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Preparation method of mycophenolate mofetil

A technology of mycophenolate mofetil and mycophenolic acid, which is applied in the field of preparation of mycophenolate mofetil, can solve the problems of "three wastes" difficult to handle, residual reaction raw materials, and many impurities, so as to avoid the generation of acid gas , the effect of mild reaction conditions and simple process

Inactive Publication Date: 2017-08-18
FUJIAN INST OF MICROBIOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] 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

Method used

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  • Preparation method of mycophenolate mofetil
  • Preparation method of mycophenolate mofetil
  • Preparation method of mycophenolate mofetil

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Experimental program
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Embodiment 1

[0035] Under the protection of nitrogen, Ph 3 P (32.8g, 125mmol, 1.25eq), morpholine ethanol (13.1g, 100mmol, 1.0eq) dissolved in 200ml of dichloromethane, cooled to 0℃, controlled the temperature not to exceed 5℃, add DIAD within 20-30min (28.3g, 140mmol, 1.4eq) in dichloromethane (40ml) solution, after the addition, the yellow solution was stirred for 10 minutes. Then add a solution of mycophenolic acid (33.6g, 105mmol, 1.05eq) in dichloromethane (50ml) at 0~5℃, after the addition, stir at room temperature for 4h. The reaction solution was poured into 200 ml of water, stirred for 5 minutes, and 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. Many white turbidity precipitated, followed by extraction with 80ml of dichloromethane and 30ml of dichloromethane, combined the organic phases, ...

Embodiment 2

[0038] Under the protection of nitrogen, Ph 3 P (18.4g, 70mmol, 1.40eq), morpholine ethanol (6.6g, 50mmol, 1.0eq) dissolved in 200ml ethyl acetate, cooled to 0℃, controlled the temperature not to exceed 10℃, add DIAD within 15-20min (15.2g, 75mmol, 1.50eq) in ethyl acetate (30ml) solution. After the addition, the orange solution was stirred for 15 minutes. Then add a solution of mycophenolic acid (17.6g, 55mmol, 1.10eq) in ethyl acetate (40ml) at 0~10℃, after the addition, stir at room temperature for 6h. Pour the reaction solution into 150ml of water, stir for 5min, separate the layers, extract the organic phase once with 60ml of 1N hydrochloric acid solution, then wash the hydrochloric acid solution with 30ml ethyl acetate once, adjust the pH to 8 with saturated sodium bicarbonate solution, there are more White turbidity precipitated, and it was extracted with 50ml ethyl acetate and 20ml ethyl acetate successively. The organic phases were combined, dried over anhydrous sodium...

Embodiment 3

[0041] Under the protection of nitrogen, Ph 3 P (68.2g, 260mmol, 1.30eq), morpholine ethanol (26.2g, 200mmol, 1.0eq) were dissolved in 2-methyltetrahydrofuran (500ml), then cooled to 5℃, controlled temperature not to exceed 10℃, Add DEAD (48.8g, 280mmol, 1.40eq) in 2-methyltetrahydrofuran (80ml) solution within 30min. After the addition, the orange solution is stirred for 15min. Then add a solution of mycophenolic acid (76.9g, 240mmol, 1.20eq) in 2-methyltetrahydrofuran (150ml) at 0~10℃. After the addition, stir at room temperature for 6h. Pour the reaction solution into 400ml water, stir for 5min, separate the layers, extract the organic phase once with 240ml of 1N hydrochloric acid solution, then wash the hydrochloric acid solution with 90ml ethyl acetate once, and adjust the pH to 9 with saturated sodium bicarbonate solution. White turbidity precipitated, and it was extracted with 100ml 2-methyltetrahydrofuran and 50ml 2-methyltetrahydrofuran successively, and the organic ph...

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Abstract

The invention discloses a preparation method of mycophenolate mofetil. The preparation method of the mycophenolate mofetil comprises the following step: carrying out Mitsunobu reaction on mycophenolic acid and morpholinoethanol under the effects of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) to prepare the mycophenolate mofetil. In the method, the reaction conditions are gentle, the process is simple and convenient, the yield is high, and therefore, the mycophenolate mofetil is suitable for being produced industrially.

Description

Technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a preparation method of mycophenolate mofetil. Background technique [0002] Mycophenolate mofetil (MPM) is a new type of immunosuppressant developed by Roche, Switzerland. It was first marketed in the United States in 1995. Its trade name is MPM. It is formed after deesterification in the body A metabolite with immunosuppressive activity mycophenolic acid (mycophenolic acid, MPA). [0003] It is mainly used to prevent organ rejection after kidney and heart transplantation. Its mechanism of action is to selectively inhibit T lymphocytes and B lymphocytes related to rejection reactions, and to inhibit the proliferation of arterial smooth muscle, which is currently not available in other immunosuppressive agents. In summary, its mechanism of action has the following specificities: (1) It selectively inhibits the classical synthesis of guanine in lymphocytes, and has no toxi...

Claims

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Application Information

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IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 黄杨威罗芳林燕琴赵学清陈忠
Owner FUJIAN INST OF MICROBIOLOGY
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