N-(diethoxyphosphorylmethyl)-1-phenylmethanimine → p-methoxybenzyl N-benzylidene-alpha-amino-diethylphosphonoacetate

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Reaction Steps

To a solution of benzylamine in absolute alcohol is added a molar equivalent of 37% aqueous formaldehyde and the reaction mixture is allowed to stir at room temperature for 2 hours. The 1,3,5-tribenzyl-sym-hexahydrotriazine found in the reaction is recovered by extraction with petroleum ether which, after evaporation, yields a product melting at 48°-50° C. The latter product is heated with about 3 molar equivalents of diethyl phosphite at 100° C. for 6 hours, and the resulting reaction product is chromatographed on silica gel using 3% methanol in methylene chloride as the eluting solvent. Evaporation of the solvent affords diethyl N-benzyl-aminomethylphosphonate as a pale yellow mobile liquid. Hydrogenation of this product in absolute alcohol containing a small amount of HCl in the presence of palladium on carbon catalyst affords diethyl aminomethylphosphonate hydrochloride which is recovered by evaporating the filtered hydrogenation mixture. Reaction of this product in chloroform with ammonia and evaporation of the resulting filtered solution yields diethyl aminomethylphosphonate. Benzaldehyde is added to this product in an ice bath to produce diethyl N-benzylidene-aminomethylphosphonate which is recovered by diluting the reaction mixture with absolute alcohol and evaporating the filtered solution. The product is further purified by solution in dry benzene and evaporation of the solvent to afford the product as a pale yellow oil. To a solution of the diethyl N-benzylidene-aminomethylphosphonate in dry tetrahydrofuran is then added phenyllithium solution followed by the slow addition of p-methoxybenzyl chloroformate. After about 20 minutes, the solvent is removed under reduced pressure and the oily residue is partitioned between ethyl ether and pH 3 phosphate buffer. Evaporation of the ethyl ether affords p-methoxybenzyl N-benzylidene-α-amino-diethylphosphonoacetate which is purified by chromatography over silica gel using 1:3 ethyl acetate-ethyl ether as the eluting solvent. The product so obtained is reacted with p-toluenesulfonic acid in ethyl ether solution and cyclohexane is added to the reaction mixture. The solvent layer is decanted and the resulting oily layer is again washed with 2:1 ethyl ether-cyclohexane. Solution of the oily residue in aqueous dipotassium phosphate to pH about 7 and extraction of the solution with methylene chloride affords a solvent solution of the product which is evaporated to produce p-methoxybenzyl α-amino-diethylphosphonoacetate. Reaction of this product with ethyl thioformate in the presence of liquid hydrogen sulfide at low temperatures produces crude p-methoxybenzyl α-thioformamido-diethylphosphonoacetate. The latter product is purified over silica gel using ethyl acetate to elute the product.

Provenance & Evidence