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-11732002-B2
Application number	US-201917297231-A
Country	US
Kind code	B2
Filing date	Nov 29, 2019
Priority date	Nov 30, 2018
Publication date	Aug 22, 2023
Grant date	Aug 22, 2023

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 selected from the group consisting of formulae (2) to (10) as defined below; and
wherein the silyl-containing electrophilic species scavenger in (ii) is a compound having a formula selected from the group consisting of formulae (2)-(4), (6), (9), and (10) as defined below, provided that the compound has a silyl group:

wherein in formula 2,
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 C 1 -C 4 alkyl optionally substituted with one or more fluorine atoms;

wherein in formula 3,
R G is a silyl group substituted with one or more C 1 -C 4 alkyl;
R H is hydrogen or C 1 -C 4 alkyl; and
R I is hydrogen, or C 1 -C 4 alkyl optionally substituted with one or more fluorine atoms;

wherein in formula 4,
(a-1) R J is a substituted silyl group, R K is C 1 -C 4 alkoxy, and R M and R L are independently hydrogen or C 1 -C 4 alkyl;
(a-2) R J is a substituted silyl group, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L , together with the carbon atoms to which they are attached, form a 5- to 8-membered ring comprising an oxygen atom;
(b-1) R J is a substituted silyl group, R K is C 1 -C 4 alkyl, and R M and R L are independently hydrogen or C 1 -C 4 alkyl;
(b-2) R J is a substituted silyl group, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L together with the carbon atoms to which they are attached, form a 5- to 8-membered ring; or
(c-1) R J and R M , together with the carbon atom and oxygen atom to which they are attached, form a 5- to 7-membered ring comprising an oxygen atom, R K is hydrogen or C 1 -C 4 alkyl, and R L is C 1 -C 4 alkyl;
(c-2) R J and R M , together with the carbon atom and oxygen atom to which they are attached, form a 5- to 7-membered ring comprising an oxygen atom, and R K and R L , together with the carbon atom to which they are attached, form a 5- to 8-membered ring;
(d-1) R J is C 1 -C 4 alkyl and R M , R K , and R L are independently hydrogen or C 1 -C 4 alkyl;
(d-2) R J is C 1 -C 4 alkyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L , together with the carbon atoms to which they are attached, form a 5- to 8-membered ring;
(e-1) R J is C 1 -C 3 alkylcarbonyl and R M , R K , and R L are independently hydrogen or C 1 -C 4 alkyl;
(e-2) R J is C 1 -C 3 alkylcarbonyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L , together with the carbon atoms to which they are attached, form a 5- to 8-membered ring;
(f-1) R J is a substituted silyl group or C 1 -C 4 alkyl, R K is optionally substituted di-C 1 -C 4 alkylamino, and R M and R L are independently hydrogen or C 1 -C 4 alkyl; or
(f-2) R J is a substituted silyl group or C 1 -C 4 alkyl, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L , together with the carbon atoms to which they are attached, form a 5- to 8-membered ring comprising a nitrogen atom, wherein the 5- to 8-membered ring is optionally substituted with C 1 -C 4 alkyl;

wherein in formula 5,
R N , R N′ , and R O are independently hydrogen or C 1 -C 4 alkyl;

wherein in formula 6,
R P is a substituted silyl group; and
R Q is a substituted silyl group or C 1 -C 4 alkyl and R R is hydrogen, a substituted silyl group, or C 1 -C 4 alkyl, or
R Q and R R , together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocyclic ring optionally comprising one or more additional heteroatoms;

wherein in formula 7,
X is a single bond or a carbon atom,
wherein when X is a single bond, R S is absent, R UA and R RB , together with the carbon atom and nitrogen atom to which they are attached, form an optionally substituted 6-membered aromatic heterocyclic ring, and R UB and R T , together with the carbon atom and nitrogen atom to which they are attached, form an optionally substituted 6-membered aromatic heterocyclic ring, and
when X is a carbon atom, R UA and R UB are independently C 1 -C 4 alkyl and R RB , R S , and R T , together with the carbon atoms to which they are attached, form the structure below:

wherein in formula 8,
R V is C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;

wherein in formula 9,
R W and R X are independently C 1 -C 4 alkyl or a substituted silyl group; and

wherein in formula 10,
R Y and R Z are independently C 1 -C 4 alkyl or a substituted silyl group.

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 selected from the group consisting of formulae (2) to (10) as defined below; and
wherein the silyl-containing electrophilic species scavenger in (ii) is a compound having a formula selected from the group consisting of formulae (2)-(4), (6), (9), and (10) as defined below, provided that the compound has a silyl group:

wherein in formula 2,
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 C 1 -C 4 alkyl optionally substituted with one or more fluorine atoms;

wherein in formula 3,
R G is a silyl group substituted with one or more C 1 -C 4 alkyl;
R H is hydrogen or C 1 -C 4 alkyl; and
R I is hydrogen, or C 1 -C 4 alkyl optionally substituted with one or more fluorine atoms;

wherein in formula 4,
(a-1) R J is a substituted silyl group, R K is C 1 -C 4 alkoxy, and R M and R L are independently hydrogen or C 1 -C 4 alkyl;
(a-2) R J is a substituted silyl group, R M is hydrogen or C 1 -C 4 alkyl, and R K and R L , together with the carbon atoms to which they are attached, form a 5- to 8-membered ring comprising an oxygen atom;
(b-1) R J is a substituted silyl

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Iwasaki Kotaro
• Komiya Shio

Classifications

• C07C2603/18

  Fluorenes; Hydrogenated fluorenes · CPC title

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07K1/04 Primary

  on carriers {(C07K1/003, C07K1/006 take precedence)} · CPC title

• C07K1/06 Primary

  using protecting groups or activating agents {(C07K1/003, C07K1/006 take precedence)} · CPC title