SRINIVASAN DR NETI (IN)
KUMAR MR KOTTUR MOHAN (IN)
SEN DR SAIKAT (IN)
| WO2015191846A1 | 2015-12-17 |
| CN101861313A | 2010-10-13 |
| WE CLAIM 1. An acid addition salt of Momelotinib, wherein salt is selected from a group comprising tosylate, besylate and triflate. 2. A tosylate salt of Momelotinib, characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at 4.46°, 10.38°, 13.90°, 14.74°, 16.53°, 23.07°, 20.33°, 23.92°, 26.34° and 27.78° ± 0.2° 20 or an XRPD pattern as depicted in Figure 7. 3. The tosylate salt as claimed in claim 1 or 2, characterized by an XRPD pattern comprising peaks at 8.90°, 9.47°, 11.44°, 13.32°, 15.27°, 16.20°, 17.36°, 19.07°, 19.63°, 20.80°, and 22.26° ± 0.2° 20. 4. The tosylate salt as claimed in claim 1 or 2, characterized by an XRPD pattern comprising peaks at 22.67°, 24.41°, 24.93°, 25.87°, 28.88°, 29.84°, 31.03°, 33.63°, 34.40°, 35.39°, 36.66°, and 38.89° ± 0.2° 20. 5. A besylate salt of Momelotinib, characterized by an XRPD pattern comprising peaks at 4.77°, 14.61°, 15.15°, 16.09°, 17.54°, 18.11°, 19.19°, 23.10°, 23.70°, and 24.49° ± 0.2° 20 or an XRPD pattern as depicted in Figure 8. 6. The besylate salt as claimed in claim 5, characterized by an XRPD pattern comprising peaks at 8.29°, 9.55°, 10.31°, 10.87°, 11.62°, 13.16°, 13.85°, 14.12°, 18.93°, 19.86°, 20.72°, 21.85°, 22.54°, 23.38°, and 24.85° ± 0.2° 20. 7. The besylate salt as claimed in claim 5 or 6, characterized by an XRPD pattern comprising peaks at 25.78°, 26.35°, 27.22°, 28.06°, 28.80°, 29.92°, 31.08°, 31.60°, 33.05°, 33.63°, 34.70°, 34.87°, 35.55°, 36.88°, 37.28°, 38.37°, and 39.02° ± 0.2° 20. 8. A triflate salt of Momelotinib, characterized by an XRPD pattern comprising peaks at 15.13°, 18.09°, 19.09°, 20.24°, 21.29°, 21.71°, 22.89°, 24.10°, 27.77° and 30.32° ± 0.2° 20 or an XRPD pattern as depicted in Figure 9. The triflate salt as claimed in claim 8, characterized by an XRPD pattern comprising peaks at 5.38°, 8.40°, 9.89°, 10.14°, 10.58°, 10.88°, 11.59°, 13.56°, 13.91°, 15.33°, 15.80°, 16.30°, 17.35°, 18.52°, and 19.73° ± 0.2° 29. The triflate salt as claimed in claim 8 or 9, characterized by an XRPD pattern comprising peaks at 23.51°, 25.23°, 25.64°, 26.60°, 27.33°, 28.12°, 28.56°, 30.74°, 31.38°, 32.17°, 35.16°, 36.34°, 37.86°, 38.25°, and 38.85° ± 0.2° 29. The salt as claimed in any of claims 1 to 10, wherein the salt is crystalline. A solid dispersion comprising momelotinib dihydrochloride and at least one pharmaceutically acceptable excipient. The solid dispersion as claimed in claim 12, wherein the solid dispersion is amorphous solid dispersion. The solid dispersion as claimed in claim 12 or 13, wherein the pharmaceutically acceptable excipient is selected from a group comprising 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 acetatepolyethylene, glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, water soluble sugar excipients, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like, organic amines such as alkyl amines and guanidine or its derivatives, colloidal silica, and mixtures thereof. The process for preparation of solid dispersion as claimed in any of claims 12 to 14, comprising the step of combining momelotinib dihydrochloride with at least one pharmaceutically acceptable excipient in the presence of a suitable solvent. The process as claimed in claim 15, wherein the solvent is selected from a group comprising methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2- pentanol, 3 -pentanol, tetrahydrofuran, 2-methyl -tetrahydrofuran, 1-4-dioxane, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water, and mixtures thereof. A process for the preparation of momelotinib free base, comprising preparing momelotinib salt and converting the momelotinib salt to momelotinib free base. The process as claimed in claim 17, wherein the salt is an acid addition salt. The process as claimed in claim 17 or 18, wherein the acid addition salt is selected from a group comprising hydrochloride, dihydrochloride, bromide, sulfate, phosphate, perchlorate, formate, oxalate, trifluoroacetate, trichloroacetate, mesylate, tosylate, besylate, triflate, napsylate, camphorsulfonate and p-nitrobenzenesulfonate. The process as claimed in claim 19, wherein the acid addition salt of Momelotinib is selected from a group comprising tosylate, besylate, hydrochloride, dihydrochloride or triflate. The process as claimed in any of claims 17 to 20, wherein the final momelotinib free base has a purity of more than about 98.5% by HPLC. The process as claimed in claim 17, wherein converting the momelotinib salt to momelotinib free base comprises neutralizing the momelotinib salt with a base. The process as claimed in claim 17, wherein the base is an inorganic base selected from a group comprising a hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, and a combination thereof, or an organic base selected from a group comprising triethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine, and a combination thereof. The process as claimed in claim 22 or 23, wherein the neutralization is carried out in a solvent selected from a group comprising ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxyethanol, 1- butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and Ci-Ce alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons such as hexane and heptane; nitriles such as acetonitrile; esters such as ethyl acetate; polar aprotic solvents such as DMF, DMSO, DMAc; water and any mixtures of two or more thereof. The process as claimed in claim 24, wherein the solvent is water. The process as claimed in any of claims 17 to 25, wherein obtained momelotinib is crystalline. A solid form of momelotinib free base characterized by an XRPD pattern comprising peaks at 4.21, 12.76, 15.26, 17.45, 20.01, 20.75, 21.72, 23.53, 26.13 and 28.02° ± 0.2° 20 or an XRPD pattern as depicted in Figure 12. The solid form as claimed in 27, wherein an XRPD pattern comprising peaks at 8.36°, 10.15°, 11.13°, 11.96°, 13.96°, 15.99°, 16.37°, 18.69°, 24.12°, 24.53°, 25.53°, 27.11°, and 29.30° ± 0.2° 20. The solid form as claimed in 27, wherein an XRPD pattern comprising peaks at 29.84°, 30.88°, 31.47°, 32.87°, 33.39°, 34.07°, 34.54°, 35.11°, 35.78°, 37.23°, 38.06°, and 39.07° ± 0.2° 20. The free base as claimed in any of claims 27 to 29, wherein the free base is crystalline. A pharmaceutical composition comprising an acid addition salt as claimed in any of claims 1 to 11, or a solid dispersion as claimed in any of claims 12 to 14, or a solid form as claimed in any of claim 27 to 29, or a free base as claimed in claim 30 and optionally a pharmaceutically acceptable excipient. A method of preventing or treating a condition or a disorder or a disease in a subject, comprising administering to the subject an effective amount of an acid addition salt as claimed in any of claims 1 to 11, or a solid dispersion as claimed in any of claims 12 to 14, or a solid form as claimed in any of claim 27 to 29, or a free base as claimed in claim 30 or a pharmaceutical composition as claimed in claim 31, wherein the condition or disorder or disease can be ameliorated with Janus kinase (JAK) inhibition. An acid addition salt as claimed in any of claims 1 to 11, or a solid dispersion as claimed in any of claims 12 to 14, or a solid form as claimed in any of claim 27 to 29, or a free base as claimed in claim 30 or a pharmaceutical composition as claimed in claim 31, used for the condition or disorder or disease that can be ameliorated with Janus kinase (JAK) inhibition. |
The present invention relates to the Amorphous Solid Dispersions (ASDs) of Momelotinib di-hydrochloride and processes for preparation thereof. Also, it relates to the processes of preparing Momelotinib salts and their use as means to purify the free base.
BACKGROUND OF THE INVENTION
The IUPAC name of drug, Momelotinib is N-(Cyanomethyl)-4-{2-[4- (morpholin-4-yl)anilino]pyrimidin-4-yl} benzamide, and is represented by the structure of formula below:
Momelotinib
Momelotinib is a potent, selective, and orally bioavailable JAK1, JAK2 & ACVR1 inhibitor which is being developed by Sierra Oncology, Inc. as a therapeutic agent in the treatment of myelofibrosis.
US 9809559 B2 discloses the PXRD and thermal characterization data for two forms of the di-hydrochloride salt (anhydrous Form I and monohydrate Form II) and two forms of the mono-hydrochloride salt (anhydrous Forms I and III).
It is very well known that crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is also well known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and, in some cases, different bioavailability patterns as compared to the crystalline form (Chem. Pharm. Bull. 1990, 38, 2003). For some therapeutic indications, one bioavailability pattern may be favored over another. Amorphous form of Cefuroxime axetil, Venetoclax and Apalutamide are good examples that exhibit higher bioavailability than the crystalline form. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also have highly reproducible processes for their preparation.
Amorphous solid dispersions of drugs are known to generally improve the stability and solubility of drug products. However, such dispersions are generally unstable over time. Amorphous solid dispersions of drugs tend to convert to crystalline forms over time, which can lead to improper dosing due to differences of the solubility of crystalline drug material compared to amorphous drug material. In view of the above, it is therefore, desirable to prepare a stable amorphous form of Momelotinib salts, particularly Momelotinib di-hydrochloride. The present invention, however, provides stable amorphous dispersions of Momelotinib di-hydrochloride. Moreover, the present invention provides solid dispersions of Momelotinib di-hydrochloride which may be reproduced easily and is amenable for processing into a dosage form.
Momelotinib free base exhibits low to extremely low solubility in common organic solvents (such as methanol, ethyl acetate, isopropanol, ethanol, acetonitrile and dichloromethane) and is quite resistant to purification via usually employed techniques such as re-crystallization, trituration and column chromatography. US 8486941B2 describes the synthesis and NMR characterization of Momelotinib free base and its hydrochloride, sulfate and methanesulfonate salts. The present inventors have observed that the process of preparation of Momelotinib free base via the neutralization of certain salt forms (e.g., hydrochloride, di -hydrochloride, besylate) of Momelotinib improves the chemical purity.
Finding a suitable excipient and process to form a stable ASD with Momelotinib di-hydrochloride is no way obvious. The process required the inventors to undertake extensive screening of excipients, solvents (that will dissolve both API and excipient) and conditions for solvent removal. For example, lyophilization of a solution of Momelotinib di -hydrochloride in water or water-acetonitrile did not afford a pure amorphous phase even after being ground together with Syloid. Similarly, a mixture of Momelotinib di -hydrochloride and PVP K-30, when taken in water alone, led to an opalescent solution which soon started to flocculate. With regards to the purification of Momelotinib, it is apparent that not all salts of Momelotinib are serviceable for this purpose.
SUMMARY OF THE INVENTION
An aspect of the present invention provides an amorphous solid dispersion of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient.
Another aspect of the present invention provides a stable amorphous premix comprising an amorphous solid dispersion of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient and Syloid.
Another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of di-hydrochloride salt of Momelotinib, comprising the steps of providing a solution of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient in a solvent and removing the solvent.
Yet another aspect of the present invention provides a process for the preparation of Momelotinib, comprising the step of releasing Momelotinib free base from its salt by neutralization.
Yet another aspect of the present invention provides the salt form of Momelotinib selected from the group consisting of -toluenesulfonate (tosylate), benzenesulfonate (besylate) and trifluoromethanesulfonate (triflate) salts of Momelotinib.
Yet another aspect of the present invention provides a pharmaceutical composition comprising Momelotinib or its di-hydrochloride salt, obtained according to the processes of above aspects and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Momelotinib di -hydrochloride and PVP K-30 prepared by the method of Example No. 2(a).
Figure 2 is an illustrative X-ray powder diffraction pattern of premix of amorphous solid dispersion of Momelotinib di -hydrochloride and PVP K-30 with Syloid prepared by the method of Example No. 2(b).
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Momelotinib di-hydrochloride and Copovidone prepared by the method of Example No. 2(c).
Figure 4 is an illustrative X-ray powder diffraction pattern of premix of amorphous solid dispersion of Momelotinib di-hydrochloride and Copovidone with Syloid prepared by the method of Example No. 2(d).
Figure 5 is an illustrative X-ray powder diffraction pattern of Momelotinib dihydrochloride prepared by the method of Example No. 3(a).
Figure 6 is an illustrative X-ray powder diffraction pattern of Momelotinib mesylate prepared by the method of Example No. 3(b).
Figure 7 is an illustrative X-ray powder diffraction pattern of Momelotinib tosylate prepared by the method of Example No. 3(c).
Figure 8 is an illustrative X-ray powder diffraction pattern of Momelotinib besylate prepared by the method of Example No. 3(d).
Figure 9 is an illustrative X-ray powder diffraction pattern of Momelotinib triflate prepared by the method of Example No. 3(e).
Figure 10 is an illustrative X-ray powder diffraction pattern of Momelotinib sulfate prepared by the method of Example No. 3(f).
Figure 11 is an illustrative X-ray powder diffraction pattern of Momelotinib hydrochloride prepared by the method of Example No. 3(g).
Figure 12 is an illustrative X-ray powder diffraction pattern of Momelotinib free base prepared by the method of Example No. 4(h). DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention provides an acid addition salt of Momelotinib, wherein salt is selected from a group comprising tosylate, besylate and triflate.
Another aspect of the present invention provides an acid addition salt of Momelotinib, wherein salt is selected from a group consisting tosylate, besylate and triflate.
Yet another aspect of the present invention provides a tosylate salt of Momelotinib, characterized by X-ray powder diffraction (XRPD) pattern comprising peaks at 4.46°, 10.38°, 13.90°, 14.74°, 16.53°, 23.07°, 20.33°, 23.92°, 26.34° and 27.78° ± 0.2° 20 or an XRPD pattern as depicted in Figure 7.
Yet another aspect of the present invention provides the tosylate salt, wherein an XRPD pattern comprising peaks at 8.90°, 9.47°, 11.44°, 13.32°, 15.27°, 16.20°, 17.36°, 19.07°, 19.63°, 20.80° and 22.26° ± 0.2° 20.
Yet another aspect of the present invention provides the tosylate salt, wherein an XRPD pattern comprising peaks at 22.67°, 24.41°, 24.93°, 25.87°, 28.88°, 29.84°, 31.03°, 33.63°, 34.40°, 35.39°, 36.66° and 38.89° ± 0.2° 20.
Yet another aspect of the present invention provides a besylate salt of Momelotinib, characterized by an XRPD pattern comprising peaks at 4.77°, 14.61°, 15.15°, 16.09°, 17.54°, 18.11°, 19.19°, 23.10°, 23.70°, and 24.49° ± 0.2° 20 or an XRPD pattern as depicted in Figure 8.
Yet another aspect of the present invention provides the besylate salt, wherein an XRPD pattern comprising peaks at 8.29°, 9.55°, 10.31°, 10.87°, 11.62°, 13.16°, 13.85°, 14.12°, 18.93°, 19.86°, 20.72°, 21.85°, 22.54°, 23.38° and 24.85° ± 0.2° 20.
Yet another aspect of the present invention provides the besylate salt, wherein an XRPD pattern comprising peaks at 25.78°, 26.35°, 27.22°, 28.06°, 28.80°, 29.92°, 31.08°, 31.60°, 33.05°, 33.63°, 34.70°, 34.87°, 35.55°, 36.88°, 37.28°, 38.37° and 39.02° ± 0.2° 20. Yet another aspect of the present invention provides a triflate salt of Momelotinib, characterized by an XRPD pattern comprising peaks at 15.13°, 18.09°, 19.09°, 20.24°, 21.29°, 21.71°, 22.89°, 24.10°, 27.77° and 30.32° ± 0.2° 20 or an XRPD pattern as depicted in Figure 9.
Yet another aspect of the present invention provides the triflate salt, wherein an XRPD pattern comprising peaks at 5.38°, 8.40°, 9.89°, 10.14°, 10.58°, 10.88°, 11.59°, 13.56°, 13.91°, 15.33°, 15.80°, 16.30°, 17.35°, 18.52° and 19.73° ± 0.2° 20.
Yet another aspect of the present invention provides the triflate salt, wherein an XRPD pattern comprising peaks at 23.51°, 25.23°, 25.64°, 26.60°, 27.33°, 28.12°, 28.56°, 30.74°, 31.38°, 32.17°, 35.16°, 36.34°, 37.86°, 38.25° and 38.85° ± 0.2° 20.
Yet another aspect of the present invention provides the salt, wherein the salt is crystalline.
Yet another aspect of the present invention provides a solid dispersion comprising momelotinib di-hydrochloride and at least one pharmaceutically acceptable excipient.
Yet another aspect of the present invention provides the solid dispersion, wherein the solid dispersion is amorphous solid dispersion.
Yet another aspect of the present invention provides the solid dispersion, wherein the pharmaceutically acceptable excipient is selected from a group comprising 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 caprolactampolyvinyl acetatepolyethylene, glycol graft copolymer (PCL-PV Ac-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, water soluble sugar excipients, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like, organic amines such as alkyl amines and guanidine or its derivatives, colloidal silica, and mixtures thereof.
Yet another aspect of the present invention provides the process for preparation of solid dispersion comprising the step of combining momelotinib di-hydrochloride with at least one pharmaceutically acceptable excipient in the presence of a suitable solvent.
Yet another aspect of the present invention provides the process, wherein the solvent is selected from a group comprising methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2-pentanol, 3 -pentanol, tetrahydrofuran, 2-methyl- tetrahydrofuran, 1-4-di oxane, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water, and mixtures thereof.
Yet another aspect of the present invention provides a process for the preparation of momelotinib free base, comprising preparing momelotinib salt and converting the momelotinib salt to momelotinib free base.
Yet another aspect of the present invention provides the process, wherein the salt is an acid addition salt.
Yet another aspect of the present invention provides the process, wherein the acid addition salt is selected from a group comprising hydrochloride, di-hydrochloride, bromide, sulfate, phosphate, perchlorate, formate, oxalate, trifluoroacetate, trichloroacetate, mesylate, tosylate, besylate, triflate, napsylate, camphorsulfonate and p-nitrobenzenesulfonate. Yet another aspect of the present invention provides the process, wherein the acid addition salt of Momelotinib is selected from a group comprising tosylate, besylate, hydrochloride, di-hydrochloride or triflate.
Yet another aspect of the present invention provides the process, wherein the final momelotinib free base has a purity of more than about 98.5% by HPLC.
Yet another aspect of the present invention provides the process, wherein converting the momelotinib salt to momelotinib free base comprises neutralizing the momelotinib salt with a base.
Yet another aspect of the present invention provides the process, wherein the base is an inorganic base selected from a group comprising a hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, and a combination thereof, or an organic base selected from a group comprising tri ethylamine, diisopropylethylamine, pyridine, 2,6- dimethylpyridine, and a combination thereof.
Yet another aspect of the present invention provides the process, wherein the neutralization is carried out in a solvent selected from a group comprising ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxy ethane; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2- propanol, 2-methoxy ethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and Ci-Ce alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons such as hexane and heptane; nitriles such as acetonitrile; esters such as ethyl acetate; polar aprotic solvents such as DMF, DMSO, DMAc; water and any mixtures of two or more thereof.
Yet another aspect of the present invention provides the process, wherein the solvent is water.
Yet another aspect of the present invention provides the process, wherein obtained momelotinib is crystalline. Yet another aspect of the present invention provides a solid form of momelotinib free base characterized by an XRPD pattern comprising peaks at 4.21, 12.76, 15.26, 17.45, 20.01, 20.75, 21.72, 23.53, 26.13 and 28.02° ± 0.2° 20 or an XRPD pattern as depicted in Figure 12.
Yet another aspect of the present invention provides the solid form, wherein an XRPD pattern comprising peaks at 8.36°, 10.15°, 11.13°, 11.96°, 13.96°, 15.99°, 16.37°, 18.69°, 24.12°, 24.53°, 25.53°, 27.11° and 29.30° ± 0.2° 20.
Yet another aspect of the present invention provides the solid form, wherein an XRPD pattern comprising peaks at 29.84°, 30.88°, 31.47°, 32.87°, 33.39°, 34.07°, 34.54°, 35.11°, 35.78°, 37.23°, 38.06° and 39.07° ± 0.2° 20.
Yet another aspect of the present invention provides the free base, wherein the free base is crystalline.
Yet another aspect of the present invention provides a pharmaceutical composition comprising an acid addition salt, or a solid dispersion, or a solid form, or a free base and optionally a pharmaceutically acceptable excipient.
Yet another aspect of the present invention provides a method of preventing or treating a condition or a disorder or a disease in a subject, comprising administering to the subject an effective amount of an acid addition salt, or a solid dispersion, or a solid form, or a free base or a pharmaceutical composition, wherein the condition or disorder or disease can be ameliorated with Janus kinase (JAK) inhibition.
Yet another aspect of the present invention provides an acid addition salt, or a solid dispersion, or a solid form, or a free base or a pharmaceutical composition, used for the condition or disorder or disease that can be ameliorated with Janus kinase (JAK) inhibition.
Yet another aspect of the present invention provides pharmaceutical composition or a solid form or a free base or a process, wherein at least one pharmaceutically acceptable excipient 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 caprolactampolyvinyl acetate-polyethylene glycol graft copolymer (PCL-PV Ac-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 application. 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. Solid dispersions of the present application also include the solid dispersions obtained by combining di-hydrochloride salt of Momelotinib with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the present invention. Another aspect of the present invention provides a stable amorphous premix comprising an amorphous solid dispersion of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient and Syloid. Syloid may be Syloid 244 FP.
In another aspect of the present invention, the amorphous solid dispersion of dihydrochloride salt of Momelotinib may be combined with Syloid or any other suitable additional pharmaceutically acceptable excipient to obtain premix of this aspect.
In another aspect of the present invention, the amorphous solid dispersion of di-hydrochloride salt of Momelotinib may be combined with Syloid or any other suitable additional excipient using a technique known in art or according to the previous aspects of the present invention such as grinding together in mortar-pestle.
Yet another aspect of the present invention provides a pharmaceutical composition comprising amorphous solid dispersion of di-hydrochloride salt of Momelotinib or premix thereof.
Yet another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of di-hydrochloride salt of Momelotinib, comprising the step of providing a solution of di-hydrochloride salt of Momelotinib together with at least one pharmaceutically acceptable excipient in a solvent and removing the solvent.
In another aspect of the present invention, the process produces amorphous solid dispersion of di-hydrochloride salt of Momelotinib.
In another aspect of the present invention, the solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, 1 -butanol, 2-butanol, 1 -pentanol, 2- pentanol, 3 -pentanol, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1-4-dioxane, acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, water, and mixtures thereof. In another aspect of the present invention, providing a solution may be carried out by dissolving di-hydrochloride salt of Momelotinib and at least one pharmaceutically acceptable excipient simultaneously or separately in same or different solvents.
In another aspect of the present invention, a solution of di-hydrochloride salt of Momelotinib and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In another aspect of the present invention, a solution of di-hydrochloride salt of Momelotinib and the excipient may be filtered to make it clear and free of unwanted particles.
In another aspect of the present invention, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In another aspect of the present invention, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present inventio.
In another aspect of the present invention, removal of solvent may include, but not limited to solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying, agitated thin film drying and the like.
In a preferred aspect of the present invention, the solvent may be removed under reduced pressures, at temperatures of less than about 100 °C, less than about 80 °C, less than about 40 °C, less than about 20 °C, less than about 0 °C, less than about -20 °C, less than about -40 °C, less than about -60 °C, less than about -80 °C, or any other suitable temperatures.
In another aspect of the present invention, the isolation of an amorphous solid dispersion of di-hydrochloride salt of Momelotinib with excipient involves recovering the solid obtained. The solid may be recovered using techniques such as by scraping, or by shaking the container, or triturating with a solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In another aspect of the present invention, the amorphous solid dispersion of di-hydrochloride salt of Momelotinib and excipient obtained may be optionally dried before or after isolating.
Yet another aspect of the present invention provides a process for the preparation of Momelotinib, comprising the step of releasing Momelotinib free base from its salt by neutralization.
In another aspect of the present invention, the neutralization of a salt of Momelotinib may be carried out by treating the salt with a base. Suitable bases may include, but are not limited to hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, or the like; 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; organic bases, such as triethylamine, diisopropylethylamine, pyridine, 2,6-dimethylpyridine or the like.
In another aspect of the present invention, neutralization may be carried out at a suitable temperature of about 0 °C or above.
In yet another aspect of the present invention, the salt may be treated with a base at a suitable temperature of about 0 °C or above.
In another aspect of the present invention, Momelotinib may be obtained as solid directly on neutralization of the salt of Momelotinib.
In yet another aspect of the present invention, solid may be precipitated by cooling or addition of anti-solvent to the reaction mixture containing Momelotinib.
In another aspect of the present invention, the solid Momelotinib obtained according to the process of this aspect may be separated according suitable techniques such as filtration or centrifugation.
In another aspect of the present invention, the solid Momelotinib may be dried under suitable drying conditions such as suitable temperature and pressure. In another aspect of the present invention, the solid form of Momelotinib obtained according to the process of this aspect may be in amorphous state.
In another aspect of the present invention, the solid form of Momelotinib obtained according to the process of this aspect may be any crystalline form reported in the literature.
In another aspect of the present invention, the inventors have identified that the process of preparation of Momelotinib through the neutralization of certain salt forms of Momelotinib surprisingly improves the chemical purity significantly as illustrated below. % (NH40Hwas used for neutralization)
Yet another aspect of the present invention provides Momelotinib obtained according to the processes of the present invention, having a chemical purity of at least 99% or at least 99.5 or at least 99.9%, by HPLC.
In another aspect of present invention, Momelotinib or its pharmaceutically acceptable salt or free base may be prepared according to any of the methods known in the art (J. Heterocycl. Chem., 2017, 54, 2902-2905 and J. Chem. Res., 2016, 40, 511- 513).
In another aspect of the present invention, ASDs of Momelotinib salt is used for the treatment of cancer such as myelofibrosis.
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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
DEFINITIONS
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. The term “inert solvent” when used in the present application is a solvent that does not react with the reactants or reagents under conditions that cause the chemical reaction indicated to take place.
"Substantially" amorphous denotes that 90 %, preferably 95 % or 99 %, more preferably all of the di-hydrochloride salt of Momelotinib being present in the solid dispersion, on the adsorbate or in the pharmaceutical composition is amorphous. In other words, an "amorphous" Momelotinib di-hydrochloride salt composition denotes a Momelotinib di-hydrochloride salt-containing composition, which does not contain substantial amounts, preferably does not contain noticeable amounts, of crystalline portions of Momelotinib di-hydrochloride salt e.g., measurable upon X-ray powder diffraction analysis.
The term "solid dispersion" when used in the present application, denotes a state where most of the di -hydrochloride salt of Momelotinib, preferably 90%, 95% or all of the di-hydrochloride salt of Momelotinib of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one- phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
EXAMPLES
The scope of the present invention is illustrated by the following examples as disclosed herein which are not meant to restrict the scope of the invention in any manner whatsoever.
Example 1: Preparation of Momelotinib
Momelotinib may be prepared according to any of the methods known in the art such as Heterocycl. Chem., 2017, 54, 2902-2905 and J. Chem. Res., 2016, 40, 511-513 (Scheme 1).
Scheme 1
Example 2: Preparation of amorphous solid dispersion (ASD) of Momelotinib dihydrochloride (a): Preparation of ASD with PVP K-30.
To a mixture of acetonitrile (5 mL) and Dl-water (15 mL), Momelotinib dihydrochloride (80 mg) followed by PVP K-30 (80 mg) were added at 27 °C. The resultant mixture was stirred at the same temperature for 15 minutes. The solution obtained was filtered and was then frozen at -78 °C. The frozen solution was lyophilized for 18 hours under reduced pressure to obtain 145 mg of the title compound. PXRD: Amorphous. (b) : Preparation of ASD with PVP K-30. and its premix with Syloid
To a mixture of acetonitrile (5 mL) and DI- water (15 mL), Momelotinib dihydrochloride (80 mg) followed by povidone K-30 (80 mg) were added at 27 °C. The resultant mixture was stirred at the same temperature for 15 minutes. The solution obtained was filtered and was then frozen at -78 °C. The frozen solution was lyophilized for 18 hours under reduced pressure to obtain 145 mg of the solid dispersion. The solid dispersion (40 mg) was mixed with Syloid 244 FP (40 mg) and ground in a mortar-pestle for 10-15 minutes to obtain the title premix: PXRD: Amorphous. (c): Preparation of ASP with Copovidone.
To a mixture of acetonitrile (10 mL) and DI- water (20 mL), Momelotinib dihydrochloride (80 mg) followed by Copovidone (80 mg) were added at 27 °C. The resultant mixture was stirred at the same temperature for 15 minutes. The solution obtained was filtered and was then frozen at -78 °C. The frozen solution was lyophilized for 18 hours under reduced pressure to obtain 148 mg of the title compound. PXRD: Amorphous. (d) : Preparation of ASP with Copovidone, and its premix with Syloid
To a mixture of acetonitrile (10 mL) and DI- water (20 mL), Momelotinib dihydrochloride (80 mg) followed by Copovidone (80 mg) were added at 27 °C. The resultant mixture was stirred at the same temperature for 15 minutes. The solution obtained was filtered and was then frozen at -78 °C. The frozen solution was lyophilized for 18 hours under reduced pressure to obtain 148 mg of the title compound as solid dispersion. The solid dispersion (40 mg) was mixed with Syloid 244 FP (40 mg) and ground in a mortar-pestle for 10-15 minutes to obtain the title premix. PXRD: Amorphous.
Example 3: Preparation of Momelotinib salts (a): Preparation of Momelotinib di-hydrochloride
To a stirred suspension of Momelotinib (1.5 g, HPLC purity: 98.21%) in methanol (135 mL), saturated IPA-HC1 (6 mL) was added whereupon the suspension turned in to a clear solution. The reaction mixture turned in to a yellow colored suspension after 20- 30 min, and the suspension was stirred for 2 h at room temperature. The suspension was filtered, washed with methanol (4.5 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 1.4 g of the title compound as a yellow colored solid (HPLC purity: 99.50%, HC1 content: 14.87% w/w) (b): Preparation of Momelotinib mesylate
To a stirred suspension of Momelotinib (500 mg, HPLC purity: 98.21%) in methanol (10 mL), methanesulfonic acid (266.6 mg) was added whereupon the suspension turned in to a clear solution momentarily before converting into a suspension again. The yellow colored suspension obtained was stirred for 2 h at room temperature. The suspension was filtered, washed with methanol (1.5 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 580 mg of the title compound as a yellow colored solid (HPLC purity: 99.20%, methanesulfonic acid content: 31.86%). (c): Preparation of Momelotinib tosylate
To a stirred suspension of Momelotinib (500 mg, HPLC purity: 98.21%) in methanol (10 mL), /?-toluenesulfonic acid (478 mg) was added whereupon the suspension turned in to a clear solution momentarily before converting into a suspension again. The yellow colored suspension obtained was stirred for 2 h at room temperature. The suspension was filtered, washed with methanol (1.5 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 520 mg of the title compound as a yellow colored solid (HPLC purity: 97.68%, /?-toluenesulfonic acid content: 44.53%). 'H NMR (400 MHz, DMSO-r/e): d = 2.28 (s, 6H), 3.48 (br. s, 4H), 3.93 (br. s, 4H), 4.36 (d, J= 5.6 Hz, 2H), 6.50 (br. s, 3 H), 7.13 (d, 7=8.0 Hz, 4H), 7.50 (d, 7=8.0 Hz, 5H), 7.55 (d, J=5.2 Hz,lH), 7.91 (d, 7=8.4 Hz, 2H), 8.05 (d, 7=8.4Hz, 2H), 8.30 (d, 7=8.4 Hz, 2H), 8.62 (d, J=5.2 Hz, 1H), 9.36 (t, J =5.2 Hz, 1H), 9.99 (s, 1H). (d): Preparation of Momelotinib besylate
To a stirred suspension of Momelotinib (500 mg, HPLC purity: 98.21%) in methanol (10 mL), benzenesulfonic acid (439 mg) was added whereupon the suspension turned in to a clear solution momentarily before converting into a suspension again. The yellow colored suspension obtained was stirred for 2 h at room temperature. The suspension was filtered, washed with methanol (1.5 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 680 mg of the title compound as a yellow colored solid (HPLC purity: 99.48%, benzenesulfonic acid content: 45.30%). NMR (400 MHz, DMSO-r/e): d = 3.54 (br. s, 4H), 3.95 (br. s, 4H), 4.36 (d, J=5.2 Hz, 2H), 7.33- 7.31 (m, 5H), 7.57 (d, J=5.2 Hz, 3H), 7.63-7.61 (m, 3H), 7.94 (d, J=8.8 Hz, 2H), 8.05 (d, J= 8.4Hz, 2H), 8.30 (d, J=8.4 Hz,2H), 8.63 (d, J=8.4 Hz, 1H), 9.38 (t, J =5.2 Hz, 1H), 10.0 (s, 3H). (e): Preparation of Momelotinib triflate
To a stirred suspension of Momelotinib (500 mg, HPLC purity: 98.21%) in methanol (10 mL), trifluoromethanesulfonic acid (416.4 mg) was added whereupon the suspension turned in to a clear solution momentarily before converting into a suspension again. The yellow colored suspension obtained was stirred for 2 h at room temperature. The suspension was filtered, washed with methanol (1.5 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 620 mg of the title compound as a yellow colored solid (HPLC purity: 98.53%, triflic acid content: 41.51%). (400 MHz, DMSO-r/e): d = 3.44 (br. s, 4H), 3.91 (br. s, , 4H), 4.36 (d, J=5.2 Hz, 2H), 6.4- 7.25 (br. s, 2H), 7.42 (d, J=5.6 Hz, 2H), 7.54 (d, J=5.2Hz, 2H), 7.89 (d, J=8.8 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 8.30 (d, J =8.4 Hz, 2H), 8.62 (d, J =5.2 Hz, 2H), 9.35 (t, J= 5.2 Hz, 1H), 9.93 (s, 1H). (f): Preparation of Momelotinib sulfate
To a stirred suspension of Momelotinib (250 mg) in methanol (25 mL), concentrated sulfuric acid (1.0 mL) was added dropwise at 27 °C whereupon the suspension turned in to a clear brown solution. The reaction mixture turned in to a suspension after 5-10 min, and the suspension was stirred for 4 h at 27 °C. The suspension was filtered and dried under reduced pressure for 2 h to obtain 315 mg of the title compound as a pale yellow solid (HPLC purity: 96.95%, sulfuric acid content: 32.92%). (g): Preparation of Momelotinib hydrochloride
To a stirred suspension of Momelotinib (51 g, HPLC purity: 96.22%) in methanol (2.55 L), saturated IPA-HC1 (204 mb) was added whereupon the suspension turned in to a clear solution. After completion of addition, the reaction mixture gradually turned in to a yellow colored suspension, and the suspension was stirred for 2-3 h at room temperature. The suspension was filtered, washed with methanol (2 X 100 mb), heptane (100 mb) and dried under reduced pressure at 45 °C for 3 h to obtain 44.9 g of the title compound as a yellow colored solid (HPLC purity: 98.79%, HC1 content: 10.08% w/w).
Example 4: Preparation of Momelotinib free-base from salts (a) : Preparation of Momelotinib free-base from Momelotinib triflate
To a stirred suspension of Momelotinib triflate (100 mg) in water (4 mb), Na2CCh (45 mg) was added in a single portion whereupon the suspension turned in to a clear solution. After 5-10 min, the reaction mixture turned in to a yellow colored suspension which was stirred for 2 h at room temperature. The suspension filtered, washed with water (0.5 mb) and dried under reduced pressure at 45 °C for 3 h to afford 40 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 98.26% (b) : Preparation of Momelotinib free-base from Momelotinib besylate
To a stirred suspension of Momelotinib besylate (100 mg) in water (4 mb), Na2CO, (44 mg) was added in a single portion whereupon the suspension turned in to a clear solution. After 5-10 min, the reaction mixture turned in to a yellow colored suspension which was stirred for 2 h at room temperature. The suspension filtered, washed with water (0.5 mL) and dried under reduced pressure at 45 °C for 3 h to afford 42 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 99.01%. (c) : Preparation of Momelotinib free-base from Momelotinib tosylate.
To a stirred suspension of Momelotinib tosylate (100 mg) in water (4 mb), Na2CCh (42 mg) was added in a single portion whereupon the suspension turned in to a clear solution. After 5-10 min, the reaction mixture turned in to a yellow colored suspension which was stirred for 2 h at room temperature. The suspension filtered, washed with water (0.5 mb) and dried under reduced pressure at 45 °C for 3 h to afford 35 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 97.67% (d) : Preparation of Momelotinib free base from Momelotinib mesylate
To a stirred suspension of Momelotinib mesylate (100 mg) in water (4 mL), Na2CO, (53 mg) was added in a single portion whereupon the suspension turned in to a clear solution. After 5-10 min, the reaction mixture turned in to a yellow colored suspension which was stirred for 2 h at room temperature. The suspension filtered, washed with water (0.5 mL) and dried under reduced pressure at 45 °C for 3 h to afford 48 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 98.79%. (e) : Preparation of Momelotinib free base from Momelotinib di-hydrochloride salt
To a stirred suspension of Momelotinib di -hydrochloride salt (400 mg) in water (16 mL), Na2CO, (261 mg) was added in a single portion whereupon the suspension turned in to a clear solution. After 5-10 min, the reaction mixture turned in to a yellow colored suspension which was stirred for 2 h at room temperature. The suspension filtered, washed with water (2 mL) and dried under reduced pressure at 45 °C for 3 h to afford 300 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 99.47%. (f): Preparation of Momelotinib free base from Momelotinib besylate
To a stirred suspension of Momelotinib besylate (100 mg) in water (4 mL) was added concentrated aqueous ammonia solution dropwise. Once the pH of the reaction mixture reaches -10-12, the suspension momentarily turns in to a clear brown solution before becoming a yellow colored suspension again. The suspension was stirred for 2 h at room temperature and then filtered. The solid obtained was washed with water (0.5 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 43 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 98.52%. (g) : Preparation of Momelotinib freebase from Momelotinib di-hydrochloride salt using with ammonium hydroxide.
To a stirred suspension of Momelotinib di -hydrochloride salt (400 mg) in water (16 mL) was added concentrated aqueous ammonia solution dropwise. Once the pH of the reaction mixture reaches -10-12, the suspension momentarily turns in to a clear brown solution before becoming a yellow colored suspension again. The suspension was stirred for 2 h at room temperature and then filtered. The solid obtained was washed with water (2 mL) and dried under reduced pressure at 45 °C for 3 h to obtain 298 mg of Momelotinib free base as a yellow colored solid. HPLC purity: 99.62%. (h) : Preparation of Momelotinib freebase from Momelotinib hydrochloride salt using with ammonium hydroxide.
To a stirred suspension of Momelotinib hydrochloride (44.4 g) in water (1.776 L) was added 25% aqueous ammonia solution (310 mL) dropwise. Once the pH of the reaction mixture reaches -12, the suspension momentarily turns in to a clear solution before becoming a yellow colored suspension again. The suspension was stirred for 2-3 h at room temperature and then filtered. The solid obtained was washed with water (2X 133 mL) and dried under reduced pressure at 45 °C for 30-40 min to obtain 40.4 g of Momelotinib free base as a yellow colored solid. HPLC purity: 98.60%.