1,1,1,3,3,3-hexafluoro-2-methylpropan-2-ol

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

実験手順: 7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows. equipped with a stirrer a thermometer and a dropping funnel, and were dissolved by stirring at the same temperature for 3 hours Thereafter, the reaction solution was washed with water

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

実験手順: A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 hr). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid. was added portion-wise The reaction was stirred at RT for 48 hr and concentrated to an oil on the rotovap washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine The organic layer was dried over sodium sulfate concentrated to 25.5 g pale yellow solid

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

実験手順: A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 hr). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid. was added portion-wise The reaction was stirred at RT for 48 hr and concentrated to an oil on the rotovap washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine The organic layer was dried over sodium sulfate concentrated to 25.5 g pale yellow solid

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

実験手順: 7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows. equipped with a stirrer a thermometer and a dropping funnel, and were dissolved by stirring at the same temperature for 3 hours Thereafter, the reaction solution was washed with water

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

実験手順: 7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows. equipped with a stirrer a thermometer and a dropping funnel, and were dissolved by stirring at the same temperature for 3 hours Thereafter, the reaction solution was washed with water

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

実験手順: To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}benzamide (50 mg, 0.112 mmol, EXAMPLE 43, Step A) and 1,1′-(azodicarbonyl)dipiperidine (57 mg, 0.226 mmol) in toluene (2 ml) was added tri-n-butylphosphine (0.06 ml, 0.241 mmol). After stirring for 10 min, hexafluoro-2-methylisopropanol (0.03 ml, 0.245 mmol) was added. Tetrahydrofuran (2 ml) was added to solubilize starting material, and the mixture was stirred overnight at room temperature. The mixture was concentrated and the residue was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (8.7 mg, 0.014 mmol, 12.72% yield). Mass spectrum (ESI) 610.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.33 (d, J=8.5 Hz, 2H); 7.94 (d, J=8.5 Hz, 2H), 7.94 (d, J=1.5 Hz, 1H); 7.51 (s, 1H), 6.27 (br s, 1H), 3.72 (t, J=6.5 Hz, 2H), 3.46 (septet, J=6.5 Hz, 1H), 3.36 (t, J=6.0 Hz, 2H), 1.83 (m, 4H), 1.50-1.65 (m, 5H), 1.46 (d, J=7.0 Hz, 6H), 1.40-1.50 (m, 2H), 0.85-1.22, (m, 6H). the mixture was stirred overnight at room temperature The mixture was concentrated the residue was purified by flash chromatography on a Biotage Horizon, 25S column eluting with 1 column volume of 100% dichloromethane

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

実験手順: A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 hr). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid. was added portion-wise The reaction was stirred at RT for 48 hr and concentrated to an oil on the rotovap washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine The organic layer was dried over sodium sulfate concentrated to 25.5 g pale yellow solid

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

実験手順: 7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows. equipped with a stirrer a thermometer and a dropping funnel, and were dissolved by stirring at the same temperature for 3 hours Thereafter, the reaction solution was washed with water

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

実験手順: To a solution of 4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoic acid (80 mg, 0.1 mmol) in CH2Cl2 (4 mL) was added DMAP (73 mg, 0.6 mmol), (CF3)2MeCOH (108 mg, 0.6 mmol), followed by EDCI (114 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH2Cl2 and washed with water. The aqueous solution was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided dibenzyl (2S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[2-(3-methylpyrazol-1-yl)-4-[2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethoxy]carbonyl-phenyl]ethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid. washed with water The aqueous solution was extracted with CH2Cl2 The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated in vacuo Purification by normal phase silica gel column (EtOAc/heptane)

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

実験手順: A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 in). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dip. Citric acid, 2× with dip Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid. was added portion-wise The reaction was stirred at RT for 48 hr and concentrated to an oil on the rotovap washed with water, 2× with dip The organic layer was dried over sodium sulfate concentrated to 25.5 g pale yellow solid

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

実験手順: A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol) 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAP in 700 mL DCM was stirred until homogeneous (approximately 0.5 hr). The solution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol) EDCI was added portion-wise. The reaction was stirred at RT for 48 hr. and concentrated to an oil on the rotovap. The oil was taken up with EA and washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate and concentrated to 25.5 g pale yellow solid. was added portion-wise The reaction was stirred at RT for 48 hr and concentrated to an oil on the rotovap washed with water, 2× with dil. Citric acid, 2× with dil. Sodium bicarbonate, and brine The organic layer was dried over sodium sulfate concentrated to 25.5 g pale yellow solid

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

実験手順: 7.3 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, 0.2 g of 4-dimethylaminopyridine, 4.9 g of triethylamine and 20 g of acetone were charged into a four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and were dissolved by stirring. Then, 4.6 g of methacrylic acid chloride was dropwise added to the resulting solution at about 5° C. over 30 minutes, followed by stirring at the same temperature for 3 hours. Thereafter, the reaction solution was washed with water, thereby obtaining 7.5 g of 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate. The 1H-NMR data of the obtained 1,1,1,3,3,3-hexafluoro-2-methyl-2-propyl methacrylate were as follows. equipped with a stirrer a thermometer and a dropping funnel, and were dissolved by stirring at the same temperature for 3 hours Thereafter, the reaction solution was washed with water