Method for synthesizing palonosetron hydrochloride

A synthesis method and hydrochloric acid technology are applied in the new synthesis field of palonosetron hydrochloride, can solve the problems of complicated post-processing, difficult purification, dangerous reagents and the like, and achieve the effects of easy separation and purification, low price and low cost

Inactive Publication Date: 2008-05-28
SHENZHEN NEPTUNUS PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] There are some deficiencies in the above methods, such as low yield or complicated post-treatment, difficult purification and dangerous reagents, etc., so it must be improved

Method used

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  • Method for synthesizing palonosetron hydrochloride
  • Method for synthesizing palonosetron hydrochloride
  • Method for synthesizing palonosetron hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] [embodiment 1] the preparation of formula (11) compound (S, S)-quinuclidine tetrahydronaphthalene carboxamide

[0054] Add (S)-tetrahydronaphthoic acid (0.17mol), thionyl chloride (0.18mol) and toluene into a 250mL reaction flask, then heat up to 50°C for 1 hour, and drop (S)-3-amino - Quinucidine (0.17mol), reacted at 50° C. for 1 hour, sampling for thin-layer chromatography analysis showed that the reaction was complete, and the reaction solution changed from clear to turbid at the same time. Cool to room temperature, add 0.3 L of water and 13.5 mL of 50% sodium hydroxide solution, extract with ethyl acetate, and dry over anhydrous sodium sulfate to obtain a white solid. The solvent is distilled off under reduced pressure to obtain a white solid with a yield of 93%. TLC (plate chromatography) shows that 11 is a single compound: (S, S)-quinuclidine tetrahydronaphthalene carboxamide compound melting point (Mp) is: 190-191 ° C; optical rotation is [α] D 20 = -56.4 (c 1.0...

Embodiment 2

[0055] [embodiment 2] the preparation of formula (11) compound (S, S)-quinuclidine tetrahydronaphthalene carboxamide

[0056] Add (S)-tetrahydronaphthoic acid (0.17mol), thionyl chloride (0.26mol) and toluene into a 250mL reaction flask, then heat up to 80°C for 6 hours, and dropwise add (S)-3-amino - Quinucidine (0.26mol), reacted at 80° C. for 3 hours, sampling for thin-layer chromatography analysis showed that the reaction was complete, and the reaction solution changed from clear to turbid at the same time. Cool to room temperature, add 0.3 L of water and 13.5 mL of 50% sodium hydroxide solution, extract with ethyl acetate, and dry over anhydrous sodium sulfate to obtain a white solid. The solvent is distilled off under reduced pressure to obtain a white solid with a yield of 86%.

Embodiment 3

[0057] [embodiment 3] the preparation of formula (12) compound (S, S)-tetralin methyl quinuclidine

[0058] (S, S)-quinuclidine tetrahydronaphthalene carboxamide compound (0.16mol) and sodium borohydride (0.64mol) and tetrahydrofuran 0.9L are added in the reaction bottle of 2000ml, and temperature is controlled between-10~15 ℃, then Add boron trifluoride ether solution (0.84mol) slowly, dropwise is completed, warm up to room temperature, react for 30 minutes, the temperature rises to 60°C and react for 2 hours, sampling for thin-layer chromatography analysis shows that the reaction is complete, and the reaction solution From cloudy to clear. Cool to below 20°C, slowly add 2N hydrochloric acid (0.69L) solution, concentrate to 0.75L, add 50% potassium hydroxide (271g) under cooling, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter and concentrate to obtain an oil The product (S, S)-tetrahydronaphthylmethylquinuclidine, the total yield>98%. TLC (plate chrom...

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Abstract

The invention discloses a novel synthesis method of palonosetron hydrochloride, which comprises that (1) (S)-tetralin formic acid is reacted with thionyl chloride and (S)-3-amido-quinine cyclic amine, to obtain (S, S)-quinuclidine tetralin formamide, (2), (S, S)-quinuclidine tetralin formamide is reacted with reductant and boron trifluoride diethyl etherate, to obtain (S, S)-tetralin methyl quinine cyclic amine, (3), (S, S)-tetralin methyl quinine cyclic amine is reacted with diphosgene to be added and reacted in boron trifluoride diethyl etherate solution, while the product is added and reacted with alcaine and water, to obtain palonosetron hydrochloride. And the synthesis route is represented as above: a: SOCI2, (S)-3-aminoquinuclidine, b: NaBH4, BF3OEt2, c: BF3OEt2, CICO2CCI3.

Description

technical field [0001] The present invention relates to a novel synthesis method of palonosetron hydrochloride. Background technique [0002] Chemotherapy for cancer often causes vomiting. On July 25, 2003, Palonosetron Hydrochloride, a compound selective serotonin receptor antagonist developed by Helsinn, Switzerland, was approved by the US FDA for the prevention of acute and delayed acute and delayed disease caused by moderate to highly emetogenic chemotherapy. Nausea and vomiting, first marketed in the US 2 months later. This product has been widely accepted by the health professionals and cancer patients in the second quarter after its launch, and about 175,000 doses have been applied, and it soon became the drug of choice for the prevention of nausea and vomiting. [0003] There have been some reports in the literature on the synthesis of palonosetron hydrochloride, but there are not many reports abroad in terms of patents [1～4] (1.Synthesis 1996, 816; 2.Org.Proc.Res...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
Inventor 唐田吴永福吴筱昆朱丹黄传贯刘碧秀
Owner SHENZHEN NEPTUNUS PHARM CO LTD
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