DEPROTECTION METHOD

• US 20160024143A1
• Filed: 10/02/2015
• Published: 01/28/2016
• Est. Priority Date: 04/04/2013
• Status: Active Grant

• Current Assignee: Ajinomoto Co., Inc.
• Original Assignee: Ajinomoto Co., Inc.
• Inventors: SAJIKI, Hironao, MONGUCHI, Yasunari
• Granted Patent: US 10,442,834 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07C 319/20 by reactions not involving the formation of sulfide groups
• CPC Class Codes: C07C 321/14 of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 321/28 Sulfides, hydropolysulfides, or polysulfides having thio groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 53/16 Halogenated acetic acids
• CPC Class Codes: C07K 1/02 in solution C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/0606 the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
• CPC Class Codes: C07K 5/06069 Ser-amino acid
• CPC Class Codes: C07K 5/0812 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1013 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides a method of efficiently deprotecting a protected organic compound by catalytic hydrogenation. Specifically, the present invention provides a method of deprotecting an organic compound having at least one functional group selected from the group consisting of a carboxy group, an amino group and a hydroxy group, which is protected by a protecting group represented by the formula (I):

R¹—C(R²)(R³)-L¹-   (I)

[wherein R¹ is an aryl group optionally having substituent(s), R² and R³ are each independently, a hydrogen atom or an aryl group optionally having substituent(s), and L¹ is a single bond, —O—CO— or —O—CH₂—], comprising hydrogenation in the presence of a metal catalyst and halogenated acetic acid.

Claims

1. A method of deprotecting a sulfur-containing peptide containing at least one functional group selected from the group consisting of a carboxy group, an amino group, and a hydroxy group,

wherein said peptide:

(1) is protected by a protecting group represented by formula (I);

R¹—

C(R²)(R³)-L¹-  

 

(I)

wherein R¹ is an aryl group optionally having one or more substituent(s), R² and R³ are each, independently, a hydrogen atom or an aryl group optionally having one or more substituent(s), and L¹ is a single bond, —

O—

CO—

or —

O—

CH₂—

; and

(2) contains at least one sulfur-containing amino acid residue selected from the group consisting of methionine, cysteine with protected sulfanyl group, and cysteine,

wherein said method comprises subjecting said peptide to hydrogenation in the presence of a metal catalyst and a halogenated acetic acid.

2. The method according to claim 1, wherein said halogenated acetic acid is at least one member selected from the group consisting of trichloroacetic acid, dichloroacetic acid, monochloroacetic acid, trifluoroacetic acid, difluoroacetic acid, and monofluoroacetic acid.

3. The method according to claim 1, wherein said hydrogenation is conducted in the presence of trifluoroacetic acid.

4. The method according to claim 1, wherein said hydrogenation is conducted in the presence of said halogenated acetic acid in an amount of not less than 1 mol per 1 mol of total sulfur atom contained in said sulfur-containing peptide.

5. The method according to claim 1, wherein said metal catalyst is at least one member selected from the group consisting of a nickel catalyst, a copper catalyst, a ruthenium catalyst, a palladium catalyst, a rhodium catalyst, and a platinum catalyst.

6. The method according to claim 1, wherein said hydrogenation is conducted in the presence of a palladium catalyst.

7. The method according to claim 6, wherein said hydrogenation is conducted in the presence of palladium carbon.

8. The method according to claim 1, wherein R¹ is a phenyl group optionally having one or more substituent(s).

9. The method according to claim 1, wherein said protecting group is selected from the group consisting of:

a benzyl group optionally having one or more substituent(s),

a benzhydryl group optionally having one or more substituent(s),

a trityl group optionally having one or more substituent(s),

a 9-phenylfluorenyl group optionally having one or more substituent(s),

a benzyloxycarbonyl group optionally having one or more substituent(s), and

a benzyloxymethyl group optionally having one or more substituent(s).

10. The method according to claim 1, wherein said protecting group is selected from the group consisting of:

a benzyl group optionally having one or more substituent(s),

a benzyloxycarbonyl group optionally having one or more substituent(s), and

a benzyloxymethyl group optionally having one or more substituent(s).

11. A method of producing a sulfur-containing peptide, comprising the method according to of claim 1.

12. A method of producing a sulfur-containing peptide, comprising:

(a) reacting;

(i) a free amino group of an amino acid having a carboxy group protected by a protecting group or a first peptide having a C-terminus protected by a protecting group with

(ii) a free carboxy group of an amino acid having an amino group protected by a protecting group to obtain a second peptide; and

(b) deprotecting any C-terminus and N-terminus, which are protected by a protecting group, of said second peptide, to obtain said peptide,

wherein said peptide contains at least one functional group selected from the group consisting of a carboxy group, an amino group, and a hydroxy group, which is protected by a protecting group represented by formula (I);

R¹—

C(R²)(R³)-L¹-  

 

(I)

wherein R¹ is an aryl group optionally having one or more substituent(s), R² and R³ are each, independently, a hydrogen atom or an aryl group optionally having one or more substituent(s), and L¹ is a single bond, —

O—

CO—

or —

O—

CH₂—

; and

said peptide contains at least one sulfur-containing amino acid residue selected from the group consisting of methionine, cysteine with protected sulfanyl group, and cysteine, and

wherein said method further comprises subjecting said second peptide to hydrogenation in the presence of a metal catalyst and a halogenated acetic acid.

13. The method according to claim 12, wherein said halogenated acetic acid is at least one member selected from the group consisting of trichloroacetic acid, dichloroacetic acid, monochloroacetic acid, trifluoroacetic acid, difluoroacetic acid, and monofluoroacetic acid.

14. The method according to claim 12, wherein said hydrogenation is conducted in the presence of trifluoroacetic acid.

15. The method according to claim 12, wherein said hydrogenation is conducted in the presence of said halogenated acetic acid in an amount of not less than 1 mol per 1 mol of total sulfur atom contained in said sulfur-containing peptide.

16. The method according to claim 12, wherein said metal catalyst is at least one member selected from the group consisting of a nickel catalyst, a copper catalyst, a ruthenium catalyst, a palladium catalyst, a rhodium catalyst, and a platinum catalyst.

17. A method of producing a peptide, comprising:

(a) reacting;

(i) a free amino group of an amino acid having a carboxy group protected by a protecting group or a first peptide having the C-terminus protected by a protecting group with

(ii) a free carboxy group of an amino acid having an amino group protected by a protecting group to obtain a second peptide;

(b) deprotecting the protected N-terminus of said second peptide, to obtain a third peptide containing an unproptected amino group;

(c) repeating step (a) and step (b) as necessary; and

(d) deprotecting all of the C-terminus and N-terminus, which are protected by a protecting group, of said third peptide, to obtain said peptide,

wherein said peptide contains at least one functional group selected from the group consisting of a carboxy group, an amino group, and a hydroxy group, which is protected by a protecting group represented by formula (I);

R¹—

C(R²)(R³)-L¹-  

 

(I)

wherein R¹ is an aryl group optionally having one or more substituent(s), R² and R³ are each, independently, a hydrogen atom or an aryl group optionally having one or more substituent(s), and L¹ is a single bond, —

O—

CO—

or —

O—

CH₂—

; and

said peptide contains at least one sulfur-containing amino acid residue selected from the group consisting of methionine, cysteine with protected sulfanyl group, and cysteine, and

wherein said method further comprises subjecting said peptide to hydrogenation in the presence of a metal catalyst and a halogenated acetic acid.

18. The method according to claim 17, wherein said halogenated acetic acid is at least one member selected from the group consisting of trichloroacetic acid, dichloroacetic acid, monochloroacetic acid, trifluoroacetic acid, difluoroacetic acid, and monofluoroacetic acid.

19. The method according to claim 17, wherein said hydrogenation is conducted in the presence of trifluoroacetic acid.

20. The method according to claim 17, wherein said hydrogenation is conducted in the presence of said halogenated acetic acid in an amount of not less than 1 mol per 1 mol of total sulfur atom contained in said sulfur-containing peptide.