DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of nintedanib and conversion to its pharmaceutically acceptable salts thereof. More particularly, the present invention provides a process for the purification of nintedanib and conversion to nintedanib esylate.
BACKGROUND OF THE INVENTION
Nintedanib, a tyrosine kinase inhibitor, of Formula I is chemically known as methyl (3Z)-3-{[(4-{methyl[(4-methylpiperazin-1-yl)acetyl]amino} phenyl) amino] (phenyl)methylidene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylate shown as below:

Formula I

Nintedanib esylate salt of Formula Ia, has been approved in US and other countries for the treatment of idiopathic pulmonary fibrosis (IPF). It is marketed as soft gelatin capsule (OFEV®, VARGATEF®, and CYENDIV®) by Boehringer Ingelheim.

Formula Ia

Nintedanib and its pharmaceutically acceptable salts have been first time disclosed in US patent 6,762,180 (refer as US’180). The process describes the synthesis of nintedanib from two building blocks, one is the indolinone based key building block (Z)-methyl-1-acetyl-3-(methoxyphenyl)methylene)-2-oxoindoline-6-carboxylate, which is prepared from methyl 1-acetyl-2-oxoindoline-6-carboxylate by reacting with trimethylorthobenzoate. Afterwards, the enol ether is coupled with second key building block N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide in dimethylformamide followed by the treatment with piperidine to furnish nintedanib base. The process is depicted below:

The extant disclosure reports the chemistry to prepare several oxoindoline derivatives including nintedanib, but specific exemplified process to prepare nintedanib has not been presented.
Another US patent 8,304,541 describes a process for the preparation of nintedanib. In said patent, methyloxindole-6-carboxylate is converted to methyl 1-chloroacetyl-oxindole-6-carboxylate using chloroacetic anhydride followed by the reaction with trimethyl orthobenzoate, producing methyl (E)-1-chloroacetyl-3-(methoxyphenylmethylene)-oxindole-6-carboxylate. Then, the chloroacetyl group is removed, producing methyl (E)-3-(methoxyphenylmethylene)-oxindole-6-carboxylate and, finally, a reaction of this compound with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide provides nintedanib. The said patent does not involve preparation of nintedanib through N-acetyl nintedanib intermediate. But it has its own drawbacks, as it involves use of expensive reagent i.e., chloroacetic anhydride in the first step and formation of the toxic methyl chloroacetate as a side product in third step.
A PCT publication WO2019048974 also discloses a process for the preparation of nintedanib. In the process, (Z)-methyl 1-acetyl-3-(methoxyphenyl)methylene)-2-oxoindoline-6-carboxylate is coupled with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide in a solvent to obtain N-acetyl nintedanib which is further deprotected using piperidine in an alcoholic solvent to obtain nintedanib free base. Further the example is given only at 10 gm scale, when the similar experiment was carried out at large scale, unreacted N-acetyl nintedanib, present in unacceptable amounts and difficult to remove.
One another US patent 11,261,158 covers a similar process for the preparation of nintedanib. In said process, a heterogeneous mixture of methyl (E)-1-acetyl-3-(methoxy(phenyl)methylene)-2-oxoindoline-6-carboxylate and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide, in methanol and N,N-dimethylformamide is stirred and heated to reflux of the solvent system to obtain N-acetyl nintedanib. Thereafter piperidine is then added and the mixture is stirred under reflux for another 30-60 minutes. Finally, the mixture is cooled, and the solids are isolated by filtration to obtain nintedanib free base having purity 99.8% w/w by HPLC. The patent is silent about N-acetyl impurity. Further, when a similar experiment was carried out, unreacted N-acetyl nintedanib, present in unacceptable amounts and difficult to remove.
Another US patent 10,125,122 unveils a method of preparing nintedanib. The process involves reaction of methyl (E)-1-acetyl-3-(methoxyphenyl methylene)-oxindole-6-carboxylate with N-(4-aminophenyl)-N,4-dimethyl-1-piperazine acetamide in a solvent and subsequently treatment with a base selected from the group consisting of an alkali metal hydroxide and an alkali metal alkoxide in the presence of a solvent, without isolation of the intermediate, to get nintedanib. The patent is silent about N-acetyl impurity.
In most of the above-mentioned prior arts, when repeated, it was observed that certain impurities remain intact with final product due to the unwanted reactions of intermediates with chemical reagents or catalysts and unable to eliminate from the product even after employing purification processes. Most of these patents are silent about the impurities of nintedanib. The general impurities of nintedanib and its pharmaceutically acceptable salts as reported in literature are given below:

These impurities can be formed through a variety of side reactions, such as incomplete reaction, over reaction, isomerization, dimerization, and rearrangement. Among these impurities, N-acetyl nintedanib, is difficult to remove by simple recrystallization if remains unreacted during deacetylation step. Any impurity/ impurities that remain within the formulation or active pharmaceutical ingredient (API) even in the small amounts can influence quality, safety and efficacy (QSE) of the product, thereby causing serious health hazards.
The potential impurities in a drug substance (API) can have an influential effect on the safety and quality of the drug substance. The percentage of impurities in any drug substance are represented as per its toxicological or biological data. It is quite significant for “regulatory” aspect of drug substance approval to provide limits of “relevant impurities”. Therefore, it is mandatory to study the impurities of any drug substance and prevail it while manufacturing of a drug substance.
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
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
Nevertheless, besides the existing routes of preparation as well as purification of nintedanib, to overcome the aforementioned drawbacks associated in the prior art processes for unacceptable level of impurities specifically which are originated mainly during the synthetic process from the intermediate reactions, there is a continuing need in the art to optimize the preparation process of nintedanib or develop an efficient purification process which will purge the impurities down to the desired level as per ICH guidelines.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient process for the preparation of pure nintedanib wherein level of impurities is controlled as per the prescribed guidelines of ICH.
Another object of the present invention is to provide an efficient and industrially advantageous process for the purification of nintedanib and its conversion to pharmaceutically acceptable salts wherein individual impurity can be controlled to a level of less than 0.05% and total impurities to a minimal level.
One another object of the present invention is to provide an effective method of purification of nintedanib.
One another object of the present invention is to convert pure nintedanib to nintedanib esylate, wherein individual impurity can be controlled to a level of less than 0.05% and total impurities to a level of less than 0.15%.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of pure nintedanib. Specifically, the present invention provides an efficient method for the preparation of nintedanib and its pharmaceutically acceptable salts wherein final product is substantially free from impurities.
In one embodiment, the present invention provides an improved process for the purification of nintedanib, which comprises the steps of,
i. providing a solution of nintedanib in a suitable solvent, in the presence of a base at temperature of 60-70°C,
ii. cooling the reaction mass to ambient temperature,
iii. filtering the solution followed by washing with the solvent, and
iv. isolating pure nintedanib.
In one another embodiment, the present invention provides an improved process for the preparation of pure nintedanib esylate, which comprises the steps of,
i. providing a solution of pure nintedanib in a suitable solvent,
ii. adding ethanesulphonic acid,
iii. cooling the reaction mixture, and
iv. isolating pure nintedanib esylate salt.
In one another embodiment, the present invention provides an improved process for the preparation of pure nintedanib esylate, which comprises the steps of,
i. dissolving nintedanib in a suitable solvent in the presence of a base,
ii. heating the reaction mass to a temperature of 60-70°C,
iii. cooling the reaction mass at an ambient temperature,
iv. isolating pure nintedanib, and
v. converting pure nintedanib into its esylate salt.
In one another embodiment, the present invention provides an improved process for the preparation of pure nintedanib and pharmaceutical acceptable salt, which comprises the steps of,
i. dissolving nintedanib in a suitable solvent in the presence of a base,
ii. heating the reaction mass to a temperature of 60-70°C,
iii. cooling the reaction mass at an ambient temperature,
iv. isolating pure nintedanib, and
v. converting pure nintedanib into its pharmaceutical acceptable salt.
In one another embodiment, the present invention provides an improved process for the preparation of pure nintedanib, which comprises the steps of,
i. reacting a compound of Formula II
Formula II

with compound of Formula III,
Formula III
in the presence of a base in a suitable solvent, at a temperature of 60-70°C,
ii. cooling the reaction mass to ambient temperature,
iii. isolating crude nintedanib,
iv. dissolving nintedanib obtained in step iii) in a suitable solvent, in the presence of a base at temperature of 60-70°C,
v. cooling the reaction mass to ambient temperature, and
vi. isolating pure nintedanib.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrial advantageous process for the preparation and purification of nintedanib and its conversion to pharmaceutically acceptable salts wherein impurities are controlled as per prescribed limit of ICH guidelines and in particular less than 0.05% w/w by HPLC.
As used herein, the term “ambient temperature” represents a temperature 25? ± 5?.
As used herein, the term “pharmaceutically acceptable salts” refers to acid addition salt selected from the group which may include but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, gluconic acid, methanesulphonic acid, ethanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
The term “substantially free” herein means nintedanib and its pharmaceutically acceptable salts having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC. In particular, less than about 0.10% by area percentage of HPLC. More particular, less than about 0.05% by area percentage of HPLC. Most particularly, in the range of about 0.01% to about 0.05% by area percentage of HPLC.
As used herein, the term ‘crude’ represents a compound having impurities greater than the limits specified as per ICH guidelines, in particular having any known impurity greater than about 0.15% by area percentage of HPLC or any unknown impurity greater than about 0.10% by area percentage of HPLC.
The term “pure” herein refers to purity of nintedanib and its pharmaceutically acceptable salts, which is substantially free from, one or more impurities and having purity of greater than 99% or more of about 99.5% or more, particularly of about 99.85% or more by area percentage of HPLC.
In one general aspect there is provided nintedanib and pharmaceutically acceptable salts having a purity of about 99.5% or more by area percentage of HPLC.
As per regulatory guidance for drug manufacturers, it requires that impurities generated either through process or degradation to be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. The basic idea of the invention is to specifically develop an improved process of purification of nintedanib and pharmaceutically acceptable salts which is free from its known and unknown impurities.
In one embodiment the present invention provides an improved process for the purification of nintedanib. The process comprises of dissolving crude nintedanib in the suitable solvent in the presence of a base. The crude nintedanib can be prepared by the methods reported in the literature or by the process as given in the present specification which may have impurities greater than the limits specified as per ICH guidelines.
Particularly, the crude nintedanib can be prepared by the reaction of (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester of Formula II
Formula II
with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide of Formula III
Formula III
in the presence of a suitable solvent and base. The suitable solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene; amide solvent such as N,N-dimethylformamide, dimethylacetamide or mixture thereof. Preferably, the solvent can be methanol and N,N-dimethylformamide or mixture thereof.
The base used herein includes, but is not limited to, organic or inorganic base. Examples of organic bases may include, but are not limited to, triethylamine, ammonia, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo [4.3.0]non-5-ene, 4-dimethyl aminopyridine, diisopropylamine, N,N-diisopropylethyl amine, tributylamine, tert-butyl amine, N-methyl morpholine, N,N-dimethyl benzylamine, isopropyl ethyl amine, N-methyl pyrrolidine, propyl ethyl amine, ethanolamine, chloramines, piperidine, pyridine, picoline, lutidine their salts and mixture thereof. Examples of inorganic bases include, but are not limited to, hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof. The reaction may be carried out at a temperature of 60-75? and can be heated for 8-12 hours or more. Preferably, the reaction may be carried out at a temperature of 60-70? and can be heated for 8-9 hours.
The resulting crude nintedanib has purity of around less than 99. 6% w/w by HPLC and known impurity i.e., N-acetyl impurity at RRT 1.43 is present in an unacceptable amount i.e., in an amount greater than 0.15%, in particular greater than 0.25%. Besides that, an unknown impurity has also been found at RRT ~1.65 about ~0.08% in the crude material.
If crude nintedanib, as such, is utilized for the preparation of nintedanib pharmaceutically acceptable salts such as nintedanib esylate, the impurities present in it, may be carried forward to nintedanib esylate and product purity may be unacceptable for use as per regulatory guidelines.
It has been observed by the inventors of present invention that during reaction of (E)-1-acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester of formula II with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide of formula III, if condensed product i.e. N-acetyl nintedanib, remains unreacted during reaction, it will not further react even if additional base is added or reaction time is extended for further more hours. The reaction will become stagnant and the unreacted N-acetyl-nintedanib remains as such and deprotection of acetyl group does not go to completion. Even it is difficult to remove unreacted N-acetyl -nintedanib from crude nintedanib by simple recrystallization methods. Therefore, it becomes challenging to remove said N-acetyl nintedanib impurity from nintedanib.
After extensive experimentation, the process of present invention has been developed to remove said N-acetyl impurity from crude nintedanib. The crude nintedanib can be treated with a suitable base in an organic solvent and the reaction mixture can be heated at reflux temperature of solvent for few minutes to few hours.
Specifically, crude nintedanib can be taken in a suitable solvent in the presence of a suitable base. The reaction mass can be subjected for heating to reflux temperature of the solvent under stirring for 7-24 hours depending upon the choice of base and solvent used. Particularly, solvent may be selected from C1-C8 alcohols group then the reaction mass can be heated at a temperature of 60-75? for 16-24 hours. More preferably, reaction mass may be heated at a temperature of 60-70? for 20-24 hours. Mostly, the solvent can be selected from amide solvent group then the reaction mass may be heated at a temperature of 60-75? for 7-14 hours. More preferably, reaction mass may be heated at a temperature of 60-70? for 8-12 hours.
Thereafter, the reaction mass can be cooled at an ambient temperature and subsequently can be stirred for 1-5 hours at the same temperature. Preferably, the reaction mass may be stirred for 2-4 hours.
The suitable solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; amide solvent can be selected from N,N-dimethylformamide, dimethylacetamide or mixture thereof. Preferably, the solvent can be methanol or N,N-dimethylformamide.
The base used during the dissolution herein includes, but is not limited to, organic or inorganic base. Examples of organic bases may include, but are not limited to, triethylamine, ammonia, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 4-dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, tributylamine, tert-butyl amine, N-methyl morpholine, N,N-dimethyl benzylamine, isopropyl ethyl amine, N-methyl pyrrolidine, propyl ethyl amine, ethanolamine, chloramines, piperidine, pyridine, picoline, lutidine their salts and mixture thereof. Examples of inorganic bases include, but are not limited to, hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof.
The pure nintedanib can be isolated by using techniques known in the art such as filtration, centrifugation etc. Finally, the solid obtained after filtration can be dried at a temperature of 45-65? for 1-8 hours to obtain pure nintedanib. Preferable drying temperature can be 50-60? and preferably, the solid can be dried for 1-4 hours and more preferably for 2-4 hours.
The pure nintedanib have purity more than 99.85% w/w by HPLC, and N-acetyl nintedanib impurity level has been reduced considerably to less than 0.05%, well within acceptable limit by ICH guidelines.
In one embodiment, the present invention provides the nintedanib and its pharmaceutically acceptable salts, wherein the level of impurity, the compound of Formula IV,
Formula IV
is less than 0.05% w/w of nintedanib, as determined by HPLC.
In hands of the present inventors, it was observed that the amount of impurity can be reduced proficiently through the purification process of the present invention. It can be repeated if required, when desired purity may not have been achieved.
The conversion of highly pure nintedanib to its pharmaceutically acceptable salts i.e., nintedanib esylate can be achieved by treating pure nintedanib with ethanesulphonic acid and suitable solvent. Firstly, the solvent can be added to the nintedanib at an ambient temperature. The suitable solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol or mixture thereof. Preferably, the solvent can be alcohol, more preferably the solvent can be methanol. The dissolution of nintedanib in the solvent can be achieved by heating the mixture to reflux temperature of the solvent followed by addition of the ethanesulphonic acid. The ethanesulphonic acid source can be selected from ethanesulphonic acid or its aqueous solution. Thereafter, the mixture can be subjected for stirring and then resulting reaction mixture can be cooled at at ambient temperature. Subsequently, antisolvent can be slowly added in the reaction mass and stirred. The antisolvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of ethers such as tetrahydrofuran, dioxane, tert-butylmethylether, diethylether, diisopropylether; esters such as ethyl acetate, isopropyl acetate or mixture thereof. Preferably, the solvent can be tert-butylmethylether. Further resulting reaction mass can be cooled at 0-10°C and then stirred for 3-7 hours. Preferably, the reaction mass can be cooled at a temperature less than or equal to 5°C. Preferably, the reaction mass can be stirred for 3-4 hours. The reaction mass can be filtered and washed with the suitable solvent to get nintedanib esylate as solid. The solvent used for washing herein can be selected from any suitable organic solvent which is selected from the group consisting of ethers such as tetrahydrofuran, dioxane, tert-butylmethylether, diethylether, diisopropylether; esters such as ethyl acetate, isopropyl acetate or mixture thereof. The material can be dried for 7-12 hours at 40-65°C to get nintedanib esylate. Preferable drying temperature can be 40-50? and preferably, the solid can be dried for 8-11 hours and more preferably for 9-10 hours. The solid mass obtained from the above process can be further subjected for one or more purifications as given in the present specification to achieve the desired purity of greater than 99.8%.
The obtained pure nintedanib esylate have HPLC purity [w/w] more than 99.90% and impurities are found to be reduced considerably and present within acceptable limit wherein the level of individual specified, and unspecified impurities is controlled at a level of equal to or less than 0.15% and 0.10% respectively and total impurities at a level of less than 1.0 % as per regulatory guidelines.
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 nintedanib
(E)-1-Acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (100g) was taken in methanol (700 ml) followed by addition of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide (80g) and N,N-diisopropylethylamine (100 ml) at 10-30°C. The reaction mass was then heated at 60-70°C and stirred for 8 hours. Thereafter, the reaction mass was allowed to attain ambient temperature and further stirred at 20-30°C for around 5 hours. The reaction mass was filtered, and the resulting solid was washed with methanol (50ml). The solid was dried for 4 hours at 40-50°C to get nintedanib (142 g) having purity 99.57% w/w by HPLC; and impurity N-acetyl nintedanib was present 0.26%.
Example 2: Purification of nintedanib (prior art process)
Nintedanib (50 g having N-acetyl nintedanib = 0.26%) was taken in methanol (250 ml) and acetone (250ml) and heated to 50-60°C under stirring for 30 minutes. The reaction mass was allowed to cool at 20-30°C and stirred for 1-3 hours. Thereafter, the reaction mass was filtered nintedanib as a solid. The solid was dried at 40-50°C for 4 hours to get desired pure nintedanib (46 g) having purity 99.58% w/w by HPLC; and impurity N-acetyl nintedanib was present 0.23%.
Example 3: Preparation of nintedanib
(E)-1-Acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (100g) was taken in methanol (700 ml) followed by addition of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide (80 g) and triethylamine (100 ml) at 10-30°C. The reaction mass was heated at 60-70°C and stirred for 8 hours. Thereafter, the reaction mass was allowed to attain ambient temperature and then subjected for slow cooling at 20-30°C. The reaction mass was stirred the reaction mass for 4 hours at 20-30°C. The reaction mass was filtered at the same temperature and the resulting solid was washed with methanol (50ml). The solid was dried for 4 hours at 40-50°C to get nintedanib (142 g) having purity 99.48% w/w by HPLC; and impurity N-acetyl nintedanib was present 0.43%.

Example 4: Preparation of nintedanib
(E)-1-Acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (100g) was taken in methanol (700 ml) followed by addition of N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide (80 g) and N, N-diisopropylamine (100 ml) at 10-30°C. The reaction mass was heated at 60-70°C and stirred for 8 hours. Thereafter, the reaction mass was allowed to attain ambient temperature and then subjected for slow cooling at 20-30°C. The reaction mass was stirred for 2 hours at 20-30°C. The reaction mass was filtered at the same temperature and the resulting solid was washed with methanol (50ml). The solid was dried for 4 hours at 40-50°C to get nintedanib (142 g) having purity 99.48% w/w by HPLC; and impurity N-acetyl nintedanib was present 0.31%.
Example 5: Purification of nintedanib
Nintedanib (100g; having N-acetyl nintedanib = 0.26%) was taken in methanol (500 ml) and N, N-diisopropylethylamine (100 ml) under stirring at 10-30°C. The reaction mass was heated at 60-70°C and stirred for 20-24 hours. The reaction mass was allowed to cool at 20-30°C. Further the reaction mass was stirred for 2 hours at 20-30°C. The reaction mass was to get nintedanib as a solid. The solid was dried at 40-50°C for 4 hours to get pure nintedanib (95 g) having purity 99.85% w/w by HPLC; and impurity N-acetyl nintedanib was present 0.03%.
Example 6: Purification of nintedanib
Nintedanib (100 g; having N-acetyl nintedanib = 0.26%) was taken in N,N-dimethylformamide (300 ml) and piperidine (100 ml) and heated to 60-70°C under stirring for 8-12 hours. The reaction mass was allowed to cool at 20-30°C and stirred for 1-5 hours. The resulting reaction mass was filtered and washed with N,N-dimethylformamide (50 ml). Methanol (500 ml) was added in the reaction mass and heated to 60-70°C under stirring. The reaction mass was allowed to cool at 20-30°C. Further the reaction mass was stirred for 4 hours at 20-30°C. Again methanol (500 ml) was added in the reaction mass and heated to 60-70°C under stirring. Thereafter, the reaction mass was allowed to cool at 20-30°C. Further the reaction mass was stirred for 2 hours at 20-30°C. The resulting reaction mass was filtered to get pure nintedanib as a solid. The solid was dried at 40-50°C for 4 hours to get pure nintedanib (80 g) having purity 99.97% w/w by HPLC; and impurity N-acetyl nintedanib was not detected.
Example 7: Preparation of nintedanib esylate
Nintedanib (100 g) was taken in methanol (1200 ml) at 20-30°C. Thereafter, the reaction mass was heated at 50-60°C followed by addition of 70% aqueous solution of ethanesulphonic acid (30g) and resulting mass was stirred to get clarity. The reaction mass was filtered at 50-60°C and allowed to attain at ambient temperature, and subsequently tert-butylmethylether (700 ml) was added in the reaction mass and stirred. Further resulting reaction mass was further cooled at 0-10°C and then stirred for 6-7 hours. The reaction mass was filtered, washed with tert-butylmethylether (50 ml), dried for 10 hours at 40-50°C to get pure nintedanib esylate (99 g) having purity 99.90% w/w by HPLC; and impurity N-acetyl nintedanib was present 0.04%.
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 purification of nintedanib, which comprises the steps of,
i. providing a solution of nintedanib in a suitable solvent, in the presence of a base at temperature of 60-70°C,
ii. cooling the reaction mass to ambient temperature,
iii. filtering the solution followed by washing with the solvent, and
iv. isolating pure nintedanib.

2. The process as claimed in claim 1, wherein solvent in step (i) is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; amide solvent is selected from N,N-dimethylformamide, dimethylacetamide or mixture thereof; and base used in step (i) is selected from an organic or inorganic base.

3. The process as claimed in claim 2, wherein organic base is selected from triethylamine, ammonia, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, 4-dimethylaminopyridine, diisopropylamine, N,N-diisopropylethylamine, tributylamine, tert-butyl amine, N-methyl morpholine, N,N-dimethyl benzylamine, isopropyl ethyl amine, N-methyl pyrrolidine, propyl ethyl amine, ethanolamine, chloramines, piperidine, pyridine, picoline, lutidine their salts and mixture thereof; and inorganic base is selected from the group consisting of hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof.

4. The process as claimed in claim 1, wherein solvent used for washing in step (iii) is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol.

5. The process as claimed in claim 1, wherein level of compound of Formula IV in pure nintedanib is less than 0.05% w/w of nintedanib, as determined by HPLC.
Formula IV

6. A process for the preparation of pure nintedanib esylate, which comprises the steps of,
i. dissolving nintedanib in a suitable solvent in the presence of a base,
ii. heating the reaction mass to a temperature of 60-70°C,
iii. cooling the reaction mass at an ambient temperature,
iv. isolating pure nintedanib, and
v. converting pure nintedanib into pure nintedanib esylate.

7. The process as claimed in claim 6, wherein conversion in step (v) comprises the steps of,
i. providing a solution of pure nintedanib in a suitable solvent,
ii. adding ethanesulphonic acid,
iii. cooling the reaction mixture, and
iv. isolating pure nintedanib esylate salt

8. The process as claimed in claim 7, wherein solvent in step (i) is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol or mixture thereof; and wherein isolation in step (iv) is carried out by the addition of antisolvent in the reaction mixture of step (iii).

9. The process as claimed in claim 8, wherein antisolvent is selected from the group consisting of ethers such as tetrahydrofuran, dioxane, tert-butylmethylether, diethylether, diisopropylether; esters such as ethyl acetate, isopropyl acetate or mixture thereof.

10. A process for the preparation of pure nintedanib, which comprises the steps of,
i. reacting a compound of Formula II
Formula II
with compound of Formula III,
Formula III

in the presence of a base in a suitable solvent, at a temperature of 60-70°C,
ii. cooling the reaction mass to ambient temperature,
iii. isolating crude nintedanib,
iv. dissolving nintedanib obtained in step iii) in a suitable solvent, in the presence of a base at temperature of 60-70°C,
v. cooling the reaction mass to ambient temperature, and
vi. isolating pure nintedanib.