WO2023222946A1

WO2023222946A1 - Process for the preparation of cabozantinib

Info

Publication number: WO2023222946A1
Application number: PCT/FI2023/050267
Authority: WO
Inventors: Eila Luukkonen; Ilpo Laitinen
Original assignee: Fermion Oy
Priority date: 2022-05-18
Filing date: 2023-05-15
Publication date: 2023-11-23

Abstract

The present invention relates to a process for the preparation of cabozantinib.

Description

Process for the preparation of cabozantinib

Field of the invention

The present invention relates to a process for the preparation of cabozantinib.

Background of the invention

The heterocyclic drug cabozantinib, /V-(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)-/V-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide, is a small-molecule tyrosine kinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and tyrosine-protein kinase Met (c-Met), along with other receptor tyrosine kinases that are involved in cancer development and progression. Cabozantinib has proven to be an effective agent towards a broad range of tumours including hepatocellular carcinoma and renal cell carcinoma. The drug is currently undergoing development through multiple trials exploring new avenues, such as neoadjuvant treatments, novel combination regimens and rare renal cell carcinoma histologies.

WO 2010/083414 and WO 2016/022697 disclose processes for the preparation of 4-chloro-6,7-dimethoxyquinoline. The processes involve the use of a large amount of POCI3, which is undesirable, because a large amount of waste is generated.

Processes for the preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline by reacting 4-chloro-6,7-dimethoxyquinoline with 4-aminophenol are disclosed in WO 2016/022697 and Wu, Y. et al. J. Med. Chem., 62 (2019) 6083. The former publication discloses the use of sodium tert-butoxide as base and /V,/V-dimethylacetamide (DMA) as solvent. 4-Chloro-6,7- dimethoxyquinoline is added directly to the reaction. The process involves reprocessing in tetra hydrofuran (THF) and DMA. The latter publication discloses the use of NaH as base and dimethyl sulfoxide (DMSO) as solvent. The solvent volume used in the reactions is large and the reaction time long. The yield of the reactions is poor. The use of NaH in oil is undesirable in large scale production whereas dry NaH easily ignites in air. NaH releases H2 by the action of water. The amount of water in the recovery is large in the process disclosed in WO 2016/022697.

CN 106831707 A and WO 2005/030140 disclose processes for the preparation of l-((4-fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid. In the reaction disclosed in CN 106831707 A, a large quantity of solvents is used. The isolation of the product involves evaporation to dryness and several extractions. The reaction disclosed in WO 2005/030140 is carried out with thionyl chloride in THF. THF may react with the thionyl chloride present in the reaction.

WO 2010/083414, CN 108264482 A and CN 109836381 A disclose processes for the preparation of cabozantinib by reacting 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline with l-((4-fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid. WO 2010/083414 discloses the use of oxalyl chloride as coupling reagent, K2CO3 as base and THF as solvent. The use of oxalyl chloride results in significant gas formation and oxalyl chloride may react with THF opening the ether ring. The solvent volume is large and the process involves two exothermic steps (addition of oxalyl chloride and transfer of acid chloride). The selectivity of the reaction is poor. CN 108264482 A discloses the use of dicyclohexylcarbodiimide (DCC) as coupling agent. No base is used. The byproducts of coupling with DCC include dicyclohexylurea, which is only sparingly soluble in most solvents and purification usually requires flash chromatography. The reaction time is long and the reaction is carried out at reflux temperature. The high temperature used results in undesirable solvent evaporation and has thus a negative environmental impact. The selectivity of the reaction is poor. The isolation of the product involves undesirable evaporation to dryness. CN 109836381 A discloses the use of 2-(3H- [l,2,3]triazolo[4,5-b]pyridin-3-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (HATU) as coupling agent and triethylamine (TEA) as base. CN 109836381 A also discloses the use of 2-(l/7- benzo[cf][l,2,3]triazol-l-yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (HBTU) as coupling agent and /V,/V-diisopropyl-/V- ethylamine (DIPEA) as base. The by-products of coupling with HATU or HBTU have undesirable properties. 1,1,3,3-Tetramethylurea (TMU) is toxic and the hexafluorophosphate(V) anion may cause corrosion of the manufacturing equipment. 3H-[l,2,3]Triazolo[4,5-b]pyridin-3-ol (HOAt) and 1H- benzo[c/][l,2,3]triazol-l-ol (HOBt) are explosive in their anhydrous forms. The solvent volume is large and the reactions are carried out at elevated temperature. The selectivity of the reactions is poor.

WO 2010/083414 and WO 2016/022697 disclose processes for the preparation of cabozantinib (S)-malate. In the process disclosed in WO 2010/083414, crystalline form N-2 of cabozantinib (S)-malate is prepared by adding a solution of L-malic acid in 4-methylpentan-2-one to a solution of N- (4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-/V-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide in THF. The yield is 92 %. The amount of residual THF is above the threshold (720 ppm) of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. THF is useful in the reaction as an aid in dissolving /V-(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)-/V-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide. In the process disclosed in WO 2016/022697, /V-(4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)-/V-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide, L-malic acid, butan-2-one (MEK) and water are refluxed for approximately 2 h. The process involves the use of a large amount of water. The publication is silent as to what crystalline form of cabozantinib (S)-malate is obtained. Repeating the process disclosed in WO 2016/022697 revealed that the process yields 17 % of the undesirable crystalline form N-l of cabozantinib (S)-malate. There is a need in the art for an improved process for preparing cabozantinib and for preparing the intermediate products useful in the preparation of cabozantinib.

Summary of the invention

The object of the present invention is to provide an improved method for the preparation of cabozantinib.

A first aspect of the present invention provides a process for the preparation of cabozantinib of formula (1A)

or a pharmaceutically acceptable salt thereof, said process comprising a step of reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline of formula (II)

in the presence of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide (T3P) to obtain the compound of formula (1A) and optionally converting the compound of formula (1A) to a pharmaceutically acceptable salt thereof. In a second aspect, the present invention provides a process for the preparation of cabozantinib of formula (1A)

in the presence of l-methyl-l/7-imidazole (NMI) to obtain the compound of formula (1A) and optionally converting the compound of formula (1A) to a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides cabozantinib or a pharmaceutically acceptable salt thereof obtainable by the process of the invention.

In a further aspect, the present invention provides crystalline form N-2 of cabozantinib (S)-malate, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 5 % by weight of crystalline form N-l of cabozantinib (S)-malate, such as less than 1 % by weight of crystalline form N-l of cabozantinib (S)-malate.

In a further aspect, the present invention provides crystalline form N-2 of cabozantinib (S)-malate, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 5 % by weight of other crystalline forms of cabozantinib (S)-malate, such as less than 2 % by weight of other crystalline forms of cabozantinib (S)-malate, for example less than 1 % by weight of other crystalline forms of cabozantinib (S)-malate.

In a further aspect, the present invention provides pharmaceutical dosage forms comprising cabozantinib or a pharmaceutically acceptable salt thereof obtained by the process of the invention.

In a further aspect, the present invention provides pharmaceutical dosage forms comprising crystalline form N-2 of cabozantinib (S)-malate obtained by the process of the invention.

Detailed description of the invention

In describing the embodiments of the invention, specific terminology will be resorted to for the sake of clarity. However, the invention is not intended to be limited to the specific terms so selected, and it is understood that each specific term includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.

The synthetic route of cabozantinib involves several synthetic steps. The synthesis is typically a four-step synthesis followed by the optional step of preparing a salt of cabozantinib.

In a first step, a first intermediate, 4-chloro-6,7-dimethoxyquinoline of formula (I)

is prepared by contacting 6,7-dimethoxyquinolin-4-ol of formula (la) e presence of a solvent and a base.

In a further step, a second intermediate, 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline of formula (II)

is prepared by the condensation of 4-chloro-6,7-dimethoxyquinoline and 4- l of formula (lb)

in DMSO in the presence of sodium tert-butoxide.

In yet a further step, a third intermediate, l-((4- oyl)cyclopropane-l-carboxylic acid of formula (III)

is prepared by reacting 4-fluoroaniline of formula (Ic)

with cyclopropane-1, 1-dicarboxylic acid of formula (Id)

in the presence of NMI.

In yet a further step, cabozantinib of formula (1A)

is prepared by condensation of the second intermediate, 4-((6,7- dimethoxyquinolin-4-yl)oxy)aniline, and the third intermediate, l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid, in the presence of a coupling reagent and a base.

Optionally, a salt of cabozantinib is prepared, such as cabozantinib (S)- malate of formula (IB).

Polymorphism has been observed for cabozantinib (S)-malate. It is known to exist in at least two crystalline forms (N-l and N-2) and in amorphous form. The form N-2 is preferred for pharmaceutical development. Specific salts of active pharmaceutical ingredients are often formed to achieve desirable formulation properties. Although addressing poor aqueous solubility is one of the most important reasons to employ a salt formation, the formation of unique salt products may also address other physicochemical and biological concerns, such as stability, toxicity, poor absorption and issues related to manufacturing processes.

The present invention provides an improved method for the preparation of cabozantinib. The method of the present invention has several advantages over the method known in the prior art.

in the presence of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6- trioxide (T3P) to obtain the compound of formula (1A) and optionally converting the compound of formula (1A) to a pharmaceutically acceptable salt thereof.

The problems associated with the coupling agent used in the prior art are overcome by using T3P as coupling reagent. T3P is less toxic and less waste is formed in the reaction. The by-products of coupling with T3P are water soluble and thus easier to handle. The process involves only one exothermic step (addition of T3P).

In a second aspect, the present invention provides a process for the preparation of cabozantinib of formula (1A)

in the presence of NMI to obtain the compound of formula (1A) and optionally converting the compound of formula (1A) to a pharmaceutically acceptable salt thereof.

The inventors have discovered that the use of NMI as a base in the reaction increases the selectivity of the reaction compared to the use of K2CO3, TEA or DIPEA disclosed in the prior art.

In one embodiment, the preparation of cabozantinib of formula (1A) by the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of T3P and NMI.

In one embodiment, the preparation of cabozantinib of formula (1A) by the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of 50 % T3P in ethyl acetate.

Handling of 50 % T3P in ethyl acetate is easier than the solids DCC, HATU and HBTU used in the prior art.

In one embodiment, the amount of T3P used per amount of the compound of formula (II) is 1.0-1.5 molar equivalents.

In one embodiment, the amount of NMI used per amount of the compound of formula (II) is 1-4 molar equivalents or about 1-4 molar equivalents, such as 2-3 molar equivalents or about 2-3 molar equivalents.

In one embodiment, the reaction of the compound of formula (II) with the compound of formula (III) is carried out in chloro(Ci-2)alkane, such as dichloromethane, trichloromethane, 1,2-dichloroethane or a mixture thereof. In one embodiment, the chloro(Ci-2)alkane is dichloromethane.

In one aspect of the present invention, the invention provides the cabozantinib of formula (1A) obtainable by the method described herein. In a further embodiment of the present invention, the compound of formula (II) is prepared by reacting 4-chloro-6,7-dimethoxyquinoline of formula (I)

with 4-aminophenol of formula (lb)

in DMSO in the presence of sodium tert-butoxide to obtain the compound of formula (II).

In a further embodiment, 4-aminophenol is dissolved in DMSO followed by addition of sodium tert-butoxide prior to the addition of 4-chloro-6,7- dimethoxyquinoline to the reaction mixture. By dissolving 4-aminophenol in DMSO prior to the addition of sodium tert-butoxide, the exothermal reaction of tert-butoxide with DMSO is avoided and adding 4-chloro-6,7- dimethoxyquinoline last allows for the formation of the 4-aminophenolate anion prior to the addition of 4-chloro-6,7-dimethoxyquinoline.

In one embodiment, the amount of sodium tert- butox ide used per amount of the compound of formula (I) is 1.0-1.6 molar equivalents, such as 1.1-1.5 molar equivalents, for example 1.2-1.4 molar equivalents, such as 1.4 or about 1.4 molar equivalents.

In a further embodiment, the reagent is allowed to reaction for about 4 to 10 hours, such as about 5 to 9 hours, for example about 5 to 7 hours, such as about 6 hours.

In one aspect of the present invention, the invention provides the 4-((6,7- dimethoxyquinolin-4-yl)oxy)aniline of formula (II) obtainable by the method described herein and use thereof in the preparation of cabozantinib. In one embodiment, the process comprises the step of preparing the compound of formula (I) by converting 6,7-dimethoxyquinolin-4-ol of formula (la)

to the compound of formula (I) in the presence of POCI3 and a base, such as a base capable of binding the HCI gas released.

In another embodiment, the process comprises the step of preparing the compound of formula (I) by converting 6,7-dimethoxyquinolin-4-ol of formula (la)

to the compound of formula (I) in anisole in the presence of POCI3.

By carrying out the reaction in the presence of a base or in anisole, the use of a large amount of POCI3 can be avoided.

In a further embodiment, the conversion of the compound of formula (la) to the compound of formula (I) is carried out in anisole in the presence of POCI3 and a base, such as a base capable of binding the HCI gas released.

In one embodiment, the base capable of binding the HCI gas released is DIPEA or TEA, such as DIPEA.

In a further embodiment, the amount of the POCI3 used per amount of the compound of formula (la) is 1.0-2.5 molar equivalents or about 1.0-2.5 molar equivalents, such as 1.5-2.0 molar equivalents or about 1.5-2.0 molar equivalents, for example 1.6 molar equivalents or about 1.6 molar equivalents. In a further embodiment, the amount of the base used per amount of the compound of formula (la) is 1.0-2.5 molar equivalents or about 1.0-2.5 molar equivalents, such as 1.5-2.0 molar equivalents or about 1.5-2.0 molar equivalents, for example 1.7 molar equivalents or about 1.7 molar equivalents.

In one embodiment, the reaction is quenched with and the product crystallised from water and ammonia.

In an alternative embodiment, HCI released in the reaction may be removed by flushing the reaction mixture with an inert gas and neutralising the gas in an alkaline bath, such as NaOH.

In one aspect of the present invention, the invention provides the 4-chloro- 6,7-dimethoxyquinoline of formula (I) obtainable by the method described herein and use thereof in the preparation of cabozantinib.

In a further embodiment of the present invention, the process comprises the step of preparing the compound of formula (III) by reacting 4-fluoroaniline of formula (Ic)

with cyclopropane-1, 1-dicarboxylic acid of formula (Id)

in the presence of NMI to obtain the compound of formula (III).

In one embodiment, the reaction of the compound of formula (Ic) with the compound of formula (Id) is carried out in chloro(Ci-2)alkane. In one embodiment, the chloro(Ci-2)alkane is selected from the group consisting of dichloromethane, trichloromethane, 1,2-dichloroethane and a mixture said chloro(Ci-2)alkanes. In another embodiment, the chloro(Ci-2)alkane is dichloromethane.

In one embodiment, the amount of NMI per amount of the compound of formula (Id) in the reaction is 0.9-1.1 molar equivalents, such as 1.0-1.1 molar equivalents.

The product of the reaction may be isolated by adjusting the pH with, for example, aqueous sodium hydroxide, phase separation, addition of a base, such as aqueous sodium hydroxide, followed by crystallisation of the product with an aqueous acid, such as hydrochloric acid.

In one aspect of the present invention, the invention provides the l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid of formula (III) obtainable by the method described herein and use thereof in the preparation of cabozantinib.

In a further aspect, the present invention provides a process for the preparation of crystalline form N-2 of cabozantinib (S)-malate comprising the steps of a) mixing cabozantinib free base, butan-2-one (MEK), tetra hydrofuran and water; b) adding L-malic acid; c) isolating the product.

In one embodiment, the process comprises the steps of a) mixing cabozantinib free base, MEK, tetra hydrofuran and water; b) optionally subjecting the mixture to hot filtration; c) concentrating by azeotropic distillation; d) optionally adding MEK and repeating the azeotropic distillation until the water content is less than 0.65 weight-% (Karl Fischer titration value); e) adding L-malic acid to the solution at elevated temperature; f) allowing the solution to cool down before subjecting the precipitation to filtration and wash; g) drying the solid to obtain crystalline form N-2 of cabozantinib (S)-malate.

In one embodiment, the amount of tetra hydrofuran and water used per amount of cabozantinib free base in step a) is 0.6-1.0 molar equivalents and 0.43-0.65 volumes, respectively.

In one embodiment, L-malic acid is added in step e) as L-malic acid dissolved in MEK.

In one embodiment, L-malic acid is added in step e) at about 68 °C.

In one embodiment, the precipitation in step f) is washed with MEK.

In one embodiment, crystalline form N-2 of cabozantinib Sj-malate in step g) is vacuum dried.

The process yields crystalline form N-2 of cabozantinib (S)-malate with high purity in high yield in a reproducible manner. The amount of residual THF is below the threshold (720 ppm) set by the ICH guidelines.

In a further aspect, the present invention provides a process for the preparation of crystalline form N-2 of cabozantinib (S)-malate comprising the steps of a) preparing cabozantinib free base in situ without isolating cabozantinib free base; b) adding L-malic acid; c) isolating the product.

In one embodiment, cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid. In one embodiment, cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in the presence of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P).

In one embodiment, cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in the presence of 1- methyl-lH-imidazole (NMI).

In one embodiment, cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in the presence of T3P and NMI.

In one embodiment, the process comprises the steps of a) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in dichloromethane (DCM) in the presence of T3P and NMI; b) replacing DCM with butan-2-one (MEK); c) adding L-malic acid; d) isolating the product.

In one embodiment, the process comprises the steps of a) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in DCM in the presence of T3P and NMI; b) replacing DCM with MEK; c) extracting with sodium hydroxide and water; d) optionally subjecting the mixture to hot filtration; e) concentrating by azeotropic distillation; f) optionally adding MEK and repeating the azeotropic distillation until the water content is less than 0.65 weight-% (Karl Fischer titration value); g) adding L-malic acid to the solution at elevated temperature; h) allowing the solution to cool down before subjecting the precipitation to filtration and wash; i) drying the solid to obtain crystalline form N-2 of cabozantinib (S)-malate.

In one embodiment, L-malic acid is added in step g) as L-malic acid dissolved in MEK.

In one embodiment, L-malic acid is added in step g) at about 68 °C.

In one embodiment, the precipitation in step h) is washed with MEK.

In one embodiment, crystalline form N-2 of cabozantinib (S)-malate in step i) is vacuum dried.

In a further aspect, the present invention provides cabozantinib of formula

or a pharmaceutically acceptable salt thereof obtainable by the method described herein.

In yet a further aspect, the invention provides crystalline form N-2 of cabozantinib (S)-malate, wherein the crystalline form N-2 of cabozantinib (S)-malate contains less than 5 % by weight of crystalline form N-l of cabozantinib (S)-malate, such as less than 1 % by weight of crystalline form N-l of cabozantinib (S)-malate. In another embodiment, said crystalline form N-2 of cabozantinib (S)-malate contains less than 5 % by weight of other crystalline forms of cabozantinib (S)-malate, such as less than 2 % by weight of other crystalline forms of cabozantinib (S)-malate, for example less than 1 % by weight of other crystalline forms of cabozantinib (S)-malate.

Purity can be assessed with a method known in the art. Suitable methods include, but are not limited to, gas chromatography, column chromatography, liquid chromatography, high-pressure liquid chromatography, thin layer chromatography, mass spectrometry and high- resolution mass spectrometry.

Polymorphic purity can be assessed with a method known in the art. Suitable methods include, but are not limited to, solid state ¹³C nuclear magnetic resonance spectroscopy, X-ray powder diffraction and infrared spectroscopy.

Cabozantinib or a pharmaceutically acceptable salt thereof obtained by the process of the invention is useful as a medicament. Likewise, crystalline form N-2 of cabozantinib (S)-malate obtained by the process of the invention is useful as a medicament. Hence, they can be formulated into pharmaceutical dosage forms, such as tablets, capsules, powders or suspensions, by mixing with pharmaceutical excipients known in the art. Suitable excipients include, but are not limited to, fillers, binders, disintegrating agents, lubricants, solvents, gel forming agents, emulsifiers, stabilizers, colourants and preservatives.

When describing the embodiments of the present invention, the combinations and permutations of all possible embodiments have not been explicitly described. Nevertheless, the mere fact that certain measures are recited in mutually different dependent claims or described in different embodiments does not indicate that a combination of these measures cannot be used to advantage. The present invention envisages all possible combinations and permutations of the described embodiments. The term "chloro(Ci-2)alkane", as employed herein, refers to at least one chlorine appended to methane or ethane. When there are several chlorines, the chlorines can be attached to different carbon atoms or several chlorines can be attached to the same carbon atom. Representative examples of chloro(Ci-2)alkane include, but are not limited to, dichloromethane, trichloromethane and 1,2-dichloroethane. The term "at least one chlorine" refers to one or several chlorine(s).

The term "elevated temperature", as employed herein, refers to a temperature being higher than room temperature and being lower than or equal to the boiling point of the solvent used.

The terms "comprising", "comprise" and "comprises" herein are intended to be optionally substitutable with the terms "consisting of", "consist of" and "consists of", respectively, in every instance.

Example 1: Preparation of 4-chloro-6,7-dimethoxyquinoline

Anisole (25 g), 6,7-dimethoxyquinolin-4-ol (5 g, 24.37 mmol) and DIPEA (1.7 eq.) were charged to a reaction bottle and the mixture was stirred at room temperature for a few minutes to get homogenous mixture. POCI3 (1.6 eq.) was slowly added to the mixture while maintaining the temperature below 50 °C. The mixture was then slowly heated to about 95 °C and stirred for about 8 h. When the reaction was complete, a mixture of water and ammonia water was slowly added while maintaining the temperature below 40 °C. The product was collected at 5 °C, washed with water and dried under reduced pressure at 50 °C to yield 4-chloro-6,7-dimethoxyquinoline (yield 2.88 g / 52.9 %, purity 99.2 %).

Example 2: Preparation of 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline DMSO (11.6 kg), 4-aminophenol (1.13 kg) and sodium tert- butox ide (0.87 kg) were charged to a reactor at 20 °C. The mixture was stirred for 15 min at 20 °C. 4-Chloro-6,7-dimethoxyquinoline (1.5 kg) was added. All additions were made under nitrogen atmosphere. The mixture was heated to about 97 °C, stirred for about 6 h and cooled to about 20 °C. Water (10.5 kg) was slowly added at the same temperature. The solid was collected by filtration at 20 °C, washed with water and dried under reduced pressure at 50 °C to yield 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (1.92 kg I 96.4 %, purity 99.8 %).

Example 3: Preparation of l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid

Cyclopropane-1, 1-dicarboxylic acid (10.0 g) and dichloromethane (60 ml) were charged to a reaction flask. NMI (5.8 ml) and then thionyl chloride (5.9 ml) were added to the mixture. Both additions were made gradually at reduced temperature. A mixture of 4-fluoroaniline (7.8 ml) and TEA (11 ml) was added during about 2 h at reduced temperature. All additions were done under nitrogen atmosphere. When the rection was complete after stirring for about an hour at about 10 °C, water (40 ml) and 50 % NaOH solution (6.0 ml) were added to the mixture at ambient temperature. If necessary, the pH of the mixture was adjusted to about 4.5. The aqueous phase was separated off. Alkaline water (66 ml) was added to the organic phase. The pH of the aqueous phase was adjusted to <2 with cone. HCI solution. The reaction mixture was stirred for about 4 h at about 20 °C. The solid was collected by filtration and washed twice with water and dried under reduced pressure at 65 °C to yield l-((4-fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid (12.64 g I 73.68 %, purity 99.7 %).

Example 4: Preparation of cabozantinib

4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline (11.0 g), l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid (9.5 g), dichloromethane (60 ml) and NMI (7.5 ml) were charged to a reaction flask. 50 % T3P in ethyl acetate (28 ml) was gradually added in 1-2 h at ambient temperature. All additions were made under nitrogen atmosphere. The mixture was stirred for about 3 h at 20 °C. Ethanol (65 ml) and TEA (8 ml) were added and the product was crystallised by slowly adding water (45 ml) at 20 °C. After stirring for 8-16 h at 20 °C, the mixture was cooled to about 5 °C and the stirring was continued for 4-8 h. The solid was collected by filtration, washed with a mixture of ethanol and water and dried under reduced pressure at 55 °C to yield cabozantinib (17.92 g I 96.26 %, purity 99.5 %).

Example 5: Preparation of crystalline form N-2 of cabozantinib (S)- malate

/V-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-/V-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (30 g), MEK (507 g), THF (3.45 g) and water (13.5 g) were charged to a reactor. The mixture was heated to the boiling point and hot filtrated. Hot MEK (24.2 g) was used to flush the filter. The combined filtrates were concentrated by distilling off about 110 g of solvents at atmospheric pressure. MEK (173 g) was added to the distillation residue. The mixture was concentrated by distilling off 158 g of solvents. If the water content of the residue was not below 0.65 weight-% (Karl Fischer titration value), addition of MEK (40.3 g) and distillation were repeated so many times until the target was reached.

L-Malic was dissolved in MEK (81 g). Seed crystals were added to the distillation residue before the filtrated L-malic acid solution was slowly added to the distillation residue at about 68 °C.

The mixture was cooled to 20 °C in about 18 h and stirred at the same temperature for about 2 h.

The solid was collected by filtration at about 20 °C, washed twice with MEK and dried under reduced pressure at 60 °C to yield crystalline form N-2 of cabozantinib (S)-malate (34.75 g / 91.40 %, purity 99.9 %). Example 6: Preparation of crystalline form N-2 of cabozantinib (S)- malate

A/-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-A/-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (30 g), MEK (507 g), THF (3.45 g) and water (13.2 g) were charged to a reactor. The mixture was heated to the boiling point and hot filtrated. Hot MEK (24.2 g) was used to flush the filter. The combined filtrates were concentrated by distilling off about 149 ml of solvents at atmospheric pressure. MEK (161 g) was added to the distillation residue. The mixture was concentrated by distilling off 216 ml of solvents.

L-Malic acid (8.34 g) was dissolved in MEK (80.5 g). Seed crystals were added to the distillation residue before the L-malic acid solution was slowly added to the hot distillation residue while the temperature was allowed to decrease to 50 °C.

The mixture was stirred at 50 °C for 18 h, cooled to 20 °C in about 2 h and stirred at 20 °C for about 4 h.

The solid was collected by filtration at about 20 °C, washed twice with MEK and dried under reduced pressure at 65 °C to yield crystalline form N-2 of cabozantinib (S)-malate (36.67 g / 91.19 %, purity 99.9 %).

Example 7: Preparation of crystalline form N-2 of cabozantinib (S)- malate

/V-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-/V-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (30 g), MEK (507 g), THF (3.45 g) and water (16 g) were charged to a reactor. The mixture was heated to the boiling point and hot filtrated. Hot MEK (24.2 g) was used to flush the filter. The combined filtrates were concentrated by distilling off about 199 ml of solvents at atmospheric pressure. MEK (241.5 g) was added to the distillation residue. The mixture was concentrated by distilling off 300 ml of solvents.

L-Malic acid (8.26 g) was dissolved in MEK (80.5 g). Seed crystals were added to the distillation residue before the L-malic acid solution was slowly added to the hot distillation residue while the temperature was allowed to decrease to 65 °C.

The mixture was cooled to 50 °C in 2 h and then to 20 °C in about 12 h and stirred at 20 °C for about 6 h.

The solid was collected by filtration at about 20 °C, washed twice with MEK and dried under reduced pressure at 65 °C to yield crystalline form N-2 of cabozantinib (S)-malate (34.09 g / 89.66 %, purity 99.8 %).

Example 8: Preparation of crystalline form N-2 of cabozantinib (S)- malate

/V-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-/V-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (30 g), MEK (507 g), THF (3.45 g) and water (13.5 g) were charged to a reactor. The mixture was heated to the boiling point and hot filtrated. Hot MEK (24.2 g) was used to flush the filter. The combined filtrates were concentrated by distilling off about 147 ml of solvents at atmospheric pressure. MEK (173 g) was added to the distillation residue. The mixture was concentrated by distilling off 206 ml of solvents.

L-Malic acid (8.82 g) was dissolved in MEK (85.3 g). Seed crystals were added to the distillation residue before the L-malic acid solution was slowly added to the hot distillation residue. The temperature was about 65 °C during the addition. The mixture was cooled to 52 °C in 2 h and then stirred for about 5 h. Cooling was continued to room temperature in about 10 h and the mixture stirred at room temperature for about 1.5 h.

The solid was collected by filtration at about 20 °C, washed twice with MEK and dried under reduced pressure at 65 °C to yield crystalline form N-2 of cabozantinib (S)-malate (34.75 g I 91.40 %, purity 99.9 %).

Example 9: Preparation of crystalline form N-2 of cabozantinib (S)- malate

/V-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-/V-(4- fluorophenyl)cyclopropane-l,l-dicarboxamide (30 g), MEK (507 g), THF (3.67 g) and water (14 g) were charged to a reactor. The mixture was heated to the boiling point and hot filtrated. Hot MEK (24.2 g) was used to flush the filter. The combined filtrates were concentrated by distilling off about 144 ml of solvents at atmospheric pressure. MEK (173 g) was added to the distillation residue. The mixture was concentrated by distilling off 220 ml of solvents. To achieve a water content of the distillation residue below 0.65 weight-% (Karl Fischer titration value), MEK (40.25 g) was added to the distillation residue and the mixture was concentrated by distilling off 52 ml of solvents.

L-Malic acid (8.42 g) was dissolved in MEK (81.3 g). Seed crystals were added to the distillation residue before the addition of the L-malic acid solution to the hot distillation residue at about 68 °C.

The mixture was gradually cooled to 20 °C in 16 h and stirred at 20 °C for about 4.5 h.

The solid was collected by filtration at about 20 °C, washed twice with MEK and dried under reduced pressure at 65 °C to yield crystalline form N-2 of cabozantinib (S)-malate (32.55 g / 85.61 %, purity 99.95 %). Example 10: Preparation of crystalline form N-2 of cabozantinib (S)- malate

4-((6,7-Dimethoxyquinolin-4-yl)oxy)aniline (11.0 g), l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid (9.5 g), DCM (80 g) and NMI (4.3 g) were charged to a reaction flask. 50 % T3P in ethyl acetate (28.8 g) was gradually added in 0.5-1 h at ambient temperature. All additions were made under nitrogen atmosphere. The mixture was stirred for about 4 h at 20 °C.

MEK (130 g) was added and solvents were distilled off (66 ml). Water (60 g) and 50 % NaOH solution (1.9 g) were added to the residue at 63 °C and the phases were separated. Water (60 g) and 50 % NaOH solution (5.7 g) were added to the organic phase at 63 °C and the phases were separated. Water (60 g) was added to the organic phase and the phases were separated. MEK (68 g), activated carbon (0.6 g) and celite (0.4 g) were added at 63 °C. After stirring, the mixture was filtrated and the cake was washed with MEK (36 g).

MEK (145 g) was added. The mixture was concentrated by distilling off 60 ml of solvents. MEK (48 g) was added to the distillation residue and the mixture was concentrated by distilling off 60 ml of solvents. If the water content of the residue was not below 0.65 weight-% (Karl Fischer titration value), addition of MEK (48 g) and distillation were repeated so many times until the target was reached.

L-Malic acid (6.0 g) was dissolved in MEK (56 g). Seed crystals were added to the distillation residue before the addition of the L-malic acid solution to the hot distillation residue at about 68 °C.

The mixture was gradually cooled to 20 °C in 16 h and stirred at 20 °C for about 4 h. The solid was collected by filtration at about 20 °C, washed twice with MEK and dried under reduced pressure at 60 °C to yield crystalline form N-2 of cabozantinib (S)-malate (19.6 g / 83.3 %, purity >99.5 %).

Claims

1. A process for the preparation of cabozantinib of formula (1A)

or a pharmaceutically acceptable salt thereof, said process comprising a step of reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline of formula

with l-((4-fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid of formula (III)

in the presence of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) to obtain the compound of formula (1A) and optionally converting the compound of formula (1A) to a pharmaceutically acceptable salt thereof.

2. The process according to claim 1, wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of T3P and 1-methyl-lH-imidazole (NMI). 3. The process according to any one of claims 1 or 2, wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out in the presence of 50 % T3P in ethyl acetate.

4. The process according to any one of claims 1 to 3, wherein the amount of T3P used per amount of the compound of formula (II) is 1.0-1.5 molar equivalents.

5. The process according to claim 2, wherein the amount of NMI used per amount of the compound of formula (II) is 1-4 molar equivalents.

6. The process according to claim 5, wherein the amount of NMI used per amount of the compound of formula (II) is 2-3 molar equivalents.

7. The process according to any one of claims 1 to 6, wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out in chloro(Ci-2)alkane.

8. The process according to claim 7, wherein the chloro(Ci-2)alkane is dichloromethane, trichloromethane, 1,2-dichloroethane or a mixture thereof.

9. The process according to claim 8, wherein the chloro(Ci-2)alkane is dichloromethane.

10. The process according to any one of claims 1 to 9, wherein the compound of formula (II) is prepared by reacting 4-chloro-6,7- dimethoxyquinoline of formula (I)

with 4-aminophenol of formula (lb)

in dimethyl sulfoxide in the presence of sodium tert-butoxide to obtain the compound of formula (II).

11. The process according to claim 10, wherein the amount of sodium tert- butoxide used per amount of the compound of formula (I) is 1.0-1.6 molar equivalents.

12. The process according to any one of claims 10 or 11, wherein the compound of formula (I) is prepared by converting 6,7- dimethoxyquinolin-4-ol of formula (la)

to the compound of formula (I) in the presence of POCI3 and a base.

13. The process according to any one of claims 10 or 11, wherein the compound of formula (I) is prepared by converting 6,7- dimethoxyquinolin-4-ol of formula (la)

to the compound of formula (I) in anisole in the presence of POCI3.

14. The process according to any one of claims 12 or 13, wherein the conversion of the compound of formula (la) to the compound of formula (I) is carried out in anisole in the presence of POCI3 and a base.

15. The process according to any one of claims 12 or 14, wherein the base is a base capable of binding the HCI gas released. 16. The process according to claim 15, wherein the base capable of binding the HCI gas released is /V,/V-diisopropyl-/V-ethylamine or triethylamine.

17. The process according to claim 16, wherein the base capable of binding the HCI gas released is /V,/V-diisopropyl-/V-ethylamine.

18. The process according to any one of claims 12 to 17, wherein the amount of the POCI3 used per amount of the compound of formula (la) is about 1.0-2.5 molar equivalents.

19. The process according to claim 18, wherein the amount of the POCI3 used per amount of the compound of formula (la) is about 1.5-2.0 molar equivalents.

20. The process according to claim 19, wherein the amount of the POCI3 used per amount of the compound of formula (la) is about 1.6 molar equivalents.

21. The process according to claim 12 or any one of claims 14 to 17, wherein the amount of the base used per amount of the compound of formula (la) is about 1.0-2.5 molar equivalents.

22. The process according to claim 21, wherein the amount of the base used per amount of the compound of formula (la) is about 1.5-2.0 molar equivalents.

23. The process according to claim 22, wherein the amount of the base used per amount of the compound of formula (la) is about 1.7 molar equivalents.

24. The process according to any one of claims 1 to 23, wherein the compound of formula (III) is prepared by reacting 4-fluoroaniline of formula (Ic)

with cyclopropane-1, 1-dicarboxylic acid of formula (Id)

in the presence of NMI to obtain the compound of formula (III).

25. The process according to claim 24, wherein the reaction of the compound of formula (Ic) with the compound of formula (Id) is carried out in chloro(Ci-2)alkane.

26. The process according to claim 25, wherein the chloro(Ci-2)alkane is dichloromethane, trichloromethane, 1,2-dichloroethane or a mixture thereof. 7. The process according to claim 26, wherein the chloro(Ci-2)alkane is dichloromethane.

28. The process according to any one of claims 24 to 27, wherein the amount of NMI used per amount of the compound of formula (Id) is 0.9-1.1 molar equivalents.

29. The process according to claim 28, wherein the amount of NMI used per amount of the compound of formula (Id) is 1.0-1.1 molar equivalents.

30. A process for the preparation of crystalline form N-2 of cabozantinib (S)-malate comprising the steps of a) mixing cabozantinib free base, butan-2-one (MEK), tetra hydrofuran and water; b) adding L-malic acid; c) isolating the product. The process according to claim 30, wherein the process comprises the steps of a) mixing cabozantinib free base, MEK, tetra hydrofuran and water; b) optionally subjecting the mixture to hot filtration; c) concentrating by azeotropic distillation; d) optionally adding MEK and repeating the azeotropic distillation until the water content is less than 0.65 weight-% (Karl Fischer titration value); e) adding L-malic acid to the solution at elevated temperature; f) allowing the solution to cool down before subjecting the precipitation to filtration and wash; g) drying the solid to obtain crystalline form N-2 of cabozantinib (S)- malate. The process according to any one of claims 30 or 31, wherein the amount of tetra hydrofuran and water used per amount of cabozantinib free base in step a) is 0.6-1.0 molar equivalents and 0.43-0.65 volumes, respectively. The process according to any one of claims 31 or 32, wherein L-malic acid is added in step e) as L-malic acid dissolved in MEK. The process according to any one of claims 31 to 33, wherein L-malic acid is added in step e) at about 68 °C. The process according to any one of claims 31 to 34, wherein the precipitation in step f) is washed with MEK. The process according to any one of claims 31 to 35, wherein crystalline form N-2 of cabozantinib (S)-malate in step g) is vacuum dried. The process according to any one of claims 30 to 36, wherein said cabozantinib free base is obtained by the process of any one of claims 1 to 29. A process for the preparation of crystalline form N-2 of cabozantinib (S)-malate comprising the steps of a) preparing cabozantinib free base in situ without isolating cabozantinib free base; b) adding L-malic acid; c) isolating the product. The process according to claim 38, wherein cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline with l-((4-fluorophenyl)carbamoyl)cyclopropane-l- carboxylic acid. The process according to claim 39, wherein cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline with l-((4-fluorophenyl)carbamoyl)cyclopropane-l- carboxylic acid in the presence of 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (T3P). The process according to claim 39, wherein cabozantinib free base in step a) is prepared by reacting 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline with l-((4-fluorophenyl)carbamoyl)cyclopropane-l- carboxylic acid in the presence of 1-methyl-lH-imidazole (NMI). The process according to any one of claims 40 or 41, wherein cabozantinib free base in step a) is prepared by reacting 4-((6,7- dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in the presence of T3P and NMI. The process according to claim 42, wherein the process comprises the steps of a) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in dichloromethane (DCM) in the presence of T3P and NMI; b) replacing DCM with butan-2-one (MEK); c) adding L-malic acid; d) isolating the product. The process according to claim 43, wherein the process comprises the steps of a) reacting 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline with l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid in DCM in the presence of T3P and NMI; b) replacing DCM with MEK; c) extracting with sodium hydroxide and water; d) optionally subjecting the mixture to hot filtration; e) concentrating by azeotropic distillation; f) optionally adding MEK and repeating the azeotropic distillation until the water content is less than 0.65 weight-% (Karl Fischer titration value); g) adding L-malic acid to the solution at elevated temperature; h) allowing the solution to cool down before subjecting the precipitation to filtration and wash; i) drying the solid to obtain crystalline form N-2 of cabozantinib (S)- malate. The process according to claim 44, wherein L-malic acid is added in step g) as L-malic acid dissolved in MEK. The process according to any one of claims 44 to 45, wherein L-malic acid is added in step g) at about 68 °C. 47. The process according to any one of claims 44 to 46, wherein the precipitation in step h) is washed with MEK.

48. The process according to any one of claims 44 to 47, wherein crystalline form N-2 of cabozantinib Sj-malate in step i) is vacuum dried.

49. A process for the preparation of l-((4- fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid of formula (III)

or a pharmaceutically acceptable salt thereof, said process comprising a step of reacting reacting 4-fluoroaniline of formula (Ic)

with cyclopropane-1, 1-dicarboxylic acid of formula (Id)

in the presence of 1-methyl-lH-imidazole (NMI) to obtain the compound of formula (III) and optionally converting the compound of formula (III) to a pharmaceutically acceptable salt thereof.

50. A process for the preparation of 4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline of formula (II)

or a pharmaceutically acceptable salt thereof, said process comprising a step of reacting 4-chloro-6,7-dimethoxyquinoline of formula (I)

with 4-aminophenol of formula (lb)

in dimethyl sulfoxide in the presence of sodium tert-butoxide to obtain the compound of formula (II) and optionally converting the compound of formula (II) to a pharmaceutically acceptable salt thereof. A process for the preparation of 4-chloro-6,7-dimethoxyquinoline of formula (I)

or a pharmaceutically acceptable salt thereof, said process comprising a step of converting 6,7-dimethoxyquinolin-4-ol of formula (la)

to the compound of formula (I) in the presence of POCI3 and a base to obtain the compound of formula (I) and optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof.

52. A process for the preparation of 4-chloro-6,7-dimethoxyquinoline of formula (I)

to the compound of formula (I) in anisole in the presence of POCI3 to obtain the compound of formula (I) and optionally converting the compound of formula (I) to a pharmaceutically acceptable salt thereof.

53. Use of l-((4-fluorophenyl)carbamoyl)cyclopropane-l-carboxylic acid of formula (III)

prepared according to claim 49, 4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline of formula (II)

prepared according to claim 50 or 4-chloro-6,7-dimethoxyquinoline of formula (I)

prepared according to any one of claims 51 or 52 in the preparation of cabozantinib of formula (1A)

54. Cabozantinib of formula (1A)

or a pharmaceutically acceptable salt thereof obtainable by the process according to any one of claims 1 to 29.

55. Crystalline form N-2 of cabozantinib (S)-malate obtained by the process according to any one of claims 30 to 48.

56. Crystalline form N-2 of cabozantinib (S)-malate, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 5 % by weight of crystalline form N-l of cabozantinib (S)-malate.

57. The crystalline form N-2 of cabozantinib (S)-malate according to claim 56, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 1 % by weight of crystalline form N-l of cabozantinib (S)-malate.

58. Crystalline form N-2 of cabozantinib (S)-malate, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 5 % by weight of other crystalline forms of cabozantinib (S)-malate.

59. The crystalline form N-2 of cabozantinib (S)-malate according to claim

58, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 2 % by weight of other crystalline forms of cabozantinib (S)-malate.

60. The crystalline form N-2 of cabozantinib (S)-malate according to claim

59, wherein said crystalline form N-2 of cabozantinib (S)-malate contains less than 1 % by weight of other crystalline forms of cabozantinib (S)-malate.

61. A pharmaceutical dosage form comprising the cabozantinib of claim 54 and at least one pharmaceutically acceptable excipient.

62. A pharmaceutical dosage form comprising the crystalline form N-2 of cabozantinib (S)-malate of any one of claims 55 to 60 and at least one pharmaceutically acceptable excipient.

63. The dosage form according to any one of claims 61 or 62, wherein the dosage form is a tablet, a capsule, a powder or a suspension.