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Synthetic method of palonosetron hydrochloride

A technology of palonosetron and a synthesis method, applied in the field of organic synthesis of medicines, can solve the problems of low product yield, high price of tetrahydronaphthoic acid, unfavorable for industrialized production and the like, and achieves the effect of improving optical purity

Active Publication Date: 2013-07-03
KUNMING JIDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Raw material (S)-tetrahydronaphthoic acid price is more expensive in this method, and product yield is low, and production cost height is unfavorable for industrialized production

Method used

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  • Synthetic method of palonosetron hydrochloride
  • Synthetic method of palonosetron hydrochloride
  • Synthetic method of palonosetron hydrochloride

Examples

Experimental program
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Embodiment 1

[0033] The preparation of embodiment 1 (S, S)-quinuclidine tetrahydronaphthalene carboxamide

[0034] Add 12.6 g of racemic tetralincarboxylic acid and ethyl acetate into the reactor, stir, and add 0.2 ml of N,N-dimethylformamide. After complete dissolution, add thionyl chloride 12ml dropwise. After the dropwise addition, cool down to 10±2°C and stir for 3 hours, then raise the temperature to 50±2°C and stir for 3 hours. The reaction solution was concentrated under reduced pressure below 60±2°C, then added ethyl acetate, then concentrated under reduced pressure below 70±2°C to remove the solvent, and then added ethyl acetate to obtain a tetrahydronaphthoyl chloride-ethyl acetate solution for later use . Add 8.7g of S-3-aminoquinuclidine hydrochloride, ethyl acetate, and 25ml of triethylamine into the reactor, under nitrogen protection, stir at 30±2°C for 0.5 hours, cool to 15±2°C, and The naphthoyl chloride-ethyl acetate solution was added dropwise to the reaction solution. ...

Embodiment 2

[0035] The preparation of embodiment 2 (S, S)-quinuclidine tetrahydronaphthalene carboxamide

[0036] Add 12.6 g of tetralincarboxylic acid and ethyl acetate into the reactor, mix well, and add 0.2 ml of N,N-dimethylformamide. After complete dissolution, add 12ml of thionyl chloride dropwise. After the dropwise addition, raise the temperature to 20±2°C and stir for 1.5 hours, then raise the temperature to 55±2°C and stir for 1 hour. The reaction solution was concentrated under reduced pressure below 60±2°C, then added ethyl acetate, then concentrated under reduced pressure below 70±2°C to remove the solvent, and then added ethyl acetate to obtain a tetrahydronaphthoyl chloride-ethyl acetate solution for later use . Add 8.7g of S-3-aminoquinuclidine hydrochloride, ethyl acetate, and 25ml of triethylamine into the reactor, under nitrogen protection, stir at 10±2°C for 2 hours, and tetrahydronaphthoyl chloride-ethyl acetate The solution was added dropwise to the reaction liquid...

Embodiment 3

[0037] The preparation of embodiment 3 (S, S)-quinuclidine tetrahydronaphthalene carboxamide

[0038] Add 12.6 g of tetralincarboxylic acid and ethyl acetate into the reactor, mix well, and add 0.2 ml of N,N-dimethylformamide. After complete dissolution, add 12ml of thionyl chloride dropwise. After the dropwise addition, raise the temperature to 30±2°C and stir for 0.5 hours, then raise the temperature to 60±2°C and stir for 0.5 hours, concentrate under reduced pressure, then add ethyl acetate, and then Concentrate under reduced pressure below ±2°C to remove the solvent, then add ethyl acetate to obtain a tetrahydronaphthoyl chloride-ethyl acetate solution, which is set aside. Add 8.7g of S-3-aminoquinuclidinine hydrochloride, ethyl acetate, and 25ml of triethylamine into the reactor, under nitrogen protection, stir at 20±2°C for 1.5 hours, and tetrahydronaphthoyl chloride-ethyl acetate The solution was added dropwise to the reaction liquid. After the dropwise addition, heat...

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Abstract

The invention relates to a new synthetic method of palonosetron hydrochloride, and belongs to the field of pharmaceutical organic synthesis. The synthetic method adopts racemized tetrahydro naphthoic acid as a raw material; a reaction is carried out with thionyl chloride and (S)-3-aminoquinuclidine; after repeated washing, (S,S)-quinuclidine tetrahydronaphthalene carboxamide is obtained; the amide is reacted with sodium borohydride and boron trifluoride diethyl etherate; the product is added into a hydrochloric acid aqueous solution to obtain the palonosetron hydrochloride. According to the method, in the amide synthetic process, ethyl acetate is used as a solvent, which reduces the generation of by-products. In addition, according to the method, in the post-treatment process, impurities are removed by phase transfer, which increases product optical purity; through repeated washing, other impurities generated in the reaction are removed, and high-purity product is obtained.

Description

technical field [0001] The invention relates to a new synthesis method of organic compounds, in particular to a new synthesis method of medicinal compounds, which belongs to the field of organic synthesis of medicines. Background technique [0002] Palonosetron hydrochloride (PalonoSetron hydrochloride) is a selective 5-HT3 receptor antagonist developed by HelSinn Company in Switzerland. Its chemical name is: (3αS)-2-[(3S)-1-azabicyclo[2.2.2 ]octyl]-2,3,3α,4,5,6-hexahydro-1-oxo-1H-phenylhydrazine [de]isoquinoline hydrochloride, the structural formula is shown in the figure below. [0003] [0004] On July 25, 2003, the US FDA approved the drug for the prevention of acute or delayed nausea and vomiting caused by moderate to highly emetogenic chemotherapy, and the drug was first launched in the United States two months later. [0005] Palonosetron hydrochloride is the fourth 5-HT3 receptor antagonist approved by the FDA. The biggest feature of palonosetron is that its hal...

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCY02P20/582
Inventor 刘小龙刘荣昌黄巧萍
Owner KUNMING JIDA PHARMA