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

HRID 368831ノート

反応式

HRID 368831 の反応式
[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

参加物

10

反応物 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

生成物 1

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

試薬・触媒・溶媒 5

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒HCID 8058Hexane溶媒HCID 8471Triethylamine溶媒HCID 8857Ethyl Acetate溶媒

実験手順

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.

後処理

  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

出典と根拠

ORDレコード
ord-9d0147174f7e46e49947c75d2223a6a3
出典データセット
uspto-grants-2000_10
特許番号
US06133446

反応ノート

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