ChemicalBook CAS DataBase List Abemaciclib

Abemaciclib synthesis

12synthesis methods

Product Name:Abemaciclib
CAS Number:1231929-97-7
Molecular formula:C27H32F2N8
Molecular Weight:506.59

Abemaciclib, also known as LY2835219, is 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 inhibits CDK4 and CDK6 with low nanomolar potency. 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. Synthetic Description Reference：Chan ED. Combination of anti-human VEGFR2 antibody and abemaciclib for treatment of non-small cell lung cancer. WO 2015130540 (2015). Synthetic Description Reference：Frederick, MO.; Kjell, DP. A synthesis of abemaciclib utilizing a Leuckart-Wallach reaction. Tetrahedron Lett. 2015, 56(7); 949-951 Synthetic Description Reference： Coates, DA.; Gelbert, LM.; Knobeloch, JM.; De dios Magana, A.; De Prado GA; Filadelfa del Prado Catalina, M.; Garcia Paredes, MC.; Martin de la Nava, EM.; Martin Ortega Finger, MD.; Martinez Perez, JA.; Mateo Herranz, AI.; Perez Martinez, C.; Sanchez Martinez, C. Preparation of benzimidazolylpyrimidinylaminopyridines as CDK4/6 protein kinase inhibitors. US 20100160340 (2010).

Synthetic Routes

ROUTE 1

ROUTE 2

ROUTE 3

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ROUTE 5

ROUTE 6

Reference：Chan ED. Combination of anti-human VEGFR2 antibody and abemaciclib for treatment of non-small cell lung cancer. WO 2015130540 (2015).

1180132-17-5 Synthesis

5-((4-Ethylpiperazin-1-yl)methyl)pyridin-2-amine

1180132-17-5
196 suppliers
$25.00/250mg

1231930-33-8 Synthesis

6-Bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole

1231930-33-8
199 suppliers
$13.00/100mg

1231929-97-7
250 suppliers
$29.00/1mg

Yield:1231929-97-7 82.85%

Reaction Conditions:

with palladium diacetate;potassium carbonate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene at 98 - 100;Inert atmosphere;

Steps:

30 Example 30: Preparation of abemaciclib
Argon/Nitrogen was bubbled into a mixture of 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H- benzoimidazole (10 g, 0.0309 mol), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (6.890.0312 mol), potassium carbonate (8.65 g), and xantphos (1.07 g, 0.0018 mole) in tert-amyl alcohol (50 mL). Palladium acetate (0.2 g, 0.00089 mole) was added and the reaction mass was heated to 98-100 °C for 2-4 hours. The completion of the reaction was monitored by TLC/HPLC. The reaction mass was cooled to 30-35 °C., then diluted with dichloromethane (80 mL) and water (30 mL) and filtered through a HYFLO bed. The compound was extracted from theorganic layer using hydrochloric acid diluted in water (1:1) (2 x 30 mL). The pH of the combined aqueous layers was adjusted to 11-12 with a sodium hydroxide solution and the compound was extracted using dichloromethane. The organic layer was treated with N-acetyl-L-cysteine and the pH of the solution was adjusted to 11.0-12.0 with a sodium hydroxide solution. The mixture was stirred for 30 minutes at 30-35 °C and the layers were separated. The organic layer was washedwith water and distilled under vacuum at 40-45 °C. Acetone (100 mL) was charged to the residue and the temperature was raised to reflux for 30 minutes, and then cooled to 30-35 °C. The mixture was filtered and the solid product was washed with acetone and dried at 50-55 °C to give 13 g (82.85%) of abemaciclib with purity of 99.79%.

References:

MYLAN LABORATORIES LIMITED;JETTI, Ramakoteswara Rao;INDUKURI, Anjaneyaraju;BOMMAREDDY, Aggi Ramireddy;SRINIVASARAO, Attanti Veera Venkata;JEBARAJ, Rathinapandian;CHANDUPATLA, Shivakumar;BATHARAJU, Ramesh;KUNAMNENI, Sunil WO2019/102492, 2019, A1 Location in patent:Page/Page column 42

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1180132-17-5 Synthesis

1180132-17-5
196 suppliers
$25.00/250mg

1231930-42-9 Synthesis