Ethyl 2-amino-4-thiazolecarboxylate

white crystal powde

General procedure: A mixture of thiourea (1.2 mmol) and 2-bromoacetophenone (1 mmol) in EtOH (2 mL) was stirred at 70 oC for 1h. The reaction mixture was cooled to room temperature, poured into ice-cold water, and the resulting precipitate was filtered and dried to give the desired compounds: [6a ( 99percent) as a white solid, mp 150-152 oC (Lit.26 149-150 oC) ; 6b (100percent) as a white solid, mp 162-165 oC (Lit.26 163-164 oC); 6c (0.236 g, 93percent) as a white solid, mp 179-181 oC (Lit.26 180-181 oC); 6d (98percent) as a white solid, mp 203.6-204.2 oC (Lit.28/22 204.0-204.5 oC); 6e (94percent) as a bright yellow solid, mp 287-288 oC (Lit.26, 27 285-286 oC); 6f (100percent) as a white solid, mp 172-174 oC (Lit.29-31 172 oC).Take 3-bromo-pyruvate (5.0g, 25.6mmol), adding thiourea (1.56g, 20.5mmol, 0.8eq) at 120 °C reflux 0.5h, TLC monitoring of the reaction to completion.The reaction mixture was dissolved in ethyl acetate, washed with distilled water, the organic layer was washed with brine; the organic layer was dried over anhydrous sodium sulfate, suction filtered, the solvent was distilled off under reduced pressure to give a yellow 2-aminothiazol-4-carboxylate (4.39g, 99.5percent).To the stirred solution of thiourea (3.69 g, 1.0 eq) in ethanol (120 mL) was added 3-bromo-2-oxo-propionic acid ethyl ester (9.453 g, 1.0 eq) and the reaction mixture was stirred at 80°C until completion of the reaction. The solvent was evaporated under reduced pressure and the crude prod-uct was dissolved in water, basified with solid K 2 CO 3 and the obtained solid is filtered over Buckner funnel and dried to afford the desired compound. White solid, M.pt.: 176-178°C, yield: 98percent (5.5 g), R f (cyclohexane:ethyl acetate = 6:4): 0.42, Anal (C 6 H 8 N 2 O 2 S) calc. C 41.85 H 4.68 N 16.27 S 18.62, found: C 41.75 H 4.61 N 16.18 S 18.59. 1H-NMR (300 MHz, DMSO-d 6 ) (δ, ppm): 9.12 (brs, 2H, NH 2 ), 7.64 (s, 1H, =CH), 4.27 (q, J = 15.84 Hz, 2H, CH 2 ), 1.28 (t, J = 10.56 Hz, 3H, CH 3 ). 13C-NMR (75 MHz, DMSO) (δ, ppm): 172.31, 165.34, 143.47, 119.64, 68.26, 14.97. IR ν max (neat): 3440 (NH), 3129 (=CH, thia-zole), 1689 (C=O, ester) cm-1. LC-MS: (m/z) [M+H]+ 173.1.Thiourea (3.69 g, 48.5 mmol) was added to a solution of ethyl bromopyruvate (10 g, 46 mmol) in EtOH (92 mL), and the reaction mixture was heated to 80 step 1, In a constant pressure dropping funnel40g of ethyl pyruvate was added to the 500ml three-necked bottle of the thermometer.190g of dichloromethane, 1ml of 98percent d concentrated sulfuric acid, Stir the solution; 2-Amino-thiazole-4-carboxylic acid ethyl ester was prepared by a modification to the procedure of Kumar, R.; Rai, D. et al., Heterocyclic Communications 2002, 8, 521-530. Thiourea (18.45 g, 240 mmol) was suspended in absolute ethanol (192 mL) and to this was added ethyl bromopyruvate (52 g, 240 mmol) over 5 minutes. The solution was stirred at room temperature overnight and then concentrated in vacuo and taken into water (400 mL) and 6 N aqueous hydrochloric acid (44 mL). The aqueous mixture was washed with ethyl acetate (2.x.) and back extracted with water (50 mL). The combined aqueous solution was adjusted to pH=10 with sodium hydroxide and extracted with 10percent dichloromethane in tetrahydrofuran (3.x.200 mL). The combined organic extracts were dried over sodium sulfate, concentrated and dried in vacuum. The pale yellow solid was taken into dichloromethane (25 mL) and to the slurry was added hexanes (300 mL). The mixture was vigorously stirred for 15 minutes then filtered on a 9 cm funnel and dried in vacuum to give 2-amino-thiazole-4-carboxylic acid ethyl ester as an off white solid (38 g, 92percent).Thiourea (12.93 g, 0.170 mol) was taken in a round bottom flask and charged ethanol (45 mL), stirred for 10 min, slowly added ethyl bromopyruvate (19.36 mL, 0.155 mol). The reaction mass was heated to 90 °C for 4 h. Reaction completion was monitored by TLC. Reaction was complete. The reaction mass was filtered and the ethanol layer was concentrated under reduced pressure to give a pale yellow solid. The crude product was recrystallized in ethylacetate/hexane to afford (1) (23.58 g, 90percent) an off white solid. M.p. = 177-178 °C; General procedure: General procedure for the preparation of ethyl 2-methylthiazole-4-carboxylate (12a) A stirred solution of ethyl bromopyruvate (0.97 g, 0.62 ml, 8.54 mmol) in ethanol was reactedwith thiourea (0.5 g, 6.57 mmol) and the reaction mixture was refluxed overnight. After completion the final solution wasconcentrated under reducedpressure and the resultant residue was extracted with ethyl acetate, washed with brine, and dried over sodium sulphate. The crude mass was purified by flash column chromatography over silica gel with 4percent methanol-DCM eluent to obtain compound A as pale yellow solid (0.88 g, 85percent).1H NMR (DMSO-d6): ö 7.45 (s, 1H, ArH), 7.21 (brs, 2H, NH), 4.19 (q, 2H, JAB = 7.0 Hz, CH2), 1.25 (t, 3H, JAB= 7.5 Hz, CH3).Preparation of ethyl 2-aminothiazole-4-carboxylate hydrochloride salt (3)3-Bromo taken pyruvate (6.0g, 31mmol), added thiourea (2.3g, 31mmol, 1.0eq), at 120 ° C under nitrogen the reaction was refluxed for 0.5h, the reaction was complete by thin layer chromatography to monitor . 2--4-(4.4g, 83.0percent )0 The reaction mixture was dissolved in ethyl acetate, washed with distilled water, the organic layer was washed with saturated brine; the organic layer was dried over anhydrous sodium sulfate, and filtration, the solvent was distilled off under reduced pressure to give a yellow 2-aminothiazol-4-carboxylate (4.4g, 83.0percent)7.8 g (40 mmol) ethyl bromopyruvate and 3.1 g (40 mmol) thiourea were dissolved in 40 ml ethanol, and reacted at room temperature, to precipitate a white solid, which was filtered, washed and dried to obtain 7.5 g ethyl 2-aminothiazol-4-carboxylate (yield 74percent) with mp 177-181°C. 7.8 g (40 mmol) ethyl bromopyruvate and 3.1 g (40 mmol) thiourea were dissolved in 40 ml ethanol, and reacted at room temperature, to precipitate a white solid, which was filtered, washed and dried to obtain 7.5 g ethyl 2-aminothiazol-4-carboxylate (yield 74percent) with mp 177-181° C.Example 11:; WHO EtO2C EtO2C I Et02C C02Et Thiourea N Boc20 OMe Br NH2 g NHBoc n_guLi I /SNHBoc OMe OH Etc Et3SiH/TFA \ I SNH2TFA OMe; 2-Amino-thiazole-4-carboxylic acid ethyl ester; A mixture of ethyl bromopyruvate (100 g, 80 percent purity, 0.41 mol), thiourea (31 g, 0.41 mol) and ethanol (500 mL) was heated to reflux for 12 hours. The solvent was evaporated to dryness and the residue was washed with ether. The solid was suspended in a saturated aqueous solution of sodium bicarbonate (500 mL) for 30 minutes. The solid was filtered, washed with water, and dried over sodium sulfate to give 2-amino-thiazole-4-carboxylic acid ethyl ester (45 g, 0.26 mol, 63 percent) as an off-white solidAfter 100 ml round bottom flask, and 30 ml of ethanol was added 1.26 g of thiourea, 16.6 mmol, heated to reflux with stirring until thiourea dissolved, 3.22 g, 16.6 mmol bromopyruvate ethyl IX, after refluxing overnight, the ethanol was removed under reduced pressure and concentrated to give a yellow solid which was washed with saturated sodium carbonate solution was obtained after filtration 2.25 g 2-aminothiazol-4-carboxylic acid ethyl ester X, in a yield of 78.9 percentA mixture of ethyl 2-azidoacrylate7. 05 g (0.5 mol), Potassium thiocyanate9. 72 g (0.1 mol), 150 ml of ethanol, Heptahydrate ferrous sulfate6. 95 g (0.025 mol) was added to a 250 ml reaction flask, Stir, Heating to 80 ° C for 12 hours, TLC to detect the reaction solution(Petroleum ether: ethyl acetate = 1: 1 by volume)2'-azidoethyl acrylate disappears;The resulting reaction solution was cooled to about 40 ° C, Rotary evaporator concentrated to remove ethanol, The residue was added to 150 ml of water, extracted with 50 mL of ethyl acetate, and the organic layer (on the upper layer) was combined, washed with 50 ml of water, 50 ml of saturated brine, dried over anhydrous sodium sulfate (5.0 g) for 30 minutes, The rotary evaporator was concentrated to remove ethyl acetate and the residue was recrystallized from 40 ml of ethanol to give 6. 94 g of a white solid in 80percent yield.In a molar ratio of 1.3:1, Weigh 2-ethyl acetoacetate and thiourea into a three-necked flask.And adding potassium carbonate and ethylene glycol, the molar ratio of potassium carbonate and thiourea is 2:1, the molar ratio of ethylene glycol to ethyl 2-chloroacetoacetate is 5:1, and the three-necked flask is placed in an ice water bath. The reaction was stirred at 3 ° C for 3 h. After the reaction, 3 drops of boron tribromide were added dropwise, and the reaction was further stirred for 30 min. After the reaction, the temperature was raised to room temperature. The reaction liquid in the three-necked flask was mixed with ethyl acetate and distilled water, stirred and allowed to stand. After stratification, the oil phase is collected, washed with water and dried with anhydrous sodium sulfate. After drying, the reaction solution is rotary evaporated to dryness, and the dried product is added to an ethanol solution for recrystallization to obtain a key intermediate of ocotamine hydrochloride 2- Ethyl aminothiazole-4-carboxylate, melting point 173.4 ° C, purity 99.5percent, The yield was 86.8percent.Example 3

Used as pharmaceutical intermediate

Molecular Weight:172.21
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:172.03064868
Monoisotopic Mass:172.03064868
Topological Polar Surface Area:93.4
Heavy Atom Count:11
Complexity:154
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes