Cesium carbonate → 3-chloro-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-(2-dimethylaminoethyl)benzamide

HRID 2234323Notes

Reaction equation

HRID 2234323 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[CH:36]=[CH:35][C:26]([C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28])=[CH:25][C:24]=1[Cl:37].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.C(Cl)Cl>[Cl:37][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:23]=1[NH:22][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[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1)[C:27]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])=[O:28]

Participants

7

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 597636804-amino-3-chloro-N-(2-dimethylaminoethyl)benzamide2×

Product 1

HCID 686830583-chloro-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-(2-dimethylaminoethyl)benzamideYield 4.1%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °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) and 4-amino-3-chloro-N-(2-dimethylaminoethyl)benzamide (Intermediate 213; 89 mg, 0.37 mmol) were dissolved in 1,4 dioxane (4 mL) and caesium carbonate (234 mg, 0.72 mmol) was added. The reaction mixture was sparged with nitrogen for 15 minutes prior to addition of tris-dibenzylideneacetone dipalladium (II) (19 mg, 0.02 mmol) followed by XANTPHOS (19 mg, 0.03 mmol). The reaction mixture was heated at 100° C. overnight, cooled to room temperature and diluted with DCM (20 mL). The resultant mixture was filtered and the filtrate loaded onto an SCX-3 (5 g) cartridge. The cartridge was washed through with methanol (50 mL) and then eluted with 2M ammonia in methanol (50 mL). Evaporation of the ammoniacal fraction afforded an amber gum which was purified by acid modified reverse phase preparative HPLC. The resultant material was dissolved in MeOH/Water and poured onto an SCX-3 cartridge (2 g) and cartridge which was then washed with methanol and eluted with 2M ammonia in methanol, and the ammoniacal solution evaporated to yield the title compound as a solid (7 mg, 3%).

Workup

  1. customThe reaction mixture was sparged with nitrogen for 15 minutes
  2. temperaturecooled to room temperature
  3. filtrationThe resultant mixture was filtered
  4. washThe cartridge was washed through with methanol (50 mL)
  5. washeluted with 2M ammonia in methanol (50 mL)
  6. customEvaporation of the ammoniacal fraction
  7. customafforded an amber gum which
  8. customwas purified by acid modified reverse phase preparative HPLC
  9. dissolutionThe resultant material was dissolved in MeOH/Water
  10. additionpoured onto an SCX-3 cartridge (2 g) and cartridge which
  11. washwas then washed with methanol
  12. washeluted with 2M ammonia in methanol
  13. customthe ammoniacal solution evaporated

Sources & evidence

ORD record
ord-b2634b182b4d4610a2b52509c0b1589c
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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