Preparation method of high-purity tetraethyl ranelate and intermediate thereof

Abstract

The invention relates to a preparation method of 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate. The preparation method comprises the following steps of: (a) reacting acetonedicarboxylic acid diethyl ester with malononitrile in the presence of an acid-binding agent and ethanol to generate an active intermediate; and (b) after ammonium sulfide is added as a cosolvent, carrying out cyclization reaction on the active intermediate and sulphur under the reflux of the ethanol, cooling, separating out a crystal, filtering and collecting a filter cake to obtain the 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate. The 5-amino-4-cyano-3-(2-ethyoxyl-2-carboxymethyl)-thiophene-2-ethyl formate prepared by the invention is high in purity, high in yield and low in cost, and three-waste emission is low.

Description

Technical field: [0001] The invention belongs to the technical field of drug synthesis in the field of pharmacy, and in particular relates to a preparation method of tetraethyl ranelate and an intermediate thereof. Background technique: [0002] Strontium in strontium ranelate is an important part of human bones, which can promote the development of bones and the formation of osteoid, and has the effect of regulating calcium metabolism. The clinical data of strontium ranelate show that the drug is especially suitable for the treatment and prevention of osteoporosis in postmenopausal women, significantly reduces the risk of vertebral fractures and hip fractures, and has good clinical effects. [0003] The current methods for preparing strontium ranelate all use 5-[bis(2-ethoxy-2-carboxymethyl)amino-]-4-cyano-3-(2-ethoxy-2-carboxymethyl) )-Ethyl 2-thiophenecarboxylate (referred to as tetraethyl ranelate) as an intermediate, one method is to hydrolyze tetraethyl ranelate in so...

AI Technical Summary

Problems solved by technology

[0007] Literature Chem Ber, 1966, 99: 94-99 uses morpholine as an acid-binding agent, reacts for more than 3 hours, and the reaction yield of intermediate I is only 42.0%, and due to the high toxicity of morpholine, it is easy to cause danger and cause harm when used in large quantities in production. Potential threat to the environment

Document Journal of Chemical Technology and Biotechnology, 1990, 47:39-46 uses diethylamine instead of morpholine, although the reaction yield of intermediate I can reach 80.0%, but it needs to consume a large amount of water to wash diethylamine to neutrality, resulting in A large amount of alkaline wastewater

Chinese patent CN102321068 also uses diethylamine as an acid-binding agent, and uses water instead of ethanol as a solvent. Although a large amount of sodium sulfide (28.1% of the mass of sulfur) can increase the solubility of sulfur in water and accelerate the reaction to a certain extent, but Due to the poor solubility of the organic matter in the reaction in water, the reaction is carried out in the water-organic two-phase, and the reaction is uneven, resulting in a decrease in the overall reaction rate; in addition, due to the poor water solubility of intermediate I, crystallization occurs immediately after the reaction, and it is easy to wrap a large amount of Inorganic salts, it is difficult to completely remove a large amount of water washing during filtration, which reduces the quality of the product, and at the same time washing with water will produce a large amount of waste water

The use of above-mentioned catalyzer, can quicken reaction speed, make reaction time be shortened to within 15h, but the purity of gained tetraethyl ranelate is all≤98.0%, single impurity≥0.5%; The tetraethyl ranelate of this purity is The strontium ranelate prepared from the intermediate is difficult to make the product quality meet the pharmaceutical requirements after repeated refining

In addition, the alkyl chains of C8-C10 quaternary ammonium salts are longer and the steric hindrance is large, resulting in low catalytic efficiency. Microorganisms produce toxicity, which affects the metabolism of various substances in the environment, and has environmental risks that cannot be ignored; while polyethylene glycol is used as a catalyst, the post-treatment needs to be extracted with ethyl acetate, boiled with 80.0% ethanol for beating, and a large amount of boiling water to wash the filter cake , will produce a large amount of waste liquid, and the environmental pressure is high; the use of crown ether or KF / Al2O3, ionic liquids as catalysts has the disadvantage of being expensive, which limits its industrial application

Images