Title of Invention

"PROCESS FOR PRODUCING ALKOXY NICOTINIC ACID"

Abstract

The present invention relates to a novel single pot process for producing alkoxy nicotinic acid of formula (I) from corresponding hydroxy nicotinic acid. The process includes reaction of hydroxy nicotinic acids with dialkyl sulphate in the presence of a base and water and hydrolyzing the resulting ester in situ using dilute alkali hydroxide in presence of solvent to obtain alkoxy nicotinic acid of formula (I). Recovery and reuse of the organic solvent is also disclosed in the present invention.

Full Text

Field of the Invention This invention in general relates to a process for producing nicotinic acid derivatives. More particularly, the present invention provides for a novel single pot process for producing alkoxy nicotinic acid by alkylation of hydroxy nicotinic acid employing a suitable alkylating agent and an inorganic base. Background of the Invention Nicotinic acid is a pyridine derivative used in the manufacture of several important medicinal preparations, including vitamin RR, cordiamine, nicodan, ethiacine, etc. Further uses are also arising for the acid and its derivatives in agriculture and stock-raising. Alkoxy nicotinic acid belongs to the category of alkoxyi derivatives of nicotinic acid. It is widely used as a bulk drug intermediate. Several processes are known for the preparation of pyridine derivatives. The known processes differ from each other in respect of different process chemistry followed. EP 1250340 discloses the process for the preparation of 6-methoxypyridine-2-carboxylic acid and 5-methoxynicotinic acid. The process comprises reacting 6-hydroxy picolinic acid with silver oxide and methyl iodide and hydrolyzing the ester thus formed with alkali solution and solvent such as tetrahydrofuran. ;• Also, a process is reported in which 5-hydroxy nicotinicjiacid methyl ester, is reacted with sodium hydride in dimethyl formamide along with methyl iodide and hydrolyzing the alkoxy ester thus obtained in alkali solution and organic solvent. An article authored by L.W. Deady, O.L. Korytsky and J.E. Rowe (Australian Journal of Chemistry, 1982, 35, 2025-34) discloses, a process in which halo pyridine is alkoxylated by using sodium metal in methanol (solution of sodium in methanol). The process includes heating of halopyridine along with sodium metal in methanol in a sealed tube at high temperature for several hours and product was isolated by adjusting pH followed by extraction and evaporation in the form of residue, which was re-crystallized using 1:1 solution of benzene: light petroleum. However, the product obtained by this process was in low yield. The processes disclosed in the prior art used sodium metal and sodium hydride for the preparation of alkoxy nicotinic acid. These compounds are highly unsafe to handle in laboratory scale as well as in a commercial scale manufacturing processes. Moreover, raw materials viz, silver oxide, dimethyl formamide and methyl iodide used in the process are very expensive. Therefore, there is a need to develop a commercially feasible process for producing alkoxy nicotinic acid using commercially viable raw materialsjito avoid all the above-mentioned problems in the known prior art. Summary of the Invention It is the principal aspect of the present invention to provide a novel single-pot and commercially feasible process for producing alkoxy nicotinic acid of formula (I) from corresponding hydroxy nicotinic acid of formula (II) employing suitable alkylating agent and an inorganic base. According to the preferred embodiment of the present invention, there is provided a process for producing alkoxy nicotinic acid of formula (I), wherein the process comprises treating the hydroxy nicotinic acid of formula (II) witih dialkyl sulphate in presence of inorganic base in water at 0°C to 40°C to form alkojxy nicotinic acid alkyl ester and hydrolyzing the same in situ with dilute inorganic base, water and appropriate organic solvent to obtain corresponding alkoxy nicotinic acid of'formula (I). According to another preferred embodiment of the present invention, there is provided a process for producing alkoxy nicotinic acid of formula (I), wherein the organic solvent used in hydrolyzing step is separated through layer separation and reused in the process.Detailed Description of the Invention The disclosed embodiment of the present invention deals with a process for the preparation of alkoxy nicotinic acid that has advantage the process avoids handling of unsafe raw materials and also effectively recycle the raw materials used in the process. Moreover, the present process involves utilization of industrially suitable solvents and elimination of undesired processing steps to make it comparatively safe and more cost effective. The process disclosed in the present invention provides a single pot process for the preparation of alkoxy nicotinic acid from corresponding hydroxy nicotinic acid, the process comprising alkylation of hydroxy nicotinic acid of formula (II), (Formula Removed) where, a) R1 represents OH, and R2, R3, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; b) R2 represents OH, and R1, R3, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; c) R3 represents OH, and R1, R2, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; d) R4 represents OH, and R1, R2, and R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl group. The alkylation is carried out with an alkylating reagent and inorganic base in water at 0°C to 40°C. The reaction is followed by hydrolysis of alkoxy nicotinic acid alkyl ester with dilute inorganic base, water and appropriate organic solvent to obtain corresponding alkoxy nicotinic acid of formula (I), (Formula Removed) where, a) R1 represents OR, wherein R is selected from methyl or ethyl group and R2, R3, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; b) R2 represents OR, wherein R is selected from methyl or ethyl group and R1, R3, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; c) R3 represents OR, wherein R is selected from methyl or ethyl group and R1, R2, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; d) R4 represents OR, wherein R is selected from methyl or ethyl group and R1, R2, and R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; The said process comprises reacting hydroxy nicotinic acid preferably with alkali base in water at temperature range between 20-40°C; cooling the reaction mass to 0 to 15°C, adding dialkyl sulphate to obtain alkoxy nicotinic acid alkyl ester; hydrolyzing alkoxy nicotinic acid alkyl ester using alkali hydroxide, water and organic solvent at temperature ranging between 15- 40°C; separating the organic solvent layer and adjusting the pH of the aqueous solution to maintain the pH in the range of 2 - 4 to obtain the solid product; purifying the resulting mass to obtain alkoxy nicotinic acid with high purity. The dialkyl sulphate used in the process is selected from dimethyl sulphate or diethyl sulphate and the inorganic base is selected from the group comprising of alkali metal hydroxides and carbonate most preferable sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. ydrolysis of alkoxy nicotinic acid alkyl ester is carried out in employing organic solvent preferably tetrahydrofuran or dioxan followed by hydrolysis with sodium hydroxide solution and water at ambient temperature which resulted in the formation of sodium salt of alkoxy nicotinic acid. This sodium salt of the alkoxy nicotinic acid is highly soluble in aqueous layer and thus the organic layer, which is highly miscible in water, separates out. This ensures the complete removal of organic layer from aqueous layer without any additional workup. The sodium salt of alkoxy nicotinic acid obtained is then converted to corresponding nicotinic acid by adding mineral acid to bring the pH to 2-4. The resulting product obtained is collected as solid material. The present invention is further illustrated below with reference to the following examples with out intending to limit the scope of the present invention in any manner. Example-1 Preparation of 6-methoxy nicotinic acid Potassium hydroxide (30.2 gm) and water (75 ml) were charged into a round bottom flask fitted with thermowell and air condenser. To this was charged 6-hydroxy nicotinic acid (25.0 gm) while maintaining temperature at 25°C. The reaction mass was cooled to 10°C. To this reaction solution dimethyl sulphate (56.6 gm) was added. The reaction mixture was stirred for half an hour and then heated upto 25 °C and further stirred. The TLC was used to test the end of the reaction using solvent system (methanol:ethyl acetate :: 1:1). Tetrahydrofuran (750 ml) was added to the reaction mass followed by addition of aqueous sodium hydroxide solution (350 ml) along with water (85.0 ml). Stirring was continued for 4 hrs. The TLC was used to test the end of reaction. Organic layer (750 ml) was separated and kept aside for recycling. Aqueous layer was cooled to 5°C, pH adjusted to 2 - 4 by using 18% hydrochloric acid solution at 5°C. The white precipitate obtained, was filtered and washed with water. To the wet cake was charged water (250 ml) at 25°C. The reaction mass was slowly heated to reflux temperature. The activated charcoal (2.5 gm) was charged in homogenous solution and the reflux was maintained for 1 hr. The reaction mass was filtered while hot through hyflo bed, which was then washed with water (10 ml). The filtrate was then cooled to get solid. The cake was filtered with chilled water. Wet cake o was dried at 60 - 65 C under vacuum for 8 -10 hrs to give 6-methoxy nicotinic acid (25.1 gin). The yield of 6-methoxy nicotinic acidwas 93% and the HPLC purity was >99%. Product confirmed by mass spectroscopy and melting point (240 to 242°C). Example-2 Preparation of 6-methoxy nicotinic acid by using recovered tetrahydrofuran (THF) Potassium hydroxide (30.2 gm) and water (75 ml) were charged into a round bottom flask fitted with thermowell and air condenser. To this was charged 6-hydroxy nicotinic acid (25.0 gm) while maintaining temperature at 25°C. The reaction mass was cooled to 10°C. To this reaction solution dimethyl sulphate (56.6 gm) was added. The reaction mixture was stirred for half an hour and then heated upto 25 °C and further stirred. The TLC was used to test the end of the reaction using solvent system (methanol:ethyl acetate :: 1:1). To the reaction mixture tetrahydrofuran (750 ml) recovered from Example 1 was added, followed by addition of aqueous sodium hydroxide solution (350 ml) along with water (85.0 ml). Stirring was continued for 4 hrs. The TLC was used to test the end of reaction. Organic layer (750 ml) was separated and kept aside for recycling. Aqueous layer was cooled to 5°C, pH adjusted to 2 - 4 by using 18% hydrochloric acid solution at 5°C. The white precipitate obtained, was filtered and washed with water. To the wet cake was charged water (250 ml) at temperature 25°C. The reaction mass was slowly heated to reflux temperature. The activated charcoal (2.5 gm) was charged in homogenous solution and the reflux was maintained for 1 hr. The reaction mass was filtered while hot through hyflo bed, which was then washed with water (10 ml). The filtrate was then cooled to get solid. The cake was filtered with chilled water. Wet cake was dried at 60 - 65°C under vacuum for 8 -10 hrs to give 6-methoxy nicotinic acid (25.1 gm). The yield of 6-methoxy nicotinic acid was 93% and the HPLC purity was >99%. Product confirmed by mass spectroscopy and melting point (240 to 242°C). 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 alkoxy nicotinic acid of formula (I) comprising reacting hydroxy nicotinic acid of formula (II) with dialkyl sulphate in the presence of an inorganic base and water to prepare an alkoxy nicotinic acid alkyl ester, hydrolyzing the alkyl ester in situ with alkali hydroxide, water ana organic solvent, separating the organic solvent layer through layer seperation and purifying the resulting reaction mass to obtain alkoxy nicotinic acid of formula (I), wherein in the alkoxy nicotinic acid of formula (I): (Formula Removed) a) R1 represents OR, R is selected from methyl or ethyl group and R2, R3, and I R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; a) R1 represents OH, and R2, R3, and R4 is selected from hydrogen, straight chain or branched alkyl group; b) R2 represents OR, R is selected from methyl or ethyl group and R1, R3, and R4 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; c) R3 represents OR, R is selected from methyl or ethyl group and R1, R2, and R4 is selected from hydrogen, C1-C4straight chain or branched alkyl group; d) R4 represents OR, R is selected from methyl or ethyl group and R1, R2, and R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl group; and wherein in the hydroxy nicotinic acid of formula (II): (Formula Removed) e) R2 represents OH, and R1, R3, and R4 is selected from hydrogen, straight chain or branched alkyl group; f) R3 represents OH, and R1, R2, and R4 is selected from hydrogen, straight chain or branched alkyl group; g) R4 represents 'OH, and R1, R2, and R3 is selected from hydrogen, C\- straight chain or branched alkyl group; 2. The process as claimed in claim 1, wherein the dialkyl sulphate is dimethyl sulphate or diethyl sulphate. 3. The process as claimed in claim 1, wherein the inorganic base is a hydroxide or carbonate of alkali metal. 4. The process as claimed in claim 3, wherein the alkali metal is sodium or potassium. 5. The process as claimed in claim 1, wherein the organic solvent is water miscible cyclic ether. 6. The process as claimed in claim 5, wherein the organic solvent is selected from tetrahydrofuran or dioxane. 7. The process as claimed in claim 1, wherein said alkali hydroxide is selected from potassium hydroxide or sodium hydroxide. 8. The process as claimed in claim 1, wherein the organic solvent is recyclable. 9. A process for producing alkoxy nicotinic acid of formula (I) substantially as herein described with reference to the examples.

Documents:

1898-del-2004-abstract.pdf

1898-del-2004-claims.pdf

1898-del-2004-correspondence-others.pdf

1898-del-2004-correspondence-po.pdf

1898-del-2004-description (complete).pdf

1898-del-2004-form-1.pdf

1898-del-2004-form-19.pdf

1898-del-2004-form-2.pdf

1898-del-2004-form-26.pdf

1898-del-2004-form-3.pdf

1898-del-2004-form-5.pdf

1898-del-2004-petition-137.pdf

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