Water → 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 1014882

Reaktionsgleichung

Reaktionsgleichung von HRID 1014882
[Si]([O:8][C@H:9]([C@H:39]1[CH2:43][C@@H:42]([O:44]CCC)[CH2:41][N:40]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34]CC[C@@H:31]2[CH2:35]OC)=[O:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[C:55]1([Mg]Br)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[OH2:63].[CH2:64]1COC[CH2:65]1>>[CH2:31]([N:30]([CH3:34])[C:28](=[O:29])[C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([NH:20][C@@H:10]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C@H:9]([OH:8])[C@H:39]2[CH2:43][C:42]([OH:44])([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH2:41][NH:40]2)=[O:63])[CH:23]=1)[CH2:35][CH2:64][CH3:65]

Komponenten

5

Edukt 4

HCID 962WaterHCID 8028TetrahydrofuranHCID 67316242(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 178418255HCID 178418255, Verbindung3×

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 42 %

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

Step 6 (E): Preparation of (2R)-tent-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxy-4-phenylpyrrolidine-1-carboxylate. To a solution of (R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-oxopyrrolidine-1-carboxylate (Step 6 (D), 25 mg, 0.036 mmol) in THF (1 mL) was added phenylmagnesium bromide (3.0 M in diethyl ether, 0.0144 mL, 0.0432 mmol) at −20° C. After stirring for 20 min, the reaction mixture was warmed up to 0° C. and stirred for 30 min and another portion of phenylmagnesium bromide (3.0 M in diethyl ether, 0.0144 mL, 0.0432 mmol) was added and the reaction mixture was stirred at rt for 2 h. Another portion of phenylmagnesium bromide (3.0 M in diethyl ether, 0.024 mL, 0.072 mmol) was added and the reaction mixture was stirred at rt for 2 days. H2O (50 mL) was added and the mixture was extracted with ethyl acetate, dried (Na2SO4) and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient) to give 12 mg of the title compound (42% yield): 1H NMR (CDCl3, 500 MHz) δ 0.15 (3H, s), 0.20 (3H, s), 0.72-0.79 (1H, m), 0.86 (1H, m), 0.96 (9H, s), 1.08-1.11 (1H, m), 1.45 (9H, s), 1.58-1.62 (1H, m), 1.77 (3H, s), 2.52 (2H, d, J=5 Hz), 2.63 (1H, m), 2.87-3.04 (3H, m), 3.16 (1H, brd s), 3.28 (1H, d, J=10 Hz), 3.51 (1H, brd s), 3.66 (1H, d, J=15 Hz), 3.78 (1H, d, J=10 Hz), 3.95 (1H, m), 4.30 (1H, s), 4.56 (2H, s), 6.59 (1H, t, J=10 Hz), 6.78 (2H, d, J=5 Hz), 7.14 (1H, m), 7.24-7.27 (1H, m), 7.34 (2H, m), 7.39 (1H, m), 7.46-7.50 (3H, m), 7.68 (2H, m). MS (ESI) (M+H)+ 780.49.

Aufarbeitung

  1. stirringstirred for 30 min
  2. stirringthe reaction mixture was stirred at rt for 2 h
  3. stirringthe reaction mixture was stirred at rt for 2 days
  4. extractionthe mixture was extracted with ethyl acetate
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% EtOAc/Hexane step gradient)

Quellen und Nachweise

ORD-Eintrag
ord-eea3e1c85d1d4b5985bfea75af4b5186
Quelldatensatz
uspto-grants-2011_07
Patentnummer
US07981913B2

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