Cesium carbonate → 4-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2,5-difluoro-N-(1-methyl-4-piperidyl)benzamide

HRID 2234336Notes

Reaction equation

HRID 2234336 reaction equation
Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:20])[C:7](=[O:19])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:21][C:22]1[C:37]([F:38])=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[C:24]([F:39])[CH:23]=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][CH2:8][C:7](=[O:19])[N:6]([CH3:20])[C:5]3[C:11]2=[N:12][C:2]([NH:21][C:22]2[C:37]([F:38])=[CH:36][C:25]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:27])=[C:24]([F:39])[CH:23]=2)=[N:3][CH:4]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 671592594-amino-2,5-difluoro-N-(1-methyl-4-piperidyl)benzamide2×HCID 714750712-Chloro-9-cyclohexyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one2×

Product 1

HCID 686845714-[(2-cyclohexyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2,5-difluoro-N-(1-methyl-4-piperidyl)benzamideYield 81%

Reagents, catalysts & solvents 2

HCID 9897284tris(dibenzylideneacetone) palladium (II)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

10-chloro-2-cyclohexyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 266; 33 mg, 0.113 mmol), 4-amino-2,5-difluoro-N-(1-methyl-4-piperidyl)benzamide (Intermediate 59; 29 mg, 0.108 mmol) and caesium carbonate were added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. tris(dibenzylideneacetone) palladium (II) (4 mg, 0.006 mmol) and XANTPHOS (6 mg, 0.1 mmol) were added and the mixture heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter-cake was washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM over 30 column volumes. Fractions containing product were combined and evaporated to a solid, which was triturated with isohexane then filtered and dried to yield the title compound as a pale yellow solid (46 mg, 81%).

Workup

  1. customthe suspension bubbled with nitrogen for 10 minutes
  2. temperatureThe reaction mixture was cooled to room temperature
  3. filtrationfiltered
  4. washThe filter-cake was washed with DCM
  5. customthe filtrate evaporated
  6. dissolutionThe residue was dissolved in DCM
  7. custompurified on a silica column
  8. washeluting with a gradient of 0-5% 2M ammonia in MeOH/DCM over 30 column volumes
  9. additionFractions containing product
  10. customevaporated to a solid, which
  11. customwas triturated with isohexane
  12. filtrationthen filtered
  13. customdried

Sources & evidence

ORD record
ord-9b657fc7995e456098ea37aaf044cded
Source dataset
uspto-grants-2010_05
Patent number
US07709471B2

Reaction notes

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