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WO2008074474A1 - 4-hydroxypyridines substituées - Google Patents

4-hydroxypyridines substituées Download PDF

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Publication number
WO2008074474A1
WO2008074474A1 PCT/EP2007/011129 EP2007011129W WO2008074474A1 WO 2008074474 A1 WO2008074474 A1 WO 2008074474A1 EP 2007011129 W EP2007011129 W EP 2007011129W WO 2008074474 A1 WO2008074474 A1 WO 2008074474A1
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substituted
butyl
group
alkyl
isopropyl
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Hans-Ulrich Reissig
Jyotirmayee Dash
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Freie Universitaet Berlin
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Freie Universitaet Berlin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

Definitions

  • the present invention relates to substituted 4-hydroxypyridines as well as their derivatives, a process for producing substituted 4-hydroxypyridines and their derivatives as well as the use of these compounds.
  • pyridine derivatives can be used as anticoagulants, antihistamines, antiseptics, antiarrythmic agents and antirheumatic agents.
  • various attempts have been undertaken to chemically synthesize pyridines (cf. e.g., Konakahara et al., 1999, J. Chem. Soc, Perkin Transp. 1, 2803-2806; Lee et al., 1990, J. Org. Chem., 55, 2964-2967; Hedge S., 1991, J. Org.
  • the present invention has the task of making available a new synthesis path for the production of substituted 4-hydroxypyridines. Furthermore, the present invention has the task of making a synthesis available that supplies the named compounds in a high yield.
  • the present invention has the task of making available a synthesis that starts from readily accessible initial substances and can therefore be carried out very economically. Furthermore, the present invention has the task of making available new, highly-substituted pyridines.
  • R 1 is selected from the group comprising substituted and non-substituted alkyl, substituted and non-substituted aryl, substituted and non-substituted heteroaryl, substituted and non- substituted alkenyl, substituted and non-substituted alkinyl,
  • R 2 is selected from the group comprising H, substituted and non-substituted alkyl, substituted and non-substituted aryl, in particular substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl,
  • R is selected from the group comprising H, substituted and non-substituted alkyl, substituted and non-substituted cycloalkyl, substituted and non-substituted aryl, substituted and non-substituted heteroaryl, especially substituted and non-substituted Q- Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated alkyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, and
  • R 4 is selected from the group comprising substituted and non-substituted alkyl, especially substituted and non-substituted C I -C I2 alkyl, perhalogenated alkylsulfonyl, especially perhalogenated C J -C I2 alkylsulfonyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, e.g., trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrobenzene- sulfonyl, methanesulfonyl, 2,2,2-trifluoroethanesulfonyl, with the steps: a) Conversion of 1 ,3-diketones (1) with ammonia to a compound (2) of an ⁇ , ⁇ - unsaturated
  • the process comprises compounds, in which
  • R' is selected from the group comprising substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted phenyl, substituted and non-substituted C 5 -C 6 heteroaryl, substituted and non-substituted naphthyl, substituted and non-substituted C 7 -Ci 8 alkylphenyl, substituted and non-substituted C 3 -C 7 cycloalkyl, substituted and non-substituted C 5 -C 7 cycloalkenyl, halogenated alkyl or aryl.
  • R 2 is selected from the group comprising H, substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted phenyl, substituted and non-substituted C 7 -Ci 8 alkylphenyl.
  • R 3 is selected from the group comprising H, substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated CpCi 2 alkyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, substituted and non-substituted phenyl, substituted and non- substituted heteroaryl, substituted and non-substituted naphthyl, substituted and non- substituted C 7 -Cj 8 alkylphenyl, substituted and non-substituted C 3 -C 7 cycloalkyl, and
  • R 4 is selected from the group comprising substituted and non-substituted Ci-Cj 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, perhalogenated alkylsulfonyl, especially perhalogenated Cj-Ci 2 alkylsulfonyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, e.g., trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p- nitrobenzenesulfonyl, methanesulfonyl, 2,2,2-trifluoroethanesulfonyl.
  • the halogenide is selected from the group consisting of F, Cl, Br and I
  • R 1 is selected from the group comprising substituted and non-substituted Ci-C] 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted phenyl, substituted and non-substituted naphthyl,
  • R 2 is selected from the group comprising H, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t- butyl, substituted and non-substituted phenyl,
  • R 3 is selected from the group comprising H, substituted and non-substituted CpC 4 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated C 1 -C 9 alkyl, especially CF 3 , C 2 F ⁇ , C 3 F 7 , C 4 F 9 , C 5 Fn, C 6 F] 3 , C 7 Fi 5 , C 8 Fj 7 , and C 9 F 19 wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, substituted and non-substituted phenyl, substituted and non-substituted naphthyl, substituted and non-substituted pyridinyl, and R 4 is selected from the group comprising substituted and non-substituted C 1 -C4 alkyl.
  • halogenide is selected from the group consisting of F, Cl, Br and I, especially F, e.g., trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p- bromobenzenesulfonyl, p-nitrobenzenesulfonyl, methanesulfonyl, 2,2,2- trifluoroethanesulfonyl.
  • F e.g., trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p- bromobenzenesulfonyl, p-nitrobenzenesulfonyl, methanesulfonyl, 2,2,2- trifluoroethanesulfonyl.
  • One embodiment comprises compounds, characterized in that
  • R 1 is selected from the group comprising methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl,
  • R 2 is selected from the group comprising H, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t- butyl, phenyl
  • R 3 is selected from the group comprising H, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t- butyl, CF 3 , C 2 F 5 , C 3 F 7 , C 4 F 9 , C 5 Fn, C 6 Fi 3 , C 7 Fi 5 , C 8 F n , and C 9 F 19.
  • phenyl, halogenated phenyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, substituted and non-substituted pyridinyl, and
  • R 4 is selected from the group comprising methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p- bromobenzenesulfonyl, p-nitrobenzenesulfonyl, methanesulfonyl, 2,2,2- trifluoroethanesulfonyl.
  • One embodiment comprises compounds, characterized in that
  • R 1 is methyl
  • the process comprises compounds, wherein R 2 is H.
  • the process comprises compounds, wherein R 3 is phenyl, C 5 F 5 or pyridinyl. In one embodiment the process comprises compounds, wherein R 4 is trifluoromethanesulfonyl or nonafluorobutanesulfonyl.
  • the process comprises compounds, wherein the conversion carried out in step a) is carried out with the aid of silica gel.
  • the process comprises compounds, wherein the halogenide or anhydride reacted in step b) is produced by activating a carboxylic acid.
  • the process comprises compounds, wherein the activation of the carboxylic acid is an in situ activation selected from the carbodiimide method, the Mitsunobu reaction und the Yamaguchi esterif ⁇ cation.
  • the carbodiimide method, the Mitsunobu reaction and the Yamaguchi esterification are organic synthesis steps that are well known to those skilled in the art and are described more precisely, e.g., in the following references (Handbook of Reagents for Organic Synthesis, Activating Agents and Protecting Groups (eds. A. J. Pearson, W. J. Roush), John Wiley & Sons, Chichester 1999; pages 133-136, 402-404, 454-464; D. L. Huges, Organic Reactions, 1992, 42, 335).
  • the process comprises compounds, wherein the carboxylic acid used for the conversion to a halogenide or anhydride in step b) is reacted with a halogenation agent, the halogenation agent being a chlorination agent or a bromination agent, especially SOCl 2 , SOBr 2 , POCl 3 , POBr 3 .
  • the process comprises compounds, wherein the chlorination agent is SOCl 2 .
  • the process comprises compounds, wherein the condensation agent used for the ring formation is an alkylsilyltriflate, especially trialkylsilyltriflate (alkyl 3 SiOTf), preferably trimethylsilyltriflate (Me 3 SiOTf) in the presence of a base, especially of a tertiary amine, especially triethylamine (Et 3 N) or diisopropylethylamine (/-Pr 2 NEt).
  • alkylsilyltriflate especially trialkylsilyltriflate (alkyl 3 SiOTf), preferably trimethylsilyltriflate (Me 3 SiOTf) in the presence of a base, especially of a tertiary amine, especially triethylamine (Et 3 N) or diisopropylethylamine (/-Pr 2 NEt).
  • the process comprises compounds, wherein the acid used for the production of the halogenide converted in step d) is selected from the group comprising p- toluenesulfonic acid, p-bromobenzenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, nonafluorobutanesulfonic acid or 2,2,2- trifluoroethanesulfonic acid, and wherein the halogenation agent is a chlorination agent or a bromination agent, especially SOCl 2 , SOBr 2 , POCl 3 , POBr 3 .
  • the acid used for the production of the halogenide converted in step d) is selected from the group comprising p- toluenesulfonic acid, p-bromobenzenesulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid, trifluorome
  • the process comprises compounds, wherein the halogenide used in step d) is nonafluorobutanesulfonylfluoride (NfF).
  • NfF nonafluorobutanesulfonylfluoride
  • a coupling reaction is carried out in the presence of a palladium catalyst following step d), wherein OR 4 is a sulfonic acid ester, preferably a sulfonic acid ester as defined above.
  • One embodiment of the process is characterized in that the coupling reaction is carried out as a Suzuki coupling, Sonogashira coupling, Negishi coupling, Stille coupling and/or Heck coupling.
  • R 1 is selected from the group comprising substituted and non-substituted alkyl, substituted and non-substituted aryl, substituted and non-substituted heteroaryl, substituted and non- substituted alkenyl, substituted and non-substituted alkinyl,
  • R 2 is selected from the group comprising substituted and non-substituted alkyl, substituted and non-substituted aryl, especially substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl,
  • R 3 is selected from the group comprising H, substituted and non-substituted alkyl, substituted and non-substituted cycloalkyl, substituted and non-substituted aryl, substituted and non- substituted heteroaryl, especially substituted and non-substituted Ci-Cj 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated alkyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F,
  • R 4 is selected from the group comprising substituted and non-substituted alkyl, especially substituted and non-substituted Ci-Cj 2 alkyl, perhalogenated alkylsulfonyl, especially perhalogenated C J -C I 2 alkylsulfonyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and 1, especially F, e.g., trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrobenzene- sulfonyl, methanesulfonyl, 2,2,2-trifluoroethanesulfonyl.
  • the halogenide is selected from the group consisting of F, Cl, Br and 1, especially F, e.g., trifluoromethanesulfonyl
  • R 1 is selected from the group comprising substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted phenyl, substituted and non-substituted C 5 -C 6 heteroaryl, substituted and non-substituted naphthyl, substituted and non-substituted C 7 -Ci 8 alkylphenyl, substituted and non-substituted C 3 -C 7 cycloalkyl, substituted and non-substituted C 5 -C 7 cycloalkenyl, halogenated alkyl or aryl,
  • R 2 is selected from the group comprising H, substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted phenyl, substituted and non-substituted C 7 -Ci 8 alkylphenyl,
  • R 3 is selected from the group comprising H, substituted and non-substituted Ci-Cj 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated Ci-Ci 2 alkyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, substituted and non-substituted phenyl, substituted and non- substituted C 7 -Ci 8 alkylphenyl, substituted and non-substituted heteroaryl, substituted and non-substituted naphthyl, substituted and non-substituted C 7 -C] 8 alkylphenyl, substituted and non-substituted C 3 -C 7 cycloalkyl, and
  • R 4 is selected from the group comprising substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, perhalogenated alkylsulfonyl, especially perhalogenated Ci-Ci 2 alkylsulfonyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, e.g., trifiuoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrobenzene- sulfonyl, methanesulfonyl, 2,2,2-trifluoroethanesulfonyl.
  • the halogenide is selected from the group consisting of F, Cl, Br
  • R 1 is selected from the group comprising substituted and non-substituted Ci-Ci 2 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted phenyl, substituted and non-substituted naphthyl,
  • R 2 is selected from the group comprising H, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t- butyl, substituted and non-substituted phenyl,
  • R 3 is selected from the group comprising H, substituted and non-substituted C 1 -C 4 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated Ci-C 9 alkyl, especially CF 3 , C 2 F 5 , C 3 F 7 , C 4 F 9 , C 5 F n , C 6 F] 3 , C 7 F] 5 , C 8 F) 7 , and C 9 F] 9.
  • halogenide is selected from the group consisting of F, Cl, Br and I, especially F, substituted and non-substituted phenyl, substituted and non-substituted naphthyl, substituted and non-substituted pyridinyl, and
  • R 4 is selected from the group comprising substituted and non-substituted C 1 -C 4 alkyl, especially methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, substituted and non-substituted perhalogenated Ci-C 9 alkylsulfonyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, e.g., trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl, p-nitrobenzene- sulfonyl, methanesulfonyl, 2,2,2-trifluoroethanesulfonyl.
  • the halogenide is selected from the group consisting of F, Cl, Br and I, especially F,
  • R 1 is selected from the group comprising methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl,
  • R 2 is selected from the group comprising H, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t- butyl, phenyl
  • R 3 is selected from the group comprising H, methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t- butyl, CF 3 , C 2 F 5 , C 3 F 7 , C 4 F 9 , C 5 F n , C 6 Fi 3 , C 7 F ) 5 , C 8 Fi 7 , and C 9 Fj 9, phenyl, halogenated phenyl, wherein the halogenide is selected from the group consisting of F, Cl, Br and I, especially F, substituted and non-substituted pyridinyl, and
  • R 4 is selected from the group comprising methyl, ethyl, ⁇ -propyl, isopropyl, n-butyl, t-butyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, p- bromobenzenesulfonyl, p-nitrobenzene-sulfonyl, methanesulfonyl, 2,2,2- trifluoroethanesulfonyl.
  • One embodiment is characterized in that R is methyl.
  • R 2 is H.
  • R 3 is phenyl, C 5 F 5 or pyridinyl.
  • R is trifluoromethanesulfonyl or nonafluorobutanesulfony 1.
  • the tasks of the invention are also solved by using a compound of the present invention as initial material for the production of medicinal drugs and/or plant protective agents and/or for molecular electronics and/or for optical applications.
  • the pyridinyl derivatives produced at first can be made accessible for further reactions (alkylation, alkenylation, alkinylation, arylation, etc.) by the conversion of the 4-OH group into a better leaving group such as, e.g., triflate, nonaflate, tresylate, etc.
  • the synthesis in accordance with the invention can be readily carried out and yields the desired pyridine derivatives in high yields.
  • ,alkyl designates hydrocarbon radicals, preferably hydrocarbon radicals with 1-24 C atoms (Ci-C 24 ), more preferably hydrocarbon radicals with Ci-C 12 atoms (C 1 -Ci 2 alkyl).
  • substituted designates the substitution of one or more atoms, as a rule H atoms, by one or more of the following substituents: halogen, hydroxy, protected hydroxy, oxo, protected oxo, C 3 -C 7 cycloalkyl, phenyl, naphthyl, amino, protected amino, mono-substituted amino, protected mono- substituted amino, di-substituted amino, guanidino, protected guanidino, a heterocyclic ring, a substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, CpCi 2 alkoxy, Ci-Ci 2 acyl, C 1 -C 12 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamid, protected carboxamid, N-(Ci-Ci 2 alky
  • Examples for the above-named substituted alkyl groups include 2-oxo-prop-l-yl, 3-oxo-but-l- yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxy methyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-aminopropyl, 1 -chloroethyl, 2-chloroethyl, 1-bromoethyl, 2- bromoethyl, 1-fluoroethyl, 2-fluoroethyl, l-iodoethyl,
  • cycloalkyl comprises the groups cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl und cycloheptyl.
  • Ci-Ci 2 alkyl designates radicals such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, s-butyl, t-butyl, amyl, t-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like.
  • Preferred “Ci-Ci 2 alkyl” groups are methyl, ethyl, isobutyl, s-butyl and isopropyl.
  • Examples for the above-named substituted alkenyl groups include styrolyl, 3-chloro-propen- 1-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, l-cyano-buten-3-yl and the like.
  • the stereometry is not essential and all stereoisomers can be used for a particular substituted alkenyl.
  • the concept "alkinyl”, as it is used here, designates a group with the formula R-C ⁇ C-, in particular a group with the formula R -C ⁇ C-, as defined above, in particular "C 2 -Ci 2 alkinyl".
  • C 2 -Ci 2 alkinyls include: ethinyl, propinyl, 2-butinyl, 2-pentinyl, 3-pentinyl, 2- hexinyl, 3-hexinyl, 4-hexinyl, 2-heptinyl, 3-heptinyl, 4-heptinyl, 5-heptinyl, as well as octinyl, noninyl, decinyl, undecinyl, dodecinyl, as well as diines and triines of straight and branched alkyl chains.
  • Those alkinyl groups are preferred in which the triple bond is terminal so that if the alkinyl group occurs in the compounds in accordance with the invention, the triple bond comes to be located in the resulting pyridine product directly on the pyridine ring, that is, one of the two carbon atoms participating in the triple bond is directly connected to the pyridine ring via a single bond.
  • aryl designates aromatic hydrocarbon groups, e.g., phenyl, benzyl, naphthyl, anthryl.
  • aryl groups are aryl groups, as defined above, that are substituted with one or several substituents.
  • heterocyclic compound or “heterocyclic ring” designates facultatively substituted five-member to eight-member rings that have 1 to 4 heteroatoms such as, e.g., oxygen, sulfur and/or nitrogen, especially nitrogen, either alone or in association with sulfur or oxygen ring atoms.
  • heteroatoms such as, e.g., oxygen, sulfur and/or nitrogen, especially nitrogen, either alone or in association with sulfur or oxygen ring atoms.
  • These five-member to eight-member rings can be saturated or completely unsaturated or partially unsaturated but completely saturated rings are preferred.
  • Preferred heterocyclic rings include morpholino, piperidinyl, piperazinyl, 2-amino-imidazoyl, tetrahydrofurano, pyrrolo, tetrahydrothiophen-yl, hexylmethylene imino and heptylmethylene imino.
  • Highly substituted pyridines can be produced from readily available starting substances that subsequently make possible the access to further interesting, highly substituted pyridine derivatives. These pyridine derivatives can then serve as initial substances for medicinal drugs, plant protection agents. They can also be used in molecular electronics and/or for optical applications.
  • the process of the present invention is characterized in particular in that it was able to reduce the previously current synthesis process with at least 6 synthesis steps for the production of highly substituted pyridine compounds to a distinctly simplified three-stage synthesis process.
  • the resulting savings of cost and time make the process of the present invention highly attractive.
  • FIG. 1 shows the synthesis of the pyridine derivative (4)
  • Figure 2 shows the synthesis of the pyridine derivative 4-methoxy-6-methyl-[2,2']bipyridinyl
  • reaction mixture was compounded with a saturated solution of NaHCO 3 and extracted with CH 2 Cl 2 (3 x 10 ml), dried with Na 2 SO 4 and concentrated until dry.
  • the enamide 3 (406 mg, 2.00 mmol) was dissolved in 1 ,2-dichloroethane (10 ml). Then, /-Pr 2 NEt (1.38 ml, 8.00 mmol) and trimethylsilyltriflate (1.81 ml, 10.00 mmol) were added at 0 0 C.
  • the reaction vessel was allowed to warm up to room temperature, heated 3 days under reflux and compounded with a saturated solution Of NH 4 Cl (10 ml). After extraction with dichloromethane (3 x 10 ml) the combined organic phases were dried with Na 2 SO 4 and concentrated in order to obtain the raw pyridinol.
  • the enamide 10 (293 mg, 1.00 mmol) was dissolved in 1 ,2-dichloroethane (5 ml) in a closed tube and cooled to 0 0 C. Then, /-Pr 2 NEt (0.69 ml, 4.00 mmol) und trimethylsilyltriflate (0.90 m, 5.00 mmol) were added. The mixture was warmed to room temperature, heated 3 days under reflux and compounded with a saturated solution Of NH 4 Cl (10 ml). After extraction with CH 2 Cl 2 (3 x 10 ml) the combined organic phases were dried with Na 2 SO 4 and concentrated in order to obtain the crude pyridinol.
  • the pyridinol 11 (100 mg, 0.36 mmol) was dissolved in THF (5 ml) and NaH (42 mg, 60% in mineral oil, 1.08 mmol) was added under an atmosphere of argon.
  • Nonafluorobutanesulfonylfluoride (0.13 ml, 0.72 mmol) was added drop by drop at room temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des 4-hydroxypyridines substituées ainsi que leurs dérivés, un procédé de production de 4-hydroxypyridines substituées et de leurs dérivés et l'utilisation de ces composés.
PCT/EP2007/011129 2006-12-18 2007-12-18 4-hydroxypyridines substituées Ceased WO2008074474A1 (fr)

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WO2011161612A1 (fr) 2010-06-22 2011-12-29 Basf Se Procédé de préparation de 4-hydroxypyridines
US11889833B2 (en) 2022-01-14 2024-02-06 Enko Chem, Inc. Protoporphyrinogen oxidase inhibitors
US12503439B2 (en) 2023-04-21 2025-12-23 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain

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Publication number Priority date Publication date Assignee Title
WO2010000409A2 (fr) * 2008-07-03 2010-01-07 Bayer Schering Pharma Aktiengesellschaft Composés et procédés pour la production d’agents radiopharmaceutiques

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WO2011161612A1 (fr) 2010-06-22 2011-12-29 Basf Se Procédé de préparation de 4-hydroxypyridines
CN102947270A (zh) * 2010-06-22 2013-02-27 巴斯夫欧洲公司 制备4-羟基吡啶的方法
US8716487B2 (en) 2010-06-22 2014-05-06 Basf Se Process for preparing 4-hydroxypyridines
CN102947270B (zh) * 2010-06-22 2015-04-08 巴斯夫欧洲公司 制备4-羟基吡啶的方法
US11889833B2 (en) 2022-01-14 2024-02-06 Enko Chem, Inc. Protoporphyrinogen oxidase inhibitors
US12302900B2 (en) 2022-01-14 2025-05-20 Enko Chem, Inc. Protoporphyrinogen oxidase inhibitors
US12503439B2 (en) 2023-04-21 2025-12-23 Vertex Pharmaceuticals Incorporated Heteroaryl compounds for the treatment of pain

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