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Method for preparing natural alkaloid indoline and pyrrolidine compound

A technology for indolinopyrrolidine and alkaloids, which is applied in the field of preparation of natural alkaloid indolinopyrrolidine compounds, and can solve the problems of low total yield, toxicity, instability, etc.

Inactive Publication Date: 2014-07-02
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The shortcoming of this method is: (1) if start from tryptophan methyl ester and need 4 step reactions to synthesize target molecule, total yield is relatively low, about 57%; (2) reaction condition is harsh, needs anhydrous and oxygen-free Low temperature conditions; (3) need to use toxic or expensive solvents or reagents, such as benzene, acetonitrile, iodotrimethylsilane and tributylallyl stannane, etc.
[0009] The shortcoming of this method is: (1) productive rate is relatively low; (2) tetrakis (triphenylphosphine) palladium price is very expensive, and very unstable; (3) reaction time is longer, needs 24 hours

Method used

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  • Method for preparing natural alkaloid indoline and pyrrolidine compound
  • Method for preparing natural alkaloid indoline and pyrrolidine compound
  • Method for preparing natural alkaloid indoline and pyrrolidine compound

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0022] When R is an acetyl group, the specific operation of the reaction:

[0023] in N 2 Under protection, in a 10ml Schlenk reaction flask, add 217.0mg of tryptophan methyl ester (1.0mmol) and 11.5mg of Pd(dba) successively 2 (5mol%), while stirring, add 2ml of tetrahydrofuran solution, 70ul of allyl acetate (1.0mmol) and 0.7ml of Et 3 1.0 M solution of B in tetrahydrofuran (0.7 mmol). Stirring was then continued at room temperature for 5 h. Afterwards, the reaction solution was diluted with 20.0ml ethyl acetate, and saturated NaHCO 3 After washing with brine, the organic phase was dried with anhydrous sodium sulfate, and 268.2 mg of a colorless liquid (0.89 mmol) was obtained after column separation, with a yield of 89%. The NMR data of Compound I are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.032(t, J=7.0Hz, 2H), 6.724(t, J=7.3Hz, 1H), 6.573(d, J=7.8Hz, 1H), 5.782-5.634(m, 1H), 5.143- 5.022(m, 2H), 4.874(s, 1H), 3.905(dd, J=7.7, 3.4Hz, 1H), 3.352(s, 3H), 3.073-2.794(sb...

example 2

[0025] When R is H, the specific operation of the reaction:

[0026] in N 2 Under protection, in a 10ml Schlenk reaction flask, add 217.0mg of tryptophan methyl ester (1.0mmol) and 11.5mg of Pd(dba) successively 2 (5mol%), while stirring, add 2ml of tetrahydrofuran solution, 68ul of allyl alcohol (1.0mmol) and 0.7ml of Et 3 1.0 M solution of B in tetrahydrofuran (0.7 mmol). Stirring was then continued at room temperature for 8 h. Afterwards, the reaction solution was diluted with 20.0ml ethyl acetate, and saturated NaHCO 3 After washing with brine, the organic phase was dried over anhydrous sodium sulfate, and 247.0 mg of a colorless liquid (0.82 mmol) was obtained after column separation, with a yield of 82%. The NMR data of Compound I are as described above.

example 3

[0028] Use Pd 2 (dba) 3 When being a catalyst, the specific operation of the reaction:

[0029] in N 2 Under protection, in a 10ml Schlenk reaction flask, add 217.0mg of tryptophan methyl ester (1.0mmol) and 45.7mg of Pd successively 2 (dba) 3 (5mol%), 2ml of tetrahydrofuran solution, 70ul of allyl acetate (1.0mmol) and 0.7ml of Et3B in 1.0M tetrahydrofuran solution (0.7mmol) were added while stirring. Stirring was then continued at room temperature for 9 h. Afterwards, the reaction solution was diluted with 20.0ml ethyl acetate, and saturated NaHCO 3 After washing with brine, the organic phase was dried over anhydrous sodium sulfate, and 225.9 mg of a colorless liquid (0.75 mmol) was obtained after column separation, with a yield of 75%. The NMR data of Compound I are as described above.

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Abstract

The invention relates to a method for preparing a natural alkaloid indoline and pyrrolidine compound (full name is 3a-allyl-1,2,3,3a,8,8a-hexahydro-pyrrole [2,3-b] indole-2-methyl formate, and the structural formula is shown in formula I). The structure formula I is as shown in the specification. The preparation method mainly comprises the following step: under combined catalysis of a stable zero-valent palladium complex, triphenylphosphine and lewis acid, preparing a target compound shown in the formula I from a compound shown in a formula II and derivatives (for example, a compound shown in a formula III) of allylic alcohols by serial reactions of allylation, amination and the like. Compared with the existing method for preparing the compound I, the method has the advantages of being convenient to operate, less in dosage of catalyst, low in cost, concise in step, high in product yield and the like.

Description

technical field [0001] The invention relates to a natural alkaloid indolinopyrrolidine compound (full name 3a-allyl-1,2,3,3a,8,8a-hexahydropyrrole[2,3-b]indole-2 - the preparation method of methyl formate), specifically, relate to a kind of by palladium catalyzed allylation, the method for one-step preparation target product such as series reactions such as amination. Background technique [0002] Allyl-1,2,3,3a,8,8a-hexahydropyrrole[2,3-b]indole-2-carboxylate methyl ester is a natural alkaloid compound with very good biological activity, It has been used in the research of many new drugs, so the synthesis of this compound has certain significance in the field of new drug research. [0003] There are many synthetic methods of 3a-allyl-1,2,3,3a,8,8a-hexahydropyrrole [2,3-b]indole-2-carboxylic acid methyl ester structure, and a comprehensive review of the existing literature (Chem. Commun., 2012, 48:4344-4346; Bioorg.Chem.1977, 6:443; Org.Lett.2008, 10:77-80; J.AM.CHEM.SOC.2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 冯向阳蔡良珍
Owner EAST CHINA UNIV OF SCI & TECH
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