3-[(2-Chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2,2-difluoro-propionic acid ethyl ester → 2-Chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one

HRID 1676537Notes

Reaction equation

HRID 1676537 reaction equation
C([O:3][C:4](=O)[C:5]([F:23])([F:22])[CH2:6][N:7]([C:12]1[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)C>C(O)(=O)C.[Fe]>[Cl:21][C:14]1[N:15]=[CH:16][C:17]2[NH:18][C:4](=[O:3])[C:5]([F:23])([F:22])[CH2:6][N:7]([CH:8]3[CH2:11][CH2:10][CH2:9]3)[C:12]=2[N:13]=1

Participants

4

Reactant 1

HCID 866375013-[(2-Chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2,2-difluoro-propionic acid ethyl ester

Product 1

HCID 866375022-Chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-oneYield 73.6%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 176Acetic AcidSolvent

Procedure

To a solution of 11.6 g (0.032 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2,2-difluoro-propionic acid ethyl ester in 100 mL of acetic acid was added 15.5 g (0.191 g-atom) of iron powder. The mixture was heated to 80 degrees for 2 hours and then filtered while hot. Water and ethyl acetate were added to the filtrate and mixture was stirred for 10 minutes and then filtered. The organic layer was washed with ammonium hydroxide and water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The solid residue was washed with 50 mL of hexanes-ethyl acetate (90:10) and then air dried to give 6.8 g of 2-chloro-9-cyclobutyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-1).

Workup

  1. temperatureThe mixture was heated to 80 degrees for 2 hours
  2. filtrationfiltered while hot
  3. additionWater and ethyl acetate were added to the filtrate and mixture
  4. filtrationfiltered
  5. washThe organic layer was washed with ammonium hydroxide and water
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. washThe solid residue was washed with 50 mL of hexanes-ethyl acetate (90:10)
  10. customair dried

Sources & evidence

ORD record
ord-0f0709ae5bf24f3684f6fea1972bb8f5
Source dataset
uspto-grants-2011_08
Patent number
US08003785B2

Reaction notes

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