Dichloromethane → 3-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

HRID 2063295Notes

Reaction equation

HRID 2063295 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=O)[CH3:8])=[O:6].[NH:28]1[CH2:31][CH:30]([N:32]2[CH2:37][CH2:36][N:35]3[C:38](=[O:42])[CH2:39][CH2:40][CH2:41][CH:34]3[CH2:33]2)[CH2:29]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:67]>>[ClH:67].[ClH:67].[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH2:11][CH2:12][N:28]1[CH2:29][CH:30]([N:32]2[CH2:37][CH2:36][N:35]3[C:38](=[O:42])[CH2:39][CH2:40][CH2:41][CH:34]3[CH2:33]2)[CH2:31]1)[CH3:8])=[O:6]

Participants

6

Reactant 5

HCID 6344DichloromethaneHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 159506583-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamideHCID 161232952-azetidin-3-yloctahydro-6H-pyrido[1,2-a]pyrazin-6-one

Product 1

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 dihydrochlorideYield 70%

Procedure

To a solution of 3-bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 100 mg, 0.22 mmol) and 2-azetidin-3-yloctahydro-6H-pyrido[1,2-a]pyrazin-6-one (see Method 4; 58 mg, 0.28 mmol) in methylene chloride (3 mL) were added DIPEA (116 mg, 0.90 mmol) and sodium triacetoxyborohydride (66 mg, 0.31 mmol). The reaction mixture was stirred under nitrogen at RT for 2 h. The solution was washed twice with aqueous NaHCO3 and the organic solvent dried by a phase separator column. The solvent was removed by evaporation and the product was purified by chromatography on silica gel (ammonia saturated methanol-methylene chloride 1% to 10%). The right fractions were combined and concentrated on a rotavapor and the residue was then dissolved in a small amount of acetonitrile/water. A few drops of diluted hydrochloric acid were added and the water was removed by freeze-drying. There was obtained 114 mg (70%) of the title compound as a white solid. 1H NMR (500 MHz, CDCl3): 1.4-3.8 (cm, 27H), 4.6 (d, 1H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 640 (M+1)+.

Workup

  1. washThe solution was washed twice with aqueous NaHCO3
  2. customthe organic solvent dried by a phase separator column
  3. customThe solvent was removed by evaporation
  4. customthe product was purified by chromatography on silica gel (ammonia saturated methanol-methylene chloride 1% to 10%)
  5. concentrationconcentrated on a rotavapor
  6. dissolutionthe residue was then dissolved in a small amount of acetonitrile/water
  7. additionA few drops of diluted hydrochloric acid were added
  8. customthe water was removed
  9. customby freeze-drying

Sources & evidence

ORD record
ord-918229a6bff34e06a936842402cd13a0
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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