Water → (-)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5-(2-methylpropoxy)pyrimidine-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline-5-ol

HRID 715861Notes

Reaction equation

[F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:54][CH:55]([CH3:57])[CH3:56].O>O1CCCC1>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:54][CH:55]([CH3:57])[CH3:56])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1

Participants

Conditions

Temperature: 50 °C

Procedure

To a solution of 55 mg (0.085 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 1 ml of tetrahydrofuran, 33 mg (0.10 mmol) of cesium carbonate and 11 μl (0.094 mmol) of 1-iodo-2-methyl propane were added, and the reaction solution was stirred at room temperature for 2 hours, at 50° C. for 3 hours and further at room temperature for 14 hours. After stirring at room temperature, 50 (0.43 mmol) of 1-iodo-2-methyl propane and 50 mg (0.15 mmol) of cesium carbonate were added and the reaction solution was stirred at 70° C. for 9 hours. After stirring with heating, 50 μl (0.43 mmol) of 1-iodo-2-methyl propane and 100 mg (0.31 mmol) of cesium carbonate were further added and the reaction solution was stirred at room temperature for 14.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 41 mg of the title compound as a white solid (yield: 68%).

Workup

stirringAfter stirring at room temperature
stirringthe reaction solution was stirred at 70° C. for 9 hours
stirringAfter stirring
temperaturewith heating
stirringthe reaction solution was stirred at room temperature for 14.5 hours
customAfter completion of the reaction
extractionextracted with ethyl acetate
washThe organic layer was washed with saturated sodium chloride aqueous solution
dry with materialdried with anhydrous magnesium sulfate
distillationthe solvent was distilled off under reduced pressure
concentrationwas concentrated under reduced pressure
additionn-Hexane was added to the obtained residue
customthe precipitate was obtained by filtration

Sources & evidence

ORD record: ord-473b86ae38844de689de461e4e12034c
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09187450B2

Reaction notes

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