CN107056736A - A kind of preparation method of MMF - Google Patents
A kind of preparation method of MMF Download PDFInfo
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- CN107056736A CN107056736A CN201710315619.5A CN201710315619A CN107056736A CN 107056736 A CN107056736 A CN 107056736A CN 201710315619 A CN201710315619 A CN 201710315619A CN 107056736 A CN107056736 A CN 107056736A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
The invention discloses a kind of preparation method of MMF, i.e. Mycophenolic Acid and morpholine ethanol, in triphenylphosphine, diisopropyl azodiformate（DIAD）Under effect, reaction is prolonged through light（Mitsunobu reacts）MMF is prepared, this method reaction condition is gentle, and technique is easy, high income, is adapted to industrialized production.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of preparation method of MMF.
Background technology
MMF (mycophenolate mofetil, MPM) is researched and developed by Switzerland's Roche (Roche) company
A kind of neotype immunosuppressant, is listed, trade name MMF in the U.S. first in nineteen ninety-five, and taking off to be formed after esterification in vivo has
The metabolite Mycophenolic Acid (mycophenolic acid, MPA) of immunosuppressive activity.
It is mainly used in the prevention of organ rejection after kidney, heart transplant.Its mechanism of action is selective depression and repulsion
Reaction relevant T lymphocytes and bone-marrow-derived lymphocyte, and play the role of to suppress arterial smooth muscle hyperplasia, the latter is other at present
Immunodepressant is unexistent.Concluding its mechanism of action has following several specificity：(1) selective depression lymphocyte bird is fast
Purine classics route of synthesis, it is free of toxic effects to non-lymphocyte and organ；(2) B lymphocyte proliferation is directly suppressed；(3) efficiently
The activity of adhesion molecule is reduced, suppresses vascular smooth muscle cell proliferation, can be prevented and be treated Kidney renal transplant reaction and reduce slow
The generation of property rejection.
MMF structural formula
The synthesis technique of current document report MMF mainly has following several：
Patent WO02100855, US5247083 etc. uses direct esterification, i.e. Mycophenolic Acid contour in toluene, dimethylbenzene, butyl ether
Direct esterification generates crude product at reflux with morpholine ethanol in boiling point solvent, then post-processes to obtain finished product through a series of, this
The method reaction time is long（Generally need 60-120 h）, coloured product is deeply, it is necessary to decolorization.
Direct esterification prepares MMF
Patent WO2000034503, WO2006024582 synthesizes MMF using biological enzyme, when having the disadvantage reaction
Between longer, yield is relatively low, have a large amount of reaction raw materials to remain；Patent US4753935 use indirect esterification process, i.e., with Mycophenolic Acid with
Acyl chloride reaction generation wheat is examined after phenol acyl chlorides, then with morpholine ethanol condensation generation product, this method disadvantage is that two steps synthesis step
Suddenly, acyl chlorides and the sour gas of generation can produce corrosion to equipment, and " three wastes " are difficult, and the impurity for reacting generation is more.
Indirect esterification process prepares MMF
Light prolongs reaction（Mitsunobu reacts）It is that Wang Yang is prolonged by Japanese chemists light（Mitsunobu, O）Et al. in 1967 send out
It is existing, the reaction can by alcohol by with triphenyl phosphorus and diethylazodicarboxylate（DEAD）Reaction is converted into multiple compounds, such as
Ester, amine etc..The characteristics of this reaction is mild condition, and yield is high and with configuration reversal.
Light prolongs reaction equation
The present invention is directed to defect of the prior art, prolongs reaction using light first（Mitsunobu reacts）Examined to prepare for wheat
Phenolic ester, this method reaction condition is gentle, it is not necessary to which long-time heating flows back, and also avoids sour gas from producing, corrosion-free to equipment,
Technique is easy, high income, is adapted to industrialized production.
The content of the invention
In order to further realize the present invention, the technical solution adopted by the present invention is：
A kind of preparation method of MMF：Mycophenolic Acid and morpholine ethanol, in triphenylphosphine, azoformic acid diisopropyl
Ester（DIAD）Under effect, reaction is prolonged through light（Mitsunobu reacts）Prepare MMF.Comprise the following steps：
(1) under nitrogen protection, triphenylphosphine, morpholine ethanol is dissolved under reaction dissolvent, control temperature of reaction system and sequentially added
DIAD solution, Mycophenolic Acid solution, stirring to reaction terminate；
(2) reaction solution obtained by step (1) is through washing, and extraction obtains crude product after concentration, add alcohols solvent recrystallization once, i.e.,
It can obtain MMF.
Reaction equation is as follows：
Reaction dissolvent described in step (1) is dichloromethane, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofurans, dioxy six
Ring, toluene, preferably dichloromethane, ethyl acetate.
The mol ratio of each material is described in step (1)：Morpholine ethanol:Mycophenolic Acid:Triphenylphosphine:Azoformic acid two
Isopropyl ester（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), it is 0 DEG C to 10 DEG C that temperature of reaction system is controlled when adding DIAD solution, Mycophenolic Acid solution.It is preferred that
For 5 DEG C.
In step (1), diisopropyl azodiformate（DIAD）Can be by its analog diethyl azodiformate（DEAD）、
Tert-butyl azodicarboxylate, diphenyl azodicarboxylate are substituted, preferably diisopropyl azodiformate, azoformic acid two
Ethyl ester.
In step (1), triphenylphosphine can be substituted by its analog diphenyl methyl phosphine, tributylphosphine, preferably triphenyl
Phosphine.
In step (2), recrystallization is absolute ethyl alcohol, 95% ethanol, isopropanol, methanol, preferably anhydrous second with alcohols solvent
Alcohol.
In step (2), recrystallization temperature during recrystallization is 0-20 DEG C, preferably 10 DEG C.
The advantage of the invention is that：
The invention discloses a kind of new method for preparing MMF, reaction is prolonged using light first（Mitsunobu reacts）
To prepare MMF, this method reaction condition is gentle, it is not necessary to which long-time heating flows back, it is to avoid sour gas is produced,
Corrosion-free to equipment, technique is easy, high income, is adapted to industrialized production.
Embodiment
The present invention is described in further details by the following examples, but not above-mentioned theme of the invention should not be interpreted as with regard to this
In the range of be only limitted to following examples.Under the premise of above-mentioned technology of the invention is not departed from, according to ordinary skill knowledge and
The modification of corresponding replacement or change that customary means is made, is included within the scope of the present invention.
Embodiment 1
Under nitrogen protection, Ph3P（32.8g, 125mmol, 1.25eq）, morpholine ethanol（13.1g, 100mmol, 1.0eq）It is dissolved in
After 200ml dichloromethane, 0 DEG C is cooled to, control temperature is no more than 5 DEG C, and DIAD is added in 20-30min（28.3g,
140mmol, 1.4eq）Dichloromethane（40ml）Solution, is finished, and yellow solution continues to stir 10min.Added at 0 ~ 5 DEG C
Mycophenolic Acid（33.6g, 105mmol, 1.05eq）Dichloromethane（50ml）Solution, is finished, and 4h is stirred at room temperature.Will reaction
Liquid is poured into 200 ml water, stirs 5min, point liquid, and organic phase is extracted once with 120ml 1N hydrochloric acid solutions, and hydrochloric acid solution is then
Washed once with 50ml ethyl acetate, adjust pH to 8 with saturated sodium bicarbonate solution, there is more white casse to separate out, 80ml is used successively
Dichloromethane, the extraction of 30ml dichloromethane, merge organic phase, and anhydrous sodium sulfate drying is filtered, and concentration obtains lavender oily liquid
Body.
350ml absolute ethyl alcohols are added into lavender oily liquids, dissolving is heated to reflux, it is slightly cold, 2g activated carbons are added, after
Continuous backflow 20min, is filtered, filtrate is placed in 10 DEG C or so crystallization 4h, suction filtration, 40ml absolute ethyl alcohols are washed, and obtain white powder while hot,
For mycophenolate 30.4g, yield 70%.
Embodiment 2
Under nitrogen protection, Ph3P（18.4g, 70mmol, 1.40eq）, morpholine ethanol（6.6g, 50mmol, 1.0eq）It is dissolved in
After 200ml ethyl acetate, 0 DEG C is cooled to, control temperature is no more than 10 DEG C, and DIAD is added in 15-20min（15.2g,
75mmol, 1.50eq）Ethyl acetate（30ml）Solution, is finished, and orange solution continues to stir 15min.Add at 0 ~ 10 DEG C
Enter Mycophenolic Acid（17.6g, 55mmol, 1.10eq）Ethyl acetate（40ml）Solution, is finished, and 6h is stirred at room temperature.Will be anti-
Answer liquid to pour into 150ml water, stir 5min, point liquid, organic phase is extracted once with 60ml 1N hydrochloric acid solutions, and hydrochloric acid solution is then
Washed once with 30ml ethyl acetate, adjust pH to 8 with saturated sodium bicarbonate solution, there is more white casse to separate out, 50ml is used successively
Ethyl acetate, the extraction of 20ml ethyl acetate, merge organic phase, and anhydrous sodium sulfate drying is filtered, and concentration obtains yellow oily liquid.
180ml absolute ethyl alcohols are added into yellow oily liquid, dissolving is heated to reflux, it is slightly cold, 1g activated carbons are added, are continued
Flow back 10min, filters while hot, filtrate is placed in 5 DEG C or so crystallization 4h, suction filtration, 30ml absolute ethyl alcohols are washed, and are obtained white powder, are replaced
Mycophenolate 16.2g, yield 75%.
Embodiment 3
Under nitrogen protection, Ph3P（68.2g, 260mmol, 1.30eq）, morpholine ethanol（26.2g, 200mmol, 1.0eq）It is dissolved in
2- methyltetrahydrofurans（500ml）Afterwards, 5 DEG C are cooled to, control temperature is no more than 10 DEG C, and DEAD is added in 20-30min
（48.8g, 280mmol, 1.40eq）2- methyltetrahydrofurans（80ml）Solution, is finished, and orange solution continues to stir 15min.
Mycophenolic Acid is added at 0 ~ 10 DEG C（76.9g, 240mmol, 1.20eq）2- methyltetrahydrofurans（150ml）Solution, plus
Finish, 6h is stirred at room temperature.Reaction solution is poured into 400ml water, 5min is stirred, point liquid, organic phase is molten with 240ml 1N hydrochloric acid
Liquid is extracted once, and hydrochloric acid solution is then washed once with 90ml ethyl acetate, adjusts pH to 9 with saturated sodium bicarbonate solution, there is more
White casse is separated out, and is extracted successively with 100ml 2- methyltetrahydrofurans, 50ml 2- methyltetrahydrofurans, is merged organic phase, nothing
Aqueous sodium persulfate is dried, and is filtered, and concentration obtains yellow oily liquid.
650ml methanol is added into yellow oily liquid, dissolving is heated to reflux, it is slightly cold, 5g activated carbons are added, continue to flow back
15min, is filtered while hot, and filtrate is placed in 0 DEG C or so crystallization 3h, and suction filtration, 80ml methanol is washed, and obtains white powder, MMF
58.1g, yield 67%.
Embodiment 4
Under nitrogen protection, Ph3P（28.9g, 110mmol, 1.10eq）, morpholine ethanol（13.1g, 100mmol, 1.0eq）It is dissolved in
After 200ml dichloromethane, 0 DEG C is cooled to, control temperature is no more than 5 DEG C, and DIAD is added in 20-30min（28.3g,
140mmol, 1.4eq）Dichloromethane（40ml）Solution, is finished, and yellow solution continues to stir 10min.Added at 0 ~ 5 DEG C
Mycophenolic Acid（35.2g, 110mmol, 1.10eq）Dichloromethane（50ml）Solution, is finished, and 4h is stirred at room temperature.Will reaction
Liquid is poured into 200 ml water, stirs 5min, point liquid, and organic phase is extracted once with 130ml 1N hydrochloric acid solutions, and hydrochloric acid solution is then
Washed once with 60ml ethyl acetate, adjust pH to 8 with saturated sodium bicarbonate solution, there is more white casse to separate out, 80ml is used successively
Dichloromethane, the extraction of 30ml dichloromethane, merge organic phase, and anhydrous sodium sulfate drying is filtered, and concentration obtains lavender oily liquid
Body.
450ml isopropanols are added into lavender oily liquids, dissolving is heated to reflux, it is slightly cold, 2g activated carbons are added, are continued
Flow back 5min, filters while hot, filtrate is placed in 10 DEG C or so crystallization 6h, suction filtration, 50ml isopropanols are washed, and obtain white powder, replaces wheat
Examine phenolic ester 31.2g, yield 72%.
The foregoing is only presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, should all belong to the covering scope of the present invention.
Claims (8)
1. a kind of preparation method of MMF, it is characterised in that Mycophenolic Acid and morpholine ethanol, triphenylphosphine,
Under DIAD effects, prolong reaction through light and prepare MMF, this method comprises the following steps：
（1）Under nitrogen protection, triphenylphosphine, morpholine ethanol are dissolved under reaction dissolvent, control temperature of reaction system and sequentially added
DIAD solution, Mycophenolic Acid solution, stirring to reaction terminate；
（2）Reaction solution obtained by step (1) obtains crude product through washing, extraction after concentration, add alcohols solvent recrystallization once, obtain
To MMF.
2. the preparation method of MMF according to claim 1, it is characterised in that reacted described in step (1)
Solvent is dichloromethane, ethyl acetate, tetrahydrofuran, 2- methyltetrahydrofurans, dioxane or toluene.
3. the preparation method of MMF according to claim 1, it is characterised in that each thing described in step (1)
The mol ratio of material 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 MMF according to claim 1, it is characterised in that in step (1), adds DIAD
It is 0 DEG C to 10 DEG C that temperature of reaction system is controlled when solution, Mycophenolic Acid solution.
5. the preparation method of MMF according to claim 1, it is characterised in that in step (1), DIAD by
Its analog diethyl azodiformate, tert-butyl azodicarboxylate, diphenyl azodicarboxylate are substituted.
6. the preparation method of MMF according to claim 1, it is characterised in that in step (1), triphenylphosphine
Substituted by its analog diphenyl methyl phosphine, tributylphosphine.
7. the preparation method of MMF according to claim 1, it is characterised in that in step (2), recrystallization is used
Alcohols solvent is absolute ethyl alcohol, 95% ethanol, isopropanol or methanol.
8. the preparation method of MMF according to claim 1, it is characterised in that in step (2), during recrystallization
Recrystallization temperature be 0 DEG C to 20 DEG C.
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| CN201710315619.5A CN107056736A (en) | 2017-05-08 | 2017-05-08 | A kind of preparation method of MMF |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107987043A (en) * | 2018-02-27 | 2018-05-04 | 威海贯标信息科技有限公司 | A kind of mycophenolate mofetil novel crystal forms |
| CN111153879A (en) * | 2020-03-17 | 2020-05-15 | 南京昊绿生物科技有限公司 | Mycophenolic acid-13Synthesis method of CD3 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1520411A (en) * | 2001-06-08 | 2004-08-11 | ����˹��ҩ�﹫˾ | Method of mycophenolate mofetil prepn. |
-
2017
- 2017-05-08 CN CN201710315619.5A patent/CN107056736A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1520411A (en) * | 2001-06-08 | 2004-08-11 | ����˹��ҩ�﹫˾ | Method of mycophenolate mofetil prepn. |
Non-Patent Citations (1)
| Title |
|---|
| AARON T. WRIGHT, ET AL: "The Discriminatory Power of Differential Receptor Arrays Is Improved by Prescreening—A Demonstration in the Analysis of Tachykinins and Similar Peptides", 《ANGEW. CHEM. INT. ED.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107987043A (en) * | 2018-02-27 | 2018-05-04 | 威海贯标信息科技有限公司 | A kind of mycophenolate mofetil novel crystal forms |
| CN111153879A (en) * | 2020-03-17 | 2020-05-15 | 南京昊绿生物科技有限公司 | Mycophenolic acid-13Synthesis method of CD3 |
| CN111153879B (en) * | 2020-03-17 | 2022-09-27 | 南京昊绿生物科技有限公司 | Mycophenolic acid- 13 Synthesis method of CD3 |
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Application publication date: 20170818 |