DESC:IMPROVED AND EFFICIENT PROCESS FOR THE PREPARATION OF HIGHLY PURE 2,4-DIAMINO-6-PIPERIDINO PYRIMIDINE 3-OXIDE

Field of the Invention
The present invention relates a method of preparation of 2,4-diamino-6-piperidino pyrimidine 3-oxide (Minoxidil). More particularly, the present invention relates to a cost effective and efficient process for producing Minoxidil.

Background of the Invention
Androgenetic alopecia is a pattern hair loss issue, and its prevalence increases with aging. 2,4-diamino-6-piperidino pyrimidine 3-oxide (minoxidil) is the conventional treatment for hair loss. Its topical application has been approved by the Food and Drug Administration 68for patients. Different formulations are being studied by researchers to enhance its effect along with lesser side-effects. It also possesses antihypertensive properties.
The different processes for production of minoxidil are reported to obtain good quality, quantity of product with lesser impurities. Such as treating 6-hydroxy-2,4-diaminopyrimidine with phosphorus oxychloride to synthesize 6-chloro-2,4-diamino pyrimidine and its reaction with phenolate to produce 6-phenoxy-2,4-diaminopyrimidine followed by N-oxidation using metachloroperbenzoic acid (MCPA). Final reaction with piperidine yields minoxidil [refer US3382247A Patent no. to W.C. Anthony and J.J. Ursprung]; oxidation of 6-hydroxy-2,4-diaminopyrimidine by the action of MCPA and finally treating with piperidine [refer Patent GB-A-No. 2032434]; preparing urea derivative of the diaminopyrimidines followed by its oxidation and final treatment with piperidine to obtain minoxidil [refer EP Patent no. 0304648B1 to J. Maignan, S. Restle, and G. Lang].
All the reported reactions include a common final step of piperidine treatment which gives minoxidil as the end-product and are very expensive and time consuming. However, this step is crucial because of the presence of 2-3% of intermediate (N-oxide) impurity in the final product, i.e., minoxidil and low yield up to 45-65% [refer US Patent no. 3644364A to W.C. Anthony; T.J. Delia and D.L. Venton, Journal of Heterocyclic Chemistry, 9.1, 73-75, 1972]. Various follow-up steps are done to reduce this percentage of intermediate to produce good quality and purer minoxidil which involve re-crystallization, chromatographic separation, etc. This purification step further compromises the yield of minoxidil by 50%.
It is, therefore, desirable to provide a method to obtain pure minoxidil of ICH grade with higher yield that simplifies the process and remove the additional steps of purification, which was earlier required in obtaining minoxidil, and obviates complexity and drawbacks associated with the prior arts.

Summary of the Invention
This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary may or may not be intended to identify key features or essential features of the claimed subject matter. Nor is this summary intended to be used to limit the claimed subject matter’s scope.

Both the foregoing summary and the following detailed description provide examples and are explanatory only. Accordingly, the foregoing summary and the following detailed description should not be considered to be restrictive. Further, features or variations may be provided in addition to those set forth herein. For example, embodiments may be directed to various feature combinations and sub-combinations described in the detailed description.

One objective of the present invention is to provide a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide which is cost effective and commercially viable.

Another objective of the present invention is to provide a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide using a catalyst in a shorter duration and lowering the temperature from 1050C to 80 0C.

Another objective of the present invention is to provide a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide with improved yield and quality as per Pharmacopeia.

According to one embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1),

comprising suspending 2,4-diamino-6-chloro pyrimidine having formula (1) in a polar solvent in a ratio of 1:6 to 1:14 w/v to obtain a suspension (A); adding an oxidizing agent in drop-wise manner to the suspension (A) under stirring at 0-25oC and heating it at 25-70° C under stirring for 1-10 hours till completion of reaction, to obtain a reaction mass; concentrating the reaction mass under vacuum 65-68° C, to obtain a residual mass; treating the residual mass with sodium hydroxide solution at 0-5oC or water at 65-68oC for 30-60 minutes and cooling down the treated residual mass to 0-5° C for 1 hour, to crystallize it; filtering and washing the crystallized residual mass with demineralised water (DM water) followed by vacuum drying at 50-80° C, to obtain off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2);

adding piperidine having water content of 6 to 80% to the obtained off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide followed by adding a catalyst under stirring to obtain another suspension (B); heating the suspension (B) for 2-5 hours at 80o-90o C with continue stirring, till the completion of reaction to obtain a reaction mixture; cooling the reaction mixture to 0-5° C up to a thick slurry or distilling off the reaction mixture under reduced pressure followed by cooling it to 0-5° C up to a thick slurry, to remove the piperidine; filtering the cooled thick slurry and washing the filtered thick slurry with a solvent for obtaining crude 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3), as another off white solid;

treating the another off white solid with aqueous ammonia solution, preferably 30% aqueous ammonia solution, at 50-55°C for 1-2 hours; cooling the aqueous ammonia solution treated another off white solid to 0-15° C and stirred for 1 hour followed by filtering the cooled another off white solid; and washing the filtered another off white solid with chilled DM water and drying it under vacuum oven at 70-75°C for 8-10 hours, to obtain off white crystals of 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3), for obtaining highly pure 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3) with high assay purity and reduced impurities in short duration.

According to the one exemplary embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said polar solvent is selected from ethanol, methanol, or DM water, preferably methanol.
According to one preferred embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said an oxidizing agent is meta-chloroperbenzoic acid solution in absolute ethanol or per-benzoic acid solution in ethyl acetate, or sodium tungstate dihydrate and hydrogen peroxide.
According to the one of the above embodiments of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said residual mass is a thick slurry.
According to the one preferred embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said crystallized residual mass is washed with chilled or lukewarm water.
According to the one of the above embodiments of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said method further comprises obtaining off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2) with high chromatographic purity and yield with less moisture content, from vacuum dried crystallized residual mass.
According to just above embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said method further comprises obtaining off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2) with high chromatographic purity and yield with less moisture content, from vacuum dried crystallized residual mass, wherein said obtained off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2) is further purified using aqueous ammonia solution at room temperature to remove its inorganic impurities slightly increasing the chromatographic purity.
According to the one of the above embodiments of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said method further comprises monitoring the reaction through HPLC after the addition of the oxidizing agent till the completion of reaction.
According to the one preferred embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said a catalyst is tetra butyl ammonium bromide.
According to the one preferred embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1), wherein said another solvent is acetone or chilled DM water.

Detailed Description of the Invention
The particulars shown herein are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual embodiments/aspects of the invention. In this regard, no attempt is made to show details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.
The various objectives and embodiments of present invention as presented herein are understood to be illustrative and not restrictive and are non-limiting with respect to the scope of the invention.

According to one embodiment of the present invention, there is provided a cost effective, time efficient, and industrially feasible process for producing 2,4-diamino-6-piperidino pyrimidine 3-oxide / Minoxidil, wherein said process enables a good yield with high purity.

According to one embodiment of the present invention, a process to produce 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) involves conversion of 2,4-diamino-6-chloropyrimidine 3-oxide having formula (2) to 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) using neat piperidine, wherein invariably 2-10% of 2,4-diamino-6-chloropyrimidine 3-oxide having formula (2) remains in the reaction and therefore, purification of the crude solid sacrifices 50% of yield in purification from solvents [Purity = 97.56%, Compound (2): 2.05%].

According to one embodiment of the present invention, multiple experiments have been conducted to produce 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloropyrimidine 3-oxide (2) using piperidine and various solvents such as but not limited to methanol, ethanol, acetone, acetonitrile, water; and a catalyst tetra butyl ammonium bromide (TBAB); and combination thereof.

To overcome this, a catalyst tetra butyl ammonium bromide (TBAB) is used in the reaction alongside piperidine with moisture content 6-12% which results in a drastic reduction of impurity below 0.10% level in the very short time (around two hours).

According to one embodiment of the present invention, using the catalyst TBAB, in nucleophilic substitution reaction, reduces compound (2) below 0.10%; reaction time from 7-8 hr to 2 hr; reaction temperature from 105°C to 80-90°C.
According to one embodiment of the present invention, there is provide a method, wherein using ammonia for purification steps appreciably reduces the inorganic and organic impurity to meet the assay and HPLC purity as per Pharmacopoeia.
According to one exemplary embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) or Minoxidil, wherein a reaction is performed from 2,4-diamino-6-chloropyrimidine 3-oxide (2) to 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) followed by purifying the obtained crude 2,4-diamino-6-piperidino pyrimidine 3-oxide having formula (3) through re-reaction with piperidine and in presence of catalyst TBAB, to achieve pure minoxidil (Yield – 76%, HPLC Purity – 99.78%, Compound (2) – 0.10%).

General Reaction Scheme
According to one another exemplary embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-chloropyrimidine 3-oxide (2) from 2,4-diamino-6-chloropyrimidine (1):

EXAMPLE 1

Reaction Scheme
Preparation of 2,4-diamino-6-chloropyrimidine 3-oxide (2):
42 g of 2,4-diamino-6-chloropyrimidine (1) is dissolved in 294 mL of absolute ethanol in RB flask to make a suspension and a cool suspension of meta-chloroperbenzoic acid (0.52 moles) in absolute ethanol (504 mL) is added to it in dropwise-manner under stirring at 15-20° C and maintained for 8 hr at 25-30° C for oxidizing the 2,4-diamino-6-chloropyrimidine (1) suspension.
Further, the reaction mass is then concentrated under vacuum to residual semisolid which is further treated with 5% sodium hydroxide solution (420 mL) at 25° C for half an hour, brought down the temperature at 0-5° C to crystallize for 2 hrs. Obtained solid is filtered and washed with chilled water (42 mL), dried in vacuum oven at 55-60° C to afford off white solid 40.70 g [HPLC purity – 98.51%],
EXAMPLE 2

Reaction Scheme
Preparation of 2,4-diamino-6-chloropyrimidine 3-oxide (2):
To a stirred suspension of 90g of 2,4-Diamino-6-chloropyrimidine (1) in 1.3L methanol, a solution of oxidizing agent containing 267g of per-benzoic acid dissolved in 425mL Ethyl acetate at 0-5° C, is added in drop-wise manner. The reaction mixture is warmed to 25-30° C under stirring and further is heated at 40-45° C till completion of oxidation reaction followed by monitoring on HPLC.
Further, the reaction mass is concentrated under vacuum to get thick slurry and then treated with 1.54L of 7% aqueous sodium hydroxide solution at 0-5° C for 1 hr. Solid is filtered and treated with 920mL of water at 50-55°C. Filtered the solid and vacuum dried at 75-80°C to get the 2,4-diamino-6-chloropyrimidine 3-oxide (2) 84.6g [HPLC purity: 98.72%, ROI: 0.8%, Moisture content: 0.82].

EXAMPLE 3

Reaction Scheme
Preparation of 2,4-diamino-6-chloropyrimidin 3-oxide (2):
To a stirred suspension of 2,4-Diamino-6- chloropyrimidine (1) (50.0g) in 300 mL of Methanol, an oxidizing solution involving sodium tungstate dihydrate (1.14g) (at room temperature) followed by drop wise addition of 30 % hydrogen peroxide (30 mL), is added and stirred the reaction mass for 10 min at room temperature. The temperature of reaction mass is raised to 65-68o C under stirring for 1 hr followed by its monitored using HPLC after completion of reaction (approx. 8-10 hr).

Reaction mass is concentrated under vacuum to a thick slurry at 65-68° C followed by water treatment with 500mL at 60-65° C and is maintained for half an hour. The temperature of reaction mass is brought down to 0-5° C under stirring for 1 hr. Solid is filtered and wash with chilled water (50 mL) and dried at 70-75°C for 8-10 hr to get 2,4- Diamino-6-chloropyrimidine-3-oxide (42.60g) [HPLC Purity 97.08%, ROI: 1.19%, water content – 1.34%].

According to one embodiment of the present invention, there is provided a method for purifying crude 2,4-diamino-6-chloropyrimidine-3-oxide (2), wherein to a stirred suspension of 2,4-diamino-6-chloropyrimidine-3-oxide (2) (40.0 g) in 272 mL of DM water, 60 mL of 30% aqueous ammonia is added under stirring at room temperature and maintained for 2 hr at 50-55°C followed by bringing down the temperature of reaction mass to 10-15°C and maintained for 1 hr, wherein the cooled reaction mass is washed with 40 mL of DM water and dried under vacuum at 70-75°C for 7-8 hr to get pure 2,4-diamino-6-chloropyrimidine-3-oxide (39.90g) [HPLC Purity: 98.88%, ROI: 0.27%, water content: 0.41%].
According to another exemplary embodiment of the present invention, there is provided a method for preparing 2,4-diamino-6-piperidinopyrimidine 3-oxide (3) from 2,4-diamino-6-chloropyrimidin 3-oxide (2):

Example 4

Reaction Scheme
Preparation of 2,4-diamino-6-piperidinopyrimidine 3-oxide (3):
39 g of 2,4-diamino-6-chloropyrimidin 3-oxide (2) is refluxed with 507mL of piperidine (6-12% moisture) for 6 to 8 hr. After completion of reaction, reaction mixture is cooled to 0-5° C under stirring, the solid is filtered under vacuum, and washed with chilled water (80 mL) and dried in vacuum oven to yield 49.80 g of crude 2,4-diamino-6-piperidinopyrimidine 3-oxide (3) [HPLC Purity: 97.56%; compound (2): 2.05%].
Purifications with different solvent/(s) in combinations are tried as given in table 1, however, the desired yield and quality are not achieved.
Table 1. Different solvents used for purification.
Solvent Input (g) Output (g) Yield (%) Minoxidil N-Oxide
Water 2 1.12 56% 99.74% 0.11%
IPA:Water (6:3 v/v) 2 1.06 53% 99.74% 0.21%
Water 2 1.23 62% 99.24% 0.66%
IPA:Water (8:3 v/v) 2 0.84 42% 99.60% 0.37%
Water:Acetic acid 2 1.54 77% 99.61% 0.27%
Acetone:AcOH (5:50% v/v) 5 1.78 35.60% 99.77% 0.21%

EXAMPLE 5

Reaction Scheme
Preparation of 2,4-diamino-6-piperidinopyrimidine 3-oxide (3):
To a stirred suspension of 38g of 2,4-diamino-6-chloropyrimidin 3-oxide (2) in 600mL of piperidine (containing 6-12% moisture content), 0.76g of TBAB is added. The suspension is heated to 80-90o C under stirring for 2 hr, reaction is monitored by HPLC. After the completion of reaction, piperidine is distilled off under reduced pressure up to thick slurry, which is treated with acetone (228mL) to obtain crude 2,4-diamino-6-piperidinopyrimidine 3-oxide (3) (59.9g) [HPLC Purity: 99.56%, Compound (2): 0.12%, Deoxyminoxidil: 0.14%, Water content: 1.18%, Assay content: 63.03%].
Further for purification, crude 2,4-diamino-6-piperidinopyrimidine 3-oxide (3) (58.2g), is stirred with 395ml DM water and 30% aqueous ammonia solution at 50-55°C for 1 hr. The reaction mass is cooled to 0-5° C and maintained for 1 hr under stirring. Solid is filtered and washed with 50 mL of DM water and dried under vacuum at 70-75°C for 8-10 hr to afford off white solid Minoxidil / 2,4-diamino-6-piperidinopyrimidine 3-oxide (3) (34.05g) [HPLC purity 99.76%, Compound (2) – below detection level, Deoxyminoxidil – 0.15%, ROI-0.08%, Water content – 0.27%, Assay content – 99.07%].

EXAMPLE 6

Reaction Scheme
Preparation of 2,4-diamino-6-piperidinopyrimidine 3-oxide (3):
To a stirred suspension of 10g of 2,4-diamino-6-chloro-pyrimidine 3–oxide (2) in 80mL of demineralised water (DM water), 16g of Piperidine and 0.2g of TBAB are added and heated to 80-90o C under stirring till reaction completion (approx. 4-5 hr). The reaction is monitored by HPLC. After the completion of reaction, the reaction mass is allowed to cool to 0-5° C, stirred for 1 hr and filtered, washed the solid with 10mL of chilled DM water.
Further, it is stirred with 15mL of 30% aqueous ammonia solution at 50-55° C and maintained for 2 hr. The reaction mass is cooled to 10-15° C and stirred for 1 hr and filtered, washed with chilled DM water and dried under vacuum at 70-75°C for 8-10 hr to afford off white solid Minoxidil / 2,4-diamino-6-piperidinopyrimidine 3-oxide (3) (8.67g) [HPLC Purity: 99.65%, Compound (2): 0.02%, deoxyminoxidil: 0.28%, ROI: 0.06%, Assay content (ODB): 98.41%].

EXAMPLE 7

Reaction Scheme
Preparation of 2,4-diamino-6-piperidinopyrimidine 3-oxide (3):
To a stirred suspension of 7g of 2,4-diamino-6-chloro-pyrimidine 3–oxide (2) in 56 mL of DM water, 11.15g of piperidine is added followed by addition of 12mL of 30% aqueous ammonia solution. The mixture is heated to 80-90o C under stirring till the completion reaction (approx. 4-5 hr), with continuous monitoring of reaction by HPLC. After completion of reaction, the reaction mass is allowed to cool to 0°-5° C under stirring for 1 hr, the solid is filtered, washed with chilled DM water, and dried under vacuum at 70-75°C for 8-10 hr to obtain off white solid Minoxidil (6.42g) [HPLC Purity: 99.14%, Compound (2): 0.02%, Deoxyminoxidil: 0.64%, ROI: 0.06%, Assay content (ODB): 95.26%].
While this provisional specification has been described covering the scope of the present invention in detail with reference to certain aspect and examples, it should be appreciated that the present provisional specification is not limited to those precise aspects and examples and can be modified and expanded within the scope of the present invention while filing a complete application.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description and examples given above are intended to illustrate and not to limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof that do not depart from the spirit and scope of the invention. ,CLAIMS:We Claim:

1. A method for preparing 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3) from 2,4-diamino-6-chloro pyrimidine having formula (1),

comprising:
suspending 2,4-diamino-6-chloro pyrimidine having formula (1) in a polar solvent in a ratio of 1:6 to 1:14 w/v to obtain a suspension (A);
adding an oxidizing agent in drop-wise manner to the suspension (A) under stirring at 0-25oC and heating it at 25-70° C under stirring for 1-10 hours till completion of reaction, to obtain a reaction mass;
concentrating the reaction mass under vacuum 65-68° C, to obtain a residual mass;
treating the residual mass with sodium hydroxide solution at 0-5oC or water at 65-68oC for 30-60 minutes and cooling down the treated residual mass to 0-5° C for 1 hour, to crystallize it;
filtering and washing the crystallized residual mass with demineralised water (DM water) followed by vacuum drying at 50-80° C, to obtain off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2);

adding piperidine having water content of 6 to 80% to the obtained off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide followed by adding a catalyst under stirring to obtain another suspension (B);
heating the suspension (B) for 2-5 hours at 80o-90o C with continue stirring, till the completion of reaction to obtain a reaction mixture;
cooling the reaction mixture to 0-5° C up to a thick slurry or distilling off the reaction mixture under reduced pressure followed by cooling it to 0-5° C up to a thick slurry, to remove the piperidine;
filtering the cooled thick slurry and washing the filtered thick slurry with a solvent for obtaining crude 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3), as another off white solid;

treating the another off white solid with aqueous ammonia solution, preferably 30% aqueous ammonia solution, at 50-55°C for 1-2 hours;
cooling the aqueous ammonia solution treated another off white solid to 0-15° C and stirred for 1 hour followed by filtering the cooled another off white solid; and
washing the filtered another off white solid with chilled DM water and drying it under vacuum oven at 70-75°C for 8-10 hours, to obtain off white crystals of 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3),

for obtaining highly pure 2,4-diamino-6-piperidinopyrimidine 3-oxide having formula (3) with high assay purity and reduced impurities in short duration.

2. The method as claimed in claim 1, wherein said polar solvent is selected from ethanol, methanol, or DM water, preferably methanol.

3. The method as claimed in claim 1, wherein said an oxidizing agent is meta-chloroperbenzoic acid solution in absolute ethanol or per-benzoic acid solution in ethyl acetate, or sodium tungstate dihydrate and hydrogen peroxide.

4. The method as claimed in claim 1, wherein said residual mass is a thick slurry.

5. The method as claimed in claim 1, wherein said crystallized residual mass is washed with chilled or lukewarm water.

6. The method as claimed in claim 1, wherein said method further comprises obtaining off white solid of 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2) with high chromatographic purity and yield with less moisture content, from vacuum dried crystallized residual mass.

7. The method as claimed in claims 1 and 7, wherein said 2,4-diamino-6-chloropyrimidine-3-oxide having formula (2) is further purified using aqueous ammonia solution at room temperature to remove its inorganic impurities slightly increasing the chromatographic purity.

8. The method as claimed in claim 1, wherein said method further comprises monitoring the reaction through HPLC after the addition of the oxidizing agent till the completion of reaction.

9. The method as claimed in claim 1, wherein said a catalyst is tetra butyl ammonium bromide.

10. The method as claimed in claim 1, wherein said solvent is acetone or chilled DM water.