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Preparation method of multi-substituted indanol derivatives

A derivative and multi-substitution technology, applied in the field of pharmaceutical synthetic chemistry, can solve the problems of lack of diversity in product structure, narrow substrate applicability, harsh reaction conditions, etc., and achieve the effects of high selectivity, low cost, and simple synthetic route

Inactive Publication Date: 2013-01-23
EAST CHINA NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned traditional method for synthesizing multi-substituted indenol derivatives has great limitations: it not only needs to construct complex precursor compounds first, but also requires multi-step synthesis, cumbersome operation, harsh reaction conditions, narrow substrate applicability, and products Lack of diversity in structure

Method used

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  • Preparation method of multi-substituted indanol derivatives
  • Preparation method of multi-substituted indanol derivatives
  • Preparation method of multi-substituted indanol derivatives

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preparation example Construction

[0034] Its preparation method comprises the following steps:

[0035] First weigh the diazo compound 1a in molar ratio: o-formyl chalcone 3a: alcohol 2a: metal catalyst (rhodium acetate) = 1.2: 1.0: 1.2: 0.02, o-formyl chalcone, alcohol, rhodium acetate, and absorbent Molecular sieve and organic solvent are added in the reaction bottle, and the water-absorbing agent The addition amount of the molecular sieve is 2-5 g / mmol o-formyl chalcone, and the addition amount of the organic solvent is 25-30 ml / mmol o-formyl chalcone. Next, the diazo is dissolved in an organic solvent to obtain a diazo solution, and the amount of the organic solvent used for dissolving the diazo is 25-30 ml / mmol of imine. Then, at room temperature, the diazonium solution was added dropwise into the reaction flask through a peristaltic pump, and the dropwise addition was completed in 2 hours. After continuing to stir for 1 hour, the reaction was completed, and the solvent was removed by rotary evaporati...

Embodiment 1

[0039]

[0040]Weigh (E)-2-(3-oxa-3-phenylpropenyl)benzaldehyde (0.20mmol), rhodium acetate (1.77mg, 0.004mmol), benzyl alcohol (25.9mg, 0.24mmol), Molecular sieves (100 mg) were placed in a small test tube reactor and 5.6 ml of redistilled 1,2-dichloroethane was added at room temperature. Weigh methyl phenyldiazoacetate (0.24mmol) and dissolve it in 2.8ml redistilled 1,2-dichloroethane, and inject it into the reaction system through a peristaltic pump for 2 hours, and continue to stir at room temperature for 1 hour after the injection is completed. , filtered, and the filtrate was removed by rotary evaporation at 20-50°C to remove the solvent, and then separated by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 10-1: 5) to obtain diastereoselective Pure product of polysubstituted indenol derivatives. Yield 72%, d.r. value greater than 20:1.

[0041] 1 H NMR (500MHz, CDCl 3 , 25°C, TMS): δ=2.40(d, J(H,H)=9.8Hz, 1H), 3.57(s, 3H), 4.31(d, J(H,H)=11.6H...

Embodiment 2

[0043]

[0044] Weigh (E)-2-(3-oxa-3-phenylpropenyl)benzaldehyde (0.20mmol), bis(hexafluoroacetylacetonate)copper(II) (1.91mg, 0.004mmol), benzyl alcohol (25.9 mg, 0.24 mmol), Molecular sieves (100 mg) were placed in a small test tube reactor and 5.6 ml of redistilled 1,2-dichloroethane was added at room temperature. Weigh methyl phenyldiazoacetate (0.24mmol) and dissolve it in 2.8ml redistilled 1,2-dichloroethane, and inject it into the reaction system through a peristaltic pump for 2 hours, and continue to stir at room temperature for 1 hour after the injection is completed. , filtered, and the filtrate was evaporated at 40 ° C to remove the solvent, and then separated by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 10-1: 5) to obtain a multi-substituted compound with high diastereoselectivity. Pure products of indenol derivatives. Yield 72%, d.r. value greater than 20:1.

[0045] 1 H NMR (500MHz, CDCl 3 , 25°C, TMS): δ=2.40(d, J(H,H)=9.8Hz, 1H...

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Abstract

The invention discloses a preparation method of multi-substituted indanol derivatives. The diazo compound, alcohol and o-formyl chalcone are used as raw materials, a metal catalyst is used as a catalyst, an organic solvent is used as a solvent, and a molecular sieve is used as a water absorbent; and the multi-substituted indanol derivatives are obtained by one-step reaction. According to the preparation method disclosed by the invention, the raw materials are easily available, the operation is simple and safe, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry, and relates to a preparation method of a multi-substituted indenol derivative, which is an important chemical and pharmaceutical intermediate. Background technique [0002] Multi-substituted indenols are important intermediate skeleton structures of many natural products, and have similar structural fragments in the natural product Coleophomones D and the adrenergic blocker Atipamezole (Chem.Commun.2002, 2478-2479; J.Am.Chem.Soc.2005, 127, 8872-8888; Synth.Commun.2008, 38, 2662-2671; J.Med.Chem.2010, 53, 6986-6995; Tetrahedron Lett.2000, 41, 8705 -8709). [0003] The traditional chemical synthesis method of multi-substituted indenol derivatives is to obtain multi-substituted indanol derivatives by first synthesizing multi-substituted indanone and then selectively reducing the carbonyl group of indanone; The cyclization reaction between polysubstituted indenol derivati...

Claims

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Application Information

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IPC IPC(8): C07B53/00C07C69/738C07C67/343C07C205/56C07C201/12C07C41/26C07C43/178C07D307/54
Inventor 胡文浩江俊管晓渝郭鑫马晓初刘顺英
Owner EAST CHINA NORMAL UNIVERSITY
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