ES2347630B1 - SYNTHESIS AND USES OF 4-CIANOPENTANOATOS AND 4-CIANOPENTENOATS SUBSTITUTED. - Google Patents
SYNTHESIS AND USES OF 4-CIANOPENTANOATOS AND 4-CIANOPENTENOATS SUBSTITUTED. Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/19—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton
- C07C255/20—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same saturated acyclic carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
Síntesis y usos de 4-cianopentanoatos y 4-cianopentenoatos sustituidos.Synthesis and uses of 4-cyanopentanoates and Substituted 4-cyanopentenoates.
La presente invención se refiere a
4-clanopentanoatos sustituidos de fórmula general 1
y 4-cianopentenoatos
sustituidos de fórmula
general 2 y a un procedimiento para su obtención.The present invention relates to substituted 4-clanopentanoates of general formula 1 and 4-cyanopentenoates
substitutes of general formula 2 and a procedure for obtaining it.
Description
Síntesis y usos de 4-cianopentanoatos y 4-cianopentenoatos sustituidos.Synthesis and uses of 4-cyanopentanoates and Substituted 4-cyanopentenoates.
Preparación y uso como precursores de compuestos 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos.Preparation and use as precursors of compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced.
La presente invención se refiere a 4-cianopentanoatos sustituidos de fórmula general 1 y 4-cianopentenoatos sustituidos de fórmula general 2 y a un procedimiento para su obtención. La invención se refiere asimismo al empleo de los 4-cianopentanoatos sustituidos de fórmula general 1 y 4-cianopentenoatos sustituidos de fórmula general 2 como intermedios de síntesis en la obtención de compuestos 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos.The present invention relates to 4-substituted cyanopentanoates of general formula 1 and substituted 4-cyanopentenoates of the general formula 2 and a procedure for obtaining it. The invention relates also to the use of 4-cyanopentanoates substituted of general formula 1 and 4-substituted cyanopentenoates of general formula 2 as synthesis intermediates in obtaining compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced.
Las Proteína Quinasas (PKs) se hallan implicadas en procesos tan diversos como la angiogénesis, restenosis, arteriosclerosis y, en particular, en los procesos de crecimiento tumoral. En consecuencia, el desarrollo de inhibidores selectivos de PKs se ha convertido en un área muy activa de investigación. Los compuestos 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos 3 y sus sales farmacéuticamente aceptables han demostrado ser inhibidores selectivos de diversas proteína quinasas. Concretamente KDR (kinase insert domaincontainig receptor) y FGFR (fibroblast growth factor receptor) quinasas (US709833B2). Este hecho hace que estos compuestos dihidropiridinónicos 3 tengan actividad antiproliferativa y por lo tanto sean útiles en el tratamiento o control del cáncer, concretamente en el caso de tumores sólidos.Protein kinases (PKs) are involved in processes as diverse as angiogenesis, restenosis, arteriosclerosis and, in particular, in the growth processes tumor. Consequently, the development of selective inhibitors of PKs has become a very active area of research. The compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one substituted 3 and its pharmaceutically acceptable salts have proven to be selective inhibitors of various protein kinases. Specifically KDR (kinase insert domaincontainig receiver) and FGFR (fibroblast growth factor receptor) kinases (US709833B2). This fact makes these dihydropyridinonic compounds 3 have antiproliferative activity and therefore be useful in the cancer treatment or control, specifically in the case of solid tumors
Estos compuestos de fórmula general 3 donde R_{4} puede ser H, alquilo, arilo, heteroarilo, heterociclo, cicloalquilo, alquenilo o alquinilo sustituidos o no y R_{3} y Ar pueden ser arilo o heteroarilo sustituidos o no se obtienen en la actualidad a partir del uracilo en un mínimo de seis etapas sintéticas (US709833B2).These compounds of general formula 3 where R 4 may be H, alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkenyl or alkynyl substituted or not and R 3 and Ar they can be substituted aryl or heteroaryl or are not obtained in the actuality from uracil in a minimum of six stages synthetic (US709833B2).
En este entorno Borrell y colaboradores (Nuria Mont, Jordi Teixidó, C. Oliver Kappe, José I. Borrell, Molecular Diversily 2003 7, 153-159) desarrollaron previamente una ruta sintética para la obtención de sistemas piridopirimidínicos referibles 11 por tratamiento de un éster \alpha,\beta-insaturado 8 con un acetonitrilo con un sustituyente aceptor G (7a y 7b) y posteriormente con una guanidina o amidina sustituida 10.In this environment Borrell and collaborators (Nuria Mont, Jordi Teixidó, C. Oliver Kappe, José I. Borrell, Molecular Diversily 2003 7 , 153-159) previously developed a synthetic route for obtaining referrable pyridopyrimidine systems 11 for treatment of an ester α, β-unsaturated 8 with an acetonitrile with an acceptor substituent G (7a and 7b) and subsequently with a substituted guanidine or amidine 10.
Estos sistemas piridopirimidínicos 11 presentan un grupo amina o alcohol en posición 4 del anillo de pirimidina. Para obtener piridopirimidinas 3 con un H en posición 4 en lugar del alcohol o la amina es necesario utilizar un acetonitrilo en el que G fuese un grupo aldehído. Por lo tanto el compuesto a utilizar sería el cianoacetaldehído, compuesto no accesible sintéticamente. Una alternativa al uso de cianoacetaldehído es el 3,3-dimetoxipropanonitrilo 5 donde R_{2} es Me, que presenta el grupo aldehído protegido en forma de acetal. El grupo acetal no es un aceptor al contrario que el aldehído por lo que la acidez de los H del metileno presente en el 3,3-dimetoxipropanonitrilo disminuye drásticamente respecto los acetonitrilos usados por Borrell y colaboradores. Éste hecho hace necesaria la búsqueda de una base más fuerte que el NaOMe usado por Borrell y colaboradores. El 3,3-dimetoxipropanonitrilo da una reacción de eliminación por tratamiento con bases fuertes o bajo catálisis ácida generando 3-metoxiacrilonitrilo (US 2002028962 (A1)). Sorprendentemente el uso de bases concretas como NaOH/DMF o t-ButOK/THF permiten la ionización del 3,3-dimetoxipropanonitrilo sin que tenga lugar la citada eliminación. Esto permite su uso para la obtención de 4-cianopentanoatos sustituidos de fórmula general 1 y 4-cianopentenoatos sustituidos de fórmula general 2 sobre los que se refiere la presente invención.These pyridopyrimidine systems 11 have an amine or alcohol group in position 4 of the pyrimidine ring. To obtain pyridopyrimidines 3 with an H in position 4 instead of alcohol or amine it is necessary to use an acetonitrile in which G was an aldehyde group. Therefore the compound to be used would be cyanoacetaldehyde, a compound not synthetically accessible. An alternative to the use of cyanoacetaldehyde is 3,3-dimethoxypropanonitrile 5 where R2 is Me, which has the protected aldehyde group in the form of acetal. The acetal group is not an acceptor in contrast to the aldehyde, so the acidity of the H of the methylene present in the 3,3-dimethoxypropanonitrile decreases dramatically with respect to the acetonitriles used by Borrell et al. This fact makes it necessary to find a stronger base than the NaOMe used by Borrell and collaborators. 3,3-Dimethoxypropanonitrile gives an elimination reaction by treatment with strong bases or under acid catalysis generating 3-methoxyacrylonitrile (US 2002028962 (A1)). Surprisingly, the use of concrete bases such as NaOH / DMF or t -BOKOK / THF allow the ionization of 3,3-dimethoxypropanonitrile without the said removal taking place. This allows its use to obtain substituted 4-cyanopentanoates of general formula 1 and substituted 4-cyanopentenoates of general formula 2 on which the present invention relates.
A la vista de lo expuesto anteriormente existe en el estado de la técnica la necesidad de proporcionar una ruta sintética más sencilla para la obtención de sistemas 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos 3. Esta ruta sintética pasa por la obtención de 4-cianopentanoatos sustituidos de fórmula general 1 o 4-cianopentenoatos sustituidos de fórmula general 2, pudiendo obtenerse compuestos de fórmula general 3 en dos etapas sintéticas.In view of the above, there is in the state of the art the need to provide a route simpler synthetic for obtaining systems 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced 3. This synthetic route goes through obtaining 4-substituted cyanopentanoates of general formula 1 or substituted 4-cyanopentenoates of the general formula 2, compounds of general formula 3 can be obtained in two stages synthetic
En un aspecto la invención se refiere por tanto a 4-cianopentanoatos sustituidos de fórmula general 1 dondeIn one aspect the invention therefore relates to substituted 4-cyanopentanoates of the general formula 1 where
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- R_{1} puede ser un radical alquilo C_{1-6} y dondeR_ {1} can be a C 1-6 alkyl radical and where
- R_{2} puede ser un radical alquilo C_{1-6} y dondeR2 can be a C 1-6 alkyl radical and where
- Ar puede ser arilo, opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C_{1-6}, alcoxilo C_{1-6}, haluro;Ar can be aryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;
- un naftilo, opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C_{1-6}, alcoxilo C_{1-6}, haluro;a naphthyl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;
- un heteroarilo, opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C_{1-6}, alcoxilo C_{1-6}, haluro.a heteroaryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide
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En otro aspecto la invención se refiere por tanto a 4-cianopentenoatos sustituidos de fórmula general 2 dondeIn another aspect the invention is referred to by both substituted 4-cyanopentenoates of formula general 2 where
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- R_{1} puede ser un radical alquilo C_{1-6} y dondeR_ {1} can be a C 1-6 alkyl radical and where
- R_{2} puede ser un radical alquilo C_{1-6} y dondeR2 can be a C 1-6 alkyl radical and where
- Ar puede ser arilo, opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C_{1-6}, alcoxilo C_{1-6}, haluro;Ar can be aryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;
- un naftilo, opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C_{1-6}, alcoxilo C_{1-6}, haluro;a naphthyl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;
- un heteroarilo, opcionalmente sustituido con uno o más sustituyentes independientemente seleccionados de alquilo C_{1-6}, alcoxilo C_{1-6}, haluro.a heteroaryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide
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En una realización preferida el compuesto de fórmula 1 se selecciona del grupo formado por:In a preferred embodiment the compound of Formula 1 is selected from the group consisting of:
[1] 2-(2,6-diclorofenil)-4-ciano-5,5-dimetoxipentanoato de metilo[one] 2- (2,6-dichlorophenyl) -4-cyano-5,5-dimethoxypentanoate of methyl
[2] 4-ciano-5,5-dimetoxi-2-o-tolilpentanoato de etilo[2] 4-cyano-5,5-dimethoxy-2-o-tolylpentanoate of ethyl
[3] 4-ciano-5,5-dimetoxi-2-(2-metoxifenil)pentanoato de metilo[3] 4-cyano-5,5-dimethoxy-2- (2-methoxyphenyl) pentanoate of methyl
[4] 4-ciano-5,5-dimetoxi-2-(naftalen-1-il)pentanoato de metilo[4] 4-cyano-5,5-dimethoxy-2- (naphthalen-1-yl) pentanoate of methyl
[5] 4-ciano-5,5-dimetoxi-3-fenilpentanoato de metilo.[5] 4-cyano-5,5-dimethoxy-3-phenylpentanoate of methyl
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En una realización preferida el compuesto de fórmula 2 se selecciona del grupo formado por:In a preferred embodiment the compound of Formula 2 is selected from the group consisting of:
[6] 2-(2,6-diclorofenil)-4-ciano-5-metoxipent-4-enoato de metilo[6] 2- (2,6-dichlorophenyl) -4-cyano-5-methoxipent-4-enoate of methyl
[7] 4-ciano-5-metoxi-2-o-tolilpent-4-enoato de etilo[7] 4-cyano-5-methoxy-2-o-tolylpent-4-enoate of ethyl
[8] 4-ciano-5-metoxi-2-(2-metoxifenil)pent-4-enoato de metilo[8] 4-cyano-5-methoxy-2- (2-methoxyphenyl) pent-4-enoate of methyl
[9] 4-ciano-5-metoxi-2-(naftalen-1-il)pent-4-enoato de metilo[9] 4-cyano-5-methoxy-2- (naphthalen-1-yl) pent-4-enoate of methyl
[10] 4-ciano-5-metoxi-3-fenilpent-4-enoato de metilo.[10] 4-cyano-5-methoxy-3-phenylpent-4-enoate of methyl
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En otro aspecto la invención se refiere a un procedimiento de obtención de los 4-cianopentanoatos sustituidos 1 y 4-cianopentenoatos sustituidos 2 de fórmula general de la invención. Dicho procedimiento, en adelante procedimiento de la invención comprende tratar un éster \alpha,\beta-insaturado de fórmula general 4 con un propionitrilo de fórmula general 5 en presencia de una base en un disolvente inerte. Cuando la reacción se lleva a cabo a bajas temperaturas (-78ºC) se obtiene mayoritariamente el 4-cianopentanoato sustituido de fórmula general 1 mientras que si la reacción se hace a temperaturas mayores (60ºC) el compuesto mayoritario es el 4-cianopentenoato sustituido de fórmula general 2. La obtención de 4-cianopentenoatos sustituidos de fórmula general 2 también es posible por calefacción de los 4-cianopentanoatos sustituidos de fórmula general 1 en presencia de una base. La reacción de adición conjugada se representa en el Esquema 1, donde R_{1}, R_{2} y Ar tienen el significado anteriormente definido.In another aspect the invention relates to a procedure for obtaining 4-cyanopentanoates substituted 1 and 4-substituted cyanopentenoates 2 of general formula of the invention. Said procedure, hereinafter method of the invention comprises treating an ester α, β-unsaturated of general formula 4 with a propionitrile of general formula 5 in the presence of a base in a inert solvent. When the reaction is carried out at low temperatures (-78ºC) the majority is obtained 4-substituted cyanopentanoate of general formula 1 while if the reaction is done at higher temperatures (60ºC) the Majority compound is 4-cyanopentenoate replaced by general formula 2. Obtaining 4-substituted cyanopentenoates of general formula 2 It is also possible by heating the 4-substituted cyanopentanoates of general formula 1 in the presence of a base. The conjugate addition reaction is represented in Scheme 1, where R 1, R 2 and Ar have the previously defined meaning.
Esquema 1Scheme one
En una realización particular del procedimiento de invención la base utilizada es un alcóxido alcalino como por ejemplo tert-butóxido potásico o un hidróxido alcalino como por ejemplo hidróxido sódico. El disolvente inerte es un disolvente que no interfiere en la reacción y puede seleccionarse de un amplio grupo de disolventes orgánicos convencionales. En una realización particular se utiliza un disolvente de tipo éter, preferiblemente tetrahidrofurano u otros tipos de disolventes como dimetilformamida.In a particular embodiment of the procedure of invention the base used is an alkali alkoxide as per example potassium tert-butoxide or a hydroxide alkaline such as sodium hydroxide. The inert solvent is a solvent that does not interfere with the reaction and can be selected of a large group of conventional organic solvents. In a particular embodiment an ether type solvent is used, preferably tetrahydrofuran or other types of solvents such as dimethylformamide
Los 4-cianopentanoatos sustituidos de fórmula general 1 y los 4-cianopentenoatos sustituidos de fórmula general 2 obtenidos pueden purificarse y/o aislarse del medio de reacción según procedimientos que los expertos en la técnica conocen, por ejemplo procedimientos cromatográficos o destilación.4-cyanopentanoates substituted of general formula 1 and the 4-substituted cyanopentenoates of general formula 2 obtained can be purified and / or isolated from the reaction medium according to procedures known to those skilled in the art, by example chromatographic procedures or distillation.
Si los compuestos de fórmula general 1 o 2 se obtienen en forma de una mezcla de estereoisómeros, particularmente diastereoisómeros, dichas mezclas pueden separarse mediante procedimientos convencionales que los expertos en la técnica conocen, por ejemplo procedimientos cromatográficos.If the compounds of general formula 1 or 2 are obtained in the form of a mixture of stereoisomers, particularly diastereoisomers, said mixtures can be separated by conventional procedures that those skilled in the art They know, for example, chromatographic procedures.
En otro aspecto de la invención se relaciona el empleo de los compuestos de fórmula general 1 y 2 como precursores en la síntesis de compuestos 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos 3. En este sentido la presente invención se relaciona por tanto con un procedimiento para la preparación de sistemas dihidropirimidinónicos sustituidos 3 que comprende el paso a través de un compuesto de fórmula general 1 o 2 y que de acuerdo con una realización particular del mismo comprende las siguientes etapas de reacción (Esquema 2):In another aspect of the invention the use of the compounds of general formula 1 and 2 as precursors in the synthesis of compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one substituted 3. In this sense the present invention relates therefore with a system preparation procedure substituted dihydropyrimidinonics 3 comprising the passage through of a compound of general formula 1 or 2 and which according to a particular embodiment thereof comprises the following steps of reaction (Scheme 2):
a) ciclación del 4-cianopentanoato sustituido 1 o 4-cianopentenoato sustituido 2 por reacción con una guanidina o sal de guanidina sustituida de formula general 6, donde R_{3} puede ser H, alquilo C_{1-6}, arilo, sustituido o no, y heteroarilo, sustituido o no, obteniéndose un compuesto de fórmula general 3 con R_{4} = H.a) cyclization of 1-substituted cyanopentanoate 1 or Substituted 4-cyanopentenoate by reaction with a guanidine or substituted guanidine salt of general formula 6, where R 3 may be H, C 1-6 alkyl, aryl, substituted or not, and heteroaryl, substituted or not, obtaining a compound of general formula 3 with R 4 = H.
b) si se desea se puede derivatizar el nitrógeno lactámico en posición 8. Este puede ser arilado por tratamiento con haluros de arilo en presencia de CuI, un ligando 1,2-diamina y un carbonato alcalino como base o alquilado por reacción con un haluro de alquilo en presencia de una base como hidruro sódico. Así se obtienen compuestos 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos 3.b) if desired, nitrogen can be derivatized lactam in position 8. This can be arylated by treatment with aryl halides in the presence of CuI, a ligand 1,2-diamine and an alkali carbonate base or alkylated by reaction with an alkyl halide in the presence of a base as sodium hydride. Thus compounds are obtained 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced 3.
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Esquema 2Scheme 2
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En una realización particular, el procedimiento de obtención de compuestos 5,8-dihidro-6H-pirido[2,3-d]pirimidin-7-ona sustituidos 3 donde R_{4} es H se lleva a cabo sin aislar intermedio de fórmula general 1 o 2 tal y como se representa en el Esquema 3. De acuerdo con esta realización particular se hace reaccionar un éster \alpha,\beta-insaturado de fórmula general 4 con un propionitrilo de fórmula general 5 en presencia de tert-butóxido potásico. Se neutraliza con ácido acético, se elimina el disolvente a presión reducida y se añade la sal de guanidina 6 en presencia de piridina o Na_{2}CO_{3}. Si la sal de guanidina es un carbonato no es necesario añadir ninguna base. Se deja reaccionar a 150ºC - 180ºC bajo agitación obteniéndose el compuesto de fórmula general 3 con un rendimiento mayor.In a particular embodiment, the procedure to obtain compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one substituted 3 where R 4 is H is carried out without isolating intermediate of general formula 1 or 2 as represented in the Scheme 3. According to this particular embodiment it is done react an α, β-unsaturated ester of general formula 4 with a propionitrile of general formula 5 in presence of potassium tert-butoxide. Neutralizes with acetic acid, the solvent is removed under reduced pressure and add guanidine 6 salt in the presence of pyridine or Na 2 CO 3. If guanidine salt is a carbonate it is not You need to add no base. It is allowed to react at 150 ° C - 180 ° C under stirring obtaining the compound of general formula 3 with a higher performance
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Esquema 3Scheme 3
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En una realización preferente R_{3} es un grupo alquilo C_{1-6}, arilo, preferentemente fenilo o H.In a preferred embodiment R 3 is a C 1-6 alkyl group, aryl, preferably phenyl or H.
A continuación, para una mejor comprensión de la presente invención, sin que deba ser interpretado como limitaciones a la misma, se exponen los siguientes ejemplos.Next, for a better understanding of the present invention, without it being construed as limitations to it, the following examples are set forth.
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A una disolución de 1,15 g (5 mmol) de 4
(R_{1} = Me Ar = 2,6-diclorofenil) en 0,85 mL (7,5
mmol) de 5 (R_{2} = Me) se añadieron 50 mL de disolución 0,1M de
t-ButOK en THF. Se agitó a 60ºC durante 5 min, Se
neutralizó con AcOH glacial. Se eliminó el disolvente a P reducida.
El residuo se purificó por cromatografía flash y posteriormente por
destilación. Se obtuvieron 0,96 g (3 mmol, 61%) de aceite amarillo
correspondiente a la mezcla de diastereoisómeros del producto
deseado. Se describe espectroscopicamente de isómero mayoritario
(E). IR (KBr) \nu_{max}: 2949, 2209, 17,39, 1645, 1437, 1266,
1222, 783. ^{1}H-NMR (400 MHz, CDCl_{3}):
\delta = 7.32 (d, J= 8.0 Hz, 2H), 7.17 (t, J= 8.0
Hz),
6.69 (s), 4.68 (dd, J^{3} = 10.0 Hz,
J^{3} = 5.5 Hz), 3.71 (s, 3H), 3.66 (s, 3H), 3.12 (dd,
J^{3} = 5.5 Hz, J^{2} = 14.4), 2.92 (dd,
J^{3} = 10.0 Hz, J^{2} = 14.4).
^{13}C-NMR (100 MHz, CDCl_{3}): \delta =
171.7, 161.1, 134.4, 129.0, 128.6, 119.3, 89.3, 61.6, 52.5, 45.4,
25.5. HRMS (EI^{+}) m/z calculado para
C_{14}H_{13}Cl_{2}NO_{3} 313.0272. Obtenido 313.0271.At a solution of 1.15 g (5 mmol) of 4 (R 1 = Me Ar = 2,6-dichlorophenyl) in 0.85 mL (7.5 mmol) of 5 (R 2 = Me) 50 mL of 0.1M solution of t-ButOK in THF was added. It was stirred at 60 ° C for 5 min. It was neutralized with glacial AcOH. The solvent was removed at reduced P. The residue was purified by flash chromatography and subsequently by distillation. 0.96 g (3 mmol, 61%) of yellow oil corresponding to the mixture of diastereoisomers of the desired product were obtained. It is described spectroscopically as a major isomer (E). IR (KBr) ν max: 2949, 2209, 17.39, 1645, 1437, 1266, 1222, 783. 1 H-NMR (400 MHz, CDCl 3): δ = 7.32 ( d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz),
6.69 (s), 4.68 (dd, J3 = 10.0 Hz, J3 = 5.5 Hz), 3.71 (s, 3H), 3.66 (s, 3H), 3.12 (dd, J3 } = 5.5 Hz, J ^ {2} = 4.14), 2.92 (dd, J ^ {3} = 10.0 Hz, J ^ {2} = 4.14). 13 C-NMR (100 MHz, CDCl 3): δ = 171.7, 161.1, 134.4, 129.0, 128.6, 119.3, 89.3, 61.6, 52.5, 45.4, 25.5. HRMS (EI +) m / z calculated for C 14 H 13 Cl 2 NO 3 313.0272. Obtained 313.0271.
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A una disolución de 0.46 g (2 mmol) de 4 (R_{1} = Me Ar = 2,6-diclorofenil) en 0,35 mL (3 mmol) de 5 (R_{2} = Me) se añadieron 20 mL de disolución 0,1M de t-ButOK en THF. Se agitó a T_{amb} durante 5 min. Se neutralizó con AcOH glacial. Se realizó un filtrado cromatográfico usando como fase estacionaria gel de sílice y como fase móvil 200 mL de mezcla AcOEt/Hexano 1:1. Se eliminó el disolvente a P reducida. Se añadieron al residuo 1,07 g (6 mmol) de carbonato de fenilguanidina 6 (R_{3} = Ph) y se calentó la mezcla a 150ºC bajo agitación durante una noche. Se suspendió el residuo sólido en MeOH, se filtró y se lavó con agua y posteriormente con MeOH. Se obtuvieron 0,28 g (0,7 mmol, 36%) de sólido blanco. IR (KBr) \nu_{max}: 3289, 3204, 3145, 1685, 16,02, 1579, 1498, 1446, 1241, 756. ^{1}H-NMR (400 MHz, CDCl_{3}): \delta = 10.96 (s), 9.41 (s), 8.19 (s), 7.82 (d, J= 7.8 Hz, 2H), 7.56 (d, J= 8.2 Hz), 7.52 (d, J= 7.9 Hz), 7.39 (t, J= 8,1 Hz), 7.24 (t, J= 7.9 Hz, 2H), 6.91 (t, J= 7.3 Hz), 4.76 (dd, J^{3} = 13,8 Hz, J^{2} = 8.0 Hz), 3.23 (m), 2.99 (dd, J^{3} = 15.8 Hz, J^{2} = 8.0 Hz). ^{13}C-NMR (100 MHz, CDCl_{3}): \delta = 169.8, 158.8, 157.4, 155.6, 140.7, 135.3, 134.9, 134.8, 129.9, 129.8, 128.4 (2C), 121.0, 118.6 (2C), 104.3, 43.3, 25.0. HRMS (FAB^{+}) m/z calculado para C_{19}H_{14}Cl_{2}N_{4}O 385.0623. Obtenido 385.0622.To a solution of 0.46 g (2 mmol) of 4 (R1 = Me Ar = 2,6-dichlorophenyl) in 0.35 mL (3 mmol) of 5 (R2 = Me) was added 20 mL of 0.1M solution of t-ButOK in THF. It was stirred at T amb for 5 min. It was neutralized with glacial AcOH. Chromatographic filtering was performed using silica gel as stationary phase and 200 mL of AcOEt / Hexane 1: 1 mixture as the mobile phase. The solvent was removed at reduced P. 1.07 g (6 mmol) of phenylguanidine 6 carbonate (R 3 = Ph) was added to the residue and the mixture was heated at 150 ° C under stirring overnight. The solid residue was suspended in MeOH, filtered and washed with water and then with MeOH. 0.28 g (0.7 mmol, 36%) of white solid were obtained. IR (KBr) ν max: 3289, 3204, 3145, 1685, 16.02, 1579, 1498, 1446, 1241, 756. 1 H-NMR (400 MHz, CDCl 3): delta = 10.96 (s), 9.41 (s), 8.19 (s), 7.82 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.2 Hz), 7.52 (d, J = 7.9 Hz), 7.39 (t, J = 8.1 Hz), 7.24 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.3 Hz), 4.76 (dd, J3 = 13.8 Hz, J ^ {2} = 8.0 Hz), 3.23 (m), 2.99 (dd, J ^ {3} = 15.8 Hz, J ^ {2} = 8.0 Hz). 13 C-NMR (100 MHz, CDCl 3): δ = 169.8, 158.8, 157.4, 155.6, 140.7, 135.3, 134.9, 134.8, 129.9, 129.8, 128.4 (2C), 121.0, 118.6 (2C ), 104.3, 43.3, 25.0. HRMS (FAB +) m / z calculated for C 19 H 14 Cl 2 N 4 O 385.0623. Obtained 385.0622.
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A una disolución de 0.45 g (2 mmol) de 4 (R_{1} = Me, Ar = naftil) en 0,35 mL (3 mmol) de 5 (R_{2} = Me) se añadieron 20 mL de disolución 0,1M de t-ButOK en THF. Se agitó a T_{amb} durante 5 min. Se neutralizó con AcOH glacial. Se realizó un filtrado cromatográfico usando como fase estacionaria gel de sílice y como fase móvil 200 mL de mezcla AcOEt/Hexano 1:1. Se eliminó el disolvente a P reducida. Se añadieron al residuo 0,54 g (6 mmol) de carbonato de guanidina 6 (R_{3} = H) y 4 mL de piridina y se calentó la mezcla en microondas 1 h a 180ºC. Se añadió agua a la disolución, se filtró el precipitado obtenido y se lavó éste con agua y posteriormente con MeOH. Se obtuvieron 0,26 g (0,9 mmol, 44%) de sólido blanco. IR (KBr) \nu_{max}: 3368, 3331, 3161, 2895, 1682, 1630, 1573, 1497, 1231, 776. ^{1}H-NMR (400 MHz, CDCl_{3}): \delta = 10.80 (s), 8.10 (m), 7.95 (m), 7.90 (s), 7.85 (d, J= 8.1 Hz), 7.54 (m, 2H), 7.45 (t, J= 11 Hz), 7.35 (d, J= 7.1 Hz), 6.40 (s, 2H), 4.70 (t, J= 8.5 Hz), 3.08 (d, J= 8.5 Hz). ^{13}C-NMR (100 MHz, CDCl_{3}): \delta = 172.3, 162.5, 158.0, 155.6, 135.3, 133.6, 131.2, 128.7, 127.5, 126.1, 125.6, 125.4, 125.2, 124.0, 103.5, 42.9, 27.9. HRMS (FAB^{+}) m/z calculado para C_{17}H_{14}N_{4}O 291.1246. Obtenido 291.1247.To a solution of 0.45 g (2 mmol) of 4 (R1 = Me, Ar = naphthyl) in 0.35 mL (3 mmol) of 5 (R2 = Me) was added 20 mL of solution 0 , 1M of t-ButOK in THF. It was stirred at T amb for 5 min. It was neutralized with glacial AcOH. Chromatographic filtering was performed using silica gel as stationary phase and 200 mL of AcOEt / Hexane 1: 1 mixture as the mobile phase. The solvent was removed at reduced P. 0.54 g (6 mmol) of guanidine carbonate 6 (R 3 = H) and 4 mL of pyridine were added to the residue and the mixture was heated in microwave 1 h at 180 ° C. Water was added to the solution, the precipitate obtained was filtered and this was washed with water and then with MeOH. 0.26 g (0.9 mmol, 44%) of white solid were obtained. IR (KBr) ν max: 3368, 3331, 3161, 2895, 1682, 1630, 1573, 1497, 1231, 776. 1 H-NMR (400 MHz, CDCl 3): δ = 10.80 (s), 8.10 (m), 7.95 (m), 7.90 (s), 7.85 (d, J = 8.1 Hz), 7.54 (m, 2H), 7.45 (t, J = 11 Hz), 7.35 (d , J = 7.1 Hz), 6.40 (s, 2H), 4.70 (t, J = 8.5 Hz), 3.08 (d, J = 8.5 Hz). 13 C-NMR (100 MHz, CDCl 3): δ = 172.3, 162.5, 158.0, 155.6, 135.3, 133.6, 131.2, 128.7, 127.5, 126.1, 125.6, 125.4, 125.2, 124.0, 103.5, 42.9, 27.9. HRMS (FAB +) m / z calculated for C 17 H 14 N 4 O 291.1246. Obtained 291.1247.
Claims (20)
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J L FALCÓ et al, Molecular Diversity 2003, vol. 6, páginas 3-11. "{}Solid-phase synthesis of 2-substituted 4-amino-7-exo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidines: An example of cyclization- assisted cleavage"{}, esquemas 1 y 3, resumen. * |
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