With respect to halogenation of carboxylic acid, generally known in the art, it is very natural that an excess amount of or an equal amount as a solvent of a halogenating agent is used relative to the amount of carboxylic acid, and therefore, after the reaction, an excess halogenating agent is removed by evaporation under reduced pressure in an anhydrous condition, and the acyl halide remnant is dissolved in an inert solvent and added dropwisely to a secondary reactant.

However, as mentioned above, the acidity of a halogenating agent and its excess use result in generation of various impurities of dimers including those produced by halogenation of aromatic hydroxyl group and those produced by two molecules of mycophenolic acid, and they are also very difficult to remove.

In the present invention, in order to resolve the production of dimers fundamentally, mycophenolic acid was reacted with various amine bases to obtain a novel amine salt of mycophenolate, and then by performing a series of subsequent steps MMF was finally manufactured. As a result, dimers were not produced at all and also the amounts of various impurities were greatly reduced thus enabling MMF with more than 99.8% purity. Further, the amount of a halogenating agent to be used was greatly reduced. For example, an excess amount of a halogenating agent of greater than 3 equivalents was used in the conventional halogenation of carboxylic acid while only 1-1.2 equivalents of a halogenating agent is used in the present invention to obtain the target compound. Therefore, the present invention, with its cost effectiveness in production and environment-friendliness, is of great industrial applicability.

To date, there has never been a method disclosed on manufacturing high purity MMF by using an amine salt compound represented by the above formula 3 as an intermediate. In addition, in the manufacture of MMF, halogenation has never been successfully completed by using an amine compound as an intermediate with a halogenating agent in a stoichiometric amount.

In other words, the manufacturing method according to the present invention is an industrially useful one clearly distinguished from the conventional ones in that it can fundamentally block the generation of dimers, which have been difficult to remove by using the known methods, and minimize the production of other impurities by stabilizing the reactivity to other reaction sites, which may produce those impurities, thereby producing a target product with high purity and high yield at once.

The superiorities of the present invention can be further confirmed by conducting comparative experiments with a conventional method disclosed in U. S. Pat. No. 4,753,935.

Figs. 1 and 2 show the respective results of HPLC for the reaction mixture used in the manufacture of MMF according to the present invention by using an amine salt of mycophenolate as an intermediate and the reaction mixture used in the manufacture of MMF according to a method disclosed in U. S. Pat. No. 4,753,935. The effects on the production of an amine salt of mycophenolate based on the HPLC results of Figs. 1 and 2 were compared and are shown in the Table 1 below.

Table 1

The manufacturing method of the present invention is described in further detail as shown below.

The method of manufacturing mycophenolate mofetil represented by the above formula 1 may be performed through 3 steps. Therefore, the manufacturing method of the present invention may be performed by separation and purification of each compound produced in each step, but it is preferred that the 3-step process be preformed continuously as one pot reaction. The details of the manufacturing method of the present invention in each step may be explained as follows.

First, mycophenolic acid represented by the formula 2 below is reacted with an amine base to obtain an amine salt of mycophenolic acid represented by the formula 3 below,

wherein B represents a C _1-12 aliphatic or aromatic amine base forming a quarternary amine salt.

Then, an amine salt of mycophenolic acid represented by the following formula 3 is halogenated to produce a mycophenolic acid halide represented by the following formula 4.

In the above reaction, B represents a C _1-12 aliphatic or aromatic amine base forming a quarternary amine salt, and X represents a halogen atom.

Then, the mycophenolic acid halide represented by the following formula 4 is esterified by reacting with 2-morpholinoethanol represented by the following formula 5 to obtain mycophenolate mofetil represented by the following formula 1.

In the above reaction, X represents a halogen atom.

The reaction solvent to be used in the present invention may be any inert solvent which does not affect the reaction. For example, the solvent may be a single solvent selected from the group consisting of: an aromatic hydrocarbon-based solvent such as benzene, toluene, xylene, anisol; an ether-based solvent such as diethylether; an amide-based solvent such as dimethylformamide, diethylacetamide; an acetate-based solvent such as ethyl acetate; a nitrile-based solvent such as acetonitrile; and a halogenated hydrocarbon-based solvent such as chloroform, dichloroethane, dichloromethane; or a mixture thereof.

A preferable reaction solvent is a single solvent selected from ethyl acetate, dichloromethane, toluene, anisol, acetonitriel, 1,4-dioxane; or a mixture thereof; or a solvent comprising these as a main solvent. More preferably, the reaction solvent may be a single solvent selected from ethyl acetate, dichloromethane, anisol; or a mixture thereof; or a a solvent comprising these as a main solvent.

The reaction solvent may be used in the amount of 1-20 volume ratio relative to the amount of total reactants, preferably 5-20 volume ratio, and more preferably 8-12 volume ratio.

The reaction of the manufacturing method according to the present invention can be performed at 0-200 ℃, preferably at 5-100 ℃, more preferably at 20 - 60 ℃, and most preferably at room temperature.

Examples of a chlorinating agent to be used in the present invention include thinoylchloride, oxalylchloride, phosphoruspentachloride, and phosphorusoxychloride; and preferably thinoylchloride, oxalylchloride.

The chlorinating agent may be used in the amount of 0.5-5 equivalents relative to mycophenolic acid represented by the above formula 2, preferably 1-2 equivalents, more preferably 1-1.2 equivalents from the economical point of view.

The amine base to be used in the present invention is preferably a C _1-12 aliphatic or aromatic amine, and more preferably a single compound selected from aliphatic alkylamine such as triethylamine, diethylamine and aromatic amine such as pyridine, or a mixture thereof.

The amine base may be used in the amount of 0.5-5 equivalents relative to mycophenolic acid represented by the above formula 2, preferably 1-2 equivalents.

The amount of 2-morpholinoethanol used in esterification of the present invention is 1-10 equivalents relative to mycophenolic acid represented by the above formula 2, preferably 1-3 equivalents, and more preferably 1-1.5 equivalents from the economical point of view.

The present invention is also characterized in that it provides a special post-treatment process for the treatment of reactants generated as a result of the above reaction. That is, in the present invention, the processes of acidification and alkalinization, which are performed for the color improvement of mycophenolate mofetil and the removal of other impurities, are performed continuously.

Further, in the above post-treatment process of the present invention, there is added as a discolorant a small amount of alkali metal sulfite-based compound thereby discoloring purple-colored mycophenolate mofetil represented by the above formula 1 in an acidic solution. The above post-treatment has advantages that it can prevent discoloration without additional process by using a small amount of discolorant and ultimately obtain a white-colored compound with high purity. The effects of the post-treatment were confirmed by HPLC results shown in Fig. 3. That is, by comparing the HPLC results for the reaction mixture obtained by the manufacturing method of the present invention as shown in Fig. 1 with those for the white-colored compound obtained by additional post-treatment of the reaction mixture as shown in Fig. 3, the effects of the post-treatment were confirmed. The brief details of the effects of the post-treatment with respect to Figs. 1 and 3 are shown in Table 2 below.

Table 2

Examples of the discolorants to be used in the present invention include sodium sulfite (Na ₂ SO ₃ ), sodium metabisulfite (Na ₂ S ₂ O ₅ ), sodium hydrogensulfite (NaHSO ₃ ), sodium thiosulfate (Na ₂ S ₂ O ₃ ), preferably sodium metabisulfite (Na ₂ S ₂ O ₅ ).

The discolorant may be used in the range of 0.05-1 equivalent relative to mycophenolic acid represented by the above formula 2, preferably 0.05-0.15 equivalent.

Examples of acids to be used in the acidification as post-treatment process are hydrochloric acid, phosphoric acid, nitric acid, formic acid, sulfuric acid. The pH range of acidification is in the range of pH 1-4, and preferably pH 1-3.

Examples of alkalis to be used in the acidification as post-treatment process are sodium carbonate, sodium hydrogen carbonate, sodium hydroxide. The pH range of alkalinization is pH 6-10, and preferably pH 7-10.

The following examples illustrate the invention and are not intended to limit the same.

Examples

Example 1. Continuous synthesis 1 of mycophenolate mofetil

To 100g of mycophenolic acid were added 1L of ethyl acetate and 44g of triethylamine and the mixture was stirred for about 30 minutes. Then, 44g of thionyl chloride was dropwisely added and stirred for about 2 hours. The above reactants were added with 123g of morpholinoethanol and stirred for more than 2 hours to obtain a brown reaction mxiture, for which HPLC was performed and the result is shown in Fig. 1. According to the HPLC results shown in Fig. 1, the content of unreacted mycophenolic acid is less than 0.13%, and the presence of dimers or other impurities was not detected.

To the above brown compound was added distilled water and dropwisely added with hydrochloric acid to adjust its pH to below pH 3 and then layer separation was performed. The resulting aqueous layer was added with a small amount of sodium metasulfite and stirred. The resultant was added with 1 L of ethyl acetate and then with sodium carbonate to adjust its pH to higher than pH 7 and then stirred to obtain light yellow organic layer by layer separation. Thus obtained organic layer was dried by using anhydrous magnesium sulfate and filtrated and the resulting filtrate was concentrated under reduced pressure. The resultant was crystallized by using 0.5 L of isopropyl alcohol, filtrated, washed with a small amount of isopropyl alcohol and then dried under vacuum for more than 12 hours to obtain 124g of mycophenolate mofetil in white powder.

HPLC was performed for thus obtained white-powdered mycophenolate mofetil and the result is shown in Fig. 3.

HPLC analysis: 99.9% or higher of purity, 0% of unreacted mycophenolic acid, presence of dimers and other impurities not detected.

Example 2. Continuous synthesis 2 of mycophenolate mofetil

Experiments were performed same as in the above Example 1 except that pyridine was used as an amine base thereby obtaining 115g of white-colored mycophenolate mofetil.

HPLC analysis: 99.9% or higher or of purity, less than 0.1% of mycophenolic acid, presence of dimers and other impurities not detected.

Example 3. Continuous synthesis 3 of mycophenolate mofetil

Experiments were performed same as in the above Example 1 except that diethylamine was used as an amine base thereby obtaining 113g of white mycophenolate mofetil.

HPLC analysis: 99.8% or higher of purity, less than 0.1% of mycophenolic acid, less than 0.1% of other impurities but presence of dimers not detected.

Example 4. Continuous synthesis 4 of mycophenolate mofetil

Experiments were performed same as in the above Example 1 except that dichloromethane was used as a reaction solvent thereby obtaining 123g of white mycophenolate mofetil.

HPLC analysis: 99.9% or higher of purity, less than 0.1% of mycophenolic acid, prebsence of dimers and other impurities not detected.

Example 5. Continuous synthesis 5 of mycophenolate mofetil

Experiments were performed same as in the above Example 1 except that anisol was used as a reaction solvent thereby obtaining 120g of white mycophenolate mofetil.

HPLC analysis: 99.9% or higher of purity, less than 0.1% of mycophenolic acid, presence of dimers and other impurities not detected.

Example 6. Continuous synthesis 6 of mycophenolate mofetil

Experiments were performed same as in the above Example 1 except that phosphoric acid was used as an acid in the acidification during the treatment of reactants thereby obtaining 124g of white mycophenolate mofetil.

HPLC analysis: 99.9% or higher of purity, less than 0.1% of mycophenolic acid, presence of dimers and other impurities not detected.

Example 7. Stepwise synthesis of mycophenolate mofetil

1) Synthesis of mycophenolic acid triethylamine

To 100g of mycophenolic acid were added 1 L of ethyl acetate and then 44g of triethylamine. After mycophenolic acid was dissolved, and became white powder, it was stirred for about 30 minutes. The reaction mxiture was filtrated, washed with a small amount of ethyl acetate and then dried under vacuum for more than 12 hours to obtain 118g of mycophenolic acid triethylamine in white powder.

Melting point : 125℃-126℃; ¹ H NMR(CDCl ₃ , 400 MHz) δ1.25(t, 9H, TEA -CH ₃ ), 1.78(s, 3H, -CHC(C H ₃ )-), 2.13(s, -CH ₃ ), 2.30(s, 4H, -C H ₂ C H ₂ CO ₂ H), 2.87(q, 6H, TEA -C H ₂ ), 3.35-3.37(d, 2H, ArC H ₂ CH-), 3.74(t, -OC H ₃ ), 5.18-5.23(m, 3H, lacton 2H and -C H C(CH ₃ )-); HPLC analysis : 98% or higher of purity

2) Synthesis of mycophenolate mofetil

To 118g of mycophenolic acid triethylamine was added 1L of ethyl acetate and then dropwisely added with 44g of thionly chloride and stirred for about 2 hours. To the above reactants was added 123g of 2-morpholinoethanol and then stirred for about 2 hours to obtain brown reaction mixture. Then, the resultant was purified same as in the above Example 1 and finally 97g of white-colored mycophenolate mofetil was obtained.

HPLC analysis: 99.8% or higher of purity, less than 0.1% of mycophenolic acid, presence of dimers and other impurities not detected.

Comparative Example 1. Synthesis of mycophenolate mofetil by a conventional method (disclosed in U.S. Pat. No. 4,753,935)

Mycophenolic acid was dissolved in dichloromethane and then added with thionyl chloride and dimethyl formamide. The reaction mixture was stirred for 3 hours at room temperature and the volatile components were removed under vacuum and then mycophenolic acid chloride was obtained in an oily state. Thus obtained oily mycophenolic acid chloride was dissolved in dichloromethane, cooled down and then added with 2-morpholinoethanol, which was dissolved in dichloromethane and cooled down, and then the mixture was stirred for more than 4 hours at 4℃ to obtain a brown reaction mixture solution. The reaction mixture solution was analyzed by HPLC and the result is shown in Fig. 2. According to Fig. 2, mycophenolate mofetil had 85.99% of purity, the content of unreacted mycophenolic acid was 4.88%, and a total 9.13% of dimers or other impurities were detected.

The reaction mixture was washed with water and then washed again with aqueous sodium carbonate. The organic phase was dried using sodium sulfate and then evaporated to obtain purple mycophenolate mofetil. Thus obtained mycophenolate mofetil, as a result of HPLC analysis, was found to have 97.2% of purity and contain about 1.5% of dimers.

As explained above, the inventors of the present invention succeeded in providing a method for manufacturing mycophenolate mofetil represented by the above formula 1 with high purity to be industrially applicable and economical by reacting mycophenolic acid, which is used as a starting material, with an amine base to obtain a novel amine salt of mycophenolic acid represented by the above formula 3, as an intermediate, thereby significantly inhibiting the production of dimers and other impurities, byproducts of halogenation which have been difficult to remove.

In particular, the process for removing excess chlorinating agent by evaporation under reduced pressure in a highly acidic condition, which is used during halogenation, is no more necessary, and with this procedural advantage, the entire series of manufacturing process is proceeded with in one-pot reaction not necessitating additional process, thereby simplifying the manufacturing process. Further, the entire process time of the manufacturing method of the present invention is much reduced to 2-6 hours as compared to the long process time in the conventional methods, thereby reducing production cost and increasing industrial applicability.

Besides, in the present invention, there is added a small amount of alkali metal sulfite-based compound for color improvement of mycophenolate mofetil represented by the above formula 1 during the treatment of reactants, without additional discoloring process thereby obtaining a white-colored compound. Further, the manufacturing method of the present invention can almost completely remove a small amount of other impurities produced during the above manufacturing process and thus can obtain the mycophenolate mofetil represented by the above formula 1 with purity of 99.8% or higher.