Ethyl 2-aminothiazole-5-carboxylate

White to yellow or light brown crystal or powder

At -10°C, a solution of ethyl 3-ethoxyacrylate (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).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 ethyl 3-ethoxyacrylate 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. 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.2.2 g, 15.2 mmol 3- ethyl acrylate XIV was added to a mixed solvent of 7.5 ml of water and 7.5 ml of dioxane, cooledlarge -10 degrees Celsius, was slowly added 2.97 g, 16.72 mmol of NBS after, room temperature 1 hour, then 1.15 g, 15.2mmol) of thiourea was added, the reaction after 1 hour at 80 ° C, ice-cooling, after addition of an excess of ammonia appearedbrown solid, leaching after the obtained solid was washed with water and drying give 1.4 g of 2-amino-5-carboxylic acid ethylester XV of, in a yield of 53.8percent.A slurry of ethyl 2-aminothiazole-5-carboxylate (8; 145 g, 840 mmol), di-tert-butyl dicarbonate (275 g, 1260 mmol) and 4-Dimethylaminopyridine (DMAP) (5 mg, catalytic) in TH F (2 1 75 m L) was stirred at 30 C for 5.5 h. The reaction mixture was concentrated to dryness and EtOAc ( 1450 mL) was added. The organic solvent was washed with water ( 2 x 435 mL) and brine (2 x 145 mL), dried over MgS04 and concentrated to give ethyl 2-(tertbutoxycarbonylamino)thiazole-5-carboxylate (9; 227 g, 99.23%) as a crude product, which was used for the next step without any further purification. M S (ES I) calcd for Cn H ^^C^S (m/z) 272.32.A slurry of ethyl 2-aminothiazole-5-carboxylate (8; 145.0 g, 840 mmol), di-tert-butyl dicarbonate (275.0 g, 1260 mmol) and DMAP (5.0 mg, catalytic) in THF (2175 mL) was stirred at 30 C for 5.5 h. The reaction mixture was concentrated to dryness and EtOAc (1450 mL) was added. The organic solvent was washed with water (2 x 435 mL) and brine (2 x 145 mL), dried over MgSO4 and concentrated to give ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (227.0 g, 99.23%) as a crude product, which was used for the next step without any further purification. MS (ESI) calcd for C11H16N2O4S (m/z): 272.32.Preparation of 2ad: iV-Propyl-5-((5-((4-p-tolylthiazoI-2-ylaniino)methyl)thiazol-2-ylamino)methyl)thiazoI-2- amine trihydrochlorideelhyl vi propylamine reflux DMAP (35 mg, 0.29 mmol), Et3N (16 mL, 116 mmol) and di-tert-butyl dicarbonate (13 mL, 58 mmol) were added to a solution of ethyl 2-aminothiazole-5-carboxylate (10 g, 58.1 mmol) in THF (100 mL). The resulting solution was stirred at RT until completion of the reaction. The solvents were evaporated and the crude product was purified by precipitation with PE, yielding ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (14.2 g, 90%) as a white solid. To a solution of ethyl 2-aminothiazole-5-carboxylate (3.1 g, 18 mmol) and BoC2O (5.0 mL, 22 mmol) in anhydrous THF (40 mL) was added DMAP (0.15 g, 1.3 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 19 h. Heptane (20 mL) was added slowly and the mixture was stirred at room temperature for 1 h. The solid that separated out was filtered and washed with a mixture of ethyl acetate and heptanes (1 : 1 ; 2 x 5 mL) to give the desired product (2.9 g) as a yellow solid. The mother liquor was concentrated and the solid First of all, ready to clean 50 ml three-neck bottle a, a package weighing paper, an aluminum spatula; needed raw material to identify and placed in designated areas to be weighing; after the completion of the preparations for the, open the electronic balance power switch, treats the reading stability after three mouth bottle placed in zero balance and, for to aluminum bucket 50m1 of three added in the flask 2 - amino thiazole -5 - ethyl formate 1.00g, zero, aluminum bucket to clean 50 ml three-neck bottle plus 4 - dimethyl aminopyridine 141.89 mg, adding 15m1 of redistilled over anhydrous THF stirring 15min to mix uniformly, for weighing the two carbonic acid di-tert-butyl balance 1.52g, dissolved in 2 ml in water-free THF, under the room temperature condition, there are two drip carbon acid tert-butyl ester anhydrous THF solution (2m1), then completing, room temperature stirring 8h, evaporate in a reaction solvent to the remaining about 1/5 volume, filter, a small amount of THF cake washing, drying to obtain a kind of white powder product (1.3g), yield 82.21%. The total reaction equation is as follows: Nuclear magnetic with the mass spectrometry data:Step A. Ethyl 2-[(ter?-butoxycarbonyl)aminol-1.3-thiazole-5-carboxylate A mixture of ethyl 2-amino-l, 3-thiazole-5-carboxylate (4.33 g, 25.1 mmol), (Boc^O (6.13 ml, 26.4 mmol) and DMAP (0.061 g, 0.50 mmol) in THF (50 ml) was stirred for 16 h. White solid resulted, and it was collected by filtration and washed with ethyl acetate to give ethyl 2-[(tert-butoxycarbonyl)amino]-l, 3-thiazole-5-carboxylate (5.46 g, 20.12 mmol, 80% yield) as a pale white solid. MS (ES~) m/z: 271.10 [M-l]~.Into a clean and dry 1 L, 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket is charged with ethyl 2-aminothiazole-5-carboxylate (2-ATC) (50 g), dimethylaminopyridine (DMAP) (3.2 g), di-tertiary-butyldicarbonate (DIBOC) (95.2 g), dimethylformamide (DMF) (250 mL) in the presence of N2 atmosphere and stirred the reaction mass for 24 h at 25-30 C. After TLC compliance, filter the reaction mass through a Buchner funnel and flask kept under plant vacuum. Washed the wet cake with 100mL of acetonitrile and dried the wet material in the dryer at 60-65 C for 4-6 h. Purification: Into a clean and dry 1 L 4-neck round bottom flask connected to a mechanical stirrer, condenser, thermometer socket and charged above crude (60.0 g) and 300 mL of acetonitrile under stirring at 25-30 C and stirred the reaction mass for 45-60 min at 75-80 C. After completion of the maintenance time, cooled the reaction mass temperature to 25-30 C and transferred the reaction mass into a Buchner funnel and flask kept under plant vacuum. Washed the wet cake with 25 mL of acetonitrile and dried the component in the dryer at 60-65C for 4-6 h to furnish 59 g of the title compound with purity above 99 %. Light brown colour solid; Elemental analysis C11H16N2O4Scalcd (found) %: C 48.52 (48.22), H 5.92 (5.98), N 10.29 (10.40), O 23.50 (23.20), S 11.77 (11.91). IR (KBr, numax, cm-1): 3417.47-3388.20, 3162.53-2905.33, 1716.15, 1572.53, 1529.19; 1H NMR(400 MHz, DMSO-d6): delta1.272-1.308 (t, 3H, -CH3), 1.508 (s, 9H, -3CH3), 4.242-4.295 (q, 2H, -CH2), 8.052 (s, 1H, ArH), 12.040 (s, 1H, -NH); 13C NMR (100 MHz, DMSO-d6): delta164.58, 161.77, 152.99, 145.78, 121.21, 82.66, 61.24, 28.06, 14.43;ESI-MS (m/z): 273.17 (M+1), 274.18 (M+2)Ethyl 2-aminothiazole-5-carboxylate (71; 10.0 g, 58.1 mmol) was taken up in 150 mL of anhydrous THF along with di-tert-butyl carbonate (12.67 g, 58.1 mmol) along with 10 mg of 4-(dimethyl)aminopyridine. The reaction mixture was stirred at 5O0C for 4 h and then at room temperature for 18 h. It was then concentrated under reduced pressure to obtain a thick oil. Pentane was added and the resulting crystalline materials were collected by filtration and dried to afford 10.5 g of ethyl 2- (tert-butoxycarbonylamino)thiazole-5-carboxylate 72. This material (10.5 g, 38.5 mmol) was dissolved in 300 mL of anhydrous THF and cooled to -78 0C. A solution of 1 M Super Hydride in THF (85 mL) was then added over a period of 10 min. The resulting reaction mixture was stirred at -450C for 2 h. Another portion of 1 M Super Hydride in THF (35 mL) was then added and the reaction mixture was stirred for an additional 2 h at -450C. The reaction was quenched at -450C by the addition of 50 mL of brine. Upon warming to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford tert-butyl 5-(hydroxymethyl)thiazol-2-ylcarbamate 73. MS (ESI) calcd for C9Hi4N2O3S (m/z): 230.07, found 231[M+H].A slurry of ethyl 2-aminothiazole-5-carboxylate (8; 145.0 g, 840 mmol), di-tert-butyl dicarbonate (275.0 g, 1260 mmol) and DMAP (5.0 mg, catalytic) in THF (2175 niL) was stirred at 30 C for 5.5 h. The reaction mixture was concentrated to dryness and EtOAc (1450 mL) was added. The organic solvent was washed with water (2 x 435 mL) and brine (2 x 145 mL), dried over MgSO4 and concentrated to give ethyl 2-(tert-butoxycarbonylamino)thiazole-5-carboxylate (227.0 g, 99.23%) as a crude product, which was used for the next step without any further purification. MS (ESI) calcd for C11H16N2O4S (m/z): 272.32Into a clean and dry 1.0. L 4-neck RB flask connected to a mechanical stirrer, condenser, thermometer socket is charged Ethyl2-aminothiazole-5-carboxylate (0061) (50gm), DMAP(3.2gm), DIBOC (95gm), DMF (250ml) in presence of N2 atmosphere at 25-30C, maintained the reaction mass temperature at 25-30C for (0062) 24hrs, after completion of the reaction, transferred the reaction mass into a buchner funnel and flask kept under plant vacuum. Washed the wet cake with 100.0 ml of acetonitrile, suck dried for 10-15 min. Transfered the wet material into a clean and dry petridish, dried the above wet material in drier at temperature 60-65C for 4-6 hrs. Weight: 60.0 g b) purification of ethyl 2-tert-butoxy-carbonylamino-thiazole-5-carboxylate (0064) Into a clean and dry 1.0. L 4-neck RB flask, charged ethyl 2-tert-butoxy- carbonylamino-thiazole-5-carboxylate (60gm) and acetonitrile (300ml, Lot-I) under stirring at temperature 25-30C. Raised the reaction mass temperature to 75-80C. Maintained the reaction mass temperature at 75-80C for 45-60 min. Cooled the reaction mass temperature to 25-30C. Transferred the reaction mass is into a buchner funnel and flask kept under plant vacuum. Washed the wet cake with 25.0 ml of acetonitrile. Suck dried thoroughly for 10-15 min. Transfered the wet material into a clean and dry petridish. Dried the above wet material in drier at temperature 60-65 C for 4-6 hrs. (0065) Weight: 59gm2.2 g, 15.2 mmol 3- ethyl acrylate XIV was added to a mixed solvent of 7.5 ml of water and 7.5 ml of dioxane, cooledlarge -10 degrees Celsius, was slowly added 2.97 g, 16.72 mmol of NBS after, room temperature 1 hour, then 1.15 g, 15.2mmol) of thiourea was added, the reaction after 1 hour at 80 C, ice-cooling, after addition of an excess of ammonia appearedbrown solid, leaching after the obtained solid was washed with water and drying give 1.4 g of 2-amino-5-carboxylic acid ethylester XV of, in a yield of 53.8%.EXAMPLE 26B 2-Amino-5-(ethoxycarbonyl)thiazole To a -10 C. solution of potassium tert-butoxide (150 g, 1.3 mol) in THF (1.35 L) was added a solution of ethyl chloroacetate (139 mL, 1.3 mol) and ethyl formate (103 mL, 1.27 mol) in THF (150 mL) dropwise over 75 minutes, with good mechanical stirring. A THF rinse (25 mL) was added over 5 minutes. The thick solution was stirred another 3 hours at ca. -5 to 0 C., then the reaction was quenched by addition of a solution of NaCl (240 g) and conc. HCl (90 mL) in water (960 mL). The mixture was allowed to warm to 15 C. and the lower aqueous layer was discarded. Thiourea (97 g, 1.27 mol) was dissolved in the crude THF solution of chloroaldehyde. The solution was warmed to 65 C. and refluxed for 1 hour, then cooled to 30 C. Addition of a solution of K2 CO3 (88 g, 0.64 mol) in 1500 mL water produced two layers (aqueous pH=7). The THF was removed under vacuum at '45 C., causing the product to precipitate as a yellow solid. The slurry was cooled to 15 C., and the product was collected on a fitted Buchner funnel and washed with 3*200 mL water, then dried 24 hours in a vacuum oven at 55 C. to provide 151 g of title compound as a yellow solid, m.p. 155-158 C. 1 H NMR (DMSO-d6) delta7.8 (br s, 2H, NH2), 7.62 (s, 1H), 4.13 (q, 2H), 1.18 (t, 3H). 13 C NMR (DMSO-d6) delta173.4, 161.3, 147.9, 114.5, 60.1, 14.3.Example 23B 2-Amino-5-(ethoxycarbonyl)thiazole To a -10 C. solution of potassium tert-butoxide (150 g, 1.3 mol) in THF (1.35 L) was added a solution of ethyl chloroacetate (139 mL, 1.3 mol) and ethyl formate (103 mL, 1.27 mol) in THF (150 mL) dropwise over 75 minutes, with good mechanical stirring. A THF rinse (25 mL) was added over 5 minutes. The thick solution was stirred another 3 hours at ca. -5 to 0 C., then the reaction was quenched by addition of a solution of NaCl (240 g) and conc. HCl (90 mL) in water (960 mL). The mixture was allowed to warm to 15 C. and the lower aqueous layer was discarded. Thiourea (97 g, 1.27 mol) was dissolved in the crude THF solution of chloroaldehyde. The solution was warmed to 65 C. and refluxed for 1 hour, then cooled to 30 C. Addition of a solution of K2 CO3 (88 g, 0.64 mol) in 1500 mL water produced two layers (aqueous pH=7). The THF was removed under vacuum at '45 C., causing the product to precipitate as a yellow solid. The slurry was cooled to 15 C., and the product was collected on a fritted Buchner funnel and washed with 3*200 mL water, then dried 24 hours in a vacuum oven at 55 C. to provide 151 g of title compound as a yellow solid, m.p. 155-158 C. 1 H NMR (DMSO-d6) delta7.8 (br s, 2H, NH2), 7.62 (s, 1H), 4.13 (q, 2H), 1.18 (t, 3H). 13 C NMR (DMSO-d6) delta173.4, 161.3, 147.9, 114.5, 60.1, 14.3.

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