A kind of process for preparing cadoxtril by 3-phenyl-1-propyne

A process method, the technology of Cardotril, which is applied in the field of pharmaceutical intermediates, can solve the problems of complex production process, increased work difficulty, and many reaction steps, and achieve the effects of low cost, energy saving, and simplified production process

Active Publication Date: 2020-09-29
大连万福制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of preparing caduotri, the yield and purity of the intermediate benzyl acrylic acid are the most important. In the traditional process, the preparation of benzyl acrylic acid basically undergoes more than three steps of reaction, the reaction time is more than 40 hours, and there are many reaction steps. The rate is poor, the difficulty of work is greatly increased, and the production process is more complicated, which increases the cost of production

Method used

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  • A kind of process for preparing cadoxtril by 3-phenyl-1-propyne
  • A kind of process for preparing cadoxtril by 3-phenyl-1-propyne
  • A kind of process for preparing cadoxtril by 3-phenyl-1-propyne

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] Example 1: Benzyl Acrylic Acid

[0015]

[0016] In a 500mL three-necked flask, 3-phenyl-1-propyne (11.6g, 0.1moL), monoethyl carbonate (9g, 0.1moL), Pd 2 (dba) 3 (0.46g, 0.01moL) ， dppp (0.4g, 0.02moL), and finally add 200mL solvent anhydrous toluene, stir for 10min under nitrogen protection, and slowly raise the temperature to 100°C. React for 24 hours. After the reaction, the reaction liquid was cooled to room temperature. Filter the catalyst, then add 100mL of 20% NaOH solution, heat to reflux for 2h, cool to room temperature and let stand to separate layers, add concentrated hydrochloric acid to adjust the pH=1, extract the aqueous phase with ethyl acetate, combine the organic phase, spin to dry the solvent, and dry in vacuum; Recrystallization with ethanol gave 13 g of white solid benzyl acrylic acid. Yield 80%. MS(EI):m / z:162.07([M] + ).

Embodiment 2

[0017] Example 2: 2-acetylthiomethyl-3-phenylpropionic acid

[0018]

[0019] Add benzylacrylic acid (13g, 0.08moL) and thioacetic acid (7.3g, 0.096moL) into a 500mL three-necked reaction flask, and stir at 100°C for 2h; Thioacetic acid, then add 100mL toluene solvent, continue pressure distillation to completely remove thioacetic acid, recrystallize with ethanol to obtain white solid 2-acetylthiomethyl-3-phenylpropionic acid 17g. Yield 90%. MS(EI):m / z:238.07([M] + ).

Embodiment 3

[0020] Embodiment 3: Cardotril

[0021]

[0022] Add 2-acetylthiomethyl-3-phenylpropionic acid (17g, 0.072moL) and solvent 150mL DMF into a 500mL three-necked reaction flask, cool to 0°C, add glycine benzyl ester p-toluenesulfonate (24.2 g, 0.072moL), triethylamine 10mol, and finally add HOBT (11g, 0.072moL), DCC (15.7g, 0.072moL) DMF solution 30mL. Stir for 1 h, then rise to room temperature and stir for 15 h. After the reaction is completed, filter out the DMF solvent to obtain the crude product cadotril, which is recrystallized with ethanol to obtain 19.4 g of white crystalline powder with a yield of 70%. MS(EI):m / z:385.13([M] + ).

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Abstract

The invention relates to a technology method for preparing racecadotril through 3-phenyl-1-allylene and belongs to the technical field of medical intermediates. In the process of preparing the racecadotril, the yield and purity of an intermediate benzylacrylic acid are most important. By means of the method, the 3-phenyl-1-allylene is adopted as a raw material, and under catalysis of a palladium catalyst Pd2(dba)3 and a ligand dppp, the 3-phenyl-1-allylene and ethyl carbonate react for one-step synthesis of the benzylacrylic acid. The method is characterized in that an addition reaction can becompleted at normal pressure, the tolerance of functional groups is good, the efficiency and purity are high, the production process is greatly simplified, and the yield and purity of the obtained target product racecadotril are higher than those of the racecadotril obtained through a traditional technology. The method has the advantages that the yield is greatly increased, the cost is lowered, the safety is improved, and energy is saved and meets the production requirement of modern chemical industry for an environment-friendly reaction.

Description

technical field [0001] The invention relates to a process for preparing cadoxtril by using 3-phenyl-1-propyne as an initial raw material, which belongs to the technical field of pharmaceutical intermediates. Background technique [0002] Cardotril is mainly used to selectively and reversibly inhibit enkephalinase, so as to protect endogenous enkephalins from degradation and prolong the physiological activity of endogenous enkephalins in the digestive tract. Clinically, it is mainly used to treat gastrointestinal diseases such as acute diarrhea, and cardotril does not affect the activity of enkephalinase in the central nervous system, and has no obvious effect on gastrointestinal peristalsis and intestinal basic secretion. It has a rapid effect and is safe to take. In addition, racecadotril can be taken with food, water or breast milk, which is convenient to use, and can also be used as an intermediate in organic synthesis such as spices and dyes. In the process of preparing...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C327/32
Inventor 倪妮孙庆发方典军钟良伟魏克思赵庆迪姜云功高业枝
Owner 大连万福制药有限公司
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