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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, many by-products, harsh conditions, etc., and achieve the effects of less by-products, improved yield, and improved reaction speed.

Active Publication Date: 2015-12-23
嘉善县魏塘资产管理有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The object 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 preparing minodronic acid for treating osteoporosis

Method used

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  • Preparation method of minodronic acid for treating osteoporosis
  • Preparation method of minodronic acid for treating osteoporosis
  • Preparation method of minodronic acid for treating osteoporosis

Examples

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Embodiment 1

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

[0040](1) Add 10.83g (51.8mmol) of 4-bromo-ethyl acetoacetate and 0.97g of reaction accelerator M0.97g into a three-necked flask with a mixed solvent of water and 1,4-dioxane in 100ml, and stir at room temperature for 15 minutes, then add 5.36g (57mmol) of 2-aminopyridine and stir the reaction at 70°C for 3.5 hours, monitor by TLC until the reaction of ethyl 4-bromo-acetoacetate is complete, filter, concentrate under reduced pressure, add water, extract with ethyl acetate (50mL × 3 times), washed with saturated brine (50 mL × 3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to obtain 10.17 g of light yellow oil, namely 2-(imidazo[1,2-α]pyridine- 3-yl) ethyl acetate, yield 94.1%, purity 97.9%; wherein, reaction accelerator M is composed of zinc nitrate and glycine with a weight ratio of 7:1, and the mixed solvent is co...

Embodiment 2

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

[0045] (1) Add 10.83g (51.8mmol) of 4-bromo-ethyl acetoacetate and 1.08g of reaction accelerator M1.08g into a three-necked flask with a mixed solvent of water and 1,4-dioxane in 100ml, and stir at room temperature for 15 minute, then added 2-aminopyridine 7.31g (77.7mmol) and stirred at 65°C for 3 hours, monitored by TLC until the reaction of 4-bromo-ethyl acetoacetate was complete, filtered, concentrated under reduced pressure, added water, and extracted with ethyl acetate ( 50mL×3 times), combined the organic phases, removed the solvent under reduced pressure, and dried to obtain 10.08g of light yellow oil, which was 2-(imidazo[1,2-α]pyridin-3-yl)ethyl acetate, yield 93.6%, with a purity of 98.2%. Among them, the reaction accelerator M is composed of zinc nitrate and glycine with a weight ratio of 8:1, and the mixed solvent is formed by mixing 10ml of water ...

Embodiment 3

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

[0050] (1) 10.83g (51.8mmol) of 4-bromo-ethyl acetoacetate and 0.98g of reaction accelerator M0.98g are added in the there-necked flask of the mixed solvent of 100ml water and 1,4-dioxane, stirred at room temperature for 15 minute, then added 2-aminopyridine 6.09g (64.75mmol) and stirred at 68°C for 4 hours, monitored by TLC until the reaction of 4-bromo-ethyl acetoacetate was complete, filtered, concentrated under reduced pressure, added water, and extracted with ethyl acetate ( 50mL×3 times), the organic phases were combined, and the solvent was removed under reduced pressure to obtain 10.15g of a light yellow oily substance, namely 2-(imidazo[1,2-α]pyridin-3-yl)ethyl acetate, yield 93.9 %, with a purity of 97.9%; wherein, the reaction accelerator M is composed of zinc nitrate and glycine at a weight ratio of 7.5:1, and the mixed solvent is formed by mixing 1...

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Abstract

The invention discloses a preparation method of minodronic acid for treating osteoporosis. The preparation method comprises the following steps of firstly, reacting a compound as shown in a formula (I) with 2-aminopyridine to obtain a compound as shown in a formula (II); secondly, hydrolyzing the compound as shown in the formula (II) obtained in the first step to obtain a compound as shown in a formula (III); thirdly, phosphorylating the compound as shown in the formula (III) obtained in the second step to obtain the minodronic acid, wherein X is chlorine or bromine, and R is alkyl radicals of C1 to C4; in the first step, a reaction promotor M is added and consists of one or more substances selected from zinc nitrate, silver nitrate and copper nitrate and one or more substances selected from glycine and alanine. According to the preparation method, the yield of a key intermediate in a preparation process of the minodronic acid can be greatly improved; the preparation method has the advantages of few side products, easiness in purification, mild conditions and higher reaction speed, 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 third generation of nitrogen-containing heteroaryl bisphosphonate derivatives jointly developed by 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 present, researchers in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561
Inventor 陈令浩
Owner 嘉善县魏塘资产管理有限公司
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