8-Azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride → 3-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamide

HRID 2063298Notes

Reaction equation

HRID 2063298 reaction equation
Cl.[NH:2]1[CH2:5][CH:4]([N:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][O:10][CH2:11][C:12]3=[O:16])[CH2:7]2)[CH2:3]1.Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([CH:53]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:55]=1)[C:23]([N:25]([CH2:27][C@H:28]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[CH2:29][CH2:30]N1CC(N2CCN3C(=O)CCCC3C2)C1)[CH3:26])=[O:24]>CO.O.C(O)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:53]=[C:54]([C:56]([F:59])([F:57])[F:58])[CH:55]=1)[C:23]([N:25]([CH2:27][C@H:28]([C:46]1[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=1)[CH2:29][CH2:30][N:2]1[CH2:5][CH:4]([N:6]2[CH2:15][CH2:14][N:13]3[CH:8]([CH2:9][O:10][CH2:11][C:12]3=[O:16])[CH2:7]2)[CH2:3]1)[CH3:26])=[O:24]

Participants

6

Reactant 2

HCID 161232898-Azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochlorideHCID 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 161231803-Bromo-N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)azetidin-1-yl]butyl}-N-methyl-5-(trifluoromethyl)benzamideYield 45.8%

Reagents, catalysts & solvents 3

HCID 962WaterCatalystHCID 176Acetic AcidSolventHCID 887MethanolSolvent2×

Conditions

Temperature
120 °C

Procedure

8-Azetidin-3-ylhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride (see Method 8; 43 mg, 0.17 mmol) was dissolved in methanol (3 mL) together with a few drops of water and acetic acid (0.2 mL). 3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see Method 3; 80 mg, 0.18 mmol) dissolved in methanol (1 mL) was added to the former solution together with (polystyrylmethyl)-trimethylammonium cyanoborohydride (4.2 mmol/g, 47 mg, 0.25 mmol). The reaction mixture was heated to 120° C. for 5 min using microwave single node heating. The resin was filtered off and washed with methanol. The filtrate was concentrated by evaporation. The product was purified by reversed phase chromatography (acetonitrile-aqueous solution of ammonium formate 0.1M and formic acid 0.1M, 10% to 50%). The solvent of the collected fractions was removed by evaporation followed by freeze-drying. The residue was partitioned between methylene chloride and aqueous NaHCO3. The two phases were separated by means of a phase separator column and then the solvent of the organic solution was removed by evaporation. There was obtained 50 mg (44%) of the title compound. 1H NMR (500 MHz, CD3OD): 1.5-1.7 (b, 1H), 1.7-2.0 (cm, 3H), 2.2-4.2 (cm, 21H), 4.5 (d, 1H), 7.0-7.6 (cm, 6H), 7.9 (d, 1H); LCMS: m/z 642 (M+1)+.

Workup

  1. temperatureheating
  2. filtrationThe resin was filtered off
  3. washwashed with methanol
  4. concentrationThe filtrate was concentrated by evaporation
  5. customThe product was purified by reversed phase chromatography (acetonitrile-aqueous solution of ammonium formate 0.1M and formic acid 0.1M, 10% to 50%)
  6. customThe solvent of the collected fractions was removed by evaporation
  7. customby freeze-drying
  8. customThe residue was partitioned between methylene chloride and aqueous NaHCO3
  9. customThe two phases were separated by means of a phase separator column
  10. customthe solvent of the organic solution was removed by evaporation

Sources & evidence

ORD record
ord-d7aa92af84b6498c828ac19b770c8352
Source dataset
uspto-grants-2012_10
Patent number
US08288370B2

Reaction notes

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