The Mannich process is the most widely used and most widely developed method for the synthesis of glyphosate and its derivatives.There are, however, a very wide range of methods for the synthesis of glyphosate and its derivatives which do not proceed via a Mannich condensation.In this section i will talk about them in very general and brief terms because they hold less significance than the Mannich process.
The second most important synthetic method for the synthesis of gyphosate and its derivatives proceeds via symmetrical hexahydro-1,3,5-triazines (HHT). The aldimine product which is normally formed between glycine and formaldehyde is pre-formed as a trimer before the reaction with the phosphite reagent takes place. The 1,3,5-trialkyl hexahydro-1,3,5-triazines thus formed readily hydrolyze in acid or decompose back to the reagents, used in its formation, on heating in water. The corresponding amino-methylated adducts can be formed by ring opening of the HHT's by compounds containing either reactive -OH or -SH groups. This reaction proceeds with the use of acid catalysts.
The formation of the glyphosate backbone is commonly undertaken using the Michealis-Arbuzov reactions. This method uses the reaction of alpha-halomethyl amides with trialky phosphites to form the glyphosate backbone.An example of construction of the glyphosate backbone type of reaction is a stepwise process starting with the N-methylol derivative of trifluoroacetamide via the chloromethyl trifluoroamide. This is then converted to the trifluoroacetyl-aminomethylphosphonate and a subsequent alkylation completes the formation of the glyphosate backbone.
The next method of synthesis which i will mention is conceptually the easiest as it involves the formation of the glyphosate backbone by a substitution of a leaving group in an alpha-substituted methylphosphonates. The leaving groups here are frequently tosylates and triflates. The only problem with this method is that nitrogen nucleophiles are not all that strong and the resultant yields can be poor. In fact the stronger sulfur and selnium nucleophiles give much better yields in the substitution reaction and these can then be converted to the glyphosate backbone with reasonable yields.
This last method of synthesis is currently the most novel i know of. It is a chemoenzymatic synthesis of glyphosate. It involves the use of permeabilized, metabolically-inactive transformants of methylomorphic yeasts which contain relatively large quantities of the enzyme spinach glycolate oxidase ((S)-2-hydroxyacid oxidase), Saccharomyces cerevisiae catalase T, and endogeneous catalase have been used as catalysts for the oxidation of glycolic acid by oxygen to produce glyoxylic acid in aqueous mixtures containing (aminomethyl)phosphonic acid. After separation and recovery of the microbial catalyst for reuse, the resulting solution of glyoxylic acid and (aminomethyl)phosphonic acid was subsequently hydrogentated with a palladium/carbon catalyst to produce glyphosate. The complete conversion of (aminomethyl)phosphonic acid in the hydrogenation allows the use of a simple acid precipitation for isolation of the glyphosate from the hydrogenation product mixture in high purity and yield.
