FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED PROCESS FOR THE PREPARATION OF MYCOPHENOLATE MOFETIL"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Research Centre, "Zydus Tower", Satellite Cross Roads, Ahmedabad-380015, Gujarat, India.
The following specification particularly describes the nature of the invention:


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FIELD OF INVENTION
The present invention relates to the preparation of Mycophenolate Mofetil and in particular the process for the preparation of Mycophenolate Mofetil and its subsequent purification, which improves the purity of the product.
BACKGROUND OF THE INVENTION
Mycophenolate mofetil is the morpholinoethyl ester of Mycophenolic acid; it has the following formula (I).

Mycophenolate mofetil
Mycophenolate mofetil is an immunosuppressant. It is derived from mycophenolic acid which was isolated from a fungus and chemically modified to improve oral absorption. Mycophenolate mofetil and its pharmaceutically acceptable salt thereof is used as an immunosuppresive agent, anti-inflammatory, anti-tumor and anti-viral agent.
US 4753935 discloses Mycophenolate mofetil and also describes three different routes for synthesis. One of the routes disclosed therein is an acid halide condensation route (Scheme-1), which requires two steps and has a high dimeric impurity, requiring a subsequent recrystallization step. Color problem with the finished product is also associated with this synthetic route due to trace iron contamination. Use of thionyl chloride in the acid chloride step causes corrosion of plant and reactors.
A second carbodiimide route is also disclosed in the same patent. This route has proven impractical for the synthesis of pharmaceutical grade Mycophenolate mofetil due to unacceptable percentage of impurity in the final product.


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CH3
l.SOCl2
2- O N-CH2CH2OH

Scheme 1
Preparation of Mycophenolate mofetil via the direct esterification of mycophenolic acid in organic solvents that are capable of removing water during the course of the reaction is also disclosed in various patents. Thus, US 5247083 describes preparation of Mycophenolate mofetil by refluxing Mycophenolic acid (MPA) and 2-morpholinoethanol in solvents such as toluene, xylene and dichloro methane or their mixtures with azeotropic water separation. The disadvantages of this process are long reaction period necessary to reach sufficient conversion depending on the solvent used (about 60 to 100 hrs) and presence of color in the product (light violet crystal).
WO 0034503 discloses biochemical synthesis of Mycophenolate mofetil as well as chemical synthesis of Mycophenolate mofetil without the use of. catalyst. The synthesis according to this specification also takes a long time, in hours or days for completion and when converting MPA to Mycophenolate mofetil, it was observed that a large part of the MPA is left unconverted, and impurities are formed.
WO 02100855 teaches the use of high boiling dialkyl ethers such as dibutyl ether as solvents. This route also suffers from the disadvantages described above like long reaction periods and formation of colored Mycophenolate mofetil.
WO 2004089946 disclosed synthesis of Mycophenolate mofetil using microwave irradiation. Obviously, the process is costly and difficult to practice on an industrial scale. WO 2003042393, WO '2000034503 and WO 2006024582 describes synthesis of Mycophenolate mofetil using enzyme as catalyst but there are several disadvantages of the use of enzymatic catalysis on an industrial scale, for instance in terms of volume, work-up and overall cost.


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US 20040167130 disclosed a process for making Mycophenolate mofetil comprising the transesterification of mycophenolic acid with 2-(4-morpholinyl) ethanol using a catalyst selected from an alkaline or alkaline earth metal salt, tin oxide or stannous oxide. This method suffer from the disadvantage that the document only describes the use of one catalyst, dibutyl tin oxide, which is highly toxic, an irritant and expensive. No other alkaline or alkaline earth metal catalyst is used and no other example are found in the application.
WO 2005023791 describes a process for making Mycophenolate mofetil as well as purification of Mycophenolate mofetil by treating it with a primary or secondary amine. In this process also the reaction takes place under acidic reaction condition.
WO 2006076802 describes a process for making Mycophenolate mofetil using Zn and Ca salt or oxide as catalyst but this route also suffer from the disadvantage like long reaction time.
WO 2005105769 discloses a specific impurity 2-(4-morpholinyl)ethyl (E)-6-(l,3-dihydro-4-[2-(4-morpholinyl)ethoxy]-6-methoxy-7-methyl-3-oxo-isobenzofuran-5-yl)-4-methyl-hex-4-enolate(bismorpholine) formed during the synthesis of Mycophenolate mofetil.
The application also describes the routes of the synthesis of the impurity and the characterization of the impurity formed. However it does not describe process for removing the impurity.
Thus, there remains a need for developing a process which overcomes one or more of the deficiencies of the prior art and thereby develop a modified process for preparing Mycophenolate mofetil which gives better yields, improved purity and reduces the overall reaction time. Further, in the prior art most or all the processes for making Mycophenolate mofetil take place under acidic or thermal reaction conditions. We herein disclose an improved process for preparing Mycophenolate mofetil using basic reaction conditions, which reduces the reaction time and gives better purity.
OBJECTS OF THE INVENTION
It is an object of the present invention is to provide an improved processes for preparing Mycophenolate mofetil.
In an embodiment is provided a purification process for preparing Mycophenolate mofetil with better purity.
In a further embodiment is provided a process for preparing Mycophenolate mofetil using novel intermediates. The above and other embodiments are further described in the following paragraphs.


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DETAILED DESCRIPTION
The improved process for preparing Mycophenolate mofetil is described in the following scheme:
Scheme: 2

Kl, solvent,reflux
OM
OH
MHCO3-

HClL^o
M = Na, K

The mycophenolic acid was converted to the corresponding metal salt (sodium or potassium) by reacting it with alkali metal carbonates and bicarbonates in polar solvents (e.g. acetonitrile, acetone, DMF, DMSO etc). The metal salt formed was reacted insitu with chloroethyl morpholine hydrochloride (1-3 mol.eq.), with or without catalyst (potassium iodide or sodium iodide), at temperature ranging from 45 to 180 C, to get E-6-(l,3-dihydro-4-hydroxy-6methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid 2-morpholin-4-yl-ethyl ester. Mycophenolate mofetil formed by this method have purity almost 85-97 % with 0.1-5 % impurity of 6-[6-Methoxy-7-methyl-4-(2-morpholin-4-yl-ethoxy)-3-oxo-l,3 dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-morpholin-4-yl-ethyl ester (Bismorpholine compound), which can be removed by treating crude mycophenolate mofetil with weak organic acids such as citric acid, fumaric acid, malic acid, maleic acid and the like, used alone or in combination.
The invention thus describes preparation and purification of mycophenolate mofetil.
The invention is further described by following examples, which are provided for illustration only and should not be construed to limit the scope of invention.
Example 1
Preparation and purification of E-6-(l<3-dihvdro-4-hydroxv-6methoxv-7-methvl-3-oxo-5-isobenzofuranvD-4-methvl-4-hexenoic acid 2-morpholin-4-yl-ethvl ester.
A mixture of mycophenolic acid (l0g), sodium bicarbonate (5.8g) and 150ml acetonitrile was stirred at 55 °C for 10 min. Then into it 140mg of potassium iodide, 5.8g chloroethyl morpholine hydrochloride added and it was refluxed for 25h. It was cooled to
room temperature. After suitable work up E-6-(l,3-dihydro-4-hydroxy-6methoxy-7-methyl-


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3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid 2-morpholin-4-yl-ethyl ester was obtained (12.8g), having 1.8 % impurity of 6-[6-Methoxy-7-methyl-4-(2-morpholin-4-yl-ethoxy)-3-oxo-l,3 dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-morpholin-4-yl-ethyl ester. This impurity was removed by washing mycophenolate mofetil with citric acid, which on further purification gave >99% purity.
Example 2
Preparation of E-6-d ,3-dihydro-4-hvdroxv-6methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid 2-morpholin-4-vl-ethyl ester
A mixture of mycophenolic acid (2.5g), sodium bicarbonate (1.96g) and 37ml acetone was stirred at 45 °C for 15 min. Then into it 1.45g chloroethyl morpholine hydrochloride was added and refluxed for 4h. Again into the mixture 1.45g of chloroethyl morpholine was added and it was refluxed for 24 h. The reaction mixture was cooled to room temperature. After suitable work up E-6-(l,3-dihydro-4-hydroxy-6methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid 2-morpholin-4-yl-ethyl ester obtained (3.5g; % HPLC=83 %), which on further purification as in Example 1, gave >99% purity.
Example 3
Preparation of E-6-0.3-dihvdro-4-hydroxv-6methoxv-7-methvl-3-oxo-5-isobenzofuranyl)-4-methvl-4-hexenoic acid 2-morpholin-4-vl-ethvl ester, reacting mycophenolic acid with chloroethyl morpholine.
A mixture of mycophenolic acid (2.5g), sodium bicarbonate (1.44g) and 12.5ml DMF was stirred at room temperature for 15 min. Then into it 1.45g chloroethyl morpholine hydrochloride was added and it was heated for 34h at 130 °C. The reaction mixture was cooled to room temperature. After suitable work up E-6-(l,3-dihydro-4-hydroxy-6methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid 2-morpholin-4-yl-ethyl ester obtained (2.5g %; HPLC=65.5%), which on further purification as in Example 1 gave >99% purity.
Example 4
Preparation of E-6-(,1.3-dihydro-4-hydroxv-6methoxy-7-methyl-3-oxo-5-isobenzofuranvn-4-methyl-4-hexenoic acid 2-morpholin-4-yl-ethvl ester.
A mixture of mycophenolic acid (2.5g), sodium bicarbonate (1.44g) and 12.5ml DMSO was stirred at room temperature for 15 min. Then into it 1.45g chloroethyl morpholine hydrochloride was added and it was heated for 12h at 70 C. The mixture was then cooled to room temperature. After suitable work up E-6-(l,3-dihydro-4-hydroxy-6methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid 2-morpholin-4-yl-


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ethyl ester obtained(2.5g; % HPLC=68%), which on further purification as in Example 1,