Intermediate used for biologically active polypeptide and method for preparing same

A resin composite compound represented by Chemical Formula 3 below:

• wherein A to D are protecting groups;
• A to D are each independently selected from the group consisting of triphenylmethyl (Trt), tert-butyl (tBu), t-butyloxycarbonyl (Boc), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf);
• R is selected from the group consisting of H, linear or branched C1-12 alkyl, linear or branched C1-12 alkyloxycarbonyl, linear or branched C2-12 alkenyl, C3-10 cycloalkyl, heterocycloalkyl, C6-12 aryl, C6-12 aryloxycarbonyl, C1-6 alkyl C6-12 aryl, C1-6 alkyl C6-12 aryloxycarbonyl, and heteroaryl;
• X′ is a resin;
• and these substituents may be further substituted with one or more identical or different substituents selected from the group consisting of H, halogen, cyano, linear or branched C1-6 alkyl, linear or branched C2-10 alkenyl, C3-10 cycloalkyl, halo C1-5 alkyl, hydroxy C1-6 alkyl, amino, mono or di C1-6 alkylamino, oxo, hydroxy, C1-6 alkoxy, C6-12 arylsulfonyl, and C1-6 alkylsulfonyl.

A method for preparing a resin composite compound represented by Chemical Formula 3 below, comprising the steps of:

• (1) swelling a resin in a polar aprotic solvent to give a deprotected resin;
• (2) coupling by adding an activated protected amino acid to the deprotected resin in a reactor;
• (3) repeating step (2) until a peptide comprising the amino acid sequence of SEQ ID NO:
• 1 is formed to give a synthesized peptide;
• (4) preparing a partially deprotected resin by reacting the synthesized peptide of step (3) with tetrakispalladium, N-methylaniline, and phenylsilane in a solvent;
• and
• (5) cyclizing the synthesized peptide obtained in step (4) by adding a coupling reagent in a polar aprotic solvent:
• wherein A to D are protecting groups;
• A to D are each independently selected from the group consisting of triphenylmethyl (Trt), tert-butyl (tBu), t-butyloxycarbonyl (Boc), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf);
• R is selected from the group consisting of H, linear or branched C1-12 alkyl, linear or branched C1-12 alkyloxycarbonyl, linear or branched C2-12 alkenyl, C3-10 cycloalkyl, heterocycloalkyl, C6-12 aryl, C6-12 aryloxycarbonyl, C1-6 alkyl C6-12 aryl, C1-6 alkyl C6-12 aryloxycarbonyl, and heteroaryl;
• X′ is a resin;
• and these substituents may be further substituted with one or more identical or different substituents selected from the group consisting of H, halogen, cyano, linear or branched C1-6 alkyl, linear or branched C2-10 alkenyl, C3-10 cycloalkyl, halo C1-5 alkyl, hydroxy C1-6 alkyl, amino, mono or di C1-6 alkylamino, oxo, hydroxy, C1-6 alkoxy, C6-12 arylsulfonyl, and C1-6 alkylsulfonyl.

A method for preparing a physiologically active polypeptide represented by Chemical Formula 2 below or a pharmaceutically acceptable salt thereof, comprising:

• (1) a reaction step of obtaining a peptide-resin composite by reacting the resin composite compound of Chemical Formula 3 below with amino acids to form a physiologically active polypeptide of Chemical Formula 2;
• and
• wherein A to D are protecting groups;
• A to D are each independently selected from the group consisting of triphenylmethyl (Trt), tert-butyl (tBu), t-butyloxycarbonyl (Boc), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf);
• R is selected from the group consisting of H, linear or branched C1-12 alkyl, linear or branched C1-12 alkyloxycarbonyl, linear or branched C2-12 alkenyl, C3-10 cycloalkyl, heterocycloalkyl, C6-12 aryl, C6-12 aryloxycarbonyl, C1-6 alkyl C6-12 aryl, C1-6 alkyl C6-12 aryloxycarbonyl, and heteroaryl;
• X′ is a resin;
• and these substituents may be further substituted with one or more identical or different substituents selected from the group consisting of H, halogen, cyano, linear or branched C1-6 alkyl, linear or branched C2-10 alkenyl, C3-10 cycloalkyl, halo C1-5 alkyl, hydroxy C1-6 alkyl, amino, mono or di C1-6 alkylamino, oxo, hydroxy, C1-6 alkoxy, C6-12 arylsulfonyl, and C1-6 alkylsulfonyl
• H-His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-cyclo (Glu-Lys-Arg-Ala-Lys) Glu-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Cys-NH2 (SEQ ID NO:
• 2)
• (2) a cleavage step of cleaving the physiologically active polypeptide of Chemical Formula 2 from the peptide-resin composite.