Praziquantel preparation process

A praziquantel and process technology, applied in the field of drug synthesis, can solve the problems that praziquantel is not suitable for large-scale industrial production, does not meet industrial production requirements, affects the quality of final products, etc., achieves low risk, simplifies operations, and avoids side effects. effect of reaction

Active Publication Date: 2014-02-12
SHANGHAI DESANO CHEM PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] Though this route has the advantages such as reaction raw material is easy to get, and condition is gentle, and yield is higher (about 55.0%), but the methanesulfonic acid that adopts in the reaction is difficult to remove, can remain in final product, affects final product quality, and step It is cumbersome and costly; a large amount of concentrated sulfuric acid is used in the cyclization reaction, which is prone to carbonization side reactions and will also have adverse effects on the environment, which does not meet the requirements of industrial production
[0021] In summary, it can be seen that the preparation process of praziquantel in the prior art has defects and deficiencies that are not suitable for large-scale industrial production, and this area needs to study a kind of process suitable for industrialization to prepare high-purity praziquantel

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: the preparation of formula II compound

[0062]

[0063] Method 1: Add (83g, 1.1mol) glycine and (88g, 2.2mol) sodium hydroxide to 750mL water, under the protection of argon, cool down to 5-10°C, add dropwise (146g, 1.0mol) cyclohexanecarbonyl chloride After the addition, the reaction at room temperature was complete; the pH of the reaction system was adjusted to 1-2 with hydrochloric acid, and a large amount of solid was precipitated, filtered and dried to obtain 178 g of the compound of formula II (96.2% yield).

[0064] Method 2: Add (83g, 1.1mol) glycine and (201g, 2.0mol) triethylamine into 750mL water, under the protection of argon, cool down to -10~-5°C, add dropwise (146g, 1.0mol) cyclohexane After the addition of formyl chloride, the reaction was complete at room temperature; the pH of the reaction system was adjusted to 1-2 with hydrochloric acid, and a large amount of solid precipitated, filtered and dried to obtain 156 g of the compound of f...

Embodiment 2

[0065] Embodiment 2: the preparation of formula IV compound

[0066]

[0067] Method 1: Add (242.36g, 2.0mol) phenethylamine and (44.0g, 1.1mol) sodium hydroxide into the reactor, raise the temperature to 120-125°C, add dropwise (124.57g, 1.0mol) 2-chloroethyl Dimethyl acetal, after dripping, keep warm and continue to react for 6 to 8 hours; finish the reaction, filter, and distill the filtrate under reduced pressure to remove phenethylamine, and the distillation residue is the compound of formula IV (200g), which is directly used for the next reaction.

[0068] Method 2: Add (242.36g, 2.0mol) phenethylamine and (152g, 1.1mol) potassium hydroxide into the reactor, raise the temperature to 130-140°C, and add (152.0g, 1.0mol) 2-chloroacetaldehyde dropwise Diethyl ether, after dropping, keep warm and continue to react for 6 to 8 hours; finish the reaction, filter, and distill the filtrate under reduced pressure to remove phenethylamine, and the distillation residue is the comp...

Embodiment 3

[0069] Embodiment 3: the preparation of formula V compound

[0070]

[0071] Method 1: Add (18.5g, 0.1mol) compound of formula II and (10.0g, 0.157mol) methyl chloroformate (compound of formula III) into 150mL of dichloromethane, and cool down to 0-5°C under the protection of argon , add (10.5g, 0.1mol) triethylamine dropwise, after dropping, continue the reaction for 1h; add (20.9g, 0.1mol) 2,2-dimethoxy-N-phenethylethylamine (compound of formula IV) After the addition, warm up to room temperature and react for 6 to 8 hours; at room temperature, add 4 mL of concentrated sulfuric acid with a mass fraction of 98%, after the addition, continue to react for 16 to 20 hours at room temperature; to end the reaction, add 100 mL of water, separate the liquid, and concentrate Dichloromethane in the dry organic phase; refined with methyl tert-butyl ether; 30.0 g of the compound of formula V was obtained (yield: 96.3%).

[0072] Method 2: Add (18.5g, 0.1mol) compound of formula II an...

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Abstract

The present invention discloses a praziquantel preparation process, which comprises the following one-pot reaction, wherein R1 and R2 in the reaction formula are respectively and independently selected from C1-C4 alkane. According to the present invention, the existing multi-step reaction is combined into the one-pot reaction without any separation and purification operations so as to reduce the material feeding ratio during the reaction process, save the raw materials, reduce the cost, substantially simplify the operations and reduce the three-waste treatment, the high purity product can be obtained with the simple post-treatment, the yield can be up to more than 95%, and the important significance is provided for large-scale praziquantel preparation; and with the process technology, synthesis of the high purity praziquantel by using inexpensive and easily available raw materials, simple operations and mild reaction conditions in the low toxicity, low risk and low cost manner can be achieved, and the industrial production requirements are met.

Description

technical field [0001] The invention relates to a process for preparing praziquantel, which belongs to the technical field of medicine synthesis. Background technique [0002] Praziquantel (Praziquante1), also known as cyclic praziquantel, 8440, is a broad-spectrum antiparasitic drug. It has a wide anti-helminth spectrum, and has killing effects on Schistosoma japonicum, Schistosoma haematobium, and Schistosoma mansoni. In addition, it also has a killing effect on paragonimus (lung fluke), clonorchis sinensis, hydatid, cysticercosis, sparganus monstii, fasciola, tapeworm, etc. The chemical structural formula of praziquantel (I) is as follows: [0003] [0004] At present, there are mainly 6 routes for the synthesis of praziquantel: [0005] Route 1: Using isoquinoline as a starting material, praziquantel was prepared through Reissert reaction, catalytic hydrogenation, acylation, cyclization, hydrolysis and acylation (Experientia, 1977, 33(8): 1036-1037), The reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D241/08C07C217/48C07C213/02C07C233/63C07C231/10
CPCC07C213/02C07C231/02C07D241/08C07D471/04C07C2601/14C07C217/40C07C233/63
Inventor 李金亮赵楠熊毅
Owner SHANGHAI DESANO CHEM PHARMA
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