Process for preparing a solid form of abemaciclib

Abstract

The presented invention relates to processes for preparation of Abemaciclib, compound of formula (1), or a salt or a solvate, preferably and N,N-dimethylformamide hemisolvate, or a cocrystal or solid forms thereof:

Description

[0001] PROCESS FOR ABEMACICLIB

[0002] BACKGROUND OF THE INVENTION The presented invention relates to a process for preparation of Abemaciclib, compound of formula (1), or a salt or a solvate or a cocrystal or a solid forms thereof or N,N-dimethyl- formamide hemisolvate thereof: BACKGROUND OF THE INVENTION

[0003] Abemaciclib, chemically N-[5-(4-Ethylpiperazin-l-ylmethyl)pyridin-2-yl]-5-fluoro-4-

[0004] (4-fluoro-l-isopropyl-2-methyl-lH-benzimidazol-6-yl)pyrimidin-2-amine, compound of formula (1): is a CDK4 / 6 inhibitor. Abemaciclib is marketed in combination with fulvestrant or an aromatase inhibitor, for the treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. It is also approved as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

[0005] Abemaciclib was disclosed in W02010075074 by Eli Lilly. There are several applications describing a process for preparation of Abemaciclib, for example WO20 1 / 0075074 by Eli Lilly or WO2019102492 by Mylan.

[0006] There is still a need for an improved process for preparing of Abemaciclib. In particular, it would be desirable to have a process which is efficient in terms of yield and chemical purity, cost effective in terms of reagents and reaction conditions, and which can be effectively applied at an industrial scale.

[0007] There are several solvates of Abemaciclib described in prior art, for example methanol solvate or hydrate described in WO2019195569 by Johnson Matthey. There are also several solid forms of Abemaciclib described in the prior art, for example Form III described in WO20 10075074 by Eli Lilly.

[0008] BRIEF DESCRIPTION OF THE INVENTION

[0009] The presented invention relates to a process for preparation of Abemaciclib, compound of formula (1), or a salt or a solvate, preferably N,N-dimethylformamide hemisolvate, or a cocrystal or a solid forms thereof.

[0010] The presented invention relates to a process for preparation of a solid form of Abemaciclib, compound of Formula 1, preferably the solid Form III: the process comprising: a. Dissolving Abemaciclib or a solvate thereof in a solvent selected from dimethyl sulfoxide or 2-butanone; b. Cooling the mixture to a temperature between 60°C and 95°C, preferably between 80°C and 90°C; c. Stirring the mixture at this temperature for between 30 and 180 minutes; d. Cooling the mixture to a temperature between 0°C and 30°C; e. Isolating the solid form of Abemaciclib. The solid Form III can be characterized by XRPD pattern comprising peaks at 10.91°,

[0011] 11.54°, 12.13°and 21.29° degrees 2 theta ( 4^0.2 degrees 2 theta), when measured with CuKal radiation (k = 1.54060 A).

[0012] The presented invention also relates to Abemaciclib N,N-dimethylformamide hemisolvate, compound of formula (1 A) and a solid form thereof. <1 A)

[0013] The presented invention further relates to a process for preparation of Abemaciclib or a solvate thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form, Form L, of

[0015] Abemaciclib N,N-dimethylformamide hemisolvate (molar ratio of Abemaciclib :N,N- dimethylformamide 1 :0.5), prepared by the process described in Example 1 or Example 4.

[0016] Figure 2 depicts the X-Ray Powder Diffractogram (XRPD) of solid form, Form III, of Abemaciclib prepared by the process described in Examples 2 or 3 or 5.

[0017] DETAILED DESCRIPTION OF THE INVENTION

[0018] The presented invention relates to a process for preparation of a solid form of Abemaciclib, preferably the solid Form III, the process comprising: a. Dissolving Abemaciclib or a solvate thereof in a solvent selected from dimethyl sulfoxide or 2-butanone; b. Cooling the mixture to a temperature between 60°C and 95°C, preferably between 80°C and 90°C; c. Stirring the mixture at this temperature for between 30 and 180 minutes; d. Cooling the mixture to a temperature between 0°C and 30°C; e. Isolating the solid form of Abemaciclib.

[0019] The concentration of Abemaciclib in the solvent can be between 0.09 g / ml and 0.15 g / ml. Abemaciclib or a solvate thereof is dissolved in the solvent preferably at a temperature between 78°C and 105°C. The mixture is then cooled to a temperature between 60°C and 95°C, preferably between 80°C and 90°C. To the mixture water can be optionally added. The volume ratio between water and the solvent used in step a. can be between 0.01 : 1 and 0.13: 1. Water can be added in several portions, for example 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 portions. Preferably the water is added drop-wise. The addition of water further improves the yield and purity of obtained Abemaciclib. The mixture is stirred at the temperature between 60°C and 95°C, preferably between 80°C and 90°C for between 30 and 180 minutes. The mixture is then cooled to a temperature between 0°C and 30°C and stirred at this temperature for between 0.5 and 24 hours. Obtained suspension is filtered and isolated solid can be optionally washed and dried to provide a solid form of Abemaciclib, compound of Formula (1), preferably the solid Form III. The solid form of Abemaciclib used in step a. can be preferably Abemaciclib N,N-dimethylformamide hemisolvate (molar ratio between Abemaciclib and N,N-dimethylformamide is 1 :0.5), compound of formula (1 A):

[0020] .1 / 2 DMF

[0021] (1A) Obtained solid form, preferably solid Form III, of Abemaciclib can be transformed into a salt or a solvate or a cocrystal of Abemaciclib.

[0022] The presented invention also relates to a process for preparation of Abemaciclib N,N- dimethylformamide hemisolvate (molar ratio between Abemaciclib and N,N-dimethyl- formamide is 1 :0.5), the process comprising: a. Reacting compound of Formula (2) with compound of Formula (3) in a presence of a base and a catalyst in N,N-dimethylformamide to provide Abemaciclib N,N- dimethylformamide hemisolvate (molar ratio of Abemaciclib :N,N- dimethylformamide 1 :0.5): b. Precipitating of Abemaciclib N,N-dimethylformamide hemisolvate from reaction mixture

[0023] The concentration of compound of formula (2) in N,N-dimethylformamide (DMF) can be between 0.05 g / ml and 0.2 g / ml. The concentration of compound of formula (3) N,N- dimethylformamide (DMF) can be between 0.04 g / ml and 0.15 g / ml. The molar ratio between compound of formula (2) and the compound of formula (3) can be between 1 : 1 and 1 : 1.5. The base can be selected from an organic or an inorganic base. The inorganic base can be for example selected from a carbonate, such as sodium carbonate or potassium carbonate or lithium carbonate or cesium carbonate. The organic base can be selected for example from an amine such as triethyl amine or diisopropylethylamine or an alcoholate such as potassium tert-butoxide or an acetate such as sodium or potassium acetate. The concentration of the base in N,N-dimethylformamide can be between 0.07 g / ml and 0.2 g / ml. The molar ratio between the base and the compound of formula (2) can be between 2: 1 and 3: 1. The catalyst can be selected for example from Palladium (II) acetate or Pd2dba3 (Tris(dibenzylideneacetone) dipalladium(O)) or PdCh(PPh3)2 or Pd(PPh3)4 or PdCh or Pd (acac)2 (Palladium(II) acetyl- acetonate) or PdC12(dppf). The catalyst can be optionally used in combination with an ligand for example with XPhos (Dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl] phosphane) or Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or DPEPhos (Bis(2-diphenylphosphinophenyl)ether) or AmPhos (Bis(di-tert-butyl(4-dimethylamino- phenyl)phosphine) or dppf (l,l'-Bis(difenylfosfino)ferrocene) or QPhos (1,2,3,4,5-Penta- phenyl-l'-(di-tert-butylphosphino)ferrocene) or SPhos (2-Dicyclohexylphosphino-2',6'- dimethoxybiphenyl). The molar ratio between the catalyst and the ligand can be between 1 :2 and 3: 1. The concentration of the catalyst in N,N-dimethylformamide can be between 0.0006 g / ml and 0.0015 g / ml, preferably between 0.0008 g / ml and 0.0011 g / ml. The molar ratio between the catalyst and the compound of formula (2) can be between 0.01 : 1 and 0.015: 1.

[0024] The reaction between compound of formula (2) and compound of formula (3) is preferably performed under inert atmosphere, for example under argon or nitrogen atmosphere. Compound of formula (2) is mixed with compound of formula (3), the base, the catalyst, optionally with the ligand and N,N-dimethylformamide. N,N-dimethylformamide is preferably degassed, for example with argon or nitrogen, before being used in the reaction. The reaction mixture is heated to a temperature between 80°C and 120°C and stirred at this temperature for between 0.5 and 6 hours, preferably between 0.5 and 2 hours. The reaction progress can be monitored by any conventional analytical techniques, e.g. by HPLC or GC. After the reaction is finished, the reaction mixture can be optionally filtered at a temperature between 60°C and 100°C. The mixture is then cooled to a temperature between 10°C and 50°C. The mixture is stirred at this temperature for between 1 and 24 hours. The Abemaciclib N,N-dimethylformamide hemisolvate precipitates from the reaction mixture. Precipitated Abemaciclib N,N-dimethylformamide hemisolvate is isolated from the reaction mixture for example by filtration or by the use of a centrifuge. The solid form is preferably Form L of Abemaciclib N,N-dimethylformamide hemisolvate.

[0025] The advantage of the presented process in comparison with the processes to prepare Abemaciclib described in the prior art is, that obtained Abemaciclib N,N-dimethylformamide hemisolvate precipitates directly from the reaction mixture. In the processes described in the prior art the work-up of the reaction mixture is done by either extraction processes or the reaction solvent is concentrated. Both extraction and solvent evaporation are time consuming processes resulting in high amounts of used solvents and high amount of consumed energy.

[0026] The presented invention also relates to a solid form of Abemaciclib N,N-dimethyl- formamide hemisolvate, Form L, compound of formula (1 A).

[0027] .1 / 2 DMF

[0028] (1A)

[0029] The Form L can be characterized by XRPD powder diffraction pattern comprising the peaks at about 9.7°, 13.4°, 14.5° and 21.4°degrees 2 theta, when measured with CuKal radiation ( = 1.54060 A). The solid form can be also characterized by XRPD powder diffraction pattern comprising the peaks at about 8.3°, 9.7°, 12.7°, 13.4°, 13.8°, 14.5° and 21.4° degrees 2 theta, when measured with CuKal radiation ( = 1.54060 A). The solid form can be further characterized by XRPD powder diffraction pattern described in following Table:

[0030] The presented invention further relates to a process for preparation of a solid form of

[0031] Abemaciclib, or a salt or a solvate or a cocrystal thereof, preferably solid Form III, the process comprising: a. Reacting compound of Formula (2) with compound of Formula (3) in a presence of a base and a catalyst in dimethyl sulfoxide: b. Isolating the solid form of Abemaciclib from the reaction mixture.

[0032] In a preferred embodiment the step b. comprises: (i.) Cooling the mixture to a temperature between 60°C and 95°C, preferably between 80°C and 90°C;

[0033] (ii.) Stirring the mixture at this temperature for between 30 and 180 minutes;

[0034] (iii.) Cooling the mixture to a temperature between 0°C and 30°C;

[0035] (iv.) Isolating the solid form of Abemaciclib. The concentration of compound of formula (2) in dimethyl sulfoxide can be between 0.05 g / ml and 0.2 g / ml. The concentration of compound of formula (3) in dimethyl sulfoxide can be between 0.04 g / ml and 0.15 g / ml. The molar ratio between compound of formula (2) and the compound of formula (3) can be between 1 : 1 and 1 : 1.5. The base can be selected from an organic or an inorganic base. The inorganic base can be for example selected from a carbonate, such as sodium carbonate or potassium carbonate or lithium carbonate or cesium carbonate. The organic base can be selected for example from an amine such as triethyl amine or diisopropylethylamine or an alcoholate such as potassium tert-butanol ate or an acetate such as sodium or potassium acetate. The concentration of the base in dimethyl sulfoxide can be between 0.07 g / ml and 0.2 g / ml. The molar ration between the base and the compound of formula (2) can be between 2: 1 and 3: 1. The catalyst can be selected for example from Palladium (II) acetate or Pd2dba3 (Tris(dibenzylideneacetone)dipalladium(O)) or PdCh(PPh3)2 or Pd(PPh3)4 or PdCh or Pd (acac)2 (Palladium(II) acetyl acetonate) or PdCh(dppf). The catalyst can be optionally used in combination with an ligand such as XPhos (Dicyclohexyl[2',4',6'-tris(propan-2-yl)[l,l'-biphenyl]-2-yl]phosphane) or Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene) or DPEPhos (Bis(2-diphenyl-phosphino- phenyl)ether) or AmPhos (Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) or dppf (1,1'- Bis(difenylfosfino)ferrocene) or QPhos (l,2,3,4,5-Pentaphenyl-l'-(di-tert-butyl-phosphino) ferrocene) or SPhos (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl). The molar ratio between the catalyst and the ligand can be between 1 :2 and 3: 1. The concentration of the catalyst in dimethyl sulfoxide can be between 0.0006 g / ml and 0.0015 g / ml, preferably between 0.0008 g / ml and 0.0011 g / ml. The molar ratio between the catalyst and the compound of formula (2) can be between 0.01 : 1 and 0.015: 1.

[0036] The reaction between compound of formula (2) and compound of formula (3) is preferably performed under inert atmosphere, for example under argon or nitrogen atmosphere. Compound of formula (2) is mixed with compound of formula (3), the base, the catalyst, optionally with the ligand, and dimethyl sulfoxide. Dimethyl sulfoxide is preferably degassed, for example with argon or nitrogen, before being used in the reaction. The reaction mixture is heated to a temperature between 80°C and 120°C and stirred at this temperature for between 2 and 6 hours. The reaction progress can be monitored by any conventional analytical techniques, e.g. by HPLC or GC. After the reaction is finished, the mixture is then cooled to a temperature between 60°C and 95°C, preferably between 80°C and 90°C, and stirred at this temperature for between 30 and 180 minutes. The mixture is then cooled to a temperature between 0°C and 30°C and stirred at this temperature for between 1 and 24 hours. Obtained suspension is filtered and isolated solid can be optionally washed and dried to provide a solid form of compound of formula (1), preferably solid Form III. The solid form of Abemaciclib can be transformed into a salt or a solvate or a cocrystal of Abemaciclib.

[0037] The advantage of the presented process in comparison with the processes described in the prior art is, that obtained solid form of Abemaciclib can be easily isolated from the reaction mixture after reaction between compound of formula (2) and compound of formula (3). In the processes described in the prior art the work-up of the reaction mixture is done by either extraction processes or the reaction solvent is concentrated. Both extraction and solvent evaporation are time consuming processes resulting in high amounts of used solvents and high amount of consumed energy.

[0038] The solid form of Abemaciclib, compound of formula (1), prepared according to presented invention can be processed into a suitable pharmaceutical formulation. In the pharmaceutical formulation the solid forms can be mixed with pharmaceutically acceptable adjuvants, diluents or carriers. The amount of solid form of Abemaciclib in the formulation depends on the condition and a patient to be treated. The pharmaceutical formulation can be if form of a solid oral formulation, for example a capsule, a pill, a powder or a granule. In the formulation the solid form of Abemaciclib according to presented invention can be mixed with one or more additives such as fillers or extenders or binders or wetting agents or disintegrating agents or absorbents or lubricants or buffering agents. The formulation in a form of a tablet or a dragee or a capsule or a pill or a granule can be coated with a coating or shell such as enteric or other coating. The oral formulation can be in a form of an oral emulsion or a solution or a suspension or a syrup. The formulation can contain suitable additives such as diluent(s) or wetting agent(s) or emulsifying agent(s) or suspending agent(s) or sweetening agent(s) or flavoring agent(s). The examples of suitable additive(s) are known to those skilled in the art.

[0039] The suitable pharmaceutical formulation can be in a parenteral form such as an injection or an infusion or an injectable depot or in a liposomal form comprising pharmaceutically acceptable aqueous or non-aqueous solution(s) or dispersion(s) or emulsions. The pharmaceutical formulation can be also in a form of a powder for reconstitution into an injection or infusion. The formulation can further comprise additives such as preservative(s) or wetting agent(s) or emulsifying agent(s) or dispersing agent(s) or antibacterial or antifungal agents. The examples of suitable additive(s) are known to those skilled in the art.

[0040] The suitable pharmaceutical formulation can be in a form suitable for rectal or vaginal administration further comprising suitable additive(s). The examples of suitable additive(s) are known to those skilled in the art.

[0041] The solid forms of Abemaciclib prepared according to presented invention or a pharmaceutical formulation comprising the forms can be used for the treatment of conditions treatable with Abemaciclib.

[0042] The invention will be further described with reference to the following examples. EXAMPLES

[0043] XRPD spectrum was obtained using the following measurement conditions:

[0044] Panalytical Empyrean diffractometer with 0 / 20 geometry (transmition mode), equipped with a PixCell 3D detector;

[0045] Example 1 : Preparation of compound of Abemaciclib N.N-dimethylformamide hemi solvate

[0046] 22.4 g of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl-lH- benzo[d]imidazole (compound of formula 2) is mixed with 15.44 g of compound of formula

[0047] (3), 19.38 g of Potassium carbonate, 0.156 g of Palladium (II) acetate and 0.803 g of 4,5- bis(diphenylphosphino)-9 9-dimethylxanthene (Xantphos). The solids were placed under

[0048] Argon by 3x evacuaton / backfilling cycles.

[0049] The reaction is performed under argon atmosphere.

[0050] In a separate flask, 200 ml of N,N-dimethylformamide (DMF) was degassed by 3 cycles of evacuation for 7 min while stirring, backfilling with Argon. The mixture was heated to 110°C and stirred at this temperature for 3 hours. Reaction mixture was filtered hot (at 60°C).

[0051] The mixture was allowed to cool to 25°C to obtain a suspension. The suspension was filtered off, the cake was washed with about 50 ml of acetone, suction dried on the filter for 15 min and then vacuum dried at 40°C for 2 hours. This afforded 31.7 g (83% of theoretical yield) of Abemaciclib N,N-dimethylformamide hemisolvate, in purity 99.43% (HPLC IN). XRPD of obtained solid corresponds to XRPD pattern depicted in Fig 1.

[0052] Example 2: Preparation of solid Form III of Abemaciclib

[0053] 1 g of Abemaciclib N,N-dimethylformamide hemisolvate was mixed with 8 ml of dimethyl sulfoxide. The mixture was heated to 100°C to obtain a solution. Then temperature was decreased to 80°C and the mixture was stirred for 5 minutes until solid material was formed. Then the mixture was stirred for 1 hour and subsequently allowed to cool to 25°C over 1 hour. The solid was filtered off, briefly washed with 3ml of acetone, suction dried on the filter for 5 min and then vacuum dried at 40°C for 12 hours affording 0.885 g of

[0054] Abemaciclib (89 % of theoretical yield) in purity: 99.88% (HPLC IN).

[0055] XRPD of obtained solid form corresponds to solid Form III. Example 3: Preparation of solid Form III of Abemaciclib

[0056] (2) (3)

[0057] 7.17 g of compound of formula (3), 8.56 g of Potassium carbonate, 0.07 g of Palladium (II) acetate and 0.179 g of 4,5-bis(diphenylphosphino)-9 9-dimethylxanthene (Xantphos) were mixed with 90 ml of dimethyl sulfoxide (DMSO). The suspension was degassed by 3x evacuating for 10 min and backfilling with Argon. Then the mixture was heated to 100°C and stirred at this temperature for 2.5 hours. The mixture was filtered through Celite on a frit and was brought back to 100°C. The mixture was cooled to 80°C over 30 minutes and was stirred at this temperature for 1 hour. Then the mixture was allowed to cool to 20-25°C over 1 hour and then was stirred at this temperature for 1 hour. The suspension was filtered off. The cake was washed with 50 ml of acetone, suction dried on the filter followed by vacuum drying at 40°C for 1 hour. 12.83 g of Abemaciclib was obtained (80 % yield) in purity 99.5% (HPLC IN) in solid Form III.

[0058] Example 4: Preparation of compound of Abemaciclib N.N-di methyl formamide hemi solvate

[0059] 45.0 g of 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-l-isopropyl-2-methyl-lH- benzo[d]imidazole (compound of formula 2) was mixed with 31.64 g of compound of formula (3), 57.81 g of Potassium carbonate and with 270 ml of N,N-dimethylformamide (DMF). Suspension was degassed by stream of nitrogen for 15 minutes. To the mixture 0.313 g of Palladium (II) acetate and 0.887 g of 4,5-bis(diphenylphosphino)-9 9-dimethylxanthene (Xantphos) was added. The mixture was degassed by stream of nitrogen for 15 minutes.

[0060] The reaction is performed under nitrogen atmosphere.

[0061] The mixture was heated to 100°C and stirred at this temperature for 1 hour. Reaction mixture was filtered hot (at 80°C).

[0062] The mixture was allowed to cool to 20°C to obtain a suspension. The suspension was filtered off, the cake was washed with about 200 ml of acetone, suction dried on the filter for 15 minutes and then vacuum dried at 80°C for 16 hours. This afforded 62.96 g (89% of theoretical yield) of Abemaciclib N,N-dimethylformamide hemisolvate, in purity 99.43% (HPLC IN). XRPD of obtained solid corresponds to XRPD pattern depicted in Fig 1.

[0063] Example 5: Preparation of solid Form III of Abemaciclib

[0064] 25 g of Abemaciclib N,N-dimethylformamide hemisolvate was mixed with 275 ml of dimethylsulfoxide. The mixture was heated to 100°C to obtain a solution. The mixture was cooled down to 95 °C and 12.5 ml of water was added drop-wise. Then temperature was decreased to 90°C and the mixture was stirred for 30 minutes until solid material was formed. Then the mixture was stirred for 1 hour and subsequently allowed to cool to 20°C over 1 hour. The solid was filtered off, washed with 115 ml of acetone, suction dried on the filter for 5 min and then vacuum dried at 80°C for 12 hours affording 22.5 g of Abemaciclib (90 % of theoretical yield) in purity: 99.88% (HPLC IN).

[0065] XRPD of obtained solid form corresponds to solid Form III.

Claims

CLAIMS1. A process for preparation of a solid form of Abemaciclib, compound of Formula (1) or a salt or a solvate or a cocrystal thereof:the process comprising: a. Dissolving Abemaciclib or a solvate thereof in a solvent selected from dimethyl sulfoxide or 2-butanone; b. Cooling the mixture to a temperature between 60°C and 95°C; c. Stirring the mixture at this temperature for between 30 and 180 minutes; d. Cooling the mixture to a temperature between 0°C and 30°C; e. Isolating a solid form of Abemaciclib.

2. The process according to claim 1 wherein the mixture in step b. is cooled to a temperature between 80°C and 90°C.

3. The process according to claim 1 or 2 wherein water is added into the mixture prepared in step b., wherein the volume ratio between water and the solvent used in step a. is 0.01 : 1 and 0.13: 1.

4. The process according to any one of claims 1 to 3 wherein Abemaciclib or a solvate thereof in step a. is dissolved at a temperature between 78°C and 105°C.

5. The process according to any one of claims 1 to 4 wherein the Abemaciclib or a solvate thereof in step a. is Abemaciclib N,N-dimethylformamide hemisolvate, compound offormula (1 A):

6. The process according to claim 5 wherein the Abemaciclib N,N-dimethylformamide hemisolvate is in solid form that is characterized by XRPD powder diffraction pattern comprising the peaks at about 9.7°, 13.4°, 14.5° and 21.4°degrees 2 theta, when measured with CuKal radiation ( = 1.54060 A).

7. The process according to claim 1 wherein the prepared solid form of Abemaciclib is Form III characterized by characterized by XRPD pattern comprising peaks at 10.91°, 11.54°, 12.13°and 21.29° degrees 2 theta ( 4^0.2 degrees 2 theta), when measured with CuKal radiation (k = 1.54060 A).

8. The process according to any one of claims 1 to 7 wherein Abemaciclib isolated in step e. is further transformed into a salt or a solvate or a cocrystal of Abemaciclib.

9. Abemaciclib N,N-dimethylformamide hemisolvate, compound of formula (1 A):

10. A solid form of the compound according to claim 9.

11. The solid form according to claim 10, Form L, characterized by XRPD powder diffraction pattern comprising the peaks at about 9.7°, 13.4°, 14.5° and 21.4°degrees 2 theta, when measured with CuKal radiation ( = 1.54060 A).A process for preparation of the compound according to anyone of claims 10 or 11, the process comprising: a. Reacting compound of Formula (2) with compound of Formula (3) in a presence of a base and a catalyst in N,N-dimethylformamide to provide Abemaciclib N,N-dimethylformamide hemisolvate:b. Precipitating of the solid form of Abemaciclib N,N-dimethylformamide hemisolvate from reaction mixture.

13. A process for preparation of a solid form of Abemaciclib comprising: a. Reacting compound of Formula (2) with compound of Formula (3) in a presence of a base and a catalyst in dimethyl sulfoxide:b. Isolating the solid form of Abemaciclib from the reaction mixture14. The process according to claim 13 wherein the step b. comprises(i.) Cooling the mixture to a temperature between 60°C and 95°C;(ii.) Stirring the mixture at this temperature for between 30 and 180 minutes;(iii.) Cooling the mixture to a temperature between 0°C and 30°C;(iv.) Isolating the solid form of Abemaciclib.

5. The process according to claim 13 or 14 wherein the solid form is Form III characterized by XRPD pattern comprising peaks at 10.91°, 11.54°, 12.13°and 21.29° degrees 2 theta ( +_0.2 degrees 2 theta), when measured with CuKal radiation ( = 1.54060 A).

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