Diethyl cyanophosphonate → 2-(Isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one

HRID 368831

반응식

HRID 368831 반응식
[CH:1]1([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1.O.Cl.Cl.C1(CC[N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3OC)[CH2:34][CH2:33]2)C2C(=CC=CC=2)CCO1.[CH2:46]([O:48]P(C#N)(=O)OCC)C.C(=O)(O)[O-].[Na+]>CCCCCC.C(OCC)(=O)C.ClCCl.CN(C=O)C.C(N(CC)CC)C>[CH:1]1([C:11]([CH3:16])([CH3:15])[C:12]([N:32]2[CH2:33][CH2:34][N:35]([C:38]3[CH:39]=[CH:40][C:41]([O:48][CH3:46])=[CH:42][CH:43]=3)[CH2:36][CH2:37]2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][O:2]1

참가 물질

10

반응물 4

HCID 76257Diethyl cyanophosphonateHCID 516892Sodium BicarbonateHCID 232888942-(Isochroman-1-yl)-2-methylpropionic acidHCID 232889511-[2-(Isochroman-1-yl)ethyl]-4-(2-methoxyphenyl)piperazine dihydrochloride monohydrate

생성물 1

HCID 232887702-(Isochroman-1-yl)-1-[4-(4-methoxyphenyl)piperazin-1-yl]-2-methylpropan-1-one

시약·촉매·용매 5

HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 8058Hexane용매HCID 8471Triethylamine용매HCID 8857Ethyl Acetate용매

실험 절차

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.

후처리

  1. stirringthe mixture is stirred for 70 min
  2. customThe mixture is then partitioned between dichloromethane and saline
  3. customthe phases separated
  4. dry with materialthe organic phase is dried over magnesium sulfate
  5. concentrationconcentrated
  6. customThe residue is chromatographed on silica gel eluting with methanol/dichloromethane (1/99)
  7. concentrationconcentrated
  8. customto give a residue
  9. customthe solids are collected
  10. customdried

출처 및 근거

ORD 기록
ord-9d0147174f7e46e49947c75d2223a6a3
출처 데이터셋
uspto-grants-2000_10
특허 번호
US06133446

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