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European Patent Office of Opposition to That Patent, in Accordance with the Implementing Regulations (19) TZZ _T (11) EP 2 666 772 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 409/04 (2006.01) C07D 209/16 (2006.01) 01.03.2017 Bulletin 2017/09 C07D 209/18 (2006.01) C07D 209/38 (2006.01) (21) Application number: 13173141.6 (22) Date of filing: 12.12.2003 (54) Synthesis of amines and intermediates for the synthesis thereof Synthese von Aminen und Zwischenverbindungen für die Synthese davon Synthèse d’amines et intermédiaires pour leur synthèse (84) Designated Contracting States: • DEMERSON C A ET AL: "ETODOLIC ACID AND AT BE BG CH CY CZ DE DK EE ES FI FR GB GR RELATED COMPOUNDS CHEMISTRY AND HU IE IT LI LU MC NL PT RO SE SI SK TR ANTIINFLAMMATORY ACTIONS OF SOME POTENT DI-AND TRISUBSTITUTED (30) Priority: 20.12.2002 EP 02406128 1,3,4,9-TETRAHYDROPYRANO not 3,4-B 3/4 INDOLE-I-ACETIC ACIDS", JOURNAL OF (43) Date of publication of application: MEDICINALCHEMISTRY, AMERICAN CHEMICAL 27.11.2013 Bulletin 2013/48 SOCIETY, vol. 19, no. 3, 1 March 1976 (1976-03-01), pages391-395, XP000940626, ISSN: (62) Document number(s) of the earlier application(s) in 0022-2623, DOI: 10.1021/JM00225A010 accordance with Art. 76 EPC: • HARUYASU ET ALL: "Possible metabolic 03799560.2 / 1 572 647 Intermediatesfrom IAA to beta-acid in Rice Bran", AGR. BIOL. CHEM., vol. 40, no. 12, 1976, pages (73) Proprietor: BASF SE 2465-2470, XP002714693, 67056 Ludwigshafen am Rhein (DE) • SOLL R M ET AL: "Multigram preparation of 1,8-diethyl-7-hydroxy-1,3,4,9-tetrahydropy (72) Inventors: rano[3,4-b]indole-1-acetic acid, a phenolic • Berens, Ulrich metabolite of the analgesic and antiinflammatory 79589 Binzen (DE) agent etodolac", THE JOURNAL OF ORGANIC • Dosenbach, Oliver CHEMISTRY, AMERICAN CHEMICAL SOCIETY 79415 Bad Bellingen (DE) [NOT]ETC. , US, vol. 53, no. 12, 1 January 1988 • Sprenger, Daniel (1988-01-01), pages 2844-2847, XP002244796, 4058 Basel (CH) ISSN: 0022-3263, DOI: 10.1021/JO00247A037 • KENIJIROTADERA, KATSUAKI ORITE: "Isolation (74) Representative: BASF IP Association and Structure of a New Vitamine B6 Conjugate in BASF SE Rice Bran", JOURNAL OF FOOD SCIENCE, vol. ZRX-C6 56, no. 1, 1991, pages 268-269, XP002714694, 67056 Ludwigshafen (DE) (56) References cited: WO-A1-02/28831 WO-A1-95/09858 WO-A2-02/062290 US-A- 3 577 430 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 2 666 772 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 666 772 B1 • DATABASECA [Online] CHEMICAL ABSTRACTS • REVIAL, GILBERT ET AL: "Aromatization of SERVICE, COLUMBUS, OHIO, US; KATO, 1,6,7,7a-Tetrahydro-2H-indol-2-ones by a Novel TADAHIRO ET AL: "In vitro oxidation of Process. Preparation of Key-Intermediate Methyl indoleacetic acid by crude enzyme from rice husk 1-Benzyl-5-methoxy-1H-indole-3-acetate and the - an aspect of preharvest sprouting", Syntheses of Serotonin, Melatonin, and XP002714695, retrieved from STN Database Bufotenin", JOURNAL OF ORGANIC accession no. 1998:187348 & KATO, TADAHIRO CHEMISTRY, vol. 67, no. 7, 2002, pages ET AL: "In vitro oxidation of indoleacetic acid by 2252-2256, XP002714697, ISSN: 0022-3263, DOI: crude enzyme from rice husk - an aspect of 10.1021/jo0110597 preharvestsprouting", HETEROCYCLES ( 1998 ), • E.M. BECCALLI ET AL.: "Synthesis of [a] 47(1), 497-500 CODEN: HTCYAM; ISSN: Annulated Carbazoles from indol-2,3-dione", 0385-5414, 1998, TETRAHEDRON, vol. 49, no. 21, 1993, pages • GARDEN, SIMON J. ET AL: "A versatile synthetic 4741-4758, XP002714698, methodology for the synthesis of tryptophols", • KOZIKOWSKI A P ET AL: JOURNAL OF TETRAHEDRON10.1016/S0040-4020(02)01048-7, MEDICINALCHEMISTRY, AMERICAN CHEMICAL vol. 58, no. 42, 2002, pages 8399-8412, SOCIETY, US, vol. 36, no. 20, 1 January 1993 XP002393288, ISSN: 0040-4020 (1993-01-01), pages 2908-2920, XP002118394, • DATABASECA [Online] CHEMICAL ABSTRACTS ISSN: 0022-2623, DOI: 10.1021/JM00072A010 SERVICE, COLUMBUS, OHIO, US; CANOIRA, LAUREANO ET AL: "Synthesis of indole and oxindole derivatives from N-.beta.-alkenyl-o-chloroanilines and N-.beta.-alkenyl-o-chloroanilides with tetrakis(triphenylphosphine)nickel(0) and zerovalent pyridine-nickel complexes", XP002714696, retrieved from STN Database accession no. 1989:94911 & CANOIRA, LAUREANO ET AL: "Synthesis of indole and oxindole derivatives from N-.beta.-alkenyl-o-chloroanilines and N-.beta.-alkenyl-o-chloroanilides with tetrakis(triphenylphosphine)nickel(0) and zerovalent pyridine-nickel complexes", JOURNAL OF CHEMICAL RESEARCH, SYNOPSES ( 1988 ), (2), 68-9 CODEN: JRPSDC; ISSN: 0308-2342, 1998, 2 EP 2 666 772 B1 Description Summary of the invention 5 [0001] The present invention provides a novel process (= method) for the manufacture of derivatives, especially precursors, of tryptamine, horsfiline or coerulescine, novel partial reactions and novel intermediates. The derivatives or precursors of tryptamine, horsfiline and coerulescine are useful e.g. in the pharmaceutical area. Background of the Invention 10 Derivatives of tryptamine 1 [0002] 15 20 have been synthesized from substituted anilines. Some pertinent anilines are prepared from 4-nitro benzyl chloride 25 (precursors for anti migraine pharmaceuticals such as Sumatriptan 2 see: DE 3,320,521, US 4,816,470, Almotriptan 3 see: Res. Discl. 1998, 412, 1088, Rizatriptan 4 see: EP 0497512A2) or Zolmitriptan 5 from 4-nitro phenyl alanine see: WO 91/18897. 30 35 40 Scheme 1 Synthesis of aniline precursors for tryptamine derivatives (R = the para-substituents of the aniline moiety in 3, 4, 5 or 6) [0003] A variety of strategies have been disclosed for the conversion of the anilines2, 3, 4 or 5 into the related 45 tryptamine derivative 1. In the most common approach (scheme 2), the aniline A is converted into the corresponding phenyl hydrazine B. This is then reacted with a 4-halogeno-butyraldehyde derivative C (e.g. the dimethyl acetal (see: US 4,816,470) or the sodium sulfite addition product (see: EP 462 837 A2 or US 5,103,020)) or with a derivative of 4- amino butyraldehyde to give tryptamine D. Methylation of the amine of D provides the corresponding drug H. Alternatively, aniline A may be converted into indole E. A variety of pathways for the subsequent conversion of E into H is disclosed 50 in US 5,037,845. 55 3 EP 2 666 772 B1 5 10 15 20 25 Scheme 2. Synthesis of tryptanes from their aniline precursors [0004] One important problem regarding these approaches is the conversion of aniline A into phenyl hydrazine B. The reduction of the diazonium salt derived from A has been performed using tin(II)chloride in a three to five-fold excess. A 30 range of environmentally more suitable reducing agents has been identified, and is claimed in patent application WO 01/34561. [0005] For a detailed account of problems in the preparation of the phenyl hydrazine that is derived from2 and its transformation into Sumatriptan see: Heterocycles 1998, 48, 1139. Similar problems can be expected for phenyl hydra- zines that are derived from anilines 3, 4, and 5. Thus, the use of α-keto-δ-valerolactone as the carbonyl component for 35 the Fischer-cyclisation has been suggested as an alternative, see: SK 280586B (Applicant: QUMICA SINT S A (ES); VITA INVEST, Publication date 2000-4-10). 40 45 Scheme 3: Alternative Carbonyl compounds for the Fischer cyclisation [0006] A quite different approach to synthesize Sumatriptan also requires aniline 2, but the preparation of the phenyl hydrazine is avoided, see: Heterocycles 2000, 53, 665. Here, the diazonium salt from 2 is reacted with a β-ketocarboxylic acid ester, and the formed hydrazone is cyclised to the indole 2-carboxylic acid which is decarboxylated to a derivative of 1. 50 55 4 EP 2 666 772 B1 Scheme 4: Alternative to the preparation of a phenyl hydrazone (synthesis of the N,N-dimethylpropyl-malonic acid ethyl ester is inconvenient) [0007] A major problem of the Fischer indolisation is that frequently only low yields of the indole are obtained due to 5 the lack of stability of the product under the rather strongly acidic reaction conditions. Moreover, a problem of the Grandberg indolisation is that the reductive di-methylation of the primarily formed tryptamine in an alternative way is prone to low yields as side reactions such as formation of carbazoles and methylation of the indole nitrogen can take place. A solution to both of these problems is provided by using a derivative of N,N-dimethyl-4-aminobutyraldehyde in a modified Fischer indolisation protocol, see: J. Org. Chem. 1994, 59, 3738. 10 [0008] In all synthesis variants for derivatives of tryptamine 1 presented so far, the nature of the final product is determined early at the aniline stage. The final product is then obtained through the identical steps of hydrazine synthesis and Fischer indole cyclisation with all the described limitations. The present invention describes a route to late common intermediatesfor the synthesisof derivativesof tryptamine suchas 1which avoids both the synthesisof phenylhydrazones and variations of the Fischer indolisation. 15 [0009] The reaction of isatin (or a derivative) with malonic acid in acetic acid, either in the presence or absence of sodium acetate, furnishes the quinolone carboxylic acid 6 instead of the expected product 7, see J. Chem. Soc. 1926, 2902 and Chem. Ber. 1914, 47, 354. 20 25 Scheme 5: Condensation of isatin with malonic acid in acetic acid 30 [0010] However, compounds such as 7 are known, and have been prepared for example by reacting isatin or a derivative of it with the Reformatzky reagent of a derivative of bromo acetic acid,see Chem.
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