Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-2021122768-A1
Application number	US-202017060611-A
Country	US
Kind code	A1
Filing date	Oct 1, 2020
Priority date	Nov 12, 2018
Publication date	Apr 29, 2021
Grant date	—

Abstract

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

First claim

1 - 36 . (canceled)

37 . A method of preparing a compound of formula (IVA′):

comprising the steps of:
1) reacting a compound of formula (IA′):

with cyanuric chloride to form a compound of formula (IIA′):

2) reacting the compound of formula (IIA′) with a compound of formula (b):

to form a compound of formula (VA′):

3) reacting the compound of formula (VA′) with an imine reducing agent to form a compound of formula (IIIA′):

and
4) reacting the compound of formula (IIIA′) with a compound of formula (b):

to form the compound of formula (IVA′).

38 . The method of claim 37 , wherein, in step 1), 0.6 to 1.0 molar equivalent of cyanuric chloride relative to the compound of formula (IA′) is used.

39 . The method of claim 38 , wherein between 0.7 and 0.8 molar equivalent of cyanuric chloride is used.

40 . The method of claim 38 , wherein 0.75 molar equivalent or 0.85 molar equivalent of cyanuric chloride is used.

41 . The method of claim 37 , wherein the reaction in step 1) is carried out in DMF.

42 . The method of claim 37 , wherein, in step 2), the reaction between the compound of formula (IIA′) and the compound of formula (b) is carried out in the presence of an alcohol activating agent and an azodicarboxylate.

43 . The method of claim 42 , wherein the alcohol activating agent is tributylphosphine or triphenylphosphine, and the azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD).

44 . The method of claim 43 , wherein the alcohol activating agent is triphenylphosphine and the azodicarboxylate is diisopropyl azodicarboxylate (DIAD).

45 . The method of claim 44 , wherein the triphenylphosphine and diisopropyl azodicarboxylate are mixed together first to form an triphenylphosiphosphine-azodicarboxylate complex before mixing the complex with the compound of formula (IIA′) and the compound of formula (b).

46 . The method of claim 37 , wherein, in step 3), the imine reducing agent is selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium aluminum hydride, hydrogen gas, ammonium formate, borane, diborane, borane-tetrahydrofuran complex (borane-THF), borane-dimethyl sulfide complex (BMS), borane-1,4-oxathaine complex, 9-borabicyclo[3.3.1]nonane (9-BBN), diisobutylaluminium hydride (DIBAL), lithium borohydride (LiBH 4 ), potassium borohydride (KBH 4 ), and sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al).

47 . The method of claim 37 , wherein, in step 4), the compound of formula (IIIA′) is reacted with the compound of formula (b) in the presence of a base.

48 . The method of claim 47 , wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

49 . The method of claim 48 , wherein the base is potassium carbonate.

50 . The method of claim 37 , wherein, in step 4), the reaction between the compound of formula (IIIA′) and the compound of formula (b) is carried out in the presence of potassium iodide or cesium iodide.

51 . A method of preparing a compound of formula (IVA′):

comprising the steps of:
1) reacting a compound of formula (IA′):

with cyanuric chloride to form a compound of formula (IIA′):

2) reacting the compound of formula (IIA′) with a compound of formula (b):

to form a compound of formula (VIIA′):

3) reacting the compound of formula (VITA′) with an imine reducing agent to form a compound of formula (IXA′):

4) reacting the compound of formula (IXA′) with a sulfonating agent to form a compound of formula (XA′):

5) reacting the compound of formula (XA′) with a compound of formula (b):

to form the compound of formula (IVA′), wherein Xi is a sulfonate ester.

52 . The method of claim 51 , wherein, in step 1), 0.6 to 1.0 molar equivalent of cyanuric chloride relative to compound (IA′) is used.

53 . The method of claim 52 , wherein 0.7 to 0.8 molar equivalent of cyanuric chloride is used.

54 . The method of claim 52 , wherein 0.75 molar equivalent or 0.85 molar equivalent of cyanuric chloride is used.

55 . The method of claim 52 , wherein the reaction in step 1) is carried out in DMF.

56 . The method of claim 51 , wherein, in step (2), the compound of formula (IIA′) is reacted with the compound of formula (b) in the presence of a base.

Assignees

• Immunogen Inc

Inventors

• Reardon Michael
• Silva Richard A

Classifications

• C07K5/06026 Primary

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C07C231/12 Primary

  by reactions not involving the formation of carboxamide groups · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title

• C07C323/25

  the carbon skeleton being acyclic and saturated · CPC title