CN107056736A - A kind of preparation method of mycophenolate mofetil - Google Patents

Abstract

The invention discloses a method for preparing mycophenolate mofetil, that is, mycophenolic acid and morpholine ethanol are reacted by Mitsunobu under the action of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) ( Mitsunobu reaction) to prepare mycophenolate mofetil, the method has mild reaction conditions, simple process, high yield, and is suitable for industrial production.

Description

A kind of preparation method of mycophenolate mofetil

technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of mycophenolate mofetil.

Background technique

Mycophenolate mofetil (MPM) is a new type of immunosuppressant developed by Roche, Switzerland. It was first launched in the United States in 1995. Its trade name is Xiaoxi, and it is formed after deesterification in the body. The metabolite mycophenolic acid (MPA) with immunosuppressive activity.

It is mainly used for the prevention of organ rejection after kidney and heart transplantation. Its mechanism of action is to selectively inhibit T lymphocytes and B lymphocytes related to rejection, and has the effect of inhibiting the proliferation of arterial smooth muscle, which is not found in other immunosuppressants at present. Its mechanism of action has the following specificities: (1) selectively inhibits the classic synthesis pathway of guanine in lymphocytes, and has no toxic effect on non-lymphocytes and organs; (2) directly inhibits the proliferation of B lymphocytes; (3) is highly effective Reducing the activity of adhesion molecules and inhibiting the proliferation of vascular smooth muscle cells can prevent and treat vascular rejection and reduce the occurrence of chronic rejection.

Mycophenolate Mofetil Structural Formula

At present, the synthesis process of mycophenolate mofetil reported in the literature mainly contains the following types:

Patents WO02100855, US5247083, etc. adopt the direct esterification method, that is, mycophenolic acid is directly esterified with morpholine ethanol in high boiling point solvents such as toluene, xylene, and butyl ether under reflux to form a crude product, and then undergoes a series of post-treatments to obtain Finished products, this method takes a long time to react (usually 60-120 h), and the product is dark in color and needs to be decolorized.

Preparation of mycophenolate mofetil by direct esterification

Patents WO2000034503 and WO2006024582 use biological enzymes to catalyze the synthesis of mycophenolate mofetil. The disadvantages are that the reaction time is long, the yield is low, and a large amount of reaction raw materials remain; After the reaction produces mycophenolic acid chloride, it is condensed with morpholine ethanol to produce the product. The disadvantage of this method is that it requires two steps of synthesis. The acid gas and the acid gas produced will corrode the equipment. The "three wastes" are difficult to deal with, and the impurities generated by the reaction are relatively many.

Preparation of mycophenolate mofetil by indirect esterification

Mitsunobu reaction (Mitsunobu reaction) was discovered by Japanese chemist Mitsunobu, O and others in 1967. This reaction can react alcohol with triphenylphosphine and diethyl azodicarboxylate (DEAD) Converted into a variety of compounds such as esters, amines, etc. This reaction is characterized by mild conditions, high yield and configuration inversion.

Mitsunobu Reaction Equation

In view of the defects in the prior art, the present invention adopts the Mitsunobu reaction (Mitsunobu reaction) to prepare mycophenolate mofetil for the first time. The method has mild reaction conditions, does not need long-term heating and reflux, and avoids acid gas generation, and has no corrosion to equipment , the process is simple, the yield is high, and it is suitable for industrial production.

Contents of the invention

In order to further realize the present invention, the technical scheme adopted in the present invention is:

A preparation method of mycophenolate mofetil: Mycophenolic acid and morpholine ethanol are prepared by Mitsunobu reaction under the action of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) mycophenolate mofetil. Include the following steps:

(1) Under the protection of nitrogen, dissolve triphenylphosphine and morpholine ethanol in the reaction solvent, add DIAD solution and mycophenolic acid solution successively under controlling the temperature of the reaction system, and stir until the reaction ends;

(2) The reaction solution obtained in step (1) is washed with water, extracted, and concentrated to obtain a crude product, which is recrystallized once by adding an alcohol solvent to obtain mycophenolate mofetil.

The reaction formula is as follows:

The reaction solvent described in step (1) is dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, toluene, preferably dichloromethane and ethyl acetate.

The mol ratio of each material described in step (1) is: morpholine ethanol: mycophenolic acid: triphenylphosphine: diisopropyl azodicarboxylate (DIAD)=1.0: (1.0 ~ 2.5): (1.0 ~3.0):(1.0~3.0), preferably 1.0:1.05:1.25:1.40.

In step (1), when adding the DIAD solution and the mycophenolic acid solution, the temperature of the reaction system is controlled from 0°C to 10°C. Preferably it is 5°C.

In step (1), diisopropyl azodicarboxylate (DIAD) can be replaced by its analogs diethyl azodicarboxylate (DEAD), di-tert-butyl azodicarboxylate, diphenyl azodicarboxylate, Preferred are diisopropyl azodicarboxylate and diethyl azodicarboxylate.

In step (1), triphenylphosphine can be replaced by its analogs diphenylmethylphosphine and tributylphosphine, preferably triphenylphosphine.

In step (2), the alcohol solvent for recrystallization is absolute ethanol, 95% ethanol, isopropanol, methanol, preferably absolute ethanol.

In step (2), the crystallization temperature during recrystallization is 0-20°C, preferably 10°C.

The advantages of the present invention are:

The invention discloses a new method for preparing mycophenolate mofetil. For the first time, the Mitsunobu reaction is used to prepare mycophenolate mofetil. The method has mild reaction conditions, does not need long-term heating and reflux, and avoids acid gas Produced, no corrosion to equipment, simple process, high yield, suitable for industrial production.

detailed description

The present invention will be further described in detail through the following examples, but it should not be understood that the scope of the above subject of the present invention is limited to the following examples. On the premise of not departing from the above technical premise of the present invention, the corresponding replacements or alterations made according to the common technical knowledge and customary means in this field are included in the scope of the present invention.

Example 1

Under the protection of nitrogen, Ph ₃ P (32.8g, 125mmol, 1.25eq) and morpholine ethanol (13.1g, 100mmol, 1.0eq) were dissolved in 200ml of dichloromethane, cooled to 0°C, and the temperature was controlled not to exceed 5°C. A solution of DIAD (28.3g, 140mmol, 1.4eq) in dichloromethane (40ml) was added within 20-30min. After the addition was complete, the yellow solution continued to stir for 10min. Then add a solution of mycophenolic acid (33.6g, 105mmol, 1.05eq) in dichloromethane (50ml) at 0~5°C, after the addition is complete, stir at room temperature for 4h. The reaction solution was poured into 200 ml of water, stirred for 5 min, separated, the organic phase was extracted once with 120 ml of 1N hydrochloric acid solution, the hydrochloric acid solution was washed once with 50 ml of ethyl acetate, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. A lot of white turbidity was precipitated, extracted with 80ml dichloromethane and 30ml dichloromethane successively, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a lavender oily liquid.

Add 350ml of absolute ethanol to the lavender oily liquid, heat to reflux to dissolve, cool slightly, add 2g of activated carbon, continue to reflux for 20min, filter while it is hot, crystallize the filtrate at about 10°C for 4h, suction filter, wash with 40ml of absolute ethanol, Obtain white powder, mycophenolate mofetil 30.4g, yield 70%.

Example 2

Under the protection of nitrogen, Ph ₃ P (18.4g, 70mmol, 1.40eq) and morpholine ethanol (6.6g, 50mmol, 1.0eq) were dissolved in 200ml of ethyl acetate, cooled to 0°C, and the temperature was controlled not to exceed 10°C. A solution of DIAD (15.2g, 75mmol, 1.50eq) in ethyl acetate (30ml) was added within 15-20min. After the addition was complete, the orange solution continued to stir for 15min. Then add a solution of mycophenolic acid (17.6g, 55mmol, 1.10eq) in ethyl acetate (40ml) at 0~10°C, after the addition is complete, stir at room temperature for 6h. Pour the reaction solution into 150ml of water, stir for 5min, separate the liquids, extract the organic phase once with 60ml of 1N hydrochloric acid solution, then wash the hydrochloric acid solution once with 30ml of ethyl acetate, and adjust the pH to 8 with saturated sodium bicarbonate solution. White turbidity was precipitated, extracted with 50ml ethyl acetate and 20ml ethyl acetate successively, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily liquid.

Add 180ml of absolute ethanol to the yellow oily liquid, heat to reflux to dissolve, cool slightly, add 1g of activated carbon, continue to reflux for 10min, filter while it is hot, crystallize the filtrate at about 5°C for 4h, suction filter, wash with 30ml of absolute ethanol, and get White powder, mycophenolate mofetil 16.2g, yield 75%.

Example 3

Under nitrogen protection, Ph ₃ P (68.2g, 260mmol, 1.30eq) and morpholine ethanol (26.2g, 200mmol, 1.0eq) were dissolved in 2-methyltetrahydrofuran (500ml), cooled to 5°C, and the temperature was controlled Over 10°C, a solution of DEAD (48.8g, 280mmol, 1.40eq) in 2-methyltetrahydrofuran (80ml) was added within 20-30min. After the addition was complete, the orange solution continued to stir for 15min. Then add a solution of mycophenolic acid (76.9g, 240mmol, 1.20eq) in 2-methyltetrahydrofuran (150ml) at 0~10°C, after the addition is complete, stir at room temperature for 6h. Pour the reaction solution into 400ml of water, stir for 5min, separate the liquids, extract the organic phase once with 240ml of 1N hydrochloric acid solution, wash the hydrochloric acid solution once with 90ml of ethyl acetate, adjust the pH to 9 with saturated sodium bicarbonate solution, there are more White turbidity precipitated, extracted with 100ml 2-methyltetrahydrofuran and 50ml 2-methyltetrahydrofuran successively, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow oily liquid.

Add 650ml of methanol to the yellow oily liquid, heat to reflux to dissolve, cool slightly, add 5g of activated carbon, continue to reflux for 15min, filter while it is hot, crystallize the filtrate at about 0°C for 3h, filter with suction, wash with 80ml of methanol, and get a white powder. Mycophenolate mofetil 58.1g, yield 67%.

Example 4

Under the protection of nitrogen, Ph ₃ P (28.9g, 110mmol, 1.10eq) and morpholine ethanol (13.1g, 100mmol, 1.0eq) were dissolved in 200ml of dichloromethane, cooled to 0°C, and the temperature was controlled not to exceed 5°C. A solution of DIAD (28.3g, 140mmol, 1.4eq) in dichloromethane (40ml) was added within 20-30min. After the addition was complete, the yellow solution continued to stir for 10min. Then add a solution of mycophenolic acid (35.2g, 110mmol, 1.10eq) in dichloromethane (50ml) at 0~5°C, after the addition is complete, stir at room temperature for 4h. The reaction solution was poured into 200 ml of water, stirred for 5 min, separated, the organic phase was extracted once with 130 ml of 1N hydrochloric acid solution, the hydrochloric acid solution was then washed once with 60 ml of ethyl acetate, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. A lot of white turbidity was precipitated, extracted with 80ml dichloromethane and 30ml dichloromethane successively, combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a lavender oily liquid.

Add 450ml of isopropanol to the lavender oily liquid, heat to reflux to dissolve, cool slightly, add 2g of activated carbon, continue to reflux for 5 minutes, filter while it is hot, crystallize the filtrate at about 10°C for 6 hours, suction filter, wash with 50ml of isopropanol, Obtain white powder, mycophenolate mofetil 31.2g, yield 72%.

The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims (8)

1. a kind of preparation method of mycophenolate mofetil, it is characterized in that, mycophenolic acid and morpholine ethanol, under the effect of triphenylphosphine, DIAD, prepare mycophenolate mofetil through Mitsunobu reaction, the method Include the following steps: (1) Under nitrogen protection, dissolve triphenylphosphine and morpholine ethanol in the reaction solvent, add DIAD solution and mycophenolic acid solution in sequence under temperature control of the reaction system, and stir until the reaction is complete; (2) The reaction solution obtained in step (1) was washed with water, extracted, and concentrated to obtain a crude product, which was recrystallized once by adding an alcohol solvent to obtain mycophenolate mofetil. 2. the preparation method of mycophenolate mofetil according to claim 1 is characterized in that, the reaction solvent described in step (1) is dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane Hexane or toluene. 3. the preparation method of mycophenolate mofetil according to claim 1, is characterized in that, the mol ratio of each material described in step (1) is: morpholine ethanol: mycophenolic acid: triphenylphosphine : DIAD=1.0: (1.0~2.5):(1.0~3.0):(1.0~3.0). 4. The preparation method of mycophenolate mofetil according to claim 1, characterized in that, in step (1), when adding DIAD solution and mycophenolic acid solution, the temperature of the reaction system is controlled to be 0°C to 10°C. 5. the preparation method of mycophenolate mofetil according to claim 1 is characterized in that, in step (1), DIAD is made of its analog diethyl azodicarboxylate, di-tert-butyl azodicarboxylate , Diphenyl azodicarboxylate instead. 6. The preparation method of mycophenolate mofetil according to claim 1, characterized in that, in step (1), triphenylphosphine is replaced by its analog diphenylmethylphosphine and tributylphosphine. 7. the preparation method of mycophenolate mofetil according to claim 1 is characterized in that, in step (2), the alcoholic solvent for recrystallization is dehydrated alcohol, 95% ethanol, isopropanol or methyl alcohol. 8. The method for preparing mycophenolate mofetil according to claim 1, characterized in that, in step (2), the crystallization temperature during recrystallization is 0°C to 20°C.