RU2277090C9 - Method for preparing mycophenolic acid sodium salt representing immunosuppressant agent - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing mycophenolic acid sodium salt representing an immunosuppressant agent of the formula (I):

. Method involves interaction of acid of the formula (I) with (C₂-C₁₀)-carboxylic acid sodium salt. Method provides preparing mycophenolic acid sodium salt with the high yield.

EFFECT: improved preparing method.

6 cl, 6 ex

Description

FIELD OF THE INVENTION

The present invention provides a method for producing the sodium salt of a compound of formula I.

State of the art

Mycophenolic acid is an immunosuppressant that inhibits the synthesis of de novo purine nucleotides by inhibiting IMP (inosine monophosphate) dehydrogenase and inhibits the formation of HMP (xanthosine monophosphate) and GMP (guanosine monophosphate).

Existing patent and non-patent literature have widely discussed the use of mycophenolic acid sodium salt or ERL 080 in the treatment of diseases and in transplantation.

The use of mycophenolic acid sodium salt in the treatment of hyperuricemia is presented in US Pat. No. 3,705,946. US Pat. Nos. 6,025,391 and 6,172,107 describe an enteric coated composition. In US Pat. No. 6,025,391, an enteric coating composition comprising HPMC (hydroxypropyl methylcellulose) phthalate and triacetin is formulated for capsules that contain monosodium mycophenolate adapted to release mycophenolate in the upper intestine.

South African patent 6814951 relates to the sodium salt of MPA (mycophenolic acid).

Toxicology, 157, 207-215 (2001) reviewed materials regarding the tolerance profile of sodium mycophenolate and mofetil mycophenolate in combination with cyclosporine or without cyclosporine.

Acta Crystallographica (Section C: Crystal Structure Communications, C56 (4), 432-433 (2000)) presents materials on the crystalline structure of sodium mycophenolate.

Disclosure of invention

The present invention discloses a method for preparing the sodium salt of a compound of formula I, which comprises reacting a compound of formula I with a sodium salt of a C ₂ -C ₁₀ carboxylic acid.

The implementation of the invention

The invention describes a method for preparing the sodium salt of a compound of formula I

by reaction of a compound of formula I with a sodium salt of a C ₂ -C ₁₀ carboxylic acid.

Alternatively, a compound of formula I can be converted to its ammonium or dibenzylamine form by reacting a compound of formula I with a sodium salt of a C ₂ -C ₁₀ carboxylic acid.

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

A dibenzylamine or dicyclohexylamine salt of a compound of formula I is prepared by reaction with dibenzylamine or dicyclohexylamine, respectively.

The C ₂ -C ₁₀ carboxylic acid sodium salt is selected from sodium acetate, sodium 2-ethylhexanoate or sodium caprylate.

The compound of formula I is converted to its ammonium salt by reaction with ammonia. To obtain the sodium salt of a compound of formula I, the ammonium salt of a compound of formula I is reacted with sodium acetate or sodium 2-ethylhexanoate, or sodium caprylate.

The following Examples further illustrate the invention. It should be understood that it is not intended to limit the invention to the details given in this context.

EXAMPLE 1

10 g of sodium acetate are dissolved in 55 ml of methanol. To this solution was added 74 g of mycophenolic acid and stirred for half an hour at room temperature. The contents are cooled to 10 ° C and filtered. The solid is washed with 50 ml of acetone and dried under vacuum at a temperature of 40-50 ° C. The final yield is 90% (70 g).

EXAMPLE 2

To a suspension of mycophenolic acid (25 g) in 125 ml of methanol, 15.5 g of dicyclohexylamine in 25 ml of methanol are slowly added dropwise. The reaction mixture was cooled to approximately 5 ° C and stirred for one hour. Then the precipitated solid is filtered and dried (yield 31 g), and then treated with an aqueous solution of sodium acetate (5.6 g of sodium acetate in 100 ml of water) with stirring at room temperature for half an hour. The reaction mixture was cooled to 0 ° C, and the precipitated solid was filtered and dried in vacuo (yield 19 g).

EXAMPLE 3

25 g of sodium 2-ethylcaprylate are dissolved in 175 ml of methanol. To this solution, 250 g of mycophenolic acid was added and stirred for half an hour at room temperature. The contents are cooled to 10 ° C and filtered. The solid is washed with 50 ml of acetone and dried under vacuum at a temperature of 40-50 ° C. The final yield is 90% (22 g).

EXAMPLE 4

25 g of sodium 2-ethylhexanoate are dissolved in 175 ml of ethyl acetate. To this solution, 250 g of mycophenolic acid was added and stirred for half an hour at room temperature. The contents are cooled to 10 ° C and filtered. The solid is washed with 50 ml of acetone and dried under vacuum at a temperature of 40-50 ° C. The final yield is 90% (22 g).

EXAMPLE 5

Take 100 g of mycophenolic acid in 175 ml of methanol and mix for half an hour at room temperature. The solution was bubbled with ammonia gas for 30 minutes, followed by the addition of an aqueous solution of sodium acetate. The contents are cooled to 10 ° C and filtered. The solid is washed with 50 ml of acetone and dried under vacuum at a temperature of 40-50 ° C. The final yield is 90% (95 g)

EXAMPLE 6

To a suspension of mycophenolic acid (25 g) in 250 ml of ethyl acetate was added 17 g of dibenzylamine in 25 ml of ethyl acetate. The reaction mixture was cooled to approximately 5 ° C and stirred for one hour. Then, the precipitated solid is filtered off, washed with ethyl acetate and dried to obtain 34 g of a dibenzylamine salt. Then, the obtained salt is treated with an aqueous solution of sodium acetate (5.9 g of sodium acetate in 100 ml of water) with stirring at room temperature for half an hour. The reaction mixture was cooled to 0 ° C., and the precipitated solid was filtered and dried in vacuo to yield 23 g.

Claims (6)

1. The method of preparation of the sodium salt of the compounds of formula I, characterized in that the reaction of the compounds of formula I

with the sodium salt of a C ₂ -C ₁₀ carboxylic acid. 2. The method according to claim 1, characterized in that the compound of formula I is converted to an ammonium salt, or a dibenzylamine salt, or a dicyclohexylamine salt before converting it to the sodium salt. 3. The method according to claim 2, characterized in that the compound of formula I is converted into its ammonium salt by treatment with ammonia. 4. The method according to claim 2, characterized in that the dibenzylamine salt of the compounds of formula I is obtained by reaction with dibenzylamine. 5. The method according to claim 2, characterized in that the dicyclohexylamine salt of the compound of formula I is obtained by reaction with dicyclohexylamine. 6. The method according to claim 1, characterized in that the sodium salt of a C ₂ -C ₁₀ carboxylic acid is selected from sodium acetate, sodium 1-ethylhexanoate or sodium caprylate.