FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF N-OXIDE OF HETEROCYCLES
2. APPLICANT:
(a) Name : LOBA CHEMIE PRIVATE LIMITED
(b) Nationality: An Indian Registered Company
(c) Address : 107, Woodhouse Road, Meherjit Co- Soc. Ltd, Colaba, Mumbai City, Mumbai-400005, Maharashtra, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD
The present disclosure relates to an improved, safe and scalable process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system. The process is simple, meets the industrial requirement of safety, cost-effectiveness and utility minimization.
BACKGROUND
In recent years, the importance of heterocyclic N-oxides is continuously growing in the field of research and industrial application. The N-oxide derivatives are integral part of several drug molecules and agrochemicals such as tirapazamine, an anticancer; pyrithione zinc as fungistatic and bacteriostatic. They have also been a promising lead compound in the new drug discoveries for HIV, Cancer, Tuberculosis and Type II Diabetes. Moreover N-oxide derivatives of substituted pyridine serve as a key raw material for synthesis of rabeprazole and antiulcer; lansoprazole, a proton pump inhibitor. The 2- and 4-substituted pyridine and quinoline N-oxides have high demand in drug development and are synthesized by Polonovski rearrangement in presence of acetic anhydride or trifluoroacetic acid.
There are several reagents used for the N-oxidation of heterocycles like peracetic acid/AcOH, perbenzoic acid, monoperpthalic acid, H2O2/AcOH, H2O2/[Mn (TDCPP)Cl], H2O2/MTO, BTSP/HOReO3, dimethyl dioxirane. The aforesaid reagents/methods have restricted application at the industrial scale due to safety concerns like explosions at elevated temperatures with the decomposition of oxidant and the product. Further all the methods have yield reported up to 78-80% at high temperature.
In recent year’s use of m-CPBA as an oxidation has increased. The journal article Current Med Chem. 2015; 22(24): 2819–2857 describes the synthesis of aminopyridine N-oxide using m-CPBA in dichloromethane, which is class 2 solvent being poses toxicity and high volatility. In journal article, inorganic Chemistry, 54(21), 10483-10489; 2015, N-oxidation of bromo substituted pyridine is given using m-CPBA and ether solvent and product yield was only 81% reported.
In PCT Publication No. WO2007/128694 oxidation of pyrifenchloride with m-CPBA in dichloromethane is given wherein, N-oxide is obtained in 91% yield but in the process, there is no mention of generated m-chlorobenzoic acid. US patent publication

US20050209274 describes the preparation of piperidinyl chromene carboxamides as antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor wherein 7-methyl quinoline is oxidized using m-CPBA in ethyl acetate solvent, this patent publication is silent about the yield of product and separation of m-chlorobenzoic acid. Chinese patent publication CN106810552 discloses the preparation of N-oxide-6-hydroxyquinoline in 83% in 6 hours heating and the product directly used in the next reaction without separating m-chlorobenzoic acid. PCT publication WO2012058529 describes the N-oxidation of quinoline-6-ol in ethyl acetate using m-CPBA as an oxidizing agent, after long 8 hours of heating, product yield was only 84%. US patent publication US20120149729 also discloses the similar process and reported product yield was 83%. Similarly, PCT publication(s) WO2003092695, WO2012064943, WO2014123167, WO2013024895, WO2006124863, WO2008072634, WO2012064943, WO2012064943, WO2015148597, WO2007125320 and US Patent publication(s) US20110144105, US8163732, and many others although disclose the N-oxidation of heterocycles using m-CPBA in ester especially ethyl acetate solvent, but none of these talks about separation of m-chlorobenzoic acid and solvent recovery.
WO2007096763 discloses the preparation of 5-methoxy-2-methylpyridine-1-oxide using m-CPBA in and ester solvent, wherein final product was 1:1 mixture of n-oxide and m-chlorobenzoic acid and without purification this mixture is used in further step.
It is apparent from the discussed prior arts that the literature is silent about the recovery of m-chlorobenzoic acid and recovery of solvent. Further in all these disclosed processes biphasic extractive workup used and due to water solubility of n-oxides this work up is not advisable options for product separation. To scale up the N-oxides manufacture in higher volumes, there arises a need for the development of a simplified process which meets the industrial requirement of safety, cost-effectiveness, minimizing utilities and waste.
The inventors of the present disclosure disclosed/invented the industrial process for the preparation of N-oxides of heterocycles using an organic oxidant m-CPBA under controlled conditions of solvent compatibility, mode of addition, temperature along with scavenging of excess peroxides in the reaction mixture and m-chlorobenzoic acid and solvent recovery. This process modification gives the highly pure product in higher yield.

OBJECTIVE
The objective of present disclosure is to provide an improved, safe and scalable process for
the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system.
Another objective of present disclosure is to provide an improved, safe and scalable
process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system
which is simple, meets the industrial requirement of safety, cost-effectiveness and utility
minimization.
Yet another objective of the present disclosure is to provide an improved, safe and scalable
process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system
which gives product N-oxides of heterocycles in quantitative yield and high purity.
Further objective of present disclosure is to provide an isolation process of N-oxides of
heterocycles from the reaction mixture in quantitative yield and high purity.
Further objective of present disclosure is to provide an improved, safe and scalable process
for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system wherein
generated m-chlorobenzoic acid is recovered by converting it to its ammonium salt.
A still further object of present disclosure is to provide an improved, safe and scalable
process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system
wherein 90% solvent is recovered from the reaction medium.
A still further object of present disclosure is to provide an improved, safe and scalable
process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system
wherein hazards-free workup procedure is developed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: Schematic diagram of the process flow of N-oxidation of pyridine.
FIG. 2a: 1 H NMR Spectra of pyridine-N-oxide
FIG. 2b: 13C NMR Spectra of pyridine-N-oxide
FIG. 2c: HRMS Spectra of pyridine-N-oxide
FIG. 2d: GC Chromatogram of pyridine N-oxide
FIG. 3a: 1 H NMR Spectra of 2-methyl pyridine-N-oxide
FIG. 3b: GC Mass Spectra of 2-methyl pyridine-N-oxide
FIG. 4a: 1 H NMR Spectra of 3-methyl pyridine-N-oxide
FIG. 4b: GC Mass Spectra of 3-methyl pyridine-N-oxide
FIG. 5a: 1 H NMR Spectra of 4-methyl pyridine-N-oxide
FIG. 5b: 13C NMR Spectra of 4-methyl pyridine-N-oxide

FIG. 5c: HRMS Spectra of 4-methyl pyridine-N-oxide
FIG. 6a: 1 H NMR Spectra of 2,3-dimethyl pyridine-N-oxide
FIG. 6b: 13C NMR Spectra of 2,3-dimethyl pyridine-N-oxide
FIG. 6c: HRMS Spectra of 2,3-dimethyl pyridine-N-oxide
FIG. 7a: 1 H NMR Spectra of 2,6-dimethyl pyridine-N-oxide
FIG. 7b: GC Mass Spectra of 2,6-dimethyl pyridine-N-oxide
FIG. 8a: 1 H NMR Spectra of 3,5-dimethyl pyridine-N-oxide
FIG. 8b: GC Mass Spectra of 3,5-dimethyl pyridine-N-oxide
FIG. 9a: 1 H NMR Spectra of 2-benzyl pyridine-N-oxide
FIG. 9b: GC Mass Spectra of 2-benzyl pyridine-N-oxide
FIG. 10a: 1 H NMR Spectra of 4-benzyl pyridine-N-oxide
FIG. 10b: 13C NMR Spectra of 4-benzyl pyridine-N-oxide
FIG. 10c: HRMS Spectra of 4-benzyl pyridine-N-oxide
FIG. 11a: 1 H NMR Spectra of 4-(4-nitro-benzyl) pyridine-N-oxide
FIG. 11b: 13C NMR Spectra of 4-(4-nitro-benzyl) pyridine-N-oxide
FIG. 11c: HRMS Spectra of 4-(4-nitro-benzyl) pyridine-N-oxide
FIG. 12a: 1 H NMR Spectra of 2, 2'-bipyridine-N, N'-dioxide
FIG. 12b: 13C NMR Spectra of 2, 2'-bipyridine-N, N'-dioxide
FIG. 12c: HRMS Spectra of 2, 2'-bipyridine-N, N'-dioxide
FIG. 13a: 1 H NMR Spectra of quinoline N-oxide
FIG. 13b: 13C NMR Spectra of quinoline N-oxide
FIG. 13c: HRMS Spectra of quinoline N-oxide
FIG. 14a: 1 H NMR Spectra of 2-methyl quinoline-N-oxide
FIG. 14b: 13C NMR Spectra 2-methyl quinoline-N-oxide
FIG. 14c: HRMS Spectra of 2-methyl quinoline-N-oxide
FIG. 15a: 1 H NMR Spectra of 8-hydroxy quinoline-N-oxide
FIG. 15b: GC Mass Spectra of 8-hydroxy quinoline-N-oxide

DETAILED DESCRIPTION
Accordingly, the present disclosure provides an improved, safe and scalable process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system.
Accordingly, the present disclosure relates to the process of the preparation of compounds of general formula (I) and (II),

Wherein,
R1 represents H, alkyl, hydroxy, nitro, C6H5CH2, O2NC6H4CH2, 2-pyridyl;
R2 represents H, alkyl, hydroxy, nitro;
R3 represents H, alkyl, hydroxy, nitro, unsubstituted or substituted cyclic ring structure
attached with the ring as “fused”, “bridged bicyclic” or “spiro” attachment and this ring
may be further substituted.
According to one other embodiment, compounds of general formula (I) and (II) are prepared by the process described in below scheme 1:

Scheme 1: Process for the preparation of N-oxide of heterocycles

According to another embodiment, the present disclosure provides an improved, safe and scalable process for the preparation of N-oxides of heterocycles of compound of general formula (I) and (II) using m-CPBA-NH3(g) system which comprises steps of:
a) charging the solvent and heterocyclic moiety in reaction vessel;
b) cooling the reaction solution of step, a) at suitable temperature;
c) adding the m-CPBA portion-wise to a solution of heterocyclic moiety of step b) while stirring;
d) stirring the solution of step c) for a suitable time at suitable temperature;
e) adding the solid sodium sulphite to the reaction mixture of step d);
f) lowering the reaction temperature of reaction mixture of step e);
g) purging the anhydrous ammonia gas to the reaction mixture of step f);
h) filtering the resultant slurry of step g);
i) isolating the product from the filtrate of step h);
j) recovering the solvent from the reaction mixture of step h); and
k) recovering the generated m-chlorobenzoic acid as a salt of ammonium m-chlorobenzoate from the filtered of reaction step of g). According to one another embodiment, the present disclosure provides an isolation process of N-oxides of heterocycles from the reaction mixture in quantitative yield and high purity. According to one another embodiment, the present disclosure provides an improved, safe and scalable process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system wherein generated m-chlorobenzoic acid is recovered by converting it to its ammonium salt.
According to one another embodiment, the present disclosure provides an improved, safe and scalable process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system wherein 90% solvent is recovered from the reaction medium.
According to one another embodiment, the present disclosure provides an improved, safe and scalable process for the preparation of N-oxides of heterocycles using m-CPBA-NH3(g) system wherein hazards-free workup procedure is developed.
As used herein, N-oxides of heterocycles refers to oxides of heterocycles having nitrogen in the ring system. The term heterocycles as referred in chemistry is the cyclic ring system in which one or more carbon atoms may be replaced by heteroatoms selected from the group consisting of N, O, and S; For the purpose of the present disclosure heterocycles is

N-heterocycles having nitrogen in the ring system. This heterocyclic ring may be 5-7 membered ring wherein atleast one of the ring carbon atoms is replaced by nitrogen atom. This heterocycles ring may be unsubstituted or substituted at one or more ring carbon atoms by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy; alkylthio; hydroxy; nitro; sulfoxy; carboxy; cyano; amide; halogen; haloalkyl and the like; when heterocyclic ring carbon atoms is substituted by another cyclic system, then 2 ring may be attached by “fused” ring structure; “bridged bicyclic” ring structure or “spiro” ring structure. When heterocyclic ring carbon atoms is substituted by another cyclic system then this cyclic system may also be substituted by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy, alkylthio, hydroxy; nitro; sulfoxy; carboxy; cyano, amide; halogen; haloalkyl and the like; For the purpose of present disclosure the preferred N-heterocycles includes pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, indole, pyridine, pyridazine, pyrimidine pyrazine, quinoline, isoquinoline and the like which may be unsubstituted or substituted at one or more ring carbon atoms by groups as described above.
As used herein, in the compounds of general formula (I) and (II), R1 represents H, alkyl, hydroxy, nitro, C6H5CH2, O2NC6H4CH2, 2-pyridyl; R2 represents H, alkyl, hydroxy, nitro; R3 represents H, alkyl, hydroxy, nitro, unsubstituted or substituted cyclic ring structure attached with the ring as “fused”, “bridged bicyclic” or “spiro” attachment and this ring may be further substituted by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy, alkylthio, hydroxy; nitro; sulfoxy; carboxy; cyano, amide; halogen; haloalkyl and the like. For the purpose of the present disclosure compounds of general formula (I) and (II) refers to oxides of heterocycles having nitrogen in the ring system. The term heterocycles as referred in chemistry is the cyclic ring system in which one or more carbon atoms may be replaced by heteroatoms selected from the group consisting of N, O, and S; For the purpose of the present disclosure heterocycles is N-heterocycles having nitrogen in the ring system. This heterocyclic ring may be 5-7 membered ring wherein atleast one of the ring carbon atoms is replaced by nitrogen atom. This heterocycles ring may be unsubstituted or substituted by R1, R2 and R3 at one or more ring carbon atoms by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-

aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy; alkylthio; hydroxy; nitro; sulfoxy; carboxy; cyano; amide; halogen; haloalkyl and the like; when heterocyclic ring carbon atoms is substituted by another cyclic system, then two ring may be attached by “fused” ring structure; “bridged bicyclic” ring structure or “spiro” ring structure. When heterocyclic ring carbon atoms is substituted by another cyclic system then this cyclic system may also be substituted by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy, alkylthio, hydroxy; nitro; sulfoxy; carboxy; cyano, amide; halogen; haloalkyl and the like; For the purpose of present disclosure the preferred N-oxide of heterocycles includes pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, indole, pyridine, pyridazine, pyrimidine pyrazine, quinoline, isoquinoline and the like which may be unsubstituted or substituted at one or more ring carbon atoms by groups as described above.
In the above description, the term "alkyl", used either alone or in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers.
"Alkenyl" includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1, 2-propadienyl and 2, 4-hexadienyl.
"Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2, 5-hexadiynyl.
"Cyclic alkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cyclic alkenyl includes, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. Cyclic alkynyl, similarly refers to cyclic pentynyl, hexynyl, heptynyl and octynyl.
The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. The term "aralkyl" refers to aryl hydrocarbon radicals including an alkyl portion as defined above. Examples include benzyl, phenylethyl, and 6-napthylhexyl. As used herein, the term "aralkenyl" refers to aryl hydrocarbon radicals including an alkenyl portion, as

defined above, and an aryl portion, as defined above. Examples include styryl, 3-(benzyl) prop-2-enyl, and 6-napthylhex-2-enyl.
The term "alkaryl" refers to an aryl group which bears an alkyl group; as used herein, the term "alkaryl" includes both substituted and unsubstituted groups. One example of an alkaryl group is the 4-methylphenyl radical.
"Alkoxy" includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers.
"Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine.
As described herein the present disclosure relates to a process for the preparation of N-oxides of heterocycles of compound of general formula (I) and (II) using m-CPBA-NH3(g) system. Particularly the present disclosure provides an eco-friendly process for preparation of N-oxides of unsubstituted or substituted pyridine and quinoline in quantitative yield and high purity. Specifically, the process comprises addition of a pyridine or quinoline in solvent under stirring. The temperature of the reaction solution is maintained at the range of 5-20°C, preferably the temperature of the reaction solution is maintained at 10-15°C. In the reaction solution 75% m-CPBA is added in 10 equal portions over a period of 45-50 minutes and stirred further for1 hour at 10-15°C. The temperature and time of addition of m-CPBA is a critical factor in the process. The suitable temperature for the addition of m-CPBA is 10- 25°C, preferably 10-15°C while stirring the reaction mixture for 1 hour at this temperature. The reaction temperature was maintained below 15°C during the addition. After the complete addition of m-CPBA in the reaction solution, the reaction solution was further stirred at 20-40°C for 2-6 hours, preferably the reaction mixture is further stirred for 4 hours at temperature 30-35°C. Completion of the reaction was monitored by gas chromatography. After completion of the reaction, solid sodium sulphite was added to the reaction mixture and stirred for 15 minutes. The peroxide content was checked with MN-Quantofix peroxide strip. The reaction mixture was cooled to 10-15°C and anhydrous ammonia gas was purged from the commercially available cylinder, at the rate of 30-40 bubbles per minute till the pH was raised to 8-9. The resultant slurry was filtered through celite bed and washed with solvent preferably isopropyl acetate 2 x 200 ml. The filtrate was transferred to the rotary evaporator and the product was isolated by evaporation of

solvent with 90% solvent recovery, which resulted in the viscous oily product which eventually crystallized on standing to furnish 99% pure products in 98% yield. The filtered ammonium m-chlorobenzoate is further treated to recover m-chlorobenzoic acid from the salt, ammonium m-chlorobenzoate. The salt, ammonium m-chlorobenzoate was dissolved in a suitable quantity of demineralized water followed by acidification with suitable quantity of 20% HCl. The above mixture is filtered and dried at temperature 95°C till constant weight to give m-chlorobenzoic acid, which can be recovered upto 96% with 99% purity by HPLC. Further this recovered m-chlorobenzoic acid can be recycled to m-CPBA using known literature processes.
For the purpose of disclosure, the solvent is selected from the class of solvents viz; chlorinated solvents such as dichloroethane dichloromethane; hydrocarbon solvents such as hexanes, cyclohexane and ester solvents such as ethyl acetate, isopropyl acetate and the like. The ester solvents such as ethyl acetate, isopropyl acetate is preferred.
As described above the temperature and time of addition of m-CPBA is a critical factor in the process. The suitable temperature for the addition of m-CPBA is 10- 25°C, preferably 10-15°C while stirring the reaction mixture for 1 hour at this temperature.
As described the product N-oxides heterocycles as prepared herein, can be characterized
by various techniques such as melting point, Thin layer chromatography, Gas
Chromatography, FTIR spectra, NMR spectra and GC-MS. Thin Layer Chromatography
was done on pre-coated silica gel plates (Kiesegel 60 F254Macherey-Nagel). Gas
Chromatography was performed on Shimadzu (model) with 8% OV-17 column 1.8 meter at 200°C on Isothermal mode and also on Gas chromatography was performed on Agilent 7890B with BP-5 column (30m X 0.32µm X 0.25 µm), injection temperature 240 °C, detector temperature 250 °C, initial temperature 100 °C for 2 min hold, final temperature 250 °C for 2 min hold, flow rate 1.2 ml/min, split ratio 83:1 and runtime 19 minutes. Peroxide content was checked on Macherey-Nagel Quantofix peroxide strips. The rate of flow of ammonia gas sparging was measured by Agilent ADM flow meter (G-6691-40500). FTIR spectra were recorded on Thermo scientific (Nicolet IS 5). NMR spectra were recorded on Agilent MR-400 using CDCl3 as a solvent and chemical shift reported as ppm downfield to TMS. Melting point was recorded on Veego VMP-CM. GC-MS was recorded on Agilent. HRMS of the representative compounds were recorded using Thermofischer scientific Q-Exactive plus Biopharma-High resolution Orbitrap, by the direct infusion method. The isothermal study was carried on RC1e with the AP01-0.5-

RTC-3w reactor, PTFE cover AP01-0.5, pitch blade stirrer 3-down. DSC measurements were performed with Mettler Toledo DSC 1 module, about 4mg of sample or solution 0.1 g/mL (unless stated) was taken in a 40µl high-pressure gold-plated crucible and measured with dynamic heating run from 25 °C to 400 °C. The nth order kinetic software is used to calculate activation energy and TMR.
Accordingly, Table 1 provides compounds of general formula (I) and (II), wherein R1, R2 and R3 have been defined wherein obtained product N-oxide yield, purity and M.P./B.P. also given.

Entry Substitution Yield Purity (%) b MP/BP d
(%) c °C
R1 R2 R3


1 H H - 98 99.8 65-66
2 2-CH3 H - 98.5 99.5 43-45
3 3- CH3 H - 98.4 99.4 38-39
4 4- CH3 H - 98.7 99.8 183-185
5 2- CH3 3- CH3 - 98.5 99.7 162-163
6 2- CH3 6- CH3 - 98.2 99.9 108-110d
7 3- CH3 5- CH3 - 98.4 99.0 102-104
8 2- C6H5CH2 H - 98.3 99.4 95-97
9 4- C6H5CH2 H - 98.6 99.5 92-94
10 4-O2NC6H4CH2 H - 98.5 99.8 153-155
11 2-pyridyl H - 98.6 99.8 68-69
12 H H H 98.2 99.7 136-138
13 2- CH3 H H 98.6 99.5 54-55
14 H H 8-OH 98.2 99.0 295-298

Purity by GC. cIsolated yield.
The main advantage of the present disclosure is that it provides an improved, safe and scalable process for the preparation of N-oxides of N-heterocycles using m-CPBA-NH3(g) system. The process is simple, meets the industrial requirement of safety, cost-effectiveness and utility minimization and possess various advantages over the prior arts such as in the present disclosure oxidation showed the quantitative conversion, while successfully separating the m-chlorobenzoic acid, which is generated during the reaction, by converting it to its ammonium salt using anhydrous ammonia gas in organic solvent, the produced ammonium m-chlorobenzoate precipitated from the reaction mixture, which was separated quantitatively by filtration on celite bed. Thus, the process enables the maximum recovery of m-chlorobenzoic acid and solvent and thus producing highly pure final N-oxide products. Further advantage of the present disclosure is that it provides an improved process for the preparation of N-oxides of N-heterocycles which avoids the extensive workup, purification steps, environmental stress and utility burden. Further the present invented process for the preparation of N-oxides of N-heterocycles is safe, cost-effective and scalable.
EXAMPLES:
Example1a: Pyridine N-oxide: In a 3L, 4 necked round bottomed flask arranged with an overhead stirrer, charged with pyridine (200.0 g, 2.52 mol) and isopropyl acetate (2.0 ltr) under stirring at 125 RPM. The reaction mixture was cooled to 10-15°C followed the addition of by 75% m-CPBA (610 g, 3.53 mol, 1.40 eq) in 10 equal portions over a period of 45-50 minutes and stirred further for 1hour at 10-15°C. After the complete addition, the reaction was further stirred at 30-35°C for 4 hours. The reaction was monitored by GC. After completion of the reaction, added solid sodium sulphite (2.0 g, 0.01mol) to the reaction mixture and stir for 15 minutes. The peroxide content was checked with MN-Quantofix peroxide strip. The reaction mixture was cooled to 10-15°C and anhydrous ammonia gas was purged from the commercially available cylinder, at the rate of 30-40 bubbles per minute till the pH was raised to 8-9. The resultant slurry was filtered through celite bed and washed with isopropyl acetate 2 x 200 ml. The filtrate was transferred to the rotary evaporator and the product was isolated by evaporation of solvent with 90% recovery, which resulted in the viscous oily product which eventually crystallized on

standing to furnish 99.6% pure 235.0 g, (98% yield) pyridine-N-oxide. The purity of the
product was determined by G.C. Melting point 65-66 °C.
1H NMR (CDCl3, 400MHz) δ 8.13 (dd, J = 5.4, 2.8 Hz, 2H), 7.21 (dd, J = 8.8, 6.4 Hz, 3H);
FTIR (neat) 3361, 3108, 1733, 1716, 1653, 1605, 1558, 1540, 1506, 1460, 1223, 1171,
1070, 1015, 914, 832, 765, 672 cm-1.
GC.MS m/z 95.0.
Example 1b: Pyridine N-oxide: In a 3L, 4 neck round bottomed flask arranged with an
overhead stirrer, charged with pyridine (200.0 g, 2.52 mol) and isopropyl acetate (2.0 ltr)
under stirring at 125 RPM. The reaction mixture was cooled to 10-15 °C followed the
addition of by 75% m-CPBA (610 g, 3.53 mol, 1.40 eq) in 10 equal portions over a period
of 45-50 minutes and stirred further for 1h at 10-15 °C. After the complete addition, the
reaction was further stirred at 30-35 °C for 4h. The reaction was monitored by GC. After
completion of the reaction, added solid sodium sulphite (2.0 g, 0.01 mol) to the reaction
mixture and stir for 15 minutes. The peroxide content was checked with MN-Quantofix
peroxide strip. The reaction mixture was cooled to 10-15 °C and anhydrous ammonia gas
was sparged from the commercially available cylinder, at the rate of 30-40 bubbles per
minute till the pH was raised to 8-9 while the excess ammonia was trapped in aqueous
solution of oxalic acid(5%w/v). The resultant slurry was filtered through celite bed and
washed with isopropyl acetate 2 x 200 mL. The filtrate was transferred to the rotary
evaporator and the product was isolated by evaporation of solvent with 90% recovery,
which resulted in the viscous oily product which eventually crystallized on standing to
furnish 235.0 g pyridine-N-oxide (98% yield, 99.6% purity). The purity of the product was
determined by G.C. Melting point 65-66 °C;
1H NMR (CDCl3, 400MHz) δ 8.13 (dd, J = 5.4, 2.8 Hz, 2H), 7.21 (dd, J = 8.8, 6.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 139.0, 138.5, 126.9, 126.1, 126.0, 77.6 77.3, 76.6;
IR (neat) 3361, 3108, 1733, 1716, 1653, 1605, 1558, 1540, 1506, 1460, 1223, 1171, 1070,
1015, 914, 832, 765, 672 cm-1;
HRMS elemental calculated for C5H5NO (MH+):95.0371; found: 95.0371.
Example 1c: Pyridine N-oxide: In a 50 L glass reactor, with Teflon blade stirrer equipped
in circulation bath with an external chiller of 14-16 L/min thermal fluid flow rate, was
charged isopropyl acetate (43.7 L 17.5 vol.) followed by pyridine (2.5 kg, 31.64 mol)
under stirring at 150 RPM. The reaction mixture was cooled to 10-15 °C while maintaining
the temperature 10-15 °C, m-CPBA (75% w/w) (7.62 kg, 44.15 mol, 1.40 equiv.) was

added in 10 equal portions. Each portion of m-CPBA was added in 15 mins and was aged for further 10 min before next lot addition. After complete lot additions, the reaction mass was maintained for further for 1h at 10-15 °C. The temperature of the reaction mixture was raised to 30-35 °C and was maintained for 4h. The reaction was monitored by GC. After completion of the reaction, added solid sodium sulfite (25.0 g, 0.19 mol) to the reaction mixture and stirred for 15 minutes. The peroxide content was determined by MN-Quantofix peroxide strip. The peroxide test was negative. The reaction mixture was cooled to 10-15 °C and anhydrous ammonia gas was sparged from the commercially available cylinder, at the rate of 100-110 mL/min for 1h, then the rate was increased to 150-180 mL/min for further 1h and 180-200 mL/min for 2h maintaining the temperature of reaction mass at between 10-15 °C to achieve the pH of the reaction mass to pH 8-9. The excess ammonia was scrubbed using common scrubber facility. The resultant slurry was filtered through Celite bed on S.S 316 L Nutsche filter and the filter cake was washed with isopropyl acetate 2 x 2.0 L. The filtrate was transferred to another 50 L glass reactor and the solvent was distilled by maintaining the thermal fluid bath temperature at 40-45 °C under vacuum (20 mm of Hg). After complete distillation of solvent, the residue was degassed for 15 mins to ensure complete removal of solvent traces. The viscous oily product was unloaded hot in HDPE container which eventually crystallized on standing to furnish 2.92 kg pyridine N-oxide (97% yield, 99.4% purity). The G.C graph of kilo scale batch was concordant with the standard pyridine N-oxide. Melting point 65-66 °C. Example 2:2-methyl pyridine-N-oxide: The experimental procedure was followed as for the synthesis of Example 1, 2-methyl pyridine-N-oxide was prepared using corresponding substrate (200.0g, 2.15mol) which produced 230.8g of product as white crystalline solid in 98.5% yield and 99.5% purity by GC. M.P 43-45°C.
1HNMR (CDCl3, 400MHz) δ 8.21 (d, J = 6.0 Hz, 1H), 7.26 - 7.00 (m, 3H), 2.46 (s, 3H); IR (neat) 3369, 3046, 1930, 1734, 1604, 1565, 1514, 1453, 1424, 1382, 1334, 1269, 1238, 1212, 1137, 1092,1038,1022,972,961, 924,864,810,773,744,732,698, 652cm-1. GC.MS m/z109.0.
Example 3:3-methyl pyridine-N-oxide: The experimental procedure was followed as for the synthesis of Example 1, 3-methyl pyridine-N-oxide was prepared using corresponding substrate (200.0g, 2.15mol) which produced 230.9g of product as white crystalline solid in 98.4% yield and 99.4% purity by GC.M.P 38-39°C. 1HNMR (CDCl3, 400MHz) δ 8.01 (d, J = 9.7 Hz, 2H), 7.17 - 7.02 (m, 2H), 2.26 (s, 3H);

IR (neat) 3290, 3063, 2923, 1716, 1699, 1683, 1635, 1602, 1559, 1540, 1506, 1482,1456,1419,1358,1306,1267,1157,1089,1037,1014,946,906,853,787,747,729,675cm-1.
GC.MS m/z109.0.
Example 4:4-methyl pyridine-N-oxide: The experimental procedure was followed as for the synthesis of Example 1, 4-methyl pyridine-N-oxide was prepared using corresponding substrate (200.0g, 2.15mol) which produced 231.3g of product as light yellow crystalline solid in 98.7% yield and 99.8% purity by GC.M.P 183-185°C.
1HNMR (CDCl3, 400MHz) δ 8.43 - 7.55 (m, 2H), 7.55 - 6.71 (m, 2H), 2.60 - 2.03 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 138.5, 126.7, 77.3, 77.0, 76.7, 20.2;
IR (neat) 3360, 3089, 3055, 3013, 1654, 1487, 1458, 1384, 1244, 1211, 1178, 1043, 852, 830, 757, 701, 658cm-1;
HRMS elemental calculated for C6H7NO (MH+):109.0527; found: 109.0528. Example 5: 2,3-dimethyl pyridine-N-oxide: The experimental procedure was followed as for the synthesis of Example 1, 2,3-dimethyl pyridine-N-oxide was prepared using corresponding substrate (200.0g, 1.86mol) produced 227.3g of product as light-yellow oil in 98.9% yield and 99.7% purity by GC.B. P 162-163°C.
1HNMR (CDCl3, 400MHz) δ 8.12 (d, J = 6.1 Hz, 1H), 7.09 - 6.82 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 148.4, 137.1, 134.9, 127.3, 122.0, 77.3, 77.0, 76.6, 19.4, 13.7;
IR (neat) 3307, 3059, 2358, 1692, 1600, 1570, 1487, 1458, 1425, 1387, 1240, 1218, 1098, 1075, 1024,994,907,810,705,685cm-1;
HRMS elemental calculated for C7H9NO (MH+):123.0684; found: 123.0684. Example 6: 2,6-dimethyl pyridine-N-oxide: The experimental procedure was followed as for the synthesis of Example 1, 2,6-dimethyl pyridine-N-oxide was prepared using corresponding substrate (200.0g, 1.86mol) which produced 225.6g of product as light yellow oil in 98.2% yield and 99.9% purity by GC. B.P 108-110°C.
1HNMR (CDCl3, 400MHz) δ 7.27 - 7.07 (m, 2H), 7.02 (dd, J = 8.5, 6.6 Hz, 1H), 2.48 (s, 6H);
IR (neat) 3419, 2953, 2917, 1683, 1653, 1563, 1540, 1498, 1455, 1418, 1371, 1240, 1160, 1099, 1034, 986, 919, 840, 767, 685cm-1; GCMS m/z 123.0

Example 7: 3,5-dimethyl pyridine-N-oxide: The experimental procedure was followed as
for the synthesis of Example1, 3,5-dimethyl pyridine-N-oxide was prepared using
corresponding substrate (200.0g, 1.86mol) which produced 225.9g of product as light
yellow crystalline solid in 98.3% yield and 99.0% purity by GC. M.P 102-104°C.
1HNMR (CDCl3, 400MHz) δ 7.88 (s, 2H), 6.89 (s, 1H), 2.22 (s, 6H);
IR (neat) 3375, 3057, 2475, 1679, 1601, 1582, 1459, 1385, 1310, 1159, 1050, 1028, 1006,
964,903,842,756,680cm-1;
GCMS m/z 123.0.
Example 8: 2-benzyl pyridine-N-oxide: The experimental procedure was followed as for
the synthesis of Example1, 2-benzyl pyridine-N-oxide was prepared using corresponding
substrate (200.0g, 1.18mol) which produced 215.3g of product as light yellow crystalline
solid in 98.4% yield and 99.4% purity by GC. M.P 95-97°C.
1HNMR (CDCl3, 400MHz) δ 8.33 - 8.21 (m, 1H), 7.37 - 7.30 (m, 2H), 7.26 (dd, J = 13.5,
5.4 Hz, 3H), 7.11 (dd, J = 9.3, 5.4 Hz, 2H), 6.94 - 6.87 (m, 1H), 4.24 (s, 2H);
IR (neat) 3105, 3050, 3026, 2912, 2360, 1951, 1685, 1601, 1555, 1487, 1450,
1435,1247,1223,1210,1181,1149,1099,1074,1044,1025,1001,973,930,885,860,824,795,
774,726,692,627, 614 cm-1;
GC.MS m/z185.0.
Example 9: 4-benzyl pyridine-n-oxide: The experimental procedure was followed as for
the synthesis of Example1, 4-benzyl pyridine-N-oxide was prepared using corresponding
substrate (200.0g, 1.18mol) which produced 216.0g of product as light yellow crystalline
solid in 98.6% yield and 99.5% purity by GC. M.P 92-94°C.
1HNMR (CDCl3, 400MHz) δ 8.08 (t, J = 12.3 Hz, 2H), 7.31 (t, J = 7.2 Hz, 2H), 7.28 -
7.19 (m, 1H), 7.13 (d, J = 7.3 Hz, 2H), 7.04 (d, J = 6.5 Hz, 2H), 3.92 (d, J = 12.7 Hz, 2H);
IR (neat) 3375, 3106, 3026, 1654, 1598, 1480, 1444, 1229, 1171, 1096, 1073, 1028, 929,
848, 795, 737, 713, 696 cm-1;
HRMS elemental calculated for C12H11NO (MH+):185.0840; found: 185.0857.
Example 10: 4-(4-nitro-benzyl) pyridine-N-oxide: The experimental procedure was
followed as for the synthesis of Example1, 4-(4-nitro-benzyl) pyridine-N-oxide was
prepared using corresponding substrate (200.0g, 0.933mol) which produced 211.7g of
product as pale yellow crystalline solid in 98.5% yield and 99.8% purity by GC.M.P 153-
155°C.

1HNMR (CDCl3, 400MHz) δ 8.15 (dd, J = 21.5, 7.7 Hz, 4H), 7.32 (d, J = 8.4 Hz, 2H), 7.04
(d, J = 6.6 Hz, 2H), 4.04 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 147.0, 145.5, 139.1, 138.2, 129.7, 126.3, 124, 77.4, 77.0,
76.7, 39.8;
IR (neat) 3113, 3036, 1663, 1606, 1593, 1510, 1473, 1447, 1339, 1234, 1202,
1196,1182,1170,1154,1117,1107,1029,1014,993,945,878,851,836,801,789,741,713,
691cm-1;
HRMS elemental calculated for C12H10N2O3 (MH+):230.0691; found: 230.0005.
Example 11: 2 2'-bipyridine-N,N'-dioxide: The experimental procedure was followed as
for the synthesis of Example 1, 2 2'-bipyridine-N,N'-dioxide was prepared using
corresponding substrate (200.0g, 1.28mol) which produced 237.4g of product as yellow
crystalline solid in 98.6% yield and 99.8% purity by GC.M.P 295-298°C.
1H NMR (D2O, 400MHz) 8.35 (d, J = 6.0 Hz, 2H), 7.72 (t, J = 7.3 Hz, 2H), 7.68 - 7.55 (m,
4H);
13C NMR (100 MHz, CDCl3) δ 141.7, 139.6, 131.3, 128.8, 128.3;
IR (neat) 3085, 3036, 2494, 2362, 2091, 1929, 1835, 1663, 1618, 1567, 1503, 1472,
1424,1296,1244,1145,1116,1096,1031,1019,981,957,891,836,759,721,630;
HRMS elemental calculated for C10H8N2O2 (MH+):188.0585; found: 188.0585.
Example 12: Quinoline-N-oxide: The experimental procedure was followed as for the
synthesis of Example 1, Quinoline-N-oxide was prepared using corresponding substrate
(200.0g, 1.55mol) which produced 221.9g of product as pale yellow crystalline solid in
98.6% yield and 99.5% purity by GC.M.P 54-55°C.
1HNMR CDCl3, 400MHz) δ 3.96 (d, J = 8.8 Hz, 1H), 3.76 (d, J = 6.0 Hz, 1H), 3.09 (d, J =
8.1 Hz, 1H), 3.03 - 2.92 (m, 2H), 2.86 (t, J = 7.5 Hz, 1H), 2.55 - 2.46 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 135.6, 130.4, 128.7, 128, 126.1, 120.9, 119.7, 77.3, 77.0,
76.6;
IR (neat) 3250, 3056, 1672, 1571, 1511, 1447, 1392, 1306, 1264, 1227, 1206, 1177,
1136,1092,1053,878,795,766, 723cm-1;
HRMS elemental calculated for C9H7NO (MH+):145.0527; found: 145.0539.
Example 13: 2-methyl quinoline-N-oxide: The experimental procedure was followed as
for the synthesis of Example 1, 2-methyl quinoline-N-oxide was prepared using
corresponding substrate (200.0g, 1.25mol) which produced 219.2g of product as pale
yellow crystalline solid in 98.6% yield and 99.8% purity by GC.M.P 68-69°C.

1HNMR CDCl3, 400MHz) δ 8.74 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.71 (dd, J = 8.5, 7.2 Hz, 1H), 7.66 - 7.49 (m, 2H), 7.27 (d, J = 8.5 Hz, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 130.3, 129.1, 127.9, 127.6, 125.2, 122.9, 119.4, 77.3, 77.0, 76.6, 18.7;
IR (neat) 3369, 3046, 1930, 1734, 1604, 1565, 1514, 1453, 1424, 1382, 1334, 1269,1238,1212,1137,1092,1038,1022,972,961,924,864,810,732,698, 652cm-1; HRMS elemental calculated for C10H9NO (MH+): 159.0684; found: 159.0688. Example 14: 8-hydroxy quinoline-N-oxide: The experimental procedure was followed as for the synthesis of Example 1, 8-hydroxy quinoline-N-oxide was prepared using corresponding substrate (200.0g, 1.18mol) produced 218.0g of product as pale yellow crystalline solid in 98.2% yield and 99.8% purity by GC.M.P 136-138°C. 1HNMR CDCl3, 400MHz) δ 8.22 (d, J = 5.9 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.30 - 7.17 (m, 3H), 7.05 (d, J = 7.9 Hz, 1H);
IR (neat) 3065, 1598, 1582, 1529, 1455, 1399, 1334, 1310, 1274, 1191, 1177, 1150, 1119, 1046, 885,873,813,787,748,665,624, 612cm-1. GCMS m/z 161.0.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure with specific examples. Thus, it is intended that the present disclosure covers the modifications and variations of this disclosure that come within the scope of any claims and their equivalents. Compounds of the present disclosure as defined by general formula (I) and (II) and/or in table 1 may be prepared, by processes as described in foregoing non-limiting examples and description, the various modification in the above processes and examples may be applied as to obtained the desired products and which are known to person skilled in the art and usually applied during preparation of chemicals.

WE CLAIM:
1. An improved process for the preparation of N-oxides of heterocycles of compounds
of general formula (I) and (II) using m-CPBA-NH3(g) system,

Wherein,
R1 represents H, alkyl, hydroxy, nitro, C6H5CH2, O2NC6H4CH2, 2-pyridyl;
R2 represents H, alkyl, hydroxy, nitro; and
R3 represents H, alkyl, hydroxy, nitro, substituted or substituted cyclic ring
structure attached with the ring as “fused”, “bridged bicyclic” or “spiro” attachment
and this ring may be further substituted.
2. An improved process for the preparation of N-oxides of heterocycles of compounds
of general formula (I) and (II) comprises the reaction of N-heterocycles with m-
CPBA-NH3(g) system as shown in below reaction scheme:

Wherein,
R1 represents H, alkyl, hydroxy, nitro, C6H5CH2, O2NC6H4CH2, 2-pyridyl;

R2 represents H, alkyl, hydroxy, nitro; andR3 represents H, alkyl, hydroxy, nitro, unsubstituted or substituted cyclic ring structure attached with the ring as “fused”, “bridged bicyclic” or “spiro” attachment and this ring may be further substituted.
3. An improved process for the preparation of N-oxides of heterocycles of compounds of general formula (I) and (II),

Wherein,
R1 represents H, alkyl, hydroxy, nitro, C6H5CH2, O2NC6H4CH2, 2-pyridyl;
R2 represents H, hydroxy, nitro, alkyl; and
R3 represents H, alkyl, hydroxy, nitro, unsubstituted or substituted cyclic ring structure
attached with the ring as “fused”, “bridged bicyclic” or “spiro” attachment and this
ring may be further substituted; comprises the steps of:
a) charging the solvent and heterocyclic moiety in reaction vessel;
b) cooling the reaction solution of step, a) at suitable temperature;
c) adding the m-CPBA portion-wise to a solution of heterocyclic moiety of step b) while stirring;
d) stirring the solution of step c) for a suitable time at suitable temperature;
e) adding the solid sodium sulphite to the reaction mixture of step d);
f) lowering the reaction temperature of reaction mixture of step e);
g) purging the anhydrous ammonia gas to the reaction mixture of step f);
h) filtering the resultant slurry of step g);
i) isolating the product from the filtrate of step h);
j) recovering the solvent from the reaction mixture of step h); and
k) recovering the generated m-chlorobenzoic acid as a salt of ammonium m-chlorobenzoate from the filtered of reaction step of g).

4. The process as claimed in claim 3, wherein in step a) solvents is selected from the class of solvents such as chlorinated solvents such as dichloroethane, dichloromethane; hydrocarbon solvents such as hexanes, cyclohexane and ester solvents such as ethyl acetate, isopropyl acetate and the like, preferably solvent is selected from ester solvents such as ethyl acetate, isopropyl acetate.
5. The process as claimed in claim 3, wherein in step a) heterocycles is selected from N-heterocycles having nitrogen in the ring system of 5-7 membered ring wherein atleast one of the ring carbon atoms is replaced by nitrogen atom and the heterocycles ring is unsubstituted or substituted at one or more ring carbon atoms by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy; alkylthio; hydroxy; nitro; sulfoxy; carboxy; cyano; amide; halogen; haloalkyl and the like; when heterocyclic ring carbon atoms is substituted by another cyclic system, then two ring may be attached by “fused” ring structure, “bridged bicyclic” ring structure or “spiro” ring structure; when heterocyclic ring carbon atoms is substituted by another cyclic system then this cyclic system is unsubstituted or substituted by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy, alkylthio, hydroxy; nitro; sulfoxy; carboxy; cyano, amide; halogen; haloalkyl and the like.
6. The process as claimed in claim 3, wherein in step a) heterocycles is selected from pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, indole, pyridine, pyridazine, pyrimidine pyrazine, quinoline, isoquinoline and the like which may be unsubstituted or substituted at one or more ring carbon atoms by groups by groups selected from C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl; cyclic C3-8-alkyl, C4-8-alkenyl, C5-8-alkynyl; C5-18-aryl, C7-19-aralkyl, C7-19-alkaryl; alkoxy; alkylthio; hydroxy; nitro; sulfoxy; carboxy; cyano; amide; halogen; haloalkyl and the like.
7. The process as claimed in claim 3, wherein in step b) the temperature of the reaction solution is in the range of 5-20°C, preferably the temperature of the

reaction solution is 10-15°C, and in step d) the temperature of the reaction solution is in the range of 20-40°C for 2-6 hours, preferably the reaction mixture is stirred for 4 hours at temperature 30-35°C and in step f) the temperature of the reaction solution is in the range of 10-15°C.
8. The process as claimed in claim 3, wherein in step j) 90% solvent is recovered from the reaction medium and in step k) generated m-chlorobenzoic acid is recovered by converting it to its ammonium salt.
9. An improved process for the preparation of highly pure N-oxides of heterocycles of compounds of general formula (I) and (II) in quantitative yield,

Wherein,
R1 represents H, alkyl, hydroxy, nitro, C6H5CH2, O2NC6H4CH2, 2-pyridyl; R2 represents H, alkyl, hydroxy, nitro; and
R3 represents H, alkyl, hydroxy, nitro, unsubstituted or substituted cyclic ring structure attached with the ring as “fused”, “bridged bicyclic” or “spiro” attachment and this ring may be further substituted; comprises the steps of oxidizing the N-heterocycles using m-CPBA-NH3(g) system while separating the generated m-chlorobenzoic acid by converting it to its ammonium salt using anhydrous ammonia gas in organic solvent and separating the ammonium m-chlorobenzoate by precipitation.
10. An improved process for the preparation of N-oxides of heterocycles of compounds
of general formula (I) and (II) using m-CPBA-NH3(g) system wherein compounds
of general formula (I) and (II) is/are pyridine-N-oxide, 2-methyl pyridine-N-oxide,
3-methyl pyridine-N-oxide, 4-methyl pyridine-N-oxide, 2,3-dimethyl pyridine-N-
oxide, 2,6-dimethyl pyridine-N-oxide, 3,5-dimethyl pyridine-N-oxide, 2-benzyl

pyridine-N-oxide, 4-benzyl pyridine-N-oxide, 4-(4-nitro-benzyl) pyridine-N-oxide, 2, 2'-bipyridine-N, N'-dioxide, quinoline N-oxide, 2-methyl quinoline-N-oxide, 8-hydroxy quinoline-N-oxide.