Methods of producing esters of mycophenolate

Details Methods of producing esters of mycophenolate Methods of producing esters of mycophenolate

2001-06-07

2004-03-23

Kifle, Bruck (Department: 1624)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing heterocyclic carbon compound having only o, n, s,...

C544S153000

Reexamination Certificate

active

06709846

ABSTRACT:

This invention relates to an improved process for the manufacture of Mycophenolate Mofetil by a biochemical method using enzymes or chemically without the use of any catalyst
BACKGROUND
Mycophenolate mofetil of formula I is the morpholinoethyl ester of Mycophenolic acid (MPA).
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, the pharmaceutically acceptable salt thereof is used as an immunosuppressive agent, antiinflammatory, anti-tumor and anti-viral agent.
Chemical synthesis route for the manufacture of Mycophenolate mofetil already exists. An acid halide condensation route for the synthesizing the Mycophenolate mofetil has been described in U.S. Pat No. 4,753,935; which requires two steps and has a high dimeric impurity(2%) among others requiring additional recrystallization step. Those skilled in the field of esterification reactions will appreciate that the conventional teachings for the synthesis of an ester through the reaction of an acid and an alcohol require the use of a chemical catalyst to achieve acceptable yields. Furthermore, catalytic reaction entail the added cost of the catalyst and the additional steps of its addition and separation from the reaction mixture. The direct esterification of mycophenolic acid without any catalyst too has been disclosed in U.S. Pat. No. 5,247,083, in which the reaction is carried out in the presence of an inert organic solvent.
It has surprisingly been discovered that good yields of mycophenolate mofetil can be obtained without the disadvantage of prior described methods, without the use of a third organic solvent and without the use of chemical catalysts. It has also been found that it is possible to produce mycophenolate mofetil under very mild conditions using enzymes, in the presence of water and organic solvents and no other chemical catalysts. These processes reduce the chances of unwanted side reaction and lead to purer products.
SUMMARY OF THE INVENTION
The present invention concerns methods for making Mycophenolate mofetil by:
(i) reacting the Mycophenoiic acid and a molar excess of 2-morpholino ethanol in an organic solvent along with an enzyme and an appropriate quantity of water.
(ii) refluxing Mycophenolic acid with a large excess of 2-morpholino ethanol in the absence of any other organic solvent or a catalyst.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a process for the conversion of Mycophenolic acid and 2-morpholino ethanol into Mycophenolate Mofetil.
According to one method of this invention the substrates, MPA and 2-morpholino ethanol are added in an organic solvent or a mixture of more than one organic solvents water is added to the system to adjust the water content and pH in the microenvironment, enzyme is added to this system, the mixture is incubated at a temperature between 20 to 55 deg C., the reaction is carried out for a time upto 120 hr, the esterified product is analyzed by HPLC method.
The MPA is used in a concentration range of 0.03 to 5%. The 2-morpliolino ethanol is used in molar equivalent of 1 to 15 with respect to MPA. The MPA and 2-morpholino ethanol are added to the organic solvent or mixture of organic solvents more than one, where the organic solvent is a C6-C12 alkane such as iso-octane, n-hexane, cyclohexane, heptane, octane or a C2-C12 alcohol such as ethanol, propanol, 2-propanol, hexanol, octanol, or isopropanol. A surfactant is added to the organic solvent or in the mixture of the organic solvents which is Sodium bis (ethylhexyl) sulfosuccinate (Aerosol OT or AOT), Cetyl trimethyl ammonium bromide or Trimethyl octyl ammonium chloride (TOMAC). The water content (Wo), which is the molar ratio of the water to the surfactant, is adjusted to a value in the range of 1 to 30. The pH of the microenvironment is adjusted in a range of 3 to 8 using buffer such as acetate or phosphate buffer. The enzyme, which is used for the bioconversion is a hydrolase which may be lipase cutinase, esterase or a protease from microbial, animal or plant origin. The enzyme is added in organic solvent in absence or presence of a surfactant. The reaction is carried out at a temperature in a range of 20 to 55 deg C. The time period of reaction is upto 120 hrs. The esterified product is analyzed by HPLC method.
Another method for producing mycophenolate mofetil comprises heating and or refluxing MPA (mycophenolic acid) with a large excess of 2-morpholino ethanol in the absence of any other organic solvent or catalyst. The MPA is heated and optionally refluxed with a large excess of 2-morphoiino ethanol at a temperature between 80 to 150 deg C. The reaction is carried out for a time period of 6 to 120 hrs.
Both of these methods are illustrated with examples below which are not intended to be limiting.


REFERENCES:
patent: 4753935 (1988-06-01), Nelson et al.
patent: 5247083 (1993-09-01), Knox et al.
patent: WO 95/07902 (1995-03-01), None

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