OLIGOPEPTIDE LINKER INTERMEDIATE AND PREPARATION METHOD THEREOF

1 . An oligopeptide linker intermediate having the structure represented by formulas (1)-(4):

wherein, the AA 1 , AA 2 , AA 3 , AA 4 are any amino acid.

2 . The oligopeptide linker intermediate according to claim 1 , wherein the AA 1 , AA 2 , AA 3 , and AA 4 are each independently selected from the group consisting of -valine- (-Val-), -citrulline -(-Cit-), -alanine- (-Ala-), -lysine- (-Lys-), -lysine(trityl)- (-Lys(Trt)-), -lysine(monomethoxytrityl)-(-Lys(Mmt)-), -lysine(fluorenylmethyloxycarbonyl)- (-Lys(Fmoc)-), -arginine- (-Arg-), -phenylalanine- (-Phe-), -glycine- (-Gly-), -leucine- (-Leu-) and -isoleucine- (-Ile-).

3 . The oligopeptide linker intermediate according to claim 2 , wherein

the -AA 1 -AA 2 - is selected from the group consisting of -valine-citrulline- (-Val-Cit-), -valine-alanine-(-Val-Ala-), -valine-lysine- (-Val-Lys-), -valine-lysine(trityl)- (-Val-Lys(Trt)-), -valine-lysine(monomethoxytrityl)-(-Val-Lys(Mmt)-), -valine-lysine(fluorenylmethyloxycarbonyl)-(-Val-Lys(Fmoc)-), -valine-arginine- (-Val-Arg-), -phenylalanine-citrulline-(-Phe-Cit-), -phenylpropyl-lysine- (-Phe-Lys-), -phenylalanine-lysine(trityl)-(-Phe-Lys(Trt)-), -phenylalanine-lysine(monomethoxytrityl)- (-Phe-Lys (Mmt)-), -phenylalanine-lysine (fluorenylmethyloxycarbonyl)- (-Phe-Lys(Fmoc)-), leucine-citrulline- (-Leu-Cit-), isoleucine-citrulline- (-Ile-Cit-) and -phenylalanine-arginine- (-Phe-Arg-);

the -AA 1 -AA 2 -AA 3 - is -phenylalanine-arginine-arginine-(-Ala-Arg-Arg-); and

the -AA 1 -AA 2 -AA 3 -AA 4 - is selected from the group consisting of -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-), -glycine-phenylalanine-leucine-glycine- (-Gly-Phe-Leu-Gly-) and -alanine-leucine-alanine-leucine (-Ala-Leu-Ala-Leu-).

4 . The oligopeptide linker intermediate according to claim 3 , wherein the oligopeptide linker intermediate includes the following structure:

5 . An antibody-drug conjugate having a linker, wherein the precursor of the linker used in the antibody-drug conjugate is the oligopeptide linker intermediate according to claim 1 .

6 . A method for preparing the oligopeptide linker intermediate according to claim 1 , wherein the method for preparing the oligopeptide linker intermediate of formulas (1) to (3) comprising:

1) performing a condensation reaction between a carbonylation reagent, 2-(trimethylsilyl)ethanol and amino acid AA 1 , and then amino acid AA 2 , or amino acid AA 1 , amino acid AA 2 and amino acid AA 3 in sequence, or amino acid AA 1 , amino acid AA 2 , amino acid AA 3 and amino acid AA 4 in sequence, to obtain a 2-(trimethylsilyl)ethoxycarbonyl-oligopeptide condensate;

2) reacting the resulting 2-(trimethylsilyl)ethoxycarbonyl-oligopeptide condensate and p-aminobenzyl alcohol to obtain a 2-(trimethylsilyl)ethoxycarbonyl-oligopeptide-p-aminobenzyl alcohol condensate,

wherein the carbonylation reagent is any compound containing a carbonyl group; or

a method for preparing the oligopeptide linker intermediate of formula (4) comprising:

1′) performing a condensation reaction between a carbonylation reagent, 2-(trimethylsilyl)ethanol and amino acid AA 1 , amino acid AA 2 , amino acid AA 3 and amino acid AA 4 in sequence, to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tetrapeptide condensate, wherein the carbonylation reagent is any compound containing a carbonyl group.

7 . The method according to claim 6 , wherein the oligopeptide linker intermediate of formula (1) is obtained via the following reaction path:

wherein the method comprises the following steps:

1) performing a condensation reaction between a carbonylation reagent, 2-(trimethylsilyl)ethanol and amino acid AA 1 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate;

2) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate and amino acid AA 2 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate; and

3) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate and p-aminobenzyl alcohol to obtain a 2-(trimethylsilyl)ethoxycarbonyl-dipeptide-p-aminobenzyl alcohol condensate.

8 . The method according to claim 6 , wherein the oligopeptide linker intermediate of formula (2) is obtained via the following reaction path:

wherein the method comprises the following steps:

1) performing a condensation reaction between a carbonylation reagent, 2-(trimethylsilyl)ethanol and amino acid AA 1 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate;

2) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate and amino acid AA 2 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate;

3) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate and amino acid AA 3 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tripeptide condensate; and

4) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-tripeptide condensate and p-aminobenzyl alcohol to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tripeptide-p-aminobenzyl alcohol condensate.

9 . The method according to claim 6 , wherein the oligopeptide linker intermediate of formula (3) is obtained via the following reaction path:

wherein the method comprises the following steps:

1) performing a condensation reaction between a carbonylation reagent, 2-(trimethylsilyl)ethanol and amino acid AA 1 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate;

2) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate and amino acid AA 2 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate;

3) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate and amino acid AA 3 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tripeptide condensate;

4) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-tripeptide condensate and amino acid AA 4 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tetrapeptide condensate; and

5) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-tetrapeptide condensate and p-aminobenzyl alcohol to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tetrapeptide-p-aminobenzyl alcohol condensate.

10 . (canceled)

11 . The method according to claim 6 , wherein the oligopeptide linker intermediate of formula (4) is obtained via the following reaction path:

1) performing a condensation reaction between a carbonylation reagent, 2-(trimethylsilyl)ethanol, and amino acid AA 1 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate;

2) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-amino acid condensate and amino acid AA 2 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate;

3) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-dipeptide condensate and amino acid AA 3 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tripeptide condensate; and

4) performing a condensation reaction between the 2-(trimethylsilyl)ethoxycarbonyl-tripeptide condensate and amino acid AA 4 to obtain a 2-(trimethylsilyl)ethoxycarbonyl-tetrapeptide condensate.

12 . The method according to claim 6 , wherein

the carbonylation reagent has a structure of formula (5):

wherein:

the R 1 and R 2 are each independently selected from the group consisting of:

13 . The method according to claim 12 , wherein the carbonylation reagent is selected from the group consisting of:

14 . The method according to claim 6 , wherein the AA 1 , AA 2 , AA 3 , and AA 4 are each independently selected from the group consisting of: -valine-(-Val-), -citrulline -(-Cit-), -alanine- (-Ala-), -lysine- (-Lys-), -lysine(trityl)- (-Lys(Trt)-), -lysine(monomethoxytrityl)-(-Lys(Mmt)-), -lysine(fluorenylmethyloxycarbonyl)- (-Lys(Fmoc)-), -arginine- (-Arg-), -phenylalanine- (-Phe-), -glycine- (-Gly-), -leucine- (-Leu-) and -isoleucine- (-Ile-).

15 . The method according to claim 14 , wherein

the -AA 1 -AA 2 - is selected from the group consisting of -valine-citrulline- (-Val-Cit-), -valine-alanine-(-Val-Ala-), -valine-lysine- (-Val-Lys-), -valine-lysine(trityl)- (-Val-Lys(Trt)-), -valine-lysine(monomethoxytrityl)-(-Val-Lys(Mmt)-), -valine-lysine(fluorenylmethyloxycarbonyl)-(-Val-Lys(Fmoc)-), -valine-arginine- (-Val-Arg-), -phenylalanine-citrulline-(-Phe-Cit-), -phenylpropyl-lysine- (-Phe-Lys-), -phenylalanine-lysine(trityl)-(-Phe-Lys(Trt)-), -phenylalanine-lysine(monomethoxytrityl)- (-Phe-Lys (Mmt)-), -phenylalanine-lysine (fluorenylmethyloxycarbonyl)- (-Phe-Lys(Fmoc)-), leucine-citrulline- (-Leu-Cit-), isoleucine-citrulline- (-Ile-Cit-) and -phenylalanine-arginine- (-Phe-Arg-);

the -AA 1 -AA 2 -AA 3 - is -phenylalanine-arginine-arginine-(-Ala-Arg-Arg-); and

the -AA 1 -AA 2 -AA 3 -AA 4 - is selected from the group consisting of -glycine-glycine-phenylalanine-glycine-(-Gly-Gly-Phe-Gly-), -glycine-phenylalanine-leucine-glycine- (-Gly-Phe-Leu-Gly-), and -alanine-leucine-alanine-leucine (-Ala-Leu-Ala-Leu-).

16 . The method of claim 15 , wherein the -AA 1 -AA 2 - is selected from the following structures:

17 . The method according to claim 15 , wherein the -AA 1 -AA 2 -AA 3 - is

18 . The method according to claim 15 , wherein the -AA 1 -AA 2 -AA 3 -AA 4 - is selected from the following structures:

19 . The method according to claim 6 , wherein solvent used in the condensation reaction is a polar solvent or non-polar solvent; preferably, the solvent is one or more selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, DMF, DMSO, DMAc, DMPU, HMPA, ethylene glycol dimethyl ether, diethyl ether, tert-butyl methyl ether, tert-butanol, water, ethyl acetate, methanol, ethanol, isopropanol, dichloromethane, chloroform, and carbon tetrachloride; more preferably, the solvent is one or more selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, DMF, DMSO, water, methanol, dichloromethane, chloroform, carbon tetrachloride and ethanol.

20 - 21 . (canceled)