Methods of preparing cytotoxic benzodiazepine derivatives

A method of preparing a compound of formula (IV-1):

• or a salt thereof, comprising the steps of:
• 1) reacting a compound of formula (I):
• with hydrochloric acid in toluene to form a compound of formula (II), wherein the hydrochloric acid is 30-38 w/w % of hydrochloric acid in water:
• and
• wherein the compound of formula (II) is purified by crystallization by cooling a concentrated solution of the compound in toluene;
• 2) reacting the compound of formula (II) with a monomer compound of formula (a) in the presence of an alcohol activating agent and an azodicarboxylate,
• to form a compound of formula (III):
• or a salt thereof, wherein the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine, and 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);
• 3) reacting the compound of formula (III) or a salt thereof with a monomer compound of formula (b) in the presence of a base:
• to form the compound of formula (IV-1) or a salt thereof, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

A method of preparing a compound of formula (A-1):

• or a salt thereof, comprising the steps of:
• 1) reacting a compound of formula (I):
• with hydrochloric acid in toluene to form a compound of formula (II), wherein the hydrochloric acid is 30-38 w/w % of hydrochloric acid in water:
• and
• wherein the compound of formula (II) is purified by crystallization by cooling a concentrated solution of the compound in toluene;
• 2) reacting the compound of formula (II) with a monomer compound of formula (a) in the presence of an alcohol activating agent and an azodicarboxylate,
• to form a compound of formula (III):
• or a salt thereof, wherein the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine, and 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);
• 3) reacting the compound of formula (III) or a salt thereof with a monomer compound of formula (b) in the presence of a base:
• to form a compound of formula (IV-1):
• or a salt thereof, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride;
• 4) reacting the compound of formula (IV-1) or a salt thereof with a reducing agent to form a compound of formula (V-1):
• or a salt thereof;
• and
• 5) reacting the compound of formula (V-1) or a salt thereof, with a compound of formula (X-1):
• to form the compound of formula (A-1) or a salt thereof, wherein E is OH, halide or —C(═O)E is an activated ester.