Indian Patents. 279270:"PREPARATION OF SUBSTITUTED 1H-IMIDAZO[4,5-C] QUINOLINE"

Title of Invention	"PREPARATION OF SUBSTITUTED 1H-IMIDAZO[4,5-C] QUINOLINE"
Abstract	Disclosed herein a process for the preparation of compound 4-amino-1-isobutyI-lH-imidazo[4,5-c] quinoline [Imiquimod] of Formula I;

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) AND The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "PREPARATION OF SUBSTITUTED ltf-IMIDAZO[4,5-c]QUINOLlNE" 2. APPLICANT: (a) NAME: INDOCO REMEDIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956 (c) ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India. 3.PREAMBLE TO THE DESCRIPTION: The following specification describes the invention and the manner in which it is to be performed- FIELD OF INVENTION: The present invention provides a process for the preparation of 4-amino-l -isobutyl-H-imidazo[4,5-c]quinoline of Formula I. BACKGROUND AND PRIOR ART: The compound 4-amino-l-isobutyI-lH-imidazo[4,5-c]quinoline of Formula I commonly known as Imiquimod is an immune response modifier indicated for the treatment of actinic keratosis, superficial basa! cell carcinoma, and external genital warts. The synthesis of imiquimod was described in U.S. patent No. 4,689,348, wherein the compound l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula 11 is subjected to oxidation using hydrogen peroxide in acetic acid or peracids to get the compound 1-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. After recrystallisation the compound of Formula III is heated with phosphorous oxychloride, which after work up and recrystallisation yields the compound 4-chloro-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula IV. The compound of Formula IV on reaction with ammonium hydroxide in an autoclave at 150°C for 16 hrs results in the compound 4-amino-l-isobutyl-1H-imidazo[4,5-c]quinoline of Formula I. The reaction sequence is as shown in scheme 1 below. Scheme 1 The disadvantage of the above prior art are; i. use of hazardous, explosive and environment unfriendly reagents, hydrogen peroxide for oxidation and phosphorous oxychloride for chlorination; ii. longer duration of reaction ; iii. use of autoclave at high temperature which is unsafe on industrial scale. Other reagents disclosed in the prior art for the oxidation of the compound 1-isobutyl-lH-imidazo[4,5-c]quinoLine of Formula II to get the compound l-isobutyl-lH-imidazo[4,5-c] quinoIin-5-oxide of Formula III are peracetic acid and meta-chloroperbenzoic acid in various solvents. The reagents used for oxidation are hygroscopic and unstable which is undesired for use on industrial scale. The US patent No. 5,175,296 describes a process, wherein the compound 1-isobutyl-lH-imidazo[4,5-c] quinolin-5-oxide of Formula III is reacted with benzoyl isocyanate to get the compound N-benzoyl-l-(2-methylpropyI)-IH-imidazo[4,5-c]quinolin-4-amine of Formula V which on hydrolysis with sodium methoxide results in the compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I. The reaction sequence can be represented as in scheme 2 below; Scheme 2 The drawback of the process is increased number of steps and use of industrially toxic and unsafe reagent. WO2004/009593 disclose a process wherein the compound l-isobutyl-lH-imidazo[4,5-c] quinolin-5-oxide of Formula III is reacted with phthalimide in presence of benzoyl chloride and tri-n-butylamine to get l-isobutyl-lH-imidazo[4,5-c]quinolin-4-phthalimide of Formula VI. The compound of Formula VI is reacted with hydrazine hydrate in presence of antifoaming agent isooctyl alcohol to get imiquimod of Formula I. Another application WO2008/048683 describes the process for preparing imiquimod, wherein the compound l-isobutyl-177-imidazo[4,5-c]quinolin-5-oxide of Formula III is reacted with phthalimide in presence of benzoyl chloride and tributylamine to get l-isobutyl-lH-imidazo[4,5-c]quinolin-4-phthalimide of Formula VI. The compound of Formula VI is reacted with ethylenediamine at 70°C yields imiquimod of Formula I. The reaction sequence of above prior arts can be represented as in scheme 3 below; The drawbacks of the above prior arts are; i. the intermediate phthalimido compound needs treatment with methanol to get pure compound; ii. foaming during the breaking of phthalimido group to get amino group at C4 position. iii. increased number of steps and processing time to get the compound. Another application WO 2006/070379 discloses a process for preparing imiquimod, wherein the compound l-isobutyI-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III is reacted with phosphorous oxychloride at heating to get 4-chloro-l-isobutyI-l//-imidazo[4,5-c]quinoline of Formula IV. The compound of Formula IV is reacted with sodium iodide in acetone to get 4-iodo-l-isobutyl-1Himidazo[4,5-c]quinoline of Formula VII which is then reacted with methanolic ammonia at 150 - 155°C in an autoclave to isolate crude imiquimod of Formula I. The crude compound is purified by acid base method to get pure imiquimod. The disadvantages of the process are; i. increased number of steps which affects the economy of the process; ii. uses autoclave and higher temperature reaction to get the final compound. It therefore remains a need to develop an alternative and improved process for the preparation of imiquimod which overcomes the problems associated with the processes known in the art. The present inventors ameliorates the problems of the prior art processes by using cost effective and safe reagent for oxidation, avoiding the recrystallisation of intermediate, use of autoclave and reducing the number of steps to prepare 4-amino-l-isobutyI-l//-imidazo[4,5-c]quinoline of Formula -1. OBJECTIVE OF THE INVENTION: The main objective of the present invention is to prepare the compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod] of Formula I with a cost effective and robust process. Another objective of the present invention is to prepare the compound 4-amino-l-isobutyl-1H-imidazo[4,5-c]quinoIine [Imiquimod] of Formula I with good yield and high purity. SUMMARY OF THE INVENTION: Accordingly the present invention provides a process for preparation of compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod] of Formula I; Formula I comprising the steps of; i. oxidation of the compound l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula II; Formula II with an oxidizing agent in presence of polar solvent, and base to get the compound l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. ii. reacting the compound of Formula III with an aminating agent in presence of solvent and benzoyl chloride to isolate the compound 4-amino-l-isobutyl-l//-imidazo[4,5-c]quinoline of Formula I. DESCRIPTION OF THE INVENTION: The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The present invention provides a simple process for preparing highly pure compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I by using environmental and industrial friendly reagents. The sequence of present invention is represented as shown in scheme 4 below; Scheme 4 In one of the embodiments of the present invention the compound 1-isobutyl-lH-imidazo[4,5-c]quinoline of Formula II is subjected to N-oxidation of the quinoline nitrogen with an oxidizing agent in presence of a base and polar solvent to get the compound l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. The oxidizing agent used in the present invention is potassium peroxymonosulfate having commercial trade name Oxone. The base used in the oxidation reaction is selected from alkali metal, alkaline earth metal hydroxide, carbonates or bicarbonates. The preferred base used for the oxidation reaction are sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate, wherein the most preferred base used for the oxidation reaction is sodium carbonate. The polar solvents used for the oxidation reaction are selected from C1 - C3 linear or branched chain alcohol and water or mixture thereof. The preferred C1 - C3 linear or branched chain alcohol used for the oxidation are methanol, ethanol, n-propanol and isopropanol, wherein the most preferred solvent for oxidation reaction is methanol. The oxidation reaction is carried out in the temperature range of 20°C to 60°C. The preferred temperature for oxidation reaction is 25 - 50°C, wherein the most preferred temperature for the reaction is 45 - 50°C The oxidizing agent potassium peroxymonosulfate is a non-inflammable, non-hazardous stable solid compound which is safe to handle on the industrial scale. Accordingly the compound l-isobutyl-lHimidazo[4,5-c]quinoline of Formula II was taken in the polar solvent methanol either alone or in mixture thereof at 20 - 30°C, under stirring charged the oxidizing agent potassium peroxymonosulfate and. the base sodium carbonate followed by addition of water in 15 to 20 minutes. The reaction mixture was heated to 50°C and maintained the reaction at 50 ± 5°C. The progress of the reaction was monitored on HPLC. After completion of the reaction, cooled the reaction mass to 35 -40°C, filtered the reaction mass and washed with methanol. Combined filtrate and washing concentrated under reduced pressure to obtain residual solution of the reaction mass. Charged dichloromethane to the residual solution of the reaction mass and separated the organic layer. The dichloromethane was distilled out under reduced pressure to get the crude residual mass of l-isobutyI-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. The crude product is purified in the solvent selected from acetone, ethyl acetate, acetonitrile, cyclohexane, toluene, and diisopropyl ether. The preferred solvent used for purification is toluene. The compound l-isobutyl-lH-irnidazo[4,5-c]quinoline of Formula II used for the preparation of the compound l-isobutyl-lH-imidazo[4,5-c]quinoIin-5-oxide of Formula III can be prepared as per the process described in the U. S. Patent No. 4,689,338 [Gerster John f]. In another embodiment of the present invention the compound 1-isobutyl-lH-imidazo[4,5-c]quinoIin-5-oxide of Formula III reacted with an aminating agent in presence of solvent and benzoyl chloride to get the compound 4-amino-l-isobutyI-lH-imidazo[4,5-c]quinoline of Formula I. The suitable aminating agent used is selected from ammonia gas, ammonium hydroxide and ammonium salts selected from ammonium carbonate, ammonium bicarbonate, ammonium chloride and ammonium phosphate. The preferred aminating agent used for the reaction is ammonium hydroxide. The solvent used in the reaction is selected from dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile and acetone, wherein the preferred solvent used for the reaction is dichloromethane. The reaction is carried out at the temperature of-10°C to 20°C. The work up of the reaction was done by quenching the reaction mass with water and stirring at 0 - 5°C for 30 minutes. Concentrated the reaction mass under reduced pressure below 40°C to get crude compound 4-amino-l-isobutyl-1H-imidazo[4,5-c]quinoline of Formula I. the crude compound was further treated with solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetone, acetonitrile, toluene, diisopropyl ether, tert-butyl methyl ether to isolate the pure compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I. The product is further purified by acid base treatment and recrystallized to get pure 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I by suitable process as per the given example. Accordingly the compound l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III was taken in the solvent dichloromethane and ammonium hydroxide was added at temperature of 25 - 30°C. Cooled the reaction mixture to -10°C ± 5°C and charged solution of benzoyl chloride maintaining the temperature at -5°C ± 5°C in 1 to 2 hours time. The solution of benzoyl chloride was prepared in the solvent used for the reaction. Raised the temperature of the reaction mixture to 0 - 5°C and maintained for one hour. Charged water to the reaction mass and stirred for 30 minutes at 0 - 5°C concentrated under reduced pressure below 40°C to get the residual mass. Charged isopropanol solvent to the crude residual mass and raised the temperature to 50 - 55°C, maintained for one hour. Cooled the reaction mass to 25 - 30°C and stirred one hour. Filtered the solid compound to get 4-amino-I-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I. Certain specific aspects and embodiments of the present invention is further illustrated in detail with reference to the following examples, which are provided solely for the purpose of illustration and are not to be construed as limiting the scope of the invention in any manner. Examples: Example 1: Preparation of 4-isobutyIamino-3-nitroquinoline: To a cooled solution of 4-ch!oro-3-nitroquinoline (50 gms) in methanol (200 ml), charged a solution of isobutylamine (26.2 ml) and triethylamine (40 ml) through addition funnel maintaining temperature at 0 - 5°C within 30min. Raised the temperature of the reaction mixture to 25 - 30°C and stirred for 4 - 5 hours. After completion of reaction, charged DM water (250 ml) at 25 - 30°C and stirred for one hour. Filtered the reaction mass and washed the product with water. The wet cake of 4-isobutyIamino-3-nitroquinoline was dried at 45°C till constant weight. Yield = 53.0 gms. Example 2: Preparation of 3-amino-(4-isobutylamino)quinoline: Charged 4-isobutylamino-3-nitroquinoline (40 gms) and 5% Pd-C in toluene (400 ml) in an autoclave. Flushed the reaction mixture with nitrogen, and purged with constant pressure of 3 - 4 Kg hydrogen at 45°C and maintained the reaction for 3 - 4 hours. After completion of the reaction the mass was filtered through hyflo bed and washed the bed with methanol (80 ml). Concentrated the solvent under reduced pressure to afford the crude product quantitatively. Yield = 35.12 gms. Example 3: Preparation of l-isobutyl-l//-imidazo[4,5-c]quinoIine: Charged 3-amino-(4-isobutylamino)quinoline (30 gms) in toluene (300 ml) and raised the temperature to reflux. Maintaining the temperature at reflux, charged formic acid (1.57 ml) followed by addition of triethylorthoformate (34.8 ml) through addition funnel within 30 minutes, and continued stirring for additional one hour with simultaneous removal of ethanol, formed during the reaction. After completion of reaction, the reaction mixture was distilled under reduced pressure to get l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula II. Yield = 28 gms. Example 4: Preparation of 4-isobutylamino-3-nitroquinoline: Charged 4-hydroxy-3-nitroquinoline (105 gm) to dichloromethane (1.05 lit) and stirred for 15min. Charged thionyl chloride (48.36gm) through dropping funnel within 10-15 minutes maintaining temperature at 25 - 28°C followed by addition of N,N -dimethylformamide (51.3ml). Slowly raised the temperature to 42 - 45°C and maintained reaction mixture at 42 - 45°C for 3.5 to 4 hrs and monitor the reaction for completion on HPLC. After completion of the reaction cooled the reaction mixture to 0°C. Meanwhile prepared solution of isobutylamine (82.31ml) and triethylamine (130.84 ml) and added slowly through dropping funnel to cooled reaction mass maintaining temperature at 0 -5°C in 30minutes to 45minutes. Raised the temp gradually to 25 - 30°C and applied heating to attain the temperature of 40 - 45°C. Maintained the reaction at 40 - 45°C monitoring for completion of reaction on HPLC. After completion of the reaction concentrated the reaction mass under reduced pressure below 35°C to get the residual mass. Charged water (840 ml) and distilled out traces of dichloromethane completely to get free slurry of reaction mass, stirred the reaction mass for 2hrs at 38 - 42°C. Cooled the reaction mass to 25 - 30°C and stirred further for 1 hour. Filtered slurry and washed the solid mass with water (2 x 262.5ml) and dried the product at 50 - 55°C to obtain 4-isobutylamino-3-nitroquinoline. Wt of solid =132gm; %Yield = 97.67% Example 5: Preparation of l-Isobutyl-lH-imidazo[4,5-c]quinoline: In a dry autoclave charged 4-isobutyIamino-3-nitroqumoline (120 gm), toluene (1200 ml) and 5% Pd/C (12 gm) under nitrogen atmosphere maintaining temperature at 25 - 30°C. Apply 4.5 Kg Hydrogen pressure and raised the temperature to 50 - 55°C and maintained for 4 - 6 hrs monitoring the reaction for completion by HPLC. Cooled the reaction mass and filtered through hyflo bed. Washed the autoclave container and hyflo bed with methanol (360 ml) each. Combined filtrate and washing was concentrated under reduce pressure maintaining temperature below 45°C. To the residual mass charged formic acid (516 ml) at 25 - 30°C, raised the temperature to 110 - 115°C and maintained the reaction mass for 12 - 14 hours monitoring the completion of reaction by HPLC. After completion of the reaction cooled to 50°C and concentrated the reaction mass under vacuum maintaining temperature below 50°C to get the oily residual mass. Cooled the reaction mass to 25 - 30°C, charged water (1200 ml) and stirred for 15 minutes. Cooled the reaction mass to 10°C and adjusted the pH of the reaction mass to 10-11 using aqueous 30% sodium hydroxide solution (330 ml) while maintaining the internal temperature between 5 - 10°C. Stirred the reaction mass at 10°C for 3 hours filtered the solid and washed with cold water (2 x 240 ml). Dried the product at 25 - 30°C under vacuum till constant weight to get l-isobutyl-lH-imidazo[4,5-c]quinoline. Wt of solid = 102 gm; %Yield = 92%. Example 6: Preparation of l-Isobutyl-lH-imidazol[4,5-c]quinoline-5-oxide: Charged l-isobutyl-lH-imidazo[4,5-c]quinoIine (90 gm) in a dry reaction flask containing methanol (630 ml) and stirred. Charged potassium peroxymonosulfate (368.4 gm), sodium bicarbonate (144.28 gm) followed by addition of water (630 ml) slowly maintaining the temperature at 25 - 30°C within 15-20 minutes. Applied heating and raised the temperature of the reaction to 48 - 50°C and maintained for 3 to 4 hours monitoring the completion of reaction by HPLC. After complete reaction cooled the reaction mass 40°C and filtered, washed the solid with methanol (2 xl80 ml). Combined the filtrate & distilled out methanol solvent under reduced pressure below 40°C to get the residual solution of the reaction mass. Cooled and extracted the reaction mass with dichloromethane (4 x 450 ml) at 25 - 30°C. Combined the organic layer and distilled out under reduced pressure below 40°C to get the residual mass. Charged toluene (270 ml) and stirred the slurry at 25-30°C for 2 hours. Filtered the solid product and washed with toluene (45 ml). Dried the product at 50-55°C till constant weight to get I-isobutyl-1H-imidazo[4,5-c]quinoline-5-oxide. Wtofsolid = 90.2gm; %Yield = 93.5% Example 7: Preparation of 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod]: In a dry round bottom flask containing dichloromethane (640 ml) charged 1-isobutyl-lH-imidazo[4,5-c]quinoline-5-oxide (80.0 gm) and aqueous ammonia (240 ml) at 25 - 30°C. Cooled the reaction mass to -10°C. To the cooled reaction mass slowly charged benzoyl chloride solution (58 ml) prepared in dichloromethane (160 ml) maintaining the temperature at -10 to -5 °C within the period of 60-90 minutes. After complete addition maintained the reaction mass at 0 - 5°C for lhour. Decomposed the reaction mass with water (240 ml) and stirred at 0 - 5°C for 30 minutes. Concentrated the reaction mass completely under reduced pressure below 40°C to get the residual mass. To the residual mass charged isopropanol (160 ml), raised the temperature to 55°C and maintained at 50 -55°C for 1 hour. Cooled the reaction mass gradually to 25 - 30°C and stirred for 1 hour. Filtered the solid and washed with isopropanol (240 ml). The compound is dried in drying oven under vacuum at 45-50°C till constant weight to obtain crude 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod]. Dry weight = 62 gm; %Yield = 77.5% Example 8: Purification of Crude Imiquimod: Crude Imiquimod (60gm) was taken in Round bottom flask containing concentrated hydrochloric acid (240 ml). Charged sodium dithionite (26.4 gm) at 25 - 30°C and applied heating, raised the temperature to 90 - 95°C and maintained for one hour. Stopped heating and cooled reaction mass gradually to 25 - 30°C. Diluted the reaction mass with water (720 ml) and stirred at 25-30°C for one hour. Filtered the reaction mass & washed the solid mass with water (120 ml) to obtain imiquimod hydrochloride. The hydrochloride salt of imiquimod was taken in methanol (1040 ml). Applied heating and raised the temperature to reflux. Added charcoal (16 gm) at reflux temperature and maintain for 1.5 hours. Filtered the reaction mass at hot condition through hyflow bed and washed with hot methanol (240 ml). Combined filtrate and washing cooled gradually to 25 - 30°C and adjusted the pH 9-10 of the solution with aqueous ammonia maintaining temperature at 25 - 30°C. Stirred the reaction mass for 2 hours. Filtered the solid and washed the product with methanol (160 ml) followed by water (2 x 160ml). Dried the isolated pure 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod] under vacuum at 45 - 50°C till constant weight. Yield-42 gm; % Yield = 52.7%; HPLC purity = NLT 99.5%. We Claims: 1. A process for the preparation of compound 4-amino-l-isobutyl-lH-imidazo[4,5-c] quinoline [Imiquimod] of Formula I; wherein the process comprises the steps of; i. reacting the compound I-rsobutyl-1H-imidazo[4,5-c]quinoIine of Formula II; Formula II with potassium peroxymonosulfate in presence of polar solvent, and base to get the compound l-isobutyl-l/f-imidazo[4,5-c]quinolin-5-oxide of Formula III. ii. reacting the compound of Formula III with an animating agent in presence of solvent and benzoyl chloride to isolate the compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I. iii. optionally purifying the compound 4-amino-l-isobutyl-lH-imidazo[4,5-cjquinoline of Formula I. 2. The process as claimed in claim I, wherein the polar solvent used in step (i) is selected from the group consisting of C1 - C3 linear or branched chain alcohol and water or mixture thereof. 3. The process as claimed in claim 2, wherein the C1 - C3 linear or branched chain alcohol used are selected from the group consisting of methanol, ethanol, n-propanol and isopropanol, 4. The process as claimed in claim 1, wherein the base used in step (i) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate. 5. The process as claimed in claim 1, wherein the reaction in step (i) is carried out at temperature of 20°C to 60°C. 6. The process as claimed in claim 1, wherein the aminating agent used in step (ii) is selected from the group consisting of ammonia gas, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium chloride and ammonium phosphate. 7. The process as claimed in claim 6, wherein the aminating agent used is ammonium hydroxide. 8. The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile and acetone. 9. The process as claimed in claim 8, wherein the solvent used is dichloromethane.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PREPARATION OF SUBSTITUTED ltf-IMIDAZO[4,5-c]QUINOLlNE"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed-

FIELD OF INVENTION:
The present invention provides a process for the preparation of 4-amino-l -isobutyl-H-imidazo[4,5-c]quinoline of Formula I.

BACKGROUND AND PRIOR ART:
The compound 4-amino-l-isobutyI-lH-imidazo[4,5-c]quinoline of Formula I commonly known as Imiquimod is an immune response modifier indicated for the treatment of actinic keratosis, superficial basa! cell carcinoma, and external genital warts.
The synthesis of imiquimod was described in U.S. patent No. 4,689,348, wherein the compound l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula 11 is subjected to oxidation using hydrogen peroxide in acetic acid or peracids to get the compound 1-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. After recrystallisation the compound of Formula III is heated with phosphorous oxychloride, which after work up and recrystallisation yields the compound 4-chloro-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula IV. The compound of Formula IV on reaction with ammonium hydroxide in an autoclave at 150°C for 16 hrs results in the compound 4-amino-l-isobutyl-1H-imidazo[4,5-c]quinoline of Formula I. The reaction sequence is as shown in scheme 1 below.

Scheme 1 The disadvantage of the above prior art are;
i. use of hazardous, explosive and environment unfriendly reagents, hydrogen
peroxide for oxidation and phosphorous oxychloride for chlorination;
ii. longer duration of reaction ;
iii. use of autoclave at high temperature which is unsafe on industrial scale.
Other reagents disclosed in the prior art for the oxidation of the compound 1-isobutyl-lH-imidazo[4,5-c]quinoLine of Formula II to get the compound l-isobutyl-lH-imidazo[4,5-c] quinoIin-5-oxide of Formula III are peracetic acid and meta-chloroperbenzoic acid in various solvents. The reagents used for oxidation are hygroscopic and unstable which is undesired for use on industrial scale.
The US patent No. 5,175,296 describes a process, wherein the compound 1-isobutyl-lH-imidazo[4,5-c] quinolin-5-oxide of Formula III is reacted with benzoyl isocyanate to get the compound N-benzoyl-l-(2-methylpropyI)-IH-imidazo[4,5-c]quinolin-4-amine of Formula V which on hydrolysis with sodium methoxide results in the compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I. The reaction sequence can be represented as in scheme 2 below;

Scheme 2
The drawback of the process is increased number of steps and use of industrially toxic and unsafe reagent.
WO2004/009593 disclose a process wherein the compound l-isobutyl-lH-imidazo[4,5-c] quinolin-5-oxide of Formula III is reacted with phthalimide in presence of benzoyl chloride and tri-n-butylamine to get l-isobutyl-lH-imidazo[4,5-c]quinolin-4-phthalimide of Formula VI. The compound of Formula VI is reacted with hydrazine hydrate in presence of antifoaming agent isooctyl alcohol to get imiquimod of Formula I.
Another application WO2008/048683 describes the process for preparing imiquimod, wherein the compound l-isobutyl-177-imidazo[4,5-c]quinolin-5-oxide of Formula III is reacted with phthalimide in presence of benzoyl chloride and tributylamine to get l-isobutyl-lH-imidazo[4,5-c]quinolin-4-phthalimide of Formula VI. The compound of Formula VI is reacted with ethylenediamine at 70°C yields imiquimod of Formula I. The reaction sequence of above prior arts can be represented as in scheme 3 below;

The drawbacks of the above prior arts are;
i. the intermediate phthalimido compound needs treatment with methanol to get pure
compound; ii. foaming during the breaking of phthalimido group to get amino group at C4
position. iii. increased number of steps and processing time to get the compound.
Another application WO 2006/070379 discloses a process for preparing imiquimod, wherein the compound l-isobutyI-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III is reacted with phosphorous oxychloride at heating to get 4-chloro-l-isobutyI-l//-imidazo[4,5-c]quinoline of Formula IV. The compound of Formula IV is reacted with sodium iodide in acetone to get 4-iodo-l-isobutyl-1Himidazo[4,5-c]quinoline of Formula VII which is then reacted with methanolic ammonia at 150 - 155°C in an autoclave to isolate crude imiquimod of Formula I. The crude compound is purified by acid base method to get pure imiquimod. The disadvantages of the process are;
i. increased number of steps which affects the economy of the process;
ii. uses autoclave and higher temperature reaction to get the final compound.
It therefore remains a need to develop an alternative and improved process for the preparation of imiquimod which overcomes the problems associated with the processes known in the art.
The present inventors ameliorates the problems of the prior art processes by using cost effective and safe reagent for oxidation, avoiding the recrystallisation of intermediate, use of autoclave and reducing the number of steps to prepare 4-amino-l-isobutyI-l//-imidazo[4,5-c]quinoline of Formula -1.
OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to prepare the compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod] of Formula I with a cost effective and robust process.

Another objective of the present invention is to prepare the compound 4-amino-l-isobutyl-1H-imidazo[4,5-c]quinoIine [Imiquimod] of Formula I with good yield and high purity.
SUMMARY OF THE INVENTION:
Accordingly the present invention provides a process for preparation of compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod] of Formula I;

Formula I comprising the steps of;
i. oxidation of the compound l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula II;

Formula II with an oxidizing agent in presence of polar solvent, and base to get the compound l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III.

ii. reacting the compound of Formula III with an aminating agent in presence of
solvent and benzoyl chloride to isolate the compound 4-amino-l-isobutyl-l//-imidazo[4,5-c]quinoline of Formula I.

DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention provides a simple process for preparing highly pure compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I by using environmental and industrial friendly reagents. The sequence of present invention is represented as shown in scheme 4 below;

Scheme 4 In one of the embodiments of the present invention the compound 1-isobutyl-lH-imidazo[4,5-c]quinoline of Formula II is subjected to N-oxidation of the quinoline nitrogen with an oxidizing agent in presence of a base and polar solvent to get the compound l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. The oxidizing agent used in the present invention is potassium peroxymonosulfate having commercial trade name Oxone. The base used in the oxidation reaction is selected from alkali metal, alkaline earth metal hydroxide, carbonates or bicarbonates. The preferred base used for the oxidation reaction are sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate, wherein the most preferred base used for the oxidation reaction is sodium carbonate. The polar solvents used for the oxidation reaction are selected from C1 - C3 linear or branched chain alcohol and water or mixture thereof. The preferred C1 - C3 linear or branched chain alcohol used for the oxidation are methanol, ethanol, n-propanol and isopropanol, wherein the most preferred solvent for oxidation reaction is methanol. The oxidation reaction is carried out in the temperature

range of 20°C to 60°C. The preferred temperature for oxidation reaction is 25 - 50°C, wherein the most preferred temperature for the reaction is 45 - 50°C
The oxidizing agent potassium peroxymonosulfate is a non-inflammable, non-hazardous stable solid compound which is safe to handle on the industrial scale.
Accordingly the compound l-isobutyl-lHimidazo[4,5-c]quinoline of Formula II was taken in the polar solvent methanol either alone or in mixture thereof at 20 - 30°C, under stirring charged the oxidizing agent potassium peroxymonosulfate and. the base sodium carbonate followed by addition of water in 15 to 20 minutes. The reaction mixture was heated to 50°C and maintained the reaction at 50 ± 5°C. The progress of the reaction was monitored on HPLC. After completion of the reaction, cooled the reaction mass to 35 -40°C, filtered the reaction mass and washed with methanol. Combined filtrate and washing concentrated under reduced pressure to obtain residual solution of the reaction mass. Charged dichloromethane to the residual solution of the reaction mass and separated the organic layer. The dichloromethane was distilled out under reduced pressure to get the crude residual mass of l-isobutyI-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III. The crude product is purified in the solvent selected from acetone, ethyl acetate, acetonitrile, cyclohexane, toluene, and diisopropyl ether. The preferred solvent used for purification is toluene.
The compound l-isobutyl-lH-irnidazo[4,5-c]quinoline of Formula II used for the preparation of the compound l-isobutyl-lH-imidazo[4,5-c]quinoIin-5-oxide of Formula III can be prepared as per the process described in the U. S. Patent No. 4,689,338 [Gerster John f].
In another embodiment of the present invention the compound 1-isobutyl-lH-imidazo[4,5-c]quinoIin-5-oxide of Formula III reacted with an aminating agent in presence of solvent and benzoyl chloride to get the compound 4-amino-l-isobutyI-lH-imidazo[4,5-c]quinoline of Formula I. The suitable aminating agent used is selected from ammonia gas, ammonium hydroxide and ammonium salts selected from ammonium carbonate, ammonium bicarbonate, ammonium chloride and ammonium phosphate. The preferred aminating agent used for the reaction is ammonium hydroxide. The solvent used

in the reaction is selected from dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile and acetone, wherein the preferred solvent used for the reaction is dichloromethane. The reaction is carried out at the temperature of-10°C to 20°C. The work up of the reaction was done by quenching the reaction mass with water and stirring at 0 - 5°C for 30 minutes. Concentrated the reaction mass under reduced pressure below 40°C to get crude compound 4-amino-l-isobutyl-1H-imidazo[4,5-c]quinoline of Formula I. the crude compound was further treated with solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, acetone, acetonitrile, toluene, diisopropyl ether, tert-butyl methyl ether to isolate the pure compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I.
The product is further purified by acid base treatment and recrystallized to get pure 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I by suitable process as per the given example.
Accordingly the compound l-isobutyl-lH-imidazo[4,5-c]quinolin-5-oxide of Formula III was taken in the solvent dichloromethane and ammonium hydroxide was added at temperature of 25 - 30°C. Cooled the reaction mixture to -10°C ± 5°C and charged solution of benzoyl chloride maintaining the temperature at -5°C ± 5°C in 1 to 2 hours time. The solution of benzoyl chloride was prepared in the solvent used for the reaction. Raised the temperature of the reaction mixture to 0 - 5°C and maintained for one hour. Charged water to the reaction mass and stirred for 30 minutes at 0 - 5°C concentrated under reduced pressure below 40°C to get the residual mass. Charged isopropanol solvent to the crude residual mass and raised the temperature to 50 - 55°C, maintained for one hour. Cooled the reaction mass to 25 - 30°C and stirred one hour. Filtered the solid compound to get 4-amino-I-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I. Certain specific aspects and embodiments of the present invention is further illustrated in detail with reference to the following examples, which are provided solely for the purpose of illustration and are not to be construed as limiting the scope of the invention in any manner.

Examples:
Example 1: Preparation of 4-isobutyIamino-3-nitroquinoline:
To a cooled solution of 4-ch!oro-3-nitroquinoline (50 gms) in methanol (200 ml), charged a solution of isobutylamine (26.2 ml) and triethylamine (40 ml) through addition funnel maintaining temperature at 0 - 5°C within 30min. Raised the temperature of the reaction mixture to 25 - 30°C and stirred for 4 - 5 hours. After completion of reaction, charged DM water (250 ml) at 25 - 30°C and stirred for one hour. Filtered the reaction mass and washed the product with water. The wet cake of 4-isobutyIamino-3-nitroquinoline was dried at 45°C till constant weight. Yield = 53.0 gms.
Example 2: Preparation of 3-amino-(4-isobutylamino)quinoline:
Charged 4-isobutylamino-3-nitroquinoline (40 gms) and 5% Pd-C in toluene (400 ml) in an autoclave. Flushed the reaction mixture with nitrogen, and purged with constant pressure of 3 - 4 Kg hydrogen at 45°C and maintained the reaction for 3 - 4 hours. After completion of the reaction the mass was filtered through hyflo bed and washed the bed with methanol (80 ml). Concentrated the solvent under reduced pressure to afford the crude product quantitatively. Yield = 35.12 gms.
Example 3: Preparation of l-isobutyl-l//-imidazo[4,5-c]quinoIine:
Charged 3-amino-(4-isobutylamino)quinoline (30 gms) in toluene (300 ml) and raised the temperature to reflux. Maintaining the temperature at reflux, charged formic acid (1.57 ml) followed by addition of triethylorthoformate (34.8 ml) through addition funnel within 30 minutes, and continued stirring for additional one hour with simultaneous removal of ethanol, formed during the reaction. After completion of reaction, the reaction mixture was distilled under reduced pressure to get l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula II. Yield = 28 gms.

Example 4: Preparation of 4-isobutylamino-3-nitroquinoline:
Charged 4-hydroxy-3-nitroquinoline (105 gm) to dichloromethane (1.05 lit) and stirred for 15min. Charged thionyl chloride (48.36gm) through dropping funnel within 10-15 minutes maintaining temperature at 25 - 28°C followed by addition of N,N -dimethylformamide (51.3ml). Slowly raised the temperature to 42 - 45°C and maintained reaction mixture at 42 - 45°C for 3.5 to 4 hrs and monitor the reaction for completion on HPLC. After completion of the reaction cooled the reaction mixture to 0°C. Meanwhile prepared solution of isobutylamine (82.31ml) and triethylamine (130.84 ml) and added slowly through dropping funnel to cooled reaction mass maintaining temperature at 0 -5°C in 30minutes to 45minutes. Raised the temp gradually to 25 - 30°C and applied heating to attain the temperature of 40 - 45°C. Maintained the reaction at 40 - 45°C monitoring for completion of reaction on HPLC. After completion of the reaction concentrated the reaction mass under reduced pressure below 35°C to get the residual mass. Charged water (840 ml) and distilled out traces of dichloromethane completely to get free slurry of reaction mass, stirred the reaction mass for 2hrs at 38 - 42°C. Cooled the reaction mass to 25 - 30°C and stirred further for 1 hour. Filtered slurry and washed the solid mass with water (2 x 262.5ml) and dried the product at 50 - 55°C to obtain 4-isobutylamino-3-nitroquinoline. Wt of solid =132gm; %Yield = 97.67%
Example 5: Preparation of l-Isobutyl-lH-imidazo[4,5-c]quinoline:
In a dry autoclave charged 4-isobutyIamino-3-nitroqumoline (120 gm), toluene (1200 ml) and 5% Pd/C (12 gm) under nitrogen atmosphere maintaining temperature at 25 - 30°C. Apply 4.5 Kg Hydrogen pressure and raised the temperature to 50 - 55°C and maintained for 4 - 6 hrs monitoring the reaction for completion by HPLC. Cooled the reaction mass and filtered through hyflo bed. Washed the autoclave container and hyflo bed with methanol (360 ml) each. Combined filtrate and washing was concentrated under reduce pressure maintaining temperature below 45°C. To the residual mass charged formic acid (516 ml) at 25 - 30°C, raised the temperature to 110 - 115°C and maintained the reaction mass for 12 - 14 hours monitoring the completion of reaction by HPLC. After completion of the reaction cooled to 50°C and concentrated the reaction mass under vacuum

maintaining temperature below 50°C to get the oily residual mass. Cooled the reaction mass to 25 - 30°C, charged water (1200 ml) and stirred for 15 minutes. Cooled the reaction mass to 10°C and adjusted the pH of the reaction mass to 10-11 using aqueous 30% sodium hydroxide solution (330 ml) while maintaining the internal temperature between 5 - 10°C. Stirred the reaction mass at 10°C for 3 hours filtered the solid and washed with cold water (2 x 240 ml). Dried the product at 25 - 30°C under vacuum till constant weight to get l-isobutyl-lH-imidazo[4,5-c]quinoline. Wt of solid = 102 gm; %Yield = 92%.
Example 6: Preparation of l-Isobutyl-lH-imidazol[4,5-c]quinoline-5-oxide:
Charged l-isobutyl-lH-imidazo[4,5-c]quinoIine (90 gm) in a dry reaction flask containing methanol (630 ml) and stirred. Charged potassium peroxymonosulfate (368.4 gm), sodium bicarbonate (144.28 gm) followed by addition of water (630 ml) slowly maintaining the temperature at 25 - 30°C within 15-20 minutes. Applied heating and raised the temperature of the reaction to 48 - 50°C and maintained for 3 to 4 hours monitoring the completion of reaction by HPLC. After complete reaction cooled the reaction mass 40°C and filtered, washed the solid with methanol (2 xl80 ml). Combined the filtrate & distilled out methanol solvent under reduced pressure below 40°C to get the residual solution of the reaction mass. Cooled and extracted the reaction mass with dichloromethane (4 x 450 ml) at 25 - 30°C. Combined the organic layer and distilled out under reduced pressure below 40°C to get the residual mass. Charged toluene (270 ml) and stirred the slurry at 25-30°C for 2 hours. Filtered the solid product and washed with toluene (45 ml). Dried the product at 50-55°C till constant weight to get I-isobutyl-1H-imidazo[4,5-c]quinoline-5-oxide. Wtofsolid = 90.2gm; %Yield = 93.5%
Example 7: Preparation of 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod]:
In a dry round bottom flask containing dichloromethane (640 ml) charged 1-isobutyl-lH-imidazo[4,5-c]quinoline-5-oxide (80.0 gm) and aqueous ammonia (240 ml) at 25 - 30°C. Cooled the reaction mass to -10°C. To the cooled reaction mass slowly charged benzoyl

chloride solution (58 ml) prepared in dichloromethane (160 ml) maintaining the temperature at -10 to -5 °C within the period of 60-90 minutes. After complete addition maintained the reaction mass at 0 - 5°C for lhour. Decomposed the reaction mass with water (240 ml) and stirred at 0 - 5°C for 30 minutes. Concentrated the reaction mass completely under reduced pressure below 40°C to get the residual mass. To the residual mass charged isopropanol (160 ml), raised the temperature to 55°C and maintained at 50 -55°C for 1 hour. Cooled the reaction mass gradually to 25 - 30°C and stirred for 1 hour. Filtered the solid and washed with isopropanol (240 ml). The compound is dried in drying oven under vacuum at 45-50°C till constant weight to obtain crude 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod].
Dry weight = 62 gm; %Yield = 77.5%
Example 8: Purification of Crude Imiquimod:
Crude Imiquimod (60gm) was taken in Round bottom flask containing concentrated hydrochloric acid (240 ml). Charged sodium dithionite (26.4 gm) at 25 - 30°C and applied heating, raised the temperature to 90 - 95°C and maintained for one hour. Stopped heating and cooled reaction mass gradually to 25 - 30°C. Diluted the reaction mass with water (720 ml) and stirred at 25-30°C for one hour. Filtered the reaction mass & washed the solid mass with water (120 ml) to obtain imiquimod hydrochloride. The hydrochloride salt of imiquimod was taken in methanol (1040 ml). Applied heating and raised the temperature to reflux. Added charcoal (16 gm) at reflux temperature and maintain for 1.5 hours. Filtered the reaction mass at hot condition through hyflow bed and washed with hot methanol (240 ml). Combined filtrate and washing cooled gradually to 25 - 30°C and adjusted the pH 9-10 of the solution with aqueous ammonia maintaining temperature at 25 - 30°C. Stirred the reaction mass for 2 hours. Filtered the solid and washed the product with methanol (160 ml) followed by water (2 x 160ml). Dried the isolated pure 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline [Imiquimod] under vacuum at 45 - 50°C till constant weight. Yield-42 gm; % Yield = 52.7%; HPLC purity = NLT 99.5%.

We Claims:
1. A process for the preparation of compound 4-amino-l-isobutyl-lH-imidazo[4,5-c] quinoline [Imiquimod] of Formula I;

wherein the process comprises the steps of;
i. reacting the compound I-rsobutyl-1H-imidazo[4,5-c]quinoIine of Formula II;

Formula II with potassium peroxymonosulfate in presence of polar solvent, and base to get the compound l-isobutyl-l/f-imidazo[4,5-c]quinolin-5-oxide of Formula III.

ii. reacting the compound of Formula III with an animating agent in presence of solvent and benzoyl chloride to isolate the compound 4-amino-l-isobutyl-lH-imidazo[4,5-c]quinoline of Formula I.
iii. optionally purifying the compound 4-amino-l-isobutyl-lH-imidazo[4,5-cjquinoline of Formula I.

2. The process as claimed in claim I, wherein the polar solvent used in step (i) is selected from the group consisting of C1 - C3 linear or branched chain alcohol and water or mixture thereof.
3. The process as claimed in claim 2, wherein the C1 - C3 linear or branched chain alcohol used are selected from the group consisting of methanol, ethanol, n-propanol and isopropanol,
4. The process as claimed in claim 1, wherein the base used in step (i) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate.
5. The process as claimed in claim 1, wherein the reaction in step (i) is carried out at temperature of 20°C to 60°C.
6. The process as claimed in claim 1, wherein the aminating agent used in step (ii) is selected from the group consisting of ammonia gas, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium chloride and ammonium phosphate.
7. The process as claimed in claim 6, wherein the aminating agent used is ammonium hydroxide.
8. The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile and acetone.
9. The process as claimed in claim 8, wherein the solvent used is dichloromethane.

Documents:

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Patent Number

279270

Indian Patent Application Number

2204/MUM/2011

PG Journal Number

03/2017

Publication Date

20-Jan-2017

Grant Date

17-Jan-2017

Date of Filing

03-Aug-2011

Name of Patentee

INDOCO REMEDIES LIMITED

Applicant Address

INDOCO HOUSE,166 C.S.T.ROAD, SANTACRUZ(EAST),MUMBAI-400 098, MAHARASHTRA,INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAJADHYAKSHA, MANGESH NARAYAN	INDOCO REMEDIES LIMITED, R & D CENTRE,R/92-93,TTC INDUSTRIAL AREA, MIDC,RABALE,NAVI MUMBAI-400 701, MAHARASHTRA,INDIA
2	NAIR, RANJEET	INDOCO REMEDIES LIMITED, R & D CENTRE,R/92-93,TTC INDUSTRIAL AREA, MIDC,RABALE,NAVI MUMBAI-400 701, MAHARASHTRA,INDIA
3	SHRIGADI, NILESH BALKRISHNA	INDOCO REMEDIES LIMITED, R & D CENTRE,R/92-93,TTC INDUSTRIAL AREA, MIDC,RABALE,NAVI MUMBAI-400 701, MAHARASHTRA,INDIA
4	PANANDIKAR, ADITI MILIND	INDOCO REMEDIES LIMITED INDOCO HOUSE,166 C.S.T.ROAD, SANTACRUZ(EAST),MUMBAI-400 098, MAHARASHTRA,INDIA

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA