1-(4-Chloro-butyl)-5-(2-methyl-pyridin-4-yl)-1H-pyrimidine-2,4-dione → 5-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione dihydrochloride

HRID 12774노트

반응식

HRID 12774 반응식
[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)[C:9](=[O:19])[NH:8][C:7]1=[O:20].[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>CCO>[ClH:1].[ClH:1].[CH3:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][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:11]=2)[CH:17]=[CH:16][N:15]=1

참가 물질

4

반응물 2

HCID 589941791-(4-Chloro-butyl)-5-(2-methyl-pyridin-4-yl)-1H-pyrimidine-2,4-dioneHCID 59337591(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

생성물 1

HCID 686885325-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione dihydrochloride수율 43.1%

시약·촉매·용매 1

HCID 702Ethanol용매

실험 절차

A solution of 1-(4-Chloro-butyl)-5-(2-methyl-pyridin-4-yl)-1H-pyrimidine-2,4-dione (Prep46, 74 mg, 0.25 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 57 mg, 0.25 mmol), and TEA (101 μl, 1 mmol) in absolute EtOH (3 mL) was refluxed for 48 hours. The reaction was then evaporated under vacuum and the residue was dissolved in 2N HClaq and washed with ethyl acetate. The aqueous phase was then basified with solid NaHCO3 and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated; the residue was dissolved in DCM and treated with PS-isocyanate (250 mg) resin under stirring for 2 h. After filtration and evaporation of the solvent the crude was purified by LC-MS preparative and then loaded on SCX cartridge washing with MeOH and eluting with MeOH/NH3 95:5 to give 30 mg of the title compound as free base (33%, yield). 5-(2-methyl-4-pyridinyl)-1-(4-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}butyl)-2,4(1H,3H)-pyrimidinedione was dissolved in dioxane and then treated with a solution of 4N HCl in dioxane (2 eq) to give the title compound as a pale yellow solid. (33 mg, 23.5%)

후처리

  1. customThe reaction was then evaporated under vacuum
  2. dissolutionthe residue was dissolved in 2N HClaq
  3. washwashed with ethyl acetate
  4. extractionextracted with ethyl acetate
  5. dry with materialThe organic phase was dried (Na2SO4)
  6. customevaporated
  7. dissolutionthe residue was dissolved in DCM
  8. additiontreated with PS-isocyanate (250 mg) resin
  9. filtrationAfter filtration and evaporation of the solvent the crude
  10. customwas purified by LC-MS preparative
  11. washwashing with MeOH
  12. washeluting with MeOH/NH3 95:5

출처 및 근거

ORD 기록
ord-e3ea523a27f644ab864edfee748199ee
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07727988B2

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