Sodium cyanoborohydride → 3-Bromo-N-[(2S)-4-{3-[4-(cyclopropylcarbonyl)piperazin-1-yl]azetidin-1-yl}-2-(4-fluorophenyl)butyl]-N-methyl-5-(trifluoromethyl)benzamide dihydrochloride

HRID 2063300노트

반응식

HRID 2063300 반응식
[ClH:1].Cl.[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:18][CH:17]([N:19]2[CH2:24][CH2:23][N:22]3[C:25](=[O:29])[CH2:26][CH2:27][CH2:28][CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN(C(C3CC3)=O)CC2)C1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[ClH:1].[ClH:1].[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH2:13][CH2:14][N:15]1[CH2:16][CH:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([CH:26]3[CH2:27][CH2:28]3)=[O:29])[CH2:23][CH2:24]2)[CH2:18]1)[CH3:10])=[O:8]

참가 물질

6

반응물 3

HCID 5003444Sodium cyanoborohydrideHCID 16124373Methanone, [4-(3-azetidinyl)-1-piperazinyl]cyclopropyl-HCID 866483133-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(6-oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide dihydrochloride

생성물 1

HCID 866483153-Bromo-N-[(2S)-4-{3-[4-(cyclopropylcarbonyl)piperazin-1-yl]azetidin-1-yl}-2-(4-fluorophenyl)butyl]-N-methyl-5-(trifluoromethyl)benzamide dihydrochloride수율 61.8%

시약·촉매·용매 2

HCID 3007855Zincchloride촉매HCID 887Methanol용매2회

실험 절차

To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 450 mg, 1.0 mmol) and 1-azetidin-3-yl-4-(cyclopropylcarbonyl)piperazine (see Method 14; ˜0.9 mmol) in methanol (50 mL) was added a solution of sodium cyano borohydride (250 mg, 4.0 mmol) and zinc chloride (270 mg, 2.0 mmol) in methanol (30 mL). The reaction mixture was stirred at RT for 15 min and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic solution was washed with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The product was purified by means of silica gel chromatography first eluting with ethyl acetate and then with a mixture of ethyl acetate, methanol and triethylamine (9:1:1). The proper fractions were combined and concentrated on a rotavapor and then the residue was co-evaporated twice using methylene chloride. The residue was dissolved in methylene chloride and to the solution was added HCl-saturated diethyl ether (1 mL). The solvent was removed by evaporation and then the residue was co-evaporated twice with methylene chloride. There was obtained 220 mg (30%) of the title compound. 1H NMR (400 MHz, CDCl3): 0.8-1.0 (cm, 4H), 1.2-4.7 (cm, 24H), 6.9-8.0 (cm, 7H): m/z 640 (M+1)+.

후처리

  1. customthe solvent was removed by evaporation
  2. customThe residue was partitioned between ethyl acetate (50 mL) and water (20 mL)
  3. washThe organic solution was washed with brine
  4. dry with materialdried over Na2SO4
  5. customThe solvent was removed by evaporation
  6. dissolutionthe residue was dissolved in ethyl acetate
  7. customThe product was purified by means of silica gel chromatography
  8. washfirst eluting with ethyl acetate
  9. additionwith a mixture of ethyl acetate, methanol and triethylamine (9:1:1)
  10. concentrationconcentrated on a rotavapor
  11. dissolutionThe residue was dissolved in methylene chloride and to the solution
  12. additionwas added HCl-saturated diethyl ether (1 mL)
  13. customThe solvent was removed by evaporation

출처 및 근거

ORD 기록
ord-7ebf1b2d840c48579c4e7dd4d9f46942
출처 데이터셋
uspto-grants-2012_10
특허 번호
US08288370B2

반응 노트

불러오는 중…