DESC:FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of pyridazinone derivative. More specifically, the present invention relates to an efficient process which is operationally simple and suitable for industrial application and will eliminate or limit the presence of impurities in the pyridazinone derivative, an investigational new drug.
BACKGROUND OF INVENTION
The pyridazinone derivative is a potent and selective thyroid hormone receptor [THR] ß agonist for the treatment of non-alcoholic steatohepatitis (NASH) by increasing hepatic fat metabolism and reducing lipotoxicity. Specifically, the pyridazinone derivative, namely, 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile is selective THRß agonist in vitro, and in preclinical NASH models in vivo it reduced hepatic steatosis. It is represented by formula I as given below and known as resmetirom [MGL-3196].

Formula I
Since there is no approved treatment for non-alcoholic steatohepatitis (NASH) which can lead to progressive liver diseases like fibrosis, cirrhosis and hepatocellular carcinoma. U.S. Food and Drug Administration (FDA) have accepted Priority Review for New Drug Application (NDA) of MGL-3196 for the treatment of adult patients with NASH with liver fibrosis. However, resmetirom has not been approved by any regulatory authorities till date.
The synthesis of pyridazinone derivative, MGL-3196, is first time described in a patent family, WO2007/009913, by Hoffman-La-Roche, as shown in scheme below:

In one of the specific example, the process comprises the steps of condensation of 4-amino-2,6-dichlorophenol with 3,6, dichloro-4-isopropylpyridazine in presence of an inorganic base to produce 4- (6-chloro-5-isopropylpyridazin-3-yloxy)-3,5-dichlorobenzenamine, which is further oxidized in presence of sodium acetate/acetic acid to obtain a 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl pyridazin-3(2H)-one. Subsequently, the resulting derivative is diazotized using sodium nitrite and hydrochloric acid in acetic acid/water or water and then condensed with N-acetylcyanothiourea in the presence of sodium acetate or pyridine in water to yield ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate, herein refers as substituted pyridazinone intermediate. Finally, the substituted pyridazinone intermediate undergoes intra-cyclization by means of sodium acetate and acetic acid to yield a final product as shown in the above scheme.
In our hands when the inventors of present invention have repeated the experiment, specifically the intra-cyclization of substituted pyridazinone intermediate it has been found that there is a formation of one critical impurity. The level of this impurity is about 8-14% which results in huge yield loss during repeated purification to remove this impurity at final stage. Moreover, the said patent is silent about the purity of key pyridazinone intermediate as well as of final novel pyridazinone derivative i.e., MGL-3196.
Another PCT publication WO 2014/043706 discloses an alternate synthetic route for the preparation of pyridazinone derivative as shown in scheme below:

The process involves condensation of 4-amino-2,6-dichlorophenol with 3,6-dichloropyridazine in the presence of cesium carbonate (Cs2CO3) in dimethylacetamide at 110°C to produce ether intermediate, which is N-benzylated with benzoic anhydride in acetic acid at 100°C to yield benzylated precursor. Treatment of the protected benzylated precursor with sodium acetate at 120°C gives ketone derivative, which upon Grignard reaction with isopropenylmagnesium bromide in the presence of lithium chloride in tetrahydrofuran affords isopropylene derivative. Treatment of isopropylene derivative with potassium hydroxide furnishes free amine, which is subsequently diazotized using sodium nitrite and hydrochloric acid in acetic acid/water or water and condensed with N-cyanoacetylurethane in the presence of sodium acetate to yield crude substituted pyridazinone intermediate, which is subjected for purification by using acetic acid to obtain substituted pyridazinone intermediate. Finally, the resulting compound undergoes intra-cyclization by means of potassium acetate in dimethylacetamide at 120°C to yield pyridazinone derivative as final product.
In order to obtain the desired purity of pyridazinone derivative i.e. final product, multiple purifications have been performed via formation of solvates in the above disclosure. Firstly, the crude product which is obtained by intra-cyclization of substituted pyridazinone intermediate is converted into dimethylacetamide (DMAC) solvate having a HPLC purity of 93.67% and then into dihydrate having a HPLC purity of 96.4%. Finally, the dihydrate of crude compound is purified via formation of methyl isobutyl ketone (MIBK) solvate, wherein solvate has a HPLC purity of 98.5% and need one more purification to achieve purity of 99.6% and overall yield around 57% from substituted pyridazinone intermediate. On the contrary, these multiple purifications via solvate formation require maximum use of utilities, prolonged hours for intermittent operations and tedious isolation procedures to prepare pyridazinone derivative and loss of yield, thereby making the processes commercially unviable. Moreover, the synthesis pyridazinone derivative requires the use of large quantities of solvents often being generated a large quantity of chemical waste which is difficult to treat, by making process environmentally unfriendly.
A Chinese publication CN116768802 unveils a process for the preparation of pyridazinone derivative by using substituted acetimidoyl cyanide intermediate. The process comprises the steps of, ring enlargement reaction of 3-isopropylfuran-2,5-dione, by reacting the dione precursor with hydrazine hydrate to obtain 4-isopropyl-1,2-dihydropyridazine-3,6-dione, chlorinating the obtained product with chlorinating reagent to obtain 3,6-dichloro-4-isopropyl-pyridazine, hydrolyzing the dichloro intermediate under the action of an additive to obtain 3-chloro-5-isopropyl-1H-pyridazin-6-one, condensing the pyridazin-6-one derivative and 4-amino-2,6-dichloro-phenol under the action of alkali to obtain 3-(4-amino-2,6-dichloro-phenoxy)-5-isopropyl-1H-pyridazin-6-one. Thereafter, the resulting intermediate is condensed with cyanoacetamide to obtain 2-amino-N-[3,5-dichloro-4-[(5-isopropyl-6-oxo-1H-pyridazin-3-yl)oxy]anilino]-2-oxo-acetimidoyl cyanide. Finally, the substituted acetimidoyl cyanide intermediate undergoes intra-cyclization under the action of carbonylation reagent to yield a final product i.e., MGL-3196, as depicted in below scheme:

Several other Chinese patent publications CN117263870, CN117164568 also discloses different processes for preparing pyridazinone derivative.
In Chinese publication CN117263870, N-[3,5-dichloro-4-[(1,6-dihydro-6-oxo-3-pyridazinyl)oxy]phenyl]amide is condensed with 2-substituted propane to obtain key intermediate of MGL-3196 i.e., 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl pyridazin-3(2H)-one. Thereafter, the resulting key intermediate is diazotized using sodium nitrite and hydrochloric acid in acetic acid/water or water and condensed with N-cyanoacetylurethane in the presence of sodium acetate to yield substituted pyridazinone intermediate. Finally, the resulting compound is given washing with water and isopropyl ether and dried. The dried solid material is subjected to intra-cyclization using potassium acetate in dimethylformamide to yield final API.
In Chinese publication CN117164568, 4-isopropyl-6-(phenylsulfonyl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one is condensed with 2,6-dichloro-4-aminophenol at 70-80°C and caustic soda to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropyl-2H-pyridazin-3-one. Further, the key intermediate is converted into final API i.e., MGL-3196 by using the conventional method as disclosed in the prior art. The process is depicted in scheme as shown below scheme:


The said Chinese publications focus on the preparation and purification of intermediate 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one and are silent about the purity of pyridazinone derivative.
Most of the prior arts as cited above are either silent about the purity of final API or more often require multiple purifications for obtaining the final product of desired purity. Like any synthetic compound, the final product can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Consequently, to get the desired purity of final product, the formation of impurities needs to be controlled in accordance with ICH guidelines.
During laboratory experimentation, the present inventors were found that most of the process disclosed in the prior art for the preparation of pyridazinone derivative via for intra-cyclization of substituted pyridazinone intermediate led to provide inadequate purity wherein quality of final product was ruined due to the presence of elevated level of impurities. Impurities in MGL-3196 or any active pharmaceutical ingredient (API) are undesirable and, in utmost cases, might even be harmful to a patient being treated with a dosage form containing the API.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
In order to overcome the aforementioned drawbacks in the prior art processes mainly due to the presence of impurities in pyridazinone derivatives, there is a need in the art to provide an industrially viable process for the preparation of pyridazinone derivative with high purity and high yield. Keeping this in mind, the present invention aims to provide pure pyridazinone derivative, wherein impurities, known or unknown have been controlled as per ICH guidelines. Since this is the final step in the synthesis of pyridazinone derivative, mild conditions along with a simple process need to be opted to minimize the formation of the impurities or by-products and avoid multiple purifications to prevent the yield loss and synthesize pyridazinone derivative with high purity and high yield.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient process for the preparation of pyridazinone derivative that overcomes the limitations of prior art methods i.e. low purity, low yield, maximum use of utilities, prolonged hours for intermittent operations and cumbersome workup procedures.
Another object of the present invention is to provide an industrially viable process for the preparation of pyridazinone derivative in high yield and high purity.
Another object of the present invention is to provide an industrially viable process for the preparation of pyridazinone derivative, wherein the levels of known and unknown impurities are controlled at different RRT (relative retention time) levels.
Yet one another object of the present invention is to provide a process for the preparation of pyridazinone derivative, which would be operationally simple and cost-effective and suitable at commercial scale.
Yet another object of the present invention is to go for mild conditions during the preparation of pyridazinone derivative minimize the formation of the impurities or by-products.
SUMMARY OF INVENTION
Accordingly, the present invention provides an efficient process for the preparation pyridazinone derivative of formula I,

Formula I
the process comprising the steps of:
i. intra-cyclizing substituted pyridazinone intermediate of formula II using a base in a suitable solvent,

Formula II
ii. cooling the reaction mixture obtained in step (i),
iii. extracting the reaction mass obtained in step (ii) in a suitable solvent medium,
iv. isolating the pure pyridazinone derivative.
In an embodiment, the present invention provides a process for the preparation pyridazinone derivative of formula I,

Formula I
the process comprising the steps of:
i. intra-cyclizing substituted pyridazinone intermediate of formula II using a base in a suitable solvent,

Formula II
ii. cooling the reaction mixture obtained in step (i),
iii. extracting the reaction mass obtained in step (ii) in a suitable solvent medium,
iv. separating the layers,
v. distilling the organic layer,
vi. optionally, treating with a suitable solvent followed by removal of solvent to obtain residue,
vii. optionally recrystallizing the residue obtained in step (vi) with a suitable solvent,
viii. isolating the pure pyridazinone derivative.
In another embodiment, the present invention provides a process for the preparation of pyridazinone derivative of formula I with a high purity wherein all impurities are controlled as per ICH guidelines.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of pyridazinone derivative of formula I, namely, resmetirom, wherein formation of impurities is minimized and controlled by using mild work-up conditions.
As used herein, the term “pure” represents a compound having purity greater than 99.00% w/w by HPLC, preferably greater than 99.50% w/w by HPLC and any individual known impurity present in an amount less than 0.15% w/w by HPLC, any unknown impurity presents in an amount of less than 0.10% w/w by HPLC, and total impurities present in an amount less than 0.50% w/w by HPLC.
As used herein, the term “ambient temperature” represents a temperature range of 25? ± 5?.
In the first aspect the present invention provides a process for the preparation of pyridazinone derivative of formula I. The process comprises treating substituted pyridazinone intermediate of formula II with a base in a suitable solvent at an ambient temperature.
The base used during the reaction herein includes, but is not limited to, the conjugate base of the organic acid. In one embodiment, the conjugate base of the organic acid is the sodium, potassium, or ammonium salt of the conjugate base of the organic acid. The organic acid includes, but is not limited to, acetic acid, formic acid, lactic acid, citric acid, malic acid, maleic acid, glycine, phosphoric acid, glycylclycine, succinic acid, TES (2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), PIPES (piperazine-N,N'-bis(2- ethanesulfonic acid)), and MES (2-(N-morpholino)ethanesulfonic acid). Preferably, organic acid is acetic acid, and the conjugate base of acetic acid is sodium or potassium salt, such as sodium acetate, potassium acetate.
The suitable solvent used herein may include aprotic solvents or mixture of aprotic solvents with organic acid. Aprotic solvents can be selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide and N-methylpyrrolidone (NMP) and/or mixtures of two or more thereof. The organic acid includes, but is not limited to, acetic acid, formic acid, lactic acid, citric acid, malic acid, maleic acid, phosphoric acid, succinic acid and/or mixture thereof.
Thereafter, the reaction can be accomplished at the temperature ranging from about 100 to 120°C, preferably 105-115°C for few minutes to few hours, till completion of the reaction. Further, the mode of addition of solvent and reagent does not alter the rate of the reaction.
After completion of the reaction, the reaction mixture can be cooled to an ambient temperature and subsequently subjected to extraction in a suitable solvent medium at the same temperature.
The suitable solvent medium used herein may include solvent but not limited to esters such as ethyl acetate, n-butyl acetate, tert-butyl acetate; ethers such as tetrahydrofuran (THF), methyl tetrahydrofuran (Me-THF), dioxane, diisopropyl ether, diethylether, tert-butylmethylether, cyclopentyl methyl ether (CPME) and 1,2-dimethoxyethane; water and/or any mixtures of two or more solvents thereof. Preferable solvent medium can be a mixture of two or more solvents i.e., the mixture of water with one or more solvent. The extraction process using a specific solvent system can be repeated more than once if required to extract maximum quantity of the desired material.
Subsequently, the layers can be separated, and the resulting organic layer can be subjected for washing using brine solution. Organic layer can be washed with brine solution more than once if required. After brine treatment, organic layer can optionally be subjected for drying using sodium sulphate. Thereafter solvent can be distilled out completely under vacuum at 60-70°C to obtain solid material, which can be purified using a suitable solvent to get the pure material.
The suitable solvent can be added in the resulting solid residue and stirred the resulting mass, thereafter solvent can be subjected for recovery from the reaction mass under vacuum at 60-70°C.
Thereafter, the resulting compound can be taken in a suitable solvent and heated at reflux temperature for 20 to 60 minutes, preferably for 25 to 40 minutes. The reaction mass may be either in suspension or dissolved form depending upon the quantity of solvent used. The mixture can be heated either at a temperature ranging from about 55-75°C, preferably 60-70°C or reflux temperature of the solvent used.
The suitable solvent used herein may include but not limited "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane-1,2-diol, propane-1,2-diol and the like; "polar solvents" such as water /or mixtures thereof.
Afterwards, the reaction mass can be cooled to an ambient temperature and stirred for 1-5 hours for complete crystallization. The resulting solid can be filtered, and optionally, washed with a suitable solvent as given above. The filtration can be done using various filtration techniques such as pressure filtration, gravity filtration, vacuum filtration, and other techniques that are familiar to those skilled in the art.
Thereafter, the resulting solid can be isolated from the reaction medium and dried to obtain the pure pyridazinone derivative of formula I. Particularly the resulting solid can be dried at 50-80? for about 5-30 hours to obtain pure pyridazinone derivative of formula I. The preferable drying temperature can be 60-70°C and preferably, the solid can be dried for 14-26 hours, and more preferably for 15-25 hours. Drying procedures mentioned above may include all techniques known to those skilled in the art, such as heating, applying vacuum, circulating air or gas, adding a desiccant, evaporating, or the like, or any combination thereof.
In an alternate manner, the resulting compound can be isolated by directly heating or drying at a temperature of 130-160°C for few minutes to few hours to get the desired pyridazinone derivative of formula I i.e. resmetirom. It is advantageous to dry at a temperature of 130-160°C to control any amount of residual solvent if present in the compound. Preferably the drying may be carried out at 140-150°C for 5-10 hours.
The resulting pure pyridazinone derivative of formula I, i.e. resmetirom of present invention have yield of greater than 90%w/w and purity of greater than 99.0 %, preferably 99.50 % and more preferably 99.60% and all impurities have been reduced to less than 0.5% w/w by HPLC. It is advantageous to prepare pyridazinone derivative of formula I via using process of the present invention, as the process leads to results in purity of greater than 99.0%, preferably 99.50 % and more preferably 99.60% and any individual known impurity = 0.15% and unknown = 0.10% as per ICH guidelines.
According to the invention it is also unexpectedly found that a good reproducibility of the pyridazinone derivative of formula I in terms of purity and yield can be obtained by electing the process sequences as given in the present invention wherein process is enough capable to reduce the level of impurities as well as eliminate the use of purification by performing solvation and desolvation method.
Optionally, the resulting product can further be purified using charcoalization if required to have desired appearance. Further the resulting product can optionally be recrystallized from a suitable solvent or mixture of the solvent to achieve the desired purity including controlled the content of residual solvent as per ICH guidelines and desired polymorph, if required.
The suitable solvent used herein for recrystallization may include but not limited to "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, ethane- 1,2-diol, propane- 1,2-diol and the like; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, methyl tetrahydrofuran (Me-THF), cyclopentyl methyl ether (CPME), 1,4-dioxane; and "polar solvents" such as water; or mixtures thereof.
In one another embodiment of the present invention, the substituted pyridazinone intermediate of formula II can be prepared by the methods reported in the literature or by the process as given in the present specification. The process for the preparation of substituted pyridazinone intermediate of formula II comprises condensation of 4-amino-2,6-dichlorophenol with 3,6-dichloropyridazine in the presence of inorganic base (potassium carbonate) to produce 4- (6-chloro-5-isopropylpyridazin-3-yloxy)-3,5-dichlorobenzenamine, which is further oxidized in presence of sodium acetate/acetic acid to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one. Subsequently, the said resulting compound is diazotized using sodium nitrite and hydrochloric acid in acetic acid/water or water and condensed with N-cyanoacetylurethane in the presence of sodium acetate or pyridine in water to yield substituted pyridazinone intermediate of formula II.
Major advantages of present invention lie in its high yield [greater than 90%] and high purity [=99.5% w/w by HPLC] of pyridazinone derivative of formula I, which is achieved by mild reaction work-up, no isolation of API-solvate as an intermediate, less number of steps and hence reduce time cycle, makes it industrially advantageous and efficient at commercial scale.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.

EXAMPLES:
Example 1: Preparation of pyridazinone derivative of formula I
Substituted pyridazinone intermediate of formula II (100g) was taken in N,N-dimethylacetamide (200 ml) along with sodium acetate (85g).The reaction mass was heated at 105-115°C and stirred till completion of reaction. Thereafter, the reaction mass was cooled to 20-30°C and water (1000ml), tetrahydrofuran (400ml) and ethyl acetate (400ml) were added to the reaction mass and layers were separated. The organic layer was washed with brine solution and then solvent was removed completely from the organic layer under vacuum at temperature 60-70°C to obtain a residue. Acetonitrile (200ml) was added to the residue and stirred and then solvent was removed completely under vacuum at temperature 60-70°C. Again acetonitrile (500ml) was added to the residue and refluxed for 30 minutes and then cooled to 20-30°C and stirred for 1 hour. The resulting solid was filtered at 20-30°C and was dried at 60-70°C for 15-25 hours under vacuum to get pure title compound (83g) having HPLC purity [w/w] = 99.50%; having single highest impurity - 0.09%.
Example 2: Preparation of pyridazinone derivative of formula I
Substituted pyridazinone intermediate of formula II (100g) was taken in N,N-dimethylacetamide (200 ml) along with sodium acetate (85g). The reaction mass was heated at 105-115°C and stirred till completion of reaction. Thereafter, the reaction mass was cooled to 20-30°C and addition of water (1000ml), tetrahydrofuran (400ml) and ethyl acetate (400ml) were added to the reaction mass and layers were separated. The organic layer was washed with brine solution and then solvent was removed completely under vacuum from the organic layer at temperature 60-70°C to obtain a residue. Acetonitrile (200ml) was added to the residue and stirred and then solvent was removed completely under vacuum at temperature 60-70°C. Acetonitrile (500ml) was added to the residue and refluxed for 30 minutes and then, cooled to 20-30°C and stirred for 1 hour. The resulting solid was filtered at 20-30°C and washed with acetonitrile (100ml) and was dried at 60-70°C for 15-25 hours to get title compound (85g) having HPLC purity [w/w] = 99.66%; having single highest impurity- 0.08%.
Example 3: Preparation of pyridazinone derivative of formula I
Substituted pyridazinone intermediate of formula II (100g) was taken in N,N-dimethylacetamide (200 ml) along with sodium acetate (85g). The reaction mass was heated at 105-115°C and stirred till completion of reaction. Thereafter, the reaction mass was cooled to 20-30°C followed by addition of water (1000ml), tetrahydrofuran (400ml) and ethyl acetate (400ml). The reaction mass was stirred, and layers were separated. The organic layer was washed with brine solution and then solvent was removed completely under vacuum from the organic layer temperature 60-70°C to obtain a residue. Acetonitrile (200ml) was added to the residue and stirred and then solvent was removed completely under vacuum at temperature at 60-70°C. Acetonitrile (500ml) was added to the residue and refluxed for 30 minutes and then, cooled to 20-30°C and stirred for 1 hour The resulting solid was filtered at 20-30°C and washed with acetonitrile (100ml) and was dried at 60-70°C for 15-25 hours to get title compound (87g) having HPLC purity [w/w] = 99.78%; having single highest impurity -0.03%.
Example 4: Preparation of resmetirom
Substituted pyridazinone intermediate of formula II (100g) was taken in N,N-dimethylacetamide (200 ml) along with sodium acetate (85g). The reaction mass was heated at 105-115°C and stirred till completion of reaction. Thereafter, the reaction mass was cooled to ambient temperature and water (1000ml), tetrahydrofuran (400ml) and ethyl acetate (400ml) were added and layers were separated. The organic layer was washed with brine solution and then solvent was removed completely under vacuum from the organic layer at temperature 60-70°C to obtain a residue. Acetonitrile (200ml) was added to the residue and stirred and then solvent was removed completely under vacuum at temperature 60-70°C. Acetonitrile (500ml) was added to the residue, refluxed and cooled and thereafter stirred for 1 hour at 20-30°C. The resulting solid was filtered, washed with acetonitrile (100ml) and dried at 60-70°C for 15-25 hours to get title compound. A portion (10g) of resulting compound was heated at 140-150°C in an oven for 8 hours to get title compound (9.8g) having HPLC purity [w/w]=99.83%; having single highest impurity=0.06%, methanol = 31 ppm, acetonitrile = 10 ppm, ethyl acetate = 21 ppm, tetrahydrofuran = 8 ppm, dimethyl acetamide = 536 ppm.
Example 5: Preparation of resmetirom
Substituted pyridazinone intermediate of formula II (100g) was taken in N,N-dimethylacetamide (200 ml) along with sodium acetate (85g). The reaction mass was heated at 105-115°C and stirred till completion of reaction. Thereafter, the reaction mass was cooled to ambient temperature followed by addition of water (1000ml), tetrahydrofuran (400ml) and ethyl acetate (400ml). The resulting reaction mass was stirred and layers were separated. The organic layer was washed with brine solution and then solvent was removed completely at 60-70°C under vacuum to obtain a residue. Acetonitrile (200ml) was added to the resulting residue with stirring and then solvent was removed completely under vacuum at 60-70°C. Acetonitrile (500ml) was added to the residue and refluxed for 30 minutes and then, cooled to 20-30°C and stirred for 1 hour. The resulting solid was filtered, washed with acetonitrile (100ml) and dried at 60-70°C for 15-25 hours to get title compound. A portion (10g) of resulting compound was heated at 140-150°C for 7 hours to get title compound (9.7g) having HPLC purity [w/w] = 99.79%; having single highest impurity =0.04%; acetonitrile = 121 ppm, ethyl acetate = 22 ppm, tetrahydrofuran = 15 ppm, dimethyl acetamide = 438 ppm.
Example 6: Preparation of resmetirom
Substituted pyridazinone intermediate of formula II (2.0Kg) was taken in N,N-dimethylacetamide (4.0L) along with sodium acetate (1.7Kg). The reaction mass was heated at 105-115°C and stirred till completion of reaction. Thereafter, the reaction mass was cooled to 20-30°C and water (20.0L), tetrahydrofuran (8.0L) and ethyl acetate (8.0L) were added to the reaction mass and layers were separated. The organic layer was washed with brine solution and then solvent was removed completely under vacuum from the organic layer at temperature 60-70°C to obtain a residue. Acetonitrile (4.0L) was added to the residue and stirred and then solvent was removed completely under vacuum at temperature 60-70°C. Acetonitrile (10.0L) was added to the residue and refluxed for 30 minutes, and then cooled to 20-30°C and stirred for 1 hour. The resulting solid was filtered, washed with acetonitrile (2.0L) and dried at 60-70°C for 22 hours to get title compound (1.80Kg).
A portion of resulting compound (460g) was heated at 140-150°C in an oven for 8 hours to get title compound (455g) having HPLC purity [w/w]=99.88%; having single highest impurity=0.05%; methanol=83 ppm, acetonitrile=208 ppm, tetrahydrofuran = 5 ppm.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We claim:
1. A process for the preparation pyridazinone derivative of formula I

Formula I
which comprises of:
i. intra-cyclizing substituted pyridazinone intermediate of formula II using a base in a suitable solvent,

Formula II
ii. cooling the reaction mixture obtained in step (i),
iii. extracting the reaction mass obtained in step (ii) in a suitable solvent medium,
iv. isolating the pure pyridazinone derivative.

2. The process as claimed in claim 1, wherein the base in step (i) is selected from sodium, potassium, or ammonium salt of the conjugate base of an organic acid.

3. The process as claimed in claim 2, wherein the organic acid is selected from acetic acid, formic acid, lactic acid, citric acid, malic acid, maleic acid, glycine, phosphoric acid, glycylclycine, succinic acid, TES (2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid), MOPS (3-(N-morpholino)propanesulfonic acid), PIPES (piperazine-N,N'-bis(2-ethane- sulfonic acid)), and MES (2-(N-morpholino)ethanesulfonic acid).

4. The process as claimed in claim 1, wherein the solvent in step (i) is selected from an aprotic solvent or mixture of an aprotic solvent with organic acid.

5. The process as claimed in claim 1, wherein the solvent medium used for extraction in step (iii) is selected from the ester solvent, ether solvent, water and/or any mixtures of two or more solvents thereof.

6. A process for the preparation pyridazinone derivative of formula I

Formula I
which comprises of:
i. intra-cyclizing substituted pyridazinone intermediate of formula II using a base in a suitable solvent,

Formula II
ii. cooling the reaction mixture obtained in step (i),
iii. extracting the reaction mass obtained in step (ii) in a suitable solvent medium,
iv. separating the layers,
v. distilling the organic layer,
vi. optionally, treating with a suitable solvent followed by removal of solvent to obtain residue,
vii. optionally recrystallizing the residue obtained in step (vi) with a suitable solvent,
viii. isolating the pure pyridazinone derivative.

7. The process as claimed in claim 6, wherein the solvent in step (i) is selected from aprotic solvent or a mixture of aprotic solvents with organic acid.

8. The process as claimed in claim 6, wherein the solvent medium in step (iii) is selected from the ester solvent, ether solvent, water and/or any mixtures of two or more solvents thereof.

9. The process as claimed in claim 6, wherein the solvent in step (vi) is selected from ketone solvent, nitrile solvent, alcohol solvent and polar solvent or mixture thereof.
10. The process as claimed in claim 6, wherein the solvent used for recrystallization in step (vii) is selected from ketone solvent, nitrile solvent, alcohol solvent, ester solvent, ether solvent, polar solvent or mixture thereof.