(S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide → (2s)-2-[(3r)-3-(Acetylamino)-3-(2-Methylpropyl)-2-Oxopyrrolidin-1-Yl]-N-{(1r,2s)-3-(3,5-Difluorophenyl)-1-Hydroxy-1-[(2r,4r)-4-Propoxypyrrolidin-2-Yl]propan-2-Yl}-4-Phenylbutanamide

HRID 132949Notes

Reaction equation

HRID 132949 reaction equation
COC1C=CC(C[N:8]2[CH2:12][C@H:11]([O:13][CH2:14][CH:15]=[CH2:16])[CH2:10][C@@H:9]2[C@@H:17]([OH:54])[C@@H:18]([NH:28][C:29](=[O:53])[C@@H:30]([N:39]2[CH2:43][CH2:42][C@:41]([NH:48][C:49](=[O:51])[CH3:50])([CH2:44][CH:45]([CH3:47])[CH3:46])[C:40]2=[O:52])[CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:49]([NH:48][C@:41]1([CH2:44][CH:45]([CH3:46])[CH3:47])[CH2:42][CH2:43][N:39]([C@@H:30]([CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:29]([NH:28][C@@H:18]([CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[C@H:17]([OH:54])[C@H:9]2[CH2:10][C@@H:11]([O:13][CH2:14][CH2:15][CH3:16])[CH2:12][NH:8]2)=[O:53])[C:40]1=[O:52])(=[O:51])[CH3:50]

Participants

4

Reactant 1

HCID 69195642(S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide

Product 1

HCID 11578322(2s)-2-[(3r)-3-(Acetylamino)-3-(2-Methylpropyl)-2-Oxopyrrolidin-1-Yl]-N-{(1r,2s)-3-(3,5-Difluorophenyl)-1-Hydroxy-1-[(2r,4r)-4-Propoxypyrrolidin-2-Yl]propan-2-Yl}-4-PhenylbutanamideYield 64.1%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 887MethanolSolvent

Procedure

Step 1 (B): Preparation of(S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide. To a solution of (S)-N-((1S,2S)-1-((2R,4R)-1-(4-methoxybenzyl)-4-(allyloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-4-phenylbutanamide (Step 1 (A), 55 mg, 0.071 mmol) in MeOH (5 ml) was added a catalytic amount of Pd(OH)2. The reaction mixture was stirred under 1 atm. of H2 for 18 h. The mix was then filtered through Celite and concentrated in vacuo. Flash chromatography (silica gel, 0-30% methanol/chloroform) gave 29.9 mg (64%) of (S)-2-((R)-3-acetamido-3-isobutyl-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide, the title compound of Example 1 as an opaque glass: 1H NMR (CDCl3, 500 MHz) δ 0.88 (3H, t, J=7.5 Hz), 1.00 (6H, dd, J=5, 7.5 Hz), 1.54 (3H, q, J=5 Hz), 1.69 (1H, dd, J=5, 15 Hz), 1.85 (1H, m), 1.92-1.97 (1H, m), 1.99 (3H, s), 2.11-2.17 (3H, m), 2.36-2.48 (3H, m), 2.52-2.57 (1H, m), 2.72 (1H, dd, J=10, 15 Hz), 2.92 (1H, dd, J=5, 15 Hz), 3.12-3.19 (3H, m), 3.29-3.42 (4H, m), 3.62 (1H, dd, J=5, 10 Hz), 3.98 (1H, m), 4.09-4.15 (1H, m), 4.63 (2H, brd s), 6.06 (1H, s), 6.52 (1H, m), 6.84 (2H, d, J=5 Hz), 7.10 (2H, d, J=5 Hz), 7.15 (1H, t, J=7.5 Hz), 7.24 (2H, t, J=7.5 Hz), 7.54 (1H, d, J=10 Hz). HPLC retention time: 1.69 min (method A). MS (ESI) (M+H)+ 657.38.

Workup

  1. filtrationThe mix was then filtered through Celite
  2. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-ed016ad4195041debe3500ac941f9a5a
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

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