CN1772745A - Prepn process of mofe-til mycophenolate - Google Patents
Prepn process of mofe-til mycophenolate Download PDFInfo
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- CN1772745A CN1772745A CN 200510100489 CN200510100489A CN1772745A CN 1772745 A CN1772745 A CN 1772745A CN 200510100489 CN200510100489 CN 200510100489 CN 200510100489 A CN200510100489 A CN 200510100489A CN 1772745 A CN1772745 A CN 1772745A
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- mycophenolate mofetil
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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
The present invention relates to the preparation method of mycophenolate mofetil (I) (Mycophenolate Mofetil), more specifically to a kind of mycophenolate mofetil preparation method who adopts catalyzer.
Background technology
Mycophenolate mofetil (I)
R wherein
1=2-(4-morpholinyl) ethyl, R
2=H,
It is a kind of microbiotic that mainly has immunosuppressive action, it is the prodrug of mycophenolic acid, mycophenolic acid can the mould activity of noncompetitive effectively inhibition inosine-monophosphate dehydrogenation, thereby hinder the approach that starts anew of guanosine Nucleotide, thereby lymphocytic propagation is suppressed, and lymphocytic growth and breeding restraining effect is higher than other cells.Mycophenolate mofetil is mainly used in kidney and heart transplantation postoperative organ rejection's prevention, and can share with ciclosporin, reduces the latter's dosage and toxicity.The synthetic method of existing mycophenolate mofetil mainly contains direct esterification and indirect esterification two big classes.As adopt the European patent EP 281713B1 of indirect esterification process, and earlier by mycophenolic acid and the mould phenol acyl chlorides of thionyl chloride reaction generation, get mycophenolate mofetil with excessive 2-morpholino ethanol synthesis again, but its instability easily forming multipolymer, there is color problem in product; And for example adopt the U.S. Pat 5247083 of direct esterification method, by backflow mycophenolic acid under the azeotropic water sepn in appropriate solvent or solvent mixture and 2-morpholino ethanol preparation mycophenolate mofetil, need the long reaction period of about 6～100h just can reach sufficient transformation efficiency, and the lavender of product can't be removed.Above-mentioned correlation technique has improved productive rate to a certain extent to the preparation technology of mycophenolate mofetil, but also has variety of problems: there are color problem in long reaction time, product, need polystep reaction or are difficult for realizing industrialization.
Summary of the invention:
Technical problem to be solved by this invention is the defective that remedies prior art, and a kind of catalyzer cheap and easy to get, work simplification, the reaction times is short, transformation efficiency is high and product purity is high mycophenolate mofetil preparation method of adopting is provided.
Technical problem of the present invention is solved by the following technical programs.
This mycophenolate mofetil preparation method may further comprise the steps successively:
(1) be (2.5～4) with volume ratio: 1 the toluene and the mixed solvent of dimethylbenzene drop into reactor, drop into mycophenolic acid and 2-morpholino ethanol according to (600～1500) mL/ mole, (600～1500)/(1.02～1.20) mL/ mole respectively again, mechanical stirring is to dissolving fully;
(2) be (0.01～0.10) according to the mol ratio with mycophenolic acid: 1 drops into catalyzer C
1～6Lipid acid continues to stir;
(3) elevated temperature to 126 ℃～131 ℃ stirs, reflux water-dividing, keeps 6h～24h, and the mycophenolic acid direct esterification becomes mycophenolate mofetil;
(4) be (0.05～0.10) according to the mass ratio with mycophenolic acid: 1 drops into the discoloring agent gac, in 70 ℃ of following evaporated under reduced pressure organic phases of temperature, makes crude product again;
(5) according to (4～8) mL/g input ethyl acetate, mechanical stirring is (0.05～0.10) according to the mass ratio with crude product to dissolving fully then: 1 drops into the discoloring agent vitamins C, successively uses the Na of concentration 10% again
2CO
3Each washing of solution and water once;
(6) behind the elevated temperature to 60 ℃～80 ℃, be cooled to immediately below 30 ℃ and separate out solid, wash solid with ethyl acetate again,, make elaboration at last in 40 ℃～60 ℃ following vacuum-dryings of temperature.
Technical problem of the present invention can further be solved by the following technical programs.
Described catalyzer C
1～6Lipid acid be in formic acid, acetate and the propionic acid any one, two or three mixture.
Described catalyzer C
1～6Lipid acid is mixture any two kinds in formic acid, acetate and the propionic acid, is main a kind of 70%～98% of total amount that accounts for.
Described catalyzer C
1～6Lipid acid is the mixture of formic acid, acetate and propionic acid, is main a kind of 60%～98% of total amount that accounts for.
Preparation method of the present invention adopts C
1～6Lipid acid is done catalyst for making direct esterification, can significantly shorten the reaction times, and C
1～6Lipid acid is inexpensive to be easy to get, and can reduce preparation cost greatly; Preparation method of the present invention drops into the discoloring agent vitamins C in aftertreatment, can thoroughly solve the product color problem that exists in the prior art; Preparation method's yield of the present invention can reach 83%, and the purity after product is refining is at least 99.6%.
Embodiment
Embodiment 1:
Use formic acid to make catalyzer and remove the mycophenolate mofetil preparation method of purple, may further comprise the steps successively with dropping into the discoloring agent vitamins C:
(1) the 20g mycophenolic acid is taken back the reactor of flow point water device with the mixed solvent input of 60mL toluene and dimethylbenzene (3: 1), be stirred to dissolving after, drop into 11.5g morpholino ethanol;
(2) drop into the rudimentary fat of 1g catalyzer and acid-formic acid;
(3) elevated temperature to 130 ℃ stirs, reflux water-dividing, keeps the direct esterification of lowering the temperature behind the 10h, follows the tracks of by purity (HPLC), and 8h left and right sides reaction conversion ratio reaches 85%;
(4) drop into the 1.5g gac and decoloured 0.5 hour down for 80 ℃ in temperature, suction filtration, mother liquor is in 70 ℃ of following evaporated under reduced pressure of temperature;
(5) using the 150ml acetic acid ethyl dissolution, drop into the 0.1g vitamins C, successively is 10% Na with 90ml concentration
2CO
3Solution, 40ml deionized water respectively wash 1 time;
(6) filtrate is concentrated into 50ml, is cooled to temperature and separates out solid crystal for 30 ℃, filters the back with the washing of 20ml cold ethyl acetate, suction filtration, makes the 22.15g mycophenolate mofetil in 60 ℃ of vacuum-dryings of temperature, purity (HPLC) 99.6%, yield 83.5%.
Embodiment 2:
Use acetate to make catalyzer and remove the mycophenolate mofetil preparation method of purple, may further comprise the steps successively with dropping into the discoloring agent vitamins C:
(1) with the step (1) of embodiment 1;
(2) drop into 1g catalyzer lower fatty acid-acetate,
(3) elevated temperature to 129 ℃ stirs, reflux water-dividing, keeps the direct esterification of lowering the temperature behind the 24h;
(4) with the step (4) of embodiment 1;
(5) substantially with the step (5) of embodiment 1, the vitamins C input amount is 0.07g;
(6) substantially with the step (1) of embodiment, make the 22.00g mycophenolate mofetil, purity (HPLC) 99.7%, yield 83.0%.
Embodiment 3:
Use propionic acid to make catalyzer and remove the mycophenolate mofetil preparation method of purple, may further comprise the steps successively with dropping into the discoloring agent vitamins C:
(1) substantially with the step (1) of embodiment 1, morpholino ethanol input amount is 11.5g;
(2) drop into 1g catalyzer lower fatty acid-propionic acid,
(3) be warming up to 127 ℃, stirring, reflux water-dividing, the direct esterification of lowering the temperature behind the maintenance 24h;
(4) with the step (4) of embodiment 1;
(5) substantially with the step (5) of embodiment 1, the vitamins C input amount is 0.16g;
(6) substantially with the step (1) of embodiment 1, make the 21.20g mycophenolate mofetil, purity (HPLC) 99.6%, yield 80.0%.
Embodiment 4:
Use formic acid and acetate mixture to make catalyzer and remove the mycophenolate mofetil preparation method of purple, may further comprise the steps successively with dropping into the discoloring agent vitamins C:
(1) with the step (1) of specific embodiment 1
(2) mixture-formic acid of input 1g catalyzer lower fatty acid: quality of acetic acid is than=20: 80;
(3) elevated temperature to 130 ℃ stirs, reflux water-dividing, keeps the direct esterification of lowering the temperature behind the 20h;
(4) with the step (4) of embodiment 1;
(5) substantially with the step (5) of embodiment 1, the vitamins C input amount is 0.20g;
(6) substantially with the step (1) of embodiment 1, make the 21.50g mycophenolate mofetil, purity (HPLC) 99.6%, yield 81.1%.
Embodiment 5:
Use formic acid, acetate and propionic acid mixture as catalyst to remove the mycophenolate mofetil preparation method of purple, may further comprise the steps successively with dropping into the discoloring agent vitamins C:
(1) with the step (1) of embodiment 2
(2) mixture-formic acid of input 1g catalyzer lower fatty acid: acetate: the mass ratio of propionic acid=30: 65: 5;
(3) elevated temperature to 131 ℃ stirs, reflux water-dividing, keeps the direct esterification of lowering the temperature behind the 24h;
(4) with the step (4) of embodiment 1;
(5) with the step (5) of embodiment 4;
(6) substantially with the step (1) of embodiment 1, make the 21.3g mycophenolate mofetil, purity (HPLC) 99.6%, yield 80.4%.
Claims (4)
1, a kind of mycophenolate mofetil preparation method is characterized in that:
May further comprise the steps successively:
(1) be (2.5～4) with volume ratio: 1 the toluene and the mixed solvent of dimethylbenzene drop into reactor, drop into mycophenolic acid and 2-morpholino ethanol according to (600～1500) mL/ mole, (600～1500)/(1.02～1.20) mL/ mole respectively again, be stirred to dissolving fully;
(2) be (0.01～0.10) according to the mol ratio with mycophenolic acid: 1 drops into catalyzer C
1～6Lipid acid continues to stir;
(3) elevated temperature to 126 ℃～131 ℃ stirs, reflux water-dividing, keeps 6h～24h, and the mycophenolic acid direct esterification becomes mycophenolate mofetil;
(4) be (0.05～0.10) according to the mass ratio with mycophenolic acid: 1 drops into the discoloring agent gac, 70 ℃ of following evaporated under reduced pressure organic phases, makes crude product again;
(5) dropping into ethyl acetate according to (4～8) mL/g, be stirred to dissolving fully under the normal temperature, is (0.05～0.10) according to the mass ratio with crude product then: 1 drops into the discoloring agent vitamins C, successively uses the Na of concentration 10% again
2CO
3Each washing of solution and water once;
(6) behind the elevated temperature to 60 ℃～80 ℃, be cooled to below 30 ℃ and separate out solid, wash solid with ethyl acetate again,, make elaboration at last 40 ℃～60 ℃ following vacuum-dryings.
2, mycophenolate mofetil preparation method as claimed in claim 1 is characterized in that:
Described catalyzer C
1～6Lipid acid be in formic acid, acetate and the propionic acid any one, two or three mixture.
3, mycophenolate mofetil preparation method as claimed in claim 1 or 2 is characterized in that:
Described catalyzer C
1～6Lipid acid is mixture any two kinds in formic acid, acetate and the propionic acid, is main a kind of 70%～98% of total amount that accounts for.
4, mycophenolate mofetil preparation method as claimed in claim 3 is characterized in that:
Described catalyzer C
1～6Lipid acid is the mixture of formic acid, acetate and propionic acid, is main a kind of 60%～98% of total amount that accounts for.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101004890A CN100402516C (en) | 2005-10-18 | 2005-10-18 | Prepn process of mofe-til mycophenolate |
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|---|---|---|---|
| CNB2005101004890A CN100402516C (en) | 2005-10-18 | 2005-10-18 | Prepn process of mofe-til mycophenolate |
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| CN1772745A true CN1772745A (en) | 2006-05-17 |
| CN100402516C CN100402516C (en) | 2008-07-16 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009003878A1 (en) * | 2007-06-29 | 2009-01-08 | Dsm Ip Assets B.V. | Method for the preparation of mycophenolate mofetil |
| CN100484930C (en) * | 2007-03-16 | 2009-05-06 | 重庆大新药业股份有限公司 | Preparation method of mycophenolate mofetil |
| CN1974564B (en) * | 2006-12-15 | 2010-05-12 | 丽珠集团新北江制药股份有限公司 | Preparation process of mycophenolate mofetil |
| CN102924413A (en) * | 2012-10-23 | 2013-02-13 | 福建科瑞药业有限公司 | Method for purifying and decolorizing mycophenolate mofetil |
| CN106866595A (en) * | 2017-03-04 | 2017-06-20 | 丽珠集团新北江制药股份有限公司 | A kind of MMF preparation method |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4753935A (en) * | 1987-01-30 | 1988-06-28 | Syntex (U.S.A.) Inc. | Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions |
| US5247083A (en) * | 1992-07-10 | 1993-09-21 | Syntex (U.S.A.) Inc. | Direct esterification of mycophenolic acid |
| US5380879A (en) * | 1994-02-18 | 1995-01-10 | Syntex (U.S.A.) Inc. | Derivatives of mycophenolic acid |
| IN188985B (en) * | 1998-12-09 | 2002-11-30 | Biocon Ltd | |
| CZ292123B6 (en) * | 2001-06-08 | 2003-08-13 | Ivax Pharmaceuticals S.R.O. | Process for preparing mofetil mycophenolate |
-
2005
- 2005-10-18 CN CNB2005101004890A patent/CN100402516C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1974564B (en) * | 2006-12-15 | 2010-05-12 | 丽珠集团新北江制药股份有限公司 | Preparation process of mycophenolate mofetil |
| CN100484930C (en) * | 2007-03-16 | 2009-05-06 | 重庆大新药业股份有限公司 | Preparation method of mycophenolate mofetil |
| WO2009003878A1 (en) * | 2007-06-29 | 2009-01-08 | Dsm Ip Assets B.V. | Method for the preparation of mycophenolate mofetil |
| CN102924413A (en) * | 2012-10-23 | 2013-02-13 | 福建科瑞药业有限公司 | Method for purifying and decolorizing mycophenolate mofetil |
| CN102924413B (en) * | 2012-10-23 | 2014-12-31 | 福建科瑞药业有限公司 | Method for purifying and decolorizing mycophenolate mofetil |
| CN106866595A (en) * | 2017-03-04 | 2017-06-20 | 丽珠集团新北江制药股份有限公司 | A kind of MMF preparation method |
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|---|---|
| CN100402516C (en) | 2008-07-16 |
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Assignee: HEC Pharmaceutical Company Assignor: Dongyangguang Pharmaceutical Co., Ltd., Guangdong Contract record no.: 2011440000028 Denomination of invention: Prepn process of Mycophenolate mofetil Granted publication date: 20080716 License type: Common License Open date: 20060517 Record date: 20110120 |
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