Cesium carbonate → HCID 58015047, compound

HRID 1676762Notes

Reaction equation

HRID 1676762 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.[NH2:22][C:23]1[C:31]([F:32])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:33])[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[C:31]([F:32])=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([F:33])[CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 201514774-Amino-2,5-difluorobenzoic acidHCID 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 58015047HCID 58015047, compoundYield 40.7%

Reagents, catalysts & solvents 2

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

Procedure

To a mixture of 0.9503 g (3.0 mmole) 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), 0.6252 g (3.611 mmole) of 4-amino-2,5-difluorobenzoic acid, and 48 mL of dioxane, was added 1.96 g (6.01 mmole) of cesium carbonate and 0.0682 g (0.304 mmole) of palladium acetate. The mixture was deoxygenated with argon, 0.386 g (0.621 mmole) of 1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenyl phosphine was added and the reaction mixture was heated at 100 degrees for 3 hrs. The cooled mixture was concentrated under reduced pressure, dissolved in ethyl acetate, made slightly acidic by the addition of 1M hydrochloric acid, washed with water, brine, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.5533 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)-2,5-difluoro-benzoic acid (I-232) as off-white solid.

Workup

  1. additionwas added
  2. temperaturethe reaction mixture was heated at 100 degrees for 3 hrs
  3. concentrationThe cooled mixture was concentrated under reduced pressure
  4. dissolutiondissolved in ethyl acetate
  5. additionmade slightly acidic by the addition of 1M hydrochloric acid
  6. washwashed with water, brine
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customPurification by silica gel chromatography
  10. washeluting with dichloromethane-methanol (gradient, 95:5-80:20)

Sources & evidence

ORD record
ord-082adb8b8fde484693c320a356ad7d51
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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