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(11) EP 1 633 750 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 471/04 (2006.01) 01.12.2010 Bulletin 2010/48 (86) International application number: (21) Application number: 04717703.5 PCT/GB2004/000946

(22) Date of filing: 05.03.2004 (87) International publication number: WO 2004/078757 (16.09.2004 Gazette 2004/38)

(54) SYNTHESIS OF 5-SUBSTITUTED 7-AZAINDOLES AND 7-AZAINDOLINES SYNTHESE VON 5-SUBSTITUIERTEN 7-AZAINDOLEN UND 7-AZAINDOLINEN SYNTHÈSE DE 7-AZAINDOLES ET 7-AZAINDOLINES SUBSTITUÈS EN POSITION 5

(84) Designated Contracting States: • BHATIA, G., AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Eisai London Research Labs. Ltd. HU IE IT LI LU MC NL PL PT RO SE SI SK TR London WC1E 6BT (GB)

(30) Priority: 06.03.2003 GB 0305142 (74) Representative: Crooks, Elizabeth Caroline et al Kilburn & Strode LLP (43) Date of publication of application: 20 Red Lion Street 15.03.2006 Bulletin 2006/11 London WC1R 4PJ (GB)

(73) Proprietor: Eisai R&D Management Co., Ltd. (56) References cited: Tokyo 112-8088 (JP) WO-A-03/000688 US-A- 5 705 515

(72) Inventors: •PI-TAICHOU, ET AL.: "Excited-State Amine- Imine • GRACZYK, P., Double Proton Transfer in 7-Azaindoline" J. Eisai London Research Labs. Ltd. PHYS. CHEM. B, vol. 104, 2000, pages 7818-7829, London WC1E 6BT (GB) XP002280766 • KHAN, A., • SANDERSON, P. E. J.; ET AL.: "Azaindoles: Eisai London Research Labs. Ltd. Moderately Basic P1 Groups for Enhancing the London WC1E 6BT (GB) Selectivity of Thrombin Inhibitors" BIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 13, 2003, pages 795-798, XP002290822

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 633 750 B1

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Description

[0001] The present invention provides a novel substituted azaindoline intermediate and a method for its synthesis. The invention further provides the use of the intermediate in the manufacture of 5-substituted 7-azaindolines and 5- 5 substituted 7-azaindoles. [0002] The 7-azaindole system forms the core structure of various pharmaceutically important substances such as antitumour agents, ligands of melatoninergic receptor, dopamine D 4 receptors, serotonin receptor, 5- HT6 receptor, p38 kinase inhibitors, renin inhibitors, thrombin inhibitors, and antitussive agents. Furthermore, antifungal activity of some 7-azaindoles in plant systems has recently been discovered. 10 [0003] Synthesis and reactivity of 7-azaindoles has recently been extensively reviewed (Merour and Joseph Current Org. Chem. 2001, 5, 471). Functionalization of the 7-azaindole system at position 5 is a fundamental transformation used in the synthesis of melatoninergic ligands and JNK inhibitors. Such functionalization is achieved by initial installation of the atom at position 5, which is considered to be the key step in each of these synthetic routes. However, despite the importance of this process, the most widely used approach to introduce the bromine atom in position 5 15 requires dibromide (2) as an intermediate (Scheme 1). The two bromine atoms at C(3) serve as temporary and expensive temporary protection against bromination of the five-membered ring. [0004] Synthesis of dibromide (2) is troublesome due to the use of large excess of perbromide (4 equivalents) and difficult workup procedure. If direct conversion of (1) into (3) is undertaken, large excess of bromine - usually over 12 molar equivalents is required. 20

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35 [0005] Furthermore, th