Title of Invention

PROCESS FOR PRODUCING 6-ALKYL-2,3-DIAMINOPYRIDINE

Abstract A novel process for producing 6-alkyl-2,3-diaminopyridines represented by formula (I), wherein, alkyl is selected from C1 to C4 straight chain or branched chain is disclosed. The process includes bromination of 2-amino-6-alkylpyridine followed by nitration, reduction and subsequently the neutralization of resulting intermediate to produce 6-alkyl-2,3-diaminopyridines of formula (I).
Full Text Field of the Invention
This invention, in general relates to the process for producing substituted diaminopyridines. More specifically, but without restriction to the preferred embodiments hereinafter described in accordance with the best mode of practice, the present invention is directed to a novel and simple route for producing 6-alkyl-2,3-diaminopyridine employing non hazardous and commercially viable raw materials.
Background of the Invention
Substituted diaminopyridines are well known for their use in the composition of hair dyes and in the synthesis of alkyl substituted imidazolo pyridine derivatives.
Very few relevant processes are reported in the prior arts for the production of substituted diaminopyridines.
United State Patent No. 5977101 to Ali, et al. describes a process for the preparation of 2,3-diamino-6-methylpyridine by the reduction of 2-amino-6-methyl-3-nitropyridine, which in turn is obtained by the nitration of 2-amino-6-methylpyridine. However, when the process was carried out in the laboratory, the nitration of 2-amino-6-methyl pyridine gave a mixture of 2-amino-6-methyl-3-nitropyridine and 2-amino-6-methyl-5-nitropyridine in a ratio of 1:2 respectively. The formation of isomers on nitration of 2-amino-6-methylpyridine has been reported in US Patent 5874427. In the process disclosed in this patent, the nitration of 2-amino-6-methyl pyridine gives a mixture of 2-amino-6-methyl-3-nitro pyridine and 2-amino-6-methyl-5-nitro pyridine in the ratio of 1:2. The nitration isomers are separated by sublimation.
As described in foregoing, the prior art processes for the preparation of 6-alkyl-2,3-diaminopyridine have not been advantageous in the productivity and industrial viability as nitration of 2-amino-6-alkyl pyridine involves the formation of mixture of isomers, resulting into lower yields and also limiting its suitability for large scale production.
Thus, to overcome all the disadvantages associated with the processes disclosed in the prior arts, the present invention provides a novel process, which avoids the formation of isomer and is amenable to large-scale production.
Summary of the Invention
Accordingly, the present invention pertains to a novel process for producing 6-alkyl-2,3-diaminopyridine represented by formula (I), wherein there is provided a simple, efficient and commercially viable process employing non hazardous and cost efficient raw materials.
The objective of the present invention to provide a novel process for producing 6-alkyl-2,3-diaminopyridine represented by formula (I) is described herein by the various preferred embodiments, wherein one preferred embodiment of the present invention provides a process comprising brominating 6-alkyl-2-aminopyridine of formula (II) with a brominating agent in the presence of a polar solvent to prepare 2-amino-5-bromo-6-alkyl pyridine of formula (III), nitrating the compound 2-amino-5-bromo-6-alkyl pyridine of formula (III) with nitrating agent at 0-60°C to form 2-amino-5-bromo-3-nitro-6-alkyl pyridine of formula (IV), reacting the compound 2-amino-5-bromo-3-nitro-6-alkyl pyridine of formula (IV) with metal catalyst in the presence of a polar solvent at 40-80°C and H2 pressure between 5-25 kg to prepare 6-alkyl-2,3-diaminopyridine dihydrochloride of formula (V) and neutralizing the resultant compound 6-alkyl-2,3-diaminopyridine dihydrochloride of formula (V) with a base in the presence of a polar solvent to obtain 6-alkyl-2,3-diaminopyridine of formula (I).
In one other preferred embodiment of the present invention for producing 6-alkyl-2,3-diaminopyridine, there is provided a selective protection of more activated C-5 carbon atom of the compound 6-alkyl-2-aminopyridine of formula (II) to avoid the formation of other isomers.
In yet another preferred embodiment of the present invention for producing 6-alkyl-2,3-diaminopyridine of formula (I), there is provided a process for the reduction of 6-alkyl-2-amino-3-nitro-5-bromopyridine of formula (IV) employing metal catalyst in a polar
solvent to form 6-alkyl-2,3-diaminopyridine dihydrochloride which on neutralization produce 6-alkyl-2,3-diaminopyridine of formula (I).
Detailed Description of the Invention
The disclosed preferred embodiment of the present invention describing a novel process for producing 6-alkyl-2,3-diaminopyridines of formula (I) can be more readily understood through reading the following detailed description of the invention and the reaction scheme I.
(Scheme Removed)
With reference to the above reaction scheme I, the non-limiting substituent R is any alkyl group selected from C1 to C4 straight chain or branched chain.
The process step 1 in the reaction scheme I disclosed herein provides a step wherein the compound 6-alkyl-2-amino pyridine of formula (II) is treated with suitable brominating agent in a polar solvent at a temperature between 10-20°C to prepare a compound 2-amino-5-bromo-6-alkyl pyridine of formula (III). Any polar solvent can be used in the process preferably the solvent used herein is selected from acetic acid, methanol or ethanol. More preferred is acetic acid.
The compound 2-amino-5-bromo-3-nitro-6-alkyl pyridine of formula (IV) is obtained according to step 2 of scheme I, wherein nitration of compound 2-amino-5-bromo-6-alkyl pyridine of formula (III) is carried out in presence of sulfuric acid and nitric acid at 0-60°C. Further, after the completion of reaction, the reaction mass is poured in ice water and 2-amino-5-bromo-3-nitro-6-alkyl pyridine of formula (IV) is collected by filtration or extraction, preferably by filtration.
According to step 3 of the reaction scheme I of the present invention, wherein the compound 6-alkyl-2,3-diaminopyridine dihydrochloride of formula (V) is obtained by simultaneous reduction and debromination of 2-amino-5-bromo-3-nitro-6-alkyl pyridine of formula (IV) with metal catalyst at a temperature between 40 - 80°C, preferably 50 - 65°C and H2 pressure between 5 to 25 kg, preferably 10-15 kg. The metal catalyst used herein is selected from palladium, platinum or raney nickel. The reduction is carried out in the presence of a polar solvent preferably methanol, ethanol or water. More preferred is methanol. Further, after the completion of the reaction, the catalyst is collected by filtration. The dry HC1 gas is purged in the filtrate at a temperature between 10-25°C, preferably at 20°C. The solid is collected by filtration to get 6-alkyl-2,3-diaminopyridine dihydrochloride of formula (V).
According to step 4 of scheme I wherein the neutralization is carried out by suspending the 6-alkyl-2,3-diaminopyridine dihydrochloride of formula (V) in a polar solvent to prepare the compound 6-alkyl-2,3-diaminopyridine of formula (I) at a temperature between 10-30°C, preferably 12-20°C by using a base. The polar solvent used herein is selected from any of the suitable polar solvent, preferably water, methanol or ethanol, more preferably water. The base used herein is selected from any inorganic or organic bases preferably selected from alkali hydroxide, triethyl amine, ammonia or aqueous ammonia. More preferred is aqueous ammonia. The pH of the reaction mass is adjusted to 7-8, preferably 7.5. The 6-alkyl-2,3-diaminopyridine of formula (I) thus precipitated is extracted with water immiscible solvents. The water immiscible solvents used herein is selected from hexane, ethyl acetate, dichloromethane or toluene, preferably ethyl acetate.
Further, the present invention is illustrated in detail by way of the following examples. The examples are given herein for illustration of the invention and are not intended to be limiting thereof.
Example 1
Synthesis of 2-amino-5-bromo-6-methylpyridine
In a mixture of 25.0 gm (0.231 mole) of 2-amino-6-methyl pyridine and 75.0 gm of acetic acid, 37.0 gm (0.231 mole) bromine was added slowly at 15°C. The reaction mixture was stirred for half an hour at this temperature. The completion of reaction was monitored with TLC. After the completion of reaction, the solid was filtered off and dried. 2-Amino-5-bromo-6-methyl pyridine hydrobromide thus obtained was suspended in 56.0 ml water and the mixture was cooled to 15°C. The pH of resulting mass was adjusted to 7-8 by using aqueous sodium hydroxide, and was stirred for half an hour. 2-Amino-5-bromo-6-methyl pyridine obtained was collected by filtration and dried. After drying 28.0 gm of 2-amino-5-bromo-6-methylpyridine was obtained with 98.0 % purity by HPLC and 65.0 % yield. 1H NMR (DMSO D6)δ 2.32 (s, 3H, -CH3), δ 6.07 ( bs, 2H,-NH2), δ 6.22 (d, 1H), δ 7.45 (d, 1H).
Example 2
Synthesis of 2-amino-5-bromo-6-methvl-3-nitropyridine
25.0 gm (0.133 mole) of 2-amino-5-bromo-6-methylpyridine was slowly added in 66.0 gm (0.665 mole) sulfuric acid while maintaining the temperature below 20°C. To the resulting mixture 8.8 gm of concentrated nitric acid (90%, 0.127 mole) was added slowly while maintaining the temperature below 25°C. The reaction mixture was then heated to 50-60°C. The completion of reaction was monitored with TLC. After the completion of reaction, reaction mass was cooled to room temperature and poured in ice water. The resulting solid was collected by filtration and dried. After drying, 23.25 gm of 2-amino -5-bromo-6-methyl-3-nitro pyridine was obtained with 75.0 % yield and 98.0% purity by HPLC.
Example 3
Synthesis of 6-methvl-2,3-diaminopvridine dihydrochloride
To a mixture of 25.0 gm (0.107 mole) 2-amino-5-bromo-6-methyl-3-nitro-pyridine and 250.0 ml methanol, 2.5 gm 5 % Pd/C was added in an autoclave at room temperature. To this reaction mixture, 10.0 kg hydrogen pressure was applied at room temperature. The solution was then heated to about 55°C and maintained at this temperature and pressure till the completion of reaction. After the completion of reaction catalyst was separated by filtration. In the filtrate, dry HC1 gas was purged at a temperature between 20-25°C. The precipitate thus obtained was collected by filtration. After drying 17.5 gm of 6-methyl-2,3-diaminopyridine dihydrochloride with 85 % yield and 98 % purity by HPLC was obtained.
Example 4
Synthesis of 2,3-diamino-6-methvrpvridine
25.0 gm (0.128 mole) 6-Methyl-2,3-diaminopyridine dihydrochloride was suspended in 50 ml water and mixture was cooled to 15-20°C. The pH of resulting mass was adjusted to 7-8 by aqueous ammonia (25%). The resulting 6-methyl-2,3-diaminopyridine was extracted with ethylacetate. The distillation of organic layer under vacuum gave 13.47 gm 6-methyl-2,3-diaminopyridine (85.0 % yield) with 99 % purity by HPLC. 1H NMR (DMSO D6), δ 2.38 ppm (s, 3H, -CH3), δ 7.04 ppm (d, 1H), δ 7.28 ppm (d, 1H), Mass = 124 (M+H)+.
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 of skill in the art without departing from the scope and spirit of this invention.









We Claim:
1. A process for producing 6-alkyl-2, 3-diaminopyridine represented by formula (I),
(Formula Removed)
the process comprising:
(a) brominating the compound 6-alkyl-2-aminopyridine represented by
formula (II) with a brominating agent in the presence of a polar solvent to prepare
a compound 2-amino-5-bromo-6-alkyl pyridine represented by formula (III);
(Formula Removed)
(b) nitrating the compound 2-amino-5-bromo-6-alkyl pyridine of
formula (III) with a nitrating agent to form a compound 2-amino-5-bromo-3-nitro-
6-alkyl pyridine represented by formula (IV);
(Formula Removed)
(c) reducing the compound 2-amino-5-bromo-3-nitro-6-alkyl pyridine
of formula (IV) with a metal catalyst in the presence of a polar solvent to prepare a
compound 6-alkyl-2,3-diaminopyridine dihydrochloride represented by formula
(V);
(Formula Removed)
(d) neutralizing the compound 6-alkyl-2,3-diaminopyridine dihydrochloride of formula (V) with a base in the presence of a polar solvent to obtain the compound 6-alkyl-2,3-diaminopyridine of formula (I),
wherein, substituent R is alkyl group selected from C1 to C4 straight chain or branched
chain.
2. The process as claimed in claim 1 wherein the brominating reagent is molecular bromine.
3. The process as claimed in claim 1, wherein the polar solvent used in the bromination is selected from acetic acid, methanol or ethanol.
4. The process as claimed in claim 3, wherein the polar solvent is preferably acetic acid.
5. The process as claimed in claim 1, wherein the nitrating reagent is a mixture of nitric acid and sulfuric acid.
6. The process as claimed in claim 1, wherein the nitration is carried out at a temperature of 0-60°C.
7. The process as claimed in claim 1, wherein the metal catalyst is selected from palladium, platinum or raney nickel.
8. The process as claimed in claim 7, wherein the metal catalyst is palladium on carbon.
9. The process as claimed in claim 1, wherein the reduction is carried out at a
temperature of 40-80°C and H2 pressure between 5-25 kg.
10. The process as claimed in claim 1, wherein the polar solvent used in reduction is selected from methanol, ethanol or water.
11. The process as claimed in claim 10, wherein the polar solvent is methanol.
12. The process as claimed in claim 1, wherein the base is selected from organic or inorganic bases.
13. The process as claimed in claim 12, wherein the base is selected from alkali hydroxide, triethyl amine, ammonia or aqueous ammonia.
14. The process as claimed in claim 13, wherein the base is aqueous solution of
ammonia.
15. The process as claimed in claim 1, wherein the polar solvent used in the neutralization is selected from water, methanol or ethanol.
16. The process as claimed in claim 15, wherein the polar solvent is water.
17. A process for producing 6-alkyl-2,3-diaminopyridine represented by
formula (I) as substantially herein described with reference to the examples.

Documents:

669-del-2005-abstract.pdf

669-DEL-2005-Claims-(22-03-2010).pdf

669-del-2005-claims.pdf

669-DEL-2005-Correspondence-Others-(22-03-2010).pdf

669-del-2005-correspondence-others.pdf

669-del-2005-description (complete).pdf

669-DEL-2005-Form-1-(22-03-2010).pdf

669-del-2005-form-1.pdf

669-del-2005-form-18.pdf

669-del-2005-form-2.pdf

669-del-2005-form-26.pdf

669-del-2005-form-3.pdf

669-DEL-2005-Form-5-(22-03-2010).pdf

669-del-2005-form-5.pdf

669-DEL-2005-GPA-(22-03-2010).pdf

abstract.jpg


Patent Number 243670
Indian Patent Application Number 669/DEL/2005
PG Journal Number 45/2010
Publication Date 05-Nov-2010
Grant Date 29-Oct-2010
Date of Filing 29-Mar-2005
Name of Patentee JUBILANT ORGANOSYS LIMITED
Applicant Address PLOT 1A, SECTOR 16 A, NOIDA-201 301, UP,INDIA
Inventors:
# Inventor's Name Inventor's Address
1 THAKRE, D.B JUBILANT ORGANOSYS LTD, C-26, SECTOR-59, NOIDA (U.P)INDIA
2 SINGH, YASHBIR JUBILANT ORGANOSYS LTD, C-26, SECTOR-59, NOIDA (U.P)INDIA
3 AGARWAL, ASHUTOSH JUBILANT ORGANOSYS LTD, BHARTIAGRAM, GAJRAULA, JYOTIBA PHULEY NAGAR DISTRICT MORADABAD 244223, U.P.INDIA
PCT International Classification Number C07D 213/74
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA