To create the necessary acidic condtions to allow the formation of the glyphosate it would first be necessary to reflux an aqueous solution of glycine hydrochloride, phosphorous acid, and conc. hydrochloric acid. Over a period of about two hours excess aqueous fomaldehyde is then added and glyphosate can then be separated from the resulting product mixture. Using glycine is, however, problematic because the yield of glyphosate is quite low. This is because glyphosate reacts faster than glycine and so a second phosphonomethylation takes place leading to the formation of the diphosphonomethyl adduct as the major product. Even at lower temperature and with the reactants in stoichiometric amounts the diphosphonomethyl adduct predominates.

Glyphosate often forms N-Methylglyphosate as a side product in this reaction. This occurs via a reductive alkylation of glyphosate by formaldehyde. The mechanism of this reaction is thought to be an Eschweiler - Clarke process.

The tendency for the glyphosate to react to form the diphosphonomethylated adduct, under acidic, as the major product can be overcome by using an N-substituted glycine in the place of glycine, ie. a secondary amine. This will lead to more steps being added to the synthesis (ie. the removal of the N-substituent),but it can frequently result in higher isolated yields of glyphosate.

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