USRE41008E1 - Method for producing 5-aryl nicotinaldehydes - Google Patents

Method for producing 5-aryl nicotinaldehydes Download PDF

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USRE41008E1
USRE41008E1 US11/371,308 US37130801A USRE41008E US RE41008 E1 USRE41008 E1 US RE41008E1 US 37130801 A US37130801 A US 37130801A US RE41008 E USRE41008 E US RE41008E
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monosubstituted
ocf
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Andreas Bathe
Heinz Bokel
Ralf Knieriemen
Christoph Muermann
Thomas Keil
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Merck Patent GmbH
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Definitions

  • the invention relates to a process for the preparation of 5-arylnicotinaldehydes by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex, characterized in that the molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands.
  • 5-Arylnicotinaldehydes are important intermediates and end products in industrial organic chemistry.
  • Appropriately substituted derivatives are, in particular, valuable intermediates in the synthesis of highly value-added end products or are themselves such end products, in particular for crop protection, such as, for example, fungicides, insecticides, herbicides or pesticides, or for the preparation of substances having high pharmaceutical activity.
  • Production of the corresponding 5-arylnicotinaldehydes on an industrial scale makes highly economical and environmentally friendly preparation necessary.
  • the 5-arylnicotinaldehydes are distinguished by an unexpected sensitivity to oxidation and disproportionation. Consequently, the methods described in the literature for the preparation of these compounds by chemoselective reduction of aromatic acids or their esters or by oxidation of aromatic alcohols cannot be applied to a satisfactory extent to the corresponding 5-arylnicotinic acid or the corresponding 5-arylnicotinyl alcohol.
  • the object on which the invention is based was to discover a process for the preparation of 5-arylnicotinaldehydes which makes inexpensive and environmentally friendly access even to this class of substances possible without the above-mentioned disadvantages.
  • 5-arylnicotinaldehydes can be obtained by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex if a molar ratio between palladium and ligand of from 1:5 to 1:15 is observed in the case of monodentate ligands and of from 1:2.5 to 1:7.5 in the case of bidentate ligands.
  • the measure according to the invention also allows the use of other carboxylic anhydrides, which are less expensive than pivalic anhydride and which, without an excess of ligand, give only a low yield of product.
  • the invention thus relates to a process for the preparation of 5-arylnicotinaldehydes by reduction of the corresponding 5-arylnicotinic acids by catalytic hydrogenation in the presence of carboxylic anhydrides in which the catalyst used is a palladium/ligand complex, characterized in that the molar ratio between palladium and ligand is from 1:5 to 1:15 in the case of monodentate ligands and from 1:2.5 to 1:7.5 in the case of bidentate ligands.
  • the invention preferably relates, in particular, to a process for the preparation of 5-arylnicotinaldehydes of the formula I in which
  • the invention furthermore relates to the use of the 5-arylnicotinaldehydes for the preparation of N-alkylated amines by reaction of the 5-arylnicotinaldehydes with primary amines to give the corresponding imines, followed by reduction.
  • reaction of the aldehydes with the amines and also the reduction of the imines can be carried out by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart, or Organikum [Organic Chemistry], 17 th Edition, VEB Deutscher Verlag dermaschineen, Berlin, 1988), to be precise under reaction conditions which are known and are suitable for the said reactions.
  • the compounds of the formula I are, in particular, highly suitable for the preparation of N-alkylated amines of the formula X: In which
  • R is H, an alkyl or alkoxy group having 1 to 10 carbon atoms or an alkenyl group having 2 to 7 carbon atoms.
  • A is preferably a phenyl group, a phenyl group which is monosubstituted or disubstituted by F, a 4-fluorophenyl group, a pyrimidyl, a pyridyl, a pyrazyl or a pyridazyl group, in particular a 4-fluorophenyl group.
  • branched wing groups R may be of importance. Branched groups of this type generally contain not more than two chain branches. R is preferably a straight-chain group or a branched group having not more than one chain branch.
  • the radical R may also be optically active organic radical containing one or more asymmetrical carbon atoms.
  • the process according to the invention is very particularly suitable for the preparation of the aldehydes of the formulae I1 to I10:
  • R 1 and R 2 independently of one another, are as defined for R and are in particular F, —CF 3 , —OCF 3 , —OCHF 2 or H, and are very particularly preferably F.
  • 5-arylnicotinaldehydes which can be prepared by the process according to the invention are the compounds of the formulae I1, I2, I9 and I10.
  • the 5-arylnicotinic acids used as starting materials for the process according to the invention are either known or are prepared by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for said reactions.
  • use can also be made of variants which are known per se, but are not mentioned here in greater detail.
  • the 5-arylnicotinic acids are preferably prepared by Suzuki coupling (N. Miyaura, A. Suzuki, Chem. Rev. 95, 2457 (1995)) by reacting 5-bromonicotinic acid, an alkyl 5-bromonicotinate, 5-bromonicotinyl alcohol or the alkylcarboxylic acid ester thereof with the corresponding arylboronic acids under known reaction conditions to give a compound of the formula II, III, IV or V:
  • A is as defined above, and R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, subsequently hydrolysing the ester of the formulae III or V by conventional processes to give the free acid of the formula II or the alcohol of the formula IV, and oxidizing the alcohol of the formula IV by conventional methods to give the acid of the formula II.
  • R 3 is preferably methyl or ethyl, in particular methyl.
  • the invention likewise relates to the novel compounds of the formulae I, II, III and IV.
  • the reaction in the process according to the invention for the preparation of 5-arylnicotinaldehydes is simple to carry out, with the 5-arylnicotinic acids in question preferably being hydrogenated in organic solvents, at temperatures of from 10 to 180° C., preferably at from 20 to 150° C. and very particularly preferably from at 40 to 100° C., and at a pressure of from 1 to 150 bar, preferably at from 1.5 to 120 bar and in particular at from 2 to 100 bar, with addition of a carboxylic anhydride in the presence of a palladium/ligand complex.
  • the solvents used for the process according to the invention are preferably ethers, such as, for example, diethyl ether or tetrahydrofuran, ketones, such as, for example, acetone, hydrocarbons, such as, for example, toluene, benzene, hexane or heptane, amides, such as, for example, dimethylformamide or N-methylpyrrolidone, or acid anhydrides, such as, for example, acetic anhydride.
  • ethers such as, for example, diethyl ether or tetrahydrofuran
  • ketones such as, for example, acetone
  • hydrocarbons such as, for example, toluene, benzene, hexane or heptane
  • amides such as, for example, dimethylformamide or N-methylpyrrolidone
  • acid anhydrides such as, for example, acetic anhydride.
  • ethers in particular tetrahydrofuran.
  • Mixtures of the said solvents can likewise be used.
  • the amount of solvent is not crucial; from 10 g to 500 g of solvent can preferably be added per g of the compound of the formula II to be reacted.
  • the duration of the reaction depends on the selected reaction conditions. In general, the reaction duration is from 0.5 hour to 10 days, preferably from 1 to 24 hours.
  • the end of the reduction to the aldehyde is determined by suitable analytical methods, for example HPLC, and the reduction is interrupted.
  • the hydrogenation catalyst used is a palladium/ligand complex.
  • Preferred ligands are the following: triphenylphosphine, diphenylphosphinoferrocene, tri-o-tolylphosphine, 1,2-bis (diphenylphosphino)ethane, 2,4-bis(diphenylphosphino) pentane, bis(diphenylphosphino)methane and tris(tertbutyl) phosphine. It is likewise possible to use mixtures of the ligands.
  • Palladium is generally employed as a palladium compound, from which the corresponding catalyst is prepared by addition of ligands. It is likewise possible to employ palladium as a complex having the correct stoichiometric composition to which, in accordance with the invention, an amount of ligand is added so that the ligand excess defined in accordance with the invention is observed.
  • Suitable palladium compounds employed in the presence of the excess of ligand are preferably the following: Tetrakis (triphenylphosphine)palladium(0), dibenzylidenepalladium (0) complexes, palladium on carbon (preferably 5%), PdCl 2 dppf, palladium acetate/tri-O-tolylphosphine complex, Pd(0)*dppe, Pd(0)*dppp, Pd(0)*dppm, Pd(COD) Cl 2 , PdCl 2 , Pd(OAc) 2 and PdBr 2 .
  • the molar ratio between palladium and the acid to be hydrogenated is preferably from 1:500 to 1:200, in particular from 1:50 to 1:100.
  • the molar ratio between palladium and ligand is from 1:5 to 1:15, preferably from 1:5 to 1:10, in particular from 1:5 to 1:6, in the case of monodentate ligands and from 1:2.5 to 1:7.5, preferably from 1:2.5 to 1:5, in particular from 1:2.5 to 1:3, in the case of bidentate ligands.
  • Non-solvent anhydrides used for the process are preferably pivalic anhydride, acetic anhydride, isobutyric anhydride, 5-norbornene-2,3-dicarboxylic anhydride, 1,2,3,6-tetrahydrophthalic anhydride and naphthalene-1,8-dicarboxylic anhydride.
  • the molar ratio between the carboxylic anhydride and the 5-arylnicotinic acid is preferable from 10:1 to 8:1, preferably from 7:1 to 6:1 and in particular from 5:1 to 2:1.
  • the compounds of the formula I can be obtained, after removal of the solvent, by conventional work-up steps, such as, for example, addition of water to the reaction mixture and extraction. It may be advantageous, for further purification of the product, subsequently to carry out a distillation or crystallization.
  • the compounds of the formula I which can be prepared by the process according to the invention are important intermediates or end products in industrial organic chemistry.
  • Appropriately substituted derivatives are, in particular, valuable intermediates in the synthesis of highly value-added end products or are such end products themselves, for crop protection, such as, for example, fungicides, insecticides, herbicides or pesticides, or for the preparation of substances having high pharmaceutical activity.
  • 5-Bromo-3-acetoxymethylpyridine is reacted with 4-fluorobenzeneboronic acid as described in Example 1.
  • the 5-(4-fluorophenyl)pyridin-3-ylmethyl acetate obtained is saponified by conventional methods and subsequently oxidized to give 5-(4-fluorophenyl)nicotinic acid.
  • 5-(4-Fluorophenyl)nicotinic acid is dissolved in tetrahydrofuran in an autoclave, three equivalents of the respective acid anhydride are added, and the mixture is rendered inert by repeatedly injecting a protective gas.
  • a solution of Pd(OAc) 2 and PPh 3 in tetrahydrofuran is added in a countercurrent of protective gas, and the reaction solution is subsequently hydrogenated at 80° C. under a hydrogen pressure of 8 bar with stirring. Conventional work-up gives the aldehyde in a yield of 98%.

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  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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DE10120619A1 (de) * 2001-04-26 2002-10-31 Merck Patent Gmbh 2-(5-(4-Fluorphenyl)-3-pyridylmethylaminomethyl-chroman
DE102004028561A1 (de) * 2004-06-15 2006-01-05 Merck Patent Gmbh Verfahren zur Herstellung von 5-Arylnicotinaldehyden
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JPH0748370A (ja) * 1993-06-25 1995-02-21 Fujisawa Pharmaceut Co Ltd 新規複素環化合物
US5585388A (en) * 1995-04-07 1996-12-17 Sibia Neurosciences, Inc. Substituted pyridines useful as modulators of acetylcholine receptors
WO1997005131A1 (en) 1995-08-02 1997-02-13 J. Uriach & Cia. S.A. New carboxamides with antifungal activity
WO1997032873A1 (en) 1996-03-09 1997-09-12 Pfizer Research And Development Company, N.V./S.A. Quinoxalinediones
EP0905458A2 (de) 1997-09-24 1999-03-31 Robert Bosch Gmbh Gasbeheizter Wassererhitzer mit Abgasüberwachungseinrichtung
WO1999020617A1 (en) 1997-10-21 1999-04-29 Active Biotech Ab Antiinflammatory thiadiazolyl ureas which act as lfa-1 and mac-1 inhibitors
WO1999042446A1 (fr) 1998-02-19 1999-08-26 Kowa Co., Ltd. Composes cycliques d'amide
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US6703509B2 (en) 2004-03-09
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KR100742767B1 (ko) 2007-07-25
MEP6108A (xx) 2010-02-10
NO20023702D0 (no) 2002-08-06
RU2256653C2 (ru) 2005-07-20
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