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Histamine dihydrochloride synthesis method

A technology of histamine dihydrochloride and synthesis method, which is applied in the field of drug synthesis, can solve problems such as increased energy consumption and production cost, is not suitable for industrial production, and has unknown complexes and complexes, and achieves simplified operations, large-scale production, The effect of reducing the difficulty of the process

Inactive Publication Date: 2015-03-11
JINAN CHENGHUI SHUANGDA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dihydrochloride is formed by adding hydrogen chloride in methylcyclohexanol solution dropwise. The higher decarboxylation temperature puts higher requirements on the equipment, and there are certain difficulties and risks in production, while increasing energy consumption.
In addition, this route needs to prepare a methylcyclohexanol solution of hydrogen chloride, which is cumbersome in technology
[0005] Therefore, in the method reported in the above literature, the product contains more unknown impurities and is not easy to remove, and the decarboxylation temperature is high (160~175°C), which increases energy consumption and production cost, and is not suitable for industrial production.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 15g of L-histidine, 1.5g of ketone bromide, 4ml of p-methylacetophenone and 120ml of methylcyclohexanol into a 200ml flask equipped with a mechanical stirrer and a thermometer. After vacuuming, fill it with nitrogen to protect it from light. Heat to 100~110°C and react for 10 hours. Cool down to below 30°C, pass in hydrogen chloride gas, use an ice bath to control the temperature below 30°C, and pass the gas for 2 to 3 hours. The solid was filtered and washed with dichloromethane, and the filter cake was dried in vacuo for 4 hours to give an off-white solid. Dissolve the solid in 85% methanol solution, pass hydrogen chloride gas twice under stirring, and use an ice bath to control the temperature below 30°C. After the reaction, add Bailu Z activated carbon for decolorization, and after filtration, the filtrate cools down and crystallizes. The solid was vacuum-dried after suction filtration to obtain 4.11 g of a white solid with a yield of 23%. Related substances ...

Embodiment 2

[0032] Add 15g of L-histidine, 1.0g of ketone bromide, 4ml of p-methylacetophenone and 120ml of methylcyclohexanol into a 200ml flask equipped with a mechanical stirrer and a thermometer. After vacuuming, fill it with nitrogen and protect it from light. Heat to 100~110°C and react for 10 hours. Cool down to below 30°C, pass in hydrogen chloride gas, use an ice bath to control the temperature below 30°C, and pass the gas for 2 to 3 hours. The solid was filtered and washed with dichloromethane, and the filter cake was dried in vacuo for 4 hours to give an off-white solid. Dissolve the solid in 85% methanol solution, pass hydrogen chloride gas twice under stirring, and use an ice bath to control the temperature below 30°C. After the reaction, add Bailu Z activated carbon for decolorization, and after filtration, the filtrate cools down and crystallizes. The solid was vacuum-filtered and dried to obtain 4.01 g of a white solid with a yield of 22.5%. Related substances <0.3, sin...

Embodiment 3

[0035] Add 15g of L-histidine, 0.75g of ketone bromide, 4ml of p-methylacetophenone and 120ml of methylcyclohexanol into a 200ml flask equipped with a mechanical stirrer and a thermometer, vacuumize and fill with nitrogen to protect it from light. Heat to 100~110°C and react for 10 hours. Cool down to below 30°C, pass in hydrogen chloride gas, use an ice bath to control the temperature below 30°C, and pass the gas for 2 to 3 hours. The solid was filtered and washed with dichloromethane, and the filter cake was dried in vacuo for 4 hours to give an off-white solid. Dissolve the solid in 85% methanol solution, pass hydrogen chloride gas twice under stirring, and use an ice bath to control the temperature below 30°C. After the reaction, add Bailu Z activated carbon for decolorization, and after filtration, the filtrate cools down and crystallizes. The solid was vacuum-filtered and dried to obtain 4.01 g of a white solid with a yield of 22.5%. Related substances <0.39, single i...

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Abstract

The invention discloses a histamine dihydrochloride synthesis method. Through addition of a catalyst (copper bromide), the decarboxylation temperature is reduced, the types and the contents of unknown impurities are reduced, the raw material conversion rate is increased, the end product purity is improved, and energy consumption reduction and easy industrialisation are realized. Through the step of injecting hydrogen chloride gas to prepare hydrochlorate, the step of preparing a hydrogen chloride solution is omitted and the operation is simplified.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a synthesis method of histamine dihydrochloride. Background technique [0002] Histamine dihydrochloride for sustained remission and prevention of relapse after first remission therapy in adult patients with acute myeloid leukemia (AML). The drug can reduce the generation of oxygen from phagocytes, inhibit nicotinamide adenine dinucleoside phosphate oxidase and prevent interleukin-2 from activating NK cells and T cells. The approval of histamine dihydrochloride injection for marketing is based on the complete remission of its combination with interleukin-2, which significantly reduces the recurrence of AML patients. The long-term leukemia-free rate of patients receiving Ceplene / Interleukin-2 combination therapy is greater than 50%, and the patients tolerate this product well. [0003] The synthesis of histamine dihydrochloride generally uses L-histidine as a raw material...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64
CPCC07D233/64
Inventor 王庭见皇甫功凯杨彦军李跃东
Owner JINAN CHENGHUI SHUANGDA CHEM
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