FORM 2
THE PATENTS ACT, 1970
(39 of 1970) The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"AN IMPROVED AND EFFICIENT PROCESS FOR THE PREPARATION OF PEMETREXED DISODIUM"
We, CADILA HEALTHCARE LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad - 380 015, Gujarat, India.
The following specification particularly describes the nature of the invention and the manner in which it is performed:

FIELD OF INVENTION
The present invention provides an improved process for the preparation of Pemetrexed disodium. The present invention also provides an improved process that gives highly pure Pemetrexed disodium.

BACKGROUND OF THE INVENTION
Pemetrexed disodium is chemically described as L-G!utamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-disodium salt, represented by the chemical structure of Formula (I).

Pemetrexed is an anti-folate anti-neoplastic agent that exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. It is believed to work by inhibiting three enzymes that are required in purine and pyrimidine biosynthesis thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). Pemetrexed disodium heptahydrate is a multitargeted antifolate drug approved for treatment of mesothelioma and for second-line treatment of non small cell lung cancer.
Pemetrexed disodium heptahydrate is marketed by Eli Lilly and Company under the trade name ALIMTA as a sterile lyophilized powder for intravenous administration. This member of the folic acid family has been approved for treatment of malignant pleural mesothelioma and for second-iine treatment of non small cell lung cancer. See Physicians ' Desk Reference, 60th ed., pp. 1722- 1728 (2006). The commercial product is reported to be a lyophilized powder of heptahydrate Pemetrexed disodium and mannitol.
Taylor et al., in US 5,344,932 describe Pemetrexed, its related compounds and pharmaceutically acceptable cation. Chelius et al., in WO 01/14379 disclose Pemetrexed disodium crystalline hydrate Form I and process for preparation thereof.
Chelius et al., in WO 01/62760 disclose Pemetrexed disodium heptahydrate crystalline Form II and process for the preparation thereof
European publication No. 0432677 reports one of the syntheses of Pemetrexed disodium heptahydrate. This route of synthesis, however, is not very suitable for industrial production due to the number of steps and the poor overall yield.

U.S. patent No. 5,416,211 also disclosed the syntheses of Pemetrexed disodium heptahydrate follow a different route through 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid and L-Glutamic acid diethyl ester hydrochloride. The drawback associated with this process is use of L-Glutamic acid diethyl ester hydrochloride which leads to the formation of impurity at 1.08 RRT, which are difficult to remove in later phase.
However, in addition to the disadvantages of use of L-Glutamic acid diethyl ester hydrochloride which resulted in the formation of undesired impurities (1.08 RRT), a very slow conversion was found in our hand. The document (US 5,416,211) stated nothing about the purity and yield of compound obtained through this process. However it was observed that use of L-Glutamic acid diethyl ester hydrochloride leads to the formation impurity in the further process, which is difficult to remove in later phase. So, a robust process for the preparation of compound of formula (I) has been required, which must be smooth and easy to operate at commercial scale production.
Journal of Organic Process Research & Development, Volume 3, 1999, page 184 describes a process for the preparation of Pemetrexed diacid. Busolli et al., in WO2008021411 disclose process for preparation of pharmaceutically acceptable salt of Pemetrexed diacid.
Busolli et al., in WO2008021405A1 disclose seven crystalline forms of Pemetrexed diacid designated as Form A, B, C, D, E, F, & G and processes for preparation thereof
Though, several processes for preparing both the compound formula (VII) as well as its disodium salt are known, only few are environmental friendly and economically viable processes for the preparation of highly pure Pemetrexed disodium. Further, in most of the prior art references, the L-Glutamic acid diethyl ester has been used as its HCl salt. We have surprisingly found that the use of the L-Glutamic acid diethyl ester reduces the formation of the impurities and also substantially increases the yield of the final compound (I)

. SUMMARY OF THE INVENTION
In one general aspect there is provided an improved process for the preparation of highly
pure Pemetrexed disodium. The process includes:
i) reaction of L-glutamic acid diethyl ester hydrochloride of formula (II),

with suitable base in suitable solvent to give L-glutamic acid diethyl ester as a free base of formula (III).


ii) reaction of 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid of formula (IV),

with L-glutamic acid diethyl ester free base of formula (III) in presence of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and N-methyl morpholine at suitable temperature in suitable solvent to give 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 of formula (V),

which is further reacted in situ with PTSA.H2O in suitable solvent to give 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 4-methylbenzenesulfonic acid salt of formula (VI).

iii) Optionally, 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 4-methylbenzenesulfonic acid salt of formula (VI) was purified by suitable solvent.
iv) hydrolysis 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 4-methylbenzenesulfonic acid salt of formula (VI) by using suitable base at suitable temperature and by pH adjustment using suitable acid in suitable solvent to give N-[4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid of formula (VII).


v) basification of N-[4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid of formula (VII) by using aqueous sodium hydroxide solution and precipitation using suitable anti solvent to give Pemetrexed disodium of formula (I).
In another general aspect there is provided a Pemetrexed disodium which is free from the impurity obtained at RRT 1.08 and 0.82.
The process may include the steps of further formulating the product so obtained, into a finished dosage form.
In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of the Pemetrexed disodium and one or more pharmaceutically acceptable carriers, excipients or diluents.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.
BRIEF DESCRIPTION OF THE DRAWING. Figure 1 (Fig. 1) - PXRD of Pemetrexed disodium hemipentahydrate. Figure 2 (Fig. 2) - TGA of Pemetrexed disodium hemipentahydrate. Figure 3 (Fig. 3) - DSC of Pemetrexed disodium hemipentahydrate.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "reflux temperature" refers to the boiling point of the solvent. As used herein, the term "THF" refers to tetrahydrofuran, the term "DCM" refers to dichloromethane, the term "DMF" refers to dimethylformamide, the term "PTSA" refers to p-toluene sulphonic acid, the term "NMM" refers to N-methyl morpholine, the term "CDMT" refers to (2-chloro-4,6-dimethoxy-1,3,5-triazine. the term "DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene, the term "TEA" refers to triethyl amine.
The present invention is directed to an improved process for the preparation of high purity Pemetrexed disodium. This can be achieved by using L-glutamic acid diethyl ester instead of L-glutamic acid diethyl ester hydrochloride.

The inventors have developed a process for the preparation of highly pure Pemetrexed disodium of formula (I). The process includes:
i) reaction of L-glutamic acid diethyl ester hydrochloride of formula (II),

with suitable base in suitable solvent to give L-glutamic acid diethyl ester as a free base of formula (III).

ii) reaction of 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid of formula (IV),

with L-glutamic acid diethyl ester free base of formula (III) in presence of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and N-methyl morpholine at suitable temperature in suitable solvent to give 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 of formula (V),

which is further reacted in situ with PTSA.H2O in suitable solvent to give 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 4-methylbenzenesulfonic acid salt of formula (VI).

iii) Optionally, 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 4-methylbenzenesulfonic acid salt of formula (VI) was purified by suitable solvent.
iv) hydrolysis 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 4-methylbenzenesulfonic acid salt of formula (VI) by using suitable base at suitable temperature and by pH adjustment using suitable acid in suitable solvent to give N-[4-[2-(2-amino-4, 7-.dihydro-4-oxo-1H-pyrrolo [2, 3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid of formula (VII).

v) basification of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid of formula (VII) by using aqueous sodium hydroxide solution and precipitation using suitable anti solvent to give Pemetrexed disodium of formula (I).
In general, the conversion of L-glutamic acid diethyl ester hydrochloride of formula (II) to L-glutamic acid diethyl ester of formula (III) may be carried out in the presence of a suitable base in a suitable solvent. Suitable bases may include one or more of bicarbonates, carbonate, hydroxide, organic bases such as N-methyl morpholine, triethylamine, diethylamine and the like.
In particular sodium carbonate may be used. Suitable solvents which can be used at step (i) may include one or more of chlorinated solvents or their suitable mixtures. In particular, the reaction may be carried out in dichloromethane.
The reaction of 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid of formula (IV) with L-glutamic acid diethyl ester may be carried out by using 2-chloro-4, 6-dimethoxy-l, 3, 5-triazine and N-methyl morpholine at suitable temperature in suitable solvents. The product obtained is further converted to its suitable salts in situ; more particularly its PTSA salt.
The reaction may be performed at higher or lower temperature such as any temperature between - 30 °C to 50 °C. The reaction may be carried out from about 5 hours at about -20 °C to 30 °C. In particular, the reaction may be carried out for about 3 hours at about -15 °C to 15 °C. Suitable solvents used at step (ii) may include one or more of dimethyl formamide, dimethyl acetamide, dichloromethane, chloroform, acetonitrile, ethanol, isopropyl alcohol and the like or mixtures thereof

Optionally, the product formed in step-(ii) may be purified by using a suitable solvent. Solvent used in this step may include dimethyl formamide, dimethyl acetamide, dichloromethane, chloroform, acetonitrile, dimethyl sulphoxide, dioxane, ethanol, isopropyl alcohol, or mixtures thereof
In general, the hydrolysis 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 4-methylbenzenesulfonic acid salt of formula (VI) can be carried out by using suitable base at suitable temperature and by pH adjustment using suitable acid.
Suitable solvents used at this step may include water, ethanol, methanol, dimethyl formamide, dimethyl acetamide, acetonitrile and the like. In particular water may be used. Suitable bases used in the process may include bicarbonates, carbonates, hydroxide, DBU one or more of, and the like. In particular sodium hydroxide is used.
Suitable acids used in this step may include one or more of hydrochloric acid, sulphuric acid, formic acid, acetic acid and the like.
Suitable temperature used in step iv) is 0-25°C, preferably 0-10°C, most preferably 0-5°C.
Suitable pH used in step iv) is 3.5-4.5, more preferably 3.8-4.2. Suitable anti-solvents used at step (v) may include one or more polar solvents such as alcohols, ketons, water and the like. Preferably water and ketones such as acetone, methyl ethyl ketone, methyl-n-propyl ketone, mesityl oxide, cyclohexanone and the like.
We have surprisingly found that the use of the L-Glutamic acid diethyl ester reduces the formation of the impurities and also substantially increases the yield of the final compound (I)-In one of the embodiment of the invention is provided a Pemetrexed disodium which is free from the impurity obtained at RRT 1.08 and 0.82.
The Pemetrexed disodium prepared by the process as mentioned above, has purity as measured by HPLC of at least 99.9 %. Analytical method:
i) the complete x-ray powder spectrum, which was recorded with a Rigaku multifelx
2.0 Kilowatt X-ray powder diffractometer model using copper radiation. The X-ray diffraction pattern was recorded by keeping the instrument parameters listed below: X-ray: Cu/40kv/30mA, Diverging slit: 1°, Scattering slit; 1°, Receiving slit: 0.15 mm. Counter: Scintillation counters;
Scan mode: Continuous, Scan speed: 4.000 deg./min., Sampling width : 0.010°, Scan axes : 2 theta vs CPS, Scan range : 2° to 40.0°C, Theta offset: 0.000.

ii) differential scanning calorimetric analysis was carried out in a Pyris-1 model from Perkinelmer by keeping fo!lowing parameters, Sample Size: Approx. l-2mg. Sample Pans: Hermetic/Crimping Pans, Start Temperature: 50°C, End Temperature: 300°C, Rate of Heating: 10 °C/min., Purge Gas: Nitrogen, Flow rate: 20 ml/min. Pemetrexed disodium hemipentahydrate of the present invention is characterized by its powder X-ray diffraction pattern having peaks expressed as 20 at about 4.80, 9.52, 14.28, 15.60, 18.06, 18.54, 19.06, 22.96, 23.92 and 27.12 ±0.2 degree 20. (Fig. 1).
Pemetrexed disodium hemipentahydrate of the present invention is further characterized by its TGA (Fig. 2). Pemetrexed disodium hemipentahydrate according to the present invention has a Thermogravimetric Analysis (TGA) thermogram showing a weight loss of about 8.78% up to 200° C determined over the temperature range of 35° C to 300° C and heating rate 10°C/min, which is substantially in accordance with (Fig. 2).
Pemetrexed disodium hemipentahydrate of the present invention is characterized by its DSC (Fig. 3). Pemetrexed disodium hemipentahydrate according to the present invention has a DSC spectrum with endothermic peaks at about 161.5°C ± 2°C, 239.8 ± 0.2°C and 243 °C ± 2°C, which is substantially in accordance with (Fig. 3).
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of a person skilled in the art.
Example-1: Preparation of L-Glutamic acid diethyl ester.
In a suitable vessel L-Glutamic acid diethyl ester hydrochloride 11 gm (45.89mmoI) and 110 ml dichloromethane was charged. The reaction mixture was cooled to 0-5 °C and pH was adjusted to 8.5 to 9.5 by cold aqueous sodium carbonate solution. The temperature was raised to 20 to 30 °C and stirred for 30 min. The organic layer was separated and subsequently, aqueous layer was extracted with dichloromethane. The combined organic layer was washed with aqueous sodium carbonate solution. Organic layer was dried over sodium sulphate and concentrated completely under reduced pressure to obtain 7.93gm free base of L-glutamic acid diethyl ester.
Yield: 85%, Quality: Single spot on TLC
Example-2: Preparation of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-lH-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoyl]-L-glutamic acid diethyl ester 4-methylbenzenesulfonic acid salt.

In a suitable vessel L-glutamic acid diethyl ester free base (prepared in example 1) and

30 ml N, N-dimethyl formamide was charged under stirring and the reaction mixture was cooled

to -5 to 0°C under nitrogen atmosphere. Subsequently, 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-
pyrrolo[2,3-d] pyrimidin-5-yl)ethyl]benzoic acid 10 gm (33.52 mmol), N-methyl morpholine
(NMM) 4.24 gm (41.92 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) 7.063 gm

(44.82 mmol) was added and stirred for 2 hrs at temp. -5 to 5 °C. After completion of reaction
the temperature was raised to 20 to 30 °C and solution of p-toluene sulfonic acid monohydrate

(PTSA) 15.94 gm (83.8 mmol) in 20 ml ethanol and 5 ml N, N-dimethyl formamide was added
followed by 130 ml ethanol. The slurry was heated to 75 to 85 °C for 2 hrs, cooled to 20 to 30
°C and stirred for 1hr. The reaction mass was filtered and washed with ethanol and dried under
vacuum at 50 °C for 3 hrs to obtain PTSA salt of N-[8-[2-(2-amino-4, 7-dihydro-4-oxo-1H-
pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoyl]-L-glutamic acid diethyl ester as crude.

To it was added dimethyl sulphoxide 43 ml was charged and heated to 60 to 70 °C. Subsequently, acetonitrile 344 ml was added maintaining the temperature at 60 to 70 °C. After
addition, the temperature of reaction mixture was maintained at 60 to 70 °C for 30 min and the
reaction mass was cooled to 15 to 20°C and stirred for 1 hr. After that the reaction mass was

filtered, washed with acetonitrile and dried under vacuum at 50°C for 4H.

Weight of solid: 16.67 gm, Purification yield: 75.89%, HPLC purity: 99.57%, HPLC
assay: 99.23%.
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 diethyl ester 4-methylbenzenesulfonic acid
salt.
In a suitable vessel L-glutamic acid diethyl ester free base (prepared in example 1) and

30 ml N, N-dimethyl formamide was charged under stirring and the reaction mixture was cooled

to -5 to 0°C under nitrogen atmosphere. Subsequently, 1-[2-(2-amino-4,7-dihydro-4-oxo-1 H-

pyrrolo[2,3-d] pyrimidin-5-yl)ethyl]benzoic acid 10 gm (33.52 mmol), N-methyl morpholine

(NMM) 4.24 gm (41.92 mmol) and 2-chloro-4,6-dimethoxy-1,3,5- triazine (CDMT) 7.063 gm

(44.82 mmol) was added and stirred for 2 hrs at temp. -5 to 5 °C. After completion of reaction

the temperature was raised to 20 to 30 °C and solution of p-toluene sulfonic acid monohydrate

(PTSA) 15.94 gm (83.8 mmol) in 20 ml ethanol and 5 ml N, N-dimethyl formamide was added
followed by 130 ml ethanol. The slurry was heated to 75 to 85 °C for 2 hrs, cooled to 20 to 30

°C and stirred for 1hr. The reaction mass was filtered and washed with ethanol and dried under

vacuum at 50 °C for 3 hrs to obtain PTSA salt 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 as crude.

To it was added dimethyl suiphoxide 43 ml was charged and heated to 60 to 70 °C. Subsequently, ethanol 344 ml was added maintaining the temperature at 60 to 70 °C. After addition, the temperature of reaction mixture was maintained at 60 to 70°C for 30 min and the reaction mass was cooled to 15 to 20°C and stirred for 1hr. After that the reaction mass was filtered, washed with ethanol and dried under vacuum at 50°C for 4 H.
Weight of solid: 16.67 gm, Purification yield: 75.89 %, HPLC purity: 99.57%, HPLC assay: 99.23%.
Example-4: 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 diacid)
In a suitable vessel purified 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 4-methylbenzenesulfonic acid salt 15gm (22.88 mmol) and water 75 ml was charged and the reaction mixture was cooled to 0 to 5 °C. Subsequently, cold sodium hydroxide solution 53 ml (8.65% w/v, 114.61 mmol) was added and the temperature was maintained at 0-5°C for 2 hrs under nitrogen atmosphere. After completion of reaction, ethanol 120 ml was added and pH of reaction mixture was adjusted to 3.8 to 4.2 using 10% HCl solution and stirred for 30 min. The slurry was heated to 45 to 50 °C for 30 min, cooled to 20 to 30°C and stirred for 1hr. The reaction mass was filtered, washed with water and dried under vacuum at 50°C for 6 hrs to obtain Pemetrexed diacid. Weight: 9.70 gm. Yield: 99.21%, HPLC purity: 99.85%, Assay by HPLC 99.85%
Example- 5: Preparation of Pemetrexed Disodium hemipentahydrate
In a suitable vessel Pemetrexed diacid 9 gm (21.06 mmol) and water 36 ml was taken and cooled to 0 to 5 °C under nitrogen atmosphere. The pH of reaction mixture was adjusted to 8 to 8.5 using 35 ml 5 % cold sodium hydroxide solution. The temperature of reaction mixture was then raised to 20 to 25°C and stirred for 30 min and filtered through hyflo bed under suction. The bed was washed with water and subsequently acetone was added for the precipitation of Pemetrexed disodium. After addition, the slurry was stirred for 1 hr at 20 to 30°C and then 1 hr at 0 to 5 °C. The reaction mass was filtered, washed with acetone and dried under vacuum for 10 hrs at 50 °C to obtain Pemetrexed Disodium hemipentahydrate. Weight: 9.65gm, Yield; 89.66%, HPLC purity: 99.89%, HPLC assay (OAB): 99.94%, Water content: 9.27%.

We claims:
1. A process for the preparation of highly pure Pemetrexed disodium comprising:
i) reacting L-glutamic acid diethyl ester hydrochloride of formula (II),

with suitable base in suitable solvent to give L-glutamic acid diethyl ester as a free base of formula (HI).

ii) reacting 4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d] pyrimidin-5-yl) ethyl] benzoic acid of formula (IV),

with L-glutamic acid diethyl ester free base of formula (III) in presence of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and N-methyl morpholine at suitable temperature in suitable solvent to give 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 of formula (V),

which is further, reacted in situ with PTSA.H2O in suitable solvent to give 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 4-methylbenzenesulfonic acid salt of formula (VI).

iii) optionally, purifying 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 4-methylbenzenesulfonic acid salt of formula (VI) by using suitable solvent.
iv) hydrolysis of N-[4-[2-(2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2, 3-d]pyrimidin-5-yl)ethyl] benzoyI]-L-glutamic acid diethyl ester 4-methylbenzenesulfonic acid salt of formula (VI) by using suitable base at suitable temperature and by pH adjustment using suitable acid in suitable solvent to give N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo [2, 3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid of formula (VII).

v) basifying N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoyl]-L-glutamic acid of formula (VII) by using aqueous sodium hydroxide solution and precipitation using suitable anti solvent to give Pemetrexed disodium of formula (I).
2. The process as claimed in claim 1 wherein in step (i), suitable base used is selected from bicarbonates, carbonate, hydroxide, organic bases such as N-methyl morpholine, triethylamine, diethylamine, preferably sodium carbonate.
3. The process as claimed in claim 1 wherein in step (i), suitable solvent used is selected from chlorinated solvents or their suitable mixtures, preferably dichloromethane.
4. The process as claimed in claim 1 wherein in step (ii), suitable temperature used is selected from temperature between - 30 °C to 50 °C, preferably -20°C to 30°C, more preferably at about -15°C to 15°C.
5. The process as claimed in claim 1 wherein in step (ii), suitable solvent used is selected from dimethyl formamide, dimethyl acetamide, dichloromethane, chloroform, acetonitrile, ethanol, isopropyl alcohol or mixtures thereof.
6. The process as claimed in claim 1 wherein m step (iii), suitable solvent used is selected from dimethyl formamide, dimethyl acetamide, dichloromethane, chloroform, acetonitrile, dimethyl sulphoxide, dioxane, ethanol, isopropyl alcohol or mixtures thereof.

7. The process as claimed in claim 1 wherein suitable solvent used is selected from water, ethanol, methanol, dimethyl formamide, dimethyl acetamide, acetonitrile or mixtures thereof..
8. The process as claimed in claim 1 wherein in step (iv), suitable base used is selected from bicarbonates, carbonates, hydroxide, DBU or mixtures thereof
9. The process as claimed in claim I wherein in step (iv), suitable acid comprises of one or more of hydrochloric acid, sulphuric acid, formic acid, acetic acid and the like.
10. A process as claimed in claim 1 wherein in step (iv), suitable temperature is 0-25°C, preferably, 0-10°C, most preferably 0-5°C.
11. A process as claimed in claim 1 wherein in step (iv), pH is adjusted to 3.5 to 4.5, preferably, 3.8 to 4.2.
12. The process as claimed in claim 1 wherein in step (v), suitable anti-solvent used is selected from alcohols, water, ketones, preferably water and acetone.
13. Pemetrexed disodium free from the impurities obtained at RRT 1.08 and 0.82.