Method for producing peptide compound

Patent metadata

Field	Value
Publication number	US-12240871-B2
Application number	US-202017439601-A
Country	US
Kind code	B2
Filing date	Mar 16, 2020
Priority date	Mar 15, 2019
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

Abstract

The present invention is to provide a method for producing a peptide containing an N-alkylamino acid, which comprises the following Steps (1) to (3). Step (1): a step of mixing an N-terminal protected amino acid or an N-terminal protected peptide with a carboxylic acid halide or a halogenated alkyl formate; Step (2): a step of mixing an amino acid or a peptide in which the N-terminal and the C-terminal are not protected with a trialkylsilylating agent; and Step (3): a step of mixing the product obtained in Step (1) with the product obtained in Step (2).

First claim

The invention claimed is:

1. A method for producing a peptide which comprises the following Steps (1) to (3):
(1) a step of mixing an N-terminal protected amino acid or an N-terminal protected peptide represented by the formula (I) P-A 1 -OH
wherein P is an N-terminal protective group, and A 1 represents a group derived from an amino acid, a group derived from an N—C 1-6 alkylamino acid, where the C 1-6 alkyl may have a substituent(s), or a group derived from a peptide,
with an activating agent represented by the formula (II)

wherein X represents a halogen atom, and R 1 represents a secondary C 5-40 alkyl group which may have a substituent(s);
(2) a step of mixing an amino acid or a peptide represented by the formula (IV): H-A 2 -OH
wherein A 2 represents a group derived from an N—C 1-6 alkylamino acid, where the C 1-6 alkyl may have a substituent(s), or a group derived from a 4- to 6-membered cyclic secondary amino acid, where the 4- to 6-membered ring may be fused with a cyclic compound selected from the group consisting of a C 6-14 aryl ring, a C 6-14 haloaryl ring and a C 3-8 cycloalkyl ring, or a group derived from a peptide in which the N-terminal residue is an N—C 1-6 alkylamino acid, where the C 1-6 alkyl may have a substituent(s), or a 4- to 6-membered cyclic secondary amino acid, where the 4- to 6-membered ring may be fused with a cyclic compound selected from the group consisting of a C 6-14 aryl ring, a C 6-14 haloaryl ring and a C 3-8 cycloalkyl ring,
with a silylating agent; and
(3) a step of mixing a product obtained in Step (1) and a product obtained in Step (2).

2. The method for producing a peptide of claim 1 , which comprises the following Steps (1) to (3):
(1) a step of mixing an N-terminal protected amino acid represented by the formula (I): P-A 1 -OH
wherein P is an N-terminal protective group, and A 1 represents a group derived from an amino acid or a group derived from an N—C 1-6 alkylamino acid, where the C 1-6 alkyl may have a substituent(s),
with an activating agent represented by the formula (II):

wherein X represents a halogen atom, and R 1 represents a secondary C 5-40 alkyl group which may have a substituent(s);
(2) a step of mixing an amino acid or a peptide represented by the formula (IV): H-A 2 -OH
wherein A 2 represents a group derived from an N-methylamino acid, a group derived from an N—C 1-6 alkylglycine, where the C 1-6 alkyl may have a substituent(s), or a group derived from a 4- to 6-membered cyclic secondary amino acid, or a group derived from a peptide in which the N-terminal residue is an N-methylamino acid, an N—C 1-6 alkylglycine, where the C 1-6 alkyl may have a substituent(s), or a 4- to 6-membered cyclic secondary amino acid,
with a silylating agent; and
(3) a step of mixing a product obtained in Step (1) and a product obtained in Step (2).

3. The method for producing a peptide of claim 1 , which comprises the following Steps (1) to (3):
(1) a step of mixing an N-terminal protected peptide represented by the formula (V): P-A 3 -OH
wherein P is an N-terminal protective group, and A 3 represents a group derived from a peptide,
with an activating agent represented by the formula (II)

wherein X represents a halogen atom, and R 1 represents a secondary C 5-40 alkyl group which may have a substituent(s);
(2) a step of mixing an amino acid represented by the formula (IV′): H-A 2′ -OH
wherein A 2′ represents a group derived from an N-methylamino acid, a group derived from an N—C 1-6 alkylglycine, where the C 1-6 alkyl may have a substituent(s), or a group derived from a 4- to 6-membered cyclic secondary amino acid,
with a silylating agent; and
(3) a step of mixing a product obtained in Step (1) and a product obtained in Step (2).

4. The method for producing a peptide according to any one of claims 1 to 3 , which comprises a step of removing the protective group of the N-terminal of the peptide obtained in Step (3).

5. The method for producing a peptide according to any one of claims 1 to 3 , which further comprises repeating one or more times of the following Steps (4) and (5):
(4) a step of removing the protective group of the N-terminal of the peptide obtained in Step (3) or (5);
(5) a step of reacting an N-terminal protected amino acid or an N-terminal protected peptide with the N-terminal of the peptide obtained in Step (4).

6. The method for producing a peptide according to claim 1 or 3 , wherein the amino acid positioned at the C-terminal in the N-terminal protected peptide represented by the formula (I): P-A 1 -OH or the formula (V): P-A 3 -OH
wherein P is an N-terminal protective group, and A 1 and A 3 each represent a group derived from a peptide,
is an amino acid other than the N—C 1-6 alkylamino acid, where the C 1-6 alkyl may have a substituent(s), or a 4- to 6-membered cyclic secondary amino acid, where the 4- to 6-membered ring may be fused with a cyclic compound selected from the group consisting of a C 6-14 aryl ring, a C 6-14 haloaryl ring and a C 3-8 cycloalkyl ring.

7. The method for producing a peptide according to claim 1 or 2 , wherein A 1 is a group derived from an amino acid.

8. The method for producing a peptide according to claim 1 or 2 , wherein the N-terminal protected amino acid represented by the formula (I) or the amino acid positioned at the C-terminal in the N-terminal protected peptide represented by the formula (I) is an α-amino acid, a β-amino acid or a γ-amino acid.

9. The method for producing a peptide according to claim 8 , wherein the N-terminal protected amino acid represented by the formula (I) or the amino acid positioned at the C-terminal in the N-terminal protected peptide represented by the formula (I) is an α-amino acid.

10. The method for producing a peptide according to claim 1 , wherein the amino acid represented by the formula (IV) or the amino acid positioned at the N-terminal in the peptide represented by the formula (IV) is an N—C 1-6 alkyl-α-amino acid, where the C 1-6 alkyl may have a substituent(s), or a 4- to 6-membered cyclic secondary-α-amino acid.

11. The method for producing a peptide according to claim 1 , wherein the amino acid represented by the formula (IV) or the amino acid positioned at the N-terminal in the peptide represented by the formula (IV) is an N-methyl-α-amino acid or an N-ethyl-α-amino acid, where N-methyl and N-ethyl each may have a substituent(s), or a 4- to 6-membered cyclic secondary-α-amino acid.

12. The method for producing a peptide according to any one of claims 1 to 3 , wherein R 1 is a secondary C 5-20 alkyl group and X is a chlorine atom.

13. The method for producing a peptide according to any one of claims 1 to 3 , wherein the activating agent is

14. The method for producing a peptide according to any one of claims 1 to 3 , wherein the activating agent is

15. The method for producing a peptide according to any one of claims 1 to 3 , wherein the activating agent is

Assignees

• Nissan Chemical Corp
• Peptidream Inc

Inventors

• Takeuchi Hisayuki
• ASAKA Yukio
• Nagaya Akihiro
• Handa Michiharu
• Masuya Keiichi
• TAGURI Tomonori
• Nemoto Yoshitaka
• Kobayashi Yutaka
• MATSUDA Ayumu
• Kurasaki Haruaki
• Cary Douglas Robert

Classifications

• C07C69/96

  Esters of carbonic or haloformic acids · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07K5/1016

  and aromatic or cycloaliphatic · CPC title

• C07K5/1021

  with the first amino acid being acidic · CPC title

• C07K5/1024

  with the first amino acid being heterocyclic · CPC title