DESC:FIELD OF THE INVENTION
The present invention relates to an efficient process for the purification of substituted pyridazinone intermediate. More specifically, the present invention relates to a purification method of ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate, a key intermediate in the preparation of a pyridazinone derivative, an investigational new drug.
BACKGROUND OF THE 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 THR ß 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 is a progressive liver disease, U.S. Food and Drug Administration (FDA) has 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 [WO 2007/009913] 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 the 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 intermediate is diazotized using sodium nitrite and hydrochloric acid in acetic acid/water or water and then condensed with N-cyanoacetylurethane 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. Thereafter, the resulting intermediate is subjected to intra-cyclization using sodium acetate and acetic acid to yield a final product, as shown in the above scheme.
In the above process, pyridazinone intermediate, ethyl(Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazine-ylidene)acetyl)carbamate has been used as key [penultimate] intermediate for preparation of MGL-3196. However, the process involves the use of column/flash chromatography for purification of one of the intermediates, thereby making the whole process lengthy and cumbersome at industrial scale. 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. 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, as depicted in below scheme:

The above disclosure reported purity of crude substituted pyridazinone intermediate as 90.4% and is used as such in next step. In another example, said substituted pyridazinone intermediate has been purified using acetic acid, but purity of purified material is not mentioned. Moreover, the low purity material is not feasible for the preparation of a pharmaceutical grade end product due to the presence of unacceptable impurities level which are carried forward with synthetic precursor to final product and ultimately impact the quality of the final product thereby making the process unfeasible at industrial scale.
Several Chinese patent publications CN117164568, CN117263870 unveil similar method of preparing substituted pyridazinone intermediate as disclosed in above mentioned prior arts. In said Chinese publications, 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one is diazotized using sodium nitrite and hydrochloric acid in water and then condensed with N-cyanoacetylurethane in the presence of sodium acetate in water to yield substituted pyridazinone intermediate. Thereafter, the resulting compound is given washing with water and isopropyl ether and dried. Finally, dried solid material is subjected to intra-cyclization using potassium acetate in dimethylformamide to yield final API. The process is represented as given below:

The said 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 substituted pyridazinone intermediate.
Most of the prior arts as cited above are either silent about the purity of the substituted pyridazinone intermediate or require column/flash chromatographic purification at intermediate stage. Like any synthetic compound, final product can contain extraneous compounds or impurities that can be generated from numerous sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Consequently, to get the desired quality of the final product, product needs to be subjected to recrystallization or any other purification method. However, the inclusion of purification step in the final stage decreases the overall yield of the process and makes the process unattractive from the cost point of view.
During laboratory experimentation, the present inventors found that most of the process disclosed in the prior art for the preparation of substituted pyridazinone intermediate led to provide inadequate purity of the said intermediate, which was further employed with asserted purity for intra-cyclization to afford desire final product in which quality of product was ruined due to the presence of carry forwarded known and unknown impurities from intermediates. 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 substituted pyridazinone intermediate, there is a need in the art to provide an efficient industrially viable process for the purification of substituted pyridazinone intermediate. Keeping this in mind, the present invention aims to provide pure substituted pyridazinone intermediate, wherein impurities, known or unknown have been controlled in such a manner that final API should be pure as per ICH guidelines and multiple purifications are avoided at final stage.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an industrial advantageous process for the purification of substituted pyridazinone intermediate that overcomes the limitations of the prior methods i.e., low purity.
Another object of the present invention is to provide an effective process for the purification of substituted pyridazinone intermediate wherein the removal of impurities is controlled at different RRT (relative retention time) levels by simple purification method.
Yet another object of the present invention is to provide a process for the purification of substituted pyridazinone intermediate, which would be easy to implement on a commercial scale and economically viable.
Yet another object of the present invention is to control the level of known and unknown impurities in the substituted pyridazinone intermediate.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an efficient process for the purification of substituted pyridazinone intermediate of formula II,

Formula II
the process comprising the steps of:
i. dissolving crude substituted pyridazinone intermediate of formula II in a first solvent to form a solution at a suitable temperature,
ii. adding a second solvent to the solution obtained in step (i),
iii. cooling the reaction mixture to obtain a solid,
iv. isolating the pure substituted pyridazinone intermediate.
In an embodiment, the present invention provides a process for the preparation of pyridazinone derivative, resmetirom of formula I,

Formula I
which comprises the steps of:
i. dissolving crude substituted pyridazinone intermediate of formula II in a first solvent to form a solution,
ii. adding a second solvent to the solution obtained in step (i),
iii. cooling the reaction mixture to obtain a solid,
iv. isolating the pure substituted pyridazinone intermediate,
v. converting pure substituted pyridazinone intermediate to resmetirom.
In another embodiment, the present invention provides a process for the purification of substituted pyridazinone intermediate of formula II with a high purity which is further utilized to prepare pyridazinone derivative of formula I, having controlled level of impurities.
In yet another embodiment, the present invention provides a process for the preparation of pyridazinone derivative of formula I,

Formula I
which comprises the steps of:
i. providing the pure substituted pyridazinone intermediate,
ii. intra-cyclizing the intermediate obtained in step (i),
iii. isolating pure pyridazinone derivative.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a purification process of substituted pyridazinone intermediate of formula II.
As used herein, the term “pure” represents a compound having purity greater than 99.0% w/w by HPLC, preferably greater than 99.2% w/w by HPLC and any individual impurity [known] present in an amount less than 0.60% w/w by HPLC, any unknown impurity present in an amount of less than 0.30% w/w by HPLC and total impurities present in an amount less than 0.80% w/w by HPLC.
As used herein, the term “ambient temperature” represents a temperature range of 25? ± 5?.
As used herein, the term ‘crude’ represents a compound having impurities greater than the limits specified as per regulatory guidelines.
In a specific embodiment, the present invention provides a process to purify the substituted pyridazinone intermediate of formula II from purity of 98.14% to greater than 99.2%.
Specifically, the present invention provides a process to reduce the level of des-monochloro impurity, namely, ethyl (Z)-(2-(2-(3-chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)-2-cyanoacetyl) carbamate of formula III and some unknown impurities.

Formula III
Precisely, the des-monochloro impurity of formula III has been reduced from 0.80% w/w to less than 0.52% w/w and an unknown impurity (at RRT 0.81) from 0.47% w/w to less than 0.14% w/w and other impurities at different RRT’s such as RRT 0.61, RRT 1.12 and RRT 1.40 have been removed and not detected by HPLC.
The des-monochloro impurity of formula III can generate from the starting material, 4-amino-2,6-dichlorophenol, when it is contaminated with its corresponding monochloro derivative. Although it is wise to control the impurity at initial stage, if unknowingly it is not controlled and detected in later stages, it is advisable to control at least at penultimate stage of API.
In the first aspect the present invention provides a process for the purification of substituted pyridazinone intermediate of formula II. The process comprises dissolving crude substituted pyridazinone intermediate of formula II in a first solvent to form a solution. The dissolution of substituted pyridazinone intermediate in the first solvent can be achieved by heating the mixture. The mixture can be heated at a temperature ranging from about 55-75°C, preferably 60-70°C.
Generally, the first solvent used herein may include solvents in which substituted pyridazinone intermediate is slightly soluble. Examples of such solvents are, but not limited to aprotic solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide and/or mixtures of two or more thereof.
Subsequently, after dissolution, a second solvent can be added to the clear solution at the same temperature. The reaction mass can be stirred for 15 to 120 minutes. Preferably, the reaction can be stirred for 30 to 60 minutes. The second solvent used herein may include but not limited to esters such as ethyl acetate, n-butyl acetate, t-butyl acetate and/or mixtures of two or more thereof.
Afterwards, the reaction mass can be cooled to an ambient temperature and stirred for 1-5 hours for precipitation of solid. The resulting solid can be filtered using various filtration techniques such as pressure filtration, gravity filtration, vacuum filtration, and other techniques that are familiar to those skilled in the art. The resulting solid can be washed with a suitable solvent used during purification.
Thereafter, the resulting solid can be dried at 50-80? for about 5-25 hours to obtain pure substituted pyridazinone intermediate of formula II with negligible amount of des-monochloro and other impurity. The preferable drying temperature can be 50-60°C and preferably, the solid can be dried for 7-15 hours and more preferably for 10-12 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.
It was found by the inventors of the present invention that due to the presence of either known or unknown impurities which are difficult to remove during the synthesis and that, at the end, contaminate the final pharmaceutical product MGL-3196, resmetirom. In particular, already at early stages of the synthesis, it has been observed the presence of impurities which contaminated the synthetic precursor i.e., substituted pyridazinone intermediate of formula II, impurities having high relative retention times in the HPLC chromatograms.
Generally, side products, by-products, such as the impurity (des-monochloro), and adjunct reagents (collectively "impurities’) are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. Thereafter, the impurity can be identified, by its relative position in the chromatogram of the HPLC, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time.”
The retention time can vary by a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations, have upon accurate identification of an impurity, practitioners use the “relative retention time” (“RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
In another preferred embodiment, the present invention provides conversion of pure substituted pyridazinone intermediate of formula II into pyridazinone derivative of formula I by intra-cyclizing substituted pyridazinone intermediate of formula II in presence of base, in a suitable solvent. Further, the reaction can be carried out at a temperature of about 100-120°C. The resulting pyridazinone derivative of formula I have purity of greater than 99.0% w/w. It is advantageous to purify the substituted pyridazinone intermediate of formula II via using process of the present invention, as using pure intermediate final product results in purity of greater than 99.0% and any individual known impurity =0.15% and unknown =0.10% as per ICH guidelines.
In one another embodiment of the present invention, the crude 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 crude substituted pyridazinone intermediate of formula II.
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: Purification of substituted pyridazinone intermediate of formula II
Crude substituted pyridazinone intermediate of formula II (200 g) (having HPLC purity = 98.14%; individual impurities - 0.08% at RRT 0.61; 0.47% at RRT 0.81; 0.80% des-monochloro at RRT 0.92; 0.12% at RRT 1.12 and 0.12% at RRT 1.40) was taken in N,N-dimethylformamide (400ml) and stirred at 20-30 °C. The reaction mixture was heated and kept at 60-70°C for complete dissolution. Thereafter, ethyl acetate (800 ml) was added to the reaction mass and stirred for a further 30-60 minutes. After stirring, the reaction mass was cooled to 20-30°C and stirred at same temperature for 2-3 hours. The resulting mixture was filtered at the same temperature and washed with ethyl acetate (5 ml). Finally, the resulting residue was dried at 50-60°C for 10-12 hours to obtain pure title compound (150 g) having HPLC purity [w/w] = 99.40%; other impurities - 0.14% at RRT 0.80; des-monochloro = 0.44% at RRT 0.93; impurities at RRT 0.61; RRT 1.12 and RRT 1.40 are not detected.
Example 2: Purification of substituted pyridazinone intermediate of formula II
Crude substituted pyridazinone intermediate of formula II (200 g) (having HPLC purity = 98.14%; individual impurities - 0.08% at RRT 0.61; 0.47% at RRT 0.81; 0.80% des-monochloro at RRT 0.92; 0.12% at RRT 1.12 and 0.12% at RRT 1.40) was taken in N, N-dimethylformamide (400ml) and stirred at 20-30 °C. The reaction mixture was heated at 60-70°C for complete dissolution. Thereafter, ethyl acetate (800 ml) was added to the reaction mass and stirred for 30-60 minutes. After stirring, the reaction mass was cooled at 20-30°C and again stirred for 2-3 hours. The resulting mixture was filtered at the same temperature and washed with ethyl acetate (5 ml). Finally, the resulting residue was dried at 50-60°C for 10-12 hours to obtain pure title compound having HPLC purity [w/w] = 99.28%; other impurities - 0.13% at RRT 0.81; des-monochloro = 0.46% at RRT 0.93; impurities at RRT 0.61, RRT 1.12 and RRT 1.40 are not detected.
Example 3: Purification of substituted pyridazinone intermediate of formula II
Crude substituted pyridazinone intermediate of formula II (25 g) (having HPLC purity = 98.14%; individual impurities - 0.08% at RRT 0.61; 0.47% at RRT 0.81; 0.80% des-monochloro at RRT 0.92; 0.12% at RRT 1.12 and 0.12% at RRT 1.40) was taken in N, N-dimethylformamide (50ml) and stirred at 20-30 °C. The reaction mixture was heated at 60-70°C for complete dissolution. Thereafter, ethyl acetate (100 ml) was added to the reaction mass and stirred 30-60 minutes. After stirring, the reaction mass was cooled at 20-30°C and again stirred at same temperature for 2-3 hours. The resulting mixture was filtered at the same temperature and washed with ethyl acetate (5 ml). Finally, the resulting residue was dried at 50-60°C for 10-12 hours to obtain pure title compound (18 g) having HPLC purity [w/w] = 99.43%; other impurities - 0.06% at RRT 0.82; des-monochloro = 0.51% at RRT 0.92; impurities at RRT 0.61, RRT 1.12 and RRT 1.40 are not detected.

Example 4: Purification of substituted pyridazinone intermediate of formula II
Crude substituted pyridazinone intermediate of formula II (200 g) (having HPLC purity = 98.14%; individual impurities 0.08% at RRT 0.61, 0.47% at RRT 0.81; 0.80% des-monochloro at RRT 0.92; 0.12% at RRT 1.12 and 0.12% at RRT 1.40) was taken in N, N-dimethylformamide (400ml) and stirred at 20-30 °C. The reaction mixture was heated at 60-70°C for complete dissolution. Thereafter, ethyl acetate (800 ml) was added to the reaction mass and stirred for 30-60 minutes. After stirring, the reaction mass was cooled at 20-30°C and again stirred for 2-3 hours. The resulting mixture was filtered at the same temperature and washed with ethyl acetate (5 ml). Finally, the resulting residue was dried at 50-60°C for 10-12 hours to obtain pure title compound having HPLC purity [w/w] =99.21%; other impurities - 0.08% at RRT 0.82; des-monochloro = 0.50% at RRT 0.92; impurities at RRT 0.61, RRT 1.12 and RRT 1.40 are not detected.
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:1. A process for the purification of substituted pyridazinone intermediate of formula II,

Formula II
comprising the following steps:
i. dissolving crude substituted pyridazinone intermediate of formula II in a first solvent to form a solution,
ii. adding a second solvent to said solution obtained in step (i),
iii. cooling the reaction mixture to obtain a solid,
iv. isolating the pure substituted pyridazinone intermediate.
2. The process as claimed in claim 1, wherein in the step (i) said first solvent is selected from the aprotic solvents.
3. The process as claimed in claim 2, wherein the aprotic solvent is consisting of dimethylformamide, dimethylacetamide and dimethylsulfoxide and/or mixtures of two or more thereof.
4. The process as claimed in claim 1, wherein in the step (ii) said second solvent is selected from the group of esters consisting of ethyl acetate, n-butyl acetate, t- butyl acetate and/or mixtures of two or more thereof.

5. The process as claimed in claim 1, wherein pure substituted pyridazinone intermediate of formula II have purity of greater than 99.0% w/w by HPLC.
6. The process as claimed in claim 1, wherein level of des-monochloro impurity of formula III is reduced from 0.80% w/w to less than 0.52%, and unknown impurity (at RRT 0.81) from 0.47% w/w to less than 0.14%, as determined by HPLC, in pure substituted pyridazinone intermediate of formula II.

Formula III
7. A process for the preparation of pyridazinone derivative of formula I,

Formula I
comprising the following steps:
i. dissolving crude substituted pyridazinone intermediate of formula II in a first solvent to form a solution,
ii. adding a second solvent to said solution obtained in step (i),
iii. cooling the reaction mixture to obtain a solid,
iv. isolating the pure substituted pyridazinone intermediate,
v. converting pure substituted pyridazinone intermediate to resmetirom.
8. The process as claimed in claim 7, wherein in the step (i) said first solvent is selected from the aprotic solvents consisting of dimethylformamide, dimethylacetamide and dimethylsulfoxide and/or mixtures of two or more thereof.
9. The process as claimed in claim 7, wherein in the step (ii) said second solvent is selected from the group of esters consisting of ethyl acetate, n-butyl acetate, t- butyl acetate and/or mixtures of two or more thereof.
10. The process as claimed in claim 7, wherein in the step (v) said conversion is carried out by intra-cyclizing the pure substituted pyridazinone intermediate of formula II.