Diisopropylethylamine → 1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

HRID 1507283Notes

Reaction equation

[F:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[F:14])[CH:5]=[CH:4][C:3]=1[OH:15].C(N(C(C)C)CC)(C)C.CS(O[C@H:30]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:31]1=[O:43])(=O)=O.CO.ClCCl>C(#N)C.C(=O)(O)[O-].[Na+]>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][N:32]2[CH2:33][CH2:34][CH:30]([N:11]3[CH2:12][CH2:13][C@@H:8]([C:6]4[CH:5]=[CH:4][C:3]([OH:15])=[C:2]([F:1])[CH:7]=4)[C@H:9]([F:14])[CH2:10]3)[C:31]2=[O:43])=[CH:41][CH:40]=1

Participants

Conditions

Temperature: 60 °C

Procedure

To a solution of 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (1.0 g, 4.7 mmol, from example 114, step E) in acetonitrile (25 mL) was added diisopropylethylamine (2.5 mL, 14 mmol) and it was heated to 60° C. for 30 min. To this preheated mixture was then added (S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.710 g, 5.63 mmol, from step C) in acetonitrile (15 mL). The reaction mixture was heated at 90° C. for 16 h. The reaction was diluted with sat. aqueous sodium bicarbonate and extracted with EtOAc. The organic layers were combined and concentrated to a black oil. The oil was purified using silica gel column chromatography (20-100% EtOAc/hexanes then 0-20% MeOH/dichloromethane) to afford 1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (752 mg, 38% yield). Chiral HPLC analysis revealed that the final product was a (3:1) mixture of diasteromers, due to partial epimerization. The diastereomeric mixture (750 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=35% methanol in CO2, 150 bar; temp=35° C.; flow rate=40 mL/min; injection volumn=0.75 mL (˜42 mg/mL in MeOH) stacked intervals; λ=220 nM; Peak 1=5.5 min, Peak 2=7.9 min) to afford the titled compound (482 mg) of Example 116 (the second peak to elute). Data for Example 116: LC-MS m/z 421 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.17-7.03 (m, 1H), 6.88 (s, 2H), 4.78-4.46 (m, 1H), 4.38 (d, J=11.5 Hz, 2H), 3.70-3.48 (m, 1H), 3.45-3.37 (m, 1H), 3.28-3.03 (m, 2H), 2.82-2.63 (m, 2H), 2.61-2.53 (m, 1H), 2.40-2.21 (m, 1H), 2.18-2.02 (m, 1H), 1.98-1.84 (m, 1H), 1.82-1.50 (m, 2H).

Workup

temperatureThe reaction mixture was heated at 90° C. for 16 h
extractionextracted with EtOAc
concentrationconcentrated to a black oil
customThe oil was purified

Sources & evidence

ORD record: ord-d0c788d0d6854340ba1858a31166b6ba
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09221796B2

Reaction notes

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