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

HRID 2063301Notes

Reaction equation

HRID 2063301 reaction equation
[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:41])([F:42])[F:43])[CH:39]=1)[C:7]([N:9]([CH2:11][C@H:12]([C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=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])[CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24]2)[CH2:16]1)[CH3:10])=[O:8]

Participants

6

Reactant 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

Product 1

HCID 866483163-Bromo-N-[(2S)-4-[3-(4-butyrylpiperazin-1-yl)azetidin-1-yl]-2-(4-fluorophenyl)butyl]-N-methyl-5-(trifluoromethyl)benzamide dihydrochlorideYield 61.6%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent2×

Procedure

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 15; ˜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 stiffed 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 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, CD3OD): 0.8-1.0 (t, 3H), 1.5-1.6 (qt, 2H), 1.8-2.2 (cm, 3H), 2.4 (t, 2H), 2.6-4.6 (cm, 20H), 7.0-7.6 (cm, 6H), 7.9 (d, 1H); LCMS: m/z 642 (M+1)+.

Workup

  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

Sources & evidence

ORD record
ord-e63e72ef603d4366b01a7ff4ee15c912
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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