DESC:ROCILETINIB SALTS

FIELD OF THE INVENTION
The present application relates to novel salts of Rociletinib, crystalline forms thereof, and a pharmaceutical composition comprising novel salts of Rociletinib or said crystalline forms thereof; and methods of preparing said Rociletinib salts or said crystalline forms thereof and said pharmaceutical composition.

BACKGROUND OF THE INVENTION
The compound, N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)- 5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide, known as Rociletinib, having the following structure:

Rociletinib is a novel, oral, targeted covalent (irreversible) mutant-selective inhibitor of the cancer-causing mutant forms of epidermal growth factor receptor (EGFR) currently under review with the U.S. and E.U. regulatory authorities for the treatment of advanced non-small cell lung cancer (NSCLC) in patients with activating EGFR mutations, as well as the dominant resistance mutation T790M. Rociletinib is designed to selectively target both the initial activating EGFR mutations and the dominant acquired T790M resistance mutation.
Heterocyclic pyrimidine compounds, such as Rociletinib, administration of the compounds and pharmaceutical compositions containing them are described in WO2012061299A1.
WO2013138502A1 describes various salts of Rociletinib such as benzenesulfonic acid, camphorsulfonic acid, 1,2-ehanedisulfonic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, 1,5-naphthalenedisulfonic acid, oxalic acid, 4-toluenesulfonic acid and 2,4,6-trihydroxybenzoic acid. The WO2013138502A1 also describes various polymorphic forms of Rociletinib hydrobromide and Rociletinib benzenesulfonate salts.
Discovering new salts, solvates and new polymorphic forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates 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 salts of Rociletinib and their polymorphic forms.

SUMMARY OF THE INVENTION
The present application generally provides new salts of Rociletinib, polymorphic forms of the salts and compositions thereof.
In the first embodiment, the present application provides Rociletinib trifluoroacetate, Rociletinib hydrogensulfate, Rociletinib perchlorate, Rociletinib isethionate, and Rociletinib phosphate.
In the second embodiment, the present application provides polymorphic forms Rociletinib trifluoroacetate, Rociletinib hydrogensulfate, Rociletinib perchlorate, Rociletinib isethionate, and Rociletinib phosphate.
In the third embodiment, the present application provides processes for preparation of Rociletinib trifluoroacetate, Rociletinib hydrogensulfate, Rociletinib perchlorate, Rociletinib isethionate, and Rociletinib phosphate.
In the fourth embodiment, the present application provides use of the rociletinib salts of the present application in the preparation of Rociletinib hydrobromide.
In the fifth embodiment, the present application provides a process for salt transformation comprising:
(a) providing a solution or a suspension of Rociletinib salt other than hydrobromide salt;
(b) adding hydrobromic acid to the solution or suspension of step (a); and
(c) isolating Rociletinib hydrobromide salt.
In the sixth embodiment, the present application provides pharmaceutical composition comprising any of the Rociletinib salts of the present application and a pharmaceutically acceptable excipient.
In the seventh embodiment, the present application provides pharmaceutical composition comprising Rociletinib hydrobromide prepared by the processes of the present application and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction pattern of Rociletinib trifluoroacetate prepared according to Example 1.
Figure 2 is 1H-NMR spectrum of Rociletinib trifluoroacetate prepared according to Example 1.
Figure 3 is powder X-ray diffraction pattern of Rociletinib hydrogensulfate prepared according to Example 2.
Figure 4 is 1H-NMR spectrum of Rociletinib hydrogensulfate prepared according to Example 2.
Figure 5 is powder X-ray diffraction pattern of Rociletinib perchlorate prepared according to Example 3.
Figure 6 is 1H-NMR spectrum of Rociletinib perchlorate prepared according to Example 3.
Figure 7 is powder X-ray diffraction pattern of Rociletinib isethionate prepared according to Example 4.
Figure 8 is 1H-NMR spectrum of Rociletinib isethionate prepared according to Example 4.
Figure 9 is powder X-ray diffraction pattern of Rociletinib phosphate prepared according to Example 5.
Figure 10 is 1H-NMR spectrum of Rociletinib phosphate prepared according to Example 5.
Figure 11 is powder X-ray diffraction pattern of Rociletinib hydrobromide prepared according to Example 7.

DETAILED DESCRIPTION
The present application provides new salts of Rociletinib and their polymorphic forms that have advantageous properties over other salts of Rociletinib or their polymorphic forms, selected from at least one of: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as thermal and mechanical stability to polymorphic conversion, stability to dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.
It is therefore an object of the present invention to provide new salts of Rociletinib and polymorphic forms thereof. Furthermore, pharmaceutical compositions comprising these novel salts, which do not encounter the above problems, are presented
In the first embodiment, the present application provides Rociletinib salts such Rociletinib trifluoroacetate, Rociletinib hydrogensulfate, Rociletinib perchlorate, Rociletinib isethionate, and Rociletinib phosphate.
In another embodiment of the application, generally the acid compound to Rociletinib free base ratio in the salt is from 1:3 to 3:1, preferably the ratio is from 1:2 to 2:1, more preferably from 1:1.5 to 1.5: 1.
In an alternative embodiment, the application relates to the hydrate and/or solvate forms of Rociletinib salts of the present invention. The salts according to the invention, their hydrates and/or solvates generally exhibit the improved properties.
The invention also relates to the polymorphic forms of the Rociletinib salts. Depending on the respective salt, the polymorphic forms show different properties, e.g., with regard to flowability and storage stability.
In alternative embodiment, the salts of the invention are formed in an amorphous form.
In one embodiment, the Rociletinib salt is Rociletinib trifluoroacetate salt. The salt can be a mono trifluoroacetate or a bis- trifluoroacetate. A trifluoroacetate salt is optionally solvated or hydrated, such as a monohydrated.
According to one embodiment, a trifluoroacetate salt has a powder X-ray diffraction pattern substantially similar to that depicted in Figure 1. According to another embodiment, a trifluoroacetate salt has a 1H-NMR spectrum substantially similar to that depicted in Figure 2.
In another embodiment, the Rociletinib salt is Rociletinib hydrogensulfate (bisulfate) salt. A bisulfate salt is optionally solvated or hydrated.
According to one embodiment, a bisulfate salt has a powder X-ray diffraction pattern substantially similar to that depicted in Figure 3. According to another embodiment, a bisulfate salt has a 1H-NMR spectrum substantially similar to that depicted in Figure 4.
In another embodiment, the Rociletinib salt is Rociletinib perchlorate salt. The salt can be a mono-perchlorate or a bis-perchlorate. A perchlorate salt is optionally solvated or hydrated.
According to one embodiment, a perchlorate salt has a powder X-ray diffraction pattern substantially similar to that depicted in Figure 5. According to another embodiment, a perchlorate salt has a 1H-NMR spectrum substantially similar to that depicted in Figure 6.
In another embodiment, the Rociletinib salt is Rociletinib isethionate salt. The isethionate salt can be a mono-isethionate or a bis-isethionate. A Rociletinib isethionate salt is optionally solvated or hydrated.
According to one embodiment, an isethionate salt has a powder X-ray diffraction pattern substantially similar to that depicted in Figure 7. According to another embodiment, an isethionate salt has a 1H-NMR spectrum substantially similar to that depicted in Figure 8.
In another embodiment, the Rociletinib salt is Rociletinib phosphate salt. The phosphate salt can exist in form of a dihydrogen phosphate, a monohydrogen phosphate or a tribasic phosphate or a bis-phosphate. A Rociletinib phosphate salt is optionally solvated or hydrated.
According to one embodiment, a phosphate salt has a powder X-ray diffraction pattern substantially similar to that depicted in Figure 9. According to another embodiment, a phosphate salt has a 1H-NMR spectrum substantially similar to that depicted in Figure 10.
In another embodiment, the application provides process for preparation of Rociletinib salts. The Rociletinib salts are prepared form Rociletinib base by combining Rociletinib base with either one or two equivalents of trifluoroacetic acid, sulphuric acid, perchloric acid, isethionic acid or phosphoric acid.
Rociletinib base used as the input in the process for preparation of novel salts of the present application can be prepared by any process known in the art.
As described generally above, Rociletinib base is dissolved or suspended in a suitable solvent, optionally with heating. In certain embodiments Rociletinib base is suspended at about 20 to about 60 °C. In other embodiments, Rociletinib base is suspended at about 20 to about 25 °C, such as about ambient temperature. In still other embodiments, Rociletinib base is dissolved at the boiling temperature of the solvent. In other embodiments, Rociletinib base is dissolved without heating.
In certain embodiments, about 1 equivalent of trifluoroacetic acid, sulphuric acid, perchloric acid, isethionic acid or phosphoric acid is added to Rociletinib base to afford the Rociletinib salt. In other embodiments, about 2 equivalents of trifluoroacetic acid, sulphuric acid, perchloric acid, isethionic acid or phosphoric acid is added to Rociletinib base to afford the Rociletinib salt. In yet other embodiments, greater than 2 equivalents of trifluoroacetic acid, sulphuric acid, perchloric acid, isethionic acid or phosphoric acid is added to Rociletinib base to afford the Rociletinib salt. In still other embodiments, about 0.9 to about 1.1 equivalents of trifluoroacetic acid, sulphuric acid, perchloric acid, isethionic acid or phosphoric acid is added to Rociletinib base to afford the Rociletinib salt. In further embodiments, about 1.8 to about 2.2 equivalents, such as about 1.98 to 2.02 equivalents, of trifluoroacetic acid, sulphuric acid, perchloric acid, isethionic acid or phosphoric acid is added to Rociletinib base to afford the Rociletinib salt.
A suitable solvent may solubilize one or more of the reaction components i.e. Rociletinib base and the acid, or alternatively, the suitable solvent may facilitate the agitation of a suspension of Rociletinib and the acid. Examples of suitable solvents useful in the present invention are a protic solvent, a polar aprotic solvent, a non-polar solvent or mixtures thereof. In certain embodiments, suitable solvents include water, an ether, an ester, an alcohol, a halogenated solvent, a ketone or a mixture thereof. In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, ethylacetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone or acetone. In certain embodiments, the suitable solvent is dichloromethane. In other embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is cyclohexane. In certain embodiments the suitable solvent is selected from those above and is anhydrous.
In certain embodiments, the resulting mixture containing Rociletinib salt is cooled. In other embodiments, the mixture containing Rociletinib salt is cooled below 20 °C, such as below 10 °C.
In certain embodiments, Rociletinib salt precipitates from the mixture. In another embodiment, Rociletinib salt crystallizes from the mixture. In other embodiments, Rociletinib salt crystallizes from solution following seeding of the solution (i.e., adding a small quantity of the Rociletinib salt to the solution.
Crystalline Rociletinib salt can precipitate out of the reaction mixture, or be generated by removal of part or all of the solvent through methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an anti-solvent such as water, MTBE or heptane, by cooling or by different combinations of these methods.
As described generally above, Rociletinib salt is optionally isolated. It will be appreciated that Rociletinib salt may be isolated by any suitable physical means known to one of ordinary skill in the art. In certain embodiments, precipitated solid Rociletinib salt is separated from the supernatant by filtration. In other embodiments, precipitated solid Rociletinib salt is separated from the supernatant by decanting the supernatant.
In certain embodiments, isolated Rociletinib salt is dried in air. In other embodiments isolated Rociletinib salt is dried under reduced pressure, optionally at elevated temperature.
In another embodiment, the present application provides a composition comprising Rociletinib salt and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of Rociletinib salt in compositions of this invention it is such that is effective to measurably inhibit a protein kinase, particularly an EGFR kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.
Rociletinib salt and compositions described herein are generally useful for the inhibition of protein kinase activity of one or more enzymes. Examples of kinases that are inhibited by Rociletinib salt and compositions described herein and against which the methods described herein are useful include EGFR kinase or a mutant thereof.
In another embodiment, the present application provides the use of above described salts of Rociletinib or any other Rociletinib salts for the preparation of desired salt of Rociletinib and their crystalline forms thereof, e.g. by conversion of the above described Rociletinib salts to Rociletinib hydrobromide and other salts and solid state forms thereof, and optionally further preparing a pharmaceutical formulation of the resulting Rociletinib hydrobromide and other salts.
In another embodiment, the present application provides process for preparation of Rociletinib hydrobromide, comprising:
(a) providing Rociletinib salt other than hydrobromide salt in a solvent or a mixture of solvents;
(b) adding hydrobromic acid to the mixture of step (a); and
(c) isolating Rociletinib hydrobromide salt.
Step (a) of the process involves providing Rociletinib salt other than hydrobromide salt in a suitable solvent or a mixture of solvents. Examples of suitable solvents useful in the present invention are a protic solvent, a polar aprotic solvent, a non-polar solvent or mixtures thereof. In certain embodiments, suitable solvents include water, a ketone, an ester, an alcohol, a halogenated solvent or a mixture thereof. In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, ethylacetate, isopropyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetone or water. In certain embodiments, the suitable solvent is a mixture of acetone and water.
Step (b) of the process involves addition of hydrobromic acid to the mixture obtained in step (a). Optionally the hydrobromic acid may be diluted using a suitable solvent. The solvent may the same solvent used in step (a). After addition of hydrobromic acid, the mixture may be stirred for about 30 minutes to about 15 hours or more preferably at about 20 to about 30 °C, such as about ambient temperature. Optionally the reaction mixture may be warmed or heated to about 50 °C.
Step (c) involves isolation of Rociletinib hydrobromide salt. The resulting mixture containing Rociletinib hydrobromide is cooled. In other embodiments, the mixture containing Rociletinib hydrobromide is cooled below 20 °C, such as below 10 °C.
Rociletinib hydrobromide may be isolated by any suitable physical means known to one of ordinary skill in the art. In certain embodiments, precipitated solid Rociletinib hydrobromide is separated from the supernatant by filtration. In other embodiments, precipitated solid Rociletinib hydrobromide is separated from the supernatant by decanting the supernatant.
In certain embodiments, isolated Rociletinib hydrobromide is dried in air. In other embodiments isolated Rociletinib hydrobromide is dried under reduced pressure, optionally at elevated temperature.
In another embodiment, the present application provides a composition comprising Rociletinib hydrobromide prepared by the process described above, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of Rociletinib hydrobromide in compositions of this invention it is such that is effective to measurably inhibit a protein kinase, particularly an EGFR kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
The term “anti-solvent” refers to a liquid that, when combined with a solution of Rociletinib, reduces solubility of the Rociletinib in the solution, causingcrystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating.
An “alcohol solvent” is an organic solvent containing a carbon bound to ahydroxyl group. “Alcohol solvents” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropylalcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentylalcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or the like.
A “hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may belinear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3- dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, Examples of aromatic hydrocarbon solvents include, but are not limited to benzene, toluene, ethylbenzene, m-xylene, o xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, or mixtures thereof.
An “ester solvent” is an organic solvent containing a carboxyl group -(C=O)-Obondedto two other carbon atoms. “Ester solvents” include, but are not limited to, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or the like.
A “halogenated hydrocarbon solvent” is an organic solvent containing acarbon bound to a halogen. “Halogenated hydrocarbon solvents” include, but are not limited to, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.
A “ketone solvent” is an organic solvent containing a carbonyl group -(C=O)-bonded to two other carbon atoms. “Ketone solvents” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, C3-6ketones, 4- methyl-pentane-2-one or the like.
A “nitrile solvent” is an organic solvent containing a cyano -(C=N) bonded to another carbon atom. “Nitrile solvents” include, but are not limited to, acetonitrile, propionitrile, C2-6nitriles, or the like.
A “polar aprotic solvent” has a dielectric constant greater than 15 and is atleast one selected from the group consisting of amide-based organic solvents, such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethylphosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane,nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).
An “ether solvent” is an organic solvent containing an oxygen atom –O bonded to two other carbon atoms. “Ether solvents” include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.

EXAMPLES
Example 1: Preparation of Rociletinib trifluoroacetate
Acetone (20 mL) and Rociletinib (2 g) were charged into a 2-necked 100 mL round bottom flask and stirred for 15 minutes at 28°C. To the suspension obtained a solution of trifluoroacetic acid (0.275 mL of trifluoroacetic acid in 5 mL of acetone) added slowly over a period of 5 minutes at 28°C. The reaction mixture was stirred for 16 hours at 28°C. The reaction mixture was cooled to 3°C and stirred for 4 hours. The precipitate was filtered and the wet solid was washed with acetone (12 mL). The product was dried under normal conditions for 3 hours, and then the product was dried under desiccator for 1 day. The product was dried under reduced pressure at 37°C for 3 hours to get 2.125 g of title salt as pale yellow solid. Purity: 99.55% by HPLC. 1H NMR (400 MHz, DMSO-d6) d 10.22 (s, 1H), 9.21 (brs, 1H), 8.63 (brs, 1H), 8.36 (s, 1H), 7.77 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.14 (brs, 1H), 6.63 (d, J = 1.7 Hz, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.9 Hz, 1H), 6.23 (brs, 1H), 5.77 (dd, J = 10.1, 1.9 Hz, 1H), 3.78 (s, 3H), 3.61-3.51 (m, 4H), 3.18-3.07 (m, 2H), 3.07-2.96 (m, 2H), 2.05 (s, 3H). PXRD pattern is shown in Fig.1; 1H-NMR spectrum is shown in Fig.2.

Example 2: Preparation of Rociletinib hydrogensulfate
Acetone (50 mL) and Rociletinib (2.5 g) were charged into a 2-necked 250 mL round bottom flask and stirred for 15 minutes at 28°C. To the suspension obtained a solution of sulfuric acid (441 mg of conc. sulfuric acid in 4.5 mL of acetone) added slowly over a period of 5 minutes at 28°C. The reaction mixture was stirred for 72 hours at 28°C. The precipitate was filtered under nitrogen atmosphere and the wet solid was washed quickly with acetone (25 mL). The product was dried in a vacuum desiccator at 27°C for 3 days and then the product was dried under reduced pressure at 37°C for 3 hours to get 2.84 g of title salt as yellow colored free-flowing powder. Purity: 98.24% by HPLC.1H NMR (400 MHz, DMSO-d6) d 10.31 (s, 1H), 10.07 (brs, 1H), 9.34 (brs, 1H), 8.57 (brs, 1H), 7.81 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.38 (brs, 1H), 7.11 (brs, 1H), 6.72 (s, 1H), 6.46 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 1.9 Hz, 1H), 6.26 (brs, 1H), 5.78 (dd, J = 10.1, 1.9 Hz, 1H), 3.81 (s, 3H), 3.67 – 3.51 (m, 4H), 3.30 – 3.15 (m, 2H), 3.15 – 2.99 (m, 2H), 2.06 (s, 3H). PXRD pattern is shown in Fig.3; 1H-NMR spectrum is shown in Fig.4.

Example 3: Preparation of Rociletinib perchlorate
Acetone (30 mL) and Rociletinib (2 g) were charged into a 2-necked 100 mL round bottom flask and stirred for 15 minutes at 28°C. To the suspension obtained added slowly a solution of perchloric acid (517 mg of 70% perchloric acid in 10 mL of acetone) over a period of 5 minutes at 28°C. The reaction mixture was stirred for 48 hours at 28°C. The precipitate was filtered under vacuum and the wet solid was washed with acetone (20 mL) and the solid was suck dried for 3 hours. The product was dried under vacuum desiccator for 3 days. The product was dried twice under reduced pressure in a rotavapor at 37°C for 5 hours to get 2.029 g of title salt as pale yellow colored free-flowing powder. Purity: 99.56% by HPLC. 1H NMR (400 MHz, DMSO-d6) d 10.27 (s, 1H), 9.95 (brs, 1H), 9.18 (brs, 1H), 8.53 (brs, 1H), 7.80 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.38 (brs, 1H), 7.12 (brs, 1H), 6.68 (s, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.26 (dd, J = 17.0, 1.9 Hz, 1H), 6.22 (brs, 1H), 5.78 (dd, J = 10.1, 1.9 Hz, 1H), 3.81 (s, 3H), 3.64-3.50 (m, 4H), 3.23-3.12 (m, 2H), 3.12-2.99 (m, 2H), 2.05 (s, 3H). PXRD pattern is shown in Fig.5; 1H-NMR spectrum is shown in Fig.6.

Example 4: Preparation of Rociletinib isethionate
Acetone (50 mL) and isethionic acid (802 mg) were charged into a 2-necked 250 mL round bottom flask and stirred for 15 minutes at 28°C. Rociletinib (2.5 g) was added at 28°C to the clear solution obtained. The reaction mixture was diluted with acetone (12.5 mL) and the reaction mixture was stirred for 72 hours at 28°C. The reaction mixture was cooled to 5°C and stirred for 1 hour. The precipitate was filtered rapidly under nitrogen atmosphere and the wet solid was washed quickly with acetone (25 mL). The product was dried in a vacuum desiccator at 27°C for 3 days and then the product was dried in a rotavapor under reduced pressure at 37°C for 3 hours to get 2.65 g of title salt as pale yellow colored free-flowing powder. Purity: 99.53% by HPLC.1H NMR (400 MHz, DMSO-d6) d 10.29 (s, 1H), 9.96 (brs, 1H), 9.23 (brs, 1H), 8.53 (brs, 1H), 7.80 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.37 (brs, 1H), 7.11 (s, 1H), 6.69 (s, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 1.5 Hz, 1H), 6.23 (brs, 1H), 5.78 (dd, J = 10.1, 1.7 Hz, 1H), 3.81 (s, 3H), 3.68 – 3.53 (m, 6H), 3.24 – 3.12 (m, 2H), 3.12 – 2.99 (m, 2H), 2.62 (t, J = 6.8 Hz, 2H), 2.05 (s, 3H). PXRD pattern is shown in Fig.7; 1H-NMR spectrum is shown in Fig.8.

Example 5: Preparation of Rociletinib phosphate
Acetone (50 mL) and Rociletinib (2 g) were charged into a 2-necked 250 mL round bottom flask and stirred for 15 minutes at 28°C. To the suspension obtained a solution of orthophosphoric acid (352 mg of crystalline orthophosphoric acid in 10 mL of acetone) added slowly over a period of 10 minutes at 28°C. The reaction mixture was stirred for 16 hours at 28°C. The precipitate was filtered under nitrogen atmosphere and the wet solid was washed with acetone (20 mL) and the wet solid was suck dried for 3 hours. The product was dried in a vacuum desiccator at 27°C for 3 days and then the product was dried in a rotavapor under reduced pressure at 37°C for 3 hours to get 1.55 g of title salt as pale yellow colored free-flowing powder. Purity: 99.74% by HPLC.1H NMR (400 MHz, DMSO-d6) d 10.16 (s, 1H), 8.66 (brs, 1H), 8.28 (s, 1H), 8.10 (s, 1H), 7.74 (brs, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.16 (brs, 1H), 6.60 (d, J = 2.2 Hz, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.25 (dd, J = 17.0, 2.0 Hz, 1H), 6.22 (brs, 1H), 5.76 (dd, J = 10.1, 2.0 Hz, 1H), 3.77 (s, 3H), 3.62-3.49 (m, 4H), 3.13-3.03 (m, 2H), 3.03-2.92 (m, 2H), 2.04 (s, 3H). PXRD pattern is shown in Fig.9; 1H-NMR spectrum is shown in Fig.10.

Example 6: Preparation of Rociletinib maleate
Acetone (25 mL) and Rociletinib (2.5 g) were charged into a 2-necked 100 mL round bottom flask and stirred for 15 minutes at 28°C. To the suspension obtained a solution of maleic acid (522 mg of maleic acid in 5 mL of acetone) added slowly over a period of 5 minutes at 28°C. The reaction mixture was stirred for 16 hours at 28°C. The reaction mixture was cooled to 5°C and stirred for 2 hours. The precipitate was filtered under nitrogen atmosphere and the wet solid was washed with acetone (10 mL) and the wet solid was suck dried for 2 hours. The product was dried in a vacuum desiccator at 25°C for 3 days and then the product was dried in a rotavapor under reduced pressure at 40°C for 3 hours to get 2.6 g of title salt as pale yellow colored free-flowing powder. Purity: 99.09% by HPLC.

Example 7: Preparation of Rociletinib hydrobromide by salt metathesis
10% water-acetone (5 mL) and Rociletinib maleate (1 g) were charged into a 50 mL round bottom flask and stirred for 10 minutes at 28°C. A solution of hydrobromic acid (251 mg of 48% HBr in 5 mL of 10% water-acetone) added slowly over a period of 5 minutes at 28°C. The reaction mixture was stirred for 16 hours at 28°C. The reaction mixture was cooled to 5°C and stirred for 2 hours. The precipitate was filtered and the wet solid was washed with acetone (5 mL) and the wet solid was suck dried for 2 hours. The product was dried in a rotavapor twice under reduced pressure at 40°C for 5 hours to get 700mg of title salt as pale yellow colored free-flowing powder. Purity: 99.56% by HPLC.

Example 8: Preparation of Rociletinib hydrobromide by salt metathesis
10% water-acetone (0.5 mL) and Rociletinib perchlorate (50 mg) were charged into a 2 mL Eppendorf centrifuge vial equipped with a micro stir bar and stirred for 10 minutes at 28°C. A solution of hydrobromic acid (12.8 mg of 48% HBr in 0.5 mL of 10% water-acetone) added slowly over a period of 2 minutes at 28°C. The reaction mixture was stirred for 48 hours at 28°C. The reaction mixture was centrifuged at 5000 rpm for 15 minutes. The precipitate pellet and supernatant liquid were separated and the pellet was washed with acetone (0.5 mL). The pellet was dispersed in acetone (0.5 mL) by sonicating for 10 minutes and the suspension was centrifuged at 5000 rpm for 15 minutes. The precipitate pellet and supernatant liquid were separated and the wet solid was dried in a vacuum desiccator at 30°C for two days. The solid was dried under reduced pressure at 40°C for 3 hours to get 30 mg of title salt as light pink colored solid. Purity: 99.57% by HPLC.

Example 9: Preparation of Rociletinib hydrobromide by salt metathesis
10% water-acetone (0.5 mL) and Rociletinib isethionate (50 mg) were charged into a 2 mL Eppendorf centrifuge vial equipped with a micro stir bar and stirred for 10 minutes at 28°C. A solution of hydrobromic acid (12.3 mg of 48% HBr in 0.5 mL of 10% water-acetone) added slowly over a period of 2 minutes at 28°C. The reaction mixture was stirred for 48 hours at 28°C. The reaction mixture was centrifuged at 5000 rpm for 15 minutes. The precipitate pellet and supernatant liquid were separated and the pellet was washed with acetone (0.5 mL). The pellet was dispersed in acetone (0.5 mL) by sonicating for 10 minutes and the suspension was centrifuged at 5000 rpm for 15 minutes. The precipitate pellet and supernatant liquid were separated and the wet solid was dried in a vacuum desiccator at 30°C for two days. The solid was dried under reduced pressure at 40°C for 3 hours to get 33 mg of title salt as off-white colored powder. Purity: 99.16% by HPLC.
CLAIMS:We Claim:
1. A process for preparation of Rociletinib hydrobromide, comprising:
(a) providing a solution or a suspension of Rociletinib salt other than hydrobromide salt;
(b) adding hydrobromic acid to the solution or suspension of step (a); and
(c) isolating Rociletinib hydrobromide salt.
2. The process according to claim 1, wherein the Rociletinib salt is selected from the group comprising: Rociletinib trifluoroacetate, Rociletinib hydrogensulfate, Rociletinib perchlorate, Rociletinib isethionate, Rociletinib maleate and Rociletinib phosphate.
3. The process according to claim 1, wherein the Rociletinib salt is Rociletinib maleate.
4. The process according to claim 1, wherein the Rociletinib salt is Rociletinib isethionate.
5. The process according to claim 1, wherein the Rociletinib salt is Rociletinib perchlorate.
6. Rociletinib maleate.
7. Rociletinib isethionate.
8. Rociletinib perchlorate.
9. Rociletinib trifluoroacetate.
10. A pharmaceutical composition comprising Rociletinib hydrobromide prepared by the process of claim 1, and a pharmaceutically acceptable carrier.