Methanesulfonyl chloride → 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

HRID 715901Notes

Reaction equation

HRID 715901 reaction equation
[F:1][C:2]1([F:56])[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][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH:57](N(C(C)C)CC)(C)[CH3:58].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[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]([CH2:42][O:43][CH2:57][CH3:58])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1

Participants

7

Reactant 4

HCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 86682431HCID 86682431, compound

Product 1

HCID 866824354-(4,4-Difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinolineYield 85%

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of 78 mg (0.10 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, in 2 ml of dichloromethane, 340 μl (2.0 mmol) of diisopropylethylamine and 77 μl (1.0 mmol) of methanesulfonyl chloride were added, and 2 ml of ethanol was added thereto immediately after initiation of stirring at room temperature and the reaction solution was further stirred at room temperature for 0.25 hour. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution 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=98/2-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 68 mg of the title compound as a foam (yield: 85%).

Workup

  1. stirringthe reaction solution was further stirred at room temperature for 0.25 hour
  2. customAfter completion of the reaction
  3. extractionextracted with ethyl acetate
  4. washThe organic layer was washed with saturated sodium chloride aqueous solution
  5. dry with materialdried with anhydrous magnesium sulfate
  6. distillationthe solvent was distilled off under reduced pressure
  7. concentrationwas concentrated under reduced pressure

Sources & evidence

ORD record
ord-cfabff5cbccc4ff681aa96b976351b49
Source dataset
uspto-grants-2015_11
Patent number
US09187450B2

Reaction notes

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