Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-10787463-B2
Application number	US-201916433117-A
Country	US
Kind code	B2
Filing date	Jun 6, 2019
Priority date	Jul 21, 2015
Publication date	Sep 29, 2020
Grant date	Sep 29, 2020

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 (15A):

or a salt thereof, said method comprising reacting a sulfonating reagent or an esterification reagent with a compound of formula (14A),

wherein:
X 3 is —Cl; and
X 4 is a sulfonate ester or an activated ester.

2. The method of claim 1 , wherein the sulfonating reagent is methanesulfonyl anhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, or trifluoromethanesulfonyl anhydride.

3. The method of claim 1 , wherein the sulfonate ester represented by X 4 is mesylate, tosylate, brosylate, or triflate.

4. The method of claim 3 , wherein the sulfonate ester represented by X 4 is mesylate.

5. The method of claim 1 , wherein the sulfonate ester is reacted with a compound of formula (14A) in the presence of a non-nucleophilic base.

6. The method of claim 5 , wherein the non-nucleophilic base is triethylamine, imidazole, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylformamide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or tetramethylpiperidine.

7. The method of claim 6 , wherein the amine base is diisopropylethylamine.

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

or a salt thereof, said method comprising reacting a compound of formula (15A)

with a monomer compound of formula (b),

wherein:
X 3 is —Cl; and
X 4 is a sulfonate ester or an activated ester.

9. The method of claim 8 , wherein the compound of formula (15A) is reacted with a monomer compound of formula (b1) in the presence of a base.

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

11. The method of claim 8 , wherein the compound of formula (15A) is reacted with a monomer compound of formula (b1) in the presence of a polar aprotic solvent.

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

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

or a salt thereof, said method comprising reacting a compound of formula (15A)

with a monomer compound of formula (d 1 ),

wherein:
X 3 is —Cl;
X 4 is a sulfonate ester or an activated ester; and
P 3 is H or an amine protecting group.

14. The method of claim 13 , wherein the compound of formula (15A) is reacted with a monomer compound of formula (d 1 ) in the presence of a base.

15. The method of claim 14 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

16. The method of claim 15 , wherein the base is potassium carbonate.

17. The method of claim 13 , wherein the compound of formula (15A) is reacted with a monomer compound of formula (d 1 ) in the presence of a polar aprotic solvent.

18. The method of claim 17 , wherein the polar aprotic solvent is dimethylacetamide.

19. The method of claim 13 , wherein the compound of formula (15A) is reacted with the monomer compound of formula (d 1 ), wherein P 3 is H, to form a compound of formula (17′A):

20. The method of claim 13 , wherein P 3 is an amine protecting group.

21. The method of claim 20 , further comprising the step of reacting the compound of formula (17A) with an amine deprotecting reagent to form a compound of formula (17′A):

22. The method of claim 21 , 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, or trifluoroacetic acid.

23. A method of preparing a compound of formula (18A),

or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14A),

to form a compound of formula (15A):

or a salt thereof;
(2) reacting the compound of formula (15A) with a monomer compound of formula (b1),

to form a compound of formula (16A):

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

to form a compound of formula (18A), or a pharmaceutically acceptable salt thereof, wherein:
X 3 is —Cl;
X 4 is a sulfonate ester or an activated ester; and
P 3 is H or an amine protecting group.

24. The method of claim 23 , wherein the compound of formula (18A) is further reacted with an amine deprotecting reagent to form a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.

25. A method of preparing a compound of formula (IA),

or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) reacting a sulfonating reagent or an esterification reagent with the compound of formula (14A)

to form a compound of formula (15A):

or a salt thereof;
(2) reacting the compound of formula (15A) with a monomer compound of formula (a 1 ),

to form a compound of formula (19A):

or a salt thereof;
(3) reacting the compound of formula (19A) wit

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

• C07C309/65

  of a saturated carbon skeleton · CPC title

• C07F7/188

  by reactions involving the formation of Si-O linkages · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title