Abemaciclib (Bemaciclib)

N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine

2-Pyrimidinamine, N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)

[5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine

Abemaciclib; 1231929-97-7; LY2835219; LY2835219 free base; UNII-60UAB198HK; LY 2835219 (free base);

Treatment of Advanced Cancer

Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity. Abemaciclib specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of theserine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.

LY2835219 is a potent and selective inhibitor of CDK4 and CDK6 with IC50 of 2 nM and 10 nM, respectively.
IC50 Value: 2 nM(CDK4); 10 nM(CDK6)
Target: CDK4/6
in vitro: LY2835219 is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathway, with potential antineoplastic activity. LY2835219 specifically inhibits CDK4 and 6, thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. Inhibition of Rb phosphorylation prevents CDK-mediated G1-S phase transition, thereby arresting the cell cycle in the G1 phase, suppressing DNA synthesis and inhibiting cancer cell growth. Overexpression of the serine/threonine kinases CDK4/6, as seen in certain types of cancer, causes cell cycle deregulation.
in vivo: LY2835219 saturates BBB efflux with an unbound plasma IC50 of about 95 nM. The percent of dose in brain for LY2835219-MsOH is 0.5–3.9%. In both a subcutaneous and intracranial human glioblastoma model (U87MG), LY2835219-MsOH suppressed tumor growth in a dose-dependent manner both as a single agent, and in combination with temozolomide.

Methane sulfonate

cas 1231930-82-7, C28H36F2N8O3S, 602.7

SYNTHESIS

US20100160340

Example 1

[5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine
• [0112]
• Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (15.9 g), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (10.85 g), cesium carbonate (32.10 g), tris(dibenzylideneacetone) dipalladium (1.82 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.35 g) in 1,4-dioxane (197.06 mL). Heat the mixture in a pre-heated oil bath at 110° C. for 2 h. Cool to RT, dilute with DCM and filter over a celite pad. Remove the solvent under vacuum and purify by silica gel column chromatography, eluting with DCM/methanol (2%) and then DCM/methanol-NH₃ 2 M 2% to afford 22.11 g of the title compound. MS (ES⁺): m/z=507 (M+H)⁺.

Example 33

[5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amineCrystalline Form IIIRoute B
• [0135]

a. 1-(6-Bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine

• Add neat 1-ethylpiperazine (5.6 kg) to a mixture of 6-bromo-pyridine-3-carbaldehyde (8.3 kg) and DCM (186 kg). Then, add sodium triacetoxyborohydride (10.9 kg) in portions and stir at 20-30° C. for 12 h. Quench the reaction into a mixture of DCM (36 kg) and aqueous solution of sodium hydroxide 2 N (46 kg). Separate the layers and extract twice the aqueous layer with DCM (24×2 kg). Combine the organic layers, wash with brine (50×2 kg) and remove the solvent under vacuum to afford 11.5 kg of the title compound. MS (ES⁺): m/z=285 (M+H)⁺.

b. 5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine

• Add liquid ammonia (50.0 kg) to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (14.2 kg), cuprous oxide (200 g), and MeOH (57 kg) at T≦40° C. Heat the mixture at 65-75° C. overnight. Cool to 20-30° C. and filter over a Celite® pad. Concentrate the filtrate and add DCM (113 kg) and adjust the pH to 12-14 with sodium hydroxide 2N (23 kg) separate the phases and wash the organic phase with DCM (58×2 kg) and combine the organic layers. Filter the mixture through Celite® and concentrate. Dissolve the residue in toluene (9.7 kg) and crystallize by the addition of MtBE (8.3 kg) to give 6.0 kg of the title compound. Obtain further purification through a toluene recrystallization. MS (ES⁺): m/z=221 (M+H)⁺.

c. N-Isopropyl-acetamide

• Add potassium carbonate (28 kg) to a solution of 2-propanamine (12 kg) in ethyl acetate (108 kg) at <20° C. Cool the mixture to 5-0° C. and add acetyl chloride (16.7 kg) at about 2-3 kg/h. Stir until complete by gas chromatography. Quench the reaction with water (0.8 kg) and filter the reaction mixture and concentrate to afford 13.4 kg of the title compound. NMR (CDCl₃) 4.06 (m, 1H), 1.94 (s, 3H), 1.14 (d, 6H).

d. N-(4-Bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine

• Add phosphoryl chloride (16.0 kg) to a mixture of 4-bromo-2,6-difluoro-phenylamine (14.5 kg), N-isopropyl acetamide (8.5 kg), TEA (10.6 kg) in toluene (115 kg) at <20° C. Stir at 10-20° C. until complete by HPLC. Remove the solvent under vacuum and add MtBE (64 kg). Adjust the pH of the mixture with 10% aq. sodium carbonate (250 kg). Filter the mixture and rinse the cake with MtBE (11×2 kg). Separate the phases and wash the aqueous layer with MtBE (22×2 kg). Combine the organic layers and concentrate, filter and wash with cyclohexane (0.6 kg) and dry to afford 17.2 kg of the title compound. MS (ES⁺): m/z=292 (M+H)⁺.

e. 6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole

• Add potassium tert-butoxide (6.9 kg) in portions to a solution of N-(4-bromo-2,6-difluoro-phenyl)-N′-isopropyl-acetamidine (16.2 kg) in N-methyl formamide (76 kg) while maintaining the temperature at T<30° C. Heat the mixture at 70-75° C. until complete by HPLC. Cool to 20-30° C. and quench by adding into water (227 kg) then extract with MtBE (37×4 kg). Wash the combined organic phases with brine (49×2 kg) and concentrate to 25-30 L, add n-hexane (64 kg) and filter the slurry to give 11 kg of the title compound. MS (ES⁺): m/z=272 (M+H)⁺.
• Obtain additional purification by dissolving the crude compound in DCM and filtering through a silica gel and Celite® pad followed by isolation from an MtBE/hexane mixture.

f. 4-Fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole

• Bubble nitrogen into a mixture of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (600 g), bis(pinacolato)diboron (843 g), tricyclohexylphosphine (106 g), potassium acetate (652 g), and DMSO (3.6 L). Add palladium acetate (49 g) and heat at 100° C. until complete by HPLC. Cool the reaction mixture and dilute with water (18 L), then filter to isolate the solid. Dissolve the crude material in 1,2-dimethoxyethane (450 mL) and filter through Celite®. Use the filtrate directly in part g.

g. 6-(2-Chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole

• Bubble nitrogen into a mixture of 2,4-dichloro-5-fluoro-pyrimidine (517 g), sodium carbonate (586 g) in water (1.7 L) and 1,2-dimethoxyethane (3.4 L). Add bis(triphenylphosphine)palladium(II) chloride (4.9 g) and heat the reaction at 80±3° C. and add drop wise a solution of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazole in 1,2-dimethoxyethane from part f (5.1 L). Stir the mixture at 80±3° C. until complete by HPLC. Cool to RT and dilute with cold water (2.1 L, 5° C.). Stir for 1 hour then isolate the crude solid by filtration. Achieve further purification of the solid by trituration with IPA to give 472 g of the title compound. MS (ES⁺): m/z=323 (M+H)⁺.

h. [5-(4-Ethyl-piperazin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine Crystalline form III

• [0144]
• Bubble nitrogen into a mixture of 6-(2-chloro-5-fluoro-pyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzoimidazole (465 g), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (321 g), potassium carbonate (403 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 g) in t-amyl alcohol (2.3 L). Heat tris(dibenzylideneacetone) dipalladium (13.2 g) and the mixture at 100±5° C. until complete by HPLC. Cool to RT, dilute with DCM (1.2 L) and filter over a Celite® pad. Extract the filtrate with 4M HCl (2.3 L×2). Combine the aqueous layers and stir with charcoal (32 g). Filter through Celite®, add DCM (1.7 L) and adjust pH with NaOH (28% aq., 1.5 L). Collect the organic layer and wash the aqueous layer with DCM (1.7 L). Combine organic layers, wash with brine (1 L), and dry over magnesium sulphate. Use a solid supported Si-Thiol treatment to remove residual palladium and the solvent is exchanged to acetone. Filter the slurry and dry to give 605 g of crude product as Form I. Mix 605 g of Form I and 4.3 L of dry acetone. Slurry the suspension at 56-57° C. (reflux) for at least 18 hours and then at ambient temperature for 4 hours. Isolate the solid by vacuum filtration, producing a light yellow cake. Dry the solid in a vacuum oven at 35° C. until a constant weight of 570 g is obtained. Confirm the material by XRPD to be Form III of the title compound. MS (ES+): m/z=507 (M+H)⁺.

Synthesis….http://www.joygooo.com/news_110.htm?pageNum=21

OTHERS

/////////LY 2835219, Abemaciclib, Bemaciclib

CCN1CCN(CC1)Cc2ccc(nc2)Nc3ncc(c(n3)c4cc5c(c(c4)F)nc(n5C(C)C)C)F