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

HRID 2063296Notes

Reaction equation

HRID 2063296 reaction equation
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]

Participants

7

Reactant 4

HCID 8471Triethylamine2×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

Product 1

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

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

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)+.

Workup

  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%)

Sources & evidence

ORD record
ord-d88d172b71664b9f8a25bc420e6b3246
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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