FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003 COMPLETE SPECIFICATION (See Section 10 and rule 13)
1. A NOVEL PROCESS FOR THE PRODUCTION OF MYCOPHENOLATE MOFETIL.
2. (a) Name: CONCORD BIOTECH LIMITED

(b) Nationality: An Indian Company
(c) Address: 1482-1486, Trasad Road,
Dholka, Dist. Ahmedabad- 387810. INDIA
3. The following specification particularly describes the
invention and the manner in which it is to be performed.

Field of Invention:
The present invention describes about a novel process for the production of Mycophenolate Mofetil of formula I from Mycophenolic Acid of Formula II.

CH3
(II)
The main object of the present invention is to develop a low cost method for production of highly pure Mycophenolate mofetil free from dimer impurity, wherein the production is carried out by condensation of Mycophenolic acid and morpholine-2-ethanol at 40-50° C in presence of a reagent N, N- Carbonyl diimidazole.

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Background of the invention:
Mycophenolic acid is known for its immunosuppressive, antiinflammatory, antiviral and anti-tumor activity since 1893. However, Mycophenolic acid as such is not being used as a potent drug because of its lower bioavailability. Hence, a need was felt to develop certain derivatives, which can help in increase of its bioavailability. One such derivative developed was Mycophenolate mofetil. This form of ester has found to be of much better bioavailability as compared to other ester derivatives. Mycophenolate mofetil is an ester form of Mycophenolic acid is use as active ingredient for pharmaceutical compositions, e.g. in the prevention of rejection reactions following transplantations, in the treatment of autoimmune diseases, psoriasis, inflammatory disorders such as rheumatic arthritis, as well as viral illnesses and tumors. Chemical name of Mycophenolate Mofetil is Morpholinoethyl E-6-(l, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexanoate according to Merck Index /13th Edition / Monograph number 6352.
Mycophenolic Acid is a fermentation product; is produced by several species of Penicillium, including P. brevi-compactum, P. scabrum, P. nagemi, P. roqueforti, P. patris-meri and P. viridicatum (Clutterbuck et. Al. 1932, Jens and Filtenborg 1983). It is isolated by Gosio in 1893, is the first well characterized antibiotic (Bentley 2001). This
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product is used as a starting material for the production of Mycophenolate Mofetil.
Mycophenolate Mofetil is prepared by different methods. As per known procedure Mycophenolic Acid is directly esterified without using catalyst. This esterification procedure require long reaction time to form the end product.
As disclosed in WO 05/023791, Mycophenolic Acid is esterified under acidic reaction condition with 4-(2-hydroxyethyl) morpholine and subsequent extraction of Mycophenolate Mofetil through salt formation and then released as free base. This method claims about removal of dimeric impurities by salt formation and free base regeneration. However, this method is tedious and under acidic conditions the product contains other impurities like demethylated Mycophenolate Mofetil. Moreover, this esterification procedure is cumbersome because it needs separate purification from the byproducts and it involves high reaction time.
One another patent WO 00/34503 discloses about the conversion of Mycophenolic acid to Mycophenolate mofetil without the use of catalyst and a third solvent. In the said esterification procedure, it was observed that a large part of the Mycophenolate left unconverted and impurities had formed.
As disclosed in EP 281713, Mycophenolic Acid is esterified with 2-morpholino ethanol in presence of catalyst dicyclohexylcarbodiimide. Here also formation of side product i.e dicyclohexyl urea (DCU)
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inhibits crystallization to pure form and column chromatography is being used for removal of DCU.
Another patent WO 94/01427 discloses that Mycophenolate mofetil is produced by refluxing mycophenolic acid with 2-morpholinoethanol without using any catalyst in an inert organic solvent capable of azeotropic removal of water. This reaction procedure involves high temperature, high reaction time with high possibility of dimer impurity formation.
Other known procedures are carried out for the production of Mycophenolate mofetil, wherein an acid chloride of mycophenolic acid produced by reacting with thionyl chloride is being used for condensation with morpholine-2-ethanol. These methods however are non suitable for producing pure form of Mycophenolate Mofetil. Formation of dimer impurities during the reaction also reduces the outcome of pure ester form of Mycophenolic acid. Besides that color contamination during acid chloride conversion is also a problem. Thus, an alternative way for synthesizing Mycophenolate Mofetil was desired. It had been discovered that pure form of Mycophenolate Mofetil is obtained with the use of N, N-Carbonyl diimidazole without causing any impurity formation, lower reaction timing and lower reaction temperature.
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Summary of the invention:
One aspect of the present invention involves a novel process for production of Mycophenolate Mofetil in presence of a reagent to catalyze the reaction at faster rate in the presence of inert organic solvents.
The solvents can be selected from hydrocarbons, halogenated solvents and the like or mixtures thereof. Particularly preferable inert organic solvents selected from the group comprising of toluene, xylene, hexane, heptane, cumene, dichloromethane, chloroform, dichloromethane, esters like ethyl acetate, isobutyl acetate and the like or mixtures thereof.
Detailed Description of the invention:
The invention involves reaction of Mycophenolic acid with
morpholine-2-ethanol in presence of N, N-Carbonyl diimidazole to
produce Mycophenolate Mofetil. The reaction is carried out in inert
organic solvents.
The production of Mycophenolate mofetil in the said invention can
also be carried out in the absence of inert organic solvents.
In the present invention the production of Mycophenolate mofetil is
by direct esterification, and product can be isolated directly from the
solvent system. The purity of the product isolated is more than 99%.
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Recrystalisation further in isobutyl acetate yielded Mycophenolate mofetil of EP grade.
The esterification reaction can be carried out at temperature ranging from room temperature to reflux preferably at 40-60° C wherein the reaction completes in moderate time. The production of Mycophenolate mofetil according to one of the embodiment of present invention is shown in the following scheme (I).
Scheme (I)

CH3
COOH ^^-^^^N O N, N - Carbonyl dimidazole
^ ' Organic Solvents

OCH3 CH3

The present invention is further described in detail with reference to the following examples, which is given for illustration only and therefore should not be construed as limitation to the scope of invention.

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EXAMPLE 1:
To a solution of Mycophenolic acid (10g) in toluene 100 mL, morpholine-2-ethanol (4.5mL) is added. To this solution, a reagent N,N-Carbonyl diimidazole (5.58 g) is added. The reaction mixture was stirred at 40-50° C 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 30-50° C afforded oily residue. The oily residue was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil (8.3g). Purity of Mycophenolate mofetil obtained is >99%.
EXAMPLE 2:
To a solution of Mycophenolic acid (10g) in xylene 100 mL, morpholine-2-ethanol (4.5mL) is added. To this solution, a reagent N,N-Carbonyl diimidazole (5.58g) is added. The reaction mixture was stirred at 40-50° C 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 25-30° C afforded oily residue. The oily residue was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil (8.1g). Purity of Mycophenolate mofetil obtained is > 99%
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EXAMPLE 3:
To a solution of Mycophenolic acid (10g) in ethyl acetate 100 mL, morpholine-2-ethanol (4.5mL) is added. To this solution, a reagent N,N-Carbonyl diimidazole (5.58g) is added. The reaction mixture was stirred at 40-50° C for about 10 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 30-50° C afforded oily residue. The oily residue was precipitated in Cyclohexane to yield off white solid as Mycophenolate mofetil (8.4g). Purity of Mycophenolic mofetil obtained is >99%.
EXAMPLE 4:
To a solution of Mycophenolic acid (5gm) morpholine-2-ethanol (4.5 mL) is added. To this solution, a reagent N, N- Carbonyl diimidazole (5.58g) is added. The reaction mixture was stirred at 40-50° C for about 24 hrs till the reaction is completed. Usual workup involves washing of organic layer with 5% sodium bicarbonate solution and the organic layer separated was precipitated in Cyclohexane to yield off white solid as Mycophenolate Mofetil (8.1g). Purity of Mycophenolic mofetil obtained is >99%.
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We claim,
1. A novel process for preparation of Mycophenolate Mofetil of formula I, involving condensation of Mycophenolic acid with morpholine-2-ethanol in presence of reagent N, N-Carbonyl diimidazole.
2. A novel process as claimed in claim 1, wherein the catalyst reagent used is N, N- Carbonyl diimidazole.
3. A novel process as claimed in claim 1, wherein the inert organic solvents are selected from hydrocarbon, halogenated solvent and the like or mixtures thereof.
4. A novel process as claimed in claim 1, wherein the inert organic solvents are selected from toluene, xylene, hexane, heptane, cumene, dichloromethane, chloroform, dichloroethane, esters like ethyl acetate, isobutyl acetate and the like or mixtures thereof.
5. A novel process as claimed in claim 1, wherein the reaction is carried out at temperature between 20 to 200° C.
6. A novel process as claimed in claim 1, wherein the reaction is carried out at temperature preferably between 40 to 60° C.
7. A novel process as claimed as herein described with foregoing description and examples.
Dated this on 24th day of June, 2006.
For, CONCORD BIOTECH LIMITED
Ms. Dipal Rajesh Dhabhai
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ABSTRACT
The present invention describes a novel process for the production of Mycophenolate mofetil. The reaction between Mycophenolic acid with morpholino-2-ethanol in presence of reagent N,N-Carbonyl diimidazole with or without using inert organic solvents such as hydrocarbon; halogenated solvent and the like or mixtures thereof; toluene, xylene, hexane, heptane, cumene, dichloromethane, chloroform, dichloroethane, esters like ethylacetate, isobutyl acetate and the like or mixtures thereof. The reaction is carried out at temperature from about 20 to 200° C, preferably at 40 to 60° C. The condensation reagent N,N-Carbonyl diimidazole lowers the reaction timing and lowers reaction temperature without causing any impurity formation.