WO2009010503A1

WO2009010503A1 - Mycophenolic acid recycling in a method for the preparation of mycophenolate mofetil

Info

Publication number: WO2009010503A1
Application number: PCT/EP2008/059213
Authority: WO
Inventors: De Robertus Mattheus Pater; Pieter Gijsbert Weber
Original assignee: Dsm Ip Assets B.V.
Priority date: 2007-07-18
Filing date: 2008-07-15
Publication date: 2009-01-22

Abstract

The present invention provides a method for the preparation of mycophenolate mofetil wherein mycophenoiic acid is mixed with 2-morpholinoethanol in a water-immiscible solvent, followed by addition of water and adjustment of the pH to a value ranging from 0 to 3 or ranging from 7 to 10 and separating the organic and aqueous phases. Mycophenolate mofetil is isolated from the relevant phase and the mycophenoiic acid present in the alternate phase is re-used in a conversion of mycophenoiic acid to mycophenolate mofetil.

Description

MYCOPHENOLIC ACID RECYCLING IN A METHOD FOR THE PREPARATION OF

MYCOPHENOLATE MOFETIL

Field of the invention

The present invention relates to a method for the preparation of mycophenolate mofetil.

Background of the invention

Mycophenolic acid (MPA, also known as 6-(4-hydroxy-6-methoxy-7-methyl-3- oxo-5-phthalanyl)-4-methyl-4-hexenoic acid, 6-(1 ,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid, C₁7H₂0O6, CAS 24280-93-1 ) is a compound with various advantageous properties. Next to antibiotic activity, MPA also displays antifungal, antiviral and antitumor properties and the compound has been used in the treatment of psoriasis and recently as immunosuppressant. The 2-morpholinoethyl ester of MPA, also known as mycophenolate mofetil (MPM, C₂3H₃₁NO₇, CAS 128794-94-5), is a prodrug of MPA and has similar advantageous properties. The chemical structure of MPM is:

MPM can be prepared by esterification of MPA with 2-morpholinoethanol. In US 4,753,935 an acid halide condensation route has been described. This is a two-step process requiring toxic reagents for forming the halide of MPA and/or of 2-morpholinoethanol. In EP 649,422 B1 , an improved route was disclosed concerning refluxing MPA with 2-morpholinoethanol in an inert organic solvent capable of azeotropic removal of water, without the use of additional reagents. During esterification of MPA with 2-morpholinoethanol followed by isolation of the resulting MPM, in many cases part of the MPA remains unconverted which leads to a sub-optimal degree of conversion and a relatively low overall yield. The person skilled in the art is aware of the usual methods to overcome this problem, such as prolonged reaction times, increase in reaction temperature, addition of catalysts or one or more reaction components. However, these solutions introduce new problems such as the increased formation of unwanted side products. Particularly in the case of esterification of MPA, the formation of unwanted side products is pronounced when conventional methods to increase the conversion are used. It is believed that this is caused by the formation of dimeric impurities resulting from reaction at the relatively acidic phenolic hydroxyl group in MPA. Hence, the problem associated with the synthesis of MPM is the sub-optimal yield due to insufficient conversion of MPA combined with the formation of unwanted impurities when reaction conditions are modified. Thus there is a need for a more efficient method for preparing MPM from MPA or a salt thereof and 2-morpholinoethanol.

Detailed description of the invention

It was found that the overall yield of the conversion of MPA with 2-morpholinoethanol to MPM could be significantly improved without introduction of additional chemicals and/or without increase in reaction time and/or temperature by a simple and hitherto unprecedented recycle procedure carried out during downstream processing of the esterification mixture. Although recycling of un-reacted starting materials is known in general (see for instance EP 649422, WO 02/100855, US 2005/250773, WO 2005/105768 or US 2004/167130), it has never been suggested to be used for the synthesis of MPM in connection with solving the problem of excessive formation of unwanted side products. Surprisingly however, this method does not lead to unfavorable product specifications such as formation of impurities such as dimers. The method of the present invention is characterized in that un-reacted MPA is recovered and re-used in esterification with 2-morpholinoethanol. Such re-use is meant to include both re-use in the same or another batch process, as well as re-use in the same or another continuous process. In the first aspect of the invention MPA or an amine salt of MPA is esterified in a conversion with 2-morpholinoethanol. Preferably said esterification is carried out in a water-immiscible solvent, preferably at elevated temperatures.

In the context of the present invention the term "water-immiscible solvent" refers to a solvent which, when mixed with water, forms a two-phase system and which dissolves in water to an extent that the resulting aqueous phase contains less than 10% by weight of the solvent, preferably less than 1% by weight of the solvent, more preferably less than 0.5% by weight of the solvent. While one can imagine certain inorganic liquids such as silicone fluids and halocarbon liquids which meet the definition and which are included in the definition of "water-immiscible solvents", the far more common and thus preferred "water-immiscible solvents" are organic solvents, especially solvents comprising hydrocarbons and/or halo hydrocarbons. Representative suitable water-immiscible solvents include C₄ to Ci₄ branched, cyclic, and straight chain saturated and unsaturated aliphatic hydrocarbons; C₆ to Ci₂ alkaryl hydrocarbons; and halo hydrocarbons containing up to about 4 halogen atoms, especially chlorine, and from 1 to about 8 carbon atoms. It is also very suitable to employ mixtures of these materials or distillation fractions composed primarily of these materials. Thus, representative water-immiscible solvents include suitable freons, carbon tetrachloride, chloroform, methylene chloride, trichloroethylene, dichloropropane, and similar halo hydrocarbons, n-pentane, n-hexane, cyclohexane, 2-methylpentane, hex-1-ene, benzene, n-heptane, methylcyclohexane, cyclopentanone, cyclohexanone, branched heptanes and heptenes, toluene, the normal and branched octanes and octenes, the xylenes, ethylbenzene, n-nonane and the branched nonanes, the various decanes, the dodecanes and like hydrocarbons, C₆-C₇, C₆-C₈ and C₇-C₈ naphtha fractions, mixed xylene-ethylbenzene fractions and the like, C₄ to Ci₄ branched, cyclic, and straight chain alcohols, esters such as ethyl acetate and butyl acetate, ketones such as acetone, cyclohexanone, cyclopentanone, dipropyl ketone, methylisobutyl ketone, methylpropyl ketone and ethers such as dialkyl ethers like dibutyl ether and diisopropyl ether, and mixtures of these solvents. Preferred water-immiscible solvents are the C₆ to C₈ hydrocarbons including aliphatics like n-hexane, cyclohexane, n-heptane and n-octane and fractions composed in substantial part by these aliphatics and the aromatics such as benzene, toluene, ethylbenzene, xylenes (i.e. mefa-xylene, o/t/70-xylene, and para-xylene) and fractions composed in substantial part by these aromatics. The most preferred solvents are xylene, dibutyl ether and cyclohexanone. Preferred solvents are those having a boiling point ranging from 100 to 18O⁰C, preferably of from 1 10 to 17O⁰C, more preferably of from 120 to 16O⁰C. Preferably the esterification is carried out under azeotropic separation of water and under use of an excess of 2-morpholinoethanol, for instance 1.00 to 20 molar equivalents, preferably 1.01 to 10 molar equivalents, more preferably 1.02 to 5 molar equivalents, most preferably 1.03 to 3 molar equivalents, still most preferably 1.04 to 2 molar equivalents.

When a certain degree of conversion from MPA to MPM has been reached, the reaction mixture is mixed with water. A suitable degree of conversion is anywhere from 5-99%, depending on the reaction conditions chosen and the amounts of impurities allowed during conversion or the amount of time needed for the conversion. The method of the present invention even allows for a pre-set conversion time, independent from the degree of conversion reached at that point, which may be useful for instance for the optimal planning of the occupation time of a factory. Suitably, a degree of conversion can be from 20-95% or from 30-90%. In general, for efficiency considerations a relatively high degree of conversion, such as 50-80%, or 60-90%, or 70-95%, or 80-98% is advisable although not mandatory. After admixing water, un-reacted MPA is recovered.

In a first embodiment, recovery is carried out by adjusting the pH of the reaction mixture plus added water to a value of from 0 to 3 after which the phases are separated. This pH-value can be further optimized to combine minimal loss of product resulting from degradation with maximal extraction yield. It has been found that the pH-value should be between 1.0 and 3.0, preferably between 1.5 and 2.7, more preferably between 1.8 and 2.4 and most preferably between 2.0 and 2.2.

MPM can then be isolated from the aqueous phase using standard techniques such as precipitation, crystallization, evaporation and the like, optionally after washing of the aqueous phase with a water-immiscible solvent to remove traces of impurities. Preferably, MPM present in the aqueous phase is isolated by contacting said aqueous phase with a water-immiscible solvent at a pH-value between 3.0 and 5.0 and separating the organic phase. This pH-value can be further optimized, for instance to achieve maximal reduction of unwanted dimeric impurities. It has been found that the pH-value should be between 3.0 and 5.0, preferably between 3.75 and 4.75, more preferably between 4.0 and 4.5 and most preferably between 4.2 and 4.3. It has been found that at the pH-ranges mentioned above there is an unexpected difference in extraction behavior between MPM and several of the dimeric impurities where the former appears to dissolve to a very large extent in the organic phase whereas the latter dissolve to a large extent in the aqueous phase.

MPA present in the organic phase is then re-used for reaction with 2-morpholinoethanol. This re-use may be done by using the organic phase directly in a reaction with 2-morpholinoethanol, or alternatively can be facilitated by isolating the MPA present in the organic phase, for instance by crystallization and/or precipitation and/or evaporation. If the organic phase is used directly in a reaction with 2-morpholinoethanol, the water-immiscible solvent preferably is the same as the solvent used in the subsequent esterification with 2-morpholinoethanol. If the process for preparing MPM is a (semi-)continuous process, MPA recovered as described above can be introduced in the same (semi-)continuous process. The overall process yield is improved when at least 25% of un-reacted MPA is recycled, preferably at least 50%, more preferably at least 75% and most preferably at least 90%.

Depending on the water-immiscible solvent used, there may still be MPA present in the aqueous phase after said first phase separation at pH 0 to 3.

In a second embodiment, recovery is carried out by adjusting the pH of the reaction mixture plus added water to a value of from 7 to 10 after which the phases are separated. This pH-value can be further optimized to combine minimal loss of product resulting from degradation with maximal extraction yield. It has been found that the pH-value should be between 7.0 and 10.0, preferably between 7.5 and 9.5 and more preferably between 8.0 and 9.0.

MPM can then be isolated from the organic phase using standard techniques such as precipitation, crystallization, evaporation and the like, optionally after washing of the organic phase with water to remove traces of impurities. MPA present in the aqueous phase is then re-used for reaction with

2-morpholinoethanol. This re-use can be facilitated by isolating the MPA present in the aqueous phase, for instance by crystallization, precipitation and/or extraction. When extraction is chosen, this is preferably carried out using a second water-immiscible solvent, more preferably this water-immiscible solvent is the same as the one used in the subsequent esterification with 2-morpholinoethanol. If the process for preparing MPM is a (semi-)continuous process, MPA recovered as described above can be introduced in the same (semi-)continuous process. The overall process yield is improved when at least 25% of un-reacted MPA is recycled, preferably at least 50%, more preferably at least 75% and most preferably at least 90%. In summary, the embodiments described above for the preparation of mycophenolate mofetil, comprise the steps of:

(a) contacting mycophenolic acid or a salt thereof with 2-morpholinoethanol in a water-immiscible solvent having a boiling point higher than 75⁰C at a temperature ranging from 75⁰C to the boiling point of said water-immiscible solvent whereby mycophenolate mofetil is formed;

(b) adding water to the mixture obtained in step (a);

(c) adjusting the pH of the mixture obtained in step (b) to a value ranging from 0 to 3 or ranging from 7 to 10 and separating the organic and aqueous phases;

(d) isolating mycophenolate mofetil from the aqueous phase obtained in step (c) when the pH is ranging from 0 to 3 or from the organic phase obtained in step (c) when the pH is ranging from 7 to 10;

(e) returning to step (a) at least 25% of the mycophenolic acid present in the organic phase obtained in step (c) when the pH is ranging from 0 to 3 or in the aqueous phase obtained in step (c) when the pH is ranging from 7 to 10.

In a third embodiment, in order to achieve optimal process efficiency, said second water-immiscible solvent mentioned above is a solvent wherein the solubility of mycophenolic acid is higher than 1 g/l, preferably higher than 2 g/l, more preferably higher than 5 g/l, most preferably higher than 10 g/l. Preferably, said second water-immiscible solvent is the same as said first water-immiscible solvent.

In a fourth embodiment of the present invention MPA is used in the form of a salt. Suitable salts are amines and alkali metal salts. In case of alkali metal salts, also an acid should be present in a molar amount that is at least equal to that of the molar amount of the MPA alkali metal salt. In case of amine salts, addition of acid is not mandatory, although acid can also be added in order to decrease conversion times and/or increase yields. Examples of suitable amine salts of MPA are, but are not limited to, salts from amines such as te/t-butylamine, cyclohexylamine, dibenzylamine, N,N-di/sopropyl- ethylamine, N,N-dimethylcyclohexylamine, N,N-dimethylisopropylamine, N-methyl- piperidine, morpholine, terf-octylamine, piperidine, /so-propylamine, N,N,N',N'-tetramethylbutylenediamine, N,N,N',N'-tetramethylethylenediamine, tributyl- amine, triethylamine and tripropylamine. Suitable alkali metal salts of MPA are salts from lithium and potassium, preferably from sodium. The un-reacted MPA that is to be recovered according to the present invention is preferably recovered as any or the preferred amine salts mentioned above.

In a fifth embodiment of the present invention, esterification of MPA or an MPA salt can be positively influenced (Ae. reduction of reaction time, increase of maximum conversion) by the addition of substances that are capable of absorbing water. These substances can be present in the mixture of MPA, solvent and 2-morpholinoethanol. However, these substances may also be present in the vapor phase of said mixture; despite the fact that the present invention deals with a method for esterification in non-boiling mixtures, a vapor phase nevertheless is usually present above such non-boiling mixtures. Substances that are capable of absorbing water are for instance salts of alkali and earth alkali metals and usually these salts are carbonates, halides or sulfates. Suitable examples are CaCI₂, CaSO₄, K₂CO₃, K₂SO₄, MgSO₄, Na₂CO₃, Na₂SO₄ and the like. Preferred other substances are molecular sieves, preferably those with pore sizes ranging from 0.1-0.6 nm, more preferably ranging from 0.2-0.5 nm, most preferably ranging from 0.3-0.4 nm.

Although the present invention is most suitably carried out under refluxing conditions, in a sixth embodiment esterification reactions are carried out at lower temperatures than the boiling point. The advantages of esterification at a temperature below the boiling point are that equipment for condensing solvent vapors and returning these condensed vapors are no longer required and the energy input required to reach (and maintain) the boiling point, which normally is substantial, can be circumvented. Furthermore, formation of unwanted by-products generally is lower at lower reaction temperatures. Esterification below the boiling point can be further optimized for instance by addition of substances that are capable of absorbing water and/or by addition of catalysts and/or by using additional 2-morpholinoethanol and/or by prolonging reaction times and the like.

In a second aspect of the present invention, MPM obtainable according to the first aspect can be used in pharmaceutical compositions, for instance in antifungal, antiviral and/or antitumor compositions, but also in compositions useful in the treatment of psoriasis and as immunosuppressant. EXAMPLES

General Methods

HPLC analysis was performed on a Waters Atlantis dC-iβ column (5μm; 4.6x150 mm; W 32371 X 12), using as mobile phase A MiIIiQ water with 0.1 vol% formic acid and as mobile phase B CH₃CN with 0.1 vol% HCO₂H. The run time was 13 minutes and the flow was 1.5 ml_/min. Detection wavelength was at 251 nm. The following gradient was applied:

As dilution buffer 400 mg ammonium formate was dissolved in 700 ml. water and the pH was adjusted to 3.5 with HCO₂H and next 1300 ml. acetonitrile was added. In the above system, the retention time of MPM was 1.4 min and that of MPA 4.9 min. TLC analysis was performed on Silica gel 60 F254 TLC plates (Merck 1.05715). As eluent CHCI₃/CH₃OH 9/1 (v/v) was used. Detection of components was performed using UV visualization at 254 nm and/or spraying with fosformolybdic acid hydrate (10% in ethanol) followed by heating. Sample dilution was done with HPLC dilution buffer. In this system the following Rf-values were observed: MPA -0.4 and MPM -0.55.

Example

Conversion of mycophenolic acid triethyl amine salt into mycophenolate mofetil with recycling of un-reacted mycophenolic acid

First Cycle:

A mixture of mycophenolic acid triethyl amine salt (30 g), o-xylene (90 mL) and 2-morpholino-ethanol (10.36 g) was stirred at 110⁰C. A slow stream of nitrogen was passed over the reaction mixture. Stirring was continued at 110⁰C for 44 h in which period the mixture darkened, monitored with HPLC. The mixture was cooled to room temperature and water (90 mL) was added. Next the pH was adjusted from 7.3 to 2.0 with sulfuric acid (25% w/w; 13 mL). The brownish aqueous phase was separated and extracted with ethyl acetate (50 mL and 70 mL) giving ethyl acetate extracts A1 (40 mL) and A2 (80 mL), respectively. To the dark aqueous phase ethyl acetate (140 mL) was added and the pH was adjusted to 8.0 with sodium hydroxide (10% and 25% w/w). The dark organic phase was washed with water (2x 70 mL), the intermediate dark emulsion phase was kept separately. The combined organic phases were treated with Norit SX- Ultra (3 g) and filtered, washed with ethyl acetate (50 mL). From the light-brown filtrate approx. 150 mL was distilled off under normal pressure (liquid temperature 83°C). The volume of the residue was 53 mL. Assuming approx. 35 ml of ethyl acetate in the residue, it was mixed with 150 mL of /so-propanol and cooled while stirring. The mixture was seeded at 22°C. The mixture was further cooled in ice/water and the formed white suspension was stirred overnight at 0⁰C. The next day the solids were filtered off and washed with cold /so-propanol (100 mL). The wet cake (23 g, width 7 cm, height 1.8 cm) was dried under vacuum at 35°C to give 21.36 g of product. NMR analysis: 99% purity (MPM), 0.2% ethyl acetate, 0.3% /so-propanol.

Recovery unconverted MPA as MPA.TEA salt: ethyl acetate extracts A1 and A2 were combined (including rinsing with ethyl acetate (20 mL) making a total of 140 mL) and 95 mL was distilled off at normal pressure (liquid temperature 81⁰C). The residue was cooled to 6O⁰C and the pH was adjusted from 3 to 7 with triethyl amine (7 mL). The solution was cooled and at ca 55°C crystallization started. The mixture was further cooled to O⁰C and stirred for 1 h. The solids were filtered off and washed with cold ethyl acetate (25 mL). The wet cake (4.4 g) was dried under vacuum at 35°C to give 4.47 g of product. NMR analysis: 99% (75% MPA, 24% TEA molar ratio 1 :1 , 0.2% ethyl acetate. This MPA.TEA was used in the next cycle in the conversion to MPM.

Second cycle:

A mixture of fresh mycophenolic acid triethyl amine salt (26 g), recycled MPA.TEA as obtained above (4.0 g), o-xylene (90 mL) and 2-morpholino-ethanol (10.4 g) was stirred at 1 15°C. A slow stream of nitrogen was passed over the reaction mixture. Stirring was continued at 1 15°C for 47 h during which period the mixture darkened, monitored with HPLC. The mixture was cooled to 28°C and water (90 mL) was added. Next the pH was adjusted from 7.3 to 2.0 with sulfuric acid (25% w/w; 13 mL). The brownish aqueous phase was separated and extracted with ethyl acetate (2 x 60 mL) giving ethyl acetate extracts B1 (45 mL) and B2 (62 ml_), respectively. To the dark aqueous phase ethyl acetate (140 mL) was added and the pH was adjusted to 8.0 with sodium hydroxide (25% w/w). The dark organic phase was washed with water (2x 70 mL), the intermediate dark emulsion phase was kept with the organic phase until the second washing. The combined organic phases were treated with Norit SX-Ultra (3 g) and filtered, washed with ethyl acetate (30 mL). From the light-brown filtrate approx. 120 mL was distilled off under normal pressure (liquid temperature 84°C). The volume of the residue was 45 mL. Assuming approx. 25 ml of ethyl acetate in the residue, it was mixed with 100 mL of /so-propanol and cooled while stirring. The mixture was seeded at 32°C. The mixture was further cooled in ice/water and after stirring for 4 h the formed white suspension was filtered off and washed with cold /so-propanol (100 mL). The wet cake (22.7 g, width 7 cm, height 1.7 cm) was dried under vacuum at 35°C to give 22.73 g of product. NMR analysis: 99% purity (MPM). Recovery unconverted MPA as MPA.TEA salt: ethyl acetate extracts B1 and B2 were combined (including rinsing with ethyl acetate (40 mL) making a total of 147 mL) and 100 mL was distilled off at normal pressure (liquid temperature 81⁰C). The residue was cooled to 6O⁰C and the pH was adjusted from 3 to 7 with triethyl amine (7 mL). The solution was cooled to room temperature and kept overnight. The mixture was further cooled to O⁰C and stirred for 1 h. The solids were filtered off and washed with cold ethyl acetate (25 mL). The wet cake (3.5 g) was dried under vacuum at 35°C to give 3.47 g of product. NMR analysis: 99% (MPA.TEA). This MPA.TEA was used in the next cycle in the conversion to MPM.

Third cycle: A mixture of fresh mycophenolic acid triethyl amine salt (26.65 g), recycled MPA.TEA as obtained above in the second cycle (3.35 g), o-xylene (90 mL) and 2-morpholino-ethanol (10.42 g) was stirred at 115°C. A slow stream of nitrogen was passed over the reaction mixture. Stirring was continued at 115°C for 47 h during which period the mixture darkened, monitored with HPLC. The mixture was cooled to 21⁰C and water (90 mL) was added. Next the pH was adjusted to 2.0 with sulfuric acid (25% w/w). The brownish aqueous phase was separated and extracted with ethyl acetate (2 x 60 mL) giving ethyl acetate extracts C1 (48 mL) and C2 (60 mL), respectively. To the dark aqueous phase ethyl acetate (140 mL) was added and the pH was adjusted to 8.0 with sodium hydroxide (25% w/w). The dark organic phase was washed with water (2x 70 mL), the intermediate dark emulsion phase was kept with the organic phase until the second washing. The combined organic phases were treated with Norit SX-Ultra (3 g) and filtered, washed with ethyl acetate (30 ml_). From the light-brown filtrate approx. 140 ml. was distilled off under normal pressure (liquid temperature 84°C). The volume of the residue was 40 ml_. Assuming approx. 20 ml of ethyl acetate in the residue, it was mixed with 100 ml. of /so-propanol and cooled while stirring. Crystallization started and the mixture was further cooled in ice/water and after stirring for 4 h the formed white suspension was filtered off and washed with cold /so-propanol (100 ml.) and dried to give 23.32 g of product. NMR analysis: 99% purity (MPM). Recovery unconverted MPA as MPA.TEA salt: ethyl acetate extracts C1 and C2 were combined (including rinsing with ethyl acetate (40 ml.) making a total of 148 ml.) and 100 ml. was distilled off at normal pressure (liquid temperature 81⁰C). The residue was cooled to 6O⁰C and the pH was adjusted from 3 to 7 with triethyl amine (7 ml_). The solution was cooled to O⁰C and stirred for 2 h. The solids were filtered off and washed with cold ethyl acetate (25 ml_). The wet cake was dried under vacuum at 35°C to give 3.06 g of product. NMR analysis: 98% (MPA.TEA). This MPA.TEA was used in the next cycle in the conversion to MPM.

Fourth cycle: A mixture of fresh mycophenolic acid triethyl amine salt (13 g), recycled MPA.TEA as obtained above in the third cycle (2.00 g), o-xylene (55 ml.) and 2-morpholino-ethanol (5.2 g) was stirred at 120⁰C. A slow stream of nitrogen was passed over the reaction mixture. Stirring was continued at 120⁰C for 47 h during which period the mixture darkened, monitored with HPLC. The mixture was cooled to 21 °C and water (45 ml.) was added. Next the pH was adjusted from 6.8 to 2.0 with sulfuric acid (25% w/w). The brownish aqueous phase was separated and extracted with ethyl acetate (2 x 30 ml.) giving ethyl acetate extracts D1 and D2 that were combined to 60 ml_. To the dark aqueous phase ethyl acetate (700 ml.) was added and the pH was adjusted to 8.0 with sodium hydroxide (25% w/w). The dark organic phase was washed with water (2x 25 ml_), the intermediate dark emulsion phase was kept with the organic phase until the second washing. The combined organic phases were treated with Norit SX-Ultra (1.5 g) and filtered, washed with ethyl acetate (15 ml_). From the light-brown filtrate approx. 85 ml. was distilled off under normal pressure (liquid temperature 84°C). The volume of the residue was 18 ml_. Assuming approx. 10 ml of ethyl acetate in the residue, it was mixed with 50 ml. of /so-propanol and cooled while stirring. Crystallization started and the mixture was further cooled in ice/water and after overnight at 1-3⁰C the formed white suspension was filtered off and washed with cold /so-propanol (50 ml.) and dried to give 14.61 g of product. NMR analysis: 99% purity (MPM). Recovery unconverted MPA as MPA. TEA salt: combined ethyl acetate extracts D1 and D2 (including rinsing with ethyl acetate (20 ml.) making a total of 80 ml.) and 40 ml. was distilled off at normal pressure (liquid temperature 81⁰C). The residue was cooled to 6O⁰C and the pH was adjusted from 3 to 7 with triethyl amine (3.5 ml_). The solution was cooled to O⁰C and stirred for 2 h. The solids were filtered off and washed with cold ethyl acetate (15 ml_). The wet cake was dried under vacuum at 35°C to give 2.64 g of product. NMR analysis: 98% (MPA.TEA).

Claims

1. Method for the preparation of mycophenolate mofetil comprising the steps of:

(b) adding water to the mixture obtained in step (a);

(d) isolating mycophenolate mofetil from the aqueous phase obtained in step (c) when the pH is ranging from 0 to 3 or from the organic phase obtained in step (c) when the pH is ranging from 7 to 10; (e) returning to step (a) at least 25% of the mycophenolic acid present in the organic phase obtained in step (c) when the pH is ranging from 0 to 3 or in the aqueous phase obtained in step (c) when the pH is ranging from 7 to 10.

2. Method according to claim 1 wherein said water-immiscible solvent has a boiling point ranging from 100 to 18O⁰C.

3. Method according to claim 2 wherein said water-immiscible solvent is butyl acetate, cyclohexanone, dibutylether, ethylbenzene, toluene, mefa-xylene, orf/?o-xylene, para-xylene or mixtures thereof.

4. Method according to any one of claims 1 to 3 wherein said mycophenolic acid step (e) is isolated prior to returning to step (a).

5. Method according to claim 4 wherein said mycophenolic acid is isolated as an amine salt.

6. A pharmaceutical composition comprising mycophenolate mofetil obtained according to the method of any one of claims 1 to 5.

7. Use of mycophenolate mofetil obtained according to the method of anyone of claims 1 to 5 as a medicament.