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Preparation methods for 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid hydrochloride intermediate

A technology of aminolevulinic acid hydrochloride and intermediates, which is applied in the field of preparation of photosensitizer 5-aminolevulinic acid hydrochloride and intermediates, and can solve the conditions of heavy pollution and operation in the hydrochloride preparation process Harsh, expensive raw materials and other problems, to achieve the effect of easy crystallization and purification, easy operation and high yield

Active Publication Date: 2018-08-17
XIAMEN GINPOSOME PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] The technical problem to be solved by the present invention is to overcome the defects of the existing 5-aminolevulinic acid (5-ALA) hydrochloride preparation process, such as large pollution, poor safety, expensive raw materials or harsh operating conditions, and provide a A new preparation method of 5-aminolevulinic acid hydrochloride suitable for industrialized production and intermediates

Method used

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  • Preparation methods for 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid hydrochloride intermediate
  • Preparation methods for 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid hydrochloride intermediate
  • Preparation methods for 5-aminolevulinic acid hydrochloride and 5-aminolevulinic acid hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076]

[0077] In a 2000ml four-necked flask, add 1000ml of dichloromethane, 183g DMAP, 250g of DCC and 144g of isopropylidene malonate, and after stirring at room temperature for 15 minutes, dropwise add 132g of monomethyl succinate dissolved in 200ml of dichloromethane After the addition was completed, the solution was heated to reflux, concentrated after the reaction was detected by TLC, and the obtained solid was washed with water, dried in vacuum and directly used in the next step.

[0078] The product in the previous step was dissolved in 1000ml of absolute ethanol, heated to reflux, concentrated after the TLC detection reaction, and 170g of the product obtained was directly used in the next step. (two-step yield>90%, purity>97%) 1 H NMR (300M, CDCl 3 )δ: 1.26(t, 3H), 1.30(t, 3H), 2.65(t, 2H), 2.90(t, 2H), 3.51(s, 2H), 4.15(q, 2H), 4.20(q, 2H) .

[0079] Dissolve the product in the previous step in 1000ml of acetic acid, cool to 0°C, add dropwise a solution of 69g...

Embodiment 2

[0084]

[0085] 500 liters of reaction kettle, add 250 liters of dichloromethane, add 18.3kg DMAP, 25kg DCC and 14.4kg of isopropylidene malonate, stir at room temperature for 15 minutes, dropwise add 14.6kg of monoethyl succinate to dissolve in After the addition of 50 liters of dichloromethane solution was completed, it was heated to reflux, concentrated after the reaction was detected by TLC, and the obtained solid was washed with water, dried in vacuo and directly used in the next step.

[0086] The product in the previous step was dissolved in 200 liters of anhydrous methanol, heated to reflux, concentrated after the TLC detection reaction, and 17 kg of the obtained product was directly used in the next step. (two-step yield>90%, purity>97%) 1 H NMR (300M, CDCl 3 )δ: 2.65(t, 2H), 2.90(t, 2H), 3.51(s, 2H), 3.68(s, 2H), 3.78(s, 2H).

[0087] Dissolve the product in the previous step in 100 liters of acetic acid, cool to 0 degrees, add dropwise a solution of 6.9 kg of s...

Embodiment 3

[0093]

[0094] In a 2000ml four-neck flask, add 1000ml of dichloromethane, 183g DMAP, 250g of DCC and 144g of isopropylidene malonate, and after stirring at room temperature for 15 minutes, dropwise add 160g of monopropyl succinate dissolved in 200ml of dichloromethane After the addition was completed, the solution was heated to reflux, concentrated after the reaction was detected by TLC, and the obtained solid was washed with water, dried in vacuum and directly used in the next step.

[0095] The product in the previous step was dissolved in 1000ml of absolute ethanol, heated to reflux, concentrated after the TLC detection reaction, and 200g of the product obtained was directly used in the next step (two-step yield>90%, purity>97%). 1 H NMR (300M, CDCl 3 )δ: 1.26(t, 3H), 1.30(t, 3H), 2.65(t, 2H), 2.90(t, 2H), 3.51(s, 2H), 4.15(q, 2H), 4.20(q, 2H) .

[0096] Dissolve the product in the previous step in 1000ml of acetic acid, cool to 0°C, add dropwise a solution of 69g of...

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Abstract

The invention discloses preparation methods for a 5-aminolevulinic acid hydrochloride and a 5-aminolevulinic acid hydrochloride intermediate. The preparation method for the 5-aminolevulinic acid hydrochloride intermediate comprises: (1) carrying out a reaction on a compound 2 and isopropylidene malonate in an organic solvent under the actions of an organic alkali and a condensing agent to obtain acompound 3; and (2) carrying out a reaction on the compound 3 in a C1-C4 alcohol solvent to obtain a compound 4, wherein R1 and R' are respectively and independently C1-C4 alkyl. The present invention further provides a method for preparing a 5-aminolevulinic acid hydrochloride by using the 5-aminolevulinic acid hydrochloride intermediate. According to the present invention, the intermediate product is basically solid and is easily crystallized and purified; and the method has characteristics of high yield, low production cost and easy operation, and is suitable for industrial production. Thecompounds 1, 2, 3 and 4 are defined in the specification.

Description

technical field [0001] The invention relates to a preparation method of a photosensitizer 5-aminolevulinic acid hydrochloride and an 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 main synthetic methods can be summarized as: [0004] 1. Using glycine as raw material, phthalic amidation, acyl chloride, condensation, decarboxylation, hydrolysis (J.Chem.Soc.(1954,1820)): [0005] [000...

Claims

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Application Information

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IPC IPC(8): C07C67/03C07C69/716C07C229/22C07C227/18
CPCC07C67/03C07C227/04C07C227/18C07C249/04C07D319/06C07C69/716C07C229/22C07C229/24C07C251/38
Inventor 沈鑫王丹孟强李锋缪鹏飞詹华杏
Owner XIAMEN GINPOSOME PHARM CO LTD
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