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Total synthesizing meethod for pyrrole heterocyclic alkaloid aldisin

A synthesis method and alkaloid technology, applied in the direction of organic chemistry, etc., can solve the problems of 2-pyrrolecarboxylic acid being expensive, difficult to disperse reactants, uneven dissolution, etc., and achieve low cost, short reaction time, and simple and easy-to-obtain raw materials Effect

Inactive Publication Date: 2006-09-13
JINAN UNIVERSITY
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Problems solved by technology

[0005] The existing synthetic method of pyrrole heterocyclic alkaloid aldisin has following problems: (1) take 2-pyrrole carboxylic acid as raw material to synthesize target compound through four-step reaction, but 2-pyrrole carboxylic acid is expensive; (2) 2-pyrrole carboxylic acid is processed by The acylating agent 2-pyrrolecarbonyl chloride generated by acid chlorination is difficult to preserve, and requires toxic toluene as a solvent;
[0006] (3) polyphosphoric acid is viscous body, and reactant is not easy to disperse, and dissolves inhomogeneously; (4) total productive rate is lower, only 28%

Method used

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  • Total synthesizing meethod for pyrrole heterocyclic alkaloid aldisin

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Experimental program
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Effect test

Embodiment 1

[0040] (1) Synthesis of 2-trichloroacetylpyrrole: 4.5g (55mmol) freshly steamed pyrrole, 30mL anhydrous ether, mix well, slowly drop 10g (55mmol) trichloroacetyl chloride in 20mL anhydrous ether solution under stirring, 0.5 The dropwise addition was completed within 1 hour, and stirred at room temperature for 3 hours. Stop the reaction, slowly add 4.5g K dropwise under stirring 2 CO 3 30mL aqueous solution, separate the ether layer; the aqueous layer was extracted with 15mL ether, the combined organic phases were washed with anhydrous Na 2 SO 4 Let dry overnight. Filter to remove Na 2 SO 4 . Diethyl ether was recovered from the filtrate by distillation, and the residue was recrystallized from n-hexane to obtain 9.82 g of gray flaky 2-trichloroacetylpyrrole with a yield of 84% and a melting point of 74-75°C. (yield index and physical properties are consistent with literature [Denis M.Bailey; Robert E.Johnson; and Noel F.Albertson, Org.Syn., Vol.51, 1971, 100.])

[0041]...

Embodiment 2

[0048] (1) Synthesis of 2-trichloroacetylpyrrole: same as Example 1

[0049] (2) Synthesis of N-(2-pyrroleformyl)-beta-alanine methyl ester (I)

[0050] 2.27g of β-alanine methyl ester, 4.25g of 2-trichloroacetylpyrrole and 20mL of ethyl acetate were added to a 50mL round bottom flask, and the reaction was performed under magnetic stirring at 25°C for 4 hours. Ethyl acetate was recovered by rotary evaporation under reduced pressure to obtain a yellow-brown solid residue, which was recrystallized from 95% ethanol to obtain 3.72 g of N-(2-pyrrolecarbonyl)-β-alanine methyl ester crystals, with a yield of 94.9%. The melting point is 134-135°C.

[0051] (3) Synthesis of N-(2-pyrrolecarbonyl)-β-alanine (II)

[0052] 2.94 g of N-(2-pyrroloyl)-β-aminopropionic acid methyl ester crystals, 20 mL of 15% NaOH aqueous solution, 10 mL of ethanol, stirred at room temperature for 1 hour, added dropwise 10% hydrochloric acid until slightly acidic, filtered to remove insoluble matter, The aq...

Embodiment 3

[0056] (1) Synthesis of 2-trichloroacetylpyrrole: same as Example 1

[0057] (2) Synthesis of N-(2-pyrroleformyl)-beta-alanine methyl ester (I)

[0058] 2.47g of β-alanine methyl ester, 4.25g of 2-trichloroacetylpyrrole and 20mL of ethyl acetate were added to a 50mL round bottom flask, and the reaction was performed under magnetic stirring at 35°C for 2 hours. Ethyl acetate was recovered by rotary evaporation under reduced pressure to obtain a yellow-brown solid residue, which was recrystallized from 95% ethanol to obtain 3.66 g of methyl N-(2-pyrroloyl)-β-alanine crystals, with a yield of 93.2%. The melting point is 134-135°C.

[0059] (3) Synthesis of N-(2-pyrrolecarbonyl)-β-alanine (II)

[0060] 2.94 g of N-(2-pyrrolecarbonyl)-β-aminopropionic acid methyl ester crystals, 20 mL of 10% NaOH aqueous solution, 7 mL of ethanol, stirred at room temperature for 2 hours, added dropwise 10% hydrochloric acid until slightly acidic, filtered to remove insoluble matter, The aqueous ...

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Abstract

The present invention relates to the synthesis of alkaloid, and is the total synthesis process of pyrrole heterocyclic alkaloid aldisin. Pyrrole heterocyclic alkaloid aldisin is prepared with pyrrole as initial material and through acylation to produce 2-trichloroacetic pyrrole, the reaction between 2-trichloroacetic pyrrole and beta-methyl alanine to produce N-(2-pyrroyl)-beta-methyl alanine, hydrolysis of the product to obtain N-(2-pyrroyl)-beta- alanine, and the action of phosphorus oxychloride on N-(2-pyrroyl)-beta- alanine to produce pyrrole heterocyclic alkaloid aldisin. The said synthesis process has cheap material, mild reaction condition, high product purity and high yield, and is easy use in industrial production, and the product is used in medical test and clinical use.

Description

technical field [0001] The present invention relates to the synthesis of alkaloid compounds, in particular to the total synthesis method of pyrrole heterocyclic alkaloid aldisin. Background technique [0002] At present, various pyrrole heterocyclic alkaloid aldisin compounds are isolated from various sponges (Xu Xiaohua, Yao Guangmin, Kong Chuihua, etc., Organic Chemistry, 2003, 23, 953-957; Xu Shihai, Zeng Longmei, Su Jingyu, Journal of Analysis and Testing, 1998, 17(3), 32-34; Francis J. Schmitz; Sarath P. Gunasekera; Vijai Lakshmi; et al, J. Nat. Prod., 1985, 48(1), 47-53). Aldisin is a pyrrole heterocyclic alkaloid isolated from various sponges with the chemical formula 6,7-dihydro-1H,5H-pyrrolo[2,3-c]aza-4,8-dione , Francis J.Schmitz et al named it aldisin. Studies have shown that pyrrole heterocyclic alkaloid aldisin compounds have significant anti-lipid peroxidation (Tang Xiaoli, Xu Shibo, Xu Shihai, Chinese Pharmacology Bulletin, 1998, 14(2), 148-150), and can eff...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D209/00C07D223/00
Inventor 曾向潮徐石海
Owner JINAN UNIVERSITY
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