WO2014098000A1

WO2014098000A1 - Process for preparation of a tricyclic heterocycle

Info

Publication number: WO2014098000A1
Application number: PCT/JP2013/083533
Authority: WO
Inventors: Gottumukkala NAGARAJU; Kumar Ray ANMOL; Ramesh Bhai Bhatt HARSHIT; Singh Khanna Mahavir; Nayyar Kaushal; Kumar Thaper Rajesh; Prasad Mohan
Original assignee: Daiichi Sankyo Company, Limited
Priority date: 2012-12-17
Filing date: 2013-12-09
Publication date: 2014-06-26

Abstract

The present invention provides a process for the preparation of a tricyclic heterocycle of Formula I which can be used as an intermediate for the preparation of pharmaceutical compounds.

Description

DESCRIPTION

Title of Invention

PROCESS FOR PREPARATION OF A TRICYCLIC HETEROCYCLE

Technical Field

Formula I

Background Art

WO 2003/076442, WO 2006/086484 and CN 101302216 disclose a four-step process for the preparation of tricyclic heterocycle of Formula as depicted below.

Formula I Formula V

a: bromoethylpyruvate; b: gCI₂, 2-methoxyethanol; c: NaOH, EtOH; d: Copper chromite

The above disclosed process is cumbersome, involves use of costly reagents such as copper chromite or lithium aluminium hydride and requires an additional purification step such as column chromatography for the preparation of tricyclic heterocycle of Formula I. These factors affect the cost and overall yield of the manufacturing process.

Citation List

Patent Literature

PTLl: WO 2003/076442

PTL2: WO 2006/086484

PTL3 : CN 101302216

Summary of Invention

Technical Problem

The present inventors have developed a short, convenient, - industrially advantageous and cost-effective two-step process for the preparation of tricyclic heterocycle of Formula I. The process of the present invention does not involve use of costly.reagents such as copper chromite or lithium aluminium hydride and provides tricyclic heterocycle of Formula I of high purity without the need for carrying out chromatographic purification.

Solution to Problem

A first aspect of the present invention provides a process for the preparation of tricycli heterocycle of Formula I

Formula I

comprising reacting 1 , 2 , 3 , 4 -tetrahydroquinoline of Formula

Formula II

with an acetal intermediate of Formula VI

Formula VI

(X= Leaving group; R = alkyl)

to obtain 1- (2 , 2 -dialkoxyethyl) -1, 2 , 3 , 4-tetrahydroquinoline of Formula VII

Formula VII

and cyclizing the

1- (2 , 2 -dialkoxyethyl) -1 , 2 , 3 , 4 -tetrahydroquinoline of Formula VII in the presence of a Lewis acid in a suitable solvent to obtain tricyclic heterocycle of Formula I.

A second aspect of the present invention provides a process for the preparation of tricyclic heterocycle of Formula I

Formula I

omprising reacting 1 , 2 , 3 , 4-tetrahydroquinoline of Formul

Formula II

with acetal intermediate of Formula VIII

Formula VIII

(X= Leaving group)

to obtain 1- (2 , 2 -diethoxyethyl ) -1 , 2 , 3 , 4 -tetrahydroquinoline of Formula IX

Formula IX

and cyclizing the

1- (2 , 2 -diethoxyethyl) -1,2,3, 4 -tetrahydroquinoline of Formula IX in the presence of a Lewis acid in a suitable solvent to obtain tricyclic heterocycle of Formula I.

A third aspect of the present invention provides a process for the preparation of tricyclic heteroc cle of Formula I

Formula I

comprising reacting 1 , 2 , 3 , 4- tetrahydroquinoline of Formula

Formula II

with an acetal intermediate of Formula VIII

Formula VIII

(X= Leaving group)

to obtain 1- (2 , 2-diethoxyethyl) - 1 , 2 , 3 , 4 -tetrahydroquinoline of Formula IX

Formula IX

and cyclizing the

1- (2 , 2-diethoxyethyl) -1,2,3, 4 -tetrahydroquinoline of Formula IX in the presence of aluminium chloride in a suitable solvent to obtain tricyclic heterocycle of Formula I.

A fourth aspect of the present invention provides tricyclic heterocycle of Formula I having less than 0.5% impurity of Formula X as determined by HPLC.

Formula X

A fifth aspect of the present invention provides tricyclic heterocycle of Formula I having less than 0.1% impurity of Formula XI as determined by HPLC.

Formula XI

A sixth aspect of the present invention provides tricyclic heterocycle of Formula I having HPLC purity greater than 99%.

Advantageous Effects of Invention

The present invention provides a short, convenient, industrially advantageous and cost-effective two-step process for the preparation of tricyclic heterocycle of Formula I which can be used as an intermediate for the preparation of pharmaceutical compounds. The process of the present invention does not involve use of costly reagents such as copper chromite or lithium aluminium hydride and provides tricyclic heterocycle of Formula I of high purity without the need for carrying out chromatographic

purification. Description of Embodiments

1 , 2 , 3 , 4-Tetrahydroquinoline of Formula II and acetal (s) of Formulae VI and VIII used in the present invention are available commercially.

The leaving group "X" may be selected from nucleophiles . Exemplary nucleophiles may include halides such as chloride, bromide or iodide or sulphonate esters such as tosylate, besylate, mesylate or triflate. Preferably, the leaving group may be halide.

The substituent "R" in the intermediates of Formula VI may be a straight or branched chain alkyl having 1-6 carbons such as methyl, ethyl, n-propyl or iso-propyl. Preferably, R may be ethyl.

The term "ambient temperature" as used herein may refer to a temperature of about 15°C to 35°C.

1- (2 , 2-Dialkoxyalkyl) - 1 , 2 , 3 , 4-tetrahydroquinoline may be prepared by the reaction of 1,2,3, 4-tetrahydroquinoline with acetal in the presence of a base and a phase transfer agent in a solvent at ambient temperature to the reflux temperature of the solvent. Un-reacted 1, 2 , 3 , 4-tetrahydroquinoline, if any, may be removed by adding concentrated hydrochloric acid.

In a preferred embodiment of the present invention, reaction of 1, 2 , 3 , 4-tetrahydroquinoline with acetal may be carried out by adding acetal to a reaction mixture containing

1, 2 , 3 , 4-tetrahydroquinoline, base and phase transfer catalyst in a solvent at ambient temperature. Reaction mixture may be heated to about 60 °C to reflux, stirred and cooled to ambient temperature.

De- ionized water may be added and the reaction mixture may be extracted with a chlorinated hydrocarbon such as dichloromethane .

Organic layer (s) maybe added into another reaction vessel containing de-ionized water and concentrated hydrochloric acid. Reaction mixture may be stirred at about 10 °C to ambient temperature for about

10 minutes to 3 hours. Isolation of 1- (2 , 2 -dialkoxyethyl) -1, 2 , 3 , 4 -tetrahydroquinoline may be

accomplished by filtration, concentration, precipitation, cooling, centrifugation or a combination thereof, followed by drying. Any suitable method of drying may be employed such as drying under reduced pressure, vacuum tray drying, air drying or a combination thereof. Traces of un-reacted acetal, if any, may be removed by heating at a temperature of about 50 °C to 80 °C under reduced pressure.

The base to be used for the reaction of

1,2,3 , 4 -tetrahydroquinoline with acetal may be selected from organic and inorganic bases. Exemplary organic bases may include

triethylamine, isobutylamine , tributylamine , diisopropylamine , diisopropylethylamine , pyridine, 4 -dimethylaminopyridine (DMAP) , 4-ethylmorpholine, 1 , 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 4-diazabicyclo [2.2.2] octane . Exemplary inorganic bases may include carbonates, bicarbonates and hydroxides and hydrides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium hydride. Preferably, an alkali metal carbonate such as potassium carbonate may be used.

The solvent to be used for the reaction of

1 , 2 , 3 , 4 -tetrahydroquinoline with acetal may be selected from polar aprotic solvents. Exemplary polar aprotic solvents may include amides such as N, N-dimethylformamide or N, N-diethylformamide , sulphoxides such as dimethyl sulphoxide, nitriles such as acetonitrile or benzonitrile , ketones such as acetone, ethyl methyl ketone or methyl iso-butyl ketone, ethers such as tetrahydrofuran or 1,4-dioxane, chlorinated hydrocarbons such as dichloromethane , chloroform or dichloroethane , N-methylpyrrolidone or sulpholane. Preferably, N, N-dimethylformamide may be used.

The phase transfer catalyst to be used for the reaction of 1 , 2 , 3 , 4 -tetrahydroquinoline with acetal may be selected from potassium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrapropylammonium bromide, tributylbenzylammonium chloride, tetraethylammonium bromide, tetrabutylammonium hydrogen sulphate, benzyltrimethylammonium chloride,

benzyltriethylammonium chloride, tetrabutylammonium acetate, phenyltrimethylammonium chloride or polyethylene glycols.

Preferably, potassium iodide may be used.

The phase transfer catalyst may be added in an amount ranging from 0.05 to 0.5 mole equivalent per mole equivalent of

1, 2 , 3 , 4-tetrahydroquinoline . Preferably, 0.1 mole equivalent of phase transfer catalyst may be added.

The process of the present invention provides

1- (2 , 2 -dialkoxyethyl) -1 , 2 , 3 , 4-tetrahydroquinoline of Formula IX having purity greater than 97%, as determined by gas chromatography.

The inventors of the present invention have performed several experiments for cyclization of

1- (2 , 2 -dialkoxyethyl ) -1, 2 , 3 , 4-tetrahydroquinoline to obtain tricyclic heterocycle of Formula I using various Lewis acids, solvents and temperature range. No cyclization was observed when

1- (2 , 2 -dialkoxyethyl) -1 , 2 , 3 , 4-tetrahydroquinoline was added to magnesium chloride in 2 -methoxyethanol . Changing the solvent from

2-methoxyethanol to toluene resulted in formation of tricyclic heterocycle of Formula I in low yield. When reaction mixture was stirred for longer time, degradation of cyclized product was observed Increase in reaction temperature for improving the yield of the reaction also lead to degradation of the cyclized product. Further experiments revealed that when aluminium chloride was used in place of magnesium chloride, tricyclic heterocycle of Formula I was obtained in good yield. No degradation was observed when aluminum chloride was used for cyclization. Additionally, carrying out cyclization using aluminum chloride at a temperature of about 0°C to about 25°C furnished tricyclic heterocycle of Formula I in good yield. The inventors of the present invention observed that keeping reaction temperature below 0°C affected the purity of tricyclic heterocycle of Formula I whereas increasing reaction temperature above 25°C lead to degradation of^■ tricyclic heterocycle of Formula I .

Accordingly, in a preferred embodiment of the present invention, cyclization may be carried out in an inert atmosphere by reacting ,1- (2 , 2-dialkoxyethyl) -1,2,3, 4 -tetrahydroquinoline with a Lewis acid in a suitable solvent at a temperature of about 0°C to ambient temperature. Reaction mixture may be stirred for about 15 minutes to 2 hours, quenched with water followed by completely recovering the solvent at about 10°C. to 30°C under reduced pressure . A non-polar organic solvent such as hexane,, cyclohexane or toluene and activated charcoal may be added . Contents may be stirred to obtain crude tricyclic heterocycle of Formula I. Exemplary Lewis acids to be used for cyclization may include aluminium chloride, aluminium bromide, magnesium chloride, titanium tetrachloride, zinc chloride or boron trifluoride etherate .

Preferably, aluminium chloride or aluminium bromide may be used. Exemplary solvents to be used for cyclization may include chlorinated hydrocarbons such as dichloromethane, chloroform or dichloroethane , carbon disulphide or aromatic hydrocarbons such as benzene, toluene or xylene. Preferably, dichloromethane may be used. The present inventors have observed that during quenching of the reaction mixture using water, a complex of tricyclic heterocycle of Formula I with aluminium chloride may be formed. The tricyclic heterocycle of Formula I may be liberated from this complex under acidic conditions such as by adding 0. IN hydrochloric acid or by stirring the organic layer obtained after quenching with water for about 1 to 5 hours .

Purification of crude tricyclic heterocycle of Formula I may be carried out by adding an alcohol such as methanol, ethanol, n-propanol or iso-propanol at ambient temperature to about 40 °C followed by addition of 0. IN hydrochloric acid. Reaction mixture may be heated to about 50 °C to reflux. De-ionized water may be added followed by addition of an alkyl acetate solvent such as methyl acetate, ethyl acetate, propyl acetate or butyl acetate. Contents may be stirred for about 10 minutes to 1 hour at about 50°C to reflux. Layers may be separated and the upper layer may be slowly cooled to a temperature of about 5°C to 25°C, stirred and filtered. Wet solid may be washed with a pre-cooled mixture of alcohol and de-ionized water followed by drying at about 25 °C to 60 °C under reduced pressure for about 2 to 15 hours. Purification of crude tricyclic heterocycle of Formula I may also be carried out by stirring in a mixture of a solvent such as hexane or cyclohexane and silica gel for about 2 to 5 hours.

Preparation of tricyclic heterocycle of Formula I may also be carried out without isolation of

1- (2 , 2 -dialkoxyethyl) -1,2,3, 4 -tetrahydroquinoline .

The process of the present invention provides tricyclic heterocycle of Formula I in greater than 99% yield.

Tricyclic heterocycle of Formula I obtained by the process of the present invention contains less than 0.5% of impurity of Formula X, as determined by HPLC. In one embodiment of the present invention, tricyclic heterocycle of Formula I contains less than 0.44% of impurity of Formula X. In another embodiment of the present invention, tricyclic heterocycle of Formula I contains less than 0.13% of impurity of Formula X.

Tricyclic heterocycle of Formula I, obtained by the process of the present invention, contains less than 0.5% of impurity of Formula XI, as determined by HPLC. In one embodiment of the present invention, tricyclic heterocycle of Formula I contains less than detectable limit of impurity of Formula XI. Tricyclic heterocycle of Formula I, obtained by the process of the present invention, has purity greater than 99%, as determined by HPLC.

In the foregoing section, embodiments ar described by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of the examples would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Methods :

Purity by Gas chromatography was determined using Restek Corporation,. Rtx-5 amine capillary column (30 m length x 0.53 mm ID x 3.0 μηι film thickness) with Oven temperature 1' : 50°C, Time l' : 5 min. , Rate ^λ1' : 20°C/min, Oven temperature ^λ2': 260°C, Time ^λ2': 40 min. , Inj ector temperature : 240 °C, Detector temperature : 270 °C, Carrier gas (N2) flow-. 5.0 mL/min. , Makeup (N2) flow: 20.0 mL/min, Split ratio: 10:1, Injection volume: 0.2 uL.

HPLC purity was determined using Agilent Technologies , CAPCELL PAK C18 MG II (250X4.6) mm, 5μτη column with a flow rate 1 mL/min; Column oven temperature 40 °C; Sample oven temperature 25 °C; Detector UV at 265nm; Injection volume 5yL; Run time 40 minutes; Impurity of Formula X: The peak which elutes whose retention time relative to lilolidine is about 2.99 and Impurity of Formula XI: The peak which elutes whose retention time relative to lilolidine is about 2.38. Example 1

Preparation of

1- (2 , 2 -dialkoxyethyl) -1,2,3, -tetrahydroquinoline

Method A: Preparation of

1- (2 , 2-diethoxyethyl) -1, 2 , 3 , 4 -tetrahydroquinoline

1 , 2 ,3 , 4 -tetrahydroquinoline (500 g) was added to a reaction vessel containing N, N-dimethylformamide (1000 mL) at ambient temperature. Anhydrous potassium carbonate (518.8 g) and potassium iodide (62.3 g) were added. Reaction mixture was heated to about 105 °C to 110°C and stirred for about 1 hour. Bromoacetaldehyde diethyl acetal (887.5 g) was slowly added to the above reaction mixture in about 30 minutes. Reaction mixture was heated to about 145 °C. Progress of the reaction was monitored by gas chromatography. Reaction mixture was cooled to ambient temperature followed by addition of de- ionized water (4000 mL) and dichloromethane (1000 mL) . Reaction mixture was stirred for about 10 minutes. Layers were separated and dichloromethane (1000 mL) was added to aqueous layer. Contents were stirred for about 10 minutes followed by layer separation. The organic layers were combined.

In another reaction vessel containing de-ionized water (1000 mL) , concentrated hydrochloric acid (37.5 mL) was added and the contents were cooled to about 10 °C to 15 °C. The combined organic layers, obtained above, were added. Contents were stirred at about 10°C to 15°C for about 2 hours followed by layer separation.

De- ionized water (4000 mL) was added to the organic layer and contents were stirred for about 10 minutes followed by layer separation. Solvent was recovered from the organic layer at a temperature of about 45°C under atmospheric pressure. Traces of un-reacted

bromoacetaldehyde diethyl acetal, if any, were removed by heating at a temperature of about 60 °C to about 65 °C under reduced pressure. Yield: 93%

Purity: 97.33% (by Gas chromatography)

Un-reacted 1 , 2 , 3 , 4 -tetrahydroquinoline : <0.1%

Un-reacted bromoacetaldehyde diethyl acetal: <0.15%

Method B: Preparation of

1- (2 , 2-dimethoxyethyl) -1,2,3, 4 -tetrahydroquinoline

1 , 2 , 3 , 4 -tetrahydroquinoline (500 g) was added to a reaction vessel containing N, N-dimethylformamide (1000 mL) at ambient temperature. Anhydrous potassium carbonate (778.25 g) , potassium iodide (62.3 g) and bromoacetaldehyde dimethyl acetal (729.62 g) were added. Reaction mixture was heated to about 120°C to 125°C. Progress of the reaction was monitored by gas chromatography. Reaction mixture was cooled to ambient temperature followed by addition of de-ionized water (4000 mL) and dichloromethane (2000 mL) . Reaction mixture was stirred for about 10 minutes. Layers were separated and

dichloromethane (1000 mL) was added to aqueous layer. Contents were stirred for about 10 minutes followed by layer separation. The organic layers were combined.

In another reaction vessel containing de-ionized water (4000 mL) and concentrated hydrochloric acid (37.5 mL) , the combined organic layers, above obtained, were added. Contents were stirred at about 25 °C to 30 °C for about 10 to 15 minutes followed by layer separation. The organic layer was added to a mixture of de-ionized water (4000 mL) and concentrated hydrochloric acid (37.5 mL) . Contents were stirred at about 25°C to 30°C for about 10 to 15 minutes followed by layer separation . The organic layer was added to a mixture of de-ionized water (4000 mL) and concentrated hydrochloric acid (37.5 mL) . Contents were stirred at about 25°C to 30°C for about 10 to 15 minutes followed by layer separation. De-ionized water (4000 mL) was added to the organic layer and the contents were stirred for about 10 minutes followed by layer separation. Solvent was recovered from the organic layer at a temperature of about 35°C to 55°C under atmospheric pressure. Traces of the solvent were removed by drying at a temperature of about 60°C to 65°C under reduced pressure for 1 hour.

Yield: 92.53%

Purity: 97.61% (by Gas chromatography)

Un-reacted 1 , 2 , 3 , 4-tetrahydroquinoline : 0.09%

Un-reacted bromo acetaldehyde dimethyl acetal : 0.23%

Example 2

Cyclization of

1- (2 , 2-dialkoxyethyl) -1 , 2 , 3 , 4-tetrahydroquinoline

Method A: Cyclization of

1- (2 , 2 -diethoxyethyl) -1,2,3, 4-tetrahydroquinoline

In a reaction vessel flushed with nitrogen gas,

dichloromethane (6500 mL) was added at a temperature of about 25°C to 30 °C. The contents were cooled to about 0°C to 5°C and aluminium chloride (801.15 g) was added. The contents were cooled to about 0°C to 5°C. A ^'solution of

1- (2 , 2-diethoxyethyl) -1,2,3, 4-tetrahydroquinoline in

dichloromethane (500 g in 100 mL dichloromethane) was added slowly in about 15 to 20 minutes. Reaction mixture was stirred for about 30 minutes to 1 hour at about 0°C to 5°C. Progress of the reaction was monitored by high performance liquid chromatography. Reaction mixture was slowly added into another reaction vessel containing pre-cooled de-ionized water (15000 mL) at about 0 °C to 5 °C and stirred for about 10 minutes followed by layer separation. Dichloromethane was recovered completely at about 15°C to 20°C. Hexane (1000 mL) was added followed by recovering the solvent at about 15 °C to 20 °C under reduced pressure . Hexane (15000 mL) and activated carbon (5 g) were added. The contents were heated to about 30 °C, stirred for about 30 minutes and filtered. Wet cake was washed with hexane (1000 mL) followed by completely recovering hexane at about 35 °C to 40 °C under reduced pressure.

Methanol (2250 L) was added to the crude product at about 35 °C to 60 °C followed by heating to about 65 °C. Extent of purification was monitored using thin layer chromatography. De-ionized water (2000 mL) was slowly added to the reaction vessel at about 60 °C to 65°C followed by addition of ethyl acetate (500 mL) . Reaction mixture was stirred for about 30 minutes at about 60 °C to 65 °C followed by layer separation. Lower light yellow layer was separated completely and the upper layer was slowly cooled to about 10 °C to 15 °C, stirred for about 2 hours and filtered. Wet solid was washed with pre-cooled mixture of methanol (250 mL) and de-ionized water (250 mL) and dried under reduced pressure at about 30°C to 35°C for about 8 hours to 10 hours till moisture content less than 0.2% was achieved.

Yield: 34.9%

Purity: 99.42% (by HPLC)

Impurity of Formula X: 0.124%

Impurity of Formula XI : Not detected

Method B: Cyclization of

1- (2 , 2-diethoxyethyl) -1, 2, 3 , 4-tetrahydroquinoline

In a reaction vessel flushed with nitrogen gas,

dichloromethane (800 mL) was added at about 25°C to 30°C. The contents were cooled to about 0°C to 5°C and aluminium chloride (128.33 g) was added. The contents were cooled to about 0°C to 5°C followed by slow addition of a solution of

1- (2 , 2-diethoxyethyl) -1,2,3, 4 -tetrahydroquinoline in

dichloromethane (80 g in 320 mL dichloromethane) in about 15 to 20 minutes. Reaction mixture was stirred for about 30 minutes to 1 hour at about 0°C to 5°C. Progress of the reaction was monitored by high performance liquid chromatography. Reaction mixture was slowly added into another reaction vessel containing pre-cooled de-ionized water (560 mL) at about 0°C to 5°C: The contents were stirred for about 10 minutes followed by layer separation. The organic layer was stirred for about 2 hours, washed with de-ionized water (2 x 560 mL) followed by layer separation and solvent recovery at about 35 °C to 50 °C under atmospheric pressure. Hexane (800 mL) and silica gel (100-200 mesh, 40 g) were added to the residue at about 20°C to 25°C. The contents were warmed to about 30°C to 35°C, stirred for about 30 minutes, filtered and washed with hexane (100 mL) . Hexane was recovered under reduced pressure at about 40°C to 45°C, leaving behind reaction mass (about 160 mL) . The reaction mass was cooled to about 0°C to 5°C, stirred for about 3 hours, filtered, washed with chilled hexane (20 mL)and dried under reduced pressure at about 25 °C to about 30 °C for about 7 hours.

Yield: 35.7%

Purity: 99.52% (by HPLC)

Impurity of Formula X: 0.43%

Impurity of Formula XI : Not detected

Method C: Cyclization of

1- (2,2-dimethoxyethyl ) -1,2,3,4 -1etrahydroquinoline

In a reaction vessel flushed with nitrogen gas,

dichloromethane (5000 mL) was added at about 25°C to 30°C followed by addition of aluminum chloride (980 g) and a solution of l-(2,

2 -dimethoxyethyl) -1 , 2 , 3 , 4 -tetrahydroquinoline (500 g) in

dichloromethane (2000 mL) in about 100 minutes. Reaction mixture was stirred for about 30 minutes and then slowly added into another reaction vessel containing pre-cooled de-ionized water (4000 mL) at about 0°C to 5°C. The contents were stirred for about 10 minutes followed by layer separation. Dichloromethane layer was stirred for about 3 hours followed by adding potassium carbonate solution (50 g in 160 mL Dl-water) . Dichloromethane was recovered atmospherically at a temperature of about 40°C to 55°C. Traces of dichloromethane were removed by adding hexane (300 mL) . The crude residue was extracted with hexane (5000 mL) at about ,60°C to 65°C. The contents were cooled to ambient temperature, filtered and washed twice with about IN hydrochloric acid (1000 mL) . Water was removed

azeotropically from the hexane layer. Silica gel (60-120 mesh, 250 g) was added at about 25°C to 30°C. The contents were stirred for about 2 hours, filtered and washed with hexane (300 mL) . Hexane was recovered at about 65 °C to 70 °C under atmospheric pressure. The contents were cooled to about 0°C to 5°C, stirred for about 2 hours, filtered, washed with chilled hexane (160 mL) and dried under reduced pressure at about 25°C to 30°C for about 7 hours.

Yield: 152 g (42.8 ^' %)

Purity: 99.57% (by HPLC)

Impurity of Formula X: 0.12%

Impurity of Formula XI : Not detected

Industrial Applicability

purification.

Claims

[Claim 1]

A process for the preparation of tricyclic heterocycle Formula I

Formula I

comprising reacting 1 , 2 , 3 , 4-tetrahydroquinoline of Formula

Formula II

with an acetal intermediate la VI

Formula VI

(X= Leaving group; R = alkyl)

to obtain 1- (2 , 2-dialkoxyethyl) -1 , 2 , 3 , -tetrahydroquinoline of Formula VII

and cyclizing the

1- (2 , 2 -dialkoxyethyl) -1 , 2 , 3 , 4-tetrahydroquinoline of Formula VII in the presence of a Lewis acid in a suitable solvent to obt tricyclic heterocycle of Formula I.

[Claim 2] .

A process for the preparation of tricyclic heterocycle Formula I

Formula I

comprising reacting 1, 2 , 3 , 4 quinoline of Formula

H

Formula II

with acetal intermediate of Formula VII

Formula VIII

(X= Leaving group)

to obtain 1- (2 , 2-diethoxyethyl) -1,2,3, 4-tetrahydroquinoline of Formula IX

Formula IX and cyclizing the

1- (2 , 2-diethoxyethyl) -1,2,3, 4-tetrahydroquinoline of Formula IX in the presence of a Lewis acid in a suitable solvent to obtain tricyclic heterocycle of Formula I . [Claim 3]

A process for the preparation of tricyclic heterocycle of Formula I