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WO2013157018A1 - Procédé de préparation de la structure centrale d'antibiotiques appartenant aux classes quinolone et naphthyridone - Google Patents

Procédé de préparation de la structure centrale d'antibiotiques appartenant aux classes quinolone et naphthyridone Download PDF

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Publication number
WO2013157018A1
WO2013157018A1 PCT/IN2013/000199 IN2013000199W WO2013157018A1 WO 2013157018 A1 WO2013157018 A1 WO 2013157018A1 IN 2013000199 W IN2013000199 W IN 2013000199W WO 2013157018 A1 WO2013157018 A1 WO 2013157018A1
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vii
hydroxy
mmol
ibx
alkoxy
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PCT/IN2013/000199
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English (en)
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Kannoth Manheri Muraleedharan
Victor Napoleon John
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Indian Institute Of Technology Madras
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to a process for preparing therapeutically important quinolone and naphthyridone derivatives.
  • the quinolone and naphthyridone skeletons are integral part of the structure of antibiotics such as Ciprofloxacin (I), Levofloxacin (II) and Gemifloxacin (III) shown in Figure.1.. .They ..are active .against both gram-positive. and gram-negative bacteria and are currently in clinical use to treat different types of infections.
  • Ciprofloxacin and Levofloxacin together generate ⁇ 3 billion US dollars per year in US alone show the high demand of this class of antibiotics.
  • Compounds from this class have recently been shown to possess promising anti-HIV-1 integrase, anti-cancer, antituberculosis and anti-malarial activities. This has resulted in a renewed interest in the syn
  • Compound VI Figure 2 with activity against HIV-1 and HIV-2 in both acutely and chronically infected cells.
  • Existing anti-HIV drugs such as Maraviroc, Ritonavir, Tenofovir target viral proteins such as Reverse Transcriptase, protease, and intergrase (De Clercq, . E. "New . developments in anti-HIV chemotherapy” Biochi . m. Biophys. Acta, Mo!. Basis Dis. 2002, 1587, 258-275; De Clercq, E. "Antiviral therapy for human immunodeficiency virus infections” Clin Microbiol Rev. 1995, 8, 200-39; Opar, A. "New HIV drug classes on the horizon” Nat. Rev. Drug Discovery 2007, 6, 258-259).
  • the 6-aminoquinolones on the other hand are believed to interfere with the trans-activation step of transcription which represents a new therapeutic strategy against HIV.
  • This invention relates to a novel process for the synthesis of quinolone and naphthyridone derivatives of the general formula VII through an intermediate of the general formula X.
  • Ri represents alkyl, arylalkyl, aryl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl groups etc. Represents ester, cyano, amide, aldehyde, keto, phosphonate, sulfoxide, sulphone groups etc.
  • R 3 represents hydrogen, F, CI, Br, I, C C 4 alkyl, C C 4 alkoxy, cyano, amino or - NHR-i, -N(Ri)2 groups etc.
  • R 4 represents -N0 2 , -CN, -CORL Phenyl, -F, -NH 2 , -NHRi, -N(Ri) 2 etc.
  • R 5 represents halogen, hydrogen, cyclic secondary amines, -NH 2 , -NHRi, -N(Ri) 2 etc.
  • R 4 and R 5 can also be part of a mono- or polycyclic ring systems.
  • A represents N, CH, CF, CCI, COCH 3 , CCN etc.
  • the process includes the following steps,
  • R 2 , R 3 , R 5 and A each are as defined under the formula (VII) and X represents I, Br, CI, F, OTs, OTf;
  • R 4 can be H or Ri if A represents a hetero-atom such as N. If A is CH, R 4 need to be an electron withdrawing substituent such as
  • Wan Pyo Hong and Lee developed a synthetic route towards the intermediate 21 from suitably substituted aromatic aldehyde 19 and methyl propiolate in presence of tetra butyl ammonium iodide and ZrCI 4 as shown below (Synthesis 2006, 6, 963- 68).
  • the product 20 on oxidation with Dess-Martin periodinane gave the intermediate 21 in 83-88
  • 4-Quinolones can also be constructed from precursors such as 51 , 55 and 57 under organometallic catalysis as shown below (Scheme 12).
  • Kalinin et al. (Tetrahedron Lett, 1992, 33, 373-376) and Sigeru Torii et al., (Tetrahedron 1993, 49, 6773) synthesized 2-substituted 4-quinolone 54 using palladium catalysed carbonylative coupling of o-iodoanilines with terminal arylacetylenes as shown in Scheme 12-(1).
  • Tollari et al. J. Chem. Soc, Chem. Commun.
  • This invention relates to a process for the synthesis of compounds of the general formula VII
  • the substituent Ri can be H, Ci-C 20 alkyl, C1-C20 aryl alkyl, C 3 -C 6 cycloalkyl, C -C 6 heterocycloalkyl, d-C 2 o alkoxy, -NH 2 , -NHRL -N(RI) 2 , C 2 -CI 0 alkenyl, C3-C1 0 alkynyl, phenyl, 5 to 6-membered heteroaryl, bicyclic aromatic or heteroaromatic rings, biaryls or heteroatom substituted biaryls, optionally substituted with one or more of, including, but not limited to, the substituents, such as I, Br, CI, F, lower alkyl groups such as C 1 -C5, alkoxy, cyano, nitro, amino.
  • the term 'alkyl' denotes branched or straight-chain hydrocarbons, or hydrocarbon chains with saturated/unsatu rated rings in-between or at the terminus.
  • R 2 represents an electron withdrawing group such as -COOR1, -CN, -N0 2 , - CONH 2 , -CONHR 1 , -CON(Ri) 2 , -CHO, -COR 1 , -COSEt, -PO(OEt) 2 , -PO(OMe) 2 , - S0 2 Ph, -S0 3 Ph and SOPh wherein Ri is same as defined above.
  • R 3 represents all the substituents included under Ri and others such as F, CI, Br, I, C -C 4 alkoxy, -CORi , CN, N0 2 , NH 2 , -NHR 1 ( -N(R ) 2 .
  • R ⁇ represents all the substituents included under Ri. This also includes -NO2, - CN , -CORL aryl, heteroaryl, F, CI, Br, I, -NH 2 , -NH R-, , -N(Ri) 2 .
  • R5 represents all the substituents included under Rv This also includes I, Br, CI, F, C1 -C10 alkoxy, cyano, NH 2) -N H R1 , -N(Ri) 2 , or a compound with open chain, mono-, bi- or tricyclic saturated or unsaturated system with at least one ring with a nucleophilic atom such as nitrogen.
  • R 4 and R 5 can also be part of a mono- or polycyclic ring systems which are part of non-aromatic, aromatic and heteroaromatic compounds which is optionally substituted at one or more of the ring atoms with substituents mentioned under Ri and others such as F, CI, Br, I, C C 4 alkoxy, -CORT , CN, N0 2> NH 2 , -NHR-i, - N(Ri) 2 .
  • A can be CH, CF.. CCI, CBr,. CI..CCN, C-Ri, N, COCH 3 , C-N0 2 , C-NH 2r C-NHR1-, C-NiR ,.
  • the process for the preparation of VII involves reaction of Baylis-Hillman adducts (VIII) with various amines (IX) to effect aza-Michael addition and S ⁇ r cyclization and subsequent oxidation of the intermediate X to get the target skeleton VII (Scheme 16).
  • Step a) This involves heating a solution containing a mixture of the Baylis-Hillman adduct (VIII) and the desired amine (IX) in a polar sovent (eg. NMP) in presence of a base (eg. Et 3 N) to get the 4-hydroxy-1 ,2,3,4-tetrahydroquinoline or 4- hydroxy-1 ,2,3,4-tetrahydro-1 ,8-naphthyridine derivative (X, scheme 16).
  • a polar sovent eg. NMP
  • a base eg. Et 3 N
  • the solvent used in step a) include but not limited to, N-methylpyrrolidinone (NMP), ⁇ , ⁇ -dimethylformamide (DMF), N,N-dimethyl acetamide, nitromethane, acetonitrile, methanol, tertiary butanol, dimethylsulfoxide (DMSO), methyl tert- butyl ether, _dimethoxyethane (DME), tetrahydrofuran (THF),.
  • NMP N-methylpyrrolidinone
  • DMF ⁇ , ⁇ -dimethylformamide
  • DME dimethylsulfoxide
  • DME methyl tert- butyl ether
  • THF tetrahydrofuran
  • NMP is the solvent of choice considering the efficiency and rate of Michael addition and S N Ar cyclisation steps.
  • the bases used in this reaction includes, but not limited to amines such as triethyl amine, Diisopropyl ethyl amine (DIPEA), N-alkylpyrrolidines, N-alkyl morpholines, N-alkylpiperidines, 1 ,8-Diazabicycloundec-7-ene (DBU), 1 ,4- diazabicyclo[2.2.2]octane (DABCO), 1 ,5-Diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, DMAP ( ⁇ , ⁇ -dimethylaminopyridine), pyrimidine, N-alkylpyrrole, N- alkylindole, and N-alkylimidazole.
  • Other bases include potassium carbonate, sodium carbonate, cesium carbonate, sodium tert-butoxide and potassium tert- butoxide.
  • Step b) This step involves the oxidation of the intermediate X to the target skeleton VII.
  • the solvent used in step b includes but not limited to the solvents mentioned under step (a). Other possible solvents are water, and ionic liquids such as [bmim]BF 4 and [bmim]PF 6 .
  • Alcoholic solvents such as methanol should be avoided due to their sensitivity to oxidation; acetonitrile was found superior to others in terms of the yields of products shown here.
  • the preferred temperature of the reaction for the examples presented here ranged between 70-80 °C.
  • the oxidising reagent can be selected from the group comprising of, but not limited to 2-iodoxybenzoic acid (IBX), Oxone and 2-iodoxybenzoic acid (IBX), Oxone and 2- iodo benzoic acid, Oxone and iodosobenzoic acid (IBA), N-methylmorpholine-N- oxide (NMO) and 2-iodoxybenzoic acid (IBX), 4-methoxypyridine-N-oxide (MPO) and 2-iodoxybenzoic acid (IBX), 2-iodoxybenzenesulfonic acid (IBS), 2- iodobenzenesulfonic acid and Oxone, sodium or potassium 2- iodobenzenesulfonate and Oxone; Dess-Martin periodinane or IBX substituted on the.
  • IBX 2-iodoxybenzoic acid
  • IBX Oxone and 2-iodoxybenzoic acid
  • IBA Oxone and
  • Table 1 List of quinolones and benzonaphthyridones synthesised
  • Methyl 2-((2-chloro-5-nitrophenyl)(hydroxy)methyl)acrylate (0.2 g, 0.74 mmol) was reacted with butylamine (0.108 g, 0.146 mL, 1.48 mmol) in presence of triethylamine (0.2 mL, 1.47 mmol) in NMP (2 mL) at 75 °C for 3 h and the resulting 4-hydroxy- 1,2,3,4-tetrahydroquinoline derivative was oxidized using IBX (456 mg, 1.63 mmol) by heating the mixture for 12 h according to the general procedure discussed above to get Vll-F (186 mg, 83% yield) as a pale yellow crystalline solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des dérivés de quinolone et de naphthyridone représentés par la formule générale VII, et un procédé pour les préparer à partir d'adduits de Baylis-Hillman obtenus à partir d'aldéhydes aromatiques et hétéroaromatiques et d'amines d'intérêt. Après une addition d'aza-Michael et une cyclisation SNAr, le dérivé de 4-hydroxy-1,2,3,4-tétrahydroquinoline ou de 4-hydroxy-1,2,3,4-tétrahydro-1,8-naphthyridine est soumis à une oxydation pour obtenir le squelette de quinolone ou de naphthyridone en une étape avec des rendements bons à excellents.
PCT/IN2013/000199 2012-04-18 2013-03-26 Procédé de préparation de la structure centrale d'antibiotiques appartenant aux classes quinolone et naphthyridone WO2013157018A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US10457679B2 (en) 2015-09-17 2019-10-29 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
CN111018778A (zh) * 2019-12-30 2020-04-17 杭州师范大学 一种喹诺酮类衍生物及其制备方法和应用

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DE2155113A1 (fr) 1970-11-06 1972-05-10
CA1167840A (fr) 1980-09-02 1984-05-22 Isao Hayakawa Derives de benzoxazine
CA1218067A (fr) 1981-10-29 1987-02-17 Klaus Grohe Acides 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- piperazine-quinoline-3-carboxyliques; preparation et agents antibacteriens renfermant ces acides
US5004745A (en) 1989-01-16 1991-04-02 Laboratoire Roger Bellon Benzo[1,8]naphthyridine derivatives, their preparation and the compositions which contain them
EP0538101A1 (fr) * 1991-10-10 1993-04-21 Laboratoire Roger Bellon Procédé de préparation de benzo b naphtyridines
US5639886A (en) 1993-12-10 1997-06-17 Bayer Aktiengesellschaft One-pot process for the preparation of 3-quinolonecarboxylic acid derivatives
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DE2155113A1 (fr) 1970-11-06 1972-05-10
CA1167840A (fr) 1980-09-02 1984-05-22 Isao Hayakawa Derives de benzoxazine
CA1218067A (fr) 1981-10-29 1987-02-17 Klaus Grohe Acides 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- piperazine-quinoline-3-carboxyliques; preparation et agents antibacteriens renfermant ces acides
US5004745A (en) 1989-01-16 1991-04-02 Laboratoire Roger Bellon Benzo[1,8]naphthyridine derivatives, their preparation and the compositions which contain them
EP0538101A1 (fr) * 1991-10-10 1993-04-21 Laboratoire Roger Bellon Procédé de préparation de benzo b naphtyridines
US5639886A (en) 1993-12-10 1997-06-17 Bayer Aktiengesellschaft One-pot process for the preparation of 3-quinolonecarboxylic acid derivatives
US5914401A (en) 1997-03-11 1999-06-22 Apotex, Inc. Methods for the manufacture of quinolone carboxylic acids derivatives and intermediates thereof
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9670163B2 (en) 2005-12-28 2017-06-06 Vertex Pharmaceuticals Incorporated Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
US9701639B2 (en) 2014-10-07 2017-07-11 Vertex Pharmaceuticals Incorporated Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator
US10457679B2 (en) 2015-09-17 2019-10-29 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
US10882858B2 (en) 2015-09-17 2021-01-05 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
US11613539B2 (en) 2015-09-17 2023-03-28 Astrazeneca Ab Imidazo[4,5-c]quinolin-2-one compounds and their use in treating cancer
CN111018778A (zh) * 2019-12-30 2020-04-17 杭州师范大学 一种喹诺酮类衍生物及其制备方法和应用
CN111018778B (zh) * 2019-12-30 2020-11-06 杭州师范大学 一种喹诺酮类衍生物及其制备方法和应用

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