Yield: 95%

Reaction Conditions:

with ammonium acetate in ethanol at 50 - 80;

Steps:

1 Example 1. Synthesis of tyrphostin 9 and related benzylidenemalonic acid derivatives
A) 3 mole-g (703 g) of 4-hydroxy-3,5-di-tert-butylbenzaldehyde (99.1 % pure, purchased from Yongyi Chemicals Group Co., Ltd, Changzhou, Jiangsu, China) and 2.5 L anhydrous ethanol are charged into a 5 L reactor provided with mechanical stirring and fitted with a reflux condenser. B) 3 mole-g (198 g) of malonodinitrile (99.76% pure, purchased from Aceto Corporation, Port Washington, NY, USA) are quickly added to the reactor while stirring. C) 75 g of ammonium acetate (98.5% pure, purchased from Fermont, Monterrey) are quickly added while stirring. The color of the reaction mixture goes from beige to yellow and then to orange. D) The reactor is heated to reflux using a water bath. Reflux is first observed when the bath temperature reaches about 80 °C and is maintained during 1 hour. Complete solution is observed before reflux starts. E) The water bath is removed and the temperature is allowed to drop to 50°C. F) 1.5 L of water is added to the reaction mixture under brisk stirring. A precipitate appears. G) The reaction mixture is cooted to 0°C. H) The reaction mixture is filtered under reduced pressure using a Buchner funnel attached to a Kitasato flask. I) The filter cake is thoroughly washed with water. J) The wet filter cake is dried by heating in an oven at 60°C until constant weight is achieved. This procedure yields about 800 g (about 95% yield) of a light-yellow microcrystalline solid that melts at 141-142 "C (uncorrected), presents UV absorption maxima at 247 nm and 365 nm and has an Rf value of 0.65 (using benzene as eluant and Merck^'s TLC silica gel 60 F₂₅4 plastic-backed sheets), with only one spot being observed. The mixed melting point of this compound and authentic tyrphostin 9 (acquired from Cayman Chemical) was also 141-142 (uncorrected), and its spectroscopic and chromatographic properties were identical to those of the authentic product. This compound is stable, with a shelf life of over 1 year at 25-35°C; if necessary it may be recrystallized from ethanol.

References:

NAN GLOBAL, LLC;GOJON-ZORRILLA, Gabriel;GOJON-ROMANILLOS, Gabriel WO2016/4363, 2016, A2 Location in patent:Page/Page column 40; 41