Triethylamine → 3-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin-1-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide

HRID 2063296노트

반응식

HRID 2063296 반응식
Cl.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]CC[CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].C(N(CC)CC)C.Cl.Cl.C(N1CCN(C2CNC2)CC1)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[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[CH2:20][CH2:21][N:22]([C:25](=[O:29])[CH3:26])[CH2:23][CH2:24]2)[CH2:16]1)[CH3:10])=[O:8]

참가 물질

7

반응물 4

HCID 8471Triethylamine2회HCID 5049666Sodium triacetoxyborohydrideHCID 68775862AcetylaminoazetidineHCID 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 161231823-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin-1-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide수율 54.1%

시약·촉매·용매 2

HCID 887Methanol용매HCID 962Water용매

실험 절차

3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 11.2 g, 25 mmol) was dissolved in methanol (50 mL) together with triethylamine (3.5 mL, 25 mmol). Together with another portion of triethylamine (3.5 mL, 25 mmol) the solution was transferred to a flask containing 1-acetyl-4-azetidin-3-ylpiperazine dihydrochloride (see WO 96/05193; 8.4 g, 32.6 mmol). The mixture was stirred at RT for 45 min and then sodium triacetoxyborohydride (8.0 g, 37.6 mmol) was added by installments during one hour. The reaction mixture was stirred at RT for 45 min. Water (0.45 mL) was added and then most of the solvent was removed by evaporation. The residue was dissolved in toluene (56 mL) and then an aqueous 10% solution of NaOH (55 mL) was added while heating to 40° C. The mixture was stirred vigorously at 45° C. for 5 min. The aqueous layer was separated off and the organic solution was left in the hood overnight. After several attempts to crystallize the product from different solvents the compound was purified by means of silica gel chromatography (ammonia saturated methanol-methylene chloride 1% to 10%). There was obtained 8.3 g (54%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): 1.4-1.8 (cm, 2H), 2.0 (s, 3H), 2.1-3.8 (cm, 21H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 614 (M+1)+.

후처리

  1. stirringThe reaction mixture was stirred at RT for 45 min
  2. custommost of the solvent was removed by evaporation
  3. dissolutionThe residue was dissolved in toluene (56 mL)
  4. additionan aqueous 10% solution of NaOH (55 mL) was added
  5. temperaturewhile heating to 40° C
  6. stirringThe mixture was stirred vigorously at 45° C. for 5 min
  7. customThe aqueous layer was separated off
  8. waitthe organic solution was left in the hood overnight
  9. customAfter several attempts to crystallize the product from different solvents the compound
  10. customwas purified by means of silica gel chromatography (ammonia saturated methanol-methylene chloride 1% to 10%)

출처 및 근거

ORD 기록
ord-d88d172b71664b9f8a25bc420e6b3246
출처 데이터셋
uspto-grants-2012_10
특허 번호
US08288370B2

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