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 2234338ノート

反応式

HRID 2234338 の反応式
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

参加物

7

反応物 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 回HCID 686848474-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide2 回

生成物 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-benzamide収率 11%

試薬・触媒・溶媒 2

HCID 9897284tris(dibenzylideneacetone) palladium (II)触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
110 °C

実験手順

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%).

後処理

  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

出典と根拠

ORDレコード
ord-8cf1b0615afb4667a429a67de073bf7f
出典データセット
uspto-grants-2010_05
特許番号
US07709471B2

反応ノート

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