2,4-Dichlorothiazole

White solid

2, 4-dichlorothiazoleCool to 5 A mixture of thiazole-2, 4-dione (25 g), POClStep 1 : 2, 4-Dichloro-thiazole To a stirred solution of thiazolidine-2, 4-dione (4 g, 26 mmol) in anhydrous MeOH (100 mL) was added POClTo a mixture of thiazolidine-2, 4-dione (5.00 g, 42.69 mmol) in phosphorous oxychloride (25 mL) at 0 °C was added pyridine (3.80 mL, 46.96 mmol) dropwise. The mixture was then stirred at reflux for 3 hours, then cooled and poured onto ice-water. The aqueous layer was then extracted by DCM, and the combined organic layers dried and evaporated. Column (0508) chromatography with 19: 1 hexanes/EtOAc afforded the product 103. Yield = 0.94 g, 14percent. 1H MR (CDC150 g (427 mmol) thiazolidine-2, 4-dione was dissolved in 240 ml POCITo a solution of General procedure: 3-(3-(4-(aminomethyl)benzyl)isoxazol-5-yl)pyridin-2-amine diformate (Intermediate D, 80mg, 0.22mmol) was dissolved in DMSO (0.5mL). N-ethyl-N-isopropylpropan-2 -amine (83mg, 0.65mmol) and 2, 6-difluoropyridine (l48mg, l .29mmol) were added and the mixture was stirred for 2h at l20C. The mixture was diluted with water (l5mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Si02, hexane/ethyl acetate) to yield N-(4-((5-(2-aminopyridin-3-yl)isoxazol-3-yl)methyl)benzyl)-6-fluoropyridin-2 -amine (47mg, 0T3mmol, 58%) as a white solid. 500 MHz NMR (DMSO-d6) d 8.08 (dd, .7= 4.8, 1.8 Hz, 1H), 7.86 (dd, J= 7.7, 1.8 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.28 (s, 4H), 6.79 (s, 1H), 6.69 (dd, J= 7.7, 4.8 Hz, 1H), 6.35 (dd, J= 8.0, 2.5 Hz, 1H), 6.25 (s, 2H), 6.08 (dd, J= 7.6, 2.2 Hz, 1H), 4.38 (d, J= 6.0 Hz, 2H), 4.00 (s, 2H). MS: 376.3 [M+H]+.To a mixture of 2 , 4-[0164] A solution of N, N-diisopropylamine (0.93 mL, 6.65 mmol) in THF (30 mL, dist. Na) was cooled to -40 C, -BuLi (3.33 mL, 6.65 mmol) was added and the solution was stirred at -40 C for 15 min, then cooled to -78 C. A solution of 103 (0.98 g, 6.043 mmol) in THF (20 mL, dist. Na) was added dropwise, the orange solution was stirred at -78 C for 2 hours, then a solution of 104 (1.78 g, 6.043 mmol) in THF (20 mL, dist. Na) was added. The mixture was stirred at -78 C for 2 hours, then water (20 mL) was added and the solution was allowed to warm to r. . The solvent was removed and the residue partitioned between EtOAc and water, and the organic fraction was dried and evaporated. Column chromatography with 9: 1 hexanes/EtOAc gave the product 105 as a white solid. Yield = 1.98 g, 78%. 1H NMR (CDC13) delta 7.92-7.87 (2H, m), 7.74- 7.68 (2H, m), 6.25 (1H, dd, 0.8, 4.8 Hz), 4.11 (3H, s), 3.43 (1H, d, J = 4.8 Hz). Found: (0516) [M+H]=421.9.Step 1:4-chloro-2-methylthiazole General procedure: To a solution of the corresponding 4-chloroaryl reagent (0.9 mmol) in THF (10 mL) was added dropwise n-BuLi (0.392 mL, 0.98 mmol) at -78C under N2. After 1 h stirring at -78C, a solution of tert-butyl l-oxa-6-azaspiro[2.5]octane-6- carboxylate (200 mg, 0.98 mmol) in 1 mL of THF was added dropwise to the reaction mixture, followed by BF3.OEt2 (299.3 mg, 0.98 mmol) at -78C under N2. The reaction mixture was stirred at -78C for 3 h, and then the reaction mixture was allowed to warm to r.t. and stirred at r.t. overnight. The reaction mixture was cooled to -30C and quenched by Sat. NH4C1. The resulting mixture was extracted with EtOAc (50 mL, twice). The combined organic phase was washed with brine, dried over anhy. Na2S04 and concentrated in vacuo. The residue was purified by standard methods to afford 52B.

Molecular Weight:154.02
XLogP3:2.9
Hydrogen Bond Acceptor Count:2
Exact Mass:152.9206756
Monoisotopic Mass:152.9206756
Topological Polar Surface Area:41.1
Heavy Atom Count:7
Complexity:70
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes