CN109942468B - Process method for preparing cadotril from 3-phenyl-1-propyne - Google Patents
Process method for preparing cadotril from 3-phenyl-1-propyne Download PDFInfo
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Abstract
A process method for preparing cadotril by 3-phenyl-1-propyne, which belongs to the technical field of medical intermediates. In the process of preparing cadotril, the yield and purity of the intermediate benzyl acrylic acid are most important, and the method firstly adopts 3-phenyl-1-propyne as a raw material and adopts palladium as raw materialCatalyst Pd2(dba)3And ligand dppp to react with ethyl carbonate under catalysis, so that one-step synthesis of benzyl acrylic acid is realized, the method has the advantages that addition reaction can be completed under normal pressure, the tolerance of functional groups is good, the efficiency is high, the purity is high, the production flow is greatly simplified, and the yield and the purity of the obtained target product cadotril are much higher than those of the traditional technological process. The method has the advantages of greatly improving the yield, reducing the cost, improving the safety, saving energy and the like, and meets the modern chemical production requirement of green reaction.
Description
Technical Field
The invention relates to a process method for preparing cadotril by using 3-phenyl-1-propyne as an initial raw material, belonging to the technical field of medical intermediates.
Background
The cadotril is mainly used for selectively and reversibly inhibiting enkephalinase, so that endogenous enkephalin is protected from being degraded, and the physiological activity of the endogenous enkephalin in the digestive tract is prolonged. The clinical application is mainly used for treating digestive tract diseases such as acute diarrhea, and the cadotril does not affect the enkephalinase activity of the central nervous system, has no obvious influence on gastrointestinal peristalsis and intestinal basal secretion, and has quick effect and safe taking. In addition, racecadotril can be taken together with food, water or breast milk, is convenient to apply, and can also be used as an organic synthesis intermediate such as perfume and dye. In the process of preparing cadotril, the yield and the purity of an intermediate benzyl acrylic acid are most important, the benzyl acrylic acid is basically prepared by more than three steps in the traditional process, the reaction time is more than 40 hours, the reaction steps are more, the yield is poor, the working difficulty is greatly increased, the production flow is more complex, and the production cost is increased.
Disclosure of Invention
The purpose of the invention is to use 3-phenyl-1-propyne as the initial raw material and to use Pd as the palladium catalyst2(dba)3The method has the advantages that the method realizes one-step synthesis of benzyl acrylic acid by reacting with ethyl carbonate under the catalysis of (tris (dibenzylideneacetone) dipalladium) and ligand dppp (1, 3-bis (diphenylphosphino) propane), prepares cadotril with high purity, high selectivity and high yield at mild temperature, greatly simplifies the process, reduces the production cost, greatly improves the experimental safety, and meets the requirements of green modern production.
The technical scheme adopted by the invention is as follows: synthetic route to cadotril by reference to 3-phenyl-1-propyne as starting material:
the cadotril structure is as follows:
the method comprises the following steps:
adding 3-phenyl-1-propyne, monoethyl carbonate and Pd into a 500mL three-neck flask2(dba)3，dppp, finally adding solvent anhydrous toluene, stirring for 10min under the protection of nitrogen, and slowly heating to 100 ℃. The reaction was carried out for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Filtering the catalyst, adding a 20% NaOH solution, heating and refluxing for 2h, cooling to room temperature, standing for layering, adding concentrated hydrochloric acid to adjust the pH to 1, extracting an aqueous phase with ethyl acetate, combining organic phases, spin-drying the solvent, and drying in vacuum; recrystallizing with ethanol to obtain white solid benzyl acrylic acid;
stirring benzyl acrylic acid and thioacetic acid in a 500mL three-port reaction bottle at 100 ℃ for 2 hours; after the reaction is finished, the reaction liquid is cooled to room temperature, partial thioacetic acid is distilled under pressure, then toluene solvent is added, the thioacetic acid is continuously distilled under pressure to completely remove, and recrystallization is carried out by ethanol to obtain white solid 2-acetylthiomethyl-3-phenylpropionic acid.
2-acetylthiomethyl-3-phenylpropionic acid and DMF (solvent) are added into a 500mL three-mouth reaction bottle, cooled to 0 ℃, added with glycine benzyl ester p-toluenesulfonate and triethylamine, and finally added with DMF solution of HOBT (1-hydroxybenzotriazole) and DCC (dicyclohexylcarbodiimide). Stirring for 1h, heating to room temperature, stirring for 15h, filtering out DMF solvent after the reaction is finished to obtain crude product cadotril, and recrystallizing with ethanol to obtain white crystalline powder.
The invention has the beneficial effects that: 3-phenyl-1-propyne is taken as a starting material, and is subjected to Pd catalysis by palladium catalyst2(dba)3And the ligand dppp is catalyzed to react with the ethyl carbonate to realize one-step synthesis of the benzyl acrylic acid, and the cadotril with high purity, high selectivity and high yield, low cost, environmental protection and health can be prepared at mild temperature. In the process of preparing cadotril, the yield and purity of the intermediate benzyl acrylic acid are most important, and the method firstly adopts 3-phenyl-1-propyne as raw material and introduces Pd2(dba)3And ligand dppp catalyst, the reaction is realized under normal pressure, the tolerance of functional groups is good, the efficiency is high, the production flow is greatly simplified, and the yield and the purity of the obtained cadotril are much higher than those of the traditional technological process. The final product was a white crystalline powder; no odor, and high purity. The improved synthetic route has the advantages of greatly improving the yield, improving the safety, saving energy and the like, meets the requirement of modern chemical production of green reaction, reduces the production cost and leads the reaction steps to be improved constructively.
Detailed Description
The invention is further illustrated by the following examples, which are intended to provide a better understanding of the contents of the invention. The examples given therefore do not limit the scope of protection of the invention.
Example 1: benzyl acrylic acid
In a 500mL three-necked flask, 3-phenyl-1-propyne (11.6g, 0.1moL), monoethyl carbonate (9g,0.1moL), Pd were added2(dba)3(0.46g,0.01moL)，dppp (0.4g,0.02moL), 200mL of solvent anhydrous toluene was added, stirred for 10min under nitrogen protection, and slowly warmed to 100 ℃. The reaction was carried out for 24 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Filtering the catalyst, adding 100mL of 20% NaOH solution, heating and refluxing for 2h, cooling to room temperature, standing for layering, adding concentrated hydrochloric acid to adjust the pH to 1, extracting the aqueous phase with ethyl acetate, combining the organic phases, spin-drying the solvent, and drying in vacuum; recrystallization from ethanol gave 13g of benzylacrylic acid as a white solid. The yield was 80%. MS (EI) M/z 162.07([ M ]]+)。
Example 2: 2-acetylthiomethyl-3-phenylpropionic acid
Benzylacrylic acid (13g, 0.08moL) thioacetic acid (7.3g,0.096moL) was added to a 500mL three-necked reaction flask and stirred at 100 ℃ for 2 h; after the reaction was completed, the reaction solution was cooled to room temperature, a part of the thioacetic acid was distilled off under pressure, then 100mL of a toluene solvent was added, the thioacetic acid was further distilled off under pressure completely, and recrystallization from ethanol gave 17g of 2-acetylthiomethyl-3-phenylpropionic acid as a white solid. The yield was 90%. MS (EI) M/z 238.07([ M ]]+)。
Example 3: cadotril
2-acetylthiomethyl-3-phenylpropionic acid (17g,0.072moL), solvent 150mL DMF was added to a 500mL three-necked reaction flask, cooled to 0 deg.C, added glycine benzyl ester p-toluenesulfonate (24.2g,0.072moL), triethylamine 10moL, and finally added 30mL of a DMF solution of HOBT (11g,0.072moL), DCC (15.7g,0.072 moL). Stirring for 1h, stirring at room temperature for 15h, ending the reaction, filtering out DMF solvent to obtain crude product cadotril, and recrystallizing with ethanol to obtain white crystalline powder 19.4g, yield 70%. MS (EI) M/z 385.13([ M ]]+)。
Example 4: the new process is compared with the conventional process
TABLE 1 comparison of various data of the new process and the conventional process
As can be seen from the above table, the intermediate benzylacrylic acid obtained in the conventional process basically undergoes more than three steps of reaction, the reaction time is more than 40 hours, the number of reaction steps is large, the yield is poor, the working difficulty is greatly increased, the production process is complex, and the production cost is increased. The process adopts 3-phenyl-1-propyne as a starting material and adopts Pd as a palladium catalyst2(dba)3And the ligand dppp is catalyzed to react with the ethyl carbonate to realize one-step synthesis of the benzyl acrylic acid, so that the yield and the purity of the product are improved, the process is simple, the operation is safe, and the process is green and environment-friendly.
Claims (1)
1. A process for preparing cadotril from 3-phenyl-1-propyne is characterized by comprising the following steps:
adding 3-phenyl-1-propyne, monoethyl carbonate, tris (dibenzylideneacetone) dipalladium and a ligand 1, 3-bis (diphenylphosphino) propane into a 500mL three-neck flask, finally adding a solvent of anhydrous toluene, stirring for 10min under the protection of nitrogen, slowly heating to 100 ℃, and reacting for 24 hours; after the reaction is finished, cooling and filtering, adding a 20% NaOH solution, heating and refluxing for 2h, cooling, adding concentrated hydrochloric acid to adjust the pH to 1, extracting an aqueous phase with ethyl acetate, combining organic phases, spin-drying the solvent, and drying in vacuum; recrystallizing with ethanol to obtain white solid benzyl acrylic acid; the 3-phenyl-1-phenylalkyne: tris (dibenzylideneacetone) dipalladium: the molar ratio of the 1, 3-bis (diphenylphosphino) propane is 10:1: 2;
stirring benzyl acrylic acid and thioacetic acid in a 500mL three-mouth reaction bottle at 100 ℃ for 2h, cooling after the reaction is finished, evaporating the thioacetic acid, and recrystallizing with ethanol to obtain white solid 2-acetylthiomethyl-3-phenylpropionic acid; the benzyl acrylic acid: the mol ratio of thioacetic acid is 1: 1.2;
adding 2-acetylthiomethyl-3-phenylpropionic acid and a solvent DMF (dimethyl formamide) into a 500mL three-mouth reaction bottle, cooling to 0 ℃, adding glycine benzyl ester p-toluenesulfonate and triethylamine, and finally adding 1-hydroxybenzotriazole and a DMF solution of dicyclohexylcarbodiimide; the 2-acetylthiomethyl-3-phenylpropionic acid: glycine benzyl ester p-methylbenzenesulfonate: 1-hydroxybenzotriazole: the molar ratio of dicyclohexylcarbodiimide is 1:1:1: 1; stirring for 1h, then heating to room temperature and stirring for 15h, after the reaction is finished, filtering out DMF solvent to obtain crude product cadotril, and recrystallizing with ethanol to obtain white crystal powder.
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