Method for preparing laminine and pharmaceutically acceptable salts thereof

Abstract

The invention relates to methods for preparing and using laminine and pharmaceutically acceptable salts thereof. L-lysine is used an initiative material, and the method comprises the following steps of: protecting alpha-amino groups and carboxyl with metallic salts under an alkaline condition to form a chelate complex; performing separation and purification to obtain the chelate complex with the purity of 99 to 100 percent, and performing methylation on the chelate complex on epsilon-amino groups under the action of a phase transfer catalyst with a methylating agent to generate trimethyl lysine salts; removing metallic ions with a precipitator or chelating agent to obtain crude laminine and crude pharmaceutically acceptable salts thereof; and re-crystallizing the crude laminine and the crude pharmaceutically acceptable salts thereof with a solvent to obtain the medicinal laminine and the pharmaceutically acceptable salts thereof. The methylation of the separated and purified L-lysine metallic ion chelate complex and the phase transfer catalyst are simultaneously adopted, so the method remarkably reduces the generation of monomethyl substances, dimethyl substances and other byproducts, improves the yield and achieves the product purity of over 98.5 percent (HPLC).

Description

technical field [0001] The invention relates to a preparation method and a use method of a medicinal chemical for treating hypertension, in particular to a preparation method and a use method of laminamic acid and a pharmaceutically acceptable salt thereof. Background technique [0002] Laminin is a non-protein amino acid (5-amino-5-carboxypentyltrimethylammonium) with antihypertensive activity in kelp, molecular formula: C 9 h 21 N 2 o 2 , Molecular weight: 189.22, its pharmaceutically acceptable salts include: (1) Lamininine hydrochloride, molecular formula: C 9 h 21 N 2 o 2 ·HCL, molecular weight: 225.68; (2) lamininic acid besylate, molecular formula: C 9 h 21 N 2 o 2 ·C 6 h 6 o 3 S molecular weight: 347.4; (3) laminin maleate, molecular formula: C 9 h 21 N 2 o 2 ·C 4 h 4 o 4 , Molecular weight: 305.22; (4) Molecular formula of lamininic acid mesylate: C 9 h 21 N 2 o 2 ·CH 4 o 3 S, molecular weight: 285.32. [0003] Antihypertensive experiments...

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Problems solved by technology

[0004] Chinese patent CN97123269.5 discloses a preparation method of laminin. The specific method is to use copper carbonate and lysine to undergo a chelation reaction to form a chelate between copper ions and lysine, thereby masking the α-amino and carboxyl groups. , the methylating reagent adopts dimethyl sulfate, and the unshielding reagent adopts hydrogen sulfide, both of which are toxic and harmful raw materials, which are unfavorable for industrial production and the environment, and the obtained product is a yellow oily solid with a purity of 60.7%, which cannot Reach the medicinal standard

[0005] Chinese patent CN200410024504.3 also discloses a production and application method of cleaning N-trimethyllysine. In this patent, the copper carbonate in the patent CN97123269.5 is replaced by zinc sulfate, and the methylating reagent is replaced by The environmentally friendly dimethyl carbonate was used, and the deshielding reagent was replaced by EDTA-2Na. The product was purified by an ion exchange column, but the purity data was not given, so the yield cannot be obtained

[0006] Chinese patent CN200610069978.9 further improved the technology of patent CN200410024504.3, replaced sodium hydroxide with ammonia water, and purified the product with two ion exchange columns, the purity reached 98.3%, and the yield was not given

[0009] 2. The methylation reagent used in the above two patents (CN200610069978.9, CN200410024504.3) is dimethyl carbonate, but dimethyl carbonate is insoluble in the water phase during the methylation process. In fact, the reaction is between two Completed in the phase system, increasing the difficulty of the reaction, the reaction is not complete, resulting in an increase in monomethylated and dimethylated products

Moreover, in order to increase the reaction speed, the reaction temperature has to be increased, which further increases the side reactions, reduces the product yield, and increases the cost of product purification

Therefore, this technical defect must be improved

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