DESC:FIELD OF INVENTION
The present invention relates to a process for preparing Momelotinib of Formula (I) or its acid addition salts.

BACKGROUND OF THE INVENTION
Momelotinib Di HCl monohydrate is chemically described as N-(cyano methyl)-4-{2-[4- (morpholin-4-yl) anilino] pyrimidin-4-yl} benzamide di hydrochloride monohydrate.

Momelotinib dihydrochloride monohydrate is a kinase inhibitor indicated for the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF or secondary MF [post-polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia.

US 8,486,941(IN282013) describes Momelotinib or its pharmaceutical acceptable salts and its process for preparation, wherein the process involves hydrolysis of ethyl 4-(2-(4-morpholinophenylamino) pyrimidin-4-yl) benzoate to obtain 4-(2-(4-morpholinophenylamino) pyrimidin-4-yl) benzoic acid, followed by reacting with aminoacetonitrile hydrochloride in presence of EDC and HOBT to obtain Momelotinib.

US 9,604,935 describes the reaction of deuterated 4-(2-(4-(d8-morpholino) phenyl amino) pyrimidin-4-yl) methyl benzoate with amino acetonitrile HCl in presence of potassium carbonate and THF to obtain deuterated Momelotinib.

US RE48285 describes Momelotinib dihydrochloride anhydrous Form I and Momelotinib dihydrochloride monohydrate Form II.

Considering the importance of Momelotinib dihydrochloride in the pharmaceutical field, there remains to find a process with minimum step that produce Momelotinib in high yield and high purity in pharmaceutically acceptable quality.
SUMMARY OF THE INVENTION
In one aspect, present invention provides a process for the preparation of Momelotinib or its acid addition salt comprising the steps of:
(a) reacting compound of formula (III) with amino acetonitrile or its salts in a suitable solvent in presence of BBr3 ;

wherein R is alkyl;
(a) isolating Momelotinib or its salt.
In another aspect, present invention provides a process for the preparation of Momelotinib dihydrochloride substantially free from impurities selected from Formula (II), Formula (IV) and Formula (V) comprising the steps of:
i. obtaining the solution of Momelotinib in a suitable solvent;
ii. adding HCl to the reaction mass of step (a) or vice versa; and
iii. isolating Momelotinib dihydrochloride substantially free from Formula (II), Formula (IV) and Formula (V).

,

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: X-ray powder diffraction pattern of anhydrous crystalline Form I of Momelotinib di-hydrochloride.
Figure-2: X-ray powder diffraction pattern of product as obtained from Example 3, Step 2.
Figure-3: X-ray powder diffraction pattern of lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid.
Figure-4: X-ray powder diffraction pattern of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid.
DETAILED DESCRIPTION OF INVENTION
Definitions
The term “Alkyl” as used herein refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon mono radical having from one to about twenty carbon atoms, or from one to ten carbon atoms or from one to six carbon atoms, containing the indicated number of carbon atoms, for example, a C1-C6 alkyl group may have from 1 to 6 (inclusive) carbon atoms in it. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1- propyl and the like.

The term Momelotinib dihydrochloride substantially free from compound of Formula (II) , Formula (IV) and Formula (V) " refers to the of Momelotinib dihydrochloride having the content of compound of Formula (II) , Formula (IV) and Formula (V) in less than about 0.15% by weight, preferably less than about 0.1% by weight and still more preferably less than about 0.05% by weight compound of Formula (II) , Formula (IV) and Formula (V) as measured by HPLC method.

In an embodiment of the present invention, solvent as used in step (a) selected from including but not limited to chlorinated solvents such as dichloromethane, dichloroethane, chlorobenzene, chloroform, carbon tetrachloride and the like and hydrocarbons such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and the like.

In still another embodiment of the present invention, the reaction as defined in step (a) is carried out at temperature ranging from about 20?C to about 60?C or higher to obtain a reaction mixture. The reaction may be carried out for time periods ranging from about 30 minutes to about 5 hours, or longer.

In yet another embodiment of the present invention, reaction mixture obtained in step (a) is treated with aminoacetonitrile or its salts at temperature ranging from about 20?C to about 60?C or higher to obtain Momelotinib. The reaction may be carried out for time periods ranging from about 40 minutes to about 7 hours, or longer.

In an embodiment of the present invention, Momelotinib obtained is dissolved in suitable solvent; treated with a suitable acid in a suitable solvent or vice versa; to obtain Momelotinib acid addition salt.

In another embodiment of the present invention, the solvent used for dissolving Momelotinib is selected from solvent such as suitable alcohol solvents include ethanol, n-propanol, 2-propanol and butanol; ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate; ketones such as acetone, methyl ethyl ketone ,methyl isobutyl ketone; ethers include tetrahydrofuran, MTBE, dioxane; suitable polar aprotic solvent includes N,N-dimethylformamide, ?,?-dimethylacetamide, dimethyl sulphoxide, and N-methyl pyrrolidone.
In yet another embodiment of the present invention, suitable acid is selected from the group comprising but not limited to hydrochloric acid, phosphoric acid, sulfuric acid, p-toluene sulfonic acid, acetic acid, citric acid, nitric acid, tartaric acid, benzene sulfonic acid, benzoic acid, maleic acid, formic acid, trifluoroacetic acid and like. Suitable solvent is selected from the group comprising but not limited to alcohol solvents include ethanol, n-propanol, 2-propanol and butanol; ester solvents include ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers include tetrahydrofuran, MTBE, dioxane; suitable polar aprotic solvent includes N, N-dimethylformamide, ?, ?-dimethylacetamide, dimethyl sulphoxide, and N-methyl pyrrolidone.
In still another embodiment of the present invention provides process for the preparation of Momelotinib dihydrochloride substantially free from Formula (II), Formula (IV) and Formula (V) comprising the steps of:
i. obtaining a solution of Momelotinib in a suitable solvent;
ii. adding HCl to the reaction mass of step (a) or vice versa;
iii. isolating Momelotinib dihydrochloride substantially free from Formula (II), Formula (IV) and Formula (V).
,

In an embodiment of the present invention, the solution of Momelotinib in suitable solvent is obtained by (i) dissolving Momelotinib in suitable solvent is selected from alcohol solvents such as methanol, ethanol n-propanol, 2-propanol and butanol; ester solvents such as ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, MTBE, dioxane; polar aprotic solvent such as N,N-dimethylformamide, ?,?-dimethylacetamide, dimethyl sulphoxide, and N-methyl pyrrolidone.
In another embodiment of the present invention, the solution of Momelotinib in suitable solvent is obtained by dissolving Momelotinib in suitable solvent at a suitable temperature ranging from about room temperature to a reflux temperature of the solvent used.
In still another embodiment of the present invention, the HCl used in step (ii) is Conc. HCl, aqueous HCl or in the gaseous form or dissolved in a solvent such as alcohol solvents include methanol, ethanol, n-propanol and 2-propanol; ethers include MTBE, dioxane; ester solvents include ethyl acetate, isopropyl acetate, and n-butyl acetate; ketones such as acetone and methyl isobutyl ketone, More preferably methanolic HCl. or Conc. HCl is used.
Anhydrous Form I of Momelotinib DiHCl as obtained by the process of present invention is having PXRD pattern as shown in Fig. 1.
Alternatively, Momelotinib used for the preparation of Momelotinib dihydrochloride substantially free from Formula (II), Formula (IV) and Formula (V) can be prepared by the process as defined in below Scheme-I.

Scheme-I

In an embodiment the present invention provides lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid characterized by an X-ray powder diffraction pattern comprising peaks at 14.6°, 18.7°, 19.8°, 21.3°, 23.1° and 28.3°± 0.2° 2?.

In another embodiment the present invention provides use of lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid characterized by an X-ray powder diffraction pattern comprising peaks at 14.6°, 18.7°, 19.8°, 21.3°, 23.1° and 28.3°± 0.2° 2? in the preparation of Momelotinib or a salts thereof.

In yet another embodiment the present invention provides 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid characterized by an X-ray powder diffraction pattern comprising peaks at 12.93°, 15.31 °, 15.43 °, 18.19 °, 18.5°, 22.41 ° and 26.49 ° ± 0.2° 2? and its used in the preparation of Momelotinib or a salts thereof.

In still another embodiment the present invention provides a mixture of methyl 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoate and 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoic acid characterized by an X-ray powder diffraction pattern comprising peaks at 12.8, 24.2, 24.8 and28.3° ± 0.2° 2? and its used in the preparation of Momelotinib or a salts thereof.

In another embodiment of the present invention, Momelotinib DiHCl obtained according to the present invention can be optionally subjected to particle size reduction procedures before or after the completion of drying of the product to produce desired particle sizes and distributions. milling or micronization can be performed to achieve the desired particle sizes or distributions. Equipment that may be used for particle size reduction include, without limitation thereto, ball mills, roller mills, hammer mills, and jet mills.

In still another embodiment of the present invention, Momelotinib Di HCl used in the pharmaceutical compositions of the present invention, wherein 90 volume-percent of the particles (D90) have a size of less than or equal to about 200 microns, specifically less than or equal to about 150 microns, more specifically less than or equal to about 100 microns, still more specifically less than or equal to about 60 microns, and most specifically less than or equal to about 40 microns.

In an embodiment, the present application relates to a solid pharmaceutical composition comprising Momelotinib dihydrochloride of Formula (I), an antioxidant, and one or more other pharmaceutically acceptable excipients. The antioxidant may be selected from, but not limited to, ascorbic acid (vitamin C), ascorbate salt (such as sodium ascorbate), alpha-tocopherol/ tocopherol (vitamin E), or propyl gallate, triphenylphosphine, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid disodium salt, sodium sulfite, sodium metabisulfite, sodium bisulfite, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, thioglycerol, thioglycolic acid, D-a tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS).”

The present invention adopts following general method for the isolation such as methods including cooling, crash cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization or evaporation or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.

Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material like EDTA, N-acetyl-L-cysteine, SilaMetS thiol to remove metallic impurity, color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product.

In some embodiment anti-oxidants such as such as, but not limited to, citric acid, ascorbic acid, triphenylphosphine, 2,6-di-tert-butyl-4-methylphenol (BHT), butylated hydroxyanisole, a mixture of 2-tert-butylhydroxy anisole and 3-tert-butylhydroxy anisole (BHA), ethyl gallate (EtG) and propyl gallate (PrG) are used during synthesis, crystallization, isolation or storage of the product. The use of antioxidant may provide the Momelotinib dihydrochloride free of genotoxic impurity, like nitrosoamine impurity.

In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.
EXAMPLES
The chemical purity was measured by HPLC under the following conditions:
Column : XBridge C18 (250 x 4.6) mm, 3.5 µm
[Make : Waters, Part No.: 186003943]
: Ghost Buster (50 x 4.6) mm
[Make : Welch , Part No.: 06100-31000]
Detector wavelength : UV at 280 nm
Flow rate : 1.0 mL/minute
Injection volume : 10 µL
Run time : 70 minutes
Column oven temperature : 55 °C
Sample cooler temperature : 15 °C
Elution : Gradient
Diluent-I : Water
Diluent-II : Transfer 1.0 mL of triethylamine into 1000 mL water and mix well.
Example: 1
Preparation of Momelotinib
To a solution of methyl 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoate (1.0 eq.) in dichloromethane, solution of boron tri bromide (1.12 eq.) in dichloromethane was added at 20-30°C to obtain reaction mixture. To the reaction mixture, aminoacetonitrile. HCl (1.2 eq.) was added and the reaction mixture was stirred till completion of reaction. After completion of reaction, saturated aqueous sodium bicarbonate solution was added and layers were separated. Organic layer was distilled and Momelotinib was isolated using dimethylformamide and water mixture (1:3 ratio) at 20-30°C , dried under vacuum at 50-55°C to get the Momelotinib free base (75% yield).

Example: 2
Preparation of Momelotinib
To a solution of ethyl 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoate (1.0 eq.) in dichloromethane, solution of boron tri bromide (1.12 eq.) in dichloromethane was added at 20-30°C to obtain reaction mixture. To the reaction mixture, aminoacetonitrile. HCl (1.5 eq.) was added and the reaction mixture was stirred till completion of reaction. After completion of reaction, saturated aqueous sodium bicarbonate solution was added and layers were separated. Organic layer was distilled and Momelotinib was isolated using dimethylformamide and water mixture (1:3 ratio) at 20-30°C , dried under vacuum at 50-55°C to get the Momelotinib free base (76% yield).

Example: 3
Preparation of Momelotinib
Step 1: To a solution of dimethyl formamide-dimethyl acetal (375 mL), methyl-4-acetyl benzoate was added at 27±3°C. The reaction mixture was heated to 70-95°C and then stirred for 15 hours at the same temperature. After the completion of reaction, reaction mixture was cooled to 27±3°C, acetonitrile was added, stirred, filtered and dried under VTD to obtain methyl 4-(3-dimethylamino) -2-propenoyl) benzoate (70-85 % Yield).

Step 2: To a solution of methyl 4-(3-dimethylamino)-2-propenoyl) benzoate (100g) in DMF (700 mL), N-[4-(morpholin-4-yl) phenyl] guanidine and potassium carbonate (118.57 g) was added at 27±3°C. The reaction mixture was heated to 120- 130°C and then stirred for 15 hours at the same temperature. After the completion of reaction, reaction mixture was cooled to 27±3°C, THF was added, stirred, filtered, washed with mixture of DMF and THF and dried under VTD to obtain a mixture of methyl 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoate and 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoic acid.
The X-ray powder diffraction pattern is the same as that shown in FIG. 2.

Step 3: To a solution of methyl 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoate and 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoic acid in THF (150 ml), MeOH (750 mL) and lithium hydroxide (26.98 g) in water (250 ml) was added at 27±3°C. The reaction mixture was heated to 60-75°C and then stirred for 6 hours at the same temperature. After the completion of reaction, reaction mixture was cooled to 27±3°C, stirred, filtered, washed with THF and water and dried under VTD to obtain lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid.
The X-ray powder diffraction pattern is the same as that shown in FIG. 3.

Step 4: To a solution of lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid in acetone (800 ml), Conc. HCl (80 ml) was added at room temperature. The reaction mixture was stirred, filtered, washed with acetone and dried under VTD to obtain 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid. 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid was further treated with water at 60-65 °C, stirred, cooled to room temperature, stirred, filtered, washed with water and dried under vacuum to obtain 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid.
The X-ray powder diffraction pattern is the same as that shown in FIG. 4.

Alternatively, A solution of ethyl 4-(2-(4-morpholinophenyl amino) pyrimidin-4-yl)benzoate (35.39 g, 87.6 mmol) in 3:1 methanol/ tetrahydrofuran (350 mL) was treated with lithium hydroxide (4.41 g, 183.9 mmol) in water (90 mL). The mixture was heated at reflux for 2 h., cooled, concentrated and acidified with hydrochloric acid (2M, 92.5 mL, 185 mmol). The dark precipitate was filtered, washed with water and dried under vacuum. The Solid was ground to a powder with a mortar and pestle, triturated with methanol (500 mL) then filtered again to yield 4-(2-(4-morpholinophenylamino) pyrimidin-4-yl) benzoic acid as a muddy solid. This material was washed with ether, air dried overnight, and ground to a fine powder with mortar and pestle.
The X-ray powder diffraction pattern is the same as that shown in FIG. 4.

Step 5: To a solution of amino acetonitrile HCl (30.71 g) in DMF (700 mL), DIPEA (171.90 g), 4-(2-((4-morpholinophenyl) amino) pyrimidin-4-yl) benzoic acid (100g) and HBTU (125.91 g) was added at -15 to 5°C and then stirred for 4-5 hours at the same temperature. After the completion of reaction, the reaction mixture was filtered through hyflo, washed with DMF to obtain filtrate. To the obtained filtrate, water was added at 22±3°C, stirred, filtered, washed with mixture of water and DMF and dried to obtain Momelotinib free base (65-85% yield).

Example: 4
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in MeOH (5 mL), MeOH-HC1 (3 eq.) solution was added at -10±3°C. The obtained solution was stirred for 4 hours, filtered to obtain the solid. The obtained solid was washed with methanol and dried under reduced pressure at 30-35 °C for 9 hrs to obtain Momelotinib di-hydrochloride.

Example: 5
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in DMF (6 mL), Con. HC1 (5 eq.) solution was added at room temperature. The obtained solution was stirred for 4 hours at room temperature, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 6
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in DMAc (5.5 mL), dioxane -HC1 (5 eq.) solution was added at room temperature. The obtained solution was stirred for 4 hours at room temperature, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 7
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in DMSO (10 mL), EtOAc -HC1 (10 eq.) solution was added at room temperature. The obtained solution was stirred for 4 hours at room temperature, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 8
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g.) in DMSO (5 mL), MeOH-HC1 (5 eq.) solution was added at room temperature. The obtained solution was stirred 30 mins. methanol (10 mL) was added and further stirred for 4 hours at room temperature, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 9
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g.) in DMSO (5 mL), water was added, stirred, filtered to obtain wet cake. To the obtained wet cake, methanol (5mL) was added, filtered and dried. To the obtained dried Momelotinib, methanol and methanolic HCl (5 eq.) was added at room temperature, stirred for 4 hours, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 10
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1.5 g,) in DMSO (3.5 mL), HCl gas purged for 3-4 hours to obtain clear solution. The obtained solution was stirred for 2 h at room temperature, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 11
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in DMSO (10 mL), acetone. HC1 solution (3 eq.) was added at room temperature. The obtained solution was stirred for 4 hours at room temperature, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 12
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in DMSO (5mL), methanol was added and stirred for 1 hour. To the obtained solution, MeOH-HC1 (5 eq.) was added at room temperature, stirred for 4 hours, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 13
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in IPA (10 mL), MeOH-HC1 (5 eq.) solution was added at -10±3°C. The obtained solution was stirred for 4 hours, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 14
Preparation of Momelotinib di-hydrochloride
To a solution of Momelotinib (1 g) in ethanol (10 mL), MeOH-HC1 (5 eq.) solution was added at -10±3°C. The obtained solution was stirred for 4 hours, filtered, washed with methanol and dried under reduced pressure at 45 °C for 3 h to obtain Momelotinib di-hydrochloride.

Example: 15
Preparation of Momelotinib di-hydrochloride Monohydrate
To a solution of Momelotinib (500 mg) in methanol (3.0 mL), 0.25 ml 1 M of diluted hydrochloric acid was slowly added at room temperature. The obtained solution was stirred and filtered to obtained the solid. The solid was washed with methanol, water:Con. HCl (1:1) and dried under reduced pressure at 30-35°C for 3 h to obtain Momelotinib di-hydrochloride.

The Momelotinib DiHCl prepared according to the Example 4-15 is substantially free from impurities selected from Formula (II), Formula (IV) and Formula (V) as analyzed by HPLC and may exist either Form I or Form II. ,CLAIMS:We claim:
1. A process for the preparation of Momelotinib or its acid addition salt comprising the steps of:
(b) reacting compound of formula (III) with amino acetonitrile or its salts in a suitable solvent in presence of BBr3;

wherein R is alkyl;
(b) isolating Momelotinib or its salt.

2. The process as claimed in claim 1, wherein R is selected from methyl, ethyl, n-propyl, isopropyl and 2-methyl-1- propyl.

3. The process as claimed in claim 1, wherein suitable solvent is selected from the group consisting of dichloromethane, dichloroethane, chlorobenzene, chloroform, carbon tetrachloride benzene, toluene, xylene, pentane, hexane, heptane and cyclohexane.

4. A process for the preparation of Momelotinib dihydrochloride substantially free from impurities selected from Formula (II), Formula (IV) and Formula (V) comprising the steps of:
i. obtaining the solution of Momelotinib in a suitable solvent;
ii. adding HCl to the reaction mass of step (a) or vice versa; and
iii. isolating Momelotinib dihydrochloride substantially free from Formula (II), Formula (IV) and Formula (V).
,

5. The process as claimed in claim 4, wherein suitable solvent is selected from n-propanol, methanol, ethanol, 2-propanol and butanol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, MTBE, dioxane, N, N-dimethylformamide, ?, ?-dimethylacetamide, dimethyl sulphoxide, and N-methyl pyrrolidone.

6. The process as claimed in claim 4, wherein HCl as used in step (ii) is in the gaseous form or dissolved in a solvent or Con. HCl.

7. The process as claimed in claim 6, wherein solvent is selected from the group consisting of methanol, ethanol, n-propanol and 2-propanol, MTBE, dioxane, include ethyl acetate, isopropyl acetate, n-butyl acetate, acetone and methyl isobutyl ketone.

8. A lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid characterized by an X-ray powder diffraction pattern comprising peaks at 14.6°, 18.7°, 19.8°, 21.3°, 23.1° and 28.3°± 0.2° 2?.

9. Use of lithium salt of 4-[2-[[4-(4-morpholinyl) phenyl] amino]-4-pyrimidinyl] benzoic acid as claimed in claim 8 in the preparation of Momelotinib or a salts thereof.

Dated this 23rd of Apr. 2025 Dr. S. Ganesan