DESC:
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(see section 10 and rule 13)
1. TITLE OF THE INVENTION
“PROCESS FOR THE PREPARATION OF NINTEDANIB; AN INTERMEDIATE AND/OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF”
2. APPLICANT
Name Nationality Address
UNICHEM LABORATORIES LTD. INDIAN UNICHEM BHAVAN
47, KANDIVALI INDUSTRIAL ESTATE,
KANDIVALI (WEST),
MUMBAI - 400067,
MAHARASHTRA, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION
The present invention relates to a process for the preparation of Nintedanib and/or its pharmaceutically acceptable salts. Furthermore, it relates to a novel intermediate and process for preparing the same. The present invention may be carried out in minimum steps, require less number of solvents, obtained Nintedanib or its salt with improved yield and purity.

BACKGROUND OF INVENTION
Nintedanib ethanesulfonate salt also known as esylate salt is a kinase inhibitor developed by Boehringer Ingelheim used in the treatment of idiopathic pulmonary fibrosis. The chemical name of Nintedanib esylate is 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo- methylester, (3Z) -, ethanesulfonate, represented by a compound of formula (8)

Compound of formula (8)
The impurities may affect the quality and safety of drug products, henceforth, impurity identification and profiling are an integral part of drug quality control and is particularly important for newly developed medications. The quality of any API depends on its synthetic process, potential degradation pathway, and possible side reactions. Consequently, API manufacturers attempt to minimize impurity levels; nevertheless, the formation of impurities cannot be fully avoided. Therefore, there is a need to develop a process for manufacturing of API with minimum amount (concentration) or without impurity formation to get the regulatory approval for marketing the medication.
Following are the references which discloses processes for preparation of Nintedanib.
WO2009071523 A1 describes the process for preparation of Nintedanib esylate, wherein said preparation is carried out by reacting 6-methoxycarbonyl-2 oxindole with chloroacetic anhydride in presence of toluene, methyl cyclohexane and methanol, followed by condensing the obtained compound with trimethylorthobenzoate, acetic anhydride and toluene. Further upon dechlorination of the acetyl group, it is reacted with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide to form Nintedanib which is further reacted with ethanesulfonic acid to obtain Nintedanib esylate. A schematic representation above preparation is provided below.

WO’523 disclosed process involves use of monochloroacetic anhydride (MCAA) as an acylating agent which is hazardous to human health. Breathing of chloroacetic anhydride can irritate the nose, throat, skin, eye and lungs causing coughing, wheezing and/or shortness of breath. It reacts with water evolving hydrochloric acid. Corrosive nature of MCAA that can cause injury to the skin, eyes, and respiratory tract; causes lacrimation and may cause edema and chemical pneumonitis after inhalation (Laboratory Chemical Safety Summary (LCSS) Datasheet; https://pubchem.ncbi.nlm.nih.gov/compound/Chloroacetic-anhydride).
Furthermore, it generates toxic methyl chloroacetate as impurity or by product and hence due to impurity or by product formation, desired purity and/or yield of Nintedanib may not be achieved. Furthermore, it may require purification step to obtain desired purity of the compound. Purification step involves use of solvent(s), energy consumption which results in increased production cost. Thus, the process involves tedious, difficult to operate and lengthy steps thereby increasing the cost of production of Nintedanib esylate.
CN104844499 A discloses one pot synthesis of Nintedanib, wherein the process is carried out by reacting 2-oxindole-6-carboxylic acid methyl ester, methyl benzoate, potassium carbonate or sodium carbonate in N,N-dimethylformamide, adding N-(4-aminophenyl) -N-methyl-2-(4-methylpiperazin-1-yl)acetamide and stirring at room temperature, further the reaction solution is poured into water, recrystallized and dried to obtain Nintedanib.

However, in the one pot synthesis method, it is extremely difficult to control the quality of final product formed. It is also difficult to keep control of impurities formed during the preparation of Nintedanib. Designing of one pot synthesis, a major disadvantage is to figure out a way to optimize and ensure compatibility of chemicals and/or solvents and/or starting materials and products. It is challenging doing work up of the reaction to isolate desired product. Impurities formed also troubles for purifying desired product(s). These methods generally show disadvantages of slow reaction rates and material loss and are often non-economical for commercial or scaled-up production.
Gerald J. Roth et. al., (2009) describes process for preparation of Nintedanib, wherein 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester is reacted with acetic anhydride to form 6-Acetyl-2-oxo-2,3-dihydro-1H-indole-6-carboxylic Acid Methyl Ester (yield: 73%), which is further reacted with acetic anhydride and ortho-benzoic acid trimethyl ester to form (E)-1-Acetyl-3-(methoxy-phenyl-methylene)-2-oxo-2,3-dihydro-1Hindole-6-carboxylic Acid Methyl Ester (yield: not mentioned), the obtained compound is reacted with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide in presence of solvent dimethylformamide and base piperidine to obtain Nintedanib (yield: 77%). A schematic representation of synthesis process is provided below.


This process involves use of acetic anhydride reagent which is easily not available since it is one of the controlled listed substances due to its narcotic nature and its use require special permission. The consumers of specified acetic anhydride, a controlled substance, is required to maintain records and file quarterly returns with the Narcotics Control Bureau (Under the Section 9A of the NDPS (Regulation of Controlled Substances) Act 1985). Furthermore, it also involves use of solvent such as piperidine and dimethylformamide from which isolation of product becomes tedious and require high energy consumption. Moreover, the yield obtained is low, i. e. 73% of intermediate obtained from step 1 and 77% (overall yield) of Nintedanib product.
Therefore, above mentioned problems associated with cited references, there is a need to develop an improved process for preparation of Nintedanib which is easy to operate; catalyst & reagent used are cheaper (less expensive) that can be easily available and safe to handle, non-toxic, environmentally friendly; with short production cycle; improve yield and production quality; decrease impurity formation; suitable for low-cost large-scale industrialization production.
The present invention provides an improved process for preparing of Nintedanib which has advantageous properties such as easy to operate, catalyst and reagent used are cheaper (less expensive) to save production cost, with short production cycle, yield and production quality is all improved, less or no impurity formation, suitable for large-scale industrialization production.

OBJECTS OF THE INVENTION
The principal object of the present invention is to provide a techno-economically viable and environmentally friendly an improved process for preparation of Nintedanib and/or its salts.
One of the objects of the present invention is to provide an improved process for preparation of Nintedanib and/or its salts with yield ranging about 60% to about 100% as well as purity ranging from about 80% to about 100%.
Another object of the present invention is to provide an improved process for preparation of Nintedanib and/or its salts which require minimum steps to be performed for preparation of said compounds.
Another object of the present invention is to provide a novel intermediate(s) used in process for preparation of Nintedanib and/or its salts.
Yet another object of the present invention is to provide a novel process for preparation of intermediate(s) used in process for preparation of Nintedanib and/or its salts.
Another object of the present invention is to provide catalysts or reagents or chemicals or solvents that can be easily available and safe to handle, non-toxic, environmentally friendly, easy to recover and recycle.
Another object of the present invention is to provide minimum number of reagents and solvents.
Yet still another object of the present invention is to provide an improved process for preparation of Nintedanib and/or its salts that can be precise, re-producible and industrially feasible.
Another object of the present invention is to provide Nintedanib and/or its salts with an impurity less than from about 5% to about 20%.
Another object of the present invention is to isolate the impurity and further characterise.
Yet another object of the present invention is to provide a process for preparation of the present invention which is easy to operate; catalyst or reagent used are cheaper (less expensive) to save synthesis cost, with short production cycle; improved production quality and yield and less or no impurity formation and suitable for large-scale production.

SUMMARY OF THE INVENTION
One of the aspects of present invention provides a process for the preparation of Nintedanib (compound of formula (7)) or its pharmaceutically acceptable salt (compound of formula (8)) substantially free of impurity, the process comprising steps of:
a) treating a compound of formula (1) with a compound of formula (2) in a solvent to obtain a compound of formula (3);

b) contacting the compound of formula (3) with the compound of formula (2) and trimethylbenzoate in presence of a solvent to obtain a compound of formula (4);

c) treating the compound of formula (4) with compound of formula (5) in a solvent to obtain a compound of formula (6);

d) combining the compound of formula (6) with a base in a solvent to obtain a compound of formula (7); followed by converting the compound of formula (7) in presence of ethanesulphonic acid in a solvent to obtain compound of formula (8);

Wherein the compound of formula (7) is optionally isolated; and
R, R1 is selected from methyl (-CH3), ethyl (-CH2CH3), propyl (-CH2-CH2-CH3), butyl (-CH2-CH2-CH2-CH3), pentyl (-CH2-CH2-CH2-CH2-CH3) group.
Another aspect of the present invention provides a novel intermediate(s) of compound of formula (3) or its salts used in the process for preparation of Nintedanib and/or its pharmaceutically acceptable salts is represented as follows.

Yet another aspect of the present invention provides a novel process for the synthesis of intermediates (compound of formula (3)) used in the process for preparation of Nintedanib and/or its pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION
In the specification, different terms are used for describing the invention. The definitions of the terms have been provided below.
The term ‘Nintedanib’ or ‘compound of formula (7)’ or ‘Nintedanib free base’ used herein refers to active pharmaceutical ingredient for the treatment of idiopathic pulmonary fibrosis and along with other medications for some types of non-small-cell lung cancer. The term ‘Nintedanib’, ‘compound of formula (7)’ and ‘free base’ can be used interchangeably in the specification.
The term ‘Nintedanib free base’ refers to the ‘Nintedanib’ or ‘compound of formula (7)’ in non-salt form.
The term ‘compound of formula (8)’, ‘pharmaceutically acceptable salts’ or ‘its salt(s)’ or used herein refer to a salt form of an active pharmaceutical ingredient (API) that is considered safe, effective, and suitable for use in pharmaceutical formulations. Said salt is prepared by modifying the parent compound by using acid or base.
In the present invention the “pharmaceutically acceptable salts” may be made by reacting Nintedanib free base or compound of formula (7) with an acid, wherein acid may include such as but is not limited to organic and/or inorganic acid. The inorganic acids that can be used, include, but are not limited to a mineral acid such hydrochloric acid, phosphoric acid, sulphuric acid or the like; organic acids such as formic acid, acetic acid, citric acid, oxalic acid etc. or organosulfonic acids such as but is not limited to ethanesulfonic acid.
The terms ‘compound of formula (8)’, ‘pharmaceutically acceptable salts’, ‘it’s salt(s)’, can be used interchangeably in the specification.
The term, ‘impurity’ used herein refers to a substance that is present in small amounts with main or desired product, making it of poor quality. The said impurity may be as side product or by-product formed during the any step of synthesis of Nintedanib, intermediate, and/or its salt. The impurity may include such as but is not limited to methyl (Z)-3-(1-hydroxypropylidene)-2-oxo-1-propionylindoline-6-carboxylate.
The term ‘substantially free of’ used herein refers to Nintedanib containing impurity content of less than equal to about 20%; preferably less than about 10%, more preferably less than equal to (=) 5%. In the present invention, said impurity is methyl (Z)-3-(1-hydroxypropylidene)-2-oxo-1-propionylindoline-6-carboxylate.
The term ‘solvent’ used herein refers to a substance that can have maximum capacity to dissolve a solute, resulting in a solution. In the present invention solvent used can be polar and/or non-polar; organic and/or inorganic solvent. The solvent may include such as but is not limited to water, ketone, alcohol, ether, acids, ester, amide, aromatic hydrocarbon, halogenated solvents and combinations thereof.
The term ‘base’ used herein refers to a chemical compound that has the capacity to remove a proton from a molecule of even a very weak acid in an acid-base reaction. In the present invention the base may be used organic and/or inorganic base.
One of the embodiments of the present invention there is provided a process for the preparation of Nintedanib or compound of formula (8) substantially free of impurity, the process comprising steps of:
a) treating a compound of formula (1) with a compound of formula (2) in a solvent to obtain a compound of formula (3);

b) contacting the compound of formula (3) with the compound of formula (2) and trimethylbenzoate in presence of a solvent to obtain a compound of formula (4);

c) treating the compound of formula (4) with compound of formula (5) in a solvent to obtain a compound of formula (6);

d) combining the compound of formula (6) with a base in a solvent to obtain a compound of formula (7) followed by converting the compound of formula (7) in presence of ethanesulphonic acid in a solvent to obtain compound of formula (8);

Wherein the compound of formula (7) is optionally isolated; and
R, R1 is selected from methyl (-CH3), ethyl (-CH2CH3), propyl (-CH2-CH2-CH3), butyl (-CH2-CH2-CH2-CH3), pentyl (-CH2-CH2-CH2-CH2-CH3) group.
Another embodiment of the present invention provides novel intermediate(s) of compound of formula (3) which may be used in the process for preparation of Nintedanib and/or its salts, wherein the intermediate of formula (3) is represented by

Another embodiment of the present invention provides a process for synthesizing the intermediate of formula (3), wherein said synthesis is carried out by treating a compound of formula (1) with a compound of formula (2) in a solvent at a temperature in the range from about 50oC to about 200oC, preferably from about 110oC to about 115°C, for time period in the range from about 8 hrs to about 18 hrs, preferably from about 16 hrs to about 18 hrs.

Wherein R, R1 is independently selected from hydrogen, alkyl, aryl group.
In another embodiment of the present invention there is provided a process for synthesising the intermediate(s) compound of formula (3), wherein R, R1 in the compound of formula (2) and/or formula (3) is C1 to C10 alkyl group; more preferably C1 to C8 alkyl group; most preferably C1 to C5 alkyl group.
In an embodiment, wherein C1 to C5 alkyl group is methyl (-CH3), ethyl (-CH2CH3), propyl (-CH2-CH2-CH3), butyl (-CH2-CH2-CH2-CH3), pentyl (-CH2-CH2-CH2-CH2-CH3) group; preferably propyl (-CH2-CH2-CH3), butyl (-CH2-CH2-CH2-CH3) group; more preferably propyl (-CH2-CH2-CH3).
Another embodiment of the present invention provides a process for the preparation of Nintedanib or its pharmaceutically acceptable salts (8), wherein the synthesis of compound of formula (4) is carried out by contacting the compound of formula (3) with the compound of formula (2) and trimethylbenzoate in presence of a solvent at a temperature in the range from about 50oC to about 150oC; preferably from about 100oC to about 125oC for a time period in the range from about 2 hrs to about 24 hrs; preferably from about 5 hrs to about 20 hrs; more preferably from about 10 hrs to about 12 hrs.
Another embodiment of the present invention provides a process for the preparation of Nintedanib or its salts (8), wherein the synthesis of compound of formula (6) is carried out by treating the compound of formula (4) with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (compound of formula (5)) in a solvent at a temperature in the range from about 5oC to about 75oC; preferably from about 50oC to about 60oC for the period from about 2 hrs to about 24 hrs; preferably from about 5 hrs to about 12 hrs; more preferably from about 8 hrs to about 10 hrs; most preferably from about 16 hrs to about 20 hrs.
In another embodiment of the present invention there is provided a process for preparation of Nintedanib, intermediate or its salt, wherein the compound formula (6) may carry forward without isolating for the synthesis of formula (7).
Another embodiment of the present invention provides a process for the preparation of compound of formula (8), wherein the preparation of compound of formula (8) may be carried out without isolating any intermediate compounds selected from compounds of formula (3), formula (4), formula (6), and formula (7).
In an embodiment of the present invention, wherein the synthesised compound of formula (7) is carried forward without isolating for the synthesis of compound of formula (8).
In another embodiment of the present invention there is provided a process synthesis of compound of formula (7), wherein said synthesis is carried out by combining the compound of formula (6) with a base in a solvent at a temperature in the range from about 30oC to about 75oC; preferably from about 40oC to about 50oC for a period in the range from about 2 hrs to about 24 hrs; preferably from about 5 hrs to about 15 hrs; more preferably from about 8 hrs to about 10 hrs.
Another embodiment of the present invention provides a process for the preparation of Nintedanib salts (formula (8)), wherein the compound of formula (7) is converted into its pharmaceutically acceptable salt (compound of formula (8)).
Yet another embodiment of the present invention provides a process for the preparation of pharmaceutically acceptable salt of Nintedanib, wherein said pharmaceutically acceptable salt (8) is prepared by reacting Nintedanib or compound of formula (7) with an organic and/or inorganic acid.
Another embodiment of the present invention provides a process for the preparation of Nintedanib or its salts (8), wherein the base used may be organic and/or inorganic base.
In an embodiment, inorganic acids that can be used, include, but are not limited to a mineral acid such hydrochloric acid, phosphoric acid, sulphuric acid or the like; organic acids such as formic acid, acetic acid, citric acid, oxalic acid etc. or organosulfonic acids such as but is not limited to ethanesulfonic acid.
In an embodiment, the acid is ethanesulfonic acid.
In an embodiment of the present invention, wherein the base may be organic and/or inorganic base. The inorganic base may include such as but is not limited to sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrogen, barium monoxide, calcium hydroxide, caesium hydroxide, sodium acid carbonate, potassium carbonate, sodium carbonate, strontium carbonate, caesium carbonate, vulcanized sodium or sodium hydrogen.
In an embodiment, the base is potassium carbonate.
In another embodiment of the present invention there is provided a process for the preparation of Nintedanib (7) or its salts (8), wherein the organic base may include such as but is not limited to metal alkoxide (sodium alkoxide, potassium alkoxide), butyl lithium, pyridine, quinoline, or an amine; wherein the sodium alkoxide is selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropylate, n-butanol sodium or sodium tert-butoxide; and wherein the potassium alkoxide can be selected from potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, n-butanol potassium or potassium tert-butoxide.
In another embodiment of the present invention there is provided a process for the preparation of compound of formula (7) or its pharmaceutically acceptable salts, wherein amine can be selected from triethylamine, diethyl amine, tri-n-butylamine, tripropylamine, diisopropylamine or diisopropylethylamine.
In another embodiment of the present invention there is provided a process for the preparation of Nintedanib or its salts, wherein solvent include polar and/or non-polar solvent.
In another embodiment of the present invention there is provided a process for the preparation of compound of formula (7) or its salts (formula 8), wherein the solvent may include such as but is not limited to water, C1-C5 Lower alcohol (such as methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine), N, N- dimethylformamide formamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, methylene dichloride, chloroform, ether, methyl t-butyl ether (MTBE), glycol dimethyl ether, diethylene glycol dimethyl ether, glycol mono-ethyl ether, Aliphatic (alkanes, alkenes, alkynes, and cyclic or cyclic-alkanes) and/or aromatic hydrocarbon (for example benzene, toluene, xylene, cumene) etc. and combinations thereof.
In an embodiment of the present invention, the solvent is aromatic hydrocarbon, preferably toluene.
In another embodiment of the present invention there is provided a process for the preparation of Nintedanib or its salts, wherein the free base of the compounds of the present invention can be protonated at the N atom(s) of an amine and/or N containing heterocyclic moiety to form a salt.
In another embodiments of the present invention there is provided a process for the preparation of Nintedanib or its salts, for example, the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
The free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
Another embodiment of the present invention provides a process for the synthesising an intermediate(s) compound of formula (3), wherein the synthesised compound of formula (3) is obtained in the yield in the range from about 65% to about 100%, more preferably from about 80% to about 99.99%.
In another embodiment of the present invention, there is provided a process for the preparation of Nintedanib or its salts (8), wherein Nintedanib or its salts (8) is obtained with yield in the range from about 60% to about 100%, more specifically from about 65% to about 99.99%; and purity in the range from about 80% to about 100%, preferably from about 85% to about 99.99%, more preferably from about 95% to about 99.99%.
Another embodiment of the present invention provides a process for the preparation of compound of formula (7) or it’s salt (8), wherein the Nintedanib salt (8) or it’s salt (8) is obtained with impurity less than from about 5% to about 20%.
In yet another embodiment, wherein the said impurity may be as side product or by-product formed during the any step of synthesis of Nintedanib free base, intermediate, and/or its salt.
Another embodiment of the present invention provides a process for the preparation of Nintedanib or it’s salt (8), wherein the said impurity is Methyl (Z)-3-(1-hydroxypropylidene)-2-oxo-1-propionylindoline-6-carboxylate; and having following probable structure.

Another embodiment of the present invention provides synthesis of compound of formula (3), wherein the said impurity is formed during the synthesis of compound formula (3) is provided in the following schematic representation.

In an embodiment of the present invention, wherein the Nintedanib, its intermediate compound, or its salt is purified by any known conventional method including crystallisation or recrystallisation, column chromatography, precipitation and combinations thereof.
Another embodiment of the present invention provides a process for the preparation of Nintedanib (formula 7) or its salt (formula 8) with impurity less than from about 5% to about 20%, wherein the process comprises steps of:
a) treating a compound of formula (1) with a compound of formula (2) in a solvent to obtain a compound of formula (3);

b) contacting the compound of formula (3) with the compound of formula (2) and trimethylbenzoate in presence of a solvent to obtain a compound of formula (4);

c) treating the compound of formula (4) with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (compound of formula (5)) in a solvent to obtain a compound of formula (6);

d) combining the compound of formula (6) with a base in a solvent to obtain a compound of formula (7); and converting the compound of formula (7) in presence of ethane sulphonic acid in a solvent to compound of formula (8);

wherein, compound of formula (7) is optionally isolated; and
R, R1 is selected from methyl (-CH3), ethyl (-CH2CH3), propyl (-CH2-CH2-CH3), butyl (-CH2-CH2-CH2-CH3), pentyl (-CH2-CH2-CH2-CH2-CH3) group; preferably methyl (-CH3), ethyl (-CH2CH3); more preferably ethyl (-CH2CH3).
Another embodiment of the present invention there is provided a composition, the composition comprising:
i. therapeutically effective amount of Nintedanib or its pharmaceutically acceptable salt; and
ii. one or more pharmaceutically acceptable excipient.
Advantages of the present invention:
1. The present invention requires less reaction time as compared to cited reference.
2. The present invention involves use of less or minimum number of solvents (for example methanol, toluene).
3. The present invention provides recovery of reaction solvent used and thereafter recycle of recovered solvent for continuous production of desired product, resulting in reduced production cost.
4. The present invention involves use of green solvent.
5. The present invention involves use of cheaper and less hazardous reagent and/or catalyst (K2CO3, propionic anhydride).
6. The present invention is carried out in minimum number of steps (3 steps); and
7. The present invention provides nintedanib or its salt or its intermediates with less or without impurity formation.
The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of present disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the claimed subject matter.
EXAMPLES
Example 1: Preparation of Methyl 2-oxo-1-propanoyl-2,3-dihydro-1H-indole-6-carboxylate (compound of formula (3))
Methyl 2-oxo-2,3-dihydro-1H-indole-6-carboxylate (100g) was reacted with propionic anhydride (204.2g) in toluene (300ml) and the reaction mixture was heated at 110-115°C for 16 hrs to 18 hrs and further cooled to 75-80°C and concentrated below 80°C. 200 ml of methanol was stripped out below 65°C. Thereafter, 300ml of methanol was charged and stirred at 60±5°C for 60-120 min. Further, it was cooled to 30±5°C. The crude product was filtered and washed with 100ml methanol. The solid was dried in vacuum oven at 55±5°C for 360-480 min to get Methyl 2-oxo-1-propanoyl-2,3-dihydro-1H-indole-6-carboxylate (compound of formula (3)) (Weight: 103g -117g, Yield: about 80% to about 90%).
Reaction scheme:

Example 2: Preparation of Methyl (3Z)-3-[methoxy(phenyl)methylidene]-2-oxo-1-propanoyl-2,3-dihydro-1H-indole-6-carboxylate (compound of formula (4))
Methyl 2-oxo-1-propanoyl-2,3-dihydro-1H-indole-6-carboxylate (100g) obtained from example 1 was reacted with propionic anhydride (52.63g) in 100ml of toluene at 110±5°C. To it a solution of trimethylbenzoate (221.09g) and toluene (100ml) was added at 110±5°C and maintained for 10 hrs to 12hrs. Reaction mixture was cooled to 55-65°C and concentrated below 65°C. 200 ml methanol was stripped out below 65°C. Methanol (400ml) was charged and stirred at 60±5°C for 60-120min. The reaction mixture was cooled to 30±5°C and maintained for 60-120min. The precipitate was filtered and washed with 100ml methanol. The solid was dried in vacuum oven at 55±5°C for 360-480 min to get Methyl (3Z)-3-[methoxy(phenyl)methylidene]-2-oxo-1-propanoyl-2,3-dihydro-1H-indole-6-carboxylate (compound of formula (4)) (Weight: 110g-126g, Yield: about 75% to about 85%).
Reaction scheme:

Example 3: Preparation of Nintedanib free base (compound of formula (7))
Methyl(3Z)-3-[methoxy(phenyl)methylidene]-2-oxo-1-propanoyl-2,3-dihydro-1H-indole-6-carboxylate (100g) was reacted with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (70.36g) in 700ml of Methanol at 55±5°C for 8 hrs to 10hrs. The reaction mixture was cooled to 30±5°C and Potassium carbonate (18.92g) was charged to it. The reaction mixture was heated at 45±5°C for 8 hrs to 10 hrs and was further cooled to 30±5°C and 500ml of water was charged for 1 hr to 2hrs. The precipitate was filtered and washed with 100ml of methanol. The obtained wet cake was suspended in 700ml of methanol and heated to 60±5°C for 1 hrs to 2hrs. The reaction mixture was cooled to 30±5°C and maintained for 1 hrs to 2 hrs. The obtained precipitate was filtered and washed with 100ml of methanol. The wet cake was suspended in 700ml of methanol and heated to 60±5°C for 1 hr to 2hrs under stirring. The reaction mixture was cooled to 30±5°C and maintained for 1 hr to 2hrs. The obtained precipitate was filtered and washed with 100ml of methanol. Weight of Wet cake obtained: 170g-180g. Half portion (~90g) of wet cake was dried in vacuum oven at 55±5°C for 360-480min to get dried Nintedanib free base (compound of formula (7)) (Wt. 80-85g Yield: about 88% to about 90%).
Reaction scheme:

Example 4: Preparation of Nintedanib esylate (compound of formula (8)) from isolated Nintedanib free base
Dried Nintedanib free base (example 3) was charged in 1000ml of methanol and heated at 50±5°C, and to it 70% ethanesulfonic acid (30.61g) was added at 50±5°C. The reaction mixture was stirred at 50±5°C for 1 hr to 2hrs. 2g of activated charcoal was charged at 50±5°C and stirred for 30-60min. The reaction mixture was filtered, washed with 50ml hot methanol and the filtrate was collected. Further, the filtrate was heated to 40±5°C and add to it methyl ter-butyl ether (575ml) was added. The reaction mixture was cooled to 30±5°C and stirred for 1hr to 2hrs. Further, the reaction mixture was cooled to 0±5°C and stirred for 1 hr to 2 hrs. The compound was filtered and washed with 100ml methyl ter-butyl ether. The solid was dried in vacuum oven at 55±5°C for 360-480min to get Nintedanib esylate (compound of formula (8)) (Weight: 55g-65g, Yield: about 60% to about 65%).
Reaction scheme:

Example 5: Preparation of Nintedanib esylate from crude Nintedanib free base (without isolating).
The remaining wet cake of Nintedanib free base (~90g) obtained from example 3 was charged in 1000ml of methanol and heated at 50±5°C, and to it 70% ethanesulfonic acid (30.61g) was added at 50±5°C. The reaction mixture was stirred at 50±5°C for 1 hr to 2hrs. 2g of activated charcoal was charged at 50±5°C and stirred for 30-60min at 50±5°C. The reaction mixture was filtered, washed with 50ml hot methanol and the filtrate was collected. Further the filtrate was heated to 40±5°C and add to it methyl ter-butyl ether (575ml) at 40±5°C was added. The reaction mixture was cooled to 30±5°C and stirred at 30±5°C for 1 hr to 2 hrs. The reaction mixture was cooled to 0±5°C and stirred at 0±5°C for 1 hr to 2 hrs. The compound was filtered and washed with 100ml methyl ter-butyl ether. The solid was dried in vacuum oven at 55±5°C for 360-480min to get Nintedanib esylate (compound of formula (8)) (Weight: 91g-112g, Yield: about 77% to about 87%).
,CLAIMS:We claim:
1. A process for the preparation of Nintedanib (formula (7)) or its pharmaceutically acceptable salt (formula (8)) substantially free of impurity, the process comprising:
a) treating a compound of formula (1) with a compound of formula (2) in a solvent to obtain a compound of formula (3);

b) contacting the compound of formula (3) with the compound of formula (2) and trimethylbenzoate in presence of a solvent to obtain a compound of formula (4);

c) treating the compound of formula (4) with compound of formula (5) in a solvent to obtain a compound of formula (6);

d) combining the compound of formula (6) with a base in a solvent to obtain a compound of formula (7); and converting the compound of formula (7) in presence of ethanesulphonic acid in a solvent to compound of formula (8);

wherein, compound of formula (7) is optionally isolated; and
R, R1 is selected from methyl (-CH3), ethyl (-CH2CH3), propyl (-CH2-CH2-CH3), butyl (-CH2-CH2-CH2-CH3), pentyl (-CH2-CH2-CH2-CH2-CH3) group.
2. The process as claimed in claim 1, wherein the impurity is methyl (Z)-3-(1-hydroxypropylidene)-2-oxo-1-propionylindoline-6-carboxylate.
3. The process as claimed in claim 1, wherein treating a compound of formula (1) with a compound of formula (2) in a solvent is carried out at a temperature in the range from about 50°C to about 200°C, preferably from about 110°C to about 115°C for period in the range from about 8 hrs to about 18 hrs, preferably from about 16 hrs to about 18 hrs.
4. The process as claimed in claim 1, wherein contacting the compound of formula (3) with the compound of formula (2) and trimethylbenzoate in presence of a solvent at a temperature in the range from about 50oC to about 150oC; preferably from about 100oC to about 125oC for a period in the range from about 2 hrs to about 24 hrs; preferably from about 5 hrs to about 20 hrs; more preferably from about 10 hrs to about 12 hrs.
5. The process as claimed in claim 1, wherein treating the compound of formula (4) with N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl) acetamide (compound of formula (5)) in a solvent is carried out at a temperature in the range from about 5oC to about 75oC; preferably from about 50oC to about 60oC for the period from about 2 hrs to about 24 hrs; preferably from about 5 hrs to about 12 hrs; more preferably from about 8 hrs to about 10 hrs; most preferably from about 16 hrs to about 20 hrs.
6. The process as claimed in claim 1, wherein combining the compound of formula (6) with a base in a solvent is carried out at a temperature in the range from about 30oC to about 75oC; preferably from about 40oC to about 50oC for a period in the range from about 2 hrs to about 24 hrs; preferably from about 5 hrs to about 15 hrs; more preferably from about 8 hrs to about 10 hrs followed by converting the compound of formula (7) in presence of ethanesulphonic acid in a solvent is carried out at a temperature ranging from about 40oC to 60oC, preferably 45oC to 55oC for a period ranging from 0.5 hr to 180 hrs, preferably 1 hr to 2 hrs.
7. The process as claimed in claim 1, wherein solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, N, N- dimethylformamide formamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, methylene dichloride, chloroform, ether, methyl t-butyl ether (MTBE), glycol dimethyl ether, diethylene glycol dimethyl ether, glycol mono-ethyl ether, benzene, toluene, xylene, cumene and like or combinations thereof.
8. The process as claimed in claim 1, wherein base used is organic or inorganic base.
9. The process as claimed in claim 8, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, strontium hydroxide, lithium hydroxide, hydrogen, barium monoxide, calcium hydroxide, caesium hydroxide, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, strontium carbonate, caesium carbonate, vulcanized sodium or sodium hydrogen; and organic base is selected from sodium alkoxide, potassium alkoxide, butyl lithium, pyridine, quinoline, or an amine.
10. The process as claimed in claim 1, wherein Nintedanib or its pharmaceutically acceptable salts (formula 8) is obtained with yield in the range from about 60% to about 100%, more specifically from about 65% to about 99.99%; and purity in the range from about 80% to about 100%, preferably from about 85% to about 99.99%, more preferably from about 95% to about 99.99%.

Dated this: 21st Day of November 2024.

For Unichem Laboratories Ltd.

Mr. Gautam Bakshi IN/PA- 1069, Head- IPM

To
The Controller of Patents
The Patent Office, Mumbai.