Method for producing antibody-drug conjugate

Patent metadata

Field	Value
Publication number	US-11318212-B2
Application number	US-201816642277-A
Country	US
Kind code	B2
Filing date	Aug 30, 2018
Priority date	Aug 31, 2017
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

A method for producing a compound represented by formula (C) wherein R1 represents an amino group protected with a protecting group, the method comprising a step of subjecting a compound represented by formula (B) wherein R1 represents the same meaning as above, to intramolecular cyclization to convert the compound into the compound represented by formula (C).

First claim

The invention claimed is:

1. A method for producing a compound represented by formula (C):

wherein R 1 represents an amino group protected with a protecting group,
the method comprising a step of subjecting a compound represented by formula (B):

wherein R 1 represents the same meaning as above, to intramolecular cyclization to convert the compound represented by formula (B) into the compound represented by formula (C).

2. The production method according to claim 1 , wherein R 1 is an amino group protected with an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a trichloroacetyl group, a pivaloyl group, a formyl group, or a benzoyl group.

3. The production method according to claim 1 , wherein R 1 is an amino group protected with an acetyl group or a trifluoroacetyl group.

4. The production method according to claim 1 , wherein R 1 is an amino group protected with an acetyl group.

5. The production method according to claim 1 , wherein the intramolecular cyclization is performed by a method comprising reacting the compound represented by formula (B) with trifluoroacetic anhydride.

6. The production method according to claim 5 , wherein the intramolecular cyclization is performed in a solvent comprising trifluoroacetic acid.

7. The production method according to claim 1 , wherein the intramolecular cyclization is performed by a method comprising reacting the compound represented by formula (B) with thionyl chloride.

8. The production method according to claim 7 , wherein the intramolecular cyclization is performed in the presence of aluminium chloride.

9. A method for producing a compound represented by formula (C):

wherein R 1 represents an amino group protected with a protecting group,
the method comprising a step of subjecting a compound represented by formula (J):

wherein Y represents a leaving group, and R 1 represents the same meaning as above, to intramolecular cyclization to convert the compound represented by formula (J) into the compound represented by formula (C).

10. The production method according to claim 9 , wherein R 1 is an amino group protected with an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a trichloroacetyl group, a pivaloyl group, a formyl group, or a benzoyl group.

11. The production method according to claim 9 , wherein R 1 is an amino group protected with an acetyl group or a trifluoroacetyl group.

12. The production method according to claim 9 , wherein R 1 is an amino group protected with an acetyl group.

13. The production method according to claim 9 , wherein Y is a chloro group.

14. The production method according to claim 9 , wherein Y is a trifluoroacetoxy group.

15. The production method according to claim 13 , wherein the intramolecular cyclization is performed in the presence of aluminium chloride.

16. The production method according to claim 14 , wherein the intramolecular cyclization is performed in a solvent comprising trifluoroacetic acid.

17. A method for producing a compound represented by formula (C):

wherein R 1 represents an amino group protected with a protecting group,
the method comprising the steps of:
coupling a compound represented by formula (D):

wherein X represents a leaving group, and R 1 represents the same meaning as above, with 3-butenoic acid to convert the compound represented by formula (D) into a compound represented by formula (E):

wherein R 1 represents the same meaning as above; then
reducing the compound represented by formula (E) to convert the compound represented by formula (E) into a compound represented by formula (B):

wherein R 1 represents the same meaning as above; and then
subjecting the compound represented by formula (B) to intramolecular cyclization to convert the compound represented by formula (B) into the compound represented by formula (C).

18. The production method according to claim 17 , wherein X is a bromo group, an iodo group, a trifluoromethanesulfonyloxy group, or an arylsulfonyloxy group.

19. The production method according to claim 17 , wherein X is a bromo group.

20. The production method according to claim 17 , wherein X is an iodo group.

21. The production method according to claim 17 , wherein R 1 is an amino group protected with an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a trichloroacetyl group, a pivaloyl group, a formyl group, or a benzoyl group.

22. The production method according to claim 17 , wherein R 1 is an amino group protected with an acetyl group or a trifluoroacetyl group.

23. The production method according to claim 17 , wherein R 1 is an amino group protected with an acetyl group.

24. The production method according to claim 17 , wherein the step of coupling the compound represented by formula (D) with 3-butenoic acid to convert the compound represented by formula (D) into the compound represented by formula (E) is performed in the presence of a palladium complex prepared from palladium(II) acetate and tri(o-tolyl)phosphine.

25. The production method according to claim 17 , comprising the steps of: dissolving the compound represented by formula (E) in a basic aqueous solution to wash the compound represented by formula (E) with a first organic solvent and separating the solvents; and then adding an acid to the basic aqueous solution to extract the compound represented by formula (E) with a second organic solvent and separating the solvents.

26. The production method according to claim 25 , wherein the first organic solvent is 2-methyltetrahydrofuran.

27. The production method according to claim 25 , wherein the second organic solvent is 2-methyltetrahydrofuran.

28. The production method according to claim 25 , wherein the basic aqueous solution is an aqueous sodium hydroxide solution.

29. The production method according to claim 17 , wherein the step of reducing the compound represented by formula (E) to convert the compound represented by formula (E) into the compound represented by formula (B) is performed by a method comprising reacting the compound represented by formula (E) with hydrogen in a solvent in the presence of a palladium carbon catalyst.

30. The production method according to claim 17 , wherein the step of subjecting the compound represented by formula (B) to intramolecular cyclization to convert the compound represented by formula (B) into the compound represented by formula (C) is performed b

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Nishi Yoshio
• SAKANISHI Kohei
• Noguchi Shigeru
• Takeda Tadahiro

Classifications

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• A61K47/68037

  the drug being a camptothecin [CPT] or derivatives · CPC title

• A61K47/6889 Primary

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4745

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title