1231929-97-7

Basic information

• Product Name: LY2835219
• Synonyms: CDK4/6 dual inhibitor;LY 2835219 (free base);LY2835219 (free base);LY-2835219 (free base);N-[5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-2-pyrimidinamine;Abemaciclib;abemaciclib(CDK 4/6 inhibitor);Abemaciclib (LY2835219)
• CAS NO: 1231929-97-7
• Molecular Formula: C₂₇H₃₂F₂N₈
• Molecular Weight: 506.5933864
• Product Categories: Inhibitors
• Mol File: 1231929-97-7.mol
• Article Data: 8

Chemical Properties

• Boiling Point: 689.3±65.0 °C(Predicted)
• Appearance: /
• Density: 1.32±0.1 g/cm3(Predicted)
• Solubility: insoluble in H2O; ≥4.83 mg/mL in DMSO with gentle warming and ultrasonic; ≥6.34 mg/mL in EtOH with gentle warming
• PKA: 7.69±0.10(Predicted)
• CAS DataBase Reference: LY2835219(CAS DataBase Reference)
• NIST Chemistry Reference: LY2835219(1231929-97-7)
• EPA Substance Registry System: LY2835219(1231929-97-7)

Safety Data

• Hazardous Substances Data: 1231929-97-7(Hazardous Substances Data)

Usage

Biological Activity

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. cdk4/6 dual inhibitor 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.

Enzyme inhibitor

This oral cell cycle inhibitor (FWfree-base = 506.61 g/mol; FWmesylate-salt = 602.70 g/mol; CAS 1231930-82-7 (mesylate salt) ), also known as LY2835219 and N-[5-[ (4-ethyl-1-piperazinyl) methyl]-2-pyridinyl]-5- fluoro-4-[4-fluoro-2-methyl-1- (1-methylethyl) -1H-benzimidazol-6-yl]-2- pyrimidinamine, targets the cyclin-dependent kinase CDK4, or cyclin D1 (IC50 = 2 nM) and CDK6, or cyclin D3 (IC50 = 6 nM), inhibiting retinoblastoma (Rb) protein phosphorylation in early G1, thereby arresting the cell cycle in the G1, suppressing DNA synthesis, and inhibiting cancer cell growth. LY2835219 inhibits activation of AKT and ERK, but not mTOR.

Synthetic route

6-(3-N,N-dimethylamino-2-fluoro-2-acrylketone-1-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole + N-[5-(4-ethylpiperazine-1-yl-methyl)pyridine-2-yl]guanidine nitrate → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Stage #1: N-[5-(4-ethylpiperazine-1-yl-methyl)pyridine-2-yl]guanidine nitrate With sulfuric acid; sodium methylate In methanol; N,N-dimethyl-formamide at 30 - 35℃; for 2h; Stage #2: 6-(3-N,N-dimethylamino-2-fluoro-2-acrylketone-1-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole at 80 - 85℃; for 7h;	90.8%
With sodium hydroxide In butan-1-ol at 90 - 100℃; Inert atmosphere;	73.1%

5-((4-ethylpiperazin-1-yl)methyl)-6-methylpyridin-2-amine (1180132-17-5) + 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (1231930-33-8) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene at 98 - 100℃; Inert atmosphere;	82.85%

4-ethylpiperazine (5308-25-8) + 6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)nicotinaldehyde → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
With formic acid; trimethyl orthoformate In acetonitrile at 80℃; for 16h; Reagent/catalyst; Leukardt-Wallach Amination; Sealed tube;	74%

5-((4-ethylpiperazin-1-yl)methyl)-6-methylpyridin-2-amine (1180132-17-5) + 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (1231930-42-9) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
With potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0) In tert-Amyl alcohol at 100℃; for 19h;	57.3%
With caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 2h; Product distribution / selectivity; Inert atmosphere;
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 2h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	22.11 g

4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-benzo[d]imidazole (1231930-37-2) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / water; 1,2-dimethoxyethane / 80 °C / Inert atmosphere 1.2: 5.5 h / 80 °C / Inert atmosphere 2.1: palladium dichloride; potassium carbonate / tert-Amyl alcohol / 18 h / 100 °C / Inert atmosphere 3.1: trimethyl orthoformate; formic acid / acetonitrile / 16 h / 80 °C / Sealed tube View Scheme
Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 - 84 °C / Inert atmosphere 2: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme

N-isopropylacetamide (1118-69-0) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine; trichlorophosphate / toluene / 3 h / Reflux 2: potassium tert-butylate; N-Methylformamide / 70 - 75 °C / Large scale 3: tricyclohexylphosphine; potassium acetate; palladium diacetate / dimethyl sulfoxide / 1 h / 90 °C / Inert atmosphere 4: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 - 84 °C / Inert atmosphere 5: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: trichlorophosphate; triethylamine / toluene / 10 °C / Reflux 2: potassium hydroxide / toluene; dimethyl sulfoxide / 30 °C / Reflux 3: potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; palladium diacetate / 98 - 100 °C / Inert atmosphere View Scheme

N-(4-bromo-2,6-difluorophenyl)-N'-isopropylacetamidine (1231930-29-2) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions

Yield

Multi-step reaction with 4 steps 1: potassium tert-butylate; N-Methylformamide / 70 - 75 °C / Large scale 2: tricyclohexylphosphine; potassium acetate; palladium diacetate / dimethyl sulfoxide / 1 h / 90 °C / Inert atmosphere 3: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 - 84 °C / Inert atmosphere 4: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme

6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (1231930-33-8) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions

Yield

Multi-step reaction with 3 steps 1: tricyclohexylphosphine; potassium acetate; palladium diacetate / dimethyl sulfoxide / 1 h / 90 °C / Inert atmosphere 2: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 - 84 °C / Inert atmosphere 3: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme

4-ethylpiperazine (5308-25-8) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 12 h / 20 - 30 °C / Large scale 2: ammonia / methanol / 40 - 75 °C 3: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme

6-bromonicotinaldehyde (149806-06-4) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 12 h / 20 - 30 °C / Large scale 2: ammonia / methanol / 40 - 75 °C 3: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme

1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine (1231930-25-8) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonia / methanol / 40 - 75 °C 2: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme

4-bromo-2,6-difluoroaniline (67567-26-4) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: triethylamine; trichlorophosphate / toluene / 3 h / Reflux 2: potassium tert-butylate; N-Methylformamide / 70 - 75 °C / Large scale 3: tricyclohexylphosphine; potassium acetate; palladium diacetate / dimethyl sulfoxide / 1 h / 90 °C / Inert atmosphere 4: bis-triphenylphosphine-palladium(II) chloride; sodium carbonate / water; 1,2-dimethoxyethane / 1 h / 80 - 84 °C / Inert atmosphere 5: caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 2 h / 110 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: trichlorophosphate; triethylamine / toluene / 10 °C / Reflux 2: potassium hydroxide / toluene; dimethyl sulfoxide / 30 °C / Reflux 3: potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; palladium diacetate / 98 - 100 °C / Inert atmosphere View Scheme

1-(4-amino-3,5-difluorophenyl)-2-fluoroethanone → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: phosphorus trichloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 0 - 105 °C / Inert atmosphere 2: sodium hydride / toluene; mineral oil / 5 - 115 °C / Inert atmosphere 3: 5,5-dimethyl-1,3-cyclohexadiene / 120 - 130 °C / Inert atmosphere 4: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: N,N-dimethyl-formamide / 140 - 150 °C / Inert atmosphere 2: phosphorus trichloride; triethylamine / toluene / 0 - 115 °C / Inert atmosphere 3: potassium tert-butylate / N,N-dimethyl-formamide / 5 - 150 °C 4: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

2,6-difluoroaniline (5509-65-9) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: trifluorormethanesulfonic acid / dichloromethane / 50 °C 2: phosphorus trichloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 0 - 105 °C / Inert atmosphere 3: sodium hydride / toluene; mineral oil / 5 - 115 °C / Inert atmosphere 4: 5,5-dimethyl-1,3-cyclohexadiene / 120 - 130 °C / Inert atmosphere 5: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: trifluorormethanesulfonic acid / dichloromethane / 50 °C 2: N,N-dimethyl-formamide / 140 - 150 °C / Inert atmosphere 3: phosphorus trichloride; triethylamine / toluene / 0 - 115 °C / Inert atmosphere 4: potassium tert-butylate / N,N-dimethyl-formamide / 5 - 150 °C 5: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

1-(4-amino-2,6-difluorophenyl)-3-N,N-dimethylammonium-2-fluoro-2-acrylketone → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus trichloride; triethylamine / toluene / 0 - 115 °C / Inert atmosphere 2: potassium tert-butylate / N,N-dimethyl-formamide / 5 - 150 °C 3: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

N-[2,6-difluoro-4-(3-N,N-dimethylamino-2-fluoro-2-acrylketone-1-yl)phenyl]-N’-isopropylethanamidine → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / N,N-dimethyl-formamide / 5 - 150 °C 2: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

N'-[2,6-difluoro-4-(2-fluoroethanone-1-yl)phenyl]-N-isopropylethanamidine → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / toluene; mineral oil / 5 - 115 °C / Inert atmosphere 2: 5,5-dimethyl-1,3-cyclohexadiene / 120 - 130 °C / Inert atmosphere 3: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

6-(2-fluoroethanone-1-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzimidazole → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: 5,5-dimethyl-1,3-cyclohexadiene / 120 - 130 °C / Inert atmosphere 2: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

5-((4-ethylpiperazin-1-yl)methyl)-6-methylpyridin-2-amine (1180132-17-5) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: nitric acid / ethanol; water / 0 - 80 °C / Inert atmosphere 2: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

1-(4-amino-3,5-difluorophenyl)ethan-1-one (811799-69-6) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: Selectfluor / methanol / 48 h 2: phosphorus trichloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / 0 - 105 °C / Inert atmosphere 3: sodium hydride / toluene; mineral oil / 5 - 115 °C / Inert atmosphere 4: 5,5-dimethyl-1,3-cyclohexadiene / 120 - 130 °C / Inert atmosphere 5: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: Selectfluor / methanol / 48 h 2: N,N-dimethyl-formamide / 140 - 150 °C / Inert atmosphere 3: phosphorus trichloride; triethylamine / toluene / 0 - 115 °C / Inert atmosphere 4: potassium tert-butylate / N,N-dimethyl-formamide / 5 - 150 °C 5: sodium hydroxide / butan-1-ol / 90 - 100 °C / Inert atmosphere View Scheme

N-(4-bromo-2,6-difluorophenyl)-N'-isopropylethanimidamide → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide / toluene; dimethyl sulfoxide / 30 °C / Reflux 2: potassium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; palladium diacetate / 98 - 100 °C / Inert atmosphere View Scheme

3,5-difluoro-4-nitro-benzonitrile (1123172-88-2) → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 5 h / 60 - 65 °C / Autoclave 2.1: hydrogen / N,N-dimethyl-formamide / 9 h / 50 - 95 °C / 2250.23 - 3000.3 Torr / Autoclave; Inert atmosphere 3.1: tetrahydrofuran / 5 h / 30 - 35 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 6 h / 95 - 100 °C 5.1: sulfuric acid; sodium methylate / N,N-dimethyl-formamide; methanol / 2 h / 30 - 35 °C 5.2: 7 h / 80 - 85 °C View Scheme

3-fluoro-4-nitro-5-isopropylaminobenzonitrile → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydrogen / N,N-dimethyl-formamide / 9 h / 50 - 95 °C / 2250.23 - 3000.3 Torr / Autoclave; Inert atmosphere 2.1: tetrahydrofuran / 5 h / 30 - 35 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 6 h / 95 - 100 °C 4.1: sulfuric acid; sodium methylate / N,N-dimethyl-formamide; methanol / 2 h / 30 - 35 °C 4.2: 7 h / 80 - 85 °C View Scheme

1-isopropyl-2-methyl-4-fluoro-6-cyano-1H-benzimidazole → N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 5 h / 30 - 35 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 6 h / 95 - 100 °C 3.1: sulfuric acid; sodium methylate / N,N-dimethyl-formamide; methanol / 2 h / 30 - 35 °C 3.2: 7 h / 80 - 85 °C View Scheme

methanesulfonic acid (75-75-2) + N-(5-((4-ethyl-1-piperazinyl)methyl)-2-pyridinyl)-5-fluoro-4-(4-fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl)-2-pyrimidinamine (1231929-97-7) → [5-(4-ethylpiperazin-1-ylmethyl)pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)pyrimidin-2-yl]amine methanesulfonate

Conditions	Yield
In methanol; dichloromethane for 1h;
In methanol; dichloromethane for 1h;	20.4 g

Upstream product

• 1231930-37-2 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-benzo[d]imidazole 
• 5308-25-8 4-ethylpiperazine 
• 1123172-88-2 3,5-difluoro-4-nitro-benzonitrile 
• 69879-22-7 6-amino-3-pyridinecarbaldehyde 
• 811799-69-6 1-(4-amino-3,5-difluorophenyl)ethan-1-one 
• 1180132-17-5 5-((4-ethylpiperazin-1-yl)methyl)-6-methylpyridin-2-amine 
• 5509-65-9 2,6-difluoroaniline 
• 67567-26-4 4-bromo-2,6-difluoroaniline 
• 1231930-25-8 1-((6-bromopyridin-3-yl)methyl)-4-ethylpiperazine 
• 149806-06-4 6-bromonicotinaldehyde 
• 1231930-33-8 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole 
• 1231930-29-2 N-(4-bromo-2,6-difluorophenyl)-N'-isopropylacetamidine 
• 1118-69-0 N-isopropylacetamide 
• 1231930-42-9 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole 

Downstream Products

• 1231930-82-7 abemaciclib 
• 1231930-82-7 LY2835219 

Relevant articles and documents

A synthesis of abemaciclib utilizing a Leuckart-Wallach reaction

A concise total synthesis of CDK 4/6 inhibitor abemaciclib is described. The synthesis uses a Suzuki coupling, followed by a Hartwig-Buchwald amination to join three of the four subunits. The final step is a reductive amination utilizing Leuckart-Wallach conditions. Key to the Leuckart-Wallach reaction was the addition of trimethyl orthoformate to remove water formed during the reaction, allowing the reaction to go to completion.

CRYSTALLINE POLYMORPHS OF ABEMACICLIB

The present disclosure provides novel polymorphs of abemaciclib, solid dispersions of abemaciclib with pharmaceutical excipients, and processes for the preparation thereof. The disclosure further provides methods for preparing crystalline abemaciclib form I, amorphous abemaciclib, and methods for synthesizing abemaciclib.

PREPARATION METHOD FOR BEMACICLB

Disclosed are an intermediate of bemaciclib or abemaciclib and a preparation method therefor. The preparation method comprises condensation, amidine reaction, cyclization and other unit reactions. Serving the intermediate of bemaciclib as a raw material, bemaciclib is obtained through the guanidination reaction and the cyclization reaction. According to the preparation method, the raw material is easily available, the procedure is simple, and the preparation method is economical, environmentally friendly and suitable for industrial production.