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Preparation method of 5-aminolevulinic acid hydrochloride and intermediate of 5-aminolevulinic acid hydrochloride

A technology for aminolevulinic acid hydrochloride and intermediates, which is applied in the field of preparation of 5-aminolevulinic acid hydrochloride and its intermediates, can solve the problems of cumbersome operation steps and low yield, and achieve simple process, The effect of high yield and simplified operation process

Inactive Publication Date: 2015-05-27
SHANGHAI JIUZHOU MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0026] The technical problem to be solved by the present invention is to overcome the preparation method of 5-aminolevulinic acid hydrochloride in the prior art, the by-product of 3-position bromination is removed through column chromatography or high vacuum rectification, the operation Steps are loaded down with trivial details and the defect of low yield provides a kind of preparation method of 5-aminolevulinic acid hydrochloride and its intermediate

Method used

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  • Preparation method of 5-aminolevulinic acid hydrochloride and intermediate of 5-aminolevulinic acid hydrochloride
  • Preparation method of 5-aminolevulinic acid hydrochloride and intermediate of 5-aminolevulinic acid hydrochloride
  • Preparation method of 5-aminolevulinic acid hydrochloride and intermediate of 5-aminolevulinic acid hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0057] Add 348g (3.0mol) of levulinic acid and 3500mL of methanol into a 5-liter four-necked flask, and add 480g (3.0mol) of liquid bromine dropwise under cooling in an ice-water bath (ie 0°C). Control the drop rate so that the temperature is between 0 and 10°C. After the dropwise addition, heat to reflux for 4-5 hours, and TLC detects that the reaction is complete. The reaction solution was cooled to room temperature and concentrated. The concentrated solution was poured into water and ethyl acetate, neutralized with sodium bicarbonate, and the organic phase was separated.

Embodiment 2

[0059] In a 5-liter four-necked bottle, add the ethyl acetate solution obtained in Example 1, add dropwise 200 mL of triethylamine, and detect by gas chromatography (GC detection) that after the content of methyl 3-bromolevulinate is lower than 1%, Add 2000 mL of DMF and 362 g (2.0 mol) of potassium phthalimide, and heat at 50°C for 1 hour. It was detected by TLC that the reaction was complete, cooled, filtered, and the filtrate was poured into ice water to precipitate a solid. Filter, wash, and dry to obtain 500 g of off-white solid with a purity of 95% as measured by HPLC.

Embodiment 3

[0061] In a 5-liter four-neck flask, add 500 g of the off-white solid obtained in Example 2, 3500 mL of 6N hydrochloric acid, heat to reflux, and react until the hydrolysis is complete. Cool, filter, decolorize the filtrate with activated carbon, and concentrate the aqueous phase to obtain an off-white solid. The mixed solution of methanol and ethyl acetate was recrystallized at 1:1 (volume ratio) to obtain 270 g of white crystals, with a yield of 53.7% (based on levulinic acid). mp: 149-152°C, 97% pure as measured by HPLC. The NMR data are as follows:

[0062] 1 HNMR (300M, D 2 o 2 )δ:2.50(2H,t,-CH 2 -),2.69(2H,t,-CH 2 -),3.92(2H,s,-CH 2 NH 2 ).

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Abstract

The invention discloses a preparation method of a 5-aminolevulinic acid hydrochloride and an intermediate of the 5-aminolevulinic acid hydrochloride. The intermediate compound of the 5-aminolevulinic acid hydrochloride is represented by formula 3. The preparation method comprises following steps: (1) in an organic inert solvent, a compound represented by formula 1 and liquid bromine are subjected to bromination reaction; step (2), a reaction system obtained via step (1) is mixed with an alkali for reaction; and step (3), after the reaction of step (2), an obtained reaction system is directly subjected to Gabriel reaction with phthalimide potassium salt without post-processing purification so as to obtain the compound represented by formula 3, wherein R is used for representing H or C1-C4 alkyl groups. The preparation method is simple, is easy for operation, is high in yield, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of 5-aminolevulinic acid hydrochloride and its intermediate. Background technique [0002] Photodynamic therapy (PDT) was created in the 1970s. Due to the development and progress of photosensitive substances in recent years, it has gradually become one of the basic methods for treating tumors. 5-aminolevulinic acid hydrochloride (5-ALA·HCl) is the hydrochloride salt of a new generation of photodynamic therapy drug 5-aminolevulinic acid (5-ALA), which is clinically used for actinic keratosis Disease (Actinic Keratoses, AK) treatment. [0003] [0004] Although the structure of 5-aminolevulinic acid hydrochloride is simple, its synthesis is quite difficult, especially the process for industrial production. Its main synthetic methods are summarized as follows: [0005] 1. Using glycine as raw material, phthaloamide, acyl chloride, condensation, decarboxylation, hydrolysis (J.Chem.Soc. (1954,1820)). [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07C229/22C07C227/20
CPCC07D209/48C07C227/20
Inventor 姚云龙沈鑫杨继东
Owner SHANGHAI JIUZHOU MEDICAL TECH
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