Sodium Hydroxide → 5-(2-chloro-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 12806Notes

Reaction equation

HRID 12806 reaction equation
[Cl:1][C:2]1[C:7]([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:6][CH:5]=[C:4]([CH3:20])[N:3]=1.[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.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C.CC(O)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][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:36])[F:35])=[CH:28][CH:27]=5)([CH2:34]4)[CH2:30]3)[CH:13]=2)=[CH:6][CH:5]=[C:4]([CH3:20])[N:3]=1

Participants

7

Reactant 4

HCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydrideHCID 58994243HCID 58994243, compoundHCID 59337591(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Product 1

HCID 866159675-(2-chloro-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 15%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 3-[5-(2-chloro-6-methylpyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep109, 78 mg, 0.26 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 60 mg, 0.26 mmol), and AcOH (19 μl) in dichloroethane (4 ml) was cooled to 0° C. NaBH(AcO)3 (58 mg, 0.26 mmol) was added portionwise. The mixture was stirred at 0° C. for further 2 hours and then basified with 1N NaOH. The product extracted with DCM, the organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred overnight in presence of PS-isocyanate. The mixture was filtered and the solvent was evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) and then was passed over a SCX cartridge to give 20 mg of the free base of title compound (15% yield).

Workup

  1. extractionThe product extracted with DCM
  2. dry with materialthe organic phase was dried (Na2SO4)
  3. customevaporated
  4. dissolutionThe residue was redissolved in DCM
  5. stirringstirred overnight in presence of PS-isocyanate
  6. filtrationThe mixture was filtered
  7. customthe solvent was evaporated
  8. customThe crude was purified by flash chromatography
  9. washeluting with DCM-MeOH—NH4OH (98:2:0.2)

Sources & evidence

ORD record
ord-36e68fd23dd04b4380aff8747596301f
Source dataset
uspto-grants-2010_06
Patent number
US07727988B2

Reaction notes

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