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Synthesis method of Ramosetron

A technology of ramosetron and a synthetic method, which is applied in the field of chemical synthesis, can solve the problems of low economic benefit and low yield, and achieve the effects of reducing reaction activation energy, improving economic benefit, and increasing reaction yield

Inactive Publication Date: 2016-06-15
ITIC MEDCHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But its total yield is only about 13%, and the yield is low, and the economic benefit is low and poor

Method used

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  • Synthesis method of Ramosetron
  • Synthesis method of Ramosetron
  • Synthesis method of Ramosetron

Examples

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Effect test

Embodiment 1

[0043] A synthetic method for ramosetron, using 3,4-diaminobenzoic acid as a starting material, through seven steps of synthesizing ramosetron, comprising the following steps:

[0044] Step 1: Synthesis of benzimidazole-5-carboxylic acid

[0045] Add 500ml of formic acid to 40g of 3,4-diaminobenzoic acid, stir and heat to reflux for 4h, concentrate under reduced pressure, add 700ml of water, adjust the pH to 5-6 with ammonia water, filter and dry to obtain off-white solid benzimidazole-5-carboxylic acid;

[0046] The second step: synthesis of benzimidazole-5-carboxylate methyl sulfate

[0047] Add 500ml of anhydrous methanol to the benzimidazole-5-carboxylic acid prepared in the first step, add 45ml of thionyl chloride dropwise at a temperature of 7-8°C, and raise the temperature to 50-52°C for reflux reaction for 5h after dropping, then reflux reaction After cooling down to room temperature, add 800ml of water, adjust the pH to 8-9 with ammonia water, filter and dry to obtai...

Embodiment 2

[0059] A synthetic method for ramosetron, using 3,4-diaminobenzoic acid as a starting material, through seven steps of synthesizing ramosetron, comprising the following steps:

[0060] Step 1: Synthesis of benzimidazole-5-carboxylic acid

[0061] Add 500ml of formic acid to 40g of 3,4-diaminobenzoic acid, stir and heat to reflux for 4h, concentrate under reduced pressure, add 700ml of water, adjust the pH to 5-6 with ammonia water, filter and dry to obtain off-white solid benzimidazole-5-carboxylic acid;

[0062] The second step: synthesis of benzimidazole-5-carboxylate methyl sulfate

[0063] Add 500ml of anhydrous methanol to the benzimidazole-5-carboxylic acid prepared in the first step, add 45ml of thionyl chloride dropwise at 8°C, raise the temperature to 50°C for reflux reaction for 5h after the dropwise reaction, and cool down to room temperature after the reflux reaction Add 800ml of water, adjust the pH to 9 with ammonia water, filter and dry to obtain a taupe solid;...

Embodiment 3

[0075] A synthetic method for ramosetron, using 3,4-diaminobenzoic acid as a starting material, through seven steps of synthesizing ramosetron, comprising the following steps:

[0076] Step 1: Synthesis of benzimidazole-5-carboxylic acid

[0077] Add 500ml of formic acid to 40g of 3,4-diaminobenzoic acid, stir and heat to reflux for 4h, concentrate under reduced pressure, add 700ml of water, adjust the pH to 5-6 with ammonia water, filter and dry to obtain off-white solid benzimidazole-5-carboxylic acid;

[0078] The second step: synthesis of benzimidazole-5-carboxylate methyl sulfate

[0079] Add 500ml of anhydrous methanol to the benzimidazole-5-carboxylic acid prepared in the first step, add 45ml of thionyl chloride dropwise at a temperature of 7-8°C, raise the temperature to 53-55°C for reflux reaction for 5 hours after dropping, and then reflux reaction After cooling down to room temperature, add 800ml of water, adjust the pH to 8-9 with ammonia water, filter and dry to ...

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Abstract

The invention discloses a method for synthesizing ramosetron, which uses 3,4-diaminobenzoic acid as a starting material, and synthesizes benzimidazole-5-carboxylic acid, benzimidazole-5-carboxylic acid methyl ester sulfuric acid salt, 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid methyl ester sulfate, 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate, N-[( 4,5,6,7-tetrahydrobenzimidazol-5-yl)]pyrrole hydrochloride, 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7- Tetrahydrobenzimidazole was eventually made into ramosetron. Compared with the prior art, the inventive method of the present invention has optimized the reaction conditions, and the optimized reaction is indeed feasible, and the 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid sulfate, N-[(4, The yield of 5,6,7-tetrahydrobenzimidazol-5-yl)]pyrrole hydrochloride, etc., the total reaction yield reaches more than 30%, and has relatively high economic benefits.

Description

Technical field: [0001] The invention relates to a synthesis method of ramosetron, which belongs to the field of chemical synthesis. Background technique: [0002] Ramosetron, whose chemical name is (R)-5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole hydrochloride, is a synthetic An important raw material of ramosetron hydrochloride. [0003] In the prior art, the methods for synthesizing ramosetron mainly contain the following: [0004] The synthetic route reported by Japan’s Yamanouchi Company in 1990 requires oxidation after ring formation, and the steps are cumbersome, and dichloroethane is used as a solvent to participate in the reaction. This reagent belongs to the national first-class control reagent, which is highly toxic and unfavorable for industrialization. Production should be avoided. At this stage, 5-methyl-3-nitroaniline is no longer used to synthesize ramosetron. Its synthetic route is shown in formula one. [0005] In 2005, Li Weiliang a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06
CPCC07D403/06
Inventor 胡海威丁靓闫永平郑辉严辉
Owner ITIC MEDCHEM CO LTD
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