ES2611077T3 - Forma solida de ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridin-2-il) benzoico - Google Patents

Forma solida de ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridin-2-il) benzoico Download PDF

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ES2611077T3
ES2611077T3 ES08855812.7T ES08855812T ES2611077T3 ES 2611077 T3 ES2611077 T3 ES 2611077T3 ES 08855812 T ES08855812 T ES 08855812T ES 2611077 T3 ES2611077 T3 ES 2611077T3
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difluorobenzo
cyclopropanecarboxamide
dioxol
methylpyridin
benzoic acid
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Ali Keshavarz-Shokri
Beili Zhang
Mariusz Krawiec
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Vertex Pharmaceuticals Inc
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Abstract

Ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridin-2-il) benzoico, denominado Forma I; de manera que la Forma I se caracteriza por mostrar uno o más picos a 15,2-15,6 grados, 16,1-16,5 grados y 14,3-14,7 grados en una difracción de rayos X por el método de polvo que se ha obtenido usando radiación alfa de Cu K a 40 kV, 35 mA.

Description

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Esquema 2. Síntesis del segmento o fracción de amina.
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Esquema 3. Formación de una sal ácida de ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico.
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25 Usando, por ejemplo la forma salina de HCl del ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico como punto de inicio o punto de partida, la Forma I puede producirse en grandes cantidades dispersando o disolviendo la forma salina de HCl del ácido 3-(6-(1-(2,2difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico en un disolvente adecuado durante un periodo de tiempo efectivo. Pueden usarse otras formas salinas de ácido 3-(6-(1-(2,2
30 difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico como, por ejemplo, otras formas ácidas minerales u orgánicas. Las otras formas salinas son el resultado de la hidrólisis del t-butil éster con el correspondiente ácido. Otras formas ácidas o salinas incluyen nítrico, sulfúrico, fosfórico, bórico, acético, benzoico, malónico y similares. La forma salina del ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico puede ser soluble o no dependiendo del disolvente utilizado,
35 pero la falta de solubilidad no impide la formación de la Forma I. Por ejemplo, en una realización, el disolvente adecuado puede ser agua o una mezcla alcohol/agua como una mezcla al 50% de metanol/agua, a pesar de que la forma salina de HCl del ácido 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina2-il) benzoico sólo es ligeramente soluble en agua. En una realización, el disolvente adecuado es agua.
40 El periodo de tiempo efectivo para la formación de la Forma I a partir de la forma salina del ácido 3-(6-(1-(2,2difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico puede ser de entre 2 y 24 horas o mayor. Normalmente, no se necesitan más de 24 horas para obtener un alto rendimiento (~98%), pero algunos disolventes pueden requerir periodos de tiempo más largos. También se sabe que el periodo de tiempo que se necesita es inversamente proporcional a la temperatura. Es decir, cuanto mayor es la temperatura menor es el
45 tiempo necesario para provocar la disociación del ácido y formar la Forma I. Cuando el disolvente es agua, removiendo la dispersión durante aproximadamente 24 horas a temperatura ambiente se obtiene la Forma I con un rendimiento del 98% aproximadamente. Si se requiere una solución de la forma salina del ácido 3-(6-(1-(2,2difluorobenzo[d][1,3]dioxol-5-il) ciclopropanocarboxamida)-3-metilpiridina-2-il) benzoico por necesidades del proceso, puede utilizarse una temperatura elevada. Después de remover la solución durante un periodo de tiempo efectivo a
50 una temperatura elevada, la recristalización por enfriamiento produce formas básicamente puras de la Forma I. En una realización, 'básicamente puro(a)' hace referencia a mayor que alrededor del 90% de pureza. En otra realización, 'básicamente puro(a)' hace referencia a mayor que alrededor del 95% de pureza. En otra realización,
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del paciente; el tiempo de administración, la vía de administración y el ritmo de excreción del compuesto específico utilizado; la duración del tratamiento; los fármacos utilizados en combinación o de manera simlutánea con el compuesto específico empleado, y factores similares que son bien conocidos en el ámbito médico. Tal y como se utiliza en el presente texto, el término 'paciente' significa animal, preferiblemente un mamífero, y más preferiblemente un humano.
Las composiciones farmacéuticamente aceptables de la presente invención pueden administrarse a los humanos y a otros animales de forma oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, tópica (como mediante polvos, ungüentos o gotas) o bucal; mediante un espray oral o nasal; y de otras formas similares, dependiendo de la gravedad de la infección que se está tratando. En algunas realizaciones, los compuestos de la invención pueden administrarse de forma oral o parenteral con unos niveles de dosis de entre alrededor de 0,01 mg/kg y alrededor de 50 mg/kg, y preferiblemente de entre alrededor de 1 mg/kg y alrededor de 25 mg/kg, en relación con el peso corporal del sujeto y por cada día, una o más veces al día, para obtener el efecto terapéutico deseado.
En algunas realizaciones, la cantidad de la dosis de la Forma I en la forma de dosificación unitaria va de 100 mg a 1000 mg. En otra realización, la cantidad de la dosis de la Forma I va de 200 mg a 900 mg. En otra realización, la cantidad de la dosis de la Forma I va de 300 mg a 800 mg. En otra realización, la cantidad de la dosis de la Forma I va de 400 mg a 700 mg. En otra realización, la cantidad de la dosis de la Forma I va de 500 mg a 600 mg.
Las preparaciones inyectables, por ejemplo, las suspensiones acuosas u oleaginosas inyectables y esterilizadas, pueden prepararse de acuerdo con las técnicas y métodos conocidos utilizando agentes humectantes o de dispersión adecuados y agentes de suspensión adecuados. La preparación inyectable estéril también puede ser una solución, suspensión o emulsión estéril inyectable en un disolvente o diluyente no tóxico y parenteralmente aceptable, por ejemplo, como solución en 1,3-butanediol. Entre los vehículos aceptables y los disolventes que pueden emplearse están el agua, la solución de Ringer, una solución U.S.P. y una solución isotónica de cloruro de sodio. Además, los aceites fijos y estériles se utilizan habitualmente como disolventes o como medio de suspensión. Para este propósito se puede utilizar cualquier aceite fijo suave, incluyendo monoglicéridos o diglicéridos sintéticos. Además, los ácidos grasos como el ácido oleico se utilizan en la preparación de inyectables.
Las preparaciones inyectables pueden esterilizarse, por ejemplo, mediante filtrado a través de un filtro de retención bacteriana, o añadiendo agentes esterilizadores en forma de composiciones sólidas estériles que pueden disolverse
o dispersarse en agua esterilizada o en otro medio esterilizado inyectable antes de su uso.
Preferiblemente, las composiciones para una administración rectal o vaginal son supositorios que pueden prepararse mezclando los compuestos de la presente invención o excipientes o portadores adecuados y no irritantes como mantequilla de cacao, polietilenglicol o cera para supositorios, que son sólidos a temperatura ambiente pero líquidos a temperatura corporal y, por lo tanto, se derriten en el recto o en la cavidad vaginal y liberan el compuesto activo.
Las dosis en forma sólida usadas para la administración oral incluyen cápsulas, comprimidos, pastillas, polvos y gránulos. En estas dosis en forma sólida, el compuesto activo se mezcla con al menos un excipiente o portador inerte y farmacéuticamente aceptable, como el citrato de sodio o el fosfato de dicalcio; y/o a) rellenos o expansores como almidones, lactosa, sucrosa, glucosa, manitol y ácido silícico; b) aglutinantes como, por ejemplo, carboximetilcelulosa, alginatos, gelatina, polivinilpirrolidinona, sucrosa y acacia; c) humectantes como glicerol; d) agentes desintegrantes como agar-agar, carbonato de calcio, almidón de patata o tapioca, ácido algínico, algunos silicatos y carbonato de sodio; e) agentes retardantes como parafina; f) acelerantes de la absorción como los compuestos de amonios cuaternarios; g) agentes para humedecer como, por ejemplo, alcohol cetílico y monoestearato de glicerol; h) absorbentes como caolinita y arcilla de bentonita; e i) lubricantes como talco, estearato de calcio, estearato de magnesio, polietilenglicoles sólidos, lauril sulfato de sodio, y mezclas de estos compuestos. En el caso de las cápsulas, comprimidos y pastillas, la dosis también puede incluir agentes amortiguadores.
Las composiciones sólidas similares también se pueden usar como relleno para cápsulas de gelatina blandas o duras utilizando excipientes como lactosa o azúcar lácteo, así como polietilenglicoles con un alto peso molecular y similares. Las dósis en forma -sólida-de comprimidos, grageas, cápsulas, pastillas y gránulos pueden prepararse utilizando revestimientos y carcasas como revestimientos entéricos y otros revestimientos bien conocidos en el campo de las preparaciones farmacéuticas. Opcionalmente, pueden contener agentes opacantes y también pueden tener una composición que hace que liberen los ingredientes activos sólo, o preferentemente, en ciertas partes del tracto intestinal y, opcionalmente, de manera retardada. Los ejemplos de composiciones aislantes que pueden utilizarse incluyen sustancias poliméricas y ceras. Las composiciones sólidas similares también pueden utilizarse como relleno en cápsulas de gelatina duras y blandas usando excipientes como lactosa o azúcar lácteo, así como polietilenglicoles con un elevado peso molecular y similares.
Los componentes activos también pueden estar en forma de microcápsulas, con uno o más excipientes, tal y como se ha explicado previamente. Las dósis en forma -sólida-de comprimidos, grageas, cápsulas, pastillas y gránulos pueden prepararse utilizando revestimientos y carcasas como revestimientos entéricos, revestimientos que controlan la liberación y otros revestimientos bien conocidos en el campo de las preparaciones farmacéuticas. En estas dosis en forma sólida, el compuesto activo puede mezclarse con al menos un diluyente inerte como sucrosa, lactosa o
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El (2,2-difluoro-1,3-benzodioxol-5-il)-ciclopropanocarbonitrilo se hidroliza usando 6 M de NaOH (8 equiv.) en etanol (5 vol) a 80ºC durante la noche. La mezcla se enfría hasta alcanzar la temperatura ambiente y se evapora el etanol al vacío. El residuo o sobrante se pone en agua y MTBE, se añade 1 M de HCl y las capas se separan. Después se trata la capa de MTBE con diciclohexilamina (0,97 equiv). La lechada se enfría hasta 0ºC, se filtra y se lava con heptano para obtener la correspondiente sal de DCHA. La sal se pone en MTBE y 10% de ácido cítrico, y se remueve hasta que se disuelvan todos los sólidos. Se separan las capas y la capa de MTBE se lava con agua y salmuera. Si se intercambia el solvente al heptano y después se filtra, se obtiene ácido 1-(2,2-difluoro-1,3benzodioxol-5-il)-ciclopropanocarboxílico después de secar en una estufa u horno de vacío a 50ºC durante la noche.
Síntesis de 1-(2,2-difluoro-1,3-benzodioxol-5-il)-ciclopropanocarbonil cloruro.
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mezcla se calienta hasta 60ºC. Se añade SOCl2 (1,4 eq) con un embudo de adición. El tolueno y el SOCl2 se destilan de la mezcla de reacción después de 30 minutos. Se añade tolueno adicional (2,5 vol) y se destila de nuevo.
El segmento o fracción de amina Síntesis de tert-butil-3-(3-metilpiridin-2-il)benzoato.
imagen14
Se disuelve 2-Bromo-3-metilpiridina (1,0 eq) en tolueno (12 vol). Se añade K2CO3 (4,8 eq) seguido de agua (3,5 vol), y la mezcla se calienta hasta 65ºC bajo un chorro de N2 durante 1 hora. Después, se añaden ácido 3-(tButoxicarbonil)fenilborónico (1,05 eq) y Pd(dppf)Cl2-CH2Cl2 (0,015 eq), y la mezcla se calienta hasta 80ºC. Después de 2 horas, se detiene el calor, se añade agua (3,5 vol) y se deja que las capas se separen. Después se lava la fase orgánica con agua (3,5 vol) y se extrae con una solución acuosa (10%) de ácido metanosulfónico (2 eq de MsOH; 7,7 vol). Se hace que la fase acuosa sea básica con una solución acuosa (50%) de NaOH (2 eq) y se extrae con EtOAc (8 vol). Después se concentra la capa orgánica para obtener tert-butil-3-(3-metilpiridin-2-il)benzoato crudo (82%), que se usa directamente en el siguiente paso.
Síntesis de 2-(3-(tert-butoxicarbonil)fenil)-3-metilpiridina-1-óxido.
imagen15
peróxido de hidrógeno de urea (3 eq). Se añade anhídrido ftálico (3 eq) en partes como sólido para mantener la temperatura en el reactor por debajo de 45ºC. Después de completar la adición de anhídrido ftálico, la mezcla se calienta hasta 45ºC. Después de remover durante 4 horas más, se detiene el calor. Se añade una solución acuosa (10% de porcentaje en peso) de Na2SO3 (1,5 eq) con un embudo de adición. Después de completar la adición de Na2SO3, se remueve la mezcla durante 30 minutos más y las capas se separan. Se remueve la capa orgánica y se añade una disolución acuosa (10% de porcentaje en peso) de Na2CO3 (2 eq). Después de remover durante 30 minutos, se deja que las capas se separen. La fase orgánica se lava con una solución acuosa (13% de peso en volumen [p/v]) de NaCl. Después, se filtra la fase orgánica y se concentra para obtener 2-(3-(tertbutoxicarbonil)fenil)-3-metilpiridina-1-óxido crudo (95%), que se usa directamente en el siguiente paso.
Síntesis de tert-butil-3-(6-amino-3-metilpiridin-2-il)benzoato.
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  1. imagen1
    imagen2
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