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With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 2.25 h; Inert atmosphere; Reflux
[00363] A suspension of ethyl 2-amino-1,3-thiazole-5-carboxylate (1.72 g, 10 mmol) in anhydrous THF (100 mL) was cooled in an ice bath and treated with LiAIH4 (0.76 g, 20 mmol) portionwise, under nitrogen. The reaction mixture was warmed to room temperature and stirred for 90 minutes. After this time, additional LiAIH4 (0.76 g, 20 mmol) was added and thesuspension was heated to reflux for 45 minutes. After this time, the suspension was cooled in an ice bath and cautiously treated with ice chips, followed by concentrated aqueous ammonium hydroxide solution (10 mL) and stirred for 60 hours. The orange suspension was filtered through CeliteTM, washing with MeOH. The filtrate was evaporated under reduced pressure, adsorbed onto silica and purified by flash column chromatography, eluting with MeOH/DCM (5-10percent), with the desired fractions combined and concentrated under reduced pressure to afford the title compound (225 mg). LCMS method: Method 5, RT: 0.55 mm, Ml: 131 [M+1]
With ammonium hydroxide; N-Bromosuccinimide; thiourea; In 1,4-dioxane; water;
Step 1 Preparation of ethyl 2-amino-1,3-thiazole-5-carboxylate To a mixture of B-ethoxyacrylic acid ethyl ester (2.0 g, 13.9 mmol) in 1:1 dioxane/water (15 mL) at -10°0C. was added NBS (2.72 g, 15.3 mmol). Thiourea (1.06 g, 13.9 mmol) was added and the mixture was heated to 80° C. and stirred for 1.5 h. The reaction mixture was cooled to 0° C. and 5 mL of saturated ammonium hydroxide was added. A precipitate formed in 15 min. The solid was filtered, washed with water and dried under vacuum, yielding a light orange solid.
[0096] At -10°C, a solution of <strong>[1001-26-9]ethyl 3-ethoxyacrylate</strong> (14.4 g, 0.1 mol) in water/dioxane (1:1) (100 mL) is treated withN-bromo-succinimide (19.6 g, 0.11 mol). The reaction mixture is stirred at room temperature for 1 hour, then thiourea(7.6 g, 0.1 mol) is added and the reaction mixture is heated to 80 °C for 1 hour. After the reaction solution is cooled toroom temperature, aqueous ammonia (20 mL) is added therein. The paste produced is stirred at room temperature for10 minutes, and filtered. The resultant filter cake is washed with water and dried under vacuum to give compound (2-1)(12.1 g, 70percent).
66%
Example 4: 6-phenylimidazo[2,l-b][l,3]thiazole-2-carboxylic acid; Step 1: ethyl 2-amino-l,3-thiazole-5-carboxvlate; A solution (1 M) of <strong>[1001-26-9]ethyl 3-ethoxyacrylate</strong> in water/dioxane (1:1) at -10°C was treated with NBS (1.1 eq.). The reaction mixture was stirred at RT for 1 hour, then thiourea (1 eq.) was added and the reaction was heated at 80°C for 1 h. After cooling at RT aqueous NH4OH (saturated solution) was added. The resulting slurry was stirred at RT for 10 min and filtered. The resulting cake was washed with water and dried to afford the title compound (66percent) as a pale yellow solid. .H NMR (400 MHz, DMSO,300 K) 8 1.23 (t, J6.8 Hz, 3H), 4.17 (q, J6.S Hz, 2H), 7.66 (s, 1H), 7.83 (s, 2H); MS (ES+) m/z 173 (M+H)+.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2.25h;Inert atmosphere; Reflux;
[00363] A suspension of ethyl 2-amino-1,3-thiazole-5-carboxylate (1.72 g, 10 mmol) in anhydrous THF (100 mL) was cooled in an ice bath and treated with LiAIH4 (0.76 g, 20 mmol) portionwise, under nitrogen. The reaction mixture was warmed to room temperature and stirred for 90 minutes. After this time, additional LiAIH4 (0.76 g, 20 mmol) was added and thesuspension was heated to reflux for 45 minutes. After this time, the suspension was cooled in an ice bath and cautiously treated with ice chips, followed by concentrated aqueous ammonium hydroxide solution (10 mL) and stirred for 60 hours. The orange suspension was filtered through CeliteTM, washing with MeOH. The filtrate was evaporated under reduced pressure, adsorbed onto silica and purified by flash column chromatography, eluting with MeOH/DCM (5-10%), with the desired fractions combined and concentrated under reduced pressure to afford the title compound (225 mg). LCMS method: Method 5, RT: 0.55 mm, Ml: 131 [M+1]
With potassium sulfide; copper; In tetrahydrofuran; water; at 55℃; for 1.5h;Inert atmosphere;
A method for the synthesis of an intermediate of dasatinib,The method comprises: under nitrogen protection,Ethyl 3-ethoxyacrylate (14.4 g, 100 mmol)And urea 12 g (200 mmol)And potassium sulfide 33. lg (300 mmol) of nano-copper powder 1.4 g (10percent1 OOnm) under the catalytic 55 ° C contact reaction 1.5 hours,The solvent for the contact reaction was 100 ml of a 6: 1 by volume mixture of THF and H20,Cooled to room temperature,Poured into ice water,Dichloromethane extraction,The organic phase was concentrated,Washed,Then recrystallized from ethanol,Amino-thiazole-5-carboxylic acid ethyl ester of dasatinib as an intermediate, 16.5 g,The yield was 95.7percentPurity 99.34percent.
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