A scaleable synthesis of BAY 43-9006: A potent Raf kinase inhibitor for the treatment of cancer

被引：104

作者：

Bankston, D ^{[1
]}

Dumas, J ^{[1
]}

Natero, R ^{[1
]}

Riedl, B ^{[1
]}

Monahan, MK ^{[1
]}

Sibley, R ^{[1
]}

机构：

[1] Bayer Res Ctr, Div Pharmaceut, West Haven, CT 06516 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2002年 / 6卷 / 06期

关键词：

D O I：

10.1021/op020205n

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

Urea 3 (BAY 43-9006), a. potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

引用

页码：777 / 781

页数：5

共 15 条

[1]

BANKSTON D, UNPUB

[2] APPROACHES TO PROTECTION AGAINST NERVE AGENT POISONING - (NAPHTHYLVINYL)PYRIDINE DERIVATIVES AS POTENTIAL ANTIDOTES [J].

GRAY, AP ;

PLATZ, RD ;

HENDERSON, TR ;

CHANG, TCP ;

TAKAHASHI, K ;

DRETCHEN, KL .

JOURNAL OF MEDICINAL CHEMISTRY, 1988, 31 (04) :807-814

[3] The discovery of potent cRaf1 kinase inhibitors [J].

Lackey, K ;

Cory, M ;

Davis, R ;

Frye, SV ;

Harris, PA ;

Hunter, RN ;

Jung, DK ;

McDonald, OB ;

McNutt, RW ;

Peel, MR ;

Rutkowske, RD ;

Veal, JM ;

Wood, ER .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (03) :223-226

[4] NOVEL ORALLY ACTIVE INHIBITORS OF PASSIVE CUTANEOUS ANAPHYLAXIS IN RATS - N-[2-(4-PYRIDINYL)-4-PYRIMIDINYL]UREAS AND DIALKYL[[[2-(4-PYRIDINYL)-4-PYRIMIDINYL]AMINO]METHYLENE]MALONATES [J].

LESHER, GY ;

SINGH, B ;

MIELENS, ZE .

JOURNAL OF MEDICINAL CHEMISTRY, 1982, 25 (07) :837-842

[5] Improved large-scale preparation of 4-iodopicolinic acid [J].

Lohse, O .

SYNTHETIC COMMUNICATIONS, 1996, 26 (10) :2017-2025

[6]

LOWINGER TB, 2000, 11 NCI EORTC AACR S

[7] New substituted 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)piperidin-4-yl derivatives with α2-adrenoceptor antagonist activity [J].

Mayer, P ;

Brunel, P ;

Chaplain, C ;

Piedecoq, C ;

Calmel, F ;

Schambel, P ;

Chopin, P ;

Wurch, T ;

Pauwels, PJ ;

Marien, M ;

Vidaluc, JL ;

Imbert, T .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (20) :3653-3664

[8]

MEYER H, 1928, CHEM BER, V61, P2202

[9] SYNTHESIS AND ANTIULCER ACTIVITY OF N-SUBSTITUTED N'-[3-[3-(PIPERIDINOMETHYL)PHENOXY]PROPYL]UREAS - HISTAMINE-H2-RECEPTOR ANTAGONISTS WITH A POTENT MUCOSAL PROTECTIVE ACTIVITY [J].

MIYASHITA, M ;

MATSUMOTO, T ;

MATSUKUBO, H ;

IINUMA, F ;

TAGA, F ;

SEKIGUCHI, H ;

HAMADA, K ;

OKAMURA, K ;

NISHINO, K .

JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (13) :2446-2451

[10] SERINE-SPECIFIC AND THREONINE-SPECIFIC PROTEIN-KINASE ACTIVITIES OF PURIFIED GAG-MIL AND GAG-RAF PROTEINS [J].

MOELLING, K ;

HEIMANN, B ;

BEIMLING, P ;

RAPP, UR ;

SANDER, T .

NATURE, 1984, 312 (5994) :558-561

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