Malonic Acid → 2-Propenoic acid, 3-[6-[1-hydroxy-1-(4-methylphenyl)-3-(1-pyrrolidinyl)propyl]-2-pyridinyl]-, methyl ester, (E)-

Participants

Reaction Steps

A solution of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (91 g) in toluene (50 mL) was added under nitrogen to a stirred mixture of butyllithium (260 mL, 1.6M) and toluene (1.1 L) between -60° and -70°. After 2 h a solution of 1-pyrrolidino-3-(4-tolyl)propan-3-one (prepared from 85 g of the corresponding hydrochloride and dried) in toluene (200 mL) was added at -70° and the mixture stirred for a further 3 hours at this temperature. The solution was allowed to warm to -20° and treated with hydrochloric acid (510 ml, 2M). The separated aqueous layer was washed with ether, basified with sodium hydroxide solution (10M) at 0° and extracted with toluene. Evaporation of the dried extracts gave an oil (120 g). This was dissolved in hydrochloric acid (200 ml, 2M) and heated on the steam bath for 30 minutes. Cooling, basification and re-isolation gave 2-[1-hydroxy-3-pyrrolidino-1-(4-tolyl)-propyl]pyridine-6-aldehyde as an oil (115 g). The crude aldehyde was dissolved in pyridine (133 mL) and reacted with malonic acid (58 g) in presence of piperidine (2 mL) at reflux for one hour. After evaporation in vacuo, the residue was dissolved in a small volume of glacial acetic acid, diluted with ater (2 L) and set aside at 0 to crystallise. The solid product was esterified with methanol and sulphuric acid giving methyl-(E)-3-{6-[1-hydroxy-3-pyrrolidino-1-(4-tolyl)propyl]-2-pyridyl}acrylate as a dark oil (27 g). A small sample crystallized from petroleum ether in colourless prisms, m.p. 75°-77°. A mixture of the crude ester (25 g) and concentrated sulfuric acid (50 ml) was heated in an oil bath at 160° for 20 minutes. Re-isolation and saponification by the method described in example 5 gave (E)-3-{6-3-[pyrrolidino-1-(4-tolyl)prop-1E-enyl]-2-pyridyl}acrylic acid as off-white crystals, m.p. 218-9° (decomp.) A further recrystallization from isopropanol raised the melting point to 222-3°.

Provenance & Evidence