Water → 1-(3-{(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-5-(2-thienyl)-2,4(1H,3H)-pyrimidinedione hydrochloride

HRID 12755Notes

Reaction equation

HRID 12755 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:25](=[O:33])[NH:24][C:23]1=[O:34].O>CN(C=O)C>[ClH:18].[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][N:14]([CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25](=[O:33])[NH:24][C:23]1=[O:34])[CH2:13]2

Participants

5

Reactant 3

HCID 962WaterHCID 593375931-(3-chloropropyl)-5-(2-thienyl)-2,4(1H,3H)-pyrimidinedioneHCID 59346768(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Product 1

HCID 686961361-(3-{(1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-5-(2-thienyl)-2,4(1H,3H)-pyrimidinedione hydrochloride

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (29 mg, prepared following a similar procedure to that reported in WO 2005080382), 1-(3-chloropropyl)-5-(2-thienyl)-2,4(1H,3H)-pyrimidinedione (Prep15, 35 mg) and TEA (0.034 mL) in DMF (1.5 mL) was heated at 100° C. for 24 hours. Water was then added and the solution was extracted with dichloromethane. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude obtained was loaded over a SCX cartridge and eluted with ammonia (1M in methanol). The resulting product was further purified by silica flash chromatography (DCM/MeOH 98:2) to obtain 13 mg of the title compound as free base. To a solution of this product (13 mg) in dichloromethane (0.5 mL), HCl (1M in Et20, 1 eq) was added, the solvent was evaporated in vacuo and the material thus obtained triturated with Et2O to give 13 mg of the title compound as a yellow solid.

Workup

  1. customprepared
  2. extractionthe solution was extracted with dichloromethane
  3. dry with materialThe organic phase was dried over Na2SO4
  4. concentrationconcentrated in vacuo
  5. customThe crude obtained
  6. washeluted with ammonia (1M in methanol)
  7. customThe resulting product was further purified by silica flash chromatography (DCM/MeOH 98:2)

Sources & evidence

ORD record
ord-f965f41cf43f401da9c8de03f9c778ac
Source dataset
uspto-grants-2010_06
Patent number
US07727988B2

Reaction notes

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