TITLE OF INVENTION
MICROWAVE SYNTHESIS OF MYCOPHENOLATE
MOFETIL
FIELD OF INVENTION
This invention relates to a method for chemical synthesis of mycophenolate mofetil (MMF) using microwave. More particularly, the present invention relates to a process for synthesis of MMF by reacting mycophenolic acid (MPA) and 2-hydroxy ethyl morpholine (HEM) under microwave irradiation. BACKGROUND INFORMATION
MMF is the morpholino ethyl derivative of MPA.
MMF is an immunosuppressant It is derived from MPA, which was isolated from a fungus and chemically modified to improve oral absorption. MMF is used as an immunosuppressive agent, antiinflammatory, anti-tumor and anti-viral agent.
Chemical synthesis route for the manufacture of MMF is prior art. An acid halide condensation route for the synthesizing the MMF has been described in US 4,753,935; which requires two steps and has a high dimeric impurity.
The carbodiimide route described in the US 4,753,935 has unacceptable percentage of impurities in the final product making the process impractical.
The direct preparation of MPA without any catalyst too has been disclosed in US 5,247,083, in which the synthesis is carried out in the presence of an inert organic solvent, which takes a very long time i.e. in hours 30 to 100.
WO 00/34503 discloses biochemical synthesis of MMF as well as chemical synthesis of MMF without the use of catalyst and a third

solvent, but the synthesis takes a long time i.e. in hours or days to completion.
It is therefore important to develop a process for synthesis of MMF which gives purer product with high yields in less time and wherein the reactants, reagents, catalyst and support material are recycled resulting in economy of the cost Use of high concentrations of reactants also increases the economy of the cost per batch.
Microwave ovens have been utilized for rapid heating domestically for several years, it is only recendy that their use for batch-wise organic synthesis has been reported. It has been demonstrated that microwave heating can provide a means for dramatically increasing the rate of reactions.
US 3,535,482 discloses microwave apparatus for rapidly heating fluids, namely foods such as fruit juice, soup, puree, etc. for blanching, concentrating, pasteurization and sterilization.
GB 1 425 624 discloses chemical modification of starch which is carried out by subjecting a mixture of starch and modifying agents to microwave energy such that the water content during radiation is <10 wt % of the starch, or is reduced to this value.
US 4,599,365 discloses preparation of polyimide foam by (a) reacting an aromatic di-anhydride with an oximine in a mole ratio of (II):(I) of 0.05-1.5:1 (x=2-4) to form an N-substituted aliphatic imide; (b) dissolving the imide in a reactive solvent esterifying agent; (c) adding a diamine to the esterified imide; (d) drying the resulting solution.; and (e) exposing the material to microwave energy at a level of 5-80 KW, pref. at an optimum level of 10 KW for 10 min to spontaneously foam and cure the material.
WO 92/19390 discloses production of an adhesive mass

composition comprising reacting by microwave heating of (pref. 5-50 wt. %) of a first component of a copolymer of formula (T) with (pref. 5-50 wt. %) of a second component comprising a hydroxylated compound capable of hydrolyzing or esterifying the first component in the presence of water and optionally a surfactant.
GB 2 361 918 discloses activation of mono- and bi-saccharides and hydrolysis of triglycerides contained in natural chemical substances, which involves irradiating the substances with microwaves. The reactions are performed in absence of solvent.
There are no reports on synthesis of MMF using microwave. It has surprisingly been discovered that good yields of MMF can be obtained without the disadvantage of prior described methods, very long time for the process to complete as well as high impurity levels.
The process of instant invention is advantageous in following ways a) very less synthesis time e.g. in minutes to a few hours, b) eco-friendly process c) economic process d) non-corrosive process e) pure product and £) high yields.
SUMMARY OF THE INVENTION
Accordingly the present invention provides a process for the synthesis of MMF (FORMULA I).

FORMULA I

Said process comprises treating the MPA and HEM in a solvent or solvent free system under the microwave radiation in the absence or presence of a catalyst and a support. The said process comprises
a) treating MPA and HEM in a solvent or solvent free system
b) optionally, treating mixture of MPA and HEM with a catalyst
c) optionally, treating MPA and HEM with a solid support DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a process of preparation of MMF by treating MPA and HEM under microwave irradiation.
MMF is synthesized by treatment of MPA with HEM in absence or presence of solvent system in absence or presence of catalyst and solid support.
In one embodiment of the invention, the synthesis is carried out in a solvent system. The solvent used is anhydrous. The solvent used is a mixture of solvents. The solvent is selected from a group comprising C2 to C12 hydrocarbon, aliphatic or cyclic or heterocyclic solvents. The solvent is selected from one or more among benzene, toluene, xylene, hexane, pentane, heptane, or pyridine.
In a further embodiment the synthesis is carried out in solvent free system.
In another embodiment, the catalyst used is acidic. The catalyst is selected from a group comprising mineral acid, carboxylic acid, and phenol. The catalyst is selected from a group comprising hydrochloric acid, sulphuric acid, nitric acid, sulphonic acid, phosphoric acid or derivatives thereof.
In another embodiment, the support used is selected from a group comprising diatomaceous earth, polymeric material or carbon. The

support is selected from a group comprising bentonite, zeolite, silica, charcoal, carbon or Montmorrillonite.
In yet another embodiment of the invention, the synthesis is carried out for a time period between 1 to 600 minutes.
By using a solvent system the yields of the synthesis were higher than yields of a synthesis without solvent system.
By using a catalyst, the yields of the synthesis were higher than yields of a synthesis without catalyst system.
By using solid support the yields of the synthesis were higher than yields of a synthesis without solid support.
By using a solvent system, catalyst and solid support the yields were the highest
The reactants, reagents and support material can be recycled many times to increase the yields further and increase the economy of the cost
The method is illustrated with examples below, which, are not intended to be limiting. EXAMPLE 1
Synthesis of MMF in solvent system, without catalyst and with support.
ImM of MP A and 3mM of HEM taken in a 50ml beaker and added to 0.1 g silica gel in 2ml of Toluene and mixed well. The mixture was exposed to microwave radiation at 1000W for 30 minutes. The yield of MMF was calculated from HPLC assay to 24%.

EXAMPLE 2
Synthesis of MMF in mixture of solvent, without catalyst and
without support.
ImM of MPA and 3mM of HEM taken in a 50 ml beaker and added 2ml of Toluene and Xylene (5:1). The mixture was exposed to microwave radiation at 1000W for 30 minutes. The yield of MMF was is 23 %.
EXAMPLE 3 Synthesis of MMF in solvent system, with catalyst and without
support
ImM of MPA and 3 mM of HEM taken in an open 250ml beaker and added 50 ml of Toluene and 0.05ml of Sulfuric acid. The mixture was exposed to microwave radiation in at 1000W for 30 minutes. The yield of MMF was 37.3% EXAMPLE 4 Synthesis of MMF in solvent free system, without catalyst and with
support
ImM of MPA and 3mM of HEM taken in an open 250 ml beaker and added 2g bentonite, mixed well with small amount of solvent Allowed the solvent to evaporate. The mixture was irradiated under microwave for 30 minutes. The yield of MMF was 10 % EXAMPLE 5
Synthesis of MMF in mixture of solvent, with catalyst and with support
ImM of MPA and 3mM of HEM taken in a 250ml beaker and added to 0.05ml sulphuric acid and 2g silica gel in 50ml toluene. The mixture was irradiated under microwave for 30 minutes. The yield of MMF was 57 %.

EXAMPLE 6
Synthesis of MMF in solvent free system, without catalyst and with
support with extended time.
ImM of MPA and 3mM of HEM taken in an open 250ml beaker and added 2g silica, mixed well with small amount of solvent. Allowed the solvent to evsiporate. The mixture was irradiated under microwave for 100 minutes. The yield of MMF was 52%

aWE CLAIM
1. A process for the synthesis of compound of formula I

FORMULA I
said process comprising treating mycophenolic acid or it's salt with 2-
hydroxy ethyl morpholine under microwave irradiation
2. A process as in claim 1, wherein the synthesis is carried out in absence of solvent
3. A process as in claim 1, wherein the synthesis is carried out in presence of a solvent system.
4. A process as in claim 3, wherein the solvent system is a mixture of more than one solvents.
5. A process as in claim 4, wherein the solvent is selected from a group comprising C2 to C12 hydrocarbon, aliphatic or cyclic or heterocyclic solvents.
6. A process as in claim 5, wherein the solvent is selected from one or more among benzene, toluene, xylene, hexane, pentane, heptane, or pyridine.
7. A process as in claim 1, wherein the synthesis is carried out in presence of a catalyst.

8. A process as in claim 7, wherein the catalyst used is an acid.
9. A process as in claim 8 wherein the catalyst is selected from a

group comprising hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, p-toluene sulphonic acid, methane sulphonic acid, pivalic acid or tri-fluoro acetic acid.
10. A process as in claim 1, wherein the synthesis is carried'out in
presence of a support.
11. A process as in claim 10, wherein the support used is
diatomaceous earth material.
12. A process as in claim 11, wherein the support is selected from a
group comprising silica, bentonite or Montmorrillonite.
13. A process as in claim 10, wherein the support is activated carbon,
charcoal, natural or synthetic polymer.
14. A process as in claim 1, wherein the synthesis is carried out for a
time period between 1 to 600 minutes.