Preparation method of 5-aminolevulinic acid hydrochloride intermediate

A technology of aminolevulinic acid hydrochloride and intermediates, which is applied in the field of preparation of 5-aminolevulinic acid hydrochloride intermediates, can solve the problems of low purity, high price and high cost of intermediates, and achieve simple process , easy to operate, mild response effect

Pending Publication Date: 2020-08-28
上海奈及生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Above-mentioned synthetic routes 1 and 2 all use furylamine as the starting raw material, the yield of the photooxidation step of route 1 is low, the purity of the obtained intermediate is not high, and the industrialization prospect is uncertain; synthetic route 2 uses expensive ruthenium catalyst The use of the key step oxidation reaction yield is low, the quality of the product is poor, especially the intermediate has to be purified by silica gel column twice, the cost is high, and it is obviously not the best solution for industrialization
At present, these two routes have not seen relatively mature industrialization reports and large-scale industrialization production.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] A preparation method of 5-aminolevulinic acid hydrochloride intermediate, comprising the following steps:

[0111]

[0112] Put 99.0g (0.34mol) of 2-phthalimidomethyl-2,5-dimethoxytetrahydrofuran into the reaction flask, add 700ml of acetone and stir to dissolve, then add 140ml of water; add 4g of 36% sulfuric acid and slowly Add 209g (0.34mol) potassium monopersulfate compound salt (Oxone), and stir at 20°C for 3 hours; after the reaction, filter the inorganic salt, wash the filter cake with acetone, combine the washing liquid and the filtrate to remove the solvent, add 400ml of water, and stir for half Filtrate after 1 hour, vacuum-dry after filter cake washing, obtain 5-phthalimide levulinic acid 87.0g, m.p.163 ℃, purity (HPLC, a / a%) 99.5%, yield 98.0% (with 2-phthalimidomethyl-2,5-dimethoxytetrahydrofuran).

[0113] Its proton nuclear magnetic resonance spectrum data are as follows: 'H NMR (δppm ín CDCl 3 ,400MHZ):2.71(2H,t),2.84(2H,t),4.56(2H,s),7.77-7.72(2H,m...

Embodiment 2

[0127] A preparation method of 5-aminolevulinic acid hydrochloride intermediate, comprising the following steps:

[0128]

[0129] Take 130.2g (0.25mol) of cis, trans-2-phthalimidomethyl-2,5-dialkoxydihydrofuran, add a catalytic amount of Raney nickel, and react with hydrogen until the hydrogen absorption is complete. Reacted for 2 hours, heated and distilled to reclaim methanol after filtering off Raney nickel, added 500ml of acetone and stirred to dissolve, then added 100ml of water; after adding 3g of 36% sulfuric acid, slowly dropped into 153.7g (0.25mol) potassium monopersulfate compound salt (Oxone), Stir at 15°C for 3 hours; after the reaction, filter the inorganic salts, wash the filter cake with acetone, combine the washing liquid and the filtrate, concentrate under reduced pressure to remove the solvent, add 300ml of water, stir for half an hour, filter, wash the filter cake, recrystallize with ethyl acetate, and vacuum dry Dry, 58.8g of 5-phthalimide levulinic ac...

Embodiment 3

[0143] A kind of preparation method of 5-aminolevulinic acid hydrochloride intermediate, the difference with embodiment 1 is:

[0144]

[0145] Take 65.1g (0.25mol) of cis, trans-2-phthalimidomethyl-2,5-dialkoxydihydrofuran, heat and distill to remove the solvent, add 500ml of acetone and stir to dissolve, then add 100ml of water; add Slowly add 153.7g (0.25mol) of potassium monopersulfate compound salt (Oxone) after 3g of 36% sulfuric acid, and stir for 3 hours at 25°C; after the reaction, filter the inorganic salt, wash the filter cake with acetone, and combine the washing liquid and the filtrate to reduce pressure Concentrate to remove the solvent; add 1500mL of methanol and stir to dissolve, then add a catalytic amount of Raney nickel, pass hydrogen to the end of the hydrogenation reaction, filter off the Raney nickel, heat and distill to remove the solvent, add 300ml of water, stir for half an hour, filter, and wash the filter cake with water Vacuum drying, 5-phthalimi...

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Abstract

The invention relates to a preparation method of a 5-aminolevulinic acid hydrochloride intermediate, and belongs to the field of synthesis of medical compounds. The method is characterized in that: inthe method a, a compound of a formula (5) is prepared from a compound of a formula (1) or formula (2) under the action of a reaction solvent a and an oxidant a, and is hydrogenated to obtain a compound of a formula (6); or in the method b, the compound shown as the formula (6) is obtained from a compound shown as a formula (3) or a formula (4) under the action of a reaction solvent b and an oxidizing agent b. The compound in the formula (6) is subjected to acidic hydrolysis after purification to remove a protecting group, or is directly subjected to acidic hydrolysis to remove the protectinggroup to obtain the 5-aminolevulinic acid hydrochloride. According to the method, the environment-friendly oxidants are adopted, so that the cost can be reduced, the quality requirements of high-quality medicinal raw materials can be met, the production efficiency can be improved, and the requirements of industrial large-scale production are met.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical compounds, more specifically, it relates to a preparation method of a 5-aminolevulinic acid hydrochloride 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 is the hydrochloride salt of a new generation of photodynamic therapy drug 5-aminolevulinic acid (5-ALA), which is clinically used for actinic keratosis (Actinic Keratoses, AK) Treatment. [0003] Although the structure of 5-aminolevulinic acid hydrochloride is simple, its synthesis is quite difficult, especially the process for industrial production. The most relevant prior art is: [0004] 1. Using furylamine as raw material, phthaloamide, photooxidation, reduction, and hydrolysis (EP607,952): [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48
CPCC07D209/48Y02P20/55
Inventor 胡志奇王强胡尚薇苏虎
Owner 上海奈及生物医药科技有限公司
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