Hydrochloric Acid → (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

HRID 632609Notes

Reaction equation

HRID 632609 reaction equation
[F:1][C:2]1([F:65])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18]CC4C=CC(OC)=CC=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]([O:42][CH2:43][C:44]5([CH3:52])[CH2:49][O:48]C(C)(C)[O:46][CH2:45]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:4][CH2:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:65][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[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]([O:42][CH2:43][C:44]([CH2:49][OH:48])([CH3:52])[CH2:45][OH:46])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:61])([F:63])[F:62])=[CH:56][CH:55]=2)[CH2:6][CH2:7]1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 516892Sodium BicarbonateHCID 89524013(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline

Product 1

HCID 71656789(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-olYield 72%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 375 mg (0.411 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 18, in 5 ml of 1,4-dioxane, 1 ml of 6 N hydrochloric acid was added, and the reaction mixture was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate twice. 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=50/50-25/75 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Heptane was added to the obtained residue, and the precipitate was obtained by filtration to provide 221 mg of the title compound as a white solid (yield: 72%).

Workup

  1. customAfter completion of the reaction
  2. extractionextracted with ethyl acetate twice
  3. washwashed with saturated sodium chloride aqueous solution
  4. distillationthe solvent was distilled off under reduced pressure
  5. concentrationwas concentrated under reduced pressure
  6. additionn-Heptane was added to the obtained residue
  7. customthe precipitate was obtained by filtration

Sources & evidence

ORD record
ord-3cfa57e9ef42414b871368d88f206a7d
Source dataset
uspto-grants-2016_04
Patent number
US09321747B2

Reaction notes

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