Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound

Patent metadata

Field	Value
Publication number	US-12331072-B2
Application number	US-202318203371-A
Country	US
Kind code	B2
Filing date	May 30, 2023
Priority date	Nov 30, 2018
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

Abstract

The present inventors found that peptide compounds/amide compounds in which the protecting groups of interest are removed and/or which are removed from resins for solid-phase synthesis can be produced without main chain damage by contacting starting peptide compounds/amide compounds with silylating agents.

First claim

The invention claimed is:

1. A method of producing a peptide compound in which a protecting group removable by a silylating agent is removed, the method comprising the step of contacting a starting peptide compound comprising natural amino acid residues and/or amino acid analog residues with the silylating agent in a solvent and thereby removing the protecting group from the starting peptide compound,
wherein the silylating agent is prepared by:
(i) mixing a silyl compound with an electrophilic species scavenger, or
(ii) mixing an acid with a silyl-containing electrophilic species scavenger,

wherein the starting peptide compound comprises at least one protecting group removable by the silylating agent, and
wherein the starting peptide compound comprises at least one N-alkylated amino acid residue;
wherein the electrophilic species scavenger in (i) has a formula of formula (11) as defined below; and
wherein the silyl-containing electrophilic species scavenger in (ii) is a compound having a formula of formula (11) as defined below, provided that the compound has a silyl group:

wherein in formula 11,
R B is a substituted silyl group and R C is a substituted silyl group, or
R B and R C , together with the nitrogen atom and oxygen atom to which they are attached, form a 5- to 7-membered ring; and
R D is optionally substituted methylene.

2. A method of producing a peptide compound in which a resin for solid-phase synthesis that is removable by a silylating agent is removed, the method comprising the step of contacting a starting peptide compound comprising natural amino acid residues and/or amino acid analog residues with the silylating agent in a solvent and thereby removing the resin for solid-phase synthesis from the starting peptide compound,
wherein the silylating agent is prepared by:
(i) mixing a silyl compound with an electrophilic species scavenger, or
(ii) mixing an acid with a silyl-containing electrophilic species scavenger,

wherein the starting peptide compound is linked to the removable resin for solid-phase synthesis, and
wherein the starting peptide compound comprises at least one N-substituted amino acid residue;
wherein the electrophilic species scavenger in (i) has a formula of formula (11) as defined below; and
wherein the silyl-containing electrophilic species scavenger in (ii) is a compound having a formula of formula (11) as defined below, provided that the compound has a silyl group:

wherein in formula 11,
R B is a substituted silyl group and R C is a substituted silyl group, or
R B and R C , together with the nitrogen atom and oxygen atom to which they are attached, form a 5- to 7-membered ring; and
R D is optionally substituted methylene.

3. The method of claim 1 , wherein the starting peptide compound comprises at least one structure in which at least two amino acid residues are linked to each other, wherein the structure is represented by general formula (I) below:

wherein
R 1 is hydrogen, PG 1 , a natural amino acid residue, or an amino acid analog residue;
R 2 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R 2 and R 4 or R 2 and R 4′ , together with the nitrogen atom and carbon atom to which they are attached, form a 3- to 7-membered heterocyclic ring optionally substituted with hydroxy or C 1 -C 4 alkoxy, wherein R 4 , is hydrogen when R 2 and R 4 together form the heterocyclic ring, and R 4 is hydrogen when R 2 and R 4′ together form the heterocyclic ring;
except when R 2 and R 4 , or R 2 and R 4′ together form the heterocyclic ring,
(a) R 4′ is hydrogen, and R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, —CH 2 SPG 2 , N-PG 3 -indol-3-ylmethyl, 4-(PG 2 O)benzyl, PG 2 -O-methyl, 1-(PG 2 O)ethyl, 2-(PG 2 O)ethyl, PG 2 -OCO(CH 2 )—, PG 2 —OCO(CH 2 ) 2 —, PG 3 N-n-butyl, —CON(R 14A )(R 14B ), —CH 2 —CON(R 14A )(R 14B ), and —(CH 2 ) 2 CON(R 14A )(R 14B ),
(b) R 4 and R 4′ are independently optionally substituted C 1 -C 6 alkyl, or
(c) R 4 and R 4′ , together with the carbon atom to which they are attached, form a 3- to 7-membered alicyclic ring;
R 5 is a single bond or —C(R 5A )(R 5B )—;
R 5A and R 5B are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C 1 -C 4 alkyl, and optionally substituted heteroaryl-C 1 -C 4 alkyl;
R 6 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or R 6 and R 7 or R 6 and R 7′ , together with the nitrogen atom and carbon atom to which they are attached, form a 3- to 7-membered heterocyclic ring optionally substituted with hydroxy or C 1 -C 4 alkoxy, wherein R 7′ is hydrogen when R 6 and R 7 together form the heterocyclic ring, and R 7 is hydrogen when R 6 and R 7′ together form the heterocyclic ring;
except when R 6 and R 7 or R 6 and R 7′ together form the heterocyclic ring,
(a) R 7′ is hydrogen, and R 7 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl, optionally substituted phenyl, optionally substituted phenylmethyl, optionally substituted phenylethyl, 2-(methylthio)ethyl, —CH 2 SPG 4 , N-PG 5 -indol-3-ylmethyl, 4-(PG 4 O)benzyl, PG 4 -O-methyl, 1-(PG 4 O)ethyl, 2-(PG 4 O)ethyl, PG 4 -OCO(CH 2 )—, PG 4 -OCO(CH 2 ) 2 —, PG 5 N-n-butyl, —CON(R 15A )(R 15B ), —CH 2 —CON(R 15A )(R 15B ), and —(CH 2 ) 2 CON(R 15A )(R 15B ), or
(b) R 7 and R 7′ are independently optionally substituted C 1 -C 6 alkyl, or
(c) R 7 and R 7′ , together with the carbon atom to which they are attached, form a 3- to 7-membered alicyclic ring;
R 8 is a single bond or —C(R 5A )(R 5B )—;
R 8A and R 8B are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl-C 1 -C 4 alkyl, and optionally substituted heteroaryl-C 1 -C 4 alkyl;
R 9 is hydroxy, —O—PG 6 , a natural amino acid residue, an amino acid analog residue, —O—RES, or —NH—RES;
RES is a resin for solid-phase synthesis;
R 14A and R 14B are independently hydrogen or C 1 -C 4 alkyl, or R 14A and R 14B , together with the nitrogen atom to which they are attached, form a 4- to 8-membered ring optionally comprising one or more additional heteroatoms;
R 15A and R 15B are independently hydrogen or C 1 -C 4 alkyl, or R 15A and R 15B , together with the nitrogen atom to which they are attached, form a 4- to 8-membered ring optionally comprising one or more additional heteroatoms;
PG 1 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;
PG 2 and PG 4 are independently selected from the group consisting of hydrogen, t-Bu, trityl, methoxytrityl, cumyl, benzyl, THP, 1-ethoxyethyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C 1 -C 4 alkyl, optionally substituted heteroaryl-C 1 -C 4 alkyl, and 2-(trimethylsilyl)ethyl;
PG 3 and PG 8 are independently selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, methoxycarbonyl, t-Bu, trityl, cumyl, and benzyl; and
PG 6 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Iwasaki Kotaro
• Komiya Shio

Classifications

• C07C231/00

  Preparation of carboxylic acid amides · CPC title

• C07K5/10

  Tetrapeptides · CPC title

• C07K5/08

  Tripeptides · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K1/02

  in solution {(C07K1/003, C07K1/006 take precedence)} · CPC title