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Method for preparing minodronate

A phosphorylation and compound technology, which is applied in the field of minophosphoric acid preparation, can solve the problems of being unsuitable for large-scale production in the pharmaceutical industry, high toxicity, and difficulty in realization, and achieves low cost, short reaction steps, and mild and controllable reaction conditions. Effect

Active Publication Date: 2011-04-20
JIANGSU LEEWAY BIOLOGICAL TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In the preparation method disclosed by CN101531681 (publication date: 2009-09-16), when preparing ethyl 4-formyl butyrate, anhydrous and oxygen-free are required, and the reaction temperature is -80°C, which is difficult to achieve
When preparing ethyl 3-bromo-4-formyl butyrate, the reagents used involve liquid bromine and carbon tetrachloride, which are highly toxic and not suitable for large-scale production in the pharmaceutical industry

Method used

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  • Method for preparing minodronate

Examples

Experimental program
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Embodiment 1

[0028] 1. Preparation of (E)-4,4-dimethoxy-2-butenoic acid ethyl ester

[0029] Add 120g of 2,2-methoxyacetaldehyde and 4L of cyclohexane into a four-neck flask, add 900g of anhydrous potassium carbonate while stirring, and stir for 1h. Add 500 mL of triethyl phosphonoacetate dropwise and react for 6 h. After the reaction was completed, 1.5 L of water was added to the reaction liquid, and the liquids were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a colorless oily liquid. The oily liquid was distilled under reduced pressure to obtain a colorless Oil 150g, yield 71%.

[0030] 2, Preparation of 2-(imidazo[1,2-a]pyridin-3-yl) ethyl acetate

[0031] Under the protection of nitrogen, 200g of ethyl (E)-4,4-dimethoxy-2-butenoate, 1000mL of acetonitrile and 100mL of water were added to a three-necked flask, and then 10g of p-toluenesulfonic acid was added and stirr...

Embodiment 2

[0037] 1. Preparation of (E)-4,4-dimethoxy-2-butenoic acid ethyl ester

[0038] Add 180g of 2,2-dimethoxyacetaldehyde, 1300g of anhydrous potassium carbonate and 5800mL of cyclohexane into a round bottom flask, stir, add 670mL of triethyl phosphonoacetate dropwise, and react for 6h after the addition. After the reaction, add 2200mL, separate the layers, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, filter off the desiccant, concentrate the filtrate under reduced pressure to obtain a colorless oily liquid, distill the oily liquid under reduced pressure to obtain 210g of the product , yield 70%.

[0039] 2, Preparation of 2-(imidazo[1,2-a]pyridin-3-yl) ethyl acetate

[0040] Under nitrogen protection, add 196g (E)-4,4-dimethoxy-2-butenoic acid ethyl ester, 1000mL acetonitrile and 80mL water into the three-necked flask, stir, add 10g p-toluenesulfonic acid, then add 65g 2- Aminopyridine was heated and refluxed for 4h. After the reaction, filte...

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Abstract

The invention discloses a method for preparing minodronate, which comprises the following steps of: condensing a compound II and a compound III to form a compound IV, closing rings of the compound IV and 2-aminopyridine to obtain a compound V, hydrolyzing the compound V into a compound VI, and finally performing phosphonation to form a compound I. The method avoids using virulent chemical reagents such as sodium cyanide or bromine and the like, has mild and controllable reaction condition, short reaction step, high yield and low cost, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of minophosphoric acid. Background technique [0002] Minodronate, the chemical name is 1-hydroxy-2-[(imidazo[1,2-a]pyridin-3-yl]ethylene-1,1-diphosphonic acid, produced by Japan Yamanouchi The new heterocyclic bisphosphonic acid compounds developed by the company are used to treat hypercalcemia caused by osteoporosis and malignant tumors. Their bone resorption inhibitory activities are disodium incadronate, sodium alendronate and 2 times, 10 times and 100 times of pamidronate disodium. This product has significant benefits in the incidence of spinal fractures, and at the same time has a great reduction in gastrointestinal side effects, and has now been identified as an effective anti-osteoporosis It is a new drug to prevent fractures. The research and development of this drug will undoubtedly provide a safer, more effective and convenient treat...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 徐峰张孝清刘科举蒋玉伟
Owner JIANGSU LEEWAY BIOLOGICAL TECH
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