CN1772745A - Prepn process of mofe-til mycophenolate - Google Patents

Abstract

The invention discloses a method for preparing mycophenolate morphinate, which is characterized in that it comprises the following steps in sequence: (1) stirring and dissolving a mixed solvent of toluene and xylene with mycophenolic acid and 2-morpholinoethanol; (2) ) into catalyst C _1-6 fatty acid; (3) heating up and stirring, reflux water separation, direct esterification; (4) dropping into decolorizing agent activated carbon; (5) dropping into ethyl acetate, decolorizing agent vitamin C, and then successively using concentration 10% The Na ₂ CO ₃ solution and water were washed at least once; (6) heating up, cooling to precipitate a solid, washing with ethyl acetate, vacuum drying, and finally obtaining a fine product. The preparation method of the present invention uses C _1-6 fatty acids as a catalyst for direct esterification, which can significantly shorten the reaction time, and C _1-6 fatty acids are cheap and easy to obtain, which can greatly reduce the preparation cost; in the post-treatment, the decolorizing agent vitamin C is added, The product color problem existing in the prior art can be completely solved; the yield can reach 83%, and the purity of the product after purification is at least 99.6%.

Description

A kind of preparation method of mycophenolate morphinate

technical field

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

Mycophenolate Mofetil (I)

wherein R ₁ =2-(4-morpholinyl)ethyl, R ₂ =H,

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 toxicity of the latter. The existing synthetic methods of mycophenolate mofetil mainly include direct esterification and indirect esterification. 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 the product has color problems; another example is the US patent US5247083 using the direct esterification method, which prepares mycophenolate mofetil by refluxing mycophenolic acid and 2-morpholinoethanol under azeotropic water separation in a suitable solvent or solvent mixture Esters need a long reaction period of about 6 to 100 hours to achieve sufficient conversion, and the lavender color of the product cannot be removed. The above-mentioned related technology improves 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.

Invention content:

The technical problem to be solved by the present invention is to make up for the defects of the prior art, and to provide a method for preparing mycophenolate mofetil with a cheap and easy-to-obtain catalyst, simplified process, short reaction time, high conversion rate and high product purity.

The technical problems of the present invention are solved by the following technical solutions.

This mycophenolate morphinate preparation method comprises the following steps successively:

(1) Put the mixed solvent of toluene and xylene with a volume ratio of (2.5～4):1 into the reactor, and then use (600～1500)mL/mole, (600～1500)/(1.02～1.20)mL respectively Add mycophenolic acid and 2-morpholino ethanol per mole, and mechanically stir until completely dissolved;

(2) according to the mol ratio with mycophenolic acid is (0.01～0.10): 1 drops into catalyst C _1～6 fatty acid, continue to stir;

(3) Raise the temperature to 126°C to 131°C, stir, reflux and divide the water, keep for 6h to 24h, and the mycophenolic acid is directly esterified into mycophenolate morphinate;

(4) According to the mass ratio to mycophenolic acid (0.05-0.10): 1, put into the decolorizing agent activated carbon, and then evaporate the organic phase to dryness under reduced pressure at a temperature below 70°C to obtain the crude product;

(5) Add ethyl acetate according to (4~8)mL/g, mechanically stir until it is completely dissolved, then put in the decolorizing agent vitamin C according to the mass ratio of the crude product (0.05~0.10): 1, and then successively use the concentration of 10 % Na ₂ CO ₃ solution and water to wash once;

(6) After raising the temperature to 60°C-80°C, immediately cool down to below 30°C to precipitate a solid, then wash the solid with ethyl acetate, dry it in vacuum at a temperature of 40°C-60°C, and finally obtain a fine product.

The technical problems of the present invention can be further solved by the following technical solutions.

The catalyst C _1-6 fatty acid is a mixture of any one, two or three of formic acid, acetic acid and propionic acid.

The catalyst C _1-6 fatty acid is a mixture of any two of formic acid, acetic acid and propionic acid, and the main one accounts for 70%-98% of the total amount.

The catalyst C _1-6 fatty acid is a mixture of formic acid, acetic acid and propionic acid, and the main one accounts for 60%-98% of the total amount.

The preparation method of the present invention uses C _1-6 fatty acids as catalysts for direct esterification, which can significantly shorten the reaction time, and the C _1-6 fatty acids are cheap and easy to obtain, which can greatly reduce the preparation cost; the preparation method of the present invention invests The decolorizing agent vitamin C can completely solve the problem of product color in the prior art; the yield of the preparation method of the invention can reach 83%, and the purity of the product after purification is at least 99.6%.

Detailed ways

Example 1:

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:

(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;

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

(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;

(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.;

(5) Dissolve in 150ml of ethyl acetate, add 0.1g of vitamin C, _wash with 90ml of 10% _Na2CO3 solution and 40ml of deionized water;

(6) The filtrate is concentrated to 50ml, cooled to 30°C of temperature to separate out solid crystals, washed with 20ml of cold ethyl acetate, suction filtered, and vacuum-dried at 60°C of temperature to obtain 22.15g mycophenolate mofetil, purity (HPLC ) 99.6%, yield 83.5%.

Example 2:

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:

(1) with the step (1) of embodiment 1;

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

(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;

(4) with the step (4) of embodiment 1;

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

(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%.

Example 3:

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:

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

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

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

(4) with the step (4) of embodiment 1;

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

(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%.

Example 4:

Use the mixture of formic acid and acetic acid as catalyst and drop into the decolorizing agent vitamin C to remove the preparation method of purple mycophenolate mofetil, comprising the following steps in turn:

(1) with the step (1) of specific embodiment 1

(2) drop into the mixture-formic acid of 1g catalyst lower fatty acid: acetic acid mass ratio=20: 80;

(3) Raise the temperature to 130°C, stir, reflux and divide the water, keep the temperature for 20 hours, and then directly esterify with cooling;

(4) with the step (4) of embodiment 1;

(5) basically with the step (5) of embodiment 1, vitamin C input amount is 0.20g;

(6) Basically the same as the step (1) of Example 1, 21.50 g of mycophenolate mofetil was obtained, the purity (HPLC) was 99.6%, and the yield was 81.1%.

Example 5:

Use the mixture of formic acid, acetic acid and propionic acid as catalyst and drop into the decolorizing agent vitamin C to remove the preparation method of mycophenolate mofetil, which comprises the following steps in turn:

(1) with the step (1) of embodiment 2

(2) drop into the mixture-formic acid of 1g catalyst lower fatty acid: acetic acid: the mass ratio=30:65:5 of propionic acid;

(3) Raise the temperature to 131°C, stir, reflux and divide water, keep the temperature for 24 hours, and then directly esterify with cooling;

(4) with the step (4) of embodiment 1;

(5) with the step (5) of embodiment 4;

(6) Basically the same as the step (1) of Example 1, 21.3 g of mycophenolate mofetil was obtained, the purity (HPLC) was 99.6%, and the yield was 80.4%.

Claims (4)

1, a kind of mycophenolate morphine ester preparation method, it is characterized in that: Include the following steps in order: (1) Put the mixed solvent of toluene and xylene with a volume ratio of (2.5～4):1 into the reactor, and then use (600～1500)mL/mole, (600～1500)/(1.02～1.20)mL respectively Add mycophenolic acid and 2-morpholino ethanol per mole and stir until completely dissolved; (2) according to the mol ratio with mycophenolic acid is (0.01～0.10): 1 drops into catalyst C _1～6 fatty acid, continue to stir; (3) Raise the temperature to 126°C to 131°C, stir, reflux and divide the water, keep for 6h to 24h, and the mycophenolic acid is directly esterified into mycophenolate morphinate; (4) According to the mass ratio to mycophenolic acid (0.05-0.10): 1, put into the decolorizing agent activated carbon, and then evaporate the organic phase to dryness under reduced pressure below 70°C to obtain the crude product; (5) Add ethyl acetate according to (4~8)mL/g, stir at room temperature until it is completely dissolved, then put in the decolorizing agent vitamin C according to the mass ratio of the crude product (0.05~0.10): 1, and then successively use the concentration Wash once with 10% Na ₂ CO ₃ solution and water; (6) After raising the temperature to 60°C to 80°C, cool to below 30°C to precipitate a solid, then wash the solid with ethyl acetate, dry it in vacuum at 40°C to 60°C, and finally obtain the refined product. 2. The method for preparing mycophenolate morphinate as claimed in claim 1, characterized in that: The catalyst C _1-6 fatty acid is a mixture of any one, two or three of formic acid, acetic acid and propionic acid. 3. The method for preparing mycophenolate mofetil according to claim 1 or 2, characterized in that: The catalyst C _1-6 fatty acid is a mixture of any two of formic acid, acetic acid and propionic acid, and the main one accounts for 70%-98% of the total amount. 4. The method for preparing mycophenolate morphine mofetil according to claim 3, characterized in that: The catalyst C _1-6 fatty acid is a mixture of formic acid, acetic acid and propionic acid, and the main one accounts for 60%-98% of the total amount.