Preparation method of tadalafil and intermediate of tadalafil

Abstract

The invention relates to a preparation method of a selective and reversible inhibitor tadalafil of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5). The method comprises the following steps: carrying out an esterification reaction on D-tryptophan as an initial raw material and methanol under catalysis of sulfuric acid to generate D-tryptophan methyl ester (an intermediate1); carrying out a Pictet-Spengler (P-S) reaction on the D-tryptophan methyl ester and heliotropin to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (an intermediate 2); carrying out an amidation reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride and chloroacetyl chloride to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (an intermediate 3); andfinally carrying out a cyclization reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester and a methylamine alcohol solution to obtain the tadalafil. The method provided by the invention has the advantages of easily available raw materials, simple operation, greenness, environmental protection and low costs, andis suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method of tadalafil and an intermediate thereof. Background technique [0002] Tadalafil, chemical name (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexa Hydrogenated pyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, white crystalline powder, hardly soluble in water. The English common name is Tadalafil, and the trade names are: Cialis (Cialis), Cialis, Cialis, etc. Its structural formula is as follows: [0003] [0004] Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5) jointly developed by Aix and Eli Lilly and belongs to the second generation of phosphodiesterase inhibitors , it inhibits the combination of cGMP and PDE5 competitively, inactivates PDE5, reduces the hydrolysis of cGMP, and increases the concentration of cGMP to enhance erectile fun...

AI Technical Summary

Problems solved by technology

[0006] At present, there are many synthetic methods for tadalafil. U.S. Patent No. 5,859,006 firstly reports the synthesis of tadalafil. First, D-tryptophan methyl ester is used as a raw material, and trifluoroacetic acid is added as a catalyst in dichloromethane. The aldehyde completes the P-S reaction, and then separates and purifies the desired cis-tetrahydro-β-carboline compound by column chromatography. The cis-carboline compound reacts with chloroacetyl chloride, triethylamine catalyzes the reaction, and finally reacts with methylamine in Synthesis of tadalafil in tetrahydrofuran, this route is a common step to construct carboline compounds through asymmetric synthesis, but it will produce cis and trans isomers, and column chromatography separation is required, which not only causes the loss of the product, but also improves the production efficiency. cost, and is not conducive to industrial green production

[0007] U.S. Patent US7550479 discloses a new process, using isopropanol as a solvent for P-S reaction, through the CIAT process (crystallization-induced asymmetric transformation), so that unwanted diastereoisomers are converted into required cis compounds , but it still doesn't quite convert it,

[0008] At present, the domestic process has also been improved, such as patents CN201710120730.9, CN201510502098.5, CN201310518973.X, CN201310472456.3, etc., which have been optimized, but there are still high raw material prices, complex preparation processes, and difficult to achieve Large-scale production, large environmental pollution and other disadvantages

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