Lithium Hydroxide → (S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-phenoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

HRID 132956Notes

Reaction equation

HRID 132956 reaction equation
N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CN=2)CN1C(C1C=CC=CC=1)C1C=CC=CC=1)O.[NH2:39][C@@H:40]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@@H:41]([C@H:43]1[CH2:47][C@@H:46]([O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:45][N:44]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:42].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OC3C=CC=CC=3)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[C:117]([NH:120][C@:121]1([C@@H:170]([CH2:172][CH3:173])[CH3:171])[CH2:125][CH2:124][N:123]([C@@H:126]([CH2:161][CH2:162][C:163]2[CH:168]=[CH:167][CH:166]=[CH:165][CH:164]=2)[C:127](N[C@@H](CC2C=C(F)C=C(F)C=2)[C@@H]([C@H]2CCCCN2C(C2C=CC=CC=2)C2C=CC=CC=2)O)=[O:128])[C:122]1=[O:169])(=[O:119])[CH3:118].[Li+].[OH-]>CCO.O>[C:117]([NH:120][C@:121]1([C@@H:170]([CH2:172][CH3:173])[CH3:171])[CH2:125][CH2:124][N:123]([C@@H:126]([CH2:161][CH2:162][C:163]2[CH:164]=[CH:165][CH:166]=[CH:167][CH:168]=2)[C:127]([NH:39][C@@H:40]([CH2:68][C:69]2[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=2)[C@H:41]([OH:42])[C@H:43]2[CH2:47][C@@H:46]([O:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:45][NH:44]2)=[O:128])[C:122]1=[O:169])(=[O:119])[CH3:118]

Participants

8

Reactant 5

HCID 3939Lithium HydroxideHCID 69193954(4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)oxazolidin-2-oneHCID 69194179(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1S,2S)-1-((R)-1-benzhydrylpiperidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-4-phenylbutanamideHCID 69194468(1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-olHCID 69195403(1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol

Product 1

HCID 69195625(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-phenoxypyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 962WaterSolvent

Procedure

Step 11 (B): (1S,2S)-2-amino-1-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)oxazolidin-2-one (Step 11 (A), (34.7 mg, 0.064 mmol) in EtOH (3 mL) was added a solution of LiOH (31 mg, 1.28 mmol) in H2O (0.75 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 0-10% MeOH/chloroform) gave 29 mg of the title compound: 1H NMR (CDCl3, 300 MHz) δ 2.16-2.29 (2H, m), 2.49-2.59 (2H, m), 2.78-3.42 (8H, m), 4.68 (1H, s), 4.95 (1H, s), 6.63-6.74 (3H, m), 6.88-6.93 (2H, m), 6.95-6.98 (1H, m), 7.09-7.36 (11H, m), 7.46-7.48 (1H, m). HPLC retention time: 1.59 min (method A). MS (ESI) (M+H)+ 515.19.

Workup

  1. temperatureat reflux for 4 h
  2. concentrationthe mixture was concentrated
  3. customto remove EtOH and H2O
  4. additionwas added
  5. extractionThe mixture was extracted with ethyl acetate
  6. washthe organic phase was washed with sat. aqueous NaCl
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-799d186e6a9d4342bdd56edd56ef16d2
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

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