Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-9873708-B2
Application number	US-201615216512-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	Jul 21, 2015
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The invention relates to novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.

First claim

The invention claimed is:

1. A method of preparing a compound of formula (17A):

or a salt thereof, said method comprising reacting a compound of formula (14A)

with a monomer compound of formula (d 1 ),

wherein:
X 3 is —Cl; and
P 3 is H or an amine protecting group.

2. The method of claim 1 , wherein the compound of formula (14A) is reacted with a monomer of formula d 1 in the presence of an alcohol activating agent and an azodicarboxylate.

3. The method of claim 2 , wherein the compound of formula (14A) is reacted with the monomer compound of formula (d 1 ), wherein P 3 is H, to form a compound of formula (17A′):

4. The method of claim 2 , wherein P 3 is an amine protecting group and the method further comprises the step of reacting the compound of formula (17A) with an amine deprotecting reagent to form a compound of formula (17A′):

5. A method of preparing a compound of formula (18A),

or a pharmaceutically acceptable salt thereof, said method comprising reacting a compound of formula of (17A):

with a monomer of formula (b1):

wherein:
X 3 is —Cl; and
P 3 is H or an amine protecting group.

6. The method of claim 5 , wherein the compound of formula (17A) is reacted with a monomer compound of formula (b1) in the presence of a base.

7. The method of claim 6 , wherein the compound of formula (17A) is reacted with monomer of formula (b1), wherein P 3 is H, to form a compound of formula (IA):

8. The method of claim 6 , wherein P 3 is an amine protecting group and the compound of formula (18A) is further reacted with an amine deprotecting reagent to form a compound of formula (IA):

9. A method of preparing a compound of formula (18A),

or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting the compound of formula (14A)

with a reduced monomer compound of formula (d 1 ),

to form a compound of formula (17A):

or a salt thereof; and
(2) reacting the compound of formula of (17A) with a monomer of formula (b1):

to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein:
X 3 is —Cl; and
P 3 is H or an amine protecting group.

10. The method of claim 9 , wherein the compound of formula (17A) is reacted with monomer of formula (b1), wherein P 3 is H, to form a compound of formula (IA):

11. The method of claim 9 , wherein P 3 is an amine protecting group and the compound of formula (18A) is further reacted with an amine deprotecting reagent to form a compound of formula (IA):

12. The method of claim 9 , wherein the compound of formula (14A) or a salt thereof is prepared by a method comprising the steps of:
(1) reacting a chlorinating reagent with a compound of formula (2A):

to form a compound of formula (13A):

or a salt thereof; and
(2) reacting the compound of formula (13A) with an alcohol deprotecting reagent to form the compound of formula (14A) or a salt thereof.

13. The method of claim 12 , wherein the compound of formula (2A) is prepared by reacting a compound of formula (1A) with an alcohol protecting reagent

14. The method of claim 10 , wherein the compound of formula (IA) is reacted with a reducing agent to form a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the reducing agent is selected from the group consisting of: hydrogen gas, sodium hydrosulfite, sodium sulfide, stanneous chloride, titanium (II) chloride, zinc, iron and samarium iodide.

16. The method of claim 15 , wherein the reducing agent is Fe/NH 4 Cl or Zn/NH 4 Cl.

17. The method of claim 2 , wherein the alcohol activating agent is triphenylphosphine and the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD).

18. The method of claim 6 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

19. The method of claim 9 , wherein the compound of formula (14A) is reacted with a monomer of formula d 1 in the presence of an alcohol activating agent and an azodicarboxylate.

20. The method of claim 19 , wherein the alcohol activating agent is triphenylphosphine and the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1 , 1 ′-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD).

21. The method of claim 9 , wherein the compound of formula (17A) is reacted with the monomer compound of formula (b1) in the presence of a base.

22. The method of claim 21 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

Assignees

• Immunogen Inc

Inventors

• Gérard Baudouin
• Shizuka Manami
• Miller Michael Louis
• Silva Richard A

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07C303/28 Primary

  by reaction of hydroxy compounds with sulfonic acids or derivatives thereof · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07K5/0804

  and aliphatic · CPC title