DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

AN IMPROVED PROCESS FOR PREPARING 2-CHLOROMETHYL-3, 4-DIMETHOXY PYRIDINE HYDROCHLORIDE

We, AKTINOS PHARMA PRIVATE LIMITED,
a company incorporated under the companies act, 1956 having address at 4 & 5th Floor, Sri Lakshmi Spaces, Plot No. 7, Phase-I, Kavuri Hills, Madhapur, Hyderabad- 500033, Telangana, India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Pantoprazole intermediate or its pharmaceutically acceptable salts.

The present invention specifically relates to an improved process for the preparation of compound of Formula (I).

Formula (I)

The present invention more specifically relates to an improved process for the preparation of compound of Formula (I) using maltol or 3-hydroxy-2-methyl-pyran-4-one or 4-chloro-3-methoxy-2-methylpyridine.

The present invention more specifically relates to an improved process for the preparation of compound of Formula (I) using maltol or 3-hydroxy-2-methyl-pyran-4-one or 4-chloro-3-methoxy-2-methylpyridine, wherein the intermediates formed in some of the steps are not isolated.

BACKGROUND OF THE INVENTION
The active ingredient in PROTONIX (Pantoprazole sodium) is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical Formula is C16H14F2N3NaO4S x 1.5 H2O, with a molecular weight of 432.4. The structural Formula is:

Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane.

The compound of Formula (I) is a key intermediate in the preparation of Pantoprazole.

Formula (I)
Pantoprazole is disclosed first time in US 4,758,579 A. The compound of Formula (I) can be prepared according to the disclosure of this patent starting from 3-hydroxy-5-alkyl pyridines which are known or conventionally prepared from known starting materials.

US 4,686,230 A discloses preparation of 2-chloromethyl-3,4-dimethoxy pyridine using acetic anhydride and NaOH followed by chlorination using thionyl chloride in dichloromethane. However, the patent does not enable the use of methanol and acetone in the preparation of chloromethyl pyridine intermediate.

US 6,525,066 B2 specifically discloses process for the preparation of 4-chloro-3-methoxy-2-methylpyridine-N-oxide using acetic acid, CHCl3 and Na2CO3.

Journal of Medicinal Chemistry, 1992, Vol 35 (6), Page 1049–1057 discloses a process for the preparation of 3,4-dimethoxy-2-methylpyridine-N-oxide using POCl3, H2O2 followed by methoxylation using sodium methoxide. The dimethoxy intermediate is extracted using hot toluene.

However, the journal does not disclose the use of aq.NH3/NH3 gas, sodium tungstate and in-situ dimethoxy intermediate.

Journal of Medicinal Chemistry, 1995, Vol 38, pg 4906-4916 discloses a process for the preparation of chloromethoxy-2-methylpyridine using methyl iodide and K2CO3 followed by amination using conc. NH3 then chlorination using POCl3 as depicted in the scheme given below.

CN 101875629 B discloses an industrial preparation method of Pantoprazole intermediate as shown below:

However, the patent neither envisaged nor enabled a process for the preparation of 4-chloro-3-methoxy-2-methylpyridine-N-oxide using CHCl3 in methoxylation and sodium tungstate in addition to H2O2 in in-situ formation of N-oxide formation.

CN 102060760 B claims a method for preparing pyridine N-oxide, using pyridine, phosphorus-tungsten-silicon composite catalyst. However, this patent does not disclose the use of NaOH and CHCl3 in oxidation reaction.

CN 102304083 A claims a method for preparing 2-chloromethyl-3,4-dimethoxypyridine hydrochloride using maltol as a raw material, followed by methylation, amination, chlorination, oxidation, methoxy substitution, hydroxymethylation, and secondary chlorination give 2-chloromethyl-3,4-dimethoxypyridine hydrochloride.

However, the patent does not enable the use of ammonia or ammonia gas and toluene in amination reaction for aminating ring oxygen.

CN 107129466 A claims a method for synthesizing Pantoprazole intermediate 4-chloro-3-methoxy-2-methylpyridine-N-oxide using phosphotungstic acid solution.

Environmental Clearance–RP industries discloses preparation of dimethoxy chloromethyl pyridine HCl using thionyl chloride in acetone.

It is evident from the prior art that multiple steps are required for the synthesis of compound of the present invention. The intermediates involved for the synthesis need to be isolated at various steps and further purification is required to get the desired purity of the final product. The use of multiple steps in the prior art results in a lower yield of compound of Formula (I).

None of the prior art discloses a process for preparing compound of Formula (I) without isolating the intermediates. The present invention is an improved process for preparing compound of Formula (I) without isolating the intermediates in each step involved in the synthesis and by using sodium tungstate-hydrogen peroxide for N-oxidation step in good yields.

OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide an improved process for the preparation of pantoprazole intermediate.

Another objective of the invention is to provide a process for the preparation of compound of Formula (I) using maltol or 3-hydroxy-2-methyl-pyran-4-one or 4-chloro-3-methoxy-2-methylpyridine, wherein the intermediates formed in some of the steps are not isolated.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of Formula (I)

Formula (I)
comprising:
a) oxidizing pyridine ring nitrogen of compound of Formula (II)

Formula (II)
using an oxidation catalyst in an acid and optionally in a solvent to give compound of Formula (III),

Formula (III)
b) converting chlorine group of compound of Formula (III) to methoxyl group using methoxylating agent in presence of solvent to give compound of Formula (IV),

Formula (IV)
c) 2-hydroxylation of compound of Formula (IV) using acetic anhydride in presence of a base and solvent to give compound of Formula (V)

Formula (V)
in one pot reaction without isolating intermediate compounds of Formula (III), (IV) and (V),
d) chlorinating the 2-hydroxy methyl group of compound of Formula (V) with chlorinating agent in presence of a solvent to give compound of Formula (I) or its salts, and
e) isolating compound of compound of Formula (I) using a solvent as its hydrochloride salt.

In another aspect, the present invention provides an in-situ process for preparation of compound of Formula (V)

Formula (V)
comprising
a) oxidizing pyridine ring nitrogen of compound of Formula (II)

Formula (II)
using an oxidation catalyst in an acid and optionally in a solvent to give compound of Formula (III),

Formula (III)
b) converting chlorine group of compound of Formula (III) to methoxyl group using methoxylating agent in presence of solvent to give compound of Formula (IV), and

Formula (IV)
c) 2-hydroxylation of compound of Formula (IV) using acetic anhydride in presence of a base and solvent to give compound of Formula (V)

Formula (V)
in one pot reaction without isolating intermediates compounds of Formula (III) and (IV).

In yet another aspect, the present invention provides an improved process for the conversion of compound of Formula (V)

Formula (V)
prepared as per the process of the present invention to compound of Formula (I).

Formula (I)

In yet another aspect, the present invention provides an improved process for
the preparation of compound of Formula (II)

Formula (II)
wherein the process comprising:
a) methylating hydroxyl group of compound of Formula (VIII)

Formula (VIII)
using methylating agent in presence of a base and a solvent selected from dichloromethane, chloroform, ethers, esters or hydrocarbons to form compound of Formula (VII),

Formula (VII)

b) aminating 4-H pyran ring oxygen of the compound of Formula (VII)

Formula (VII)
using aqueous NH3 in presence of a solvent to give compound of Formula (VI),

Formula (VI)
and
c) chlorinating the hydroxyl group of compound of Formula (VI)

Formula (VI)
using chlorinating agent to give compound of Formula (II).

In yet another aspect the present invention provides an improved process for the conversion of compound of Formula (VI)

Formula (VI)
prepared as per the process of the present invention to compound of Formula (I).

Formula (I)

In yet another aspect the present invention provides an improved process for the conversion of compound of Formula (VII)

Formula (VII)
prepared as per the process of the present invention to compound of Formula (I).

Formula (I)

In yet another aspect the present invention provides an improved process for the conversion of compound of Formula (VIII)

Formula (VIII)
prepared as per the process of the present invention to compound of Formula (I).

Formula (I)

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for preparing pantoprazole intermediate or its pharmaceutically acceptable salts.

In one embodiment of the present invention, the oxidation catalyst as used herein is selected from a salt of tungstate or molybdate and hydrogen peroxide, preferably sodium tungstate in acetic acid and hydrogen peroxide. The temperature ranges from 40-60 ºC or 70-80 ºC and reaction generally requires 6-10 hours. Pure compound may be obtained by adjusting pH to basic followed by extraction with a solvent like chloroform and concentration of the solvent. Addition of sodium methoxide solution followed by maintaining the reaction at 70-80 ºC for 8-9 hours accomplishes the conversion of chloro to methoxy group and to obtain compound of Formula (IV). The pH of the reaction mass at this stage is basic and can be adjusted to pH 7.0-7.5 by adding acid like acetic acid. Impurities any may be removed by adding methanol and distilling, followed by toluene. Hydroxylation of 2-methyl group can be achieved by adding acetic anhydride in a solvent like chloroform and maintaining the reaction mixture at 80-85 ºC for about 8 hrs. The pH may be adjusted to basic. Solvent like chloroform or dichloromethane may be used for extraction of required compound followed by distillation of solvent to obtain compound of Formula (V). Finally the compound of Formula (I) may be isolated by reacting 2-hydroxymethyl-3,4-dimethoxy pyridine of Formula (V) with a chlorinating agent, preferably thionyl chloride in a solvent like dichloromethane, at a temperature preferably ranging from 0 to 35 ºC. Product may be extracted with a solvent like dichloromethane and purified with a solvent like acetone.

In another embodiment of the present invention, the methoxylating agent used herein is an alkali metal methoxide, preferably sodium or potassium methoxide.

In another embodiment, the acid is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, pivalic acid, acetic acid, formic acid and the like.

In another embodiment of the present invention, the methylating agent in step-1 is any conventional agent like methyl iodide, dimethyl sulfate and like. The reaction is performed in the presence of a base like sodium hydroxide. Reaction is performed in water. Progress of the reaction can be monitored by either TLC, GC or HPLC. Reaction temperature is chosen from 20-80 ºC for 30 minutes to 12 hours. Workup usually involves extraction with an organic solvent like chloroform, followed by concentration of organic layer.

The compounds of Formula III, IV and V used in the present invention are not isolated. The above reactions may also be carried out in-situ reactions to obtain compound of Formula (I). The above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.

The crude compound of Formula (I) as prepared according to the present invention may be recrystallized using a suitable solvent to give highly pure compound.

Solvent as used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

Base as used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

In preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula (I)

Formula (I)
comprising:
a) oxidizing pyridine ring nitrogen of compound of Formula (II)

Formula (II)
using sodium tungstate as an oxidation catalyst in acetic acid and hydrogen peroxide to give compound of Formula (III),

Formula (III)
b) converting chlorine group of compound of Formula (III) to methoxyl group using sodium methoxide as methoxylating agent in presence of methanol to give compound of Formula (IV),

Formula (IV)
c) 2-hydroxylation of compound of Formula (IV) using acetic anhydride in presence of chloroform as a solvent and sodium hydroxide as a base to give compound of Formula (V)

Formula (V)
in one pot reaction without isolating intermediates compounds of Formula (III), (IV) and (V),
d) chlorinating the 2-hydroxy methyl group of compound of Formula (V) with thionyl chloride as chlorinating agent in presence of a solvent selected from methanol or acetone to give compound of Formula (I) or its salts, and
e) isolating compound of Formula (I) using acetone as its hydrochloride salt.

In another preferred embodiment, the present invention provides an in-situ process for preparation of compound of Formula (V)

Formula (V)
comprising
a) oxidizing pyridine ring nitrogen of compound of Formula (II)

Formula (II)
using sodium tungstate as an oxidation catalyst in acetic acid and hydrogen peroxide to give compound of Formula (III),

Formula (III)
b) converting chlorine group of compound of Formula (III) to methoxyl group using sodium methoxide as methoxylating agent in presence of methanol to give compound of Formula (IV), and

Formula (IV)
c) 2-hydroxylation of compound of Formula (IV) using acetic anhydride in presence of chloroform as a solvent and sodium hydroxide as a base to give compound of Formula (V)

Formula (V)
in one pot reaction without isolating intermediates compounds of Formula (III) and (IV).

In another preferred embodiment, the present invention provides an improved process for the conversion of compound of Formula (V)

Formula (V)
prepared as per the process of the present invention to compound of Formula (I).

Formula (I)

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:

Example 1: Preparation of 2-methyl-3-methoxy-pyran-4-one [Formula VII]:
To a four necked round bottom flask equipped with a condenser, thermometer pocket, and overhead stirring apparatus was charged maltol (Formula VIII) (50 g) and Lye solution (sodium hydroxide: 19 g and Water:67.5 ml). The reaction mass was stirred for 10 minutes. Dimethyl sulphate (56 g) was added into the reaction mass and maintained for 1 hour at 30-35ºC. Lye solution (1.9 g) and dimethyl sulphate (5.6 g) were added into the reaction mass and maintained for 1 hour at 30-35ºC. Again, lye solution (0.95 g) and dimethyl sulphate (2.8 g) were charged into the reaction mass and maintained for 1 hour at 30-35ºC. After reaction completion, chloroform (100 ml) was charged into the reaction mass and stirred for 1 hour. The layers were separated. Aqueous layer was extracted with chloroform (3 x 50 ml). The combined organic layer was concentrated to get 2-Methyl-3-methoxypyran-4-one.
Output: 55 g

Example 2: Preparation of 2-methyl-3-methoxy-pyridine-4-one (Formula VI):
2-methyl-3-methoxy-pyran-4-one (Formula VII) (75 g) and aqueous ammonia (50 ml) were charged into RBF. The reaction mass temperature was raised to 65-70ºC. Ammonia gas was purged into the reaction mass and maintained the reaction mass for 1-2 hours. After reaction completion, toluene (160 ml) was charged into the reaction mass. Water was removed from the reaction mass azeotropically. The reaction mass was cooled to 40-50 ºC. The solid product formed was filtered and washed with toluene (10 ml). The wet material was dried to yield the product 2-methyl-3-methoxy-pyridine-4-one.
Output: 70 g.

Example 3: Preparation of 4-chloro-3-methoxy-2-methyl pyridine [Formula (II)]:
To a four necked dry round bottom flask equipped with a condenser, thermometer pocket, and overhead stirring apparatus was charged phosphorus oxychloride (66.7 g). 2-methyl-3-methoxypyridine-4-one (Formula VI) (50 g) was added into the reaction mass. The reaction mass temperature was raised to 75-80 ºC and maintained for 1-2 hours at 75-80 ºC. The progress of the reaction was checked by TLC. After reaction completion, the reaction mass was quenched into ice water and then pH of reaction mass was adjusted to 9.0-9.5 using aqueous ammonia (87 ml). The reaction mass was maintained for 30 minutes at 30-35 ºC and the solid product obtained was filtered.
Output: 45 g.

Example 4: Preparation of 2-chloromethyl-3,4-dimethoxy pyridine Hydrochloride [Formula (I)]:
To a four necked dry round bottom flask equipped with a condenser, thermometer pocket, and overhead stirring apparatus was charged 4-chloro-3-methoxy-2-methyl pyridine [Formula (II)] (50 g) and Acetic acid (18 g). Then sodium tungstate solution (0.65 g sodium tungstate, water: 30 ml) was charged and stirred for 10 minutes. The reaction mass temperature was raised to 50-55 ºC and hydrogen peroxide (34.3 g) was charged into the reaction mass. The temperature of reaction mass was further raised to 70-75 ºC and maintained for 8 hours. The progress of the reaction was checked by TLC. After reaction completion, the reaction mass was quenched into sodium hydroxide solution (15.8 g in 52.5 mL water) and stirred for 30 minutes. The pH of the reaction mass was adjusted to 12.0-14.0. The product was extracted with chloroform. The organic layer was concentrated and methanol was added. Further, the solvent was distilled out completely under vacuum to get the product 4-chloro-3-methoxy-2-methylpyridine-N-oxide [Formula (III)].

The above concentrated mass was diluted with methanol and added to sodium methoxide solution (74.3 g) and the reaction mass temperature was raised to 70-75 ºC. The reaction mass was stirred for 8 hours at 70-75 ºC. After reaction completion, the reaction mass was cooled to 10-15 ºC. Then the pH of the reaction mass was adjusted to 7.0-7.5 using acetic acid (7.0-15.0 g). The reaction mass was stirred for 30 minutes and filtered. Then washed with methanol (27.5 ml). The solvent methanol was distilled out completely and removed the traces by toluene to get the product 3,4-dimethoxy-2-methylpyridine-N-oxide [Formula (IV)].

The above concentrated mass was cooled to 40-45 ºC and stirred for 30 minutes. acetic anhydride solution (450 g, chloroform: 280 ml) was added and raised the temperature to 80-85 ºC. The reaction mixture was maintained for 8 hours at 80-85 ºC under stirring. The progress of the reaction was checked by TLC. After reaction completion, the reaction mass was cooled to 25-35 ºC and water (440 ml) was charged into the reaction mass. The pH of the reaction mass was adjusted to 12.0-14.0 using sodium hydroxide solution. The reaction mass was stirred for 4 hours at 40-45 ºC. To the reaction mass, dichloromethane (75 ml) was charged and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 50 ml). The organic layer contains the product 2-hydroxymethyl-3,4-dimethoxypyridine [Formula (V)].

To the above reaction mass, thionyl chloride (31.6 g) was added at 0-10 ºC. The reaction mass temperature was raised to 25-35 ºC and maintained for 2-3 hours. After reaction completion, dichloromethane was distilled out completely and charged with acetone (10 ml). Acetone (38 ml) was charged into the reaction mass maintained for 30-60 minutes at 30-35 ºC. The reaction mass was cooled to 10-15 ºC and maintained for 1 hour at 10-15 ºC. The product formed was filtered and washed with Acetone (8.5 ml). The wet product was further purified by acetone-methanol mixture followed by drying to get the final compound, 2-chloromethyl-3,4-dimethoxy pyridine hydrochloride Formula (I).
Output: 50 g

,CLAIMS:We Claim:
1. An improved process for the preparation of Pantoprazole intermediate
compound of Formula (I)

Formula (I)
using 4-chloro-3-methoxy-2-methylpyridine, wherein the intermediates formed in some of the steps are not isolated.

2. The process for the preparation of compound of Formula (I) as claimed in claim 1,

Formula (I)
wherein the process comprising:
a) oxidizing pyridine ring nitrogen of compound of Formula (II)

Formula (II)
using an oxidation catalyst in an acid and optionally in a solvent to give compound of Formula (III),

Formula (III)
b) converting chlorine group of compound of Formula (III) to methoxyl group using methoxylating agent in presence of solvent to give compound of Formula (IV),

Formula (IV)
c) 2-hydroxylation of compound of Formula (IV) using acetic anhydride in presence of a base and solvent to give compound of Formula (V)

Formula (V)
in one pot reaction without isolating intermediate compounds of Formula (III), (IV) and (V),
d) chlorinating the 2-hydroxy methyl group of compound of Formula (V) with chlorinating agent in presence of a solvent to give compound of Formula (I) or its salts, and
e) isolating compound of compound of Formula (I) using a solvent as its hydrochloride salt.

3. An in-situ process for preparation of compound of Formula (V),

Formula (V)
wherein the process comprising:
a) oxidizing pyridine ring nitrogen of compound of Formula (II)

Formula (II)
using an oxidation catalyst in an acid and optionally in a solvent to give compound of Formula (III),

Formula (III)
b) converting chlorine group of compound of Formula (III) to methoxyl group using methoxylating agent in presence of solvent to give compound of Formula (IV), and

Formula (IV)
c) 2-hydroxylation of compound of Formula (IV) using acetic anhydride in presence of a base and solvent to give compound of Formula (V)

Formula (V)
in one pot reaction without isolating intermediates compounds of Formula (III) and (IV).

4. An improved process for the preparation of compound of compound of Formula (II)

Formula (II)
wherein the process comprising:
a) methylating hydroxyl group of compound of Formula (VIII)

Formula (VIII)
using methylating agent in presence of a base and a solvent selected from dichloromethane, chloroform, ethers, esters or hydrocarbons to form compound of Formula (VII),

Formula (VII)

b) aminating 4-H pyran ring oxygen of the compound of Formula (VII) using aqueous NH3 in presence of a solvent to give compound of Formula (VI),
,
Formula (VI)
and
c) chlorinating hydroxyl group of compound of Formula (VI) using chlorinating agent and aqueous NH3 in presence of a optional solvent to give compound of Formula (II).

5. An improved process for the conversion of compound of Formula (V)

Formula (V)
prepared as per the process of the present invention to give compound of Formula (I).
6. The process as claimed in claims 2-3, wherein the oxidation catalyst is selected from a salt of tungstate or molybdate, preferably sodium tungstate.

7. The process as claimed in claims 2-3, wherein the methoxylating agent is an alkali metal methoxide, preferably sodium or potassium methoxide.

8. The process as claimed in claim 2-3, wherein the acid is selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, sulfuric acid, pivalic acid, acetic acid, formic acid.

9. The process as claimed in claims 4, wherein the methylating agent is selected from methyl iodide, dimethyl sulfate.

10. The process as claimed in claims 2-3 and 5, wherein the compounds of Formula III, IV and V used in the present invention are not isolated, and reactions may also be carried out in-situ reactions to obtain compound of Formula (I).

11. The process as claimed in claim 2-4, wherein the solvent is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

12. The process as claimed in claims claim 2-4, wherein the base is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

Dated this Thirty First (31st) day of July, 2019

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883