WO2012095691A1 - An improved process for producing aminopyridines - Google Patents

An improved process for producing aminopyridines Download PDF

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Publication number
WO2012095691A1
WO2012095691A1 PCT/IB2011/003073 IB2011003073W WO2012095691A1 WO 2012095691 A1 WO2012095691 A1 WO 2012095691A1 IB 2011003073 W IB2011003073 W IB 2011003073W WO 2012095691 A1 WO2012095691 A1 WO 2012095691A1
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Prior art keywords
aminopyridine
process according
solvent
pyridine carboxamide
reaction
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PCT/IB2011/003073
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French (fr)
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Bhawani Singh RATHORE
Sheo Prakash PANDEY
Pradeep Kumar Verma
Ashutosh Agarwal
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Jubilant Life Sciences Ltd.
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Publication of WO2012095691A1 publication Critical patent/WO2012095691A1/en

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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

Definitions

  • the present invention relates to an improved process for producing aminopyridine compounds. More particularly, the present invention provides an improved cost effective, single pot and eco-friendly process for large-scale industrial production of aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
  • Aminopyridines are important intermediates for chemicals, pharmaceuticals and agrochemical industry.
  • Several aminopyridine derivatives are known to be important intermediates for the preparation of various herbicides, antibacterial, antiviral drugs and dyes.
  • 4-aminopyridine as fampridine, is used for the treatment of multiple sclerosis. It has been found that fampridine improve impulse conduction in nerve fibers in which the insulating layer, called myelin, has been damaged.
  • 4-Aminopyridine is also used as an intermediate for antineoplastic, anticoagulant, anti-inflammatory, antispasmodic and antiasthmatic drugs and as additives for foodstuffs.
  • 3 -aminopyridine and 2-aminopyridine derivatives are used as an intermediate for fungicides, herbicides and several drugs.
  • Camps in Arch. Pharm., 1902, 240, 354 reported preparation of 4- aminopyridine from 4-methylpyridine in three steps with 28-30% yield.
  • US Patent No. 1,879,324 discloses preparation of 4-aminopyridine via l-(4- pyridyl) pyridinium chloride hydrochloride. The process involves reaction of pyridine and thionyl chloride to give 1 -(4-pyridyl) pyridinium chloride hydrochloride intermediate which is heated with concentrated ammonium hydroxide to get 4- aminopyridine in 36-40% yield.
  • US Patent No. 3,812,137 reported the preparation of aminopyridine compounds from corresponding carboxylic acid compounds by reacting with ammonia in the presence of polyvalent metal selected from copper and palladium.
  • Maier-Bode in Ber., 1936, 69, 1534 prepared 3-aminopyridine from 3- bromopyridine in the presence of ammonium hydroxide and copper sulfate in 60% yield.
  • DE586879 discloses a method of preparing 3-aminopyridine from 3- bromopyridine in the presence of CuS0 4 and ammonia.
  • GB 1467839 discloses preparation of amines by reacting carboxamides with hypochlorites in the presence of bromine, iodine, polymerisation inhibitors and/or haloamides and excess of alkali metal hydroxide.
  • the 3-aminopyridine is obtained in 72% yield.
  • the patent does not disclose the purity of the products formed.
  • Japanese Patent No. 01038072 discloses preparation of 4-aminopyridine derivatives as intermediate for plant growth-regulating N-(2-chloro-4-pyridyl)ureas. The process involves conversion of carboxamide derivative into amino derivative in the presence of trivalent aryl iodide compound PhI(OAc) 2 and acetonitrile.
  • US Patent No. 6,034,241 discloses a process of converting hydroxy pyridine compound to corresponding aminopyridine compound by treating salt of hydroxy pyridine compound with 2-bromo-2-methyl-propanamide as an alkylating agent, in the presence of dioxane, cesium carbonate and sodium hydride for 16 hours; and subsequent treatment of the reaction mixture obtained with a Smiles solvent system to obtain corresponding aminopyridine compound.
  • Chinese Patent No. CN1319947 discloses preparation of 4-aminopyridine by Hofmann degradation reaction of isoniacinamide using iodine based catalyst.
  • the process involves the use of analytically pure reagents and solvents as also raw materials. Moreover, deionized water is used in the process to obtain pure product.
  • the crystallization step involves the use of benzene as solvent.
  • an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the reaction is carried out in absence of solvent.
  • an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the aminopyridine is isolated in presence of a solvent and at a temperature range of 5- 120°C at atmospheric, subatmospheric or superatmospheric pressures.
  • an improved industrial process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof wherein the process comprises of isolating aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
  • aminopyridine is isolated at a temperature range of 5-120°C at atmospheric, subatmospheric or superatmospheric pressures.
  • the disclosed embodiment of the present invention provides an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
  • the process of the present invention is advantageous as it eliminates undesired processing steps, thereby making the process commercially viable and feasible for large-scale.
  • the disclosed embodiment of the present invention deals with a process for the large-scale industrial production of said aminopyridine compounds that has several advantages over prior art processes in that it avoids the formation of hazardous byproducts, reduction in the number of reaction steps, no isolation of the intermediate step product, effective consumption of raw materials, and minimum generation of effluents to make it comparatively safe and more cost-effective.
  • the disclosed embodiment of the present invention deals with an improved industrial process for the production of aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof with high purity and yield.
  • the present process avoids tedious extraction and purification process, and thus easy to operate on a commercial scale.
  • an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the reaction is carried out in absence of solvent.
  • hypohalite used herein includes alkali metal and alkaline earth metal hypochlorites, hypobromites, hypoiodites and mixtures thereof.
  • the alkali metal or alkaline earth metal hypohalite is selected from the group comprising of sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, sodium hypoiodite, potassium hypoiodite, magnesium hypochlorite, lithium hypochlorite and calcium hypochlorite, and mixtures thereof.
  • the reaction of pyridine carboxamide compound with hypohalite is optionally carried in the presence of catalyst.
  • the catalyst is selected from the group comprising of ion and/or compound of alkali metal, alkaline metal, ammonium salt and mixtures thereof.
  • the catalyst used is preferably selected from calcium chloride, magnesium chloride, ammonium chloride and mixtures thereof.
  • the process is carried out in the absence of an organic solvent.
  • the reaction is carried out at a temperature range of -20 to 20 °C, preferably from -10 to 10 °C.
  • an improved industrial process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof wherein the process comprises of isolating aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
  • the isolation is performed in the temperature range of 5-120 °C at atmospheric, subatmospheric or superatmospheric pressures, preferably 30-90 °C at atmospheric, subatmospheric or superatmospheric pressures.
  • the solvent used herein in the process during extraction is selected from the group comprising of cetyl alcohol, cyclohexanol, decanol, 2-hexanol, butanol, isobutanol, 2-methyl-THF, pentanol, octanol, tert. amyl alcohol, n-propanol, isopropanol, furfuryl alcohol, acetonitrile, diethyl ether, tetrahydrofurfuryl alcohol.
  • the aminopyridine used herein is substituted aminopyridine and the pyridine carboxamide is substituted pyridine carboxamide, wherein the substitution group is H or any alkyl groups having straight or branched chain.
  • the pyridine carboxamide compound is 4- pyridine carboxamide and the aminopyridine obtained is 4-aminopyridine.
  • the pyridine carboxamide compound is 3- pyridine carboxamide and the aminopyridine obtained is 3 -aminopyridine.
  • the pyridine carboxamide compound is 2- pyridine carboxamide and the aminopyridine obtained is 2-aminopyridine.
  • a process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof wherein the process comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and extracting the resultant aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
  • the isolation is performed in the temperature range of 5-120 °C at atmospheric, subatmospheric or superatmospheric pressures, preferably 30-90 °C at atmospheric, subatmospheric or superatmospheric pressures.
  • the solvent used in the isolation is recovered and reused in the process.
  • aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof produced by the process of the present invention is characterized by having HPLC purity of more than 99%.
  • “Pharmaceutically acceptable salts, esters, amides, and prodrugs” as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonatc, lactobionate and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • esters of the compounds of this invention examples include C1-C6 alkyl esters, wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred.
  • Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines, wherein the alkyl groups are straight or branched chain.
  • the amine may also be in the form of a 5-or 6-membered heterocycle containing one nitrogen atom.
  • Amides derived from ammonia, C1-C3 alkyl primary amines, and C1-C2 dialkyl secondary amines are preferred.
  • Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrugs refers to compounds that are rapidly transformed in vivo to yield the parent compounds of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • the present invention is further illustrated below with reference to the following examples without intending to limit the scope of the invention in any manner.

Abstract

Disclosed herein is an improved process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof with high purity and yield at industrial scale.

Description

An Improved Process For Producing Aminopyridines
Field of the Invention
The present invention relates to an improved process for producing aminopyridine compounds. More particularly, the present invention provides an improved cost effective, single pot and eco-friendly process for large-scale industrial production of aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof.
Background of the Invention
Aminopyridines are important intermediates for chemicals, pharmaceuticals and agrochemical industry. Several aminopyridine derivatives are known to be important intermediates for the preparation of various herbicides, antibacterial, antiviral drugs and dyes. For example, 4-aminopyridine, as fampridine, is used for the treatment of multiple sclerosis. It has been found that fampridine improve impulse conduction in nerve fibers in which the insulating layer, called myelin, has been damaged. 4-Aminopyridine is also used as an intermediate for antineoplastic, anticoagulant, anti-inflammatory, antispasmodic and antiasthmatic drugs and as additives for foodstuffs. 3 -aminopyridine and 2-aminopyridine derivatives are used as an intermediate for fungicides, herbicides and several drugs.
To meet the ever increasing demand of these aminopyridine compounds, several processes are reported in the prior art for the preparation of aminopyridines. The known processes differ with respect to different chemical processes followed, use of different raw materials, solvents and in terms of experimental parameters.
Camps in Arch. Pharm., 1902, 240, 354 reported preparation of 4- aminopyridine from 4-methylpyridine in three steps with 28-30% yield.
Riegel and Reinhard in J. Am. Chem. Soc, 1926, 48, 1344 reported synthesis of 4-aminopyridine from Chelidamic acid in four steps with 30% yield.
US Patent No. 1,879,324 discloses preparation of 4-aminopyridine via l-(4- pyridyl) pyridinium chloride hydrochloride. The process involves reaction of pyridine and thionyl chloride to give 1 -(4-pyridyl) pyridinium chloride hydrochloride intermediate which is heated with concentrated ammonium hydroxide to get 4- aminopyridine in 36-40% yield. US Patent No. 3,812,137 reported the preparation of aminopyridine compounds from corresponding carboxylic acid compounds by reacting with ammonia in the presence of polyvalent metal selected from copper and palladium.
Maier-Bode in Ber., 1936, 69, 1534 prepared 3-aminopyridine from 3- bromopyridine in the presence of ammonium hydroxide and copper sulfate in 60% yield.
DE586879 discloses a method of preparing 3-aminopyridine from 3- bromopyridine in the presence of CuS04 and ammonia.
GB 1467839 discloses preparation of amines by reacting carboxamides with hypochlorites in the presence of bromine, iodine, polymerisation inhibitors and/or haloamides and excess of alkali metal hydroxide. The 3-aminopyridine is obtained in 72% yield. However, the patent does not disclose the purity of the products formed.
Japanese Patent No. 01038072 discloses preparation of 4-aminopyridine derivatives as intermediate for plant growth-regulating N-(2-chloro-4-pyridyl)ureas. The process involves conversion of carboxamide derivative into amino derivative in the presence of trivalent aryl iodide compound PhI(OAc)2 and acetonitrile.
US Patent No. 6,034,241 discloses a process of converting hydroxy pyridine compound to corresponding aminopyridine compound by treating salt of hydroxy pyridine compound with 2-bromo-2-methyl-propanamide as an alkylating agent, in the presence of dioxane, cesium carbonate and sodium hydride for 16 hours; and subsequent treatment of the reaction mixture obtained with a Smiles solvent system to obtain corresponding aminopyridine compound.
Yong et al. in Huaxue Shiji, 1998, 20, 240 reported a three step process for the preparation of 4-aminopyridine from pyridine. The process involves oxidation of pyridine with hydrogen peroxide and acetic acid followed by nitration with nitric acid and sulphuric acid, and subsequent reduction of nitropyridine with Fe HOAc to give 4-aminopyridine in 55% overall yield.
US Publication No. 2001/0047013 reported process for the preparation of arylamines from aryl halides/methanesulfonates using ammonia and copper reagent under mild reaction conditions.
Yang et al. in Yingyong Huaxue, 2004, 21 , 530 have reported catalytic hydrolysis of 4-cyanopyridine in the presence of Mg-Fe oxides followed by Hofmann reaction of isonicotinamide obtained in the presence of iodobenzene as catalyst to give 4-aminopyridine in 83-85% yield. However, the process involves several isolation steps and the purity of the product obtained is not mentioned.
Chinese Patent No. CN1319947 discloses preparation of 4-aminopyridine by Hofmann degradation reaction of isoniacinamide using iodine based catalyst. The process involves the use of analytically pure reagents and solvents as also raw materials. Moreover, deionized water is used in the process to obtain pure product. The crystallization step involves the use of benzene as solvent.
Thus, the processes disclosed in the prior art have several disadvantages to be used for the commercial manufacturing of aminopyridine derivatives. For example, some of these processes are time consuming or involve costly raw materials.
There are also many prior art references, which involve use of hazardous and industrially unsuitable chemicals and hence not suitable for industrial production.
Moreover, the processes disclosed in the prior art include production of impure product thereby requiring several steps for extraction and tedious isolation to obtain the desired products.
Thus, it is difficult to achieve the desired purity and yield of aminopyridine derivatives in cost effective manner by prior art methods. Therefore, there remains a need for an efficient process for synthesis of aminopyridine derivative which can overcome these drawbacks.
In view of ever increasing demand for producing these aminopyridine derivatives of high purity and yield, there is provided an improved cost effective process, suitable for large scale industrial production of aminopyridine compounds with high purity and yield.
Summary of the Invention
It is a principal object of the present invention to provide a process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof wherein the process enables single pot production of the compounds at industrial scale with minimum generation of effluents.
It is another object of the present invention to provide a cost effective and commercially viable process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein the process provides pure product simplifying isolation steps.
In accordance with one embodiment of the present invention, there is provided an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein the process comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the reaction is carried out in absence of solvent.
In accordance with one embodiment of the present invention, there is provided an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the aminopyridine is isolated in presence of a solvent and at a temperature range of 5- 120°C at atmospheric, subatmospheric or superatmospheric pressures.
In accordance with yet another embodiment of the present invention, there is provided an improved industrial process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein the process comprises of isolating aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
In accordance with one other embodiment of the present invention, aminopyridine is isolated at a temperature range of 5-120°C at atmospheric, subatmospheric or superatmospheric pressures.
Other aspects will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples. The disclosed embodiment of the present invention provides an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof. The process of the present invention is advantageous as it eliminates undesired processing steps, thereby making the process commercially viable and feasible for large-scale.
The disclosed embodiment of the present invention deals with a process for the large-scale industrial production of said aminopyridine compounds that has several advantages over prior art processes in that it avoids the formation of hazardous byproducts, reduction in the number of reaction steps, no isolation of the intermediate step product, effective consumption of raw materials, and minimum generation of effluents to make it comparatively safe and more cost-effective.
The disclosed embodiment of the present invention deals with an improved industrial process for the production of aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof with high purity and yield. The present process avoids tedious extraction and purification process, and thus easy to operate on a commercial scale.
In accordance with one embodiment of the present invention, there is provided an improved industrial process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein the process comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the reaction is carried out in absence of solvent.
According to the present invention, the hypohalite used herein includes alkali metal and alkaline earth metal hypochlorites, hypobromites, hypoiodites and mixtures thereof.
The alkali metal or alkaline earth metal hypohalite is selected from the group comprising of sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, sodium hypoiodite, potassium hypoiodite, magnesium hypochlorite, lithium hypochlorite and calcium hypochlorite, and mixtures thereof.
According to the present invention, the reaction of pyridine carboxamide compound with hypohalite is optionally carried in the presence of catalyst. The catalyst is selected from the group comprising of ion and/or compound of alkali metal, alkaline metal, ammonium salt and mixtures thereof. The catalyst used is preferably selected from calcium chloride, magnesium chloride, ammonium chloride and mixtures thereof.
According to the present invention, the process is carried out in the absence of an organic solvent.
According to the present invention, the reaction is carried out at a temperature range of -20 to 20 °C, preferably from -10 to 10 °C.
According to one of the embodiment of the present invention, there is provided an improved industrial process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein the process comprises of isolating aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
According to the present invention, the isolation is performed in the temperature range of 5-120 °C at atmospheric, subatmospheric or superatmospheric pressures, preferably 30-90 °C at atmospheric, subatmospheric or superatmospheric pressures.
The solvent used herein in the process during extraction is selected from the group comprising of cetyl alcohol, cyclohexanol, decanol, 2-hexanol, butanol, isobutanol, 2-methyl-THF, pentanol, octanol, tert. amyl alcohol, n-propanol, isopropanol, furfuryl alcohol, acetonitrile, diethyl ether, tetrahydrofurfuryl alcohol.
According to the process of the present invention, the aminopyridine used herein is substituted aminopyridine and the pyridine carboxamide is substituted pyridine carboxamide, wherein the substitution group is H or any alkyl groups having straight or branched chain.
According to the present invention, the pyridine carboxamide compound is 4- pyridine carboxamide and the aminopyridine obtained is 4-aminopyridine.
According to the present invention, the pyridine carboxamide compound is 3- pyridine carboxamide and the aminopyridine obtained is 3 -aminopyridine.
According to the present invention, the pyridine carboxamide compound is 2- pyridine carboxamide and the aminopyridine obtained is 2-aminopyridine. According to another preferred embodiment of the present invention, there is provided a process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof, wherein the process comprises of reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and extracting the resultant aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
According to the present invention, the isolation is performed in the temperature range of 5-120 °C at atmospheric, subatmospheric or superatmospheric pressures, preferably 30-90 °C at atmospheric, subatmospheric or superatmospheric pressures.
According to the present invention, the solvent used in the isolation is recovered and reused in the process.
According to another preferred embodiment of the present invention, wherein the aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof produced by the process of the present invention is characterized by having HPLC purity of more than 99%.
The term "Pharmaceutically acceptable salts, esters, amides, and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonatc, lactobionate and laurylsulphonate salts, and the like.
These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C1-C6 alkyl esters, wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred.
Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines, wherein the alkyl groups are straight or branched chain. In the case of secondary amines, the amine may also be in the form of a 5-or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines, and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrugs" refers to compounds that are rapidly transformed in vivo to yield the parent compounds of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward I I B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention. The present invention is further illustrated below with reference to the following examples without intending to limit the scope of the invention in any manner.
Example -1
Synthesis of 4-Aminopyridine:
DM water (525 g) and sodium hydroxide flakes (170 g) were charged into a round bottom flask and mass was cooled to 5 °C. Chlorine gas (1 15-120 g) was then purged into the solution and isoniacinamide (200 g) was added slowly at -5-0 °C in 1 to 2 hrs. After the reaction, caustic lye solution (260 g) was added and mass was reacted for 1 hr. The completion of reaction was monitored by HPLC. After the completion of reaction the crude product was extracted with isopropanol at slightly elevated temperature. The solvent was recovered from organic layer and mass was crystallized to get white to off-white crystal of 4-aminopyridine (122 g) with 99.5% purity. The product was confirmed by mass spectroscopy and Ή NMR.
Melting point: 154.5-159.2°C; 1H NMR( CDC13) δ 5.956-6.439 (m, 4H, Ar); δ
7.93 (s, 2H, NH2); MS (70eV): m/e 94 (M+).
Example -2
Synthesis of 4-Aminopyridine:
Sodium hypochlorite (800 g, prepared as example- 1) was charged in a round bottom flask. Isoniacinamide (200 g) was added slowly to the solution at -5-0 °C in 1 to 2 hrs. After the reaction, caustic lye solution (260 g) was added and mass was reacted for 1 hr. The completion of reaction was monitored by HPLC. After the completion of reaction, the crude product was extracted with recovered isopropanol at slightly elevated temperature. The solvent was recovered from organic layer and mass was crystallized to get white to off-white crystal of 4-aminopyridine (121 g) with 99.5% purity. The product was confirmed by mass spectroscopy and Ή NMR.
Melting point: 154.5-159.2°°C; 1H NMR: δ 5.956-6.439 (m, 4H, Ar); δ 7.93 (s, 2H, NH2); MS (70eV): m/e 94 (M+).
Example -3
Synthesis of 3-Aminopyridine:
Sodium hypochlorite (800 g, prepared as example- 1) and ammonium chloride (0.6 g) was charged in a round bottom flask. Niacinamide (200 g) was added slowly to the solution at -5-0 °C in 1 to 2 hrs. After the reaction, caustic lye solution (260 g) was added and mass was reacted for 1 hr. The completion of reaction was monitored by HPLC. After the completion of reaction, the crude product was extracted with 2- methyl THF at slightly elevated temperature. The solvent was recovered from organic layer and mass was crystallized to get yellow to brown crystals of 3-aminopyridine (120 g) with 99.5% purity. The product was confirmed by mass spectroscopy and Ή NMR.
Melting point: 57-60 °C; 1H NMR(TMS) δ 6.156-6.469 (m, 4H, Ar); δ 7.97 (s, 2H, NH2); MS (70eV): m/e 94 (M+).
Example -4
Synthesis of 4-amino-2-methyl pyridine:
Sodium hypochlorite (800 g, prepared as example- 1) was charged in a round bottom flask. 2-Methyl-isonicotinamide (200 g) and magnesium chloride (0.8 g) was added slowly to the solution at -5-0 °C in 1 to 2 hrs. After the reaction, caustic lye solution (260 g) was added and mass was heated to 90-100 °C for 1 hr. The completion of reaction was monitored by HPLC. After the completion of reaction, the crude product was extracted with tert. amyl alcohol at slightly elevated temperature. The solvent was recovered from organic layer and mass was crystallized to get 4-amino-2-methyl pyridine (102.5 g) with 99.5% purity. The product was confirmed by mass spectroscopy and Ή NMR.
Melting point: 95.5-98.5 °C; 1H NMR: δ 6.45-6.55 (m, 3H, Ar); δ 7.87 (s, 2H, NH2) and δ 2.48 (s, 3H, CH3); MS (70eV): m/e 108(M+).
Example -5
Synthesis of 5-amino-2-methyl pyridine:
Sodium hypochlorite (800 g, prepared as example- 1) was charged in a round bottom flask. 2-Methyl-5-nicotinamide (200 g) was added slowly to the solution at -5- 0 °C in 1 to 2 hrs. After the reaction, caustic lye solution (260 g) was added and mass was heated to 90-100 °C for 1 hr. The completion of reaction was monitored by HPLC. After the completion of reaction, the crude product was extracted with butanol at slightly elevated temperature. The solvent was recovered from organic layer and mass was crystallized to get 5-amino-2-methyl pyridine (106.3 g) with 99.5% purity. The product was confirmed by mass spectroscopy and Ή NMR. Melting point : 96.5-99.5 °C; Ή NMR: δ 6.75-7.12 (m, 3H, Ar); δ 7.68 (s, 2H, NH2) and δ 2.41 (s, 3H, CH3); MS (70eV): m/e 108(M+).
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations, would present themselves to those skilled in the art without departing from the scope and spirit of this invention. This invention is susceptible to considerable variation in its practice within the spirit and scope of the appended claims.

Claims

We Claim:
1. A process for producing aminopyridine compounds analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof comprising:
reacting pyridine carboxamide with hypohalite followed by hydrolysis of the resultant and isolating the aminopyridine, wherein the reaction is carried out in absence of solvent.
2 The process according to claim 1, wherein the aminopyridine is isolated in presence of a solvent and at a temperature range of 5-120 °C at atmospheric, subatmospheric or superatmospheric pressures.
3. The process according to claim 2, wherein the solvent is selected from cetyl alcohol, cyclohexanol, decanol, 2-hexanol, butanol, isobutanol, 2-methyl-THF, pentanol, octanol, tert. amyl alcohol, n-propanol, isopropanol, furfuryl alcohol, acetonitrile, diethyl ether and tetrahydrofurfuryl alcohol.
4. The process according to claim 1, wherein the reaction is carried out optionally in presence of a catalyst.
5. The process according to claim 4, wherein the catalyst is selected from the group comprising of ion and/or compound of alkali metal, alkaline metal, ammonium salt and mixtures thereof.
6. The process according to claim 5, wherein the catalyst is selected from calcium chloride, magnesium chloride, ammonium chloride and mixtures thereof.
7. The process according to claim 1, wherein the aminopyridine is substituted aminopyridine and the pyridine carboxamide is substituted pyridine carboxamide.
8. The process according to claim 7, wherein the substitution group is H or any alkyl groups having straight or branched chain.
9. The process according to claim 7, wherein the pyridine carboxamide is 2-pyridine carboxamide, 3 -pyridine carboxamide or 4-pyridine carboxamide and aminopyridine is 2-aminopyridine, 3 -aminopyridine or 4-aminopyridine respectively.
10. The process according to claim 1, wherein the hypohalite is selected from alkali metal and alkaline earth metal hypochlorites, hypobromites, hypoiodites and mixtures thereof.
1 1. The process according to claim 10, wherein the hypohalite is selected from sodium hypochlorite, potassium hypochlorite, sodium hypobromite, potassium hypobromite, sodium hypoiodite, potassium hypoiodite, magnesium hypochlorite, lithium hypochlorite and calcium hypochlorite, and mixtures thereof.
12. The process according to claim 1, wherein the reaction is carried out at a temperature range of -20 to 20°C.
13. The process according to claim 12, wherein the reaction is carried out at a temperature range of -10 to 10°C.
14. A process for producing aminopyridine compounds, analogs, substituted forms, derivatives, or the pharmaceutically acceptable salts, esters, amides and prodrugs thereof comprising:
isolating aminopyridine compound employing a solvent followed by filtering and optionally drying the resultant mass.
15. The process according to claim 14, wherein the isolation is performed at a temperature range of 5-120°C at atmospheric, subatmospheric or superatmospheric pressures.
16. The process according to claim 15, wherein the isolation is performed at a temperature range of 30-90°C at atmospheric, subatmospheric or superatmospheric pressures.
17. The process according to claim 14, wherein the solvent is selected from cetyl alcohol, cyclohexanol, decanol, 2-hexanol, butanol, isobutanol, 2-methyl- THF, pentanol, octanol, tert. amyl alcohol, n-propanol, isopropanol, furfuryl alcohol, acetonitrile, diethyl ether and tetrahydrofurfuryl alcohol.
18. The process according to claim 14, wherein the solvent used is recyclable.
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CN102993144A (en) * 2012-12-07 2013-03-27 青岛前线生物工程有限公司 One-kettle method synthesis process of 4-aminotetrahydropyran
CN111138352A (en) * 2020-01-08 2020-05-12 山东泓达生物科技有限公司 Preparation method and post-treatment process of 4-aminopyridine
CN111170937A (en) * 2020-01-08 2020-05-19 山东泓达生物科技有限公司 Preparation method of 3-aminopyridine
CN113149896A (en) * 2021-03-09 2021-07-23 利尔化学股份有限公司 Preparation method of 3-aminopyridine

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CN102993144A (en) * 2012-12-07 2013-03-27 青岛前线生物工程有限公司 One-kettle method synthesis process of 4-aminotetrahydropyran
CN102993144B (en) * 2012-12-07 2016-04-13 青岛前线生物工程有限公司 The one pot process technique of 4-amino tetrahydro pyran
CN111138352A (en) * 2020-01-08 2020-05-12 山东泓达生物科技有限公司 Preparation method and post-treatment process of 4-aminopyridine
CN111170937A (en) * 2020-01-08 2020-05-19 山东泓达生物科技有限公司 Preparation method of 3-aminopyridine
CN111138352B (en) * 2020-01-08 2023-03-24 山东泓达生物科技有限公司 Preparation method and post-treatment process of 4-aminopyridine
CN113149896A (en) * 2021-03-09 2021-07-23 利尔化学股份有限公司 Preparation method of 3-aminopyridine

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