Method for peptide synthesis

A method for the synthesis of a target peptide comprising a first cycle peptide P-1, wherein the method comprises the following steps:

• (a) providing a first component C-1 selected from the group consisting of an amino acid and a peptide, wherein C-1 comprises one free primary or secondary aliphatic amino group, wherein any other primary or secondary aliphatic amino groups and any carboxyl groups in C-1 are protected,
• (b) providing a second component C-2 selected from the group consisting of a chiral alpha-amino acid and a peptide, wherein C-2 comprises one free carboxyl group, which is the alpha-carboxyl group of a chiral alpha-amino acid moiety comprising one hydrogen-substituent bonded to the alpha-carbon atom, wherein any primary or secondary aliphatic amino groups and any other carboxyl groups in C-2 are protected, and
• (c) condensing C-1 of step (a) and C-2 of step (b) in the presence of:
• a carbodiimide coupling agent,
• a first additive A-1 of formula A-I:
• wherein:
• R1 is at each occurrence independently selected from the group consisting of hydrogen, C1-C5-alkyl, and an electron-withdrawing substituent,
• a second additive A-2 selected from the group consisting of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 5-(hydroxyimino)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Oxyma-B), ethyl 1-hydroxy-1,2,3-triazole-4-carboxylate (HOCt), and mixtures thereof, and
• a first cycle solvent,
• to form an amide bond between the free primary or secondary aliphatic amino group C-1 and
• the free alpha-carboxyl group of C-2 to obtain a first cycle peptide P-1,
• wherein in step (c), A-2 is used in a total molar amount of 1.0 to 5.0 equivalents relative to the total molar amount of C-1.

A composition comprising:

• a first component C-1 selected from the group consisting of an amino acid and a peptide, wherein C-1 comprises one free primary or secondary aliphatic amino group, wherein any other primary or secondary aliphatic amino groups and any carboxyl groups in C-1 are protected,
• a second component C-2 selected from the group consisting of a chiral alpha-amino acid and a peptide, wherein C-2 comprises one free carboxyl group, which is the alpha-carboxyl group of a chiral alpha-amino acid moiety comprising one hydrogen-substituent bonded to the alpha-carbon atom, wherein any primary or secondary aliphatic amino groups and any other carboxyl groups in C-2 are protected,
• a carbodiimide coupling agent,
• a first additive A-1 of formula A-I:
• wherein:
• R1 is at each occurrence independently selected from the group consisting of hydrogen, C1-C5-alkyl, and an electron-withdrawing substituent,
• a second additive A-2 selected from the group consisting of ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 5-(hydroxyimino)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (Oxyma-B), ethyl 1-hydroxy-1,2,3-triazole-4-carboxylate (HOCt), and mixtures thereof, and
• one or more solvents,
• wherein:
• C-2 is present in a total molar amount of 1.0 to 5.0 equivalents,
• the carbodiimide coupling agent is present in a total molar amount of 1.0 to 6.0 equivalents,
• A-1 is present in a total molar amount of 1.0 to 6.0 equivalents, and
• A-2 is present in a total molar amount of 1.0 to 5.0 equivalents,
• wherein all equivalents are given relative to the total molar amount of C-1.