Biphenyl → 5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinamine

Participants

Reaction Conditions

Reaction Steps

Add lithium 1,1,1,3,3,3-hexamethyl-disilazane (1055 mL) slowly to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (250 g), dicyclohexylphosphino)biphenyl (18.50 g), tris(dibenzylideneacetone)dipalladium (24.17 g) and THF (250 mL) at 50° C. Heat the mixture at 65° C. overnight. Cool to 37° C. and add water (500 mL). Remove half of the solvent under vacuum and add DCM (2.5 L). Filter over a celite pad and remove part of the solvent. Add methanol (300 mL) and methyl tert-butyl ether (MtBE, 600 mL) to the mixture and cool in an ice bath. Then, add hydrochloric acid 2 M in ethyl ether (800 mL) and a 32% aqueous solution of hydrochloric acid (100 mL). Remove the organic layer, and add an aqueous solution of sodium hydroxide 2 M (2500 mL). Extract the aqueous phase three times with DCM and remove the solvent under vacuum. Solve in 90 mL of toluene at 50° C. until complete dissolution and then add 80 mL of MtBE. Stir overnight at RT. Add additional MtBE (100 mL) for complete precipitation. Filter the solid and dry to afford 108.24 g of the title compound. MS (ES+): m/z=221 (M+H)+.

Provenance & Evidence