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,4S)-4-(pyridin-2-yloxy)pyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamide

HRID 132954Notes

Reaction equation

HRID 132954 reaction equation
N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@H](OC2C=CC=CC=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][N:50]=2)[CH2:45][N:44]1C(C1C=CC=CC=1)C1C=CC=CC=1)[OH:42].[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[C:87](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:88])[C:82]1=[O:129])(=[O:79])[CH3:78].[Li+].[OH-]>CCO.O.CO.C(Cl)(Cl)Cl>[C:77]([NH:80][C@:81]1([C@@H:130]([CH2:132][CH3:133])[CH3:131])[CH2:85][CH2:84][N:83]([C@@H:86]([CH2:121][CH2:122][C:123]2[CH:124]=[CH:125][CH:126]=[CH:127][CH:128]=2)[C:87]([NH:39][C@@H:40]([CH2:68][C:69]2[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=2)[C@H:41]([OH:42])[C@H:43]2[CH2:47][C@H:46]([O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)[CH2:45][NH:44]2)=[O:88])[C:82]1=[O:129])(=[O:79])[CH3:78]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 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 69195403(1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-olHCID 69195486(1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-phenoxypyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol

Product 1

HCID 69196428(S)-2-((S)-3-acetamido-3-((R)-sec-butyl)-2-oxopyrrolidin-1-yl)-N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4S)-4-(pyridin-2-yloxy)pyrrolidin-2-yl)propan-2-yl)-4-phenylbutanamideYield 61%

Reagents, catalysts & solvents 3

HCID 702EthanolSolventHCID 962WaterSolventHCID 21584188Chloroform methanolSolvent

Procedure

Step 10 (B): (1S,2S)-2-amino-1-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)-3-(3,5-difluorophenyl)propan-1-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-(pyridin-2-yloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step 10 (A), 50 mg, 0.092 mmol) in EtOH (5 mL) was added a solution of LiOH (44 mg, 1.84 mmol) in H2O (1.5 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 29.0 mg (61% yield) of the title compound: 1H NMR (CDCl3, 300 MHz) δ 2.03-2.11 (2H, m), 2.23-2.42 (2H, m), 2.69 (2H, s), 2.92-2.97 (2H, m), 3.48 (1H, dd, J=3, 12 Hz), 3.73 (1H, m), 5.07 (1H, s), 5.44 (1H, s), 6.61-6.68 (4H, m), 6.82 (1H, m), 7.12-7.29 (6H, m), 7.32-7.44 (4H, m), 7.54 (1H, m), 8.06 (1H, dd, J=3, 6 Hz). HPLC retention time: 1.54 min (method C). MS (ESI) (M+H)+ 516.35.

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-fe25c4ffaa0141eb85623e726668cbe8
Source dataset
uspto-grants-2008_06
Patent number
US07388007B2

Reaction notes

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