DESC:FORM-2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF PEMETREXED AND ITS INTERMEDIATES

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Pemetrexed and its intermediates, which are substantially free of N-methyl impurities.

BACKGROUND OF THE INVENTION

Pemetrexed (1) is chemically known as N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid. Pemetrexed is approved as disodium salt (2). Pemetrexed disodium (2) is marketed under the brand name of Alimta®. Alimta® is an Antineoplastic agent, which is a Folate analog metabolic inhibitor indicated for Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer.

Formula 1

Formula 2

Pemetrexed (1) and its sodium salt (2) are first disclosed in US 5,344,932. US ‘932 patent discloses a lengthy process for the preparation of Pemetrexed disodium (2), wherein 4-hydroxy-6-aminopyrrolo[2,3-d]pyrimidine (A) is reacted with pivaloyl chloride to produce a Compound of Formula (B), which is treated with N-iodosuccinimide to produce a Compound of Formula (C). The resulting compound is reduced with Zinc powder to produce Compound of Formula (D). Compound (D) is condensed with Compound (E) to produce Compound of Formula (F), which undergoes reduction using palladium carbon to produce Compound (G), which is treated with sodium hydroxide to get Pemetrexed disodium salt (2).

The process as shown in Scheme-I below:

Scheme-I

It is recognized that this procedure is especially problematic for large-scale operations with few disadvantages, like the process is troublesome and time consuming as it involves 63 hours to complete the reaction of reduction and hydrolysis steps.

US 5,416,211, reported a different process for the preparation of Pemetrexed (1), wherein 2-bromo-4-(4-carbomethoxyphenyl)butanal is reacted with 2,4-diamino-6-hydroxypyrimidine to produce a Compound of Formula (H), which is hydrolyzed with aqueous hydrochloric acid to produce Compound of Formula (3). The resulting compound (3) is treated with L-glutamic acid dimethyl ester hydrochloride in presence of N-methylmorpholine and 4-chloro-2,6-dimethoxytriazine to produce Pemetrexed dimethyl ester (I). Pemetrexed dimethyl ester undergoes hydrolysis to produce Pemetrexed.

The process as shown in Scheme-II below:

Scheme-II

The process is not industrial viable because it results in less yield of only 43% overall. It has been observed that the product obtained by repeating the process, is green in color and has purity of about 50% due to the presence of several undesired by-products as impurities. It has been practically experienced that the removal of green color of the product is difficult and it carries up to Pemetrexed Disodium. Further, N-methyl Pemetrexed dimethyl ester impurity is formed in condensing step using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CMDT) and N-methyl morpholine (NMM).

US 6,013,828, reported another process for the preparation of Pemetrexed disodium (2), wherein the Compound (3) is treated with L-glutamic acid diethyl ester hydrochloride in the presence of N-methylmorpholine and 4-chloro-2,6-dimethoxytriazine to produce Pemetrexed diethyl ester (4), which is treated with p-toluenesulfonic acid (p-TSA) to produce Pemetrexed diethyl ester p-TSA salt (J), which is hydrolyzed to get Pemetrexed (1). The obtained Pemetrexed is treated with sodium hydroxide to produce Pemetrexed disodium (2).

The process as shown in Scheme-III below:

Scheme-III

The above route has disadvantages like additional step of p-TSA salt formation to remove the N-methyl impurity during the process. Additional control is needed in Pemetrexed disodium drug substance for Pemetrexed diethyl ester p-TSA salt (J).

US 8,981,090, reported another process for the preparation of Pemetrexed (1), wherein the Compound (3) is treated with L-glutamic acid diethyl ester in the presence of chemical agent being selected from 2-chloro-4,6-dimethoxy-1,3,5-triazine, N,N'-dicyclohexylcarbodiimide, hydroxybenzotriazole and 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide to produce Pemetrexed diethyl ester (4), which is hydrolyzed to get Pemetrexed (1).

The process as shown in Scheme-IV below:

Scheme-IV

The above process has disadvantages like use of coupling reagent 2-chloro-4,6-dimethoxy-1,3,5-triazine is required N-Methylmorpholine as a base, which results in the formation of N-methyl impurity. Using other coupling reagents such as N,N'-dicyclohexylcarbodiimide, hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide are difficult to remove the formation of corresponding by-products. N,N'-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), are very difficult to remove from reaction mass. In addition of this DCC is not water soluble and highly hazardous.

WO 2012056285, reported another process for the preparation of Pemetrexed, wherein the Compound (3) is treated with L-glutamic acid diethyl ester hydrochloride in presence of acid activating reagent having carbodiimide group to produce Pemetrexed diethyl ester (4), which is hydrolyzed to get Pemetrexed (1).

Pemetrexed obtained by the processes described in the prior art are often associated with various impurities especially N-Methyl impurities of a compound of formula (5) and (6). Unacceptable amounts of impurities are generally formed along with Pemetrexed.

Formula 5

Formula 6

Considering the importance of Pemetrexed (1) and Pemetrexed disodium (2), there is always a need for an alternative and improved process, which involves the use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. There remains a need for an improved process for the preparation of Pemetrexed and its intermediates, which minimizes or eliminates the above problems and is convenient to operate on a commercial scale.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is an improved process for the preparation of Pemetrexed disodium and its intermediates with high purity and good yield on commercial scale, which is substantially free of N-methyl impurities.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of Pemetrexed disodium (2):

Formula 2
which comprises:
(i) reacting a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or protecting group,
with a Compound of Formula (7);

Formula 7
wherein R1 is a carboxyl protecting group;
in the presence of TBTU as a coupling agent to produce a Compound of Formula (4A);

Formula 4A
wherein R1 is a carboxyl protecting group,
(ii) hydrolyzing the obtained Compound of Formula (4A) to produce Pemetrexed (1); and

Formula 1
(iii) optionally converting Pemetrexed (1) to Pemetrexed disodium (2).

In another embodiment, the present invention provides an improved process for the preparation of Pemetrexed disodium (2):

Formula 2
which comprises:
(i) reacting a Compound of Formula (3);

Formula 3
with L-glutamic acid diethyl ester;

in the presence of TBTU as a coupling agent to produce a Compound of Formula (4);

Formula 4
(ii) hydrolyzing the obtained Compound of Formula (4) to produce Pemetrexed (1); and

Formula 1
(iii) optionally converting Pemetrexed (1) to Pemetrexed disodium (2).

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of Pemetrexed disodium (2):

2
which comprises:
(i) reacting a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or protecting group,
with a Compound of Formula (7);

Formula 7
wherein R1 is a carboxyl protecting group;
in the presence of TBTU as a coupling agent to produce a Compound of Formula (4A);

Formula 4A
wherein R1 is a carboxyl protecting group,
(ii) hydrolyzing the obtained Compound of Formula (4A) to produce Pemetrexed (1); and

Formula 1
(iii) converting Pemetrexed (1) to Pemetrexed disodium (2).

In still another embodiment, wherein, R is a hydrogen or protecting group comprises alkyl group such as methyl, ethyl, propyl and/or butyl.

In still another embodiment, R1 is a carboxyl protecting group comprising of methyl, ethyl, propyl and/or butyl.

In still another embodiment, step (i) is carried out in the presence of 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) as a coupling agent.
The major advantage of using TBTU as a coupling agent is that the formed corresponding by-products, which are water soluble and can be easily removed from reaction mass, whereas in case of other coupling agents, the corresponding by-products are difficult to remove. In addition to above, the other coupling agent like DCC is not water soluble and highly hazardous.

Further the use of TBTU avoids the formation of N-methyl Pemetrexed diethyl ester impurity (5) and gives the final product with high yield.

In still another embodiment, step (i) is carried out in the presence of a base in a solvent.

In still another embodiment, the base is organic or inorganic base. The organic base comprises diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and/or mixtures thereof.

In still another embodiment, solvent comprises water, dimethyl formamide (DMF), acetone, acetonitrile, ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol, petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether and/or mixtures thereof.

In another embodiment, the step (i) reaction is carried out at a temperature of about 10°C to about 90°C.

In another embodiment, the step (i) reaction of is carried out from about 2 hours to 10 hours. In an embodiment of the present invention, the reaction is carried out from about 2 hours to 4 hours.

In another embodiment, hydrolysis reaction of step (ii) is carried out in an acid or alkali media, using a group comprising of hydrochloric acid, sodium hydroxide and/or sodium methoxide to produce Pemetrexed (1).

In another embodiment, the step (ii) reaction is carried out at a temperature of about 10°C to about 40° C.

In another embodiment, the step (ii) reaction of is carried out in about 2 hours to about 18 hours. In an embodiment of the present invention, the reaction is carried out in about 2 hours to about 4 hours.

In another embodiment, after completion of the step (ii) reaction adjusted the pH of the reaction mass to 3.0-3.5 by adding acid such as hydrochloric acid.

In another embodiment, converting Pemetrexed (1) to Pemetrexed disodium (2) is carried out using alkaline solution by adjusting the pH.

In another embodiment, alkaline solution comprises sodium hydroxide and/or sodium hydroxide in water media.

In one more embodiment, the step (iii) reaction are carried out at room temperature or 10°C to about 60°C depending upon the solvent used in the reaction for a time period of about 2 to 5 hours.

In still another embodiment, after adjusting the pH with alkali the reaction mass and maintained for 2 h at 20-50° C. Filtering the reaction mixture and dried at 30-55° C under reduced pressure.

In still another embodiment, the present invention provides an improved process for the preparation of Pemetrexed disodium (2):

Formula 2
which comprises:
(iv) reacting a Compound of Formula (3);

Formula 3
with L-glutamic acid diethyl ester;

in the presence of TBTU as a coupling agent to produce a Compound of Formula (4);

Formula 4
(v) hydrolyzing the obtained Compound of Formula (4) to produce Pemetrexed (1); and

Formula 1
(vi) converting Pemetrexed (1) to Pemetrexed disodium (2) in an alkaline solution.

In another embodiment, Compound of Formula (3) can be prepared by known methods available in the literature.

In another embodiment, purification of Pemetrexed (1) and Pemetrexed disodium (2) is carried out by conventional methods like crystallization using a solvent or mixture of solvents.

In another embodiment, the present invention provides that Pemetrexed disodium (2) obtained is in crystalline form or a hydrate form.

As used herein, the term "reduced pressure" refers to a pressure below 50 mm of Hg.

Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying may be carried out at temperature of less than 100°C, or less than about 70°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or any other suitable time period.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Preparation of N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester (Pemetrexed diethyl ester) (4).

N,N-Diisopropylethylamine (DIPEA, 32.5 g) was added to a suspension of 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d]pyrimidin-5-yl)ethyl] benzoic acid (3) (25 g) and L-glutamic diethyl ester hydrochloride (23.8 g), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 32.2 g) in N,N-Dimethylformamide (100 ml) was added under nitrogen atmosphere at 20-30°C. Further, reaction mixture was stirred for ~2 h and progress of reaction was monitored by qualitative HPLC. Thereafter, purified water was added to the reaction mixture and stirred for 3 h at 20-30°C. The product was filtered and washed with purified water and suck dried under vacuum. The dried material was purified from ethanol-acetone followed by isopropyl alcohol-purified water in the presence of aqueous sodium dithionite and dried at 40-50°C temperature under reduced pressure (100-20 mm Hg) for 12h to afford N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]-pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid diethyl ester (Pemetrexed diethyl ester) (4) (30.8 g, 76% yield) with Chromatographic Purity (by HPLC): 99.7%.

Example 2: Preparation of N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl]- L-glutamic acid (Pemetrexed) (1).
Sodium hydroxide (16.55 g) was charged in water for injection (700 ml) at below 30°C and stirred the solution at 22-27°C for 15 min to obtained aq. sodium hydroxide solution. Pemetrexed diethyl ester (3) (50 g) was added to this aq. sodium hydroxide solution at 22-27°C under nitrogen atmosphere. Further, reaction mixture was stirred for ~1 h and the progress of reaction was monitored by qualitative HPLC. Thereafter, ethanol was added at 20-30°C under nitrogen atmosphere. pH of the reaction mass was adjusted to 3.0-3.5 by adding hydrochloric acid solution (~17% w/w hydrochloric acid solution) at 20-30°C under nitrogen atmosphere. Stirring was continued at 20-30°C under nitrogen atmosphere for 15 min. Further, the reaction mass temperature was raised to 60-70°C and continued the reaction mass at this temperature for 30 min. The product was filtered and washed with a mixture of ethanol and water for injection (200 ml, -prepared by mixing 100 ml ethanol with 100 ml water for injection at 20-30 °C) under nitrogen atmosphere. The wet filtered mass (~35 g) was dried under reduced pressure (~100 mm Hg) for 12 h at 40-50°C. The obtained crude Pemetrexed was purified from dimethyl Sulfoxide-ethanol in the presence of aqueous sodium dithionite followed by ethanol-purified water, filtered and dried at 40-50°C temperature under reduced pressure (100-20 mm Hg) for 12h to afford N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl]-L-glutamic acid (Pemetrexed) (1) (36.5 g, 82% yield) with Chromatographic Purity (by HPLC): 99.9%.

Example 3: Preparation of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl]- L-glutamic acid, disodium salt (Pemetrexed disodium) (2).
Pemetrexed (35 g) was suspended in water for injection (350 ml) at 20-30°C under nitrogen atmosphere and pH was adjusted to 7.5-8.0 by slowly adding ~9% w/w aqueous sodium hydroxide solution (70 ml, prepared by dissolving 6.7 g of sodium hydroxide in 70 ml of water for injection at 20-30°C) at 20-30°C under nitrogen atmosphere. The stirring was continued for 15 min. Ethanol (1050 ml) was added to this reaction mass and it was stirred for 2 h, later the solid was filtered and dried at 40-50°C temperature under reduced pressure (100-20 mm Hg) for 4 h to afford N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl]- L-glutamic acid, disodium salt (Pemetrexed disodium) (2) (35.1 g, 82% yield) with Chromatographic Purity (by HPLC): 99.9%. ,CLAIMS:WE CLAIM:

1. An improved process for the preparation of Pemetrexed disodium (2):

Formula 2

which comprises:
(i) reacting a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or protecting group,
with a Compound of Formula (7);

Formula 7
wherein R1 is a carboxyl protecting group;
in the presence of TBTU as a coupling agent to produce a Compound of Formula (4A);

Formula 4A
wherein R1 is a carboxyl protecting group,
(ii) hydrolyzing the obtained Compound of Formula (4A) to produce Pemetrexed (1); and

Formula 1
(iii) converting Pemetrexed (1) to Pemetrexed disodium (2).

2. The process as claimed in claim 1, wherein, the protecting group comprises alkyl group like methyl, ethyl, propyl and/or butyl and R1 is a carboxyl protecting group which comprises methyl, ethyl, propyl and/or butyl.

3. The process as claimed in claim 1, wherein step (i) is carried out in the presence of a base and a solvent.

4. The process as claimed in claim 3, suitable base comprises diisopropylamine, diisopropylethylamine, triethylamine, dimethylamine, trimethyl amine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and/or mixtures thereof.

5. The process as claimed in claim 3, suitable solvent used in step (i) comprises, water, dimethyl formamide (DMF), acetone, acetonitrile, ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol, petroleum ether, diispropyl ether, methyl tert-butyl ether, diethyl ether and/or mixtures thereof.

6. An improved process for the preparation of a Compound of Formula (4A):

Formula 4A
which comprises:
(i) reacting a Compound of Formula (3A);

Formula 3A
wherein R is a hydrogen or protecting group,
with a Compound of Formula (7);

Formula 7
wherein R1 is a carboxyl protecting group;
in the presence of TBTU as a coupling agent;
(ii) optionally converting the obtained Compound of Formula (4A) to Pemetrexed (1):

Formula 1

7. The process as claimed in claim 6, wherein, the protecting group comprises alkyl group like methyl, ethyl, propyl and/or butyl and R1 is a carboxyl protecting group comprises methyl, ethyl, propyl and/or butyl.

8. An improved process for the preparation of Pemetrexed disodium (2):

Formula 2
which comprises:
(i) reacting a Compound of Formula (3);

Formula 3
with L-glutamic acid diethyl ester;

in the presence of TBTU as a coupling agent to produce a Compound of Formula (4);

Formula 4
(ii) hydrolyzing the obtained Compound of Formula (4) to produce Pemetrexed (1); and

Formula 1
(iii) converting Pemetrexed (1) to Pemetrexed disodium (2).