WO2021229605A1

WO2021229605A1 - Process for preparation of savolitinib and its intermediates

Info

Publication number: WO2021229605A1
Application number: PCT/IN2021/050457
Authority: WO
Inventors: Srinivas ORUGANTI; Saikat Sen; Magesh SAMPATH; Arun AEDHUNURI; Deepika PATHIVADA
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2020-05-14
Filing date: 2021-05-13
Publication date: 2021-11-18

Abstract

The present application relates to a process for preparation of chiral amine fragment (IV) of savolitinib. The present application also relates to a process for preparation of savolitinib using the chiral amine (IV), as prepared by the process of the present application. The present application also discloses new intermediates useful for the synthesis of savolitinib. The present application further relates to crystalline forms of savolitinib, namely AA1, formic acid solvate and AA2. The present application also relates to amorphous solid dispersion of savolitinib.

Description

PROCESS FOR PREPARATION OF SAVOLITINIB AND ITS

INTERMEDIATES

FIELD OF INVENTION

The present application relates to a process for preparation of chiral amine fragment (IV) of savolitinib. The present application also relates to a process for preparation of savolitinib using the chiral amine (IV), as prepared by the process of the present application. The present application also discloses new intermediates useful for the synthesis of savolitinib. The present application also relates to crystalline forms of Savolitinib.

BACKGROUND ART

Savolitinib (AZD6094/HMPL-504) (I) is a potential first-in-class selective inhibitor of c-MET receptor tyrosine kinase, developed by AstraZeneca and its partner Chi- Med. Savolitinib is currently in advanced clinical trials for the treatment of various tumors including non-small cell lung cancer (NSCLC), advanced or metastatic Papillary Renal Cell Carcinoma (PRCC). Savolitinib is chemically known as 1 -[(15)- 1 -(imidazo [ 1 ,2-a]pyridin-6-yl)ethyl] -6-( 1 -methyl- 1 H-pyrazol-4-yl)- 1 H- 1 ,2,3 -triazolo [4,5-b]pyrazine.

US8987269B2 (herein after referred as US’269) first discloses savolitinib along with the process for preparation thereof. The process of US’269 patent involves the resolution of racemic mixture by chiral HPLC to produce optically pure savolitinib. Non-patent literature, J. Org. Chem. 2019, 84, 4735-4747, by Howel et al. discloses an optimized Suzuki-Miyura procedure for preparation of Savolitinib using chiral amine fragment as starting material. However, the article does not disclose any specific process for synthesis of chiral amine fragment. Further CN105503906B (herein after referred as CN’906) & CN105503905B (herein after referred as CN’905) discloses crystal form A & B of Savolitinib respectively. There remains a need for a commercially feasible process for the preparation of savolitinib (I) and its intermediates.

New polymorphic forms, solvates and solid dispersions of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of savolitinib.

SUMMARY

First aspect of the present application relates to a process for preparation of chiral amine fragment of formula (IV) or a salt thereof comprising

(i) reacting compound of formula (VII) with ( R ) -/tv7-b uty 1 s ul fi nam i de (Xa) to form compound of formula (Via)

(ii) reacting compound of formula (Via) with a suitable reducing agent to form compound of formula

(iii) conversion of compound of formula (Va) to form chiral amine fragment of formula (IV) or a salt thereof

Second aspect of the present application relates to a process for preparation of chiral amine fragment of formula (IV) or a salt thereof comprising

(i) reacting compound of formula (VII) with fY)-/ /7-butylsulfinamide (Xb) to form compound of formula (VIb)

(ii) reacting compound of formula (VIb) with a suitable reducing agent to form compound of formu

Reducing agent

(VIb)

(iii) conversion of compound of formula (Vb) to form chiral amine fragment of formula (IV) or a salt thereof

Third aspect of the present application relates to a process for preparation of compound of formula (Via) comprising reacting compound of formula (VII) with (i?)-/er/-butylsulfinamide (Xa) to form compound of formula (Via)

Fourth aspect of the present application relates to a process for preparation of compound of formula (Va) comprising reducing compound of formula (Via) in presence of a suitable reducing agent;

Fifth aspect of the present application relates to a process for preparation of chiral amine fragment of formula (IV) or a salt thereof comprising converting compound of formula (Va) to chiral amine fragment of formula (IV) or a salt thereof

Sixth aspect of the present application relates to a process for preparation of compound of formula (Vlb) comprising reacting compound of formula (VII) with (S)-/er/-butylsulfinamide (Xb) to form compound of formula (Vlb)

( )

Seventh aspect of the present application relates to a process for preparation of compound of formula (Vb) comprising reducing compound of formula (Vlb) in presence of a suitable reducing agent; s

N ·¾

Reducing agent

(Vlb)

Eighth aspect of the present application relates to a process for preparation of chiral amine fragment of formula (IV) or a salt thereof comprising converting compound of formula (Vb) to chiral amine fragment of formula (IV) or a salt thereof e.

Ninth aspect of the present application relates to compound of formula (Va) and/or (Vb)

(Va) (Vb)

Tenth aspect of the present application relates to compound of formula (Via) and/or

(VIb)

(Via) (VIb)

Eleventh aspect of the present application relates to the use of compound of formula (Va) and/or (Vb) and/or (Via) and/or (VIb) for the preparation of savolitinib.

Twelfth aspect of the present application relates to a process for preparation of savolitinib comprising converting compound of formula (IV) or a salt thereof, prepared by any aspect of this application to savolitinib.

Thirteenth aspect of the present application relates to crystalline form AA1 of savolitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.45, 8.83 and 21.67 ± 0.2° 2Q. In embodiments, the present application provides crystalline form AA1 of savolitinib characterized by its PXRD pattern having additional peaks located at about 10.93, 13.95 and 17.77 ± 0.2° 2Q. Fourteenth aspect of the present application relates to crystalline form AA1 of savolitinib characterized by a PXRD pattern substantially as illustrated in Figure 1. Fifteenth aspect of the present application relates to a process for preparing crystalline form AA1 of savolitinib; the process comprising; a) providing a suspension comprising savolitinib and ethyl formate by mixing savolitinib with a solvent comprising ethyl formate; b) isolating crystalline form AA1 of savolitinib from the mixture of step a); and; c) optionally, drying the isolated product at suitable temperature.

Sixteenth aspect of the present application provides a pharmaceutical composition comprising crystalline form AA1 of savolitinib and at least one pharmaceutically acceptable carrier.

Seventeenth aspect of the present application provides amorphous solid dispersion comprising savolitinib and one or more pharmaceutically acceptable excipient. Eighteenth aspect of the present application provides a process for preparation of amorphous solid dispersion comprising savolitinib and one or more pharmaceutically acceptable excipient; the process comprising; a) providing a solution comprising savolitinib and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture threreof, b) removing solvent form the solution obtained in step (a), and c) recovering the solid dispersion comprising savolitinib and one or more pharmaceutically acceptable excipients.

Nineteenth aspect of the present application provides a pharmaceutical composition comprising amorphous solid dispersion of savolitinib and at least one pharmaceutically acceptable carrier.

Twentieth aspect of the present application relates to novel crystalline form of savolitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.4, 8.77 and 21.61 ± 0.2° 2Q. In embodiments, the present application provides crystalline form of savolitinib characterized by its PXRD pattern having additional peaks located at about 10.87, 13.89 and 17.71 ± 0.2° 2Q.

Twenty first aspect of the present application relates to a novel crystalline form of savolitinib characterized by a PXRD pattern substantially as illustrated in Figure 5. Twenty second aspect of the present application relates to a process for preparing a crystalline form of savolitinib; the process comprising; a) mixing savolitinib with formic acid in presence of a suitable solvent; b) isolating crystalline form of savolitinib from the mixture of step a); and; c) optionally, drying the isolated product at suitable temperature.

Twenty third aspect of the present application provides a pharmaceutical composition comprising crystalline form of savolitinib and at least one pharmaceutically acceptable carrier.

Twenty fourth aspect of the present application relates to crystalline form AA2 of savolitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 4.81, 7.37, 8.37 and 17.54 ± 0.2° 2Q. In embodiments, the present application provides crystalline form AA2 of savolitinib characterized by its PXRD pattern having additional peaks located at about 14.57, 16.88 ± 0.2° 2Q.

Twenty fifth aspect of the present application relates to crystalline form AA2 of savolitinib characterized by a PXRD pattern substantially as illustrated in Figure 1. Twenty sixth aspect of the present application relates to a process for preparing a crystalline form of savolitinib; the process comprising ball milling a mixture of savolitinib and propionic acid.

Twenty seventh aspect of the present application provides a pharmaceutical composition comprising crystalline form AA2 of savolitinib and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is powder X-ray diffraction ("PXRD") pattern of crystalline from AA1 of savolitinib.

Figure 2 is powder X-ray diffraction ("PXRD") pattern of amorphous solid dispersion of savolitinib prepared according to Example 19. Figure 3 is powder X-ray diffraction pattern of amorphous solid dispersion of savolitinib prepared according to Example 20.

Figure 4 is powder X-ray diffraction pattern of amorphous solid dispersion of savolitinib prepared according to Example 21.

Figure 5 is powder X-ray diffraction ("PXRD") pattern of crystalline from of savolitinib.

Figure 6 is powder X-ray diffraction ("PXRD") pattern of crystalline from AA2 of savolitinib.

DETAILED DESCRIPTION

(VII) (Via)

(ii) reacting compound of formula (Via) with a suitable reducing agent to form compound of formul

(Via) (Va) (iii) conversion of compound of formula (Va) to form chiral amine fragment of formula (IV) or a salt thereof

(Va) (IV)

In embodiments of step (i) compound of formula (VII) is treated with ( R)-tert - butylsulfinamide (Xa) in a suitable solvent in presence of titanium (IV) reagent to form corresponding compound of formula (Via). The suitable solvent may include but not limited to ethers such as 1 ,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the aromatic hydrocarbon solvent may be toluene. Non limiting examples of titanium (IV) reagent may include but not limited to titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide, titanium (IV) chloride; preferably titanium (IV) ethoxide. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.

In embodiments of step (ii) compound of formula (Via) is treated with a suitable reducing agent in a suitable solvent to form compound of formula (Va). Suitable reducing agent include but not limited to L-selecteride, K-selectride, Na-selectride, lithiumtri ethyl borohydride_. sodium borohydride, lithium borohydride, diisobutylaluminium hydride (DIBAL-H), borane dimethylsulfide, borane tetrahydrofuran complex, borane pyridine complex, catecholborane, 9- borabicyclo[3.3.1]nonane (9-BBN), decaborane, Sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al) and the like. The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloromethane and the like. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be tetrahydrofuran. The reaction may be carried out at a temperature of about -80 °C to about -40 °C. Specifically, the reaction may be carried out at a temperature about -50 °C to about -60 °C.

In one specific embodiment of step (ii) the compound of formula (Via) is treated with L-selectride to form compound of formula (Va).

In another specific embodiment of step (ii) the compound of formula (Via) is treated with Sodiumborohydride to form compound of formula (Va).

Yet in another specific embodiment of step (ii) the compound of formula (Via) is treated with diisobutylaluminium hydride to form compound of formula (Va).

Still in another specific embodiment of step (ii) the compound of formula (Via) is treated with borane dimethylsulfide to form compound of formula (Va).

In embodiments of step (iii), conversion of compound of formula (Va) to compound of formula (IV) is carried out in presence of an acid reagent in a suitable solvent. The acid reagent may include but not limited to mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid and the like; sulfonic acids such as methanesulfonic acid, triflic acid and the like. Specifically, the acid reagent may be a mineral acid. More specifically, the acid reagent may be hydrochloric acid. The suitable solvent may include but not limited to alcoholic solvent such as, methanol, isopropanol and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloromethane and the like. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be 1,4-dioxane. The reaction may be carried out at a temperature of about 0 °C to about ambient temperature.

(i) reacting compound of formula (VII) with fY)-/tv7-butylsulfinamide (Xb) to form compound of formula (VIb)

(ii) reacting compound of formula (VIb) with a suitable reducing agent to form compound

(VIb) (Vb)

In embodiments of step (i) compound of formula (VII) is treated with ( S )- tert- butylsulfinamide (Xb) in a suitable solvent in presence of titanium (IV) reagent to form corresponding compound of formula (VIb). The suitable solvent may include but not limited to ethers such as 1 ,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. Specifically, the solvent may be an aromatic hydrocarbon solvent. More specifically, the aromatic hydrocarbon solvent may be toluene. Non limiting examples of titanium (IV) reagent may include but not limited to titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) isopropoxide, titanium (IV) chloride; preferably titanium (IV) ethoxide. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.

In embodiments of step (ii) compound of formula (VIb) is treated with a suitable reducing agent in a suitable solvent to form compound of formula (Vb). Suitable reducing agent include but not limited to L-selecteride, K-selectride, Na-selectride, lithiumtri ethyl borohydride_. sodium borohydride, lithium borohydride, diisobutylaluminium hydride (DIBAL-H), borane dimethylsulfide, borane tetrahydrofuran complex, borane pyridine complex, catecholborane, 9- borabicyclo[3.3.1]nonane (9-BBN), decaborane, Sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al) and the like. The suitable solvent may include but not limited to alcoholic solvent such as, methanol, isopropanol and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloromethane and the like. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be tetrahydrofuran. The reaction may be carried out at a temperature of about -90 °C to about -50 °C. Specifically, the reaction may be carried out at a temperature about -60 °C to about -80 °C. In one specific embodiment of step (ii) the compound of formula (VIb) is treated with diisobutylaluminium hydride to form compound of formula (Vb).

In other specific embodiment of step (ii) the compound of formula (VIb) is treated with L-selectride to form compound of formula (Vb).

Third aspect of the present application relates to a process for preparation of compound of formula (Via) comprising reacting compound of formula (VII) with (R)- tw-buty 1 s ul fi nam i de (Xa) to form compound of formula (Via)

Sixth aspect of the present application relates to a process for preparation of compound of formula (VIb) comprising reacting compound of formula (VII) with (S)- /er/-butylsulfinamide (Xb) to form compound of formula (VIb)

Seventh aspect of the present application relates to a process for preparation of compound of formula (Vb) comprising reducing compound of formula (VIb) in presence of a suitable reducing agent;

(Vlb) (Vb)

Eighth aspect of the present application relates to a process for preparation of chiral amine fragment of formula (IV) or a salt thereof comprising converting compound of formula (Vb) to chiral amine fragment of formula (IV) or a salt thereof

(Vlb)

In a specific aspect, the present application relates to the screening of various reducing agents in the diastereoselective reduction of compound of formula (Via) to compound of formula (Va) and compound of formula (VIb) to compound of formula (Vb). The following table depicts the results of such diastereoselective reduction reactions:

In one embodiment, the compound of formula (IV) is converted to Savolitinib by any method known in the art. In one specific embodiment the compound of formula (IV) is converted to Savolitinib by a method disclosed in J Org. Chem. 2019, 84, 4735-4747.

In another embodiment, the compound of formula (VII) is prepared by any method known in the art. In one specific embodiment compound of formula (VII) is prepared by a method disclosed in US8987269B2.

In embodiments of step a), the solvent may be a mixture of ethyl formate and an organic solvent. The organic solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; water. In another embodiment of step a), the solvent may be a mixture of ethyl formate and water. In a specific embodiment, the solvent may be ethyl formate.

In one of the embodiments of step a), any physical form of savolitinib may be utilized, which may be crystalline or amorphous, for providing the suspension of savolitinib in a solvent comprising ethyl formate. In another embodiment of step a), any physical form of savolitinib may be utilized, which may be anhydrous or hydrate, for providing the suspension of savolitinib in a solvent comprising ethyl formate. In yet another embodiment, crystalline forms I, II, III and IV of savolitinib, as reported in the W0’198 application may be used in step a). In still yet another embodiment, crystalline forms A, B of savolitinib, as reported in the CN’906, CN’905 applications respectively may be used in step a).

Isolation of crystalline form AA1 of savolitinib in step b) may be performed by any technique known in the art. Specifically, crystalline form AA1 of savolitinib may be isolated from the mixture of step a) by filtration.

The resulting compound obtained in step (b) may be further washed with a suiable solvent such as hexane, heptane and the like. In a specific embodiment, the solvent may be n-heptane. The resulting compound obtained in step (b) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the savolitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

The crystalline form AA1 of savolitinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form AA1 of savolitinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill. The crystalline form AA1 of savolitinib of the present application is stable and has excellent physico-chemical properties. The crystalline form AA1 of savolitinib of the present application may be easily formulated into a pharmaceutical composition comprising savolitinib.

Sixteenth aspect of the present application relates to a pharmaceutical composition comprising crystalline form AA1 of savolitinib and one or more pharmaceutically acceptable excipient.

Seventeenth aspect of the present application provides amorphous solid dispersion comprising savolitinib and one or more pharmaceutically acceptable excipient. Eighteenth aspect of the present application provides a process for preparing amorphous solid dispersion comprising savolitinib and one or more pharmaceutically acceptable excipient, the process comprising; a) providing a solution comprising savolitinib and one or more pharmaceutically acceptable excipients by dissolving in a suitable solvent or mixture thereof; b) removing solvent from the solution obtained in step (a); and c) recovering amorphous solid dispersion comprising Savolitinib and one or more pharmaceutically acceptable excipient.

Providing a solution in step (a) includes direct use of a reaction mixture containing Savolitinib that is obtained in the course of its synthesis or dissolving savolitinib and pharmaceutically acceptable excipient in a solvent or a mixture of solvents.

Any physical form of Savolitinib may be utilized for providing the solution of step (a).

Suitable pharmaceutically acceptable excipients which can be used in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, Copovidone, Soluplus, Silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses such as hydroxypropyl methylcellulose acetate succinate (HPMC-AS). hydroxypropyl methylcellulose phthalate (HPMCP), HPMC-15 CPS; pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like. In a preferred embodiment, the pharmaceutically acceptable expicients are PVP-K30, hydroxypropyl methylcellulose-acetate succinate (HPMC-AS) and hydroxypropyl methylcellulose phthalate (HPMCP).

Suitable solvent of step a) may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate and the like; mixture thereof. Specifically suitable solvent may be selected from methanol, acetone or mixture thereof.

After dissolution in step (a), optionally undissolved particles, if any, may be removed suitably by filtration, centrifugation, decantation, and any other known techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

Step (b) involves removing solvent from the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze -drying, filtration or any other technique known in the art.

Step (c) involves recovering amorphous solid dispersion comprising savolitinib and one or more pharmaceutically acceptable excipient. The said recovery can be achieved by using the processes known in the art.

The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Savolitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

When the active ingredient is hygroscopic or the formulation contains a hygroscopic ingredient, and to increase the stability of the amorphous form or a solid dispersion comprising Savolitinib, addition of other carriers such as syloid, methyl cellulose, colloidal silicon dioxide, Eudragit, amorphous silica, micro crystalline cellulose, and the like, in the formulation has been found to be of particular value. Therefore these ingredients may be combined during the preparation of solid dispersion or after the preparation of amorphous Savolitinib or solid dispersion to control hygroscopicity and to improve stability.

Nineteenth aspect of the present application provides a pharmaceutical composition comprising amorphous Savolitinib solid dispersion of the present invention and a pharmaceutically acceptable carrier.

Twentieth aspect of the present application relates to a crystalline form of savolitinib characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.4, 8.77 and 21.61 ± 0.2° 2Q. In embodiments, the present application provides a crystalline form of savolitinib characterized by its PXRD pattern having additional peaks located at about 10.87, 13.89 and 17.71 ± 0.2° 2Q.

Twenty first aspect of the present application relates to a crystalline form of savolitinib characterized by a PXRD pattern substantially as illustrated in Figure 1. Crystalline form of savolitinib of present invention may be formic acid solvate. The content of formic acid in the crystalline form of savolitinib of present invention may be in a range of about 6.0 to 14.0 % w/w. Specifically, formic acid content in the present crystalline form is about 10.68 % w/w. Twenty second aspect of the present application relates to a process for preparing crystalline form of savolitinib; the process comprising; a) mixing savolitinib with formic acid in presence of a suitable solvent; b) isolating crystalline form of savolitinib from the mixture of step a); and; c) optionally, drying the isolated product at suitable temperature.

In embodiments of step a), suitable solvent may include but not limited to, alcohols such as methanol, isopropanol and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran and the like; esters such as ethyl acetate, propyl acetate, ethyl formate and the like; water or mixture thereof. Preferably the suitable solvent may be an ether solvent. More preferably, the suitable solvent is methyl tertiary butyl ether (MTBE).

In one of the embodiments of step a), any physical form of savolitinib may be utilized, which may be crystalline or amorphous. In another embodiment of step a), any physical form of savolitinib may be utilized, which may be anhydrous or hydrate. In yet another embodiment, crystalline forms I, II, III and IV of savolitinib, as reported in the W0’198 application may be used in step a). In still yet another embodiment, crystalline forms A, B of savolitinib, as reported in the CN’906, CN’905 applications respectively may be used in step a).

In embodiments of step b) the isolation of crystalline form of savolitinib as obtained in step a) may be performed by any technique known in the art. Specifically, crystalline form of savolitinib may be isolated from the mixture of step a) by filtration.

In embodiments of step c) the resulting compound of step b) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the savolitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.

The crystalline form of savolitinib of the present application may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form of savolitinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

The crystalline form of savolitinib of the present application is stable and has excellent physico-chemical properties. The crystalline form of savolitinib of the present application may be easily formulated into a pharmaceutical composition comprising savolitinib.

Twenty third aspect of the present application relates to a pharmaceutical composition comprising crystalline form of savolitinib and one or more pharmaceutically acceptable excipient.

Twenty fifth aspect of the present application relates to crystalline form AA2 of savolitinib characterized by a PXRD pattern substantially as illustrated in Figure 1. Crystalline form AA2 of savolitinib of present invention may be a propionic acid solvate. The content of propionic acid in the crystalline form of savolitinib of present invention may be in a range of about 10.0 to 20.0 % w/w. Specifically, propionic acid content in the present crystalline form is about 16.6 % w/w. Twenty sixth aspect of the present application relates to a process for preparing a crystalline form of savolitinib; the process comprising ball milling a mixture of savolitinib and propionic acid.

Propionic acid may be used in the range of 0.01% - 50% (w/w) with respect to the amount of savolitinib. Specifically, propionic acid may be used in the range of 0.1% - 10% (w/w).

In one of the embodiments, any physical form of savolitinib may be utilized, which may be crystalline or amorphous. In another embodiment of step a), any physical form of savolitinib may be utilized, which may be anhydrous or hydrate. In yet another embodiment, crystalline forms I, II, III and IV of savolitinib, as reported in the W0’198 application may be used in step a). In still yet another embodiment, crystalline forms A, B of savolitinib, as reported in the CN’906, CN’905 applications respectively may be used.

In one of the embodiments, ball milling may be performed for a period of about 30 seconds to about 3 minutes. Specifically, the ball milling may be performed for a period of about 1 minute.

In one of the embodiments, the resulting compound, obtained by ball milling, may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 75°C, less than about 50°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the savolitinib is not degraded in its quality. The drying can be carried out for any desired time until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours. Specifically, the resulting compound, obtained by ball milling, may be dried in a vacuum drier for about 4 hours at about 20°C to about 40°C. The crystalline form AA2 of savolitinib of the present application may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of crystalline form of savolitinib. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.

Twenty seventh aspect of the present application relates to a pharmaceutical composition comprising crystalline form of savolitinib and one or more pharmaceutically acceptable excipient.

Yet another aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of savolitinib, crystalline form AA1 of savolitinib, formic acid solvate of savolitinib and crystalline form AA2 of savolitinib and one or more pharmaceutically acceptable excipient. Crystalline form AA1 of savolitinib with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

X-ray powder diffractograms of crystalline forms of savolitinib is recorded on PANalytical X-ray diffractometer, Model: panalytical empyrean. System description: CuK- Alpha 1 wavelength=l.5405980 A, voltage 45 kV, current 40 mA. The diffractograms were collected over a 2Q range of 3-40 °.

DEFINITION

The following definitions are used in connection with the present application unless the context indicates otherwise. The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

In general, a diffraction angle (2Q) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2Q±0.2^°) of 19.6 " means "having a diffraction peak at a diffraction angle (2Q) of 19.4^° to 19.8^°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

Example 1: Preparation of imidazo[l,2-a]pyridine-6-carboxylic acid (IX):

A mixture of chloroacetaldehyde dimethylacetal (247.3 mL), 1M hydrochloric acid (800 mL) and ethanol (150 mL) was heated to 100 °C and stirred for 1 hour at the same temperature. The reaction mass was then cooled to 25 °C and its pH adjusted to 6.5-7.0 with solid sodium bicarbonate (68 g). 6-Amino nicotinic acid (100 g) was added to the above reaction mass in a portion wise manner at 25-30 °C. The reaction mass was slowly heated to 85 °C and stirred for 24 hours at the same temperature. The reaction mass was cooled to 0 °C and its pH adjusted to ~6 with a saturated solution of sodium bicarbonate. The resulting precipitate was filtered and dried at 40 °C for 4 hours to afford the title compound.

Yield: 80.3 g

Example 2: Preparation of N-methoxy-N-methylimidazo[l,2-a]pyridine-6- carboxamide (VIII):

To a 0 °C pre-cooled solution of imidazo[l,2-a]pyridine-6-carboxylic acid (IX) (80 g) in dichloromethane (800 mL) was added oxalyl chloride (127.1 mL) and dimethylformamide (7 mL) under nitrogen atmosphere. The reaction mass was stirred for 30 minutes at 0 °C. The reaction mass was then slowly warmed to 25-35 °C and stirred for 4 hours at the same temperature. The reaction mass was completely evaporated under reduced pressure and the resulting residue was diluted with dichloromethane (1200 mL). Triethylamine (275 mL) and N, O-dimethyl hydroxylamine hydrochloride (67.37 g) were added to the above reaction mass at 0 °C under nitrogen atmosphere. The reaction mass was slowly warmed to 25-35 °C and stirred for 16 hours at the same temperature under nitrogen atmosphere. The reaction mass was diluted with water (500 mL) and dichloromethane (1 L). Organic layer was separated and aqueous layer was extracted with methanol-dichloromethane (1: 9, 2 x 100 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The product was purified by silica gel chromatography (methanol: dichloromethane = 1:9) to provide the title compound.

Yield: 68.0 g

Example 3: Preparation of l-(imidazo[l,2-a]pyridin-6-yl)ethan-l-one (VII):

To a solution of N-methoxy-N-methylimidazo[l,2-a]pyridine-6-carboxamide (VIII) (68.0 g) in anhydrous tetrahydrofuran (680 mL) was added methylmagnesium bromide (165 mL, 3 M in diethylether) at -30 °C under nitrogen atmosphere. The reaction mass was allowed to warm to -20 °C stirred for 3 hours at the same temperature. The reaction mass was then quenched with 10% aqueous citric acid solution at -20 °C. The reaction mass was allowed to warm to 25-35°C and stirred for 30 minutes at the same temperature. The precipitated solids were filtered and washed with ethyl acetate. Organic layer was separated and aqueous layer was extracted with ethyl acetate (3 X 500 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the solid material. The aqueous layer was adjusted its pH to ~7. The solid precipitated from the aqueous layer was filtered and dried under vacuum. The solids as obtained from both organic and aqueous layers were mixed with each other and suspended in methyl tert-b\xiy\ ether (200 mL). The resulting suspension was stirred for 1 hour, filtered and dried under vacuum to afford the title compound. Yield: 43.0 g Example 4: Preparation of (/?)-N-(l-(imidazo[l,2-a]pyridin-6-yl)ethylidene)-2- methylpropane-2-sulfinamide (Via):

To a solution of l-(imidazo[l,2-a]pyridin-6-yl)ethan-l-one (VII) (10 g) in toluene (200 mL) was added (i?)-/er/-butylsulfinamide (Xa) (11.35 g) and titanium(IV) ethoxide (32.96 mL) under nitrogen atmosphere at 25-35 °C. The temperature of the reaction mass was raised to 80-85 °C and stirred for 20 h at the same temperature. The reaction mass was then diluted with ethyl acetate (200 mL). Water (50 mL) was added to the above reaction mass in a drop wise manner at 25-35 °C and stirred for 15 minutes at the same temperature. The reaction mass was filtered and washed with ethyl acetate (300 mL). Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product, which was taken as such to the next step without any further purification. Yield: 14.2 g (crude)

Example 5: Preparation of (X)-N-(l-(imidazo[l,2-a]pyridin-6-yl)ethylidene)-2- methylpropane-2-sulfinamide (VIb):

To a solution of l-(imidazo[l,2-a]pyridin-6-yl)ethan-l-one (VII) (1.0 g) in toluene (20 mL) was added (S)-/er/-butylsulfinamide (Xb) (1.13 g) and titanium(IV) ethoxide (3.3 mL) under nitrogen atmosphere at 25-35 °C. The temperature of the reaction mass was raised to 85 °C and stirred for 20 h at the same temperature. The reaction mass was then diluted with ethyl acetate (20 mL). Water (5.0 mL) was added dropwise to the above reaction mass at 25-35 °C and stirred for 30 minutes at the same temperature. The reaction mass was filtered and washed with ethyl acetate (30 mL). Organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford crude product, which was taken as such to the next step without any further purification.

Example 6: Preparation of ((i?)-N-((X)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide (Va): (using (L)-selectride) To a solution of (i?)-N-(l-(imidazo[l,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (Via) (14.0 g) in anhydrous tetrahydrofuran (140 mL) was added (L)- selectride (106.0 mL, 1M in tetrahydrofuran) at -70 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at -60 °C to -50 °C. The reaction mass was allowed to warm to -20 °C. The reaction mass was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (2 x 500 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 1 : 39) to provide the title compound.

Yield: 7 3 g

Example 7: Preparation of ((i?)-N-((Y)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide (Va): (using (L)-selectride)

To a solution of (i?)-N-(l-(imidazo[l,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (Via) (285.0 g) in anhydrous tetrahydrofuran (2.85 L) was added (L)- selectride (1.62 L, 1M in tetrahydrofuran) at -70 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at -60 °C to -50 °C. The reaction mass was quenched with saturated ammonium chloride solution (1.425 L) at -50 °C. The reaction mass was allowed to warm to room temperature and stirred for 16 hours at the same temperature. The reaction mass was then extracted with ethyl acetate (2 x 1 L). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel (100-200 mesh) chromatography (methanol: dichloromethane = 1: 19) to provide the title compound.

Yield: 138 g

Diastereomeric ratio by HPLC: 98.78 % (i¾, 6 : L22 % (i¾, R )

Example 8: Preparation of ((i?)-N-((Y)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfmamide (Va): (using Sodium borohydride) To a solution of (i?)-N-(l-(imidazo[l,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (Via) (200 mg) in anhydrous tetrahydrofuran (2 mL) was added sodium borohydride (58 mg) at -78 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at the same temperature. The reaction mass was allowed to warm to 25-35 °C and stirred for 18 hours at the same temperature. The reaction mass was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product.

Yield: 180 mg (crude)

Diastereomeric ratio by HPLC: 23.13 % (i¾, S): 76.87 % (i¾, R )

Example 9: Preparation of ((i?)-N-((Y)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide (Va): (using DIBAL-H)

To a solution of (i?)-N-(l-(imidazo[l,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (Via) (300 mg) in anhydrous tetrahydrofuran (3 mL) was added DIBAL-H (2.30 mL, 1 M in hexane) at -78 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at the same temperature. The reaction mass was diluted with ethyl acetate (5 mL) and quenched with 10% aqueous sodium potassium tartrate solution (10 mL) at -78 °C. The reaction mass was then allowed to warm to 25-35 °C. The organic layer is separated and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 1: 19) to provide the title compound. Yield: 160 mg (crude)

Diastereomeric ratio by HPLC: 2.14 % (i¾, S ): 97.86 % (i¾, R )

Example 10: Preparation of ((/?)-N-((A)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfmamide (Va): (using BH3.DMS)

To a solution of (A)-N-( l -(imidazo[ 1 ,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (Via) (200 mg) in anhydrous tetrahydrofuran (2 mL) was added borane dimethylsulfide (BH₃.DMS) (0.15 mL, 10 M in dimethysulfide) at -78 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at the same temperature. The reaction mass was allowed to warm to 25-35 °C and stirred for 18 hours at the same temperature. The reaction mass was quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product.

Yield: 189 mg (crude)

Diastereomeric ratio by HPLC: 4.11 % (i¾, S): 95.89 % (i¾, R)

Example 11: Preparation of ((A)-N-((S)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide (Vb): (using DIBAL-H)

To a solution of (L')-N-(1 -(imidazof l ,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (VIb) (200 mg) in anhydrous tetrahydrofuran (2 mL) was added DIBAL-H (1.52 mL, 1 M in hexane) at -78 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at the same temperature. The reaction mass was quenched with 10% aqueous sodium potassium tartrate solution (5 mL) at -78 °C. The reaction mass was then allowed to warm to 25-35 °C and stirred for 30 minutes at the same temperature. The reaction mass was extracted with ethyl acetate (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 1: 19) to provide the title compound.

Yield: 185 mg

Diastereomeric ratio by HPLC: 94.66 % (Ss, S): 5.34 % (Ss, R )

Example 12: Preparation of ((A)-N-((S)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfmamide (Vb): (Using L-selectride)

To a solution of (L')-N-(1 -(imidazof l ,2-a]pyridin-6-yl)ethylidene)-2-methylpropane- 2-sulfinamide (VIb) (1.0 g) in anhydrous tetrahydrofuran (10 mL) was added L- selectride (7.6 mL, 1M in tetrahydrofuran) at -78 °C under nitrogen atmosphere. The reaction mass was stirred for 3 hours at the same temperature. The reaction mass was slowly quenched with saturated ammonium chloride solution (10 mL) followed by ethyl acetate (10 mL). The reaction mass was slowly warmed to 25-35 °C. The organic layer was separated and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (using 60-120 mesh) (methanol: dichloromethane = 1: 19) to provide the title compound. Yield: 510 mg

Diastereomenc ratio by HPLC: 0.72 % (S_s, S): 99.28 % (S_s, R)

Example 13: Preparation of (V)-l-(imidazo[l,2-a|pyridin-6-yl)ethan-l -amine dihydrochloride (IV):

To a solution of ((i?)-N-((S)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2-methylpropane-2- sulfinamide (Va) (7.0 g) in 1,4-dioxane (7 mL) was added 4M solution of hydrogen chloride in dioxane (70 mL) in a drop wise manner at 0 °C under nitrogen atmosphere and stirred for 1 hour at the same temperature. The reaction mass was allowed to warm to 25-35 °C and stir for 30 minutes at the same temperature. The reaction mass was evaporated under reduced pressure. The resulting solid was washed with methyl tert- butyl ether (2 x 20 mL), filtered and dried under vacuum to afford the title compound, which was taken as such to the next step without any further purification. Yield: 6.1 g (crude)

Example 14: Preparation of (V)-l-(imidazo[l,2-a|pyridin-6-yl)ethan-l -amine dihydrochloride (IV):

To a solution of ((S)-N-((S)-l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-2-methylpropane-2- sulfinamide (Vb) (100 mg) in 1,4-dioxane (2 mL) was added 4 M solution of hydrogen chloride in dioxane (2 mL) in a drop wise manner at 10 °C under nitrogen atmosphere. The reaction mass was slowly warmed to 25-35 °C and stirred for 3 hour at the same temperature. The precipitate obtained was separated from the supernatant liquid by decantation, was washed with methyl tert- butyl ether (2 x 5 mL), filtered and dried under vacuum to afford the title compound, which was taken as such to the next step without any further purification.

Yield: 75 mg (crude)

Example 15: Preparation of (A)-6-bromo-N-2-(l-(imidazo[l,2-a]pyridin-6- yl)ethyl)pyrazine-2, 3-diamine (III) :

To a solution of (L')-1 -(imidazo[ 1 ,2-a]pyridin-6-yl)ethan- 1 -amine dihydrochloride (IV) (6.0 g) in /V-methylpyrrolidone (18 mL) was added diisopropylethylamine (16.94 mL) and 2-amino-3,5-dibromopyrazine (8.42 g) at 25-35 °C under nitrogen atmosphere. The reaction mass was slowly heated to 130 °C and stirred for 48 hours at the same temperature under nitrogen atmosphere. The reaction mass was then cooled to 25-35 °C, diluted with water (20 mL) and extracted with ethyl acetate (200 mL). Organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 1 : 19) to provide the title compound.

Yield: 1.85 g

Example 16: Preparation of (Y)-6-bromo-l-(l-(imidazo[l,2-a]pyridin-6-yl)ethyl)- lH-[l,2,3]triazolo[4,5-b]pyrazine hydrochloride (II):

A solution of (5)-6-bromo-N-2-(l-(imidazo[l,2-a]pyridin-6-yl)ethyl)pyrazine-2,3- diamine (III) (1.0 g) in a mixture of acetic acid (2.0 mL) and water (3.0 mL) was cooled to 0-5 °C. Aqueous sodium nitrite solution (0.279 g in 2.5 mL water) was added to the above pre-cooled solution in a drop wise manner at 0-5 °C and stirred for 2 hours at the same temperature. The reaction mass was slowly warmed thereafter to 25-35 °C and stirred for 2 hours at the same temperature. The reaction mass was then diluted with 2-methyl tetrahydrofuran (20 mL). Organic layer was separated and aqueous layer was washed with ethyl acetate (50 mL). Combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was dissolved in 2- methyltetrahydrofuran (5 mL) and cooled to 0 °C. 4 M hydrochloric acid in dioxane (1 mL) was added to the pre cooled solution at 0 °C, which is then stirred for 1 hour at the same temperature. The reaction mass was concentrated under reduced pressure to provide hydrochloride salt. The resulting salt was further washed with methyl tert- butyl ether (2 x 10 mL) and dried under vacuum to afford the title compound, which was taken as such to the next step without any further purification Yield: 1.0 g

Example 17: Preparation of Savolitinib (I):

To a solution of (_<S -6-bromo-l-(l-(imidazo[l,2-a]pyridin-6-yl)ethyl)-lH- [l,2,3]triazolo[4,5-b]pyrazine hydrochloride (II) (1.0 g) in a mixture of 1,4-dioxane (20 mL) and water (50 mL) was added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (1.16 g) and cesium carbonate (3.42 g) at 25-35 °C under nitrogen atmosphere. The reaction mass was degassed with nitrogen for 30 minutes at 25-35 °C. To the degassed reaction mass was added Pd(dppf)Cl2 (0.19 g) at 25-35 °C. The reaction mass was again degassed with nitrogen for 30 minutes at 25-35 °C. The reaction mass was heated to 110 °C and stirred for 16 hours at the same temperature. The reaction mass was then filtered through a Celite bed, which was washed afterwards with ethyl acetate (2 x 20 mL). The combined filtrate and washings were washed with brine. Organic layer was separated and dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (methanol: dichloromethane = 1 : 19) to provide the title compound.

Yield: 0 35 g

Example 18: Preparation of crystalline form AA1 of savolitinib

Savolitinib (1 g) was suspended in ethyl formate (30 mL) at 25°C. The mixture was sonicated for about 90 minutes at the same temperature. The resulting reaction mixture was filtered and washed with heptane (40 mL) to obtain the title compound. PXRD pattern is shown in Figure 1. Examplel9: Preparation of amorphous solid dispersion of Savolitinib and Polyvinylpyrrolidone K-30 (PVP K-30)

Savolitinib (200 mg) and Polyvinylpyrrolidone K-30 (PVP K-30, 200 mg), were dissolved in methanol (100 mL) at 25°C. The mixture was sonicated for about 30 minutes at the same temperature to get a clear solution. The resulting clear solution was concentrated under reduced pressure at 50°C to obtain the title compound. PXRD pattern is shown in Figure 2.

Example 20: Preparation of amorphous solid dispersion of Savolitinib and Hydroxypropyl methyl cellulose Acetate Succinate (HPMC-AS)

Savolitinib (200 mg) and Hydroxypropyl methyl cellulose Acetate Succinate (HPMC-AS-LG, 200 mg), were dissolved in methanol (100 mL) at 25°C. The mixture was sonicated for about 30 minutes at the same temperature to get a clear solution. The resulting clear solution was concentrated under reduced pressure at 50°C to obtain the title compound. PXRD pattern is shown in Figure 3.

Example 21: Preparation of amorphous solid dispersion of Savolitinib and Hydroxypropyl methyl cellulose phthalate (HPMCP)

Savolitinib (200 mg) and Hydroxypropyl methyl cellulose phthalate (HPMCP, 200 mg), were dissolved in a mixture of methanol (70 mL) and acetone (30 mL) at 25°C. The mixture was sonicated for about 30 minutes at the same temperature to get a clear solution. The resulting clear solution was concentrated under reduced pressure at 50°C to obtain the title compound. PXRD pattern is shown in Figure 4.

Example 22: Preparation of crystalline form of savolitinib

Savolitinib (1 g) was mixed with formic acid (2 mL) in methyl tertiary butyl ether (MTBE) (20 mL) at 25°C. The mixture was stirred for about 28 hours at the same temperature. The resulting reaction mixture was filtered and dried under vacuum. The resulting solid was then dried in vacuum tray drier at about 50 °C for about 3 hours to obtain the title compound. PXRD pattern is shown in Figure 5. Example 23: Preparation of crystalline form AA2 of savolitinib

A mixture of savolitinib (500 mg) and propionic acid (0.5 mL) was ball milled for 60 minutes at 24°C. The resulting compound was collected and dried in a vacuum drier at 28°C for 3 hours and 45 minutes to obtain the title compound. PXRD pattern is shown in Figure 6.

Claims

WE CLAIM:

1. A process for preparation of compound of formula (Via) or compound of formula (VIb) comprising:

Reacting a compound of formula (VII) with (//)-/c/7-butylsulfinamide (Xa) to form compound of formula (Via)

Or reacting compound of formula (VII) with fS')-/t77-butylsulfinamide (Xb) to form compound of formula (VIb)

2. The process of claim 1, further comprises reacting a compound of formula (Via) or compound of formula (VIb) with a reducing agent to provide compound of formula (Va) or compound of formula (Vb), respectively

3. The process of claim 2, further comprises conversion of compound of formula (Va) or compound of formula (Vb) to form chiral amine fragment of formula (IV) or a salt thereof

4. The process of claim 2, wherein the reducing agent is selected from a group of L- selecteride, K-selectride, Na-selectride, lithiumtriethylborohydride_, sodium borohydride, lithium borohydride, diisobutylaluminium hydride (DIBAL-H), borane dimethylsulfide, borane tetrahydrofuran complex, borane pyridine complex, catecholborane, 9-borabicyclo[3.3.1]nonane (9-BBN), decaborane and Sodium bis(2- methoxyethoxy)aluminium hydride (Red-Al).

5. The process of claim 2, wherein the reducing agent is selected from a group of L- selecteride, K-selectride, Na-selectride, sodium borohydride, DIBAL-H and borane dimethylsulfide,

6. The process of claim 2, wherein the conversion of compound of formula (Va) or compound of formula (Vb) to form chiral amine fragment of formula (IV) or a salt thereof is carried out in acidic medium.

7. The process of claim 3, further comprises conversion of compound of formula (IV) or a salt thereof to savolitinib.

8. A compound of formula (Va) or formula (Vb)

(Va) (Vb)

9. A compound of formula (Via) or formula (

(Via)

10. Use of compounds of formula (Va), (Vb), (Via) or (VIb) as intermediates for preparation of savolitinib.