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Synthesis method of minodronate midbody and synthesis of minodronate

A technology of minodronic acid and a synthesis method, which is applied in the synthesis of minodronic acid and the synthesis of minodronic acid intermediates, can solve the problems of high cost of raw materials, harsh conditions, and many by-products, and achieve stable product quality. , the effect of short reaction steps and reduced raw material cost

Active Publication Date: 2013-04-17
福建太平洋制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, the existing preparation method has low yield and harsh conditions
According to these methods, when synthesizing minodronic acid some need to use sodium cyanide highly toxic chemicals, the steps are long and loaded down with trivial details, many by-products, ultra-low temperature reaction (-80 ℃), raw material cost is high, in these disclosed preparations method, there is no effective solution to the above problems

Method used

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  • Synthesis method of minodronate midbody and synthesis of minodronate
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  • Synthesis method of minodronate midbody and synthesis of minodronate

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Embodiment 1

[0040] Embodiment 1, the preparation of A1

[0041] Add 7.21g of 2-aminopyridine and 48ml of ethyl acetate to a dry and anhydrous 250ml three-necked flask in sequence, stir well, protect with nitrogen, and dissolve all the solids. Control the temperature at 5--30°C and slowly add ethyl 4-chloroacetoacetate dropwise 6g / ethyl acetate 6ml mixed solution, dropwise completed in 15--30 minutes, keep warm at 30°C for 10 minutes, slowly raise the temperature to reflux for 2-3 hours, monitor the reaction solution by TLC until the spots of ethyl 4-chloroacetoacetate disappear (developing agent: ethyl acetate), after the reaction is completed, stop heating, reduce the temperature and concentrate to dryness under reduced pressure, and the concentrated residue is fully dissolved with 80 ml of purified water, and the aqueous layer is washed 8 times with 40 ml of n-hexane to remove impurities, and the n-hexane layer is discarded. The water layer was extracted 6 times with 50 ml of ethyl acet...

Embodiment 2

[0042] Embodiment 2, the preparation of A1

[0043] Add 7.21g of 2-aminopyridine and 48ml of absolute ethanol to a dry and anhydrous 250ml three-necked flask in sequence, stir well, protect with nitrogen, and dissolve all the solids. Control the temperature at 5--30°C and slowly add ethyl 4-chloroacetoacetate dropwise 6g / absolute ethanol 6ml mixed solution, add dropwise in 15--30 minutes, keep warm at 30°C for 10 minutes, slowly raise the temperature to reflux for 2-3 hours, monitor the reaction solution by TLC until the spots of ethyl 4-chloroacetoacetate disappear (developing agent: ethyl acetate), after the reaction is completed, stop heating, reduce the temperature and concentrate to dryness under reduced pressure, and the concentrated residue is fully dissolved with 80 ml of purified water, and the aqueous layer is washed 8 times with 40 ml of n-hexane to remove impurities, and the n-hexane layer is discarded. The water layer was extracted 6 times with 50 ml of ethyl acet...

Embodiment 3

[0044] Embodiment 3, the preparation of A1

[0045] Add 7.21g of 2-aminopyridine, 48ml of absolute ethanol, and 0.24g of potassium iodide to a dry and anhydrous 250ml three-necked flask in sequence, stir well, protect with nitrogen, and dissolve all the solids. Slowly add 4-chloropyridine at a temperature of 5-30°C. Ethyl acetoacetate 6g / absolute ethanol 6ml mixed solution, add dropwise in 15--30 minutes, keep warm at 30°C for 10 minutes, slowly raise the temperature to reflux for 3 hours, TLC monitors the reaction solution to 4-chloroacetoacetate ethyl Spots disappear (developing agent: ethyl acetate), after the reaction is complete, stop heating, reduce the temperature and concentrate to dryness under reduced pressure, and the concentrated residue is fully dissolved with 80ml of purified water, and the aqueous layer is washed 8 times with 40ml of n-hexane to remove impurities. The layer was discarded, the aqueous layer was extracted 6 times with 50 ml of ethyl acetate, the e...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a synthesis method of a minodronate midbody and synthesis of minodronate. The preparation method of minodronate includes the following steps: using organic solvent to dissolve 2-aminopyridine, adding 4-acetyl chloride ethyl acetoacetate for reaction, monitoring the reaction solution by TLC(Thin-Layer Chromatography) until spots of 4-acetyl chloride ethyl acetoacetate disappear, concentrating to a dry state, dissolving concentrate in water, washing a water layer to remove impurities, extracting the water layer with the organic solvent, washing extract liquor, separating out an organic layer, conducting filtration, and concentrating the concentrate to be in a dry state, thereby obtaining A1.

Description

Technical field: [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing a minodronic acid intermediate and the synthesis of minodronic acid Background technique: [0002] Minodronic acid, English name: Minodronic acid, chemical name: 1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethane-1,1-bisphosphonic acid, molecular formula: C 9 h 12 N 2 o 7 P 2 , molecular weight: 322.15, CAS RN: 180064-38-4 (127657-42-5), the chemical structure is as follows: [0003] [0004] Minodronic acid is used to treat osteoporosis. It inhibits the bone resorption function of osteoclasts by inhibiting farnesyl pyrophosphate synthase in osteoclasts, thereby reducing the bone metabolism cycle. [0005] The existing methods for synthesizing minodronic acid mainly include some foreign patents and the following Chinese patents: [0006] Such as: EP0354806; J Med.Chem., 1969, 12(1): 122-126; literature Chinese Journal of Pharmaceutical Industry 3...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/38C07D471/04
Inventor 刘山
Owner 福建太平洋制药有限公司
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