Sodium cyanoborohydride → 3-Bromo-N-((2S)-2-(4-fluorophenyl)-4-{3-[(9aS)-4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]azetidin-1-yl}butyl)-N-methyl-5-(trifluoromethyl)benzamide

HRID 2063299Notes

Reaction equation

HRID 2063299 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]C[CH2:28][CH:21]3[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8].N1CC(N2CCN3[C@H](C[O:52]CC3=O)C2)C1.C([BH3-])#N.[Na+]>C(O)C.CO.[Cl-].[Zn+2].[Cl-]>[Br:3][C:4]1[CH:5]=[C:6]([CH:37]=[C:38]([C:40]([F:42])([F:41])[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[CH2:24][CH2:23][N:22]3[C@H:21]([CH2:28][O:52][CH2:26][C:25]3=[O:29])[CH2:20]2)[CH2:16]1)[CH3:10])=[O:8]

Participants

7

Reactant 3

HCID 5003444Sodium cyanoborohydrideHCID 16124476(9aS)-8-azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCID 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 596128753-Bromo-N-((2S)-2-(4-fluorophenyl)-4-{3-[(9aS)-4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]azetidin-1-yl}butyl)-N-methyl-5-(trifluoromethyl)benzamideYield 62.4%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 702EthanolSolventHCID 887MethanolSolvent

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 (9aS)-8-azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (see Method 12; ˜0.20 mmol) in ethanol (20 mL) was added a solution of sodium cyano borohydride (125 mg, 2.0 mmol) and zinc chloride (135 mg, 0.99 mmol) in methanol (10 mL). The reaction mixture was stirred at RT for 10 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 a mixture of acetonitrile (10 mL), acetic acid (100 mg) and water (20 mL). The product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate. The proper fractions were combined and concentrated on a rotavapor. The aqueous residue was extracted with ethyl acetate and the organic solution was dried over Na2SO4. The solvent was removed by evaporation. There was obtained 80 mg (55%) of the title compound. 1H NMR (400 MHz, CDCl3): 0.9-3.8 (cm, 21.5H), 3.9 (d, 1H), 4.1-4.2 (qt, 2H), 4.4 (b, 0.5H), 4.5-4.6 (d, 1H), 6.6-7.5 (cm, 6H), 7.8 (s, 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 a mixture of acetonitrile (10 mL), acetic acid (100 mg) and water (20 mL)
  7. customThe product was purified by means of reversed phase chromatography
  8. additiona mixture of acetonitrile and aqueous 0.1 M ammonium acetate
  9. concentrationconcentrated on a rotavapor
  10. extractionThe aqueous residue was extracted with ethyl acetate
  11. dry with materialthe organic solution was dried over Na2SO4
  12. customThe solvent was removed by evaporation

Sources & evidence

ORD record
ord-42077c7ef2544d7bb4f90a4be36cd8d8
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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