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Prepn process of mofe-til mycophenolate

A technology of mycophenolate morphinate and mycophenolic acid, which is applied in the field of preparation of mycophenolate mofetil, can solve problems such as multi-step reaction, product lavender cannot be removed, and instability, so as to shorten the reaction time and solve the problem of Product color problem, the effect of reducing production cost

Active Publication Date: 2006-05-17
YICHANG HEC CHANGJIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the European patent EP281713B1 using the indirect esterification method first reacts mycophenolic acid with thionyl chloride to generate mycophenolic acid chloride, and then reacts with excess 2-morpholinoethanol to obtain mycophenolate mofetil, but it is unstable. It is easy to form a copolymer, and there is a color problem in the product; another example is the US patent US5247083 that uses the direct esterification method to prepare mycophenolate mofetil by refluxing mycophenolic acid and 2-morpholinoethanol under azeotropic water separation in a suitable solvent or solvent mixture Ester, it takes about 6-100h long reaction period to achieve sufficient conversion rate, and the lavender color of the product cannot be removed
The above-mentioned related technology has improved the production rate to a certain extent in the preparation process of mycophenolate morphinate, but there are still various problems: the reaction time is long, the product has color problems, multi-step reactions are required or it is difficult to realize industrialization

Method used

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  • Prepn process of mofe-til mycophenolate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Using formic acid as a catalyst and dropping into a decolorizing agent vitamin C to remove purple mycophenolate mofetil preparation method comprises the following steps in turn:

[0022] (1) Put 20g of mycophenolic acid and 60mL of a mixed solvent of toluene and xylene (3:1) into a reactor with a reflux water separation device, stir until dissolved, and then put in 11.5g of morpholinoethanol;

[0023] (2) drop into 1g catalyst low-grade fat and acid-formic acid;

[0024] (3) Raise the temperature to 130°C, stir, reflux and divide the water, keep the temperature for 10 hours, then cool down and directly esterify, track the purity (HPLC), and the reaction conversion rate reaches 85% in about 8 hours;

[0025] (4) 1.5 g of activated carbon was added to decolorize at a temperature of 80° C. for 0.5 hours, suction filtered, and the mother liquor was evaporated to dryness under reduced pressure at a temperature below 70° C.;

[0026] (5) Dissolve with 150ml of ethyl acetate,...

Embodiment 2

[0029] Using acetic acid as a catalyst and dropping into the decolorizer vitamin C to remove the purple mycophenolate morphinate preparation method comprises the following steps in turn:

[0030] (1) with the step (1) of embodiment 1;

[0031] (2) drop into 1g catalyst lower fatty acid-acetic acid,

[0032] (3) Raise the temperature to 129°C, stir, reflux and divide the water, keep the temperature for 24 hours, then cool down and directly esterify;

[0033] (4) with the step (4) of embodiment 1;

[0034] (5) basically with the step (5) of embodiment 1, vitamin C input amount is 0.07g;

[0035] (6) Basically the same as the step (1) of the embodiment, 22.00 g of mycophenolate mofetil was obtained, the purity (HPLC) was 99.7%, and the yield was 83.0%.

Embodiment 3

[0037] Using propionic acid as a catalyst and dropping into the decolorizing agent vitamin C to remove purple mycophenolate mofetil preparation method comprises the following steps in turn:

[0038] (1) substantially with the step (1) of embodiment 1, the input amount of morpholino ethanol is 11.5g;

[0039] (2) drop into 1g catalyst lower fatty acid-propionic acid,

[0040] (3) Heating up to 127°C, stirring, reflux and water separation, keeping the temperature for 24 hours, and then cooling down for direct esterification;

[0041] (4) with the step (4) of embodiment 1;

[0042] (5) basically with the step (5) of embodiment 1, vitamin C input amount is 0.16g;

[0043] (6) Basically the same as the step (1) of Example 1, 21.20 g of mycophenolate mofetil was obtained, the purity (HPLC) was 99.6%, and the yield was 80.0%.

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Abstract

The preparation process of mofetil mycophenolate includes the following successive steps: 1. dissolving mycophenolic acid and 2-morpyolinyl ethanol in the mixed solvent of toluene and xylene via stirring; 2. throwing in catalyst C1-6 fatty acid; 3. heating, stirring and refluxing for direct estification; 4. throwing in decolorizing agent active carbon; 5. throwing in ethyl acetate and decolorizing agent vitamin C, and washing with 10 % concentration sodium carbonate solution and water successively; and 6. heating, cooling to separate solid, washing with ethyl acetate and final vacuum drying to obtain the product. The preparation process of the present invention has short reaction time, low preparation cost, complete product decolorizing, yield up to 83 % and product purity over 99.6 %.

Description

technical field [0001] The present invention relates to the preparation method of mycophenolate mofetil (I) (Mycophenolate Mofetil), more specifically relate to a kind of preparation method of mycophenolate mofetil using catalyst. Background technique [0002] Mycophenolate Mofetil (I) [0003] [0004] where R 1 = 2-(4-morpholino) ethyl, R 2 =H, [0005] It is an antibiotic with mainly immunosuppressive effect and a prodrug of mycophenolic acid. Mycophenolic acid can effectively inhibit the activity of inosine monophosphate dehydromycetes non-competitively, thereby hindering the de novo production of guanosine nucleotides Start pathway, thus the proliferation of lymphocytes is inhibited, and the growth and reproduction inhibition of lymphocytes is higher than that of other cells. Mycomorpha mofetil is mainly used for the prevention of organ rejection after kidney and heart transplantation, and can be used in combination with cyclosporine to reduce the dose and toxici...

Claims

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Application Information

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IPC IPC(8): C07D307/88
Inventor 刘遗松陈松刘勇娥
Owner YICHANG HEC CHANGJIANG PHARMA CO LTD
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