Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-11420982-B2
Application number	US-202016991700-A
Country	US
Kind code	B2
Filing date	Aug 12, 2020
Priority date	Jul 21, 2015
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

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

First claim

What is claimed is:

1. A method of preparing a compound of formula (20A):

or a salt thereof, said method comprising the step of reacting a brominating or iodinating reagent with a compound of formula (14A):

or a salt there of, wherein
X 3 is —Cl; and
X 5 is —Br or —I.

2. The method of claim 1 , wherein the brominating or iodinating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.

3. A method of preparing a compound of formula (16A):

or a salt thereof, comprising the steps of
(i) reacting a brominating or iodinating reagent with a compound of formula (14A):

or a salt there of, to form a compound of formula (20A):

or a salt thereof, wherein X 3 is —Cl, and X 5 is —Br or —I, and
(ii) reacting the compound of formula (20A) or a salt hereof with a monomer compound of formula (b1):

to form the compound of formula (16A)
or a salt thereof.

4. The method of claim 3 , wherein the compound of formula (20A) is reacted with the monomer compound of formula (b1) in the presence of a base.

5. The method of claim 4 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

6. The method of claim 5 , wherein the base is potassium carbonate.

7. The method of claim 3 , wherein the compound of formula (20A) is reacted with a monomer compound of formula (b1) in the presence of a polar aprotic solvent.

8. The method of claim 7 , wherein the polar aprotic solvent is dimethylacetamide.

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

or a salt thereof, comprising the steps of:
(i) reacting a brominating or iodinating reagent with a compound of formula (14A):

or a salt there of, to form a compound of formula (20A):

or a salt thereof, wherein X 3 is —Cl, and X 5 is —Br or —I, and
(ii) reacting the compound of formula (20A) or a salt thereof with a monomer compound of formula (d 1 ):

to form the compound of formula (17A)
or a salt thereof, wherein P 3 is H or an amine protecting group.

10. The method of claim 9 , wherein the compound of formula (20A) is reacted with the monomer compound of formula (d 1 ) in the presence of a base.

11. The method of claim 10 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

12. The method of claim 11 , wherein the base is potassium carbonate.

13. The method of claim 9 , wherein the compound of formula (20A) is reacted with the monomer compound of formula (d 1 ), wherein P 3 is H, to form a compound of formula (17A′):

14. The method of claim 9 , 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′):

15. The method of claim 14 , wherein the amine deprotecting reagent is selected from the group consisting of tetra-n-butylammonium fluoride, acetic acid, hydrogen fluoride pyridine, cesium fluoride, piperidine, morpholine, and trifluroacetic acid.

16. A method of preparing a compound of formula (18A):

or a pharmaceutically acceptable salt thereof, comprising the steps of:
(i) reacting a brominating or iodinating reagent with a compound of formula (14A):

or a salt there of, to form a compound of formula (20A):

or a salt thereof, wherein X 3 is —Cl, and X 5 is —Br or —I,
(ii) reacting the compound of formula (20A) or a salt hereof with a monomer compound of formula (b1):

to form a compound of formula (16A):

or a salt thereof; and
(iii) reacting the compound of formula of (16A) or a salt thereof with a monomer compound of formula (d 1 ):

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

17. The method of claim 16 , wherein the compound of formula (16A) is reacted with the monomer compound of formula (d 1 ), wherein P 3 is H, to form a compound of formula (IA):

18. The method of claim 16 , wherein P 3 is an amine protecting group and the method further comprise reacting the compound of formula (18A) with an amine deprotecting reagent to form a compound of formula (IA):

19. A method of preparing a compound of formula (18A):

or a pharmaceutically acceptable salt thereof, comprising the steps of:
(1) reacting a brominating or iodinating reagent with a compound of formula (14A):

or a salt there of, to form a compound of formula (20A):

or a salt thereof;
(2) reacting the compound of formula (20A) or a salt thereof with a monomer compound of formula (d 1 ):

to form a compound of formula (17A):

Assignees

• Immunogen Inc

Inventors

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

Classifications

• 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

• C07K5/06017 Primary

  and aliphatic · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title