Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-9890179-B2
Application number	US-201615216517-A
Country	US
Kind code	B2
Filing date	Jul 21, 2016
Priority date	Jul 21, 2015
Publication date	Feb 13, 2018
Grant date	Feb 13, 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; P 3 is H or an amine protecting group; and R 101 is (C 1 -C 3 )alkyl, pyridyl, or nitropyridyl.

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 alcohol activating agent is triphenylphosphine.

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

5. 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′):

6. 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′):

7. 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 (a 1 ):

wherein X 3 is —Cl; P 3 is H or an amine protecting group; and R 101 is (C 1 -C 3 )alkyl, pyridyl, or nitropyridyl.

8. The method of claim 7 , wherein the compound of formula (17a) is reacted with a monomer compound of formula (a 1 ) in the presence of a base.

9. The method of claim 8 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

10. The method of claim 9 , wherein the base is potassium carbonate.

11. The method of claim 8 , wherein the compound of formula (17a) is reacted with a monomer compound of formula (a 1 ) in the presence of a polar aprotic solvent.

12. The method of claim 11 , wherein the polar aprotic solvent is dimethylformamide or dimethylacetamide.

13. The method of claim 8 , wherein the compound of formula (17a) is reacted with monomer of formula (a 1 ), wherein P 3 is H, to form a compound of formula (Ia′):

14. The method of claim 8 , 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′):

15. 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):

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

in the presence of an alcohol activating agent 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 (a 1 ):

to form a compound of formula (18a), or a pharmaceutically acceptable salt thereof, wherein X 3 is —Cl; P 1 is an alcohol protecting group; P 3 is H or an amine protecting group; and R 101 is (C 1 -C 3 )alkyl, pyridyl, or nitropyridyl.

16. The method of claim 15 , wherein the compound of formula (17a) is reacted with monomer of formula (a 1 ), wherein P 3 is H, to form a compound of formula (Ia′):

17. The method of claim 15 , 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′):

18. The method of claim 15 , wherein the compound of formula (14a) or a salt thereof is prepared a method comprising the following steps:
(1) reacting a chlorinating reagent with a compound of formula (2a),

to form a compound a compound of formula (13a),

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

19. The method of claim 18 , wherein the compound of formula (2a) is prepared by reacting a compound of formula (1a) with an alcohol protecting reagent

Assignees

• Immunogen Inc

Inventors

• Gerard 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07K5/0804

  and aliphatic · 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