N,N-Dimethylglycine → 5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione

HRID 1925054Notes

Reaction equation

HRID 1925054 reaction equation
I[C:2]1[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C@H:15]3[C@:13]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)([CH2:14]3)[CH2:12]2)[CH:7]=1.CN(C)CC(O)=O.C([O-])([O-])=O.[K+].[K+].[F:42][C:43]([F:54])([F:53])[C:44]1[C:45]2[CH2:52][O:51][CH2:50][CH2:49][C:46]=2[NH:47][N:48]=1>CS(C)=O.CCOC(C)=O.[Cu]I>[F:53][C:43]([F:42])([F:54])[C:44]1[C:45]2[CH2:52][O:51][CH2:50][CH2:49][C:46]=2[N:47]([C:2]2[C:3](=[O:28])[NH:4][C:5](=[O:27])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C@H:15]4[C@:13]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)([CH2:14]4)[CH2:12]3)[CH:7]=2)[N:48]=1

Participants

8

Reactant 4

HCID 673N,N-DimethylglycineHCID 11430Potassium CarbonateHCID 509927963-(Trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazoleHCID 675197195-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione

Product 1

HCID 252531395-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)-yl]-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
150 °C

Procedure

5-iodo-1-(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-2,4(1H,3H)-pyrimidinedione (Prep10, 150 mg, 0.282 mmol), copper (1+) iodide (59.1 mg, 0.310 mmol), N,N-dimethylglycine (32.0 mg, 0.310 mmol) and K2CO3 (86 mg, 0.620 mmol) were dissolved in Dimethyl Sulfoxide (DMSO) (2 ml) to give a light blue solution with a white precipitate. To this mixture, 3-(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole (starting material prepared according to a similar procedure to that described in Prep38 followed by Prep39, 179 mg, 0.931 mmol) was added. After 18 h shaking at 150° C., the reaction mixture was diluted with EtOAc (5 ml) and the organic phase was washed with water (4×10 ml), then brine (5 ml), dried over Na2SO4, then filtered and the solvent evaporated. The obtained crude was passed through an SCX cartridge and eluted with 2M solution of ammonia in MeOH. The resulting mixture was further purified by preparative LC-MS to obtain 9.6 mg of the title compound as a free base.

Workup

  1. customto give a light blue solution with a white precipitate
  2. customprepared
  3. additionwas added
  4. washthe organic phase was washed with water (4×10 ml)
  5. dry with materialbrine (5 ml), dried over Na2SO4
  6. filtrationfiltered
  7. customthe solvent evaporated
  8. customThe obtained crude
  9. washeluted with 2M solution of ammonia in MeOH
  10. customThe resulting mixture was further purified by preparative LC-MS

Sources & evidence

ORD record
ord-21e71c7c369849b0938375c731106738
Source dataset
uspto-grants-2012_05
Patent number
US08178549B2

Reaction notes

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