Synthesis, Chromatographic Purification, and Isolation of Epothilone-Folic Add Conjugate BMS-753493

被引：6

作者：

Kim, Soong-Hoon ^{[1
]}

de Mas, Nuria ^{[2
]}

Parlanti, Luca ^{[2
]}

Lyngberg, Olav K. ^{[2
]}

Stroehlein, Guido ^{[5
]}

Guo, Zhenrong ^{[2
]}

Dambalas, Konstantinos ^{[2
]}

Rosso, Victor W. ^{[2
]}

Yang, Bing-Shiou ^{[2
]}

Girard, Kevin P. ^{[2
]}

Manaloto, Zerene A. ^{[2
]}

D'Arasmo, Germano ^{[6
]}

Frigerio, Riccardo E. ^{[6
]}

Wang, Wei ^{[3
]}

Lu, Xujin ^{[3
]}

Bolgar, Mark S. ^{[3
]}

Gokhale, Madhushree ^{[4
]}

Thakur, Ajit B. ^{[4
]}

机构：

[1] Bristol Myers Squibb Co, Oncol Discovery Chem, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Co, Proc Res & Dev, New Brunswick, NJ 08901 USA

[3] Bristol Myers Squibb Co, Analyt Res & Dev, New Brunswick, NJ 08901 USA

[4] Bristol Myers Squibb Co, Biopharmaceut, New Brunswick, NJ 08901 USA

[5] ChromaCon AG, CH-8005 Zurich, Switzerland

[6] Nerviano Med Sci Grp, NerPharMa DS, I-20014 Milan, Italy

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2011年 / 15卷 / 04期

关键词：

REGIOSELECTIVE SYNTHESIS; EC145; ACID; DISCOVERY; CANCER;

D O I：

10.1021/op200023g

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

We describe the synthesis, chromatographic purification, and isolation of the epothilone folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10-30 g) of cGMP quality BMS-753493.

引用

页码：797 / 809

页数：13

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