Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-2021230114-A1
Application number	US-202117143723-A
Country	US
Kind code	A1
Filing date	Jan 7, 2021
Priority date	Nov 12, 2018
Publication date	Jul 29, 2021
Grant date	—

Abstract

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

First claim

1 - 32 . (canceled)

33 . A method of preparing a compound of formula (III):

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

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

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

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

34 . The method of claim 33 , wherein the method further comprises reacting the compound of formula (III) with a compound of formula (IV):

to form a compound of formula (V):

35 . The method of claim 33 , wherein P 1 is —O t Bu, —OMe, —OBn, or —O-silyl.

36 . The method of claim 35 , wherein P 1 is —O t Bu.

37 . The method of claim 33 , wherein E is —OH and the reaction between the compound of formula (I) and the compound of formula (a) is carried out in the presence of an activating agent.

38 . The method of claim 37 , 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.

39 . The method of claim 38 , wherein the activating agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.

40 . The method of claim 33 , wherein the carboxylic acid deprotecting agent in step (b) is an acid.

41 . The method of claim 40 , wherein the acid is trifluoroacetic acid (TFA).

42 . The method of claim 33 , 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.

43 . A method of preparing a compound of formula (V):

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

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

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

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

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

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

44 . The method of claim 43 , wherein P 1 is —O t Bu, —OMe, —OBn, or —O-silyl.

45 . The method of claim 44 , wherein P 1 is —O t Bu.

46 . The method of claim 43 , wherein E is —OH and the reaction between the compound of formula (I) and the compound of formula (a) is carried out in the presence of an activating agent.

47 . The method of claim 46 , 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.

48 . The method of claim 47 , wherein the activating agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.

49 . The method of claim 43 , wherein the carboxylic acid deprotecting agent in step (b) is an acid.

50 . The method of claim 49 , wherein the acid is trifluoroacetic acid (TFA).

Assignees

• Immunogen Inc

Inventors

• Reardon Michael
• Silva Richard A

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/4015

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

• C07D207/452 Primary

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