Water → 2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

HRID 715845Notes

Reaction equation

HRID 715845 reaction equation
[F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1

Participants

6

Reactant 4

HCID 962WaterHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 6066655-Bromo-2-chloropyrimidineHCID 86682426(-)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline

Product 1

HCID 866824252-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolineYield 64%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 1.0 g (1.5 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 5 ml of N,N-dimethylformamide, 0.58 g (3.0 mmol) of 5-bromo-2-chloropyrimidine and 0.27 ml (1.8 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added, and the reaction solution was stirred at 100° C. for 3 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. 5% Ethyl acetate/n-hexane solution was added to the obtained residue and the precipitate was obtained by filtration to provide 0.78 g of 2-[1-(5-Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline as a white solid (yield: 64%).

Workup

  1. customAfter completion of the reaction
  2. extractionextracted with ethyl acetate
  3. washThe organic layer was washed with saturated sodium chloride aqueous solution
  4. dry with materialdried with anhydrous magnesium sulfate
  5. distillationthe solvent was distilled off under reduced pressure
  6. addition5% Ethyl acetate/n-hexane solution was added to the obtained residue
  7. customthe precipitate was obtained by filtration

Sources & evidence

ORD record
ord-768824469a3d451ea52ef1f23afdb7bc
Source dataset
uspto-grants-2015_11
Patent number
US09187450B2

Reaction notes

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