Novel method of producing strontium ranelate heptahydrate

Abstract

The invention relates to a new preparation method of strontium ranelate heptahydrate. The products produced by the method have water content of 19.0 per cent to 20.4 per cent and the relevant substances are lower than 0.5 per cent. The strontium ranelate heptahydrate produced by the method is stable under room temperature, has little water content differences between batches and is kept for a long time under natural environment with unchangeable moisture, content and relevant substances. The method is characterized in that: (1) the reflux of the 2-[N, N- 2(carboxymethyl)amino]-3-cyano-group-4-thiopheneacetic-5-carboxylic acid tetra ester (b) is carried out in the proper sodium hydroxide aqueous solution of alcohol for 5h to 6h and the pH value is kept over 10 during hydrolysis; (2) the ethanol of 20 per cent to 60 per cent is added and then the strontium chloride aqueous solution with 2times to 2.5times molal weight is directly added, precipitates the crystal, is filtered and dried; (3) water is added to carry out the reflux and the little salt packed in the crude product is removed, and the product is collected through heat filtration. The invention discloses the drug combination containing the strontium ranelate heptahydrate which is used for the treatment of osteoporosis of women after menopause.

Description

technical field [0001] The present invention relates to a new preparation method of strontium ranelate heptahydrate and a pharmaceutical composition containing it. The compound has activity in the treatment of osteoporosis in postmenopausal women. Background technique [0002] The structural formula of strontium ranelate heptahydrate is as follows: [0003] [0004] Strontium ranelate heptahydrate chemical name: [0005] 3-Thiopheneacetic acid, 5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano, strontium salt(1:2)heptahydrate [0006] That is, 5-[di(carboxymethyl)amino]-2-carboxy-4-cyano-3-thiophene acetate distrontium salt heptahydrate, which has very valuable pharmacological activities, especially in anti-osteoporotic properties On the one hand, it can both inhibit bone resorption and promote bone formation, making this compound useful in the treatment of osteoporosis in postmenopausal women. [0007] EP0415850 has described the preparation and therapeutic use of stront...

AI Technical Summary

Problems solved by technology

In this way, the octahydrate of distrontium ranelate can be produced, dried under a dry air stream to generate the heptahydrate, and dried under reduced pressure (10mmHg) at 55°C to obtain the corresponding tetrahydrate, but the preparation method is cumbersome

[0014] The second method: Add 2-[N,N-bis(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid tetraethyl ester to the sodium hydroxide solution mixed with alcohol and water Medium hydrolysis, after hydrolysis, the alcohol and water are evaporated to dryness to obtain a tetrasodium salt solid, and then strontium chloride is added to form a salt, but the tetrasodium salt has strong hygroscopicity, and the actual operation is also troublesome;

[0016] The applicant uses these methods, the related substance of the product that makes is higher (more than 2%), and the hydrate water content of generation is unstable, brings difficulty to the formulation of raw material quality standard and the preparation of preparation

Strontium ranelate is insoluble in most solvents, and the purification operation is quite difficult, so the products prepared by these methods are not qualified as pharmaceutical raw materials

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