ChemicalBook CAS DataBase List Pixantrone

Pixantrone synthesis

4synthesis methods

Product Name:Pixantrone
CAS Number:144510-96-3
Molecular formula:C17H19N5O2
Molecular Weight:325.37

Pixantrone dimaleate, also known as BBR 2778, was originally synthesized by professors Krapcho and Hacker at the University of Vermont, and determination of in-vitro tumor cell cytotoxicity was co-identified by the Boehringer Mannheim Italia research center and the University of Vermont. After the merger of Boehringer Mannheim with La-Roche, Novuspharm, and Cell Therapeautics, Inc., pixantrone dimaleate has been developed and marketed by Cell Therapeutics, Inc.
The manufacturing scale synthesis of pixantrone dimaleate relies on several process modifications, from the original synthesis reported by Krapcho in 1994.169 This modified procedure has provided active pharmaceutical ingredient (API) in high purity (>99%) and is acceptable for use in pharmaceutical applications (the scheme). Beginning with pyridine 3,4-dicarboxylic acid (129), generation of the corresponding anhydride 130 proceeded in 76% yield upon treatment with refluxing Ac2O. Next, an AlCl3-promoted Friedel-Crafts reaction of 1,4-difluorobenzene (131) with 130 under reflux conditions provided a mixture of nicotinic acid isomers 132a/132b in 84% yield, which were carried directly to the next step. Cyclization with fuming H2SO4 yielded the desired difluorobenzoisoquinoline- dione core 133, which was further functionalized with ethylenediamine (134) to provide the free base of pixantrone. Subjection of the pixantrone free base to aqueous acetic anhydride and maleic acid provided pixantrone dimaleate (XX) in 92% yield over 3 steps.

490-11-9 Synthesis

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Yield:-

Steps:

Multi-step reaction with 3 steps
1: 76 percent / acetic anhydride / 2 h / Heating
2: 1.) AlCl₃, 2.) f.H₂SO₄ / 1.) reflux, 22 h, 2.) from 135 to 140 deg C, 3 h
3: pyridine / 1.) RT, 12 h, 2.) 50 deg C, 2 h

References:

Krapcho, A. Paul;Petry, Mary E.;Getahun, Zelleka;Landi, John J.;Stallman, John;et al. [Journal of Medicinal Chemistry,1994,vol. 37,# 6,p. 828 - 837]

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4664-08-8 Synthesis