Production technique of hydrochloric acid palonosetron

A technology of palonosetron and hydrochloric acid, which is applied in the field of new production technology, can solve the problems of product yield reduction, difficulty, and purity difficulty, and achieve the effects of improving product quality, simplifying operation steps, and optimizing technology

Active Publication Date: 2008-04-09
HANGZHOU JIUYUAN GENE ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method requires multiple recrystallizations to remove impurities, which will lead to a reduction in product yield, and the overall synthesis yield is only about 6%.
Moreover, although multiple recrystallization methods can barely make the purity of the finished product reach about 99%, it is very difficult to continue to improve its purity on this basis, especially it is very difficult to control a single impurity below 0.1%

Method used

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  • Production technique of hydrochloric acid palonosetron
  • Production technique of hydrochloric acid palonosetron
  • Production technique of hydrochloric acid palonosetron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 1,2,3,4-tetrahydro-1-naphthoic acid preparation

[0028] ①Reaction formula:

[0029]

[0030] ②Operation method:

[0031] In a 250ml three-neck flask, add 7.4g (66mmol) potassium tert-butoxide, vacuumize, and blow nitrogen three times. Then add 170ml of n-hexane and 7.8ml (52mmol) tetramethylbutanediamine with a needle tube, cool to -30°C, stir for 10 minutes, slowly add 33ml of n-butyllithium with a needle tube, after the dropwise addition is complete, stir for another 10 minutes , add 8.5ml (63mmol) tetrahydronaphthalene, stir at -30°C for 30 minutes, then naturally warm up to room temperature, feed carbon dioxide for 30 minutes, then slowly add 120ml of water, separate layers, take the water layer and acidify it with hydrochloric acid, and use Extracted with ethyl acetate three times, combined the ethyl acetate layers, washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and recovered the solvent under...

Embodiment 2

[0032] Example 2 Preparation of N-[1-azabicyclo(2.2.2)octyl-3S-yl]-1,2,3,4-tetrahydronaphthalene-1S-carboxamide

[0033] ①Reaction formula:

[0034]

[0035] ②Operation method:

[0036]In a 100ml three-neck flask, add 5.81g (33mmol) of compound and 50ml of toluene, and then add 12ml of thionyl chloride. Heat to reflux and stir the reaction at reflux for 1 hour. Reaction complete, distill off most of toluene, remaining toluene solution is dripped slowly in the solution (80ml) of ethyl acetate that is dissolved with 5.97g (S)-3-aminoquinuclidine hydrochloride (30mmol), The reaction was continued for 3 hours at room temperature. After the reaction was completed, 50% sodium hydroxide solution was added to adjust the pH to alkaline. Then extract twice with ethyl acetate, combine the ethyl acetate layers, wash once with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and recover the solvent under reduced pressure to obtain a crude product, whic...

Embodiment 3

[0037] Example 3 Preparation of [1-azabicyclo (2.2.2) octane-3S-yl]-(1,2,3,4-tetrahydronaphthalene-1S-methyl)amine

[0038] ①Reaction formula:

[0039]

[0040] ②Operation method:

[0041] In a 100ml three-necked flask, add 5g (17.6mmol) of compound and 100ml of tetrahydrofuran, add 2.8g (70.4mmol) of sodium borohydride in one go, add 12ml of boron trifluoride ether solution dropwise at room temperature, and then The reaction was stirred for 1 hour, then heated to reflux, and the reaction was continued for 2 hours. Cool to room temperature, add 6N hydrochloric acid under ice bath, adjust pH to about 1, and then reflux for 2 hours. Cool to room temperature, evaporate THF under reduced pressure, add 50% sodium hydroxide solution to adjust pH to alkaline, extract twice with chloroform, wash twice with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and recover solvent under reduced pressure , to obtain crude compound 4.70g.

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Abstract

The invention relates to a new production process of palonosetron hydrochloride with high purity. The final product of palonosetron hydrochloride can be obtained by that the synthesized crude palonosetron hydrochloride is dissolved and is carried out the silica gel column chromatography, the target components are collected after a plurality of elutions, and the target components are carried out the recrystallization to get the final product. The HPLC detection shows that the purity of the product can achieve more than 99.5 percent, and a single impurity is below 0.1 percent. The new production process can improve the yield of palonosetron hydrochloride to more than 20 percent, but the synthesis yield of an existing process is only 6 percent, so the invention has significant progress by comparison.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a new production process for preparing high-purity palonosetron hydrochloride. Background of the invention [0002] Palonosetron hydrochloride (Palonosetron hydrochloride, trade name Aloxi) is a selective 5-HT3 receptor antagonist developed by Switzerland Helsinn company, chemical name: (3aS)-2-[(3S)-1-aza Bicyclo[2.2.2]octyl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hphenylhydrazine[de]isoquinoline hydrochloride, its molecular structure is shown in the figure below. On July 25, 2003, the product was approved by the US Food and Drug Administration (FDA) for the treatment of acute and delayed nausea and vomiting caused by moderate or highly emetogenic chemotherapy. [0003] [0004] Palonosetron hydrochloride is the fourth approved 5-HT3 receptor antagonist. The reason why tumor chemotherapy drugs cause vomiting in patients is because chemotherapy drugs, especially cisplatin, can cause ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
Inventor 金飞徐飞虎李辉孙汉栋
Owner HANGZHOU JIUYUAN GENE ENG
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