Dabco → N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide

HRID 20958

Reaktionsgleichung

Reaktionsgleichung von HRID 20958
C([O:4][C@H:5]1[CH2:9][N:8](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:7]([C@@H:23]([OH:52])[C@@H:24]([NH:34][C:35](=[O:51])[C:36]2[CH:50]=[CH:49][CH:48]=[C:38]([C:39]([N:41]([CH2:45][CH2:46][CH3:47])[CH2:42]CC)=[O:40])[CH:37]=2)[CH2:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)[CH2:6]1)C=C.C(OC([C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](O)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.[CH2:95](O[C@H]1CN(C(OC(C)(C)C)=O)[C@@H]([C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](C(OCC2C=CC=CC=2)=O)CC2C=C(F)C=C(F)C=2)C1)C=C.C1N2CCN(CC2)C1.[OH-].[Na+].[O-][Mn](=O)(=O)=O.[K+]>O.CCO.CCOC(C)=O.CCCCCC.CO>[CH2:45]([N:41]([CH3:42])[C:39](=[O:40])[C:38]1[CH:48]=[CH:49][CH:50]=[C:36]([C:35]([NH:34][C@@H:24]([CH2:25][C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)[C@H:23]([OH:52])[C@H:7]2[CH2:6][C:5]([OH:4])([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:9][NH:8]2)=[O:51])[CH:37]=1)[CH2:46][CH2:47][CH3:95]

Komponenten

10

Edukt 6

HCID 9237DabcoHCID 14798Sodium HydroxideHCID 516875Potassium PermanganateHCID 67316089(2R,4R)-tert-butyl 2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylateHCID 67316571(2R,4R)-tert-butyl 4-(allyloxy)-2-((1S,2S)-2-(benzyloxycarbonyl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)pyrrolidine-1-carboxylateHCID 68497616N1-((1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide

Produkt 1

HCID 11848528N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamideAusbeute 77 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 887MethanolLösungsmittelHCID 19096565Water ethanolLösungsmittelHCID 21226206Ethyl acetate hexaneLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

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.

Aufarbeitung

  1. temperaturecooled to rt
  2. stirringThe reaction mixture was stirred at rt for 1.5 h
  3. customquenched with H2O
  4. extractionThe mixture was extracted with ethyl acetate (300 mL) twice
  5. customsolvent was removed

Quellen und Nachweise

ORD-Eintrag
ord-719388049b5449748b24e4fb5551634a
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07745470B2

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