Potassium Carbonate → (1-{4-Difluoromethoxymethyl-2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 417683Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 417683
[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][CH:18]([F:20])[F:19])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:34][O:35][C:36](=[O:69])[NH:37][CH:38]([C:42]([N:44]1[CH2:48][CH2:47][CH2:46][CH:45]1[C:49]1[NH:50][C:51]([C:54]2[CH:59]=[CH:58][C:57](B3OC(C)(C)C(C)(C)O3)=[CH:56][CH:55]=2)=[CH:52][N:53]=1)=[O:43])[CH:39]([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([CH2:16][O:17][CH:18]([F:20])[F:19])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:57]3[CH:58]=[CH:59][C:54]([C:51]4[NH:50][C:49]([CH:45]5[CH2:46][CH2:47][CH2:48][N:44]5[C:42](=[O:43])[CH:38]([NH:37][C:36]([O:35][CH3:34])=[O:69])[CH:39]([CH3:41])[CH3:40])=[N:53][CH:52]=4)=[CH:55][CH:56]=3)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]

Komponenten

6

Edukt 3

HCID 11430Potassium CarbonateHCID 66619939[2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl esterHCID 66620824(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Produkt 1

HCID 66620796(1-{4-Difluoromethoxymethyl-2-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterAusbeute 30 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 80711,2-DimethoxyethaneLösungsmittel

Reaktionsbedingungen

Temperatur
85 °C

Versuchsvorschrift

(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (42 mg, 0.174 mmol), [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (95 mg, 0.191 mmol), Pd(PPh3)4 (20 mg, 0.0174 mmol) and K2CO3 (2M in H2O, 0.191 mL, 0.383 mmol) were combined in 1,2-dimethoxyethane (2 mL). The mixture was degassed with bubbling N2 for 12 min then heated to 85° C. for 4 h. After cooling to RT, the reaction mixture was diluted with EtOAc then washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by HPLC to provide the title compound (42 mg, 30%). MS (ESI) m/z 819 [M+H]+.

Aufarbeitung

  1. customThe mixture was degassed with bubbling N2 for 12 min
  2. temperatureAfter cooling to RT
  3. additionthe reaction mixture was diluted with EtOAc
  4. washthen washed with water and brine
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude residue was purified by HPLC

Quellen und Nachweise

ORD-Eintrag
ord-a41192cded9845bbb49fba8d41b6a84a
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08088368B2

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