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WO2010089773A2 - Process for preparation of nitropyridine derivatives - Google Patents

Process for preparation of nitropyridine derivatives Download PDF

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Publication number
WO2010089773A2
WO2010089773A2 PCT/IN2010/000055 IN2010000055W WO2010089773A2 WO 2010089773 A2 WO2010089773 A2 WO 2010089773A2 IN 2010000055 W IN2010000055 W IN 2010000055W WO 2010089773 A2 WO2010089773 A2 WO 2010089773A2
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formula
compound
nitropyridine
preparation
group
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WO2010089773A3 (en
Inventor
Ketan Dhansukhlal Vyas
Ranjeet Nair
Vidyadhar Kashinath Jadhav
Nikunj Bhatt
Sandip Kacharu Deshmukh
Prakash Popat Pansare
Rajesh Kumar Singh
Aditi Milind Panandikar
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Indoco Remedies Ltd
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Indoco Remedies Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • 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;
  • Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH- C (O) - R 3 ;
  • R 3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3 - 6 carbon atoms;
  • R 2 is selected from hydroxyl group, halogen atom, alkoxy group,
  • 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 - 1
  • Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH- C (O) - R 3 ;
  • R 3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3 - 6 carbon atoms;
  • R 2 is selected from hydroxyl group, halogen atom, and alkoxy group.
  • 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.
  • 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 disclosed by Kogl, F., et al, in Reel. Trav. Chim.
  • the US application US20030225131A1 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 0 C. After the work up the compound 2 - Chloro - 3 - nitropyridine - 4 - ol is isolated.
  • the major drawbacks of the prior art processes include:
  • the present invention provides a novel process for the preparation of nitropyridine precursor and derivatives which involves stable and cost effective reagents, less number of steps and therefore industrially useful.
  • 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.
  • the present invention provides a process for the preparation of nitropyridine derivatives of Formula I, its precursors and its salts,
  • Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH - C (O) - R 3 ;
  • R 3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3 - 6 carbon atoms;
  • R 2 is selected from hydroxyl group, halogen atom, and alkoxy group comprising the steps of: a) reacting picolinic acid hydrochloride with thionyl chloride, followed by treatment with ammonia to obtain compound 4 - chloropyridine - 2 — carboxamide of formula III;
  • the invention provides a process for preparation of compound of formula X by reacting the compound of formula V
  • the invention discloses preparation of compound of formula X by reacting the compound of formula V with cyclopropyl carbonyl chloride in chlorinated solvent in presence of base, wherein cyclopropyl carbonyl chloride is prepared insitu.
  • the invention provides an efficient process for preparation of compound of formula IV, a precursor, useful in the preparation of nitropyridine derivatives comprising the following steps: ⁇ a. reacting compound picolinic acid hydrochloride of formula II with thionyl chloride, followed by treatment with ammonia to obtain compound 4 - chloropyridine - 2 - carboxamide of formula III;
  • the present invention encompasses the process for preparation of nitropyridine derivatives and precursors such as compound of formula IV, compound of formula V, compound of formula VI, compound of formula VII, compound of formula VIII and compound of formula X.
  • 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,
  • Ri is selected from amino group, hydroxyl group, acyl group, alkyl amino group, halogen atom, -NH- C (O) - R 3 ;
  • R 3 is branched or linear alkyl group having 1 - 6 carbon atoms, or cycloalkyl group having 3 — 6 carbon atoms;
  • R 2 is selected from hydroxyl group, halogen atom, and alkoxy group.
  • the present invention encompasses the process for preparation of nitropyridine derivatives and precursors viz., compound of formula IV, compound of formula V, compound of formula VI, compound of formula VII, compound of formula VIII and compound of formula X as exemplified below:.
  • picolinic acid or its hydrochloride salt of formula II is reacted with thionyl chloride at 20 - 40 0 C for one hour.
  • thionyl chloride is distilled out completely under reduced pressure and charged toluene to the residue, stirred and cooled to -5 to 1O 0 C.
  • the product is dried at 55 - 65 0 C.
  • the 4 - chloropyridine - 2 - carboxamide is subjected to Hoffmann degradation by charging the same in the premixed solution of sodium hydroxide and liquid bromine at temperature of -10 to 10 0 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 0 C, maintained for one hour at 0 - 5 0 C and filtered to isolate the precursor 4 - chloro - 2 - amino pyridine (compound of formula IV). Washed the compound with chilled water and dried the product at 50 - 60 0 C.
  • the precursor compound 4 - chloro - 2 - amino pyridine thus obtained is further subjected to nitration using nitrating mixture (nitric acid and sulphuric acid), which results in the formation of nitropyridine compound, 4 - chloro - 2 - amino - 3 nitropyridine (compound of formula V).
  • nitrating mixture nitric acid and sulphuric acid
  • the reaction sequence for the precursor preparation is as per Scheme I below; Formula - Il
  • the compound 4 - chloro - 2 - amino - 3 nitropyridine (compound of formula V) is subjected to diazotization using sodium nitrite and hydrochloric acid at 0 - 5°C.
  • the reaction mass is stirred at 0 - 5 0 C for 30 minutes to 1 hour and raised the temperature and maintained at 60 - 80 0 C for 3 hours for complete hydrolysis.
  • the reaction mass is cooled to 25 - 3O 0 C and extracted with dichloromethane. Separated and dried the organic layer on anhydrous sodium sulfate, concentrated under reduced pressure to isolate 4 -chloro-3-nitropyridine - 2 - ol of formula VI.
  • the compound 4 - chloro - 3 - nitropyridine - 2 - ol is reacted with phosphorous oxychloride in presence of base to isolate 2, 4 — dichloro — 3 - nitropyridine of formula VII.
  • the compound 4 - chloro - 3 - nitropyridine - 2 - ol is charged in phosphorous oxychloride at temperature of 20 -.3O 0 C and stirred.
  • the base charged is selected from Triethylamine, diisopropyl - ethylamine, dimethylamine, tributylamine and pyridine at temperature 20 - 50 0 C.
  • the reaction is further maintained at 80 - 100 0 C for 4 - 6 hours. After the completion of the reaction, cooled. the reaction mass to 1O 0 C and quenched in ice water mixture.
  • the reaction mass is stirred and filtered the solid mass to isolate the compound 2, 4 - dichloro - 3 - nitropyridine.
  • the compound thus obtained is washed with chilled water and dried.
  • the compound 2, 4 - dichloro - 3 - nitropyridine of formula VII undergoes selective substitution at para position in presence of solvents selected from polar protic solvent and aromatic hydrocarbon solvent and reagents selected from sodium acetate and cesium carbonate with acetic acid, to isolate the nitropyridine derivative 2 - chloro - 3 - nitropyridin - 4 - ol of formula VIII.
  • the preferred solvent used for the reaction is polar protic solvent selected from acetonitrile, N 5 N - dimethylformamide and N,N - dimethylacetamide, and the most preferred solvent used for the reaction is N 5 N - dimethylformamide.
  • the nitropyridine derivative, N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide of formula X is prepared by using the compound 4 - chloro - 2 - amino - 3 nitropyridine of formula V, and reacting the same with cyclopropanecarbonyl chloride.
  • the amino group at ortho position is either protected or free, reacts with the cyclopropanecarbonyl chloride in presence of chlorinated solvent and base to yield the compound N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropanecarboxamide.
  • the chlorinated solvent is selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane.
  • the preferred solvent used is dichloromethane.
  • the base used for the reaction is selected from triethyl amine, diethyl amine, and pyridine.
  • the preferred base used for the reaction is triethyl amine.
  • the reaction sequence for the nitropyridine derivative is as per Scheme III below;
  • the nitropyridine derivative, N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide (compound of formula X) is prepared directly using cyclopropyl carboxylic acid by insitu generation of cycl ⁇ propylcarbonyl 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 0 C.
  • the chlorinated solvent used in the above reaction is selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane.
  • Step - 1 Preparation of 4- chlorbpyridine-2-carboxamide:
  • Step - II Preparation of 4-chloro 2-aniino pyridine:
  • Step - III Preparation of 4 -Chloro- 2-Amino - 3 - Nitropyridine:
  • Step-II Synthesis of 2, 4-dichloro-3-nitropyridine from 4-chloro-3-nitropyridin-2- ol:
  • Step-III Synthesis of 2-chloro-3-nitropyridin-4-ol from 2, 4-dichloro-3-nitro- pyridine:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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; 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,

Description

"PROCESS FOR PREPARATION OF NITROPYRIDINE DERIVATIVES"
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;
Figure imgf000002_0001
Formula - 1 Wherein;
Ri 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,
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 - 1
Figure imgf000003_0001
Formula - 1 Wherein;
Ri 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, 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 - chloropicolinate. 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 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 US20030225131A1 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 800C. 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. The present invention provides a novel process for the preparation of nitropyridine precursor and derivatives which involves stable and cost 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.
SUMMARY OF THE INVENTION
In accordance with the above objectives, the present invention provides a process for the preparation of nitropyridine derivatives of Formula I, its precursors and its salts,
Figure imgf000005_0001
Formula - 1 Wherein;
Ri 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, and alkoxy group comprising the steps of: a) reacting picolinic acid hydrochloride with thionyl chloride, followed by treatment with ammonia to obtain compound 4 - chloropyridine - 2 — carboxamide of formula III;
Figure imgf000006_0001
Formula - III
b) subjecting compound of formula III to Hoffman degradation to obtain compound of formula IV;
Figure imgf000006_0002
Formula - IV c) treating the compound of formula IV with nitrating agent to obtain compound of formula V;
Figure imgf000006_0003
Formula - V d) subjecting the compound of formula V to diazotization followed by hydrolysis to obtain compound of formula VI;
Formula - Vl
e) reacting the compound of formula VI with phosphorous oxychloride in presence of a base to obtain compound of formula VII; and
Figure imgf000007_0002
Formula -VlI
f) subjecting the compound of formula VII to selective substitution at para position in presence of polar protic solvent and the reagent sodium acetate or cesium carbonate with acetic acid to obtain compound of formula VIII;
Figure imgf000007_0003
Formula - VIII
In another aspect, the invention provides a process for preparation of compound of formula X by reacting the compound of formula V
Figure imgf000007_0004
Formula - V with cyclopropanecarbonyl chloride in presence of chlorinated solvent and base to obtain compound N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropanecarboxamide of formula X.
Figure imgf000008_0001
In a further aspect, the invention discloses preparation of compound of formula X by reacting the compound of formula V with cyclopropyl carbonyl chloride in chlorinated solvent in presence of base, wherein cyclopropyl carbonyl chloride is prepared insitu.
In yet another aspect, the invention provides an efficient process for preparation of compound of formula IV, a precursor, useful in the preparation of nitropyridine derivatives comprising the following steps: ■ a. reacting compound picolinic acid hydrochloride of formula II with thionyl chloride, followed by treatment with ammonia to obtain compound 4 - chloropyridine - 2 - carboxamide of formula III;
Figure imgf000008_0002
Formula -
Figure imgf000008_0003
b. subjecting the compound of formula III toΗoffmann degradation to obtain compound 4 - chloro - 2 - amino pyridine of formula IV, .
Figure imgf000009_0001
Formula - IV
Thus, the present invention encompasses the process for preparation of nitropyridine derivatives and precursors such as compound of formula IV, compound of formula V, compound of formula VI, compound of formula VII, compound of formula VIII and compound of formula X.
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,
Figure imgf000009_0002
Formula - 1 Wherein;
Ri 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, and alkoxy group.
The present invention encompasses the process for preparation of nitropyridine derivatives and precursors viz., compound of formula IV, compound of formula V, compound of formula VI, compound of formula VII, compound of formula VIII and compound of formula X as exemplified below:.
Accordingly, in one of the embodiments of the present invention, picolinic acid or its hydrochloride salt of formula II is reacted with thionyl chloride at 20 - 400C 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 1O0C. Charged methanol to the reaction solution and stirred at -5 to 100C, filtered the solid mass and charged the wet cake in DM water under stirring. Charged 25 - 30% ammonia solution till pH is highly basic, and stirred at 20 - 300C. Filtered the solid and washed with water to get 4 - chloropyridine - 2 - carboxamide of formula III. The product is dried at 55 - 650C.
In another embodiment of the present invention, the 4 - chloropyridine - 2 - carboxamide is subjected to Hoffmann degradation by charging the same in the premixed solution of sodium hydroxide and liquid bromine at temperature of -10 to 100C. 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 00C, maintained for one hour at 0 - 50C and filtered to isolate the precursor 4 - chloro - 2 - amino pyridine (compound of formula IV). Washed the compound with chilled water and dried the product at 50 - 600C.
The precursor compound 4 - chloro - 2 - amino pyridine thus obtained is further subjected to nitration using nitrating mixture (nitric acid and sulphuric acid), which results in the formation of nitropyridine compound, 4 - chloro - 2 - amino - 3 nitropyridine (compound of formula V). The reaction sequence for the precursor preparation is as per Scheme I below;
Figure imgf000011_0001
Formula - Il
Figure imgf000011_0002
Formula - IV
Formula - V
Scheme - 1
In yet another embodiment of the present invention the compound 4 - chloro - 2 - amino - 3 nitropyridine (compound of formula V) is subjected to diazotization using sodium nitrite and hydrochloric acid at 0 - 5°C. The reaction mass is stirred at 0 - 50C for 30 minutes to 1 hour and raised the temperature and maintained at 60 - 800C for 3 hours for complete hydrolysis. The reaction mass is cooled to 25 - 3O0C and extracted with dichloromethane. Separated and dried the organic layer on anhydrous sodium sulfate, concentrated under reduced pressure to isolate 4 -chloro-3-nitropyridine - 2 - ol of formula VI.
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 of formula VII.
The compound 4 - chloro - 3 - nitropyridine - 2 - ol is charged in phosphorous oxychloride at temperature of 20 -.3O0C and stirred. The base charged is selected from Triethylamine, diisopropyl - ethylamine, dimethylamine, tributylamine and pyridine at temperature 20 - 500C. The reaction is further maintained at 80 - 1000C for 4 - 6 hours. After the completion of the reaction, cooled. the reaction mass to 1O0C and quenched in ice water mixture. The reaction mass is stirred and filtered the 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 of formula VII undergoes selective substitution at para position in presence of solvents selected from polar protic solvent and aromatic hydrocarbon solvent and reagents selected from sodium acetate and cesium carbonate with acetic acid, to isolate the nitropyridine derivative 2 - chloro - 3 - nitropyridin - 4 - ol of formula VIII. The preferred solvent used for the reaction is polar protic solvent selected from acetonitrile, N5N - dimethylformamide and N,N - dimethylacetamide, and the most preferred solvent used for the reaction is N5N - dimethylformamide. The reaction sequence for the preparation of nitropyridine derivatives is depicted in Scheme II below;
Figure imgf000012_0001
Formula - V Formula - Vl
Figure imgf000012_0002
Formula - Vl" Formula - VII
Scheme - II
In yet another embodiment of the present invention the nitropyridine derivative, N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide of formula X is prepared by using the compound 4 - chloro - 2 - amino - 3 nitropyridine of formula V, and reacting the same with cyclopropanecarbonyl chloride. The amino group at ortho position is either protected or free, reacts with the cyclopropanecarbonyl chloride in presence of chlorinated solvent and base to yield the compound N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropanecarboxamide. The chlorinated solvent is selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane. The preferred solvent used is dichloromethane. The base used for the reaction is selected from triethyl amine, diethyl amine, and pyridine. The preferred base used for the reaction is triethyl amine. The reaction sequence for the nitropyridine derivative is as per Scheme III below;
Figure imgf000013_0001
Scheme - III
In yet another embodiment of the present invention, the nitropyridine derivative, N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropane carboxamide (compound of formula X) is prepared directly using cyclopropyl carboxylic acid by insitu generation of cyclόpropylcarbonyl 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 -100C.
Charged 4 - chloro - 2 - amino - 3 nitropyridine of formula V in chlorinated solvent and cooled to -15 to -50C. To the cooled solution the freshly prepared cyclopropyl carbonyl chloride solution is charged and stirred at -15 to -50C. 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 O0C and then to 25 - 350C and maintained for 2 - 4 hours. After completion of the reaction water was added to the reaction and stirred for 30 minutes. 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 for one hour. Cooled the reaction mass to 0 - 50C 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 above reaction is selected from dichloromethane, dichloro ethane, trichloro ethane and 1,1,2,2 - tetrachloro ethane.
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: Preparation of 4- chlorbpyridine-2-carboxamide:
Figure imgf000014_0001
Charged picolinic acid hydrochloride. (100 gm) in thionyl chloride (250 ml) and stirred for one hr at 25 - 300C. Added drop wise water (14 ml), 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 toluene completely. Again charged toluene (100 ml) and cooled the reaction mass to 0° C. Charged methanol (40 ml) slowly at O0C and stirred for one hour. Filtered the solid mass and washed with chilled toluene. Charged wet cake inlOOml DM Water, stirred for 15 minutes, added drop wise ammonia solution (250ml), and stirred one hr at room temperature. Filtered the solid, washed with water, and dried at 55 to 60°c. Step - II: Preparation of 4-chloro 2-aniino pyridine:
Figure imgf000015_0001
Dissolved sodium hydroxide in water (120 gm, 900 ml) and cooled to 0 to 5° C. Charged Bromine (45 ml) slowly at 0° C and stirred for half hour. Charged 4- chloropyridine-2- carboxamide (60 gm) of at 0° C and stirred for 5 minutes. Heated the reaction mass to 1000C and maintained at reflux to get clear solution. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0 to 5° C in one hr, filtered the precipitated solid, washed with chilled water, and dried at 50 to 55° C for 3 to 4 hrs. Dry wt: 28gm (Stage II)
Step - III: Preparation of 4 -Chloro- 2-Amino - 3 - Nitropyridine:
Figure imgf000015_0002
Dissolved 4-chloro 2-amino pyridine (28 gm) in cone, sulphuric acid (224 ml) under stirring. Added nitrating mixture [8.4ml fuming Nitric acid +17ml cone. H2SO4] slowly to the above solution and stirred for 1 hr at 25 - 300C. The reaction progress was monitored by TLC. After completion of the reaction the reaction solution was quenched on ice (1120 gm) and stirred for 15 minutes. The reaction mixture was extracted with dichloromethane (420 ml). The pH of the reaction mass was adjusted to pH 6 by 30% sodium carbonate solution.
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 get crude 4 - chloro - 2 - amino - 3 - nitropyridine.
The crude 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 and distilled completely to yield a yellow solid. To this solid, 105 ml Methanol was added and heated for 500C forl hr. This mixture was then cooled to 0 to -5°c and stirred for half hour 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: Synthesis of 2-ChIoro-3-nitropyridin-4-ol:
Step-I: Preparation of 4-chIoro-3-nitropyridin-2-oI
Charged 2-amino-4-chloro-3-nitropyridine (50.0 gm) in D.M. water (1.0 lit) under stirring at 25 - 300C. Charged cone, hydrochloric acid (450 ml) in one lot. Cooled the reaction mass to 0° to 5°C and started the addition of sodium nitrite solution (23 gm in 500 ml D. M. water) maintaining temperature at 0° to 5°C. Stirred the reaction mixture at 0° to 50C for 30 min. slowly raised the temperature of the reaction mass to 25 - 300C and then to 60° to 70°C, maintained for 2 hrs. After 2 hrs cooled the reaction to 25 - 300C and extracted reaction mass with dichloromethane (4x250 ml). Collected all the organic layers and dried over anhydrous sodium sulphate, concentrated the solvent under vacuum to get desired product. Dry wt = 30 gm (60%)
Step-II: Synthesis of 2, 4-dichloro-3-nitropyridine from 4-chloro-3-nitropyridin-2- ol:
Charged in a R.B. flask phosphorous oxychloride (81. 0 ml) and 4-chloro-3-nitropyridin- 2-ol (79 gm) in one lot under stirring at 25 - 300C. Charged slowly drop wise diisopropylethylamine (11.5 ml) at 25 - 3O0C. Stirred the reaction mass and raised the temperature to 90° to 100°C and maintain for 4 - 6 hrs. Cooled the reaction mass to 10° to 150C and quenched in ice: water mixture. Stirred the reaction mass at 15° to 2O0C for 60 min. Filtered the solid product, wash with cold water, dried well to get 2, 4-dichloro-3- nitropyridine. Dry wt = 50 gm (57.5%)
Step-III: Synthesis of 2-chloro-3-nitropyridin-4-ol from 2, 4-dichloro-3-nitro- pyridine:
Charged in a R.B. flask dimethylformamide (500 ml), . 2,4-dichlo-3-nitropyridine (100 gm) and sodium acetate (102.4 gm) at 25— 300 C. Heated the reaction mass to 120° to 125°C and maintained for 2 hrs. Stopped heating and cooled the reaction mass gradually to 30° to 35°C. Charged saturated ammonium chloride solution (800 ml) and stirred for 1045 min. Concentrated the reaction mass at 65° to 7O0C under vacuum to get crude solid product. Charged to the residue saturated ammonium chloride solution (1600 ml) DM water (800 ml) and dichloromethane (1000 ml) and stirred for 15 minutes. Separated the organic layer and extracted the aqueous layer further with dichloromethane (4x500 ml). Combined the organic layer and concentrated under vacuum to get thick solid mass. Charged toluene (1200 ml) to the residue and stirred at 25 - 30°C for 30-45 minutes. Filtered the product, washed with cold toluene (400 ml), and dried under vacuum at 40° to 45°C to get 2-chloro-3-nitropyridin-4-ol. Dry wt = 45 gm (50%).
Example - 4: Preparation of N - (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropanecarboxamide:
Figure imgf000017_0001
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 dichloromethane (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.
Example 5: 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 -50C 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 - 50C. 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.

Claims

We claim,
1. A process for the preparation of nitropyridine derivatives of Formula I, its precursors and its salts
Figure imgf000019_0001
Formula - 1 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, and alkoxy group comprising the steps of: a) reacting picolinic acid hydrochloride with thionyl chloride, followed by treatment with ammonia to obtain compound 4 - chloropyridine — 2 — carboxamide of formula III; .
Figure imgf000019_0002
b) subjecting compound of formula III to Hoffman degradation to obtain compound of formula IV;
Figure imgf000019_0003
Formula - IV c) treating the compound of formula IV with nitrating agent to obtain compound of formula V; .
Figure imgf000020_0001
d) subjecting the compound of formula V to diazotization followed by hydrolysis to obtain compound of formula VI;
Figure imgf000020_0002
Formula - Vl e) reacting the compound of formula VI with phosphorous oxychloride in presence of a base to obtain compound of formula VII; and
Figure imgf000020_0003
Formula - VII
f) subjecting the compound of formula VII to selective substitution at para position in presence of polar protic solvent and the reagent sodium acetate or cesium carbonate with acetic acid to obtain compound of formula VIII
Figure imgf000020_0004
Formula - VlII
2. The process as claimed in claim 1, wherein, the base used in step e) is selected from triethylamine, diisopropylethylamine, dimethylamine, tributylamine and pyridine.
3. The process as claimed in claim 1, wherein step e) is carried out at temperature ranging
80 to l00°C.
4. The process as claimed in claim 1, wherein in step f), the preferred reagent used for selective substitution is sodium acetate.
5. The process as claimed in claim 1, wherein in step f) the preferred polar protic solvent used is selected from acetonitrile, N5N - dimethylformamide and N5N - dimethylacetamide.
6. The process as claimed in claim 1, further comprising a step of reacting the compound 4 - chloro - 2 - amino - 3 nitropyridine of formula V with cyclopropanecarbonyl chloride in presence of chlorinated solvent and base to obtain compound N — (4 - chloro - 3 - nitropyridine - 2 - yl) cyclopropanecarboxamide of formula X.
F
Figure imgf000021_0001
ormula -V
7. The process as claimed in claim 6, wherein cyclopropyl carbonyl chloride is prepared insitu by mixing cyclopropanecarboxylic acid with a chlorinating agent.
8. The process as claimed in claim 7, wherein said chlorinating agent is selected from oxalyl chloride, thionyl chloride, phosphorous oxychloride or phosphorous pentachloride.
9. The process as claimed in claim 6, wherein said chlorinated solvent is selected from dichloromethane, dichloroethane, trichloroethane and 1,1,2,2 - tetrachloroethane.
10. The process as claimed in claim 6, wherein said base is selected from triethylamine, diethylamine, and pyridine.
11. A process for preparation of compound of formula IV, a precursor, useful in the preparation of nitropyridine derivatives comprising the steps of: a. reacting compound picolinic acid hydrochloride of formula II with thionyl chloride, followed by treatment with ammonia to obtain compound of formula III; and
Figure imgf000022_0001
Formula - Il
Figure imgf000022_0002
b. subjecting the compound of formula III to Hoffmann degradation to obtain compound of formula IV, 4 - chloro - 2 - amino pyridine.
Figure imgf000022_0003
Formula - IV
12. The process for preparation of nitropyridine derivatives and precursors according to any one of preceding claims encompasses the preparation of compound of formula IV, compound of formula V, compound of formula VI, compound of formula VII, compound of formula VIII and compound of formula X.
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