Method for preparing 5-aminolevulinic acid hydrochloride

Abstract

The invention relates to the field of medicaments, in particular to a method for preparing 5-aminolevulinic acid hydrochloride. The method of the invention comprises the following steps of: performing monoester esterification on succinic anhydride serving as a raw material and methanol to obtain a compound A1; performing condensation reaction on the compound A1 and ethyl potassium malonate under the action of N,N-dicarbonylimidazole to obtain a compound A2; performing hydroxylamine amination reaction on the compound A2 and sodium nitrite under the action of glacial acetic acid to obtain a compound A3; reducing the compound A3 by using Zn powder to obtain a compound A4; and hydrolyzing the compound A4 in the solution of hydrochloric acid to obtain the 5-aminolevulinic acid hydrochloride. The method of the invention has the characteristics of readily available raw material, low reaction cost, high yield, safe industrial production and the like.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a method for preparing 5-aminolevulinic acid hydrochloride. Background technique [0002] 5-Aminolevulinate (ALA) is a photodynamic therapy drug. [0003] Photodynamic therapy (PDT) refers to an emerging treatment method that produces therapeutic effects only after the administration of drugs (photosensitizers) under the irradiation of light of a certain wavelength. The therapy has low toxicity, does not affect other treatments, has no drug tolerance, and has a short treatment time. It has been widely used in the treatment of cancers that traditional therapies are ineffective or have serious side effects. [0004] 5-ALA is the second-generation photosensitizer developed in recent years. It is an endogenous substance of organisms and a precursor for the biosynthesis of animal heme and plant chlorophyll. It can be used clinically for acne, various skin diseases, bladder Treatment of cance...

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Problems solved by technology

[0005] In the prior art, such as the technology disclosed in the document (Ha et al.1994, Selective Bromination of Ketoness.A ConvenientSynthesis of 5-Aminolevulinic Acid, Synthetic Communications 24(18):2557-2562.), the method is The method of obtaining 5-aminolevulinic acid hydrochloride (or called: aminolevulinic acid hydrochloride) through bromination, azidation and hydrogenolysis reaction, although the raw material is simple and easy to obtain, the use of Poisonous sodium azide is unsafe in industrial production; meanwhile, a preparation method is also disclosed in the literature (MacDonald, S.F.1974, Methyl 5-bromolevulinate [J]. Canadian Journal of Chemistry, 52 (18): 3257-3258.) The method of 5-aminolevulinic acid hydrochloride (or called: aminolevulinic acid hydrochloride), which uses levulinic acid as a raw material, is prepared through bromination, Gabriel reaction, and hydrolysis reaction. The raw material of this method is Easy to get and cheap, without azidation, it is most suitable for industrial production, but in the bromination process of levulinic acid, a large number of by-products (3-bromo-substituted products) are produced, which need to be purified by column chromatography or high vacuum distillation To separate and purify, and because the bromide has greater irritation to the human body, the above separation process will cause different degrees of harm to the operator

[0006] Patent EP483,714 also discloses a method for preparing 5-aminolevulinic acid hydrochloride. The method uses furanylamine as a starting material, and is prepared by reduction, imidization, ruthenium-catalyzed oxidation, and hydrolysis reaction. Get, this method has adopted precious metal ruthenium to make catalytic oxidation, and cost is very high; Simultaneously the reaction yield of this method is low (only 37%), and disguised form has increased cost, so also undesirable

[0007] In addition, the technique disclosed in the literature (Anwar, S.; Pfaltz, A.1984, Synthesis of alpha-aminoketones via selective reduction of acyl cyanides., Tetrahedron Lett 25(28), 2977) uses succinic anhydride as the starting material , the method of obtaining 5-aminolevulinic acid hydrochloride through monoesterification, acyl chloride, cyanation, reduction, and hydrolysis reactions. The raw materials of this method are simple and easy to obtain, but the highly toxic substance cyanide is used for cyanation, causing pollution , especially during industrialized production, it is unsafe and may cause great harm to the surrounding environment

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