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

HRID 1507273Notes

Reaction equation

HRID 1507273 reaction equation
CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([F:20])[F:19])=[CH:14][CH:13]=2)[C:7]1=[O:21])(=O)=O.Cl.[F:23][C@H:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][CH:18]([F:20])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][CH:6]([N:26]3[CH2:27][CH2:28][C@@H:29]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[C@H:24]([F:23])[CH2:25]3)[C:7]2=[O:21])=[CH:13][CH:14]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 1182073504-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochlorideHCID 118207439(5)-1-(4-(Difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate

Product 1

HCID 1182072891-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-oneYield 35.8%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Conditions

Temperature
85 °C

Procedure

A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in 5.0 mL of acetonitrile was added dropwise over 1.5 h to a stirred mixture of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57 mmol, from example 46, step M) and N,N-diisopropylethylamine (1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After complete addition, the reaction mixture was stirred at 85° C. for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-100% EtOAc/hexanes) to afford a diasteromeric mixture of 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (235 mg, 35% yield) due to partial epimerization. A sample of the diastereomeric mixture (780 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20% methanol (with 15 mM ammonia)/80% CO2; temp=35° C.; flow rate=60 mL/min; injection volumn=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals; λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford 389 mg of Example 114, P-1 and 242 mg of Example 114, P-2. Data for Example 114, P-1: LC-MS m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)). The relative and absolute configuration of Example 114, P-1 was confirmed by single crystal X-ray analysis. Data for Example 114, P-2: LC-MS m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.87-6.81 (m, 2H), 6.65 (t, J=56.5 Hz, 1H), 4.95 (s, 1H), 4.74-4.42 (m, 3H), 3.66 (t, J=8.9 Hz, 1H), 3.28-3.15 (m, 3H), 3.07-2.99 (m, 1H), 2.72-2.58 (m, 2H), 2.49-2.40 (m, 1H), 2.20-2.12 (m, 1H), 2.04 (dq, J=13.0, 8.7 Hz, 1H), 1.93-1.87 (m, 2H).

Workup

  1. additionAfter complete addition
  2. concentrationThe resulting mixture was concentrated in vacuo
  3. customThe residue was purified
  4. customto afford

Sources & evidence

ORD record
ord-993a67d3cfcc42ec861db2bec3377e03
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

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