Peptide synthesis method for suppressing defect caused by diketopiperazine formation
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsMirai KAGE, Minoru TAMIYA, Junichiro KANAZAWA, Kenichi NOMURA
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Abstract
Synthesis of a peptide has a problem that a desired elongation reaction is prevented from proceeding by diketopiperazine and a 6-membered diamine skeleton compound formed when a protective group at the N-terminal is removed. The present inventors have found that when in production of a peptide, a peptide in which an amino group at the N-terminal is protected with a protective group having an Fmoc skeleton is treated in a specific solvent with a base having a pKa of 23 or more in acetonitrile as a conjugate acid, and a peptide chain is then elongated, it is possible to solve the problem described above.
Claims22
A method for producing a peptide, comprising the steps of:
- (1) providing a first peptide having a protective group containing an Fmoc skeleton;
- (2) treating the first peptide with one or more bases including at least one base whose conjugate acid has a pKa of 23 or more in acetonitrile in a solvent containing a sulfoxide solvent after the step (1);
- and
- (3) condensing the first peptide with a carboxylic acid or a carboxylic acid analog in a solvent in the presence or absence of a condensation agent to obtain a third peptide after the step (2).
A method for reducing an amount of a diketopiperazine impurity and/or a 6-membered cyclic amidine skeleton compound impurity formed in production of a peptide, comprising the steps of:
- (1) providing a first peptide having a protective group containing an Fmoc skeleton;
- and
- (2) treating the first peptide with one or more bases including at least one base whose conjugate acid has a pKa of 23 or more in acetonitrile in a solvent containing a sulfoxide solvent after the step (1).
A method for reducing an amount of at least one impurity selected from the group consisting of a diketopiperazine impurity, a 6-membered cyclic amidine skeleton compound impurity and a dimer urea compound impurity formed in production of a peptide, comprising the steps of:
- (1) providing a first peptide having a protective group containing an Fmoc skeleton;
- and
- (2) treating the first peptide with one or more bases including at least one base whose conjugate acid has a pKa of 23 or more in acetonitrile in a solvent containing a sulfoxide solvent after the step (1).
Dependencies are inferred from the claim text.