Syntheses of p-Apo-8-carotenoic acid ethyl esters

Synthesis of 2-methylbut-3-enoic acid ethyl ester (3) 

In a 4-litre round-bottomed flask a solution of 405 g 2-methylbut-3-ene-nitrile (2) (Fluka Art. 66987, ca. 80%, ca. 4.0 mol) in 560 g EtOH is prepared. Then 630 g HCl gas is blown into the reaction vessel for 7 h via a gas inlet tube mounted above the surface of the solution. The reaction temperature is kept at 30°C by cooling during this time. 2.4 1 H2O is added over a period of 20 min., while the temperature is kept at 30-40°C. At this temperature, 810 g of an aqueous solution of NaOH (50%, 10 mol) is added to give pH 2. The reaction mixture is stirred for an additional 30 min. After phase separation, the aqueous phase is extracted twice with 500 ml Et20. The ether phases are combined and the solvent is evaporated. The product is purified by fractional distillation (60 cm packed column) to give 332 g (64.8%) of 3 (purity 97.5%, b.p. 89°C/205 mbar [1]). 

The toluene solution of y-bromotiglic acid ethyl ester (4) is added at 70°C to 311 g (1.87 mol) triethyl phosphite within 1.5 h. The temperature slowly increases to 110°C and, simultaneously, ethyl bromide, EtOH and toluene are distilled off. After the addition of 4 is completed, distillation is continued for 1.5 h at normal pressure and the temperature of the oil bath is raised to 140°C. The pressure is reduced gradually to 0.5 mbar and the low-boiling solvents (b.p. 100°C) are distilled off. The residue is heated to 160°C for 1.5 h. Fractional distillation with a 10 cm vigneux column at 0.08 mbar and 101-105°C gives 285 g (78.8%) of 5 (purity 99%, (E/Z) = 7.7 1) [2]. 

A solution of 142 g (1 mol) f )-3-formylbut-2-enyl acetate (6) (BASF), 109.2 g (1.05 mol) 2,2-dimethylpropane-l,3-diol and 0.35 g (ca. 2 mmol) p-toluenesulphonic acid in 600 ml toluene is refluxed for 2 h. The H2O formed is removed continuously by means of a water trap. After cooling to r.t. the reaction mixture is washed with aq. NaHC03 and the solvent is evaporated. High vacuum distillation gives 216 g (90.7%) of 7 (b.p. 94-96°C, 0.1 mbar) [3]. 

To a solution of 228 g (1 mol) 7 in 300 ml MeOH, 2.0 g NaOMe is added. The MeOH is distilled off (bath temperature 60°C, 600 mbar, 20 cm vigreux column) and the distillation is repeated after the addition of 150 ml MeOH. The residue is dissolved in 600 ml CH2CI2, washed twice with 400 ml H2O and the solvent is evaporated. High-vacuum distillation gives 172 g (92%) of (b.p. 106-110°C, 0.4 mbar) [3]. 

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