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One-pot Synthesis of Risedronic Acid

A technology of risedronic acid and phosphonate, applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problem of low yield, long reaction route, high cost, etc. question

Active Publication Date: 2017-04-19
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Risedronic acid is a key intermediate in the synthesis of risedronic acid sodium for the treatment of osteoporosis. The quality of risedronic acid plays a decisive role in the raw material drug of risedronate sodium. The reaction route of sodium is long, usually more than five steps are required, and the yield is low, generally below 30%, so that the cost of risedronate sodium API remains high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Add 11g of 3-acetylpyridine, 3.5g of sulfur and 9g of morpholine into the reaction kettle, stir and reflux for 8 hours, lower to room temperature, add 56g of hydrochloric acid and 20g of water, heat and reflux for 6 hours, distill to dryness under reduced pressure, and then dilute the chlorine Add 110g of benzene, 20g of phosphorous acid and 26g of phosphorus trichloride into the reaction kettle, stir and heat to reflux for 10 hours, cool to room temperature, remove chlorobenzene, add 30g of concentrated hydrochloric acid and 50g of water, and then reflux for 12 hours, add activated carbon Decolorize, filter, evaporate the filtrate to dryness, disperse with ethanol, filter, and dry at 90°C to obtain 16.5 g of off-white or light yellow solid.

[0013] Purity by HPLC: 99.3%

Embodiment 2

[0015] Add 12g of 3-acetylpyridine, 4.0g of sulfur and 10g of morpholine into the reaction kettle, stir and reflux for 8 hours, lower to room temperature, add 75g of sulfuric acid and 20g of water, heat and reflux for 10 hours, distill to dryness under reduced pressure, and then distill the chlorine Add 120g of benzene, 20g of phosphorous acid and 30g of phosphorus trichloride into the reaction kettle, stir and heat to reflux for 10 hours, cool to room temperature, remove chlorobenzene, add 30g of concentrated hydrochloric acid and 50g of water, and then reflux for 12 hours, add activated carbon Decolorize, filter, evaporate the filtrate to dryness, disperse with ethanol, filter, and dry at 80°C to obtain 16.2 g of off-white or light yellow solid.

[0016] HPLC detection purity: 98.6%

Embodiment 3

[0018] Add 11g of 3-acetylpyridine, 3.5g of sulfur and 9g of morpholine into the reaction kettle, stir and reflux for 8 hours, cool down to room temperature, add 90g of glacial acetic acid and 20g of water, heat and reflux for 10 hours, distill to dryness under reduced pressure, and then Add 110g of chlorobenzene, 20g of phosphorous acid and 26g of phosphorus trichloride into the reaction kettle, stir and heat to reflux for 10 hours, cool to room temperature, remove chlorobenzene, add 30g of concentrated hydrochloric acid and 50g of water, and then reflux for 12 hours, add active Decolorize with carbon, filter, evaporate the filtrate to dryness, disperse with ethanol, filter, and dry at 70°C to obtain 16.0 g of off-white or light yellow solid.

[0019] HPLC purity: 99.6%

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Abstract

The invention provides a risedronic acid synthesized by a one-pot process. The risedronic acid is synthesized from 3-acetylpyridine as an initial material through Willgerodt-Kindle reaction, hydrolysis, diphosphonation and acidification employing the one-pot process. The risedronic acid has the advantages of being simple and convenient to operate, few in three wastes, mild and complete in reaction conditions, and suitable for industrial production, and has relatively high practical value; the reaction is finished in one container; the obtained product is stable in quality; and the purity can reach over 98%.

Description

technical field [0001] The invention relates to a preparation method of medicines, in particular to a preparation method of risedronic acid. Background technique [0002] Risedronic acid is a key intermediate in the synthesis of risedronate sodium, a drug for the treatment of osteoporosis. The quality of risedronic acid plays a decisive role in the raw material drug of risedronate sodium. The reaction route of sodium is long, generally needs more than five steps, and the yield is low, generally below 30%, so that the cost of risedronate sodium bulk drug remains high. Therefore, the industry has always hoped to find a new synthesis process for risedronate sodium to obtain more stable quality and higher yield. Contents of the invention [0003] The present invention aims to solve the foregoing problems, and provides a method for preparing risedronic acid, wherein 3-acetylpyridine is used as a starting material, through Willgerogt-Kindler reaction (Willgerogt-Kindler reactio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/58
Inventor 李卫民樊振石庆东吴相永王丽孔卫红祝立新王九牛景丽赵春霞刘慧敏王颖慧崔莹戴军许凌云
Owner TOPFOND PHARMA CO LTD
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