Potassium Carbonate → 4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester

HRID 417667Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 417667
[CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63](Br)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([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>[C:39]([O:43][C:44]([N:46]1[CH2:50][CH:49]([C:51]#[N:52])[CH2:48][CH:47]1[C:53]1[NH:54][C:55]([C:58]2[CH:67]=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63]([C:26]4[CH:25]=[CH:24][C:23]([C:20]5[NH:19][C:18]([CH:17]6[CH2:16][C:13]7([CH2:14][CH2:15]7)[CH2:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=5)=[CH:28][CH:27]=4)[CH:64]=3)[CH:59]=2)=[CH:56][N:57]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40]

Komponenten

6

Edukt 3

HCID 11430Potassium CarbonateHCID 66620446[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl esterHCID 666210142-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester

Produkt 1

HCID 666211324-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl esterAusbeute 51 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418397HCID 178418397, VerbindungKatalysatorHCID 80711,2-DimethoxyethaneLösungsmittel

Versuchsvorschrift

[2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (997 mg, 1.91 mmol), 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester, Pd(PPh3)4 (184 mg, 0.159 mmol), and K2CO3 (2 M in H2O, 1.9 mL, 3.8 mmol) were combined in 1,2-dimethoxyethane (16 mL). The reaction mixture was degassed with bubbling N2 for 10 minutes then heated to reflux for 3.5 h. After heating, the reaction mixture was cooled to RT, diluted with EtOAc and washed with H2O and brine. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc to afford the title compound (641 mg, 51%).

Aufarbeitung

  1. customThe reaction mixture was degassed with bubbling N2 for 10 minutes
  2. temperaturethen heated
  3. temperatureto reflux for 3.5 h
  4. temperatureAfter heating
  5. additiondiluted with EtOAc
  6. washwashed with H2O and brine
  7. dry with materialThe organic phase was dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe resulting residue was purified with silica column chromatography 0% to 100% (10% MeOH/DCM)/EtOAc

Quellen und Nachweise

ORD-Eintrag
ord-efd55b8ae095443b9b4093e3d0749e11
Quelldatensatz
uspto-grants-2012_01
Patentnummer
US08088368B2

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