CS207577B2 - Method of making the derivatives of the 2-/2-amino-4-thiazolyl/-vinegar acid - Google Patents

Description

The present invention relates to a process for the preparation of 2- (2-amino-4-thiazolyl) acetic acid derivatives. These derivatives are useful as intermediates for the production of novel oxime derivatives of 7-aminothiazolylacetamidocephalosporanic acid, which have very good antibiotic activity on both Gram-positive bacteria such as staphylococci and streptococci, especially against penicillin-resistant staphylococci and Gram-negative bacteria. such as conformal bacteria, Klebsielly, Salmonella and Proteus.

The present invention provides a process for the preparation of 2- (2-amino-4-thiazolyl) acetic acid derivatives of the general formula I

NH-Rd

ORd (if in which

Rd is trityl or chloroacetyl, and

R'd is trityl, chloroacetyl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, and when R'd is chloroethyl, Rd is also a chloroacetyl group which is characterized in that: The compound of formula II is treated with thiourea and then with a base

X — CH2 — C-C-CO2alk,

II II o N

OR‘b (Π) in which

X is chlorine or bromine,

R‘b represents a hydrogen atom, a trityl group or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, when X represents a chlorine atom, or

R‘b represents a hydrogen atom or a saturated alkyl group having 1 to 4 carbon atoms, when X represents a thunder atom, and alk represents an alkyl group having 1 to 4 carbon atoms, to form a compound of formula III

(III) wherein

R 'represents a hydrogen atom, a trityl group or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, and alk represents an alkyl group having 1 to 4 carbon atoms, after which the compound of formula III is either treated with trityl chloride or wherein R 'represents a hydrogen atom or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, the compound of formula III is treated with monochloroacetic anhydride to form a compound of formula IV

(IV) wherein

Rd is trityl or chloroacetyl,

R'd is trityl, chloroacetyl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, provided that when R'd is chloroacetyl then Rd is chloroacetyl, and alk is C1-4 alkyl after which the compound of formula (IV) is treated with a base and then with an acid to form a compound of formula (I).

Preferably, the above method uses a compound of formula II wherein X is chlorine, R'b is hydrogen, trityl, or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms and alk is an alkyl group of 1 to 4 carbon atoms. carbon atoms.

Preferably, the above method uses a compound of formula II wherein X is chlorine, R'b is hydrogen, trityl, or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms and alk is an alkyl group of 1 to 4 carbon atoms. The resulting product of formula (III) is treated with trityl chloride to give a compound of formula (IV) wherein Rd is trityl and R'd is trityl or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms and alk is (C 1 -C 4) -alkyl followed by treatment of IV with a base followed by acid to form a compound of formula (I) wherein R d is trityl and R 'd is trityl or a saturated or unsaturated alkyl group having 1; up to 4 carbon atoms.

It is also possible to use in the above process a compound of formula II wherein X is atom, thunder, R'b is a saturated alkyl group having 1 to 4 carbon atoms, and alk is an alkyl group of a compound of formula III wherein R 'is saturated alkyl C1-C4 and alk is C1-C4alkyl, followed by treatment of III with trityl chloride to form IV, wherein Rd is trityl, R'd is saturated alkyl C 1-4 alkyl and alk is C 1-4 alkyl, and the compound of formula IV is treated with a base and then acid to give a compound of formula I wherein Rd is trityl and R'd represents a saturated alkyl group having 1 to 4 carbon atoms.

The present invention also provides a process for the preparation of a compound of formula (I) of the syn configuration by treating with a thiourea and then base on a compound of formula (II) wherein X is chlorine or bromine, R'b is hydrogen, trityl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms when X is a chlorine atom, or R * b represents a hydrogen atom or a saturated alkyl group having 1 to 4 carbon atoms when X is a bromine atom and alk is an alkyl group of 1 up to 4 carbon atoms, either in an aqueous solvent or at ambient temperature in the presence of a stoichiometric amount of thiourea at a reaction time of 1 to 3 hours, or using all of these conditions together to form a compound of formula III wherein R 'is hydrogen, trityl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms atoms and alk represents an alkyl radical having 1 to 4 carbon atoms, syn, and then this product of general formula III is further treated under the above conditions to give a compound of formula I ^1, syn.

Preferably, the aforementioned method is treated with a thiourea and then a base of a compound of formula II wherein X is chlorine, R'b is hydrogen, trityl or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms, and alk is C 1 -C 4 alkyl, either in an aqueous solvent or at ambient temperature in the presence of a stoichiometric amount of thiourea at a reaction time of 1 to 3 hours, or using all of these conditions together to form a compound of formula III wherein R ' represents a hydrogen atom, a trityl group or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms and alk represents an alkyl group having 1 to 4 carbon atoms, after which the product of formula III is further processed under the conditions given above to give a compound of formula I son.

The present invention also provides a process for the preparation of a compound of formula I wherein Rd is trityl and R'd is trityl or a saturated or unsaturated alkyl group having from 1 to 4 carbon atoms by treating with thiourea and thereafter base to a compound of formula II wherein X is chlorine, R'b is hydrogen, trityl or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms and alk is alkyl group of 1 to 4 carbon atoms, either in the environment % of an aqueous solvent, or at ambient temperature in the presence of a stoichiometric amount of thlomocoyin at a reaction time of 1 to 3 hours, or using all of these conditions together.

Preferably, in the above process for the preparation of compounds of formula I in which Rd is trityl and R'd is a saturated alkyl group having 1 to 4 carbon atoms, thiourea is then treated with a base and then a base of the compound of formula II wherein X is a bromine atom, R'b represents a saturated alkyl group having 1 to 4 carbon atoms, fully filled with 1 to 4 carbon atoms, and alk represents an alkyl group with 1 to 4 carbon atoms, either in an aqueous hydrogen sulphate, netio _; at ambient temperature in the presence of a stoichiometric amount of thiourea at a reaction time of 1 to 3 hours, or using all of these conditions together.

The present invention also relates to a process for the preparation of 2- (tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid corresponding to the general formula (I), in which Rd represents a trityl group and R'd represents a methyl group which comprises: ethanol at room temperature acts on the stoichiometric amount of thiourea for two hours with γ-chloro-α-methoxyiminoacetyloctane, corresponding to the compound of formula II wherein X is chlorine, R'b is methyl and alk is ethyl, the reaction product is treated with potassium acetate and the product of formula III in which R 'is methyl and alk is ethyl is treated with trityl chloride at a temperature of -10 to -35 ° C in the presence of triethylamine, followed by treatment with the product. of formula IV wherein Rd is trityl, R'd is methyl and alk is an ethyl group, treating with dilute sodium hydroxide while heating the reaction mixture to reflux and then dilute hydrochloric acid.

As the base to be used to obtain the compound of formula (III), potassium acetate is preferably used. It is also possible to use alkali metal carbonates and bicarbonates such as sodium carbonate or potassium carbonate in the form of a dilute aqueous solution. The compound of formula (III) is preferably treated with trityl chloride in the presence of triethylamine or other tertiary amine bases such as trialkylamines, methylmorpholine or pyridine. The base used for saponification of the compound of formula (IV) is preferably sodium hydroxide. In addition, other bases such as potassium carbonate or barium hydroxide may also be used. Dilute hydrochloric acid is preferably used as the acid used to isolate the compound of formula (I). In addition, acetic acid or formic acid may also be used.

The alkylating agent used to convert the compound of Formula V to the compound of Formula IV is preferably an alkyl halide such as an alkyl chloride, an alkyl bromide or an alkyl iodide, or an alkyl sulfate having 1 to 4 carbon atoms.

It has been found that the configuration of the syn or anti products of formula I is already governed by the configuration of the compounds of formula III since the configuration of the following products of formulas IV and I is already maintained.

Configuration of compounds of general formula

III depends on the maintenance of certain conditions during their production. Thus, it has been found that when the thiourea treatment of the compounds of formula (II) is carried out a) either in an aqueous solvent such as an aqueous acetone solution or an aqueous ethanol solution, bj or at ambient temperature using a steehiometric amount of thiourea. up to 3 hours

(c) or, while maintaining all of the above conditions in (a) and (b), a compound of formula III of the syn configuration is obtained.

Compounds of formula II, which are not yet known, can be prepared from the ethyl (γ-chloro-α-oximacetyl acetate) described in J. of Medicinal Chemistry 1973, Vol. 16, No. 9.

Compounds in which R‘b represents a trityl group are obtained by classical reactions using functional derivatives of said group.

Compounds in which R‘b represents a saturated or unsaturated alkyl group having 1 to 4 carbon atoms are obtained by treating the corresponding ethyl halides or alkyl sulphates with ethyl (γ-chloro-α-oximihoacetyl acetate).

Compounds of formula (II) wherein X is bromine and R‘b is hydrogen may be prepared by treating the compound of formula (II) with a coupling agent.

CWňC'C-CO, alk ³ II II ²

O N

OH, wherein the brominating agent is preferably bromine.

The process according to the invention is explained in more detail in the following examples, which are illustrative only and do not limit the scope of the invention.

Example 1

Grade A

Ethyl [2- (2-amino-4-thiazolyl) -2-hydroxyimino] acetate

To 5 ml of ethanol and 0.76 g of thiourea were added 2 g of ethyl (χ-chloro-α-ω-oxinoiacetyl) acetate, and the mixture thus obtained was stirred at ambient temperature for a total of 16 hours, whereupon the hydrochloride crystallized. The reaction mixture was centrifuged and the solid was washed with ethanol-ether (1: 1) and then with ether to give 1.55 g of hydrochloride.

1.55 g of the above hydrochloride are dissolved in 8 ml of water at 40 DEG-50 DEG C. and the solution is neutralized to pH 5-6 by addition of sodium acetate. The free amine crystallizes. The reaction mixture was cooled in an ice bath and centrifuged; The solid was washed with water and dried to give 1.22 g of the anti isomer.

Mp 154 ° C.

The mother liquors and washings were combined and the fraction so combined was concentrated and precipitated with water; After washing with ether, sodium bicarbonate is added and the mixture is centrifuged. The solid was then washed with water to give 1.9 g of product which was separated into two patches by thin layer chromatography. The product was purified by chromatography on silica eluting with ether. The pure fraction of the syn isomer is combined and concentrated. The residue was triturated with ether and centrifuged; the solid was dried to give 50 mg of the isomer.

Grade B

Ethyl [2- (2-tritylamino-4-thiazolyl) -2-tritylhydroxyimyl acetate

To a solution of 5.4 g of the product of Step A in 54 ml of chloroform and 7.5 ml of triethylamine was added at 10 ° C a solution of 15 mg of trtyl chloride in 30 ml of chloroform. After standing for 1 hour at rest, the reaction mixture is washed with 40 ml of water and 20 ml of water containing 4 ml of hydrochloric acid, decanted, dried and concentrated to dryness.

The residue was extracted with 10 mL of ether; after addition of 50 ml of methanol, the mixture is stirred, centrifuged and the solid is washed with methanol to give 14.2 g of the desired product in two portions.

Grade C

2- (2-Tritylamino-4-thiazolyl) -2-tritylhydroxyiminoacetic acid

10.5 g of the ester obtained in step B are suspended at 55 ° C in 55 ml of dioxane at a temperature close to the reflux temperature. 17 ml of 2 N sodium hydroxide solution are then slowly added to the resulting suspension. The reaction mixture is still heated to moderate reflux until the mixture is cooled and the precipitated salt is centrifuged. The salt obtained is extracted in 60 ml of methylene chloride, 20 ml of water and 2 ml of acetic acid. The resulting acid is centrifuged and washed with water to give a first crop of 7 g of acid.

20 ml of methylene chloride, 10 ml of water and 1 ml of acetic acid are added to the mother liquor from which the dioxane has been evaporated.

A second crop of 1.5 g of the same product is then isolated. A total of 8.5 g is thus obtained.

Analysis: for C 43 H 33 O 3 N 3 S. 0.5 H2O calculated:

H, 5.03; N, 6.17; S, 4.7%. Found:

75.80 a / _o C, 4.90% H, 5.90% N, 4.6% P. EXAMPLE 2

Grade A

Ethyl 12- (2-amino-4-thiazolyl) -2-methoxyixino] acetate

To 3 ml of absolute ethanol was added 1 g of ethyl (γ-chloro-α-methoxyiminoacetyl) aceltate, followed by the addition of 0.42 g of triturated thiourea to the solution thus obtained. The resulting mixture was then stirred at ambient temperature for two hours. The mixture is then diluted with 60 ml of ether to crystallize the resulting hydrochloride, agitating the mixture, centrifuging, washing and drying to give 685 mg of the hydrochloride.

The hydrochloride obtained is dissolved in 4 ml of 50 ° C warm water and potassium acetate is added to the resulting solution to obtain a pH of solution 6, whereupon the amine liberated crystallizes. Cooling, centrifugation, washing with water and drying are then carried out. 270 mg of the expected product are obtained.

Mp 161 ° C.

The obtained product has a syn configuration.

NMR Spectrum (CDCl3, 60 MHZ) p / m:

(N — OCH3)

6.7 (thiazole ring proton).

Grade B

Ethyl [2- (2-tritylamino-4-thiazolyl) -2-methoxyimino] acetate

4.6 g of the product obtained in the preceding step are dissolved in 92 ml of methylene chloride at 30 ° C. The resulting solution was cooled to -10 ° C and triethylamine (2.9 mL) was added to the cooled solution; The mixture is then cooled to -35 ° C and 6.1 g of trityl chloride are added over 15 minutes. The reaction mixture was then allowed to stand at ambient temperature for two and a half hours. The reaction mixture was washed with water, then with 0.5 N hydrochloric acid and finally with aqueous sodium acetate solution. Drying, concentration, ether extraction, re-concentration, dissolution in methanol, addition of water and ether, crystallization, centrifugation and washing with ether to give

6.15 g of the desired product.

The melting point of the product is 120 ° C.

The obtained product has a syn configuration.

Grade C

2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid

The ester (7.01 g) obtained in Step B is dissolved in 35 ml of dioxane. The solution thus obtained is heated in an oil bath to 110 ° C and 9 ml of 2 N sodium hydroxide solution are then added to the solution over five minutes; the reaction mixture is then heated to reflux for thirty minutes. The sodium salt crystallizes. The reaction mixture is cooled, centrifuged; washing with dioxane and then ether gave a first salt of 5.767 g.

The mother liquor is then concentrated to give a second crop of 1.017 g; a total of 6.784 g of salt is thus obtained.

3.06 g of said salt are added to 65 ml of methylene chloride and 6.5 ml of 2 N hydrochloric acid; after washing with water, drying and concentration to dryness, the free acid is obtained in quantitative yield.

The obtained product has a syn configuration.

NMR Spectrum (DMSO4, 60 MHZ) p / m:

3.68 (N-OCH 3),

6.6 (proton of the thiazole ring).

The ethyl [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetate used in Example 2 was also prepared as follows. Stage a

Ethyl (2-acetyl-2-methoxyimino) acetate

180 g of ethyl (2-acetyl-2-hydroxyimino) acetate in the crude state is added to 900 ml of pure acetone. 234 g of potassium carbonate are added to the resulting mixture under a nitrogen atmosphere at 10 ° C; then 103 ml of dimethyl sulfate are added. The reaction mixture is stirred for three hours at ambient temperature, ice is added and the mixture is poured into 4 liters of water; After extraction with methylene chloride, washing with water and drying, the solvent is distilled off. 185 g of the expected product are obtained.

Step b

Ethyl (4-bromo-2-methoxyiminoacetyl) acetate

197 g of the product obtained in the preceding step a are added to 1 liter of methylene chloride and 200 mg of paratoluenesulphonic acid are added to the mixture obtained. Then one-tenth of a total of 191 g of pure bromine in 200 ml of methylene chloride is added at 20 ° C. When the reaction starts, the rest is added

207377 amount of bromine solution per hour at 20 ° C. The temperature was then allowed to rise to 25 ° C. After washing with ice water, re-extraction with methylene chloride and drying, the solvent is distilled off. 268 g of the expected product are obtained.

Stage c

Ethyl [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetate is added to 270 ml of ethanol and 340 ml of water. 268 g of the product obtained in step b in 270 ml of ethanol are then added to the mixture under a nitrogen atmosphere over half an hour. The reaction mixture was then stirred at 20 ^° C for one hour. The mixture was then cooled to 15 ^Q C and the cooled mixture was added in small portions, potassium bicarbonate to pH 5. After centrifugation, washing with water and drying to obtain 133.8 g of the desired product. The product obtained is identical to the product obtained in step A.

Example 3

Grade A

Ethyl [2- (2-amino-4-thiazolyl) -2- (2-propenyl) oxyimino) acetate

(a) 9.7 g of ethyl 2-hydroxyimino-4-chloroacetyl acetate, 30 ml of acetone and 9,15 ml of 3-iodopropene are cooled in an ice bath and 27,5 ml of 2 N sodium hydroxide solution are added to the cooled mixture. and the reaction mixture is then allowed to stand at ambient temperature for two and a half hours;

(b) 3.8 g of thiourea are added to the reaction mixture, whereupon the reaction mixture is heated at 60 ° C for 15 minutes and then for 45 minutes at ambient temperature. The acetone was distilled off and methylene chloride, water and potassium carbonate were added. After stirring, decanting, re-extracting with methylene chloride, drying and concentrating to dryness, 9.75 g of a residue is obtained which is chromatographed on silica eluting with ether; 2.7 g of product are isolated, which is converted into isopropylethe.ru. The separated crystals are centrifuged, rinsed and dried. 783 mg of the expected product is obtained.

The melting point of the product is 100 ° C.

Grade B

Ethyl [2- (2-tritylamino-4-thiazolyl) -2- (2-propenyloxoimino)] acetate

511 mg of the product prepared in Step A were mixed with 0.92 ml of dimethylformamide, 1.8 ml of methylene chloride and 0.29 ml of triethylamine. The mixture was cooled to -15 ° C and 615 mg of trityl chloride was added. After standing at room temperature for one and a half hours, 1N hydrochloric acid is added in an amount of > 2 ml and then 5 ml of water. After decantation, drying and concentration to dryness, 1.28 g of crude product are obtained.

The obtained product has a syn configuration. Grade C

2- (2-Tritylamino-4-thiazolyl) -2 - [(2-propenyl) oxyimino] acetic acid

A mixture of 1.28 g of the product obtained in Step B, 6.2 ml of dioxane and 3 ml of 2 N sodium hydroxide solution is heated to 120 ° C. The mixture was then heated under reflux for one hour. The sodium salt crystallized, which was centrifuged, washed with ether / dioxane and dried, yielding 805 mg of product.

The product is taken up in 10 ml of methylene chloride and 3 ml of hydrochloric acid and the mixture is stirred until dissolved. After decantation, drying, concentration to dryness, transfer into ether, centrifugation, 715 mg of the desired product is isolated.

Mp 170 ° C.

The obtained product has a syn configuration.

Example 4

Grade A

Ethyl [2- (2-amino-4-thiazolyl) -2-ethoxyimino] acetate

(a) 19.4 g of ethyl (γ-chloro-α-oxyiminoacetoacetate) are added to 60 ml of acetone and 14.3 ml of diethyl sulphate, and the mixture is then cooled in an ice bath and 55 ml of 2 are added over 30 minutes. The reaction mixture was then stirred for 40 minutes;

b] 7.6 g of thiourea were added to the reaction mixture, followed by heating at 55 ° C for 20 minutes. Next, stripping off the acetone, previously into ethyl acetate, adding 6.9 g of potassium carbonate, stirring, decanting, reextracting with ethyl acetate, drying and concentrating to dryness. 17.4 g of residue are isolated, which is chromatographed on silica eluting with ether. Transfer of the isolated product to isopropyl ether, centrifugation, washing and drying afforded 2.8 g of the desired product.

The melting point of the product is 129 ^° C.

The obtained product has a syn configuration. Grade B

Ethyl [2- (2-tritylamino-4-thiazolyl-2-ethoxyimino) acetate

3.16 g of the product obtained in Step A, 6 ml of anhydrous dimethylformamide, 12 ml of methylene chloride and 1.89 ml of triethylamine are mixed under an inert atmosphere. The mixture was cooled to -15 ° C and added to the cooled mixture

2.98 g of triethyl chloride. The reaction mixture is allowed to stand for thirty minutes, the temperature rising to 10 ° C; then the mixture is maintained at ambient temperature for three and a half hours. Add 13 ml of 1N hydrochloric acid and decant, wash with hydrochloric acid (1N) and water. Extraction with methylene chloride, drying and concentration to dryness yielded 7.89 g of crude product.

The obtained product has a syn configuration. Grade C

2- (2-Tritylamino-4-thiazolyl) -2-ethoxyiminoacetic acid

A mixture of 7.89 g of the product obtained in Step B, 40 ml of dioxane and 19.5 ml of 2N sodium hydroxide solution is heated at 110 DEG C. for 1 hour. Centrifuge, wash with ether / dioxane and then with ether alone and dry. 6.25 g of sodium salt are obtained, which is taken up in 60 ml of methylene chloride and 20 ml of 1N hydrochloric acid; the two phases are mixed, 20 ml of methanol are added and decanted, washed again with water, reextracted with methyl chloride-methanol, dried and concentrated; 5.85 g of pure 2- (2-tritylamino-4-thiazolyl) -2-ethoxyiminoacetic acid are isolated.

The obtained product has a syn configuration.

Example 5

Grade A

Ethyl [2-acetyl-2- (1-methylethoxyimino)] acetate

39.8 g of ethyl (2-acetyl-2-hydroxyimino) acetate are added to 200 ml of pure acetone. The mixture thus obtained is cooled in an ice bath and 52 g of potassium carbonate are added thereto, followed by 25 ml of 2-iodopropane over half an hour. The mixture is then stirred for two hours, 800 ml of water and 500 ml of methylene chloride are added and 41.5 g of the desired product are isolated after decantation, re-extraction with methylene chloride, drying, centrifugation and concentration. Grade B

Ethyl [4-bromo-2- (1-methylethoxyimino) acetyl] acetate

41.5 g of the product obtained in the previous column are added to 190 ml of methylene chloride containing traces of paratoluenesulfonic acid. The mixture is stirred and a solution of 11.9 ml of bromine in 50 ml of methylene chloride is added over 1 hour at ambient temperature. After stirring, addition of ice water, decantation, re-extraction with methylene chloride, rinsing with ice water, drying and concentration, 55 g of the desired product are isolated.

Grade G

Ethyl [2- (2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetate

14.9 g of thiourea are added to 35 ml of ethanol and 105 ml of water, and then a solution of 55 g of the product prepared in Step B in 55 ml of ethanol is added over 40 minutes. The mixture is stirred for two hours and thirty minutes at ambient temperature, then 220 ml of a 10 ^% aqueous sodium bicarbonate solution are added; the mixture obtained is stirred and, after centrifugation, washing and drying, 42.15 g of crude product is isolated which is chromatographed on silica eluting with ether; The desired product-rich fractions were collected, concentrated, the crystals formed were washed with isopropyl ether, centrifuged and washed to give 10.75 g of the desired product.

The obtained product has a syn configuration. Grade D

Ethyl [2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino)] acetate g of the product obtained in Step C is mixed with 20 ml of anhydrous dimethylformamide, 40 ml of methylene chloride and 6.2 ml of triethylamine. The resulting mixture was cooled, 13.2 g of trityl chloride were slowly added, the mixture was stirred for two and a half hours and then 43 ml of normal hydrochloric acid was added thereto, followed by stirring, decanting, washing. 40 ml of water, extracted with methylene chloride, dried, centrifuged and concentrated to dryness

27.7 g of the desired product.

The obtained product has a syn configuration. Grade E

2- (2-Tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid

A mixture of 27.7 g of the product obtained in Step D, 150 ml of dioxane and 65 ml of 2 N sodium hydroxide solution is heated to reflux for two hours. The sodium salt crystallizes, which, after cooling, is centrifuged, washed with ether / dioxane (1: 1) and dried to give 16.85 g of crude sodium salt.

15.9 g of this sodium salt are dissolved in 15.9 g of dimethylformamide, 100 ml of water and about 500 ml of methanol. 30 ml of a 2 N hydrochloric acid solution are then added to the solution thus obtained, after which methanol is stripped off; after dilution with water, centrifugation, washing and drying, 9.8 g of the viscous product obtained are transferred to 220 ml of a 50:50 mixture of methylene chloride and methanol and, after concentration to dryness, taken up in ether, separation in water, centrifugation, centrifugation, washing and drying, 4.9 g of the desired acid is obtained.

Mp 170 ° C. Preparation of the analytical sample:

300 mg of the crude product was dissolved in ml of methylene chloride and 1 ml of methanol, then diluted with water and methylene chloride, after stirring, removal of crystals, washing with methylene chloride and water and drying.

Analysis:

calculated:

68.77 θ / o C, 5.34% H, 8.91% N, 6.8 o / _o S, found:

68.60% C, 5.50 ϋ / ₀ H, 8.80% N, 6.8% P.

The obtained product has a syn configuration.

Example 6

Grade A

Ethyl [2- (2-tritylamino-4-thiazolyl) -2-hydroxyimino] acetate, anti isomer

11.5 g of ethyl [2- (2-amino-4-thiazolyl) -2-hydroxyimino] acetate (anti-isomer) prepared in Step A of Example 1 are added to 90 ml of anhydrous dimethylformamide and then added to this mixture. 24 ml triethylamine. 47.6 g of trityl chloride are then added in small portions over a half hour period and the mixture is left to stand for two and a half hours under self-heating. Next, 150 ml of 2 N hydrochloric acid and 600 ml of water are added. The mixture is stirred for 15 minutes, triturated three times with ether, taken up in a mixture of methanol, triethylamine and water and stirred. After centrifugation, washing and drying, 60.2 g of the desired product is isolated.

The crude product (3.4 g) is recrystallized to give the pure product in grams.

Mp 260 ° C.

Grade B

Ethyl [2- (2-tritylamino-4-thiazolyl) -2-ethoxyimino) acetate, anti isomer

11.5 g of the product obtained in Step A above and 8.85 g of potassium carbonate are added to 25 ml of anhydrous dimethyl-1-formamide. The mixture was cooled to 15 ° C, 16.7 mL of ethyl sulfate was added and the mixture was allowed to stand at ambient temperature for 4 hours. 420 ml of water and 250 ml of ethyl acetate are then added to the reaction mixture, after which 6.6 g of the desired product are obtained after stirring, centrifuging, leaching with ethanol, crystallization, washing, trituration and drying.

Mp 165 ° C.

This product can be recrystallized as follows:

797 mg of the product is dissolved in a mixture of methylene chloride and ethanol (50:

After centrifugation, concentration to evaporate the methylene chloride, crystallization, centrifugation, washing and drying, 596 mg of pure product is isolated.

Grade C

2- (2-Tritylamino-4-thiazolyl) -2-ethoxyiminoacetic acid, anti-isomer

7.29 g of the product prepared in step B are added to 45 ml of dioxane and 9 ml of 2N sodium hydroxide solution. The mixture thus obtained is heated in a water bath with stirring at 50 ° C for one hour and 50 minutes, then cooled and seeded to crystallize in ice water; then centrifuging, washing; 4.2 g of sodium salt are obtained. This salt is leached with 50 ml of methylene chloride, 40 ml of water and 11 ml of normal acid, after stirring, decanting, reextracting, washing, drying, centrifuging and concentrating to dryness, the residue is taken up in 50 ml of ether and centrifuged after stirring. then the separated crystals are washed with ether to obtain 3.27 g of the desired product.

The resulting product melts with decomposition at about 200 ° C.

NMR Spectrum (60 MHz, CDCl3) p.

7.66 (thiazole ring proton),

7.36 (proton of the trityl group).

Example 1 a d 7

Grade A

Ethyl [2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetate, anti-isomer

Under argon, 6.86 g of ethyl [2- (2-triethylamino-4-thiazolyl) -2-hydroxyimino] acetate (anti-isomer), prepared according to step A of Example 6, was mixed with 3.51 g of potassium carbonate. ; 15 ml of dimethylformamide and 7.7 ml of isopropyl iodide. The mixture is then left to stand for four and a half hours, 250 ml of distilled water and 150 ml of ethyl acetate are added, after stirring, decanting, washing, reextracting with ethyl acetate, drying, centrifuging, bringing to dryness, transfer to ethanol, seeding for crystallization, centrifugation to give 3.26 g of the desired product.

The melting point of the resulting product is 182 ° C.

Grade B

2- (2-Trityl-arylamino-4-thiiazolyl) -2- (1-methylethoxyimino) -acetic acid, isorner anti

6.8 g of the product obtained in Step A are mixed with 41 ml of dioxane and 8.15 ml of 2N sodium hydroxide solution. The mixture thus obtained is heated in an aromatic bath at 55 ° C for two hours, then cooled and 9.5 ml of 2N hydrochloric acid are added to the cooled mixture (the solution then has a pH of 2 to 3). Removal of the dioxane, crystallization, dilution with water, washing, trituration with ether and drying afforded 5.87 g of the desired product.

The resulting product melts with decomposition at 240 ° C.

NMR Spectrum (CDCl3, 60 MHZ) p / m:

7.66 (thiazole ring proton),

7.31 (trtyl).

Example 8

Grade A

Ethyl [2- (2-tritylamino-4-thiazolyl) -2- (2-pPOpenyloxyimino)] acetate

Under argon, 6.86 g of ethyl 2- (2-tritylamino-4-thiiazolyl) -2-hydroxylamine imoacetate (isorner anti) prepared according to the procedure described in Example 6, Step A, were mixed with 3.51 g of potassium carbonate. ml of dimethylformamide and 7 ml of allyl iodide, the mixture is stirred for five hours at ambient temperature, 250 ml of water and 150 ml of ethyl acetate are added thereto, after stirring, decanting, washing, reextracting with ethyl acetate, drying, centrifuging, concentration to dryness, ethanol precipitation, seeding for crystallization, cooling in ice water, crystallization for half an hour with stirring and removal and washing of the separated crystals, 4.72 g of the desired product are obtained.

The product is purified as follows:

215 mg of the above product are dissolved in 2 ml of ethanol and 2 ml of methylene chloride. The filtrate is concentrated and then diluted with ethanol and crystallized in ice water. After centrifugation, washing and drying of the precipitated crystals, 70 mg of purified product is obtained.

Melting point ^90? C (pasty consistency); above 160 ° C (liquid consistency). Grade B

2- (2-Tritylamino-4-thiazolyl) -2- (2-propenyloxyiminiodic acid), isorner anti

3.71 g of the product obtained in Step A above are mixed with 22 ml of dioxane and

4.5 ml of 2N sodium hydroxide solution. The mixture is heated in a water bath at 55 ° C for 50 minutes, cooled and then treated with 5.25 ml of 2N hydrochloric acid to pH 2. After stripping of dioxane, a gum is obtained, which is diluted with water, cooled in ice water, centrifuged, rinsed with water and then triturated three times with ether. 2.85 g of the expected product are obtained.

Mp 198 ° C (decomposes).

NMR Spectrum (CDCl3 90 MHz) p.p.m. = 7.64 (thiazole ring proton); 7.27 (trityl proton).

Example 9

Grade A

Ethyl [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetate

45.8 g of ethyl [2- (2-amino-4-thiazolyl) -2-methoxyimino] acetate (isorner syn), prepared as described in Step A of Example 12, are added to 200 ml of methylene chloride. It is distilled to dryness (20 ml) and, after cooling to 10 DEG C., 50 ml of pyridine are added. 41 g of acetic anhydride are added and the mixture is gently heated to dissolve the solid. The mixture is left under nitrogen at 20 ° C for 6 hours, 5 ml of water are added, the mixture is stirred and then poured into 300 ml of 2N hydrochloric acid (ice-cooled). After decantation, extraction with methylene chloride, washing with water and sodium bicarbonate solution, drying, purification with charcoal, concentration 300 ml of isopropyl ether is added. The product crystallizes. The mixture was concentrated to give a thick palst and after cooling with ice, centrifugation, washing and drying, 45.4 g of product was obtained.

The melting point of the product is 113 ° C.

A pure sample of the product was obtained by recrystallization in methylene chloride / isopropylpylether.

The melting point of the purified product is 118 ° C.

NMR Spectrum (CDCl3, 60 MHz)

O

H ~ NC ~ CH _from Cl (f) I (c, (&) O-CH 2 Cl phyCH _{3 (b)}

(a) triplet centered at 1.38 ppm, J = 7 Hz;

(b) singlet 4.05 µm;

(c) a quadruplet centered at 4.44 µm, 1 = 7 Hz;

(d) singlet 4.33 µm;

(ej singlet 7.27 p. m .;

(f) singlet 9.95 µm.

Grade B

2- (2-Broroacetamido-4-thiazolyl) -2-methoxyiminoacetic acid, isomer syn g of the product obtained in Step A above, is added to 230 ml of absolute ethanol. 30 ml of pure sodium hydroxide are added to the mixture thus obtained at 20 ° C and under a nitrogen atmosphere. The product dissolves and the sodium salt begins to crystallize as the reaction medium thickens. After 16 hours, the crystals were centrifuged and washed. The salt obtained is dissolved in water, frozen, 100 ml of 2N hydrochloric acid are added, saturated with sodium chloride and extracted with ethyl acetate containing 10% ethanol. After drying, passing through activated carbon, distilling under vacuum, removing the water with benzene, 34.5 g of the desired product are obtained in methylene chloride, frozen, centrifuged, washed and dried.

The melting point of the product is about 200 ° C.

This product was purified by recrystallization in acetone / isopropyl ether.

Analysis:

Calcd for C 6 H 16 N 5 ClS (277.68):

34.60% C, 2.90% H, 12.77 o / ₀ Cl, 15.13% N,

11.55% S;

found:

34.81% C, 2.8 _0/0 H 12 '6% Cl, 14.8% N,

11,5% S.

NMR Spectrum (DMSO 60 MHz) (a) singlet 3.92 µm;

(b) singlet 4.38 µm;

(c) a singlet of about 5 µm;

(d) singlet 7.58 µm;

(e) singlet 12.6 µm.

Example 10

Grade A

Ethyl (2-acetyl-2-methoxyimino) acetate

4.69 kg of ethyl (2-acetyl-2-hydroxyiminoacetyl) acetate (corresponding to 4.21 kg of pure product) is added to 21 liters of anhydrous pure acetone. 6.1 kg of potassium carbonate are added at 20-25 ° C. The resulting suspension was stirred for 10 minutes and then 3.72 kg of dimethyl sulfate was added at 25 ° C. The reaction mixture was stirred for three hours at 20-25 ° C. The mixture is poured into 126 liters of demineralized water and extracted 4 times with 5 liters and then with 2 liters of methylene chloride. Washing with 10 liters of demineralized water, drying, centrifugation, washing with 12 liters of methylene chloride and distillation under vacuum yielded 4.88 kg of the desired product.

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

The product obtained is identical to the product obtained in step a) of Example 3. Step B

Ethyl (4-bromo-2-methoxyiminoacetyl) acetate

3.53 kg of the product obtained in Step A are added to 18.6 liters of methylene chloride and 3.5 grams of paratoluenesulfonic acid. To the resulting solution over 30 minutes while maintaining the temperature between 22 ° C ± 1 ^Q C a solution of 2.96 kg of bromine in 3.5 liters of methylene chloride. After 15 minutes of addition of the above solution, release of hydrobromic acid was observed. The reaction mixture was stirred at 22 ° C for 45 minutes, poured from vessel to vessel, and then washed twice with 14 L of ice-cold demineralized water.

The washings are re-extracted twice

3.5 liters of methylene chloride. After drying, filtering, washing and distillation under vacuum, 4.73 kg of the desired product is obtained.

This product is identical to the product obtained in step b of Example 3.

Grade C

Ethyl [2- (2-amino-4-thiazolyl) -2-methoximino] acetate, isomer syn

1.43 kg of thiourea are mixed with 3.55 liters of ethanol and 7.1 liters of demineralized water. The mixture thus obtained is stirred for 10 minutes at 20 DEG C., and 4.730 kg of the product prepared in Step B in 3.55 liters of ethanol are then added thereto at 20 DEG to 25 DEG. The mixture is stirred for three hours at 20-25 ° C, then cooled to 15-20 ° C and neutralized to pH = 7 with 1.6 L ammonia (184.6 g / L).

The mixture was stirred for 15 minutes at 20-25 ° C, then centrifuged and washed 5 times with 1.8 L of demineralized water. 2,947 kg of the expected product is obtained.

The melting point of the product is 162 ° C.

The product obtained is identical to the product obtained in steps A and C of Example 2, Sieve, foam D

Ethyl 2- (2-trityl-amino-4-thiazolyl) -2-methoxyimino] acetate

3.41 kg of the product obtained in the previous step C are mixed with 17 liters of methylene chloride and 2.275 liters of triethylamine. The mixture thus obtained is stirred for 15 minutes, and then 4.55 kg of trityl chloride are added over a period of 1 hour under stirring and under a nitrogen atmosphere at 20-25 ° C. The mixture was stirred for 20 hours at 20-25 ° C under nitrogen atmosphere to crystallize triethylamine hydrochloride.

The mixture is washed with 10.2 liters of 0.5 N hydrochloric acid (glacial) and twice 10.2 liters of demineralized water (also glacial). The water was re-extracted in a total of 1.7 liters of methylene chloride. After drying, filtering, rinsing with 1.7 liters of methylene chloride and distilling to dryness under vacuum at a temperature below 50 ° C, 8.425 kg of crude product is obtained.

This product was dissolved at 20-25 ° C in 8.4 liters of methanol and added over one hour with stirring to promote crystallization of 2.8 liters of demineralized water. The mixture is then stirred for an additional hour, then centrifuged, triturated twice with 1.7 liters of methanol containing 25% water, dried at 40 ° C and isolated 7.165 kg of the desired product.

The product obtained is identical to the product obtained in step B of Example 2. Step E

2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid sodium salt, isomer syn

4.175 kg of the product obtained in step D are mixed with 20.9 liters of ethanol. The mixture is then heated to reflux, under a nitrogen atmosphere and with stirring. Already at 55 ° C complete dissolution is achieved.

To the refluxing mixture under a nitrogen atmosphere was added 5.235 liters of about 2N sodium hydroxide solution. Rapid crystallization occurs. The reaction mixture was stirred for one hour at reflux, under a nitrogen atmosphere. The temperature was then lowered to 20-25 ° C and maintained at this temperature for two hours. After centrifugation, washing four times with 2.1 liters of ethanol and drying, 4.02 kg of the desired product is obtained.

Grade F

2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, syn isomer

500 g of the product obtained in the previous step E (corresponding to 440 g of dry product) are mixed with 2.5 liters of methylene chloride. Thereafter, 2 liters of about 1N hydrochloric acid were added at 20-25 ° C with stirring under nitrogen.

The mixture was stirred for two hours at 20-25 ° C under nitrogen atmosphere.

The chloromethylene fraction was separated by defcanting and washed three times with 2 liters of demineralized water. After reextraction in series with one liter of methylene chloride, drying, addition of 25 g of activated carbon, centrifugation, rinsing and distillation to dryness, 481 g of product are isolated.

This product was transferred to 2.1 L of iso-. propylether. After centrifugation, washing with 420 ml of isopropyl ether (twice) and drying under vacuum to constant weight, 424.6 kg of the desired product are obtained.

The product obtained is identical to the product obtained in Step C of Example 2.

Claims (9)

Subject Process for preparing 2- (2-amino-4-thiazolyl) acetic acid derivatives of the general formula I (I) in which: Rd is trityl or chloroacetyl and R‘d represents a trityl group, a chloroacetyl group or a saturated or unsaturated α, 1, keel group having 1 to 4 carbon atoms, provided that when R‘d represents a chloroacetyl group, then Rd represents a chloroacetyl group, characterized by treatment with thiourea and then a base on a compound of the formula II O N L OR b (II) wherein X is chlorine or bromine, R‘b represents a hydrogen atom, a trityl group or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, when X represents a chlorine atom, or R‘b represents a hydrogen atom or a saturated alkyl group having 1 to 4 carbon atoms, when X represents a bromine atom, and alk represents an alkyl group having 1 to 4 carbon atoms, to give a compound of formula III ynAlez in which: R * represents a hydrogen atom, a trityl group or a saturated or unsaturated alkyl group having from 1 to 4 carbon atoms and alk represents an alkyl group having from 1 to 4 carbon atoms, whereby the compound of formula (III) is either treated with triethyl chloride or when R ' represents a hydrogen atom or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, the compound of formula III is treated with monochloroacetic anhydride to form a compound of formula IV () V) in which Rd is trityl or chloroacetyl, R'd is trityl, chloroacetyl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, provided that when R'd is chloroacetyl, then 1 Rd is chloroacetyl, and r is 1 to 4 alkyl. The compound of formula (IV) is treated with a base and then with an acid to form a compound of formula (I). 2. A process according to claim 1 wherein X is chlorine, R ' b is hydrogen, trityl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms and alk is alkyl. a group having 1 to 4 carbon atoms. 3. A process according to claim 1, wherein X is a chlorine atom, R ' b is a hydrogen atom, a trityl group or a saturated or unsaturated alkylol group having 1 to 4 carbon atoms. an alkyl siuipine (IHJ of 1 to 4 carbon atoms), (treated with trityl chloride to form a compound of formula III to form a compound of formula IV wherein R d is trityl and R 'd is trityl or saturated or unsaturated alkyl) with 1-4 carbon atoms and alk represents a C1-4 alkyl group, then the compound of formula IV is treated with a base and then an acid to form a compound of formula I wherein Rd is trityl and R'd is trityl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms. 4. A process according to claim 1, wherein X is bromine, R ' b is C1 -C4 saturated alkyl and alk is C1 -C4 alkyl, to form a compound of formula III wherein R 'is a saturated alkyl group of 1 to 4 carbon atoms and alk is an alkyl group of 1 to 4 carbon atoms, then the compound of formula III is treated with trityl chloride to form a compound of formula IV, wherein Rd represents a trityl group, R'd represents a saturated alkyl group having 1 to 4 carbon atoms and alk represents an alkyl group having 1 to 4 carbon atoms, and the compound of formula IV is treated with a base and then an acid to form a compound of formula I wherein Rd represents a trityl group and R'd represents a saturated alkyl group having 1 to 4 carbon atoms. 5. A process according to claim 1 wherein the compound of formula I is treated with a thiourea and then a base is treated with a compound of formula II: wherein X is chlorine or bromine, R'b is hydrogen, trityl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms when X is an atom. chloro, or R'b represents a hydrogen atom or a saturated alkyl group having 1 to 4 carbon atoms when X represents a bromine atom, and alk represents an alkyl group having 1 to 4 carbon atoms, either in an aqueous solvent medium or at ambient temperature in the presence a stoichiometric amount of iamourea at a reaction time of 1 to 3 hours, or using all of the above conditions to form a compound of formula III wherein R 'is hydrogen, trityl or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms and alk is (1-4C) alkyl group, syn configuration, whereupon the product of formula (III) is further processed under UVB conditions in point 1 (2a) of the compounds of formula (I) in the syn configuration; 6. A process according to claim 2, wherein the compound of formula I is treated with a thiourea and then a base of a compound of formula II wherein X is chlorine, R'b is hydrogen, trityl or saturated or an unsaturated alkyl group having 1 to 4 carbon atoms and alk means an alkyl group having 1 to 4 carbon atoms, either in an aqueous solvent environment or at ambient temperature in the presence of a stoichiometric amount of thiourea at a reaction time of 1 to 3 hours, or all together to form a compound of formula III wherein R 'is hydrogen, trityl or a saturated or unsaturated alkyl group of 1 to 4 carbon atoms and alk is alkyl group of 1 to 4 carbon atoms, whereupon the product of formula III below It is processed under the conditions of point 1 to form a compound · Formula I configuration syn. 7. A process according to clause 3 for the preparation of a compound of the formula I in which Rd represents a trityl group and R 'denotes a trityl group or a saturated or unsaturated alkyl group having from 1 to 4 carbon atoms, characterized in that the thiourea is treated with a base. to a compound of formula (II) in which X represents: chlorine, R'b represents hydrogen, trityl or a saturated or unsaturated alkyl group having 1 to 4 carbon atoms, and alk represents an alkyl group having 1 to 4 carbon atoms, either in medium or at ambient temperature in the presence of a stoichiometric amount of thiourea at a reaction time of 1 to 3 hours, or using all of the above conditions together. 8. A process according to item 4 for the preparation of compounds of formula I in which Rd represents a trityl group and R'd represents a saturated alkyl group having from 1 to 4 carbon atoms, characterized in that the thiourea is treated with a base, wherein X is bromine, R'b is saturated, C 1 -C 4 alkyl, and alk is C 1 -C 4 alkyl, either in an aqueous solvent or at ambient temperature in the presence of a stoichiometric amount of thiourea in the reaction for 1 to 3 hours, or using all of the above conditions together. 9. A process according to item 3 for the preparation of 2- (tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, corresponding to the general formula I, in which Rd represents a trityl group and R'd represents a methyl group, characterized in that in ethanol at ambient temperature, the reaction is carried out for two hours with γ-chloro-α-methoxyimino and cetyl and not ethylene, 207S77 II to the corresponding compound of formula II, in which X is chlorine, R‘b is methyl, and alik is ethyl, on a stoichiometric amount of thiourea, followed by treatment with potassium acetate and the product of formula II III, wherein R * is methyl and alk is ethyl, is treated with trityl chloride at a temperature of -10 to -315 ° C in the presence of triethylamine, followed by the formation of the product of formula IV in which Rd is trityl, R ' d is methyl and talk is ethyl, treated with dilute sodium hydroxide while heating the reaction mixture to reflux and then dilute hydrochloric acid.