Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-10913713-B2
Application number	US-201916679593-A
Country	US
Kind code	B2
Filing date	Nov 11, 2019
Priority date	Nov 12, 2018
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

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 (IIIa):

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

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

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

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

2. The method of claim 1 , wherein the method further comprises reacting the compound of formula (IIIa) with a compound of formula (IV):

to form a compound of formula (Va):

3. The method of claim 1 , wherein P 1 is —O t Bu, —OMe, —OBn, or —O-silyl.

4. The method of claim 3 , wherein P 1 is —O t Bu.

5. The method of claim 1 , wherein E is —OH and the reaction between the compound of formula (Ia) and the compound of formula (a) is carried out in the presence of an activating agent.

6. The method of claim 5 , wherein the activating agent is a 2,4,6-trialkyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide, carbodiimide, a uronium, an activated ester, a phosphonium, 2-alkyl-1-alkylcarbonyl-1,2-dihydroquinoline, 2-alkoxy-1-alkoxycarbonyl-1,2-dihydroquinoline, or alkylchloroformate.

7. The method of claim 6 , wherein the activating agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.

8. The method of claim 1 , wherein the carboxylic acid deprotecting agent in step (b) is an acid.

9. The method of claim 8 , wherein the acid is trifluoroacetic acid (TFA).

10. The method of claim 1 , wherein the method comprises the steps of:
(a) reacting a compound of formula (Ia1):

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

or a salt thereof, in the presence of an activating agent to form a compound of formula (IIa1):

(b) reacting the compound of formula (IIa1) with a carboxylic acid deprotecting agent to form the compound of formula (IIIa).

11. A method of preparing a compound of formula (Va):

comprising the steps of:
(a) reacting a compound of formula (Ia):

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

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

(b) reacting the compound of formula (IIa) with a carboxylic acid deprotecting agent to form the compound of formula (IIIa):

or a salt thereof; and
(c) reacting the compound of formula (IIIa) with a compound of formula (IV):

to form the compound of formula (Va), wherein E is —OH, halide or —C(═O)E is an activated ester; and P 1 is a carboxylic acid protecting group.

12. The method of claim 11 , wherein P 1 is —O t Bu, —OMe, —OBn, or —O-silyl.

13. The method of claim 12 , wherein P 1 is —O t Bu.

14. The method of claim 11 , wherein E is —OH and the reaction between the compound of formula (Ia) and the compound of formula (a) is carried out in the presence of an activating agent.

15. The method of claim 14 , wherein the activating agent is a 2,4,6-trialkyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide, carbodiimide, a uronium, an activated ester, a phosphonium, 2-alkyl-1-alkylcarbonyl-1,2-dihydroquinoline, 2-alkoxy-1-alkoxycarbonyl-1,2-dihydroquinoline, or alkylchloroformate.

16. The method of claim 15 , wherein the activating agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.

17. The method of claim 11 , wherein the carboxylic acid deprotecting agent in step (b) is an acid.

18. The method of claim 17 , wherein the acid is trifluoroacetic acid (TFA).

19. The method of claim 11 , wherein the method comprises the steps of:
(a) reacting a compound of formula (Ia1):

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

or a salt thereof, in the presence of an activating agent to form a compound of formula (IIa1):

(b) reacting the compound of formula (IIa1) with a carboxylic acid deprotecting agent to form a compound of formula (IIIa):

or a salt thereof; and
(c) reacting the compound of formula (IIIa) with a compound of formula (IV):

to form the compound of formula (Va).

20. The method of claim 1 , wherein E, when present, is —OH and the reaction in step (a) is carried out in the presence of an activating agent that is HATU and HOAt.

Assignees

• Immunogen Inc

Inventors

• Reardon Michael
• Silva Richard A

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D207/452 Primary

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

• A61K31/4015

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title

• C07D207/448 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide · CPC title

• C07D519/00

  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