METHOD OF SYNTHESIS OF COMPOUND FOR DUAL INHIBITION OF JAK2 AND BET

Abstract

Embodiments of the invention include quinoline compounds and methods of synthesis. Ohm-581 has demonstrated dual inhibition of JAK2 and BET and acts as a therapeutic agent for micosis fungoides (MF) and other hematologic malignancies. Embodiments also include an efficient process for the preparation of Ohm-581 and pharmaceutically acceptable salts. The process is suited for large-scale production of quinoline compounds including Ohm-581.

Claims

1. A process for preparation of a compound with the structure: ##STR00011## a stereoisomer, or a salt thereof, said process comprising steps of: a) oxidizing a sulfone intermediate with an oxidizing agent in a solvent, b) condensing the solvent in presence of a metal halide and a catalyst, c) isolating one or more reaction products from the solvent at one or more pH levels, and d) identifying a reaction product.

2. The process of claim 1, including a step of treating the reaction product to form a pharmaceutically acceptable acid salt.

3. The process of claim 1, including a step of preparing organic and inorganic acid salts of the reaction product.

4. The process of claim 1, including a step washing and/or rinsing the solution with a base; wherein the base is selected from carbonates, bicarbonates, hydroxides and organic bases including amines and pyridines, and wherein the reaction temperature range is −10 to 50° C. and preferably ambient temperature during the washing and/or rinsing steps.

5. The process of claim 1, wherein the oxidizing agent is KMnO.sub.4, H.sub.2O.sub.2, or m-CPBA, wherein the solvent is an ester, a toluene, protonated, a ketone, chlorinated, dioxane, DMF, DMAC, other organic solvents, or a C1-C5 alcohols and water, and wherein the reaction temperature is −10 to 50° C. and preferably ambient temperature.

6. The process of claim 1, wherein the step of condensing the solvent in presence of a metal halide and a catalyst includes a base, wherein the base is a carbonate, bicarbonate, hydroxide or organic base such as an amine and pyridine, and wherein the solvents are preferably esters, toluene, protonated, ketones, dioxanes chlorinated, DMF, DMAC and other organic solvents, C1-C5 alcohols and water, wherein the reducing agents are 5-10% Pd/C, Zn/NH.sub.4Cl, Fe/HCl, wherein the reaction pressure is 0 to 10 Kg, and wherein the reaction temperature is 0 to 100° C., preferably 50-90° C.

7. The process of claim 1, wherein the step of condensing the solvent in presence of a metal halide and a catalyst includes a solvent that is preferably an ester, toluene, protonated, ketones, dioxanes, chlorinated, DMF, DMAC and other organic solvents, or C1-C5 alcohols and water, wherein the reaction pressure is 0 to 15 Kg, and wherein the reaction temperature is 0 to 140° C., preferably less than 90° C.

8. The process of claim 1, including a step washing and/or rinsing the solution with a base, wherein the base is selected from carbonates, bicarbonates, hydroxides and organic bases such as amines and pyridines, wherein solvents are preferably esters, toluene, protonated, ketones, dioxanes, chlorinated, DMF, DMAC and other organic solvent, C1-C5 alcohol and water, wherein the reaction pressure is 0 to 15 Kg, wherein the reaction temperature is 0 to 140° C., preferably less than 90° C., wherein the purification solvents are preferably esters, toluene, protonated, ketones, dioxanes, chlorinated, DMF, DMAC, other organic solvent, or C1-C5 alcohol and water, and wherein the isolation pH is 0.5-11.0.

9. The process of claim 1, wherein an isolation solvent is used in the step isolating one or more reaction products from the solvent at one or more pH levels, wherein the isolation solvent is an ester, toluene, protonated, ketone, dioxane, chlorinated, DMF, DMAC or other organic solvent, C1-C5 alcohol, ethyl acetate, methanol, ethanol or isopropanol or chlorinated solvent such as dichloromethane, wherein the temperature for isolation is 0 to 140° C., preferably greater than 20° C., and wherein a crystalline form of the reaction product has X-ray diffraction 2Θ values of 8.2, 13.0, 13.5, 16.5, 18.8, 20.1, 20.6±0.2.

10. The process of claim 1, wherein an isolation solvent is used in the step isolating one or more reaction products from the solvent at one or more pH levels, wherein the isolation solvent is an ester, toluene, protonated, ketone, dioxane, chlorinated, DMF, DMAC or other organic solvent, C1-C5 alcohol, ethyl acetate, methanol, ethanol or isopropanol or chlorinated solvent such as dichloromethane, wherein the reaction product is a crystalline of a mono, di or tri acid salt with hydrate form, wherein isolated acid hydrate salts are maleate salts, and wherein a crystalline form of the reaction product of maleate salt X-ray diffraction has 2Θ values 39.8, 37.6, 36.7, 35.3, 34.9±0.2.

11. The process of claim 1, wherein an isolation solvent is used in the step isolating one or more reaction products from the solvent at one or more pH levels, wherein the isolation solvent is an ester, toluene, protonated, ketone, dioxane, chlorinated, DMF, DMAC or other organic solvent, C1-C5 alcohol, ethyl acetate, methanol, ethanol or isopropanol or chlorinated solvent such as dichloromethane, wherein the reaction product is a crystalline of a mono, di or tri acid salt with hydrate form, wherein isolated acid hydrate salts are succinate salts, wherein a crystalline form of the reaction product of succinate salt X-ray diffraction has 2Θ values 34.6, 33.1, 31.6, 28.5, 26.4, 25.7, 24.7±0.2.

12. The process of claim 1, wherein an isolation solvent is used in the step isolating one or more reaction products from the solvent at one or more pH levels, wherein the isolation solvent is an ester, toluene, protonated, ketone, dioxane, chlorinated, DMF, DMAC or other organic solvent, C1-C5 alcohol, ethyl acetate, methanol, ethanol or isopropanol or chlorinated solvent such as dichloromethane, wherein the reaction product is a crystalline of a mono, di or tri acid salt with hydrate form, wherein isolated acid hydrate salts are preferably hydrochloride range mono to tri salt hydrates, and wherein a crystalline form of the reaction product of hydrochloride salt X-ray diffraction has 2Θ values 27.4, 26.1, 24.5, 24.0, 22.6, 20.9, 19.4, 17.9, 10.3±0.2.

13. The process of claim 1, wherein an isolation solvent is used in the step isolating one or more reaction products from the solvent at one or more pH levels, wherein the isolation solvent is an ester, toluene, protonated, ketone, dioxane, chlorinated, DMF, DMAC or other organic solvent, C1-C5 alcohol, ethyl acetate, methanol, ethanol or isopropanol or chlorinated solvent such as dichloromethane, wherein the reaction product is a crystalline of a mono, di or tri acid salt with hydrate form, wherein isolated acid hydrate salts are hydrochloride range mono to tri salt hydrates, wherein a crystalline form of the reaction product isolated from acid salts X-ray diffraction has 2Θ values of 8.2, 13.0, 13.5, 16.5, 18.8, 20.1, 20.6±0.2.

Description

DESCRIPTION OF PREFERRED EMBODIMENTS

[0060] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology as claimed. Additional features and advantages of the subject technology are set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subject technology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the written description and claims hereof.

[0061] Bromodomain and extra terminal domain (BET) proteins include Brd2, Brd3, Brd4, and BrdT, each of which contain two bromodomains in tandem that can independently bind to acetylated lysines. BET inhibitors are a class of drugs that reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated histones and transcription factors.

[0062] BET inhibitors have many potential therapeutic uses including the treatment of various cancers. BET inhibitors may also be efficacious in atherosclerosis and associated conditions because of anti-inflammatory effects as well as ability to increase transcription of Apo A-I, the major constituent of HDL. BET inhibitors may also be useful in the prevention and treatment of conditions associated with ischemia-reperfusion injury such as myocardial infarction, stroke and acute coronary syndromes.

[0063] OHM-581 is a dual inhibitor of JAK2 and BET that has potential as a therapeutic agent for micosis fungoides (MF) and other hematologic malignancies. In vitro biochemical assays show OHM-581 to inhibit BRD4 BD1 and BD2 as well as JAK2. OHM-581 displays significant anti-proliferative activity against multiple liquid cancer cell lines. Consistent with its mechanism of action, OHM-581 robustly down-regulates cMYC expression and JAK2 signaling.

[0064] In one embodiment, the invention is directed to the compound OHM-581, also referred to as “Formula I.”

##STR00002##

[0065] The compound can also be described as of N-(3-(2((4-(4-(dimethylamino)piperidin-1-yI)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropane-2-sulfonamide.

[0066] It will be appreciated that the invention covers compounds of Formula I, analogues and salts thereof. In one embodiment, the invention relates to compounds of Formula I in the form of a free base. In another embodiment, the invention relates to compounds of Formula I or a pharmaceutically acceptable salt thereof.

[0067] Because of their potential use in medicine, salts of the compound of Formula I are may be preferred as pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts can include acid addition salts. A pharmaceutically acceptable salt can be readily prepared by using a desired acid or base as appropriate. The resultant salt can precipitate from solution and be collected by filtration or recovered by evaporation of the solvent. The compound can exist as a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof:

##STR00003##

Utility and Administration

[0068] The compounds described herein are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to reversibly bind the bromodomains of Bromodomain and Extra-Terminal motif (BET) proteins. The compounds described herein can also be used for the treatment of certain conditions in oncology such as myeloproliferative neopplasm (P vera, ET, post-MPN MDS/sAML), de novo and secondary MDS/AML, premalignant breast disease, CMML, acute and chronic GvHD, HSCT applications, gliomas/glioblastoma, Hodgkin lymphoma, diffuse large B-cell lymphoma, head and neck carcinomas, triple-negative breast cancer, prostate cancer (as one illustrative but not all inclusive example, androgen-independent prostate cancer), hypereosinophilic syndrome/primary eosinophilic disorders, T-cell leukemia/lymphoma including peripheral T-cell lymphomas, blastic plasmacytoid dendritic cell neoplasm, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Hemophagocytic Lymphohistiocytosis, multiple myeloma, Chuvash polycythemia, Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative, Chronic Neutrophilic Leukemia, Hodgkin Lymphoma and Primary Mediastinal Large B-cell Lymphoma, pretreatment of MF patients prior to allogeneic HSCT.

[0069] The compounds described herein can also be used for treatment of various autoimmune conditions including rheumatoid arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease and other forms of inflammatory bowel disease, noninfective uveitis and scleritis, various forms of spondyloarthritis including ankylosing spondylitis, reactive arthritis, enteropathic arthritis, juvenile enthesitis-related arthritis, non-radiographical axial spondyloarthritis, and undifferentiated spondyloarthritis, Sjogren's syndrome, chronic synovitis, atopic dermatitis, vitiligo, alopecia areata and alopecia universalis, frontal fibrosing alopecia, pemphigus, multiple sclerosis, scleroderma, lupus, dermatomyositis, juvenile arthritis of various forms such as juvenile rheumatoid arthritis.

[0070] Other potential uses include treatment of fibrotic diseases of multiple types including idiopathic pulmonary fibrosis and others, Bronchiolitis Obliterans Syndrome (BOS) After Allogeneic Hematopoietic Cell Transplantation (HCT), OHM-581 as a therapy to effect the numbers and functional activities of Tumor Infiltrating Myeloid Cells and Tumor Infiltrating Lymphocytes to reprogram tumor cells with resistance to cancer immunotherapies, HIV, treatment of cancer cachexia, lichen planus, lichen planoplaris, thalassemia major (to reduce spleen size), recalcitrant palmoplantar pustulosis, amyopathic dermatomyositis-associated interstitial lung disease, sarcoidosis, asthma, allergy-induced airway inflammation, familial Mediterranean fever, pyoderma gangrenosum, STING-associated vasculopathy with onset in infancy (SAVI), prevention of transplant rejection (as one example, prevention of chronic renal allograft rejection).

Pharmaceutical Compositions

[0071] For use as treatment of human and animal subjects, the compounds of the invention can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylaxis, or therapy) the compounds are formulated in ways consonant with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 21″ Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0072] The compounds described herein may be present in amounts totaling 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical., transdermal, sublingual., nasal, vaginal, intravesicular, intraurcthral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, gastrointestinal, reproductive or oral mucosa. Thus, the pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice.

Synthesis

[0073] The reaction scheme, steps and examples are intended to illustrate the synthesis of a representative number of compounds. Accordingly, the Examples are intended to illustrate but not to limit the invention. Additional compounds not specifically exemplified may be synthesized using conventional methods in combination with the methods described herein.

[0074] Embodiments include a process for the synthesis of the compound of Formula I and pharmaceutically acceptable acids, salts and organic, inorganic (ionic and covalent) salts and complexes thereof, substantially free of impurity. The process includes a step of oxidation of sulfone by an oxidizing agent in a solvent. FIG. 1 depicts the reaction scheme which is further detailed below. The process comprises steps of: [0075] a) Oxidizing sulfone intermediate with an oxidizing agent in a solvent, [0076] b) Condensation in the presence of a metal halide, catalyst at various pressures, [0077] c) Isolation using high purity techniques at different pH levels, [0078] d) Isolation and polymorph study of the Formula I compound, and [0079] e) Treating the Formula I compound with different acids and organic/inorganic ionic complexes.

Step I

[0080] Preparation of N-(3-bromophenyl)-2-methylpropane-2-sulfinamide

[0081] The compound of Formula I can be prepared by the procedure depicted in FIG. 1. The procedure can be divided into several steps. Step I begins with 3-Bromo Aniline and pyridine as described below.

##STR00004##

[0082] 3-Bromo Aniline (100.0 g, 581.4 mmol) and pyridine (300 mL) were charged into a round bottom flask and stirred at room temperature. Tert-Butyl sulfuryl chloride (79.6 mL, 639.48 mmol) was added drop wise under nitrogen atmosphere at 0-5° C. over a period of 60-120 minutes. The reaction mass was gradually warmed to room temperature (25-30° C.) and stirred at this temperature for 3-4 hours. The reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mass was cooled to 0-5° C. and quenched by the addition of water (1000 mL) below 5° C. It was then warmed to room temperature and stirred at this temperature for 1 hour. The solid was collected by filtration, washed with water (500 mL), and suction dried for 1 hour. After suck drying for about an hour, the wet material was taken in hexane (300 mL) and heated to 50-55° C. for 3-4 h. The suspension was cooled to 25-30° C., the solid separated was filtered, washed with hexane (100 mL) and the material was dried for 10-15 h at 50-55° C. to get the product as off white solid.

[0083] The method described as Step I produced the following results:

[0084] H1-NMR Values: 7.187(s, 1H), 7.149-7.096(d, 2H), 6.918-6.945(m, 1H), 1.327(s, 9H)

[0085] Mass (ESI): m/z 275.8/276.6[m+H]+

[0086] Purity by HPLC: NLT 98.0%

[0087] Yield: 90-93%

Step II

[0088] Preparation of 1-(2-fluoro-4-nitrophenyl)-N,N-dimethylpiperidin-4-amine

[0089] Step II begins with 4-Dimethyl amino piperidine as described below.

##STR00005##

[0090] 4-Dimethyl amino piperidine (100.0 g, 779.9 mmol) and DMF (500 mL) were combined in a round bottom flask, cooled to 0-5° C. and then stirred for 10-15 min. To this solution, potassium carbonate was added (323.36 g, 2339.6 mmol) lot wise at 0-5° C. The temperature was slowly raised to room temperature. Charged 1,2-di fluoro-4-nitrobenzene (123.76 g, 777.9 mmol) as added drop wise at 25-30° C. and the solution was stirred at room temperature for 2-3 hours. Chilled water (1000 mL) was added to the reaction mass and stirred for 1 hour, filtered and washed with water (1000 mL). The pale yellow solid was suction dried for 1-2 hours and used as such for next reaction.

[0091] The method described as Step II produced the following results:

[0092] H1-NMR Values: 7.953-7.953(dd, 1H), 7.874-7.912(dd, 1H), 6.886-6.931(t, 1H), 3.745-3.776(d, 2H), 2.866-2.927(t, 2H), 2.322-2.368(s, 7H), 1.936-1.967(d, 2H), 1.627-1.722(m, 2H)

[0093] Mass (ESI): m/z 268/270[m+H]+

[0094] Purity by HPLC: NLT 97.0%

[0095] Yield: 95-98%

Step III

[0096] Preparation of 1-(4-amino-2-fluorophenyl)-N,N-dimethylpiperidin-4-amine

[0097] Step III begins with the nitro compound produced in Step II.

##STR00006##

[0098] The nitro compound (100.0 g, 374.1 mmol) was dissolved in water (1000 mL) and ammonium chloride (100.0 g, 1872.6 mmol) at room temperature then stirred for 15 minutes. Zn dust (122.0 g, 1868.3 mmol) was added and the temperature was slowly raised to 75-80° C. The solution was stirred for 2 hours. After completion of the reaction, aqueous ammonia (150 mL) was slowly added to reaction mass while maintaining the temperature below 30° C. (to control exothermicity). The reaction mass was filtered through a celite bed, washed with water (500 mL) and DCM (200 mL). The aqueous layer was washed with DCM (2×200 mL). Combined organic layers were completely distilled out under vacuum below 45° C. Charged n-heptane (mL) was added to the crude mass and stirred for 1 hour. The brown solid was filtered, washed with n-hexane (100 mL) suction dried and then dried at 55° C. for 10 hours.

[0099] The method described as Step Ill produced the following results:

[0100] H1-NMR Values: 6.792-6.809(t, 1H), 6.378-6.443(t, 2H), 3.525(br, 2H), 3.323-3.349(d, 2H), 2.580-2.638(t, 2H), 2.236-2.322(m, 7H), 1.865-1.894(d, 2H), 1.677-1.736(d, 2H)

[0101] Mass (ESI): m/z238.1/239.1 [m+H]+

[0102] Purity by HPLC: NLT 98.0%

[0103] Yield: 85-90%

Step IV

[0104] Preparation of N-(3-bromophenyl)-2-methylpropane-2-sulfonamide

[0105] Step IV begins with N-(3-bromophenyl)-2-methylpropane-2-sulfinamide.

##STR00007##

[0106] Ethyl acetate (800 mL) and N-(3-bromophenyl)-2-methylpropane-2-sulfinamide (100.0 g, 362.06 mmol) were charged into a round bottom flask at 25° C. and stirred for 15 min. The solution was cooled to 0° C. and mCPBA (97.47 g, 564.8 mmol) was added and stirred at the same temperature for 30 minutes. The temperature was then raised to 25° C. and the mass was stirred for 4 hours. The separated solids were filtered off, the solid (Lot-1) was washed with Ethyl acetate (200 mL). The filtrate was washed with and 5% NaHCO.sub.3 solution (2×600 mL) and the layers were separated. The organic phase was concentrated under reduced pressure. n-Hexane (100 mL) is added and the mixture was stirred for 1 hour at 25° C. The formed solid (Lot-2) was separated by filtration and washed with n-hexane (50 mL). Both the solid lots were combined and slurred in dichloromethane (150 mL) for 1 hour and filtered to get the product as a white solid. The solid was suction dried for 30 minutes and then dried at 55° C. for 6 hours.

[0107] The method described as Step IV produced the following results:

[0108] H1-NMR Values: 7.440(s, 1H), 7.143-7.241 (m, 3H), 6.355(br, 1H), 1.426(s, 9H)

[0109] Mass (ESI): m/z 289.8/291.8 [M-H]+

[0110] Purity by HPLC: 98.0%

[0111] Yield: 93-95%

Step V

[0112] Preparation of N-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropane-2-sulfonamide

[0113] Step V begins with 1,4-Dioxane (1200 mL), N-(3-bromophenyI)-2-methylpropane-2-sulfonamide.

##STR00008##

[0114] Tert-Butanol (3250 mL), N-(3-bromophenyl)-2-methylpropane-2-sulfonamide (325.0 g, 1.12 mol) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (171 g, 1.12 mol) were charged into an autoclave and stirred for 15 minutes at 25° C. Potassium triphosphate (630 g, 2.97 mol), copper iodide (64 g, 0.34 mol) and N, N′-dimethylethylene diamine (59.24 g, 0.67 mol) were added and stirred at 25° C. for 15 minutes. Nitrogen pressure (5 kg/cm2) was applied and the reaction mass temperature was raised to 110° C. The mass was maintained at this temperature for 24 hours. The reaction mass was then cooled to 25-30° C.; diluted with EtOAc (3250 mL.), filtered through hyflow bed. The hyflow bed was washed with EtOAc (1575 mL.). The combined filtrate and washings was concentrated completely under vacuum below 60° C. To the crude material obtained was added 1N HCl (3250 mL.) and EtOAc (3250 mL) at 25-30° C. The reaction mass was stirred for 30 minutes, the solid suspension was filtered on hyflow bed to remove the undissolved solids and layers were separated. The aqueous layer was back extracted with EtOAc (3250 mL) and the combined organic layer was washed with saturated NaHCO.sub.3 solution (3250 mL) followed by water (3250 mL). Concentrated the organic layer completely and the crude material obtained was dissolved in Methanol (675 mL), stirred at 60-65° C. for 0.5-1.0 h. The reaction mass was cooled to 25-30° C., the solid was filtered, washed with methanol (325 mL). The solid obtained was dried under vacuum at 55-60° C. for 10-12 h to get the product as a pale brown colour solid in 36% yield with 98.55% purity by HPLC (specification limit is not less than 98.0%).

[0115] The method described as Step V produced the following results:

[0116] H1-NMR Values: 9.986(s, 1H), 7.978-7.987(d, 1H), 7.785(s, 1H), 7.466-7.506(t, 1H), 7.371-7.391(d, 1H), 7.292-7.313(d, 1H), 6.912-9.921(d, 1H), 1.337(s, 9H)

[0117] Mass (ESI): m/z 364.8/366.9 [M+H]+

[0118] Purity by HPLC: NLT 98.0%

[0119] Yield: 35-38%

Step VI

[0120] Preparation of N-(3-(2-((4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropane-2-sulfonamide

[0121] Step VI combines the structures produced from step III and step V.

##STR00009##

[0122] To a stirred solution of N-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropane-2-sulfonamide (250 g, 685 mmol) in t-Butanol (2500 mL) in autoclave, were added 1-(4-amino-2-fluorophenyl)-N,N-dimethylpiperidin-4-amine (162.7 g, 685 mmol) K.sub.2CO.sub.3 (236.4 g, 1712 mmol Pd.sub.2(dba).sub.3 (31.4 g, 34.25 mmol.), X-Phos (32.7 g, 68.5 mmol) sequentially at 25-30° C. The autoclave was closed and the reaction mixture was degassed using N.sub.2 gas for about 15 min. The reaction mixture was heated to 105-110° C. under a Nitrogen pressure of 1-2 Kg/cm.sup.2 and maintained for about 4-5 h at the same temperature. The reaction was monitored by HPLC for the content of N-(3-(2-chloro-7H-pyrrolo [2, 3-d]pyrim idin-7-yl)phenyl)-2-methylpropane-2-sulfonamide (Limit: NMT 1%). The reaction mass was cooled to 20-30° C. and diluted with 10% Methanol/DCM (2500 mL). Unloaded the reaction mass from autoclave and filtered through hyflow bed. The hyflow bed was washed with 10% Methanol/DCM (1250 mL). Added charcoal (35 g) to the combined filtrate and washings and the reaction mass was heated to 65-70° C. for 1 h. The reaction mass was filtered at the same temperature over hyflow and the hyflow bed was washed with DCM (1000 mL).

[0123] The combined filtrate and washings was concentrated to dryness and to the residue was added MeOH (1000 mL) and stirred for 0.5 h at 25-30° C. The solid suspension was filtered, washed with MeOH (1000 mL), and the material was dried under vacuum at 55-60° C. for 5-6 h to get the target base as off white crystalline solid.

[0124] The method described as Step VI produced the following results:

[0125] X-ray diffraction 2Θ values 8.2, 13.0, 13.5, 16.5, 18.8, 20.1, 20.6+0.2

[0126] H1-NMR Values: 9.985(br, 1H), 9.550(s, 1H), 8.795(s, 1H), 7.711-7.768(d, 2H), 7.470- 7.530(m, 4H), 7.282-7.298(d, 1H), 6.949-6.990(t, 1H), 6.671(s, 1H),3.288-3.313(d, 2H), 2.563-2.616(t,2H),2.393(s, 6H),1.900-1.922(d,2H), 1.603-1.627(d, 2H),1.293(s, 9H)

[0127] Mass (ESI): m/z 566/566.8 [m+H]+

[0128] Purity by HPLC: NLT 98.0%

[0129] Yield: 80-82%

Step VII

[0130] Preparation of N-(3-(2((4-(4-(dimethvlamino)piperidin-1-yl)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropane-2-sulfonamide salts

[0131] Step VII produces a salt of the compound of Formula I.

##STR00010##

[0132] In an alcoholic solvent (Ethanol, Isopropanol, Methanol), N-(3-(2((4-(4-(dimethylamino)piperidin-1-yl)-3-fluorophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropane-2-sulfonamide base was maintained at room temperature and an equal molar ratio of respective acids in water was added. The mass was stirred at reflux and isolated by filtration at room temperature. The yield was 80-90% with an HPLC purity of greater than 98%. All acid salts taken into alcoholic solvents and isolated pH >8 gave the compound of Formula I. A crystalline form of the Formula I base X-ray diffraction 2Θ values were 8.2, 13.0, 13.5, 16.5, 18.8, 20.1, 20.6+0.2

[0133] It will be appreciated that in any of the routes described above, the precise order of the synthetic steps by which the various groups and moieties are introduced into the molecule can be varied. It will be within the skill of the practitioner in the art to ensure that groups or moieties introduced at one stage of the process will not be affected by subsequent transformations and reactions, and to select the order of synthetic steps accordingly. Certain intermediate compounds described above form a yet further aspect of the invention.

[0134] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0135] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0136] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0137] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and/or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.