1-(Diphenylmethyl)azetidin-3-one → (9aS)-8-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one

HRID 2063318Notes

Reaction equation

HRID 2063318 reaction equation
[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]1[C@@H:24]2[CH2:25][NH:26][CH2:27][CH2:28][N:23]2[C:22](=[O:29])[CH2:21][O:20]1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:26]3[CH2:27][CH2:28][N:23]4[C@H:24]([CH2:19][O:20][CH2:21][C:22]4=[O:29])[CH2:25]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

Participants

6

Reactant 3

HCID 37355581-(Diphenylmethyl)azetidin-3-oneHCID 5003444Sodium cyanoborohydrideHCID 16124477(9AS)-Hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one

Product 1

HCID 16124478(9aS)-8-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-oneYield 69.3%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 887MethanolSolvent2×

Procedure

To a solution of 1-(diphenylmethyl)azetidin-3-one (see Bioorg. Med. Chem. Lett.; 13; 2003; 2191-2194, ˜0.65 mmol) and (9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (0.65 mmol), in methanol (10 mL) was added a solution of sodium cyano borohydride (125 mg, 2.0 mmol) and zinc chloride (135 mg, 1.0 mmol) in methanol (20 mL). The reaction mixture was stirred 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 a mixture of acetonitrile (10 mL), acetic acid (100 mg) and water (10 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 and there was obtained 170 mg (69%) of (9aS)-8-[1-(diphenylmethyl)azetidin-3-yl]hexahydropyrazino-[2,1-c][1,4]oxazin-4(3H)-one. 1H NMR (400 MHz, CDCl3): 1.6-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.6 (d, 1H), 2.7-2.8 (m, 21-1), 2.8-2.9 (m, 2H), 3.0 (qn, 1H), 3.3-3.7 (m, 4H), 3.9 (dd, 1H), 4.0-4.2 (qt, 2H), 4.4 (s, 1H), 4.5 (dd, 1H), 7.2 (t, 2H), 7.3 (m, 4H), 7.4 (m, 4H); LCMS: m/z 378 (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 (10 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-03842597cb39463889d1d23776583d4e
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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