WO2015083033A1

WO2015083033A1 - An improved process for the preparation of fosaprepitant having improved purity

Info

Publication number: WO2015083033A1
Application number: PCT/IB2014/066279
Authority: WO
Inventors: Dhileepkumar Krishnamurthy; Raghavendar Rao Morthala; Ashutosh JAGTAP; Prashant LADKAT; Ajay KUMBHAR
Original assignee: Piramal Enterprises Ltd
Current assignee: Piramal Enterprises Ltd
Priority date: 2013-12-02
Filing date: 2014-11-24
Publication date: 2015-06-11
Anticipated expiration: 2016-06-02
Also published as: IN2013MU03772A

Abstract

The present invention relates to an improved process for the preparation of [3-{[(2R,3S)-2- [(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4- yl]methyl}-5-oxo-2H-1,2,4-triazol-1-yl]phosphonic acid (Fosaprepitant or the compound of formula I) or its pharmaceutically acceptable salt, having palladium (Pd) content less than 1 ppm comprising catalytic hydrogenation of the compound of formula II with Pd catalyst optionally in the presence of base, to give the compound of formula I or the pharmaceutically acceptable salt thereof, optionally isolating the compound of formula I or the pharmaceutically acceptable salt and treating the compound of formula I or the pharmaceutically acceptable salt thereof twice with the metal scavenger to obtain the compound of formula I or the pharmaceutically acceptable salt thereof having Pd content less than 1 ppm.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF

FOSAPREPITANT HAVING IMPROVED PURITY

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of [3-{ [(2R,35)-2-[(lR)- 1 - [3 ,5-bis(trifluoromethyl)phenyl]ethoxy] -3 -(4-fluorophenyl)morpholin-4-yl]methyl } -5- oxo- 2H-l,2,4-triazol-l-yl]phosphonic acid (Fosaprepitant or the compound of formula I) or its pharmaceutically acceptable salt, particularly bis(N-methyl-D-glucamine) salt; having improved purity, particularly having palladium (Pd) content less than 1 ppm.

BACKGROUND OF THE INVENTION

Fosaprepitant, [3-{ [(2R,35)-2-[(lR)-l-[3,5-bis(trifluoromethyl)phenyl] ethoxy]-3-(4- fluorophenyl)morpholin-4-yl]methyl}-5-oxo-2H- l,2,4-triazol-l-yl]phosphonic acid is a prodrug of Aprepitant (5-([(2 ?,3S)-2-(( ?)-l-[3,5-bis(trifluoromethyl)phenyl]ethoxy)-3-(4- fluorophenyl)morpholino]methyl)-lH- l,2,4-triazol-3(2H)-one); and is represented by following formula I (alternatively referred to as "the compound of formula I").

Formula

Fosaprepitant is an anti-emetic drug, which is administered intravenously. Fosaprepitant and its bis(N-methyl-D-glucamine) salt is approved for the treatment of chemotherapy induced nausea and vomiting and is available in the market by brand name EMEND® for injection in the US and IVEMEND® in the Europe. The compound of formula I and its process of the preparation are disclosed in US Patent No. 5691336.

There are several methods known in the art for the preparation of the compound of formula I (Fosaprepitant) and its pharmaceutically acceptable salt. One of the preferred process is disclosed in US Patent No. 5691336 (US'336 Patent). The process disclosed in US'336 Patent involves reaction of the compound, 2-( ?)-(l-( ?)-(3,5- bis(trifluormethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(lH,4H-5-oxo- 1,2,4- triazolo)methylmorpholine with tetrabenzyl pyrophosphate in dry tetrahydrofuran at 0°C to obtain a reaction mixture. To the resulting reaction mixture, a solution of sodium bis(trimethylsilyl)-amide (NaHMDS) is added and the resulting reaction mixture is stirred at 0°C for 15 minutes. After completion of the reaction, the reaction mixture is quenched with saturated aqueous sodium bicarbonate solution. The quenched mixture is extracted with ethyl ether and the resulting ether extract is first washed with aqueous potassium bisulphate solution followed by saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The ether extract is further dried over magnesium sulphate and evaporated to dryness to obtain dibenzyl{ 3-[2( ?J-[(1 ?)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-yl]-5-oxo-4,5- dihydro-[l,2,4]-triazol- l-yl]phosphonic acid (referred to as "the compound of formula Π") in the form of an oily residue. To this oily residue, methanol is added to make a solution of the compound of formula II. To the solution of the compound of formula II, an aqueous solution of N-methyl-D-glucamine and 10% palladium on carbon catalyst are added and the resulting reaction mixture is hydrogenated at 40 psi for 2 hours. The reaction mixture is then filtered and the filtrate is concentrated under vacuum to obtain crude bis(N-methyl-D- glucamine) salt of the compound of formula I. This crude product is recrystallised by using the mixture of methanol and iso-propyl alcohol (IPA) to obtain pure bis(N-methyl-D- glucamine) salt of the compound of formula I. The pure bis(N-methyl-D-glucamine) salt of the compound of formula I obtained by the said method, have palladium (Pd) content above 30 part per million (ppm). The pharmacopeial limit of Pd content in injectable Active Pharmaceutical Ingredient (API) is set below 1 ppm. Thus there is need to provide an improved process for preparation of the compound of formula I and its pharmaceutically acceptable salt having Pd content less than 1 ppm. PCT application publication WO2012164576 describes a process for producing the compound of formula I (Fosaprepitant) and its bis(N-methyl-D-glucamine) salt having Pd content less than 3 ppm using siliabond metal scavenger. The process involves the hydrogenation reaction of the compound of formula II using palladium carbon in the presence of N-methyl-D-glucamine. To the reaction mass siliabond metal scavenger is added and reaction mass is maintained for 15 hours at room temperature. The reaction mass is then filtered through hyflo-bed. The filtrate is collected and distilled off under reduced pressure at 30-35°C to obtain solid. The obtained solid is then co-distilled with isopropyl alcohol and acetonitrile. To the reaction mass acetonitrile is added and the resulting reaction mass is stirred for 15 hours at room temperature. The reaction mass is then filtered and dried to yield bis(N-methyl-D-glucamine) salt of the compound of formula I having Pd content less than 3 ppm. This limit again exceeds the pharmacopeal limit of Pd content in injectable API which is required to be less than 1 ppm. The process described in said patent application does not provide the compound of formula I meeting this requirement of having Pd content less than 1 ppm. Hence, the compound of formula I obtained by using the process of the said patent application does not meet the requirement of pharmaceutical acceptable purity.

US Patent No. 7915407 describes a process for the preparation of the compound of formula I and its N-methyl-D-glucamine salt by catalytic hydrogenation of monobenzyl fosaprepitant with Pd catalyst in the presence of N-methyl-D-glucamine using methanol- water as a solvent. After completion of the reaction, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure to obtain the concentrated solution. To the concentrated solution, tri-n-butylphosphine is added as the metal scavenger at room temperature and the reaction mixture is stirred for 12 hours. The reaction mixture is further added to the mixture of methanol- acetonitrile to precipitate the solid. The precipitated solid is filtered and washed with (1: 1) mixture of methanol- acetonitrile. Though the process described in said patent application involves the use of tri-n-butylphosphine as the metal scavenger, it does not specify Pd content in the compound of formula I as obtained by the said process. It is evident from the above discussion of the processes reported in the prior art that the reported process generally involve the treatment of the compound of formula I with a metal scavenger such as trialkyl phosphine or siliabond metal scavenger and that that these process do not result producing the compound of formula I having the desired purity profile i.e. having Pd content less than 1 ppm.

The inventors of the present invention have been successful in providing the compound of formula I having Pd content less than 1 ppm through an improved process. Moreover, the improved process for the preparation of the compound of formula I provides the said compound in good yield and enhanced purity.

OBJECTS OF THE INVENTION

An object of the present invention is to provide an improved process for preparation of the compound of formula I having Pd content less than 1 ppm. Another object of the present invention is to provide an improved process for the preparation of the compound of formula I having Pd content less than 1 ppm by treating the compound of formula I twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

Yet another object of the present invention is to provide an improved process for producing the compound of formula I having Pd content less than 1 ppm with yield of 80% and purity of > 99.0% %.

SUMMARY OF THE INVENTION

In accordance with the first aspect of the present invention, there is provided an improved process for the preparation of the compound of formula I (Fosaprepitant) or the pharmaceutically acceptable salt thereof having palladium (Pd) content less than 1 ppm, wherein said process comprises the steps of; a. catalytic hydrogenation of the compound of formula II with Pd catalyst optionally in the presence of a base, to provide the compound of formula I or the pharmaceutically acceptable salt thereof; b. treating the compound of formula I or the pharmaceutically acceptable salt thereof obtained in the step (a) in situ with a metal scavenger; wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

In the second aspect of the present invention, there is provided an improved process for the preparation of the compound of formula I or the pharmaceutically acceptable salt thereof; having Pd content less than 1 ppm, comprising treating the compound of formula I or the pharmaceutically acceptable salt thereof twice with a metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

Accordingly, the process of the present invention involves reducing Pd content in the compound of formula I or the pharmaceutically acceptable salt thereof to less than 1 ppm and the said process involves catalytic hydrogenation of the compound of formula II with a Pd catalyst optionally, in the presence of a base, to provide the compound of formula I or the pharmaceutically acceptable salt thereof, and which process involves optionally isolating the compound of formula I or the pharmaceutically acceptable salt thereof; and treating the compound of formula I or the pharmaceutically acceptable salt thereof; twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger to obtain the compound of formula I or the pharmaceutically acceptable salt thereof having Pd content less than 1 ppm. DETAIL DESCRIPTION OF THE INVENTION

In accordance with the first aspect of the present invention, there is provided an improved process for producing the compound of formula I or the pharmaceutically acceptable salt thereof having Pd content less than 1 ppm,

Formula I wherein said process comprises the steps of: a. catalytic hydrogenation of the compound of formula II with palladium (Pd) catalyst optionally, in the presence of a base, to provide the compound of formula I or a pharmaceutically acceptable salt thereof; b. treating the compound of formula I or the pharmaceutically acceptable salt thereof as obtained in the step (a) in situ with a metal scavenger; wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

In an embodiment of the present invention, a base is used to obtain the pharmaceutically acceptable salt of the compound of formula I. In an embodiment of the invention, the base used in the step (a) of the process is selected from the group consisting of potassium bicarbonate, sodium bicarbonate and N- methyl D-glucamine.

In an embodiment of the invention, in step (a) of the process, Pd catalyst is used in an amount ranging from 1% to 10% based on the compound of formula II.

In an embodiment of the invention in the step (b) of the process, the metal scavenger is used in an amount ranging from 10% to 30% based on the compound of formula II.

In an embodiment of the invention, the metal scavenger used in step (b) of the process is smopex^® 234.

Smopex^® 234, a trade mark of Johnson Matthey, is a metal scavenger which is used to remove and recover various metals from aqueous and organic solutions. In Smopex^® 234, mercaptoethylacrylate is grafted onto fibres.

Smopex®-234

Mercaptoethylacrylate

grafted fibre

In an embodiment of the invention, the metal scavenger used in step (b) of the process is selected from the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger.

In specific embodiment of the invention, the siliabond metal scavenger is selected from the group consisting of siliabond thiol, siliabond thiourea, and siliabond amine and siliabond diamine.

In an embodiment of the invention, the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with metal scavenger such that two different metal scavengers are used. Accordingly, in an embodiment the compound of formula I or the pharmaceutically acceptable salt thereof is treated with TPP as the first metal scavenger followed by treatment with smopex^® 234 as the second metal scavenger. In another embodiment of the invention, the compound of formula I or the pharmaceutically acceptable salt thereof is treated with smopex^® 234 as the first metal scavenger followed by treatment with TPP as the second metal scavenger.

In second aspect of the present invention, there is provided a process for the preparation of the compound of formula I or the pharmaceutically acceptable salt thereof; having Pd content less than 1 ppm, comprising treating the compound of formula I or the pharmaceutically acceptable salt thereof with a metal scavenger; wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

In an embodiment of the second aspect of the present invention, the metal scavenger used is in an amount ranging from 10% to 30% based on the compound of formula II.

In an embodiment of the second aspect of the present invention, the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with smopex^® 234 as the metal scavenger.

In an embodiment of the second aspect of the present invention, the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with a metal scavenger selected from the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger.

In a specific embodiment of the second aspect of the present invention, siliabond metal scavenger is selected from the group consisting of siliabond thiol, siliabond thiourea, siliabond amine or siliabond diamine.

In an embodiment of the second aspect of the present invention, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with metal scavenger such that two different metal scavengers are used. Accordingly, in an embodiment, the compound of formula I or the pharmaceutically acceptable salt thereof is treated with TPP as the first metal scavenger followed by treatment with smopex^® 234 as the second metal scavenger. In another embodiment of the second aspect of the present invention, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated with smopex^® 234 as the first metal scavenger followed by treatment with TPP as the second metal scavenger. The compound of formula I or the pharmaceutically acceptable salt thereof obtained by using the process of the present invention is of pharmaceutically acceptable purity with Pd content less than 1 ppm.

The compound of formula II, used as a starting material in step (a) of the above process, is a known compound. The compound of Formula II can be obtained by following the methods known in the literature. For example, the process described in the US patent no. 5,691,336 (the US '336 Patent) can be used to obtain the compound of formula II. The process described in the US'336 Patent involves reaction of 2-(R)-(l-(R)-(3,5- bis(trifluormethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(lH,4H-5-oxo-l,2,4- triazolo)methylmorpholine with tetrabenzyl pyrophosphate in dry tetrahydrofuran at 0°C to obtain the reaction mixture. To the resulting reaction mixture, a solution of sodium bis(trimethylsilyl)-amide (NaHMDS) was added and the reaction mixture was stirred at 0°C for 15 minutes. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution. The quenched reaction mixture was extracted with ethyl ether. The ethyl ether extract was then washed with aqueous potassium bisulphate solution followed by saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution and further, dried over magnesium sulphate. The ethyl ether extract was then evaporated to dryness to obtain the compound of formula II.

According to the first aspect of the present invention, the process for obtaining the compound of formula I or the pharmaceutically acceptable salt thereof; having Pd content less than 1 ppm involves hydrogenating the compound of formula II with Pd catalyst in an organic solvent optionally, in the presence of a base at 35-50°C to obtain the compound of formula I or the pharmaceutically acceptable salt thereof. The compound of formula I or the pharmaceutically acceptable salt thereof as obtained by the said process; was optionally isolated or treated in situ with the metal scavenger. The compound of formula I or the pharmaceutically acceptable salt thereof; can be treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that when the compound of formula I or the pharmaceutically acceptable salt thereof; was treated with TPP as one of the metal scavenger, the other metal scavenger used was smopex^® 234. After treatment with the metal scavenger, the compound of formula I or the pharmaceutically acceptable salt thereof was isolated using isopropyl alcohol (IPA). Thus, the compound of formula I or the pharmaceutically acceptable salt thereof obtained by using the process of present invention having Pd content less than 1 ppm which meets the pharmacopeial requirement .

The inventors of the present invention have observed that the compound of formula I or the pharmaceutically acceptable salt thereof; when treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that when the compound of formula I or the pharmaceutically acceptable salt thereof was treated with TPP as one of the metal scavenger, the other metal scavenger was smopex^® 234 to obtain the compound of formula I or the pharmaceutically acceptable salt thereof; the Pd content is reduced to less than 1 ppm. When the compound of formula I or the pharmaceutically acceptable salt thereof treated with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger only once, it reduces the Pd content to some extent but does not provide the product, the compound of formula I or its pharmaceutically acceptable salt having Pd content less than 1 ppm. Thus, the treatment of the compound of formula I only once with the metal scavenger is not sufficient to provide the compound of formula I or the pharmaceutically acceptable salt thereof having pharmaceutically acceptable purity. Accordingly, in the process of the present invention, the compound of formula I or the pharmaceutically acceptable salt thereof with Pd content less than 1 ppm is obtained by treating the compound of the formula I or the pharmaceutically acceptable salt thereof twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger. The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be considered in any way limiting the scope of the present invention.

Examples

Example 1:

To the autoclave, the compound of formula II (30g), methanol (240ml), N-methyl D- glucamine (14.75ml) and Pd/C (1.5g) were charged and the reaction mass was hydrogenated at 3.0 kg/cm² hydrogen pressure at 20-30°C for 24 h. After completion of the reaction, the catalyst was filtered through hyflo. To the filtrate smopex^® 234 (1.5g) was added and reaction mixture was stirred for 24 hours at 20-30°C. The reaction mixture was filtered through hyflo. To the filtrate triphenyl phosphine (1.5g) was added and reaction mixture was stirred for 24 hours at 20-30°C. The reaction mixture was filtered through 0.4 micron. The filtrate was collected and concentrated under vacuum up to 2 to 3 volume to obtain concentrated solution. To the concentrated solution 11% orthophosphuric acid solution (5.5ml) was added to maintain the pH 6.5-7.5. To the reaction mixture methanol (80ml) was added. The resulting reaction mixture was added to the isopropyl alcohol (750ml) to precipitate a solid. The precipitated solid was then filtered and washed with 30% methanol- isopropyl alcohol solution (30ml) followed by acetone (90ml). The solid was then dried under vacuum at a temperature of 20-30°C to yield dimeglumine salt of the compound of formula I having Pd content less than 1 ppm. Yield 80%, purity 99%, Pd content 0.3 ppm.

Example 2:

To the reactor, dimeglumine salt of the compound of formula I (30g; Pd content 49ppm), methanol (150ml) and smopex^® 234 (1.5g) were added and the reaction mixture was stirred for 24 hours at 20-30°C. The reaction mixture was filtered through hyflo. To the filtrate triphenyl phosphine (1.5g) was added and the reaction mixture was stirred for 24 hours at 20-30°C. The reaction mixture was filtered through 0.4 micron. The filtrate was collected and added to the isopropyl alcohol (750ml) to precipitate a solid. The precipitated solid was then filtered and washed with 30% methanol- isopropyl alcohol solution (30ml) followed by acetone (90ml). The solid was then dried under vacuum at a temperature of 20-30°C to yield dimeglumine salt of the compound of formula I. Yield 80%, purity 99%, Pd content: 0.57 ppm.

Effect of the various metal scavengers on reducing the Pd content in the compound of formula I:

The results presented in the above Table- 1 are discussed herein below:

As indicated in Sr. No. 1, the compound of formula I, without any treatment with the metal scavenger having Pd content 49.75 ppm.

As indicated in Sr. No. 2, 3 and 4 when the compound of formula I having 49.75 ppm of Pd content was treated with the metal scavenger only one time it was observed that the compound of formula I contains 1-10 ppm of Pd content. Thus, the compound of formula I obtained does not having pharmaceutically acceptable purity.

As indicated in Sr. No. 6 when the compound of formula I containing 49.75 ppm of Pd content was treated twice with TPP, it was observed that the compound of formula I contains 5.73 ppm of Pd content.

As indicated in Sr. No. 5 and 9 when the compound of formula I having 49.75 ppm of Pd content was treated twice with smopex^® 234, the mixture of TPP and siliabond metal scavenger it was observed that the compound of formula I obtained having Pd content is less than 1 ppm. As indicated in Sr. No. 7 and 8 when the compound of formula I having 49.75 ppm of Pd content was treated with TPP as the first metal scavenger followed by treatment with smopex^® 234 as the second metal scavenger or vice versa it was observed that the compound of formula I obtained having Pd content is less than 1 ppm.

Analysis of Pd content present in the compound of Formula I or its pharmaceutically acceptable salt

Instrumentation :

Inductively Coupled Plasma Mass Spectrometer, Thermofisher X-series with computerized data collection system.

Apparatus and Equipment:

Appropriate glass volumetric flasks and glass pipettes. All glassware, plastic ware, flasks and containers must be rinsed thoroughly with deionized or HPLC grade water before use.

Operating Procedure

Sr. No Parameter Settings

1 Auxiliary gas flow (Ar) 0.70 L/minute

2 Nebulizer gas flow 0.90 L/minute

3 Dwell Time 10 milliseconds

4 Sweeps 50

5 Pump rate 45 rpm

Analyte and Analyte

6 Palladium (Pd-195amu)

mass 6 Point calibration (0, 5, 10, 15, 20 and

7 Standardisation

30 ppb)

8 Number of replicates 2

3 for Standard, Sample and 5 for Blank

9 Readings

In-between

10 Diluent HPLC Grade water

Sample Preparation (3mg/ Ml in water):

Take 150mg of the compound of formula I into 50 ml volumetric add about 30-40 ml of diluent sonicate to dissolve, cool and made up to the volume with the diluent, again sonicate for 1 min. Prepare in duplicate.

Calculation:

(Instrument response for Instrument response

15ppb check std initial for 15ppb final check std)

% difference = X 100

Instrument response for 15ppb check std initial

Corrected instrument response in ppb for Pd = Instrument response of Pd in ppb in sample - Instrument response for Pd in matrix blank

Instrument response (ppb)

Concentration of Analyte (Pd in ppm)

Concentration of Sample

(in mg/ mL)

Claims

We claim,

1. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof; having palladium (Pd) content less than 1 ppm,

Formula I

wherein the said process comprises the steps of: a. catalytic hydrogenation of the compound of formula II with a palladium (Pd) catalyst;

Formula II

optionally, in the presence of a base, to obtain the compound of formula I pharmaceutically acceptable salt thereof; b. treating the compound of formula I or the pharmaceutically acceptable salt thereof obtained in the step (a) in situ with a metal scavenger; wherein the compound of formula I or the pharmaceutically acceptable salt thereof; is treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger; provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

The process as claimed in claim 1, wherein the base used in step (a) is selected from the group consisting of potassium bicarbonate, sodium bicarbonate and N-methyl D- glucamine.

The process as claimed in claim 1, wherein in the step (a), Pd catalyst is used in an amount ranging from 1% to 10% based on the compound of formula II.

The process as claimed in claim 1, wherein in the step (b), the metal scavenger is used in an amount ranging from 10% to 30% based on the compound of formula II.

The process as claimed in claim 1, wherein in the step (b), the compound of formula I or the pharmaceutically acceptable salt thereof; is treated twice with smopex^® 234 as the metal scavenger.

The process as claimed in claim 1, wherein in the step (b), the compound of formula I or the pharmaceutically acceptable salt thereof, is treated twice with the metal scavenger selected from the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger .

The process as claimed in claim 1, wherein in the step (b), the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger such that TPP is used as the first metal scavenger followed by use of smopex^® 234 as the second metal scavenger. The process as claimed in claim 1, wherein in the step (b), the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger such that smopex^® 234 is used as the first metal scavenger followed by use of TPP as the second metal scavenger.

A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof having Pd content less than 1 ppm,

Formula I wherein said process comprises, treating the compound of formula I or the pharmaceutically acceptable salt thereof with a metal scavenger; wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger selected from the group consisting of smopex^® 234, triphenyl phosphine (TPP), a mixture of triphenyl phosphine (TPP) and smopex^® 234 or a mixture of triphenyl phosphine (TPP) and siliabond metal scavenger provided that the compound of formula I or the pharmaceutically acceptable salt thereof is not treated twice with triphenyl phosphine (TPP) alone as the metal scavenger.

The process as claimed in claim 9, wherein the metal scavenger used is in an amount ranging from 10% to 30% based on the compound of formula II.

11. The process as claimed in claim 9, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with smopex^® 234 as the metal scavenger.

12. The process as claimed in claim 9, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger selected from the mixture of triphenyl phosphine (TPP) and smopex^® 234 or the mixture of triphenyl phosphine (TPP) and siliabond metal scavenger.

13. The process as claimed in claim 9, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger such that TPP is used as the first metal scavenger followed by use of smopex^® 234 as the second metal scavenger.

14. The process as claimed in claim 9, wherein the compound of formula I or the pharmaceutically acceptable salt thereof is treated twice with the metal scavenger such that smopex^® 234 is used as the first metal scavenger followed by use of TPP as the second metal scavenger.