WO2014199313A1

WO2014199313A1 - Substantially pure vilazodone hydrochloride and a process thereof

Info

Publication number: WO2014199313A1
Application number: PCT/IB2014/062132
Authority: WO
Inventors: Nitin Vilas PATIL; Mahesh Ganpatrao DESHPANDE; Sachin Arun Sasane; Dnyaneshwar Bapurao THAKARE; Rajesh Vyas; Nandu Baban Bhise; Girij Pal Singh
Original assignee: Lupin Ltd
Current assignee: Lupin Ltd
Priority date: 2013-06-12
Filing date: 2014-06-11
Publication date: 2014-12-18
Anticipated expiration: 2015-12-12
Also published as: IN2013MU02001A

Abstract

The present invention relates to a process for preparation of substantially pure Vilazodone Hydrochloride and also relates to an isolated impurity of Vilazodone. The said process for producing Vilazodone, 1-[4-(5-cyanoindol-3-yl) butyl]-4-(2-carbonyl benzofuran-5-yl) piperazine represented by formula (1) or a pharmaceutically acceptable salt thereof comprises condensing the compound of formula (2) With a compound of formula (3) in an alcoholic solvent to obtain a white to yellow solid; isolating the solid obtained therefrom; slurry washing the solid obtained with water miscible solvent; dissolving the solid obtained therefrom in an amide solvent to obtain a solution; adding an aqueous solution of sodium metabisulphite and an inorganic base to the solution obtained to obtain the compound of formula (1) and optionally converting the solid obtained in step (v) to its pharmaceutically acceptable salt.

Description

SUBSTANTIALLY PURE VILAZODONE HYDROCHLORIDE

AND A PROCESS THEREOF

Field of the invention

The present invention relates to substantially pure Vilazodone Hydrochloride, process for preparation of the same and also relates to an isolated impurity of Vilazodone.

Background and the prior art

Vilazodone, l-[4-(5-cyanoindol-3-yl) butyl] -4-(2-carbonyl benzofuran-5-yl) piperazine represented by formula (1), and its pharmaceutically acceptable acid addition salts are useful as anxiolytics, antidepressants and antipsychotic neuroleptic and / or antihypertensive agents.

(1 )

A pharmaceutical preparation of Vilazodone and their pharmaceutically acceptable salt is mentioned in US5532241 for treating disorders of the central nervous system.

Vilazodone Hydrochloride represented by formula 1(a) is indicated for the treatment of major depressive disorder (MDD).

(1 a)

Process for preparation of vilazodone free base or its hydrochloride are described in US patent Nos. 5,532,241, 5,723,614 , 7,799,916 or 7,834,020.

Like any synthetic compound, Vilazodone hydrochloride can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by product of the reaction, products of side reactions, impurities coming from the starting material or degradation products. It is essential to verify the identity of the source material and to establish its quality otherwise impurities associated with the raw materials may be carried through the manufacturing process to contaminate the final product.

It is always desirable to prepare pharmaceutical products of high purity having minimum amount of impurities, in order to reduce adverse side effects and to improve the shelf life of active ingredient, as well as its formulation. In some cases it has been found that high purity also facilitates in the formulation process. Impurities in any API are undesirable and in extreme cases might even be harmful to a patient being treated with a dosage form containing the API.

Moreover, submissions are made to regulatory authorities along with the analytical data which demonstrate that impurities are absent from the drug at the time of manufacture, or are present only at a negligible level. These data are usually obtained by testing the drug against a reference, which is a suitably pure sample of a potential impurity. Preparation of compound of formula (1) was first disclosed in US5532241A. The process for preparation of Vilazodone illustrated in example-4 of US'241 involves reacting 5-(4-(4-(5- cyano-lH-indol-3-yl)butyl)piperazinyl-l-yl)benzofuran-2-carboxylic acid with 2-chloro-l- methylpyridinium methanesulfonate in the presence of N-methyl pyrrolidine followed by treatment with dried ammonia gas to afford compound of formula I after customary workup. The Vilazodone thus obtained was further converted to its hydrochloride salt. The experimental procedure of the salification step is not elaborated in the specification.

However said patent does not disclose how to obtain a pure Vilazodone Hydrochloride acceptable as per regulatory norms. The other drawback of the process is that it involves expensive reagent, 2-chloro-l- methylpyridinium methanesulfonate requiring controlled reaction conditions and tedious work up not suitable for commercial scale.

So there exists a scope to develop an improved process that yields substantially pure Vilazodone hydrochloride free of impurities meeting the regulatory norms. Brief description of the drawing

Figure - 1 is an illustration of NMR spectrum of compound of formula (5)

Figure - 2 is an illustration of IR spectrum of compound of formula (5)

Figure - 3 is an illustration of Mass spectrum of compound of formula (5)

Figure - 4 is a representative HPLC chromatogram from an analysis of isolated compound of formula (5) labeled as VLZRC-6

Figure - 5 is a representative HPLC chromatogram from an analysis of pure Vilazodone containing compound of formula (4) and formula (5) labeled as VLZRC-5 and VLZRC-6, respectively. Description of the invention

Accordingly, the present invention is directed to provide an improved process for preparation and purification of Vilazodone, which when subsequently converted to its hydrochloride provides a substantially pure Vilazodone Hydrochloride free of undesired by-products or impurities. The present invention provides an environment friendly cost effective process for obtaining Vilazodone in higher purity and higher yield.

According to the present invention the crude Vilazodone used in the present invention for purification purpose can be obtained as per a process demonstrated in prior art or by the process of the present invention.

One aspect of the present invention provides an improved process for the preparation of the crude Vilazodone comprising of condensing 5-(piperaziny-l-yl)-l-benzofuran-2- carboxamide (PBA) of formula (2) with 3-(4-chlrobutyl)-lH-indole-5-carbonitrile (CBCI) of formula (3) in the presence of a condensing agent and solvent. Thereafter the crude Vilazodone is isolated from the reaction mixture by techniques known in the art such as filtration, centrifugation or the like and subjected to purification. The purification process affords the substantially pure Vilazodone of formula (1) which is optionally converted to its pharmaceutically acceptable salts. I

(2) (3) Another aspect of the present invention provides condensation of compound of formula (2) and formula (3) to obtain compound of formula (1) in the presence of condensing agent and solvent.

In yet another aspect of the present invention, the suitable solvent medium for the reaction is an alcoholic solvent, unless mentioned otherwise the term "alcoholic solvent" refers to alcoholic solvent selected from CI to C4 straight or branched chain alcohol containing more than 50% of water, more preferably more than 70% of water or most preferably more than 80% of water. The CI to C4 straight or branched chain alcohols include methanol, ethanol, propanol, isopropanol and butanol. The preferred alcohol of the present invention is isopropanol.

In a further aspect of the present invention, the condensing agent is a base selected from a group consisting of inorganic base. The suitable inorganic base includes sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, magnesium bicarbonate, calcium carbonate and cesium bicarbonate.

Yet a further aspect of the invention provides that the condensation of compound of formula (2) with compound of formula (3) is carried out at a temperature of about 5 °C to about 110 °C, more preferably at about 25 °C to 90 °C or more preferably at reflux temperature of the reaction mixture. The reaction of compound of formula (2) with compound of formula (3) may be carried for about 5 hrs to about 24 hrs, more preferably for about 5 hrs to 12 hrs.

The crude Vilazodone can be isolated using known techniques in the art such as decantation, filtration by gravity or suction or centrifugation.

In yet another aspect of the invention the crude vilazodone obtained by reaction of compound of formula (2) and (3) is slurry washed with water miscible solvent. The suitable water miscible solvent may be alcohol such as methanol and ketones such as acetone. As used herein, the term "slurry washing and/or wash and/or washes" refers to a agitating a compound with solvent and thereafter isolating the compound by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.

In one aspect of the present invention, the process involves purification of crude Vilazodone by charcoalisation of a solution of crude Vilazodone base in an amide solvent such as dimethylformamide(DMF) and N-Methyl pyrrolidine(NMP), followed by treating the filtrate with aqueous sodium metabisulfite, whereupon the pure Vilazodone precipitates which is collected by filtration.

In another aspect of the present invention, the process involves purification of crude Vilazodone by agitating a solution of crude Vilazodone in an amide solvent such as dimethylformamide (DMF) and N-Methyl pyrrolidine with aqueous sodium metabisulfite and an aqueous inorganic base.

In yet another aspect of the present invention, the process involves purification of crude Vilazodone by agitating a solution of crude Vilazodone in dimethylformamide with aqueous sodium metabisulfite and aqueous inorganic base solution added in combination or separately in sequence.

In another aspect the aqueous sodium metabisulfite and aqueous inorganic base solution, in combination or separately in sequence, is gradually added to solution of crude Vilazodone in dimethylformamide . The inorganic base is selected from sodium carbonate, potassium carbonate and cesium carbonate.

The aqueous inorganic base used in combination with sodium metabisulphite or separately is preferably sodium carbonate.

The said addition is done in about 15 min. to 90 min., more preferably in 45 min. to 60 min. The addition is carried out at a temperature of 5 °C to 60 °C, more preferably at 20 °C to 40 °C and the resulting reaction mixture is stirred for 60-90 min, at 20-35 °C, whereupon the precipitated Vilazodone is collected and washed with water and acetone at ambient temperature to afford pure Vilazodone.

The compound of formula ( 1 ) obtained by the present invention can be optionally converted into its pharmaceutically acceptable salts, for example hydrochloride salt by any of the method known in the art. The Vilazodone hydrochloride salt can be isolated by techniques known in the art such as filtration by gravity or suction, decantation or centrifugation

In one embodiment of the present invention the above mentioned production method is employed to prepare compound of formula (1) substantially free of dimer impurity, 5-(4-(4- (5-cyano-l-(4-(5-cyano-lH-indol-3-yl) butyl)- lH-indol-3-yl) butyl) piperazin-l-yl) benzofuran-2-carboxamide, compound of formula (4)

(4)

In another embodiment of the present invention the process involves purification of crude Vilazodone base involving acid-base treatment of solution of crude Vilazodone base in an amide solvent, which is preferably dimethylformamide ( DMF) before treatment with aqueous sodium metabisulphite to obtain pure Vilazodone, in effect, free of impurity of formula (5) as illustrated in example-4.

In an embodiment the invention is directed towards isolated Vilazodone impurity, 5-(4-((3- (4-(4-(2-carbamoylbenzofuran-5-yl) piperazin-l-yl) butyl)-5-cyano-lH-indol-l-yl) methyl) piperazin-l-yl) benzofuran-2-carboxamide of formula (5).

The isolated compound (5) of the present invention is used as reference marker and/or standard while testing the purity of Vilazodone and its pharmaceutically acceptable salt.

A reference marker/standard is used for qualitative analysis and is also used to quantify the amount of the compound of the reference standard in an unknown mixture.

(5)

The impurity of formula (5) was isolated by preparative HPLC and characterized by NMR, IR and Mass spectroscopy.

As used herein, the term "isolated" refers to a compound that is at least 80%, preferably at least 90%, even more preferably at least 93% pure measured as area percentage by HPLC. In another embodiment of the present invention, the formation of impurity of formula (5) in Vilazodone can be controlled within regulatory limits by purifying the commercially obtained raw material 5-(piperaziny-l-yl)-l-benzofuran-2-carboxamide (PBA) compound of formula (2) by acid-base treatment in water, as per example-5. Surprisingly the present inventors have found out that the formaldehyde (chemical formula: HCHO) content in compound of formula (2) is accountable for the impurity of formula (5) formed during the condensation of compound of formula (2) with compound of formula (3) to afford crude Vilazodone (Table- 1).

Table- 1

In one aspect of the present invention the compound of formula (2) used for preparation of Vilazodone and its pharmaceutically acceptable salt has formaldehyde content not more than 500ppm (parts per million), more preferably not more than 300 ppm , most preferably not more than lOOppm. In one aspect of the present invention the impurity of formula (5) in crude Vilazodone is removed by treating a solution of crude Vilazodone with IPA-HCl, collecting the precipitated solid, treating the collected solid with dimethylformamide and liquor ammonia to obtain a solution which is further treated with aqueous sodium metabisulphite and sodium carbonate as illustrated in example-4.

In another aspect of the present invention, it is possible to remove the impurity of formula (5), if at all present in Vilazodone hydrochloride, by treatment of Vilazodone hydrochloride solution in DMF with liquor ammonia to obtain Vilazodone base essentially free of impurity of formula (5) as illustrated in Example-6 and reconverting Vilazodone substantially free of impurities to Vilazodone hydrochloride in presence of IPA-HCl as per Example-3.

Pure Vilazodone obtained by the process of the present invention is further converted to its pharmaceutically acceptable salts by the processes known in the art. For example, substantially pure Vilazodone hydrochloride is obtained by treating pure Vilazodone with IPA-HCl at 60-70°C, cooling the reaction mass to room temperature and then collecting the desired substantially pure Vilazodone Hydrochloride by filtration.

The term "IPA-HCl" used herein refers to solution of hydrochloride gas in isopropanol.

Purity obtained of the purified Vilazodone using the process of the present invention is >99% by HPLC and that of substantially pure Vilazodone hydrochloride is >99% by HPLC.

In an aspect of the invention Vilazodone base and Vilazodone hydrochloride prepared according to the processes of the present invention can be substantially pure having purity greater than about 99% or greater than about 99.5% , or greater than about 99.7% or greater than about 99.9% as determined using high performance liquid chromatography (HPLC). Vilazodone base and Vilazodone hydrochloride produced by a method of present invention can be substantially pure having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Vilazodone base and Vilazodone hydrochloride produced by the methods of present invention can be substantially pure having purity in amounts greater than about 99.8% and containing no single impurity in amounts greater than about 0.1% by HPLC.

Unless otherwise specified crude Vilazodone and/or crude Vilazodone base refers to solid obtained after condensation of compound (2) and (3) which is subjected to a purification process.

Unless otherwise specified Vilazodone and/or Vilazodone base and/or pure Vilazodone and/or pure Vilazodone base refers to substantially pure compound of formula (1).

Unless otherwise specified Vilazodone hydrochloride refers to hydrochloride salt of compound of formula (1). For the purpose of the present invention a compound is substantially pure if it comprises less than 0.2 %, preferably less than 0.15%, more preferably less than 0.1 % or most preferably less than 0.05% of impurity of formula (4) & (5) measured as area percentage by HPLC.

In another embodiment the compound (5) of the invention has utility as a reference marker for Vilazodone and Vilazodone hydrochloride because it is a potential contaminant arising from side reactions which occur during the synthesis of the drug substance.

In an embodiment the test sample of drug substance to be analyzed is assayed by one or more conventional analytical techniques. The analytical technique includes high performance liquid chromatography (HPLC) which is used for detection and quantification of impurities in a principal compound such as the drug substance. Detection and especially quantification of components of a mixture can be accomplished with the use of response factors. The response of a detector in HPLC (e.g. UV detectors or refractive index detectors) can be and typically is different for each compound eluting from the HPLC column. Response factors, as known, account for this difference in the response signal of the detector to different compounds eluting from the column. Analytical Methods: Vilazodone Hydrochloride impurities may be determined using HPLC with the following chromatographic conditions

Instrument: HPLC equipped with Pump, Injector, UV detector and Recorder

Column: waters X Bridge™ C18 (4.6x 150mm), 3.5μπι Flow rate: l.OmL/min

Wavelength: UV at 241nm

Injection volume: 5μί_^

Column oven temperature: 45 °C

Auto sampler temperature: 10 °C Mobile phase-A: Homogenous mixture of Buffer- A (aqueous ammonium acetate; 1.54 gm in 1000ml HPLC grade water) and acetonitrile (95:05). Adjust pH of the mixture to 8.9±0.05 with ammonia. Mix well and sonicate to degas.

Mobile phase-B: Homogenous mixture of Buffer-B (aqueous ammonium acetate; 4.62 gm in 350ml HPLC grade water) and acetonitrile (35:65). Adjust pH of the mixture to 8.9±0.05 with ammonia. Mix well and sonicate to degas.

Time (min.) Mobile phase-A Mobile Phase-B

(%) (%)

0.01 65 35

7.00 45 55

15.00 20 80

25.00 5 95 30.00 5 95

31.00 65 35

35.00 STOP

Typical retention times that may be obtained are as follows:

The percentage of each specified identified and isolated impurity is calculated using following formula:

AT X WS X DT X RE X P

% impurity = X 100

AS X WT X DS X 100

Where;

AT = Area of respective impurity peal from teat chromatogram

AS = Average area of Vilazodone peak from standard chromatograms

WT = Weight of test taken in mg DS= Dilution of standard preparation DT= Dilution of test preparation RF = Response factor for respective impurity P = Potency of Vilazodone Hydrochloride working standard Present invention is further illustrated with the following non-limiting examples. Example- 1 :

Preparation of crude Vilazodone

To a 4-neck round bottomed flak was added 5-(piperazin-l-yl)-l-benzofuran-2- carboxamide (PBA) (lOOg, 0.4078 mol), 3-(4-chlorobutyl)-lH-indole-carbonitrile (CBCI) (104.39g, 0.4486 mol), sodium carbonate (130g, 1.2235 mol) and 1000 ml water. The reaction mass was stirred for 10-15 min. The reaction mass was heated to 90 to 100 °C and maintained for about 10 hrs (PBA content is NMT 2.0%).Then the reaction mass was gradually cooled to room temperature and the deposited solid was filtered, washed with isopropyl alcohol and suck dried. The solid thus obtained was slurried with methanol (500 ml) and stirred for 1 hour. The product was collected by filtration. The solid obtained was washed with methanol (500ml), suck dried and dried under vacuum to yield crude Vilazodone.

Yield = 72 to 94%

HPLC purity = 90-95% Example-2:

Purification of crude Vilazodone

To a clean round bottomed flask was added dimethylformamide (700ml) and crude Vilazodone (100g).The reaction mass was stirred to obtain a solution of Vilazodone in DMF to which was added 5g activated charcoal (pH-6-7.5).The reaction mass was stirred for additional 30 min. and filtered through celite bed. The bed was washed with DMF (100ml). To the filtrate was added aqueous sodium metabisulfite solution (500ml, 6% W/V). The reaction mass was stirred for 1 hour, filtered and the solid obtained was washed with water (300 ml) and then with methanol (300ml), suck dried and dried under vacuum to obtain pure Vilazodone.

Yield = 75 to 85%

HPLC purity = > 99%

Example-3

Preparation of Vilazodone Hydrochloride

To a clean round bottomed flask was added pure Vilazodone (100 g) and isopropyl alcohol (6500ml).The reaction mass was refluxed for 45 min to obtain a solution. IPA-HC1 (2500ml, 0.1 N) was added to the reaction mass at 60-70°C till precipitation of material. The reaction mass was gradually cooled to room temperature. The reaction mass was stirred for additional 60 min at room temperature. The solid obtained was filtered washed with 300ml isopropyl alcohol, suck dried and dried under vacuum.

Yield = 90 to 98 %

HPLC purity = > 99% Example-4:

Preparation of pure Vilazodone

To a clean round bottomed flask was added PBA (lOOgm, 0.408 mol) and DM water (900ml). To the reaction mass was added dil.HCl at 20-35°C till pH is in the range of 6.5-7. The reaction mass was stirred for 30 to 45 min. at room temperature and filtered through celite. The filtrate obtained was charged into a 4-neck round bottomed flask and to this were added 3-(4-chlorobutyl)-lH-indole-carbonitrile (CBCL) (95g, 0.408 mol), sodium carbonate (50g, 1.1 mol) and 200ml isopropyl alcohol. The reaction mass was heated to reflux (75-85 °C) and maintained for about 12 hrs (CBCI content is NMT 5.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) and the wet solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (500ml) and filtered through celite to remove insoluble. To the filtrated was added IPA.HC1 and the reaction mass was stirred for 60-90 min. The precipitated solid was collected by filtration, washed with DMF suck dried well. The wet cake was taken in a RBF and to it was added dimethylformamide. Thereafter liquor ammonia was added till pH 8.0-10.0 is obtained, the reaction mass was stirred for 30-45 min. and filtered through celite. To the filtrate was gradually added an aq. solution of sodium metabisulphite (15gm) and sodium carbonate (15 gm) in 400ml water in 45-60 min. The reaction mass was stirred for 60-90 min. the precipitated solid was collected by filtration and slurried with water, suck dried followed by slurry wash with acetone. The wet solid obtained after filtration was dried under vacuum to yield pure Vilazodone base.

Yield = 72 to 94% HPLC purity = >99%

Example-5

Purification of PBA by acid base treatment

To a clean round bottomed flask was added PBA and DM water. To the reaction mass was added dil.HCl at 20-35°C till pH is in the range of 6.5-7. The reaction mass was stirred for 30 to 45 min. at room temperature and filtered through celite. The filtrate obtained was washed with 100 ml and basified with aq. sodium carbonate (75gm Na2C03 and 500ml water, pH=8.5-9.5) and stirred for 45-60 min. The precipitated solid is filtered, washed with water and dried under vacuum.

Example-6

Purification of Vilazodone Hydrochloride Method A:

To a clean round bottomed flask were added DMF (600ml) and Vilazodone Hydrochloride (lOOgm). To the reaction mass was added dil.HCl at 20-35°C till pH is in the range of 6.5-7. The reaction mass was basified with liquor ammonia (pH=8.5-9.0).The reaction mass was stirred for 30 min. The reaction mass was filtered and washed with DMF (100ML). To the filtrated and washings combined together was gradually added water (500ml) in about 45 min. Thereafter the reaction mass was stirred for 60 min. The reaction mass was filtered and the solid obtained was washed with water. The wet solid thus obtained was slurry washed with acetone and dried under vacuum to yield pure Vilazodone.

Method B: To a clean round bottomed flask were added DMF (600ml) and Vilazodone Hydrochloride (lOOgm). To the reaction mass was added dil.HCl at 20-35°C till pH is in the range of 6.5-7. The reaction mass was basified with liquor ammonia (pH=8.5-9.0).The reaction mass was stirred for 30 min. The reaction mass was filtered and washed with DMF (100ML). To the filtrated and washings combined together was gradually added water (500ml) in about 45 min. Thereafter the reaction mass was stirred for 60 min. The reaction mass was filtered and the solid obtained was washed with water. The wet solid thus obtained was slurry washed with acetone and suck dried. The wet solid thus obtained was dissolved in DMF (600ml) and filtered and to the filtrate was added water (500ml) in about 45 min. The reaction mass was stirred for 60 min. filtered, washed with water and suck dried. The wet solid obtained was slurried with acetone, filtered, washed with acetone, suck dried and dried under vacuum to yield pure Vilazodone. Example-7

Preparation of pure Vilazodone

To a clean round bottomed flask were added DM water (900ml) and sodium carbonate (26g, 1.1 mol) The reaction mass was stirred for 15-20 min. Then PBA (lOOgm, 0.408 mol) was added and the reaction mass was stirred for 5-10 min. To this was added 3-(4-chlorobutyl)- lH-indole-carbonitrile (CBCL) (95g, 0.408 mol), stirred for 5-10 min. and flushed with DM water (lOOml).Thereafter isopropyl alcohol (200ml) was added and reaction mass was stirred for 5-10 min. The reaction mass was then heated to reflux (75-85deg) and maintained for about 12 hrs (till CBCI content NMT 2.0%).Then the reaction mass was cooled to room temperature and the deposited solid was filtered, washed with DM water (500ml) and suck dried. The wet solid thus obtained was slurried with acetone (700 ml) for 30-45min. The solid was collected by filtration and again washed with 200ml acetone. The wet solid obtained was dissolved in DMF (700ml) and filtered through celite to remove insoluble. The celite bed was washed with DMF (lOOml).The DMF filtrate and washings were combined and preserved. Thereafter an aqueous solution of sodium carbonate (15gm) and sodium metabisulphite (15gm) prepared in DM water (600ML) was gradually added (in about 60 min, temp. 20-40 deg.) to the preserved DMF filtrate and washings taken in a RBF. The resulting mixture was stirred for 60-90 min at 20-35 deg and the precipitated solid was filtered. The wet solid was slurry washed with water (1500ml; 30-45 min.) followed by slurry wash with acetone (700ml; 30-45min.), filtered, suck dried and dried in vacuum oven to yield pure vilazodone.

Yield = 72 to 94%

HPLC purity = >99%

Characterization data of compound of formula (5):

1. NMR Spectra:

Instrumentation and sample preparation: An NMR spectrum is recorded by dissolving sample in DMSO-d6+D20 using Bruker AVANCE-II.

Note: three extra protons are due to unexchanged -NH2 and traces of formic acid

2. Infra-red Spectra: Instrumentation and sample preparation: IR spectra is recorded in KBr by using Perkin- Elmer-400 series FTIR

Frequency cm^"1 Assignment

3370 -NH stretch

2934,2827 Aliphatic -CH stretch

2217 -CN stretch

1671 C=0 stretch

3. MASS Spectra is recorded by dissolving sample in methanol using Xevo G2 QT of mass spectrometer m/z amu (atomic mass unit) Assignment

699.32 (M+H)⁺

721.30 (M+Na)⁺

Claims

1. A process for producing a compound of formula (1)

(1 )

or a pharmaceutically acceptable salt thereof; comprising the steps of:

Condensing the compound of formula (2)

(2)

With a compound of formula (3)

(3)

in an alcoholic solvent to obtain a white to yellow solid

(ii) isolating the solid obtained in step (i),

slurry washing the solid obtained in step(ii) with water miscible solvent (iv) dissolving the solid obtained in step (iii) in an amide solvent to obtain a solution,

(v) adding an aqueous solution of sodium metabisulphite and an inorganic base to the solution obtained in step (iii) to obtain the compound of formula ( 1 )

(vi) optionally converting the solid obtained in step (v) to its pharmaceutically acceptable salt.

2. The process according to claim 1 wherein the compound of formula (2) comprises of not more than lOOppm of formaldehyde.

3. The process according to claim -1 wherein the condensing agent used in step (i) is an inorganic base selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, magnesium bicarbonate, calcium carbonate and cesium carbonate.

4. The process according to claim-3, wherein the inorganic base is sodium carbonate.

5. The process according to claim- 1 wherein the alcoholic solvent is selected from CI to C4 straight or branched chain alcohol containing more than 80% of water.

6. The process according to claim-5, wherein the alcohol is isopropanol.

7. The process according to claim- 1, wherein the solid of step (ii) is slurry washed with acetone.

8. The process according to claim- 1, wherein the solid of step (iii) is dissolved in an amide selected from N-methylpyrrolidone, dimethylformamide and a mixture thereof.

9. The process according to claim- 1, wherein the solution of step (iii) is treated with aqueous solution of sodium metabisulphite and an inorganic base selected from sodium carbonate, potassium carbonate and cesium carbonate.

10. The process according to claim-9, wherein the inorganic base is sodium carbonate.

11. The process according to claim -9 wherein a mixture of an aqueous solution of sodium metabisulphite and sodium carbonate is gradually added to the solution of step(iii) of claim 1 in 15 min. to 90 min at 20 °C to 40 °C.

12. The process according to claim- 1 wherein the pharmaceutically acceptable salt is hydrochloride salt.

13. The process according to claim- 12 wherein the compound of formula (1) is converted to its hydrochloride salt in the presence of IPA-HC1.

14. Substantially pure hydrochloride salt of compound of formula (1) containing

compound of formula (4) not more than 0.15%.

15. An isolated compound of formula (5)

(5)

16 A process for producing a compound of formula (1)

or a pharmaceutically acceptable salt thereof; comprising the steps of:

(i) condensing the compound of formula (2) having formaldehyde content less than lOOppm

(2) with a compound of formula (3) I

in an alcoholic solvent to obtain a white to yellow solid, wherein the compound of formula (2) comprises of not more than lOOppm of formaldehyde

(ii) Isolating the solid obtained in step (i),

(iii) Slurry washing the solid obtained in step(ii) with water miscible solvent

(iv) Dissolving the solid obtained in step (iii) in dimethylformamide to obtain a solution,

(v) adding IPA-HC1 to the solution of step (iv),

(vi) isolating the solid obtained in step (v)

(vii) adding dimethylformamide and liquor ammonia to the solid obtained in step (v) to obtain a solution (viii) adding an aqueous solution of sodium metabisulphite and sodium carbonate to the solution obtained in step (vi) to obtain the compound of formula (1)

(ix) optionally converting the solid obtained in step (v) to its pharmaceutically acceptable salt.

17. The process according to claim- 15 wherein the compound of formula (2) is optionally purified by acid-base treatment in water.

18. Substantially pure hydrochloride salt of compound of formula (1) containing

compound of formula (5) not more than 0.15%.