Ethanol → 5-(2-methyl-3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione dihydrochloride

HRID 12776Notes

Reaction equation

HRID 12776 reaction equation
[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10](C2(C)C=CC=CN2)[C:9](=[O:19])[NH:8][C:7]1=[O:20].[F:21][C:22]([F:36])([F:35])[C:23]1[CH:28]=[CH:27][C:26]([C@:29]23[CH2:34][C@H:33]2[CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=1.CC[N:39]([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])C.[CH3:46]CO>>[ClH:1].[ClH:1].[CH3:45][C:43]1[C:44]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:32][C@H:33]4[C@:29]([C:26]5[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:35])[F:36])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:11]=2)=[CH:46][CH:42]=[CH:40][N:39]=1

Participants

5

Reactant 4

HCID 702EthanolHCID 81531DiisopropylethylamineHCID 59337591(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexaneHCID 686953191-(4-chloro-butyl)-5-(2-methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione

Product 1

HCID 686908255-(2-methyl-3-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione dihydrochlorideYield 36%

Procedure

A solution of 1-(4-chloro-butyl)-5-(2-methyl-pyridin-2-yl)-1H-pyrimidine-2,4-dione (Prep48, 100 mg, 0.34 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 77 mg, 0.34 mmol), and DIPEA (132 μl, 1 mmol) in absolute EtOH (3 mL) was heated at 125° C. for 3 hours in a microwave oven. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The residue was dissolved in DCM and treated with PS-isocyanate resin (250 mg) under stirring for 3 h. After filtration and evaporation of the solvent, the crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2) to give the title compound (60 mg, 36% yield) as free base.

Workup

  1. customThe solvent was removed under vacuum
  2. customthe residue was partitioned between water and ethyl acetate
  3. dry with materialThe organic phase was dried (Na2SO4)
  4. filtrationfiltered
  5. customevaporated
  6. dissolutionThe residue was dissolved in DCM
  7. additiontreated with PS-isocyanate resin (250 mg)
  8. filtrationAfter filtration and evaporation of the solvent
  9. customthe crude was purified by flash chromatography with DCM-MeOH—NH4OH (98-2-0.2)

Sources & evidence

ORD record
ord-8fb00b688f9142ad93c4feb8cbde5bf8
Source dataset
uspto-grants-2010_06
Patent number
US07727988B2

Reaction notes

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