2-chloro-N-cyclopentyl-5-(3,3-diethoxy-1-propyn-1-yl)-4-Pyrimidinamine synthesis

Yield:1211442-87-3 54%

Reaction Conditions:

Stage #1: 5-bromo-2-chloro-N-cyclopentylaminopyrimidine-4-amine;Propiolaldehyde diethyl acetalwith triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ in tetrahydrofuran at 20; for 0.166667 h;Inert atmosphere;
Stage #2: copper(l) iodide in tetrahydrofuran at 60; for 48 h;Product distribution / selectivity;Inert atmosphere;

Steps:

104

To a stirred solution of (5-bromo-2-chloro pyrimidin-4-yl)-cyclopentyl-amine (1.00 g, 3.62 mmol) and PdCl₂(dppf)-dichloromethane (148 mg, 0.181 mmol) in THF (10 mL) is added Et₃N (0.757 mL, 5.43 mmol) and 3,3-diethoxy-propyne (0.778 mL, 5.43 mmol) sequentially at room temperature. The mixture is degassed under a stream of N₂ and stirred at room temperature for 10 minutes before CuI (29 mg, 0.154 mmol) is added. The reaction vessel is evacuated and back-filled with N₂ (x3) and heated at 60 °C for 48 hours. The mixture is allowed to cool, diluted with EtOAc, filtered and partitioned between H₂O and ethyl acetate. The phases are separated and the aqueous layer is further extracted with EtOAc (x3), combined organic extracts are dried (MgSO^, filtered and concentrated. The residue is purified by SiO₂ chromatography, eluting with a gradient of 5% EtO Ac/petrol to 20% EtOAc / petrol to give [2-chloro-5-(3,3-diethoxy-prop-1-ynyl)-pyrimidin-4-yl]-cyclopentyl amine (636 mg, 54%). MS(ESI) m/z 324.2 (M+H)⁺

References:

WO2010/20675,2010,A1 Location in patent:Page/Page column 51; 52