Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-10385071-B2
Application number	US-201815878991-A
Country	US
Kind code	B2
Filing date	Jan 24, 2018
Priority date	Jan 25, 2017
Publication date	Aug 20, 2019
Grant date	Aug 20, 2019

Abstract

The invention provides 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 (A):

or a salt thereof, comprising reacting a compound of formula (V):

or a salt thereof, with a compound of formula (X):

wherein:
each double line between N and C independently represents a single bond or a double bond, provided that when it is a double bond X is absent and Y is —H, and when it is a single bond, X and Y are both —H; and
E is —OH, halide or —C(═O)E is an activated ester.

2. The method of claim 1 , wherein the compound of formula (V) is prepared by reacting a compound of formula (IV):

or a salt thereof, with a reducing agent to form the compound of formula (V):

or a salt thereof.

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

or a salt thereof, comprising the steps of:
1) reacting a compound of formula (VIII):

or a salt thereof, with a compound of formula (c):

or a salt thereof, to form a compound of formula (IX):

or a salt thereof; and
2) reacting the compound of formula (IX) with a carboxylic acid deprotecting agent to form the compound of formula (Xa) or a salt thereof, wherein E 1 is —OH, halide or —C(═O)E 1 is an activated ester; and P 1 is a carboxylic acid protecting group.

4. A method of preparing a compound of formula (II),

comprising reacting a compound of formula (I):

with hydrochloric acid in toluene.

5. A method of preparing a compound of formula (IV-1):

or a salt thereof, comprising the steps of:
1) reacting a compound of formula (I):

with hydrochloric acid in toluene to form a compound of formula (II):

2) reacting the compound of formula (II) with a monomer compound of formula (a),

to form a compound of formula (III):

or a salt thereof;
3) reacting the compound of formula (III) or a salt thereof with a monomer compound of formula (b):

to form the compound of formula (IV-1) or a salt thereof.

6. A method of preparing a compound of formula (A-1)

or salt thereof, comprising the steps of:
1) reacting a compound of formula (I):

with hydrochloric acid in toluene to form a compound of formula (II):

2) reacting the compound of formula (II) with a monomer compound of formula (a),

to form a compound of formula (III):

or a salt thereof;
3) reacting the compound of formula (III) or a salt thereof with a monomer compound of formula (b):

to form a compound of formula (IV-1):

or a salt thereof;
4) reacting the compound of formula (IV-1) or a salt thereof with a reducing agent to form a compound of formula (V-1):

or a salt thereof; and
5) reacting the compound of formula (V-1) or a salt thereof, with a compound of formula (X-1):

to form the compound of formula (A-1),
or a salt thereof, wherein E is —OH, halide or —C(═O)E is an activated ester.

7. The method of claim 5 , wherein 30-38 w/w % of hydrochloric acid in water is reacted with the compound of formula (I).

8. The method of claim 7 , wherein the reaction between the compound of formula (I) and hydrochloric acid is carried out at a temperature between 40° C. and 105° C., between 90° C. and 100° C. or the reaction is carried out at 95° C.

9. The method of claim 5 , wherein the compound of formula (II) is purified by crystallization.

10. The method of claim 9 , wherein the compound of formula (II) is crystalized in toluene.

11. The method of claim 5 , wherein in step 2), the compound of formula (II) is reacted with the monomer compound of formula (a) in the presence of an alcohol activating agent.

12. The method of claim 11 , wherein the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine.

13. The method of claim 12 , wherein in step 2) the compound of formula (II) is reacted with the monomer compound of formula (a) in the presence of an azodicarboxylate.

14. The method of claim 13 , wherein the alcohol activating agent is tributylphosphine 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).

15. The method of claim 13 , wherein in step 3), the compound of formula (III) or a salt thereof is reacted with the monomer compound of formula (b) in the presence of a base.

16. The method of claim 15 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

17. The method of claim 15 , wherein in step 3), the reaction between the compound of formula (III) or a salt thereof and the monomer compound of formula (b) is carried out in the presence of potassium iodide.

18. The method of claim 6 , wherein in step 4), the reducing agent is Fe/NH 4 Cl.

19. The method of claim 6 ,

Assignees

• Immunogen Inc

Inventors

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

Classifications

• 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

• C07D207/452

  with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom · CPC title

• C07C205/19 Primary

  having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D519/04

  Dimeric indole alkaloids, e.g. vincaleucoblastine · CPC title