Process for preparing eptifibatide

A process for preparation of eptifibatide of Formula I (SEQ ID NO:1):

• wherein Mpr is mercaptopropionic acid, Har is homoarginyl, Gly is glycyl, Asp is aspartyl, Trp is tryptophanyl, Pro is prolyl, and Cys-NH2 is cysteinamide, the process comprising the steps of:
• a) coupling Cys(P5)—NH2 and Trp(P4)-Pro-OH to obtain a peptide fragment of formula Trp(P4)-Pro-Cys(P5)—NH2;
• b) coupling the peptide fragment of formula Trp(P4)-Pro-Cys(P5)—NH2 and Asp(P3)—OH to obtain a peptide fragment of formula Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2 (SEQ ID NO:5);
• c) coupling the peptide fragment of formula Asp(P3)-Trp(P4)—Pro-Cys(P5)—NH2 (SEQ ID NO:5) and Gly-OH to obtain a peptide fragment of formula Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2 (SEQ ID NO:6);
• d) purifying the peptide fragment of formula Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2 (SEQ ID NO:6) produced in step c) to less than 0.1% Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)(D)-NH2 (SEQ ID NO:7), Gly-Asp(P3)(D)-Trp(P4)-Pro-Cys(P5)—NH2 (SEQ ID NO:8), Gly-Asp(P3)-Trp(P4)(D)-Pro-Cys(P5)—NH2 (SEQ ID NO:9), or Gly-Asp(P3)-Trp(P4)-Pro(D)-Cys(P5)—NH2 (SEQ ID NO:10) by HPLC;
• e) coupling the peptide fragment of formula Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2(SEQ ID NO:6) and a 1-2 peptide fragment of formula Mpr(P1)-Har(P2)—OH to obtain protected linear peptide of formula Mpr(P1)-Har(P2)-Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2 (SEQ NO:3);
• f) optionally purifying Mpr(P1)-Har(P2)-Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2(SEQ NO:3);
• g) deprotection of the Mpr(P1)-Har(P2)-Gly-Asp(P3)-Trp(P4)-Pro-Cys(P5)—NH2(SEQ NO:3) to obtain linear peptide of formula Mpr-Har-Gly-Asp-Trp-Pro-Cys-NH2 (SEQ ID NO:4);
• and
• h) cyclizing the two sulphur atoms of the Mpr-Har-Gly-Asp-Trp-Pro-Cys-NH2 (SEQ ID NO:4) to obtain eptifibatide of Formula I (SEQ ID NO:1),
• wherein each one of P1 and P5 is one of hydrogen and a sulphur protecting group, each one of P2 and P4 is one of hydrogen and an amino protecting group, and P3 is one of hydrogen and a carboxyl protecting group.