Hydrochloric Acid → 1-[2-(Isochroman-1-yl)-2-methylpropyl]-4-(4-methoxyphenyl)piperazine dihydrochloride

HRID 368832Notes

Reaction equation

HRID 368832 reaction equation
B.CSC.[CH:5]1([C:15]([CH3:33])([CH3:32])[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1.C1COCC1.[ClH:39]>CO>[ClH:39].[ClH:39].[CH:5]1([C:15]([CH3:33])([CH3:32])[CH2:16][N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][O:6]1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 12423031(Dimethyl sulfide)trihydroboronHCID 232887702-(Isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one

Product 1

HCID 232889331-[2-(Isochroman-1-yl)-2-methylpropyl]-4-(4-methoxyphenyl)piperazine dihydrochloride

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Triethylamine (1 ml) is added dropwise to a mixture of 2-(isochroman-1-yl)-2-methylpropionic acid (LXXII, 0.502 g, 2.3 mmol), 1-(4-methoxyphenyl)piperazine dihydrochloride (XI, 0.668 g, 2.5 mmol), diethylcyanophosphonate (0.44 ml, 2.9 mmol), DMF (2.4 ml) and dichloromethane (2.4 ml). After the mixture had stirred for 2.5 hr, aqueous saturated sodium bicarbonate is added and the mixture is stirred for 70 min. The mixture is then partitioned between dichloromethane and saline, the phases separated and the organic phase is dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with methanol/dichloromethane (1/99). The appropriate fractions are pooled and concentrated to give a residue. Ethyl acetate and hexane are added and the solids are collected and dried to give 2-(isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXIII), mp 119.5-121°. Borane-methyl sulfide (1.1 ml) is added to a mixture of 2-(isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one (LXXIII, 0.397 g, 1.0 mmol) and THF (98 ml). The mixture is heated for 3.5 hr at 76° and then cooled in an ice/water bath. Hydrochloric acid (10%, 1.3 ml) is added, followed by methanol. The mixture is concentrated and methanol is again added and removed under reduced pressure. The methanol addition/removal is repeated twice more and the resulting material is partitioned between dichloromethane and saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with ethyl acetate/hexane (5/95) followed by ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give the free base of the title compound.

Workup

  1. temperatureThe mixture is heated for 3.5 hr at 76°
  2. temperaturecooled in an ice/water bath
  3. concentrationThe mixture is concentrated
  4. additionmethanol is again added
  5. customremoved under reduced pressure
  6. customThe methanol addition/removal
  7. customthe resulting material is partitioned between dichloromethane and saturated sodium bicarbonate
  8. dry with materialThe combined organic phases are dried over magnesium sulfate
  9. concentrationconcentrated
  10. customthe residue chromatographed on silica gel eluting with ethyl acetate/hexane (5/95)
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-50cc728f594c423bac86db02fee2bd0c
Source dataset
uspto-grants-2000_10
Patent number
US06133446

Reaction notes

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