Hydrochloric Acid → (4S,9aS)-8-acetyl-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride

HRID 1006372Notes

Reaction equation

HRID 1006372 reaction equation
[CH:1]([C@@H:14]1[N:19]2[CH2:20][CH2:21][N:22]([C:24]([O:26]CC3C=CC=CC=3)=O)[CH2:23][C@@H:18]2[CH2:17][N:16]([CH2:34][C:35]2[CH:40]=[C:39]([N:41]3[C:45]([C:46]([F:49])([F:48])[F:47])=[N:44][N:43]=[N:42]3)[CH:38]=[CH:37][C:36]=2[O:50][CH3:51])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:52](N(CC)C(C)C)(C)C.C([Cl:64])(=O)C.C(=O)([O-])O.[Na+].[ClH:70]>O1CCCC1.ClCCl.C(OCC)(=O)C.[Pd].C(N(CC)CC)C>[ClH:64].[ClH:70].[C:24]([N:22]1[CH2:21][CH2:20][N:19]2[C@@H:14]([CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15][N:16]([CH2:34][C:35]3[CH:40]=[C:39]([N:41]4[C:45]([C:46]([F:47])([F:48])[F:49])=[N:44][N:43]=[N:42]4)[CH:38]=[CH:37][C:36]=3[O:50][CH3:51])[CH2:17][C@H:18]2[CH2:23]1)(=[O:26])[CH3:52]

Participants

11

Reactant 5

HCID 313Hydrochloric AcidHCID 6367Acetyl chlorideHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 69819381(4S,9aS)-4-benzhydryl-8-benzyloxycarbonyl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine

Product 1

HCID 69819804(4S,9aS)-8-acetyl-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

(4S,9aS)-4-Benzhydryl-8-benzyloxycarbonyl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine (740 mg) was dissolved in tetrahydrofuran (8 ml), and triethylamine (0.296 ml) was added to it at room temperature. The solution was hydrogenated over 10% palladium-charcoal (50% wet, 150 mg) at room temperature under atmospheric pressure for 2 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give a colorless syrup. To a solution of the syrup in dichloromethane (10 ml) was added N,N-diisopropylethylamine (0.374 ml) and acetyl chloride (0.114 ml) under ice-cooling. After stirred at the same temperature for 2 hours, the mixture was poured into aqueous sodium hydrogen carbonate and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (10 g) using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup. To a solution of the syrup in ethyl acetate (3 ml) was added a solution of 4N hydrogen chloride in ethyl acetate (0.70 ml), and triturated with diisopropyl ether. The precipitate was collected by filtration and dried under reduced pressure for 5 hours at 40° C. to give (4S,9aS)-8-acetyl-4-benzhydryl-2-[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]octahydro-2H-pyrazino[1,2-a]pyrazine dihydrochloride (580 mg) as a colorless powder.

Workup

  1. customAfter removal of the catalyst
  2. filtrationby filtration
  3. customthe filtrate was evaporated under reduced pressure
  4. customto give a colorless syrup
  5. temperaturecooling
  6. extractionextracted with dichloromethane
  7. washThe organic layer was washed with brine
  8. dry with materialdried over sodium sulfate
  9. customevaporated under reduced pressure
  10. customThe resulting residue was purified by column chromatography on silica gel (10 g)
  11. additionThe fractions containing the objective compound
  12. customwere collected
  13. customevaporated under reduced pressure
  14. customto give a syrup
  15. customtriturated with diisopropyl ether
  16. filtrationThe precipitate was collected by filtration
  17. customdried under reduced pressure for 5 hours at 40° C.

Sources & evidence

ORD record
ord-d373107b87bb499d91656c75fd3abd1c
Source dataset
uspto-grants-2004_09
Patent number
US06787543B2

Reaction notes

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