Claims:We Claim:
1. A process for the preparation of highly pure 2-amino-5-chloropyridine of formula I:

or an acid addition salt thereof, which comprises:
a) reacting 2-aminopyridine of formula III:

or an acid addition salt thereof, with a suitable protecting agent of formula IV(a), IV(b), IV(c) or IV(d):

wherein the radical ‘R’ represents C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; to produce a reaction mass containing N-protected-amino-pyridine intermediate, followed by subsequent reaction with a suitable chlorinating agent to produce N-protected-amino-5-chloropyridine of formula II:

wherein the group ‘P’ represents an amino-protecting group selected from –C(O)R and –C(O)OR, and wherein the radical R is as defined above; and
b) deprotecting the N-protected-amino-5-chloropyridine of formula II by reacting with a suitable deprotecting agent in a suitable solvent to produce highly pure 2-amino-5-chloropyridine of formula I, and optionally converting the compound of formula I into an acid addition salt thereof.
2. The process as claimed in claim 1, wherein the protecting agent used in step-(a) is selected from the group consisting of acetyl chloride, acetyl bromide, propionyl chloride, butanoyl chloride, pivaloyl chloride, benzoyl chloride, di-tert-butyldicarbonate, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tertiarybutyl chloroformate, n-butyl chloroformate, benzyl chloroformate, 4-nitrophenyl chloroformate and acetic anhydride; wherein the radical ‘R’ in the compounds of formulae II, IV(a), IV(b), IV(c) and IV(d) is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, fluoromethyl, trifluoromethyl, phenyl, p-tolyl, benzyl, 4-nitrophenyl, 4-chlorophenyl, 3-nitrophenyl, 4-chlorobenzyl and p-methoxybenzyl; and wherein the amino-protecting group ‘P’ in the compound of formula II is selected from the group consisting of acetyl, propanoyl, butanoyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl, trichloroethxoycarbonyl (Troc), allyloxycarbonyl, t-butoxycarbonyl (BOC) and pivaloyl.
3. The process as claimed in claim 2, wherein the protecting agent used in step-(a) is acetic anhydride; wherein the radical ‘R’ in the compounds of formulae II, IV(a), IV(b), IV(c) and IV(d) is methyl; and wherein the amino-protecting group ‘P’ in the compound of formula II is acetyl.
4. The process as claimed in claim 1, wherein the chlorinating agent used in step-(a) is selected from the group consisting of N-chlorosuccinimide, t-butyl hypochlorite, oxalyl chloride, sulphuryl chloride, phosphorus pentachloride and phosphorous oxychloride; wherein the solvent used in step-(a) is selected from the group consisting of water, an alcohol, a ketone, an ester, a polar aprotic solvent, a halogenated hydrocarbon, and mixtures thereof; wherein the deprotecting agent used in step-(b) is an acid or a base; and wherein the solvent used in step-(b) is selected from the group consisting of water, an alcohol, a ketone, an ester, a halogenated hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.
5. The process as claimed in claim 4, wherein the chlorinating agent used in step-(a) is N-chlorosuccinimide; wherein the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; wherein the deprotecting agent used in step-(b) is a base selected from the group consisting of triethylamine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; wherein the deprotecting agent used in step-(b) is an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, trifluoracetic acid, and mixtures thereof; and wherein the solvent used for deprotection in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
6. The process as claimed in claim 5, wherein the solvent used in step-(a) is N,N-dimethylformamide; wherein the deprotecting agent used in step-(b) is sodium hydroxide; and wherein the solvent used in step-(b) is a mixture of water and methanol.
7. The process as claimed in claim 1, wherein the N-protected-amino-5-chloropyridine of formula II obtained in the step-(a) is 2-acetylamino-5-chloropyridine of formula IIa (Formula II, wherein P is acetyl):

8. A process for the preparation of highly pure 2-amino-5-chloropyridine of formula I:

or an acid addition salt thereof, comprising deprotecting the N-protected-amino-5-chloropyridine of formula II:

wherein ‘P’ represents an amino-protecting group selected from –C(O)R and –C(O)OR, and wherein the radical ‘R’ represents C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
by reacting with a suitable deprotecting agent in a suitable solvent to produce highly pure 2-amino-5-chloropyridine of formula I, and optionally converting the compound of formula I into an acid addition salt thereof.
9. The process as claimed in claim 8, wherein the amino-protecting group ‘P’ in the compound of formula II is selected from the group consisting of acetyl, propanoyl, butanoyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl, trichloroethxoycarbonyl (Troc), allyloxycarbonyl, t-butoxycarbonyl (BOC) and pivaloyl; wherein the deprotecting agent used is an acid or a base; and wherein the solvent used for deprotection is selected from the group consisting of water, an alcohol, a ketone, an ester, a halogenated hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof.
10. The process as claimed in claim 9, wherein the amino-protecting group ‘P’ in the compound of formula II is acetyl; wherein the deprotecting agent used is a base selected from the group consisting of triethylamine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and wherein the solvent used for deprotection is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
, Description:FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous process for the preparation of 2-Amino-5-chloropyridine with high yield and high purity.

BACKGROUND OF THE INVENTION
US Patent No. US 6,444,673 (hereinafter referred as the US’673 patent) discloses Eszopiclone, (which is a dextrorotatory isomer of Zopiclone), processes for preparation, pharmaceutical compositions containing it, and methods of use thereof. Eszopiclone is a non-benzodiazepine hypnotic agent that is a pyrrolopyrazine derivative of the cyclopyrrolone class. Eszopiclone is useful as a hypnosedative, tranquilliser, muscle relaxant and anticonvulsant. Eszopiclone is chemically named as (+)-(5S)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methyl-piperazine-1-carboxylate. Eszopiclone is represented by the following structural formula:

Eszopiclone is approved by USFDA for use in the United States for the treatment of insomnia. Eszopiclone is marketed under the trade name LUNESTA®. LUNESTA has been shown to decrease sleep latency and improve sleep maintenance. It is orally administered as tablets 1 mg, 2 mg, and 3 mg tablet formulation.
Various processes for the preparation of Eszopiclone, its intermediates and related compounds are described in U.S. Patent Nos. US3862149, US3955918, US6444673, US7476737, US7786304 and US8309723; EP Publication No. EP2058313A2; PCT Publication No. WO2009079939A1; and Scientific Journals: Drugs of the Future 28(7), 640-646, 2003; Synthesis 2012, 44, 1074–1078; and Synthesis, (12), 905-8; 1989.
In the synthesis of Eszopiclone, the compound, 2-Amino-5-chloropyridine, of formula I:

is a key intermediate.
The synthesis of Eszopiclone was first described in the US’673 patent. Various processes for the preparation of 2-Amino-5-chloropyridine were reported in German Patent No. DE 400191C; U.S. Patent Nos. US 3,985,759 and US 5,274,100; and Scientific Journals: Journal of American Chemical Society 1946, 68, 3, 453-458; and Synthesis 2012, 44, 1074-1078.
The German Patent No. DE 400191 (hereinafter referred to as the DE’191 patent) discloses process for the preparation of 2-amino-5-chloropyridine and 2-amino-3,5-dichloropyridine is depicted in the below Scheme-1:

The synthesis of 2-amino-5-chloropyridine as described in scheme-1 of the DE‘191 patent involves the reaction of 2-aminopyridine with chlorine gas in presence of chloroform to produce a mixture of 2-amino-5-chloropyridine and 2-amino-3,5-dichloropyridine, which is treated with soda solution. Extraction is carried out either with chloroform or ether or the masses which separate out are distilled directly in vacuo to obtain a solid which was recrystallized from benzene or benzene petroleum ether.
The US Patent No. US 3,985,759 (hereinafter referred to as US‘759 patent) discloses various synthetic routes for the preparation of 2-amino-5-chloropyridine. The synthetic routes for the preparation of 2-amino-5-chloropyridine disclosed in the US‘759 patent [see Examples 1 to 3 of the US‘759 patent] are depicted in the below Scheme-2:

The synthesis of 2-amino-5-chloropyridine as disclosed in Examples 1 to 3 of the US‘759 patent involves the reaction of 2-Aminopyridine with liquid chlorine in presence of sulphuric acid or hydrochloric acid or acetic acid followed by tedious workup procedure to produce 2-amino-5-chloropyridine as a solid.
However, the processes for the preparation of 2-amino-5-chloropyridine described in the aforementioned prior art have the following disadvantages and limitations:
i) the prior art processes involve the use of chlorine gas or liquid chlorine which is very reactive with the human body and very toxic - it irritates the eyes and skin and, even at quite low levels, can cause permanent lung damage - breathing high levels of chlorine causes pulmonary edema-fluid buildup in the lungs - thereby making the process commercially unfeasible;
ii) the prior art processes produce huge amounts of the unwanted by-product 2-amino-3,5-dichloropyridine - thereby making the prior art processes commercially not viable; and
(iii) the yields and purity of 2-amino-5-chloropyridine obtained according to the prior art processes are very low;
(iv) the prior art processes involve the use of high toxic, highly flammable and carcinogenic solvents such as benzene or benzene petroleum ether; and
(v) the prior art processes involve the use of tedious and cumbersome workup methods and recrystallizations using highly toxic, highly flammable and carcinogenic solvents such as benzene or benzene petroleum ether.
The object of the present invention is to provide an improved, cost effective and industrially advantageous process for the preparation of 2-amino-5-chloropyridine with high purity to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
In one aspect, provided herein is a novel, commercially viable and industrially advantageous process for the preparation of 2-amino-5-chloropyridine.
It has been further surprisingly and unexpectedly found that 2-amino-5-chloropyridine of formula I can be prepared with high yield and high purity by reacting 2-aminopyridine of formula III with an acylating agent in a suitable solvent to produce a reaction mass containing N-acetylamino-pyridine intermediate, which is, in situ, reacted with a suitable chlorinating agent to produce N-acetylamino-5-chloropyridine of formula IIa, which is finally deprotected with a suitable deprotecting agent in a suitable solvent to produce 2-amino-5-chloropyridine of formula I.
The specific process for the preparation of 2-amino-5-chloropyridine of formula I as disclosed in the present invention may be represented by a schematic diagram as depicted below in Scheme-3:

The present invention avoids the problems associated with the processes described in the prior art, and which is more convenient to operate at laboratory scale and on commercial scale operations.
The process for the preparation of 2-amino-5-chloropyridine disclosed herein has the following advantages over the processes described in the prior art:
i) the process of the present invention involves the use of cheaper and easy to handle reagents like acetic anhydride and N-chlorosuccinimide thereby making the process cost effective;
ii) the process of the present invention produces the product with high yield and high purity - thereby making the process commercially viable and industrially advantageous;
iii) the process of the present invention avoids the use of highly toxic and highly reactive chlorine gas or liquid chlorine, thereby making the process environmental friendly;
iv) the process of the present invention avoids the use of tedious and cumbersome workup methods and recrystallizations involving the use of highly toxic, highly flammable and carcinogenic solvents;
v) the process of the present invention avoids the use of highly toxic, highly flammable and carcinogenic solvents such as benzene or benzene petroleum ether; and
vi) the process of the present invention avoids the formation of unwanted by-product 2-amino-3,5-dichloropyridine - thereby making the process commercially viable and industrially advantageous.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of highly pure 2-amino-5-chloropyridine of formula I:

or an acid addition salt thereof, which comprises:
a) reacting 2-aminopyridine of formula III:

or an acid addition salt thereof, with a suitable protecting agent of formula IV(a), IV(b), IV(c) or IV(d):

wherein the radical ‘R’ represents C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; to produce a reaction mass containing N-protected-amino-pyridine intermediate, followed by subsequent reaction with a suitable chlorinating agent to produce N-protected-amino-5-chloropyridine of formula II:

wherein the group ‘P’ represents an amino-protecting group selected from –C(O)R and –C(O)OR, and wherein the radical R is as defined above; and
b) deprotecting the N-protected-amino-5-chloropyridine of formula II by reacting with a suitable deprotecting agent in a suitable solvent to produce highly pure 2-amino-5-chloropyridine of formula I, and optionally converting the compound of formula I into an acid addition salt thereof.
Unless otherwise specified, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
Unless otherwise specified, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC. For example, “room temperature” can refer to a temperature of about 25ºC to about 30ºC.
Unless otherwise specified, the term ‘acid addition salts’, as used herein, include the salts that are derived from organic and inorganic acids. For example, the acid addition salts are derived from an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
The term “alkyl”, as used herein, denotes an aliphatic hydrocarbon group which may be straight or branched having 1 to 12 carbon atoms in the chain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain. The alkyl may be substituted with one or more “cycloalkyl groups”. Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, t-butyl, and n-pentyl.
The term “cycloalkyl”, as used herein, denotes a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms, preferably of about 5 to 10 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term “aralkyl”, as used herein, denotes an aryl-alkyl group wherein the aryl and alkyl are as herein described. Preferred aralkyls contain a lower alkyl moiety.
Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.
The term “aryl”, as used herein, denotes an aromatic monocyclic or multicyclic ring system of 6 to 10 carbon atoms. The aryl is optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Exemplary aryl groups include phenyl, tolyl, nitrophenyl or naphthyl.
Specifically, the radical ‘R’ in the compounds of formulae II, IV(a), IV(b), IV(c) and IV(d) is selected from the group consisting of methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, fluoromethyl, trifluoromethyl, phenyl, p-tolyl, benzyl, 4-nitrophenyl, 4-chlorophenyl, 3-nitrophenyl, 4-chlorobenzyl, p-methoxybenzyl and the like; and most specifically, R is methyl, ethyl, tert-butyl or p-tolyl.
In one embodiment, the amino-protecting group ‘P’ in the compound of formula II is selected from the group consisting of acetyl, propanoyl, butanoyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl, trichloroethxoycarbonyl (Troc), allyloxycarbonyl, t-butoxycarbonyl (BOC), pivaloyl and the like. A most preferred amino-protecting group ‘P’ is acetyl.
A most preferable N-protected-amino-5-chloropyridine of formula II obtained in the step-(a) is 2-acetylamino-5-chloropyridine of formula IIa (Formula II, wherein P is acetyl):

The use of the N-protected-amino-5-chloropyridine of formula II, specifically 2-acetylamino-5-chloropyridine of formula IIa, as a key intermediate in the preparation of 2-amino-5-chloropyridine of formula I as disclosed herein allows the product to be easily isolated with high purity and high overall yield.
Exemplary protecting agents used in step-(a) include, but are not limited to, acetyl chloride, acetyl bromide, propionyl chloride, butanoyl chloride, pivaloyl chloride, benzoyl chloride; carbonates such as di-tert-butyldicarbonate; alkyl chloroformates such methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tertiarybutyl chloroformate, n-butyl chloroformate; aryl chloroformates such as benzyl chloroformate, 4-nitrophenyl chloroformate; acid anhydrides such as acetic anhydride; and the like.
Specific protecting agent used in step-(a) is selected from the group consisting of acetyl chloride, acetic anhydride, propionyl chloride, benzoyl chloride and di-tert-butyldicarbonate; and a most preferable protecting agent is acetic anhydride.
Exemplary chlorinating agents used in step-(a) include, but are not limited to, N-chlorosuccinimide, t-butyl hypochlorite, oxalyl chloride, sulphuryl chloride, phosphorus pentachloride, phosphorous oxychloride, and the like. A most specific chlorinating agent used in step-(a) is N-chlorosuccinimide.
Exemplary solvents used in step-(a) include, but are not limited to, water, an alcohol, a ketone, an ester, a polar aprotic solvent, a halogenated hydrocarbon, and mixtures thereof. The term solvent also includes mixture of solvents.
Specifically, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. A most preferable solvent used in step-(a) is N,N-dimethylformamide.
In one embodiment, the reaction of 2-aminopyridine with the protecting agent in step-(a) is carried out at a temperature of about 20ºC to the reflux temperature of the solvent used; more specifically at a temperature of about 25ºC to about 100ºC, and most specifically at a temperature of about 50ºC to about 80ºC. The reaction time may vary between about 30 minutes to about 8 hours; and more specifically about 45 minutes to about 4 hours.
In another embodiment, the reaction of the N-protected-amino-pyridine intermediate formed, in situ, in the reaction with the chlorinating agent in step-(a) is carried out at a temperature of about 15ºC to about 80ºC; and more specifically at a temperature of about 40ºC to about 65ºC. The reaction time may vary between about 1 hour to about 45 hours; and more specifically about 20 hours to about 40 hours.
The reaction mass containing the N-protected-amino-5-chloropyridine of formula II obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula II may be isolated, purified and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula II obtained in step-(a) may be isolated, purified and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
In one embodiment, the deprotecting agent used in step-(b) is an acid or a base.
In another embodiment, the deprotecting agent used in step-(b) is an organic or inorganic base. Exemplary bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals; ammonia, sodium acetate, collidine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine, 1-alkylimidazole and the like. Specific bases are triethylamine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. A most preferable deprotecting agent used in step-(b) is sodium hydroxide or potassium hydroxide.
In another embodiment, the deprotecting agent used in step-(b) is an organic or inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, trifluoracetic acid, and mixtures thereof.
Exemplary solvents used in step-(b) include, but are not limited to, water, an alcohol, a ketone, an ester, a halogenated hydrocarbon, an ether, a polar aprotic solvent, and mixtures thereof. The term solvent also includes mixture of solvents.
In one embodiment, the solvent used for deprotection in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, dichloromethane, dichloroethane, chloroform, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. Specifically, the solvent used for deprotection in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, and mixtures thereof; and a most specific solvent used for deprotection is a mixture of water and methanol.
In one embodiment, the deprotection in step-(b) is carried out at a temperature of about 15ºC to about 100ºC; and more specifically at a temperature of about 30ºC to about 90ºC. The reaction time may vary between about 10 minutes to about 15 hours; and most specifically about 1 hour to 10 hours.
The reaction mass containing the 2-amino-5-chloropyridine of formula I obtained in step-(b) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the compound of formula I may be isolated, purified and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation, purification and/or recrystallization of the compounds of formula I and II obtained by the process described herein is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used for work up, isolation and/or recrystallization of the compounds of formula I and II obtained by the process described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, di-isopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.
The 2-amino-5-chloropyridine of formula I obtained by the above processes may be further dried to further lower residual solvents. Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 30°C to about 90°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 20 hours, and more preferably about 2 hours to 15 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The compound of formula IIa obtained by the process disclosed herein has a purity of greater than about 97%, specifically greater than about 98%, more specifically greater than about 99%, and most specifically greater than about 99.5% as measured by HPLC.
The compound of formula I obtained by the process disclosed herein has a purity of greater than about 97%, specifically greater than about 98%, more specifically greater than about 99%, and most specifically greater than about 99.5% as measured by HPLC.
The highly pure 2-amino-5-chloropyridine of formula I obtained by the process disclosed herein can be further converted to Eszopiclone by known methods described in the art, for example, as per the processes described in one or more of the following prior art patents and/or patent applications: US3862149, US3955918, US6444673, US7476737, US7786304, US8309723, EP2058313A2, and WO2009079939A1.
According to another aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of highly pure 2-amino-5-chloropyridine of formula I:

or an acid addition salt thereof, comprising deprotecting the N-protected-amino-5-chloropyridine of formula II:

wherein ‘P’ represents an amino-protecting group selected from –C(O)R and –C(O)OR, and wherein the radical ‘R’ represents C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl;
by reacting with a suitable deprotecting agent in a suitable solvent to produce highly pure 2-amino-5-chloropyridine of formula I, and optionally converting the compound of formula I into an acid addition salt thereof.
The preparation of the 2-amino-5-chloropyridine of formula I as described in the above process step can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
INSTRUMENTAL DETAILS:
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC system with UV detector or its equivalent under the following conditions: Inertsil ODS-3V, (250 × 4.6) mm, 5 µm; Detector wavelength = 235 nm; Flow Rate = 1.0 ml/minute; Injection volume = 10μL; Oven temperature = 30°C; Run time = 50 minutes; Diluent = A mixture of buffer and Acetonitrile 50:50 (v/v); Elution = Gradient; and Sample Concentration: 0.25 mg/ml.
Mobile Phase-A: A mixture of buffer and Acetonitrile 80:20 (v/v)
Mobile Phase-B: A mixture of buffer and Acetonitrile 30:70 (v/v)
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES
Example 1
Preparation of 2-Acetylamino-5-chloropyridine
N,N-dimethylformamide (200 mL) and 2-amino pyridine (100 g) were taken into a reaction flask at 25-30ºC and the resulting mixture was stirred for 5-15 minutes at the same temperature to obtain a clear solution. Acetic anhydride (131 g) was added to the resulting solution and the resulting mass was heated to 60-70ºC and then stirred for 2 hours to 2 hours 30 minutes at the same temperature. After completion of reaction, the resulting mass was cooled to 25-30ºC, followed by the addition of N-Chlorosuccinimide (171 g), and then stirring for 30 minutes to 1 hour at the same temperature. The reaction mass was heated to 40-45ºC and then stirred for 40 minutes at the same temperature. The reaction mixture was further heated to 50-55ºC and then stirred for 33-37 hours at the same temperature. The reaction mass was cooled to 25-30ºC, followed by the addition of water (1500 ml). The resulting mass was cooled to 20-25ºC and then stirred for about 1 hour to about 1 hour 15 minutes at the same temperature. The separated solid was filtered and then washed with water (120 ml) to produce 140 g of N-2-Acetylamino-5-chloropyridine as a light brown colored solid (Purity by HPLC: 99.77%).
Example 2
Preparation of 2-Amino-5-chloro pyridine
Methanol (140 ml) and 2-Acetylamino-5-chloropyridine (140 g) were taken into a reaction flask at room temperature. To the resulting mass, Sodium hydroxide solution [prepared by dissolving sodium hydroxide flakes (66 g) in water (400 ml)] was added, the resulting mixture was heated to 70-75ºC and then stirred for 3-4 at the same temperature. After completion of the reaction, excess of methanol solvent was distilled off under vacuum until the reaction mass volume reaches to half of its actual quantity. To the resulting residue, water (320ml) was added, followed by cooling the resulting mass to 20-25ºC and then stirred for 25-35 minutes at the same temperature. The separated solid was filtered and washed with water (115 ml) to obtain a wet material. Water (230 ml) was added to the resulting wet material, cooled the resulting mass to 20-25ºC and then stirred for 25-35 minutes at the same temperature. The separated solid was filtered, washed with water (100 ml) and then dried the material at 60-65ºC for 10-12 hours to produce 96 g of 2-Amino-5-chloro pyridine as a pale brown colour solid (Purity by HPLC: 99.68%).