Potassium Carbonate → 3-(Dipropylcarbamoyl)benzoic acid

HRID 1014868

Reaktionsgleichung

Reaktionsgleichung von HRID 1014868
F[C:2]1[CH:3]=C(C=C(F)[CH:27]=1)C[C@@H]([C@@H](C1COCCN1C(OC(C)(C)C)=O)O)C(O)=O.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:38]([NH:48][C:49](=[O:61])[C:50]1[CH:55]=[C:54](C)[CH:53]=[C:52]([C:57]([O:59]C)=[O:58])[CH:51]=1)[CH2:39][C:40]1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.BrC1C=C(C=C(C(OC)=O)C=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[CH2:27]([N:48]([CH2:38][CH2:39][CH3:40])[C:49]([C:50]1[CH:51]=[C:52]([CH:53]=[CH:54][CH:55]=1)[C:57]([OH:59])=[O:58])=[O:61])[CH2:2][CH3:3]

Komponenten

9

Edukt 5

HCID 11430Potassium CarbonateHCID 574072Trimethylboroxine3×HCID 67315749(2R,4R)-tert-butyl 2-((1S,2S)-2-(3-bromo-5-(methoxycarbonyl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67315777(2S,3S)-2-(3,5-difluorobenzyl)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-3-hydroxypropanoic acidHCID 67316204(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

Produkt 1

HCID 1827693-(Dipropylcarbamoyl)benzoic acidAusbeute 77 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

Step G (4): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-bromo-5-(methoxycarbonyl)benzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step G (3). 163 mg, 0.21 mmol) in DMF (10 mL) were added potassium carbonate (87 mg, 0.63 mmol), Pd(PPh3)4 (24 mg, 0.021 mmol), and trimethylboroxine (53 mg, 0.42 mmol) and the reaction mixture was stirred at 100° C. with sealed cap for 5 h. Then another portion of trimethylboroxine (53 mg, 0.42 mmol) was added and the reaction was stirred at 60° C. overnight. Another portion of trimethylboroxine (53 mg, 0.42 mmol) was added and the reaction was stirred at 100° C. for 6 h. Ethyl acetate (100 mL) was added and the mixture was washed with H2O and concentrated under vacuum. The crude mixture was purified by silica gel Flash Chromatography (0% to 5% to 10% to 15% EtOAc/Hexane step gradient) to give 110 mg of the title compound (77% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.85 (9H, s), 0.88 (3H, m), 1.45-1.52 (11H, m), 2.02-2.07 (1H, m), 2.20 (1H, d, J=15 Hz), 2.41 (3H, s), 2.66 (1H, dd, J=10, 15 Hz), 2.94 (1H, m), 3.28-3.37 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.90 (3H, s), 3.99 (1H, m), 4.07-4.13 (2H, m), 4.62 (1H, m), 6.59 (1H, m), 6.77 (1H, s), 6.79 (1H, s), 7.91 (1H, s), 7.94 (1H, s), 8.20 (1H, brd s), 8.34 (1H, s). MS (ESI) (M+H)+ 705.41.

Aufarbeitung

  1. customwith sealed
  2. customcap for 5 h
  3. stirringthe reaction was stirred at 60° C. overnight
  4. stirringthe reaction was stirred at 100° C. for 6 h
  5. washthe mixture was washed with H2O
  6. concentrationconcentrated under vacuum
  7. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 5% to 10% to 15% EtOAc/Hexane step gradient)

Quellen und Nachweise

ORD-Eintrag
ord-fd2a66bda81042b2acdbcb7b4a292529
Quelldatensatz
uspto-grants-2011_07
Patentnummer
US07981913B2

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