4-(Trifluoromethyl)-2-thiazolamine

Preparation 214-Trifluoromethyl-thiazole-2-ylamineAdd thiourea (4.0 g, 52.3 mmol) and 3-bromo-l, l, l-trifluoropropan-2-one (5.5 mL, 10 g, 52.3 mmol) to ethanol (100 mL) and heat at 50 Step 5: A solution consisting of 1.0 g of 2-(phenylsulfonyl)-3- (trifluoromethyl)oxirane and 2 equiv of thiourea in 4 mL of dimethylformamide was heated overnight at 90 Step 5: A solution consisting of 1.0 g of 2-(phenylsulfonyl)-3- (trifluoromethyl)oxirane and 2 equiv of thiourea in 4 mL of dimethylformamide was heated overnight at 90°C. After cooling, 40 mL of CHPreparation 214-Trifluoromethyl-thiazole-2-ylamineAdd thiourea (4.0 g, 52.3 mmol) and 3-bromo-l, l, l-trifluoropropan-2-one (5.5 mL, 10 g, 52.3 mmol) to ethanol (100 mL) and heat at 50 0C for 2 h. Cool to room temperature and concentrate to dryness. Dissolve the residue in water and adjust the pH to >12 with 2 M NaOH. Extract with diethyl ether (4*). Dry the combined organic extracts with sodium sulfate, filter, and concentrate under vacuum. Purify the resulting material by silica gel chromatography (CH2Cl2) to obtain the title compound (6.9 g, 79percent). ES/MS m/z 169 (M+ 1)+.Step 1: 4-(Trifluoromethyl)-1, 3-thiazol-2-amine A solution of 3-bromo-1, 1, 1-trifluoroacetone (5.0 g, 26.184 mmol) and thiourea (2.0 g, 26.184 mmol) in ethanol was heated to 50-55° C. for 2.0 h till TLC indicated completion of the reaction. The reaction mixture was concentrated and the residue made basic with 5percent NaOH. The mixture was then extracted with ethyl acetate and concentrated to yield a residue which was column purified to afford 3.8 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) delta 7.25 (s, 1H), 7.43 (br s, 2H); ESI-MS (m/z) 169.37 (M+H)+.4-(Trifluoromethyl)-1, 3-thiazol-2-amine (0.1117 g, 0.664 mmol) is prepared from thiourea and 3-bromo-1, 1, 1-trifluoroacetone by the procedure described in Biotechnology and Bioengineering (Combinatorial Chemistry), 2000, 71(1), 9. The free base is obtained by the procedure described in the preparation of N-(4-ethyl-1, 3-thiazol-2-yl)-N'-(4-methoxy-2-methylphenyl)urea). The free base and DMAP (0.0041 g) are dissolved in THF (3 mL). 4-Methoxy-2-methylphenylisocyanate (0.097 mL, 0.108 g, 0.664 mmol) is added and the reaction mixture is stirred at 50° C. under N2 for 6 days. The reaction mixture is cooled to RT and concentrated. The residue is taken up in CH2Cl2 and insoluble N, N'-bis(4-methoxy-2-methylphenyl)urea (0.0334 g) is collected by filtration. The filtrate is concentrated and the residue is chromatographed (SiO2, 8:1 CHCl3:EtOAc) to yield Example 149 (0.0791 g) in 36percent yield. MS (ESI+) for C13H12F3N3O2S m/z 332.1 (M+H)+.A solution of 3-bromo-l, l, l-trifluoro-2-propanone (4 g, 20.95 mmol) and thiourea (1.595 g, 20.95 mmol) in EtOH (40 ml) was heated to 70°C and stirred at that temperature for 2 hours. Reaction was gone to completion thus the mixture was cooled down to room temperature, solvent eliminated under reduced pressure and crude was triturated with Et20 affording the title compound as hydrochloride salt. The latter was therefore treated with NaHCC saturated solution and extracted with DCM. Organic phase was dried over phase separator filter tube and concentrated under reduced pressure affording the title compound D33 (3.1 g).UPLC (GEN_QC_SS): rt = 0.58 min, peak observed: 169 (M+l). C4H3F3N2S requires 168. 1H NMR (400 MHz, CHLOROFORM-^ delta ppm 5.50 (br. s., 2 H) 6.98 (s, 1 H)A solution of 3-chloro-1, 1, 1-trifluoropropan-2-one (3.74 g, 39.3 mmol, 1.15 equiv) in EtOH (70 mL) was treated with thiourea (5.00 g, 34.3 mmol, 1.0 equiv) and refluxed for 9 h. After removing the solvent under reduced pressure, the reaction mixture was dissolved in H20 and then adjusted to pH 10 by slowly adding 5percent aqueous sodium hydroxide. The resulting solution was extracted (Et20), washed (brine), dried (Na2S04), and concentrated under reduced pressure. Hexane was added to the residue to recrystallize the product, which was then filtered to obtain 3.2 g of the pure product as a yellow solid (19.0 mmol).General procedure: The reaction mixture obtained with 11b-f was dissolved in 0.5 mL DCM and then diluted with toluene (10 mL). Then, phosphorus pentoxide (P2O5) was added and the reaction mixture was heated under reflux. After 1 h, the mixture was neutralized with saturated, aqueous NaHCO3 solution and extracted with DCM (4 x 15 mL), the combined organic phases were dried over anhydrous Na2SO4, the drying agent was filtered off, and the solvents were evaporated at reduced pressure. Obtained products were purified by standard column chromatography (SiO2, eluent: petroleum ether with increasing amounts (up to 30%) of AcOEt. (12a, 0.5 mmol, 84 mg) was dissolved in anhydrous DCM (3 mL), then 2, 2, 2-trichloroethyl chloroformate (16, 0.75 mmol, 159 mg), triethylamine (TEA, 0.55 mmol, 87.5 mg) and 4-dimethylaminopyridine (DMAP, 0.05 mmol, 6 mg) were added. This solution was stirred initially at 0 C for 45 min, then warmed to room temperature and stirred for 12 h. Then, the reaction mixture was washed with saturated, aqueous NaHCO3 solution and water. The product was extracted with DCM (4 x 10 mL). The organic layers were collected and dried over anhydrous Na2SO4 and the organic solvent was evaporated under reduced pressure. The obtained product was purified by standard column chromatography (SiO2, eluent: petroleum ether with increasing amounts (up to 20%) of AcOEt). It was crystallized from a mixture of hexane, heptane and DCM by slow evaporation of the solvent. 2, 2, 2-Trichloroethyl-N-[4-(trifluoromethyl)thiazol-2-yl]carbamate (17). Yield: 154 mg (90%). Colourless crystals, mp 118-120 C (PE). 1H NMR (CDCl3, 600 MHz): delta=4.89 (s, 2H, CH2), 7.41 (s, 1H, CH thiazole), 8.77 (s, 1H, NH). 13C NMR (CDCl3, 151 MHz): delta=75.4 (CH2), 94.3 (CCl3), 115.7 (q, 3JC, F=3.0 Hz, CHthiazole), 120.3 (q, 1JC, F=268.5 Hz, CF3), 140.3 (q, 2JC, F=37.5 Hz, CCF3) 151.6 (C(2)thiazole), 160.0 (C=O). 19F NMR (CDCl3, 565 MHz): delta = -64.58 (CF3).IR (KBr): nu 3188br.m (NH), 3076m, 2968m, 2789w, 1748vs (C=O), 1567vs, 1458m, 1374s, 1289vs, 1147-1110vs (CF3), 923vs cm-1. ESI-(-)-MS: m/z 341 (100, [M-H]-), 343 (43, [M-H]-). EA calcd. for C7H4Cl3F3N2O2S (343.53): C 24.57, H 1.17, N 8.15; found: C 24.49, H1.32, N 8.22. (12a, 0.5 mmol, 84 mg) was dissolved in anhydrous DMSO (3.0 mL), then 1-bromo-2-phenylethane (14, 1.5 mmol, 278 mg) and cesium carbonate (2.5 mmol, 815 mg) were added. This solution was heated at 80 C for 2 h. Then it was extracted with DCM (4 x 15 mL), the organic phases were combined and dried over anhydrous Na2SO4, and the solvent was evaporated 'in vacuo?. The obtained product was purified by standard column chromatography (SiO2, eluent: petroleum ether with increasing amounts (up to 20%) ofAcOEt). It was crystallized from a mixture of hexane, heptane and DCM by slow evaporation of the solvent. N-Phenylethyl-To a DMF (4 mL) solution of (frans)-3-(quinolin-8-yloxy)cyclobutanecarboxylic acid (Intermediate 79) (100 mg, 0.41 1 mmol) was added HATU (188 mg, 0.493 mmol) and N, N- diisopropylethylamine (0.22 mL, 1 .2 mmol). After 5 minutes,

Molecular Weight:168.14
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Exact Mass:167.99690376
Monoisotopic Mass:167.99690376
Topological Polar Surface Area:67.2
Heavy Atom Count:10
Complexity:126
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes