# US 10,370,389 B2 · Methods of preparing cytotoxic benzodiazepine derivatives

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- Number: US 10,370,389 B2
- Document ID: US10370389B2
- Status: Granted
- Kind: B2
- Application number: 15/837,832
- Filed: 2017-12-11
- Published: 2018-07-19
- Granted: 2019-08-06
- Earliest claimed: 2015-07-21
- Assignees: ImmunoGen, Inc.
- Applicants: Immunogen, Inc.
- Inventors: Baudouin Gérard; Manami Shizuka; Michael Louis Miller; Richard A. Silva
- Web page: https://patentgrep.com/patent/US10370389B2

## CPC

- C07D 519/00: 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
- A61P 35/00: Antineoplastic agents
- C07C 303/28: by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
- C07D 487/04: Ortho-condensed systems
- C07K 5/0804: {and aliphatic}
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

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

## Claims

### Claim 1

A method of preparing a compound of formula (3A),
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 (1) by reacting the compound of formula (1A) with an alcohol protecting reagent,
to form a compound of formula (2A),
or a salt thereof; and
(ii) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the compound of formula (2A),
wherein:
P1 is an alcohol protecting group; and,
X1 is a leaving group selected from the group consisting of: —Br, —I, —Cl, a sulfonate ester, and an activated ester.

### Claim 2 (depends on 1)

The method of claim 1, wherein the sulfonate ester represented by X1 is mesylate, tosylate, brosylate, or triflate.

### Claim 3 (depends on 2)

The method of claim 2, wherein the sulfonate ester represented by X1 is mesylate.

### Claim 4 (depends on 1)

The method of claim 1, wherein the method comprising reacting the compound of formula (2A) with a sulfonating reagent in the presence of a non-nucleophilic base.

### Claim 5 (depends on 4)

The method of claim 4, 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.

### Claim 6 (depends on 5)

The method of claim 5, wherein the non-nucleophilic base is triethylamine or diisopropylethylamine.

### Claim 7 (depends on 4)

The method of claim 4, wherein the sulfonating reagent is methanesulfonic anhydride or methanesulfonyl chloride (MsCl).

### Claim 8 (depends on 1)

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

### Claim 9

A method of preparing a compound of formula (IA),
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 (1A),
to form a compound of formula (2A),
(2) reacting the compound of formula (2A) with a halogenating reagent, a sulfonating reagent or an esterification reagent to form a compound of formula (3A),
(3) reacting the compound of formula (3A) with a monomer compound of the formula (a1),
to form a compound of formula (4A),
(4) reacting the compound of formula (4A) with an imine reducing agent to form a compound of formula (5A),
(5) reacting the compound of formula (5A) with an alcohol deprotecting reagent to form a compound of formula (6A),
(6) reacting the compound of formula (6A) with a second halogenating reagent, a second sulfonating reagent or a second esterification reagent to form a compound of formula (7A),
and
(7) reacting the compound of formula (7A) with a monomer compound of the formula (b1),
to form the compound of formula (IA); wherein:
P1 is an alcohol protecting group; and,
X1 and X2 are each independently a leaving group selected from the group consisting of: —Br, —I, —Cl, a sulfonate ester and an activated ester.

### Claim 10

A method of preparing a compound of formula (IA),
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 (1A),
to form a compound of formula (2A),
(2) reacting a halogenating reagent, a sulfonating reagent or an esterification reagent with the compound of formula (2) to form a compound of formula (3A),
(3) reacting the compound of formula (3A) with a monomer compound of the formula (b1),
to form a compound of formula (8A),
(4) reacting the compound of formula (8A) with an alcohol deprotecting reagent to form a compound of formula (9A),
(5) reacting a second halogenating reagent, a second sulfonating reagent or a second esterification reagent with the compound of formula (9A) to form a compound of formula (10A),
(6) reacting the compound of formula (10A) with a monomer compound of the formula (d1)
to form a compound of formula (18A),
(7) when P3 is an amine protecting group; reacting the compound of formula (18A) with an amine deprotecting reagent to form the compound of formula (IA), wherein:
P3 is H or an amine protecting group;
P1 is an alcohol protecting group; and
X1 and X2 are each independently a leaving group selected from the group consisting of: —Br, —I, —Cl, a sulfonate ester, and an activated ester.

### Claim 11 (depends on 10)

The method of claim 10, wherein P3 is H and the compound of (10A) is reacted with the monomer compound of (d1) to form the compound of (IA).

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

The method of claim 12, 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.

### Claim 14 (depends on 12)

The method of claim 12, wherein the silyl protecting group is triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl.

### Claim 15 (depends on 12)

The method of claim 12, wherein the silyl protecting group is tert-butyldimethylsilyl.

### Claim 16 (depends on 13)

The method of claim 13, wherein the silyl protecting group is introduced by reacting the compound of formula (1A) with R3—Cl, R3—Br, R3—I or R3—OSO2CF3 in the presence of a base, wherein R3 is dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, trimethylsilyl, triisopropylsilyl, tribenzylsilyl, triphenylsilyl, 2-norbornyldimethylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

### Claim 17 (depends on 16)

The method of claim 16, wherein the base is imidazole, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicycloundec-7-ene, or tetramethylpiperidine.

### Claim 18 (depends on 16)

The method of claim 16, wherein the reaction 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).

### Claim 19 (depends on 9)

The method of claim 9, wherein X1 is —Cl, P1 is tert-butyldimethylsilyl; and X2 is mesylate.

### Claim 20 (depends on 9)

The method of claim 9, wherein X1 is mesylate, P1 is tert-butyldimethylsilyl; and X2 is mesylate.

### Claim 21 (depends on 10)

The method of claim 10, wherein X1 is —Cl, P1 is tert-butyldimethylsilyl; and X2 is mesylate.

### Claim 22 (depends on 10)

The method of claim 10, wherein X1 is mesylate, P1 is tert-butyldimethylsilyl; and X2 is mesylate.