Title of Invention

"IMPROVED PROCESS FOR PRODUCING 4-DIMETHYL AMINO PYRIDINE (4-DMAP)"

Abstract

This invention relates to an improved process for producing 4-Dimethyl amino pyridine whereby quaternizing pyridine with a suitable quaternizing agent in presence of organic solvent is performed, isolating the salt and animating the salt, N-[4-Pyridyl] pyridinium chloride hydrochloride with N,N-Dimethyl formamide is followed. The resultant reaction mass is hydrolysed in presence of a base, extracted with suitable organic solvent & distilled under vacuum to produce 4-Dimethyl amino pyridine.

Full Text

IMPROVED PROCESS FOR PRODUCING 4-DIMETHYL AMINO PYRIDINE (4-DMAP) 1. Field of the Invention This invention in general relates to a process for producing 4-Dimethyl amino pyridine (4-DMAP). More particularly, this invention relates to an improved process for producing large quantities of 4-Dimethyl amino pyridine (4-DMAP). 2. Background of the Invention 4-Dimethyl amino pyridine (C7HioN2) belongs to the category of 4-position substitution derivatives of pyridine. It is widely used as a hypernucleophilic acylation catalyst. 4-Dimethyl amino pyridine is a highly efficient catalyst for acylation reactions as compared to other traditional acylation catalytic agents due to its effectiveness, cost efficiency and long time efficiency property. Several processes are known for the preparation of 4-Dimethyl amino pyridine. The known processes differ from each other in respect of different process chemistry followed. U. S. Patent No. 4,220,785 to Oude Alink, et al. discloses the substituted pyridines prepared by reacting aldehydes, amines, lower carboxylic acids such as acetic acid in the presence of oxygen. The N-substituted pyridinium salts formed is then converted to pyridines by thermal dealkylation. U. S. Patent No. 4,158,093 to Baily et al. discloses a process in which 4-substituted pyridine base is first quaternized with 2-vinyl pyridine in presence of a strong acid to give a pyridyl ethyl quaternery salt. This activated quaternery salt is subjected to nucleophilic substitution at 4- position and then dequaternized in presence of sodium hydroxide. U.S. Patent No. 4,672,121 and U.S. Patent No. 4,772,713 to Nummy et al. disclose a process for preparing a 4-substituted pyridine product from a starting pyridine substituted in the 4-position by a leaving group susceptible to nucleophilic displacement when the starting pyridine is quaternized, the process comprises, quaternizing the starting pyridine, with acrylamide, N-monoalkylacrylamide or N-dialkylacrylamide under effective acidic conditions; subjecting the resultant, corresponding quaternized starting pyridine to a nucleophilic displacement reaction with a reagent which reacts to produce the corresponding 4-substituted pyridine; and dequaternizing the latter under effective basic conditions to liberate the desired 4-substituted pyridine product. An article authored by Xi Guan Gen et al. published in Chemical Reagent, 1998, 20(2), 119-120 discloses a process, in which pyridine is quaternized with thionyl chloride (SOCh) in presence of ethyl acetate, and then aminating the resulting salt N-[4-Pyridyl]pyridinium chloride hydrochloride with N,N-Dimethyl formamide. The resulting reaction mass is hydrolysed in presence of a base, and extracted with Chloroform. This is an improved process compared to the one disclosed in the Chinese article authored by Li Bao Qing, the Department of Chemical Industry, Costume Academy, Beijing 100029. A significant problem in the prior art processes is that of the formation of highly hazardous/unsafe by-products like hydrogen cyanide and sodium cyanide, which is very unsafe to handle at laboratory as well as at commercial scale manufacture. Also, costlier raw materials like cyanopyridine and vinyl pyridine were used in the process. Most of these problems have been well addressed by Xi Guan Gen et al. However, the processing of reaction mass involves many undesired steps. Also the product quality & yield is not found satisfactory, so the process was not found suitable for industrial applications. Therefore there was the need to devise an improved process for producing 4-Dimethyl amino pyridine especially suitable for large-scale manufacture. Large-scale manufacturing requires the production of title compound in a cost efficient manner. This lead to the enquiry for an improved process for producing the title compound with high purity and with a better yield. Also one of the concerns with respect to the present invention is to provide a process for producing 4-DMAP wherein no hazardous byproducts are formed and hence the process is suitable for industrial use. Also, the known methods do not address recoverability and recyclablity of the byproducts. Known processes are not techno-economically viable. The product quality/yield could be higher, thus making the process unviable for industrial application. It is therefore important and essential to develop a suitable process addressing all the above-mentioned problems in the known prior art. 3. Summary of the Invention Accordingly, we have sought to devise an improved process for the preparation of 4-Dimethyl amino pyridine, the process devised to produce high yields and quality products, which are free of disadvantages and complications associated with processes heretofore disclosed. The achievements of these objectives will be made apparent in the description that follows. It is a principal aspect of the present invention to provide for an improved process for the manufacture of 4-Dimethyl amino pyridine by first quatemizing pyridine with a suitable quatemizing agent, thionyl chloride, in presence of an organic solvent, ethyl acetate and then aminating the resulting salt N-[4-Pyridyl]pyridinium chloride hydrochloride with N,N-Dimethyl formamide. The resulting reaction mass is hydrolysed in presence of a base, extracted with suitable aromatic solvent, wherein the preferred solvent is benzene, and distilled under vacuum employing fractionating column to give 4-Dimethyl amino pyridine with excellent quality and yield. In yet another aspect, the present invention is addressed at an improved process for producing 4-Dimethyl amino pyridine, the process provides for the recovery of ethyl acetate having unreacted thionyl chloride and pyridine, during salt formation and recycling the same. The process comprises quaternizing the recovered pyridine with thionyl chloride in presence of recovered ethyl acetate having unreacted thionyl chloride to achieve 641.0 gm N-[4-Pyridyl]pyridinium chloride hydrochloride with 52.1% yield and 94.99% assay and then aminating the resulting salt with N,N-Dimethyl formamide. The resulting reaction mass is hydrolysed in presence of a base, extracted with benzene & distilled under vacuum to give 4-Dimethyl amino pyridine with the desired quality and yield. In still another aspect of the present invention, a process for producing 4-Dimethyl amino pyridine has been provided. The improved process comprises refluxing N-[4-Pyridyl] pyridinium chloride hydrochloride (641.0 gm, % assay 94.99, 2.657 mole) with N,N-Dimethyl formamide (421 gm, 99% min. assay, 5.709 mole) for 2-3 hrs. After completion of the reaction, pyridine is distilled off. The resultant reaction mass is hydrolysed in presence of a base and extracted with benzene. The reaction mass thus obtained upon extraction is distilled under vacuum employing fractionating column to get the desired results, i.e. high yield with high quality. 4. Detailed Description of the Invention The preferred embodiment of the present invention deals with the process for the preparation of 4-DMAP, which has an advantage from prior art processes in avoiding formation of hazardous byproducts, effective recycling of raw materials, use of industrially suitable solvents and elimination of undesired processing steps to make it comparatively safe and more cost effective. The major raw materials viz. pyridine and thionyl chloride and organic solvents ethyl acetate, ethyl alcohol and aromatic solvents like toluene, benzene etc. are well known compounds and are easily available. In one embodiment of the present invention, a process for producing 4-Dimethyl amino pyridine has been provided. The process comprises charging initially ethyl acetate and pyridine, one by one, under agitation, maintaining the pot temp, at 25±5 deg.c. Now, thionyl chloride is charged gradually maintaining temp, below 35 deg.c. After the addition, the reaction mass is refluxed for 4 hours at 77-80 deg.c. After refluxing, the ethyl acetate and unreacted thionyl chloride are distilled off at atmospheric pressure. Finally, mild vacuum (400-600 mm Hg) is applied to ensure maximum recovery of ethyl acetate and thionyl chloride. Left over reaction mass is cooled to 40 deg.c. Now, anhydrous ethyl alcohol is added slowly maintaining temp, below 60 deg.c. Resulting reaction mass is stirred well, then cooled up to 10 deg.c. and filtered, washed with anhydrous ethyl alcohol and dried under vacuum to get desired salt N-[4-Pyridyl] Pyridinium chloride hydrochloride. Mother liquor obtained after filtration is first atmospherically distilled to recover ethyl alcohol & then hydrolysed with caustic lye solution followed by extraction with benzene & then fractional distillation to recover benzene & pyridine, which can be recycled back in the process. In one another embodiment of the present invention the process described as above, obtained salt N- [4-Pyridyl] pyridinium chloride hydrochloride is aminated by N, N-Dimethyl formamide. The process comprising, salt N-[4-Pyridyl] pyridinium chloride hydrochloride & N,N-Dimethyl formamide are charged one by one . Reaction mass is slowly heated to raise the temp, to 50-60 deg.c. The agitator is started and reaction mass is further slowly heated to reflux temp. 140-150 deg.c. Reflux is continued for 2 hours at 150-155 deg.c. After 2 hours of refluxing, reaction mass is distilled first atmospherically and then under vacuum to recover pyridine to a maximum possible extent. The reaction mass is cooled upto 40 deg.c. and then hydrolysed by adding 10% caustic lye solution, maintaining pH 11-12. Neutralised reaction mass is further cooled to 20 deg.c. and precipitated inorganic cake is filtered off. The mother liquor is extracted with benzene in a 3 multiple steps to ensure almost complete extraction. The extracted reaction mass is distilled atmospherically and then under vacuum to recover benzene. The crude 4-DMAP left in the pot is distilled under high vacuum employing fractionating column to get white to off white crystals of 4-DMAP in high yield & purity. The present invention is illustrated below with reference to the following examples: Examplel Preparation of N-[4-Pyridyl]pyridinium chloride hydrochloride: Ethyl acetate (1127.5 g) and pyridine (807.0 g) were charged in a 5 litre round bottom flask fitted with thermowell & double surface condenser. To this was gradually added thionyl chloride (1019.37 g) maintaining temperature 25±5 deg.c. Reaction mass was slowly heated to reflux temp. (77-80 deg.c.) and refluxing was maintained for 4 hours. After the reaction, ethyl acetate and unreacted thionyl chloride were distilled off. Anhydrous ethyl alcohol (1000 ml) was added to the left over mass at 40-60 deg.c. Vigorous stirring was done till yellow brownish colour solid was precipitated out after cooling to 10-20 deg.c. Precipitated mass was filtered and washed with ethyl alcohol. Wet salt was dried at 60-70 deg.c. under vacuum to get N-4[Pyridyl] pyridinium chloride hydrochloride 636.0 g, % assay 96.5 (acidimetry), % yield 52.50 based on pyridine charged. Mother liquor was distilled to recover ethyl alcohol which can be recycled back in the process. The left over mass was hydrolysed with dil. caustic lye solution and then extracted with benzene. Extracted mass was fractionally distilled to recover benzene and pyridine, which can be recycled back in the process. Example Preparation of N-K-Pyridvllpyridinium chloride hvdrochloride by using recovered raw materials: Recovered ethyl acetate (1127.5 g) and recovered pyridine 1 degree (807.0 g) were charged in a 5 litre round bottom flask fitted with thermowell & double surface condenser. To this was gradually added thionyl chloride (1019.37 g) maintaining temperature 25±5 deg.c. Reaction mass was slowly heated to reflux temp. (77-80 deg.c.) and refluxing was maintained for 4 hours. After the reaction, ethyl acetate and unreacted thionyl chloride were distilled off. Anhydrous ethyl alcohol (1000 ml) was added to the left over mass at 40-60 deg.c. Vigorous stirring was done till yellow brownish colour solid was precipitated out after cooling to 10-20 deg.c. Precipitated mass was filtered and washed with ethyl alcohol. Wet salt was dried at 60-70 deg.c. under vacuum to get N-4[Pyridyl] pyridinium chloride hydrochloride 641.0 gm, %assay 94.99, % yield 52.1. Mother liquor was distilled to recover ethyl alcohol which can be recycled back in the process. The left over mass was hydrolysed with dil. caustic lye solution and then extracted with benzene. Extracted mass was fractionally distilled to recover benzene and pyridine, which can be recycled back in the process. Example3 Dequaternization of N-f4-Pyridyl1 pyridinium chloride hydrochloride N-[4-Pyridyl] pyridinium chloride hydrochloride (641.0 gm, % assay 94.99, 2.657 mole) and N,N-Dimethyl formamide (421 gm, 99% assay, 5.709 mole) were charged in a 2 litre round bottom flask fitted with stirrer, thermometer pocket and double surface condenser. Reaction mass was slowly heated to reflux temperature (150-155 deg.c.) and refluxing continued for 2-3 hours. After the completion of reaction, pyridine was distilled off. The reaction mass was hydrolysed with 10% caustic lye solution (approx. 2846 ml) to maintain the pH 10-12. The hydrolysed mass was cooled to 20 deg.c. and then filtered to get a clear aqueous mother liquor (3540.0 gm). The mother liquor was extracted with benzene (1770 g x 1 and 885 g x 3). Aqueous phase was disposed off. Total organic extracts were taken for benzene recovery. After benzene recovery (4181.6 gm, 94.5% recovery) 4-DMAP was distilled under vacuum employing fractionating column. 4-DMAP, 211.5 g, 65.05 mole% yield, (based on net double pyridine salt charged) and 99.85% assay by G.C. obtained. Example 4 (Comparative) Preparation of 4-Dimethyl amino pyridine by using chloroform for extraction: N-[4-Pyridyl] pyridinium chloride hydrochloride (641.0 gm, % assay 94.99, 2.657 mole) and N,N-Dimethyl formamide(421 gm, 99% assay, 5.709 mole) were charged in a 2 litre round bottom flask fitted with stirrer, thermometer pocket and double surface condenser. Reaction mass was slowly heated to reflux temperature (150-155 deg.c.) and refluxing continued for 2-3 hours. After the completion of reaction, pyridine was distilled off. The aqueous mother liquor obtained after alkaline hydrolysis and filtration was extracted with chloroform (2940 g x 1) and (1470 g x 3). Lot of emulsion was observed after extraction, which creates problem in layer separation. Total organic phase was taken for chloroform recovery. After chloroform recovery (6394.5 gm, 87.0% recovery), 4-DMAP was distilled under vacuum employing fractionating column. 4-DMAP, 208.5 g, 63.83 mole% yield based on net double pyridine salt charged and 99.38% assay achieved. Recovery of chloroform was less as compared to benzene. Example 5 (Comparative) Preparation of 4-Dimethvl amino pyridine: N-[4-Pyridyl] pyridinium chloride hydrochloride (641.0 gm, % assay 94.99, 2.657 mole) and N,N-Dimethyl formamide(421 gm, 99% assay, 5.709 mole) were charged in a 2 litre round bottom flask fitted with stirrer, thermometer pocket and double surface condenser. Reaction mass was slowly heated to reflux temperature (150-155 deg.c.) and refluxing continued for 2-3 hours. After the completion of reaction, pyridine was distilled off. The aqueous mother liquor obtained after alkaline hydrolysis and filtration was extracted with chloroform (2940 g x 1) and (1470 g x 3). Lot of emulsion was observed after extraction, which creates problem in layer separation. After extraction with chloroform, organic phase was separated out and treated with charcoal for shedding off colour impurities. Light yellow mother liquor was taken for chloroform recovery. After chloroform recovery 700.0 gm ethyl acetate was added for the crystallization of crude 4-DMAP. After cooling to 0 deg.c., followed by filtration, 180 g 4-DMAP, with 98.97% assay by G.C, and 54.88% yield achieved. This clearly indicates that in spite of additional steps involved, yield and assay of the 4-DMAP is also less as compared to process followed in the present invention. Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims. We Claim: 1. A process for producing 4-dimethyl amino pyridine comprising: quaternizing pyridine using a quatemizing agent in the presence of an organic solvent to form a salt; isolating the salt; animating the salt employing an animating agent to produce an organic mass; extracting the organic mass using an aromatic solvent; and distilling the extracted organic mass to produce 4-dimethyl amino pyridine. 2. The process according to claim 1, wherein the quaternizing agent is thionyl chloride. 3. The process according to claim 1, further comprising recovering the organic solvent by distillation. 4. The process according to claim 3, wherein the organic solvent is ethyl acetate. 5. The process according to claim 1, wherein the salt formed is N- [4-pyridyl] pyridinium chloride hydrochloride. 6. The process according to claim 1, wherein the animating agent is N,N-dimethyl formamide. 7. The process according to claim 1, further comprising recovering unquaternized pyridine during isolation of the salt. 8. The process according to claim 1, wherein the extracted organic mass is distilled using a fractionating column. 9. A process for producing 4-dimethyl amino pyridine according to claim 1, the process comprising: quaternizing pyridine using thionyl chloride in the presence of ethyl acetate to form N-[4-pyridyl] pyridinium chloride hydrochloride; isolating N-[4-pyridyl] pyridinium chloride hydrochloride in the presence of ethyl alcohol; animating the N-[4-pyridyl] pyridinium chloride hydrochloride employing N,N-dimethyl formamide; hydrolyzing the resultant organic mass in the presence of a base; extracting the organic mass using an aromatic solvent; and distilling the extracted organic mass first atmospherically and then under vacuum to produce 4-dimethyl amino pyridine. 10. The process according to claim 9, further comprising recovering the aromatic solvent during the distillation. 11. The process according to claim 10, wherein the aromatic solvent is benzene. 12. The process according to claim 9, further comprising recovering ethyl acetate. 13. The process according to claim 9, further comprising recovering unquaternized pyridine during the isolation of the N-[4-pyridyl]pyridinuim chloride hydrochloride.

Documents:

1197-del-2002-abstract.pdf

1197-del-2002-claims.pdf

1197-del-2002-correspondence-others.pdf

1197-del-2002-correspondence-po.pdf

1197-del-2002-description (complete).pdf

1197-del-2002-form-1.pdf

1197-del-2002-form-13.pdf

1197-del-2002-form-19.pdf

1197-del-2002-form-2.pdf

1197-del-2002-form-26.pdf

1197-del-2002-form-3.pdf

1197-del-2002-form-5.pdf

1197-del-2002-petition-138.pdf