188 81 19 ^CH 3 ^C 2 ^H 5 Slovanik M 640 157-161 82 20 H ^C 2 «5 Slovasol 205 200-202 78 21 ^CH 3 C ₂ «5 Slovasol 205 159-162 81 22 ^CH 3 ^C 2 «5 Slovamine S-7 160-162 89 23 H ^Cři 3 Slovamine S-7 185-187 87 24 ^CH 3 ^C 2 ^H 5 Slovamine 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. 0.76 g of thiourea was added to the emulsion formed. After the pH of the reaction mixture had stabilized at 1.8 to 1.4, the reaction mixture was stirred for an additional 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-methoxyimino acetate

To a mixture of 2.5 g of methyl 2-methoxyimino-3-oxo-4-chlorobutyrate and 0.25 g of Slovasol EL is added 20 ml of water successively at 35-37 ° C and 0.98 g of thiourea are added. The procedure is as described in Example 1. 2.4 g of methyl (2-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate, i. 86% m.p. Mp 159-165 ° C.

Example 27

Ethyl (2-aminothiazol-4-yl) - (Z) -2-methoxyimino acetate

To a mixture of 2.5 g of ethyl 2-methoxyimino-3-oxo-4-bromobutyrate and 0.2 g of Slovasol O is added 20 ml of water. 0.76 g of thiourea is added to the resulting emulsion. 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-aminothiazol-4-yl) - (Z) -2-methoxyiminoacetate is obtained, i. 87% m.p. 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, 0.5 g of Slovasol EL is added at 30 ° C and, after dissolution at this temperature, 10 ml of water are added in three portions.

1.06 g of thiourea are added in one portion. After stirring for 0.5 h, the pH of the reaction mixture was adjusted to 5.2 by addition of 10% sodium hydroxide. The precipitate was filtered off and washed with 15 ml of petrol. 2.3 g of methyl (2-aminothiazol-4-yl) - (Z) -2-hydroxyiminoacetate, i. 82%.

Example 29

Proceed as in Example 1, using Slovasol 3520 and washing the crude product with 20 ml of a 5: 1 mixture of petrol and dichloromethane.

Example 30 to 34 *

The following aminothiazole derivatives were prepared analogously to Example 26 except that the surfactants listed in Table 2 were used. «2nd

Table no. 2

Example no. ^R 2 ^R 1 surfactants mp (° C) Yield (%> 30 ^CH 3 ^{c H} Slovanik T-610 157-161 82 31 ^CH 3 c ₂ h ₅ Slovanik M 340 158-162 87 32 ^CH 3 ^ 2 ^R 5 Slovanik PV-370 160-162 81 33 ch ₃ ^C 2 ^H 5 Slovanik 310 159-161 89 34 H ^C 2 ^H 5 Slovanik T-610 200-202 91

OBJECT OF THE INVENTION

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of aminothiazole derivatives of the general formula I ^H 2 ^N C COoRj II ^X N or ₂ goes R2 is hydrogen or methyl; R ^ is methyl or ethyl, as well as the hydrochloride or hydrobromic acid addition salts thereof, characterized in that 1 molar part of the compound of formula II is reacted in water XCH _o C0C-C0 _o R ₁ ² II ²¹ N (II) no or ₉ where X represents a bromine or chlorine atom and R | and having the above meaning 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 on the combination of II-cationic, anionic or non-ionic surfactants, or mixtures thereof, characterized by a hydrophilic-lipophilic equilibrium of 8 to 17.5 and the ability to reduce the micelle size of the compound of formula II in an aqueous emulsion at a temperature of -5 to 60 ° C with a carbon chain length greater than that of the compound of formula II; at a final pH of 4.5 to 4.5 6.5, a compound of formula I and hydrochloric or hydrobromic acid addition salts thereof are prepared at a final pH of 1.2 to 3.5.