Acetic Acid → 5-(6-methyl-3-pyridinyl)-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione dihydrochloride

HRID 12789Notes

Reaction equation

HRID 12789 reaction equation
[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].[Cl:56]C(Cl)C>>[ClH:56].[ClH:56].[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:13]=2)=[CH:4][CH:3]=1

Participants

7

Reactant 6

HCID 176Acetic AcidHCID 63651,1-DichloroethaneHCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydrideHCID 58994250HCID 58994250, compoundHCID 59337591(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Product 1

HCID 686939375-(6-methyl-3-pyridinyl)-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione dihydrochlorideYield 40%

Conditions

Temperature
0 °C

Procedure

To a solution of 3-[5-(6-Methyl-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep59, 90 mg, 0.35 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 71 mg, 0.31 mmol) and AcOH (21 mg, 0.35 mmol) in dichloroethane (2 mL), NaBH(AcO)3 (77 mg, 0.36 mmol) was added portionwise at 0° C. The mixture was stirred at 0° C. for further 45 minutes, then a 1N solution of NaOH was added and the mixture extracted with EtOAc. The organic phase was dried and evaporated, the residue redissolved in DCM and treated with PS-isocyanate resin (400 mg) under stirring for 4 h. After filtration, the solvent was evaporated under vacuum, and the crude was purified by flash chromatography with DCM-MeOH—NH4OH (95-5-0.5) to give the title compound (65 mg, 40% yield) as free base.

Workup

  1. extractionthe mixture extracted with EtOAc
  2. customThe organic phase was dried
  3. customevaporated
  4. dissolutionthe residue redissolved in DCM
  5. additiontreated with PS-isocyanate resin (400 mg)
  6. stirringunder stirring for 4 h
  7. filtrationAfter filtration
  8. customthe solvent was evaporated under vacuum
  9. customthe crude was purified by flash chromatography with DCM-MeOH—NH4OH (95-5-0.5)

Sources & evidence

ORD record
ord-d8dae211059640d2bc49875a0ff069d4
Source dataset
uspto-grants-2010_06
Patent number
US07727988B2

Reaction notes

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