Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-10899775-B2
Application number	US-201816129008-A
Country	US
Kind code	B2
Filing date	Sep 12, 2018
Priority date	Jul 21, 2015
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

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 (3d),

or a salt thereof, said method comprising the steps of:
(i) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (1d) by reacting the compound of formula (1d) with an alcohol protecting reagent,

to form a compound formula (2d),

or a salt thereof; and
(ii) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the compound of formula (2d),
wherein P 1 is an alcohol protecting group; X 1 is a leaving group selected from the group consisting of: —Br, —I, —Cl a sulfonate ester, and an activated ester; and R 100 is (C 1 -C 3 )alkoxy.

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

3. The method of claim 1 , wherein the sulfonate ester represented by X 1 is mesylate.

4. The method of claim 1 , wherein the method comprising reacting a halogenating reagent with the compound of formula (2d) and the halogenating reagent is bromine, hydrobromic acid, carbon tetrabromide, phosphorus tribromide, potassium bromide, hydroiodic acid, iodine, carbon tetraiodide, phosphorus triiodide, sodium iodide, or potassium iodide.

5. The method of claim 1 , wherein the method comprising reacting the compound of formula (2d) with a sulfonating reagent 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 non-nucleophilic base is triethylamine or diisopropylethylamine.

8. The method of claim 5 , wherein the sulfonating reagent is methanesulfonic anhydride or methanesulfonyl chloride (MsCl).

9. The method of claim 1 , wherein the alcohol protecting group is a silyl protecting group.

10. The method of claim 9 , wherein the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl.

11. The method of claim 9 , wherein the silyl protecting group is tert-butyldimethylsilyl.

12. The method of claim 9 , wherein the silyl protecting group is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 2-trimethyethylsilyl (TEOC), or [2-(trimethylsilyl)ethoxy]methyl.

13. The method of claim 12 , wherein the silyl protecting group is introduced by reacting the compound of formula (1A) with R 3 —Cl, R 3 —Br, R 3 —I or R 3 —OSO 2 CF 3 in the presence of a base, wherein R 3 is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

14. The method of claim 13 , wherein the base is imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicycloundec-7-ene, or tetramethylpiperidine.

15. The method of claim 13 , wherein the reaction in step (i) is carried out in the presence of a catalyst selected from the group consisting of 4-dimethylaminopyridine (DMAP), 1,1,3,3-tetramethylguanidine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

16. A method of preparing a compound of formula (Id′),

or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of a compound of formula (1d),

to form a compound of formula (2d),

(2) reacting the compound of formula (2d) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3d),

(3) reacting the compound of formula (3d) with a monomer compound of the formula (a 1 ),

to form a compound of formula (4d),

(4) reacting the compound of formula (4d) with an imine reducing agent to form a compound of formula (5d),

(5) reacting the compound of formula (5d) with an alcohol deprotecting reagent to form a compound of formula (6d),

(6) reacting the compound of formula (6d) with a second halogenating reagent, a second sulfonating reagent or a second esterification reagent to form a compound of formula (7d),

and
(7) reacting the compound of formula (7d) with a monomer compound of the formula (a 1 ),

to form the compound of formula (Id′); wherein P 1 is an alcohol protecting group; X 1 and X 2 are each independently a leaving group selected from the group consisting of: —Br, —I, —Cl, a sulfonate ester and an activated ester; and R 100 is (C 1 -C 3 )alkoxy.

17. The method of claim 16 , wherein X 1 is Cl, P 1 is tert-butyldimethylsilyl; and X 2 is mesylate.

18. The method of claim 16 , wherein X 1 is mesylate, P 1 is tert-butyldimethylsilyl; and X 2 is mesylate.

19. A method of preparing a compound of formula (Id′),

or a pharmaceutically acceptable salt thereof, said method comprising the steps of:
(1) introducing an alcohol protecting group onto one of the primary alcohols of the compound of formula (1d),

to form a compound of formula (2d),

(2) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the compound of formula (2d) to form a compound of formula (3d),

(3) reacting the compound of formula (3d) with a monomer compound of the formula (a 1 ),

to form a compound of formula (4d),

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