|Title of Invention||
"NOVEL SUBSTITUTED 1,2,4-TRIOXANES"
|Abstract||Novel substituted 1,2,4-Trioxanes This invention relates to Novel substituted 1,2,4-Trioxanes useful as antimalarial agents. The trioxanes are new chemical entities and they have not been prepared earlier. Some of these compounds have been tested against multi drug resistant malaria in mice and have shown promising antimalarial activity.|
|Full Text||Field of the Invention
The invention, in general, relates to a process for producing substituted diaminopyridines. More particularly, this invention provides for a novel, and industrially more suitable process for producing 2,3-diamino-6-methoxypyridine employing suitable raw materials.
Background of the Invention
Diaminopyridines and substituted diaminopyridines are well known for their use in the composition of hair dye and in the synthesis of substituted imidazole derivatives. In the dying of hair, a dye intermediate is used, which upon oxidation, develops to form the respective dye. Oxidation dyes have acquired substantial significance for hair coloration.
There are few methods known in the prior art for producing diaminopyridines and substituted diaminopyridines and the use thereof in the preparation of hair dye and in the synthesis of substituted imidazole derivatives.
German patent DE 3233540 discloses oxidation hair dye compositions, which consist of 2,3-diamino-6-methoxy pyridine and aromatic amines or diamines as precursors.
US Patent No. 3200040 discloses a composition suitable for use in the oxidative dying of hair, which comprises 6-methoxy-2,3-diaminopyridine, as a dye intermediate.
Voker (Seifen-Ole-Fette-Wachse, 1991, 117(4), 133-136) has investigated about 100 pyridines for their suitability as hair dyeing material and it is reported that 2,3-diamino-6-methoxypyridine dihydrochloride is one of the most potential oxidative dye coupler.
US Patent No. 0226216 discloses dye compositions, comprising one oxidation base and at least one coupler chosen from 6-alkoxy-2,3-diamino pyridine derivatives.
JP Patent No. 9241259 discloses the process for the preparation of 2,3-diamino-6-methoxy pyridine and use thereof in the synthesis of 2-mercaptoimidazole condensed ring compound. The process comprises of the preparation of 2,3-diamino-6-methoxypyridine by the catalytic reduction of 2-amino-6-methoxy-3-nitro pyridine. The catalytic reduction is not found suitable for commercial production due to catalyst leaching and poisoning. In addition, the free base obtained is highly colored.
US Patent No. 0226216 discloses a process for the preparation of 6-alkoxy-2,3-diamino pyridine derivatives, where 6-alkoxy-3-nitro-2-halo pyridine derivative is reacted with various amines in a polar solvent chosen from alcohols, acetic acid, formic acid, dioxane and dimethyl formamide at a temperature of 75 - 140°C to obtain the corresponding 2-amino-3-nitropyridine derivative. The reduction of 2-amino-3-nitro-6-alkoxy pyridine derivative is performed by hydrogenation catalyzed with palladium on carbon. This approach is not found suitable for 2,3-diamino-6-methoxypyridine.
In Aust. J. Chem., 1982, 35, 2025-34, Deady et al. has reported the route for the preparation of 2-amino-3-nitro-6-methoxy pyridine, the precursor of 2,3-diamino-6-methoxypyridine. In this method, 2-amino-6-methoxypyridine was nitrated with potassium nitrate and sulfuric acid. The use of potassium nitrate is not advisable at commercial scale due to its high cost and hazardous nature. In addition, the starting material viz., 2-amino-6-methoxypyridme is also very expensive.
EP 735025 discloses the synthesis of 6-methoxy-2-amino-3-nitropyridine by amination of 6-methoxy-3-nitropyridine by using methoxyamine, potassium-tert-butoxide and zinc chloride. The raw materials used in this process are very costly and difficult to handle.
In view of the increasing demand of 2,3-diamino-6-methoxy pyridine and lack of robust economically viable commercial process there is a need to develop a commercially and economically sound process.
Summary of the Invention
It is the principal aspect of this invention to provide a novel, commercially viable process for producing 2,3-diamino-6-methoxypyridine employing cost efficient and non-hazardous raw materials.
In accordance with one preferred embodiment of the present invention, there is provided a process for producing 2,3-diamino-6-methoxypyridine, wherein the process comprises neutralizing 2,3-diamino-6-methoxy pyridine dihydrochlonde with a base in presence of a polar solvent.
In accordance with another preferred embodiment of the present invention, there is provided a novel process for producing 2,3-diamino-6-methoxypyridine, wherein the 2,3-diamino-6-methoxypyridine dihydrochloride used in the process is prepared by the metallic reduction of 2-amino-6-methoxy-3-nitro pyridine with a reducing agent in aqueous acidic medium.
In accordance with yet another preferred embodiment of the present invention, there is provided a novel process for producing 2,3-diamino-6-methoxypyridine, wherein 2-amino-6-methoxy-3-nitro pyridine used in process is prepared by methoxylation of 2-amino-6-chloro-3-nitro pyridine using sodium methoxide in polar solvent.
Detailed Description of the Invention
According to the preferred embodiments of the invention, there is provided a process for producing 2,3-diamino-6-methoxypyridine using cost efficient raw materials and avoiding the drawback related to prior art processes.
(Scheme Removed)The present invention relates to a novel process for preparing 2,3-diamino-6-methoxypyridine (V) by the neutralization of 2,3-diamino-6-methoxypyridine dihydrochloride (IV) with a base in polar solvent as described in Scheme I. The dihydrochloride derivative is prepared by the metallic reduction of 2-amino-6-methoxy-3-nitropyridine (III). The compound (III) in turn is prepared by the methoxylation of 2-amino-6-chloro-3-nitropyridine (II).
The 2,3-diammo-6-methoxy pyridine dihydrochloride is suspended in polar solvent, preferably water and alcohol, more preferably in water. The pH is adjusted to 7-8 and more preferably 7.5 at a temperature between 10-30°C, preferably at 15°C by using inorganic or organic base. The inorganic or organic bases, which can be used, are preferably alkali hydroxide, alkaline hydroxide, dimethylamine triethylamine, ammonia, aqueous ammonia more preferably aqueous ammonia. The 2,3-diamino-6-methoxy pyridine thus precipitated is isolated by filtration or extraction, preferably by filtration.
Accordingly, in the present invention, the 2,3-diamino-6-methoxypyridine dihydrochloride is obtained by metal reduction of 2-amino-3-nitro-6-methoxy pyridine. The reduction is carried out by dissolving metal reducing agents in polar proton donating solvents preferably water, an alcohol or an acid. The reducing agent used is preferably iron, tin, zinc, tin chloride, zinc chloride and tin chloride dihydrate
in the presence of concentrated hydrochloric acid at a temperature between 25 - 80°C, more preferably the reduction is carried out in concentrated hydrochloric acid by using stannous chloride dihydrate at 35 - 40°C. After the reaction is over, the mixture is cooled and 2,3-diamino-6-niethoxy pyridine dihydrochloride is collected by filtration or extraction preferably by filtration.
According to the present invention, 2-amino-3-nitro-6-methoxy pyridine is obtained by methoxylation of 2-amino-3-nitro-6-chloropyridine by sodium methoxide in presence of methanol at a temperature between 10-60°C, more preferably at 25-30°C. The mole ratio of sodium methoxide is between 1.0 and 1.5 moles, more preferably 1.05 moles. After the completion of reaction, the reaction mass is quenched in water at a temperature range between 10 - 40°C, more preferably at 25 - 30°C. The product is obtained by extraction or filtration, more preferably by filtration at ambient temperature.
The 2-amino-3-nitro-6-chloropyridine is obtained by the ammonolysis of 2,6-dichloro-3-nitropyridine by the process reported in prior art. The ammonolysis is carried out by using solution of aqueous ammonia in methanol at 35-40°C. After reaction is over, product is obtained by filtration.
The 2,6-dichloro-3-nitropyridine is synthesized by the nitration of 2,6-dichloropyridine with a mixture of concentrated sulfuric acid and nitric acid by the process reported in the literature. After reaction is over, the product obtained is cooled and poured in ice water. The precipitated 2,6-dichloro-3-nitropyridine is collected by filtration.
The following examples are intended to illustrate the invention and are not to be construed as limiting the invention thereto.
Synthesis of 2,6-dichloro-3-nitropyridine
2,6-Dichloropyridine, 25.0 gm (0.168 mole) was added slowly under constant stirring to concentrated sulfuric acid at 20 - 25°C. To this solution, 75.0 gm of concentrated nitric acid (98.0 %) was added slowly, keeping the reaction temperature below 50°C.
After the addition, the resulting mixture was heated to 100 - 105°C for 5.0 hrs. The progress of the reaction was monitored by TLC. After the reaction was over, the reaction mixture was cooled to 50°C and poured in ice water. The resulting precipitate was filtered and washed with water. The wet cake thus obtained was dried to give 24.5 gm of 2,6-dichloro-3-nitropyridine. The yield of 2,6-dichloro-3-nitropyridine was 75.38 % and the GC purity was 99.5%.
Synthesis of 2-amino-6-chloro-3-nitro pyridine
2,6-Dichloro-3-nitropyridine, 25.0 gm (0.129 mole) was dissolved in methanol (50.0 ml) at room temperature. To the solution thus obtained, 25.0% aqueous ammonia solution 12.2 ml (0.179 mole) was charged at room temperature. The resulting mixture was heated to 35-40°C for 2.0 hrs. The reaction was monitored by TLC. After the completion of reaction, the mixture was cooled to 20°C. The solid obtained was washed, filtered with methanol and dried to yield 12.50 gm of 2-amino-6-methoxy-3-nitro pyridine (56.45%) with the HPLC purity of 99.3%: Melting point 192 - 195°C; 1HNMR: (DMSO D6) 86.75 - 6.77 ppm (d, 1H), 58.38 - 8.40 (d, 1H).
Synthesis of 2-amino-6-methoxy -3-nitro pyridine
Sodium methoxide, 7.78 gm (0.144 mole) and methanol 50.0 ml were mixed and cooled to 15°C. To this solution, 25.0 gm of 2-amino-6-chloro-3-nitropyridine (0.144 mole) was added while maintaining the temperature at 15°C by external cooling. The resulting mixture was heated to 25-30°C and maintained at this temperature for 4 - 5 hrs with constant stirring. The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was poured in water. The precipitate thus obtained was filtered and washed with water. On drying 21.0 gm of 2-amino-3-nitro-6-methoxy pyridine (86.5% yield) was obtained, with the HPLC purity of 99.0%. Melting point 167 - 169°C; 1HNMR (CDC13) 53.89 ppm (s,-3H, OCH3), 66.14 - 6.16 ppm (d, 1H), 68.24 - 8.27 ppm (d, 1H), 58.16 ppm (s, -2H, -NH2).
Synthesis of 2.3-diamino-6-methoxy pyridine dihydrochloride To the concentrated hydrochloric acid (250 ml), 25.0 gm of 2-amino-6-methoxy-3-nirro pyridine (0.147 mole) was added at room temperature. The resulting solution was cooled to 15°C and 66.7 gm of stannous chloride dihydrate (0.294 mole) was added slowly. The reaction mass was heated to 35 - 40°C and mixed for 5 - 6 hrs with constant stirring. The reaction was monitored by TLC. After the reaction was over, the reaction mixture was cooled to 20°C and stirred for one hour. The resulting mixture was filtered and dried to give 27.0 gm of 2,3-diamino-6-methoxypyridine dihydrochloride (yield=86.4%); Melting point 211 to 213°C; HPLC purity was 99.0%.
Synthesis of 2,3-diamino-6-methoxypyridine
2,3-Diamino-6-methoxy pyridine dihydrochloride, 25.0 gm (0.117 mole) was
suspended in water (50.0 ml) and the mixture was cooled to 15°C. After cooling, the
reaction mixture was neutralized with 25% aqueous ammonia solution to the pH of 7.0
to 8.0. The separated precipitate was stirred for half an hour and then filtered out. After
drying under vacuum 14.95 gm of 2,3-diamino-6-methoxypyridine (92.0% yield) was
obtained with a purity of 99.01% by HPLC.
1HNMR (OMSO D6) 53.67 ppm (s, 3H, -OCH3), 67.47 - 7.49 (d, 1H), 56.01 - 56.11
1. A process for producing 2,3-diamino-6-methoxypyridine comprising:
neutralizing 2,3-diamino-6-methoxy pyridine dihydrochloride with a base in presence of a
polar solvent such as herein described.
2. The process as claimed in claim 1, wherein the base is selected from
triethylamine and aqueous ammonia.
3. The process as claimed in claim 2, wherein the base is an aqueous solution
4. The process as claimed in claim 1, wherein the polar solvent is selected
from water or alcohols.
5. The process as claimed in claim 4, wherein the polar solvent is water.
6. A process for producing 2,3-diamino-6-methoxypyridine as claimed in
claim 1, comprising methoxylating the 2-amino-6-chloro-3-nitro pyridine by using sodium
methoxide in presence of a polar solvent to prepare 2-amino-6-methoxy-3-nitro pyridine,
reducing the resultant 2-amino-6-methoxy-3-nitro pyridine with a reducing agent in
presence of aqueous acidic medium to prepare 2,3-diamino-6-methoxy pyridine
dihydrochloride and neutralizing the same with a base in presence of a polar solvent.
7. The process as claimed in claim 6, wherein the reducing agent is selected
from dissolving metals reducing agents in the presence of polar proton donating solvent.
8. The process as claimed in claim 7, wherein the reducing agent is stannous
9. The process as claimed in claim 7, wherein the polar proton donating
solvent is concentrated hydrochloric acid.
10. The process as claimed in claim 6, wherein the reduction is carried out at a
temperature of 25-80 °C.
11. The process as claimed in claim 9, wherein the reduction is carried out
preferably at a temperature of 30-40 °C.
12. The process as claimed in claim 6, wherein the polar solvent used in
methoxylation is methanol.
13. The process as claimed in claim 6, wherein the methoxylation is carried out
at a temperature of 10-60°C.
14. The process as claimed in claim 13, wherein the methoxylation is carried
out preferably at a temperature of 25 - 30 C.
|Indian Patent Application Number||2057/DEL/2004|
|PG Journal Number||07/2009|
|Date of Filing||20-Oct-2004|
|Name of Patentee||COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH|
|Applicant Address||RAFI MARG, NEW DELHI-110 001, INDIA.|
|PCT International Classification Number||A61K 31/335|
|PCT International Application Number||N/A|
|PCT International Filing date|