Industrial preparation method of palonosetron hydrochloride

Abstract

The invention provides an industrial preparation method of palonosetron hydrochloride. The method comprises the following steps: firstly carrying out a reaction on the raw material [1-azabicyclo(2.2.2)octyl-3s-yl]-(1,2,3,4-tetralin-1s-methyl)amine and triphosgene and boron trifluoride diethyl etherate, then adding dilute acid and a stabilizing agent for reflux and obtaining palonosetron hydrochloride free base through extraction; and salifying the palonosetron hydrochloride free base with concentrated hydrochloric acid in mixed solvents including C1-C3 alkyl alcohols and acetone, thus obtaining palonosetron hydrochloride. By the method, the defects of column purification, complex aftertreatment and multiple refining in the prior art are overcome. The method has the following beneficial effects: the method is simple and convenient to operate; the production period is short; and the purity of the obtained product is more than 99.5% and the individual impurity is below 0.1%.

Description

technical field [0001] The invention relates to an industrial preparation method of palonosetron hydrochloride, which belongs to the field of organic synthesis. Background technique [0002] Palonosetron Hydrochloride (Palonosetron Hydrochloride) is a new generation of selective 5-HT3 receptor antagonist, developed by the Swiss Helsinn company, on July 25, 2003, the US FDA approved it for the prevention of moderate or high emesis Acute and delayed vomiting caused by sexual chemotherapy, first launched in the United States under the trade name Aloxi 2 months later. [0003] Palonosetron hydrochloride is the fourth approved 5-HT3 receptor antagonist. Its important feature is a long half-life of about 40 hours, while the half-life of other 5-HT3 receptor antagonists is only a few hours. Moreover, Palonosetron can selectively bind to the 5-HT3 receptor with a strong affinity, and the affinity with the receptor is almost 100 times that of other 5-HT3 antagonists. Palonosetron ...

AI Technical Summary

Problems solved by technology

According to its synthesis process, the resulting palonosetron free base has many impurities and is oily, which is difficult to purify

The salt-forming process requires the use of hydrogen chloride ethanol solution, and hydrogen chloride ethanol solution is difficult to prepare for long-term storage in industrial production

Finally, the purity of the salt-forming product needs to be recrystallized multiple times with isopropanol to reach 99%, and the content of a single impurity is difficult to control below 0.1%. It is very difficult to further improve the purity of the product

[0013] According to the preparation method disclosed in the known technology, the palonosetron hydrochloride crude product is carried out to column purification, and it is found that in industrial production, the amount of solvent required for this step of column purification is very large, it takes a long time, and the toxicity of chloroform is relatively large, which is not necessary. conducive to industrial production

[0014] The salt formation and refining methods disclosed in the current literature are all salt formation with isopropanol system of hydrogen chloride or recrystallization and refinement with isopropanol. Hydrogen chloride is difficult to measure and quantify in large-scale production, and there are also big problems in storage; isopropanol is used as a refining solvent It has the disadvantages of poor impurity removal effect and difficult drying of residual solvents