Preparation method of minodronic acid

A technology of minodronic acid and phosphoric acid, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., can solve problems such as long synthetic routes, difficult purification of products, and dangerous operation, and achieve Mild reaction conditions, short reaction steps, and less environmental pollution

Inactive Publication Date: 2015-04-08
HARBIN PHARMA GROUP TECH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] 2-Aminopyridine is used as the starting material, and minodronic acid is obtained through ring closure, formylation, aldehyde group reduction, chlorination, cyanation, cyanohydrolysis, and phosphorylation. This method has a total of 7 steps of reaction, and the synthetic route is relatively long. The yield is low, and the highly toxic substance sodium cyanide is used, which is dangerous to operate, and there are many side reactions generated at the same time, and the product is difficult to purify
[0014] Using 2-imidazo[1,2-a]pyridine as the starting material, minodronic acid is obtained through ring closure, amination, cyanation, cyanohydrolysis and phosphorylation. This method has a total of 6 steps and a long synthetic route , the starting material is not easy to obtain, and the highly toxic sodium cyanide is used, the operation is dangerous, and at the same time, there are many side reactions, and the product is difficult to purify
In addition, 2-(imidazo[1,2-a]pyridin-3-yl)acetic acid has good water solubility, and the sodium cyanide reaction is carried out in aqueous solution, so it is difficult to obtain 2-(imidazo[1,2-a]pyridine-3 -yl)acetic acid

Method used

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  • Preparation method of minodronic acid
  • Preparation method of minodronic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0041] 1, Preparation of ethyl 4-oxobutenoate

[0042] Add 25.2g (E)-4,4-dimethoxy-2-butenoic acid ethyl ester, 40mL acetone, 20mL purified water and 2.14g p-toluenesulfonic acid into a 250ml three-necked flask; stir and heat to 40 -50°C, keep warm for 1-1.5h, concentrate the reaction solution, add 30mL of acetone, heat to 50-60°C, continue to stir for 1-2h, monitor by GC, and stop the reaction if it meets the internal control standards. The reaction solution was concentrated to obtain a yellow oily liquid.

[0043] Weigh 1.05g of sodium bicarbonate and prepare a saturated solution with 12mL of purified water for later use. Add 30mL of ethyl acetate to the above yellow liquid, cool down to 5-15°C, slowly add the pre-prepared saturated sodium bicarbonate solution, stir for 10-15min, let stand for 10-15min, separate the layers, and separate the organic layer (upper layer ); the aqueous phase was extracted once with 30mL ethyl acetate, the organic layer was separated, and the o...

Embodiment 2

[0049] 1, Preparation of ethyl 4-oxobutenoate

[0050] Add 50.4g (E)-4,4-dimethoxy-2-butenoic acid ethyl ester, 80mL acetone, 40mL purified water and 4.28g p-toluenesulfonic acid into a 500ml three-necked flask; stir and heat to 40 -50°C, keep warm for 1-1.5h, concentrate the reaction solution, add 30mL of acetone, heat to 50-60°C, continue to stir for 1-2h, monitor by GC, and stop the reaction if it meets the internal control standards. The reaction solution was concentrated to obtain a yellow oily liquid.

[0051] Weigh 2.1g of sodium bicarbonate and prepare a saturated solution with 24mL of purified water for later use. Add 60mL of ethyl acetate to the above yellow liquid, cool down to 5-15°C, slowly add the pre-prepared saturated sodium bicarbonate solution, stir for 10-15min, let stand for 10-15min, separate the layers, and separate the organic layer (upper layer ); the aqueous phase was extracted once with 60mL ethyl acetate, the organic layer was separated, and the or...

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Abstract

The invention discloses a preparation method of minodronic acid. The preparation method comprises the following steps: performing acetal hydrolysis on a compound I to obtain a compound II, performing closed-loop treatment and hydrolysis on the compound II and 2-aminopyridine to obtain a compound III, and finally, performing phosphorylation on the compound III to obtain a compound IV. By adopting the preparation method disclosed by the invention, highly toxic chemical reagents including sodium cyanide or bromine and the like are avoided, the reaction conditions are mild and controllable, the reaction steps are relatively short, the yield is relatively high, and the cost is relatively low, so that the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a preparation method of minodronic acid. Background technique [0002] Minodronate, the chemical name is 1-hydroxy-2-{imidazo[1,2-a]pyridin-3-yl}ethylene-1,1-bisphosphonic acid, produced by Japan Yamanouchi Co., Ltd. A new type of heterocyclic bisphosphonic acid compounds developed for the treatment of hypercalcemia caused by osteoporosis and malignant tumors. 2 times, 10 times and 100 times of disodium midronate. This product has a significant benefit 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 new drug against osteoporosis to prevent fractures. The research and development of this drug will undoubtedly provide a safer, more effective and convenient treatment drug for patients with clinical diseases, and it will certainly produce good social and econo...

Claims

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Application Information

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IPC IPC(8): C07F9/6561
Inventor 袁淑杰杨新春刘佳吉李郑武王忠高晶丁辉齐岩徐岩
Owner HARBIN PHARMA GROUP TECH CENT
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