Title of Invention	"PROCESS FOR PRODUCING 4-AMINO-3, 5-DIHALOPYRIDINE-N-OXIDE"
Abstract	Disclosed herein a novel process for producing 4-amino-3,5-dihalopyridine-N-oxide from 4-aminopyridme. The process comprises halogenation of 4-aminopyridine followed by oxidation with suitable oxidizing agent.

Full Text

PROCESS FOR PRODUCING 4-AMINO-3, 5-DIHALOPYRIDINE-N- OXIDE FIELD OF THE INVENTION This invention, in general, relates to the process for production of 4-amino-3,5-dihalopyridine-N-oxide. More specifically, but without restricting to the particular embodiments hereinafter described in accordance with the best mode of practice, this invention relates to a novel way to produce 4-amino-3,5-dihalopyridine-N-oxide by the halogenation of 4-aminopyridine followed by oxidation. BACKGROUND OF THE INVENTION 4-Amino-3,5-dihalopyridine-N-oxide is an intermediate in the preparation of furopyridines, ben/.ofuran-4-carboxamides and indole-N-oxides, which are useful for inhibiting the production or physiological effects of tumor necrosis factor and inhibiting cyclic-AMP phosphodiesterase. 4-Amino-3,5-dihaloopyridine-N-oxide is used as an intermediate for the preparation of some dibenzofuran/diben/othiophene derivatives which are useful for the treatment of inflammatory and allergic disorders, insulin resistant diabetes and diseases of the central nervous system. Prior arts disclose different conventional methods for the preparation of 4-amino-3,5-dihalopyridine-N-oxide. Pandler et al. in J. Org. Chem., 48, 1064-1068 (1983) has reported the preparation of 4-amino-3,5-dibromopyridine-N-oxide by the bromination of 4-arninopyridine-N-oxide. The yield of the product reponed is 34% along with 61% of 4-amino-3-bromo-pyridine-N-oxide as a side product. Tadeusz et al. in Prace Naukowe Akademii Ekonomicznej imienia Oskara Langego we Wroclawiu (Russian), 238, 97-106 (1983) discloses the preparation of 4-amino-3,5-dichloropyridine-N-oxide from 4-acylaminopyridine-N-oxide by chlorination. 4-Acylaminopyridine-N-oxide in turn can be prepared by selective reduction followed by acylation of 4-nitropyridine-N-oxide as reported by Undheim et al. in Acta Chemica Scand. B, 28, 743-749 (1974). However there are some disadvantages of these processes as they involve various steps, side products are formed and the final product is obtained in very low yield. Chambers et al. in J. Chem. Soc., Perkin Trans. 1, 1705 (1998) discloses the synthesis of 4-amino-3,5-dichloropyridine-N-oxide from 3,5-dichloropyridine in 20.4 mole % yield, by N-oxidation, nitration and amination. This process involves several steps and product obtained was in very low yield, thereby making the process unattractive. Disclosed prior arts provide the process for the preparation of 4-amino-3,5-dihalopyridine-N-oxide by multi step process involving protection followed by de-protection of the functional groups, resulting into lower yields and economically unattractive processes. Therefore, there is a need to develop a process for producing 4-amino-3,5-dihalopyridine-N-oxide, which overcomes all the disadvantages associated with the processes disclosed in the known prior art. Present invention provides a process for preparing 4-amino-3,5-dihalopyridine-N-oxide from 4-amino pyridine, which is an easily available and cheaper starting material. Moreover, the synthesis involves only two steps and the product yield is much higher compared to any processes reported in prior art. SUMMARY OF THE INVENTION It is, therefore, a principal aspect of the present invention to provide a novel process for producing 4-amino-3,5-dihalopyridine-N-oxide which overcome the limitations reported in the prior art. These and other objects are attained in accordance with the present invention wherein there is provided several embodiments of the process for producing 4-amino-3,5-dihalopyridine-N-oxide by using 4-aminopyridine. In one preferred embodiment of the present invention there is provided a novel process for producing 4-amino-3,5-dihalopyridine-N-oxide wherein the process comprises oxidizing 4-ammo-3,5-dihalopyridin with aqueous hydrogen peroxide in acidic medium. In another preferred embodiment of the present invention there is provided a novel process for producing 4-arnino-3,5-dihalopyridine-N-oxide, wherein the process comprises of oxidation of 4-amino-3,5-dihaopyridine in a single step with good yield and selectivity. In yet another preferred embodiment of the present invention there is provided a novel process for producing 4-arnino-3,5-dihalopyridine-N-oxide, wherein the unreacted raw material is recovered and lecycled in the process. DETAILED DESCRIPTION OF THE INVENTION The disclosed embodiment of the present invention deals with a process for the preparation of 4-amino-3,5-dihalopyridine-N-oxide that has the advantage oi involvement of two steps and also effectively recycling of the raw materials used in the process. 4-Amino-3,5-dihalopyridine-N-oxide of formula (III) is prepared by the oxidation of corresponding 4-amino-3,5-dihalopyridine of formula (II) with hydrogen peroxide in acidic medium as described in Scheme I. NHn (Scheme Removed) Scheme I where Xi =\2, represents F, Cl or Br. The oxidant used in the process is prepared in situ from aqueous hydrogen peroxide and an organic acid preferably acetic acid. The concentration of aqueous hydrogen peroxide in the reaction mass is 4-20 % (w/w), preferably 5-14% (w/w), most preferably 6-9%(w/w). The process according to the present invention comprises the addition of hydrogen peroxide in 1-6 equal lots, preferably 2-4 lots. It is preferable that the hydrogen peroxide is added in the solution of 4-amino-3,5-dichloropyridine in acetic acid at a temperature between 20-100°C, more preferably at 30-80°C, most preferably at 50-75°C. According to the present invention the process for the production of 4-amino-3,5-dichloropyridine-N-oxide comprises of the recovery and recycle of unreacted raw material. 4-Amino-3,5-dihalopyridine is prepared by the halogenation of 4-aminopyridine by the process reported in prior art. 4-Substituted pyridine derivatives are generally preferred to be made prior to protecting tertiary nitrogen of pyridine ring via its N-oxidation to get good yields. However, it adds to steps. The present invention is aimed to derive higher selectivity of N-oxide of pyridine even starting from 4-substituted pyridine and using an effective recovery process of starting material for recycling. By this way the process route is simplified and made far more operational friendly, which saves time and is techno-commercially viable. Thus, the present invention provides a single step and commercially viable process for the production of 4-amino-3,5-dihalopyridine-N-oxide from 4-amino-3,5-dihalopyridine by using aqueous hydrogen peroxide in acidic medium. By this process good yield and selectivity of the desired product is obtained. The following examples are illustrative of the invention and should not be construed as limiting the scope of the invention in any manner. It is understood that the variation of the process described below are possible without departing from the scope and spirit of the invention. Example-1 4-Amino-3,5-dichloropyridine was prepared from 4-aminopyridine by stirring a solution of 4-aminopyridine in concentrated hydrochloric acid. To the above mass, hydrogen peroxide solution was added dropwise. The reaction mass was cooled and basified. The resulting precipitate was filtered to give the desired product 4-amino-3,5-dichloro pyridine (m.p. 162-164°C). Example-2 In a flask fitted with a mechanical stirrer, 150 ml of glacial acetic acid was charged at 30-35°C. 4-Amino-3,5-dichloropyridine (20 gm; prepared in example-1) was added with stirring and thereafter 243 gm of hydrogen peroxide (27.5% purity) was added in one lot. The reaction mixture was heated to 60-65°C and maintained at this temperature for 18 hours. The mixture was cooled to 5°C and pH adjusted to 4.0 - 4.2 with 10% caustic solution. The resulting precipitate was filtered off, washed with chilled water and dried to get 8.2 gm of 4-amino-3,5-dichloropyridine-N-oxide (Purity 94.69% by HPLC) which on purification with methanol gave 7.0 gm product (Purity 99%) with m.p. 208-210°C (dec). The methanolic filtrate was charged for distillation and methanol was recovered. To this, water was added and basified to pH 8-8.5 by 10% caustic solution at 5°C. The precipitated solid was collected by filtration and dried to obtain 10.5 gm crude material containing 81.63% of 4-amino-3,5-dichloropyridine and 18.3% of 4-amino-3,5-dichloropyridine-N-oxide. Example-3 A round bottom flask fitted with a mechanical stirrer was charged with 100 ml of glacial acetic acid at room temperature. 4-Amino-3,5-dichloropyridine (25 gm; prepared in example-1) was added to the flask with stirring. The reaction mass was heated to 50-75°C and 46% of 80 gm of hydrogen peroxide was added in 4 equal lots. Time interval between two lots was kept of 8 hours. After the addition of fourth lot, the reaction mixture was kept at 70-85°C for 8 hours. The mixture was then chilled to 5°C and pH was adjusted to 3.7-4.2 by the addition of 48% caustic solution (15 gm). The precipitated solid was collected by filtration, washed with chilled water and dried to get 8.0 gm product with 98.8% purity (first crop) by HPLC. The filtrate was again chilled to 5°C and pH was adjusted to 8-8.5 by the addition of 120 gm 48% caustic lye. The precipitated solid was filtered, washed with DM water and dried to get 18.6 gm crude material which on purification with water and then with methanol gave 8.7 gm product with 99% HPLC purity (second crop). Methanol was recovered from methanolic filtrate and aqueous filtrate obtained during water purification was charged in the distillation kettle and chilled to 5°C. The crude raw material thus obtained was filtered and dried to get 7.2 gm product containing 13.2% w/w product and 48.06% w/w raw material which was kept aside for recycling in subsequent batches. Overall yield of 4-amino-3,5-dichloropyridine was 53.86 mole % based on 4-aminopyridine. Example-4 In a round bottom flask, fitted with a mechanical stirrer 480 ml glacial acetic acid was charged at room temperature and thereafter 121 gm of 4-amino-3,5- dichloropyridine (prepared in example-1) was added to the flask while stirring. The reaction mixture was heated to 60-75°C and 290 gm of hydrogen peroxide (48%) was added in three equal lots. The time interval between two lots was kept of 8 hours. After the addition of third lot, the reaction mass was kept at 60-80°C for 8 hours. Acetic acid was recovered from the reaction mass under vacuum and 100 ml water was added to the rest mass to recover the maximum acetic acid. After maximum recovery of acetic acid, 650 ml water was charged in the kettle and chilled to 5°C. The pH of the mass was adjusted to 8-8.5 by the addition of 176 gm of 20% caustic solution. The precipitated solid was filtered off and the 270-300 gm of wet cake obtained was purified three times with DM water to remove inorganic salt and dried to get 138 gm crude product. This crude product on purification with methanol gave 92.6 gm pure product with 99% purity by HPLC. The methanol was recovered from the filtrate and the aqueous filtrate obtained during purification was charged to the kettle and chilled. The precipitated solid was collected and dried to get 37 gm crude material containing 14.74% of 4- amino-3,5-dichloropyridine-N-oxide and 82.51 % of 4-amino-3,5- dichloropyridine. Recycling of crude material (37 gm) was done by same procedure as in Example-3. 18.3 gm of dry 4-amino-3,5-dichloropyridine-N-oxide was obtained with 99% purity. An overall 74.4 % molar yield against 4-aminopyridine was obtained and again 8-10 gm crude material was obtained which can further be recycled. 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. CLAIMS OCR NOT PREPARE DUE TO PRINT PROBLEM

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2605-del-2004-abstract.pdf

2605-del-2004-claims.pdf

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2605-del-2004-description (complete).pdf

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