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Preparation method of Tadalafil compounds

A technology of tadalafil and compounds, which is applied in the field of drug synthesis, can solve problems such as trans isomers, and achieve the effects of improving selectivity, facilitating procurement, and easy reaction process

Active Publication Date: 2017-06-09
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] It can be seen that the prior art of synthesizing tadalafil is mainly based on D-tryptophan methyl ester hydrochloride and piperonal as starting materials, through condensation cyclization, acylation, aminolysis cyclization synthetic route, Constructing the β-tetrahydrocarboline ring by asymmetric synthesis is the key to the whole synthetic route. On the one hand, the Pictet-Spengler (condensation ring closure) reaction is the most effective and commonly used means to construct the β-tetrahydrocarboline ring, but this reaction It is easy to lead to the production of cis- and trans-isomers, and usually requires cumbersome treatments such as column chromatography separation or recrystallization to obtain high-purity cis-carboline intermediates. On the other hand, the important raw material piperonal is subject to "dangerous Chemicals controlled by the Regulations on the Safety Management of Chemicals and the Regulations on the Management of Precursor Chemicals

Method used

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  • Preparation method of Tadalafil compounds
  • Preparation method of Tadalafil compounds
  • Preparation method of Tadalafil compounds

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Preparation of compound Ⅳ

[0028] Add 25.47g of D-tryptophan methyl ester hydrochloride, 16g of NaOH, and 300ml of dichloromethane in turn into the reaction vessel, stir to dissolve, keep the temperature in the ice bath at 0-5°C, and dropwise add dichloromethane containing 11.29g of chloroacetyl chloride 20ml of methane solution was stirred for 2h to complete the reaction to obtain compound III.

[0029] Keep the temperature at 0-5°C in an ice bath, add 17.26 g of 3,4-dihydroxy-benzoyl chloride in 30 ml of dichloromethane solution to the above-prepared compound III, and stir for 2 h to complete the reaction. After the reaction, it was washed 3 times with distilled water (150ml×3), dried by adding sodium sulfate, the solvent was distilled off, and crystallized with 95% ethanol to obtain 37.92g of compound IV with a yield of 88% and a purity of 99.98%.

Embodiment 2

[0031] Preparation of compound Ⅳ

[0032] Add 25.47g of D-tryptophan methyl ester hydrochloride, 11.22g of KOH, and 300ml of dichloromethane in turn into the reaction vessel, stir to dissolve, keep the temperature in an ice bath at 0-5°C, add dropwise the solution containing 11.29g of chloroacetyl chloride 20ml of dichloromethane solution was stirred for 2h to complete the reaction to obtain compound III.

[0033] Keep the temperature at 0-5°C in an ice bath, add 17.26 g of 3,4-dihydroxy-benzoyl chloride in 30 ml of dichloromethane solution to the above-prepared compound III, and stir for 2 h to complete the reaction. After the reaction, it was washed 3 times with distilled water (150ml×3), dried by adding sodium sulfate, the solvent was distilled off, and crystallized with 95% ethanol to obtain 35.77g of compound IV with a yield of 83% and a purity of 99.96%.

Embodiment 3

[0035] Preparation of compound Ⅳ

[0036] Add 25.47g of D-tryptophan methyl ester hydrochloride, 21.2g of sodium carbonate, and 300ml of dichloromethane in turn into the reaction vessel, stir to dissolve, keep the temperature in an ice bath at 0-5°C, and add 11.29g of chloroacetyl chloride dropwise. 20ml of dichloromethane solution, stirred for 2h to complete the reaction, and compound III was obtained.

[0037] Keep the temperature at 0-5°C in an ice bath, add 17.26 g of 3,4-dihydroxy-benzoyl chloride in 30 ml of dichloromethane solution to the above-prepared compound III, and stir for 2 h to complete the reaction. After the reaction, it was washed 3 times with distilled water (150ml×3), dried by adding sodium sulfate, the solvent was distilled off, and crystallized with 95% ethanol to obtain 36.64g of compound IV with a yield of 85% and a purity of 99.96%.

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Abstract

The invention discloses a preparation method of Tadalafil compounds. In the synthetic method, the compound IV is obtained by two-step acylation reaction of a starting material D-tryptophan methyl ester hydrochloride with chloroacetyl chloride and 3,4-dyhydroxy-benzoyl chloride, the compound is obtained by cyclization reaction of the compound IV with phosphorus acyl halide, the compound VI is generated from the compound V via asymmetric hydride reaction and is then reacted with methylamine, and the final Tadalafil compounds are obtained through cyclization reaction of dibromomethane. With the method, use of heliotropin of state controlled chemicals is avoided, cis-type carbine intermediate is obtained by adopting asymmetric hydrogenation, and ee value is above 99%; the preparation method is simple in operation and synthetic reaction, moderate in reaction condition, high in purity and yield, and suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of a tadalafil compound. Background technique [0002] Tadalafil is a phosphodiesterase type V (PDE5) inhibitor. When sexual stimulation leads to the local release of nitric oxide, PDE5 is inhibited by tadalafil, which increases the level of cyclic guanosine monophosphate in the cavernous body of the penis, which leads to Smooth muscles relax and blood flows into the penile tissue, producing an erection. The compound was originally developed by GlaxoSmithKline and subsequently transferred to ICOS, and later jointly developed by ICOS and Eli Lilly. Approved by the FDA in 2003, tadalafil was listed in the United States as a drug for the treatment of male erectile dysfunction. At the beginning of 2014, the drug was approved by the US FDA as a new indication for the treatment of benign prostatic hyperplasia, and the future market capacity will be even wi...

Claims

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Application Information

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IPC IPC(8): C07D471/14C07D471/04C07D209/20
CPCC07D209/20C07D471/04C07D471/14
Inventor 王军刘林叶淼
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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