1-(2-AMINO-1,3-THIAZOL-4-YL)ETHANONE

Trifluoroacetic acid (5 ml) was added to a solution (10 ml) of the above-produced acetyl compound in chloroform followed by stirring at room temperature for one and a half hour. The reaction solution was concentrated, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and filtered to give 149 mg (yield: 59percent) of the title compound as a white solid.1H-NMR (CDCl3) δ: 2.48 (3H, s), 7.35 (1H, s) ESI-MS (m/e): 143 [M+H]+(1c) To a solution of thiourea (6.79 g, 89.2 mmol) in absolute ethanol (100 mL) was added 1-chloro-butane-2, 3-dione (prepared as described by Bonnema, J. et al., Rec. Trav. Chim. Pays-Bas 1960, 79, 1137) (10.75 g, 89.2 mmol) and the mixture stirred at room temperature for 72 hours. The dark brown suspension was concentrated in vacuo, the residue taken up in water (350 mL), acidified with 1M aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (2.x.100 mL). The aqueous layer was then neutralized with solid sodium bicarbonate to form a light brown solid which was isolated by filtration. The precipitate was washed with 1:1 hexanes/ether (100 mL), 1:1 hexanes/ethyl acetae (100 mL) and then dried in vacuo over potassium hydroxide to give 1-(2-amino-thiazol-4-yl)-ethanone as a light brown solid (9.91 g, 78percent).Step 2 1-(2-Aminothiazol-4-yl)ethanone: A mixture of 1-bromobutane-2, 3-dione (10.4 g, 63.41 mmol) and thiourea (1.6 g, 21.05 mmol) in EtOH (100 mL) was stirred at room temperature overnight. A solid was collected by filtration. The filter cake was washed with CHTrifluoroacetic acid (5 ml) was added to a solution (10 ml) of the above-produced acetyl compound in chloroform followed by stirring at room temperature for one and a half hour. The reaction solution was concentrated, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and filtered to give 149 mg (yield: 59percent) of the title compound as a white solid.1H-NMR (CDCl3) δ: 2.48 (3H, s), 7.35 (1H, s) ESI-MS (m/e): 143 [M+H]+(1c) To a solution of thiourea (6.79 g, 89.2 mmol) in absolute ethanol (100 mL) was added 1-chloro-butane-2, 3-dione (prepared as described by Bonnema, J. et al., Rec. Trav. Chim. Pays-Bas 1960, 79, 1137) (10.75 g, 89.2 mmol) and the mixture stirred at room temperature for 72 hours. The dark brown suspension was concentrated in vacuo, the residue taken up in water (350 mL), acidified with 1M aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (2.x.100 mL). The aqueous layer was then neutralized with solid sodium bicarbonate to form a light brown solid which was isolated by filtration. The precipitate was washed with 1:1 hexanes/ether (100 mL), 1:1 hexanes/ethyl acetae (100 mL) and then dried in vacuo over potassium hydroxide to give 1-(2-amino-thiazol-4-yl)-ethanone as a light brown solid (9.91 g, 78percent).Step 2 1-(2-Aminothiazol-4-yl)ethanone: A mixture of 1-bromobutane-2, 3-dione (10.4 g, 63.41 mmol) and thiourea (1.6 g, 21.05 mmol) in EtOH (100 mL) was stirred at room temperature overnight. A solid was collected by filtration. The filter cake was washed with CHTo a solution of thiourea (6.79 g, 89.2 mmol) in absolute ethanol (100 mL) was added 1-chloro-butane-2, 3-dione (prepared as described by Bonnema, J. et al., Rec. Trav. Chim. Pays-Bas 1960, 79, 1137) (10.75 g, 89.2 mmol) and the mixture stirred at room temperature for 72 hours. The dark brown suspension was concentrated in vacuo, the residue taken up in water (350 mL), acidified with 1M aqueous hydrochloric acid (20 mL) and extracted with ethyl acetate (2×100 mL). The aqueous layer was then neutralized with solid sodium bicarbonate to form a light brown solid which was isolated by filtration. The precipitate was washed with 1:1 hexanes/ether (100 mL), 1:1 hexanes/ethyl acetae (100 mL) and then dried in vacuo over potassium hydroxide to give 1-(2-amino-thiazol-4-yl)-ethanone as a light brown solid (9.91 g, 78%).To a DMF (4 mL) solution of (frans)-3-(4-fluoro-2- methoxyphenoxy)cyclobutanecarboxylic acid (Intermediate 1 15) (80 mg, 0.33 mmol) was added HATU (152 mg, 0.400 mmol) and N, N-diisopropylethylamine (0.17 mL, 0.99 mmol). After 5 minutes, 1 -(2-aminothiazol-4-yl)ethanone (57 mg, 0.40 mmol) was added, and the mixture was stirred for 3 h, poured into water, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SC>4, filtered and concentrated. This residue was purified on silica gel, eluting with 0%-100% EtOAc: EtOH (3:1 ) in hexanes to give the title compound (46 mg, 35%). 1H NMR (400 MHz, CD3SOCD3) delta 2.23-2.38 (m, 2 H), 2.49 (s, 3 H), 2.60-2.69 (m, 2 H), 3.35-3.47 (m, 1 H), 3.78 (s, 3 H), 4.78 (t, J = 6 Hz, 1 H), 6.58-6.65 (m, 1 H), 6.72-6.78 (m, 1 H), 6.92 (d, J = 3 Hz, 1 H), 8.08 (s, 1 H), 12.46 (s, 1 H); LC-MS (LC-ES) M+H = 365.To a DMF (4 mL) solution of (fraiis)-3-(5-chloro-2- methoxyphenoxy)cyclobutanecarboxylic acid (Intermediate 1 14) (80 mg, 0.31 mmol) was added HATU (141 mg, 0.370 mmol) and N, N-diisopropylethylamine (0.16 mL, 0.93 mmol). After 5 minutes, 1 -(2-aminothiazol-4-yl)ethanone (52 mg, 0.37 mmol) was added, and the mixture was stirred for 3 h, poured into water, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SC>4, filtered and concentrated. This residue was purified on silica gel, eluting with 0%-100% EtOAc: EtOH (3:1 ) in hexanes to give the title compound (33 mg, 23%) as a white solid. 1H NMR (400 MHz, CD3SOCD3) delta 2.19-2.35 (m, 2 H), 2.50 (s, 3 H), 2.59-2.70 (m 2 H), 3.32-3.42 (m, 1 H), 3.76 (d, J = 6 Hz, 3 H), 4.72-4.89 (m, 1 H), 6.72-6.78 (m, 1 H), 6.89-7.01 (m, 2 H), 8.08 (s, 1 H), 12.46 (br s, 1 H); LC-MS (LC-ES) M+H = 381 , 383 (CI pattern).To a DMF (4 mL) solution of (frans)-3-(5-chloro-2- (difluoromethoxy)phenoxy)cyclobutanecarboxylic acid (Intermediate 1 13) (80 mg, 0.27 mmol) was added HATU (125 mg, 0.328 mmol) and N, N-diisopropylethylamine (0.14 mL, 0.82 mmol). After 5 minutes, 1 -(2-aminothiazol-4-yl)ethanone (39 mg, 0.27 mmol) was added, and the mixture was stirred for 5 h, poured into water, and extracted with EtOAc (3X). The combined organic layers were dried over Na2S04, filtered and concentrated. This residue was purified on silica gel, eluting with 0%-1 00% EtOAc: EtOH (3:1 ) in hexanes to give the title compound (28 mg, 20%). 1H NMR (400 MHz, CD3SOCD3) delta 2.22-2.39 (m, 2 H), 2.60-2.69 (m, 2 H), 2.69 (s, 3 H), 3.35-3.45 (m, 1 H), 4.89-4.99 (m, 1 H), 6.89-7.09 (m, 3 H), 7.13-7.22 (m, 1 H), 8.08 (s, 1 H), 12.47 (br s, 1 H); LC-MS (LC-ES) M+H = 417, 419 (CI pattern).To a DMF (5 mL) solution of (trans)- 3-((3-bromobenzofuran-7- yl)oxy)cyclobutanecarboxylic acid (Intermediate 1 12) (100 mg, 0.321 mmol) was added HATU (147 mg, 0.386 mmol) and N, N-diisopropylethylamine (0.17 mL, 0.96 mmol). After 5 minutes, 1 -(2-aminothiazol-4-yl)ethanone (50 mg, 0.35 mmol) was added, and the mixture was stirred for 12 h, poured into water, and extracted with EtOAc (3X). The combined organic layers were dried over Na2SC>4, filtered and concentrated. This residue was purified on silica gel, eluting with 0%-100% EtOAc: EtOH (3:1 ) in hexanes to give the title compound (97 mg, 58%). 1H NMR (400 MHz, CD3SOCD3) delta 2.37-2.44 (m, 2 H), 2.66 (s, 3 H), 2.67-2.75 (m, 2 H), 3.42 (d, J = 5 Hz, 1 H), 5.03 (t, J = 6 Hz, 1 H), 6.72 (d, J = 8.40 Hz, 1 H), 6.82-6.94 (m, 1 H), 7.32-7.41 (m, 1 H), 8.03-8.15 (m, 2 H), 12.50 (s, 1 H); LC-MS (LC-ES) M+H = 435, 437 (Br pattern).

Molecular Weight:142.18
XLogP3:0.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:142.02008399
Monoisotopic Mass:142.02008399
Topological Polar Surface Area:84.2
Heavy Atom Count:9
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes