Synthetic method of histamine dichloride

Abstract

The invention discloses a synthetic method of histamine dichloride, and belongs to the field of drug synthesis. The synthetic method comprises the following steps: preparing a cyano methylimidazole intermediate through oxidization of TCCA (Trichloroisocyanuric Acid) under an alkaline condition by taking L-histidine as an original raw material, and then preparing medicinal histamine dichloride through catalytic hydrogenation and one-step salifying process. In the histamine dichloride compounded through the synthetic method, the content of related substances is less than 0.5 percent, the content of a single impurity is less than 0.1 percent, and the histamine dichloride accords with medicinal level. A reagent adopted by the technology is cheap and of low-toxicity, the reaction is safe and reliable, an alcohol solvent can be recycled, after-treatment operation is simple and convenient, and the technology is environment-friendly and is beneficial for large-scale industrial production.

Description

technical field [0001] The invention relates to a non-enzymatic method for synthesizing histamine dihydrochloride, which belongs to the field of drug synthesis. Background technique [0002] Histamine dihydrochloride injection (0.5 mg / 0.5 ml) is an immunomodulatory drug developed by EpiCept, which is used for the maintenance treatment of patients with acute myeloid leukemia (AML) after the first remission. It was first approved for marketing under the special conditions of the European Union in October 2008. Clinical trials have shown that the combination of histamine dihydrochloride and interleukin-2 prolongs the survival of AML patients in first remission significantly better than the placebo group. Histamine dihydrochloride can reduce oxygen generated from phagocytes, inhibit nicotinamide adenine dinucleoside phosphate (NADPH) oxidase, and protect interleukin-2 from activating NK cells and T cells. [0003] The chemical synthesis of histamine dihydrochloride usually a...

AI Technical Summary

Problems solved by technology

The product prepared by this method is high in related substances and cannot meet medical standards

The invention patent with the application number 201010576353.8 uses p-methylacetophenone as a catalyst and methylcyclohexanol as a solvent to realize the decarboxylation process, but the decarboxylation requires high temperature conditions of 170-175°C, resulting in large energy consumption, and requires two-step reactions at the same time to become salt

[0005] The document "Synthetic experiments in the histamine series. III. New methods of the reduction of 4(5)-(cyanomethyl)imidazole to histamine" (Chemicke Listypro Vedu a Prumysl. 1952, 46, 772-3) reported that cyanomethylimidazole was A method for preparing histamine under Raney nickel catalytic hydrogenation, but this method requires a hydrogen pressure of 10Mpa, which is dangerous and has a low yield, which is not conducive to large-scale industrial production

[0006] In summary, the amino acid decarboxylation method reported in the literature at present prepares histamine dihydrochloride reaction conditions are harsh, the temperature is high, the solvent adopted is more expensive, and because the boiling point is higher, the recovery cost is increased, and the preparation of histamine dihydrochloride by acidification also requires Two steps are carried out, which all increase the production cost; the raw materials required by hydroxyl amination are relatively expensive; the catalytic hydrogenation preparation process of nitrile methylimidazole then requires too high hydrogen pressure

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