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Method for preparing high optical purity 3-substituted chiral phthalide compounds

A technology of optical purity and phthalides, which is applied in the field of preparing 3-substituted chiral phthalides with high optical purity, can solve the problems of side reactions, not very mature, and low selectivity, and achieve high selectivity and bottom good applicability

Active Publication Date: 2009-01-07
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of asymmetric catalytic reactions is the most efficient, economical and practical method. However, the currently developed methods are relatively immature, with problems such as low selectivity, side reactions, simple and practical reaction systems, and environmental friendliness.

Method used

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  • Method for preparing high optical purity 3-substituted chiral phthalide compounds
  • Method for preparing high optical purity 3-substituted chiral phthalide compounds
  • Method for preparing high optical purity 3-substituted chiral phthalide compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Synthesis of 2a

[0033] In a 5mL Schlenk bottle, add 0.0025mmol [RuCl 2 (p-cymene)] 2, 0.006mmol chiral diamine ligand, change argon protection, add 1.0mL distilled water, and stir at a certain temperature for 0.5 to 1 hour. Under the condition of increasing argon flow, open the lid and add 2.5mmol formate and 0.5mmol substrate, under the protection of argon, stir the reaction at a certain temperature, and process for 20 hours. Add 5ml of distilled water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify by flash silica gel column chromatography to obtain the corresponding phthalide compound. Refer to Table 1 for the yield and ee value (negative value indicates that the product configuration is reversed).

[0034]

[0035] Table 1

[0036]

Embodiment 2

[0038] Synthesis of 2a

[0039] In a 5mL Schlenk bottle, add 0.0025mmol [RuCl 2 (p-cymene)] 2 , 0.006 mmol of ligand (S, S)-11, under argon protection, 1.0 mL of distilled water was added, and the reaction was stirred at 40° C. for 0.5 to 1 hour. Under the condition of increasing argon flow, open the lid and add 5mmol sodium formate, 0.04mmol surfactant, 0.5mmol substrate, under the protection of argon, stir the reaction at 40°C, and react for 20 hours. Add 5ml of distilled water, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate, and purify by flash silica gel column chromatography to obtain the corresponding phthalide compound 2a. The conversion rate of the reaction is shown in Table 2.

[0040]

[0041] Table 2

[0042]

Embodiment 3

[0044] Synthesis of 2a

[0045] In a 5mL Schlenk bottle, add 0.0025mmol [RuCl 2 (p-cymene)] 2 , 0.006 mmol of ligand (S, S)-11, under argon protection, 1.0 mL of distilled water was added, and the reaction was stirred at 40° C. for 0.5 to 1 hour. Under the condition of increasing argon flow, open the lid and add 5mmol sodium formate, 0.04mmol CTAB, 1mmol substrate, and stir the reaction at 40°C under the protection of argon until the nuclear magnetic resonance shows that the conversion is complete. Added 5ml of distilled water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and purified by flash silica gel column chromatography to obtain the corresponding phthalide compound 2a with a yield of 92% and an ee of 98.3%.

[0046]

[0047] 2a: 1 H NMR (300MHz, CDCl 3 ): δ0.91(t, J=7.2Hz, 3H), 1.33-1.51(m, 4H), 1.71-1.81(m, 1H), 2.00-2.09(m, 1H), 5.49(dd, J=4.2 , 7.8Hz, 1H), 7.45(dd, 0.75, 7.7Hz, 1H), 7.53(t, J=7.5Hz, 1H), 7.68(dt, J=0.9, 7.5...

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Abstract

The invention relates to a method for preparing 3-substitution chirality phthalide compound with high optical purity, which is realized by utilizing asymmetric hydrogen transfer reaction which is performed between chiral diamine ligand and (p-methyl-isopropyl) phenyl ruthenous chloride dimer, and is catalyzed by complexes in aqueous phase. The reaction condition is mild, the operation is simple and convenient, the applicability of zymolyte is good, no secondary reaction occurs nearly, the 3-substitution chirality phthalide compound with high optical purity can be prepared in high yield in a highly stereoselective manner, and a certain industrial application prospect is possessed.

Description

technical field [0001] The invention relates to a method for preparing 3-substituted chiral phthalide compounds with high optical purity. Background technique [0002] Phthalides are a class of very important natural products and organic synthesis intermediates ((a) Games, D.E.Aromat.Heteroaromat.Chem.1974, 2, 447. (b) Murray, R.D.H.Aromat.Heteroaromat.Chem.1976, 4, 414. (c) Gilchrist, T.L.J. Chem. Soc., Perkin Trans. 11999, 2849. (d) Ghosh, S.; Banerjee, I.; Baul, S. Tetrahedron 1999, 55, 11537.). Especially the 3-substituted chiral phthalide compounds, many of them have good biological activity (Kerstin, K.; Robert, E.Z.; Stefan, B. Tetrahedron 2004, 60, 8591.). [0003] [0004] Among them, (-)-Hydrastine can act on the opioid receptor, that is, the human CCR5 receptor, which is an important anti-HIV target and interferes with HIV entering cells (Yoganathan, K.; Rossant, C.; Ng, S .; Huang, Y.; Butler, M.S.; Buss, A.D.J. Nat. Prod. 2003, 66, 1116.). (-)-Alcyopterosi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88C07B53/00B01J31/22B01J31/30
Inventor 林国强徐明华张波
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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