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US 10,370,389 B2Granted
Methods of preparing cytotoxic benzodiazepine derivatives
AssigneeImmunoGen, Inc.
InventorsBaudouin Gérard, Manami Shizuka, Michael Louis Miller, Richard A. Silva
Life of this patent
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Abstract
The invention relates to novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.
Claims22
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.
8 more elements
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.
14 more elements
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.
14 more elements
Dependencies are inferred from the claim text.