Hexane → 3,6-Diethoxy-2,5-dihydropyrazine

Participants

Reaction Conditions

Reaction Steps

1 6M n-butyllithium in hexane (788 ml, 1.26 mol) is added dropwise at -40° C. under an inert atmosphere over a period of 20 minutes to a solution of 3,6-diethoxy-2,5-dihydro-pyrazine (229.8 g, 1.35 mol) in tetrahydrofuran (3.0 liters). The batch is stirred for a further 15 minutes at -40° C. and then a solution of 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide (323.4 g, 0.90 mol) in tetrahydrofuran (1.0 liter) is added dropwise thereto over a period of 20 minutes. When the addition is complete, the temperature of the mixture is allowed to rise to -20° C. and the mixture is then stirred at that temperature over a period of 18 hours. The reaction mixture is concentrated and the residue is partitioned between ethyl acetate (1 liter) and water (1 liter). The organic phase is washed with 2×1 liter of water, and the aqueous phases are each back-extracted with 1 liter of ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution (1 liter) and dried over magnesium sulfate. After concentration, the residue is dried under a high vacuum over a period of 1 hour at 35° C. The crude title compound is obtained in admixture with a small amount of epimeric 2(R)-{2(S)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]3-methylbutyl}-3,6-diethoxy-2,5-dihydro-pyrazine (approx. 95:5 diastereoisomeric mixture) and excess 3,6-diethoxy-2,5-dihydro-pyrazine in the form of a colourless oil (472 g): Rf (ethyl acetate/hexane 1:2)=0.20. The 2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyl bromide used as starting material can be prepared, for example, as described below:

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