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Preparation method of histamine dihydrochloride

A technology of histamine dihydrochloride and hydrochloric acid, which is applied in the direction of medical preparations, drug combinations, and pharmaceutical formulas containing active ingredients, and can solve the problem that the product quality cannot meet the pharmaceutical level, cannot be used as a pharmaceutical preparation raw material, and is not suitable for Industrial production and other issues, to achieve the effect of facilitating large-scale industrial production, easy recycling, and improving product quality

Active Publication Date: 2012-05-30
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the purity of the final histamine dihydrochloride product is greatly improved, it still cannot be used as a drug preparation raw material
[0006] It can be seen from this that in the synthetic method reported in the above literature, the reaction is not complete, the product quality cannot meet the pharmaceutical level, and most of them use multiple solvents, which are difficult to recycle, increase the production cost, and are not suitable for industrial production.

Method used

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  • Preparation method of histamine dihydrochloride

Examples

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Comparison scheme
Effect test

Embodiment 1

[0023] Add 150g of L-histidine, 40ml of p-methylacetophenone and 1200ml of trans-3-methylcyclohexanol into a 2000ml three-necked flask equipped with mechanical stirring, thermometer and reflux device, replace the air with vacuum and nitrogen, and pass through the whole process. Protected under nitrogen, protected from light, heated to 170-175°C and refluxed for 24 hours. Then slowly lower the temperature to below 30°C, add dropwise a methylcyclohexanol solution containing 21.2g of hydrochloric acid, and control the temperature below 45°C. Methylcyclohexanol containing hydrochloric acid can be prepared by passing HCl gas into 180g of trans-3-methylcyclohexanol at 20-25°C, and the mass percentage of hydrochloric acid is 20-25%. After the dropwise addition is complete, stir at 20-25°C for 4 hours. Filter, collect mother liquor, filter cake rinse 3 times with 100ml dichloromethane, collect dichloromethane eluate. The filter cake was dried under vacuum for 4 hours to obtain an of...

Embodiment 2

[0025] Add 150g of L-histidine, 40ml of p-methylacetophenone and 1000ml of cis-3-methylcyclohexanol to a 2000ml three-necked flask equipped with mechanical stirring, a thermometer and a reflux device, and replace the air with vacuum and nitrogen. Protected under nitrogen, protected from light, heated to 170-175°C and refluxed for 24 hours. Slowly lower the temperature to below 30°C, add dropwise a 3-methylcyclohexanol solution containing 21.2g of hydrochloric acid, and control the temperature below 45°C. 3-methylcyclohexanol containing hydrochloric acid can be prepared by passing HCl gas into 180 g of cis-3-methylcyclohexanol at 20-25° C., and the mass percentage of hydrochloric acid is 20-25%. After the dropwise addition is complete, stir at 20-25°C for 4 hours. Filter to collect the mother liquor, rinse the filter cake 3 times with 100ml petroleum ether, and collect the petroleum ether eluent. The filter cake was dried under vacuum for 4 hours to obtain an off-white solid....

Embodiment 3

[0027]Add 150gL-histidine, 40ml p-methylacetophenone and 900ml 4-methylcyclohexanol (mixture of cis and trans isomers) in the 2000ml there-necked flask equipped with mechanical stirring, thermometer and reflux device, use vacuum and Replace the air with nitrogen, protect the whole process with nitrogen, avoid light, and heat to 170-175°C for reflux reaction for 24h. Slowly lower the temperature to below 30°C, add dropwise a 4-methylcyclohexanol solution containing 21.2g of hydrochloric acid, and control the temperature below 45°C. 4-methylcyclohexanol containing hydrochloric acid can be prepared by passing HCl gas into 180g of 4-methylcyclohexanol (mixture of cis and trans isomers) at 20-25°C, and the mass percentage of hydrochloric acid is 20 ~25%. After the dropwise addition is complete, stir at 20-25°C for 4 hours. Filter, collect mother liquor, filter cake rinse 3 times with 100ml n-hexane, collect n-hexane eluate. The filter cake was dried under vacuum for 4 hours to o...

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Abstract

The invention relates to an industrial preparation method of officinal histamine dihydrochloride. The preparation method comprises the following steps of: suspending histidine in hexahydrocresol which is used as a reaction solvent; carrying out a decarboxylation reaction at the temperature of 170 DEG C-175 DEG C; and then quantitatively dropwise adding the hexahydrocresol solution containing hydrochloric acid twice so as to synthesize histamine dihydrochloride. According to the invention, the content of the related substances in histamine dihydrochloride is less than 0.5%, and the content of a single impurity in histamine dihydrochloride is less than 0.1%, thus the histamine dihydrochloride completely meets officinal grade; and the preparation method is simple in equipment, easy and simple in process operation and safe and reliable in reaction; and the solvent can be recycled, thus the preparation method is environment-friendly and is beneficial to industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation method of histamine dihydrochloride. Background technique [0002] In 2008, the European Union approved the marketing of EpiCept's histamine dihydrochloride injection (Ceplene), which is used for sustained remission and prevention of relapse after first remission treatment in adult patients with acute myeloid leukemia (AML). Histamine dihydrochloride is able to reduce oxygen generation from phagocytes, inhibit nicotinamide adenine dinucleoside phosphate (NADPH) oxidase and prevent activation of NK cells and T cells by interleukin-2. Histamine dihydrochloride has been approved for marketing in 27 member states of the EU as well as Iceland, Liechtenstein and Norway. The approval of histamine dihydrochloride injection for marketing is based on the key phase III clinical study results of its combination with interleukin 2 on 320 patients: complete remission significantly reduces the recurrence of AML patients. The l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64A61K31/417A61P35/02
Inventor 赵志全苗宇
Owner SHANDONG NEWTIME PHARMA
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