CH628038A5 - Process for the preparation of syn oximes of substituted 2-(2-amino-4-thiazolyl)acetic acids - Google Patents

Abstract

The compounds are the syn isomers of formula: <IMAGE> in which alc represents a C1-C4 alkyl and R' represents a hydrogen atom, a group which can be removed by acid hydrolysis or by hydrogenolysis or a C1-C4 alkyl, alkenyl or alkynyl. They are prepared by treating a compound of formula: <IMAGE> in which X represents chlorine or bromine, with thiourea, the reaction being carried out either in an aqueous solvent, or at room temperature in the presence of the stoichiometric amount of thiourea for a few hours only, or by combining the above conditions, and then by treating with a base. The compounds (IV) are valuable intermediates for the synthesis of 7-(aminothiazolylacetamido)cephalosporanic acids of corresponding syn configuration.

Description

The subject of the present invention is a process for the preparation of oximes, in the syn form, derived from substituted 2- (2-amino 4-thiazolyl) acetic acids and corresponding to the formula:

NH2

wherein R 'represents a hydrogen atom, a group eliminable by acid hydrolysis or by hydrogenolysis or an alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms, and aie represents an alkyl radical having from 1 to 4 carbon atoms carbon, in the syn form, characterized in that the thiourea is reacted, then a base on a compound of formula:

X-CH2-Ç-C-COOalc

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(m-)

(IV)

COOalc

*

OR'b in which X represents a chlorine or bromine atom and R'b represents a hydrogen atom, a group which can be eliminated by acid hydrolysis or by hydrogenolysis or an alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms , when X represents a chlorine atom, or R'b represents a hydrogen atom or a saturated alkyl radical having from 1 to 4 carbon atoms, when X represents a bromine atom; and, for the reaction of thiourea, either one operates in an aqueous solvent, or one operates at room temperature, in the presence of a substantially stoichiometric amount of thiourea and by carrying out the reaction in a time limited to a few hours, or one operates by meeting all the conditions set out above.

2. Method according to claim 1, characterized in that the thiourea is reacted, then a base on a compound of formula:

Cl-CH -C-C-COOalc 2 II il

0 N & R!

(m)

In this formula, aie represents an alkyl radical having from 1 to 4 carbon atoms and R 'represents a hydrogen atom, a group which can be removed by acid hydrolysis or by hydrogenolysis or an alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms.

As groups which can easily be removed by acid hydrolysis or by hydrogenolysis, mention may be made of tert.-butoxycarbonyl, trityl, benzyl, dibenzyl, trichloroethyl, carbobenzyl-oxy, formyl, trichloroethoxycarbonyl or 2-tetrahydropyrannyl groups.

Among the other meanings of R ′, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, vinyl, propenyl, butenyl, ethynyl and propargyl radicals.

The subject of the invention is in particular a process for the preparation of the products of formula IV in which the groups which can be easily eliminated by acid hydrolysis or by hydrogenolysis are chosen from the group consisting of tert.-butoxycarbonyl, trityl, dibenzyl, trichloroethyl and carbobenzyloxy groups. .

The compounds defined above, of the syn isomer form, can be represented schematically by the following formula:

NH,

in which ale has the meaning indicated above and R 'represents a hydrogen atom, a group eliminable by acid hydrolysis or by hydrogenolysis or an alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms.

3. Method according to claim 1, characterized in that the group R ′ which can be eliminated by acid hydrolysis or by hydrogenolysis is one of the tert-butoxycarbonyl, trityl, benzyl, dibenzyl, trichloroethyl, carbobenzyloxy, formyl, trichloroethoxycarbonyl or 2-tetrahydropyrannyl groups. .

4. Method according to claim 3, characterized in that the group R 'eliminable by acid hydrolysis or by hydrogenolysis is one of the tert.-butoxycarbonyl, trityl, dibenzyl, trichloroethyl and carbobenzyloxy groups.

5. Method according to claim 1, characterized in that R 'represents one of the methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, vinyl, propenyl, butenyl, ethynyl and propargyl radicals.

6. Method according to claim 1, characterized in that R 'represents the methyl group and aie represents the ethyl group.

50

Oalc

55 It is understood that the compounds of formula IV may exist, either in the form indicated by said formula, or in the form of compounds of formula:

60

Oalc in which ale and R 'have the abovementioned meaning.

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The compounds of formula IV can be used as starting materials for the synthesis of 2- (7-amino 4-thiazolyl) acetamidocephalosporanic acids and analogous compounds, which are provided with remarkable antibiotic properties, on the one hand on Gram bacteria (+), such as staphylococci, streptococci, in particular penicillin-resistant staphylococci, on the other hand, on Gram (-) bacteria, in particular coliform bacteria, Klebsiella, Salmonella and Proteus.

These properties make the said compounds suitable for use as medicaments in the treatment of affections with sensitive germs and in particular in that of staphylococcal diseases, such as staphylococcal septicemia, malignant staphylococcal diseases of the face or skin, pyoderma, septic or suppurative wounds, anthrax, phlegmons , erysipelas, acute primary or post-influenza staphylococcal disease, bronchopneumonia, pulmonary suppurations.

These compounds can also be used as medicaments in the treatment of colibacillosis and associated infections, in Proteus, Klebsiella and Salmonella infections and in other conditions caused by Gram (-) bacteria.

It has been found that the syn or anti configuration of said cephalosporanic acids and analogous compounds is linked to the configuration of the compounds of formula IV, since the configuration of the products obtained from the compounds of formula IV can be maintained during the synthesis.

The configuration of the products of formula IV depends on a certain number of parameters involved during the preparation of these products.

It has thus been found that, when thiourea is made to act on compounds of formula:

Cl-CH_-Ç-C-COOalc

2 II II

0 N (III)

either in an aqueous solvent, such as aqueous acetone or aqueous ethanol, or at room temperature, by causing a substantially stoichiometric amount of thiourea to act and for a fairly short period, of the order of 1 to 3 h, or finally when all the preceding conditions are met, the syn isomer is obtained.

The process according to the invention is characterized in that the thiourea is reacted, then a base on a compound of formula:

X-CH-Ç-C-COOalc

ï | W)

OR 'b in which X represents a chlorine or bromine atom and R'b represents a hydrogen atom, a group which can be eliminated by acid hydrolysis or by hydrogenolysis or an alkyl, alkenyl or alkynyl radical having from 1 to 4 atoms carbon, when C represents a chlorine atom, or R'b represents a hydrogen atom or a saturated alkyl radical having from 1 to 4 carbon atoms, when X represents a bromine atom; and, for the reaction of thiourea, either one operates in an aqueous solvent, or one operates at room temperature, in the presence of a substantially stoichiometric amount of thiourea and carrying out the reaction in a time limited to a few hours , or we operate by meeting all the conditions set out above.

In a preferred embodiment of the process, the base which is used to obtain the compound of formula IV is potassium acetate. It is however possible to use the carbonates and acid carbonates of alkali metals, soda or potassium hydroxide diluted.

The subject of the invention is also a process for preparing the compounds of formula IV, as defined above, in the syn form, characterized in that the thiourea is made to act on a compound of formula:

Cl-CH.-q-C-COOalc

2 II II

in which R 'represents a hydrogen atom, a group which can be eliminated by acid hydrolysis or by hydrogenolysis or an alkyl, alkenyl or alkynyl radical having from 1 to 4 carbon atoms and aie represents an alkyl radical having from 1 to 4 carbon atoms , to obtain, after treatment with a base, the compound of formula IV; and, for the reaction with thiourea, either one operates in an aqueous solvent, or one operates at room temperature, in the presence of a substantially stoichiometric amount of thiourea and by carrying out the reaction in a time limited to a few hours, or one operates by meeting all the conditions set out above.

The products of formula III which are not known can be prepared from the ethyl y-chloro a-oximinoacetylacetate described in "J. of Medicinal Chemistry ”, 1973, vol. 16, No. 9, as shown below.

The products are obtained in which R ′ represents a group which can be easily eliminated by acid hydrolysis or by hydrogenolysis by conventional reactions using “functional derivatives of these groups.

The products are obtained in which R ′ represents an alkyl, alkenyl or alkynyl radical, having from 1 to 4 carbon atoms, by action on the y-chloro a-oximinoacetylacetate of ethyl halides or sulfates of said radicals.

The products of formula III ', in which X represents a bromine atom and R' represents a hydrogen atom can be obtained by treating, with a brominating agent, the compounds of formula:

CH -C-C-COOalc 3 II II

0 N (VI)

OH

The brominating agent which is preferably used is bromine. Reference example:

2- (2-Amino 4-thiazolyl) 2-hydroxyiminoacetate

2 g of ethyl y-chloro a-oximinoacetylacetate are placed in 5 ml of ethanol and 0.76 g of thiourea and the mixture is stirred at ambient temperature for 16 h, the hydrochloride crystallizes, diluted with 5 ml of ether, wring, rinse with ethanol / ether (1/1) then with ether and obtain 1.55 g of hydrochloride. The 1.55 g of hydrochloride obtained is dissolved at 40-50 ° C in 8 ml of water, then neutralized to pH 5-6 by addition of sodium acetate. Free amine crystallizes. It is ice-cold, then wrung, washed with water, dried and obtained 1.22 g of the anti-isomer, mp = 154 ° C.

The mother liquors and the washing liquors from several tests are combined, concentrated, taken up in water, washed with ether, added sodium hydrogen carbonate, drained, washed with water, obtained 1.9 g of product comprising two stains in thin layer chromatography, purified by chromatography on silica by elution with ether. The pure fractions of the syn isomer are combined, concentrated, paste with ether, wrung, dried and 50 mg of this isomer is obtained.

Example 1:

2- (2-Amino 4-thiazolyl) ethyl 2-methoxyiminoacetate

1 g of ethyl γ-chloro-methoxyiminoacetylacetate is introduced into 3 ml of absolute ethanol and 0.42 g of ground thiourea is added. The mixture is stirred at ambient temperature for approximately 2 hours. Diluted with 60 ml of ether, the hydrochloride obtained crystallizes, stirred, drained, washed, dried and obtained 685 mg of hydrochloride. They are dissolved in 4 ml of water at 50 ° C., potassium acetate is added until pH 6, the liberated amine crystallizes. Cool, drain, wash with water, dry and obtain 270 mg of the expected product. M = 161 ° C.

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The product obtained has the syn configuration,

NMR (CDCI3 60 MHz) ppm: 4 (N-OCH3), 6.7 (proton of the thiazolic cycle).

The ethyl y-chloro a-methoxyiminoacetylacetate used at the start was prepared as follows:

22.5 g of ethyl y-chloro a-oximinoacetylacetate are placed in 100 ml of methylene chloride.

It is placed on an ice bath and a fresh solution of diazomethane (at 21.6 g / l) is added slowly with stirring, ie 275 ml. It is left in contact for 5 min and the excess diazomethane is destroyed with a little alumina. It is concentrated and then purified by elution on silica with methylene chloride. 11.93 g of expected product are obtained.

Example 2:

2- (2-Amino 4-thiazolyl) ethyl 2-methoxyiminoacetate Stage a: Ethyl 2-acetyl 2-methoxyiminoacetate.

180 g of crude ethyl 2-acetyl 2-hydroxyiminoacetate are introduced into 900 ml of pure acetone. At 10 ° C. under nitrogen, 234 g of potassium carbonate are added; 103 ml of dimethyl sulphate are then introduced. Stirred 3 h at room temperature, add ice, pour into 41 of water, extract with methylene chloride, wash with water, dry and distill the solvents. 185 g of expected product are obtained.

Stage ß: ethyl 4-Bromo 2-methoxyiminoacetylacetate.

197 g of product obtained as in stage a are placed in 11 of methylene chloride and 200 mg of paratoluenesulfonic acid are added. At 20 ° C., 1/10 of the solution of 191 g of pure bromine in 200 ml of methylene chloride is introduced. When the reaction is started, the rest of the bromine solution is introduced over 1 hour at about 20 ° C. It is then left to rise to 25 ° C to complete the reaction. Wash with ice water, re-extract with methylene chloride, dry and distill the solvent. 268 g of expected product are obtained.

Stage y: 2- (2-Amino 4-thiazolyl) 2-methoxyiminoacetate.

80 g of thiourea are introduced into 270 ml of ethanol and 540 ml of water. 268 g of product obtained in stage β are introduced under nitrogen in Z 1 h in 270 ml of ethanol. The mixture is stirred for 1 hour at 20 ° C. It is cooled to 15 ° C. and introduced in small portions of potassium acid carbonate to pH 5. It is drained, washed with water, dried and gives 133.8 g of the expected product . The product obtained is identical to that obtained in Example 1.

Example 3:

2- (2-Amino 4-thiazolyl) 2 - ((2-propenyl) oxyimino) ethyl acetate a) 9.7 g of ethyl 2-hydroxyimino 4-chloroacetylacetate, 30 ml of acetone and 9.15 ml of 3-iodopropene are cooled in ice and 27.5 ml of 2N sodium hydroxide are added, the mixture is left to stand for 14 h at room temperature.

b) 3.8 g of thiourea are added to the reaction medium, brought to 60 ° C. for 15 min, then 45 min at room temperature, flushes out the acetone, adds methylene chloride, water, carbonate potassium, stirred, decanted, reextracted with methylene chloride, dried, concentrated to dryness, obtained 9.75 g of residue which was chromatographed on silica eluting with ether, isolated 2.7 g of product as it is taken up in isopropyl ether, the crystals are wrung, rinsed and dried. 783 mg of expected product is obtained. Mp 100 ° C. The product obtained has the syn configuration.

Example 4:

2- (2-Amino 4-thiazolyl) 2-ethyl ethoxyiminoacetate a) 19.4 g of ethyl y-chloro a-oxyiminoacetoacetate are placed in 60 ml of acetone and 14.3 ml of diethyl sulphate. It is cooled for 10 min in an ice bath and added, in 30 min, 55 ml of 2N sodium hydroxide, stirred 40 min.

b) 7.6 g of thiourea are added to the reaction medium, brought to 55 ° C. for 20 min, flushes out the acetone, takes up in ethyl acetate,

add 6.9 g of potassium carbonate, stir, decant, re-extract with ethyl acetate, dry and concentrate to dryness. 17.4 g of residue are isolated and chromatographed on silica, eluting with ether. The expected product is collected, taken up in isopropyl ether, drained, rinsed, dried and 2.8 g of the expected product are obtained. Mp 129 ° C. The product obtained has the syn configuration.

Example 5:

2- (2-Amino 4-thiazolyl) 2- (1-methylethoxyimino) ethyl acetate

Stage A: 2-Acetyl2- (1-methylethoxyimino) ethyl acetate

39.8 g of ethyl 2-acetyl 2-hydroxyiminoacetate are placed in 200 ml of pure acetone. The mixture is cooled in an ice bath and 52 g of potassium carbonate are added, then, in 1 h, 25 ml of 2-iodopropane. Then stirred for 2 h, add 800 ml of water and 500 ml of methylene chloride, stir, decant, reextract with methylene chloride, dry, spin, concentrate and isolate 41.5 g of the expected product.

Stage B: 4-Bromo 2- (1-methylethoxyimino) ethyl acetylacetate

The 41.5 g of product obtained in the previous stage are placed in 190 ml of methylene chloride with traces of paratoluene sulfonic acid. Stirred and introduced, in 1 h, at room temperature, a solution of 11.9 ml of bromine in 50 ml of methylene chloride. Stir, add ice water, decant, reextract with methylene chloride, rewash with ice water, dry, concentrate and isolate 55 g of the expected derivative.

Stage C: 2- (2-Amino 4-thiazolyl) 2- (1-methylethoxyimino) ethyl acetate

14.9 g of thiourea are placed in 55 ml of ethanol and 105 ml of water and a solution of the 55 g of product prepared in stage B in 55 ml of ethanol is added over 40 min. Stir 2 'at h and at room temperature, add 220 ml of sodium hydrogen carbonate 10% in water, stir, drain, rinse, dry and isolate 42.15 g of crude product which is chromatographed on silica eluting with ether, collect the fractions rich in the expected product, concentrate, take up the crystals with isopropyl ether, spin dry, rinse and obtain 10.75 g of the expected product. The product obtained has the syn configuration.

Example 6:

2- (2-Amino 4-thiazolyl) ethyl 2-methoxyiminoacetate, syn isomer

Stage A: Ethyl 2-acetyl2-methoxyiminoacetate

4.69 kg of ethyl 2-acetyl 2-hydroxyiminoacetylacetate, corresponding to 4.21 kg of pure product, are introduced into 211 of anhydrous pure acetone. At 20-25 ° C, 6.1 kg of potassium carbonate are added. The suspension is stirred for 10 min, then added at 20-25 ° C.

3.72 kg of dimethyl sulfate. The mixture is stirred for 3 h at 20-25 ° C. Then poured into 1261 deionized water, extracted with 4 times 51, then 21 of methylene chloride. Wash with 101 deionized water. Dry, wring, rinse with 21 methylene chloride. It is distilled under vacuum and 4.88 kg of expected product is obtained.

Rf = 0.7 (by thin layer chromatography on silica; eluent: methylene chloride / ethyl acetate 9/1).

The product is identical to that obtained in stage a of Example 2.

Stage B: ethyl 4-Bromo 2-methoxyiminoacetylacetate

3.53 kg of product obtained in stage A above is placed in 18.61 of methylene chloride and 3.5 g of paratoluene sulfonic acid. A solution of 2.96 kg of bromine in 3.51 of methylene chloride is added to the preceding solution over 30 min while maintaining the temperature at 22 + 1 ° C. A release of hydrobromic acid is observed after 15 min of introduction. Stir 45 min at 22 ° C, then transfer, wash with 2 times 141 of ice-cold demineralized water. The washes are reextracted with twice 3.51 of methylene chloride. It is dried, filtered, rinsed and distilled under vacuum. We obtain

4.73 kg of expected product.

This product is identical to that obtained in stage ß of Example 2.

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Stage C: 2- (2-Amino 4-thiazolyl) 2-methyl methoxyiminoacetate, syn isomer

1.43 kg of thiourea are introduced into 3.551 of ethanol and 7.11 of demineralized water. Stirred 10 min at 20 ° C, then added at 20-25 ° C 4.730 g of product prepared in step B above in 3.551 ethanol. The mixture is stirred for 3 h at 20-25 ° C. Cool to 15-20 ° C and neutralize to pH 7 with about 1.61 of 22 ° B ammonia.

The mixture is stirred for another 15 min at 20-25 ° C. It is drained, washed with 5 times 1.8 l of demineralized water. 2.947 kg of expected product are obtained. Mp 162 ° C.

The product is identical to that obtained in Examples 1 and 2. Example 7:

2- (2-Amino 4-thiazolyl) ethyl 2-hydroxyiminoacetate, syn isomer

0.8 g of thiourea are dissolved in 2.4 ml of ethanol and 4.8 ml of water. The solution of 2 g of ethyl 4-chloro 2-hydroxyiminoacetylacetate is added over 5 min and the mixture is stirred for 1 h at room temperature. Most of the ethanol is removed under partial vacuum and neutralized to pH 6 by adding solid sodium hydrogen carbonate. Ice, spin, wash with water, vacuum dry at 40 ° C. 1.32 g of expected product are obtained. M = 232 ° C.

Analysis for C5H903N3S:

Calculated: C 39.06 H 4.21 N 19.52 S 14.9%

Found: C38.9 H 4.4 N 19.7 S 14.6%

5 RM N (UMSO, 60 MHz)

(e)

(a) triplet centered on 1.25 ppm; J = 7 Hz 20 (b) quadruplet centered on 4.27 ppm; J = 7 Hz

(c) singlet at 6.83 ppm

(d) singlet at 7.11 ppm

(e) singlet at 11.4 ppm.

R

Claims (5)

628038 2 CLAIMS 1. Process for the preparation of compounds of formula: NH, (IV) 7. Method according to claim 1, characterized in that R 'represents the 2-propenyl group and aie represents the ethyl group. 8. Method according to claim 1, characterized in that R 'represents the ethyl group and aie represents the ethyl group. 9. Method according to claim 1, characterized in that R 'represents the 1-methylethyl group and aie represents the ethyl group. 10. Method according to claim 1, characterized in that R 'represents a hydrogen atom and aie represents the ethyl group. COOalc