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Method for preparing mycophenolate mofetil

A technology of mycophenolate mofetil and ethyl acetate, which is applied in the field of preparing mycophenolate mofetil, can solve problems such as equipment corrosion, pollution, and difficult industrialization, and achieve the effects of low production cost and low process cost

Active Publication Date: 2013-08-28
CHONGQING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this route is that it requires two steps of synthesis, the corrosion of the equipment by the acid chloride, and the generation of a large amount of dimerization impurities during the reaction.
In addition, the product has serious color problems due to contamination by trace amounts of iron
In the second route, the carboxylic acid is activated and then condensed by carboimide. This route is difficult to industrialize due to the higher cost of carboimide activators; the purity of the final product ester is also low.
[0008]WO 02100855 uses high boiling point solvents for direct esterification. It is worth noting that dibutyl ether is extremely effective in experiments, but there is still room for improvement in the color of the product

Method used

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  • Method for preparing mycophenolate mofetil
  • Method for preparing mycophenolate mofetil
  • Method for preparing mycophenolate mofetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Under the protection of nitrogen, mix 20 g of mycophenolic acid and 40 mL of dibutyl ether, stir vigorously and heat up to 60°C, add 10 mL of 2-hydroxyethyl morpholine, react for 15 h under the condition of azeotropic water removal, and cool to room temperature and added 100 mL of dichloromethane. The solution was washed twice with 20mL dilute ammonia water (1% by mass concentration), washed twice with 50mL tap water, and the organic solvent was evaporated under reduced pressure. The residue was dissolved in a mixed solvent of propanol / ethyl acetate (150 mL:30 mL) (propanol / ethyl acetate=5:1) under nitrogen protection, and the temperature was raised to 50-60°C. Subsequently, 1-ethyl-3-methylimidazolium chloride (9mg / 1mmol / 2mL hot distilled water) was added, and when the purple color of the residue disappeared, it was filtered while hot, and the solid was washed with 33 mL propanol / ethyl acetate mixture ( 50-60°C) to wash and combine the filtrates.

[0050] (1) Slowly ...

Embodiment 2

[0053] Under the protection of nitrogen, mix 20 g of mycophenolic acid and 40 mL of dibutyl ether, stir vigorously and raise the temperature to 50-60 ° C, add 10 mL of 2-hydroxyethyl morpholine, and react for 15 hours under the condition of azeotropic water removal, The organic solvent was distilled off under reduced pressure, and 150 mL of ethyl acetate was added to the residual solid. The solution was washed twice with 20 mL of saturated sodium bicarbonate and twice with 50 mL of tap water, and the organic solvent was evaporated under reduced pressure. Under the protection of nitrogen, the residue was dissolved in a mixed solvent of propanol / ethyl acetate (150 mL:30 mL) (propanol / ethyl acetate=5:1, the temperature was raised to 50-60°C). Subsequently, 1-ethyl-3-methylimidazolium bromide (12mg / 1mmol / 2 mL hot distilled water) was added, and when the purple color of the residue disappeared, it was filtered while hot, and the solid was washed with 33 mL propanol / ethyl acetate mi...

Embodiment 3

[0055] Under the protection of nitrogen, mix 20 g of mycophenolic acid and 40 mL of dibutyl ether, stir vigorously and raise the temperature to 50-60 ° C, add 10 mL of 2-hydroxyethyl morpholine, under the condition of azeotropic water removal, reflux for 15 hours, Cool to room temperature and add 150 mL of ethyl acetate. The solution was washed twice with 20 mL of dilute ammonia water (1% by mass) and twice with 40 mL of tap water. The organic solvent was evaporated under reduced pressure. Under the protection of nitrogen, the residue was dissolved in a mixed solvent of propanol / ethyl acetate (150 mL:30 mL) (propanol / ethyl acetate=5:1, the temperature was raised to 50-60°C). Subsequently, tetrabutylammonium bromide (20 mg / 1mmol / 2 mL of hot distilled water) was added, and when the purple color of the residue disappeared, it was filtered while hot, and the solid was washed with 33 mL of propanol / ethyl acetate mixture (50-60°C ), combined the filtrates, added 0.1 g of pure myco...

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Abstract

The invention discloses a method for preparing mycophenolate mofetil, which comprises the following steps of: using dibutyl ether as a solvent, performing complete reaction between MPA and 2-hydroxyethyl morpholine under inert gas protection and constant boiling water conditions so as to obtain a crude product of the mycophenolate mofetil; and using an ionic liquid as a chelating agent to decolor and purify, seeding the mycophenolate mofetil, and crystallizing a mixed solvent to obtain high-purity mycophenolate mofetil. The method has the advantages of short reaction time, high MPM purity, high reaction yield, low generation cost and the like, and has a wide industrial application prospect, and the problem of the color of a final product is solved.

Description

technical field [0001] The invention relates to a method for preparing mycophenolate mofetil. [0002] Background technique [0003] Mycophenolic acid (MPA), chemical name 6-[4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuryl]-4-methyl-4-hexyl Enenoic acid, formula C 17 h 20 o 6 , molecular weight 320.35, CAS registry number 24280-93-1. It was isolated by Gosio in 1893. It is produced by Penicillium brevicum, P. scabrum, P. nagemi, and Penicillium loudii. It has good antibacterial activity, and also has strong antiviral and antitumor activities. Clinically, it has been used in the treatment of psoriasis, the prevention of rejection in renal allograft transplantation patients and the treatment of refractory rejection. 2-Morpholinoethyl ester of MPA, also known as mycophenolate mofetil (MPM)), molecular formula C 23 h 31 NO 7 , CAS registration number 128794-94-5, is a prodrug of MPA, its characteristics and properties are similar to it, and it has less side effects a...

Claims

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Application Information

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IPC IPC(8): C07D307/88
Inventor 王锐胥秀英刘红张云玲郑一敏任杰彭术谢云张洪兰
Owner CHONGQING UNIV OF TECH
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