Crystalline amino acids modified solutions

By the aid of a modified peptide synthesizer solutions of two moles of Boc- or Ddz-amino acid salts (sodium- or triethylammonium form) in tetrahydrofuran or dichloro-methane at —40 °C are mixed for 5 minutes with one mole of phosgene in the same solvent at —40 °C, controlled by the punched tape program of the synthesizer (Fig. 44). The solution of the symmetric anhydride is added at —40 C to the gel polymer, which is contained in the centrifugal reactor (see p. 75) and is allowed to warm up to the cooling water temperature level (9—13 C) of the reactor during the peptide synthesis period of 30 minutes. Since the mode of action of the centrifugal reactor renders it possible to perfuse an external IR flow cell with the reaction solution, we are in a position to monitor directly the quality of the symmetric anhydride and its consumption, watching the characteristic absorptions on 1,830 and 1,760 cm [71]. In several cases the symmetric anhydrides were isolated in crystalline or solid form for characterization (Table 6). 

Preparative Method the title compound can be prepared in multigram scale from (5)-phenylalanine methyl ester using a modified Seebach protocol (eq 1) the ester of the amino acid, or the corresponding HCl salt, is converted to iV-methylamide with excess of ethanolic MeNH2, which, in turn, is condensed with pivalaldehyde in the presence of a catalytic amount of FeCls (20mol%) and molecular sieves. Under these conditions the Schiff base intermediate undergoes cyclization and forms a mixture of cis- and frans-imidazolidinones. After addition of 0.5 M equiv of HCl (IN in ether), the undesired tran -isomer-HCl can he filtered off and the residue recrystallized to provide the cw-(25,55)-isomer as a crystalline solid. The frans-isomer can he converted to the cw-isomer by partial epimerization in THF solution in the presence of FeCls. 

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