Preparation method for praziquantel and intermediate compounds thereof

Patent metadata

Field	Value
Publication number	US-10035798-B2
Application number	US-201515550190-A
Country	US
Kind code	B2
Filing date	Feb 12, 2015
Priority date	Feb 12, 2015
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

Disclosed is a preparation method for praziquantel and intermediates thereof. The method includes: obtaining a target product praziquantel by using β-phenethylamine as an initial raw material through a condensation reaction with chloroacetyl chloride, a substitution reaction with ethanolamine, and an acylation reaction with cyclohexanecarbonyl chloride, followed by an oxidation reaction and cyclization reaction. Also disclosed are two key intermediates, namely, a compound of formula IV and a compound of formula V for preparing praziquantel. The preparation method is reasonable and simple in its technological design, uses moderate reaction conditions, and is economical and environmentally friendly. Additionally, the raw materials are inexpensive and easy to obtain, the key intermediates are easy to prepare, and the total reaction yield and purity of the obtained target compound praziquantel is high, so that industrialized mass production is easy to achieve.

First claim

The invention claimed is:

1. A process for preparing Praziquantel, comprising the steps of:
1) subjecting β-phenethylamine and chloroacetyl chloride to condensation reaction in the presence of alkaline substance to give the compound of formula II;

2) subjecting the compound of formula II and ethanolamine to substitution reaction to give the compound of formula III;

3) subjecting the compound of formula III and cyclohexanecarbonyl chloride to acylation reaction in the presence of alkaline substance to give the compound of formula IV;

4) subjecting the compound of formula IV to oxidation reaction in the presence of oxidizing agent to give the compound of formula V; and

5) subjecting the compound of formula V to cyclization reaction in the presence of cyclizing agent to give Praziquantel as the compound of formula I

2. The process according to claim 1 , wherein,
step 1), step 2), step 3), step 4) or step 5) is performed without solvent or performed with at least one aprotic organic solvent as solvent.

3. The process according to claim 1 , wherein,
step 2) is performed without solvent and step 1), step 3), step 4) or step 5) is performed with at least one aprotic organic solvent as solvent.

4. The process according to claim 2 , wherein,
the aprotic organic solvent is at least one selected from the group consisting of ethers solvent, aromatic hydrocarbons solvent, hydrocarbons or halogenated hydrocarbons solvent and esters solvent.

5. The process according to claim 4 , wherein,
the ethers solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 1,2-dimethoxylethane, methyl tert-butyl ether and 2-methyltetrahydrofuran;
the aromatic hydrocarbons solvent is selected from the group consisting of benzene, toluene, ethylbenzene and xylene;
the hydrocarbons or halogenated hydrocarbons solvent is selected from the group consisting of n-hexane, cyclohexane, n-heptane, dichloromethane, trichloromethane and dichloroethane;
the esters solvent is selected from the group consisting of methyl formate, ethyl formate, methyl acetate, ethyl acetate and isopropyl acetate.

6. The process according to claim 1 , wherein,
the reaction temperature of step 1), step 2), step 3), step 4) or step 5) is −10° C. to 100° C.

7. The process according to claim 1 , wherein,
step 1), step 2), step 3), step 4) or step 5) is performed under ice water bath, room temperature or 0° C. to 40° C.

8. The process according to claim 1 , wherein,
step 1), step 3) or step 5) is performed under ice water bath, step 2) is performed at room temperature, and step 4) is performed at 0° C. to 40° C.

9. The process according to claim 1 , wherein,
the alkaline substance in step 1) and step 3) is one or more each independently selected from the group consisting of triethylamine, imidazole, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, diisopropylamine, dimethylisopropylamine, diisopropylethylamine, NaOH, Na 2 CO 3 , NaHCO 3 , KOH and K 2 CO 3 .

10. The process according to claim 1 , wherein,
the molar ratio of the compound of formula II to ethanolamine in step 2) is 1:2-1:15.

11. The process according to claim 1 , wherein,
the oxidizing agent in step 4) is at least one group selected from the group consisting of: NaClO/TEMPO/NaBr, Ca(ClO) 2 /TEMPO/NaBr, TCCA/TEMPO, DMSO/SO 3 -Py/Et 3 N, NaNO 2 /FeCl 3 /TEMPO/air, and NaNO 2 /FeCl 3 /TEMPO/O 2 .

12. The process according to claim 1 , wherein,
the cyclizing agent in step 5) is one or more selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, perchloric acid and concentrated sulfuric acid.

13. The process according to claim 5 , wherein,
the ethers solvent is methyl tert-butyl ether;
the aromatic hydrocarbons solvent is toluene;
the hydrocarbons or halogenated hydrocarbons solvent is dichloromethane; and
the esters solvent is ethyl acetate or isopropyl acetate.

14. The process according to claim 6 , wherein, the reaction temperature of step 1), step 2), step 3), step 4) or step 5) is 0° C. to 40° C.

15. The process according to claim 6 , wherein, the reaction temperature of step 1), step 2), step 3), step 4) or step 5) is 5° C. to 15° C.

16. The process according to claim 8 , wherein, step 1), step 3) or step 5) is performed under ice water bath, step 2) is performed at room temperature, and step 4) is performed at 5° C. to 15° C.

17. The process according to claim 8 , wherein, step 1), step 3) or step 5) is performed under ice water bath, step 2) is performed at room temperature, and step 4) is performed at 10° C. to 15° C.

18. The process according to claim 9 , wherein, the alkaline substance in step 1) and step 3) is one or more each independently selected from the group consisting of triethylamine, NaOH, Na 2 CO 3 , NaHCO 3 , KOH and K 2 CO 3 .

19. The process according to claim 10 , wherein, the molar ratio of the compound of formula II to ethanolamine in step 2) is 1:3-1:8.

20. The process according to claim 12 , wherein, the cyclizing agent in step 5) is one or more selected from the group consisting of concentrated sulfuric acid and methanesulfonic acid.

Assignees

• Zhejiang Hisun Pharm Co Ltd
• Shanghai Inst Pharmaceutical Ind

Inventors

• Zhang Fuli
• Yang Zhezhou
• Bao Rusheng
• Xu Weiwei
• Bai Hua

Classifications

• A61P33/12

  Schistosomicides · CPC title

• A61P33/10

  Anthelmintics · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• C07C231/14

  by formation of carboxamide groups together with reactions not involving the carboxamide groups · CPC title