Deprotection method and resin removal method in solid-phase reaction for peptide compound or amide compound, and method for producing peptide compound
AssigneeChugai Seiyaku Kabushiki Kaisha
InventorsKotaro IWASAKI, Shio KOMIYA
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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.
Claims19
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 mixing a silyl compound or acid with an 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-substituted amino acid residue.
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 mixing a silyl compound or acid with an 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.
A method of producing an amide compound in which a protecting group removable by a silylating agent is removed, the method comprising the step of contacting a starting amide compound with the silylating agent in a solvent and thereby removing the protecting group from the starting amide compound,
- wherein the silylating agent is prepared by mixing a silyl compound or acid with an electrophilic species scavenger,
- wherein the starting amide compound is represented by general formula (II) below:
- wherein
- R1′ is a hydrogen atom or PG7;
- R12 and R12′ are independently selected from the group consisting of hydrogen, PG10-O-methyl, —(CH2)nCOO-PG10, —(CH2)nCOO-RES, and —(CH2)nCONH-RES;
- RES is a resin for solid-phase synthesis;
- n is 0, 1, or 2;
- R6 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- R13 is C1-C4 alkyl or —(CH2)mCON(R17A)(R17B);
- m is 0, 1, or 2;
- R17A and R17B are independently hydrogen or C1-C4 alkyl, or R17A and R17B, together with the nitrogen atom to which they are attached, form a 4- to 8-membered ring optionally comprising one or more additional heteroatoms;
- PG7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;
- and
- PG10 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl, and
- wherein the starting amide compound comprises at least one protecting group removable by the silylating agent.
A method of producing an amide compound in which a resin for solid-phase synthesis is removed, the method comprising the step of contacting a starting amide compound with a silylating agent in a solvent and thereby removing the starting amide compound from the resin for solid-phase synthesis,
- wherein the silylating agent is prepared by mixing a silyl compound or acid with an electrophilic species scavenger, and
- wherein the starting amide compound is represented by general formula (II) below:
- wherein
- R1′ is a hydrogen atom or PG7;
- R12 and R12′ are independently selected from the group consisting of hydrogen, PG10-O-methyl, —(CH2)nCOO-PG10, —(CH2)nCOO-RES, and —(CH2)nCONH-RES;
- RES is a resin for solid-phase synthesis, wherein at least one of R12 and R12′ is —(CH2)nCOO-RES or —(CH2)nCONH-RES;
- RES is a resin for solid-phase synthesis;
- n is 0, 1, or 2;
- R6 is selected from the group consisting of hydrogen and C1-C6 alkyl;
- R13 is C1-C4 alkyl or —(CH2)mCON(R17A)(R17B);
- m is 0, 1, or 2;
- R17A and R17B are independently hydrogen or C1-C4 alkyl, or R17A and R17B, together with the nitrogen atom to which they are attached, form a 4- to 8-membered ring optionally comprising one or more additional heteroatoms;
- PG7 is selected from the group consisting of Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;
- and
- PG10 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.
An amide compound represented by general formula (A) below or a salt thereof:
- wherein
- R1′ is selected from the group consisting of hydrogen, Fmoc, Boc, Alloc, Cbz, Teoc, and trifluoroacetyl;
- R17A and R17B are both methyl, or R17A and R17B, together with the nitrogen atom to which they are attached, form piperidine or morpholine;
- and
- R18 is hydrogen or PG10, wherein PG10 is selected from the group consisting of t-Bu, trityl, cumyl, benzyl, methyl, ethyl, allyl, optionally substituted aryl, optionally substituted aryl-C1-C4 alkyl, optionally substituted heteroaryl-C1-C4 alkyl, and 2-(trimethylsilyl)ethyl.
Dependencies are inferred from the claim text.