A kind of one pot method prepares the method for tadalafil

A tadalafil and aprotic solvent technology, applied in the field of chemical raw material preparation, can solve problems such as low yield, prolonged production cycle, unfavorable environmental protection, etc., to reduce solvent usage and control waste liquid discharge The effect of shortening the production cycle

Active Publication Date: 2021-04-06
四川省通园制药集团有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In summary, the above synthetic methods all need to obtain the solid intermediate product compound II, and then proceed to the next step of reaction, which makes the reaction time longer, consumes more reagents, and increases waste liquid discharge, which is not conducive to environmental protection; consumes more energy and manpower prolong the production cycle, which is not conducive to cost control and process efficiency improvement; the yield is not high, the weight yield is the lowest 45.2%, the highest 90.0%
Although there are many methods for preparing tadalafil at present, there is no bibliographical report that the intermediate product compound II does not need to be processed and can be continuously reacted to obtain the method of tadalafil

Method used

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  • A kind of one pot method prepares the method for tadalafil
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  • A kind of one pot method prepares the method for tadalafil

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Experimental program
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Effect test

Embodiment 1

[0031] Embodiment 1: a kind of one-pot method prepares the method for tadalafil, it comprises the following steps:

[0032] S1. The hydrochloride of compound I adds an organic base tetramethylguanidine to the aprotic solvent N,N-dimethylformamide, and reacts with chloroacetyl chloride at a reaction temperature of -10°C and a reaction time of 2 hours to obtain The reaction mixture of compound II; wherein, the hydrochloride of compound I uses D-tryptophan methyl ester hydrochloride and piperonal as starting materials, and obtains the hydrochloride of compound I through Pictet-Spengler reaction; The mol ratio of compound I, chloroacetyl chloride and organic base is 1:1.0:2; the mass volume ratio of compound I and aprotic solvent is 1:4;

[0033] S2. Adding a 40% mass percent methylamine aqueous solution to the compound II reaction mixture, the molar ratio of the compound I to the methylamine solution is 1:1.5, and the temperature is raised to react, the reaction temperature is 30...

Embodiment 2

[0034] Embodiment 2: a kind of one-pot method prepares the method for tadalafil, it comprises the following steps:

[0035] S1. Add the organic base N,N-diisopropylethylamine to the hydrochloride of compound I in the aprotic solvent dichloromethane, react with chloroacetyl chloride, the reaction temperature is 20°C, and the reaction time is 4h to obtain the compound The reaction mixture of II; wherein, the hydrochloride of the compound I takes D-tryptophan methyl ester hydrochloride and piperonal as starting materials, and obtains the hydrochloride of the compound I through the Pictet-Spengler reaction; the The molar ratio of compound I, chloroacetyl chloride and organic base is 1:2:5; the mass volume ratio of compound I and aprotic solvent is 1:10;

[0036] S2. Add a 40% mass percent methylamine alcohol solution to the reaction mixture of compound II, the molar ratio of compound I to methylamine solution is 1:5, heat up the reaction, the reaction temperature is 65°C, and the ...

Embodiment 3

[0037] Embodiment 3: a kind of one-pot method prepares the method for tadalafil, it comprises the following steps:

[0038] S1. Add the organic base diisopropylamine to the hydrochloride of compound I in the aprotic solvent ethyl acetate, react with chloroacetyl chloride, the reaction temperature is -5°C, the reaction time is 2.5h, and the reaction mixture of compound II is obtained Wherein, the hydrochloride of the compound I takes D-tryptophan methyl ester hydrochloride and piperonal as starting materials, and obtains the hydrochloride of the compound I through the Pictet-Spengler reaction; the compound I, ethyl chloride The mol ratio of acid chloride and organic base is 1:1.2:2.5; the mass volume ratio of compound I and aprotic solvent is 1:5;

[0039] S2. Add a 40% mass percent methylamine aqueous solution to the compound II reaction mixture, the molar ratio of the compound I to the methylamine solution is 1:2, heat up the reaction, the reaction temperature is 35°C, and th...

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PUM

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Abstract

The invention discloses a method for preparing tadalafil by a one-pot method. Using D-tryptophan methyl ester hydrochloride and piperonal as starting materials, a high-purity compound I with a single configuration is obtained through Pictet-Spengler reaction Hydrochloride, and then acylated with chloroacetyl chloride in an organic base system of an aprotic solvent to obtain a mixed reaction solution. The mixed reaction solution is not treated and directly added to methylamine solution to undergo an aminolysis and cyclization reaction. After the reaction, cooling crystallization Later got tadalafil. The method of the invention reduces the amount of solvent used, thereby effectively controlling the discharge of waste liquid, which is beneficial to environmental protection; the production cycle is shortened, the process efficiency is improved; the yield is increased and the cost is reduced. Compared with the existing process route, the present invention is more environmentally friendly, has higher efficiency and lower cost, and is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of preparation of chemical raw materials, and in particular relates to a method for preparing tadalafil by a one-pot method. Background technique [0002] Tadalafil, the chemical name is (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12, 12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione; molecular weight: 389.41; molecular formula C 22 h 19 N 3 o 4 ;The structural formula is as follows: [0003] [0004] Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5). Tadalafil was originally developed by Glaxo Wellcome Laboratories, then transferred to ICOS, and then ICOS and Eli Lilly jointly developed it. In 2003, it was approved by the U.S. FDA to go on the market. The product name is "Cialis", and the indication is male erectile dysfunction (ED). It is also approved in the United States and Europe for benign prostatic hyper...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14
CPCC07B2200/07C07D471/14
Inventor 邓俊丰高洪波
Owner 四川省通园制药集团有限公司
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