HU182568B - Process for preparing 2-/2-amino-thiazol-4-yl/-2-oximino-acetic acid derivatives - Google Patents

Abstract

The present invention relates to a process for preparing the color isomers of 2- (2-aminothiazol-4-yl) -2-oxyminoacetic acid derivatives of the formula (I). 5 R is trityl, R 'represents up to 4 carbon atoms or alkenyl, 2-tetrahydropyranyl or tri- til, and R 1 is hydrogen or C 1-4 alkyl. 4, i Compounds of formula (I) can be used to prepare pharmaceutical intermediates, cephalosporin derivatives having antibiotic activity. According to the present invention, the compounds of formula (I) are prepared by tritylation or by the substitution of dihydropyran with 2- (2-aminothiazol-4-yl) -2-oxyminoacetic acid derivatives. 182,568 NH-R11 -1

Description

The present invention relates to a process for preparing color isomers of the novel 2- (2-aminothiazol-4-yl) -2-oximinoacetic acid derivatives of formula (I). In the formula R is a trityl group,

R 'is an alkyl or alkenyl group containing up to 4 carbon atoms and is trityl or 2-tetrahydropyranyl,

R ₃ is hydrogen or C 1-4 alkyl.

? The compounds of formula I are important intermediates for the preparation of 7- (aminothiazolylacetamido) -3-acetoxymethyl-ceph-3-em-4-carboxylic acid derivatives. Because of their valuable antibacterial activity, the latter compounds are useful as active ingredients in pharmaceutical formulations. The products of the process of the invention are thus intermediates useful in the pharmaceutical industry.

The compounds of formula (I) according to the invention can be prepared by the following reactions:

a) for the preparation of compounds of formula I wherein R is trityl, R 'is alkyl, alkenyl or trityl up to 4 carbon atoms, R ₃ is hydrogen or C 1-4 alkyl, a compound of formula IV wherein R is hydrogen, alkyl or alkenyl of up to 4 carbon atoms and alk is C 1 -C 4 alkyl, reacted with a trityl halide, preferably trityl chloride, and the resulting ester of formula I optionally treated with a base and then with an acid, obsession

b) for the preparation of compounds of formula I wherein R is trityl, R ₃ is C 1-4 alkyl and R 'is 2-tetrahydropyranyl, a compound of formula X wherein R is trityl and alk is 1- C4 alkyl group, is reacted with dihydropyran, and if desired, the R _x group of the resulting ester of formula (I) is replaced by hydrolysis with hydrogen, or

c) for the preparation of compounds of formula I wherein R1 is hydrogen, R and R 'are trityl, a compound of formula IV wherein R is hydrogen and alk is C1-C4 alkyl, with a base, preferably alkali, with carbonate or hydroxide followed by reaction of the resulting compound with an acid, preferably hydrochloric acid, acetic acid or formic acid, and reacting the resulting compound of formula XV wherein R is hydrogen with at least 2 molar equivalents of trityl halide, preferably trityl chloride.

The reaction with trityl chloride is preferably carried out in the presence of triethylamine or another tertiary amine base such as a trialkylamine, methylmorpholine or pyridine.

Saponify the compounds of formula (I) R ₃ substituent containing an alkyl base is preferably used sodium hydroxide, but other bases may be used, for example, potassium hydroxide or barium hydroxide also.

For the isolation of the compounds of formula (I) in acid form, dilute hydrochloric acid is preferably used as the acid, but acetic or formic acid may also be used.

The starting compounds of formula (IV) are prepared by reacting a compound of formula (III) wherein R is hydrogen, trityl or 2-tetrahydropyranyl or alkyl or alkenyl having up to 4 carbon atoms, while alk is C 1-4 alkyl, thiourea is treated with a base.

The base used in the second step of the reaction is preferably potassium acetate, but alkali metal carbonates or bicarbonates, and dilute aqueous sodium or potassium hydroxide solutions may also be used.

Compounds of general formula (IVa), wherein Nar is a (1-4C) alkyl and R'a is (1-4C) alkyl, a narrower group of compounds of formula (IV) may also be prepared by reacting a compound of formula (VII) wherein alkyl is as defined above with an alkylating agent having from 1 to 4 carbon atoms, the resulting compound of formula (VII) wherein alk and R 'a are as defined above, of formula (III) wherein Alk and R'a are as defined above, is reacted with thiourea and finally treated with a base.

Preparation of Compounds of Formula VII from Compounds of Formula VI Preferably, alkylating agents include alkyl halides such as alkyl chlorides, bromides or iodides, and alkyl sulfates. In these compounds, the alkyl group may contain from 1 to 4 carbon atoms.

The brominating agent used in the preparation of the compounds of formula VIII is preferably bromine.

The products formed by the reaction of compounds of formula VIII with thiourea are treated with a base. The base is preferably an alkali metal carbonate or bicarbonate, but dilute aqueous sodium or potassium hydroxide solution and potassium acetate may also be used.

The spatial configuration of the compounds of formula (IV) does not change during the subsequent steps of the synthesis. Correspondingly, color-configurated compounds of formula (IV) can be converted into color-configurated compounds of formula (I).

The spatial configuration of the compounds of formula (IV) prepared as described above may be modified by appropriate choice of reaction conditions. For example, it has been found that when the compounds of formula III are reacted with thiourea in an aqueous solvent such as aqueous acetone or aqueous ethanol, or when the reaction is carried out at room temperature and the starting material is contacted for a relatively short period of time (1-3 hours). stoichiometric amounts of thio3

-2182,568 urea, the compounds of formula IV are obtained as color isomers.

Similarly, reacting compounds of formula VIII with thiourea in the presence of an aqueous solvent and / or treating compounds of formula VIII with a substantially stoichiometric amount of thiourea for several hours at room temperature yields the color isomers of compounds of formula IVa.

The preparation of the color isomers of the compounds of formula (IV) is described in detail in Examples 2, 3, 4, 5 and 7.

Compounds of formula (I) wherein R is trityl and R 'is hydrogen, alkyl or alkenyl having up to 4 carbon atoms, and R 1, as defined in the introduction, are new. Also novel are compounds of formula III wherein alk is C 1-4 alkyl and X is chloro, and R is a group which can be cleaved by acid hydrolysis or hydrogenolysis or a C 1-4 saturated or unsaturated aliphatic hydrocarbon group.

Novel derivatives of the compounds of formula (III) may be prepared from ethyl γ-chloro-α-oxyiminoacetacetic acid by the method described in J. Med. Chem. 16 (9) 1973. According to this method, compounds of formula (III) containing a group which can be cleaved by acidic hydrolysis or hydrogenolysis of R are prepared by reaction of ethyl γ-chloro-α-oxyiminoacetacetic acid with the corresponding reactive compound, and max. In the preparation of compounds of formula III having a C 4 saturated or unsaturated aliphatic hydrocarbon group, the γ-chloro-α-oxyiminoacetacetic acid ethyl ester is treated with the appropriate alkylating agent.

The compounds of formula (IV) may also be prepared from compounds of formula (III) wherein X is chlorine or bromine and when X is chlorine, R is hydrogen, trityl or 2-tetrahydropyramyl or max 4 carbon atoms, saturated or unsaturated represents an aliphatic hydrocarbon group, while X represents a bromine atom, R represents a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbon group having up to 4 carbon atoms. Compounds of formula (III) wherein X is bromine and R is hydrogen may be prepared by reacting compounds of formula (VI) wherein alk is as defined above with a brominating agent. The reaction may be carried out under the conditions described for the preparation of compounds of formula VII.

The base used for the saponification of the compound of formula (IV) is preferably sodium hydroxide, but other bases such as potassium hydroxide or barium hydroxide may also be used.

Diluted hydrochloric acid is preferably used as the acid reagent to isolate the acid of formula XV, but acetic acid or formic acid may also be used.

The reagent used to convert the compound of formula XV is preferably trityl chloride. This rea4 gene is preferably used in the presence of triethylamine or other tertiary amine bases such as other trialkylamines, methylmorpholine or pyridine.

A. The reagent used to convert a compound of formula (X) is dihydropyran.

The color configurated compounds of the present invention can be converted to color configurated 7- (aminothiazolylacetamido) -3-acetoxymethyl-cef-3-em-carboxylic acids. These color-configured cephem-carboxylic acids, according to the pharmacological data disclosed in Hungarian Patent No. 173110, show an order of magnitude better than the anti-configuration isomers.

The following examples illustrate the invention without limiting it.

Example 1

To illustrate process (a)

Step A: Ethyl 2- (2-Amino-4-thiazolyl) -2- (hydroxyimino) -acetic acid ethyl ester (0.76 g) was treated with ethyl ethyl γ-chloro-α-oximinoacetic acid (0.76 g). and the reaction mixture was stirred for 16 hours at room temperature. The hydrochloride of the product precipitates in crystalline form. The mixture was diluted with ether (5 mL), filtered in vacuo, and washed with ethanol-ether (1: 1) followed by ether and dried. 1.55 g of ethyl 2- (2-amino-4-thiazolyl) -2- (hydroxyimino) acetic acid hydrochloride are obtained.

1.55 g of the hydrochloride obtained above are dissolved in 8 ml of water at 40-5 ° C and neutralized with sodium acetate to a pH of 5 to 6. The free amine compound crystallizes out. After cooling, the product was filtered off with suction, washed with water and dried. 1.22 g of ethyl 2- (2-amino-4-thiazolyl) -2-hydroxyimino acetic acid (anti-isomer) are obtained; mp 154 ° C.

Several mother liquors and washings obtained in the above procedure were collected, concentrated and the residue taken up in water. The aqueous solution was washed with ether, sodium bicarbonate was added, and the precipitate was filtered off with suction and washed with water. 1.9 g of a solid are obtained which have two spots in the TLC. The product is purified by chromatography on silica gel; ether was used as eluent. The purified fractions containing the color isomer were combined, evaporated and the residue was triturated with ether and the solid was filtered off with suction and dried. 50 mg of the color isomer are obtained.

-31 & 2,568

Step B: Ethyl 2- (2-Tritylamino-4-thiazolyl) -2- (trityloxyimino) acetic acid

To a solution of 5.4 g of the product of Step A in 54 ml of chloroform and 7.5 ml of triethylamine is added a solution of 15 g of trityl chloride in 30 ml of chloroform at + 10 ° C. After standing for 1 hour, the mixture was washed with water (40 ml), water (20 ml) and 1N aqueous hydrochloric acid (4 ml). The organic layer was separated, dried and evaporated to dryness. The residue was dissolved in ether (10 mL), methanol (50 mL) was added and the mixture was stirred. The precipitated solid was filtered off with suction and washed with methanol. 14.2 g of ethyl 2- (2-tritylamino-4-thiazolyl) -2- (trityloxyimino) acetic acid are obtained.

Step C: 2- (2-Trityloxy-4-thiazolyl) 2- (trityloxyimino) acetic acid

10.5 g of the product of Step B are suspended in 55 ml of near-boiling dioxane and 17 ml of 2N aqueous sodium hydroxide solution are added slowly. The mixture was refluxed with gentle reflux, cooled and the salt filtered in vacuo. The salt was taken up in a mixture of methylene chloride (60 ml), water (20 ml) and acetic acid (2 ml), and the precipitated acid was filtered off with suction and washed with water. 7 g of product are obtained.

The dioxane was evaporated from the mother liquor and the residue was treated with methylene chloride (20 ml), water (10 ml) and acetic acid (1 ml). An additional 1.5 g of product was obtained, yielding a total of 8.5 g of 2- (2-tritylamino-4-thiazolyl) -2- (trityloxyimino) acetic acid.

Analysis for C ^ H ^ O, O OjNjS H ₂ O wherein:

calculated: C: 75.85%; S: 4.7%; H, 5.03%; N, 6.17%. found: 0: 75.8%; S, 4.6%. H, 4.9% N, 5.9%; Example 2

To illustrate process (a)

Step A: Ethyl 2- (2-Amino-4-thiazolyl) -2- (methoxyimino) -acetate g Ethyl ester of γ-chloro-α-methoxyiminoacetacetic acid, 3 ml absolute ethanol and 0.42 g crushed thiourea After stirring for about 2 hours at room temperature, the mixture was diluted with ether (60 mL). The hydrochloride of the product crystallizes out. The system was stirred and the solid was filtered off with suction, washed and dried. The hydrochloride salt (685 mg) was dissolved in 4 ml of water at 50 ° C and neutralized with potassium acetate to pH 6. The liberated amine crystallizes out. The mixture was cooled and the solid filtered. The product was washed with water and dried. 270 mg of ethyl 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid (color isomer) are obtained; mp 161 ° C.

Nuclear Magnetic Resonance Spectrum: (CDCl ₃ , 60 MHz): 4 (= N - OCH ₃ ), 6.7 (protons of thiazole ring) ppm.

Step B: Ethyl 2- (2-Tritylamino-4-thiazolyl) -2 (methoxyimino) acetic acid

4.6 g of the product of Step A are dissolved in 92 ml of methylene chloride at 30 ° C. The solution was cooled to -10 ° C, triethylamine (2.9 mL) was added and the mixture was cooled to -35 ° C. Get into the mix in 15 minutes

Trityl chloride (6.1 g) was added and the mixture was allowed to warm to room temperature over 2.5 hours. The mixture was washed with water, 0.5 N aqueous hydrochloric acid and finally with aqueous sodium acetate, dried and evaporated. The residue was taken up in ether and evaporated again. The residue is dissolved in methanol, water and ether are added and the mixture is allowed to crystallize. The solid product was filtered off with suction and washed with ether. 6.15 g of ethyl 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetic acid (color isomer) are obtained; Op .:

120 ° C.

Step C: 2- (2-Tritylamino-4-thiazolyl) 2- (methoxyimino) acetic acid

7.01 g of the ester from step B is dissolved in 35 ml of dioxane. The solution was heated in an oil bath to 110 ° C, treated with 9 ml of 2N aqueous sodium hydroxide solution over 5 minutes, and the mixture was stirred and refluxed for 30 minutes. The sodium salt crystallizes. After cooling, the product was filtered off with suction and washed with dioxane and ether. 5.767 g of sodium salt are obtained. An additional 1.017 g of sodium salt can be isolated by evaporation of the mother liquor to give a total of 6.784 g of sodium salt.

3.06 g of the sodium salt prepared above are added to a mixture of 65 ml of methylene chloride and 6.5 ml of 2N aqueous hydrochloric acid. The system is washed with water, the organic phase is dried and then evaporated to dryness. The free 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) acetic acid is obtained in quantitative yield. The product is a color isomer.

Nuclear Magnetic Resonance Spectrum (DMSO, 60 MHz): 3.68 (= N-OCH ₃ ), 6.5 (thiazole ring protons) ppm.

The ethyl ester of γ-chloro-α- (methoxyimino) acetic acid used as a starting material in Example 2 was prepared as follows:

To a mixture of 22.5 g of ethyl γ-chloro-α-oximinoacetacetic acid and 100 ml of methylene chloride is added 275 ml of a 21.6 g / l solution of freshly prepared diazomethane in an ice bath, while stirring slowly. The mixture was stirred for 5 minutes and then the excess diazomethane was decomposed with a little alumina. The reaction mixture was concentrated and the residue was chromatographed on silica gel for purification. Elution with methylene5

-4182 568 chloride was used to obtain 11.93 g of ethyl ethyl Y-chloro-α-methoxyiminoacetic acid.

The ethyl 2- (2-amino-4-thiazolyl) -2-methoxyimino acetic acid used as reagent in Example 2, Step B may also be prepared as follows;

Step 2: Ethyl 2-Acetyl-2- (methoxyimino) acetic acid

To a mixture of crude 2-acetyl-2- (hydroxyimino) -acetic acid ethyl ester (180 g) and pure acetone (900 ml) was added potassium carbonate (234 g) at 10 ° C under nitrogen, followed by dimethyl sulfate (103 ml). The reaction mixture was stirred for 3 hours at room temperature. Ice was added, the reaction mixture was poured into water (4 L) and extracted with methylene chloride. The extract was washed with water, dried and evaporated. 185 g of 2-acetyl-2- (methoxyimino) acetic acid ethyl ester are obtained.

Step β: 4-Bromo-2- (methoxyimino) -acetic acid ethyl ester

To a mixture of 197 g of the product obtained in Step 1 and 1 liter of methylene chloride is added 200 mg of p-toluenesulfonic acid. Dissolve 191 g of pure bromine in 200 ml of methylene chloride and add 1/10 of the solution to the previous solution at 20 ° C. After the reaction has begun, the remaining bromine solution is added to the system at 20 ° C for 1 hour. The mixture was then heated to 25 ° C. After completion of the reaction, the mixture was washed with ice-water, extracted with methylene chloride, dried and evaporated. 268 g of ethyl 4-bromo-2-methoxyimino) -acetic acid are obtained.

Step γ: 2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetic acid ethyl ester in a mixture of thiourea, 270 ml of ethanol and 540 ml of water over a period of 30 minutes under a nitrogen atmosphere, according to Step P of the product obtained and 270 ml of ethanol were added. The reaction mixture was stirred for 1 hour at about 20 ° C, then cooled to about 15 ° C and neutralized to pH 5 with small portions of potassium bicarbonate. The solid was filtered off with suction, washed with water and dried. 133.8 g of ethyl 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid are obtained, which is identical with the product obtained in Example 2, Step A.

Example 3

To illustrate process (a)

Step A: Ethyl 2- (2-Amino-4-thiazolyl) -2- (2-propenyloxyimino) -acetic acid

a) To a mixture of 9.7 g of 2- (hydroxyimino) -4-chloroacetic acetic acid ethyl ester, 30 ml of acetone and 9.15 ml of 3-iodopropane is added 27.5 ml of 2N aqueous sodium hydroxide solution under ice-cooling, and the mixture was kept at room temperature for 1.5 hours.

b) Thiourea (3.8 g) was added to the above reaction mixture and the mixture was heated at 60 ° C for 15 minutes and then at room temperature for 45 minutes. The acetone was evaporated, to the residue 6 was added methylene chloride followed by water and finally potassium carbonate, and the mixture was stirred. The liquid phase was separated by decantation and extracted with methylene chloride. The extract was dried and evaporated to dryness. The residue (9.75 g) was chromatographed on silica gel eluting with ether. The product (2.7 g) was taken up in isopropyl ether and the crystalline material was filtered off with suction, washed and dried. 783 mg of ethyl 2- (2-amino-4-thiazolyl) -2- (2-propenyloxyimino) acetic acid (color isomer) are obtained, m.p.

Step B: Ethyl 2- (2-Tritylamino-4-thiazolyl) -2- (2-propenyloxyimino) -acetic acid

A mixture of 511 mg of the product of Step A, 0.92 ml of dimethylformamide, 1.8 ml of methylene chloride and 0.29 ml of triethylamine is cooled to -15 ° C and 615 mg of trityl chloride is added. After 1.5 hours at room temperature, 2 ml of 1 N aqueous hydrochloric acid and 5 ml of water were added. The liquid phase was separated by decantation, dried and evaporated to dryness. 1.28 g of crude 2- (2-tritylamino-4-thiazolyl) -2- (2-propenyloxyimino) -acetic acid ethyl ester (color isomer) are obtained.

Step C: 2- (2-Tritylamino-4-thiazolyl) -2 (2-propenyloxyamino) acetic acid

A mixture of 1.28 g of the product of Step B, 6.2 ml of dioxane and 3 ml of 2N aqueous sodium hydroxide solution is heated to 120 ° C. The reaction mixture was heated under reflux for 1 hour, then the crystalline precipitated sodium salt was filtered off with suction, washed with a mixture of ether and dioxane and dried.

To the resulting sodium salt (805 mg) was added methylene chloride (10 ml) and 1N aqueous hydrochloric acid (3 ml), stirred until a solution was formed, the resulting solution was dried and evaporated to dryness. The residue was triturated with ether and filtered in vacuo. 715 mg of 2- (2-tritylamino-4-thiazolyl) -2- (2-propenyloxyimino) -acetic acid (color isomer) are obtained; mp 170 ° C.

Example 4

To illustrate process (a)

Step A: Ethyl 2- (2-Amino-4-thiazolyl) -2- (ethoxyimino) acetic acid

(a) A mixture of 19.4 g of ethyl γ-chloro-xoxyiminoacetacetic acid, 60 ml of acetone and 14.3 ml of diethyl sulfate is cooled in an ice bath for 10 minutes, and thereto is added 55 ml of 2N aqueous sodium hydroxide solution over 30 minutes. the mixture was stirred for 40 minutes.

b) Thiourea (7.6 g) was added to the above reaction mixture, heated at 55 ° C for 20 minutes, and the acetone was evaporated. The residue is taken up in ethyl acetate, 6.9 g of potassium carbonate are added and the mixture is stirred. The liquid phase was separated by decantation and extracted with ethyl acetate. The extract was dried and evaporated to dryness. The resulting residue weighed 17.4 g

Chromatograph on silica gel -5182 568 using ether as eluent. The resulting product is triturated with isopropyl ether, filtered off with suction, washed and dried.

2.8 g of ethyl 2- (2-amino-4-thiazolyl) -2- (ethoxyimino) acetic acid (color isomer) are obtained; mp 129 ° C.

Step B: Ethyl 2- (2-Tritylamino-4-thiazolyl) -2- (ethoxyimino) acetic acid

3.16 g of the product of Step A, 6 ml of anhydrous dimethylformamide, 12 ml of methylene chloride and

The mixture of triethylamine (1.89 ml) was cooled to -15 ° C under an inert gas atmosphere and 3.98 g of trityl chloride was added slowly. The reaction mixture was allowed to stand for 0.5 hour while being allowed to warm to +10 ° C. The mixture was then kept at room temperature for 3.5 hours. To the mixture was added 13 ml of 1 N aqueous hydrochloric acid, the mixture was stirred, the organic layer was separated and washed with 1 N aqueous hydrochloric acid and water. The mixture was extracted with methylene chloride, dried and evaporated to dryness. 7.89 g of crude 2- (2-tritylamino-4-thiazolyl) -2- (ethoxyimino) acetic acid ethyl ester (color isomer) are obtained.

Step C: 2- (2-Tritylanino-4-thiazolyl) 2- (ethoxyimino) acetic acid

A mixture of 7.89 g of the product of Step B, 40 ml of dioxane and 19.5 ml of 2N aqueous sodium hydroxide solution is heated at 110 ° C for 1 hour. The mixture is filtered under vacuum, the filter cake is washed with a mixture of ether and dioxane, then with ether and dried. The received

6.25 g of sodium salt are mixed with 60 ml of methylene chloride and 20 ml of 1 N aqueous hydrochloric acid. The mixture was stirred, methanol (20 mL) was added and the mixture was decanted, washed with water, extracted with a mixture of methylene chloride and methanol, dried and finally evaporated. 5.85 g of pure 2- (2-tritylamino-4-thiazolyl) -2- (ethoxyimino) acetic acid (color isomer) are obtained.

Analysis results

CjgH ^ OgNgS. For 1/4 H ₂ O:

H, 5.13; N, 9.09.

Found: 67.4 5.2 8.9

Example 5

To illustrate process (a)

Step A: Ethyl 2-Acetyl-2- (1-methyl-ethoxyimino) -acetic acid

To a mixture of 39.8 g of ethyl 2-acetyl-2- (hydroxymimmono) acetic acid and 200 ml of pure acetone was added 52 g of potassium carbonate under ice-cooling, followed by 25 ml of 2-iodopropane over half an hour. After stirring for 2 hours, water (800 ml) and methylene chloride (500 ml) were added. The system was stirred, decanted and extracted with methylene chloride. The methylene chloride extract was dried, filtered in vacuo and concentrated.

41.5 g of ethyl 2-acetyl-2- (1-methylethoxyimino) acetic acid are obtained.

Step B: 4-Bromo-2- (1-methylethoxyimino) -acetic acid ethyl ester

41.5 g of the product of Step A are added to 190 ml of methylene chloride containing traces of p-toluenesulfonic acid. While stirring, a solution of bromine (11.9 ml) in methylene chloride (50 ml) was added over 1 hour at room temperature. The mixture was stirred, ice-water added, then decanted and extracted with methylene chloride. The extract was washed with ice water, dried and concentrated. 55 g of ethyl 4-bromo-2- (1-methylethoxyimino) -acetic acid are obtained.

Step C: 2- (2-Amino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid, ethyl ester

To a mixture of 14.9 g of thiourea, 55 ml of ethanol and 105 ml of water was added a solution of 55 g of the product obtained in Step B in 55 ml of ethanol over 40 minutes. After stirring for 2.5 hours at room temperature, 220 ml of 10% aqueous sodium bicarbonate solution was added. The mixture is stirred and the product is filtered off with suction, washed and dried. The crude product (42.15 g) was chromatographed on silica gel using ether as the eluent. The fractions rich in the desired product were collected, evaporated, and the resulting crystals were triturated with isopropyl ether, filtered off with suction and washed. 10.75 g of ethyl 2- (2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid (color isomer) are obtained.

Step D: 2- (2-Tritylethylamino-4-thiazolyl) -2- (1-methylethoxyimino) ethoxy-ethyl ester, the product of Step C, 20 mL of anhydrous dimethylformamide, 40 mL of methylene chloride and

To the mixture of 6.2 ml of triethylamine is slowly added 13.2 g of trityl chloride with cooling and the mixture is stirred for 2.5 hours. To the mixture was added 43 ml of 1 N aqueous hydrochloric acid. The mixture was stirred, decanted, washed with water (40 mL) and extracted with methylene chloride. The extract was dried, filtered in vacuo and evaporated to dryness. 27.2 g of ethyl 2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) -acetic acid (color isomer) are obtained.

Step E: 2- (2-Tritylamino-4-thiazolyl) 2- (1-methyl-ethoxyimino) -acetic acid

27.7 g of the product of Step D, 150 ml of dioxane and 65 ml of 2N aqueous sodium hydroxide solution are added.

-6182 568 skins are refluxed for 2 hours. The sodium salt crystallizes out. The mixture was cooled, the salt was filtered off with suction, washed with 1: 1 ether-dioxane and dried. 16.85 g of crude sodium salt are obtained. 15.9 g of the crude sodium salt thus obtained are dissolved in a mixture of 15.9 g of dimethylformamide, 100 ml of water and about 500 ml of methanol. To the solution was added 30 ml of a 2N aqueous hydrochloric acid solution and the methanol was evaporated. The residue was diluted with water and the product was filtered off with suction, washed and dried. 9.8 g of a viscous material are obtained which is taken up in 220 ml of a 1: 1 mixture of methylene chloride and methanol and evaporated to dryness. The residue was triturated with ether and the crystals were filtered off with suction, washed and dried.

4.9 g of 2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid are obtained; op. 170 ° C.

To obtain an analytically pure product, a 300 mg sample of the crude product obtained above is dissolved in a mixture of 2 ml of methylene chloride and 1 ml of methanol. The resulting solution was diluted with water and methylene chloride and stirred. The precipitated crystals are filtered off with suction, washed with methylene chloride and water and dried. 230 mg of pure product of color configuration are obtained.

Analysis:

Calculated: C, 68.77; H, 5.34; N, 8.91.

S, 6.8%;

Found: C, 68.6; H, 5.5; N, 8.8;

S, 6.8%.

Example 6

To illustrate process (a) for the preparation of a compound outside the scope of the invention

Step A: Ethyl 2- (2-chloroacetamido-4-thiazolyl) -2- (methoxyimino) acetic acid (color isomer)

45.8 g of 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid ethyl ester (color isomer) prepared according to Step A of Example 2 are dissolved in 200 ml of methylene chloride and 20 ml are used to water the mixture. methylene chloride is distilled off. The residue was cooled to 10 ° C and 50 ml of pyridine was added. Thereafter, 41 g of monochloroacetic anhydride are added and the mixture is gently heated until dissolved. After 6 hours under nitrogen at 20 ° C, water (5 mL) was added and poured into 300 mL of 2N aqueous hydrochloric acid with stirring. Ice is added to the hydrochloric acid solution. The mixture was decanted and extracted with methylene chloride. The extract was washed with water and aqueous sodium bicarbonate solution, dried, filtered through charcoal and finally concentrated. To the residue is added 300 ml of isopropyl ether; this causes crystallization to begin. The mixture was concentrated to a thick paste, cooled, the solid filtered under vacuum, washed with isopropyl ether and dried. 45.4 g of product of formula (A) are obtained; mp 113 ° C.

After recrystallization from a mixture of methylene chloride and isopropyl ether, the product melts at 118 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl3 _< 60 MHz): (a): 1.38 ppm center triplet (J = 7 Hz), (b): 4.05 ppm (singlet), (c): 4.44 ppm center quadruplet (J = 7 Hz), (d): 4.33 ppm (singlet), (e): 7.27 ppm (singlet), (f): 9.95 ppm (singlet).

Step B: To a mixture of 2- (2-Chloroacetamido-4-thiazolyl) -2- (methoxyimino) -acetic acid (color isomer) g, the product of Step A and 230 ml of absolute ethanol at 20 ° C under nitrogen 30 ml of pure concentrated aqueous sodium hydroxide solution are added under an atmosphere of water. The solid dissolves, and then the sodium salt begins to crystallize and finally the mixture becomes a gelatinous mass. After 16 hours, the solid was filtered off with suction and washed with ethanol. The resulting salt was dissolved in water, treated with 2N aqueous hydrochloric acid (100 mL) under cooling, saturated with sodium chloride, and extracted with ethyl acetate (10% ethanol). The extract was dried, filtered over charcoal and concentrated in vacuo. The water was drained by treatment with benzene. The residue was taken up in methylene chloride and the mixture was evaporated to dryness. The residue is taken up in methylene chloride, the solution is cooled, and the precipitated solid is filtered off with suction, washed with methylene chloride and dried. 34.5 g of product of formula B are obtained; mp ~ 200 ° C. The product was recrystallized from acetone / isopropyl ether for purification.

Analysis calculated for C ₈ H ₈ O ₄ N ₃ ClS (M = 277.68): Calculated: C, 34.60; H, 2.90; N, 15.13.

Cl: 12.77%, S: 11.55%; Found: C, 34.81; H, 2.8; N, 14.8;

Cl: 12.6%, S: 11.5%.

Nuclear Magnetic Resonance Spectrum (DMSO, 60 MHz): (a) 3.92 ppm (singlet), (b) 4.38 ppm (singlet), (c) ~ 5 ppm (singlet), (d) 7.58 ppm (singlet), (e) 12.6 ppm (singlet).

Example 7

To illustrate process (a)

Step A: Ethyl 2-Acetyl-2- (methoxyimino) -acetic acid

To a mixture of 4.69 kg of technical ethyl 2-acetyl-2- (hydroxyimino) -acetic acid (= 4.21 kg of pure product) and 21 liters of pure anhydrous acetone at 20-25 ° C, 1 kg of potassium carbonate We are added. The suspension is stirred for 10 minutes and then 3.72 kg of dimethyl sulfate are added at 20-25 ° C. After stirring for 3 hours at 20-25 ° C, the mixture was poured into 126 L of deionized water and extracted with 4-5 L and finally 2 L of methylene chloride. The extracts were combined, washed with 10 L of deionized water, dried, filtered in vacuo and the filter cake washed with 2 L of methylene chloride. The filtrate

Distillation under vacuum at -7182 568. 4.88 kg of ethyl 2-acetyl-2- (methoxyimino) acetic acid (the same product as in Example 2, Step a) are obtained; _Rf = 0.7 (szilikagélvékonyrétegen 9: 1 methylene chloride-etilacetáteleggyel).

Step B: 4-Bromo-2- (methoxyimino) -acetic acid ethyl ester

To a mixture of 3.53 kg of the product of Step A in 18.6 liters of methylene chloride and 3.5 g of p-toluenesulfonic acid in 30 minutes at 22 ± 1 ° C is added a solution of 2.96 kg of bromine in 3.5 liters of methylene chloride. added. 15 minutes after the addition, hydrogen bromide gas evolution was observed. After stirring for 45 minutes at 22 ° C, the mixture was transferred to another flask and washed with 2 χ 14 L of cooled deionized water. The aqueous phases were extracted with methylene chloride (2 x 3.5 liters). The methylene chloride phases are dried, filtered, the filter cake is washed with methylene chloride and the filtrate is concentrated in vacuo. 4.73 kg of ethyl 4-bromo-2- (methoxyimino) -acetic acid are obtained, which is identical to the product obtained in Example 2, step fi. Melting point: 38 ° C.

Analysis for C ₇ H ₁₀ O ₄ NBr: Calculated: C 33.35%, H 3.96%, N 5.55%.

Br, 31.69%;

Found: C, 33.0%; H, 4.0%; N, 5.5%;

Br 31.7%.

Step C: Ethyl 2- (2-Amino-4-thiazolyl) -2- (methoxyimino) acetic acid (color isomer)

To a mixture of 3.55 ethanol and 7.1 L deionized water was added 1.43 kg of thiourea. After stirring for 10 minutes at 20 ° C, a solution of the product of Step B (3.75 L) in ethanol (4.755 kg) was added at 20-25 ° C. After stirring for 3 hours at 20-25 ° C, the mixture is cooled to 15-20 ° C and stirred for ca. It is neutralized with 1.6 L of aqueous ammonia at 22 ° C to pH 7. The mixture was stirred for an additional 15 minutes at 20-25 ° C and then filtered under vacuum. The product was washed with 5 X 1.8 L deionized water. 2.947 kg, Example 2

The same 2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetic acid ethyl ester (color isomer) is obtained as in Step A) and γ; mp 162 ° C.

Elemental analysis for C ₈ H ₁₄ O ₃ N ₃ S:

Calculated: C 41.91%, H 4.84%, N 18.33%,

S 13.99%

Found: C41.9%, H 4.8%, N 18.6%,

S 14.0%

Step D: To a mixture of 2- (2-Tritylamino-4-thiazolyl) -2-methoxyimino-acetic acid ethyl ester (color isomer) in methylene chloride and 2.275 liters of triethylamine, 3.41 kg of the product prepared in Step C are obtained. We are added. After stirring for 15 minutes, 4.55 kg of trityl chloride were added under nitrogen with stirring at 20-25 ° C for 1 hour. The mixture was stirred for 20 hours under nitrogen at 20-25 ° C. Meanwhile, triethylamine hydrochloride precipitates in crystalline form.

The liquid phase was poured into another flask and washed with 10.2 L of cooled 0.5 N aqueous hydrochloric acid and 2 x 10.2 L of deionized water. The washing liquids

Extract with 1.7 L of methylene chloride. The methylene chloride phases were combined, dried, filtered, and the filter cake was washed with methylene chloride (1.7 L) and the filtrate was evaporated to dryness under vacuum at a temperature below 50 ° C. 8.425 kg of crude product are obtained.

The product obtained is dissolved in 8.4 liters of methanol at 20-25 ° C and stirred at 20-25 ° C for 1 hour with stirring to initiate crystallization.

Add 2.8 liters of deionized water. After stirring for 1 hour, the solid was filtered off with suction, washed with 2 L-1.7 L of 75% aqueous methanol, then dried at 40 ° C. 7.165 kg of the ethyl 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) -acetic acid ethyl ester (color isomer) are obtained in the same manner as in Example 2 (B). 120 DEG C., value 0.7 (eluting with ethyl ether).

Step E: Sodium salt of 2- (2-Tritylamino-4-thiazolyl) -2-methoxyimino-acetic acid (color isomer)

4.175 kg product of Step D and

A mixture of 20.9 liters of ethanol was heated to reflux under nitrogen. The solid dissolves completely at about 55 ° C. 5.235 L of about 2 N aqueous sodium hydroxide solution are added to the mixture under reflux under nitrogen. Crystals suddenly precipitate out of the mixture. The mixture was heated at reflux for 1 hour under nitrogen, with stirring and then cooled to 20-25 ° C and maintained at this temperature for 2 hours. The solid was filtered off with suction, washed with 4 x 2.1 liters of ethanol and dried. 4.02 kg of the sodium salt of 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) -acetic acid (color isomer) are obtained.

Step F: 2- (2-Tritylamino-4-thiazolyl) -2- (methoxyimino) acetic acid (color isomer)

To a mixture of 500 g of the product obtained in Step E (= 400 g of dry product) and 2.5 L of methylene chloride is added 2 L of about 1 N aqueous hydrochloric acid solution under stirring at 20-25 ° C under nitrogen for 2 minutes. The reaction mixture was stirred for 2 hours at 20-25 ° C under nitrogen. The methylene chloride phase is separated off and washed with 3 to 2 liters of deionized water. The washings were extracted with 1 L of methylene chloride. The methylene chloride solutions were combined, dried, decolorized with 25 g of charcoal, filtered in vacuo, the cake was rinsed with

-8182 568 The filtrate was evaporated to dryness. 481 g of crude product are obtained. The crude product was mixed with 2.1 L of isopropyl ether, filtered in vacuo, washed with 2 x 420 mL of isopropyl ether and dried in vacuo to constant weight.

424.6 g of 2- (2-tritylamino-4-thiazolyl) -2- (methoxyimino) -acetic acid (color isomer) were obtained in the same manner as in Example 2 (C).

Analysis calculated for C ₂₅ J ₂₁ O ₃ N ₃ S: C 64.5%, H 4.3%, N 9.0%.

S 6.98%

Found: C 64.4%, H 4.4%, N 8.9%,

S 7.1%

Example 8

To illustrate process c)

Step A: Ethyl 2- (2-amino-4-thiazolyl) -2- (hydroxyimino) acetic acid, color isomer

Dissolve 0.8 g of thiourea in 2.4 ml of ethanol and

In 4.8 ml of water. A solution of 2 g of 4-chloro-2- (hydroxyimino) -acetic acid in ethyl acetate is added over 5 minutes and the. the reaction mixture was stirred for 1 hour at room temperature. Most of the ethanol is then removed in vacuo and the residue is adjusted to pH 6 with solid sodium bicarbonate. The reaction mixture was cooled in ice, the solid which precipitated was filtered off, washed with water and dried in vacuo at 40 ° C. 1.32 g of the title compound are obtained, m.p. 232 ° C.

Elemental composition: C ₇ H _e O ₃ N ₃ S Calculated: C: 39.06%, H: 4.21%, N: 19.52%,

S, 14.9%;

Found: C, 38.9; H, 4.4; N, 19.7.

S, 14.6%.

The compound of formula (E) has an NMR (DMSO, 60 MHz) spectrum of: (a) 1.25 ppm (J = 7 Hz, triplet), (b) 4.27 ppm (J = 7 Hz, quadruplet), (c) 6.83 ppm (singlet), (d) 7.11 ppm (singlet), (e) 11.4 ppm (singlet).

Step B: 2- (2-Amino-4-thiazolyl) -2- (hydroxyimino) acetic acid, color isomer

21.5 grams of the product of Step A are added to a mixture of 200 ml of absolute ethanol and 55 ml of 2N sodium hydroxide solution. The resulting reaction mixture was heated at 45 ° C for 30 minutes on a water bath and then placed in an ice-water cooling bath. The pH of the mixture was adjusted to 6 with acetic acid, whereupon a precipitate formed. It is filtered off, washed with 50% aqueous ethanol and then with ether. After drying, 16.9 g of the title compound are obtained. Rf value: 70:20:10 ethyl acetate: ethanol: water: 0.05.

Step C: Sodium salt of 2- (2-Tritylamino-4-thiazolyl) -2- (trityloxyimino) acetic acid (color isomer)

The acid (16.9 g) obtained in step B is mixed with 50 ml of dimethylformamide and 42 ml of triethylamine. After stirring for 15 minutes at room temperature the substance is completely dissolved.

The solution was cooled to -20 ° C, when the triethylamine salt partially crystallized. A solution of 54 g of trityl chloride in 100 ml of chloroform is added over 15 minutes at -20 ° C. The reaction mixture was stirred for 1 hour while being allowed to warm to room temperature. The reaction mixture was poured into 200 ml of water containing 40 ml of 2N hydrochloric acid.

The organic layer was decanted, washed with water (2 x 200 mL), dried and evaporated under reduced pressure after filtration of the desiccant. The residue was dissolved in ethyl acetate.

Saturated sodium bicarbonate solution (100 ml) was added to the solution, the solutions were shaken and the phases were separated. The sodium salt crystallizes. The crystals were cooled for 30 minutes on ice, then filtered and washed with ethyl acetate. 27 g of the title sodium salt are obtained with an Rf value of 0.33 when run with ether.

Example 9

To illustrate process b)

Step A: Ethyl 2- (2-Tritylamino-4-thiazolyl) -2 (hydroxyimino) acetic acid, color isomer

43.2 g of the ethyl isomer of 2- (2-amino-4-thiazolyl) -2-hydroxyimino-acetic acid are colorless as shown in Example 8. Prepared in step A), mixed with 120 ml of anhydrous dimethylformamide. The solution was cooled to -35 ° C and 32 ml of triethylamine was added, followed by 60 g of trityl chloride in portions over 30 minutes. The reaction mixture is then allowed to warm, whereupon the insoluble material is completely dissolved and the solution is heated to 30 ° C. After 1 hour, the reaction mixture is poured into 1.2 ml of ice water containing 40 ml of 22 ° C hydrochloric acid. The resulting system was stirred in an ice-water cooled bath, the precipitated solid filtered off, rinsed with hydrochloric acid and flushed with ether.

69.3 g of hydrochloride are obtained.

This product was dissolved in 5 volumes of methanol to which 120% triethylamine was added and then the free base was precipitated by slow addition of 5 volumes of water.

Elemental composition of C ₂₃ H _2e O Sl ₃ N _3/4 H ₂ O: Calculated: C 67.6%, H 5.1%, N: 9.1%;

S, 6.9%;

Found: C: 67.5%, H: 5.1%, N: 8.8%,

S, 6.8%.

(H) the product of formula NMR (CDC1 _3, 60 MHz): (a) 1.31 ppm (J = 2 Hz, triplet), (b) 4.37 ppm (J = 7Hz, quartet), (c ) 6.37 ppm (singlet), (d) 7.28 ppm (singlet).

-9182 568

Step B: Ethyl 2- (2-Tritylamino-4-thiazolyl) -2- (tetrahydropyranyloxyimino) acetic acid, color isomer

5.6 grams of the product obtained in Step A are added to 56 ml of freshly distilled dihydropyran. The system was immersed in an ice water bath and then 2.4 g of p-toluenesulfonic acid was added. The reaction mixture was stirred for 1.5 hours while allowing the temperature to rise to room temperature. It was then poured into a mixture of 100 ml of benzene, 100 ml of water and 2 ml of triethylamine. The phases are separated, the organic phase is washed with water, dried, filtered, rinsed with benzene, and the solvent is distilled off. The residue was dissolved in isopropyl ether, crystalline precipitated, then kept in the refrigerator overnight, filtered and washed with isopropyl ether.

4.42 g of product are obtained, m.p. 184 ° C.

Elemental composition: based on p-toluenesulfonic acid salt of formula C ₃₈ H ₃₉ O ₇ N ₃ S ₂ :

calculated: C: 63.9%; S: 9.0%; H, 5.5% N: 5.9% Found: C: 63.7%, S: 8.9%. H, 5.5% N: 5.8%

NMR spectrum of the (R) product (CDC1 _3, 60 MHz)

(a) 1.36 ppm (triplet), (b) 4.39 ppm (quadruplet), (c) 6.60 ppm (singlet), (d) 6.91 ppm (singlet).

Step C: 2- (2-Tritylamino-4-thiazolyl) -2-tetrahydropyranyloxyimino) acetic acid, color isomer

4.56 grams of the product of Step B are mixed with 45 ml of dioxane and 8.4 ml of 2N sodium hydroxide solution. The reaction mixture was heated under reflux for one and a half hours, then cooled in an ice-water bath to precipitate salt. The product is filtered off, rinsed with aqueous dioxane and then with ether.

4.66 g of sodium salt are obtained.

The free acid was obtained by dissolving the product in 50 ml of dioxane, adjusting the pH of the solution to 5 with formic acid, and precipitating the acid with 90 ml of water. The product melts at 180 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 60 MHz): 6.69 ppm (proton of thiazole ring), 7.31 ppm (aromatic).

Example 10

To illustrate process (a)

Step A: Ethyl 2- (2-Tritylamino-4-thiazolyl) (trityloxyimino) -acetic acid, color isomer

The color isomer of 2- (2-amino-4-thiazolyl) -2- (hydroxyimino) -acetic acid (1.08 g) prepared in Example 8 (A) was dissolved in 8 ml of chloroform. Triethylamine (1.5 ml) was added to the solution, followed by heating at ± 5 ° C for 25 minutes while adding a solution of 3 g of trityl chloride in 6 ml of chloroform. The reaction mixture was stirred for 1 hour at room temperature, then with 18 ml of water, 8 ml of wash with water. It is then dried, filtered and evaporated to dryness. The residue was crystallized from isopropanol. 2.3 g of the title compound are obtained, m.p. 170 ° C.

Step B: Sodium salt of 2- (2-Tritylamino-4-thiazolyl) -2- (trityloxyimino) acetic acid, color isomer

Dissolve 0.7 grams of the product of Step A in 3.5 mL of warm dioxane and add 1 mL of 1N sodium hydroxide solution at 110 ° C with stirring. The reaction mixture was stirred at reflux temperature for 1 hour and 50 minutes, then cooled. The precipitated sodium salt is filtered off. The product thus obtained is identical to Example 8

(C).

Claims (4)

Patent claims: A process for the preparation of color isomers of the 2- (2-aminothiazol-4-yl) -2-oximinoacetic acid derivatives of formula (I), wherein R is trityl, R 'is alkyl or alkenyl having up to 4 carbon atoms, trityl or 2-tetrahydropyranyl, R 1 is hydrogen or C 1-4 alkyl, characterized in that: a) for the preparation of compounds of formula I wherein R is trityl, R 'is alkyl, alkenyl or trityl up to 4 carbon atoms, R 1 is hydrogen or C 1-4 alkyl, a compound of formula IV, wherein R is hydrogen, alkyl or alkenyl having up to 4 carbon atoms and alk is C 1 -C 4 alkyl, is reacted with trityl halide, preferably trityl chloride, and the resulting ester of formula (I) is optionally treated with a base and then with an acid; b) for the preparation of compounds of formula I wherein R is trityl, R _x is C 1-4 alkyl and R 'is 2-tetrahydropyranyl, a compound of formula X wherein R is trityl and alk is 1- C 4, alk alkyl, reacted with dihydropyran, and if desired, the Rj group of the resulting ester of formula I is replaced by hydrolysis with hydrogen, or preparing c) (I) compounds wherein R _r is hydrogen, R and R 'is trityl, a compound of formula (IV) wherein R is hydrogen, and alk represents a C1-4 alkyl group, with a base - preferably alkali metal carbonate or hydroxide, and then the resulting compound with an acid, preferably hydrochloric acid, acetic acid -10182 568 Or with formic acid, and reacting the resulting compound of formula XV, wherein R is hydrogen, with at least 2 molar equivalents of trityl halide, preferably trityl chloride. (Priority 04.04.1977) A process according to claim 1 for the preparation of compounds of formula I wherein R is trityl, R 'is trityl, or C 1-4 alkyl or alkenyl, and R 1 is hydrogen. A compound of formula (IV) wherein R is hydrogen, C 1-4 alkyl or alkenyl is reacted with trityl halide, preferably trityl chloride, and reacted with a base followed by an acid. (Priority: January 23, 1976) 3. A process according to claim 1 for the preparation of compounds of formula I wherein R is trityl, R 'is tetrahydropyranyl, and R _x is C 1-4 alkyl, characterized in that wherein R is trityl and alk is C 1-4 alkyl, Reaction with 5 dihydropyran. (Priority 04.04.1977) The process of claim c) for the preparation of compounds of formula I wherein R and R 'are trityl and R' 10 is hydrogen, characterized in that a compound of formula IV, wherein R is hydrogen, and alk is a C 1 -C 4 alkyl group, with a base, preferably an alkali carbonate or hydroxide, followed by an acid - Preferably, the reaction is carried out with hydrochloric acid, acetic acid or formic acid, and the resulting compound of formula XV, wherein R is hydrogen, is reacted with at least 2 molar equivalents of trityl halide, preferably trityl chloride. (Priority: 01.04.1977,)