KR101372788B1 - Preparation method of highly pure pemetrexed disodium salt - Google Patents

Abstract

The present invention provides a preparation method of pemetrexed disodium salt. The present invention can prepare the pemetrexed disodium salt with at least 99.9% purity and preferably with 99.95% or more ultra-purity. Thus, the pemetrexed disodium salt can be sued as an active ingredient without an additional purification process.

Description

Preparation method of high purity pemetrexed disodium salt {Preparation method of highly pure pemetrexed disodium salt}

The present invention relates to a process for preparing high purity pemetrexed disodium salt.

Pemetrexed is N- [4- [2- (2-amino-4,7-dihydro-4-oxo-1 H -pyrrolo [2,3- d ] pyrimidin-5-yl) Ethyl] benzoyl] -L -glutamic acid, which is a 5-substituted pyrrolo [2,3- d ] pyrimidine compound having the structure of formula (1).

[Chemical Formula 1]

Pyrrolo [2,3- d ] pyrimidine compounds are known to have antifolate activity, and it is recognized that compounds having antifolate activity can be used as anticancer agents.

The pemetrexeds have also been found to be potent inhibitors for enzymes requiring several folates, including thymidine synthase, dihydrofolate reductase and glycineamide ribonucleotide formyltransferase.

The pemetrexed may be used as a pharmaceutically acceptable salt, and disodium salt is known to be particularly preferred. It is also known that the disodium salt is present in 2.5 or 7 hydrates.

Eli Liiy and Companny, a patent holder of pemetrexed disodium salt 7 hydrate and its preparation method, delivered Alimta, a treatment for lung cancer and pleural mesothelioma using the pemetrexed disodium salt 7 hydrate as an active ingredient. It is sold worldwide, and other manufacturers are already selling therapeutic agents containing the well-known pemetrexed disodium salt 2.5 hydrate as an active ingredient.

US Patent No. 5,416,211 discloses an improved method for synthesizing pemetrexed. Specifically, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), which is a peptide binding activator, and N -methylmorpholine, which is a base, are used in a dimethylformamide (DMF) solvent as in Scheme 1 below. NMM) discloses a process for preparing pemetrexed alkyl esters (preparation 5) and a process for converting them to pemetrexed (preparation 6).

[Reaction Scheme 1]

However, the synthesis method disclosed in the patent document has a low yield and low purity due to by-products, so it is difficult to apply on an industrial scale.

Organic Process Research & Development, volume 3 (3), pages 184-188,1999 discloses a synthesis method similar to the synthetic route disclosed in US Pat. No. 5,416,211.

[Reaction Scheme 2]

However, the method disclosed in this document does not directly convert the pemetrexed alkyl ester to pemetrexed, and as shown in Scheme 2, the pemetrexed diethyl ester is converted to pemetrexed diethyl ester p -toluenesulfonic acid. Purification with ( p- TsOH) salt is followed by conversion to pemetrexed and its disodium salt.

In addition, WO 01/14379 discloses hydrate Form I (2.5 hydrates) of pemetrexed disodium salts and methods for their preparation. To summarize the preparation method is shown in Scheme 3.

Scheme 3

That is, the patent document also describes that the pemetrexed alkyl ester can be purified with a p-toluenesulfonic acid (p-TsOH) salt to improve purity. However, the above synthesis method does not yield pemetrexed disodium salt (2.5 hydrate) having a purity of 99.9% or more.

All of the above-mentioned preparation methods are characterized by using dimethylformamide (DMF) as a solvent and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) as a peptide binding activator. It is done. However, DMF and CDMT are reacted with each other to generate the flexible materials as follows, thereby causing a problem in that the purity of the pemetrexed disodium salt is reduced.

International Patent Publication No. WO 2011/019986 discloses a method for preparing a pemetrexed alkyl ester using N -methylpyrrolidone (NMP) as a solvent for a condensation reaction, in recognition of the above problem. It is described that at least 99% of the pemetrexed disodium salt can be obtained.

[Reaction Scheme 4]

However, the ICH guideline and the US FDA guideline recommend that the impurity content is 0.1% or less and the purity of the active ingredient is 99.9% or more. In addition, the Japanese Patent Law further requires that the purity of the active ingredient be 99.95% or more.

Therefore, in order to sell a product containing the pemetrexed disodium salt as an active ingredient on the market, it is desirable to develop a method for producing the pemetrexed disodium salt with a high purity of at least 99.9%, more preferably at least 99.95%. Needed.

The inventors of the present invention have conducted a study to meet the demands of the industry, and have developed a method for producing pemetrexed disodium salt of 99.9% or more, preferably 99.95% or more.

US Patent No. 5,416,211 International Publication WO 2001/014379 International Publication WO 2011/019986

Organic Process Research & Development, volume 3 (3), pages 184-188, 1999

It is an object of the present invention to provide a process for the preparation of pemetrexed disodium salt in ultra high purity and high yield of at least 99.9%, preferably at least 99.95%.

The present invention provides a process for the preparation of high purity pemetrexed disodium salt in high yield.

According to an embodiment of the invention, the pemetrexed disodium salt is selected from (S1) N, N -dimethylacetamide (DMAc), N -ethyl-2-pyrrolidone (NEP) and 1,3-dimethyl-2- Preparing a compound of Chemical Formula 2 by condensation reaction of a compound of Chemical Formula 1 with L-glutamic acid, an ester thereof, or a salt thereof in the presence of an organic solvent selected from the group consisting of imidazolidinone (DMI);

[Chemical Formula 1]

(2)

(In Formula 2, R is H or alkyl of C ₁ ~ C ₆ )

(S2) hydrolyzing the compound of Chemical Formula 2 to prepare a pemetrexed of Chemical Formula 3; And

(3)

(S3) converting the compound of Formula 3 to a pemetrexed disodium salt of Formula 4;

[Chemical Formula 4]

It can be prepared through.

According to one embodiment of the invention, the step (S1) is more preferably carried out in the presence of an organic base or an inorganic base to promote the reaction.

The organic base may be selected from the group consisting of ammonia, C ₁ -C ₁₀ alkyl amine compounds, morphopin compounds, piperidine, and pyrrolidine, and it is most preferable to use N -methylmorpholine. However, the present invention is not limited thereto.

In addition, the inorganic base may be selected from the group consisting of metal carbonate compounds, metal bicarbonate compounds, and metal hydroxide compounds. However, the present invention is not limited thereto.

According to an embodiment of the present invention, in order to further improve the purity of the pemetrexed disodium salt, the compound of Formula 2 is preferably purified in the form of a salt, and the salt of the compound of Formula 2 is p -toluene of Formula 5 Preference is given to sulfonic acid salts.

[Chemical Formula 5]

According to an embodiment of the invention, the step (S1) is preferably carried out in the presence of a peptide binding activator to further promote the condensation reaction.

The peptide binding activators include dicyclocarbodiimide (DCC), N, N' -diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and may be selected from the group consisting of 2-chloro-4,6-dimethoxy-, 1,3,5-tri Most preferred is the use of azine (CDMT). However, the present invention is not limited thereto.

The (S1) step may be performed at room temperature, it may be carried out at 15 ~ 30 ℃. However, the present invention is not limited thereto.

The step (S2) may be carried out through a conventional ester hydrolysis reaction.

In addition, the step (S3) may be performed by the prior art, such as International Patent Publication No. WO 01/14379.

The purity of the pemetrexed disodium salt prepared through the preparation method of the present invention may be 99.9% or more, and more preferably 99.95% or more. Therefore, the pemetrexed disodium salt prepared through the preparation method of the present invention can be used as an active ingredient without the need for further purification.

The preparation method of the present invention can produce a high purity of at least 99.9% high purity, preferably at least 99.95% ultra high purity pemetrexed disodium salt. Thus, pemetrexed disodium salt can be used as an active ingredient without the need for further purification.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are illustrative of the present invention, and the present invention is not limited thereto.

Example

< Example 1 >: 2- [4- [2- (2-amino-4-oxo-4,7- Dihydro -3 H - Pyrrolo [2,3- d ] Pyrimidine -5-yl) ethyl] Benzoyl ] - L Glutamic acid Disodium  Manufacture of salt

In a flask 250 mL of 1,3-dimethyl-2-imidazolidinone (DMI) and 4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2,3- d ] 25 g (83.8 mmol) of pyrimidin-5-yl) ethyl] benzoic acid were mixed. To the mixture was added 26.54 mL (241.4 mmol) of N -methylmorpholine and 16.19 g (92.2 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine at 20-30 ° C. After the reaction solution was stirred at 20 to 30 ° C. for 1.5 hours to confirm that the reaction was completed, 18.73 g (92.2 mmol) of L -glutamic acid diethyl ester diluted in 100 mL of dichloromethane was added thereto and 2.5 hours at 20 to 30 ° C. Stirring to terminate the reaction. 500 mL of dichloromethane and 500 mL of purified water were added to the reaction solution, the mixture was stirred for 10 minutes, and the organic layer was separated. The separated organic layer was partitioned using 250 mL of purified water. The combined organic layers were washed with 250 mL of 20% brine and concentrated using a vacuum concentrator. Concentrated 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl]- L -glutamic acid diethyl ester and 250 mL of ethanol were mixed. 39.85 g (209.5 mmol) of p -toluenesulfonic acid monohydrate dissolved in 500 mL of ethanol at room temperature was added thereto, and the mixture was warmed to 75 to 80 ° C. and stirred for 1 hour. Thereafter, the reaction solution was cooled to 0-5 ° C., stirred for 1 hour, and the resulting solid was filtered and washed with 100 mL of ethanol. The filtered wet cake was added to 200 mL of ethanol and stirred at 20-25 ° C. for 1 hour, and then filtered and washed with 100 mL of ethanol. 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl by drying under reduced pressure at 35 to 40 ° C 41.95 g of) ethyl] benzoyl] -L -glutamic acid diethyl ester p -toluenesulfonic acid salt were obtained in a yield of 76.3%.

2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl prepared in flask ] -L -glutamic acid diethyl ester 37.5 g (57.2 mmol) of p -toluenesulfonic acid salt were mixed with 150 mL of purified water and cooled to 0-5 ° C. To the cooled mixture, 13.73 g (343.1 mmol) of sodium hydroxide dissolved in 450 mL of purified water were added while maintaining 0-5 ° C. The reaction solution was stirred at 0˜5 ° C. for 5 hours to confirm completion of the reaction. At this temperature, the pH was adjusted to 8.0 to 8.3 using 6N hydrochloric acid, and 3.75 g of aluminum oxide was added, stirred for 30 minutes, and filtered. 600 mL of ethanol was added to the filtrate and stirred overnight at room temperature. The resulting solid was cooled to 0-5 ° C., stirred for 3.5 hours, filtered and washed with 150 mL of ethanol. 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl by drying under reduced pressure at 35 to 40 ° C 28.6 g (yield: 96.8%) of ethyl] benzoyl] -L -glutamic acid disodium salt was obtained.

HPLC (area%): 99.96%, individual analogs 0.015% or less

< Example  2> 2- [4- [2- (2-amino-4-oxo-4,7- Dihydro -3 H - Pyrrolo [2,3- d ]Pipe Midin-5-yl) ethyl] Benzoyl ] - L Glutamic acid Disodium  Manufacture of salt

100 mL of N -ethyl-2-pyrrolidone (NEP) and 4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2,3- d ] pyridine in a flask 10 g (33.5 mmol) of midin-5-yl) ethyl] benzoic acid were mixed. To the mixture was added 10.6 mL (96.5 mmol) of N -methylmorpholine and 6.47 g (36.9 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine at 20-30 ° C. After confirming the reaction was completed by stirring the reaction solution at 20 to 30 ° C. for 1.5 hours, 18.73 g (92.2 mmol) of L -glutamic acid diethyl ester diluted in 100 mL of dichloromethane was added thereto, and the mixture was stirred at 20 to 30 ° C. for 2.5 hours. The reaction was terminated by stirring. 500 mL of dichloromethane and 500 mL of purified water were added to the reaction solution, the mixture was stirred for 10 minutes, an organic layer was separated, and the separated organic layer was partitioned using 250 mL of purified water. The combined organic layers were washed with 250 mL of 20% brine and concentrated using a vacuum concentrator. Concentrated 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl]- L -glutamic acid diethyl ester and 250 mL of ethanol were mixed. 39.85 g (209.5 mmol) of p -toluenesulfonic acid monohydrate dissolved in 500 mL of ethanol at room temperature was added thereto, and the mixture was warmed to 75 to 80 ° C. and stirred for 1 hour. Thereafter, the reaction solution was cooled to 0-5 ° C., stirred for 1 hour, and the resulting solid was filtered and washed with 100 mL of ethanol. The filtered wet cake was added to 200 mL of ethanol, stirred at 20-25 ° C. for 1 hour, and filtered and washed with 100 mL of ethanol. 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl by drying under reduced pressure at 35 to 40 ° C 17.54 g)) ethyl] benzoyl] -L -glutamic acid diethyl ester p -toluenesulfonic acid salt was obtained in a yield of 79.8%.

2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl prepared in flask ] -L -glutamic acid diethyl ester p -toluenesulfonic acid salt 14.0 g (21.3 mmol) was mixed with 56 mL of purified water and cooled to 0-5 ° C. To the cooled mixture, 5.12 g (128.1 mmol) of sodium hydroxide dissolved in 210 mL of purified water were added while maintaining 0-5 ° C. The reaction solution was stirred at 0-5 ° C. for 3 hours to confirm the completion of the reaction. At this temperature, the pH was adjusted to 7.8-8.0 using 6N hydrochloric acid, 1.0 g of aluminum oxide was added, stirred for 30 minutes, and filtered. 300 mL of ethanol was added to the filtrate and stirred overnight at room temperature. The resulting solid was cooled to 0-5 ° C., stirred for 3.5 hours, filtered and washed with 50 mL of ethanol. 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl by drying under reduced pressure at 35 to 40 ° C 9.98 g (yield: 90.5%) of sodium ethyl) benzoyl] -L -glutamic acid was obtained.

HPLC (area%): 99.97%, individual analogs 0.015% or less

< Example  3> 2- [4- [2- (2-amino-4-oxo-4,7- Dihydro -3 H - Pyrrolo [2,3- d ]Pipe Midin-5-yl) ethyl] Benzoyl ] - L Glutamic acid Disodium  Manufacture of salt

In a flask 300 mL of N, N -dimethylacetamide (DMAc) and 4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidine- 5-yl) ethyl] benzoic acid 30 g (100.6 mmol) were mixed. The mixture was cooled to −10 to −5 ° C. to give 12.2 mL (110.6 mmol) of N -methylmorpholine and 19.42 g (110.6 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine. Added. After the reaction solution was warmed to 5 to 10 ° C. and stirred for 3 hours to confirm that the reaction was completed, it was cooled to −10 to −5 ° C., and 22.47 g (110.6 mmol) of L -glutamic acid diethyl ester diluted in 100 mL of DMAc was added thereto. The reaction was terminated by warming to 5-10 ° C. and stirring for 2 hours. 300 mL of dichloromethane and 300 mL of purified water were added to the reaction solution, and the organic layer was separated by stirring for 10 minutes. The separated organic layer was partitioned using 300 mL of purified water. The combined organic layers were washed with 300 mL of purified water and concentrated using a vacuum concentrator. Concentrated 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl]- L -glutamic acid diethyl ester and 440 mL of ethanol were mixed. 47.82 g (251.4 mmol) of p -toluenesulfonic acid monohydrate dissolved in 830 mL of ethanol warmed to 70-85 ° C. was added and stirred at this temperature for 30 minutes. Thereafter, the reaction solution was cooled to 0-5 ° C., stirred for 1 hour, and the resulting solid was filtered and washed with 100 mL of ethanol. The filtered wet cake was added to 400 mL of ethanol, stirred at 20 to 25 ° C. for 1 hour, and filtered and washed with 100 mL of ethanol. 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl by drying under reduced pressure at 35 to 40 ° C 52.44 g of) ethyl] benzoyl] -L -glutamic acid diethyl ester p -toluenesulfonic acid salt were obtained in a yield of 79.5%.

2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl prepared in flask ] -L -glutamic acid diethyl ester 47.4 g (72.3 mmol) of p -toluenesulfonic acid salt were mixed with 474 mL of purified water and 100 mL of ethanol and cooled to 0-5 ° C. 17.35 g (433.7 mmol) of sodium hydroxide dissolved in 200 mL of purified water was added to the cooled mixture at 0 to 5 ° C. The reaction solution was stirred at 0-5 ° C. for 2 hours to confirm the completion of the reaction. 276 mL of purified water and 300 mL of ethanol were added thereto, and the pH was adjusted to 2.9 to 3.1 using 6N hydrochloric acid, warmed to 35 to 40 ° C, and stirred for 30 minutes. The resulting slurry was filtered to collect pemetrexeds and washed with purified water and ethanol. 300 mL of purified water and wet pemetrexed were adjusted to pH 8.0 using 2N sodium hydroxide, and 9.5 g of aluminum oxide was added. The mixture was warmed to 40 to 45 ° C, stirred for 30 minutes, filtered, and washed with 135 mL of purified water. 495 mL of ethanol was added to the filtrate, and the mixture was stirred at room temperature for 2 hours. The resulting solid was cooled to 0-5 ° C., stirred for 4 hours, filtered and washed with 100 mL of ethanol. 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl by drying under reduced pressure at 35 to 40 ° C 30.76 g)) ethyl] benzoyl] -L-glutamic acid disodium salt 2.5 hydrate was obtained in a yield of 82.4%.

HPLC (area%): 99.97%, individual analogs 0.015% or less

Comparative Example

< Comparative Example  1> 2- [4- [2- (2-amino-4-oxo-4,7- according to the method described in US Pat. No. 5,416,211. Dihydro -3 H - Pyrrolo [2,3- d ] Pyrimidine -5-yl) ethyl] Benzoyl ] - L Preparation of Glutamic Acid

2.0 g (6.74 mmol) of 4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d in 2.0 mL (6.74 mmol) in 23 mL of dimethylformamide (DMF) under nitrogen. 1.40 g (13.8 mmol) of N -methylmorpholine and 1.17 g (6.70 mmol) of 4-chloro-2,6-dimethoxytriazine were added to] pyrimidin-5-yl) ethyl] benzoic acid. Formation of active esters was investigated by HPLC analysis of aliquots. After 40 minutes at room temperature, 0.70 g (6.9 mmol) of N -methylmorpholine were added followed by 1.56 g (7.37 mmol) of L -glutamic acid diethyl ester hydrochloride. After 30 minutes HPLC analysis showed substantially complete consumption of the active ester and 2- [4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2,3- d ] Pyrimidin-5-yl) ethyl] benzoyl] -L -glutamic acid dimethyl ester is shown. The reaction mixture was filtered, the product was concentrated and purified by silica chromatography (eluent 1: 4 methanol: methylene chloride). Pure fractions were combined and 1.30 g of the product were obtained in 43% yield.

0.50 g (1.1 mmol) of 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidine-5 prepared above A mixture of -yl) ethyl] benzoyl] -L -glutamic acid dimethyl ester and 3.3 mL 2N aqueous sodium hydroxide was stirred for 48 h at room temperature and neutralized to pH 5 with 6M aqueous hydrochloric acid. The precipitate was filtered off, washed with water and dried to give 0.277 g of the product in 59% yield.

HPLC: 99.84%, individual analog 0.1% or less

< Comparative Example  2> International Publication Patent WO  2- [4- [2- (2-amino-4-oxo-4,7- according to the method described in 01/14379 Dihydro -3 H - Pyrrolo [2,3- d ] Pyrimidine -5-yl) ethyl] Benzoyl ] - L Glutamic acid Disodium  Manufacture of salt

5.0 g (7.6 mmol) 2- [4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2,3- d ] pyrimidine-5 in 500 mL flask -Yl) ethyl] benzoyl] -L -glutamic acid diethyl ester and 33.5 mL of 1N aqueous sodium hydroxide were added. The reaction mixture was stirred for 30 minutes and 16.5 mL of purified water was added. The pH of the reaction mixture was adjusted to 7.7 and warmed to 60-70 ° C. 340 mL of 3A ethanol was added while maintaining this temperature. The light blue solution was cooled to room temperature and stirred for 1 hour. The slurry was filtered and washed with 3A ethanol. Dry under reduced pressure at 40 ° C. to give 2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl 3.89 g of] benzoyl] -L -glutamic acid disodium salt were obtained in a yield of 100% (water: 9.1%).

HPLC: 99.87%

< Comparative Example  3> International Patent WO  2- [4- [2- (2-amino-4-oxo-4,7- according to the method described in 2011/019986 Dihydro -3 H - Pyrrolo [2,3- d ] Pyrimidine -5-) ethyl] Benzoyl ] - L Glutamic acid Disodium  Manufacture of salt

10 mL of N -methyl-2-pyrrolidone (NMP) and 4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2,3-] in a flask under nitrogen atmosphere d ] 1 g of] pyrimidin-5-yl) ethyl] benzoic acid were mixed at room temperature. To the mixture was added 1.06 mL of N -methylmorpholine and 0.65 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The reaction solution was warmed to 30 ~ 35 ℃ stirred for 1 hour. 0.78 g of L -glutamic acid dimethyl ester hydrochloride was added thereto and stirred for 1 hour. 10 mL of purified water and 10 mL of dichloromethane were added, and the organic layer was separated by stirring for 10 to 20 minutes. The aqueous layer was extracted with 10 mL of dichloromethane, and the combined organic layers were washed with 10 mL of saturated sodium bicarbonate solution and concentrated under reduced pressure. 1.59 g of p -toluenesulfonic acid monohydrate dissolved in 20 mL of methanol and 20 mL of methanol was added to the concentrated residue at room temperature. The mixture was warmed to 60-65 ° C., stirred for 1-2 h, cooled to 20-25 ° C., suspended and filtered. Washed with 10 mL of methanol and dried at 45 ° C. for 5 hours to remove 2- [4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2,3- d ] pyridine Midin-5-yl) ethyl] benzoyl] -L -glutamic acid diethyl ester p -toluenesulfonic acid salt 1.08 g was obtained in 51% yield (purity: 98.36%).

2- [4- [2- (2-amino-4-oxo-4,7-dihydro- 3H -pyrrolo [2,3- d ] pyrimidin-5-yl) ethyl] benzoyl] L -glutamic acid diethyl ester p -toluenesulfonic acid salt 5 g of 1.91 g of sodium hydroxide dissolved in 95.6 mL purified water under nitrogen atmosphere was added at 0-5 ° C. and stirred for 45 minutes, the pH was adjusted to 7.81 using 1N hydrochloric acid, 300 mL of acetone was added thereto, and stirred for 1 hour. Filtered. The resulting solid was washed with 15 mL of acetone and dried at 30-35 ° C. for 5 hours to give 2- [4- [2- (2-amino-4-oxo-4,7-dihydro-3 H -pyrrolo [2 4.1 g of, 3- d ] pyrimidin-5-yl) ethyl] benzoyl] -L -glutamic acid disodium salt were obtained in 99.7% yield.

HPLC (% area): 99.69%

HPLC  (High Performance Liquid Chromatography) Measurement Method

- Manufacturer: Agilent Technologies

-Device Name: SYS-LC-1100 series

Column: C ₁₈ column, 4.6 × 50mm, 5 ㎛

Mobile phase: mobile phase A: 0.1% phosphoric acid solution, mobile phase B: acetonitrile

Flow rate: 1.0 ml / min (about 16 minutes of pemetrexed disodium salt detection time)

Detector wavelength: 230 nm

Temperature: 25 ℃

Claims (12)

(S1) in an organic solvent selected from the group consisting of N, N -dimethylacetamide (DMAc), N -ethyl-2-pyrrolidone (NEP) and 1,3-dimethyl-2-imidazolidinone (DMI) , Dicyclocarbodiimide (DCC), N, N' -diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and 2-chloro-4 , 6-dimethoxy-1,3,5-triazine (CDMT) in the presence of a peptide binding activator and N -methylmorpholine, sodium carbonate (Na ₂ CO ₃ ) and potassium carbonate (K ₂ CO ₃ ) in the presence of a base selected from the group consisting of, a condensation reaction with a compound of formula 1 and L- glutamic acid C ₁ ~ C ₂ ester or salts thereof to prepare a compound of formula (2), p -toluenesul Adding ponic acid to prepare a p -toluenesulfonic acid salt of Formula 5; And
[Chemical Formula 1]

(2)

(In Formula 2, R is C ₁ ~ C ₂ alkyl)
[Chemical Formula 5]

(S2) converting into a pemetrexed disodium salt of Formula 4 by adding an aqueous sodium hydroxide (NaOH) solution to the compound of Formula 5;
[Chemical Formula 4]

To include, the purity of the prepared pemetrexed disodium salt is at least 99.9% pemetrexed disodium salt manufacturing method. delete delete The method for preparing pemetrexed disodium salt according to claim 1, wherein the base is N -methylmorpholine. delete delete delete delete delete The method of claim 1, wherein the peptide binding activator is 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT). delete The method of claim 1, wherein the prepared pemetrexed disodium salt has a purity of 99.95% or more.