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Method for preparing strontium ranelate

A strontium ranelate and compound technology, applied in the field of strontium ranelate preparation, can solve the problems of unfavorable post-processing, material stickiness, etc., and achieve the effect of reduced impurity content and simple operation method

Active Publication Date: 2010-07-14
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventor found in experiments that when diethylamine was used as the base, the material was very sticky, which was unfavorable for aftertreatment

Method used

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  • Method for preparing strontium ranelate
  • Method for preparing strontium ranelate
  • Method for preparing strontium ranelate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Add diethyl 3-oxoglutarate (20.2 g, 0.1 mol), malononitrile (6.6 g, 0.1 mol), and 10 mL of ethanol into the reaction flask, cool to 0±5°C, and add triethylamine ( 10.1 g, 0.1 mol) of ethanol mixture in 10 mL, and keep the temperature of the reaction system at 0-10 ° C, about 30 min after the dripping, and react at room temperature at 20-30 ° C for 1 h. Sulfur powder (3.2 g, 0.1 mol) was added, and the temperature was raised to 70-78° C. for reflux reaction for 4 h. Remove from heat and cool to room temperature. Add 30 mL of water, cool to 0±5°C, and precipitate crystals. Filter, and wash the filter cake successively with 10 mL of ethanol and 20 mL of water. After drying the filter cake, 23.1 g of ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate was obtained (85% yield, 99.0% purity) .

Embodiment 2

[0056]Add 5-amino-4-cyano-3-(2-ethoxyl-2-oxoethyl)-2-thiophenecarboxylic acid ethyl ester (80g, 0.283mol) obtained in Example 1, carbonic acid Potassium (98g, 0.71mol), acetone (600mL) and ethyl bromoacetate (110g, 0.658mol) were stirred rapidly, heated to 50-58°C, and refluxed for 4h. Cool to 20-40°C, filter to remove inorganic salts, and rinse with 40 mL of acetone. The filtrates were combined and concentrated to dryness under reduced pressure. Recrystallize twice with ethanol and dry to get 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyano-3-(2-ethoxy-2-oxo Ethyl)-2-thiophenecarboxylic acid ethyl ester 106g (yield 82%, purity greater than 99.5%).

Embodiment 3

[0058] Add Example 2 in the reaction flask to obtain 5-[bis(2-ethoxyl-2-oxoethyl)amino]-4-cyano-3-(2-ethoxyl-2-oxoethyl) )-Ethyl 2-thiophenecarboxylate (20g, 0.044mol), 30mL of tetrahydrofuran, 80mL of aqueous solution of sodium hydroxide (8g, 0.2mol), stirred, controlled the reaction temperature at 10-30°C, and reacted for 5h. A small amount of insoluble solid was removed by filtration, and the filtrate was concentrated under reduced pressure at 35°C to remove the organic solvent. A solution of strontium chloride hexahydrate (25.8 g, 0.092 mol) in 136 mL of water was added with stirring. Crystallize at room temperature for 15h and filter. The filter cake was added to 160 mL of hot water, heated to 95°C for 5 minutes, and filtered while hot to remove strontium hydroxide impurities. Wash with 20mL boiling water. Vacuum drying at 40°C for 12 hours gave 23.1 g of strontium ranelate heptahydrate (yield 82%, purity greater than 99.5%, and individual impurity content less than 0....

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Abstract

The invention provides a method for preparing strontium ranelate (I). The method is characterized in that: in a mixed liquor of water and an organic solvent, the compound in the formula (II) reacts with sodium hydroxide, potassium hydroxide or lithium hydroxide to obtain a compound in the formula (III); then the compound in the formula (III) is distilled to remove the organic solvent to obtain aqueous solution of the compound in the formula (III); and the obtained product reacts with strontium chloride in the aqueous solution, and filtering and separating the reaction solution to obtain strontium ranelate, wherein R and R' can be the same or different and respectively respects C1 to C6 linear chain or branched chain alkyl; and A respectively represents Na, K or Li. The strontium ranelate prepared by the method provided by the invention has obviously reduced single impurity content.

Description

technical field [0001] The invention provides a method for preparing strontium ranelate suitable for industrial production. Background technique [0002] Strontium (I) ranelate has very valuable pharmacological effects, especially in anti-osteoporosis, it can not only promote bone formation, but also inhibit bone resorption, and is especially suitable for the treatment of osteoporosis in postmenopausal women . [0003] [0004] EP0415850 discloses three preparation methods of strontium ranelate, the second method: adding compound (V) to a sodium hydroxide solution mixed with ethanol and water for hydrolysis, and after hydrolysis, the alcohol and water are evaporated to dryness to obtain a tetrasodium salt solid. Strontium chloride is then added to form strontium ranelate. In this method, the tetrasodium salt has strong hygroscopicity, and the actual operation is troublesome, and the product yield obtained according to the method is less than 70%. [0005] [0006] C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
Inventor 郭健卫甘立新蹇锋
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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