KR101308767B1 - Preparation method of Pemetrexed diethyl ester with high purity and the preparation method of pemetrexed disodium salt comprising the thereof - Google Patents

Abstract

The present invention relates to 1) a low-purity pemetrexed diethyl ester comprising one solvent selected from dimethylformamide, dimethyl sulfoxide, dimethylacetamide and N-methylpyrrolidanone and one alcohol selected from C1-4 alcohols. Dissolving in a mixed solvent with to form a solution; 2) precipitating crystals by adding one selected from C3-C6 ketone, C3-C6 ester and acetonitrile as antisolvent to the solution prepared in the first step; And 3) filtering, washing and drying the crystals prepared in the second step to provide a high purity pemetrexed diethyl ester represented by Chemical Formula 1 having a purity of 98.5% or more. The present invention also provides a process for preparing pemetrexed disodium salt comprising the process for preparing the high purity pemetrexed diethyl ester of the present invention.

Description

Preparation method of Pemetrexed diethyl ester with high purity and the preparation method of pemetrexed disodium salt comprising the

The present invention relates to a process for the preparation of high purity pemetrexed diethyl ester and to a process for the preparation of pemetrexed disodium salt.

Pemetrexed is N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl ] Benzoyl) -L-glutamic acid {N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrroro [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl ) -L-glutamic acid} has the following formula (I) and exhibits antifolate activity, Eli Lilly and It is a sterile lyophilized powder for intravenous administration with pemetrexed disodium salt ^heptahydrate under the trade name Alimta ^�� under the trade name of Alimta .

Formula I

Pemetrexed disodium salt may be prepared as shown in [Scheme 1], as described in Korean Patent Publication No. 0162654.

[Reaction Scheme 1]

As shown in [Scheme 1], pemetrexed disodium salt (2) hydrolyzes pemetrexed diethyl ester (1) in the presence of a base to prepare pemetrexed (5) and then react with sodium hydroxide. Are manufactured.

For this reason, if the purity of the pemetrexed diethyl ester is high, there is no need for a separate manufacturing process for increasing the purity of the final product of pemetrexed disodium in the subsequent reaction.

Therefore, it is important to develop a method for producing high purity and high yield of pemetrexed diethyl ester.

Accordingly, it is an object of the present invention to provide a process for the preparation of high purity fimetrexed diethyl ester to avoid separately required or complicated purification processes in the final stage of the final product, pimetrexide disodium salt.

The present invention provides a process for preparing a high purity pemetrexed diethyl ester of the following Chemical Formula 1, comprising the following steps:

1) Mixing low purity pemetrexed diethyl ester with one solvent selected from dimethylformamide, dimethyl sulfoxide, dimethylacetamide and N-methylpyrrolidinone and one cosolvent selected from alcohols of C1-4 Dissolving in a solvent to prepare a solution,

2) precipitating crystals by adding one selected from C3-C6 ketone, C3-C6 ester and acetonitrile as an antisolvent to the solution prepared in the first step;

3) a method of preparing high purity pemetrexed diethyl ester represented by the following Chemical Formula 1 having a purity of 98.5% or more by filtration, washing and drying the crystals prepared in the second step:

[Formula 1]

The pemetrexed diethyl ester of the starting material of the present invention may be commercially available, and may be prepared by a known method as described in Korean Patent Laid-Open No. 2008-0050594. For example, 4- (2- [2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid and an organic solvent After mixing, N-methylmorpholine was added, cooled to 0-5 [deg.] C., 2-chloro-4,6-dimethoxy-1,3,5-triazine was added and stirred for 1 hour. After adding L-glutamic acid diethyl ester hydrochloride and reacting at room temperature, the reaction was confirmed by TLC and the like, and water (186 ml) and an organic solvent were added to the reaction mixture to separate the layers, and the organic layer was dried with anhydrous ethanol or the like. Replaced and warmed up, and p-toluene sulfonic acid was added to produce pemetrexed diethyl ester p-toluene sulfonate. This, after adjusting the pH of the reaction solution to pH 8.0 to 9.0 in a mixed organic solvent containing water, such as sodium hydrogen carbonate can be prepared pemetrexed diethyl ester.

In the present invention, low purity means 95% or less purity, preferably 92% or less purity, high purity means 98.5% or more, preferably 99.0% or more.

In the present invention, C1-4 alcohol means methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.

In the present invention, the mixed solvent of one step is preferably a mixed solvent of ethanol as one of dimethylformamide or dimethyl sulfoxide and a cosolvent.

In the present invention, the mixing ratio of one solvent selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and N-methyl pyrrolidinone and the cosolvent may vary, but is preferably 1: 2 to 6 by volume, Preferably it is 3:10 volume ratio.

As for the mixed solvent of one step of this invention, it is more preferable that the mixing ratio of 1 type and ethanol of dimethylformamide or dimethyl sulfoxide is 3:10 volume ratio.

The first step of the present invention may be carried out at room temperature to a warmed state, preferably 40 to 70 ° C, more preferably about 50 ° C when warmed.

In the present invention, the anti-solvent of the second stage is preferably acetone, and the mixing ratio of the anti-solvent and the co-solvent of the first stage may be 1: 1 to 3 by volume, and preferably 3: 5 by volume.

In the present invention, the anti-solvent may be slowly dropwise to the reaction solution, or added at once. It is more preferable to dropwise.

The second step of the present invention can be carried out at room temperature to a warmed state, the temperature at the time of addition of the antisolvent is preferably a warmed state, the reaction is preferably carried out at room temperature.

In the present invention, the third step of washing is preferably an alcohol of C1-4, more preferably isopropanol.

Preferably, step 3 of the present invention is carried out at 0 to room temperature.

In the present invention, room temperature means 15 to 30 ℃.

In addition, in the third step of the present invention, filtration means vacuum filtration, filter filtration, etc. that are commonly used in organic experiments. In addition, washing and drying means washing and drying which are usually performed after obtaining a solid crystal in an organic experiment.

The present invention also provides a process for preparing the pemetrexed disodium salt, including the high-purity pemetrexed diethyl ester process of the present invention.

The process for preparing pemetrexed disodium salt of the present invention comprises the following steps:

1) preparing a high purity pemetrexed diethyl ester by the method for preparing high purity pemetrexed diethyl ester of the present invention;

2) preparing pemetrexed by reacting the pemetrexed diethyl ester prepared in the first step with a base, and then adding an acid to the solution to adjust the pH of the reaction solution to 2.5 to 4.0; And

3) A method of preparing pemetrexed disodium salt by reacting the pemetrexed prepared in the second step with sodium hydroxide or sodium carbonate and adding an acid to adjust the pH of the reaction solution to 7.5 to 8.5.

In the process for preparing pemetrexed disodium salt of the present invention, the base of the second step means a conventional base used for the hydrolysis reaction of the ester group, for example, NaOCH ₃ , NaOCH ₂ CH ₃ , KOCH ₃ , KOCH ₂ CH ₃ , LiOH, NaOH, KOH, RbOH, CsOH, Ca (OH) ₂ , SrOH, Ba (OH) ₂ and the like.

In the process for preparing pemetrexed disodium salt of the present invention, the reaction solvent of the second step is preferably water, an alcohol of C1-4, or an alcohol mixed solvent of water and C1-4, and the reaction temperature is preferably room temperature, When the acid is added, it can be heated to about 50 to 70 ℃.

In the method for producing pemetrexed disodium salt of the present invention, the acid of the second or third step is preferably selected from hydrochloric acid, sulfuric acid and nitric acid, more preferably hydrochloric acid.

In the method for producing pemetrexed disodium salt of the present invention, drying after the reaction of the third step, which is usually performed in an organic experiment, can be further performed.

The method of the present invention has the effect of providing high purity and high yield of pemetrexed diethyl ester and pemetrexed disodium salt.

Hereinafter, the present invention will be described in detail with reference to the following examples, but the following examples are only intended to illustrate the present invention and do not limit the scope of the present invention.

The HPLC method for monitoring the purity of the pemetrexed diethyl ester and pemetrexed disodium salts prepared in the following examples is as follows.

1) HPLC method for monitoring the purity of pemetrexed diethyl ester:

2) HPLC method for monitoring the purity of pemetrexed disodium salt:

< Manufacturing example > Low purity N- (4- [2- (2-amino-4,7- Dihydro -4-oxo-1H- Pyrrolo [2,3-d] pyrimidine -5-yl) ethyl] Benzoyl ) -L-glutamic acid Diethyl  ester( Pemetrexed Diethyl  Ester) manufacturer

In a flask, 4- (2- [2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid (10.0 g) and dimethyl Formamide (70 ml) was added and stirred for 20 minutes, followed by addition of N-methylmorpholine (10.3 g). The mixture was cooled to 5 ° C. and 2-chloro-4,6-dimethoxy-1,3,5-triazine (7.53 g) was added. After the reaction was stirred at 5 ° C. for 1 hour, L-glutamic acid diethyl ester hydrochloride (10.3 g) was added thereto, and the temperature was raised to 25 ° C. After about 1 hour, the reaction was completed by TLC. Water (186 ml) and dichloromethane (186 ml) were added to the reaction mixture, which was stirred for 15 minutes and allowed to stand. The layers were separated and the organic layer was concentrated under reduced pressure and replaced with anhydrous ethanol (340 ml). The reaction solution was heated to 75 ° C., and p-toluene sulfonic acid (16.8 g) dissolved in anhydrous ethanol (290 ml) was slowly added dropwise to the reaction mixture for 1 hour. The resulting slurry was refluxed for 1 hour, then cooled to 25 ° C. and filtered. Washed with anhydrous ethanol (134 ml) to give pemetrexed diethyl ester p-toluene sulfonate. The solid (10.0 g) thus obtained was dispersed in a mixed solvent of ethanol (100 ml), dichloromethane (100 ml) and water (50 ml), and then the pH of the reaction solution was adjusted to pH 8.0 to 9.0 with an aqueous sodium carbonate solution. Thereafter, the organic layer was separated and concentrated under reduced pressure to obtain N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidine-5- Il) ethyl] benzoyl) -L-glutamic acid diethyl ester (91.48% HPLC purity) (7.38 g) was obtained.

Example 1 N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) of high purity Preparation of ethyl] benzoyl) -L-glutamic acid diethyl ester (pemetrexed diethyl ester)

N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) having low purity obtained in Preparation Example Ethyl] benzoyl) -L-glutamic acid diethyl ester (91.48% HPLC purity) (7.38 g) was charged to the flask with dimethylsulfoxide (12 ml) and ethanol (40 ml) and heated to 50 ° C. until completely dissolved. Stirred. Acetone (24 ml) was then added dropwise for about 10 minutes and the resulting suspension was cooled to 22-25 ° C. for 1 hour. After stirring at 22-25 ° C. for 30 minutes, the suspension is filtered and the solid is washed with isopropanol (10 ml). The wet solid was dried at 50 ° C. for 5 hours to give 6.13 g (yield 83.1%) of an off-white solid in 99.18% purity.

¹ H NMR (300 MHz, DMSO) δ 1.70 (m, 6H), 1.93-2.14 (m, 2H), 2.43 (t, 2H), 2.85 (t, 2H), 2.98 (t, 2H), 4.06 (m , 4H), 4.42 (m, 1H), 5.99 (bs, 2H), 6.29 (s, 1H), 7.27 (d, 2H), 7.76 (d, 2H), 8.61 (d, 1H), 10.12 (bs, 1H), 10.58 (bs, 1H)

Example 2 N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl Preparation of) -L-Glutamic Acid (Pemetlexed)

N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) prepared in Example 1 in a flask Ethyl] benzoyl) -L-glutamic acid diethyl ester (99.18% HPLC purity) (3.00 g) was added to 20.1 ml of 1N aqueous sodium hydroxide solution and stirred until complete solid dissolution. A mixed solution of ethanol (20.1 ml) and water (20.1 ml) was added over 2.5 hours, and diluted hydrochloric acid was added to adjust the pH to 3.0 to 3.5. The resulting slurry was heated at 65 ° C. for 1 hour and then cooled to room temperature. The solid was then filtered and dried to yield 2.60 g (98.1%) of the title compound.

¹ H NMR (300 MHz, DMSO) δ 1.95-2.10 (m, 2H), 2.35 (t, 2H), 2.84 (t, 2H), 2.97 (t, 2H), 4.36 (m, 1H), 5.98 (bs , 2H), 6.29 (s, 1H), 7.26 (d, 2H), 7.76 (d, 2H), 8.49 (d, 1H), 10.11 (bs, 1H), 10.57 (bs, 1H)

Example 3 N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl Preparation of) -L-glutamic acid disodium salt (pemetrexed disodium salt)

N- (4- [2- (2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl obtained from Example 2 ) -L-glutamic acid (2.50 g) was dissolved in 2N aqueous sodium hydroxide solution (6.25 ml) and water (9.5 ml). 1N hydrochloric acid was added to adjust the pH of the mixture to 7.5-8.5. The solution was heated at 70 ° C. and anhydrous ethanol (100 ml), methanol (10 ml) and ethyl acetate (2.5 ml) mixed solvent were added. The solution was allowed to cool slowly to room temperature. The slurry was filtered and washed with a mixture of anhydrous ethanol and water (4: 1 v / v). The resulting white solid was dried under vacuum for 16 hours to give 2.68 g (yield: 88.7%) of the title compound in 99.83% purity.

¹ H NMR (300 MHz, D ₂ O) δ 2.02 (m, 1H), 2.14 (m, 1H), 2.30 (t, 2H), 2.89 (s, 4H), 4.27 (m, 1H), 6.34 (s , 1H), 7.18 (d, 2H), 7.61 (d, 2H)

Claims (10)

1) Purity is 95% or less A first step of dissolving the low purity pemetrexed diethyl ester in a mixed solvent of one solvent selected from dimethylformamide and dimethyl sulfoxide and one cosolvent selected from alcohols of C1-4;
2) a second step of precipitating crystals by adding C3-C6 ketone as an antisolvent to the solution prepared in the first step; And
3) A method for preparing high purity pemetrexed diethyl ester having a purity of 98.5% or more by filtering, washing and drying the crystals prepared in the second step. The method for producing high purity pemetrexed diethyl ester according to claim 1, wherein the mixed solvent of the first step is a mixed solvent of dimethylformamide or dimethyl sulfoxide with ethanol. The method for producing high purity pemetrexed diethyl ester according to claim 2, wherein the mixing ratio of one of dimethylformamide or dimethyl sulfoxide to ethanol is 3:10 by volume. The method of claim 1, wherein the antisolvent of the second step is acetone. The method for preparing high purity pemetrexed diethyl ester according to claim 4, wherein the mixing ratio of the antisolvent and the co-solvent of the first step is 3: 5 by volume. The method of claim 1, wherein the washing in the third step is performed with one selected from C1-C4 alcohols. The method of claim 6, wherein the third step of washing is performed with isopropanol. 1) a first step of producing a high-purity pemetrexed diethyl ester by the method of any one of claims 1 to 7;
2) the pemetrexed diethyl ester prepared in step 1 and NaOCH ₃ , NaOCH ₂ CH ₃ , KOCH ₃ , KOCH ₂ CH ₃ , LiOH, NaOH, KOH, RbOH, CsOH, Ca (OH) ₂ , SrOH and One selected from Ba (OH) ₂ A second step of preparing pemetrexed by reacting a base and adding an acid to the solution to adjust the pH of the reaction solution to 2.5 to 4.0; And
3) A method for preparing pemetrexed disodium salt by reacting the pemetrexed prepared in the second step with sodium hydroxide or sodium carbonate and adjusting the pH to 7.5 to 8.5 by adding an acid. delete 9. The process for preparing pemetrexed disodium salt according to claim 8, wherein the acid of the second or third step is selected from hydrochloric acid, sulfuric acid and nitric acid.