DESC:FIELD OF THE INVENTION
The present invention relates to process for the preparation of Ripretinib and intermediates thereof. The present invention also relates to solid state forms of Ripretinib and process for the preparation thereof.

BACKGROUND OF THE INVENTION
Ripretinib is the adopted name for a drug chemically described as 1-(4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluoro-phenyl)-3-phenylurea and is represented by structural Formula I.

Formula I
Ripretinib is a kinase inhibitor and is marketed in USA under the brand name as QINLOCK ® tablets in 50 mg strength for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.
U.S. patent no. 8,461,179 discloses general procedure for the preparation of Ripretinib.
PCT publication no. WO2020185812A1 discloses solid state forms of Ripretinib, processes for preparation thereof.
PCT publication no WO2021138483A1 discloses amorphous solid dispersion of Ripretinib with HPMC-AS.
Polymorphism is an important aspect of pharmaceutical drug in terms of its solubility and bioavailability. One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. Different crystalline forms of polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The different solubility of the drug compound affects the bioavailability of drug at target site.
The prior art process for the preparation of Ripretinib have major drawbacks such as difficulties with respect to removal of process related impurities; poor commercial viability due to use of hazardous reactants; use of column chromatography and/ or low yields and purity of intermediates and final product. Therefore, there remains a need to develop such a process, which overcomes one or more of the above drawbacks associates with prior art process for preparation of Ripretinib.
To improve the physicochemical properties of the Ripretinib compound and there remains a need for alternate solid forms of Ripretinib and their preparative processes.
The inventors of present invention have found out an improved process for the preparation of Ripretinib and intermediates thereof and solid state forms thereof.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods, and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula II’ with a compound of Formula III’ in presence of a base to obtain Ripretinib of formula I.

wherein P1 and P2 are each independently selected from group consisting of hydrogen and a suitable protecting group and X is selected from group consisting of: halogen, C1-C6 alkoxy, C6-C10 aryloxy or a 5-membered heteroaryl containing at least one nitrogen directly bonded to the C-O of the compound of formula III’, each optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, OH, C1-C6 alkoxy, and NR1R2, wherein R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl.
In another embodiment, the present invention provides a process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula II with a compound of Formula III in presence of a base to obtain Ripretinib of Formula I.

In another embodiment, the present invention provides a process for the preparation of Ripretinib intermediate of Formula IV, comprising reacting a compound of Formula V with a compound of Formula VI in presence of a base to obtain Ripretinib intermediate of Formula IV.

In another embodiment, the present invention provides a process for the preparation of Ripretinib intermediate of Formula VII, comprising treating a compound of Formula VIII with a reducing agent to obtain Ripretinib intermediate of Formula VII.


In one embodiment, the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 13.3°, 14.2°, 15.9°, 19.1°, 19.5°, 19.9°, 23.0°, 23.4°, 25.2°, 25.6°, 27.6°, 28.7° and 32.1° ± 0.2° 2?.
In another embodiment, the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 1.
In another embodiment, the present invention provides a crystalline form R1 of Ripretinib characterized by TGDTA graph as depicted in Figure 2.
In another embodiment, the present invention provides a process for the preparation of crystalline form R1 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) isolating crystalline form R1 of Ripretinib.

In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form R1 of Ripretinib and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustration of a PXRD pattern of crystalline form R1 of Ripretinib.
Figure 2 is an illustration of TGDTA graph of crystalline form R1 of Ripretinib

DETAILED DESCRIPTION OF THE INVENTION
While the specification concludes with the claims particularly pointing and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25oC and normal pressure unless otherwise designated. All temperatures are in Degrees Celsius unless specified otherwise. The present invention can comprise (open ended) of the components of the present invention as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalent 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 unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. 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.
The starting materials used in this aspect, ethyl 4,6-dichloronicotinate and ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (herein referred as compound of Formula V), may be obtained according to any method known in the art or may be procured from the commercially available sources.
In one embodiment, the present invention provides a process for the preparation of Ripretinib of Formula I,

Formula I
comprising:
reacting a compound of Formula II’,

Formula II’
with a compound of formula III’

Formula III’
in presence of a base to obtain Ripretinib of formula I;
wherein P1 and P2 are each independently selected from group consisting of hydrogen and a suitable protecting group and X is selected from group consisting of: halogen, C1-C6 alkoxy, C6-C10 aryloxy or a 5-membered heteroaryl containing at least one nitrogen directly bonded to the C-O of the compound of formula III’, each optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, halogen, CN, OH, C1-C6 alkoxy, and NR1R2, wherein R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl. In a preferred embodiment X is phenoxy.
The suitable protecting group may be selected from the group consisting of acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, phenylacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as phenylsulfonyl, benzenesulfonyl, 4-nitrobenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyl-oxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy-benzyloxycarbonyl, 2,4-dimethoxy-benzyloxycarbonyl, 4-methoxybenzyl-oxycarbonyl, 2-nitro-4,5-dimethoxy-benzyloxycarbonyl, 3,4,5-trimethoxybenzyl-oxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-di-methoxybenzyloxycarbonyl, benz-hydryloxycarbonyl, t-butyloxycarbonyl, di-isopropylmethoxycarbonyl, isopropyl-oxycarbonyl, ethoxycarbonyl, methoxy-carbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyl-oxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl (trityl), p-methoxyphenyl-diphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl or the like. Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999).
In another embodiment, the present invention provides a process for the preparation of Ripretinib of Formula I,

Formula I
comprising:
reacting a compound of Formula II

Formula II
with a compound of formula III

Formula III
in presence of a base to obtain Ripretinib of formula I.
The reaction may be carried out in the presence of suitable organic solvent. In a preferred embodiment the reaction is carried out in the presence of tetrahydrofuran.
The reaction may be carried out in the presence of a suitable base. In a preferred embodiment the reaction is carried out in the presence of 1-methylpyrrolidine.
The compound of formula III can be prepared by reaction of aniline with phenyl chloroformate in presence of a base and an organic solvent. In a preferred embodiment the compound of formula III can be prepared by reaction of aniline with phenyl chloroformate in presence of potassium carbonate and tetrahydrofuran.
In another embodiment, the present invention provides a process for the preparation of Ripretinib intermediate of Formula IV,

Formula IV
comprising:
reacting a compound of Formula V

Formula V
with a compound of Formula VI

Formula VI
in presence of a base to obtain Ripretinib intermediate of Formula IV.
The reaction may be carried out in the presence of a suitable base. In a preferred embodiment the reaction is carried out in the presence of lithium hydroxide or lithium hydroxide on alumina.
In another embodiment, the present invention relates to use of Ripretinib intermediate of Formula IV prepared according to the methods disclosed herein in the preparation of Ripretinib.

In another embodiment, the present invention provides a process for the preparation of Ripretinib intermediate of Formula VII,

Formula VII
comprising:
treating a compound of Formula VIII

Formula VIII
with a reducing agent to obtain Ripretinib intermediate of Formula VII.
The reaction may be carried out in the presence of a suitable reducing agent.
The reducing agents may be selected from the group consisting of that can potentially be employed for this transformation are: lithium aluminium hydride (LiAlH4), lithium tri-tert-butoxyaluminum hydride (LiAlH(Ot-Bu)3) diisobutylaluminium hydride (DIBAL-H), Lithium borohydride (LiBH4); Lithium triethylborohydride (LiBHEt3); Magnesium borohydride [Mg(BH4)2]; Aluminum borohydride [Al(BH4)3]; Calcium borohydride [Ca(BH4)2]; Sodium in ethanol (Bouveault–Blanc reduction); Sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al); Lithium tri-tert-butoxyaluminum hydride (LiAlH[OC(CH3)3]3); calcium alkoxyaluminium hydride (CALH) or the like. In a preferred embodiment the reaction is carried out in the presence of diisobutylaluminium hydride (DIBAL-H).
In another embodiment, the present invention relates to use of Ripretinib intermediate of Formula VII prepared according to the methods disclosed herein in the preparation of Ripretinib.
In another aspect the present invention provides Ripretinib, obtained according the processes of above aspects.
In another aspect the present invention provides a pharmaceutical composition comprising Ripretinib, obtained according the processes of above aspects and at least one pharmaceutically acceptable excipient.
In one embodiment, the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 13.3°, 14.2°, 15.9°, 19.1°, 19.5°, 19.9°, 23.0°, 23.4°, 25.2°, 25.6°, 27.6°, 28.7° and 32.1° ± 0.2° 2?.
In another embodiment, the crystalline form R1 of Ripretinib may be further characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 11.4°, 12.3°, 13.3°, 13.7°, 14.2°, 14.7°, 15.4°, 15.9°, 16.5°, 17.2°, 18.0°, 19.1°, 19.5°, 19.9°, 20.2°, 22.0°, 22.2°, 23.0°, 23.4°, 24.0°, 24.3°, 25.2°, 25.6°, 26.2°, 26.7°, 27.6°, 28.7°, 29.1°, 30.6°, 32.1°, 33.1°, 34.0°, 35.8°, 36.9° and 38.6° ± 0.2° 2?.
In another embodiment, the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 1.
In another embodiment, the present invention provides a crystalline form R1 of Ripretinib characterized by TGDTA graph as depicted in Figure 2.
In another embodiment, the present invention provides a process for the preparation of crystalline form R1 of Ripretinib, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) isolating crystalline form R1 of Ripretinib.
In a preferred embodiment the suitable organic solvent or anti-solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), dimethylacetamide (DMA), methanol, ethanol, isopropyl alcohol, water or mixtures thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form R1 of Ripretinib and at least one pharmaceutically acceptable excipient.
In another embodiment, the crystalline form R1 of Ripretinib of the present invention is stable under thermal, humid and stress conditions. Further, the crystalline form R1 of Ripretinib of the present invention exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Ripretinib.
In another embodiment, the crystalline form R1 of Ripretinib of the present invention or the pharmaceutical compositions thereof, comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
The suitable ‘organic solvent’ or "solvent" or “anti-solvent” at any stage of the process of the present invention may be selected from the group consisting of alcohols, such as methanol, ethanol, 2-propanol, n- propanol, n-butanol, isoamyl alcohol, octanol, 1,2-propanediol, S-(+)-1,2-propanediol and ethylene glycol; ethers, such as diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate and t-butyl acetate; ketones, such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; nitriles, such as acetonitrile; hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclohexane and tetraline; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone, dimethylsulfoxide, pyridine, phenol, DMA, carbon disulphide, acetic acid and the like; water; or mixtures thereof.
The suitable base at any stage of the process of the present invention may be selected from alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like; alkali metal fluorides, such as, for example, sodium fluoride, potassium fluoride, cesium fluoride or the like; metal alkoxides, such as, for example, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or the like; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) or the like; metal hydroxides such as lithium hydroxide, lithium hydroxide on alumina, sodium hydroxide, calcium hydroxide, barium hydroxide or the like; other organic base such as triethylamine, 1-methylpyrrolidine, N,N-diisopropylethylamine, or the like.
Suitable temperatures for the reaction at any stage of the process of the present invention may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures.
Suitable times for the hydrogenation step at any stage of the process of the present invention may be from about 30 minutes to about 10 hours, or longer.
The removal of solvent at any stage of the process of the present invention may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present invention may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques. The reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
In an embodiment, Ripretinib of present invention has average particle size of particles between 1 to 100 µm, less than 90 µm, less than 80 µm, less than 60 µm, less than 50 µm, less than 40 µm, less than 30 µm, less than 20 µm, less than 10 µm, less than 5 µm or any other suitable particle sizes. In another embodiment, Ripretinib of present invention may have particle size distribution: D10 of particles smaller than 20 µm, smaller than 15 µm, smaller than 10 µm, or smaller than 5 µm; D50 of particles smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm; D90 of particles smaller than 200 µm, smaller than 175 µm, smaller than 150 µm, smaller than 140 µm, smaller than 130 µm, smaller than 120 µm, smaller than 110 µm, smaller than 100 µm, smaller than 90 µm, smaller than 80 µm, smaller than 70 µm, smaller than 60 µm, smaller than 50 µm, smaller than 40 µm, smaller than 30 µm, smaller than 20 µm, smaller than 10 µm.
Particle size distributions of Ripretinib particles may be measured using any techniques known in the art. For example, particle size distributions of Ripretinib particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom. As referred herein, the term “D10” in the context of the present invention is 10% of the particles by volume are smaller than the D10 value and 90% particles by volume are larger than the D10 value. “D50” in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value. “D90” in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.
In an embodiment, Ripretinib of present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
In another embodiment, the present invention provides pharmaceutical compositions comprising Ripretinib prepared according to method disclosed herein alone or in combination with other drugs. Further the present invention provides a process of preparing a pharmaceutical composition comprising alone or in combination with other drugs. Conveniently various pharmaceutically acceptable excipients can be employed in a process according to the present invention.
In another embodiment, at least one pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present invention. A thorough discussion of pharmaceutically acceptable excipients is presented in Remington's Pharmaceutical Sciences (17th ed., Mack Publishing Company) and Remington: The Science and Practice of Pharmacy (21st ed., Lippincott Williams & Wilkins), which are hereby incorporated by reference.
The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray diffraction was measured using Rigaku Desktop X-ray diffractometer, Model: MiniFlex600. System description: CuK-Alpha 1 wavelength= 1.54060, voltage 40 kV, current 15 mA, divergence slit = 1.25°; Sample stage=Reflection. Scan type: Continuous; Detector – Scintillator NaI (T1); Measurement parameters: Start Position [°2Th.]: 3; End Position [°2Th.]: 40; Step Size [°2Th.]: 0.02; Scan Speed [°/min]: 1
Thermogravimetry-differential thermal analysis (TG-DTA) was performed on a Rigaku Thermo plus EVO2 TG-DTA8122 instrument. The measurement was carried out under a dry nitrogen stream (a flow rate of 320 mL/min) and a normal pressure at a temperature rising rate of 10 °C/min.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2o. 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 ± 0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.2o) of 7.9o" means "having a diffraction peak at a diffraction angle (2?) of 7.7o to 8.1o”. 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. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD 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. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2 degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).
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 application in any manner.
Examples

Example 1: Preparation of Ethyl 6-chloro-4-(ethylamino)nicotinate (Formula VIII):

Formula VIII
Ethyl 4,6-dichloronicotinate (10 g) and acetonitrile (80mL) were charged into a reactor at 25-35 °C under nitrogen atmosphere. Ethylamine 70% in water solution (11 g) was added to the reactor at 25-35 °C and the reaction mixture was stirred for 22-24 h at 25-35 °C. After completion of the reaction the reaction mass was concentrated under reduced pressure below 50 °C. Water (40 mL) was charged into the obtained residue and the reaction mixture was stirred for 30-40 min at room temperature. The solid was filtered and washed with water (10 mL). The solid was dried under reduced pressure at room temperature. 10% ethyl acetate in hexane (40 mL) was charged into the dried solid and the reaction mixture was stirred for 20-30 minute for at 5-10 °C. The reaction mass was filtered and the solid was dried under reduced pressure at 40 °C for 1 h to obtain the title compound of Formula VIII. [Purity by HPLC analysis 99.0%; Yield: 90.6%].

Example 2: Preparation of (6-chloro-4-(ethylamino)pyridin-3-yl)methanol (Formula VII):

Formula VII
Ethyl 6-chloro-4-(ethylamino)nicotinate (Formula VIII, 4.5 g) and dichloromethane (110 mL) were charged into a reactor at -55°C to -45°C under nitrogen atmosphere. Diisobutylaluminium hydride (DIBAL-H) in toluene (39 mL, 1.5M in toluene) was gradually added to the reactor at -50°C to -25°C and the reaction mixture was stirred for 1-2 h at -50°C to -40°C. After completion of the reaction, the reaction mass was allowed to warm to -10°C to -5°C. 10% aq. sodium potassium tartrate solution (45 mL) was added drop wise to the reaction mixture below 30 °C and the reaction mixture was stirred for 30-40 min at 25°C to 30°C. The reaction mass was filtered and residue was washed with dichloromethane (130 mL). The layers were separated and the organic layer was washed with brine (45 mL) and dried over with sodium sulfate. The Concentrate the organic layer under reduced pressure at 45-50 °C to obtain solid. Hexane (15 mL) was charged into solid at room temperature and the reaction mixture was stirred for 20-30 min. The solid was filtered and dried in a hot air oven at 25-30 °C for 2-3 h to obtain to obtain the title compound of Formula VII. [Purity by HPLC analysis 97.2%; Yield: 85.8%].

Example 3: Preparation of 6-chloro-4-(ethylamino)nicotinaldehyde (Formula VI):

Formula VI
6-chloro-4-(ethylamino)pyridin-3-yl)methanol (Formula VII, 10 g) and 1,2-dichloroethane (150 mL) were charged into a reactor at room temperature. The reaction mixture was stirred for 10-20 minute. Activated manganese dioxide (23 g) was charged into the reaction mixture and the reaction mass was stirred at room temperature. The reaction mass was heated to reflux at 80-90°C. After completion of the reaction, the reaction mass was filtered and the residue was washed with 1,2-dichloroethane (30 mL). The filtrate was concentrated under reduced pressure at 45-50°C to obtain residue. Hexane (70 mL) was charged into residue at 5-10 °C and stir for 30-40 min. The reaction mixture was filtered and the solid was dried at 40-50°C for 1-2 h to obtain the title compound of Formula VI. [Purity by HPLC analysis 99.8%; Yield: 84.9%].

Example 4: Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (Formula IV):

Formula IV
Ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (Formula V, 11 g) and N, N-dimethylacetamide (110 mL) were charged into the reactor under nitrogen atmosphere at 25-35 °C. 6-chloro-4-(ethylamino)nicotinaldehyde (Formula VI, 7.3 g) was charged into the reaction mixture at 25-35 °C. 40% KF/Al2O3 (29 g) in to the reaction at 25-35 °C and the reaction mixture was stirred for 1-2 h at 25-35 °C. After completion of the reaction the reaction mass was filtered and the residue was washed with ethyl acetate (165 mL). Saturated sodium bicarbonate solution (110 mL) was charged into the above filtrate and the reaction mixture was stirred for 20-30 min. Layers were separated and the organic layer was washed with 5% aqueous lithium chloride solution (2 X 110 mL). The layers were separated and the combined aqueous layers were extracted with dichloromethane (2 X 110 mL). The layers were separated and the combined organic layer was washed with brine (110 mL) and the organic layer was stirred with activated charcoal (1 g) at room temperature. The reaction mixture was filtered and the residue was washed with ethyl acetate (33 mL). The filtrate was dried over sodium sulfate and concentrated below 60°C to obtain residue. Water (66 mL) was charged into the residue at 25-35°C and the reaction mixture was stirred for 30-40 min. The reaction mixture was filtered and the solid was dried in hot air oven at 45 °C for 15-20 h to obtain the title compound of Formula IV. [Purity by HPLC analysis 89.9%; Yield: 79.1%].

Example 5: Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (Formula IV):

Formula IV
Ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (Formula V, 1 g) and N, N-dimethylacetamide (10 mL) were charged into the reactor under nitrogen atmosphere at room temperature. 40% LiOH/Al2O3 (1.5 g) was charged in to the reaction mixture at 25-35°C. 6-chloro-4-(ethylamino)nicotinaldehyde (Formula VI, 0.6 g) was charged into the reaction mixture at 25-35 °C and the reaction mixture was stirred for 1-2 h at 25-35 °C. After completion of the reaction the reaction mass was filtered and the residue was washed with ethyl acetate (15 mL). The filtrate was washed with water (10 mL) and layers were separated. The aqueous layer was extracted with ethyl acetate (15 mL). The layers were separated and the combined organic layer was washed with water (10 mL), followed by brine (15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 40-45°C to obtain residue. IPA (5 mL) was charged into the residue at 25-35°C and the reaction mixture was stirred for 10-20 min. The reaction mixture was filtered and the solid was washed with hexane (10 mL). The solid was dried in hot air oven at 45 °C for 4-5 h to obtain the title compound of Formula IV. [Purity by HPLC analysis 96.9%; Yield: 41.9%].

Example 6: Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (Formula IV):

Formula IV
Ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (Formula V, 10 g) and N, N-dimethylacetamide (80 mL) were charged into the reactor under nitrogen atmosphere at room temperature. 6-chloro-4-(ethylamino)nicotinaldehyde (Formula VI, 6.6 g) was charged into the reaction mixture at room temperature. Lithium hydroxide monohydrate (2.2 g) in to the reaction at 25-35 °C and the reaction mixture was stirred for 1-2 h at room temperature. After completion of the reaction, water (240 mL) was charged into the reaction mixture and the reaction mixture was stirred for 1-2h at 25-35 °C. The reaction mixture was filtered and the residue was washed with water (100 mL). Methanol (50 mL) was charged into the wet solid and the reaction mixture was stirred for 10-20 min for at 25-35 °C. The solid was filtered and washed with Methanol (25 mL). The solid was dried in hot air oven at 45 °C for 6-8 h to obtain the title compound of Formula IV. [Purity by HPLC analysis 96.3%; Yield: 83.6%].

Example 7: Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (Formula II):

Formula II
3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-1-ethyl-1,6-naphthyridin-2(1H)-one (Formula IV, 11 g) was charged into autoclave followed by 1,4-dioxane (110 mL), followed by 40% methylamine in water (165 mL). The reaction mass was heated at 100°C for 15-17 h. After completion of reaction the reaction mass was cooled to 25-35°C. The reaction mass was unloaded and the reactor was washed with ethyl acetate (55 mL). Brine (110 mL) was charged into reaction mixture. Ethyl acetate (110 mL) was charged into the reaction mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 X 110 mL) and the layers were separated. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (110 mL) and the layers were separated. The organic layer was washed with activated charcoal (1 g) at 25-35 °C for 15-20 min. The reaction mixture was filtered and ethyl acetate (33 mL) was added. The filtrate was dried over sodium sulfate and concentrated under reduced pressure at 45-50 °C to obtain residue. Water (55 mL) was charged into the residue at 25-35 °C and the reaction mixture was stirred for 20-30 min and filtered. The solid was washed with water (22 mL) and dried in hot air oven at 35-45 °C for 14-16 h to obtain residue which was purified by column chromatography to obtain the solid compound. The solid was further purified by trituration with 50% ethyl acetate in hexane (20 mL) at 25-35 °C. The solid was filtered and dried in hot air oven at 35-45 °C for 4-6 h to obtain the title compound of Formula II. [Purity by HPLC analysis 94.6%; Yield: 70.9%].

Example 8: Preparation of Ripretinib (Formula I).

Formula I
3-(5-amino-2-bromo-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (Formula II, 7.5 g) was charged into reactor. Tetrahydrofuran (150 mL) was charged followed by 1-methylpyrrolidine (6.5 g) at 25-35° C. Phenyl phenylcarbamate (Formula III, 16.3 g) at 25-35° C. The reaction mixture was refluxed for 15-17 h. After completion of the reaction, the reaction mixture was cooled to 25-35°C and stirred for 30 min. The solid was filtered and washed with tetrahydrofuran (15 mL). The solid was dried at 25-35°C for 1-2 h under suction. The solid was unloaded and dried at room temperature for 1-2 h to obtain Ripretinib (Formula I). [Purity by HPLC analysis 88.9%; Yield: 75.3%].

Example 9: Preparation of crystalline form R1 of Ripretinib.

Formula I
Ripretinib (Formula I, 7.3 g) was charged into reactor. DMF (29 mL) was charged at room temperature and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (21 mL). The solid was charged into reactor and DMF (20 mL) was added and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (20 mL). The solid was charged into reactor and water (24 mL) was added at 25-35°C and the reaction mass was stirred for 30-40 min. The solid was filtered under suction and the solid was washed with water (6 mL). The solid was dried under vacuum at 45-50° C for 1-2 h to obtain crystalline form R1 of Ripretinib (Formula I). [Purity by HPLC analysis 99.2%; Yield: 56.5%; water content (KF): 1.7%; Methanol content (GC): 36 ppm; DMF content (GC): 217 ppm].

Example 10: Preparation of crystalline form R1 of Ripretinib.

Formula I
Ripretinib (Formula I, 7.3 g) was charged into reactor. DMF (29 mL) was charged at room temperature and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (21 mL). The solid was charged into reactor and water (24 mL) was added at 25-35°C and the reaction mass was stirred for 30-40 min. The solid was filtered under suction and the solid was washed with water (6 mL). The solid was dried under vacuum at 45-50° C for 1-2 h to obtain crystalline form R1 of Ripretinib (Formula I). [Purity by HPLC analysis 99.5%].
,CLAIMS:WE CLAIM:

1) A process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula II’ with a compound of Formula III’ in presence of a base to obtain Ripretinib of Formula I.

wherein P1 and P2 are each independently selected from group consisting of hydrogen and a suitable protecting group and X is selected from group consisting of halogen, C1-C6 alkoxy, C6-C10 aryloxy or a 5-membered heteroaryl containing at least one nitrogen directly bonded to the C-O of the compound of formula III’, each optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 halo alkyl, halogen, CN, OH, C1-C6 alkoxy, and NR1R2, wherein R1 and R2 are each independently selected from hydrogen and C1-C6 alkyl.

2) The process of claim 1, wherein X is phenoxy.

3) The process of claim 1, wherein both P1 and P2 are each independently hydrogen.

4) The process of claim 1, wherein the base is selected from 1-methylpyrrolidine, triethylamine, N,N-diisopropylethylamine.

5) The process of claim 1, wherein the base is 1-methylpyrrolidine.

6) A crystalline form R1 of Ripretinib, characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 13.3°, 14.2°, 15.9°, 19.1°, 19.5°, 19.9°, 23.0°, 23.4°, 25.2°, 25.6°, 27.6°, 28.7° and 32.1° ± 0.2° 2?.

7) The crystalline form of claim 6, further characterized by X-ray diffraction pattern having characteristic peaks at about In another embodiment, the crystalline form R1 of Ripretinib may be further characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 11.4°, 12.3°, 13.3°, 13.7°, 14.2°, 14.7°, 15.4°, 15.9°, 16.5°, 17.2°, 18.0°, 19.1°, 19.5°, 19.9°, 20.2°, 22.0°, 22.2°, 23.0°, 23.4°, 24.0°, 24.3°, 25.2°, 25.6°, 26.2°, 26.7°, 27.6°, 28.7°, 29.1°, 30.6°, 32.1°, 33.1°, 34.0°, 35.8°, 36.9° and 38.6° ± 0.2° 2?.

8) A process for the preparation of crystalline form R1 of Ripretinib, as claimed in claim 6, comprising steps of:
i) providing Ripretinib in one or more suitable organic solvents;
ii) isolating crystalline form R1 of Ripretinib.

9) The process of claim 8, wherein the suitable organic solvent is selected from the group consisting of N,N-dimethylformamide (DMF), dimethylacetamide (DMA), methanol, ethanol, isopropyl alcohol, water and mixtures thereof.

10) The process of claim 9, wherein the suitable organic solvent is DMF.