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WO2018234184A1 - Procédé de préparation de quinoléines 2,3,4-trisubstituées - Google Patents

Procédé de préparation de quinoléines 2,3,4-trisubstituées Download PDF

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Publication number
WO2018234184A1
WO2018234184A1 PCT/EP2018/065969 EP2018065969W WO2018234184A1 WO 2018234184 A1 WO2018234184 A1 WO 2018234184A1 EP 2018065969 W EP2018065969 W EP 2018065969W WO 2018234184 A1 WO2018234184 A1 WO 2018234184A1
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PCT/EP2018/065969
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English (en)
Inventor
Sergii Pazenok
Jean-Pierre Vors
Frédéric LEROUX
Armen PANOSSIAN
Fallia ARIBI
Original Assignee
Bayer Aktiengesellschaft
Cnrs Centre National De La Recherche Scientifique
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Publication of WO2018234184A1 publication Critical patent/WO2018234184A1/fr

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Classifications

    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • 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
    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the invention relates to a process for preparing 2,3,4-trisubstituted quinolines from ketimines and haloalkylamino reagents.
  • Quinolines are important precursors for pharmaceuticals and agrochemicals [(a) J. Sloop, J. Phys. Org. Chem., 2009, 22, 1 10-117; (b) A. R. Surrey and H. F. Hammer, J. Am. Chem. Soc., 1946, 68, 1 13-116; (c) W. Jonhson and B. G. Buetl, J. Am. Chem. Soc., 1952, 74, 4513-4516; (d) J. Mulero, G. Martinez, J. Oliva, S. Cermeno, J. M. Cayuela, P. Zafrilla, A. Martinez-Cacha and A. Barba, Food Chem, 2015, 180, 25-31].
  • the Combes reaction starting from e-diketones and anilines is an important method for the synthesis of quinolines ⁇ Chem. Ber., 1896, 29, 2456).
  • the Combes reaction has only limited importance for the preparation of quinolines containing perhaloalkyl groups in position 2 and 4.
  • J.Sloop et al. J. Fluorine Chem., 2002, 118, 135-147) described an application of the Combes synthesis using anilines and fluorinated ⁇ -diketones in polyphosphoric acid.
  • the fluorinated yfi-diketones usually prepared via Claisen condensation are hardly accesible.
  • R 1 is Ci-Ce-haloalkyl or Ci-Ce-alkyl
  • R 3 is Ci-C6-haloalkyl or -Ci-C6-haloalkyl-Ci-C6-haloalkoxy, R 4 is H or halogen, and R 5 is Ci-Ce-alkyl, comprising the step of (a) reacting an enamine of the formula (II)
  • X is F or CI
  • R 6 and R 7 are each independently selected from Ci-C6-alkyl and Cs-Cs-cycloalkyl, in the presence of a Lewis acid.
  • R 1 is CH 2 F, CF 2 H, CF 3 , C 2 F 5 or CH 3
  • R 3 is CF 2 H, CF 3 , CFHC1, CFHCF 3 or CFHOCF3
  • R 4 is selected from H and halogen
  • X is F
  • R 6 , R 7 are each independently selected from CH 3 and C2H5.
  • R 1 is CF 2 H, CF 3 or CH 3 ,
  • R 3 is CF 2 H, CFHC1 or CFHOCF 3
  • R 4 is H or Cl
  • R 6 , R 7 are CH 3 .
  • Ci-Ce-alkyl saturated, straight-chain or branched hydrocarbyl radicals having 1 to 6 carbon atoms, for example (but not limited to) methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2- methylpropyl, 1 , 1 -dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2- dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl,
  • Ci-Ce-alkoxy saturated, straight-chain or branched alkoxy radicals having 1 to 6 carbon atoms, for example (but not limited to) methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1 -methylpropoxy, 2- methylpropoxy, 1 , 1 -dimethylethoxy, pentoxy, 1 -methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2- dimethylpropoxy, 1 -ethylpropoxy, 1 , 1 -dimethylpropoxy and 1 ,2-dimethylpropoxy.
  • This definition also applies to -Ci-C6-alkoxy as part of a composite substituent, for example -Ci-C6-haloalkyl-Ci-C6- haloalkoxy, unless defined elsewhere.
  • C3-C8-cycloalkyl monocyclic saturated hydrocarbyl groups having 3 to 8 carbon ring members, for example (but not limited to) cyclopropyl, cyclopentyl and cyclohexyl.
  • Ci-Ce-haloalkyl straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above, for example (but not limited to) -Ci-C3-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichloro fluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro- 2-flu
  • Ci-Ce-haloalkoxy straight-chain or branched alkoxy groups having 1 to 6 carbon atoms (as specified above), where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as specified above, for example (but not limited to) -Ci-C3-haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloro fluoromethoxy, dichloro fluoromethoxy, chlorodifluoromethoxy, 1 - chloroethoxy, 1 -bromoethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2,2-difluor
  • the compound of the formula (la) may be further converted to the compound of the formula (lb) by means of a conventional saponification method, for example using an aqueous hydroxide solution, such as NaOH or KOH (step b).
  • aqueous hydroxide solution such as NaOH or KOH
  • the carboxylic acid of the formula (lb) may be further converted to the compound of the formula (Ic) by means of a conventional carbamate synthesis, for example by using a Curtius reaction (step c).
  • the carboxylic acid of the formula (lb) may alternatively be converted directly to the compound of the formula (Id) by means of a Curtius reaction and addition of water (step c').
  • the compound of the formula (Ic) may be further converted to the compound of the formula (Id) by cleavage of the N-alkoxycarbonyl group according to methods known in the art (step d, see for example WO 2006/081289).
  • the compound of the formula (Id) may be further converted to the compound of the formula (Ie) by means of a Sandmeyer reaction using a nitrite, such as a -Ci-C i-alkyl nitrite, and CuCN (step e).
  • the reaction is preferably conducted using acetonitrile as solvent.
  • Enamines (II) can be prepared by the condensation of anilines (IV) and acetoacetates (V) according to the literature procedure disclosed in (a) L. Troisi et ah , Tetrahedron, 2013, 69, 3878-3884; (b) I. V. Kutovaya et ah , Eur. J. Org. Chem. , 2015, 30, 6749-6761 ; (c) S. Prakash et ah , J. Fluorine Chem. , 2007, 128, 587-594.
  • Fluoroalkylamino reagents of the formula (III) are commercially available or can prepared in situ, e.g. from amines of the formula -NHR 6 R 7 and haloalkenes.
  • the fluoroalkylamino reagents (III) are first reacted with the Lewis acid [LA] (see Scheme 3), preferably BF3, AICI3, SbCls, SbFs or ZnCL, more preferably BF3 or AICI3, and then the compound of the formula (II) is added, in substance or dissolved in a suitable solvent (cf. WO 2008/022777).
  • LA Lewis acid
  • a suitable solvent cf. WO 2008/022777
  • BF3 as Lewis Acid.
  • BF3 can be used as a gas or as a solution/complex in ether or acetonitrile.
  • reaction time is not critical and may, according to the batch size, be selected within a relatively wide range.
  • Suitable solvents are, for example, aliphatic, alicyclic or aromatic hydrocarbons, for example petroleum ether, n-hexane, n-heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin, and halogenated hydrocarbons, for example chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, 1,2- diethoxyethane or anisole; nitriles such as acetonitrile, propionitrile, n- or isobuty
  • the solvents are removed and the product is isolated by purification on flash chromatography.
  • TFEDMA 1,1,2,2-tetrafluoro-NN-dimethylethan-l -amine
  • TFEDMA a solution of TFEDMA was activated by adding BF3*Et20 (1.2 equiv., 0.628 mL, 4.96 mmol) in a solution of TFEDMA (1.2 equiv., 0.58 mL, 4.96 mmol) in dry MeCN (9 mL) and stirred for 15 min. Then a solution of ethyl-3-[(4-chlorophenyl)amino]-4,4-difluorobut-2-enoate (II. d) (1 equiv., 1.52 g, 4.13 mmol) in dry MeCN (9 mL) was slowly added to this mixture via syringe.
  • ethyl-3-[(4-chlorophenyl)amino]-4,4-difluorobut-2-enoate II. d
  • TFEDMA a solution of TFEDMA was activated by adding BF3*Et20 (1.2 equiv., 0.191 mL, 1.51 mmol) in a solution of TFEDMA (1.2 equiv., 0.176 mL, 1.51 mmol) in dry MeCN (2.70 mL) and stirred for 15 min. Then a solution of ethyl-4,4,4-trifluoro-3-(phenylamino)but-2-enoate (Il.b) (1 equiv., 406 mg, 1.26 mmol) in dry MeCN (2.70 mL) was slowly added to this mixture via syringe.
  • ethyl-4,4,4-trifluoro-3-(phenylamino)but-2-enoate Il.b
  • l,l,2-Trifluoro-2-(trifluoromethoxy)ethene (1 equiv., 0.4 mL, 3.62 mmol) was liquefied in a Schlenk apparatus under argon at -78 °C.
  • Dimethylamine 2 M in THF (1 equiv., 2 M, 1.81 mL, 3.62 mmol) was added slowly via syringe at -78 °C. After 5 min, cold bath was replaced by water bath and the mixture was stirred for 15 min.
  • BF3*Et20 (1 equiv., 0.46 mL, 3.62 mmol) was added via syringe and the reaction mixture was stirred for 30 min.
  • TFEDMA a solution of TFEDMA was activated by adding BF3*Et20 (1.2 equiv., 0.224 mL, 1.77 mmol) in a solution of TFEDMA (1.2 equiv., 0.207 mL, 1.77 mmol) in dry MeCN (3.20 mL) and stirred for 15 min. Then a solution of ethyl-3-(phenylamino)but-2-enoate (II. c) (1 equiv., 0.466 g, 1.47 mmol) in dry MeCN (3.20 mL) was slowly added to this mixture via syringe. After 15 min at room temperature, the mixture was heated at 50 °C for 19 h.
  • ethyl-3-(phenylamino)but-2-enoate II. c
  • Step e The Sandmeyer reaction 2,4-Bis(difluoromethyl)quinoline-3-carbonitrile (Ie-1)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de quinoléines 2,3,4-trisubstituées à partir de cétimines et de réactifs haloalkylamino.
PCT/EP2018/065969 2017-06-22 2018-06-15 Procédé de préparation de quinoléines 2,3,4-trisubstituées WO2018234184A1 (fr)

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EP17290083.9 2017-06-22

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4925944A (en) * 1989-03-21 1990-05-15 American Cyanamid Company Process for the preparation of o-carboxypyridyl- and o-carboxyquinolylimidazolinones
WO2006081289A2 (fr) 2005-01-25 2006-08-03 Glaxo Group Limited Agents antibacteriens
WO2008022777A2 (fr) 2006-08-25 2008-02-28 Bayer Cropscience Ag Procédé de fabrication de dérivés d'acide 3-dihalogénométhyl-pyrazol-4-carboxylique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4925944A (en) * 1989-03-21 1990-05-15 American Cyanamid Company Process for the preparation of o-carboxypyridyl- and o-carboxyquinolylimidazolinones
WO2006081289A2 (fr) 2005-01-25 2006-08-03 Glaxo Group Limited Agents antibacteriens
WO2008022777A2 (fr) 2006-08-25 2008-02-28 Bayer Cropscience Ag Procédé de fabrication de dérivés d'acide 3-dihalogénométhyl-pyrazol-4-carboxylique

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
A. R. SURREY; H. F. HAMMER, J. AM. CHEM. SOC., vol. 68, 1946, pages 113 - 116
CHEM. BER., vol. 29, 1896, pages 2456
EZZAT RAFIEE ET AL: "CsHPWOheteropoly salts catalyzed quinoline synthesisFriedlnder reaction", CHINESE CHEMICAL LETTERS, vol. 22, no. 3, 22 December 2010 (2010-12-22), pages 288 - 291, XP028127772, ISSN: 1001-8417, [retrieved on 20100922], DOI: 10.1016/J.CCLET.2010.09.036 *
F. ARIBI ET AL., ORG. CHEMISTRY. FRONT, vol. 3, 2016, pages 1392 - 1415
I. V. KUTOVAYA ET AL., EUR. J. ORG. CHEM., vol. 30, 2015, pages 6749 - 6761
J. MULERO; G. MARTINEZ; J. OLIVA; S. CERMENO; J. M. CAYUELA; P. ZAFRILLA; A. MARTINEZ-CACHA; A. BARBA, FOOD CHEM, vol. 180, 2015, pages 25 - 31
J. SLOOP, J. PHYS. ORG. CHEM., vol. 22, 2009, pages 110 - 117
J.SLOOP ET AL., J. FLUORINE CHEM., vol. 118, 2002, pages 135 - 147
L. TROISI ET AL., TETRAHEDRON, vol. 69, 2013, pages 3878 - 3884
REDDY B V SUBBA ET AL: "Chitosan-SO3H: an efficient, biodegradable, and recyclable solid acid for the synthesis of quinoline derivatives via Friedländer annulation", TETRAHEDRON LETTERS, vol. 54, no. 43, 17 August 2013 (2013-08-17), pages 5767 - 5770, XP028731277, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2013.07.165 *
S. PRAKASH ET AL., J. FLUORINE CHEM., vol. 128, 2007, pages 587 - 594
SLOOP J C: "Quinoline formation via a modified Combes reaction: examination of kinetics, substituent effects, and mechanistic pathways", JOURNAL OF PHYSICAL ORGANIC CHEMISTRY, WILEY, GB, vol. 22, no. 2, 2009, pages 110 - 117, XP002755965, ISSN: 0894-3230, [retrieved on 20080826], DOI: 10.1002/POC.1433 *
W. JONHSON; B. G. BUETL, J. AM. CHEM. SOC., vol. 74, 1952, pages 4513 - 4516

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