New preparation process of 5-aminolevulinic acid (5-ALA) hydrochloride

Abstract

The invention relates to a new preparation process of 5-aminolevulinic acid (5-ALA) hydrochloride. The 5-ALA is a second-generation photosensitizer, and has a structure shown in the specification. The 5-ALA hydrochloride has been used for treating photosensitive keratosis in America. The 5-ALA hydrochloride is used for treating dermatological condyloma acuminatum in China. Indications related to the 5-ALA are also extended in clinical application. According to the new preparation process, 4-alkenylbenzyl valerate is used as a starting raw material and is subjected to oxidation, addition, oxidation and catalytic hydrogenation to successfully synthesize the 5-ALA.

Description

technical field

[0001] The invention relates to a new preparation process of aminolevulinic acid hydrochloride (5-ALA). Photodynamic medicine is a field that has developed rapidly in the diagnosis and treatment of certain cancers and the treatment of skin diseases in recent years. Aminolevulinic acid hydrochloride, a second-generation photosensitizer, is now used in the United States for the treatment of actinic keratoses. It is used in China to treat genital warts, a skin venereal disease. The indications of 5-ALA are still expanding clinically. The invention uses benzyl 4-valerate as a starting material, and successfully synthesizes 5-ALA through oxidation, addition, oxidation and catalytic hydrogenation. technical background

[0002] There are many reports on the synthesis of 5-ALA. CN101462974 discloses following route:

[0003]

[0004] NOTE: other reagents also tried,

[0005] Reactants: 1, Reagents: 8, Solvents: 4,

[0006] Steps: 1, Stages: 7 ...

Examples

Embodiment

[0047] Preparation of epoxide 4-epoxyvalerate benzyl ester

[0048] In a 5000 milliliter flask, 155 grams of 4-alkene-pentanoic acid benzyl ester was dissolved in 1730 milliliters of dichloromethane, and 195 grams of m-chloroperoxybenzoic acid was added to maintain the reaction temperature from 30 to 35 degrees Celsius, and stirred for 24 hours. The reaction process A white solid precipitated out. TLC (developing solvent: cyclohexane-ethyl acetate 4:1) followed the reaction until the raw material 4-ene-pentanoic acid benzyl ester disappeared. Cool in a water bath, add 3% sulfurous acid solution, and test with potassium iodide starch test paper, the test paper does not show blue. Sodium bicarbonate solution was added to dissolve the solid, pH 7-8. Transfer to a separatory funnel and separate the layers. The organic matter was washed with 200 mL of brine. The organic layer was separated and dried over anhydrous sodium sulfate overnight. Suction filtration, concentration, an...

technical field

[0001] The invention relates to a new preparation process of aminolevulinic acid hydrochloride (5-ALA). Photodynamic medicine is a field that has developed rapidly in the diagnosis and treatment of certain cancers and the treatment of skin diseases in recent years. Aminolevulinic acid hydrochloride, a second-generation photosensitizer, is now used in the United States for the treatment of actinic keratoses. It is used in China to treat genital warts, a skin venereal disease. The indications of 5-ALA are still expanding clinically. The invention uses benzyl 4-valerate as a starting material, and successfully synthesizes 5-ALA through oxidation, addition, oxidation and catalytic hydrogenation. technical background

[0002] There are many reports on the synthesis of 5-ALA. CN101462974 discloses following route:

[0003]

[0004] NOTE: other reagents also tried,

[0005] Reactants: 1, Reagents: 8, Solvents: 4,

[0006] Steps: 1, Stages: 7 ...

Examples

Embodiment

[0047] Preparation of epoxide 4-epoxyvalerate benzyl ester

[0048] In a 5000 milliliter flask, 155 grams of 4-alkene-pentanoic acid benzyl ester was dissolved in 1730 milliliters of dichloromethane, and 195 grams of m-chloroperoxybenzoic acid was added to maintain the reaction temperature from 30 to 35 degrees Celsius, and stirred for 24 hours. The reaction process A white solid precipitated out. TLC (developing solvent: cyclohexane-ethyl acetate 4:1) followed the reaction until the raw material 4-ene-pentanoic acid benzyl ester disappeared. Cool in a water bath, add 3% sulfurous acid solution, and test with potassium iodide starch test paper, the test paper does not show blue. Sodium bicarbonate solution was added to dissolve the solid, pH 7-8. Transfer to a separatory funnel and separate the layers. The organic matter was washed with 200 mL of brine. The organic layer was separated and dried over anhydrous sodium sulfate overnight. Suction filtration, concentration, an...

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