Tetrahydrofuran → 2-Chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

HRID 1676683Notes

Reaction equation

HRID 1676683 reaction equation
[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.[F:32][C:33]([F:44])([F:43])[CH2:34]OS(C(F)(F)F)(=O)=O>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:34][C:33]([F:44])([F:43])[F:32])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 803662,2,2-Trifluoroethyl trifluoromethanesulfonateHCID 579556112-Chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[4,5-B][1,4]diazepin-6(7H)-one

Product 1

HCID 866375072-Chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-oneYield 38.2%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a suspension of 0.50 g (0.0017 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.50 g (0.0034 mole) of potassium carbonate and 10 mL of tetrahydrofuran was added 0.46 g (0.0020 mole) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester. After stirring at 75 degrees for four hours, the mixture was cooled and water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with ethyl acetate-hexane (gradient, 100:0-30:70) gave 0.25 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-(2,2,2-trifluoro-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-150)

Workup

  1. temperaturethe mixture was cooled
  2. extractionThe mixture was extracted with ethyl acetate twice
  3. washThe combined organic layers were washed three times with sodium carbonate, three times with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customPurification by silica gel chromatography
  8. washeluting with ethyl acetate-hexane (gradient, 100:0-30:70)

Sources & evidence

ORD record
ord-66ee1f60cb504d1da7ee4ece70651670
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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