DESC:The following specification particularly describes the invention and the manner in
which it is to be performed.
FIELD OF THE INVENTION
The present application relates to process for preparation of Abemaciclib and pharmaceutical compositions thereof. Further, the present application relates to process for preparation of crystalline Form III of Abemaciclib and pharmaceutical composition thereof.

BACKGROUND OF THE INVENTION
Abemaciclib a selective CDK4 and CDK6 inhibitor developed by Eli Lilly for the treatment of advanced or metastatic breast cancers. Abemaciclib has a chemical name N-[5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methyl ethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine and has following chemical structure:

Abemaciclib is approved by US FDA for the treatment of adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
US Patent No. 7,855,211 (US ‘211) discloses Abemaciclib, its crystalline polymorphic forms (Form I and Form III), synthetic process and pharmaceutical compositions thereof.
The process described in US ’211 is schematically represented below:

The synthetic process exemplified in US ‘211 involves use of costly reagents like tricyclohexylphosphine and Pd2(dba)3 and has low overall yield. The Example 32 and 33(h) of US ‘211 describes process to prepare Abemaciclib crystalline Form III. However, Abemaciclib prepared by the example 32 and 33(h) was found to crystalline Form I, instead of the expected crystalline Form III. There is a clear need to develop a robust and low cost process to produce Abemaciclib, specifically stable and pure crystalline Form III of Abemaciclib.

SUMMARY OF THE INVENTION
In one aspect, the present application provides a process for preparation of Abemaciclib, comprising,
(a) reacting 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (compound of Formula IV) with bis(pinacolato)diboron in presence of triphenylphosphine to form 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole (compound of Formula III);
(b) optionally, without isolating, reacting the compound of Formula III with 2,4-dichloro-5-fluoro pyrimidine in presence of a palladium catalyst to form 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (compound of Formula II); and
(c) reacting the compound of Formula Form II with a 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (compound of Formula V) in presence of palladium acetate and t-butanol to form abemaciclib.
In another aspect the present application provides a process for preparation of crystalline Form III of Abemaciclib, the process comprising mixing abemaciclib with acetone and stirring the mixture at about reflux temperature and isolating crystalline Form III of Abemaciclib.
In another aspect, the present application provides crystalline Abemaciclib having a particle size distribution characterized by a D90 value of less than about 50 µm.
In another aspect, the present application provides crystalline Form III of Abemaciclib having a particle size distribution characterized by a D90 value of less than about 50 µm.
In another aspect, the present application provides crystalline Abemaciclib having a specific surface area (SSA) in the range from about 0.1 to about 5 m2/g, preferably from about 0.2 to about 2 m2/g.
In another aspect, the present application provides crystalline Form III of Abemaciclib having a specific surface area (SSA) in the range from about 0.1 to about 5 m2/g, preferably from about 0.2 to about 2 m2/g.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Abemaciclib having a particle size distribution characterized by a D90 value of less than about 50 µm, and one or more pharmaceutically acceptable excipient.
In one aspect, the present application provides a process to produce crystalline Form III
of Abemaciclib, the process comprises,
(a) heating a mixture of acetone and Abemaciclib to reflux,
(b) gradually cooling the solution to 40-45°C,
(c) seeding the solution with crystalline Form III at 40-45°C,
(d) gradually cooling the solution to 25-30°C, and
(e) isolating crystalline Form III of Abemaciclib.

In another aspect, the present application provides a pharmaceutical composition comprising Abemaciclib prepared by the process of the present invention, and one or more pharmaceutically acceptable excipient.

DESCRIPTION OF THE FIGURES
Figure 1 is powder X-ray diffraction (PXRD) pattern of crystalline Form III of Abemaciclib prepared according to example 3.
Figure 2 is Particle Size Distribution of crystalline Abemaciclib prepared according to example 3 (batch 1) before micronization.
Figure 3 is Particle Size Distribution of crystalline Abemaciclib prepared according to example 3 (batch 1) after micronization.
Figure 4 is Particle Size Distribution of crystalline Abemaciclib prepared according to example 3 (batch 2) before micronization.
Figure 5 is Particle Size Distribution of crystalline Abemaciclib prepared according to example 3 (batch 2) after micronization.
Figure 6 is Particle Size Distribution of crystalline Abemaciclib prepared according to example 3 (batch 3) before micronization.
Figure 7 is Particle Size Distribution of crystalline Abemaciclib prepared according to example 3 (batch 3) after micronization.
Figure 8 is powder X-ray diffraction (PXRD) pattern of crystalline Form I of Abemaciclib
prepared according to example 6.

DETAILED DESCRIPTION OF THE INVENTION
The present application provides improvised process for preparation of Abemaciclib and intermediate compounds thereof.
In one aspect, the present application provides a process for preparation of Abemaciclib, comprising,
(a) reacting 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (compound of Formula IV) with bis(pinacolato)diboron in presence of triphenylphosphine to form 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole (compound of Formula III);

(b) optionally, without isolating, reacting the compound of Formula III with 2,4-dichloro-5-fluoro pyrimidine in presence of a palladium catalyst to form 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1Hbenzo[d] imidazole (compound of Formula II);
and
(c) reacting the compound of Formula II with 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (compound of Formula V) in presence of palladium acetate and t-butanol to form abemaciclib.

The step (a) of the process involves reacting compound of Formula IV with bis(pinacolato)diboron, in presence of a ligand, a base, a catalyst and a suitable solvent.
The ligand is triphenylphosphine, the catalyst is palladium acetate, the base is potassium acetate and the suitable solvent is DMSO.
The compound of Formula IV and the solvent are charged in inert gas atmosphere and bis(pinacolato)diboron is added. The ligand, base and the catalyst are added to the reaction mass and the reaction mixture is heated to about 100°C. The reaction mass is checked for the absence of compound of Formula IV, and after completion of the reaction the reaction mixture is added to water and the product, compound of Formula III, is isolated by filtration.

The step (b) involves reaction of compound of Formula III with 2,4-dichloro-5-fluoro pyrimidine in presence of a catalyst, a base, and a suitable solvent to form 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (compound of Formula II).

The catalyst is bis(triphenylphosphine)palladium chloride, the base is sodium carbonate and the solvent is 1,2-dimethoxyethane.
In an inert atmosphere the compound of Formula III, the solvent and 2,4-dichloro-5-fluoro pyrimidine are charged into a reaction vessel. Aqueous solution of the base and the catalyst are added to the mixture and the mixture is heated to about 65°C and stirred for about 2 hours. After completion of the reaction the reaction mixture is diluted with water and stirred for about 30 minutes. The product is isolated by filtration. The product may be purified using a suitable solvent.
The step (c) involves reaction of compound of Formula II with a compound of Formula V in presence of a ligand, a catalyst, a base, and a suitable solvent.

The ligand is Xantphos, the catalyst is palladium acetate, the base is potassium carbonate and the suitable solvent is tert-Butanol.
In an inert atmosphere the compound of Formula II, the solvent, compound of Formula V and the base are charged into a suitable reaction vessel, and the ligand and the catalyst are added to the mixture. The reaction mixture is heated to about 100°C and stirred for about 4 hours. After completion of the reaction the mixture may be diluted with a suitable solvent like dichloromethane. The pH of the mass is adjusted to acidic using dilute aqueous HCl and layers separated. The organic layer is concentrated to obtain crude Abemaciclib which is further purified using a suitable solvent like acetone.
In another aspect the present application provides a process for preparation of crystalline Form III of Abemaciclib, the process comprising mixing abemaciclib with acetone and stirring the mixture at about reflux temperature and isolating crystalline Form III of Abemaciclib.
In another aspect the present application provides a process for preparation of crystalline Form III of Abemaciclib, the process comprises,
(a) heating a mixture of acetone and Abemaciclib to reflux,
(b) gradually cooling the mixture to about 25-30°C, and
(c) isolating crystalline Form III of Abemaciclib.
The step (a) of the process involves mixing Abemaciclib with acetone, including direct use of a reaction mixture containing Abemaciclib that is obtained in the course of its synthesis or adding Abemaciclib into acetone. The Abemaciclib can be amorphous Abemaciclib or any other crystalline form.
Acetone solvent used can be 10 volumes to 50 volumes to the weight of Abemaciclib. Acetone and Abemaciclib are mixed and heated to reflux and maintained reflux for about 4-10 hours.
The step (b) involves gradual cooling of the solution obtained in step (a) to about 25 - 30°C. Gradual cooling means that after stopping the external heat source, the crystallization mixture is not separated from the heating bath and both together are allowed to attain the ambient temperature on their own.
The step (c) involves isolation of crystalline Form III of Abemaciclib. The crystalline Form III of Abemaciclib is isolated from the suspension by filtration or by decantation or by any suitable method. The crystalline Form III of Abemaciclib may be dried under reduced pressure.
In another aspect the present application provides a process to produce crystalline Form III of Abemaciclib, the process comprises,
(d) heating a mixture of acetone and Abemaciclib to reflux,
(e) gradually cooling the mixture to 40-45°C,
(f) seeding the mixture with crystalline Form III at 40-45°C,
(g) gradually cooling the mixture to 25-30°C, and
(h) isolating crystalline Form III of Abemaciclib.
The step (a) of the process involves mixing Abemaciclib with acetone, including direct use of a reaction mixture containing Abemaciclib that is obtained in the course of its synthesis or adding Abemaciclib into acetone. The Abemaciclib can be amorphous Abemaciclib or any other crystalline form.
Acetone solvent used can be 10 volumes to 50 volumes to the weight of Abemaciclib. Acetone and Abemaciclib are mixed and heated to reflux and maintained reflux for about 4 hours to get a hazy solution.
The step (b) involves gradual cooling of the solution obtained in step (a) to about 40 - 45°C. Gradual cooling means that after stopping the external heat source, the crystallization mixture is not separated from the heating bath and both together are allowed to attain the ambient temperature on their own. To reach 40°C temperature from reflux temperature it may take about 1 hour to about 10 hours.
The step (c) involves seeding the crystallization mixture obtained instep (b) with crystals of Form III. The Form III crystals can be added at a temperature of about 40-45°C and stirring the solution for about 5 hours at same temperature.
The step (d) involves gradual cooling of the crystallization mixture obtained in step (c) to about 25-30°C. To reach 25°C temperature it may take about 1 hour to about 10 hours. A suspension is formed.
The step (e) involves isolation of crystalline Form III of Abemaciclib. The crystalline Form III of Abemaciclib is isolated from the suspension by filtration or by decantation or by any suitable method. The crystalline Form III of Abemaciclib may be dried under reduced pressure.
The particle size distribution of the crystalline abemaciclib prepared was determined by laser light diffraction. The determination was carried out by using Malvern Mastersizer-3000 AA390 laser diffraction particle size analyzer equipped with Tornado Dry Powder System using air as dispersion medium with measurement pressure 24” H2O ±2” H2O, sample amount 10 ml, system controlled target 15% for obscuration and applying Fraunhofer optical model.
The parameters considered are the volumetric diameters in µm of the 10th, 50th, and 90th percentiles of the particles, expressed as D10, D50 and D90 respectively.
In another aspect the present application provides crystalline Abemaciclib having a specific surface area (SSA) in the range from about 0.1 to about 5 m2/g and particle size distribution characterized by a D90 value of from about 10 µm to about 200 µm.
In another aspect the present application provides a pharmaceutical composition comprising crystalline Form III of Abemaciclib prepared by the process of the present invention and one or more pharmaceutically acceptable excipients.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
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. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
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. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

Example-1: Preparation of Compound of Formula III

Compound of Formula IV (100 g) and DMSO (600 mL) were charged into a round bottom flask under N2 atmosphere. Triphenylphosphine (19.35 g) and Potassium acetate (109 g) were added to the reaction mass. N2 gas was purged into reaction mass for 20 minutes and Palladium acetate (1.656 g) was charged into the reaction mass under N2 atmosphere. The reaction mixture was heated to 100°C and stirred for 8 hours. The reaction mass was cooled to 28°C and water (3000 mL) was added slowly over a period of 1 hour. The solid formed was filtered and washed the solid with water (500 mL) to obtain 160 g of wet material.

Example-2: Preparation of Compound of Formula II

In a 500 mL round bottom flask dissolved compound of Formula III (11.74 g) in 100 mL of 1,2-dimethoxyethane and filtered through a celite and the celite was washed with 10 mL of 1,2-dimethoxyethane. Charged 2,4-dicholro-5-fluoropyrimidine (7.70 g) into above 1,2-dimethoxyethane solution. Aqueous sodium carbonate solution (prepared by dissolving 13.69 g of sodium carbonate in 41 mL of water) and bis(triphenylphosphine)palladium chloride were added to the reaction mixture. The reaction mixture was stirred for 2 hours at 65°C. The reaction mass was cooled to 28°C and pre-cooled water (200 mL). The wet solid is added to a round bottom flask having 100 mL of IPA and the mixture was stirred for 2 hours at 28°C and filtered. The solid was dried at 70°C for 2 hours. Dry weight: 9 grams. Purity: 99.82 % by HPLC.

Example-3: Preparation of Abemaciclib

Compound of Formula II (50 g) and 2-butanol (400 mL) were charged into a 1000 mL round bottom flask. Charged Xantphos (1.79 g) and compound of Formula II (34.5 g). Nitrogen was bubbled for 15 minutes. Palladium acetate (0.278 g) was added to the reaction mass. The mixture was heated to 95°C and stirred for 4 hours. Reaction mass was cooled to 27°C and DCM (300 mL) was added and stirred for 15 minutes. The mixture was filtered through celite bed and the filtrate was taken into another round bottom flask and pH was adjusted to acidic using 4M HCl solution. Layers separated and the organic layer was washed wit 4M HCl solution. The aqueous layers were combined and charged into a round bottom flask and PF-Altra carbon (5 g) was added. The mixture was filtered through celite bed and the bed was washed with water. The filtrate was taken into another round bottom flask and DCM (400 mL) was added and pH was adjusted to 12.5 using 30% aqueous NaOH solution and stirred for 10 minutes. Layers separated and the aqueous layer was extracted with DCM (200 mL). Organic layers were combined and washed with water (200 mL). Layers separated and the organic layer was concentrated until 1 volume remained in the flask. Charged acetone (500 mL) and concentrated at 50°C until 1 volume remained in the flask. Charged acetone (400 mL) and stirred for 1 hour at 28°C. The precipitate formed was filtered and washed with acetone and sucked dried under vacuum. The solid was dried in VTD for 1 hour at 45°C to yield 65 g of Abemaciclib.
10 g of the above solid and acetone (100 mL) were charged into a round bottom flask and the mixture was heated to 55°C and stirred for 10 hours. The mixture was allowed to room temperature and stirred for 1 hour at 28°C. The solid isolated by filtration and the wet material was washed with acetone. The solid was dried in VTD for 1 hour at 45°C to yield 9.2 g of Abemaciclib crystalline Form III. Purity: 99.77% by HPLC. PXRD shown in Figure 1. The PXRD matches with the PXRD of crystalline Form III of US ‘211.

Example-4: Determination of Particle Size Distribution
The particle size distribution of the crystalline abemaciclib prepared according to example-3 was determined by laser light diffraction. The determination was carried out by using Malvern Mastersizer-3000 AA390 laser diffraction particle size analyzer equipped with Tornado Dry Powder System using air as dispersion medium with measurement pressure 24” H2O ±2” H2O, sample amount 10 ml, system controlled target 15% for obscuration and applying Fraunhofer optical model. The results of the particle size analysis are shown in Figure 2 and Figure 3.

Example-5: Determination of Specific Surface Area
The specific surface area (SSA) and particle size distribution (PSD) were determined for three batches of crystalline abemaciclib prepared according to the present invention. The particles of the three batches were then milled followed by the determination of SSA and PSD. The results are shown in Table 1 and Table 2
Table 1
Batch SSA (m2/g) Volume particle size, Dv10 (µm) Volume particle size, Dv50 (µm) Volume particle size, Dv90 (µm) Figure
1 (unmilled) 0.1698 26.5 58.5 109 2
1 (milled) 0.9997 2.68 12.3 29.6 3
2 (unmilled) 0.1876 24.7 54.0 101 4
2 (milled) 1.0390 2.60 11.4 27.7 5
3 (unmilled) 0.1948 23.7 52.6 96.5 6
3 (milled) 1.0500 2.62 11.0 25.5 7

Example-6: Preparation of Abemaciclib

6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d] imidazole (40 g), 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (28 g) and 1,4-dioxane (400 mL) were charged into a round bottom flask and stirred for 10 minutes. Cesium carbonate (80 g) was added into the reaction mixture which was then sparged with nitrogen under stirring for 2 hours. Pd2(dba)3 (4.5 g) and Xantphos (5.7 g) were added to the reaction mixture and the nitrogen sparging was continued for another 30-60 minutes. The reaction mixture was heated to reflux and stirred under a nitrogen atmosphere for 2 hours. Thereafter, the reaction mixture was cooled to RT. DCM (600 mL) was added and the reaction mixture was stirred the mixture for 15 minutes. The reaction mixture was filtered and the filtrate concentrated to obtain a solid residue, which was dissolved in DCM (400 mL). 4M HCl (600 mL) was added to the DCM solution and stirred for 10 minutes. Layers were separated and the aqueous layer washed with DCM (3 X 200 mL). DCM (200 mL) was charged in to the separated aqueous layer and the pH was adjusted to ~9.5 using 4M NaOH solution. Both layers were separated and the aqueous layer was extracted with DCM (2 × 200 mL). The DCM layers were combined and washed sequentially with 5% thiourea solution (2 X 200 mL), water (200 mL) and brine (200 mL). The DCM layer was dried over sodium sulfate and concentrated under reduced pressure at 45°C to obtain a solid. Weight: 62 g; purity by HPLC: 98.03%; PXRD: amorphous.
Acetone (360 mL) was charged to the above solid and the obtained suspension stirred under reflux for 16 hours. The mixture remains a suspension. This was cooled to 25°C and stirred for 2 hours. The suspension was filtered and the wet cake was washed with acetone (40 mL), and dried under reduced pressure for 2 hours at 45°C to obtain 51 g of crystalline Abemaciclib. Purity: 99.62% by HPLC. PXRD shown in Figure 8. The PXRD matches with the PXRD of crystalline Form I of US ‘211.

Example-7: Recrystallization of Abemaciclib
Abemaciclib (crystalline Form I, 10 g) and acetone (400 mL) were charged into a round bottom flask and stirred under reflux for 3 hours. The hot mixture was filtered under suction and the filtrate obtained was refluxed for 2 hours. Form III seed (50 mg) was added to the refluxing crystallization mixture, which was then gradually cooled to 25°C (oil bath was removed and the crystallization vessel was allowed to cool with contact with ambient) and stirred for 2 hours. The mixture was further cooled to 0°C and stirred for 2 hours. The suspension obtained was filtered and dried under reduced pressure for 2 hours at 45°C to obtain 8 g of crystalline Abemaciclib. Purity: 99.58% by HPLC. PXRD shown in Figure 8. The PXRD matches with the PXRD of crystalline Form I of US ‘211.

Example-8: Recrystallization of Abemaciclib
Abemaciclib (crystalline Form I, 10 g) and acetone (400 mL) were charged into a round bottom flask and stirred under reflux for 3 hours. Form III seed (50 mg) was added to the refluxing mixture, which was then gradually cooled to 25°C (oil bath was removed and the crystallization vessel was allowed to cool with contact with ambient) and stirred for 2 hours. The suspension obtained was filtered and dried under reduced pressure for 2 hours at 45°C to obtain 8.2 g of crystalline Abemaciclib. Purity: 99.6% by HPLC. The PXRD shows that the solid is a mixture of crystalline Form I and Form III.

Example-9: Recrystallization of Abemaciclib
Abemaciclib (crystalline Form I, 10 g) and acetone (400 mL) were charged into a round bottom flask and stirred under reflux for 3 hours. The hot solution was filtered into a vessel containing Form III seed (50 mg) and stirred for 1-2 hours at 25°C. The suspension obtained was filtered and dried under reduced pressure for 2 hours at 45°C to obtain 8.4 g of crystalline Abemaciclib. Purity: 99.5% by HPLC. PXRD shown in Figure 8. The PXRD matches with the PXRD of crystalline Form I of US ‘211.

Example-10: Recrystallization of Abemaciclib
Abemaciclib crystalline Form I (50 g) and acetone (2 L) were charged into a round bottom flask. The mixture was stirred at 55°C for 4 hours and then allowed to cool to 40°C on its own (heating was stopped and the oil bath was not removed). Seed crystals of Form III (0.25 g) was added into the crystallization mixture at 40°C, which was then allowed to cool to 25°C on its own (the crystallization mixture was not separated from the heating bath and both together are allowed to cool to 25°C on their own) and stirred for 2 hours. The suspension obtained was filtered and the wet cake was washed with acetone (50 mL). The solid was dried in a hot air oven for 10 hours at 45°C to obtain 44 g of Abemaciclib crystalline Form III. Purity: 99.56% by HPLC. PXRD shown in Figure 1. The PXRD matches with the PXRD of crystalline Form III of US ‘211.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

,CLAIMS:WE CLAIM:

1. A process for preparation of Abemaciclib of Formula I, comprising,

wherein the process comprising the steps of: reacting 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (compound of Formula IV) with bis(pinacolato)diboron in presence of a ligand, a base, a catalyst and in a suitable solvent to form 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzimidazole (compound of Formula III);

(a) optionally, without isolating, reacting the compound of Formula III with 2,4-dichloro-5-fluoro pyrimidine in presence of a palladium catalyst, a base, and in a suitable solvent to form 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (compound of Formula II); and

(b) reacting the compound of Formula Form II with a 5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-amine (compound of Formula V) in presence of a ligand, a catalyst, a base, and a suitable solvent to form abemaciclib.

2. The process as claimed in claim 1, wherein in the step a) ligand is triphenylphosphine, the base is potassium acetate, catalyst is palladium acetate, and the suitable solvent is DMSO.

3. The process as claimed in claim 1, wherein in the step b) catalyst is bis(triphenylphosphine)palladium chloride, the base is sodium carbonate and the solvent is 1,2-dimethoxyethane.

4. The process as claimed in claim 1, wherein in the step c) ligand is Xantphos, the catalyst is palladium acetate, the base is potassium carbonate and the suitable solvent is tert-Butanol.

5. A process for preparation of crystalline Form III of Abemaciclib, the process comprises,
(a) heating a mixture of acetone and Abemaciclib to reflux,
(b) gradually cooling the mixture to about 25-30°C, and
(c) isolating crystalline Form III of Abemaciclib.

6. The process as claimed in claim 5, wherein the step a) is carried out at temperature of about 50-55°C.

7. The process as claimed in claim 5, wherein the crystalline Form III of Abemaciclib having a particle size distribution characterized by a D90 value of less than about 50 µm.

8. A process to produce crystalline Form III of Abemaciclib, the process comprises,
(a) heating a mixture of acetone and Abemaciclib to reflux,
(b) gradually cooling the mixture to 40-45°C,
(c) seeding the mixture with crystalline Form III at 40-45°C,
(d) gradually cooling the mixture to 25-30°C, and
(e) isolating crystalline Form III of Abemaciclib.

9. The process as claimed in claim 7, wherein the step a) is carried out at temperature of about 50-55°C.

10. A composition comprising Abemaciclib as prepared according to claim 1-9 and at least one pharmaceutically acceptable excipient.