WO2019048974A1

WO2019048974A1 - Process for the preparation of nintedanib

Info

Publication number: WO2019048974A1
Application number: PCT/IB2018/056429
Authority: WO
Inventors: Samir Naik; Sachin Srivastava; Pramod PATIL; Premchand Bansilal PATIL; Shekhar Bhaskar Bhirud
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2017-09-06
Filing date: 2018-08-24
Publication date: 2019-03-14

Abstract

The present invention relates to a process for the preparation of nintedanib or salt thereof. The process comprising reacting compound of formula VI with acetic anhydride and triethyl ortho benzoate to obtain a compound of formula V; further reacting the compound of formula V with the compound of formula IV to obtain nintedanib the compound of formula I. The present invention also relates to a process to obtain crystalline compound of formula V.

Description

PROCESS FOR THE PREPARATION OF NINTEDANIB

PRIORITY

[0001] This application claims the benefit to Indian Provisional Application No. 201721031509, filed on 6 September, 2017, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for preparation of nintedanib or salt thereof. BACKGROUND OF THE INVENTION

[0003] Nintedanib ethanesulfonate salt (esylate), also known as 7H-Indole-6-carboxylic acid,2,3- dihydro-3-[[[4-[methyl[(4-methyl-l-piperazinyl)acetyl]amino] phenyl]amino]phenylmethylene]- 2-oxo-, methyl ester, (3Z)-, ethanesulfonate (1 : 1), is represented by a compound of formula II

[0004] Nintedanib esylate marketed as OFEV is a capsule available in multiple strengths for oral administration and is indicated for the treatment of idiopathic pulmonary fibrosis (TPF).

[0005] The present invention provides a process for the preparation of nintedanib or a salt thereof, with a better purity profile without using column chromatography techniques and which can be easily performed on industrial scale.

[0006] Specifically the present invention provides a process for nintedanib or a salt thereof, wherein the level of impurity, the compound of formula B,

is less than 0.15% w/w of nintedanib, the compound of formula I, by a process comprising treating the compound of formula V,

V

with a solvent system to obtain a compound of formula V, wherein the level of transesterification impurity, the compound of formula A

A

is less than 0.15% w/w of the compound of formula V. The compound of formula V thus obtained, when reacted further ensures formation of nintedanib or salt thereof with a purity of at least 99.85% w/w and wherein the level of impurity, the compound of formula B, is less than 0.15%w/w. SUMMARY OF THE I VENTION

[0007] In one embodiment, the present invention provides a process for the preparation of nintedanib, a compound of

or a salt thereof, comprising the steps of:

reacting a compound of formula VI,

VI with acetic anhydride and triethyl rthobenzoate to obtain a compound of formula V,

V

; and

b) subjecting the compound of formula V to treatment with a solvent system selected from the group consisting of Ci-C₆ amide, Ci-C₆ ester, Ci-C₆ carboxylic acid, C2-C6 carboxylic anhydride, Ci-C₆ aliphatic ether, Ci-C₆ haloalkane, C6-C12 aromatic hydrocarbon, Ci-C₆ alcohol or mixtures thereof, to obtain a compound of formula V, wherein the level of impurity, the compound of formula A,

A

is less than 0.15% w/w of the compound of formula V, as determined by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 is a characteristic XRPD of crystalline compound V as obtained in Example 2.

[0009] Figure 2 is a characteristic XRPD of crystalline nintedanib (I) as obtained in Example 7.

[0010] Figure 3 is a characteristic XRPD of crystalline nintedanib esylate hemihydrate as obtained in Example 10.

DETAILED DESCRD7TION OF THE INVENTION

[0011] In one embodiment, the present invention provides a process for the preparation of nintedanib, a compound of formula I,

or a salt thereof, comprising the steps of:

a) reacting a compound of formula VI,

VI

with acetic anhydride and triethyl orthobenzoate to obtain a compound of formula V,

V

; and

A

is less than 0.15% w/w of the compound of formula V, as determined by HPLC.

[0012] In one embodiment, reaction of the compound of formula VI with acetic anhydride and triethyl orthobenzoate in step 'a', is carried out at a temperature in the range of about 80°C to about

150°C.

[0013] In one embodiment, reaction of the compound of formula VI with acetic anhydride and triethyl orthobenzoate in step 'a', is carried out without any solvent.

[0014] In one embodiment, reaction of the compound of formula VI with acetic anhydride and triethyl orthobenzoate in step 'a', is carried out in presence of a solvent selected from hydrocarbon solvent like toluene, xylene and the like [0015] In one embodiment, in step 'a', the low boiler solvent is distilled out simultaneously at about 100°C to about 140°C.

[0016] In one embodiment, in step 'a', the crude compound of formula V obtained in step 'a', is isolated by any method known in the art. The method, may involve any of the techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, evaporation by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the solution, cooling the solution if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.

[0017] The compound of formula V thus obtained is subjected to a treatment with solvent system in step 'b'.

[0018] In one embodiment, in step 'b', the treatment with solvent system of the compound of formula V consists of recrystallizing the compound of formula V from a solvent system.

[0019] In one embodiment, in step 'b', the treatment with solvent system of the compound of formula V consists of slurrying the compound of formula V in a solvent system.

[0020] The term slurrying denotes suspending the solid in a solvent system with or without stirring at ambient temperature or at higher temperature.

[0021] In one embodiment, the treatment with solvent system consists of dissolving the compound in a solvent followed by addition of anti-solvent to precipitate the compound.

[0022] In one embodiment, the Ci-C₆ amide solvent is selected from the group consisting of formamide, dimethylformamide (DMF), dimethylacetamide (DMA) or a mixture thereof.

[0023] In one embodiment, the Ci-C₆ ester is selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or a mixture thereof.

[0024] In one embodiment, the Ci-C₆ carboxylic acid is selected from the group consisting of formic acid, acetic acid, propionic acid or a mixture thereof.

[0025] In one embodiment, the C2-C6 carboxylic anhydride is selected from the group consisting of formic anhydride, acetic anhydride, propionic anhydride or a mixture thereof.

[0026] In one embodiment, the Ci-C₆ aliphatic ether is selected from the group consisting of dimethyl ether, diethyl ether, methyl tert-butyl ether (MTBE) or a mixture thereof. [0027] In one embodiment, the C1-C4 haloalkane is selected from the group consisting of dichloromethane (DCM), chloroform, 1 , 1 -dichloroethane, 1,2-dichloroethane or a mixture thereof.

[0028] In one embodiment, the C6-C12 aromatic hydrocarbon is selected from the group consisting of toluene, xylene or a mixture thereof.

[0029] In one embodiment, the Ci-C₆ alcohol solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, 2,2- dimethyl-1 -propanol, 1,1,-dimethyl-l-propanol or a mixture thereof.

[0030] In one embodiment, the solvent system maybe a mixture of two or more, same or different solvents.

[0031] In one embodiment, in step 'b', the compound of formula V is subjected to slurrying in a mixture of Ci-C₆ alcohol and C6-C12 aromatic hydrocarbon.

[0032] In one embodiment, in step 'b', the compound of formula V is subjected to slurrying in a mixture of methanol and toluene.

[0033] In one embodiment, in step 'b', the compound of formula V is subjected to slurrying in the mixture of methanol and toluene at the temperature of about 20°C to about 120°C.

[0034] In one embodiment, in step 'b', the compound of formula V is recrystallized from the mixture of Ci-C₆ alcohol and C6-C12 aromatic hydrocarbon.

[0035] In one embodiment, in step 'b', the compound of formula V is recrystallized from the mixture of methanol and toluene.

[0036] In one embodiment, in step 'b', the compound of formula V is recrystallized from the mixture of methanol and toluene at the temperature of about 20°C to about 120°C.

[0037] In one embodiment, the compound of formula V is obtained in a purity of at least 97.69%, as determined by HPLC (high performance liquid chromatography), without using column chromatographic techniques.

[0038] In one embodiment, the present invention rovides a crystalline compound of formula V,

v [0039] In one embodiment, the present invention provides the crystalline compound of formula V, characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 8.2, 11.2, 16.5 and 25.5 ± 0.2° 2Θ.

[0040] In one embodiment, the present invention provides the compound of formula V in a purity of at least 97.69%, as determined by HPLC.

[0041] In one embodiment, the present invention provides the compound of formula V, wherein the level of impurity, the compound f formula A,

A is less than 0.15% w/w of the compound of formula V, as determined by HPLC.

[0042] In one embodiment, the present invention provides a process for preparing the crystalline compound of formula V, wherein the level of impurity, the compound of formula A is less than 0.15%, as determined by HPLC, the process comprising recrystallizing or slurrying the compound of formula V in a solvent system of mixture of Ci-C₆ alcohol and C₆-Ci2 aromatic hydrocarbon.

[0043] In one embodiment, the present invention provides the compound of formula V, wherein the le l of one or more compounds represented by C, D, E, F and VI

VI is less than 0.15% w/w of the compound of formula V, as determined by HPLC.

[0044] In one embodiment, the present invention provides a process for the preparation of nintendanib, the compound of formula I, further comprising the steps of:

i) reacting the compound of formula V with a compound of formula IV,

IV

to obtain a compound of formul

III

ii) deprotecting the compound of formula III with a base to obtain nintedanib, the compound of formula I,

[0045] In one embodiment, the present invention provides reaction of the compound of formula V with the compound of formula IV in step 'i', wherein the compound of formula V is crystalline.

[0046] In one embodiment, in step 'i', the reaction of the compound of formula V with the compound of IV is carried out in a solvent.

[0047] In one embodiment, in step 'i', the reaction of the compound of formula V with the compound of IV is carried out in a solvent selected from the group consisting of Ci-C₆ amide, Ci- C₆ ester, Ci-C₆ carboxylic acid, Ci-C₆ carboxylic anhydride, Ci-C₆ aliphatic ether, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, Ci-C₆ alcohol or mixtures thereof.

[0048] In one embodiment, in step 'i', the reaction of the compound of formula V with the compound of IV is carried out in Ci-C₆ amide solvent selected from the group consisting of formamide, dimethylformamide (DMF), dimethylacetamide (DMA) or a mixture thereof. [0049] In one embodiment, in step 'i', the reaction of the compound of formula V with the compound of formula IV is carried out at the temperature of about 20°C to about 120°C.

[0050] In one embodiment, the compound of formula III is not isolated and carry forwarded for further reaction.

[0051] In one embodiment, the compound of formula ΙΠ formed in step 'i', is isolated by filtration.

[0052] In one embodiment, the compound of formula ΠΙ formed in step 'i', is filtered and wet cake obtained is used in next step.

[0053] In one embodiment, in step 'ii', the deprotection of the compound of formula ΠΙ maybe carried out using an organic base or an inorganic base.

[0054] In one embodiment, the organic base is selected from the group consisting of amines, organolithiums, metal alkaloids, amides, tetraalkylammonium hydroxides, phosphonium hydroxides and the like.

[0055] In one embodiment, the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines and heterocyclic amine.

[0056] In one embodiment, the cyclic aliphatic amine is selected from the group consisting of piperidine and piperazine.

[0057] In one embodiment, the trialkyl amine is selected from the group consisting of triethylamine and diisoporpylethylamine (DIPEA).

[0058] In one embodiment, the heterocyclic amine is selected from the group consisting of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (Dabco) pyridine, pyrimidine or 4-(dimethylamino)pyridine (DMAP).

[0059] In one embodiment, the inorganic base is selected from the group consisting of metal carbonate, metal bicarbonate and metal hydroxide, wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium or magnesium.

[0060] In one embodiment, in step 'ii', the deprotection of the compound of formula III is carried out using piperidine as a base.

[0061] In one embodiment, in step 'ii', the deprotection of the compound of formula III is carried out in an amide, Ci-C₆ ester, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, Ci-C₆ alcohol, water, or mixtures thereof.

[0062] In one embodiment, in step 'ii', the deprotection of the compound of formula III is carried out in an alcoholic solvent. [0063] In one embodiment, in step 'ii', the base is added at the temperature of about -10°C to about

20°C.

[0064] In one embodiment, in step 'ii', reaction of compound of formula V with the compound of formula IV is carried out at the temperature of about 0°C to about 80°C.

[0065] In one embodiment, the present invention provides a process for the preparation of nintedanib, the compound of formula I, further comprising the steps of:

i) reacting the compound of formula V with a compound of formula IV,

to obtain a compound of formula III,

III ii) deprotecting the compound of formula III with piperidine in an alcoholic solvent to obtain nintedanib, the compound of formula I,

wherein the level of impurity, the compound of formula B,

is less than 0.15% w/w of nintedanib, the compound of formula I, as determined by HPLC.

[0066] In one embodiment, crude nintedanib, the compound of formula I formed in step ii, is isolated by any method known in the art, as discussed supra.

[0067] In one embodiment, the present invention provides a process further comprising recrystallizing nintedanib, the compound of formula I, in a solvent system selected from the group consisting of Ci-C₆ amine, Ci-C₆ ester, Ci-C₆ carboxylic acid, Ci-C₆ carboxylic anhydride, Ci-C₆ aliphatic ether, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, Ci-C₆ alcohol, water or mixtures thereof, to obtain nintedanib, th

I

[0068] In one embodiment, nintedanib, the compound of formula I, is recrystallized from mixture of two or more, same or different solvents.

[0069] In one embodiment, nintedanib the compound of formula I, is recrystallized using methanol: water as solvent.

[0070] In one embodiment, the present invention provides crystalline nintedanib, the compound of formula I.

[0071] In one embodiment, nintedanib, the compound of formula I is characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 6.5, 10.7, 11.6, 12.2 and 23.2±0.2° 2Θ.

[0072] In one embodiment, the present invention provides nintedanib, the compound of formula I, in a purity of at least 99.98%, as determined by HPLC.

[0073] In one embodiment, the present invention provides nintedanib or salt thereof, the compound of formula I, wherein the level of impurity, the compound of formula B

is less than 0.15% w/w of nintedanib, as determined by HPLC.

[0074] In one embodiment, the present invention provides a process, wherein nintedanib, the compound of formula I, is further reacted with ethanesulfonic acid to obtain nintedanib esylate, a compound of formula II.

[0075] In one embodiment, nintendanib, the compound of formula I, is further reacted with ethanesulfonic acid in a solvent system.

[0076] In one embodiment, nintendanib, the compound of formula I, is further reacted with ethanesulfonic acid in a solvent system selected from the group consisting of, Ci-C₆ amide, Ci-C₆ ester, Ci-C₆ carboxylic acid, Ci-C₆ carboxylic anhydride, Ci-C₆ aliphatic ether, C1-C4 haloalkane, C6-C12 aromatic hydrocarbon, Ci-C₆ alcohol, water or mixtures thereof, to obtain nintendanib esylate, the compound of formula II.

[0077] In one embodiment, nintendanib, the compound of formula I, is further reacted with ethanesulfonic acid in an alcoholic solvent to obtain nintendanib esylate, the compound of formula II.

[0078] In one embodiment, nintendanib, the compound of formula I, is further reacted with ethanesulfonic acid to obtain nintedanib esylate, the compound of formula II, wherein nintedanib, the compound of formula I, is crystalline.

[0079] In one embodiment, the present invention provides nintedanib esylate hemihydrate, the compound of formula II.

[0080] In one embodiment, the present invention provides crystalline nintedanib esylate hemihydrate, the compound of formula II.

[0081] In one embodiment, the present invention provides crystalline nintedanib esylate hemihydrate the compound of formula II, characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 16.3, 17.4, 18.8, 19.7 and 20.0±0.2° 2Θ.

[0082] In one embodiment, the present invention provides nintedanib esylate hemihydrate, the compound of formula I, in a purity of at least 99.98%, as determined by HPLC.

[0083] In one embodiment, the present invention provides nintedanib esylate hemihydrate, the compound of formula II, wherein the level of impurity, the compound of formula B

is less than 0.15% w/w of nintedanib, as determined by HPLC. [0084] In one embodiment, the present invention provides nintendanib or nintedanib esylate hemihydrate, wherein the level of one or more impurities represented by G, H, I, J, K and ΙΠ.

is less than 0.15% w/w of nintedanib, as determined by HPLC.

[0085] In one embodiment, the present invention provides nintedanib esylate with purity of at least 99.0%, wherein the level of one or impurities represented by B, G, H, I, J, K and III, is less than 0.15%.

[0086] In one embodiment, the present invention provides a method of assessing the purity of nintedanib or salt thereof or the pharmaceutical composition containing them, by HPLC comprising the steps of:

a) providing a standard solution of the compound of formula B,

b) using the solution of step 'a', as a reference marker to determine the level of the compound of formula B.

[0087] The determination of the presence of the compound of formula B in the sample of nintedanib or a salt thereof, is effected by comparing the retention of the different components of the sample of nintedanib or a salt thereof, by the chromatographic technique with the retention of the compounds of formula B under the same chromatographic conditions.

[0088] The term "reference marker", as used herein, refers to a compound that may be used in qualitative analysis to identify components of a mixture based on their position, and/or in quantitative analysis to determine the concentration of said compound in a mixture by reference to the concentration of a solution comprising a known amount of said component.

[0089] In one embodiment, according to the present invention a reference marker solution will comprise the compound of formula B, dissolved in an appropriate solvent. Thus, assessing the purity of nintedanib or salt thereof, by using the compound of formula B as reference marker, according to step (b), means determining the concentration of the compound of formula B, respectively. Preferably, the concentration of the compound of formula B is determined by means of conventional methods known in the art for quantifying compounds, such as HPLC.

[0090] In one embodiment, the compound of formula IV is synthesized as shown in scheme 1 :

IV Scheme 1

[0091] In one embodiment, the compound of formula VI is synthesized as shown in scheme 2:

Pd/C

VI

Scheme 2

[0092] In one embodiment, the present invention provides solvates of nintedanib.

[0093] The solvates of nintedanib includes solvates with water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, ethyl acetate, n-butyl acetate, isobutyl acetate, acetonitrile, acetone, butanone, methyl isobutyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, chloroform, dichloromethane (DCM), hexane, n-heptane, toluene, N- methyl pyrrolidone, dimethyl formamide or dimethyl sulfoxide.

[0094] In one embodiment, the present invention provides nintedanib, salt or solvate thereof obtained by the processes herein described, having a D₁₀, D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 30 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state nintedanib or salt, solvate thereof into any of the foregoing desired particle size range.

[0095] X-ray powder diffraction profiles were obtained using an X-ray diffractometer (Philips X'Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X'Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40 mAmp. The samples were scanned in the full 2Θ range of 2-50° with a "time-per-step" optimized to 50 sec. [0096] HPLC Method: High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting purity:

Column: Kromasil 100-5 C8, 250 x 4.6mm, Column temperature: 30°C, Mobile phase: A= Buffer: 0.01M of Sodium perchlorate monohydrate in water. Adjust to pH 2.2 with diluted perchloric acid, B= acetonitrile: methanol: buffer (750: 150: 100 v/v/v), Diluent: water: acetonitrile (80:20 v/v); Flow Rate: l .OmL/min, Detection wavelength: UV 210nm, Injection volume: \0μL·.

Gradient Program:

[0097] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

Examples

[0098] Example 1: Preparation of methyl l-acetyl-3-[ethoxy(phenyl)methylidene]-2-oxo-2, 3-dihydro-7H-indole-6-carboxylate (V)

A mixture of compound VI (lOg) and acetic anhydride (40ml) was stirred at about 110°C-120°C for about 2h. To this reaction mass, triethyl orthobenzoate (35.18gm) was slowly added at about 115-125°C for 3h and distilled out low boiler simultaneously at about 120-125°C. Then the reaction mass was cooled to about 90°C, and concentrated under vacuum to obtain crude compound of formula V.

HPLC Purity: 95%; Imp A: 0.45%.

[0099] Example 2: Purification of compound V in methanol: toluene

The crude compound V from example 1 was diluted with methanol and refluxed for 2h. The Reaction mass was cooled to about 50-55°C, toluene was added and stirred. The reaction mass was then cooled to about 0-5°C and stirred for lh. The reaction mass was filtered and washed with methanol. The obtained solid was slurried in methanol and stirred at about 40-45°C for 30 min. The reaction mass was cooled to about 0-5°C and stirred. The reaction mass was filtered, solid was washed with methanol and dried in vacuum tray drier at about 60-70°C. Yield: 12g; HPLC purity: 97.69%; Imp A: 0.04%.

XRD peaks of compound V:

[0100] Example 3: Purification of compound V in dichloromethane (DCM): methyl t-butyl ether (MTBE)

The crude compound V from example 1 was added in DCM to obtain clear reaction mass. To this solution, MTBE was added at about 25-30°C and stirred for lh. The reaction mass was filtered, solid was washed with MTBE and dried in vacuum tray drier at about 60-70°C Yield: 11.2g; HPLC purity: 99.34%; Imp A: 0.07%.

[0101] Example 4: Purification of compound V in dimethylformamide (DMF): ethyl acetate

The crude compound V from example 1 was added in DMF and heated to get clear reaction mixture. The reaction mass was cooled to about 60°C and ethyl acetate was added. Reaction mass was then cooled to about 0-5°C and stirred for about lh. The reaction mass was filtered, solid was washed with ethyl acetate and dried in vacuum tray drier at about 60-70°C. Yield: 11.5g; HPLC purity: 95.96%; Imp A: 0.03%.

[0102] Example 5: Purification of compound V in methanol: toluene: acetic acid: acetic anhydride

The crude compound V from example 1 was added in methanol, toluene, acetic acid, acetic anhydride and stirred at about 60-65°C. Reaction mass was then cooled to about 0-5°C and stirred for lh. The reaction mass was filtered, solid was washed with methanol and dried in vacuum tray drier at about 60-70°C. Yield: 1 lg; HPLC purity: 94.58%; Imp A: 0.12%.

[0103] Example 6: Preparation of nintedanib (I)

A mixture of the compound of formula V (lOg) and N-(4-aminophenyl)-N-methyl-2-(4- methylpiperazin-l-yl)acetamide (formula IV) (7.89g) in DMF (50ml) was stirred at about 65-70°C for 4h. The reaction mass was cooled to about 25-30°C and stirred for lh. Reaction mass was filtered and solid was washed with methanol. The solid wet cake was added in methanol and stirred at about 25-30°C. Reaction mass was cooled to about 0-5°C and piperidine (6.2ml) was added under stirring. The reaction mass was heated to about 25-30°C and stirred for 5h. The reaction mass was cooled to about 0-5°C and stirred for lh. The reaction mass was filtered and solid was washed with cold methanol to obtain crude nintedanib. Yield: 12gm; HPLC purity: 99.96%; Imp B: 0.02%. [0104] Example 7: Purification of nintedanib in methanol

The crude nintedanib (I) from example 6 was purified with methanol to obtain nintendanib. Yield: lOg; HPLC purity: 99.98%; Imp B: 0.03%.

XRD peaks of nintedanib (I):

[0105] Example 8: Purification of nintedanib (I) in DMF: Methanol

Crude nintendanib (I) from example 6 was added in DMF methanol mixture and heated to obtain clear solution. The reaction was slowly cooled to about 0-5°C and stirred for lh. The reaction mass was filtered, solid was washed with methanol and dried in trey dryer at 45-50°C Yield: 0.84g; HPLC purity: 99.96%; Imp B: 0.03%.

[0106] Example 9: Purification of nintedanib (I) in DCM: Methanol

Crude nintedanib (I) from example 6 was added to DCM methanol mixture and stirred at about 25-30°C to obtain clear solution. Dichloromethane was distilled out from the reaction mass at about 25-30°C to precipitate the solid. The reaction mass was slowly cooled to about 0-5°C and stirred for lh. The reaction mass was filtered, solid was washed with methanol and dried in tray dryer at 45-50°C Yield: 0.80g; HPLC purity: 99.98%; Imp B: 0.02%.

[0107] Example 10: Preparation of Nintedanib Esylate (Formula II)

A mixture of nintedanib (I) (lOg) in methanol (140ml) was stirred at about 50-55°C for about 30min. 70% aqueous ethanesulfonic acid (3.06gm) was added to above reaction mass at about 50- 55°C and stirred to get clear solution. The reaction mass was filtered through micron filter to remove insoluble particle. MTBE (75ml) was added to clear methanol solution at about 45-50°C. Reaction mass was then cooled to about 25-30°C and stirred for 16h. The reaction mass was cooled 0-5°C and stirred for 2h. Reaction was filtered, solid was washed with MTBE and dried in vacuum trey dryer at about 40-45°C. Yield: lOg; HPLC purity: 99.94%; Imp B: 0.01%.

[0108] Comparative example 1: Preparation of methyl l-acetyl-3- [ethoxy(phenyl)methylidene]-2-oxo-2, 3-dihydro-XH-indole-6-carboxylate (V)

A mixture of compound VI (20g), acetic anhydride (72ml), triethyl ortho benzoate (117.27gm) was stirred at about 120-130°C for about 12h. Low boiler was distilled out and again stirred at about 120°C to about 130°C for about 3h. Reaction was cooled to about 80°C and reaction mass was concentrated under vacuum. MTBE was added to the residue and stirred for lh at about 20°C- to about 25°C. The reaction mass was filtered, solid was washed with MTBE and dried in vacuum tray dryer at about 40°C to about 50°C. Yield: 18.2g; HPLC purity: 83.67%; Imp A: 0.22%

[0109] Comparative example 2: Preparation of nintedanib

A mixture of compound V (5g) and N-methyl-2-(4-methyl piperazin-l-yl)-N-(4- nitrophenyl)acetamide (7.54g) in DMF (25ml) was stirred at about 65°C to about 70°C for about 4h. The reaction mixture was cooled to about 25-30°C, piperidine (3.15ml) was added and stirred for about 5h. Water was added to the reaction mass and stirred for lh. The reaction mass was filtered, solid was washed with DMF and dried at about 45°C to about 50°C. Yield: 4.8g; HPLC purity: 91.56%; Imp B: 0.20%.

Claims

WE CLAIM:

1. A process for the preparation of nintedanib, a compound of formula I,

or a salt thereof, comprising the steps of:

a) reacting a compound of formula VI,

VI

with acetic anhydride and triethyl rthobenzoate to obtain a compound of formula V,

; and

is less than 0.15% w/w of the compound of formula V, as determined by HPLC.

2. The process as claimed in claim 1, wherein the compound of formula V is obtained in crystalline form.

3. The process as claimed in claim 2, wherein the com ound of formula V,

V is in crystalline form characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 8.2, 11.2, 16.5 and 25.5±0.2° 2Θ.

4. The process as claimed in claim 1, wherein treatment with a solvent system comprises recrystallizing from a solvent system or slurrying in a solvent system at ambient temperature or at higher temperature.

5. The process as claimed in claim 1, wherein the solvent system is selected from the group consisting of dimethylformamide (DMF), ethyl acetate, methanol, dichloromethane (DCM), acetic acid, acetic anhydride, toluene, methyl t-butyl ether (MTBE) or mixtures thereof.

6. The process as claimed in claim 5, wherein the solvent system is a mixture of toluene and methanol.

7. The process as claimed in claim 2, further comprising the steps of:

i) reacting the compound of formula V with a compound of formula IV,

IV

to obtain a compound of formula ΙΠ,

ii) deprotecting the compound of formula III with piperidine in an alcoholic solvent to obtain nintedanib, the compound of

wherein the level of impurity, the compound of formula B,

8. The process as claimed in claim 7, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, sec-butanol, isobutanol, t- butanol, 1-pentanol, 2-pentanol, 3-pentanol, 2-methyl-l-butanol, 2-methyl-2-butanol, 3-methyl-2- butanol, 2,2-dimethyl-l -propanol, 1,1,-dimethyl-l-propanol or mixture thereof .

9. The process as claimed in claim 8, wherein the alcoholic solvent is methanol.

10. The process as claimed in claim 7, further comprising recrystallizing nintedanib, the compound of formula I, in a solvent system selected from the group consisting of Ci-C₆ amine, Ci-C₆ ester, Ci-Ce carboxylic acid, Ci-C₆ carboxylic anhydride, Ci-C₆ aliphatic ether, C1-C4 haloalkane, C₆- C12 aromatic hydrocarbon, Ci-C₆ alcohol, water or mixtures thereof, to obtain nintedanib, the compound of formula I,

11. The process as claimed in claim 10, wherein nintedanib, the compound of formula I is recrystallized from the mixture of methanol and water.

12. The process as claimed in claim 7, wherein nintedanib, the compound of formula I, is further reacted with ethanesulfonic acid to obtain nintedanib esylate hemihydrate, a compound of formula II.

13. A method of assessing the purity of nintedanib or a salt thereof or the pharmaceutical composition containing them, by HPLC comprising the steps of:

a) providing a standard solution of the compound of formula B; and

14. A crystalline compound of formula V

characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 8.2, 11.2, 16.5 and 25.5±0.2° 2Θ.

15. Nintedanib or a salt thereof, a compound of formula I,

wherein the level of impurity, the compound of formula B,

is less than 0.15% of nintedanib, as determined by HPLC.