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

HRID 715895Notes

Reaction equation

HRID 715895 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:23]([CH:24]([F:35])[C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[C:22]([CH:36]4[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38][CH2:37]4)[C:21]4[CH:20]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=5)[CH2:19][C:18]([CH3:55])([CH3:54])[CH2:17][C:16]=4[N:15]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1.C(O[Na])(C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)(C)(C)C>[F:42][C:39]1([F:43])[CH2:40][CH2:41][CH:36]([C:22]2[C:21]3[CH:20]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=4)[CH2:19][C:18]([CH3:54])([CH3:55])[CH2:17][C:16]=3[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:5]4[N:4]=[CH:3][C:2]([N:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)=[CH:7][N:6]=4)[CH2:13][CH2:12]3)[C:23]=2[CH:24]([F:35])[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)[CH2:37][CH2:38]1

Participants

9

Reactant 4

HCID 8083MorpholineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 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-tetrahydroquinolineHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 866824274-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolineYield 84%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 6386tert-ButanolSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 5.09 g (6.12 mmol) 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, which was prepared by a method similar to that of Reference Example 11, in 50 ml of toluene, 10 ml of tert-butanol, 1.6 ml (18 mmol) of morpholine, 1.73 g (18.0 mmol) of tert-butoxy sodium, 437 mg (0.917 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and 107 mg (0.477 mmol) of palladium acetate were added under an argon gas atmosphere, and the reaction solution was stirred at 110° C. for 2.8 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 then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=8/2-7/3-6/4 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 4.30 g of the title compound as a white solid (yield: 84%).

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. distillationthe solvent was distilled off under reduced pressure
  5. concentrationwas concentrated under reduced pressure

Sources & evidence

ORD record
ord-f8fa920c4aab4ce1a64c91b5d5d2fe9c
Source dataset
uspto-grants-2015_11
Patent number
US09187450B2

Reaction notes

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