DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

PROCESS FOR THE PREPARATION OF AMINO SUBSTITUTED ALKYL PYRIDINES

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification describes the invention.

FIELD OF THE INVENTION
The present invention provides a process for synthesis of amino substituted alkyl pyridines.

BACKGROUND OF THE INVENTION
The present invention provides a process for synthesis of amino substituted alkyl pyridines.
There are several methods known in the art for synthesis of amino substituted alkyl pyridines.
J. Org. Chem. 1988, 53, 3513-3521 discloses a process for preparation of 3-amino-5-methyl pyridine by reacting 5-methyl nicotinamide with potassium hypobromite obtained by reaction of bromine and potassium hydroxide to obtain 3-amino-5-methyl pyridine.
The potassium hypobromite is a costly raw material and makes the process expensive. It is obtained by bromine and potassium hydroxide. Bromine is expensive and toxic.
PCT Publication No. 2019087129 also discloses use of ammonium hydroxide, tetrahydrofuran, and dioxane for conversion of 5-methyl nicotinic acid chloride to 5-methyl nicotinamide in presence of oxalyl chloride.
This process is using expensive oxalyl chloride in large quantity (2eq. w.r.to. acid).
Thus, there is a need to develop an alternate process to prepare amino substituted methyl pyridine to overcome the drawbacks of the processes known in the art.
Surprisingly, the inventors of present invention found that amino substituted methyl pyridine can be prepared from alkylnicotinamide using sodium hypochlorite in presence of a base.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a simple, safe, and commercially viable process for preparation of substituted amino methylpyridines in good yield and purity.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R is an alkyl group and “n” is a number selected from 1-4.
by treating a compound of formula II,

Formula II
wherein R is an alkyl group and “n” is a number selected from 1-4.
with sodium hypochlorite in presence of an aqueous basic medium.
In another aspect, the present invention provides a process for preparation of the compound of formula II, comprising the steps of:

Formula II
wherein R is an alkyl group and “n” is a number selected from 1-4.
a) chlorinating a compound of formula IV,

Formula IV
wherein R is an alkyl group and “n” is a number selected from 1-4.
with thionyl chloride in presence of a first solvent to produce a formula III; and

Formula III
b) reacting the compound of formula III with ammonia in presence of a second solvent to produce the compound of formula II,
wherein first solvent is selected from a group consisting of toluene, xylene, chlorobenzene, o-dichlorobenzene, heptane, cyclohexane, mesitylene and benzotrifluoride.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, R is an alkyl group, wherein alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, iso butyl, tert-butyl or like. “n” is a number selected from 1-4.
In an embodiment, the compound of formula II is converted to the compound of formula I using sodium hypochlorite.
In another embodiment, the compound of formula II is converted to the compound of formula I using chlorine and aqueous sodium hydroxide.
In another embodiment, the aq. Sodium hydroxide has concentration selected in the range of 7 to 15%, preferably 10%.
In an embodiment, the present invention provides a process for preparation of 3-amino-5-alkyl pyridine by treating 5-alkylnicotinamide compound with sodium hypochlorite (5-12%) in presence of aqueous basic medium.
In another embodiment, the conversion of the compound of formula II to the compound of formula I is carried out in presence of a solvent selected from a group consisting of benzotrifluoride, n-heptane, dioxane and cyclohexane or a mixture thereof.
In another embodiment, the conversion of 5-alkylnicotinamide to 3-amino-5-alkyl pyridine is carried out in presence of a solvent selected from benzotrifluoride, n-heptane, dioxane and cyclohexane or a mixture thereof.
In another embodiment, the present invention provides a process for preparation of 5-alkylnicotinamide comprising the steps of:
a) chlorinating 5-alkylnicotinic acid with thionyl chloride in presence of a first solvent to produce 5-akylnicotinic acid chloride; and
b) reacting 5-alkylnicotinic acid chloride with ammonia in presence of a second solvent to produce 5-alkylnicotinamide,
wherein first solvent is selected from a group consisting of toluene, xylene, chlorobenzene, o-dichlorobenzene, heptane, cyclohexane, mesitylene, benzotrifluoride.
In an embodiment, the present invention provides a process for preparation of 3-amino-5-methyl pyridine by treating 5-methylnicotinamide with 5 to 12% sodium hypochlorite in presence of an aqueous basic medium.
In an embodiment, the sodium hypochlorite as used in the present invention is in aqueous solution form having concentration selected in the range of 5 to 12.
In an embodiment, the base used for aqueous basic medium is an inorganic base selected from a group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide and calcium hydroxide.
In another embodiment, the inorganic base is used in aqueous solution form having concentration selected in the range of 20% to 48%.
In an embodiment, the present invention provides a process for preparation of 3-amino-5-alkyl pyridine, comprising the steps of:
a) contacting aqueous solution of 5-alkylnicotinamide with sodium hypochlorite in presence of a base at -5? to 10? to obtain a reaction mixture;
b) contacting reaction mixture of step a) with preheated water to obtain 3-amino-5-alkyl pyridine.
In another embodiment, the present invention provides a process for preparation of 3-amino-5-methyl pyridine, comprising the steps of:
a) contacting aqueous solution of 5-methylnicotinamide with sodium hypochlorite in presence of sodium hydroxide at 0-5? to obtain a reaction mixture;
b) contacting reaction mixture of step a) with preheated water to obtain 3-amino-5-methyl pyridine.
In an embodiment, the aqueous solution of 5-alkylnicotinamide is having concentration selected in the range of 2.5% to 15%.
In an embodiment, the temperature of preheated water is selected in the range of 90-95?.
In an embodiment, the conversion of 5-alkylnicotinamide to 3-amino-5-alkyl pyridine is monitored till 5-alkylnicotinamide reduces to less than 0.3% in reaction mixture when checked by liquid chromatography.
In another embodiment, the present invention provides a process for preparation of 5-methylnicotinamide comprising the steps of:
a) chlorinating 5-methylnicotinic acid with thionyl chloride in presence of toluene to produce 5-methylnicotinic acid chloride; and
b) reacting 5-methylnicotinic acid chloride with ammonia in presence of a second solvent to produce 5-methylnicotinamide.
In an embodiment, the 5-alkylnicotinamide is isolated before converting to 3-amino-5-alkyl pyridine.
In another embodiment, the 5-alkylnicotinamide is converted in-situ to 3-amino-5-alkyl pyridine without isolating in between.
In an embodiment, the conversion of 5-alkylnicotinic acid to 5-alkylnicotinic acid chloride is monitored till 5-alkylnicotinic acid reduces to less than 0.5% in reaction mixture, when checked by high pressure liquid chromatography.
In an embodiment, the conversion of 5-alkylnicotinic acid to 5-alkylnicotinic acid chloride is catalysed using 0.011 mole equivalents of dimethyl formamide or N,N,N,N-tetramethyl urea.
In an embodiment, the 2-20 times solvent is used in the conversion of 5-alkylnicotinic acid to 5-alkylnicotinic acid chloride.
In an embodiment, the 2-20 times toluene is used in the conversion of 5-alkylnicotinic acid to 5-alkylnicotinic acid chloride.
In an embodiment, the formation of 5-alkylnicotinic acid chloride is carried out at a temperature selected in the range of 60-90?.
In an embodiment, the formation of 5-alkylnicotinic acid chloride is followed by solvent removal to obtain a slurry which is treated with ammonia in presence of alkanol or ester solvent to obtain crude mixture of 5-alkylnicotinamide. The crude mixture thus obtained is filtered followed by alcohol washing to obtain filtrate. The filtrate is then distilled to partially remove alcohol and obtain reaction mass having 50% concentration of 5-alkylnicotinamide in alcohol. The remaining mass is cooled at 0-5? and filtered to obtain pure 5-alkylnicotinamide.
In an embodiment the reaction of 5-methylnicotinic acid chloride with ammonia is carried out in presence of a second solvent selected from a group consisting of alcohol such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol and tert-butanol or esters such as es ethyl acetate, isopropylacetate, n-butyl acetate.
In an embodiment, the 3-amino-5-alkyl pyridine is obtained with a yield of more than 88% and a purity (high pressure liquid chromatography) of more than 98%.
In another embodiment, the 5-alkylnicotinamide is obtained with a yield of more than 90% and a purity (high pressure liquid chromatography) of more than 99%.
The present invention for preparation of the 3-amino-5-alkyl pyridine and 5-alkylnicotinamide has following advantages over the known methods:
The process of the present invention is converting 5-alkylnicotinic acid to 5-alkylnicotinic acid chloride by utilizing stochiometric amount of thionyl chloride.
In a preferred embodiment, the conversion of 5-alkylnicotinic acid to 5-alkylnicotinic acid chloride is carried out in a first solvent. The first solvent such as toluene can be recovered efficiently from the process and thus it is a cost-effective process. The reaction condition and product isolation are simpler. Yield is significantly high using first solvent instead of thionyl chloride as solvent and reagent.
As used herein, the starting material 5-alkylnicotinic acid may be prepared by any method known in the art or may be obtained commercially.
The 3-amino-5-methyl pyridine and 5-alkylnicotinamide can be isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 5-methylnicotinamide from 5-methyl nicotinic acid
To a 500ml four-necked flask equipped with a stirrer, a thermometer, ice-cold water condenser, toluene (260g), 5-methylnicotinic acid (22.77 g, 0.17 mol) and N,N-dimethylformamide (0.133g) as catalyst were charged. The reaction mixture was heated to 70°C and thionyl chloride (22.6g, 0.19 mol) was slowly added in 1-2 hours followed by maintaining of the reaction mixture at 70°C for 5 hours. The progress of the reaction mass was checked by HPLC, till the 5-methylnicotinic acid was less than 0.5%. Further toluene was removed at 60-70°C under reduced pressure to leave a slurry in the bottom. Methanol (200g) was added to the mixture and cooled the mixture to 0 to -5°C and ammonia gas was added slowly in 6-7 hours at 0-5°C and the reaction mixture was maintained at 20-30°C for 1 hour and reaction progress was checked using HPLC till 5-methylnicotinic acid chloride was less than 0.5%. The mixture was filtered, and the cake was washed using methanol (25-30g). A major part of methanol was removed at 60-65°C from combined filtrate mother liquor to leave a slurry of 5-methylnicotinamide (50%) in methanol. The mixture was gradually cooled, filtered and the cake was dried at 70°C and pressure was reduced to get dried 5-methylnicotinamide (20.34g).
Yield: 90% Purity: 99.2%.
Example 2: Preparation of 5-methylnicotinamide from 5-methyl nicotinic acid
To a 500ml four-necked flask equipped with a stirrer, a thermometer, ice-cold water condenser, toluene (260g), 5-methylnicotinic acid (22.77 g, 0.17 mol) and N,N-dimethylformamide (0.133g) as catalyst were charged. The reaction mixture was heated to 70°C and thionyl chloride (22.6g, 0.19 mol) was slowly added in 1-2 hours followed by maintaining of the reaction mixture at 70°C for 5hours. The progress of the reaction mass was checked by HPLC, till the 5-methylnicotinic acid was less than 0.5%. Further toluene was removed at 60-70°C under reduced pressure to leave a slurry in the bottom, ethyl acetate (220g) was added to the mixture and cooled the mixture to 0 to -5°C and ammonia gas was added slowly in 6-7 hours at 0 to -5°C and the reaction mixture was maintained at 20-30°C for 1 hour and reaction progress was checked using HPLC till 5-methyl nicotinic acid chloride was less than 0.5%. A major part of ethyl acetate was removed at 60-65°C and light reduced pressure followed by addition of water and complete removal of ethyl acetate. The mixture was gradually cooled, filtered and the cake was dried at 70°C and pressure was reduced to get dried 5-methylnicotinamide (19.21g).
Yield: 85% Purity: 97.78%.
Example 3: Preparation of 5-methyl-3-aminopyridine from 5-methylnicotinamide.
To a glass round bottom flask, sodium hypo chlorite (20g, 0.027 mol) was charged and 45% aqueous sodium hydroxide solution (5g, 0.056 mol) was slowly added at 0-5°C followed by slow addition of 5% aqueous solution of 5-methylnicotinamide (2.5g, 0.018 mol) at 0-5°C. The mixture was Stirred for 1hour. The reaction mass was cooled at 5°C and was added to a pre-heated water (50g) at 90-95°C in 1hour and the solution was maintained at 95°C for 2-3hours. The reaction progress was checked by liquid chromatography till 5-methyl nicotinamide was less than 0.3%. The reaction mixture was extracted with dichloromethane (250ml) twice. The organic phase was concentrated to give a light brown solid product (1.78g).
Yield 88%, Purity: 98%.
Example 4: Preparation of 5-methyl-3-aminopyridine from 5-methylnicotinamide
To a glass round bottom flask, sodium hypochlorite (20g, 0.027 mol) was charged and 40% aqueous potassium hydroxide solution (5g, 0.056 mol) was slowly added at 0-5°C followed by slow addition of 5% aqueous solution of 5-methylnicotinamide (2.5g, 0.018 mol) at 0-5°C. The mixture was Stirred for 1hour. The reaction mass was cooled at 5°C and was added to a pre-heated water (50g) at 90-95°C in 1h and the solution was maintained at 95°C for 2-3 hours. The reaction progress was checked by liquid chromatography till 5-methyl nicotinamide was less than 0.3%. The reaction mixture was extracted with dichloromethane (250ml) twice. The organic phase was concentrated to give a light brown solid product (1.78g).
Yield 86%, Purity: 97%.

ABSTRACT
PROCESS FOR THE PREPARATION OF AMINO SUBSTITUTED ALKYL PYRIDINES
The main object of the present invention is to provide a simple, safe, and commercially viable process for preparation of substituted amino methylpyridines in good yield and purity. These are important intermediates in the field of pharmaceuticals and agrochemicals.

,CLAIMS:WE CLAIM:
1. A process for preparation of a compound of formula I,

Formula I
by treating a compound of formula II,

Formula II
with sodium hypochlorite in presence of an aqueous basic medium.
2. The process as claimed in claim 1, wherein preparation of the compound of formula II comprising the steps of:
a) chlorinating a compound of formula IV,

Formula IV
with thionyl chloride in presence of a first solvent to produce a formula III; and

Formula III
b) reacting the compound of formula III with ammonia in presence of a second solvent to produce the compound of formula II,
wherein first solvent is selected from a group consisting of toluene, xylene, chlorobenzene, o-dichlorobenzene, heptane, cyclohexane, mesitylene and benzotrifluoride.
3. The process as claimed in claim 1, wherein the conversion of the compound of formula II to the compound of formula I is carried out in presence of a solvent selected from a group consisting of benzotrifluoride, n-heptane, dioxane and cyclohexane or a mixture thereof.
4. The process as claimed in claim 1, wherein the sodium hypochlorite used is in aqueous solution form having concentration selected in the range of 5 to 12.
5. The process as claimed in claim 1 for preparation of 5-alkylnicotinamide comprising the steps of:
a) chlorinating 5-alkylnicotinic acid with thionyl chloride in presence of a first solvent to produce 5-akylnicotinic acid chloride; and
b) reacting 5-alkylnicotinic acid chloride with ammonia in presence of a second solvent to produce 5-alkylnicotinamide,
wherein first solvent is selected from a group consisting of toluene, xylene, chloro benzene, o-dichlorobenzene, heptane, cyclohexane, mesitylene and benzotrifluoride.
6. The process as claimed in claim 1 for preparation of 3-amino-5-methyl pyridine comprising the steps of treating 5-methylnicotinamide with 5 to 12% sodium hypochlorite in presence of an aqueous basic medium.
7. The process as claimed in claim 6, wherein the base used for aqueous basic medium is an inorganic base selected from a group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide and calcium hydroxide.
8. The process as claimed in claim 2, wherein the second solvent is selected from a group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol, tert-butanol, ethyl acetate, isopropylacetate and n-butyl acetate.
9. The process as claimed in claim 7, wherein the inorganic base is used in aqueous solution form having concentration selected in the range of 20% to 48%.
10. The process as claimed in claim 1& 2 wherein the compound of formula I from the compound of formula IV is carried out in-situ without isolating any intermediate in-between.

Dated this 23rd day of Sep 2024.