Preparation method of rupatadine fumarate

A kind of rupatadine fumarate and preparation technology, applied in the field of medicine and chemical industry, can solve the problems of long reaction time, complicated side reactions, large consumption of acid water, etc., and achieve the reduction of reagent consumption, shortening of reaction time, and the production of Effect of Yield Improvement

Inactive Publication Date: 2015-12-09
SHANGHAI NEW ASIA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Comparing the above two methods, the yield of the route one bromination step is low, and the side reactions are complicated, resulting in a total yield of less than 40%. In addition, it is necessary to separate the product with qualified purity by column chromatography, so the route two is selected.
[0014] Patent US5407941 discloses a reduction method using lithium aluminum hydride as a reducing agent in tetrahydrofuran solution, but the lithium aluminum hydride reagent is relatively expensive and requires high operating equipment
[0015] Patent CN200510070952.1 discloses a method for preparing rupatadine by reducing amide with sodium dihydroaluminate (Red-Al) as a raw material, but there are long reaction times in the reaction, and the sodium dihydroaluminate (Red-Al) reagent more expensive
[0016] Patent CN200810005209.1 discloses the preparation of rupatadine by reduction reaction using acyloxy alkali metal borohydride as raw material, but the consumption of acid water is large, the reaction takes a long time, and the production cost is high

Method used

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  • Preparation method of rupatadine fumarate
  • Preparation method of rupatadine fumarate
  • Preparation method of rupatadine fumarate

Examples

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example 1

[0037] Taking rupatadine amide (i.e. the amide compound 1) and borane tetrahydrofuran complex as an example: add 43g (0.1mol) rupatadine amide in a 1000ml three-necked bottle, and 400ml borane tetrahydrofuran complex ( 1mol / L), add 300ml of tetrahydrofuran, cool and stir under nitrogen protection. Slowly raise the temperature and stir overnight. After overnight, cool the solution to below zero. Start to add 9% HCl dropwise. After the drop is completed, concentrate until the tetrahydrofuran is evaporated to dryness. Add an equal volume of water, raise the temperature to 100°C and stir for 2 hours, turn off the heating, and stir overnight. The next day, add 800ml of ethyl acetate to the solution, stir to lower the temperature, and adjust the pH of the solution to 8-9 with 20% NaOH. Wash with water, combine the organic layers, add appropriate amount of activated carbon, silica gel and anhydrous magnesium sulfate to the organic layer, stir the reaction, filter to obtain the filtra...

example 2

[0039] Take rupatadine amide and borane tetrahydrofuran complex as an example: add 4.3g (0.01mol) rupatadine amide and 40ml borane tetrahydrofuran complex (1mol / L) into a 250ml three-necked bottle, and add 30ml of tetrahydrofuran, cooled and stirred under nitrogen protection. Slowly raise the temperature and stir overnight. After overnight, cool the solution to below zero. Start to add 9% HCl dropwise. After the drop is completed, concentrate until the tetrahydrofuran is evaporated to dryness. Add an equal volume of water, raise the temperature to 100°C and stir for 2 hours, turn off the heating, and stir overnight. The next day, add 80ml of ethyl acetate to the solution, stir to lower the temperature, and adjust the pH of the solution to 8-9 with 20% NaOH. Wash with water, combine the organic layers, add appropriate amount of activated carbon, silica gel and anhydrous magnesium sulfate to the organic layer, stir the reaction, filter to obtain the filtrate, concentrate to obta...

example 3

[0041]Take rupatadine amide, sodium borohydride and boron trifluoride as an example: add 43g (0.1mol) rupatadine amide and 18.9g (0.5mol) sodium borohydride to a 2000ml three-necked bottle, and then add 560ml tetrahydrofuran, cooled and stirred under nitrogen protection. Another 98ml of boron trifluoride ether solution (46.5% BF3) was added dropwise to the above-mentioned three-necked bottle within 10 minutes. 9% HCl, dropwise, concentrated until the tetrahydrofuran was evaporated to dryness, added an equal volume of water, heated to 100°C and stirred for 2 hours, then turned off the heating, stirred overnight, the next day, added 800ml ethyl acetate to the solution, stirred to cool down, and used 20% NaOH is used to adjust the pH of the solution to 8-9. After adjustment, let stand to separate layers, wash the water layer with ethyl acetate, wash the ethyl acetate layer with water, combine the organic layers, and add an appropriate amount of activated carbon, Silica gel and a...

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Abstract

The invention provides a preparation method of rupatadine fumarate, which includes the steps of (1) reducing an amide compound 1 with a borane reagent to obtain rupatadine 2, represented as the following formula; and (2) performing a salt-forming reaction to the rupatadine with fumaric acid to prepare the rupatadine fumarate. The method is simple in operations, is reduced in use amount of reagents and is increased in production yield when compared with a method in the prior art.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation process of antiallergic drug-rupatadine fumarate. Background technique [0002] Rupatadine fumarate (Rupatadinefumarate1), the chemical name is 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidine Subunit]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate, developed by Uriach Pharmaceuticals, Spain, has antihistamine and antiplatelet activating factor (PAF) A dual-action antiallergic drug indicated for seasonal and perennial allergic rhinitis. The chemical structural formula of rupatadine fumarate is as follows: [0003] [0004] With desloratadine as raw material, there are two main routes for the preparation of rupatadine: [0005] Route 1: 3,5-lutidine is brominated by NBS to obtain 3-bromomethyl-5-picoline, which is then reacted with desloratadine to obtain rupatadine. [0006] [0007] route one [0008] Route 2: Reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 郝文婧汪建军崔万胜
Owner SHANGHAI NEW ASIA PHARMA
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