Patent
Transition metal catalyzed synthesis of 2H-indazoles
| العنوان: | Transition metal catalyzed synthesis of 2H-indazoles |
|---|---|
| Patent Number: | 8,283,476 |
| تاريخ النشر: | October 09, 2012 |
| Appl. No: | 12/644371 |
| Application Filed: | December 22, 2009 |
| مستخلص: | The present invention relates to a process for the regioselective synthesis of compounds of the formula I, [chemical expression included] wherein R0; R1; R2; R3; R4; R5; A1; A2; A3; A4, Q and J have the meanings indicated in the claims. The present invention provides a direct transition metal catalyzed process to a wide variety of multifunctional 2H-indazoles or 2H-azaindazoles of the formula (I) from 2-halo-phenylacetylenes or (2-sulfonato)phenylacetylenes and monosubstituted hydrazines. |
| Inventors: | Halland, Nis (Frankfurt am Main, DE); Nazare, Marc (Frankfurt am Main, DE); Lindenschmidt, Andreas (Frankfurt am Main, DE); Alonso, Jorge (Mannheim, DE); Rkyek, Omar (Kassel, DE); Urmann, Matthias (Frankfurt am Main, DE) |
| Assignees: | Sanofi (Paris, FR) |
| Claim: | 1. A process for preparing a compound of formula I [chemical expression included] and/or all stereoisomeric forms of the compound of formula I, and/or mixtures of these forms in any ratio, and/or a physiologically tolerated salt of the compound of formula I, wherein; A1, A2, A3 and A4 form together with the two carbon atoms in formula I form a benzene, Q is a covalent bond, —(C 1 -C 6)-alkylene, —(C 3 -C 6)-cycloalkyl, phenyl, wherein phenyl is unsubstituted or mono-, di-, tri- or four times substituted independently of one another by R13; —(C 1 -C 4)-alkylene-O—(C 1 -C 4)-alkylene, —(C 1 -C 4)-alkylene-O—; or —(C 5 -C 14)-heteroaryl is selected from pyridyl, quinolinyl, tetrahydropyranyl and thienyl, J is a covalent bond, —(C 1 -C 6)-alkylene, —(C 3 -C 6)-cycloalkyl, phenyl, naphthyl, or —(C 5 -C 14)-heteroaryl, wherein heteroaryl is as defined above, R0, R1, R2, R3 and R4 are independent of one another identical or different and are a) hydrogen atom, b) —(C 1 -C 4)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by R13, c) F, Cl or Br, d) naphthyl, wherein naphthyl is unsubstituted or substituted one, two or three times by R13, e) phenyl, wherein phenyl is unsubstituted or substituted one, two or three times by R13, f) —(C 5 -C 14)-heteroaryl, wherein heteroaryl is as defined above, g) —(C 3 -C 6)-cycloalkyl, h) —O—(C 1 -C 4)-alkyl, i) —CN, j) —OH, k) —C(O)—R10, l) —C(O)—O—R11, m) —C(O)—N(R11)-R12, n) —N(R11)-R12, or p) —O—SO 2 —R13, R5 is a) —(C 1 -C 4)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by R13, b) F, Cl or Br, c) naphthyl, wherein naphthyl is unsubstituted or substituted one, two or three times by R13, d) phenyl, wherein phenyl is unsubstituted or substituted one, two or three times by R13, e) —(C 5 -C 14)-heteroaryl, wherein heteroaryl is as defined above, f) —(C 3 -C 6)-cycloalkyl, g) —O—(C 1 -C 4)-alkyl, h) —CN, i) —OH, j) —C(O)—R10, k) —C(O)—R11, l) —C(O)—N(R11)-R12, m) —N(R11)-R12, or n) —O—SO 2 —R13, R10 is hydrogen atom or —(C 1 -C 4)-alkyl, R11 and R12 are independently of one another identical or different and are hydrogen atom or —(C 1 -C 4)-alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R13, R13 is F, Cl, —CN, —OH, —(C 1 -C 4)-alkoxy, —CF 3 or phenyl, wherein phenyl is unsubstituted or mono-, di- or trisubstituted independently of one another by R14, R14 is F, Cl, —OH, —CN, —CF 3 , —(C 1 -C 4)-alkyl or —(C 1 -C 4)-alkoxy, said process comprises reacting a compound of formula II [chemical expression included] wherein R0, R1, R2, R3, R4, A1, A2, A3, A4 and Q are as defined in formula I and X is Cl, Br, I or tosylate, with a compound of formula III or any salts thereof, [chemical expression included] wherein J and R5 are as defined in formula I, in the presence of a transition metal catalyst selected from the group Pd-halides, Pd-halide complexes, Pd-phosphine complexes and Pd-alkene complexes to give a compound of formula I and optionally the compound of formula I is converted to its physiologically tolerated salt; wherein the compounds of formula I prepared are selected from the group consisting of: 3-Benzyl-2-phenyl-2H-indazole; 2-Phenyl-3-pyridin-2-ylmethyl-2H-indazole; 2-Phenyl-3-(4-trifluoromethyl-benzyl)-2H-indazole; 2-Phenyl-3-(4-methoxy-benzyl)-2H-indazole; 3-(6-Methoxy-naphthalen-2-ylmethyl)-2-phenyl-2H-indazole; N,N-Diisopropyl-2-(2-phenyl-2H-indazol-3-yl)-acetamide; (2-Phenyl-2H-indazol-3-yl)-acetic acid tert-butyl ester; 3-(2,2-Diethoxy-ethyl)-2-phenyl-2H-indazole; 3-(2,2-Dimethyl-propyl)-2-phenyl-2H-indazole; 3-Hexyl-2-phenyl-2H-indazole; 3-Cyclopropylmethyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester; 3-Benzyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester; 3-Cyclopentylmethyl-2-phenyl-2H-indazole-6-carboxylic acid tert-butyl ester; Diethyl-[2-(2-phenyl-2H-indazol-3-yl)-ethyl]-amine; 2-Phenyl-3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-indazole; 3-Benzyl-2-phenyl-5-trifluoromethyl-2H-indazole; 3-Benzyl-6-fluoro-2-phenyl-2H-indazole; 3-Benzyl-4-methyl-2-phenyl-2H-indazole; 3-Benzyl-6-methoxy-2-phenyl-2H-indazole; 3-Benzyl-5-methoxy-2-phenyl-2H-indazole; Toluene-4-sulfonic acid 3-benzyl-2-phenyl-2H-indazol-6-yl ester; 3-Benzyl-2-phenyl-2H-indazole-5-carboxylic acid; 3-Benzyl-2-phenyl-2H-pyrazolo[4,3-c]pyridine; 3-Benzyl-2-(4-methoxy-phenyl)-2H-indazole; 3-Benzyl-2-(4-fluoro-phenyl)-2H-indazole; 3-Benzyl-2-(2-fluoro-phenyl)-2H-indazole; 4-(3-Benzyl-indazol-2-yl)-benzonitrile; 3-Benzyl-2-naphthalen-1-yl-2H-indazole; 3-Benzyl-2-pyridin-4-yl-2H-indazole; 4-(3-Benzyl-indazol-2-yl)-quinoline; 3-Benzyl-2-pyridin-4-yl-2H-indazole-6-carboxylic acid tert-butyl ester; 3-Cyclopropylmethyl-2-pyridin-4-yl-2H-indazole-6-carboxylic acid tert-butyl ester; 3-Benzyl-2-methyl-2H-indazole; 3-Benzyl-2-phenethyl-2H-indazole; 3-Benzyl-2-isopropyl-2H-indazole; 3-Benzyl-2-cyclohexyl-2H-indazole and 3-Benzyl-2-thiophen-2-ylmethyl-2H-indazole-6-carboxylic acid tert-butyl ester. |
| Current U.S. Class: | 5483/625 |
| Patent References Cited: | WO 99/43643 September 1999 |
| Other References: | Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim p. IX of Preface p. 1-15. cited by examiner Steffan, Robert J. et al., “Synthesis and Activity of Substituted 4-(Indazol-4-yl)Phenol as Pathway-Selective Estrogen Receptor Ligands Useful in the Treatment of Rheumatoid Arthritis,” Journal of Medicinal Chemistry (2004), vol. 47, pp. 6435-6438. cited by other Song, Jinhua J. et al., “A Novel Synthesis of 2-Aryl-2H-indazoles via a Palladium-Catalyzed Intramolecular Amination Reaction,” Organic Letters (2000), vol. 2, No. 4, pp. 519-521. cited by other Cacchi, Sandro et al., “Synthesis of N,N-Dialkyl-N′-arylhydrazines via Palladium-Catalyzed N-Arylation by Using N,N-Dialkylhydrazines/2LiCl Adducts,” Organic Letters (2005), vol. 7, No. 8, pp. 1497-1500. cited by other Prikhodko, T.A. et al., “Heterocyclization of o-(arylethynyl)arylhydrazines as a new procedure for the synthesis of substituted 1H- and 2H-indazoles and indoles,” Russian Chemical Bulletin, International Edition (2001), vol. 50, No. 7, pp. 1268-1273. cited by other Kamuro, Y. et al., Chemical Regulation of Plants (1982), vol. 17, pp. 65-70. cited by other |
| Primary Examiner: | Chandrakumar, Nizal |
| Attorney, Agent or Firm: | Scully, Scott, Murphy & Presser, P.C. |
| رقم الانضمام: | edspgr.08283476 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |