FORM 2
THE PATENTS ACT. 1970
(39 OF 1970)
&
PATENTS RULES. 2006
COMPLETE SPECIFICATION
(SECTION 10; RULE 13)
"IMPROVED PROCESS FOR THE PREPARATION OF SUBSTITUTED QUINOXALINES"
ALKEM LABORATORIES LIMITED. A COMPANY INCORPORATED UNDER THE COMPANIES ACT. 1956. HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE. DEVASHISR ADJACENT TO MATULYA CENTRE. S.B.MARG, LOWER PAREL. MUMBAI - 400013. MAHARASHTRA. INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention is directed to a process for the preparation of substituted quinoxalines.
BACKGROUND OF THE INVENTION
Substituted quinoxalines are useful intermediates in the preparation of aryl fused azapohcydic compounds. - viz-Varenicline.
Varenicline tartrate sait known chemically as 7,8.9,l0-tetetrahydro-6,10-methano-6 H -pyrazmo|;2.3-b][3]benzazepine, (2 R .3 R )-2.3-dihydrox\butanedioate (1:1). is described according to the following formula

Varenicline and its pharmaceuticafly salts such as varenicline tartrate is marketed by Pfizer under the trade name of CHANTJX™ as a partial agonist selective for certain subtypes of nicotinic receptors and indicated for smoking cessation.
These are also are useful in the treatment of inflammatory bowel disease (including but not limited to ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction. anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag. amyotrophic lateral sclerosis (ALS). cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochiomocytoma. progressive supranuclear palsy, chemical dependencies and addictions (e.g.. dependencies on., or addictions to nicotine (and'or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache.

migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD). psychosis. Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, irwiti-infarct dementia, age-related cognitive decline, epilepsy, including petit mat absence epilepsy, senile dementia of the Alzheimer's type (AD). Parkinson's disease (PD). attention deficit hyperactivity disorder (ADHD) and Tonrerte's Syndrome, particularly, nicotine dependency, addition and withdraws L including use ia smoking cessation therapy.
U.S. Pat. No. 6.410.550 discloses the s>nthesis. composition and methods of use of certain aryf fused aznpolycyclic compounds including the formation of substituted quinoxaline through the cyclizatton of the corresponding dianiline with aqueous gtyoxal or the addition adduct of sodium bisulfite and ethane dione. Both of these reactions required certain purification steps.
U.S. Pat. No. 6.890.927 and U.S. Pat. No. 7.265. f 19. disclose Varemdine tartrate salts (including L-tartrate. D. L-tartrate and D-tartrate salts) and their polymorphic forms, hi particular, three polymorphic forms of varenicline L-tartrate. Form A. Form B and Form C were disclosed in these patents. Among them. Form A and Form B are anhydrous varenicline L-tartrate. and Form C is vareaictine L-tartrate hydrate.
Crystalline forms of Varenicline citrate and succinate salts are described in the US Patents No. 6.787.549 and 6.794.388. respectively.
WO 02/092089 discloses preparation of the polymorphs of the L-tartrate salt of the aryi fused azapolyc\ clic compound.
US20080275051 discloses an improved process for the preparation of substituted quinoxaline by eyclization of the corresponding dianiline with aqueous glyoxal in a protic solvent.
Thus there remains an urgent and imperative need to provide sot only a more cost effective process but also a time-efficient process that would afford a superior quality product - suitable for human consumption.
Surprisingly the inventors of the present invention have found that an ion exchange resin catalyses the said cyclisation reaction in an increasingly faster reaction rate with negligible side reactions and thus affords a product of superior quality in an eco-friendly and cost-effective manner.

The following are the advantages of the improved process of the present invention over the prior art:
• Use of an Ion exchange resin for catalyzing Cyclisation instead of the conventional base as employed in the prior art resulted in the reduction of time Ehiration of the process cycle by more than 50%.
• The cyclisation reaction is completed in 4-5 hr as against 18 hrs over night as reported in the prior art i.e., more than 73% of the duration is saved.
• Ion exchange Resins used for catalyzing the Cyciisation reaction step can be reused and recycled by regeneration: thereby increasing the cost-effectiveness and industrial applicability of the present invention.
• Resins of the like of Amberlite IRA 67 being weakly basic and chemically inert resulted in cleaner reactions with virtually no side products or impurities resulting in a product of superior quality with hardly any complex re-purification steps of the like of reciystallisation or Column chromatography techniques as given in the prior art.
• Resins are also non-toxic, stable and possess regenerabilify properties and also facilitate easy storage, easy handling and easy weighing and are eco-friendly too.
SUMMARY
by cyclisation of the corresponding dianiline in the presence of ion exchange resin.
The present invention provides a cost-«ffective and time-efficient eco-friendly. judustrially viable, improved process of preparing aryl fused azapolycyclic compounds of the like of Varenicline of Formula (I)


The present invention provides a process for preparing a compound containing a chemical moiety of formula II

Formula (t!) comprising cyclizing a compound containing a chemicaf moiety of formula III

FORMULA(III)
with aqueous glvoxai in a solvent in the presence of an ion exchange resin.
A schematic representation of an improvised process of the present invention is illustrated in Scheme: 1 below:
SCHEPJ1E-1

Forr?Hi3a{V) Gl^saJ Formula OV) Formula (I)

The compound containing the chemical moiety of Dianiline compound of Formula (HI) is prepared by known prior art methods or b\ the process as disclosed in US. Pat. No. 6.410,550.
Formula (IV)
from a compound of Formula (V)
In a preferred embodiment of the present invention is disclosed a process for the synthesis of compound of the formula IV


wherein Q Is a Nitrogen protecting group selected from the group of trifluoroacetyl group, an acetyl group or a t-butoxy carbonyt group and the like. Preferably. Q is a trifluoroacetyi group, an acetyl group or a t-butoxy carbonyl group. Most preferably. Q is a trifluoroacetyi group.
The compound containing the chemical moiety of N-protected Dianiline compound of Formula (V) is prepared by known prior art methods or by the process as disclosed in U.S. Pat. No. 6,410.550.
In a preferred embodiment of the present invention the compound of Formula (V) is a compound of Formula (VA) whereas the compound of Formula (IV) is a compound of Formula (IVA)


Formula (VA) Formula (SVA)
In another embodiment of the present invention is provided a process for preparing a compound of formula (1) or its pharmaceutically acceptable salt thereof comprising the steps of:
(a) Cyctising a compound of Formula (VA) with aqueous Glyoxal in the presence of an ion exchange resin to form the corresponding Quinoxaline of Formula (IVA).
(b) Removing the nitrogen protecting Trifluoroacetyl group by hydrolysis.
(c) Optionally converting the free base from step (b) into its pharmaceutical!}" acceptable salt.
Scheme-2 illustrates an embodiment of the improvised process of the present invention for the preparation of Compound of Formula (I) starting from a compound of Formula (VA).

SCHEME-2

Formula (IVA) Formula (I)
Formula (VA) Glyoxal
The improvised process of the present invention may be summarized as follows: A. A process for preparing a compound of formula (I)

Formula (I)
or its pharmaceutical!} acceptable salt thereof comprising the steps of: (a)Cyclismg a compound of Formula (V)


Formula (V)
wherein Q is Nitrogen protecting group selected from the group of
trifiuoroacetyl group, an acetyl group or a t-butoxy carbonyi group and the like.
with aqueous Glyoxal in the presence of an ion exchange resin in a solvent to form the corresponding QuinoxaJine of Formula (IV).

Formula (IV)
(b)Removing the nitrogen protecting group Q by hydrolysis.
(c) Isolating the compound of formula I as the free base or optionally converting the free base into its pharmaceuticalK acceptable salt.
B- The process according to step A wherein the ion exchange resin is selected from a group comprising weakly basic, strongly basic, neutral. weakly acidic, strongly acidic types of ion exchange resin and the like or mixtures thereof.
C. The process according to step B wherein the wherein the ion exchange resin may be selected from a group comprising Ambertyst A-21. Amberlite fRA-96 Amberlite IRA-400(O). Amberlite IRA^K)2(OH)_ Amberlite IRA-IO(Cl). Amberlite IRA-900(CI) . Amberlite IRC-748. Ambersep 900(OH). Amberlite IRA-402 CI. Amberlite IRA-404 CI. Amberlyst A26 OH. Amberjet 4200 CI, Amberlite IRC-50. Amberlite IRC-76. Amberlite CG-50 I. Amberlite. IRC-

76. Amberiite 1RC-86. Amberiite IRA-958 (CI). Amberlte IRA-910 C. Amberiite IR-120 " hydrolysis
(c) Optionally converting the free base from step (b) into '& p'narmaceuticafcy acceptable salt.
According to an aspect of the present invention is provided a process for the preparation of Varenicline of formula J. wherein the ion exchange resin is selected fr°m the group comprising weakly basic, strongly basic, neutral, weakly acidic and strongly ^cidtc resins. The weakly resuis may be selected form the group comprising Amberlyst A-21. Amfctrfite IRA-96 and the like. The strongly basic resins may be selected from the group comprising Amberlite IRA-400(C1). Amberlite IRA-402(OH). Amberlite IRA-410(Cl). Amberlite IRA-900(Cl) . Amberlite IRC-748. Ambersep 900(OH). Amberlite IRA-402 CI. Amberlite IRA-404 CI. Amberjyst A26 OH. Amberjet 4200 CI and the like The weakly acidic resins may' be selected from the group comprising Amberlite IRC-50. Amberlite IRC-76. Amberlite CG-50 L Amberlite. IRC-76. Amberlite IRC-86. Amberlite IRA-958 (CI). Amberlite IRA-9l0 C. and the like. The strongly acidic resins may be selected from the group comprising Amberlitt" IR-l 20 (H). Amberlite IR-120 (Na). Amberlite BRA-200 (Na). Amberlite IRN-77. Ambert^t-15. Amberlite 200C (Na). Amberfvst 35. Amberlite IRA 67 and the like.
in a preferred aspect of the present invention, the inventors used resins of the iike of Amberlite IRA 67 The cyctisation reaction was thus completed in around 4-5 hrs time duration as against the 18 hours overnight time duration as reported in the prior art processes thus resulting not only

in a decreased time duration of the reaction cycle by over 73%. and about 99% product formation with just about 0.5% of unreached starting material and about 95% practical > ield. it also afforded a superior product of superlative purity of around 99.99%.
The cvclisation reaction may be carried out at any temperature between ambient temperature and the boiling point of the solvent. The term ambient temperature in the present application is intended to indicate the temperature preferably in the range of -10T to 30'C.In a preferred embodiment of the present invention, the reaction is carried out at a temperature range O'C to 30T.
The cvclisation reaction may be conducted in suitable solvent such as alcohols, esters, ethers. amides, nitriles. ketones, hydrocarbon, and tlK like or aqueous or non aqueoits solvents or mixtures tfiereof. In a preferred embodiment of the present invention, the preferred solvent for cvclisation is THF.
Removal of the nitrogen protecting group Q may be carried out by methods well known in the art, such as. heating with base in a solvent mixture of water and a water immiscible organic solvent including, for example, methanol and the like, halogenated lwxlrocarboris of the like of methylene chloride or aromatic hydrocarbons of the like of toluene. Xylene and the like or mixtures thereof. The base for h\drol\sis may be selected from the group comprising sodium or potassium carbonate, sodium or potassium hydroxide and the like or mixtures thereof..
In an embodiment of the present invention . 1-(4,5-Diamino-10-aza-tricyvlo(6.3.1.027) 2(7}.3.5-triene-l0-yl)-2.2.2-trifluoroethanone was treated with diluted aqueous 40% Glyoxal solution in the presence of resin in a solvent. After complete conversion was confirmed by HPLC . the reaction solution was filtered and concentrated under vacuum (to a volume of 15-17% of its total volume, diluted with water and the resulting suspension stirred for Ihr at 10°C. filtered and bed washed with water. The product finally dried at 50&C at hot air oven to afford l-{5.8.14-triazatetracycl(10.3.10211.049)-hexadeca-2(11)3.5.9-pentaene)-2.2.2-trifluoroethanone as a white to pale yellow solid with HPLC Purity: 99.90%
The 1-(5.8.14-triazatetracycl(10.3.1.0211.049)
trifluoroethanone was hydrolysed in Methanol in the presence of base of the like of Potassium carbonate. After the completion of hydrolysis, tie base was removed by filtration and the solvent removed under vacuum. The thick residue was dissolved in water and the aqueous phase

extracted with MDC. The organic phase was evaporated under vacuum; the residue was dissolved in methanol and concentrated again. The final residue was dissolved in methanol, treated with activated carbon and filtered through H\flo to obtain a light brown solutioa witich. was preserved for next step.
This solution of the Varenicline free Base in methanol was added to s methanolic solution of tartaric acid at 25-30C in about I hour and stirred. The resulting Varemcline tartarate salt was isolated by filtration and dried under vacuum oven to afford Varenicline tartrate as off white to pale yellow solid.
The term "'cvdizing". as used herein refers to a chemical reaction in which a linear or branched chemical moiety or a substituted ring moiety is converted into a new ring moiety.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Examples:
Although the invention has been described in terms of particular embodiments and applications. one of ordinary skill in the art. in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are preferred by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.
Example-1- Genera! Procedure for the preparatioa of 1(5,3,14-Triazatetracyclo [10.3.1.0]-hexadeca-2(ll), 3, 5, 9-pentaene)-2, 2,2-trtfluoroethanone
To a 100ml round bottom flask with thermometer, condenser and stirrer was charged THF
(20ml). water (5mi), resin (1.5g). stirred and cooled the reaction mass to 0-5°C. Add H4.5-
Diamino-10-aza-tricyclo[6.3.1 0]-dodeca-2( 7).3.5-trien-10yl)-2.2-2-triftuaroet hanone <5g_
17.5mmol). under stirring at 0-5°C. A solution of 3.3g (22 7 mmol) of 40% aqueous Glyoxal

diluted with water (1 lml> was added slowly, under stirring at 0-5°C. The resulting solution stirred for 30min at 0-5*C and by raising the pot temperature to 25-30T stirred for 4-5 hrs. The complete conversion was confirmed by HPLC analysis. The reaction solution was filtered to remove resin for reuse and concentrated under vacuum (30-50mm of Hg) to a volume of 15-17% of its total volume. Added water (50ml) and the resulting suspension stirred for Ihr at 10"C. filter and bed washed with water <25mf)- Suck dry and unload to trays, farther dried at 50°C at hot air oven to obtain the above sample 5I2g (95% yield, off white to pale yellow). HPLC Purity: 99.90%
The above experiment was repeated in a similar manner with a number of resins of different types, the results of which are tabulated as under:
EXAMPLE-2—LAB EXPERIMENTAL DATA FOR VARIOUS RESIN PERFORMANCE FOR CYCLIZATION OF DIAMINE DERIVATIVE WITH GLYOXAL IS TABULATED ASUNDER.

S.N Type of Resin Code No. Reaction mass area Percentage analysis by HPLC % Yield Obtained

Unconverted
Starting
Material in
reaction mass Product formation tu reaction mass
% Purity by HPLC
I Weak basic Amberlite IRA 67 <0.5% >99.0% 95% 99.99%
2 Strong acidic A200C 2.7% 94% 88% 93.00%
3 Weak acidic IRC-S6 3.0% 96% 82% 97.00%
4 Strong basic A260H 1.5% 97% 85% 98.00%

Exampte-3- Preparation of 5,8, 14-Triazatetraeycto [10.3.1.Q.01-bexadeca-2(11), 3, 5, 7, 9-pentsene
To a IGOml round bottom flask with thermometer, condenser and magnetic stirrer was charged Water (10ml) followed by Potassium carbonate (5g. 36.17 mmol). stir to get clear solution. Charge niethanot(25mt) and step-I [H4.5-Diamino-l0-aza-tric\T:to[6.3.t.0)-dodeca-2(7)3.5-trien-10yl)-2.2.2-tiifluorocthanone] sample{5g. 16.20 mmol). Reaction pot heated to 30-55oC and stirred for 4 hrs. The complete hydrolysis was confirmed by HPLC analysis. The reaction solution concentrated under vacuum (30-50mm of Hg> at 50°C. The thick residue dissolved in water (15-i8ml). This aqueous phase extracted with MDC(26mix2). The organic phase was evaporated under vacuum (30-5Qmm of Hg) below 40°C (waiter bath), the residue was dissolved in methanol (30ml) and concentrated again (Vacuum: 30-50mm of Hg. Bath temperature=5QaC). The final residue was dissolved in methanol (50ml) and O.lg of activated carbon was added, the mixture was stirred for 30min at room temperature. Filtered through Hyilo to obtain light brown solution and it is preserved for next step.
Ezample-4 Preparation of tartarafe salt of 5, 8, 14-Triazatetracy€lo [l0.3.1.0.0G)-Hexadeca-2(11), 3,5, 7,9-pentaeue
To a 100ml round bottom flask with thermometer, condenser and magnetic stirrer was charged methanol (30ml) and L-Tartaric acid (5.07g. 33,7 mmol). stirred at room temperature for dissolution. Filtered to remove fibrous suspension and filtrate charged back to 100ml speck-free Found bottom flask. Maintaining stirring above methanot sohition (step-H) added drop wise at 25-30 C in thr duration. The reaction solution stirred for 5 hr at 25-30°C. filtered, washed with methanot (10-15ml) and dried in an oven at 45-50°C to obtain 5.04g Vareoicline L-tartarate as a pale yellow solid with HPLC purity; 99,90%

CLAIMS:
We claim
1. A process far preparing a compound of formula (J>

Formula (I)
or its pharmaceutical!}" acceptable salt thereof comprising the step? °f; (a)Cvclising a compound of Formula (V)

Fomula (V)
wherein Q is Nitrogen protecting group selected from the group of
trifluoFoacetyl group, an acetyl group or a t-butoxy carbonyl group and the like
with aqueous Glyoxal in the presence of an ion exchange re55'11 'n a solvent to form the corresponding Quinoxaline of Formula (IV).


Formula (IV)
(b)Removing the nitrogen protecting group Q by hydrolysis.
(c) Isolating the compound of formula I as the free base or optionally converting the tree base into its pharmaceutical!}* acceptable salt.
l-The process according to claim 1 wherein the ion exchange resin is selected from a group comprising weakly basic, strongly basic, neutral, weakly acidic, strongly acidic types of ion exchange resin and the like or mixtures thereof.
3.The process according to claim 2 wherein the wherein the ton exchange resin may be selected from a group comprising AmberKsr A-21. Amberlite IRA-96 Amberlite IRA-400(C1). Ambeflite IRA-402(OH). Amberlite JRA-4I0(CI). Amberlite IRA-900(Cl) . Amberlite IRC-748. Ambersep 900(GH). Amberlite IRA-402 Ci. Amberlite JRA-404 CI. Ambertysi A26 OH. Amberjet 4200 CI, Amberlite fRC-50. Amberlite IRC-76. Amberlite CG-50 I. Amberlite. FRO 76. Amberlite IRC-86. Amberlite IRA-958 (CI). Amberiite IRA-910 C. Amberiite IR-I20 (H). Amberlite IR-120 (Na). Amberlite IRA-200 (Na). Amberlite IRN-77. Amberlyst-15. Amberiite 200C (Na). Amberlyst 35. Amberlite IRA 67 and the hfce or mixtures thereof.
4.The process according to claim 3 wherein the ion exchange resin used preferably is Amberlite IRA 67.

5.The process according to claim I wherein the solvent may be selected from a group comprising alcohols. esters, ethers, amides, nitriles. ketones, hydrocarbon, and the like or non aqueous solvents and the tike or mixtures thereof.
6.The process according to claim 5 wherein the preferred solvent is selected from the group consisting of aqueous alcohol, dioxane. tetrahydrofuran. DMF. DAfSO. toluene, and ethyl acetate.
7. The process according to claim 1 wherein the said cycliz^tion may be conducted at a temperature in the range of about -10° C. to abotri boiling point of the solvent.
8.The process according to claim 1 wherein the preferred pharmaceutical by acceptable salt is a tartarate salt.
9. The process according to claim 1 wherein the compound of Formula (I) or its pharmaceuticaUy acceptable sail thereof may be prepared by a process comprising the steps of:
with aqueous Glyoxal in the presence of an ion exchange resin to form the corresponding Quinoxalme of Formula (IVA).
(a)Cycfising a compound of Formula (VA>



Formula (1VA)
(b)Removing the nitrogen protecting Trifiuoroacetyl group by hydrolysis,
(c) Isolating the compound of formula I as the free base or optionally converting the free base into its pharmaceutical!} acceptable salt.