2-CHLORO-6-(TRIFLUOROMETHYL)BENZOTHIAZOLE

White solid

In a three-necked flask fitted with a condenser, a suspension of copper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) was treated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rt for 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500 mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. The mixture was heated at 65° C. for 30 minutes, then cooled and diluted with an excess of 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. An orange semi-solid (501 mg, 92percent) was obtained and used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.10-8.05 (m, 2H), 7.74 (d, 1H); LC-MS m/z 238.2 (MH+), ret. time 3.76 min TLC Rf=0.50 (9:1 hexanes/ethyl acetate).Sulfuryl chloride (40 mL) was added with stirring to 2-mercapto-6-(trifluoromethyl) benzothiazole (18.0 g, 76.7 mmol) at <20° C. under a nitrogen atmosphere, and the suspension was then stirred at rt for 2 h. The reaction mixture was poured into ice water with stirring. Precipitation was formed, and stirring was continued for 2 h. The solid precipitate was filtered, and rinsed with water. The wet filter cake was dissolved in 100 mL EtOAc, and the solution was washed with 100 mL water and 50 mL saturated aqueous NaHCO3 solution, then dried over Na2SO4. EtOAc was removed by rotary evaporation, and the residue was dried in vacuo to afford the desired product as a light yellow solid (16.5 g, 91percent). GC-EIMS m/z 237 (M+); 1H NMR (CDCl3) δ 8.10 (s, 1H), 8.00 (d, 1H), 7.70 (d, 1H).Sulfuryl chloride (40 mL) was added with stirring to 2-mercapto-6-(trifluoromethyl) benzothiazole (18.0 g, 76.7 mmol) at <20 C. under a nitrogen atmosphere, and the suspension was then stirred at rt for 2 h. The reaction mixture was poured into ice water with stirring. Precipitation was formed, and stirring was continued for 2 h. The solid precipitate was filtered, and rinsed with water. The wet filter cake was dissolved in 100 mL EtOAc, and the solution was washed with 100 mL water and 50 mL saturated aqueous NaHCO3 solution, then dried over Na2SO4. EtOAc was removed by rotary evaporation, and the residue was dried in vacuo to afford the desired product as a light yellow solid (16.5 g, 91%). GC-EIMS m/z 237 (M+); 1H NMR (CDCl3) delta 8.10 (s, 1H), 8.00 (d, 1H), 7.70 (d, 1H).General procedure: Method A:41 To a round bottom flask was added tryptoline (21mg, 0.100mmol), 2-chlorobenzothiazole (31mg, 0.150mmol), K2CO3 (70mg, 0.500mmol) and DMF (2.0mL), and the reaction mixture was stirred for 12h at 110C. After the reaction was then cooled to room temperature, ethyl acetate (10mL) and H2O (10mL) were added into the mixture, and the aqueous layer was extracted with 2×10mL ethyl acetate. The organic layer then was combined and washed with brine, and dried over Na2SO4. The solvents were removed under vacuum, and the residue was purified by flash chromatography on silica gel using ethyl acetate/hexane as eluent.General procedure: j00728j A mixture of aryl halide (1-2 eq.), compound A-2 (racemic or a single enantiomer, 1 eq.), palladium complex (0.05-0.10 eq.), ligand (0.05-0.10 eq), and base (1-2 eq.) in dioxane (5-10 mL/mmol) under nitrogen was heated with stirring at the indicated temperature for the indicated time. On completion, the mixture was filtered and concentrated under vacuum. The residue was purified byprep HPLC or silica gel chromatography, and mixtures of enantiomers were separated by chiral SFC. Most compounds were treated with 0.2 M hydrochloric acid and lyophilized to give hydrochloride salts.A mixture of 7, 7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2, 3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.088 g, 0.311 mmol), EXAMPLE 17 (1R, 2R)-2-[(4'-{[6-(Trifluoromethyl)-1, 3-benzothiazol-2-yl]amino}-1, 1'-biphenyl-4-yl)carbonyl]cyclopentanecarboxylic acid A mixture of methyl (1R, 2R)-2-[(4'-amino-1, 1'-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate (150 mg, 0.464 mmol) and In a three-necked flask fitted with a condenser, a suspension of copper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) was treated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rt for 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500 mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. The mixture was heated at 65° C. for 30 minutes, then cooled and diluted with an excess of 1 N aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate. The organic phase was separated, dried (MgSO4), and concentrated under reduced pressure. An orange semi-solid (501 mg, 92percent) was obtained and used without further purification. 1H NMR (300 MHz, CDCl3) delta 8.10-8.05 (m, 2H), 7.74 (d, 1H); LC-MS m/z 238.2 (MH+), ret. time 3.76 min TLC Rf=0.50 (9:1 hexanes/ethyl acetate).8.25 ml tert-butyl nitrite were added to a solution of 7.40 g copper (II) chloride in 120 ml acetonitrile. The reaction mixture was stirred ten minutes at room temperature. Then a solution of 10.0 g 2-Amino-6-(trifluoromethyl)benzonitrile were added. Then 100 ml 1 N HCI were added to the cooled reaction mixture. The reaction mixture was extracted five times with portions of 50 ml ethyl acetate. The combined organic layers were washed with water and the dried over MgSO4. The solvent was removed in vacuo to obtain 9.79 g crude 2-Chloro-6-trifluoromethyl-benzothiazole as a red oil which solidifies upon standing. This material was used without further purification. C8H3CIF3NS (237.63), MS(GC): 237.0 (M+H+), Rf(n-heptane :ethyl acetate = 1 :1) = 0.72 .

Molecular Weight:237.63
XLogP3:4.2
Hydrogen Bond Acceptor Count:5
Exact Mass:236.9626825
Monoisotopic Mass:236.9626825
Topological Polar Surface Area:41.1
Heavy Atom Count:14
Complexity:223
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes