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1. (WO2014177517) PREPARATION PROCESS OF AN AGONIST OF THE THROMBOPOIETIN RECEPTOR
Latest bibliographic data on file with the International Bureau   

Pub. No.: WO/2014/177517 International Application No.: PCT/EP2014/058610
Publication Date: 06.11.2014 International Filing Date: 28.04.2014
IPC:
C07C 205/59 (2006.01) ,C07C 201/12 (2006.01) ,C07D 231/22 (2006.01) ,C07C 227/04 (2006.01) ,C07C 249/16 (2006.01)
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
C
ACYCLIC OR CARBOCYCLIC COMPOUNDS
205
Compounds containing nitro groups bound to a carbon skeleton
49
the carbon skeleton being further substituted by carboxyl groups
57
having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
59
the carbon skeleton being further substituted by singly-bound oxygen atoms
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
C
ACYCLIC OR CARBOCYCLIC COMPOUNDS
201
Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
06
Preparation of nitro compounds
12
by reactions not involving the formation of nitro groups
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
D
HETEROCYCLIC COMPOUNDS
231
Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
02
not condensed with other rings
10
having two or three double bonds between ring members or between ring members and non-ring members
14
with 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
18
One oxygen or sulfur atom
20
One oxygen atom attached in position 3 or 5
22
with aryl radicals attached to ring nitrogen atoms
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
C
ACYCLIC OR CARBOCYCLIC COMPOUNDS
227
Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
04
Formation of amino groups in compounds containing carboxyl groups
C CHEMISTRY; METALLURGY
07
ORGANIC CHEMISTRY
C
ACYCLIC OR CARBOCYCLIC COMPOUNDS
249
Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
16
of hydrazones
Applicants:
ESTEVE QUÍMICA, S.A. [ES/ES]; Av. Mare de Déu de Montserrat, 12 E-08024 Barcelona, ES
GALCHIMIA, S.A. [ES/ES]; Cebreiro, s/n E-15823 O Pino, ES
Inventors:
BARTRA SANMARTÍ, Martí; ES
SOLSONA ROCABERT, Joan Gabriel; ES
CRUCES COLADO, Jacobo; ES
ENJO BABIO, Juan; ES
PAMPÍN CASAL, María Begoña; ES
Agent:
ZBM PATENTS- ZEA, BARLOCCI & MARKVARDSEN; Pl. Catalunya, 1 E-08002 Barcelona, ES
Priority Data:
13382158.729.04.2013EP
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.
Designated States: AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
African Regional Intellectual Property Organization (ARIPO) (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW)
Eurasian Patent Office (AM, AZ, BY, KG, KZ, RU, TJ, TM)
European Patent Office (EPO) (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR)
African Intellectual Property Organization (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG)
Publication Language: English (EN)
Filing Language: English (EN)