WO2008015693A2 - Process for the preparation of mycophenolate mofetil - Google Patents
Process for the preparation of mycophenolate mofetil Download PDFInfo
- Publication number
- WO2008015693A2 WO2008015693A2 PCT/IN2007/000192 IN2007000192W WO2008015693A2 WO 2008015693 A2 WO2008015693 A2 WO 2008015693A2 IN 2007000192 W IN2007000192 W IN 2007000192W WO 2008015693 A2 WO2008015693 A2 WO 2008015693A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mycophenolate mofetil
- preparation
- mycophenolic acid
- reaction
- organic solvent
- Prior art date
Links
Classifications
-
- 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
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
Definitions
- the present invention relates to the process for the preparation of Mycophenolate Mofetil of formula (I).
- Mycophenolate mofetil is chemically known as Morpholinoethyl E-6-(l,3-dihydro-4 ⁇ hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexanoate.
- Mycophenolate mofetil is the morpholinoethyl ester of mycophenolic acid.
- Mycophenolic acid isolated by Gosio in 1893 is the first well characterized antibiotic (Bentley 201). It is produced by several species of Penicillium, including P.brevi-compactum, P.scabrum, P.nagemi, P.roqueforti, P.patris-meri and P. viridicatum (Clutterbuck etal. 1932, Jens and Filtenborg 1983).
- US patent no. 4,753,935 describes the process for the preparation of Mycophenolate mofetil by converting Mycophenolic acid to Mycophenolic acid chloride and condensing it with morpholino ethanol in dichloromethane.
- this process suffered from various deficiencies like low yield and generation of impurities like dimer impurities.
- colour problem associated with the final product due to trace iron contamination considered secondary to corrosive conditions during acid chloride conversion.
- Another process for the preparation of Mycophenolate mofetil is reported in WO 94/01427, where Mycophenolic acid is condensed with morpholino ethanol in inert organic solvent like xylene, toluene, cumene while removing water azeotropically. This process also suffers due to high reaction time and possibility of dimeric impurity.
- Mycophenolate mofetil is prepared by esterification of Mycophenolic acid with 2- morpholino ethanol using enzyme catalyses however the method may not be commercially viable.
- Mycophenolate mofetil is prepared by esterification of
- Another object of the present invention is to provide the process for the preparation of Mycophenolate mofetil, which devoides of additional purification steps and requiring shorter time duration.
- a process for the preparation of Mycophenolate mofetil comprises reacting Mycophenolic acid with morpholino ethanol in presence of dipyridyl carbonate.
- a process for the preparation of Mycophenolate mofetil comprises reacting Mycophenolic acid with morpholino ethanol in presence of dipyridyl carbonate in inert solvent optionally in presence of dimethyl amino pyridine.
- This present invention provides an improved process for the preparation of
- Mycophenolate mofetil by reacting Mycophenolic acid with morpholino ethanol in presence of Dipyridyl carbonate.
- the reaction is preferably carried out in inert organic solvent.
- Inert organic solvent can be selected from hydrocarbon, halogenated solvent and the like or mixtures there of.
- inert solvent can be selected from the group comprising of toluene, xylene, hexane, haptene, cumuene, dichloromethane, chloroform, dichloroethane and the like or mixtures there of.
- This reaction is optionally carried out in presence of catalytic amount of dimethylaminopyridine. This reaction can also be carried out in solvent free system.
- Dipyridylcarbonate (DPC) used in the reaction can be prepared by well known methods such as by reacting 2-hydroxypyridine and triphosgene in dichloromethane using triethylamine.
- Mycophenolate mofetil is prepared by reacting Mycophenolic acid (MPA) with 2- morpholino ethanol in presence of Dipyridyl carbonate (DPC).
- MPA Mycophenolic acid
- DPC Dipyridyl carbonate
- the present invention gives a high yield and easy workup procedure for esterification reactions like of Mycophenolate mofetil as depicted in the following scheme.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
Invention provides an improved process for the preparation of Mycophenolate mofetil by reacting Mycophenolic acid with morpholino ethanol in presence of Dipyridyl carbonate.
Description
PROCESS FOR THE PREPARATION OF MYCOPHENOLATE
MOFETIL
TECHNICAL FIELD
The present invention relates to the process for the preparation of Mycophenolate Mofetil of formula (I). Mycophenolate mofetil is chemically known as Morpholinoethyl E-6-(l,3-dihydro-4~hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexanoate.
(I)
BACKGROUND ART
Mycophenolate mofetil is the morpholinoethyl ester of mycophenolic acid. Mycophenolic acid isolated by Gosio in 1893, is the first well characterized antibiotic (Bentley 201). It is produced by several species of Penicillium, including P.brevi-compactum, P.scabrum, P.nagemi, P.roqueforti, P.patris-meri and P. viridicatum (Clutterbuck etal. 1932, Jens and Filtenborg 1983).
However, considering its side effects, its morpholino ethyl ester, i.e. Mycophenolate mofetil is marketed as Cell Cept. It is useful as immunosuppressive, anti-inflammatory, anti-tumor and anti-viral activity.
US patent no. 4,753,935 describes the process for the preparation of Mycophenolate mofetil by converting Mycophenolic acid to Mycophenolic acid chloride and condensing it with morpholino ethanol in dichloromethane. However, this process suffered from various deficiencies like low yield and generation of impurities like dimer impurities. Also, colour problem associated with the final product due to trace iron contamination considered secondary to corrosive conditions during acid chloride conversion.
Another process for the preparation of Mycophenolate mofetil is reported in WO 94/01427, where Mycophenolic acid is condensed with morpholino ethanol in inert organic solvent like xylene, toluene, cumene while removing water azeotropically. This process also suffers due to high reaction time and possibility of dimeric impurity.
According to WO 00/34503, Mycophenolate mofetil is prepared by esterification of Mycophenolic acid with 2- morpholino ethanol using enzyme catalyses however the method may not be commercially viable.
According to EP 281713, Mycophenolate mofetil is prepared by esterification of
Mycophenolic acid with 2-morpholino ethanol using dicyclohexylcarbodiimide (DCC) as catalyst. However, this process requires purification by using cumbersome column chromatography technique, which is not preferable to use as commercial production level.
Therefore, there is a need to have simple and easy process to prepare Mycophenolate mofetil.
OBJECTS OF THE INVENTION:
According to the principal object of the present invention, there is provided an improved process for the preparation of Mycophenolate mofetil.
Another object of the present invention is to provide the process for the preparation of Mycophenolate mofetil, which devoides of additional purification steps and requiring shorter time duration.
According to one aspect of the present invention, there is provided a process for the preparation of Mycophenolate mofetil comprises reacting Mycophenolic acid with morpholino ethanol in presence of dipyridyl carbonate.
According to another aspect of the present invention, there is provided a process for the preparation of Mycophenolate mofetil comprises reacting Mycophenolic acid with morpholino ethanol in presence of dipyridyl carbonate in inert solvent optionally in presence of dimethyl amino pyridine.
DETAILED DESCRIPTION:
This present invention provides an improved process for the preparation of
Mycophenolate mofetil by reacting Mycophenolic acid with morpholino ethanol in presence of Dipyridyl carbonate. The reaction is preferably carried out in inert organic solvent. Inert organic solvent can be selected from hydrocarbon, halogenated solvent and the like or mixtures there of. Preferably inert solvent can be selected from the group comprising of toluene, xylene, hexane, haptene, cumuene, dichloromethane, chloroform, dichloroethane and the like or mixtures there of.
This reaction is optionally carried out in presence of catalytic amount of dimethylaminopyridine. This reaction can also be carried out in solvent free system.
Dipyridylcarbonate (DPC) used in the reaction can be prepared by well known methods such as by reacting 2-hydroxypyridine and triphosgene in dichloromethane using triethylamine.
Mycophenolate mofetil is prepared by reacting Mycophenolic acid (MPA) with 2- morpholino ethanol in presence of Dipyridyl carbonate (DPC). The present invention gives a high yield and easy workup procedure for esterification reactions like of Mycophenolate mofetil as depicted in the following scheme.
The preparation of Mycophenolate mofetil according to one of the embodiment of present invention is shown in the following scheme (I).
Scheme (T)
The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention.
EXAMPLE 1:
To a solution of Mycophenolic acid. (5 g) in toluene 100 mL added morpholino ethanol (2.2g) to obtain solution. Dipyridyl carbonate (3.4g) was added to this solution along with O.lg of Dimethylaminopyridine. The reaction mixture was stirred at RT for about 24 hrs till the reaction is completed. Usual workup involves washing of toluene layer with 5% sodium bicarbonate solution and the organic layer separated was evaporated under vacuum at 30-500C to afford an oily residue. The oily residue was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil (5.2g) Purity: >99%.
EXAMPLE 2:
To a solution of Mycophenolic acid (5g) in Dichloromethane 100 mL added morpholino ethanol (2.2g) to obtain solution. Dipyridyl carbonate (3.4g) was added to this solution along with O.lg of Dimethylaminopyridine. The reaction mixture
was stirred at RT for about 24 hrs till the reaction was completed. Usual workup involves washing of toluene layer with 5% sodium bicarbonate solution and the organic layer separated was evaporated under vacuum at 25-300C to afford an oily residue. The oily residue was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil (5. Ig) Purity: > 99%
EXAMPLE 3:
To a solution of Mycophenolic acid (5g) in toluene (100 mL) added morpholino ethanol (2.2g) to obtain solution. Dipyridyl carbonate (3.4g) was added to this solution along with O.lg of Dimethylaminopyridine. The reaction mixture was stirred at RT for about 10 hrs till the reaction completion. Usual workup involves washing of toluene layer with 5% sodium bicarbonate solution and the organic layer separated was evaporated under vacuum at 30-50 0C to afford an oily residue. The oily residue was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil (5.Ig). Purity. >99%.
EXAMPLE 4:
To a solution of Mycophenolic acid (5g), added morpholino ethanol (5.0g). Dipyridyl carbonate (3.4g) was added to this solution along with O.lg of Dimethylaminopyridine. The reaction mixture was stirred at RT for about 24 hrs till reaction completion. Usual workup involves washing of organic layer with 5% sodium bicarbonate solution and the organic layer evaporated to afford an oily residue which was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil. Purity: >99%.
Claims
1. A process for the preparation of Mycophenolic acid of formula (I)
(I) comprises, reacting Mycophenolic acid with morpholino ethanol in presence of dipyridyl carbonate.
2. A process as claimed in claim 1, wherein said reaction is carried out optionally in presence of inert organic solvent.
3. A process as claimed in claim 2, wherein said inert organic solvent is selected from hydrocarbon, halogenated solvent and the like or mixtures there of.
4. A process as claimed in claim 2, wherein said inert organic solvent is selected from the group comprising of toluene, xylene, hexane, haptene, cumuene, dichloromethane, chloroform, dichloroethane and the like or mixtures there of.
5. A process as claimed in claim 1, wherein said reaction is carried out at temperature ranges from about 20 to 100° C, preferably at about 20 to 35°C.
6. A process as claimed in claim 1, wherein said reaction is carried out optionally in presence of Dimethylaminopyridine (DMAP) catalyst.
7. Mycophenolate mofetil prepared in accordance with the process as claimed in claim 1.
8. A pharmaceutical composition comprising Mycophenolate mofetil, wherein said Mycophenolate mofetil is prepared in accordance with the process as claimed in claim 1.
9. A process for the preparation of Mycophenolate mofetil such as here in described in accompanying text, drawings and examples.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1489/MUM/2005 | 2006-06-02 | ||
IN1489MU2006 | 2006-06-02 |
Publications (3)
Publication Number | Publication Date |
---|---|
WO2008015693A2 true WO2008015693A2 (en) | 2008-02-07 |
WO2008015693A8 WO2008015693A8 (en) | 2008-03-27 |
WO2008015693A3 WO2008015693A3 (en) | 2009-04-16 |
Family
ID=38997573
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2007/000192 WO2008015693A2 (en) | 2006-06-02 | 2007-05-10 | Process for the preparation of mycophenolate mofetil |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2008015693A2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5247083A (en) * | 1992-07-10 | 1993-09-21 | Syntex (U.S.A.) Inc. | Direct esterification of mycophenolic acid |
-
2007
- 2007-05-10 WO PCT/IN2007/000192 patent/WO2008015693A2/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5247083A (en) * | 1992-07-10 | 1993-09-21 | Syntex (U.S.A.) Inc. | Direct esterification of mycophenolic acid |
Non-Patent Citations (2)
Title |
---|
DATABASE CAPLUS STN Database accession no. 1985:77975 & KIM ET AL.: 'Di-2-pyridyl carbonate: a new eficient coupling agent for the direct esterificaiton of carboxylic acids.' TETRAHEDRON LETTERS vol. 25, no. 43, 1984, pages 4943 - 4946 * |
SMITH ET AL.: 'March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure', page 1414 * |
Also Published As
Publication number | Publication date |
---|---|
WO2008015693A3 (en) | 2009-04-16 |
WO2008015693A8 (en) | 2008-03-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1149208C (en) | Method for prepn. of 5-cyanophthalide | |
EP2321421A1 (en) | Process for preparation of mycophenolic acid, its salt and ester derivatives | |
WO2008015693A2 (en) | Process for the preparation of mycophenolate mofetil | |
US10316012B1 (en) | Method of synthesizing (1S, 5R)-lactone | |
NZ250478A (en) | Enzymatic process for the stereoselective preparation of a heterobicyclic alcohol enantiomer and use as an intermediate to prepare flesinoxan | |
CN107674016B (en) | Preparation method of telaprevir intermediate and intermediate thereof | |
KR100638776B1 (en) | Processes for preparing 7-carboxy substituted steroids | |
CN107021969B (en) | The method that catalysis oxidation prepares biotin precursor ketone acid | |
SU860708A1 (en) | Method of preparing steroids | |
CN115716813A (en) | Lindane sesquiterpene intermediate, lindane type sesquiterpene polymer prepared from intermediate and preparation method | |
CN108299466B (en) | Improved dolutegravir synthesis method | |
CN110698529A (en) | Preparation method of eplerenone intermediate △ 9,11 alkenyl ester | |
EP1831150A1 (en) | Process for the preparation of (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionamide and (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionic acid alkyl ester | |
CN110903259A (en) | Process for efficiently synthesizing Cetilistat by taking 2-amino-5-methylbenzoic acid as raw material | |
Sun et al. | Synthesis and inhibitory activities of isochromophilone analogues against gp120-CD4 binding | |
WO2003042393A1 (en) | Enzymatic preparation of mycophenolate mofetil | |
CN111087436B (en) | Preparation method of obeticholic acid | |
KR20030084952A (en) | Degradation of epothilones and ethynyl substituted epotilones | |
US20080300404A1 (en) | Process for the Preparation of Mycophenolate Mofetil | |
CN114773405B (en) | Preparation method of monatiravir | |
EP1445324A1 (en) | Process for producing optically active chroman derivative and intermediate | |
CN104829644B (en) | A kind of preparation method of (S) tertiary butyl dimethyl Si base glutaric acid list benzyl ester monoamides | |
US6376230B1 (en) | Stereoselective process for producing intermediates of cryptophycins | |
CN107827811B (en) | Method for preparing N-substituted-1, 2,3, 6-tetrahydropyridine | |
TW200525036A (en) | Microbial method for hydrolysis and oxidation of androst-5-ene and pregn-5-ene steroid esters |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07827495 Country of ref document: EP Kind code of ref document: A2 |
|
NENP | Non-entry into the national phase in: |
Ref country code: RU |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07827495 Country of ref document: EP Kind code of ref document: A2 |