Title of Invention	PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES
Abstract	Disclosed here is a process for the preparation of nitropyridine derivatives of Formula I and its salt and precursors such as halogenated amino pyridines; Formula-I Wherein; R1 is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH-C(O)-R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms; R2 is selected from hydroxyl group, halogen atom, alkoxy group,

Title of Invention

PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES

Abstract

Disclosed here is a process for the preparation of nitropyridine derivatives of Formula I and its salt and precursors such as halogenated amino pyridines; Formula-I Wherein; R1 is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH-C(O)-R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms; R2 is selected from hydroxyl group, halogen atom, alkoxy group,

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) AND The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION: "PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES" 2. APPLICANT: (a) NAME: INDOCO REMEDIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian 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. FIELD OF INVENTION: The present invention provides process for the preparation of nitropyridine derivatives of Formula I and its salt and its precursors such as halogenated amino pyridines; Wherein; Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom,-NH-C(0)-R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms; R2 is selected from hydroxyl group, halogen atom, alkoxy group, BACKGROUND AND PRIOR ART: Nitropyridine compounds are important intermediates for the preparation of substituted pyridine intermediates useful in the synthesis of adenosine compounds and analogs thereof which are useful in treating hypertension and myocardial ischemia. Further, nitropyridine are also useful in the preparation of the compounds those have been found to possess a high degree of anti - inflammatory, analgesic and antipyretic activity. Such compounds are therefore valuable in the treatment of arthritic and dermatological disorder or like conditions responsive to anti - inflammatory drugs. Some of the nitropyridine compounds and precursors covered in the present invention represented by general formula - I are 2 Wherein; Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH-C(0)-R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms: R2 is selected from hydroxyl group, halogen atom, and alkoxy group. Several methods for preparing nitropyridine derivatives, and its precursor, halogenated amino pyridine have been described viz. R. Graf, Ber., 1931, vol. 64, 21 - 27; J. Lombardino, J. Med. Chem., 1961, vol. 24, 39 - 42; H. S. Mosher et al., J. Org. Chem, 1955, vol. 20(3), 283 - 286; and E. Malsumura et al., Bull. Chem. Soc. Japan, 1970, vol. 43, 3210 - 3214. In one of the prior art method, the precursor 4- chloro 2- amino pyridine is prepared from picolinic acid hydrochloride which is first reacted with thionyl chloride and subsequently with water results in 4 - chloro - picolinic acid which is converted to 2 - amino - 4 - chloro pyridine. In yet another method disclosed in H. S. Mosher et al., J. Org. Chem., 1955, vol. 20(3), 283 - 286; picolinic acid hydrochloride is first reacted with thionyl chloride and sulfer dioxide gas and subsequently with methanol to yield the ester, methyl 4 -chloropicoiinate. The ester was then reacted with hydrazine, sodium nitrite and acetic acid in water to yield 2 - amino - 4 - chloro pyridine along with the impurity of the dipyridine by product. In the literature procedure disclosed by DenHertog in Reel. Trav. Chim. Des Pays - Bas, 1946, 65, 129 - 140, the nitropyridine derivative is synthesized starting with diethyl 3 -oxopentanedioate which is treated with triethylorthoformate and acetic anhydride followed by treatment with cone, ammonia solution to yield 2, 4 - dihydroxy - 5 -carbethoxypyridine. The hydroxyl compound undergoes nitration as per the process 3 disclosed by Kogl, F., et al, in Reel. Trav. Chim. Des Pays - Bas, 1948, 67, 29 - 44 ; in presence of nitric acid and acetic acid results in 2, 4 - dihydroxy - 3 - nitro - 5 -carbethoxypyridine. The nitro compound formed is then subjected to hydrolysis followed by decarboxylation results in the formation of 2, 4 - dihydroxy - 3 - nitropyridine. In yet another prior art US6307054 the improvised process reveals the nitration with simultaneous insitu decarboxylation of the carbethoxy group by using phosphoric acid and nitric acid to get 2,4- dihydroxy - 3 - nitropyridine. The US application US20030225131AI describes the process for the preparation of compound 2 - Chloro - 3 - nitropyridine - 4 - ol, wherein 2, 4 - dihydroxy - 3 -nitropyridine is reacted with phosphorous oxychloride in presence of phase transfer catalyst benzyltriethyl ammonium chloride and solvent acetonitrile to get 2, 4 - dichloro -3 - nitropyridine which is isolated and reacted with cesium acetate in N, N -dimethyformamide (DMF) at 80°C. After the work up the compound 2 - Chloro - 3 -nitropyridine - 4 - ol is isolated. The major drawbacks of the prior art processes include: 1. The formation of dipyridine impurity during preparation of precursor 2 -.amino -4-chloro pyridine; 2. use of sulfur di oxide gas for the preparation of the ester compound of the precursor which is hazardous and not industrially useful; 3. Use of costly reagents and solvents such as triethylorthoformate, acetonitrile, phase transfer catalyst for the preparation of 2, 4 - dichloro compound; 4. use of cesium acetate which is hygroscopic, unstable and costly which prevents it's use on industrial scale; 5. Lengthy process involving number of steps to prepare the nitropyridine compound. It is evident from the prior art that there remains a need for an improved process to prepare precursor of the nitropyridine and derivatives, devoid of impurities involving less number of steps and cost effective and industrially useful. 4 The present invention provides a novel process for the preparation of nitropyridine precursor and derivatives which involves stable and cpst effective reagents, less number of steps and therefore industrially useful. OBJECTIVE OF THE INVENTION: The main object of the present invention is to prepare precursor 4 - chloro - 2 - amino pyridine with an industrial friendly process. Yet another object of the present invention is to provide process for the preparation of substituted nitropyridine derivatives useful in the synthesis of pharmaceutical compounds; Yet another object of the present invention is to prepare nitropyridine derivatives of high purity and devoid of impurity. DESCRIPTION OF THE INVENTION: The present invention provides process for the preparation of nitropyridine derivatives of Formula I and its precursors such as halogenated amino nitropyridines, hydroxyl amino nitropyridine, chloro hydroxyl nitro pyridine and its salt, R2 N R, Formula- I Wherein; Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom,-NH-C(0)-R3; Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms; 5 R2 is selected from hydroxy! group, halogen atom, and alkoxy group. In one of the embodiments of the present invention, picolinic acid or its hydrochloride salt is reacted with thionyl chloride at 20 - 40°C for one hour. Charged water slowly and raised the temperature to reflux and maintained. After the reaction thionyl chloride is distilled out completely under reduced pressure and charged toluene to the residue, stirred and cooled to -5 to 10°C. Charged methanol to the reaction solution and stirred at -5 to 10°C. filtered the solid mass and charged the wet cake in DM water under stirring. Charged 25 - 30% ammonia solution till pH is highly basic i.e. 11 or more, stirred at 20 - 30°C. Filtered the solid and washed with water to get 4 - chloropyridine - 2 -carboxamide. Dried the product at 55 - 65°C. In another embodiment of the present invention, the 4 - chloropyridine - 2 - carboxamide is charged in the premixed solution of sodium hydroxide and liquid bromine at temperature of-10 to 10°C. Stirred the reaction mixture and raised the temperature slowly to reflux. Maintained the reaction at reflux for 3 - 6 hours. After the completion of the reaction, cooled the reaction mass to 0°C, maintained for one hour at 0 - 5°C and filtered to isolate the precursor 4 - chloro - 2 - amino pyridine. Washed the compound with chilled water and dried the product at 50 - 60°C. The precursor 4 - chloro - 2 - amino pyridine compound is further subjected to nitration using nitric acid and sulphuric acid, which results in the formation of nitropyridine compound, 4 - chloro - 2 - amino - 3 nitropyridine. The reaction sequence for the precursor preparation is as per Scheme I below; 6 Scheme -1 In yet another embodiment of the present invention the compound 4 - chloro - 2 - amino - 3 nitropyridine is subjected to diazotization using sodium nitrite and hydrochloric acid at 0 - 5°C. The reaction mass is stirred at 0 - 5°C for 30 minutes to 1 hour and raised the temperature and maintained at 60 - 80°C for 3 hours for complete hydrolysis. The reaction mass is cooled to 25 - 30°C and extracted with dichloromethane. Separated and dried the organic layer on anhydrous sodium sulfate, concentrated under reduced pressure to isolate 4 -chIoro-3-nitropyridine - 2 - ol. In yet another embodiment of the present invention, the compound 4 - chloro - 3 -nitropyridine - 2 - ol is reacted with phosphorous oxychloride in presence of base to isolate 2, 4 - dichloro - 3 - nitropyridine. The compound 4 - chloro - 3 - nitropyridine -2 - ol is charged in phosphorous oxychloride at temperature of 20 - 30°C and stirred. The base charged is selected from Triethylamine, diisopropyl ethylamine, dimethylamine, tributylamine and pyridine at temperature 20 - 50°C. The reaction is further maintained at 80 - 100°C for 4 - 6 hours. After the completion of the reaction, cooled the reaction mass to 10°C and quenched in ice water mixture. The reaction mass is stirred and filtered the 7 solid mass to isolate the compound 2, 4 - dichloro - 3 - nitropyridine. The compound thus obtained is washed with chilled water and dried. In yet another embodiment of the present invention, the compound 2, 4 - dichloro - 3 -nitropyridine undergoes selective substitution at para position in presence of reagents selected from sodium acetate, cesium carbonate, cesium carbonate with acetic acid, in presence of aromatic hydrocarbon solvent to isolate the nitropyridine derivative 2 -Chloro - 3 - nitropyridine - 4 - ol. The reaction sequence for the nitropyridine derivative is as per Scheme II below; Scheme- II In yet another embodiment of the present invention the nitropyridine derivative N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide is prepared using the compound 4 - chloro - 2 - amino - 3 nitropyridine and reacting with cyclopropanecarbonyl chloride. The amino group at ortho position is either protected or free, reacts with the carbonyl compound in presence of chlorinated solvent and base to yield the compound N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide. The chlorinated solvent selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane. The base is selected from triethyl amine, diethyl amine, and pyridine. The reaction sequence for the nitropyridine derivative is as per Scheme TIT below; 8 Formula - V Formula - IX Formula - X Scheme - III In yet another embodiment of the present invention the nitropyridine derivative N - (4 -chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide is prepared directly using cyclopropyl carboxylic acid by insitu generation of Cyclopropyl carbonyl chloride. Cyclopropyl carboxylic acid is taken in chlorinated solvent and to the mixture catalytic amount of polar aprotic solvent and oxalyl chloride or thionyl chloride or phosphorous oxy chloride or phosphorous penta chloride is charged at temperature of-10 to 30°C. The solution is stirred and maintained at -10°C. Charged 4 - chloro - 2 - amino - 3 nitropyridine in chlorinated solvent and cooled to -15 to -5°C. To the cooled solution the freshly prepared cyclopropyl carbonyl chloride solution is charged and stirred at -15 to -5°C. To the reaction mass a base selected from triethyl amine, diethyl amine, and pyridine dissolved in the chlorinated solvent is charged and maintained the reaction mass at -15 to -5°C for 30 minutes to 2.0 hours. Raised the temperature of the reaction mass to 0°C and then to 25 - 35°Cand maintained for 2 - 4 hours. After completion of the reaction water was added to the reaction and stirred for sometime. Separated the organic layer and extracted the aqueous layer with chlorinated solvent used for the reaction. Washed the organic layer with water, separated and dried the organic layer over anhydrous sodium sulphate. Distilled out the solvent under reduced pressure to get residual solid mass. Charged ethyl acetate to the solid and stirred at 25 -35°C one hour. Cooled the reaction to 0 - 5°C and maintained for one hour, filtered and dried the solid to get pure compound of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide. The chlorinated solvent used in the reaction is selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane. 9 It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof. Examples: Example 1: Preparation of 4 - Chloro - 2 - amino - 3 - nitropyridine: Step -1: 4- Chloropyridine-2-carboxamide Charged lOOgm picolinic acid hydrochloride in 250 ml thionyl chloride and stirred for one hr at room temp. Added drop wise 14 ml water slowly, after addition of water, heated the reaction mass to reflux temperature and maintained the reflux for 3 days. Distilled out Thionyl chloride completely and then added 100ml of toluene and distilled off the toluene. Again added 100 ml of toluene and cooled the reaction mass to 0°c. Added Methanol (40 ml) slowly at 0°C and stirred for one hr. at 0°c. Filtered the solid obtained and washed with chilled Toluene and suck dried . Charged wet cake in 100ml DM Water, stirred for 15 minutes, added drop wise 250ml Ammonia solution [PH-above 11] , and Stirred one hr at room temperature. Filtered the solid, washed with water, sucked dried and dried at 55 to 60°c 10 Step - II: 4-Chloro 2-Amino Pyridine Dissolved 120 gm NaOH in 900ml water, cooled to 0 to 5°c , added 45ml Bromine solution slowly at 0°c and stirred for half hr. at 0°c Then, added 60gm of stage I compound at 0°c, stirred for 5 minutes. Heated the reaction mass to 100°c i.e. reflux temperature. Maintained reflux till to get clear solution. The progress of the reaction was monitored by TLC, After completion of the reaction, the reaction mass was cooled to Q to 5°c in one hr, filtered the precipitated solid, washed with chilled water, suck dried and dried at 50 to 55° 3 to 4 hrs. Dry wt: 28gm (Stage 11) Step - III: 4 -Chloro- 2-Amino - 3 - Nitro Pyridine 28gm of stage II was dissolved completely in 224ml cone. H2SO4 by stirring. Added nitrating mixture [8.4ml fuming Nitric acid +17ml cone. H2S04] to the above solution and stirred for 1 hr at RT. The reaction progress was monitored by TLC, if TLC indicated absence of stage II; the RM was quenched on 1120gm ice and stirred for 15 min. The reaction mixture was extracted with 420ml methylenedichloride (MDC) to remove non polar impurity. The pH of the reaction mass was adjusted to pH 6 by 30% sodium carbonate solution. 11 The above mass was then extracted with 4 x 420 ml ethyl acetate. The layers were separated and the organic layer neutralized with 200ml saturated sodium bicarbonate solution. The layers were again separated. It was then dried over anhydrous sodium sulphate and distilled under reduced pressure to yield a solid (21gm). The crude step - III compound was stirred in 210 ml MDC for lhr at RT. and filtered. The insoluble impurity was again washed with 2 x 105 ml MDC. Both the MDC layers were collected was distilled completely to yield a yellow solid. To this solid, 105 ml Methanol was added and heated for 50°C fori hr. This mixture was then cooled to 0 to -5°c and stirred for half hr. at this temperature. The solid precipitated was filtered and dried to yield pure stage III having HPLC purity > 95%. Dry weight- 8.4 gm. Example-2: Preparation of 2-chloro-3-nitropyridin-4-ol Step-I: Preparation of 4-chloro-3-nitropyridin-2-ol A three-necked flask equipped with a thermometer pocket, water condenser, and mechanical stirrer, was charged with DM water (10 ml), 2-amino-4-chIoro-3-nitropyridine, 0.5 g, (0.0028 mole) at RT. Cone. Hydrochloric acid, 4.5 ml was then added in one lot at RT under stirring. The mixture was cooled to a temperature of 0 °C to 5°C followed by addition of a solution of sodium nitrite (0.23 g, 0.003 mole) in DM water 10 mL at 0 °C to 5"C. Stirred the reaction mixture at 0 °C to 5"C for 30 min and the reaction mixture then warmed slowly to room temperature followed by heating to 60 °C to 70°C and maintained at this temperature for 2 h. Reaction mixture was then cooled to room temperature and extracted with methylene chloride (4 * 25 ml). Organic layer separated was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 0.300 gm (60 %) of a pale yellow solid. 12 Step-II: Preparation of 2,4-dichloro-3-nitropyridine A three-necked flask equipped with an thermometer pocket, water condenser, and mechanical stirrer, was charged with phosphorous oxychloride (0.81 ml, 0.0089 mole), and 4-chloro-3-nitropyridin-2-ol (0.79 gm, 0.0045 mole) in one lot under stirring followed by slow addition of DIPEA (1.15 ml, 0.0067 mole) at room temperature (temperature should not raise more than 50°C). The reaction mixture was then heated to 90 °C to 100°C, maintained at this temperature for 4-6 hrs. Reaction mixture was then cooled to 10 °C to 15°C and quenched in ice and water mixture. The reaction mixture was stirred at 10 °C to 15DC for 30-60 min. to obtain the solid product. The product was filtered and washed with cold water, dried well at room temperature to obtain final dark brown solid product. Stage-Ill: Preparation of 2-chloro 4-hydroxy-3-nitropyridine A three-necked flask equipped with a thermometer pocket, water condenser, and mechanical stirrer, was charged with 2, 4-dichloro-3-nitropyridine (5.00 gm, 0.025 mole), dimethylformamide, 25 ml and sodium acetate (5.12 gm, 0.062 mole). The reaction mixture was then heated to 120 °C to 125 °C, maintained at this temperature for 3 - 4 hrs. Reaction mixture was then cooled to room temperature, aqueous saturated ammonium chloride solution. 40 ml was then added and stirred at room 13 temperature for 15 min. Reaction mixture was concentrated under vacuum to obtain yellowish brown solid. Aqueous saturated ammonium chloride solution (80 ml); DM water (40 ml) and methylelne chloride, 1.0 lit was added to crude solid product and was stirred at room temperature for 30 min aqueous layer was extracted with methylelne chloride. (4 * 500 ml). Organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude solid product. Toluene, 6 ml was added and stirred at room temperature for 1 hr, cooled to 10 °C to 15 °C filtered, washed with toluene 5 ml, and dried at 60 °C to 65 till to achieve constant weight. Example 3: Preparation of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide: CI N NH2 o 4 - Chloro - 2 - amino - 3 nitropyridine (5.0 gm) is charged in dichloro methane (150 ml), under stirring and cooled to -10° C. To this charged a solution of Cyclopropane carbonyl chloride (15 gm) dissolved dichloro methane (75 ml) at -10°c and stirred for 30 minutes. To the reaction mass charged solution of the base triethyl amine (4 ml) dissolved in dichloro methane (75 ml) and continued stirring for 30 minutes at -10° C. Raised temp slowly to 0°c and subsequently to 25 - 35°C. Maintained the reaction mass under stirring at 25 - 30 °C for 5 to 6 hours. After the completion of reaction charged water (100 ml) and stirred for 15 minutes. Separated the organic layer and washed with water (100 ml). Dried the organic layer over anhydrous sodium sulphate and distilled out solvent under reduced pressure to get residual solid mass. To this solid, ethyl acetate (15 ml) was added and stirred for 30 minutes at 25 - 35°C. Cooled the reaction gradually to 0 to 5°C. The solid was then filtered and dried to yield pure N - (4 - chloro - 3 -nitropyridine - 2 - yl) cyclopropane carboxamide. 14 Example 4: Preparation of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide: Dissolved Cyclopropane carboxylic acid (12.5gm) in dichloro methane (100 ml). Charged dimethylformamide (0.12 ml), and stirred for 10 min. To this solution slowly charged Oxalyl chloride (22.5 gm) dissolved in dichloro methane (25 ml) at 25 - 35°C and continued stirring for 2 hours. Apply chilling and chill the above solution at-10° C. In another flask charged 4 - Chloro - 2 - amino - 3 nitropyridine in dichloro methane (150 ml) and stirred under cooling it to -10° C. To this add the above Cyclopropane carbonyl chloride solution maintaining temperature at -15 to -5°C in one lot and stir at this temp for half an hour. Further added triethyl amine (13 ml) dissolved in dichloro methane (25 ml) to the reaction solution and continued stirring for 30 minutes at -15 to -5°C. Raised the temperature gradually to 0°c and then to 25 - 35°C and maintained for 2 to 3 hour. After the completion of reaction charged water (100 ml) and stirred for 15 minutes. Separated the organic layer and washed with water (100 ml). Dried the organic layer over anhydrous sodium sulphate and distilled out solvent under reduced pressure to get residual solid mass. To this solid, ethyl acetate (15 ml) was added and stirred for 30 minutes at 25 - 35°C. Cooled the reaction gradually to 0 to 5°C. The solid was then filtered and dried to yield pure N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide. Dated this 2nd day of February 2009 Dr. Gopakumar G. Nair Agent for the Applicant 15

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION: "PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED

(b)NATIONALITY: Indian Company incorporated under the Indian 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.

FIELD OF INVENTION:
The present invention provides process for the preparation of nitropyridine derivatives of Formula I and its salt and its precursors such as halogenated amino pyridines;

Wherein;
Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom,-NH-C(0)-R3;
Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms; R2 is selected from hydroxyl group, halogen atom, alkoxy group,
BACKGROUND AND PRIOR ART:
Nitropyridine compounds are important intermediates for the preparation of substituted pyridine intermediates useful in the synthesis of adenosine compounds and analogs thereof which are useful in treating hypertension and myocardial ischemia. Further, nitropyridine are also useful in the preparation of the compounds those have been found to possess a high degree of anti - inflammatory, analgesic and antipyretic activity. Such compounds are therefore valuable in the treatment of arthritic and dermatological disorder or like conditions responsive to anti - inflammatory drugs.
Some of the nitropyridine compounds and precursors covered in the present invention represented by general formula - I are
2

Wherein;
Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH-C(0)-R3;
Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms: R2 is selected from hydroxyl group, halogen atom, and alkoxy group.
Several methods for preparing nitropyridine derivatives, and its precursor, halogenated amino pyridine have been described viz. R. Graf, Ber., 1931, vol. 64, 21 - 27; J. Lombardino, J. Med. Chem., 1961, vol. 24, 39 - 42; H. S. Mosher et al., J. Org. Chem, 1955, vol. 20(3), 283 - 286; and E. Malsumura et al., Bull. Chem. Soc. Japan, 1970, vol. 43, 3210 - 3214. In one of the prior art method, the precursor 4- chloro 2- amino pyridine is prepared from picolinic acid hydrochloride which is first reacted with thionyl chloride and subsequently with water results in 4 - chloro - picolinic acid which is converted to 2 - amino - 4 - chloro pyridine.
In yet another method disclosed in H. S. Mosher et al., J. Org. Chem., 1955, vol. 20(3), 283 - 286; picolinic acid hydrochloride is first reacted with thionyl chloride and sulfer dioxide gas and subsequently with methanol to yield the ester, methyl 4 -chloropicoiinate. The ester was then reacted with hydrazine, sodium nitrite and acetic acid in water to yield 2 - amino - 4 - chloro pyridine along with the impurity of the dipyridine by product.
In the literature procedure disclosed by DenHertog in Reel. Trav. Chim. Des Pays - Bas, 1946, 65, 129 - 140, the nitropyridine derivative is synthesized starting with diethyl 3 -oxopentanedioate which is treated with triethylorthoformate and acetic anhydride followed by treatment with cone, ammonia solution to yield 2, 4 - dihydroxy - 5 -carbethoxypyridine. The hydroxyl compound undergoes nitration as per the process
3

disclosed by Kogl, F., et al, in Reel. Trav. Chim. Des Pays - Bas, 1948, 67, 29 - 44 ; in presence of nitric acid and acetic acid results in 2, 4 - dihydroxy - 3 - nitro - 5 -carbethoxypyridine. The nitro compound formed is then subjected to hydrolysis followed by decarboxylation results in the formation of 2, 4 - dihydroxy - 3 - nitropyridine.
In yet another prior art US6307054 the improvised process reveals the nitration with simultaneous insitu decarboxylation of the carbethoxy group by using phosphoric acid and nitric acid to get 2,4- dihydroxy - 3 - nitropyridine.
The US application US20030225131AI describes the process for the preparation of compound 2 - Chloro - 3 - nitropyridine - 4 - ol, wherein 2, 4 - dihydroxy - 3 -nitropyridine is reacted with phosphorous oxychloride in presence of phase transfer catalyst benzyltriethyl ammonium chloride and solvent acetonitrile to get 2, 4 - dichloro -3 - nitropyridine which is isolated and reacted with cesium acetate in N, N -dimethyformamide (DMF) at 80°C. After the work up the compound 2 - Chloro - 3 -nitropyridine - 4 - ol is isolated. The major drawbacks of the prior art processes include:
1. The formation of dipyridine impurity during preparation of precursor 2 -.amino -4-chloro pyridine;
2. use of sulfur di oxide gas for the preparation of the ester compound of the precursor which is hazardous and not industrially useful;
3. Use of costly reagents and solvents such as triethylorthoformate, acetonitrile, phase transfer catalyst for the preparation of 2, 4 - dichloro compound;
4. use of cesium acetate which is hygroscopic, unstable and costly which prevents it's use on industrial scale;
5. Lengthy process involving number of steps to prepare the nitropyridine compound.
It is evident from the prior art that there remains a need for an improved process to prepare precursor of the nitropyridine and derivatives, devoid of impurities involving less number of steps and cost effective and industrially useful.
4

The present invention provides a novel process for the preparation of nitropyridine precursor and derivatives which involves stable and cpst effective reagents, less number of steps and therefore industrially useful.
OBJECTIVE OF THE INVENTION:
The main object of the present invention is to prepare precursor 4 - chloro - 2 - amino pyridine with an industrial friendly process.
Yet another object of the present invention is to provide process for the preparation of substituted nitropyridine derivatives useful in the synthesis of pharmaceutical compounds;
Yet another object of the present invention is to prepare nitropyridine derivatives of high purity and devoid of impurity.
DESCRIPTION OF THE INVENTION:
The present invention provides process for the preparation of nitropyridine derivatives of Formula I and its precursors such as halogenated amino nitropyridines, hydroxyl amino nitropyridine, chloro hydroxyl nitro pyridine and its salt,
R2

N R,
Formula- I Wherein;
Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom,-NH-C(0)-R3;
Where R3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3-6 carbon atoms;
5

R2 is selected from hydroxy! group, halogen atom, and alkoxy group.
In one of the embodiments of the present invention, picolinic acid or its hydrochloride salt is reacted with thionyl chloride at 20 - 40°C for one hour. Charged water slowly and raised the temperature to reflux and maintained. After the reaction thionyl chloride is distilled out completely under reduced pressure and charged toluene to the residue, stirred and cooled to -5 to 10°C. Charged methanol to the reaction solution and stirred at -5 to 10°C. filtered the solid mass and charged the wet cake in DM water under stirring. Charged 25 - 30% ammonia solution till pH is highly basic i.e. 11 or more, stirred at 20 - 30°C. Filtered the solid and washed with water to get 4 - chloropyridine - 2 -carboxamide. Dried the product at 55 - 65°C.
In another embodiment of the present invention, the 4 - chloropyridine - 2 - carboxamide
is charged in the premixed solution of sodium hydroxide and liquid bromine at
temperature of-10 to 10°C. Stirred the reaction mixture and raised the temperature slowly
to reflux. Maintained the reaction at reflux for 3 - 6 hours. After the completion of the
reaction, cooled the reaction mass to 0°C, maintained for one hour at 0 - 5°C and filtered
to isolate the precursor 4 - chloro - 2 - amino pyridine. Washed the compound with
chilled water and dried the product at 50 - 60°C.
The precursor 4 - chloro - 2 - amino pyridine compound is further subjected to nitration
using nitric acid and sulphuric acid, which results in the formation of nitropyridine
compound, 4 - chloro - 2 - amino - 3 nitropyridine.
The reaction sequence for the precursor preparation is as per Scheme I below;
6

Scheme -1 In yet another embodiment of the present invention the compound 4 - chloro - 2 - amino - 3 nitropyridine is subjected to diazotization using sodium nitrite and hydrochloric acid at 0 - 5°C. The reaction mass is stirred at 0 - 5°C for 30 minutes to 1 hour and raised the temperature and maintained at 60 - 80°C for 3 hours for complete hydrolysis. The reaction mass is cooled to 25 - 30°C and extracted with dichloromethane. Separated and dried the organic layer on anhydrous sodium sulfate, concentrated under reduced pressure to isolate 4 -chIoro-3-nitropyridine - 2 - ol.
In yet another embodiment of the present invention, the compound 4 - chloro - 3 -nitropyridine - 2 - ol is reacted with phosphorous oxychloride in presence of base to isolate 2, 4 - dichloro - 3 - nitropyridine. The compound 4 - chloro - 3 - nitropyridine -2 - ol is charged in phosphorous oxychloride at temperature of 20 - 30°C and stirred. The base charged is selected from Triethylamine, diisopropyl ethylamine, dimethylamine, tributylamine and pyridine at temperature 20 - 50°C. The reaction is further maintained at 80 - 100°C for 4 - 6 hours. After the completion of the reaction, cooled the reaction mass to 10°C and quenched in ice water mixture. The reaction mass is stirred and filtered the
7

solid mass to isolate the compound 2, 4 - dichloro - 3 - nitropyridine. The compound thus obtained is washed with chilled water and dried.
In yet another embodiment of the present invention, the compound 2, 4 - dichloro - 3 -nitropyridine undergoes selective substitution at para position in presence of reagents selected from sodium acetate, cesium carbonate, cesium carbonate with acetic acid, in presence of aromatic hydrocarbon solvent to isolate the nitropyridine derivative 2 -Chloro - 3 - nitropyridine - 4 - ol. The reaction sequence for the nitropyridine derivative is as per Scheme II below;

Scheme- II In yet another embodiment of the present invention the nitropyridine derivative N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide is prepared using the compound 4 - chloro - 2 - amino - 3 nitropyridine and reacting with cyclopropanecarbonyl chloride. The amino group at ortho position is either protected or free, reacts with the carbonyl compound in presence of chlorinated solvent and base to yield the compound N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide. The chlorinated solvent selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane. The base is selected from triethyl amine, diethyl amine, and pyridine. The reaction sequence for the nitropyridine derivative is as per Scheme TIT below;
8

Formula - V Formula - IX Formula - X
Scheme - III In yet another embodiment of the present invention the nitropyridine derivative N - (4 -chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide is prepared directly using cyclopropyl carboxylic acid by insitu generation of Cyclopropyl carbonyl chloride. Cyclopropyl carboxylic acid is taken in chlorinated solvent and to the mixture catalytic amount of polar aprotic solvent and oxalyl chloride or thionyl chloride or phosphorous oxy chloride or phosphorous penta chloride is charged at temperature of-10 to 30°C. The solution is stirred and maintained at -10°C.
Charged 4 - chloro - 2 - amino - 3 nitropyridine in chlorinated solvent and cooled to -15 to -5°C. To the cooled solution the freshly prepared cyclopropyl carbonyl chloride solution is charged and stirred at -15 to -5°C. To the reaction mass a base selected from triethyl amine, diethyl amine, and pyridine dissolved in the chlorinated solvent is charged and maintained the reaction mass at -15 to -5°C for 30 minutes to 2.0 hours. Raised the temperature of the reaction mass to 0°C and then to 25 - 35°Cand maintained for 2 - 4 hours. After completion of the reaction water was added to the reaction and stirred for sometime. Separated the organic layer and extracted the aqueous layer with chlorinated solvent used for the reaction. Washed the organic layer with water, separated and dried the organic layer over anhydrous sodium sulphate. Distilled out the solvent under reduced pressure to get residual solid mass. Charged ethyl acetate to the solid and stirred at 25 -35°C one hour. Cooled the reaction to 0 - 5°C and maintained for one hour, filtered and dried the solid to get pure compound of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide.
The chlorinated solvent used in the reaction is selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane.
9

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof.
Examples:
Example 1: Preparation of 4 - Chloro - 2 - amino - 3 - nitropyridine:
Step -1: 4- Chloropyridine-2-carboxamide

Charged lOOgm picolinic acid hydrochloride in 250 ml thionyl chloride and stirred for one hr at room temp. Added drop wise 14 ml water slowly, after addition of water, heated the reaction mass to reflux temperature and maintained the reflux for 3 days. Distilled out Thionyl chloride completely and then added 100ml of toluene and distilled off the toluene. Again added 100 ml of toluene and cooled the reaction mass to 0°c. Added Methanol (40 ml) slowly at 0°C and stirred for one hr. at 0°c. Filtered the solid obtained and washed with chilled Toluene and suck dried . Charged wet cake in 100ml DM Water, stirred for 15 minutes, added drop wise 250ml Ammonia solution [PH-above 11] , and Stirred one hr at room temperature. Filtered the solid, washed with water, sucked dried and dried at 55 to 60°c
10

Step - II: 4-Chloro 2-Amino Pyridine

Dissolved 120 gm NaOH in 900ml water, cooled to 0 to 5°c , added 45ml Bromine solution slowly at 0°c and stirred for half hr. at 0°c Then, added 60gm of stage I compound at 0°c, stirred for 5 minutes. Heated the reaction mass to 100°c i.e. reflux temperature. Maintained reflux till to get clear solution. The progress of the reaction was monitored by TLC, After completion of the reaction, the reaction mass was cooled to Q to 5°c in one hr, filtered the precipitated solid, washed with chilled water, suck dried and dried at 50 to 55° 3 to 4 hrs. Dry wt: 28gm (Stage 11)
Step - III: 4 -Chloro- 2-Amino - 3 - Nitro Pyridine

28gm of stage II was dissolved completely in 224ml cone. H2SO4 by stirring. Added nitrating mixture [8.4ml fuming Nitric acid +17ml cone. H2S04] to the above solution and stirred for 1 hr at RT. The reaction progress was monitored by TLC, if TLC indicated absence of stage II; the RM was quenched on 1120gm ice and stirred for 15 min. The reaction mixture was extracted with 420ml methylenedichloride (MDC) to remove non polar impurity. The pH of the reaction mass was adjusted to pH 6 by 30% sodium carbonate solution.
11

The above mass was then extracted with 4 x 420 ml ethyl acetate. The layers were separated and the organic layer neutralized with 200ml saturated sodium bicarbonate solution. The layers were again separated. It was then dried over anhydrous sodium sulphate and distilled under reduced pressure to yield a solid (21gm). The crude step - III compound was stirred in 210 ml MDC for lhr at RT. and filtered. The insoluble impurity was again washed with 2 x 105 ml MDC. Both the MDC layers were collected was distilled completely to yield a yellow solid. To this solid, 105 ml Methanol was added and heated for 50°C fori hr. This mixture was then cooled to 0 to -5°c and stirred for half hr. at this temperature. The solid precipitated was filtered and dried to yield pure stage III having HPLC purity > 95%. Dry weight- 8.4 gm.
Example-2: Preparation of 2-chloro-3-nitropyridin-4-ol
Step-I: Preparation of 4-chloro-3-nitropyridin-2-ol

A three-necked flask equipped with a thermometer pocket, water condenser, and mechanical stirrer, was charged with DM water (10 ml), 2-amino-4-chIoro-3-nitropyridine, 0.5 g, (0.0028 mole) at RT. Cone. Hydrochloric acid, 4.5 ml was then added in one lot at RT under stirring. The mixture was cooled to a temperature of 0 °C to 5°C followed by addition of a solution of sodium nitrite (0.23 g, 0.003 mole) in DM water 10 mL at 0 °C to 5"C. Stirred the reaction mixture at 0 °C to 5"C for 30 min and the reaction mixture then warmed slowly to room temperature followed by heating to 60 °C to 70°C and maintained at this temperature for 2 h. Reaction mixture was then cooled to room temperature and extracted with methylene chloride (4 * 25 ml). Organic layer separated was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 0.300 gm (60 %) of a pale yellow solid.
12

Step-II: Preparation of 2,4-dichloro-3-nitropyridine

A three-necked flask equipped with an thermometer pocket, water condenser, and mechanical stirrer, was charged with phosphorous oxychloride (0.81 ml, 0.0089 mole), and 4-chloro-3-nitropyridin-2-ol (0.79 gm, 0.0045 mole) in one lot under stirring followed by slow addition of DIPEA (1.15 ml, 0.0067 mole) at room temperature (temperature should not raise more than 50°C). The reaction mixture was then heated to 90 °C to 100°C, maintained at this temperature for 4-6 hrs. Reaction mixture was then cooled to 10 °C to 15°C and quenched in ice and water mixture. The reaction mixture was stirred at 10 °C to 15DC for 30-60 min. to obtain the solid product. The product was filtered and washed with cold water, dried well at room temperature to obtain final dark brown solid product.
Stage-Ill: Preparation of 2-chloro 4-hydroxy-3-nitropyridine

A three-necked flask equipped with a thermometer pocket, water condenser, and mechanical stirrer, was charged with 2, 4-dichloro-3-nitropyridine (5.00 gm, 0.025 mole), dimethylformamide, 25 ml and sodium acetate (5.12 gm, 0.062 mole). The reaction mixture was then heated to 120 °C to 125 °C, maintained at this temperature for 3 - 4 hrs. Reaction mixture was then cooled to room temperature, aqueous saturated ammonium chloride solution. 40 ml was then added and stirred at room
13

temperature for 15 min. Reaction mixture was concentrated under vacuum to obtain yellowish brown solid. Aqueous saturated ammonium chloride solution (80 ml); DM water (40 ml) and methylelne chloride, 1.0 lit was added to crude solid product and was stirred at room temperature for 30 min aqueous layer was extracted with methylelne chloride. (4 * 500 ml). Organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude solid product. Toluene, 6 ml was added and stirred at room temperature for 1 hr, cooled to 10 °C to 15 °C filtered, washed with toluene 5 ml, and dried at 60 °C to 65 till to achieve constant weight.

Example 3: Preparation of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide:

CI
N NH2
o

4 - Chloro - 2 - amino - 3 nitropyridine (5.0 gm) is charged in dichloro methane (150 ml), under stirring and cooled to -10° C. To this charged a solution of Cyclopropane carbonyl chloride (15 gm) dissolved dichloro methane (75 ml) at -10°c and stirred for 30 minutes. To the reaction mass charged solution of the base triethyl amine (4 ml) dissolved in dichloro methane (75 ml) and continued stirring for 30 minutes at -10° C. Raised temp slowly to 0°c and subsequently to 25 - 35°C. Maintained the reaction mass under stirring at 25 - 30 °C for 5 to 6 hours. After the completion of reaction charged water (100 ml) and stirred for 15 minutes. Separated the organic layer and washed with water (100 ml). Dried the organic layer over anhydrous sodium sulphate and distilled out solvent under reduced pressure to get residual solid mass. To this solid, ethyl acetate (15 ml) was added and stirred for 30 minutes at 25 - 35°C. Cooled the reaction gradually to 0 to 5°C. The solid was then filtered and dried to yield pure N - (4 - chloro - 3 -nitropyridine - 2 - yl) cyclopropane carboxamide.
14

Example 4: Preparation of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide:
Dissolved Cyclopropane carboxylic acid (12.5gm) in dichloro methane (100 ml). Charged dimethylformamide (0.12 ml), and stirred for 10 min. To this solution slowly charged Oxalyl chloride (22.5 gm) dissolved in dichloro methane (25 ml) at 25 - 35°C and continued stirring for 2 hours. Apply chilling and chill the above solution at-10° C.
In another flask charged 4 - Chloro - 2 - amino - 3 nitropyridine in dichloro methane (150 ml) and stirred under cooling it to -10° C. To this add the above Cyclopropane carbonyl chloride solution maintaining temperature at -15 to -5°C in one lot and stir at this temp for half an hour. Further added triethyl amine (13 ml) dissolved in dichloro methane (25 ml) to the reaction solution and continued stirring for 30 minutes at -15 to -5°C. Raised the temperature gradually to 0°c and then to 25 - 35°C and maintained for 2 to 3 hour. After the completion of reaction charged water (100 ml) and stirred for 15 minutes. Separated the organic layer and washed with water (100 ml). Dried the organic layer over anhydrous sodium sulphate and distilled out solvent under reduced pressure to get residual solid mass. To this solid, ethyl acetate (15 ml) was added and stirred for 30 minutes at 25 - 35°C. Cooled the reaction gradually to 0 to 5°C. The solid was then filtered and dried to yield pure N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide.
Dated this 2nd day of February 2009
Dr. Gopakumar G. Nair Agent for the Applicant
15

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=zbA2YOe6+emXOEWJOP4SWA==&loc=vsnutRQWHdTHa1EUofPtPQ==

« Previous Patent

Next Patent »

Patent Number

270830

Indian Patent Application Number

202/MUM/2009

PG Journal Number

05/2016

Publication Date

29-Jan-2016

Grant Date

22-Jan-2016

Date of Filing

02-Feb-2009

Name of Patentee

INDOCO REMEDIES LIMITED

Applicant Address

INDOCO HOUSE, 166 C.S.T. ROAD, SANTACRUZ (EAST), MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	SINGH RAJESH KUMAR	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
2	VYAS KETAN DHANSUKHLAL	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
3	NAIR RANJEET	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
4	JADHAV VIDYADHAR KASHINATH	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
5	DESHMUKH SANDIP KACHARU	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
6	PANSARE PRAKASH POPAT	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
7	PANANDIKAR ADITI MILIND	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,
8	BHATT NIKUNJ	INDOCO REMEDIES LIMTED R&D CENTRE, R/92-93, TTC INDUSTRIAL AREA, MIDC, RABALE, NAVI MUMBAI 400701,

PCT International Classification Number

C07D213/68; C07D213/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA