ES2554933T3 - Procedimiento de síntesis y forma cristalina de clorhidrato de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}benzamida, así como la base libre asociada y las composiciones farmacéuticas que los contienen - Google Patents

Procedimiento de síntesis y forma cristalina de clorhidrato de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}benzamida, así como la base libre asociada y las composiciones farmacéuticas que los contienen Download PDF

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ES2554933T3
ES2554933T3 ES12171118.8T ES12171118T ES2554933T3 ES 2554933 T3 ES2554933 T3 ES 2554933T3 ES 12171118 T ES12171118 T ES 12171118T ES 2554933 T3 ES2554933 T3 ES 2554933T3
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formula
compound
cis
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hexahydrocyclopenta
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Nicolas Robert
Jean-Michel Lerestif
Jean-Pierre Lecouve
Marina Gaillard
Loïc Meunier
Philippe Letellier
Mathieu Boiret
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Les Lab Serv
Les Laboratoires Servier SAS
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract

Procedimiento de síntesis industrial del compuesto de fórmula (I):**Fórmula** caracterizado porque el compuesto de fórmula (II):**Fórmula** se somete a reacción con amoníaco a una temperatura superior a 100ºC para formar el compuesto de fórmula (III):**Fórmula** que se reduce para obtener la amina bicíclica de fórmula (IV):**Fórmula** y a continuacióneste último compuesto se somete: - bien a una reacción de acoplamiento, en condiciones básicas en un medio polar, con un compuesto de fórmula (V):**Fórmula** donde Y representa -CH2-Hal, siendo Hal un halógeno, o un grupo -CH2-OSO2-R, siendo a un grupo alquilo(C1-C6) o un grupo -C6H4-CH3, - bien a una aminación reductora en un medio ácido con un compuesto de fórmula (V'):**Fórmula** donde R' y R'' representan, independientemente entre sí, un grupo alquilo(C1-C6), o R' y R'' forman juntos un grupo -(CH2)n-, donde n >= 2-3, o uno de los grupos R' y R'' representan un átomo de hidrógeno y el otro un grupo alquilo(C1-C6), - bien a una aminación reductora con un compuesto de fórmula (V''):**Fórmula** para obtener la base libre del compuesto de fórmula (I), que se pone en presencia de ácido clorhídrico para formar el compuesto de fórmula (I), que se aísla en forma de un sólido.

Description

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se cargan 34,74 kg de cis-octahidrociclopenta[c]pirrol en solución acuosa al 30%, 26,7 l de agua. La mezcla de reacción se lleva a reflujo hasta que se consume por completo la materia prima. Después se añade agua (13,3 l). El medio se enfría a 5ºC antes de filtrarlo y lavarlo con agua. Se obtiene el producto indicado en el título en forma de un sólido con un rendimiento del 81% y una pureza química de un 96%.
RMN1H: (600,13 MHz; dmso-d6; 300K): 7,82 (d, 2H, J = 9,0 Hz); 7,79 (bs, 1H); 7,14 (bs, 1H); 6,95 (d, 2H, J = 9,0 Hz); 4,06 (t, 2H, J = 6,5 Hz); 2,57 (m, 2H); 2,48 (m, 2H); 2,44 (bt, 2H, J = 6,5 Hz); 2,14 (bd, 2H, J = 7,5 Hz); 1,86 (qt, 2H, J = 6,5 Hz); 1,65-1,55 (m, 3H); 1,45-1,38 (m, 1H); 1,37-1,30 (m, 2H)
con bs: singlete ancho, bd: doblete ancho, bt: triplete ancho
Una caracterización del producto así formado con ayuda de las técnicas presentadas en los Ejemplos 6 a 8 demostró que se había obtenido la forma I de la base libre.
Etapa D: Clorhidrato de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}-benzamida
En un reactor se introducen 14,69 kg de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}benzamida y 122 l de agua. Además, se prepara una solución de 6,81 kg de ácido chlorhídrico al 37% en 11,54 l de agua. Luego se añaden al reactor 13,75 kg de esta solución ácida. La mezcla se agita durante 1 hora a temperatura ambiente y después 1h30 a 60ºC. La suspensión se filtra en caliente y después el filtro se enjuaga con agua. A continuación, se efectúa en el filtrado un cambio de disolvente con volumen constante para obtener una relación isopropanol/agua de 9/1. El producto se aísla a 0ºC y el precipitado obtenido se lava con isopropanol. Finalmente se obtiene el producto indicado en el título con un rendimiento de un 89% y una pureza química superior al 99%.
Una caracterización del producto así formado con ayuda de las técnicas presentadas en los Ejemplos 4 a 5 demostró que se había obtenido la forma I del clorhidrato.
Etapa E: Clorhidrato de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi-benzamida
La sal de clorhidrato obtenida en la Etapa D se recristaliza en una mezcla de isopropanol (264 kg) y agua (37,4 l). La mezcla se lleva a reflujo durante 45 minutos. La solución se filtra en caliente y después se enjuaga mediante isopropanol. A continuación, se inicia la cristalización a 55ºC. El medio se mantiene a esta temperatura durante 40 minutos antes de enfriarlo a 0ºC. Al cabo de unas horas, el producto se aísla por filtración. Después de lavado con isopropanol se obtiene el producto indicado en el título en forma de un polvo, con un rendimiento de un 93% y una pureza química superior al 99%.Punto de fusión: 213-215ºC
Una caracterización del producto así formado con ayuda de las técnicas presentadas en los Ejemplos 4 a 5 demostró que se había obtenido la forma I del clorhidrato.
Ejemplo 2: Clorhidrato de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}benzamida
Etapa A: Tetrahidrociclopenta[c]pirrol-1,3(2H,3aH)-diona
El protocolo es idéntico al descrito en la Etapa A del Ejemplo 1.
Etapa B: cis-octahidrociclopenta[c]pirrol
El protocolo es idéntico al descrito en la Etapa B del Ejemplo 1.
Etapa C: 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}benzamida
En un reactor se introducen 15,2 kg de 4-(3-cloropropoxi)benzamida, 40,28 kg de cisoctahidrociclopenta[c]pirrol en solución acuosa al 30%, 63,84 kg de agua, 21,48 kg de isopropanol y 14,39 kg de trietilamina. La mezcla de reacción se agita y se calienta a reflujo hasta que se consume por completo la
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Claims (1)

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ES12171118.8T 2011-06-08 2012-06-07 Procedimiento de síntesis y forma cristalina de clorhidrato de 4-{3-[cis-hexahidrociclopenta[c]pirrol-2(1H)-il]propoxi}benzamida, así como la base libre asociada y las composiciones farmacéuticas que los contienen Active ES2554933T3 (es)

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FR1101746 2011-06-08
FR1101746A FR2976285B1 (fr) 2011-06-08 2011-06-08 Procede de synthese et forme cristalline du chlorhydrate de 4-{3-[cis-hexahydrocypenta[c]pyrrol-2(1h)-yl]propoxy}benzamide ainsi que les compositions pharmaceutiques qui la contiennent

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FR3003466B1 (fr) * 2013-03-22 2015-08-07 Servier Lab Utilisation du 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide pour le traitement des douleurs neuropathiques
CN103601666B (zh) * 2013-11-28 2015-09-02 遵义医学院 八氢环戊烷[c]吡咯的制备方法
CN104387313B (zh) * 2014-10-22 2015-12-30 滨海博大化工有限公司 一种1,2-环戊二甲酰亚胺的制备方法
KR101966221B1 (ko) * 2017-06-14 2019-04-12 최상근 유해가스 처리 장치
CN115232058A (zh) * 2022-08-01 2022-10-25 上海巽田科技股份有限公司 一种格列齐特中间体1,2-环戊二甲酰胺的合成方法

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US756120A (en) * 1902-07-28 1904-03-29 Krupp Gmbh Recoil-gun with special devices for protecting the slide-tracks from dust.
NL132376C (es) * 1966-02-10
US4895840A (en) * 1987-06-10 1990-01-23 A. H. Robins Company, Incorporated N-(aryl-,aryloxy-,arylthio-arylsulfinyl-and arylsulfonyl-)alkyl-N,N'-(or n'n')alkylaminoalkyl ureas and cyanoguanidines
CN1314340A (zh) * 2000-03-21 2001-09-26 山东省医药工业研究所 环戊烷酰亚胺的制备方法
FR2866647B1 (fr) * 2004-02-20 2006-10-27 Servier Lab Nouveaux derives azabicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
CN100424077C (zh) * 2005-06-07 2008-10-08 台州市四维化工厂 一种环戊烷1，2-二酰亚胺的制备方法
FR2937251B1 (fr) * 2008-10-16 2011-03-18 Servier Lab Utilisation du 4-{3-°hexahydrocyclopenta°c!pyrrol-2(1h)-yl! propoxy}benzamide pour l'obtention de medicaments destines au traitement des troubles du sommeil
MX2011005537A (es) * 2008-11-26 2011-06-21 Abbott Lab Nuevas octahidrociclopenta[c]pirrol-4-aminas sustituidas como bloqueadores del canal de calcio.
FR2953515B1 (fr) * 2009-12-09 2011-12-23 Servier Lab Nouveaux derives du type hexahydrocyclopenta[b]pyrrole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2974729B1 (fr) * 2011-05-02 2013-04-19 Servier Lab Nouvelle association entre le 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide et un inhibiteur de l'acetylcholinesterase et les compositions pharmaceutiques qui la contiennent

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MD20120049A2 (ro) 2012-12-31
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