1-isothiocyanato-2-(trifluoromethyl)benzene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound of example 270 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-trifluoromethyl phenyl isothiocyanate. The compound of example 270 was used directly without isolation, for the preparation of compound of example 271.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the aminophenol (0.5 mmol) from above in DMF (2 mL) was added with 1-isothiocyanato-2-trifluoromethylbenzene (0.6 mmol) and DIEA (1 mmol). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The crude product was purified on a silica gel column chromatography using MeOH/DCM as eluent to provide 2-(2-trifluoromethylphenylamino)-benzooxazole-5-carboxylic acid (1H-indazol-6-yl)-amide, obtained as a yellow solid. MS: m/z 438 (M+H)+. irradiation at 120° C. for 1 h The solid formed was collected by filtration washed with water dried in vacuo The crude product was purified on a silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3,4-diaminobenzoic acid (3 mmol) in DMF (10 mL) was charged with 1-isothiocyanato-2-trifluoromethylbenzene (3.3 mmol) and the resulting solution was stirred at RT for 4 h. After thiourea formation was complete, solid K2CO3 (10 mmol) was added to the reaction mixture, and the mixture was heated at 90° C. for 10 h. The reaction mixture was cooled to RT and acidified with 10% aqueous HCl to pH 7. The contents were poured onto ice cold water (30 mL) with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid as a yellow solid. the mixture was heated at 90° C. for 10 h The reaction mixture was cooled to RT The contents were poured onto ice cold water (30 mL) with vigorous stirring The solid formed was collected by filtration washed with water dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.8 g of 3,4-diaminothiophene dihydrobromide was added to a mixture of 0.74 g of N-ethyl-N,N-diisopropylamine in 40 ml of anhydrous THF, and the mixture was stirred at room temperature for 10 minutes, and then admixed with 0.58 g of 2-trifluoromethylphenyl isothiocyanate. The mixture was stirred at room temperature for 3 hours and at 40° C. for a further 10 minutes, and left to stand at room temperature overnight. After the solvent had been distilled off, the residue was admixed with water and extracted with ethyl acetate, and the insoluble fraction was filtered off. The organic phase was washed with water and dried over sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate. The mixture was stirred at room temperature for 3 hours and at 40° C. for a further 10 minutes left to stand at room temperature overnight After the solvent had been distilled off extracted with ethyl acetate the insoluble fraction was filtered off The organic phase was washed with water dried over sodium sulfate the solvent was distilled off the residue was purified by column chromatography on silica gel using a mixture of 1 part by volume of toluene and 1 part by volume of ethyl acetate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.2 g of 2-(trifluoromethyl)-phenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. The residue was further purified by flash chromatography on silica gel (methylene chloride). Crystallization from ethanol afforded the title compound (2.7 g), m.p. 82°-85° C. Anal. Calcd. for. C12H11F3N2O S: C, 50.00; H, 3.85; N,9.72. Found: C, 50.00; H, 3.61; N, 9.61. Mass spectrum (EI, M.+) m/z 288. The title compound was prepared by the procedure The residue was further purified by flash chromatography on silica gel (methylene chloride) Crystallization from ethanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-2-trifluoromethyl-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give a (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-trifluoromethyl-phenyl)-amine as brown solid in 33% yield. was then heated at the reflux temperature for 24 hr extracted with ethyl acetate The target product was purified by gravity column chromatography (50% EtOAc in hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-2-trifluoromethyl-benzene (1.5 g, 7.2 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give a (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-trifluoromethyl-phenyl)-amine as brown solid in 33% yield. was then heated at the reflux temperature for 24 hr extracted with ethyl acetate The target product was purified by gravity column chromatography (50% EtOAc in hexane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared in a manner similar to that described in Example 5 starting with 2-(trifluoromethyl) phenyl isothiocyanate. The intermediate 4-[2-(trifluoromethyl)phenyl]-3-thiosemicarbazide (2.04 g) was treated with ethyl chloroformate (1.09 g) as in example 5. The reaction product 3-hydroxy-5-mercapto-4-[2-(trifluoromethyl)phenyl]-1,2,4-triazole (0.78 g) was reacted with 0.63 g of 2-bromo-5-nitrothiazole as in Example 5. Crystallization from ethanol and water gave 0.3 g of 3-hydroxy-5-[(5-nitrothiazol-2-yl)mercapto]-4-[2-(trifluoromethyl)phenyl]-1,2,4-triazole, a yellow solid, MP 183°-185° C. The title compound was prepared in a manner similar to Crystallization from ethanol and water

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Pipemidic acid (48 mg, 0.159 mmol) and 2-(trifluoromethyl)phenyl isothiocyanate (20 μL, 0.132 mmol) were used. Purification on silica yielded compound 12 in Table 1, below (55 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.69 (s, 1H), 7.74-7.64 (m, 1H), 7.63-7.51 (m, 2H), 7.43-7.33 (m, 1H), 4.47-3.90 (m, 10H), 1.50 (t, J=6.86 Hz, 3H) ppm. Purification on silica yielded compound 12 in Table 1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The compound of example 270 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-trifluoromethyl phenyl isothiocyanate. The compound of example 270 was used directly without isolation, for the preparation of compound of example 271.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of the aminophenol (0.5 mmol) from above in DMF (2 mL) was added with 1-isothiocyanato-2-trifluoromethylbenzene (0.6 mmol) and DIEA (1 mmol). The reaction mixture was subjected to microwave irradiation at 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo. The crude product was purified on a silica gel column chromatography using MeOH/DCM as eluent to provide 2-(2-trifluoromethylphenylamino)-benzooxazole-5-carboxylic acid (1H-indazol-6-yl)-amide, obtained as a yellow solid. MS: m/z 438 (M+H)+. irradiation at 120° C. for 1 h The solid formed was collected by filtration washed with water dried in vacuo The crude product was purified on a silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 3,4-diaminobenzoic acid (3 mmol) in DMF (10 mL) was charged with 1-isothiocyanato-2-trifluoromethylbenzene (3.3 mmol) and the resulting solution was stirred at RT for 4 h. After thiourea formation was complete, solid K2CO3 (10 mmol) was added to the reaction mixture, and the mixture was heated at 90° C. for 10 h. The reaction mixture was cooled to RT and acidified with 10% aqueous HCl to pH 7. The contents were poured onto ice cold water (30 mL) with vigorous stirring. The solid formed was collected by filtration, washed with water, and dried in vacuo to provide the product, 2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid as a yellow solid. the mixture was heated at 90° C. for 10 h The reaction mixture was cooled to RT The contents were poured onto ice cold water (30 mL) with vigorous stirring The solid formed was collected by filtration washed with water dried in vacuo