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

HRID 12779Notes

Reaction equation

HRID 12779 reaction equation
[C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1.C(N(C(C)C)C(C)C)C.[Cl:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][C@H:33]2[C@:31]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)([CH2:32]2)[CH2:30]1>CC#N.CS(C)=O>[ClH:25].[CH3:15][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][C@H:33]3[C@:31]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:37][CH:36]=4)([CH2:32]3)[CH2:30]2)[CH:12]=1

Participants

5

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 221689845-(o-tolyl)Pyrimidine-2,4-diol2×HCID 59337588(1S,5R)-3-(3-chloropropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane2×

Product 1

HCID 686917535-(2-methylphenyl)-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione hydrochlorideYield 62.5%

Reagents, catalysts & solvents 1

HCID 22251437Acetonitrile dimethylsulfoxideSolvent

Procedure

5-Phenyl-1H-pyrimidine-2,4-dione (Prep53, 52 mg, 0.25 mmol) was dissolved in MeCN-DMSO (3:1, 3 mL). Ethyl-diisopropyl-amine (132 μl, 0.8 mmol) and (1S,5R)-3-(3-chloro-propyl)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep13, 69 mg, 0.3 mmol) were added. The mixture was placed in a microwave oven and then irradiated at 150° C. for 6 hours (3 cycles×1 h). A second run was performed on 5-Phenyl-1H-pyrimidine-2,4-dione (Prep53, 123 mg, 0.43 mmol), ethyl-diisopropyl-amine (0.2 μl, 1.2 mmol) and (1S,5R)-3-(3-chloro-propyl)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep13, 130 mg, 0.43 mmol) in the same conditions. The two mixtures were mixed and evaporated under vacuum. The residue was dissolved in ethyl acetate and washed with water. The crude was purified by preparative LC-MS to give 79 mg of the title compound as trifluoroacetate salt. The compound was loaded on SCX cartridge washing with MeOH and then eluting with MeOH/NH3 95:5. The free base obtained was treated with 4N HCl in dioxane (2 eq), to give the title compound as a white powder (32 mg).

Workup

  1. customThe mixture was placed in a microwave oven
  2. customirradiated at 150° C. for 6 hours (3 cycles×1 h)
  3. additionThe two mixtures were mixed
  4. customevaporated under vacuum
  5. dissolutionThe residue was dissolved in ethyl acetate
  6. washwashed with water
  7. customThe crude was purified by preparative LC-MS

Sources & evidence

ORD record
ord-180b5e24272947e2bce6c6597ec2e050
Source dataset
uspto-grants-2010_06
Patent number
US07727988B2

Reaction notes

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