NOVEL PROCESS FOR THE PREPARATION PEMETREXED DISODIUM HEMIPENTAHYDRATE (2.5 HDYRATE) AND CRYSTALLINE FORM THEREOF

FIELD OF INVENTION

The present invention is related to a novel process for the preparation of Pemetrexed disodium hemipentahydrate, which acts as a drug for the treatment of pleural mesothelioma as well as non-small cell lung cancer.

BACKGROUND OF THE INVENTION

Pemetrexed disodium is a multitargeted antifolate agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication and treatment of pleural mesothelioma and non-small cell lung cancer.

U.S.Patent NOs.5, 416, 211, 5,344,932 and 5,539,113 disclose the processes for preparing certain substituted Pyrrolo [2, 3-D] pyrimidine derivatives including Pemetrexed.

Syntheses of a number of Pyrrolo [2, 3-D] pyrimidine based antfolates including Pemetrexed, are described in U.S.Pat.Nos. 4,966,206, 5,106,974 and 5,217,974.

C.J.Barnett et.al., 'A Practical Synthesis of Multitargeted Antifolate LY231514,"Organic Process research & Developmental 3, Pages, 184-188,1999,describe a process for the preparation of Pemetrexed disodium.

Another US patent application 2003/0216416 describes the synthesis of heptahydrate crystal form of Pemetrexed disodium.

The objective of the present invention is to provide a method for preparing a crystalline form of hemipentahydrate of Pemetrexed disodium in high purity employing an industrially viable method.

SUMMARY OF THE INVENTION

The primary aspect of the present invention is to provide a method for the preparation of Pemetrexed disodium in highly purified form comprising;

a) condensing 4-[2-(2-Amino-4,7-dihydro-4-oxo-1 H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]-benzoic acid with ester in a solvent using a coupling agent and N-Methylmorpholine and isolating the product as a salt;

b) hydrolysing of the ester obtained in step (a) using aqueous alkali and adjusting the pH to 3.5 to get Pemetrexed;

c) purifying the Pemetrexed obtained in step (b) by dissolving in an organic solvent and diluting the mixture with water and alcohol to get pure Pemetrexed crystals.

d) converting Pemetrexed diacid to Pemetrexed disodium using alkaline solution and isolate the crystalline form of Pemetrexed disodium hemipentahydrate by precipitating in water miscible solvents.

The primary aspect of the present invention is to provide a method for the preparation of novel hemipentahydrate crystalline form of Pemetrexed disodium in highly purified form.

Another aspect of the invention is to provide an industrially viable method for the preparation of Pemetrexed disodium.

DETAILED DESCRIPTION OF PRESENT INVENTION:

In the present invention Pemetrexed disodium salt is prepared using the following steps which involves;

a) condensing 4-[2-(2-Amino-4,7-dihydro-4-oxo-1 H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]-benzoic acid with ester in a solvent using a coupling agent and N-Methylmorpholine and isolating the product as a salt;

b) hydrolysing of the ester obtained in step (a) using aqueous alkali and adjusting the pH to 3.5 to get Pemetrexed;

c) purifying the Pemetrexed obtained in step (b) by dissolving in an organic solvent and diluting the mixture with water and alcohol to get pure Pemetrexed crystals.

d) converting Pemetrexed diacid to Pemetrexed disodium using alkaline solution and isolate the crystalline form of Pemetrexed disodium hemipentahydrate by precipitating in water miscible solvents.

Solvents used in step (a) is, N,N-dimethyl formamide, dimethylacetamide and most preferably N,N-dimethyl formamide

The ester used in step (a) is methyl, ethyl, propyl, isopropyl, n-butyl ester of L-Glutamic acid, more preferably methyl or ethyl ester, most preferably dimethyl ester.

The coupling agents used in step (a) is N,N'-Dicyclohexylcarbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-Chloro-4,6-dimethoxytriazine (CDMT) and most preferably 2-Chloro-4,6-dimethoxytriazine.

The product isolated as a salt in step (a) is mesylate, besylate and most preferably Tosylate salt using acids such as methyl sulfonic acid, benzene sulfonic acid and p-toluene sulfonic acid.

The aqueous alkali used for the hydrolysis of ester groups in step (b) is sodium hydroxide, potassium hydroxide, lithium hydroxide, most preferably sodium hydroxide. The acid used to adjust the pH is inorganic or organic acid, preferably inorganic acid, more preferably hydrochloric acid, sulfuric acid, nitric acid, most preferably hydrochloric acid.

The solvent used in step (c) is N, N-dimethyl formamide, N,N-dimethylacetamide and most preferably N,N-dimethyl formamide.

Solvent mixture used in step (c) is a mixture of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol in water, most preferably isopropanol in water.

The ratio of solvent and water used in step (c) between 1:5 and 5:1, most preferably 1:2. The pH of the solution adjusted in step (d) is between 7 and 9, preferably between 7.5 and 8.5, most preferably between 8.5 and 9.

The solvents used for isolating the Pemetrexed disodium in step (d) is water miscible solvents such as ethanol, methanol, isopropyl alcohol, tetrahydrofuran and t-butanol, preferably tetrahydrofuran and t-butanol, most preferably t-butanol.

The Pemetrexed disodium isolated in step (d) as crystalline form exhibits X-ray diffraction pattern with peaks as Angle °2 Theta at 4.7, 7.7, 9.4,10.4,14.2,14.9,15.5, 17.2,17.9,18.6,19.3, 20.8, 22.9, 23.8, 25.9, 27.4, 28.4, 28.9 and 39.3 ± 0.2°.

The Pemetrexed disodium isolated in step (d) as hemipentahydrate form which is more stable and recovered as a pure form.

PEMETREXED SODIUM PROCESS FLOW CHART


Examples 1:

Synthesis of Pemetrexed dimethyl ester:

To a suspension of [(4-[2-(2-Amino-4,7-Dihydro-4-oxo-1H-Pyrrolo[2,3-d]Pyrimidin-5-yl)Ethyl]Benzoic Acid (1 kg) in N,N-Dimethyl formamide(6lit) was added N-Methyl morpholine(1.1 lit) and CDMT(2-Chloro-4,6-dimethoxy triazine)(0.8kg) with stirring at 25-30°C under nitrogen atmosphere. The reaction mixture was stirred for 2 hrs at the same temperature. L-Glutamic acid Dimethyl ester hydrochloride (0.9kg) was added to the reaction mixture and stirring was continued for another 2 hrs at 25-30°C under nitrogen atmosphere. After completion of reaction, the reaction mixture was diluted with dichloromethane and water and stirred for 15 minutes. The organic layer was separated and dichloromethane was distilled out almost completely at 40-45°C to yield Pemetrexed Dimethyl ester. To the residue obtained, methanol containing p-Toluene sulfonic acid (1.5 kg) was added with stirring at 25-30°C under nitrogen atmosphere. The reaction mixture was refluxed for 2 hrs and then cooled to 20-25°C. The solid formed was filtered and dried to yield Tosylate salt of Pemetrexed Dimethyl ester.(1.5 kg)

Examples 11:

Synthesis of Pemetrexed:

To the suspension of Pemetrexed dimethyl ester (1kg) in 1N sodium hydroxide (7lit) was stirred under nitrogen atmosphere at 25-30°C for 3 hrs. After completion of reaction, the solution was diluted with 25% sodium chloride solution with stirring. The solid formed was filtered and the wet cake was again suspended in water-methanol mixture (15 lit). Adjusts the pH to 3.0 -3.5 using 6N hydrochloric acid with stirring at 25-30°C. After pH adjustment, the slurry was heated to 40-45°C for 15minutes and cooled to 25-30°C. The solid formed was filtered and washed with methanol: water mixture to yield crude Pemetrexed. The crude product was dissolved in DMF (3.25lit) at 40-45°C. The solution obtained was diluted with IPA: Water mixture (10 lit) and stirred at the same temperature for 60 minutes. The reaction mixture was cooled to 20-25°C. The crystallized material was filtered and dried to yield pure Pemetrexed. (0.6kg)

Examples 111:

Synthesis of crystalline Pemetrexed disodium hemipentahydrate (2.5 hydrate)

2-{4-[2-(2-Amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]-benzoyl]-L-Glutamic acid (Pemetrexed) (1kg) was suspended in distilled water (7 Lit). The pH of the suspension was adjusted to 8.5 to 9.0 using 1N sodium hydroxide solution. The clear solution obtained after pH adjustment was filtered through 0.2u and precipitated with t-Butanol (70 lit) at 25-30°C slowly with stirring. The solid obtained was filtered and dried under vacuum to yield crystalline form Pemetrexed disodium hemipentahydrate (2.5 hydrate).

Yield: 1 kg (w/w: 100%)
Purity by HPLC: >99.5%
Water content: Between 7.5% and 11.5%

X-Ray diffraction value for crystalline form of Pemetrexed disodium hemipentahydrate (2.5 hydrate) is tabulated in Table 1 and the XRD spectra in Fig I

We claim:

1. A process for preparing Pemetrexed sodium hemipentahydrate comprising:

a) condensing 4-[2-(2-Amino-4,7-dihydro-4-oxo-1 H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]-benzoic acid with ester in a solvent using a coupling agent and N-Methylmorpholine and isolating the product as a salt;

b) hydrolysing of the ester obtained in step (a) using aqueous alkali and adjusting the pH to 3.5 to get Pemetrexed;

c) purifying the Pemetrexed obtained in step (b) by dissolving in an organic solvent and diluting the mixture with water and alcohol to get pure Pemetrexed crystals.

2. The process as claimed in claim 1, wherein solvents used in step (a) is N,N-dimethyl formamide, N.N-dimethyl acetamide and most preferably N,N-dimethyl formamide.

3. The process as claimed in claim 1, wherein the ester used in step (a) is methyl, ethyl, propyl, isopropyl, n-butyl ester of L-Glutamic acid, more preferably methyl or ethyl ester, most preferably dimethyl ester.

4. The process as claimed in claim 1, wherein the coupling agents used in step (a) is N, N'-Dicyclohexylcarbodiimide (DCC), 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 2-Chloro-4,6-dimethoxy triazine (CDMT) and most preferably 2-Chloro-4,6-dimethoxy triazine.

5. The process as claimed in claim 1, wherein the product isolated as a salt in step (a) is mesylate, besylate and most preferably tosylate salt using acids such as methyl sulfonic acid, benzene sufonic acid and p-toluene sulfonic acid.

6. The process as claimed in claim 1, wherein the aqueous alkali used for the hydrolysis of ester groups in step (b) is sodium hydroxide, potassium hydroxide, lithium hydroxide, most preferably sodium hydroxide.

7. The process as claimed in claim 1, wherein the acid used to adjust the pH is inorganic or organic acid, preferably inorganic acid, more preferably hydrochloric acid, sulfuric acid, nitric acid, most preferably hydrochloric acid.

8. The process as claimed in claim 1, wherein the solvent used in step (c) is N,N-dimethyl formamide, N,N-dimethylacetamide and most preferably N.N-dimethyl formamide.

9. The process as claimed in claim 1, wherein the water and alcohol mixture used in step (c) is a mixture of methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol in water, most preferably isopropanol in water.

10. The process as claimed in claim 1, wherein the ratio of solvent and water used in step (c) between 1:5 and 5:1, most preferably 1:2.

11. The process as claimed in claim 1, wherein the pH of the solution adjusted in step (d) is between 7 and 9, preferably between 7.5 and 8.5, most preferably between 8.5 and 9; the solvents used for isolating the Pemetrexed disodium in step (d) is water miscible solvents such as ethanol, methanol, isopropyl alcohol, tetrahydrofuran and t-butanol, preferably tetrahydrofuran and t-butanol, most preferably t-butanol water miscible solvents such as ethanol, methanol, isopropyl alcohol, tetrahydrofuran and t-butanol, preferably tetrahydrofuran and t-butanol, most preferably t-butanol.

12. The process as claimed in claim 1, wherein the Pemetrexed disodium isolated in step (d) as crystalline form with X-ray diffraction pattern with peaks as Angle °2 Theta at 4.7, 7.7, 9.4,10.4,14.2,14.9,15.5, 17.2,17.9,18.6,19.3, 20.8, 22.9, 23.8, 25.9, 27.4, 28.4, 28.9 and 39.3 ± 0.2°.

13. The process as claimed in claim 1, wherein Pemetrexed disodium isolated in step (d) as hydrate form which is more stable and recovered as a pure form, most particularly as 2.5 hydrate (hemipentahydrate).

14. The process for the preparation of Pemetrexed disodium hemipentahydrate such as herein described and exemplified.