Cesium carbonate → Methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-B][1,4]diazepin-2-YL)amino)-2-fluoro-5-methoxybenzoate

HRID 1676701Notes

Reaction equation

HRID 1676701 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH2:33])=[CH:27][C:26]=1[F:34].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([NH:33][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:6]=3[N:21]=2)=[CH:27][C:26]=1[F:34]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 57955533Methyl 4-amino-2-fluoro-5-methoxybenzoateHCID 579555742-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-B][1,4]diazepin-6(7H)-one

Product 1

HCID 58015164Methyl 4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-B][1,4]diazepin-2-YL)amino)-2-fluoro-5-methoxybenzoateYield 80.4%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

To a mixture of 0.67 g (0.0021 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.63 g (0.00317 mole) of 4-amino-2-fluoro-5-methoxy-benzoic acid methyl ester and 30 mL of dioxane was added 0.05 g (0.00021 mole) of palladium (II) acetate and 1.91 g (0.00588 mole) of cesium carbonate. The mixture was stirred at room temperature for 5 minutes and then heated to 100 degrees for 18 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes-ethyl acetate (60:40) to give 0.81 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid methyl ester (I-168).

Workup

  1. temperatureheated to 100 degrees for 18 hours
  2. customThe solid was removed by filtration
  3. concentrationthe filtrate was concentrated under reduced pressure
  4. additionThe residue was diluted with ethyl acetate
  5. washwashed with water
  6. dry with materialbrine, dried over anhydrous magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel chromatography
  10. washeluting with hexanes-ethyl acetate (60:40)

Sources & evidence

ORD record
ord-92625ecff7b64af98ac01ebcd2d32d8b
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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