Reaction #49236

ord-719388049b5449748b24e4fb5551634a

Reaction equation

[K+].[O]=[Mn](=[O])(=[O])[O-]
KMnO4
[Na+].[OH-]
NaOH
C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)N(C(c2ccccc2)c2ccccc2)C1
( A )
C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)N(C(c2ccccc2)c2ccccc2)C1
N1-((1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide
CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)C(=O)OCc1ccccc1
(2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate
C=CCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
(2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylate
C1CN2CCN1CC2
DABCO
→
CCCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CC(O)(c3ccccc3)CN2)c1
title compound
Yield 77.0%
CCCCN(C)C(=O)c1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CC(O)(c3ccccc3)CN2)c1
N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide
Yield 77.0%

Reactants

[K+].[O]=[Mn](=[O])(=[O])[O-]
KMnO4
[Na+].[OH-]
NaOH
C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)N(C(c2ccccc2)c2ccccc2)C1
( A )
C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)N(C(c2ccccc2)c2ccccc2)C1
N1-((1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide
CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1cc(F)cc(F)c1)C(=O)OCc1ccccc1
(2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate
—
RhCl(PPh3)3
C=CCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
(2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylate
C1CN2CCN1CC2
DABCO

Reagents

None

Solvents

CO
MeOH
CCCCCC.CCOC(C)=O
EtOAc Hexane
CCO.O
H2O EtOH

Conditions

Temperature
140°CELSIUS
Detailed conditions
See reaction.notes.procedure_details.

Workup

  1. 1
    Temperaturecooled to rt
  2. 2
    workup.STIRRINGThe reaction mixture was stirred at rt for 1.5 h
  3. 3
    Otherquenched with H2O
  4. 4
    ExtractionThe mixture was extracted with ethyl acetate (300 mL) twice
  5. 5
    Othersolvent was removed

Procedure

Step 6 (A): (2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylate (Preparation A, 730 mg, 1.11 mmol) in H2O/EtOH (0.8/7 mL) were added RhCl(PPh3)3 (77 mg, 0.083 mmol) and DABCO (25 mg, 0.22 mmol). The mixture was stirred at 140° C. for 3 h and then cooled to rt. MeOH (20 mL) and 1N NaOH solution (5 mL) were added followed by 0.1% KMnO4 solution (5 mL) dropwise. The reaction mixture was stirred at rt for 1.5 h and quenched with H2O. The mixture was extracted with ethyl acetate (300 mL) twice and solvent was removed. Flash chromatography (silica gel, 0% to 10% to 20% to 35% EtOAc/Hexane step gradient) gave the title compound (530 mg, 77% yield): 1H NMR (CDCl3, 500 MHz) δ 0.10-0.13 (6H, m), 0.93 (9H, s), 1.22-1.27 (2H, m), 1.46 (9H, s), 2.13 (2H, s), 3.23-3.25 (2H, m), 3.54-3.89 (2H, m), 4.12 (1H, m), 4.22 (1H, s), 4.32 (1H, m), 4.86-5.03 (3H, m), 6.60-6.70 (3H, m), 7.17 (2H, s), 7.27-7.28 (3H, m). MS (ESI) (M+H)+ 621.25.

Source

DOI: 10.6084/m9.figshare.5104873.v1Patent: US07745470B2uspto-grants-2010_06