Method for preparing Tadalafil by one-pot method

A technology of tadalafil and aprotic solvents, which is applied in the field of preparation of chemical raw materials, can solve the problems of prolonged production cycle, low yield, unfavorable environmental protection, etc., and achieves the control of waste liquid discharge and the reduction of solvent use Quantity, the effect of shortening the production cycle

Active Publication Date: 2020-02-14
四川省通园制药集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

Method used

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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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Abstract

The invention discloses a method for preparing Tadalafil by a one-pot method. The method for preparing the Tadalafil by the one-pot method comprises the steps that D-Tryptophan methyl ester hydrochloride and piperonal are used as starting materials, and a single-configuration high-purity compound I hydrochloride is obtained through a Pictet-Spengler reaction; the compound I hydrochloride is subjected to an acylation reaction with chloroacetyl chloride in an organic base system of an aprotic solvent to obtain a mixed reaction solution; and the mixed reaction solution is directly added to a methylamine solution to undergo an aminolysis cyclization reaction without treatment, and the mixture is subjected to cooling crystallization to obtain the Tadalafil after the reaction. According to the method for preparing the Tadalafil by the one-pot method, the usage amount of the solvent is reduced, the amount of waste liquid discharge is effectively controlled, and environmental protection is facilitated; the production cycle is shortened, and the process efficiency is improved; and the yield is improved, and the cost is reduced. Compared with an existing process route, the method for preparing the Tadalafil by the one-pot method is more environmentally friendly, more efficient and lower in 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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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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