Cesium carbonate → 4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide

HRID 2234338Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 2234338
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:40]([F:41])=[CH:39][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:42])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:40]([F:41])=[CH:39][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]5)=[O:29])=[C:26]([F:42])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 579698842'-chloro-9'-cyclohexyl-5'-methyl-8',9'-dihydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepin]-6'(5'H)-one2×HCID 686848474-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide2×

Produkt 1

HCID 686845534-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamideAusbeute 11 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9897284tris(dibenzylideneacetone) palladium (II)KatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 100 mg, 0.31 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 98 mg, 0.34 mmol) and caesium carbonate (204 mg, 0.62 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) added and the mixture heated at 110° C. overnight. The mixture was filtered and the filtrate loaded onto an SCX-3 column was pre-wet with methanol and the column washed with methanol and eluted with 2% 7N ammonia/methanol. The ammoniacal fraction was evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white crystalline solid (19 mg, 11%).

Aufarbeitung

  1. customthe suspension bubbled with nitrogen for 10 minutes
  2. filtrationThe mixture was filtered
  3. washthe column washed with methanol
  4. washeluted with 2% 7N ammonia/methanol
  5. customThe ammoniacal fraction was evaporated
  6. customthe residue purified by base modified reverse phase preparative HPLC

Quellen und Nachweise

ORD-Eintrag
ord-8cf1b0615afb4667a429a67de073bf7f
Quelldatensatz
uspto-grants-2010_05
Patentnummer
US07709471B2

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