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Both solution, SPPS, and hybrid approaches have traditionally been associated with what are now classed as undesirable solvents such as dichloromethane, diethyl ether, TBME and dipolar aprotic solvents like DMF, DMAC and NMP. Several widely employed solvents, such as the dipolar aprotics, are now known to have carcinogenic, mutagenetic and reprotoxic properties (CMR) properties and should be substituted, if at all possible.
For general guidance and information on solvent selection, see:
For solvent substitution, the flowing parameters need to be considered:

  • A high degree of solubility of amino acid synthons and other reagents. High solubility of the peptide in solution phase synthesis
  • Chemistry must go to completion in highest yield possible – coupling and deprotection
  • Negligible racemization of peptide AA’s or AA synthons
  • Acceptable viscosity for SPPS
  • Acceptable resin swelling in SPPS
  • Acceptable cost – DMF is cheap and readily available at $700-$1400/ton

Alongside the coupling steps, solvents such as diethyl ether, TBME, DCM, etc., have been used in DSP – precipitation, crystallization unit operations. A considerable effort is underway to replace these materials with better alternative solvents.