Synthesis method for 5-aminolevulinic acid hydrochloride

Abstract

The invention relates to a synthesis method for 5-aminolevulinic acid hydrochloride. The synthesis method comprises the steps as follows: taking 1,3-dichloroacetone as a starting material, carrying out Gabriel reaction on the 1,3-dichloroacetone and phthalimide potassium in a water phase or an organic phase to obtain a high-purity intermediate (I), 2-(3-chloro-2-oxopropyl)isoindoline-1,3-diketone; reacting the intermediate (I) with malonic acid isopropyl ester or malonic acid diethyl ester in alkali condition to prepare an intermediate (II), 2-(3-(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-yl)-2-oxopropyl)isoindoline-1,3-diketone or an intermediate (III), 2-(3-(1,3-dioxoisobenzazole-2-yl)-2-oxopropyl)malonic acid diethyl ester; and hydrolyzing, decarboxylating and post-processing to obtain the high-purity 5-aminolevulinic acid hydrochloride.

Description

technical field [0001] The invention relates to the field of synthesis of medical compounds, in particular to a synthesis method of 5-aminolevulinic acid hydrochloride. Background technique [0002] Photochemotherapy (PDT), as a technical means for treating various abnormalities or disorders of skin, other epithelial tissues and mucous membranes, plays an important role in clinical medicine, especially in the treatment of cancer and precancerous lesions as well as some non-malignant lesions. significantly. 5-Aminolevulinic acid (5-ALA) hydrochloride, as a new generation of photosensitizer, is widely used in the clinical treatment of actinic keratosis in photodynamic therapy. [0003] At present, the route about the synthetic method of 5-aminolevulinic acid hydrochloride mainly contains: [0004] 1. Using furylamine as raw material, the target product is obtained through phthalimidization, photooxidation, reduction, and hydrolysis (see EP 0607952). [0005] [0006] 2. ...

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Problems solved by technology

[0018] The above 7 synthetic routes are relatively mature and the most representative, but there are still shortcomings: the requirements for equipment in the hydrogenation reduction process of route 1 are relatively strict, and the starting materials of furylamine and catalyst metal palladium are relatively expensive. Cause production cost higher; The catalyzer price that starting raw material tetrahydrofuryl methylamine and oxidation process are selected in route 2 is expensive; The ethanetricarboxylate sodium salt and cesium carbonate price that route 3 selects are relatively expensive, and secondly the acyl chloride process easily causes environmental pollution. Pollution, the acid gas produced is corrosive to equipment; route 4 is in the process of preparing intermediate 5-bromolevulinic acid, the proportion of accompanying by-product 3-bromolevulinic acid is quite high, and this side reaction cannot be controlled Elimination of reaction conditions requires separation by column chromatography or high vacuum rectification, which is not suitable for industrial production; although route 5 improves the synthesis process, the bromolevulinic acid mixture is directly used in the next step without separation, and finally Purify by recrystallization, but this improved route yield is too low (7%); The sodium azide used in route 4 and 7 belongs to explosive substance, and cuprous cyanide belongs to highly toxic substance, has potential safety hazard; Route 6 is proposed recently Compared with other routes, this route has certain advantages, but the starting material 5-bromolevulinate ethyl ester or 5-chlorolevulinate ethyl ester is difficult to buy in the market, if self-preparation also exists such as route 4 and 5. The problem of separation of by-products and the overall yield is not high

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