Sodium Hydroxide → 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine

HRID 602976Notes

Reaction equation

[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([CH3:13])(O)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.N1C=CC=CC=1.[FH:37].[OH-].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:10]([F:37])([CH3:13])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

Conditions

Temperature: 42 °C

Procedure

To a solution of 5.5 g (13.5 mmole) of (1S)-1-(3,5-difluorophenyl)-1-[1-(diphenylmethyl) azetidin-3-yl]-2-methylpropan-2-ol in 25 mL of CH2Cl2 was added 15 mL of hydrogen fluoride-pyridine and the two-phase mixture was stirred for 15 h at 42° C. Then the reaction mixture was poured to 100 mL of 5N NaOH, 20 mL of aq NaHCO3, 150 mL of CH2Cl2 and 100 mL ice. The pH was adjusted to 8-9 with 2N NaOH. The water layer was extracted with CH2Cl2 (3×1500 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane to afford the title compound as a white solid; 1H-NMR (CDCl3) δ 1.25 ( t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.09-3.11 (m, 2H), 3.60 (m, 1H), 4.30 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 10H); Mass Spectrum: m/e=410 (M+1)

Workup

extractionThe water layer was extracted with CH2Cl2 (3×1500 mL)
dry with materialThe combined organic layer was dried over Na2SO4
concentrationconcentrated
customThe residue was purified by silica gel chromatography with 10% methyl tert-butyl ether-hexane

Sources & evidence

ORD record: ord-9eca65054af14bc5a4c7ee5961e31963
Source dataset: uspto-grants-2011_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07906652B2

Reaction notes

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