Synthesis method for 5-aminolevulinic acid hydrochloride

A kind of technology of aminolevulinic acid hydrochloride and synthesis method, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems of unsuitability for industrial production, high production cost, and low total yield, etc. Achieve the effect of being conducive to large-scale industrial production, fewer steps in the synthetic route, and simple synthetic steps

Inactive Publication Date: 2012-08-08
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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 reacti

Method used

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  • Synthesis method for 5-aminolevulinic acid hydrochloride
  • Synthesis method for 5-aminolevulinic acid hydrochloride
  • Synthesis method for 5-aminolevulinic acid hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063]

[0064] 1) Preparation of intermediate (I) 2-(3-chloro-2-oxopropyl)isoindoline-1,3-dione:

[0065] 38.1 grams (0.3 moles) of 1,3-dichloroacetone and 25.0 grams of deionized water were added to a 150 milliliter three-necked flask, and 17.5 grams (0.1 moles) of potassium phthalimide and 11.0 grams of phthalimide potassium salt were added dropwise under mechanical stirring. gram of water, the dropwise addition was completed, and the reaction at room temperature was completed after 1 hour. The white solid intermediate (I) was obtained by filtration, washed with 20.0 g of deionized water, and dried to obtain 21.6 g of the product, with a yield of 91.1%. The filtrate can be reused, and the intermediate (I) can be directly used in the next step without purification. Melting point: 120-121°C.

[0066] 2) Intermediate (II) 2-(3-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxopropyl)isoind Preparation of Indoline-1,3-dione:

[0067] 7.2 g (0.05 mol) of isopropylidene malona...

Embodiment 2

[0072] 1) Preparation of intermediate (I) 2-(3-chloro-2-oxopropyl)isoindoline-1,3-dione:

[0073] 38.1 grams (0.3 moles) of 1,3-dichloroacetone and 35.0 grams of dimethyl sulfoxide were added to a 250 ml three-necked flask, and 17.5 grams (0.1 moles) of potassium phthalimide / 20.0 gram of dimethyl sulfoxide mixed solution, the dropwise addition is completed, and the reaction at room temperature is finished after 1 hour. Add 100 milliliters of water to the reaction solution, and extract 2 times with ethyl acetate. Each ethyl acetate consumption is 100 milliliters. Concentrate the solvent, and Add 27.0 ml of petroleum ether to the obtained solid, stir at 60°C for 40 minutes, then cool to room temperature, filter and dry to obtain 20.8 g of pure intermediate (I), with a yield of 87.7%. Melting point data is with embodiment 1.

[0074] 2) Intermediate (II) 2-(3-(2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-2-oxopropyl)isoind Preparation of Indoline-1,3-dione:

[0075] 7.2 g (0.05 mol...

Embodiment 3

[0078]

[0079] 1) Preparation of intermediate (I) 2-(3-chloro-2-oxopropyl)isoindoline-1,3-dione:

[0080] Add 38.1 grams (0.3 moles) of 1,3-dichloroacetone and 28.0 grams of methanol in a 150 ml three-necked flask, and add 17.5 grams (0.1 moles) of phthalimide potassium salt and 30.0 grams of methanol dropwise under mechanical stirring. Dubbed a mixed solution, the dropwise addition was completed, and the reaction at room temperature was completed after 1 hour. Evaporate the solvent, add 25.0 grams of water under stirring, filter to obtain the intermediate (I), add 27.0 milliliters of petroleum ether to the obtained solid, cool to room temperature after stirring at 60 ° C for 40 minutes, filter and dry to obtain the pure product intermediate (I ) 19.8 g, yield 83.5%. Melting point data is with embodiment 1.

[0081] 2) Preparation of intermediate (III) diethyl 2-(3-(1,3-dioxoisoindoline-2-yl)-2-oxopropyl)malonate:

[0082] 8.0 g (0.05 mol) of diethyl malonate and 2.7 g ...

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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. ...

Claims

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Application Information

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IPC IPC(8): C07C229/22C07C227/02
Inventor 林吉茂迟鹏利姜林海孙传伟
Owner SHANDONG UNIV
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