Preparation method of strontium ranelate

A technology of strontium ranelate and ethyl carboxylate, applied in the field of drug synthesis, can solve the problems of insoluble, difficult to purify, disparity and the like of strontium ranelate, and achieves the effects of low price and little environmental harm

Active Publication Date: 2011-09-14
CHINA PHARM UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Strontium ranelate is poorly soluble in both organic solvents and water, making it difficult to purify by recrystallization
CN1496986 uses boiling water to wash the filter cake to purify strontium ranelate, but the chemical purity is not more than 98%, which still has a certain gap from the medicinal requirements

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] 5-Amino-4-cyano-3-ethoxycarbonylmethyl-thiophene-2-carboxylic acid ethyl ester (II)

[0018] In a 1000ml four-necked bottle, add 166.8g (0.825mol) of diethyl 3-oxoglutarate, 56.7g (0.858mol) of malononitrile and 200ml of ethanol, stir mechanically, and add dropwise morpholine 71.9g under ice water cooling g (0.825mol), the control temperature is not higher than 20°C. After dripping, stir for 10 minutes, add sulfur 26.5g (0.825mol), and reflux for 2.5 hours. Stop reflux, add dropwise 300ml of water, gradually precipitate, continue to stir for 20 minutes after dropping, cool, filter with suction, filter cake is washed with about 70ml of ice-cold 50% (v / v) ethanol, and dry to obtain crude product (189.8g, 81.5% ), recrystallized twice with 50% (v / v) ethanol to obtain 148.7 g (63.8%) of light khaki crystal II, mp.137-138°C.

Embodiment 2

[0020] 5-[Di-(methoxycarbonylmethyl)amino]-4-cyano-3-ethoxycarbonylmethyl-thiophene-2-carboxylic acid ethyl ester (III)

[0021] In a 2000ml reaction flask, add II 127g (0.450mol), polyethylene glycol 600 8.1g (0.0135mol), anhydrous potassium carbonate 136.8g (0.99mol), acetone 760ml and methyl chloroacetate 107.4g (0.99mol) , stirred and refluxed for 10 hours, cooled to room temperature, and filtered off inorganic salts. The filtrate was concentrated under reduced pressure with acetone until it was exhausted, and 300ml of methanol was added to dissolve it and left to stand overnight, suction filtered, and dried at 60°C to obtain 169.3g (88.2%) of crystals, which were recrystallized with 70% (v / v) ethanol to obtain 156.6g of white crystals ( 81.6%), mp. 106-107°C.

Embodiment 3

[0023] Strontium(I) ranelate

[0024] In a 2000ml reaction flask, add 128g (0.3mol) of III and 600ml of water, stir mechanically, add a solution composed of 50.4g (1.26mol) of sodium hydroxide and 600ml of water, reflux for 8 hours, adjust the pH to 8.5~ with concentrated hydrochloric acid 9.5, after cooling to room temperature, extract twice with ethyl acetate, 500ml each time, add activated carbon to the water layer for decolorization, filter, add SrCl to the filtrate 2 ·6H 2 0 and 330ml of water, stirred and refluxed for 1 hour, suction filtered while it was hot, and the resulting solid was placed in 600ml of 80% ethanol, heated and refluxed for 30 minutes, filtered while it was hot, and the solid was washed twice with water at about 80°C, 300ml each time, Dry at 55°C to obtain 155.2 g of white solid powder with a yield of 88.3%.

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Abstract

The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of strontium ranelate, which includes the following steps: reacting 5-amino-4-cyan-3-carbethoxy methyl-thiophene-2-carboxylic acid ethyl ester with a bifunctional alkylating agent in the presence of a catalyst to generate 5-[2-(carbomethoxy)amino]-4-cyan-3-carbethoxy methyl-thiophene-2-carboxylicacid ethyl ester, and then adding strontium chloride aqueous solution after hydrolysis of III in sodium hydroxide aqueous solution for salifying, thus obtaining the strontium ranelate. The preparation method is characterized in that the catalyst is polyethylene glycol, and the bifunctional alkylating agent is methyl chloroacetate or ethyl chloroacetate. In the preparation method, the low-price and environment-friendly catalyst and bifunctional alkylating agent are adopted, so as to be beneficial to industrial production.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a preparation method of 5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3-thiophene acetate distrontium salt tetrahydrate (strontium ranelate). Background technique [0002] Strontium ranelate can be used to treat osteoporosis in postmenopausal women and reduce the risk of vertebral and hip fractures. It can simultaneously reduce bone reabsorption and stimulate bone formation. Loosening drugs. However, the dose of strontium ranelate is relatively large, 2g / time. Therefore, reducing the production cost of strontium ranelate has great practical significance. [0003] [0004] The currently disclosed main preparation method is as follows: 5-amino-4-cyano-3-ethoxycarbonylmethyl-thiophene-2-carboxylic acid ethyl ester (II) is reacted with an alkylating agent in the presence of a catalyst to generate 5-[ Di-(methoxycarbonylmethyl)amino]-4-cyano-3-ethoxycarbonylmethyl-thiophene-2-ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
Inventor 徐云根朱雄刘嵘
Owner CHINA PHARM UNIV
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