DESC:FIELD OF THE INVENTION
The present invention relates to a improved process for the preparation of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I).

Formula (I)

The present invention also relates to a purification method for 3,6-dichloro-4 –isopropyl pyridazine compound of Formula (I) having purity greater than 99%.

BACKGROUND OF THE INVENTION
Resmetirom is an experimental drug for the treatment of non-alcoholic steatohepatitis (NASH) and heterozygous familial hypercholesterolemia. It is a selective agonist of thyroid hormone receptor-ß which increases hepatic fat metabolism and reduces lipotoxicity.

The compounds, 3,6-dichloro-4–isopropyl pyridazine, 3,6-dichloropyridazin and 3,6-pyridazinediol are excellent and cost-effective intermediates for the synthesis of active pharmaceutical agents especially for Resmetirom synthesis. Therefore, it is important to provide an economical process by which 3,6-dichloro-4–isopropyl pyridazine, 3,6-dichloropyridazin and 3,6-pyridazinediol can be prepared to make easy manner in the required quality with better yields as per the pharmaceutical product’s regulatory guidelines.

Journal of American Chemical Society, 1951, 73, 1873-1874 discloses the compound of 3,6-pyridazinediol and a process for the preparation which involves reaction of maleic anhydride with hydrazine dihydrochloride in presence of water. The document also discloses a process for the preparation of 3,6-dichloropyridazine, which involves reaction of 3,6-pyridazinediol with POCl3 followed by using ammonium hydroxide, chloroform and anhydrous magnesium sulphate.
US 2671086 A discloses the compound of 3,6-dichloropyridazine and its preparation method which involves maleic hydrazide, phosphorus pentachloride or' phosphorus oxychloride.

Journal of Agricultural and Food Chemistry, 2009, 57(14), 6356-6361 discloses a process for preparation of 3,6-dichloropyridazine which involves NaHCO3 along with POCl3, water & ethyl acetate.

Journal of Molecular Structure, 2015, 1091, 88-97 discloses a process for the preparation of 3,6-dichloropyridazine by using DIPEA along with POCl3 & acetonitrile.

US 4628088 A discloses 3,6-dichloro-4-isopropylpyridazine and a method for the preparation of by using 3,6-dichloropyridazine, ammonium persulfate in water, silver nitrate, isobutyric acid, sulfuric acid in water, ammonium hydroxide, MDC, sodium hydroxide & magnesium sulphate.

Few processes disclosed in the prior art reported the use of NH4OH, POCl3 & chloroform but yields only 81%; using NaHCO3, POCl3, water & ethyl acetate yields only 85%, and using DIPEA, POCl3 & acetonitrile yields only 60%. Further, none of the prior art document discloses a process for the preparation of said intermediate compounds having a purity greater than 99% with better yield i.e more than 85%.

The common disadvantages of the above known procedures are that the process can be carried out at an uneconomical and dangerous industrial procedure and require extra equipment and were carried out at an extreme reaction condition as described above.

It is well known fact that, the active pharmaceutical ingredients (APIs) are clearly dependents of the intermediates compounds which are used in the reaction and always leads to provide better productivity in the final stage. The use of economically produced intermediates will result in the production of API at an economically affordable condition.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of 3,6-dichloro-4–isopropylpyridazine of compound of Formula (I), by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for the preparation of 3,6-dichloro-4–isopropyl pyridazine compound of Formula (I).

Formula (I)

In another objective, the present invention is to provide a method for purification 3,6-dichloro-4–isopropyl pyridazine compound of Formula (I) having purity greater than 99%.

SUMMARY OF THE INVENTION
In one aspect, the present invention is to provide a cost effective, novel and an efficient process for the preparation of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I);

Formula (I)
In another aspect, the present invention is to provide a process for the preparation of 3,6-dichloro-4 –isopropyl pyridazine compound of Formula (I)

Formula (I)
wherein the process comprising the steps of:
a) reacting maleic anhydride compound of Formula (IV)

Formula (IV)
with hydrazine hydrate in the presence of an acid and a solvent to give 3,6-pyridazinediol compound of Formula (III);

Formula (III)
b) halogenating the compound of Formula (III) obtained in step (a) by using a phosphoryl chloride in the presence of triethyl amine, toluene and cyclohexane to give 3,6-dichloropyridazin compound of Formula (II);

Formula (II)
c) converting the compound of Formula (II) obtained in step (b) by using isobutyric acid, silver nitrate, ammonium persulfate or sodium persulphate in presence of a base and solvent to give of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I); and

d) optionally purifying the step (c) compound to obtain high pure intermediate compound of Formula (I).

In another aspect, present invention is to provide a process for the preparation of 3,6-dichloropyridazin compound of Formula (II)

Formula (II)
wherein the process comprising the steps of:
a) reacting maleic anhydride compound of Formula (IV)

Formula (IV)
with hydrazine hydrate in the presence of an acid and a solvent to give 3,6-pyridazinediol compound of Formula (III);

Formula (III)
b) halogenating the compound of Formula (III) obtained in step (a) by using a phosphoryl chloride in the presence of triethyl amine, toluene and cyclohexane to give 3,6-dichloropyridazin compound of Formula (II); and
c) optionally purifying the compounds of step (b) to obtain high pure intermediate compound of Formula (II).

In another aspect, the present invention is to provide a method for purification of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I) having purity greater than 99% with better yield using simple organic solvent.

DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise stated, the following terms used in the specification have the meanings given below:

Solvents used throughout the invention is selected from the group consisting of hydrocarbon solvents such as pentane, hexane, cyclohexane, heptane, xylene, toluene; alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, amide solvent such as dimethylacetamide, dimethylformamide, formamide, N-Methyl formamide, chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride, organosulfur solvent such as dimethyl sulfoxide, dimethyl sulfone, acetic acid, water and its mixture thereof.

Base used throughout the invention is selected from the group consisting of include, but are not limited to alkylmetal base such as methyllithium, n-butyllithium, tertbutyl lithium, sec-butyllithium, phenyl lithium, phenyl sodium, and phenyl potassium; metal amide bases such as lithium amide, sodium amide, potassium amide, lithium tetramethylpiperidide, diisopropylamine, lithium diisopropylamide, lithium diethylamide or lithium dicyclohexylamide. sodium hydride, potassium hydride, NaOPt, n-butyllithium, tert-butyllithium, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, sodium bicarbonate, ammonium hydroxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide or cesium hydroxide.

Acid used throughout the invention is selected from the group consisting of sulphuric acid, sulphurous acid, nitric acid, nitrous acid, hydrochloric acid, hydrobromic acid, acetic acid, sulfonic acids or phosphoric acids.

The halogenating agent used throughout the invention is selected from the group consisting of PCl5, POCl3, oxychloride, thionyl chloride, carbonyl chloride, oxalyl chloride or mixture thereof.

The process of the present invention is advantageous from environmental point of view, economical from time duration point of view, safe from the avoiding the hazardous chemical point of view and advancement in view of good yield i.e., more than 90% and better purity i.e., more than 99%.

Accordingly, the present invention provides a process for the preparation of 3,6-dichloro-4–isopropyl pyridazine compound of Formula (I).

Formula (I)
The main embodiment of the present invention provides process for the preparation of 3,6-dichloro-4–isopropyl pyridazine compound of Formula (I) which is outlined in below scheme:

In step a), reacting maleic anhydride compound of Formula (IV) with hydrazine hydrate in the presence of an acid and a solvent to give 3,6-pyridazinediol compound of Formula (III);
The reaction is carried out at a temperature range of 85-130°C for the duration of 3-8 hours. Preferably at a temperature in the range from 100-120 oC for the duration of 4-6 hours.
In step b), halogenating the compound of Formula (III) obtained in step (a) by using a phosphoryl chloride in the presence of triethyl amine, toluene and cyclohexane to give 3,6-dichloropyridazin compound of Formula (II);

The reaction is carried out at a temperature range of 70-115°C for the duration of 3-8 hours. Preferably at a temperature in the range from 85-100 oC for the duration of 0.5-3 hours.
In step c), converting the compound of Formula (II) obtained in step (b) by using isobutyric acid, silver nitrate, ammonium persulfate or sodium persulphate in presence of a base and solvent to give of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I); and
The reaction is carried out at a room temperature for the duration of 15-30 minutes. Preferably at a for a period of 20 minutes.

In step d), optionally purifying the step (c) compound to obtain high pure intermediate compound of Formula (I).

The reaction is carried out at room temperature for 16 hours. After that the reaction is carried out at a temperature range of 40-70°C for 2-6 hours. Preferably at a temperature in the range from 50-55 oC for a duration of 3-5 hours.
In another embodiment, the present invention provides process for the preparation of 3,6-dichloropyridazin compound of Formula (II) which is outlined in below scheme:
In step a), reacting maleic anhydride compound of Formula (IV) with hydrazine hydrate in the presence of an acid and a solvent to give 3,6-pyridazinediol compound of Formula (III);
The reaction is carried out at a temperature range of 85-130°C for the duration of 3-8 hours. Preferably at a temperature in the range from 100-120 oC for the duration of 4-6 hours.
In step b), halogenating the compound of Formula (III) obtained in step (a) by using a phosphoryl chloride in the presence of triethyl amine, toluene and cyclohexane to give 3,6-dichloropyridazin compound of Formula (II);

The reaction is carried out at a temperature range of 70-115°C for the duration of 3-8 hours. Preferably at a temperature in the range from 85-100 oC for the duration of 0.5-3 hours.
In step c), optionally purifying the step (a) and step (b) compounds to obtain high pure intermediate compounds of Formulae (II) and (III);
The reaction is carried out at a room temperature for the duration of 15-30 minutes. Preferably at a for a period of 20 minutes.

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 3,6-Pyridazinediol (I)

A solution of Hydrazine hydrate (80% solution) added to conc.HCl below 10° C followed by Maleic anhydride then raise the temperature at 105-110° C and maintain for 4-6hrs. After completion of reaction cool the reaction mass to 55-60° C, dilute the reaction mass with water and stir at room temperature followed by filtration dried 3,6-Pyridazinediol (I) (Yield: 91%, HPLC Purity: > 99 %).
1H NMR (400 MHz, DMSO-d6): d 11.39 (brs, 2H), 6.92(s, 2H);
MS(ES): m/z 113 [M+H]+;

Example 2: Preparation of 3,6-dichloropyridazin (II)

A stirred solution of 3,6-Pyridazinediol (I), POCl3 in toluene/chlorobenzene/ xylene and cooled to below 10°C then add TEA dropwise over a period of 45-60 min. The reaction mass temperature slowly raises to 90-95°C and maintain for 1- 2 hrs, after completion of reaction then add the reaction mass to cooled water, layers separated, organic layer was washed with sat NaHCO3 solution followed by water, concentrated under vacuum to get crude compound. The crude compound was purified with cyclohexane to get pure 3,6-dichloropyridazin (II)
Yield: 88%,
HPLC purity: > 98 %)
1H NMR (400 MHz, DMSO-d6): d 8.02 (s, 2H);
MS(ES): m/z 148.8 [M+H] +;

Example 3: Process for the preparation of 3,6-dichloropyridazin (II)
A stirred solution of 3,6-Pyridazinediol (III), POCl3 in Dichloromethane/ chloroform and cooled to below 10 °C then add TEA dropwise over a period of 45-60 minutes. The reaction mass temperature slowly raises to 35-40 °C and maintain for 5-6 hours, after completion of reaction then add the reaction mass to cooled water, layers separated, organic layer was washed with sat NaHCO3 solution followed by water, concentrated under vacuum to get crude compound. The crude compound was purified with cyclohexane to get pure 3,6-dichloropyridazin (II).
Yield: 78%,
HPLC purity: > 98 %
1H NMR (400 MHz, DMSO-d6): d 8.02 (s, 2 hours);
MS(ES): m/z 148.8 [M+H] +;

Example 4: Preparation of 3,6-dichloro-4 -Isopropyl pyridazine (III)
Dissolve 3,6-dichloropyridazine, isobutyric acid, silver nitrate and H2SO4 in water was stirred at 25-35°C for 30-45 min, ammonium persulfate dissolved in water was slowly dropped into the reaction mass at 15-20°C. The reaction solution was stirred for 5 hrs at 15-20°C. Adjust the pH value to 9-10 with aqueous ammonia solution. Extract with ethyl acetate, combine the organic phases and dry with anhydrous sodium sulphate, filter, remove the solvent under reduced pressure to obtain the residue and then crude distilled by fractional distillation to get pure 3,6-dichloro-4 -Isopropyl pyridazine (III)
Yield: 96%,
HPLC purity: > 99%

Example 5: Preparation of 3,6-dichloro-4 -Isopropyl pyridazine (III)
Dissolved 3,6-dichloropyridazine (II), isobutyric acid, silver nitrate in water was stirred at 25-35 °C for 30-45 minutes, ammonium persulfate dissolved in water was slowly dropped into the reaction mass at 15-20 °C. The reaction solution was stirred for 5 hrs at 15-20 °C. Adjust the pH value to 9.5-10.5 with aqueous ammonia solution. Extract with Dichloro methane, combine the organic phases and dry with anhydrous sodium sulphate, filter, remove the solvent under reduced pressure to obtain the residue and then crude distilled by fractional distillation to get pure 3,6-dichloro-4 -Isopropyl pyridazine (III).
Yield: 96%,
HPLC purity: > 99%

Example 6: Preparation of 3,6-dichloro-4 -Isopropyl pyridazine (III)
Dissolved 3,6-dichloropyridazine (II), isobutyric acid, silver nitrate in water was stirred at 25-35 °C for 30-45 minutes, Sodium persulfate dissolved in water was slowly dropped into the reaction mass at 15-20 °C. The reaction solution was stirred for 5 hrs at 15-20 °C. Adjust the pH value to 9.5-10.5 with aqueous ammonia solution. Extract with Dichloro methane, combine the organic phases and dry with anhydrous sodium sulphate, filter, remove the solvent under reduced pressure to obtain the residue and then crude distilled by fractional distillation to get pure 3,6-dichloro-4 -Isopropyl pyridazine (III).
Yield: 96%,
HPLC purity: > 99%

Advantages of the present invention:
1. In prior art, chloroform was used solvent whereas, as per ICH guidelines limit is low. In our present invention toluene used as solvent. Compared to chloroform, toluene is easy for storage, handling, echo friendly and % recovery obtained was good (~95%) during the scale up.

2. In prior art, the duration of reaction also took more than 5-6 hours at reflux condition with the use of excess mole ratio of POCl3 or neat reaction with POCl3 where as in present invention reaction time is 1 hour in presence of triethylamine less mole ratio of POCl3. Because of these conditions decrease the load on utilities during the scale up.

3. In the prior art, hexane was used for isolation. It is highly volatile and highly flammable and difficult to handle during isolation time on commercial scale where as in our present invention cyclohexane is used for isolation. It is environmentally friendly and more economical solvent. Cyclohexane handling and storage is easy during the scale up. % Recovery is high.

4. In prior art, work up involved use of chloroform followed by excess POCl3. POCl3 distillation, neutralization took more time as it impacts on load on utilities. In our present invention, work up took less time, which involves adding reaction mass to water followed by separating the layers.

5. Present invention shows good yield (91%) and purity (99.61%) which are higher than the reported literature (82 %).

6. Present invention is echo friendly, robust, safe and commercially feasible process.

7. Sulphuric acid is used in prior art. Sulphuric acid is not used in our process; therefore our process is environmentally friendly.
,CLAIMS:We claim:
1) An improved process for the preparation of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I)

Formula (I)
which comprises:
a) reacting maleic anhydride compound of Formula (IV)

Formula (IV)
with hydrazine hydrate in the presence of an acid and a solvent to give 3,6-pyridazinediol compound of Formula (III);

Formula (III)
b) halogenating the compound of Formula (III) obtained in step (a) by using phosphoryl chloride in the presence of triethyl amine, toluene and cyclohexane to give 3,6-dichloropyridazin compound of Formula (II);

Formula (II)
c) converting the compound of Formula (II) obtained in step (b) by using isobutyric acid, silver nitrate, ammonium persulfate or sodium persulphate in presence of a base and solvent to give of 3,6-dichloro-4-isopropylpyridazine compound of Formula (I); and
d) optionally purifying the step (c) compound to obtain high pure intermediate compound of Formula (I).

2) An improved process for the preparation of 3,6-dichloropyridazin compound of Formula (II)

Formula (II)
which comprises:
a) reacting maleic anhydride compound of Formula (IV)

Formula (IV)
with hydrazine hydrate in the presence of an acid and a solvent to give 3,6-pyridazinediol compound of Formula (III);

Formula (III)
b) halogenating the compound of Formula (III) obtained in step (a) by using phosphoryl chloride in the presence of triethyl amine, toluene and cyclohexane to give 3,6-dichloropyridazin compound of Formula (II); and
c) optionally purifying the compounds of step (b) to obtain high pure intermediate compound of Formula (II).

3) The process as claimed in claim 1, wherein said base is selected from group consisting of triethyl amine, sodium carbonate, sodium acetate, ammonia, ammonium hydroxide, ammonium acetate or ammonium formate.

4) The process as claimed in claim 1 and claim 2, wherein said solvent is selected from group consisting of toluene, methanol, ethanol, n-butanol, propanol, isopropanol, ethyl acetate, EDTA, cyclohexane, xylene, hexane, heptanes, water and its mixture thereof.