Synthesis of N-methyl amino acids in a flow tube-in tube reactor with a gas-liquid/liquid-liquid semi-permeable membrane
Liquid-liquid transfer for Teflon® AF 2400 membrane in a tube-in-tube reactor is demonstrated. This concept was proven by application to flow-through synthesis of N-methyl amino acids (3) in two steps via oxazolidinones (2) according to Freidinger et al.1 N-Methyl amino acids are important components in biologically active peptides, e. g. in the immunosuppressant cyclosporine (4).
Scheme 1. N-Methylation of amino acids in two steps.
Both steps for N-methylation of Fmoc amino acids were carried out in a micro-structured tube-in-tube reactor with a semipermeable Teflon® AF 2400 membrane as applied in gas/liquid syntheses by Ley et al.2 In the first step, gaseous formaldehyde passed the inner membrane and provided the acid-catalyzed conversion of Fmoc amino acids to the corresponding oxazolidinones within 1 h at 75 - 80 °C. In the second step, liquid-liquid transfer of trifluoroacetic acid was used for the first time in such a reactor.3
Figure 1. Flow reactors used for the first step (left) and for the second step (right) of N-methyl amino acid synthesis.
Here, the semipermeable membrane selectively mediated permeation of trifluoroacetic acid into solution providing the reductive ring opening of oxazolidinones to give Fmoc N-methyl-amino acids within 1 - 2 h at 75 °C. In this continuous flow process various Fmoc protected α-amino acids could be N-methylated in high yields up to 91 % for the first and 99 % for the second step consistent with literature.1,4 However, flow rates of 3 - 8 mL/h in each step enabled reactions times of only 1 - 3 h in total thus, significantly shorter than performed by traditional methods.
References: R. M. Freidinger, J. S. Hinkle, D. S. Perlow, B. H. Arison, J. Org. Chem., 48, pp.77-81, 1983..
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