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Cesium carbonate → 4-(9'-cyclopentyl-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 2234324
Notes
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Reaction equation

HRID 2234324 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]3([CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:22][C:23]1[C:39]([F:40])=[CH:38][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]2)=[O:28])=[C:25]([F:41])[CH:24]=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>O1CCOCC1>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:19][CH2:18]3)[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:39]([F:40])=[CH:38][C:26]([C:27]([NH:29][CH:30]5[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]5)=[O:28])=[C:25]([F:41])[CH:24]=4)=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 579699392-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1'-cyclopropan]-6(7H)-one2×HCID 686848474-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide2×

Product 1

HCID 68682626
4-(9'-cyclopentyl-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
Yield 55%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 100 mg, 0.33 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 102 mg, 0.36 mmol) and caesium carbonate (213 mg, 0.65 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. tris-dibenzylideneacetonedipalladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated at 110° C. overnight. The mixture was filtered, and the filtrate loaded onto to an SCX-3 cartridge (10 g) pre-wet with methanol, then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a light orange gum (99 mg, 55%).

Workup

  1. customthe suspension bubbled with nitrogen for 10 minutes
  2. filtrationThe mixture was filtered
  3. washwashed with methanol
  4. washeluted with ammonia in methanol
  5. additionProduct containing fractions
  6. customevaporated
  7. customthe resultant material purified by base modified reverse phase preparative HPLC

Sources & evidence

ORD record
ord-9621e82fe5a74498887eafb6a58f40d2
Source dataset
uspto-grants-2010_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07709471B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes