ETHYL 2-CHLORO-1,3-THIAZOLE-4-CARBOXYLATE

The free based 2-amino-thiazole-4-carboxylic acid ethyl ester (306 mg, 1.78 mmol) and CuCl (238 mg, 2.4 mmol) were suspended in conc. HC1 (8 ml) and the mixture cooled on a salt/ice bath. A pre-cooled solution of NaNO2 (166 mg, 2.4 mmol) in water (2ml) was added over a period of 10 min. The mixture was allowed to warm to room temperature over 1 h and was stirred for a further 1 h. Water was added and the aqueous layer extracted with EtOAc (3 x 10 ml). The combined EtOAc layers were washed with brine, dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound. Yield: 251 mg, 74percent ; LC/MS tr 1.06 min; MS (ES+) m/z 192, 194 (M+H) ; 1H NMR (250 MHz, CDC13) 5 1.41 (t, 3H), 4.43 (q, 2H), 8.08 (s, 1H).At 23° C., a solution of ethyl 2-aminothlazole-4-formate (1.0 g, 6.35 mmol) in acetonitrile (10 mL) and tetrahydrofuran (10 mL) is added to a solution (10 mL) of t-butyl nitrite (1.3 mL, 9.52 mmol) and cuprous chloride (1.0 g, 7.6 mmol) in acetonitrile (10 mL) and tetrahydrofuran (10 mL). The reaction mixture is required to be heated at 65° C. until complete consumption of the starting materials as shown by thin-layer chromatography (40percent ethyl acetate-hexane). Then, the mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is concentrated under vacuum and purified by flash silica gel column chromatography eluted with 20percent ethyl acetate-hexane to give ethyl 2-chloro-thiazole-4-formate (compound (2-2)) (0.49 g, 40percent).Example 55. (1041) Ethyl 2-(7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1, 1'-biphenyl]-2-yl)oxy)pyrimidin- 4-yl)-2, 7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylate (1042) (1043) To a solution of 2'-((4-(2, 7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-2- cyclopropyl-5'-fluoro- [1, 1'-biphenyl]-4-carbonitrile (220 mg, 0.48 mmol) in DMF (5 mL) was added A mixture of compound 12 (0.50 g, 0.90 mmol), bis(pinacolato)diboron (0.25 g, 1.0 mmol), andpotassium acetate (0.27 g, 2.7 mmol) in dimethylsulfoxide (20 mL) was stirred at 80 C for 10 min under an argonatmosphere. To the resulting solution was added (1, 1?-Bis(diphenylphosphino)ferrocene)dichloropalladium(II)(dichloromethane complex, 20 mg, 0.027 mmol). After stirring at 100 C for 15 min under an argon atmosphere, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washedwith brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in toluene-methanol-water(5:1:1, v/v, 28 mL). To the solution were added compound 13a (0.17 g, 0.90 mmol), K2CO3 (0.63 g, 4.5 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.10 g, 0.090 mmol), and the resulting mixture was stirred at reflux for17 h under an argon atmosphere. The reaction mixture was cooled and partitioned between water and ethyl acetate.The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purifiedby column chromatography (silica gel, eluting with a gradient of 10-30% ethyl acetate in hexanes) followed bypreparative HPLC to afford the title compound 14a (0.28 g, 56%) as a white powderA mixture of Ethyl 2-chlorothiazole-4-formate (8.8 g, 45 mmol) is dissolved in ethanol (100 mL), and sodium hydroxide (2.13 g, 53.3 mmol) and water (50 mL) are added. After being stirred at room temperature overnight, ethanol is removed under reduced pressure, and the reaction mixture is diluted with water (50 mL). After being washed with ethylether (50 mL), the pH of the mixture is adjusted to about 2 with HCl . The obtained solids are collected through filtration, washed with water and dried to give compound (2-3) (5.12 g, 70%).

Molecular Weight:191.64
XLogP3:2.5
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:190.9807773
Monoisotopic Mass:190.9807773
Topological Polar Surface Area:67.4
Heavy Atom Count:11
Complexity:156
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes