AR117451A2 - ASYMMETRIC SYNTHESIS OF A SUBSTITUTE PYRROLIDINE-2-CARBOXAMIDE - Google Patents

ASYMMETRIC SYNTHESIS OF A SUBSTITUTE PYRROLIDINE-2-CARBOXAMIDE

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Publication number
AR117451A2
AR117451A2 ARP190103772A ARP190103772A AR117451A2 AR 117451 A2 AR117451 A2 AR 117451A2 AR P190103772 A ARP190103772 A AR P190103772A AR P190103772 A ARP190103772 A AR P190103772A AR 117451 A2 AR117451 A2 AR 117451A2
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AR
Argentina
Prior art keywords
compound
formula
copper
chiral
temperature range
Prior art date
Application number
ARP190103772A
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Spanish (es)
Original Assignee
Hoffmann La Roche
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 Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of AR117451A2 publication Critical patent/AR117451A2/en

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Abstract

La presente proporciona un método mejorado para la producción a gran escala del compuesto ácido 4-{[(2R,3S,4R,5S)-3-(3-cloro-2-fluoro-fenil)-4-(4-cloro-2-fluoro-fenil)-4-ciano-5-(2,2-dimetil-propil)-pirrolidín-2-carbonil]-amino}-3-metoxi-benzoico. Reivindicación 1: Procedimiento para la producción de compuesto de fórmula (1), que comprende hacer reaccionar un compuesto de fórmula (2) con un compuesto de fórmula (3), en presencia de un catalizador quiral de plata o cobre, en el que R¹ es un alquilo o bencilo no terciario u otro grupo protector de éster. Reivindicación 2: Procedimiento según la reivindicación 1, que comprende: a) hacer reaccionar un compuesto de fórmula (2) con un compuesto de fórmula (3), en presencia de plata (I), tal como acetato de plata, conjuntamente con cualquier fosfina quiral o fosfina bidentada u otro ligando quiral capaz de coordinarse con metal plata en un solvente no polar o aprótico en un intervalo de temperaturas de entre aproximadamente -10ºC y aproximadamente 20ºC del solvente seleccionado, b) isomerizar el producto de (a) mediante la reacción con una base adecuada seleccionada de entre una amina fuerte o con una base insoluble en los solventes anteriormente indicados en un intervalo de temperaturas de entre aproximadamente 20ºC y 80ºC, c) hidrolizar el producto de (b) en cualquier hidróxido adecuado en un solvente que presenta miscibilidad en agua a una temperatura de entre aproximadamente 20ºC y aproximadamente 80ºC con el fin de obtener un compuesto de fórmula (1), y en el que R¹ es un alquilo o bencilo no terciario u otro grupo protector de éster. Reivindicación 4: Procedimiento para producir un compuesto de fórmula (1) según la reivindicación 1, que comprende: a) hacer reaccionar un compuesto de fórmula (2) con un compuesto de fórmula (3) en presencia de una fuente de cobre adecuada, tal como cobre (I) o cobre (II) conjuntamente con cualquier fosfina quiral o fosfina bidentada u otro ligando quiral capaz de coordinarse con metal cobre en un solvente no polar o aprótico conjuntamente con opcionalmente una amina no nucleofílica en un intervalo de temperaturas de entre aproximadamente 0ºC y aproximadamente 40ºC, b) isomerizar el producto de (a) mediante la reacción con una base adecuada seleccionada de entre una amina fuerte o con una base insoluble en los solventes anteriormente indicados y en el intervalo de temperaturas anteriormente indicado, c) hidrolizar el producto de (b) en un hidróxido adecuado en un solvente que presenta miscibilidad en agua a una temperatura de entre aproximadamente 20ºC y aproximadamente 80ºC con el fin de obtener un compuesto de fórmula (1), en el que R¹ es un alquilo o bencilo no terciario y otro grupo protector de éster.The present provides an improved method for the large-scale production of the acid compound 4 - {[(2R, 3S, 4R, 5S) -3- (3-chloro-2-fluoro-phenyl) -4- (4-chloro- 2-fluoro-phenyl) -4-cyano-5- (2,2-dimethyl-propyl) -pyrrolidine-2-carbonyl] -amino} -3-methoxy-benzoic. Claim 1: Process for the production of compound of formula (1), which comprises reacting a compound of formula (2) with a compound of formula (3), in the presence of a chiral silver or copper catalyst, in which R¹ it is a non-tertiary alkyl or benzyl or other ester protecting group. Claim 2: Process according to claim 1, comprising: a) reacting a compound of formula (2) with a compound of formula (3), in the presence of silver (I), such as silver acetate, together with any phosphine chiral or bidentate phosphine or other chiral ligand capable of coordinating with silver metal in a nonpolar or aprotic solvent in a temperature range between about -10 ° C and about 20 ° C of the selected solvent, b) isomerizing the product of (a) by the reaction with a suitable base selected from a strong amine or with a base insoluble in the above-mentioned solvents in a temperature range between approximately 20 ° C and 80 ° C, c) hydrolyzing the product of (b) into any suitable hydroxide in a solvent having miscibility in water at a temperature between about 20 ° C and about 80 ° C in order to obtain a compound of formula (1), and in which R¹ is an alkyl or ben non-tertiary cyl or other ester protecting group. Claim 4: Process for producing a compound of formula (1) according to claim 1, comprising: a) reacting a compound of formula (2) with a compound of formula (3) in the presence of a suitable copper source, such as copper (I) or copper (II) in conjunction with any chiral phosphine or bidentate phosphine or other chiral ligand capable of coordinating with copper metal in a non-polar or aprotic solvent in conjunction with optionally a non-nucleophilic amine in a temperature range of between about 0 ° C and approximately 40 ° C, b) isomerizing the product of (a) by reacting with a suitable base selected from a strong amine or with a base insoluble in the above-indicated solvents and in the above-indicated temperature range, c) hydrolyzing the product of (b) in a suitable hydroxide in a solvent exhibiting miscibility in water at a temperature of between about 20 ° C and about 80 ° C with the fi n to obtain a compound of formula (1), wherein R¹ is a non-tertiary alkyl or benzyl and another ester protecting group.

ARP190103772A 2013-02-21 2019-12-19 ASYMMETRIC SYNTHESIS OF A SUBSTITUTE PYRROLIDINE-2-CARBOXAMIDE AR117451A2 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US201361767395P 2013-02-21 2013-02-21

Publications (1)

Publication Number Publication Date
AR117451A2 true AR117451A2 (en) 2021-08-04

Family

ID=56119044

Family Applications (2)

Application Number Title Priority Date Filing Date
ARP140100541A AR094843A1 (en) 2013-02-21 2014-02-20 ASYMMETRIC SYNTHESIS OF A REPLACED PIRROLIDIN-2-CARBOXAMIDE
ARP190103772A AR117451A2 (en) 2013-02-21 2019-12-19 ASYMMETRIC SYNTHESIS OF A SUBSTITUTE PYRROLIDINE-2-CARBOXAMIDE

Family Applications Before (1)

Application Number Title Priority Date Filing Date
ARP140100541A AR094843A1 (en) 2013-02-21 2014-02-20 ASYMMETRIC SYNTHESIS OF A REPLACED PIRROLIDIN-2-CARBOXAMIDE

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AR (2) AR094843A1 (en)

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Publication number Publication date
AR094843A1 (en) 2015-09-02

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