Field of the Invention
This invention, in general, relates to an improved process for producing 4-aminopyridines. More particularly, the present invention provides a cost effective, single pot process for large-scale industrial production of 4-alkylaminopyridine or salts thereof with high yield and purity.
Background of the Invention
The superiority of certain 4-alkylaminopyridines as catalysts for difficult acetylations or acylations has been a proven fact. 4-Alkylaminopyridines have general applicability for catalysis of a wide variety of reactions. It has been well known that some of the aminopyridines are used as catalyst in the fields of organic, polymer, analytical and biochemistry. For e.g. several pharmaceutical and agricultural products that rely on 4-dimethylaminopyridine's superior catalytic properties in their synthetic sequences have been produced for years.
Therefore, to meet the ever-increasing demand of these compound, several processes are reported in the prior art for the production of 4-alkylaminopyridines. The known processes differ from each other in respect of different process chemistry followed.
Marcoux et al in J. Org. Chem., 1997, 1568-1569 have reported synthesis of 4-N,N-(di-n-butyl)-aminopyridine by the palladium catalyzed amination of 4-bromopyridine hydrochloride salt. The process involves palladium complexes derived from ligand PPF-OMe as catalyst and sodium tert-butoxide as base. The product was purified by flash chromatography and obtained as yellow oil with 60% yield.
Japenese publication No. JP 2001.-163858 discloses the process for the manufacture of 4-N,N-(dipropyl)aminopyridine. The process involves the reaction of l-benzyl-4-piperidone with dipropyl amine in the presence of α-methylstyrene and palladium carbon catalyst in toluene for 50 hrs to give 82 % yield.

Pedersen and Carlsen in Synthesis, 1978, 11, 844-5 reported the preparation of dialkylaminopyridines by the treatment of 2(lH)pyridine or 4-pyridinol with corresponding amine and P2O5.
Pasquier et al in Heterocycles, 1997, 45, 11, 2113-2129 have reported the preparation of several derivatives of aminopyridines. The research paper reported that the complex base of NaNH2-tert-BuONa, in THF easily transforms 3-bromopyridine derivatives into the corresponding aminopyridines in good yields. Thus, the reaction of 3-bromopyridine with N,N-(diisopropyl) amine in the presence of NaNH2-tert-BuONa, in THF at -10 °C for 270 minutes gives the mixture of 4-N,N-(diisopropyl)amino pyridine and 3-N,N-(diisopropyl)amino pyridine in the ratio of 57:43 with overall 49% yield.
Penney Jonathan in Tetrahedron Letters, 2004, 45, 12, 2667-2669 reported the direct reaction of 4-cyanopyridines with lithium amides to give corresponding aminopyridines in good yield. It has been found that addition of CsF accelerates the reaction and lead to significantly higher yields.
Japenese publication No. JP 2001-08951 discloses the synthesis of 4-dimethylamino pyridine by the process involving the reaction of 4-chloropyridine under high pressure conditions (0.8 GPa) without using a catalyst. This method involves reaction of 4-chloropyridine with dimethylamine in the presence of NaOH at high pressure of >0.75 GPa and at 114 °C.
Chinese publication No. CN10l033212 disclose a process for the preparation of 4-dimethylaminopyridine which involves the reaction of pyridine solution with bromine and then with dimethylamine hydrochloride followed by the addition of sodium hydroxide. The solution is stirred, left standing to demix, cooled to 0 °C, separated and dried to obtain 4-dimethylaminopyridine.
Zhao and Yan in Shandong Huagong, 2007, 36, 5, 12-13 reported a process for producing

4-dimethylaminopyridine from pyridinyl-pyridinium. The process involves crystallization from petroleum - benzene.
The US patent No. US 6,939,972 discloses the process for producing 4-dimethylaminopyridine by quaternizing pyridine with thionyl chloride in the presence of ethyl acetate, isolating the resultant N-(4-pyridyl)pyridinium chloride hydrochloride obtained followed by amination with DMF. The resultant reaction mass is hydrolysed in the presence of a base, extracted with benzene and distilled under vacuum to provide the product.
The processes disclosed in the prior art include production of impure aminopyridine derivatives requiring several steps for extraction and isolation of the desired derivatives. Some of the processes mentioned in the prior art involve use of hazardous and industrially unsuitable solvents, thereby making them unamenable for large scale production.
In view of the above drawbacks in prior art processes and ever increasing demand for producing these 4-aminopyridine derivatives, there is provided an alternate process, suitable for large scale industrial production of 4-aminopyridines and salts thereof with high purity and yield.
Summary of the Invention
It is a principal object of the present invention to provide a process for producing 4-aminopyridine compound of. formula (I) or salts thereof, wherein the process enables production of highly pure 4-aminopyridine compounds or salts thereof 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 4-aminopyridine compound of formula (I) or salts thereof, wherein the process provides highly pure product employing minimum reaction steps and/or simplifying purification steps.

It is another object of the present invention to provide a cost effective and commercially viable process for producing 4-aminopyridine compound of formula (I) or salts thereof wherein the process comprises of recovering and recycling of raw materials and solvent.
It is further object of the present invention to provide a process for producing 4-aminopyridine compound of formula (I) or salts thereof, wherein the process comprises a single pot process employing environmentally non-hazardous raw materials.
The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiment herein after.
In accordance with one embodiment of the present invention, there is provided an improved industrial process for producing 4-aminopyridine compound of formula (I) or salts thereof, wherein the process comprises of quaternizing pyridine compound of formula (II) in presence of a catalyst followed by conversion of the resultant quaternized compound by treating with aldehyde compound of formula (III) to the 4-aminopyridine compound of formula I or salts thereof.
In accordance with one other embodiment of the present invention, there is provided an improved industrial process for producing 4-aminopyridine compound of formula (I), or salts thereof, wherein the quaternizatiqn reaction, is performed in absence of solvent.
In accordance with still another embodiment of the present invention, there is provided an improved industrial process for producing 4-aminopyridine compound of formula (I) or salts thereof, wherein the unreacted pyridine compound of formula (II) and aldehyde compound of formula (III) are recoverable and recyclable.
In accordance with still another embodiment of the present invention, there is provided an improved industrial process for producing 4-aminopyridine compound of formula (I) or

salts thereof, wherein the conversion of quaternized compound is performed by treating the quaternized compound with aldehyde compound of formula (III) under conditions effective to produce crude 4-aminopyridine compound of formula I, and recovering the pure 4-aminopyridine compound of formula I or salts thereof from the resultant crude product.
In accordance with still another embodiment of the present invention, there is provided an improved industrial process for producing 4-aminopyridine compound of formula (I) or salts thereof, wherein the recovery of pure 4-aminopyridine compound of formula I or salts thereof is performed employing distillatioh of crude 4-aminopyridine compound of formula I.
In accordance with still another embodiment of the present invention, there is provided an improved industrial process for producing 4-aminopyridine compound of formula (I) or salts thereof, wherein the recovery of pure 4-aminopyridine compound of formula I or salts thereof is performed employing solvent.
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 deals with an improved industrial process for producing 4-aminopyridine compound of formula (I) or salts thereof. The process of the present invention is advantageous as it involves better carbon efficiency and minimum effluent load. In addition, the process eliminates undesired processing steps, thereby making the process commercially viable and feasible for large-scale

manufacture of pure 4-aminopyridine compound of formula (I) or salts thereof in lesser time.
The disclosed embodiment of the present invention deals with a process for the production of 4-aminopyridine compound of formula (I) or salts thereof that has 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 recycles of raw materials, use of industrially suitable solvent, and elimination of undesired processing steps to make it comparatively safe and more cost effective.
According to the preferred embodiment of the present invention there is provided an improved industrial process for production of 4-aminopyridine compound represented by formula (I) or salts thereof with high purity and yield,
(Formula Removed)
wherein, Rt and R2 are ■ elected from the group consisting of
hydrogen, and C1-C8 alkyl
R3 is independently selected from the group consisting of hydrogen, carboxyl, hydroxyl, halogen, -NO2, -CN, C1-C6-alkyl or optionally substituted heteroaryl
m can be any integer between 1 to 4
the process comprises of quaternizing pyridine compound of formula (II) in presence of a catalyst followed by conversion of the resultant quaternized compound by treating with aldehyde compound of formula (III) to the 4-aminopyridine compound of formula I or salts thereof

(Formula Removed)
wherein R1, R2, R3 and m are defined above.
The quaternizing agent used herein the process of the present invention is selected from the group comprising of thionyl chloride, methyl halides, ethyl halides, propyl halides, benzyl chloride and benzyl bromide.
According to another preferred embodiment of the present invention the quaternization reaction is performed in absence of solvent. Thus, avoiding the use of solvents reduces the workup of the reaction mixture, and thereby reduces the overall time cycle for manufacturing process.
According to the present invention, the catalyst used in the process is ion of and/or compound of metal selected from Group VIII-XVI of the periodic table. The catalyst used herein the process of the present invention is lewis acid. The lewis acid used herein is selected from the group comprising of Boron trifluoride, aluminium trichloride, aluminium tribromide, silicon tetrachloride, tetrafluorosilane, carbon dioxide, sulphur dioxide and halides of Ag+, Cu2+, Fe2+ and Fe3+ or mixtures thereof.
According to another preferred embodiment of the present invention, converting the quaternized compound to the 4-aminopyridine compound of formula I or salts thereof comprises, reacting the quaternized compound with aldehyde compound of formula (III) under conditions effective to produce crude 4-aminopyridine compound of formula (I). Such conditions include those which are conventionally utilized. The reaction is carried out for a time period of 2 to 10 hours, preferably 5 to 9 hours, at a temperature of 30 to 125 °C.

The pure 4-aminopyridine compound of formula (I) or salts thereof is recovered from the crude product.
According to one of the preferred embodiments of the present invention, recovering of pure aminopyridine compound of formula (I) from crude product is performed employing solvent or through distillation by conventional methods or by methods known to person skilled in art.
The process according to the present invention avoids unnecessary steps of isolating the intermediate as also of removing the solvents in first step.
According to one of the preferred embodiments of the present invention, the unreacted pyridine compound of formula (II) and aldehyde compound of formula (III) are recyclable.
According to the present invention, the solvent used herein the process during extraction is water immiscible organic solvent. The water immiscible organic solvent is selected from the aromatic solvents. The aromatic solvents used are selected from the group comprising of benzene, toluene, xylenes, ethylbenzene or mixtures thereof.
According to the present invention, the, solvent .used in the extraction is recovered and reused in the process.
According to the present invention, the product obtained by the process of the present invention can be converted into desired physical forms by the processes known in the prior art.

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-(N,N-dimethylamino) pyridine (4-DMAP)
Boron trifluoride etherate (3-4 weight %) was charged in a round-bottom flask containing pyridine (500 g) and thionyl chloride (174 g) was added to this solution at 25-30 °C. The reaction mass was heated under reflux for 4 hours. After the reaction, dimethyl formamide (600 g) was added and the mixture was heated to reflux for 6-8 hours. The completion of reaction was monitored by TLC. After the completion of reaction, the mixture of pyridine and DMF was recovered. The concentrated reaction mass was cooled and basified with caustic lye solution, extracted with toluene, charcoalized, distilled and then crystallized to obtain 116 g white to off white crystals of 4-DMAP with 99.95% assay by GC. The recovered pyridine and DMF was kept aside for recycling. The product was confirmed by mass spectroscopy ancf 1H NMR.
ms:m/el21(M+); 1H NMR (CDCl3) δ 6.64-8.19 ppm (m, 4H, Ar); δ 2.62-2.99 ppm (s, 6H, CH3).
Example -2
A mixture of boron trifluoride etherate and aluminium chloride (3-4 weight %) was charged in a round-bottom flask containing pyridine (500 g) and thionyl chloride (174 g) was added to this solution at 25-30 °C. The reaction mass was heated under reflux for 4 hours. After the reaction, dimethyl formamide (600 g) was added and the mixture was heated to reflux for 6-8 hours. The completion of reaction was monitored by TLC. After the completion of reaction, the mixture of pyridine and DMF was recovered. The concentrated reaction mass was cooled and basified with caustic lye solution and
extracted with toluene. Toluene was recovered, frorn organic layer and concentrated mass
was distilled under reduced pressure to obtain, 122 g white to off white crystals of 4-
DMAP with 99.95% assay by GC. the recovered pyridine and DMF was kept aside for
recycling. The product was confirmed by mass spectroscopy and 1H-NMR.

Example -3
Synthesis of 4-(N,N-dimethylamino) pyridine by Using Recovered Raw Materials and solvent
Boron trifluoride etherate (3-4 weight %) was charged in a round-bottom flask containing recovered pyridine (1000 g) and fresh thionyl chloride (348 g) was added to this solution at 25-30 °C. The reaction mass was heated under reflux for 4 hours. After the reaction, recovered dimethyl formamide (1200 g) was added and the mixture was heated to reflux for 6-8 hour. The completion of reaction was, monitored by TLC. After the completion of reaction, the mixture of pyridine and DMF was recovered. The concentrated reaction mass was cooled and basified with caustic lye solution, extracted with toluene, charcoalized, distilled and then crystallized to obtain 230 g white to off white crystals of 4-DMAP with 99.9% assay by GC. The product was confirmed by mass spectroscopy and 'HNMR.
Example -4
Synthesis of 4-(N,N-diethylamino) pyridine
Aluminium chloride (3-4 weight %) was charged in a round-bottom flask containing pyridine (500 g) and thionyl chloride (174 g) was added to this solution at 25-30 °C. The reaction mass was heated under reflux for 4 hours. After the reaction, diethyl formamide (400 g) was added and the mixture was heated under reflux for 6-8 hours. The completion
of reaction was monitored by TLC. After the completion of reaction, the mixture of
pyridine and diethyliormamide was-recovered- The concentrated reaction mass was
cooled, the solution was basified with caustic lye solution, extracted with toluene,
charcoalized, distilled and then crystallized to give 142 g of the product with 99.95%
assay by GC. The recovered pyridine and diethylformamide was kept aside for recycling.
The product was confirmed by mass spectroscopy and 1HNMR.
ms:m/e49(M+); 1 H NMR (CDC13) δ 6.64-8.23 ppm (m, 4H, Ar); δ 2.98-3.19 ppm (q, 4H,
CH3); δ 0.99-1.12 (d,6H,CH3).

Example -5
Synthesis of 2-Chloro-4-(N,N-dimethylamino) pyridine
Aluminium trichloride (3-4 weight %) is charged in a round-bottom flask containing
pyridine (300g) and 2-Chloropyridine (200g). To this mixture thionyl chloride (174 g) is
added at 25-30 °C. The reaction mass is heated under reflux for 4 hours. After the
reaction, dimethylformamide (600 g) is added and the mixture is heated to reflux for 6-8
hour. The completion of reaction is monitored by TLC. The concentrated reaction mass is
cooled, the solution basified with caustic lye solution, extracted with toluene,
charcoalized, distilled and then crystallized to give the product.
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.

We claim:
1. A process for producing 4-aminopyridine compound of formula (I) or salts
thereof,
(Formula Removed)
wherein, R1 and R2 are independently selected from the group consisting of hydrogen, and C1-C8 alkyl
R3 is independently selected from the group consisting of hydrogen, carboxyl, hydroxyl, halogen, -NO2, -CN, C1-C6-alkyl or optionally substituted heteroaryl
m can be any integer between 1 to 4
the process comprising quaternizing pyridine compound of formula (II) in presence of a catalyst followed by conversion of the resultant quaternized compound by treating with aldehyde compound of formula (III) to the 4-aminopyridine compound of formula I or salts thereof

wherein R1, R2, R3 and m are defined above.
2. The process according to claim 1, wherein the conversion of quaternized
compound is performed by treating the quaternized compound with aldehyde compound
of formula (III)
(Formula Removed)
wherein R1 and R2 are defined above,
under conditions effective to produce crude 4-aminopyridine compound of formula I, and recovering the pure 4-aminopyridine compound of formula I or salts thereof from the crude product.
3. The process according to claim 2, wherein the recovery of pure 4-aminopyridine compound of formula I or salts thereof is performed employing distillation of crude 4-aminopyridine compound of formula I.
4. The process according to claim 2, wherein the recovery of pure 4-aminopyridine compound of formula I or salts thereof is performed employing a solvent.
5. The process according to claim 1, wherein the quaternization is performed using quaternizing agent selected from the group comprising of thionyl chloride, methyl halides, ethyl halides, propyl halides, benzyl chloride and benzyl bromide.
6. The process according to claim 1, wherein the quaternization is performed in the absence of a solvent.
7. The process according to claim 1, wherein the catalyst is ion of and/or compound of metal selected from Group VIII-XVI of the periodic table.
8. The process according to claim' 7, wherein the catalyst is lewis acid.
9. The process acccording to claim 8, wherein the lewis acid is selected from
the group comprising of broron trifluoride, aluminium trichloride, aluminium tribromide,
silicon tetrachloride, tetrafluorosilane, carbon dioxide, sulphur dioxide and halides of
Ag+, Cu2+, Fe2+ and Fe3+ or mixtures thereof.
10. The process according to claim 1, wherein the unreacted pyridine
compound of formula (II) and aldehyde compound of formula (III) are recyclable.