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1. WO2014177517 - PREPARATION PROCESS OF AN AGONIST OF THE THROMBOPOIETIN RECEPTOR

Publication Number WO/2014/177517
Publication Date 06.11.2014
International Application No. PCT/EP2014/058610
International Filing Date 28.04.2014
IPC
C07C 205/59 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
205Compounds containing nitro groups bound to a carbon skeleton
49the carbon skeleton being further substituted by carboxyl groups
57having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
59the carbon skeleton being further substituted by singly-bound oxygen atoms
C07C 201/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
201Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
06Preparation of nitro compounds
12by reactions not involving the formation of nitro groups
C07D 231/22 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
231Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
02not condensed with other rings
10having two or three double bonds between ring members or between ring members and non-ring members
14with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
18One oxygen or sulfur atom
20One oxygen atom attached in position 3 or 5
22with aryl radicals attached to ring nitrogen atoms
C07C 227/04 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
227Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
04Formation of amino groups in compounds containing carboxyl groups
C07C 249/16 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
249Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
16of hydrazones
CPC
C07C 201/12
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
201Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
06Preparation of nitro compounds
12by reactions not involving the formation of nitro groups
C07C 205/59
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
205Compounds containing nitro groups bound to a carbon skeleton
49the carbon skeleton being further substituted by carboxyl groups
57having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
59the carbon skeleton being further substituted by singly-bound oxygen atoms
C07C 227/04
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
227Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
04Formation of amino groups in compounds containing carboxyl groups
C07C 249/16
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
CACYCLIC OR CARBOCYCLIC COMPOUNDS
249Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
16of hydrazones
C07D 231/22
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
231Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
02not condensed with other rings
10having two or three double bonds between ring members or between ring members and non-ring members
14with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
18One oxygen or sulfur atom
20One oxygen atom attached in positions 3 or 5
22with aryl radicals attached to ring nitrogen atoms
Applicants
  • ESTEVE QUÍMICA, S.A. [ES]/[ES]
  • GALCHIMIA, S.A. [ES]/[ES]
Inventors
  • BARTRA SANMARTÍ, Martí
  • SOLSONA ROCABERT, Joan Gabriel
  • CRUCES COLADO, Jacobo
  • ENJO BABIO, Juan
  • PAMPÍN CASAL, María Begoña
Agents
  • ZBM PATENTS- ZEA, BARLOCCI & MARKVARDSEN
Priority Data
13382158.729.04.2013EP
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) PREPARATION PROCESS OF AN AGONIST OF THE THROMBOPOIETIN RECEPTOR
(FR) PROCÉDÉ DE PRÉPARATION D'UN AGONISTE DU RÉCEPTEUR DE LA THROMBOPOÏÉTINE
Abstract
(EN)
It relates to a preparation process of 2'-(benzyloxy)-3'-nitro-1,1'-biphenyl-3- carboxylic acid or a salt thereof comprising reacting 2-(benzyloxy)-1-bromo- 3-nitrobenzene with a either 3-carboxyphenylboronic acid or a salt thereof or a (C1-C4)-alkyl ester thereof in the presence of Pd(OAc)2, tricydohexylphosphine, a base, an appropriate solvent, and at an appropriate temperature; if appropriate, submitting the compound thus obtained to a hydrolysis reaction; and isolating the compound thus obtained in form of a salt of compound of formula (VI) or in form of the free acid by adding an acid. It also comprises the further preparation to eltrombopag or its salts from the new intermediate thus obtained by subsequent reduction of the nitro group and deprotection of the phenol, conversion of the amine intermediate obtained in a diazonium derivative, and either (1) subsequent reaction with ethyl acetoacetate and with (3,4-dimethylphenyl)hydrazine or a salt thereof, occurring the pyrazole ring formation by intermolecular cyclization, or (2) introduction of the pyrazole ring by reaction with 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one.
(FR)
La présente invention concerne un procédé de préparation de l'acide 2'-(benzyloxy)-3'-nitro-1,1'-biphényl-3- carboxylique ou d'un sel de celui-ci comprenant la mise en réaction d'un 2-(benzyloxy)-1-bromo-3-nitrobenzène avec un acide 3-carboxyphénylboronique ou un sel de celui-ci ou un ester d'alkyle en C1-C4 de celui-ci en présence de Pd(OAc)2, de tricyclohexylphosphine, d'une base, d'un solvant adapté, et à une température adaptée ; au besoin, la soumission du composé ainsi obtenu à une réaction d'hydrolyse ; et l'isolement du composé ainsi obtenu sous la forme d'un sel de composé de formule (VI) ou sous la forme de l'acide libre par ajout d'un acide. La présente invention concerne également la préparation d'eltrombopag ou de sels de celui-ci à partir du nouvel intermédiaire ainsi obtenu par une réduction subséquente du groupe nitro et la déprotection du phénol, la conversion de l'intermédiaire amine obtenu en un dérivé de diazonium, et soit (1) la réaction subséquente avec de l'acétoacétate d'éthyle et avec une (3,4-diméthylphényl)hydrazine ou un sel de celle-ci, la formation du cycle pyrazole se produisant par cyclisation intermoléculaire, soit (2) l'introduction du cycle pyrazol par réaction avec une 1-(3,4-diméthylphényl)-3-méthyl-3-pyrazolin-5-one.
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