AR114585A1 - PROCESS FOR PREPARING ANTAGONIST COMPOUNDS OF POTENTIAL TRANSIENT CHANNELS OF THE 1-ARYLSULFONYL-PYRROLIDIN-2-CARBOXAMIDE RECEPTOR AND CRYSTALLINE FORMS THEREOF - Google Patents

PROCESS FOR PREPARING ANTAGONIST COMPOUNDS OF POTENTIAL TRANSIENT CHANNELS OF THE 1-ARYLSULFONYL-PYRROLIDIN-2-CARBOXAMIDE RECEPTOR AND CRYSTALLINE FORMS THEREOF

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Publication number
AR114585A1
AR114585A1 ARP190100409A ARP190100409A AR114585A1 AR 114585 A1 AR114585 A1 AR 114585A1 AR P190100409 A ARP190100409 A AR P190100409A AR P190100409 A ARP190100409 A AR P190100409A AR 114585 A1 AR114585 A1 AR 114585A1
Authority
AR
Argentina
Prior art keywords
compound
formula
solvent
halo
reacting
Prior art date
Application number
ARP190100409A
Other languages
Spanish (es)
Inventor
Scott Savage
Joseph Lubach
James Levi Knippel
Chong Han
Francis Gosselin
Kyle Bradley Pascual Clagg
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 AR114585A1 publication Critical patent/AR114585A1/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/14—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 three or more hetero rings

Abstract

Métodos para preparar compuestos antagonistas de canales de potencial transitorio del receptor de 1-arilsulfonil-pirrolidin-2-carboxamida; polimorfos de solvato y cocristales de los mismos. También, se proveen métodos de preparación para las mencionadas formas cristalinas. Reivindicación 1: Un proceso para preparar el compuesto de fórmula (3), caracterizado porque comprende: (i) hacer reaccionar compuesto de fórmula (1) con un reactivo de sulfonación en un solvente para formar el compuesto de fórmula (2) de acuerdo con el paso 1, donde Y es un grupo arilsulfonilo o alquilsulfonilo; y (ii) hacer reaccionar compuesto de fórmula (2) con una fuente de nitrógeno en un solvente para formar el compuesto de fórmula (3) de acuerdo con el paso 2, donde: el compuesto de fórmula (3) es una base libre; el rendimiento del compuesto de fórmula (3) en base al compuesto de fórmula (1) es al menos 30%; R¹ se selecciona entre halo, halo-C₁₋₄ alquilo-, halo-C₁₋₄ alcoxi-, y -CN; y R² se selecciona entre H y ciclopropilo. Reivindicación 16: El proceso de la reivindicación cualquiera de las reivindicaciones 1 a 15 caracterizado porque comprende además formar el compuesto de fórmula (6) a partir del compuesto de fórmula (3) mediante un proceso que comprende: (i) hacer reaccionar el compuesto de fórmula (3), el compuesto de fórmula (4), y un reactivo de acoplamiento en un solvente para formar el compuesto de fórmula (5) de acuerdo con el paso 3, donde cada asterisco denota un centro quiral, y PG denota un grupo protector de amina; y (ii) hacer reaccionar compuesto de fórmula (5) y un reactivo de desprotección ácido en un solvente para formar el compuesto de fórmula (6) de acuerdo con el paso 4, donde R³ es C₁₋₄ alquilo- y R⁴ se selecciona entre H y -F, o R³ y R⁴ junto con los átomos del anillo a los cuales están unidos forman un anillo carbocíclico de tres miembros. Reivindicación 27: El proceso de cualquiera de las reivindicaciones 16 a 26 caracterizado porque comprende formar el compuesto de fórmula (8) cristalino, o un solvato o cocristal del mismo, a partir del compuesto de fórmula (6), mediante un proceso que comprende: (i) hacer reaccionar el compuesto de fórmula (6), el compuesto de fórmula (7), y una base en un sistema de solventes para formar el compuesto de fórmula (8) de acuerdo con el paso 5, donde: R⁵ es halo; X¹ y X² son en cada caso C, o uno de X¹ y X² es N y el otro es C; y n es 1 ó 2. Reivindicación 37: El proceso de cualquiera de las reivindicaciones 27 a 36 caracterizado porque el compuesto de fórmula (8) es de la estructura de fórmula (9). Reivindicación 38: Un proceso para preparar un compuesto de fórmula (8) cristalino, o un solvato o cocristal del mismo, el proceso caracterizado porque comprende: (i) hacer reaccionar sal de ácido del compuesto de fórmula (6), el compuesto de fórmula (7), y una base en un sistema de solventes para formar el compuesto de fórmula (8), donde, R¹ se selecciona entre halo, halo-C₁₋₄ alquilo-, halo-C₁₋₄ alcoxi-, y -CN, R² se selecciona entre H y -ciclopropilo, R³ es C₁₋₄ alquilo- y R⁴ se selecciona entre H y -F, o R³ y R⁴ junto con los átomos del anillo a los cuales están unidos forman un anillo carbocíclico de tres miembros, R⁵ es halo, X¹ y X² son en cada caso C, o uno de X¹ y X² es N y el otro es C, n es 1 ó 2, y cada asterisco representa un centro quiral; (ii) formar una solución del compuesto de fórmula (8) por transferencia por intercambio de solventes del compuesto de fórmula (8) desde el sistema de solventes del paso de reacción (i) a un solvente orgánico seleccionado entre (a) un solvente no polar que tiene una constante dieléctrica de más de 2, (b) un solvente aprótico polar, o (c) un solvente prótico polar; y (iii) poner en contacto la solución del compuesto de fórmula (8) con un antisolvente para formar una suspensión del compuesto cristalino de fórmula (8). Reivindicación 76: Un compuesto cristalino caracterizado porque es (2S,4R,5S)-4-fluoro-1-(4-fluorofenilsulfonil)-5-metil-N-((5-(trifluorometil)-2-(2-(trifluorometil)pirimidin-5-il)piridin-4-il)metil)pirrolidin-2-carboxamida. Reivindicación 77: El compuesto de la reivindicación 76, caracterizado porque el compuesto es polimorfo de base libre de anhidrato Tipo E que presenta un patrón de XRPD que tiene al menos tres, al menos cuatro o al menos cinco, picos característicos expresados en grados 2-q a ángulos de 7,5º ± 0,2º, 8,2º ± 0,2º, 12,6º ± 0,2º, 13,1º ± 0,2º, 13,4º ± 0,2º, 14,7º ± 0,2º, 15,1º ± 0,2º, 15,5º ± 0,2º, 16,1º ± 0,2º, 16,6º ± 0,2º, 18,2º ± 0,2º, 18,9º ± 0,2º, 19,9º ± 0,2º, 20,4º ± 0,2º, 21,0º ± 0,2º, 21,5º ± 0,2º, 21,8º ± 0,2º, 22,4º ± 0,2º, 22,7º ± 0,2º, 24,3º ± 0,2º, 25,0º ± 0,2º, 25,4º ± 0,2º, y 28,4º ± 0,2º.Methods for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide receptor transient potential channel antagonist compounds; solvate polymorphs and cocrystals thereof. Also, preparation methods are provided for the mentioned crystalline forms. Claim 1: A process for preparing the compound of formula (3), characterized in that it comprises: (i) reacting compound of formula (1) with a sulfonating reagent in a solvent to form the compound of formula (2) according to step 1, where Y is an arylsulfonyl or alkylsulfonyl group; and (ii) reacting compound of formula (2) with a nitrogen source in a solvent to form the compound of formula (3) according to step 2, where: the compound of formula (3) is a free base; the yield of the compound of formula (3) based on the compound of formula (1) is at least 30%; R¹ is selected from halo, halo-C₁₋₄ alkyl-, halo-C₁₋₄ alkoxy-, and -CN; and R² is selected from H and cyclopropyl. Claim 16: The process of claim any of claims 1 to 15 characterized in that it further comprises forming the compound of formula (6) from the compound of formula (3) by a process that comprises: (i) reacting the compound of formula (3), the compound of formula (4), and a coupling reagent in a solvent to form the compound of formula (5) according to step 3, where each asterisk denotes a chiral center, and PG denotes a group amine protector; and (ii) reacting compound of formula (5) and an acidic deprotection reagent in a solvent to form the compound of formula (6) according to step 4, where R³ is C₁₋₄ alkyl- and R⁴ is selected from H and -F, or R³ and R⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring. Claim 27: The process of any of claims 16 to 26 characterized in that it comprises forming the crystalline compound of formula (8), or a solvate or cocrystal thereof, from the compound of formula (6), through a process that comprises: (i) reacting the compound of formula (6), the compound of formula (7), and a base in a solvent system to form the compound of formula (8) according to step 5, where: R⁵ is halo ; X¹ and X² are in each case C, or one of X¹ and X² is N and the other is C; and n is 1 or 2. Claim 37: The process of any of claims 27 to 36 characterized in that the compound of formula (8) is of the structure of formula (9). Claim 38: A process for preparing a crystalline compound of formula (8), or a solvate or cocrystal thereof, the process characterized in that it comprises: (i) reacting the acid salt of the compound of formula (6), the compound of formula (7), and a base in a solvent system to form the compound of formula (8), where, R¹ is selected from halo, halo-C₁₋₄ alkyl-, halo-C₁₋₄ alkoxy-, and -CN, R² is selected from H and -cyclopropyl, R³ is C₁₋₄ alkyl- and R⁴ is selected from H and -F, or R³ and R⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring, R⁵ is halo, X¹ and X² are each C, or one of X¹ and X² is N and the other is C, n is 1 or 2, and each asterisk represents a chiral center; (ii) forming a solution of the compound of formula (8) by solvent exchange transfer of the compound of formula (8) from the solvent system of reaction step (i) to an organic solvent selected from (a) a non-solvent polar having a dielectric constant of more than 2, (b) a polar aprotic solvent, or (c) a polar protic solvent; and (iii) contacting the solution of the compound of formula (8) with an antisolvent to form a suspension of the crystalline compound of formula (8). Claim 76: A crystalline compound characterized in that it is (2S, 4R, 5S) -4-fluoro-1- (4-fluorophenylsulfonyl) -5-methyl-N - ((5- (trifluoromethyl) -2- (2- (trifluoromethyl) ) pyrimidin-5-yl) pyridin-4-yl) methyl) pyrrolidine-2-carboxamide. Claim 77: The compound of claim 76, characterized in that the compound is a Type E anhydrate free base polymorph that presents an XRPD pattern that has at least three, at least four or at least five, characteristic peaks expressed in degrees 2- qa angles of 7.5º ± 0.2º, 8.2º ± 0.2º, 12.6º ± 0.2º, 13.1º ± 0.2º, 13.4º ± 0.2º, 14.7º ± 0.2º , 15.1º ± 0.2º, 15.5º ± 0.2º, 16.1º ± 0.2º, 16.6º ± 0.2º, 18.2º ± 0.2º, 18.9º ± 0.2º, 19 , 9º ± 0.2º, 20.4º ± 0.2º, 21.0º ± 0.2º, 21.5º ± 0.2º, 21.8º ± 0.2º, 22.4º ± 0.2º, 22.7º ± 0.2º, 24.3º ± 0.2º, 25.0º ± 0.2º, 25.4º ± 0.2º, and 28.4º ± 0.2º.

ARP190100409A 2018-02-20 2019-02-18 PROCESS FOR PREPARING ANTAGONIST COMPOUNDS OF POTENTIAL TRANSIENT CHANNELS OF THE 1-ARYLSULFONYL-PYRROLIDIN-2-CARBOXAMIDE RECEPTOR AND CRYSTALLINE FORMS THEREOF AR114585A1 (en)

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US201862632653P 2018-02-20 2018-02-20

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AR114585A1 true AR114585A1 (en) 2020-09-23

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AR (1) AR114585A1 (en)
TW (1) TW202000201A (en)
WO (1) WO2019164778A1 (en)

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WO2019164778A1 (en) 2019-08-29

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