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Prepn process of Mycophenolate mofetil

A technology of mycophenolate morphinate and mycophenolic acid, which is applied in the field of preparation of mycophenolate morphinate, can solve the problems of long time and high reaction temperature, achieve the effect of low reaction temperature and solve the problem of product color

Active Publication Date: 2007-06-06
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

European patent EP281713B1 adopts the indirect esterification method, and the product has color problems; the preparation method of US patent No.5247083 has high reaction temperature and long time, and the product color also has problems

Method used

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  • Prepn process of Mycophenolate mofetil
  • Prepn process of Mycophenolate mofetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 30ml of tetrahydrofuran and 10g of mycophenolic acid to the reactor with reflux cooler, heat to about 50℃, mechanically stir until completely dissolved, then add 11.5ml of morpholine ethanol to the reactor, and then put 0.8 in the reactor g catalyst zinc oxide; heated to 67°C, refluxed for 24 hours, filtered to remove the catalyst zinc oxide; evaporated the organic solvent under reduced pressure to obtain crude mycophenolate mofetil, add 250ml ethyl acetate to dissolve the crude product, and then use 250ml K with a mass percentage concentration of 5% 2 CO 3 The solution is washed once, and then washed with 250ml purified water; it is concentrated to a mass percentage of 30% at a temperature of 40℃, cooled to 10℃, crystallized for 15 hours, and crystals are precipitated; filtered, and then washed with 10ml of cold ethyl acetate , Vacuum drying at a temperature of 40°C, and finally 11.5 g of a refined product with a purity of ≥99.7% (HPLC), with a yield of 85%. see pictur...

Embodiment 2

[0024] A preparation method of mycophenolate mofetil, including the following steps:

[0025] (1) Dissolve mycophenolic acid in tetrahydrofuran at a ratio of 1g:2ml in a reactor with a reflux cooler, heat to about 50°C, and stir until dissolved;

[0026] (2) Add morpholine ethanol at a ratio of 1:3 in molar ratio of mycophenolic acid to morpholine ethanol, and then add magnesium oxide as a catalyst, so that the added mass of the catalyst is 5% of the mass of mycophenolic acid;

[0027] (3) Raise the temperature to 67°C and reflux for 24 hours;

[0028] (4) Filter, remove the catalyst, and evaporate the organic solvent under reduced pressure to obtain the crude mycophenolate mofetil.

[0029] Add ethyl acetate to dissolve the crude product according to the mass ratio of crude mycophenolate morphenate to ethyl acetate of 1:15; use 1.5 times the volume of the dissolving solution with a mass percentage of K with a concentration of 5% 2 CO 3 The solution is washed once with the dissolv...

Embodiment 3

[0031] A preparation method of mycophenolate mofetil, including the following steps:

[0032] (1) Dissolve mycophenolic acid in tetrahydrofuran at a ratio of 1g:8ml in a reactor with a reflux cooler, heat to about 50°C, and stir to dissolve;

[0033] (2) Add morpholine ethanol at a ratio of 1:2 in molar ratio of mycophenolic acid to morpholine ethanol, and then add zinc oxide as a catalyst, so that the added mass of the catalyst is 8% of the mass of mycophenolic acid;

[0034] (3) Raise the temperature to 70°C and reflux for 20 hours;

[0035] (4) Filter, remove the catalyst, and evaporate the organic solvent under reduced pressure to obtain the crude mycophenolate mofetil.

[0036] It can also include the following steps:

[0037] Add ethyl acetate to dissolve the crude product according to the mass ratio of crude mycophenolate morphenate to ethyl acetate of 1:25; use K with a mass percentage concentration of 5%, which is equivalent to 2 times the volume of the dissolving solutio...

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Abstract

The present invention discloses preparation process of Mycopenolate mofetil. The preparation process includes the following steps: dissolving mycopenolic acid in tetrahydrofuran inside a reactor with reflux cooler through stirring; adding morpholine, alcohol and catalyst magnesia and / or zinc oxide; heating and refluxing; filtering to eliminate catalyst and decompression evaporating to eliminate organic solvent and obtain crude Mycopenolate mofetil product. The preparation process is simple, and has low reaction temperature, less produced impurity, conversion rate as high as 85 % and product purity not lower than 99.7 %, and easy industrial application.

Description

Technical field [0001] The invention relates to a preparation method of mycophenolate mofetil. Background technique [0002] Mycophnolate Mofetil [0003] [0004] It is an antibiotic with mainly immunosuppressive effect. It is a 2-ethyl ester derivative of mycophenolic acid (MPA). Gosio discovered mycophenolic acid in 1896, and Alsberg and Black purified it in 1913. Later, Mitsuzuki proved mycophenolic acid. Acid has potential immunosuppressive properties. An immunosuppressive antibiotic approved by the US Food and Drug Administration (FDA) in October 1998. It is mainly used to prevent organ rejection after kidney and heart transplantation. It can be combined with cyclosporine to reduce the latter’s Dosage and toxicity, its mode of action is to inhibit nucleic acid synthesis. Mycophenolic acid can effectively and non-competitively inhibit the activity of inosine monophosphate dehydrogenase, thereby hindering the de novo synthesis of guanosine nucleotides. As the synthesis of p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88
Inventor 杨亚勇陈海煌李长洪任全华
Owner LIVZON NEW NORTH RIVER PHARMA
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