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Preparation method of tadalafil

A technique for tadalafil and its compounds, which is applied in the field of preparing tadalafil, can solve the problems of expensive hydrochloride, high synthesis cost, and increased drug burden for patients, and achieves short reaction time, simple preparation method, and simple reagents Easy to get effect

Active Publication Date: 2014-05-07
优标易站(苏州)电子商务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Tadalafil can be prepared in the prior art, but the starting materials used are all unnatural, D-tryptophan methyl ester hydrochloride obtained by esterification of D-tryptophan
D-tryptophan methyl ester hydrochloride is expensive, the price per kilogram exceeds 1200 yuan, and accounts for more than 70% of the synthetic material cost of tadalafil, resulting in extremely high synthetic cost of tadalafil, increasing the number of patients drug burden

Method used

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  • Preparation method of tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of compound 6

[0037] Add 100 grams of L-tryptophan methyl ester hydrochloride to the reaction bottle, add 500 milliliters of toluene at room temperature, stir, add 1.2 equivalents of piperonal, heat to 100 ° C, react for 12 hours, cool to room temperature, filter, and use the solid Wash with 150 milliliters of toluene, then dry in oven to constant weight, obtain 148 grams of white solid as compound 6, yield 97%, chemical structural formula is:

[0038]

[0039] 1 H NMR (400 MHz, DMSO): 10.83 (s, 1H), 10.69 (s, 1H), 10.22 (s, 1H), 7.55 (d, 1H, J = 7.8 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.16-7.09 (m, 1H), 7.09-7.02 (m, 3H), 7.02 (s, 1H), 6.11 (s, 2H), 5.87 (s, 1H), 4.74 (s, 1H) , 3.85 (s, 3H), 3.38-3.24 (m, 2H).

Embodiment 2

[0040] Example 2 Preparation of Compound 6

[0041] Add 100 grams of L-tryptophan methyl ester hydrochloride to the reaction bottle, add 500 milliliters of isopropanol at room temperature, stir, add 1.5 equivalents of piperonal, heat to 80 ° C, and react for 15 hours until the raw materials are basically reacted completely. Cool to room temperature, filter, wash the solid with 150 ml of isopropanol, and then dry it in an oven to constant weight to obtain 142 g of white solid as compound 6, with a yield of 93%.

Embodiment 3

[0042] Example 3 Preparation of Compound 6

[0043]Add 100 grams of L-tryptophan methyl ester hydrochloride to the reaction flask, add 800 milliliters of ethyl acetate at room temperature, stir, add 1.3 equivalents of piperonal, heat to 70 ° C, and react for 25 hours until the raw materials are basically reacted completely. Cool to room temperature, filter, wash the solid with 150 ml of ethyl acetate, and then dry it in an oven to constant weight to obtain 136 g of white solid as compound 6 with a yield of 89%.

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Abstract

The invention discloses a preparation method of tadalafil. The concrete preparation method is used for successfully synthesizing tadalafil by taking L-tryptophan methyl ester hydrochloride as an initial raw material and utilizing the characteristics that an ortho-position of an ester group has the chiral inversion property under an alkaline condition, the reaction between ester group and Pictet-Spengler is reversible reaction, and the ester group is easily converted into a cis-form product with relatively small solubility, therefore, the preparation method is a brand new technology. The price of L-tryptophan methyl ester hydrochloride is only less than 1 / 5 of that of D-tryptophan methyl ester hydrochloride, so that the cost of the overall route is greatly lower than that of the prior art, and then the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing tadalafil, which belongs to the field of organic synthesis. Background technique [0002] Tadalafil (trade name Cialis) is the second drug for the treatment of male erectile dysfunction (Erectile Dysfunction, referred to as ED) listed in Europe and the United States after sildenafil. Compared with other anti-ED drugs, tadalafil has a rapid onset of action and the longest duration of drug effect. It is the only drug among the four anti-ED drugs that is not affected by high-fat diet and alcohol intake. In addition to ED indications, Tadalafil was also approved for pulmonary arterial hypertension (PAH) in May 2009 and benign prostatic hyperplasia (BPH) in October 2011. In 2011, the global sales of tadalafil exceeded US$1.87 billion, reaching US$515 million in the first quarter of 2013, which is a typical blockbuster drug. [0003] U.S. Patent US5859006 first described the preparation of tadalafil, specific...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 张士磊苑来旗王建强邱刚钱彭飞
Owner 优标易站(苏州)电子商务有限公司
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