| 摘要 |
This invention provides a bulk scale process for the solution synthesis of enantiomerically pure peripherally acting analgesic opioid tetrapeptides corresponding to formula (I): Tyr-(D)R1-R2-R3-NH2, where R1 is Ala or Arg; R2 is Phe or Phe(p-F); and R3 is Phe or Phe(p-F). A new and unique multi-step process is disclosed comprising the joining of two dipeptides using standard solution phase synthesis techniques, but adjusting the individual factors (e.g., solvents, activating agents, neutralizing agents etc.), to minimize racemization of the second amino acid. Tremendous cost efficiencies are achieved due to elimination of traditional sequential blocking-deblocking cycles and multiple chromatographic purification steps, which also enables these simple kilogram quantity methods to be scaled up to commercial production.
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