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

HRID 632611Notes

Reaction equation

[F:1][C:2]1([F:48])[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][NH:33][CH2:32][CH2:31]3)[C:9]=2[C@@H: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.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]2)=[CH:52][N:51]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCCC(O)CCC>CCCCCC.C(OCC)(=O)C.O>[F:48][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: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[CH2:35][CH2:34][N:33]([C:50]4[N:51]=[CH:52][C:53]([O:56][CH2:57][CH:58]5[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]5)=[CH:54][N:55]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1

Participants

Conditions

Temperature: 150 °C

Procedure

To 6.02 g (8.92 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-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, 2.16 g (8.35 mmol) of 2-chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 20, and 6.06 g (18.6 mmol) of cesium carbonate, 30 ml of 4-heptanol was added, and the reaction mixture was stirred at 150° C. for 8 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate three times. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Reaction and aftertreatment similar to those described above were further performed using 2.00 g (2.96 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, 0.72 g (2.78 mmol) of 2-chloro-5-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine and 2.02 g (5.73 mmol) of cesium carbonate. The obtained residues were combined and subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-70/30 (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 7.35 g of the title compound as a white solid (yield: 74%).

Workup

additionwas added
customAfter completion of the reaction
extractionextracted with ethyl acetate three times
washwashed with saturated sodium chloride aqueous solution
dry with materialdried with anhydrous sodium sulfate
distillationthe solvent was distilled off under reduced pressure
customReaction and aftertreatment similar to

Sources & evidence

ORD record: ord-ff59cf60722c48ae9c4112d464b91488
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09321747B2

Reaction notes

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