FIELD OF INVENTION:
The present invention provides a method for producing the sodium salt of mycophenolic acid of Formula I.

BACKGROUND OF THE INVENTION

Mycophenolic acid is an immunosuppressive agent that inhibits de nova purine nucleotide synthesis via inhibition of IMP dehydrogenase and prevents the formation of XMP and GMP.

Sodium salt of Mycophelolic acid or ERL 080 has been widely discussed in available patent and no-patent literature in treatment o diseases and in transplantation.

Use of Sodium Salt of Mycophelolic acid in treatment of hyperuricaemia has been reported in U.S. patent no. 3,705,946. 6,172,107 and US Patent Nos. 6,025,391 describes an enteric coating composition. In US Patent No. 6025391 the enteric coating composition contains HPMC phthalate and triacetin prepared for capsules containing monosodium Mycophenolate, adapted to release Mycophenolate in the upper part of the intestinal tract.

South African Patent no. 6814951 relates to the Sodium salt of MPA.

Tolerability profile of sodium mycophenolate and mycophenolate mofetil with and without cyclosporin has been discussed in Toxicology 157(2001) 207-15.

Che Journal Acta Crystallographica, Section C: Crystal Structure Communication (2000), C56 (4), 432-433 discusses Crystal structure of Sodium mycophenolate.

Mycophenolate sodium represents an alternative to the significant number of patients suffering from the common gastrointestinal intolerance associated with use of MMF. MMF was introduced commercially as an immunosuppressant for the treatment or prevention of organ or tissue transplant rejection, at daily dosages of from about 200 mg to about 3 grams. Patient compliance with MMF is not ideal because of side-effects e.g.gastro-intestinal disorder. US 6025,391 discloses that there is considerably higher bioavailability than MPA (100% for MMF and 43% for MPA). Again the report by Monica Zolezzi shows higher availability of MPA in using enteric-coated mycophenolate sodium (ECMS) than MMF and lesser side effects.

In October 2002 enteric-coated mycophenolate sodium (ECMS) (Myofortic®, Novartis Inc.) received the first regulatory approval in Switzerland, in April 2003 it was approved by the Saudi Arabian Ministry of Health. Since then, ECMS has gained approval in more than 36 countries around the world. ECMS also complied with the European Mutual Recognition Procedure (MRP) and was approved of the prevention of acute rejection in kidney allografts in adult patients in February 2004. Also, in March 2004, the U.S. Food and Drug Administration (FDA) approved it to be used in combination with cyclosporine and corticosteriods to prevent organ rejection in kidney transplant patients.

SUMMARY OF THE INVENTION:

The instant invention reveals a process for manufacture of Sodium salt of the compound of formula I, which comprise reacting the compound of formula I with one among dicyclohexyl amine, dibenzylamine or ammonia to provide an intermediate of a dicyclohexyl amine salt, a dibenzylamine salt or an ammonium salt, reacting the intermediate salt with a sodium salt of C2 to C10 carboxylic acid to afford sodium salt of MPA.

DETAILED DESCRIPTION OF THE INVENTION:

The instant invention describes a process of manufacturing sodium salt of the compound of formula I comprising:

c. reacting the compound of formula I with one among dicyclohexyl amine, dibenzylamine or ammonia to provide an intermediate of a dicyclohexyl amine salt, a dibenzylamine salt or an ammonium salt,

d. reacting the intermediate salt with a sodium salt of C2 to C10 carboxylic acid to afford sodium salt of MPA.

The compound of formula I is converted to its ammonium salt by treating with ammonia.

The dibenzyl amine salt of the compound of formula I is prepared by reacting with dibenzyl amine.

The sodium salt of C2 to C10 carboxylic acid is selected from sodium acetate, sodium 2-ethyl hexanoate or sodium caprylate.

The compound of formula I is converted to its ammonium salt by reacting with ammonia. The ammonium salt of formula I is reacted with sodium acetate or sodium 2-ethyl hexanoate or sodium caprylate to get the sodium salt of the
compound of formula I. v

The following Examples further illustrate the invention, it being understood that the invention is not intended to be limited by the details disclosed therein.

EXAMPLE 1:

To slurry of mycophenolic acid (25g) in methanol, dicyclohexyl amine was added and stirred at RT. The precipitated solid was then treated with aqueous sodium acetate solution under stirring RT. The reaction mixture was cooled to 10 °C and the precipitated solid was filtered and dried.

EXAMPLE 2:
100g of mycophenolic acid was taken in 175 ml of methanol and was stirred for half an hour at RT. Ammonia gas was bubbled for 30 min followed by addition of aqueous sodium acetate. The contents were chilled to 10°C and filtered. The solid are washed with 50 ml acetone, dried under vacuum at 40 to 50°C. A final yield 90% (95g) was observed.

Example 3:
Mycophenolic acid 25g is taken in 250 ml ethyl acetate added 17 g of Dibenzylamine in 25 ml ethyl acetate. The reaction mixture is chilled to about 5 deg C, stirred for one hour. The solid is filtered, washed with ethyl acetate and dried to get 34 g of DBA salt. 5.9 g of sodium acetate is dissolved in 100 ml water and added the above DBA salt. Stirred for half an hour, chilled to about 0 deg C and filtered. The material is dried under vacuum to get 23 g.

We Claim:

1. A process of manufacturing sodium salt of Mycophenolic acid of formula I comprising,

a. reacting the compound of formula I with one among dicyclohexyl amine, dibenzylamine or ammonia to provide an intermediate of a dicyclohexyl amine salt, a dibenzylamine salt or an ammonium salt,

b. reacting the intermediate salt with a sodium salt of C2 to C10 carboxylic acid to afford sodium salt of mycophenolic acid.

2. The process as claimed in claim 1, wherein sodium salt of C2 to C10 is carboxylic acid is selected from sodium acetate, sodium 2-etlyl hexanoate or sodium caprylate.

3. A process of manufacturing sodium salt of Mycophenolic acid of formula I substantially as herein described with reference to the foregoing examples.