ES2350683T3 - Procedimiento para la preparación de aldehídos 5-arilnicotínicos. - Google Patents

Procedimiento para la preparación de aldehídos 5-arilnicotínicos. Download PDF

Info

Publication number
ES2350683T3
ES2350683T3 ES01907409T ES01907409T ES2350683T3 ES 2350683 T3 ES2350683 T3 ES 2350683T3 ES 01907409 T ES01907409 T ES 01907409T ES 01907409 T ES01907409 T ES 01907409T ES 2350683 T3 ES2350683 T3 ES 2350683T3
Authority
ES
Spain
Prior art keywords
fluorophenyl
nicotinic
palladium
acid
aldehyde
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
ES01907409T
Other languages
English (en)
Inventor
Thomas Keil
Andreas Bathe
Heinz Bokel
Ralf Knieriemen
Christoph Murmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Application granted granted Critical
Publication of ES2350683T3 publication Critical patent/ES2350683T3/es
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D213/06—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/22—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 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/26—Radicals substituted by halogen atoms or nitro radicals
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
    • 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
    • C07D213/61—Halogen atoms or nitro radicals
    • 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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • 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
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Procedimiento para la preparación del aldehído 5-(4-fluorofenil)nicotínico por reducción del ácido 5-(4-fluorofenil)nicotínico mediante hidrogenación catalítica en presencia de anhídridos de ácidos carboxílicos, en el que se utiliza como catalizador un complejo de paladio-ligando, caracterizado porque la relación molar de paladio frente a ligando es de 1 a 5 hasta 1 a 15 con ligandos monodentados y de 1 a 2,5 hasta 1 a 7,5 con ligandos bidentados.

Description

La invención se refiere a un procedimiento para la preparación del aldehído 5-(4-fluorofenil)nicotínico por reducción del correspondiente ácido 5-arilnicotínico mediante hidrogenación catalítica en presencia de anhídridos de ácidos carboxílicos, en la que se utiliza como catalizador un complejo de paladio-ligando que se caracteriza por que la relación molar de paladio frente a ligando es de 1 a 5 hasta 1 a 15 con ligandos monodentados y de 1 a 2,5 hasta 1 a 7,5 con ligandos bidentados.
Los aldehídos 5-arilnicotínicos son importantes productos intermedios y finales en la química orgánica industrial. En particular, los derivados sustituidos correspondientes representan productos intermedios valiosos para la síntesis de productos finales de elevada calidad o ellos mismos son tales productos finales, en particular para la protección de plantas, como por ejemplo fungicidas, insecticidas, herbicidas o pesticidas, o para la preparación de sustancias farmacéuticas de elevada eficacia. Una producción de los correspondientes aldehídos 5-arilnicotínicos a gran escala hace necesaria una presentación lo más económica y respetuosa con el medio ambiente posible.
Los aldehídos 5-arilnicotínicos se caracterizan por una inesperada propensión a la oxidación y la dismutación. De esta forma, los métodos descritos en la bibliografía para la preparación de estos compuestos mediante reducción quimioselectiva de ácidos aromáticos o sus ésteres o mediante oxidación de alcoholes aromáticos, no son aplicables de forma satisfactoria al correspondiente ácido 5-arilnicotínico o al correspondiente alcohol 5-arilnicotínico.
Se conocen métodos para la reducción del ácido nicotínico. De este modo, por ejemplo, se describe la reducción del ácido nicotínico mediante hidrogenación catalizada por paladio en el documento Chemistry Letters 1998, 1143-1144. En el procedimiento que allí se da a conocer se trabaja en presencia de anhídrido piválico (anhídrido trimetilacético), por el cual se obtiene con buen rendimiento el correspondiente aldehído a partir del ácido nicotínico no sustituido.
Sin embargo, si en estos procedimientos se utilizan ácidos nicotínicos sustituidos y, en particular, ácidos nicotínicos sustituidos con grupos aromáticos, se producen pérdidas de rendimiento importantes. Además, el uso de ácido piválico implica costes importantes, de forma que este procedimiento no entra en consideración para aplicaciones industriales.
La tarea en la que se basa esta invención consiste en encontrar un procedimiento para la preparación del aldehído 5-(4-fluorofenil)nicotínico que haga posible un acceso rentable y no contaminante sin presentar los inconvenientes anteriormente mencionados.
Sorprendentemente se descubrió que el aldehído 5-(4-fluorofenil)nicotínico se obtiene por reducción del correspondiente ácido 5-arilnicotínico mediante hidrogenación catalítica en presencia de anhídridos de ácidos carboxílicos, en la que se utiliza como catalizador un complejo de paladio-ligando, si se mantiene una relación molar de paladio frente a ligando de 1 a 5 hasta 1 a 15 con ligandos monodentados y de 1 a 2,5 hasta 1 a 7,5 con ligandos bidentados.
Mediante las medidas según la invención también se pueden utilizar otros anhídridos de ácidos carboxílicos más económicos que el anhídrido piválico, que sin el exceso de ligandos sólo producen producto con un bajo rendimiento.
Por lo tanto, el objeto de la invención es un procedimiento para la preparación del aldehído 5-(4-fluorofenil)nicotínico por reducción del correspondiente ácido 5-arilnicotínico mediante hidrogenación catalítica en presencia de anhídridos de ácidos carboxílicos, en la que se utiliza como catalizador un complejo de paladio-ligando que se caracteriza porque la relación molar de paladio frente a ligando es de 1 a 5 hasta 1 a 15 con ligandos mono-dentados y de 1 a 2,5 hasta 1 a 7,5 con ligandos bidentados.
Otro objeto de la invención es el uso del aldehído 5-(4-fluorofenil)nicotínico para la preparación de aminas N-alquiladas mediante transformación del aldehído 5-(4-fluorofenil)nicotínico a las iminas correspondientes con aminas primarias y posterior reducción. La transformación del aldehído con aminas, así como la reducción de la imina se puede llevar a cabo mediante métodos conocidos, como se describe en la bibliografía (por ejemplo, en obras de referencia como Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart o Organikum, ed. 17, VEB Deutscher Verlag der Wissenschaften, Berlin 1988) y bajo condiciones de reacción que son conocidas y adecuadas para las transformaciones mencionadas.
Ya se conocen compuestos parecidos a partir del documento EP 0707007.
Preferentemente se emplea el aldehído de fórmula I, en el que A significa 4fluorofenilo, mediante la transformación con R-cromanamina y reducción de la imina obtenida mediante procedimientos de reducción tradicionales, en particular, mediante hidrogenación catalítica o mediante el uso de borohidruros, como por ejemplo el borohidruro de sodio, para la preparación de (R)-2-[5-(4-fluorofenil)-3-piridilmetilaminometil]-cromano.
El ácido 5-arilnicotínico que se utiliza como producto de partida para el procedimiento según la invención es conocidos o bien se prepara mediante métodos conocidos, como los que se describen en la bibliografía (por ejemplo en obras de referencia como Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart) y bajo condiciones de reacción conocidas y adecuadas para las transformaciones mencionadas. Sin embargo, también se pueden utilizar variantes conocidas, que no mencionaremos aquí.
Preferentemente, el ácido 5-arilnicotínico se prepara mediante un acoplamiento Suzuki (N. Miyaura, A. Suzuki, Chem. Rev. 95, 2457 (1995)) en el que se transforma ácido 5-bromonicotínico, éster alquílico del ácido 5bromonicotínico, alcohol 5-bromonicotínico o su éster alquilcarboxílico en compuestos de fórmula II, III o IV o V con los ácidos arilborónicos correspondientes bajo condiciones de reacción conocidas:
II
III
imagen1
IV
V
R3
en los que A representa 4-fluorofenilo y R3 representa metilo, etilo, n-propilo, iso-propilo, n-butilo, sec-butilo o terc-butilo,
a continuación los ésteres de fórmula III y V se hidrolizan según los procedimientos habituales para obtener el ácido libre de fórmula II o el alcohol de fórmula IV y el alcohol de fórmula IV se oxida al ácido de fórmula II mediante métodos tradicionales.
imagen2
El ácido de fórmula II obtenido de este modo puede utilizarse sin más para el procedimiento según la invención.
Preferiblemente R3 es metilo o etilo, en particular metilo.
El aldehído 5-(4-fluorofenil)nicotínico y el nuevo compuesto de fórmula II son asimismo objeto de la invención.
La realización de la reacción del procedimiento según la invención para la preparación del aldehído 5-(4-fluorofenil)nicotínico es sencilla, hidrogenándose preferentemente el ácido 5-arilnicotínico en disolvente orgánico a temperaturas de 10 a 180 ºC, preferentemente de 20 a 150 ºC y en especial de 40 a 100 ºC, y a una presión de 1 a 150 bares, preferentemente de 1,5 a 120 bares y en particular de 2 a 100 bares, bajo la adición de un anhídrido de ácido carboxílico en presencia de un complejo de paladio-ligando.
Como disolvente del procedimiento según la invención se utilizan preferentemente éteres, como por ejemplo éter dietílico o tetrahidrofurano, cetonas, como por ejemplo acetona, hidrocarburos, como por ejemplo tolueno, benceno, hexano o heptano, amidas, como por ejemplo dimetilformamida, N-metilpirrolidona, o anhídridos de ácido, como por ejemplo anhídrido acético. En especial se prefieren los éteres, en particular el tetrahidrofurano.
Asimismo se pueden utilizar mezclas de los disolventes mencionados.
La cantidad de disolvente no es crítica, preferentemente se pueden añadir de 10 g a 500 g de disolvente por gramo de compuesto de fórmula II que se debe transformar.
La duración de la transformación depende de las condiciones de reacción escogidas. Normalmente la duración de la reacción es de 0,5 horas a 10 días, preferentemente de 1 a 24 horas. En una forma de realización preferida de la invención, el final de la reducción a aldehído se determina mediante métodos de análisis adecuados, por ejemplo HPLC, y se interrumpe la reducción.
Como catalizador de hidrogenación se utiliza un complejo de paladioligando.
Como ligandos se utilizan fosfinas, preferentemente con tres restos orgánicos, en particular restos alquílicos y arílicos. En general se pueden utilizar como ligandos fosfinas monodentadas o bidentadas. Son fosfinas mono-dentadas adecuadas, por ejemplo, (CH3)3P, (C2H5)3P, (C3H7)3P, (C4H9)3P, (C5H11)3P, (C6H13)3P, (C7H15)3P, (C8H17)3P, (C6H11)3P, (C6H5)3P, (CH3C6H4)3P, (C6H5CH2)3P, (C4H9)2(C6H5)P, (C4H9) (C6H5)2P. Las fórmulas químicas anteriores incluyen restos de hidrocarburos ramificados y cíclicos. Como restos de hidrocarburos se prefieren n-propilo, n-butilo, sec-butilo, terc-butilo, así como ciclohexilo. Se prefieren fosfinas con restos idénticos.
Los ligandos bidentados adecuados son por ejemplo:
imagen3 CH2CH2 imagen3 (C6H5)2PCH2(CH2)qP(C6H5)2,
imagen3 PC6H5, CH2CH2 C6H5P
Cy imagen3 imagen3 Cy en la que Cy significa ciclohexilo P-(CH2)q-CH2-P Cy Cy
y q significa 1, 2 o 3, en particular 1 o 3.
Como ligandos se utilizan en especial: trifenilfosfina, difenilfosfinoferroceno, tri-o-tolilfosfina, 1,2-bis(difenilfosfino)etano, 2,4-bis(difenilfosfino)pentano, bis(difenilfosfino)rnetano, tris(terc-butil)fosfina. Asimismo es posible utilizar mezclas de ligandos.
Los compuestos de paladio se pueden utilizar en estado de oxidación II, es decir, en forma de sal, o en estado de oxidación 0. Preferentemente se utilizan en estado de oxidación 0, en particular complejados con fosfinas.
Normalmente el paladio se utiliza en forma de compuesto de paladio a partir del cual se prepara el catalizador correspondiente mediante la adición de ligando. Asimismo es posible utilizar el paladio en forma de complejo compuesto con la estequiometría correcta que según la invención se desplaza con una cantidad de ligando, de modo que se mantiene el exceso de ligando definido según la invención.
Como compuestos de paladio que se utilizan en presencia del exceso de ligando se tienen en cuenta preferentemente: tetrakis(trifenilfosfina)paladio(0), complejo paladio(0)-dibencilideno, paladio sobre carbón (preferentemente al 5%), PdCI2dppf, complejo acetato de paladio-(tri-o-tolilfosfina), Pd(0)*dppe, Pd(0)*dppp, Pd(0)*dppm, Pd(COD)CI2, PdCI2, Pd(OAc)2, PdBr2.
En particular se prefiere tetrakis(trifenilfosfina)paladio(0), el complejo paladio(0)-dibencilideno, paladio sobre carbón (preferentemente al 5%), PdCI2dppf, el complejo acetato de paladio-(tri-o-tolilfosfina), Pd(0)*dppe, Pd(0)*dppp, así como Pd(0)*dppm.
La relación molar de paladio frente a ácido para la hidrogenación es preferentemente de 1 a 500 hasta 1 a 200, en particular de 1 a 50 hasta 1 a 100.
La relación molar de paladio frente a ligando para ligandos monodentados es de 1 a 5 hasta 1 a 15, preferentemente de 1 a 5 hasta 1 a 10, en particular de 1 a 5 hasta 1 a 6, y para ligandos bidentados es de 1 a 2,5 hasta 1 a 7,5, preferentemente de 1 a 2,5 hasta 1 a 5, en particular de 1 a 2,5 hasta 1 a 3.
Como anhídridos que no se utilizan como disolvente, se prefieren para este procedimiento anhídrido piválico, anhídrido acético, anhídrido isobutírico, anhídrido 5-norbornen-2,3-dicarboxílico, anhídrido 1,2,3,6-tetrahidroftálico y anhídrido naftalen-1,8-dicarboxílico.
La relación molar del anhídrido de ácido carboxílico frente al ácido 5-arilnicotínico es preferentemente de 10 a 1 hasta 8 a 1, preferentemente de 7 a 1 hasta 6 a 1 yen particular de 5 a 1 hasta 2 a 1.
Mediante etapas de tratamiento tradicionales, como por ejemplo adición de agua a la mezcla de reacción y extracción, se pueden obtener los compuestos de fórmula I después de la eliminación del disolvente. Puede ser ventajoso llevar a cabo una destilación o cristalización para una mejor purificación del producto.
El aldehído 5-(4-fluorofenil)nicotínico que se puede preparar mediante el procedimiento según la invención representa un importante producto intermedio o final en la química orgánica industrial. En particular, los derivados sustituidos correspondientes representan productos intermedios valiosos para la síntesis de productos finales de elevada calidad, o ellos mismos representan tales productos finales, para la protección de plantas, como por ejemplo fungicidas, insecticidas, herbicidas o pesticidas, o para la preparación de sustancias farmacéuticas de elevada eficacia.
Incluso sin otras formas de realización, se asume que un especialista puede utilizar la descripción anterior en el alcance más amplio. Por eso, las formas de realización preferibles se deben interpretar solamente como una revelación descriptiva, en ningún caso limitante de cualquiera de las maneras.
Los siguientes ejemplos ilustran la invención sin limitarla. Si no se indica lo contrario, los datos de porcentaje son porcentajes en peso. Todas las temperaturas se indican en grados Celsius.
Ejemplo 1: Se toman 13,2 g de ácido 4-fluorobencenborónico y 10,8 g de hidrogenocarbonato sódico y se mezclan bajo agitación en atmósfera protectora con una mezcla de 16,1 g de 5-bromo-3-hidroximetilpiridina, 30 ml de agua y 60 ml de tolueno. A continuación se añaden otros 14 ml de agua, 28 ml de tolueno y 0,5 g de tetrakis(trifenifosfina)paladio (0). La mezcla de reacción se calienta a reflujo y se mantiene a esta temperatura 2 horas. Tras enfriar se realiza el tratamiento tradicional mediante el cual se obtiene el alcohol 5(4-fluorofenil)nicotínico. A continuación el alcohol se oxida a ácido 5-(4fluorofenil)nicotínico según los métodos tradicionales.
Ejemplo 2: Se añaden 1,38 kg de ácido 5-bromonicotínico, 1,10 kg de ácido 4-fluorobencenborónico y 0,40 kg de Pd-carbón activo (al 5%) en 8,5 litros de agua. La suspensión negra se alcaliniza con 1,39 kg de sosa cáustica al 32% y se calienta a 100 ºC. Tras 4 horas se realiza el tratamiento tradicional mediante el cual se obtiene el ácido 5-(4-fluorofenil)nicotínico. Punto de fusión: 198,5 ºC a 203 ºC.
Ejemplo 3: 15,3 g de éster metílico del ácido 5-(4-fluorofenil)nicotínico (que se puede obtener mediante un acoplamiento Suzuki de éster metílico del ácido 5bromopiridin-3-carboxílico con ácido 4-fluorobencenborónico, de forma análoga al ejemplo 1 o 2) se saponifican según los métodos tradicionales a ácido 5-(4-fluorofenil)nicotínico.
Ejemplo 4: 5-bromo-3-acetoximetilpiridina se transforma según el ejemplo 1 con ácido 4-fluorobencenborónico. El éster metílico del ácido 5-(4-fluorofenil)piridin-3il-acético obtenido se saponifica según los métodos tradicionales y a conti
5 nuación se oxida a ácido 5-(4-fluorfenil)nicotínico.
Ejemplo 5: Se disuelve ácido 5-(4-fluorofenil)nicotínico en tetrahidrofurano en un autoclave, se mezcla con tres equivalentes del anhídrido de ácido correspon
10 diente y la mezcla se inertiza aplicando varias veces una presión de gas protector. Se añade una disolución de Pd(OAc)2 y PPh3 en tetrahidrofurano a contracorriente del gas protector y a continuación la mezcla de reacción se hidrogena bajo una presión de hidrógeno de 8 bares a 80 ºC y bajo agitación. Mediante el tratamiento tradicional se obtiene el aldehído con un
15 rendimiento del 98%.
20
25

Claims (3)

  1. Reivindicaciones
    1. Procedimiento para la preparación del aldehído 5-(4-fluorofenil)nicotínico por reducción del ácido 5-(4-fluorofenil)nicotínico mediante hidro
    5 genación catalítica en presencia de anhídridos de ácidos carboxílicos, en el que se utiliza como catalizador un complejo de paladio-ligando, caracterizado porque la relación molar de paladio frente a ligando es de 1 a 5 hasta 1 a 15 con ligandos monodentados y de 1 a 2,5 hasta 1 a 7,5 con ligandos bidentados.
    10
  2. 2.
    Aldehído 5-(4-fluorofenil)nicotínico.
  3. 3.
    Ácido 5-(4-fluorofenil)nicotínico.
    15 4. Uso del aldehído 5-(4-fluorofenil)nicotínico para la preparación de (R)-2 [5-(4-fluorofenil)-3-piridilmetilaminometil]-cromano, caracterizado porque
    (a) el aldehído 5-(4-fluorofenil)nicotínico se prepara según el procedimiento de la reivindicación 1,
    (b) el aldehído 5-(4-fluorofenil)nicotínico así preparado reacciona con 20 (R)-cromanamina y
    (c) la imina así obtenida se reduce.
    25
    30
ES01907409T 2000-02-07 2001-01-05 Procedimiento para la preparación de aldehídos 5-arilnicotínicos. Expired - Lifetime ES2350683T3 (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10005150A DE10005150A1 (de) 2000-02-07 2000-02-07 Verfahren zur Herstellung von 5-Arylnicotinaldehyden
DE10005150 2000-02-07

Publications (1)

Publication Number Publication Date
ES2350683T3 true ES2350683T3 (es) 2011-01-26

Family

ID=7629970

Family Applications (1)

Application Number Title Priority Date Filing Date
ES01907409T Expired - Lifetime ES2350683T3 (es) 2000-02-07 2001-01-05 Procedimiento para la preparación de aldehídos 5-arilnicotínicos.

Country Status (25)

Country Link
US (2) US6703509B2 (es)
EP (1) EP1263731B1 (es)
JP (1) JP2004500379A (es)
KR (1) KR100742767B1 (es)
CN (1) CN1213031C (es)
AR (1) AR033801A1 (es)
AT (1) ATE477241T1 (es)
AU (2) AU2001235395B2 (es)
BR (1) BR0108062A (es)
CA (1) CA2399125C (es)
CZ (1) CZ20022539A3 (es)
DE (2) DE10005150A1 (es)
ES (1) ES2350683T3 (es)
HU (1) HUP0204436A2 (es)
ME (1) MEP6108A (es)
MX (1) MXPA02007584A (es)
MY (1) MY127150A (es)
NO (1) NO328306B1 (es)
PL (1) PL205973B1 (es)
RU (1) RU2256653C2 (es)
SK (1) SK10872002A3 (es)
UA (1) UA73973C2 (es)
WO (1) WO2001058873A1 (es)
YU (1) YU58702A (es)
ZA (1) ZA200207155B (es)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10120619A1 (de) * 2001-04-26 2002-10-31 Merck Patent Gmbh 2-(5-(4-Fluorphenyl)-3-pyridylmethylaminomethyl-chroman
DE10318690B3 (de) * 2003-04-24 2004-11-11 Merck Patent Gmbh Verfahren zur Herstellung von Nicotinaldehyden
DE102004028561A1 (de) * 2004-06-15 2006-01-05 Merck Patent Gmbh Verfahren zur Herstellung von 5-Arylnicotinaldehyden
CN108997224B (zh) * 2018-08-28 2023-04-28 韶远科技（上海)有限公司 一种2-氯-5-氰基含氮六元杂环化合物的制备方法

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9304191D0 (en) 1993-03-02 1993-04-21 Ciba Geigy Ag Process for the preparation of aqueous nicotinaldehyde
GB9313201D0 (en) * 1993-06-25 1993-08-11 Fujisawa Pharmaceutical Co New heterocyclic compounds
ATE210657T1 (de) * 1994-10-14 2001-12-15 Merck Patent Gmbh Zns wirksames (r)-(-)-2-(5-(4-fluorophenyl)-3- pyridylmethylaminomethyl)chroman
US5585388A (en) 1995-04-07 1996-12-17 Sibia Neurosciences, Inc. Substituted pyridines useful as modulators of acetylcholine receptors
BR9606546A (pt) 1995-08-02 1998-07-14 Uriach & Cia Sa J Novas carboxamidas com atividade fungicida
GB9605027D0 (en) 1996-03-09 1996-05-08 Pfizer Ltd Quinoxalinediones
TW530054B (en) * 1997-09-24 2003-05-01 Duphar Int Res New piperazine and piperidine compounds
DE29717072U1 (de) * 1997-09-24 1999-02-04 Robert Bosch Gmbh, 70469 Stuttgart Gasbeheizter Wassererhitzer mit Abgasüberwachungseinrichtung
AU9802198A (en) * 1997-10-21 1999-05-10 Pharmacia & Upjohn Company Antiinflammatory thiadiazolyl ureas which act as lfa-1 and mac-1 inhibitors
AU747815B2 (en) * 1998-02-19 2002-05-23 Kowa Co., Ltd. Cyclic amide compounds
GB9812709D0 (en) * 1998-06-13 1998-08-12 Glaxo Group Ltd Chemical compounds

Also Published As

Publication number Publication date
EP1263731B1 (de) 2010-08-11
DE10005150A1 (de) 2001-08-09
JP2004500379A (ja) 2004-01-08
KR100742767B1 (ko) 2007-07-25
AR033801A1 (es) 2004-01-07
CA2399125A1 (en) 2001-08-16
HK1051861A1 (en) 2003-08-22
PL356564A1 (en) 2004-06-28
RU2256653C2 (ru) 2005-07-20
BR0108062A (pt) 2003-01-21
US20030055259A1 (en) 2003-03-20
WO2001058873A1 (de) 2001-08-16
AU2001235395B2 (en) 2005-06-02
KR20020072241A (ko) 2002-09-14
SK10872002A3 (sk) 2002-12-03
US6703509B2 (en) 2004-03-09
RU2002123358A (ru) 2004-01-10
MY127150A (en) 2006-11-30
CZ20022539A3 (cs) 2002-10-16
MEP6108A (xx) 2010-02-10
MXPA02007584A (es) 2002-12-13
HUP0204436A2 (hu) 2003-08-28
ZA200207155B (en) 2003-07-14
EP1263731A1 (de) 2002-12-11
UA73973C2 (en) 2005-10-17
DE50115594D1 (de) 2010-09-23
CA2399125C (en) 2009-06-02
AU3539501A (en) 2001-08-20
PL205973B1 (pl) 2010-06-30
ATE477241T1 (de) 2010-08-15
NO20023702D0 (no) 2002-08-06
CN1213031C (zh) 2005-08-03
USRE41008E1 (en) 2009-11-24
YU58702A (sh) 2006-01-16
NO20023702L (no) 2002-08-06
NO328306B1 (no) 2010-01-25
CN1398256A (zh) 2003-02-19

Similar Documents

Publication Publication Date Title
ES2242621T3 (es) Proceso para la produccion de aminas por aminacion reductora de compuestos de carbonico catalizada homogeneamente.
ES2305095T3 (es) Procesos de hidrogenacion catalitica.
Shee et al. Cooperative photoredox and palladium catalysis: recent advances in various functionalization reactions
JP6483134B2 (ja) Ｆｅ／三座配位子錯体によるエステルの水素化
WO2012144650A1 (en) Method for producing compound with carbonyl group by using ruthenium carbonyl complex having tridentate ligand as dehydrogenation oxidation catalyst
JP5674059B2 (ja) ルテニウム錯体を含む水素移動反応用触媒及び水素移動反応物の製造方法
JP7308864B2 (ja) マンガン触媒によるエステルの水素化
Balaboina et al. Amide bond synthesis via silver (I) N-heterocyclic carbene-catalyzed and tert-butyl hydroperoxide-mediated oxidative coupling of alcohols with amines under base free conditions
DE50311061D1 (de) Verfahren zur herstellung von dialdehyden und/oder ethylenisch ungesättigten monoaldehyden durch hydroformylierung ethylenisch ungesättigter verbindungen
ES2350683T3 (es) Procedimiento para la preparación de aldehídos 5-arilnicotínicos.
CA3059761A1 (en) Process for the preparation of deuterated ethanol from d2
Yuan et al. Zinc (II)‐Catalyzed Mannich‐type Reactions of Hydrazones with Difluoroenoxysilane and Its Application in the Synthesis of Optically Active 2, 2‐Difluoro‐3‐oxo‐benzohydrazide
JP7362609B2 (ja) 四座ｐｎｎｐ配位子ルテニウム錯体でのカルボニルの水素化
Kokel et al. Application of green chemistry in homogeneous catalysis
TW200813079A (en) Method for making optically active amino phosphinylbutanoic acids
CN115141138B (zh) 一种烷基羧酸脱羧构建氟化物的方法
CN101323567B (zh) 制备肉桂酸酯及其衍生物的方法
DE602006000226T2 (de) Verfahren zur Herstellung von Adapalene
CN113200812B (zh) 1，3，5-三取代芳基化合物的合成方法
CN103553934B (zh) 一种n-异丙基-4-氟苯胺的制备方法
CN113816865B (zh) 手性α-胺基缩醛类化合物及其衍生物的制备方法
JP4727929B2 (ja) ピラゾリルアリールアルキン
CN117466744B (zh) 一种光化学铁催化合成芳胺类化合物的方法
CN108752213B (zh) 一种可见光激发二硫醚催化制备α-羟甲基-β-二羰基化合物的方法
Fairlamb Transition metals in organic synthesis: cross-coupling and C–H activation processes