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Conversion of tryptophan into beta-carboline derivatives

A tryptophan and carboline technology, applied in organic chemistry and other fields, can solve problems such as shortening

Inactive Publication Date: 2011-04-27
LEK PHARMA D D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Therefore, there remains the problem of shortening and simplifying the Pictet-Spengler operation in the synthesis of β-carboline compounds

Method used

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  • Conversion of tryptophan into beta-carboline derivatives
  • Conversion of tryptophan into beta-carboline derivatives
  • Conversion of tryptophan into beta-carboline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] (1R,3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carba Preparation of hydrochloride

[0052] D-Tryptophan (7.96 g, 39 mmol) was suspended in THF (60 ml), and the flask was purged with nitrogen. Piperonal (6.46 g, 43 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Concentrated aqueous hydrochloric acid (4ml) was added and the solution was heated to reflux. The resulting slurry was refluxed for 3 days. The suspension was then cooled to 0-5°C and the product was filtered off, washed with cold THF and dried under vacuum at room temperature for 18 hours to yield 9.6 g of product (98% area).

Embodiment 2

[0054] (1R,3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carba Preparation of hydrochloride

[0055] D-Tryptophan (2 g, 10 mmol) was suspended in acetonitrile (150 ml), and the flask was purged with nitrogen. Piperonal (1.65 g, 11 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Concentrated aqueous hydrochloric acid (1 ml) was added and the mixture was heated to reflux. The resulting slurry was refluxed for 3 days. The suspension was then cooled to 0-5°C and the product was filtered off, washed with cold water and dried under vacuum at 40°C for 18 hours to yield 3.1 g of product (99.8% area)

Embodiment 3

[0057] (1R,3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3-carba Preparation of hydrochloride

[0058] Suspend D-tryptophan (4g, 19.6mmol) in 1,4-bis Alkanes (40ml), the flask was purged with nitrogen. Piperonal (3.25 g, 21.7 mmol) was added and the mixture was stirred at room temperature for 5 minutes. Concentrated aqueous hydrochloric acid (2ml) was added and the solution was heated to 65°C. The resulting slurry was stirred at 65°C for 16 hours. The suspension was then cooled to 0-5°C, the product was filtered off and washed with 1,4-bis Washed with alkane and dried under vacuum at 40°C for 18 hours, yielding 3.6 g of product (99.7 area%).

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Abstract

The invention belongs in the field of organic chemistry and relates to a new shortened Pictet-Spengler type reaction for preparing isomerically pure beta-carboline compounds useful for the synthesis of tadalafil.

Description

field of invention [0001] The present invention belongs to the field of organic chemistry and relates to novel shortened Pictet-Spengler type reactions for the preparation of isomerically pure β-carboline compounds. [0002] More specifically, the present invention relates to the reaction of D-tryptophan with piperonal in a solvent in the presence of mineral acids to form cis-β-carboline compounds, which are further reacted with chloroacetyl chloride and methylamine to form tadala No. Background of the invention [0003] Tadalafil (Formula 1), namely (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl )-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione, belongs to the group of selective phosphodiesterase (PDE5) inhibitors Pharmaceutically active substance for the treatment of erectile dysfunction. This molecule was first disclosed in WO95 / 19978 among a wider set of potentially active molecules. [0004] [0005] The first preparation method is discl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/14
CPCC07D471/04C07D487/14
Inventor S·皮尔茨
Owner LEK PHARMA D D
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