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

HRID 2063296ノート

反応式

HRID 2063296 の反応式
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]

参加物

7

反応物 4

HCID 8471Triethylamine2 回HCID 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

生成物 1

HCID 161231823-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-acetylpiperazin-1-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide収率 54.1%

試薬・触媒・溶媒 2

HCID 887Methanol溶媒HCID 962Water溶媒

実験手順

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)+.

後処理

  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%)

出典と根拠

ORDレコード
ord-d88d172b71664b9f8a25bc420e6b3246
出典データセット
uspto-grants-2012_10
特許番号
US08288370B2

反応ノート

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