Dimethylformamide → [2-(4-{(S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl]pyrimidine-5-oxy}-2-methylbutan-2-ol

HRID 632606Notes

Reaction equation

HRID 632606 reaction equation
[F:1][C:2]1([F:55])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H: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][N:33]([C:36]4[N:41]=[CH:40][C:39]([OH:42])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[CH2:4][CH2:3]1.C1(C)C(S(O[CH2:66][CH2:67][C:68]([OH:71])([CH3:70])[CH3:69])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[F:55][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H: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[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH2:69][C:68]([CH3:70])([OH:71])[CH2:67][CH3:66])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[C@@H:43]([F:54])[C:44]2[CH:45]=[CH:46][C:47]([C:50]([F:52])([F:51])[F:53])=[CH:48][CH:49]=2)[CH2:4][CH2:3]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 89683078HCID 89683078, compoundHCID 1176879053-Hydroxy-3-methylbutyl toluenesulfonate

Product 1

HCID 131735438[2-(4-{(S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl]pyrimidine-5-oxy}-2-methylbutan-2-olYield 72%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To 570 mg (0.741 mmol) of 2-[4-((5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-2-yl)piperidin-1-yl]pyrimidin-5-ol, which was prepared by a method similar to that of Reference Example 14, 288 mg (1.11 mmol) of 3-hydroxy-3-methylbutyl toluenesulfonate and 198 mg (1.43 mmol) of potassium carbonate, 2 ml of N,N-dimethylformamide was added, and the reaction mixture was stirred at 80° C. for 2.8 hours. After completion of the reaction, toluene and water were added to the reaction solution to separate an organic phase. Further, the reaction mixture was extracted with toluene from the aqueous phase. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=78/22-50/50 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, then n-heptane was added thereto, and the precipitate was obtained by filtration to provide 455 mg of the title compound as a white solid (yield: 72%).

Workup

  1. additionwas added
  2. additionwere added to the reaction solution
  3. customto separate an organic phase
  4. extractionFurther, the reaction mixture was extracted with toluene from the aqueous phase
  5. washwashed with saturated sodium chloride aqueous solution
  6. distillationthe solvent was distilled off under reduced pressure
  7. concentrationwas concentrated under reduced pressure
  8. dissolutionThe obtained residue was dissolved in ethyl acetate
  9. additionn-heptane was added
  10. customthe precipitate was obtained by filtration

Sources & evidence

ORD record
ord-8f9c4141d3854f0d8219ffa8ecd281e1
Source dataset
uspto-grants-2016_04
Patent number
US09321747B2

Reaction notes

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