Ethyl (αZ)-2-amino-α-(hydroxyimino)-4-thiazoleacetate

light yellow to beige fine powder

Ethyl (Z)-2-(2-Aminothiazol-4-yl)-2-trityloxyiminoacetate Sodium hydride (60% dispersion in mineral oil, 13.2 g, 0.33 mol) was added portionwise to a cold (0 C.) mixture of ethyl (Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (64.5 g, 0.3 mol) in dry THF (1 L) with vigorous stirring and the mixture was stirred for 0.5 hr. at room temperature. To the mixture was added a solution of trityl chloride (92.0 g, 0.33 mol) in dry THF (0.2 L) with cooling and stirring. The mixture was stirred for 2 hr. at ambient temperature and evaporated under reduced pressure. Chloroform (1 L) was added to the residue and the mixture was washed with water. The insoluble material was filtered and the organic layer of the filtrate was separated. The insoluble material was extracted again with a mixture of chloroform (300 ml) and methanol (50 ml) by sonication for 10 min. and subsequent filtration. The extract was combined with the separated organic layer and evaporated under reduced pressure. The residue was triturated with toluene (0.3 L) to crystallize the product as colorless prisms, which were collected by filtration, washed with a small toluene and dried in vacuo. Yield, 91.2 g (66%). The filtrate was evaporated and treated with toluene to give 19.2 g of the second crop. Total yield, 110.4 g (80%). MP 181-183 C. IR numax (KBr)cm-1 3450, 1735, 1620. 1 H NMR (60 MHz, CDCl3) delta1.30 (3H, t, J=7 Hz, CH3), 4.37 (2H, q, J=7 Hz, CH2), 5.93 (2H, s, NH2), 6.42 (1H, s, thiazole-H), 7.3 (15H, s, phenyl). Anal Calcd for C26 H23 N3 O3 S 0.6 (CHCl3): C 60.38, H 4.50, N 7.94, S 6.06. Found: C: 60.68, H 4.38, N 7.95, S 6.10.REFERENCE EXAMPLE 3 To 600 ml of ethanol is added 121 g of ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate together with 47.6 g of thiourea and the mixture is stirred at room temperature for 3 hours. The ethanol is then evaporated off under reduced pressure and 350 ml of water is added. The water layer is washed with ether, neutralized with sodium hydrogen carbonate (to pH 7.5) and extracted with ethyl acetate-tetrahydofuran (1:1). The organic layer is washed with water and dried. The solvent is then distilled off to obtain 45 g of crystalline product. A 1 g portion of the above product is taken and purified by column chromatography on silica gel (eluding solvent: ethyl acetate-n-hexane). The first fraction gives 650 mg of the anti-isomer of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate and 150 mg of the syn-isomer is obtained from the second fraction. Anti-isomer: white crystals, melting point: 145.3 C. Syn-isomer: pale yellowish white crystals, melting point: 185.5 C. Elemental analysis, for C7 H9 N3 O3 S: Calcd. C, 39.06; H, 4.21; N, 19.51, Found (Anti-) C, 38.81; H, 4.20; N, 19.62. (Syn-) C, 39.28; H, 4.10; N, 19.63. NMR spectrum (60 MHz, in d6 -DMSO): Anti-isomer: 7.10 ppm(2H, br. s., NH2), 7.50 ppm(1H, s., thiazole 5-H), 12.5 ppm(1H, s., OH). Syn-isomer: 6.80 ppm(1H, s., thiazol-5-H), 7.12 ppm(2H, br. s., NH2), 11.6 ppm(1H, s., OH)STEP A: syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate 2 g of ethyl 4-chloro-2-hydroxyimino-acetyl-acetate were added over 5 minutes to a solution of 0.8 g of thiourea in 2.4 ml of ethanol and 4.8 ml of water and the mixture was stirred at room temperature for one hour. A major part of the ethanol was evaporated under reduced pressure and the pH of the solution was adjusted to 6 with solid sodium bicarbonate. The mixture was iced and vacuum filtered and the recovered product was washed with water and dried at 40 C. under reduced pressure to obtain 1.32 g of the syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate melting at 232 C. Analysis: C5 H9 O3 N3 S Calculated: %C 39.06; %H 4.21; %N 19.52; %S 14.9. Found: 38.9; 4.4; 19.7; 14.6.REFERENCE EXAMPLE 8 In 600 ml of 50% aqueous tetrahydrofuran is dissolved 67.8 g of ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate, followed by addition of 155 g of sodium acetate trihydrate and 53.2 g of thiourea. The mixture is stirred at room temperature for 4 hours. The reaction mixture is adjusted to pH 7.0 with sodium hydrogen carbonate and, following addition of sodium chloride, it is extracted twice with 300 ml of tetrahydrofuran. The extracts are combined, washed (with water) and dried. The tetrahydrofuran is then distilled off to obtain 27.5 g of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate as crystals.STEP A: ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetate A mixture of 2 g of ethyl gamma-chloro-alpha-oximinoacetylacetate, 5 ml of ethanol and 0.76 g of thiourea was stirred at room temperature for 16 hours while the hydrochloride crystallized and after dilution with 5 ml of ether, the mixture was vacuum filtered. The filter was rinsed with a 1-1 ethanol-ether mixture and then ether to obtain 1.55 g of the hydrochloride salt which was dissolved at 40-50 C. in 8 ml of water. The solution was neutralized to a pH of 5-6 by addition of sodium acetate and the free ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetate crystallized. The mixture was iced and then was vacuum filtered and the product was washed with water and dried to obtain 1.22 g of the antiisomer melting at 154 C. The combined wash waters were concentrated and the residue was taken up in water. The solution was washed with ether and sodium bicarbonate was added thereto. The mixture was vacuum filtered and the product was washed with water to obtain 1.9 g of a product having two spots in thin layer chromatography. The product was chromatographed over silica gel, was eluted with ether and the combined pure fractions of the concentrated syn isomer were empasted with ether, vacuum filtered and dried to obtain 50 mg of the syn isomer.STEP A: syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate 2 g of ethyl 4-chloro-2-hydroxyimino-acetyl acetate were added over 5 minutes to a solution of 0.8 g of thiourea in 2.4 ml of ethanol and 4.8 ml of water and the mixture was stirred for one hour at room temperature. The majority of the ethanol was distilled off under a partial pressure and the mixture was adjusted to a pH of 6 by addition of solid sodium bicarbonate. The mixture was iced and vacuum filtered and the recovered product was washed with water and dried under reduced pressure at 40 C. to obtain 1.32 g of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate melting at 232 C. Analysis: C5 H9 O3 N3 S: Calculated: %C 39.06; %H 4.21; %N 19.52; %S 14.9; Found: 38.9; 4.4; 19.7; 14.6STEP A: syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate 2 g of ethyl 4-chloro-2-hydroxyimino-acetyl acetate were added over 5 minutes to a solution of 0.8 g of thiourea in 2.4 ml of ethanol and 4.8 ml of water and the mixture was stirred for one hour at room temperature. The majority of the ethanol was distilled off under a partial pressure and the mixture was adjusted to a pH of 6 by addition of solid sodium bicarbonate. The mixture was iced and vacuum filtered and the recovered product was washed with water and dried under reduced pressure at 40 C. to obtain 1.32 g of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate melting at 232 C. Analysis: C5 H9 O3 N3 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.STEP A: syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate A solution of 2 g of ethyl 4-chloro-2-hydroxyiminoacetylacetate was added over 5 minutes to a solution of 0.8 g of thiourea in 2.4 ml of ethanol and 4.8 ml of water and the mixture was stirred at room temperature for one hour. Then, the major portion of the ethanol was distilled under reduced pressure and the mixture was neutralized to a pH of 6 by addition of solid sodium bicarbonate. The mixture was iced and vacuum filtered and the recovered precipitate was washed with water and dried at 40 C. under reduced pressure to obtain 1.32 g of the syn isomer of ethyl 2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetate melting at 232 C. Analysis: C5 H9 O3 N3 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.

Mainly used for the synthesis of cephalosporin antibiotics