A preparation method of minodronic acid for treating osteoporosis

A technology for minodronic acid and osteoporosis, applied in the field of medicine and chemical industry, can solve the problems of slow reaction speed, harsh conditions, and many by-products, and achieve the effects of increased reaction speed, increased yield, and easy removal

Inactive Publication Date: 2017-12-15
聂红梅 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The purpose of the present invention is to overcome the defects of slow reaction speed, low yield, many by-products and harsh conditions in the above-mentioned existing method for preparing minodronic acid, and provide a method for treating osteoporosis with minodronic acid. Preparation

Method used

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  • A preparation method of minodronic acid for treating osteoporosis
  • A preparation method of minodronic acid for treating osteoporosis
  • A preparation method of minodronic acid for treating osteoporosis

Examples

Experimental program
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Embodiment 1

[0039] A preparation method of minodronic acid for treating osteoporosis, the method comprises the following steps:

[0040](1) 14.19g (51.8mmol) of ethyl 3,4-dibromo-butyrate and 1.42g of reaction accelerator A were added into a three-necked flask of a mixed solvent of water and 1,4-dioxane in 100ml, Stir at room temperature for 15 minutes, then add 5.85g (61.16mmol) of 2-aminopyridine and stir at 80°C for 3 hours. TLC monitors that the reaction of ethyl 3,4-dibromo-butyrate is complete, filter, concentrate under reduced pressure, and add water , extracted with ethyl acetate (50mL×3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to give 10g of light yellow oil, which was 2-(imidazo[1,2-α]pyridin-3-yl)acetic acid Ethyl ester, yield 93.1%, purity 98.5%; Among them, the reaction accelerator A is composed of zinc nitrate and glycine with a weight ratio of 4:1, and the mixed solvent is formed by mixing 10ml water and 30ml 1,4-dioxane . ...

Embodiment 2

[0044] A preparation method of minodronic acid for treating osteoporosis, the method comprises the following steps:

[0045] (1) 14.19g (51.8mmol) of ethyl 3,4-dibromo-butyrate and 1.14g of reaction accelerator A were added in a three-necked flask of a mixed solvent of water and 1,4-dioxane in 100ml, Stir at room temperature for 15 minutes, then add 6.34g (67.34mmol) of 2-aminopyridine and stir at 85°C for 5 hours. TLC monitors that the reaction of ethyl 3,4-dibromo-butyrate is complete, filter, concentrate under reduced pressure, and add water , extracted with ethyl acetate (50mL×3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to give 10.2g of a light yellow oil, which was 2-(imidazo[1,2-α]pyridin-3-yl) Ethyl acetate, the yield is 94.7%, and the purity is 98.2%. Among them, the reaction accelerator A is composed of zinc nitrate and glycine with a weight ratio of 4.5:1, and the mixed solvent is formed by mixing 15ml of water and 30m...

Embodiment 3

[0049] A preparation method of minodronic acid for treating osteoporosis, the method comprises the following steps:

[0050] (1) 14.19g (51.8mmol) of ethyl 3,4-dibromo-butyrate and 1.28g of reaction accelerator A were added in a three-necked flask of a mixed solvent of water and 1,4-dioxane in 100ml, Stir at room temperature for 15 minutes, then add 7.31g (77.7mmol) of 2-aminopyridine and stir at 70°C for 4 hours. TLC monitors that the reaction of 3,4-dibromo-butyric acid ethyl ester is complete, filter, concentrate under reduced pressure, add water , extracted with ethyl acetate (50mL×3 times), combined the organic phases, and removed the solvent under reduced pressure to obtain 10.07g of light yellow oil, which was 2-(imidazo[1,2-α]pyridin-3-yl)acetic acid Ethyl ester, yield 93.2%, purity 97.9%; Among them, the reaction accelerator A is composed of zinc nitrate and glycine with a weight ratio of 5:1, and the mixed solvent is formed by mixing 10ml water and 25ml 1,4-dioxane ...

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Abstract

The invention discloses a preparation method of minodronic acid for treating osteoporosis. The method comprises the following steps: (1) reacting a compound expressed by the formula (I) with 2-aminopyridine to obtain a compound expressed as the formula (II); (2) hydrolyzing the compound expressed by the formula (II) obtained by the step (1) to obtain a compound expressed by the formula (III); and (3) phosphorylating the compound expressed by the formula (III) obtained in the step (2) to obtain minodronic acid, wherein the formulae (I), (II) and (III) are described in the specification; in the formulae (I), (II) and (III), X1 and X2 independently represent halogen, and R represents C1-C4 alkyl. Through the method, the yield of key intermediates in the preparation process of minodronic acid can be greatly increased; meanwhile, the method is few in impurities of product, few in by-products and mild in condition, and is suitable for large-scale production and popularization.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of minodronic acid for treating osteoporosis. Background technique [0002] The chemical name of minodronic acid is [1-hydroxy-2-(imidazo[1,2-α]pyridin-3-yl)-ethylidene]1,1-bisphosphonic acid, the compound is The third generation of nitrogen-containing heteroaryl bisphosphonate derivatives jointly developed by Japan Yamanouchi Pharmaceutical Co., Ltd. and Japan Ono Pharmaceutical Co., Ltd. In January 2009, it was approved by the Japanese Ministry of Health and Welfare for the treatment of osteoporosis and hypercalcemia caused by osteoporosis and malignant tumors. The compound has high anti-bone resorption activity, and it is alendronate and pamidronate respectively It is 10 times and 100 times that of acid, and it has the effect of antagonizing osteolysis caused by myeloma and tumor, so it has a broad market prospect. [0003] At pr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561
Inventor 聂红梅李建爱于见梅
Owner 聂红梅
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