WO2016096140A1 - Process for the preparation of 1-[(heteroaryl)-methyl]- or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas - Google Patents

Process for the preparation of 1-[(heteroaryl)-methyl]- or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas Download PDF

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WO2016096140A1
WO2016096140A1 PCT/EP2015/002552 EP2015002552W WO2016096140A1 WO 2016096140 A1 WO2016096140 A1 WO 2016096140A1 EP 2015002552 W EP2015002552 W EP 2015002552W WO 2016096140 A1 WO2016096140 A1 WO 2016096140A1
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formula
alkyl
phenyl
compound according
process according
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PCT/EP2015/002552
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French (fr)
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Alexander WESQUET
Claudia WITTLAND
Carsten Griebel
Oswald Zimmer
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Grünenthal GmbH
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1836—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from derivatives of carbamic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1854—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas by reactions not involving the formation of the N-C(O)-N- moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N21/031—Multipass arrangements
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/3581—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using far infrared light; using Terahertz radiation
    • G01N21/3586—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using far infrared light; using Terahertz radiation by Terahertz time domain spectroscopy [THz-TDS]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00—Features of devices classified in G01N21/00
    • G01N2201/06—Illumination; Optics
    • G01N2201/069—Supply of sources
    • G01N2201/0696—Pulsed
    • G01N2201/0697—Pulsed lasers

Definitions

  • the present invention relates to a process for the preparation of certain 1-[(heteroaryl)-methyl]-3-[4- (hydroxymethyl)-phenyl]-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas, in particular certain 1 -[(2-aryl-2H-pyrazol-3-yl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas or physiologically acceptable addition salts and/or solvates thereof.
  • a class of active ingredients having excellent analgesic effectiveness are 1 -[(heteroaryl)-methyl]-3-[4- (hydroxymethyl)-phenylj-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas, which are inter alia known from WO 2010/127856 A1 and WO 2013/068461 A1.
  • Compounds that are of great interest for use in the treatment of pain such as acute, visceral, neuropathic, cancer and chronic pain are in particular certain 1 -[(2-aryl-2H-pyrazol-3-yl)-methyl]-3-[4- (hydroxymethyl)-phenyl]-ureas.
  • Two particular compounds that are of great interest for use in the treatment of pain such as acute, visceral, neuropathic, cancer and chronic pain are 1-[[2-(3-chloro- phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea and 1- [[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxylmethyl)-phenyl]-urea.
  • 1-[(heteroaryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)- phenyl]-ureas (I) are conventionally prepared via a multi-step synthesis including an urea formation between an (heteroaryl-arylmethyl)amine X1 and a phenyl 4-(hydroxymethyl)phenylcarbamate X2 or between an phenyl (heteroaryl-arylmethyl)carbamate X3 and a 4-(hydroxymethyl)phenylamine [4- (hydroxymethyl)aniline] X4 as e.g. disclosed by WO 2013/068461 A1 , pages 60 and 63 (scheme 1):
  • the default TTC level is 1.5 pg/day, but has to be lowered if the impurity belongs to one of the chemical classes considered to be particularly potent.
  • aromatic amines are metabolized in vivo to the corresponding /V-hydroxyl-amines which are usually regarded to be genotoxic. Therefore, anilines are likely to give structural alerts for genotoxicity when evaluated with software packages such as DEREK or MultiCASE. Therefore, if aromatic amines are present as drug impurities and cannot be controlled below the TTC (either individually or in sum total), they need to be tested in conventional genotoxicity tests.
  • Ames test Most conventional in vitro genotoxicity tests in bacteria and mammalian cells (Ames test) employ an exogenous metabolic activation system to mimic mammalian metabolism. A negative Ames test can overrule a positive structural alert. Aniline itself, however, was negative in a number of different Ames tests with different combinations of strains (see Assmann et al, Mutat. Res. 395 (1997) 139-144), probably due to metabolic reasons. Therefore, standard Ames testing for anilines can result in false negative results, which may result in an even more reduced TTC level. Standard Ames testing is therefore not sufficient for assessing the genotoxic potential of a compound bearing an aniline moiety.
  • a further object of the present invention is to provide such a process that has advantages over conventional processes for the preparation of a compound according to formula (I), in particular with respect to influencing the formation of PGI during the process in a targeted manner.
  • a further object of the present invention is to provide a process for the preparation of a compound according to formula (I) that suppresses the formation of PGI.
  • Yet a further object of the present invention is to provide a process for the preparation of a compound according to formula (I) which allows a quantification of formed PGI with reasonable effort.
  • a first aspect of the present invention is a process for the preparation of a compound according to formula (I), optionally in the form of a physiologically acceptable addition salt and/or solvate thereof, (Het)Aryl
  • the step (A-1) comprises the reaction of a compound according to formula (S -1 ) with a compound according to formula (SM-2), in each case optionally in the form of an addition salt and/or solvate thereof, in the presence of at least one alkalizing agent in a reaction medium to form a compound according to formula (IM-1),
  • the step (A-2) comprises the reaction of a compound according to formula (IM-1), optionally in the form of an addition salt and/or solvate thereof, with at least one reducing agent in a reaction medium to form a compound according to formula (I):
  • R A , R B , R c and R D each independently represent H, F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN;
  • R 1 represents C -4 -alkyl, C -alkenyl, halo-C ⁇ -alkyl, benzyl, naphthyl or phenyl, wherein said benzyl, naphthyl or phenyl may be mono- or independently polysubstituted by one or more substituents selected from the group consisting of F, CI, Br, I, CN, N0 2 , CN, CH 3 , CHF 2 , CFH 2 ,
  • R 2 represents C ⁇ -alkyl
  • (Het)aryl represents an optionally substituted aryl or heteroaryl.
  • the compound according to general formula (I) may be present as the free base.
  • the definition of the free base of the compound according to general formula (I) as used herein includes solvates, in particular hydrates, amorphous, co-crystals and crystalline forms, preferably includes solvates, in particular hydrates, co-crystals and crystalline forms.
  • free base means that the compound according to general formula (I) is not present in form of a salt, particularly not in form of an addition salt.
  • the compound according to general formula (I) may, however, also be present in the form of a physiologically acceptable acid addition salt thereof.
  • physiologically acceptable acid addition salt comprises in the sense of this invention a salt of at least one compound according to formula (I) and at least one physiologically acceptable acid, preferably in any stoichiometric ratio of the compound according to general formula (I) and the physiologically acceptable acid.
  • the physiologically acid addition salt is in solid form, in particular in a crystalline form, co-crystalline form and/or amorphous form.
  • the physiologically acid addition salt may also include at least one solvent and therefore may also be in the form of a solvate.
  • Physiologically acceptable acids in the sense of this invention are inorganic or organic acids which are physiologically compatible - in particular when used in human beings and/or other mammals.
  • aryl for the purpose of this invention represents phenyl, 1-naphthyl or 2-naphthyl, wherein the aryl can be unsubstituted or mono- or polysubstituted.
  • heteroaryl for the purpose of this invention represents a cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted; in the case of substitution on the heteroaryl, the substituents can be the same or different and be in any desired and possible position of the heteroaryl.
  • the binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise.
  • heteroaryl residue is selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl,
  • substituted is understood as meaning replacement of a hydrogen radical by a substituent selected from the group consisting of OH, F, CI, Br, I, CN, SH, N0 2l (d-C 4 )-alkyl, (C 2 -C 4 )-alkenyl, (C 2 - C 4 )-alkinyl, (C C )-hydroxyalkyl, (C C 4 )-cyanoalkyl, (C r C 4 )-alkoxy, (C C 4 )-thioalkyl, (C r C 4 )- haloalkyl, (C,-C )-thiohaloalkyl, (C r C 4 )-haloalkoxy, (d-C 4 )-alkyl-S-(Ci-C 4 )-alkyl, (C 3 -C 6 )-
  • substituents may be identical or different.
  • the substituents may be selected from the group consisting of F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, CN, (d-d)-alkyl, (d-C 4 )-hydroxyalkyl, (d-C 4 )-alkoxy, (C 3 -C 6 )- cycloalkyl, NH 2 , NH(d-C 4 )-alkyl, N((d-C 4 )-alkyl) 2 , NHCO(d-C 4 )-alkyl, NHCONH(d-C 4 )-alkyl, NHCON((d-d)-alkyl) 2 , NHS(0) 2 (CrC 4 )-alkyl, CONH 2 , CONH(d-C 4 )-
  • d-d-alkyl (“(d-d)-alkyl”) is understood to mean branched and unbranched alkyl groups consisting of 1 to 4 carbon atoms which is optionally mono- or poly- substituted.
  • Examples of d-d-alkyl are methyl, ethyl, n-propyl, 1-methylethyl (2-propyl; isopropyl), n- butyl, 1-methylpropyl (2-butyl), 2-methylpropyl, 1 ,1-dimethylethyl (2-(2-methyl)propyl; tert-butyl).
  • d-C 3 - alkyl are particularly preferred, in particular methyl, ethyl n-propyl or iso-propyl. Unless otherwise stated, the definitions of propyl and butyl encompass all possible isomeric forms of the individual radicals.
  • d-C 4 -alkoxy is understood to mean branched and unbranched alkyl groups consisting of 1 to 4 carbon atoms which are linked to the subordinate structure residue via an oxygene atom and which is optionally mono- or polysubstituted.
  • Examples of d-C 4 -alkoxy are OCH 3 , OCH 2 CH 3 , 0(CH 2 ) 2 CH 3 , 0(CH 2 ) 3 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OCH(CH 3 )(CH 2 CH 3 ), OC(CH 3 ) 3 .
  • d-C 3 -alkoxy are particularly preferred, in particular OCH 3 , OCH 2 CH 3 or OCH(CH 3 ) 2 .
  • halo-d. -alkyl is understood to be a d. -alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably F, CI or Br, particularly preferably F.
  • the halo- d-4-alkyl can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred halo-d. 4 - alkyl are CHF 2 , CH 2 F, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 .
  • Halo-d-C 3 -alkyl are more preferred, in particular CHF 2l CH 2 F, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 and CH 2 CF 3 .
  • a "halo-d. 4 -alkoxy" is understood to be a C 1-4 -alkoxy in which at least one hydrogen is exchanged for a halogen atom, preferably F, CI or Br, particularly preferably F.
  • the halo-d. 4 -alkoxy can be branched or unbranched and optionally mono- or polysubstituted.
  • halo-C ⁇ -alkoxy are OCHF 2 , OCH 2 F, OCF 3 , OCH 2 CFH 2 , OCH 2 CF 2 H, OCH2CF3.
  • Halo-d.3-alkoxy are preferred, in particular OCHF 2 , OCH 2 F, OCF3, OCH 2 CFH 2 , OCH 2 CF 2 H, OCH 2 CF 3 .
  • a "hydroxy-C ⁇ -alkyl" radical is to be a Ci. 4 -alkyl in which at least one hydrogen is exchanged for a hydroxyl group.
  • the hydroxy-Ci. 4 -alkyl can be branched or unbranched and optionally mono- or polysubstituted.
  • hydroxy-C ⁇ -alkyl are preferred, in particular CH 2 OH, CH 2 CH 2 OH and CH 2 CH 2 CH 2 OH.
  • a is understood to be a C 1-4 -alkyl in which at least one hydrogen is exchanged for a cyano group. The can be branched or unbranched and optionally mono- or polysubstituted.
  • Cyano-C ⁇ -alkyl are preferred, in particular CH 2 CN, CH 2 CH 2 CN and CH 2 CH 2 CH 2 CN.
  • a "C ⁇ -alkoxy-C ⁇ - alkyl" is understood to be a C -4 -alkyl in which at least one hydrogen is exchanged for Ci. 4 -alkoxy.
  • the Ci.4-alkoxy-Ci.4-alkyl can be branched or unbranched and optionally mono- or polysubstituted.
  • C ⁇ - alkoxy-C ⁇ -alkyl are preferred, in particular CH 2 OCH 3 , CH 2 CH2OCH 3 , CH 2 CH2CH 2 OCH 3 ,
  • alkoxy each is understood to be a Ci_ -alkoxy in which at least one hydrogen is exchanged for a hydroxyl, a cyano or a C,. 4 -alkoxy.
  • the hydroxy-C ⁇ -alkoxy, cyano-C ⁇ -alkoxy and C,. 4 -alkoxy-Ci. 4 - alkoxy can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred hydroxy-C ⁇ 4 -alkoxy are OCH 2 CH 2 OH and OCH 2 CH 2 CH 2 OH.
  • Preferred cyano-C ⁇ -alkoxy are OCH 2 CN, OCH 2 CH 2 CN and OCH 2 CH 2 CH 2 CN.
  • Preferred C ⁇ -alkoxy-C alkoxy are OCH 2 CH 2 OCH 3 ,
  • C 3 . B -cycloalkyl means for the purposes of this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms, wherein the hydrocarbons in each case can be unsubstituted or mono- or polysubstituted.
  • the C 3 . 6 -cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the C 3 . 6 -cycloalkyl.
  • the C 3 .6-cycloalkyl can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e.
  • C 3 . 6 -cyclo- alkyls are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, in particular cyclopropyl.
  • the C 3 .
  • C 3 . 7 -heterocycloalkyl can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloalkyl, heterocycloalkyl, aryl or heteroaryl residues.
  • the C 3 . 7 -heterocycloalkyl may be bound to the superordinate general structure via any possible ring member of the heterocycloalkyl if not indicated otherwise.
  • the symbol used in the formulae or part structures denotes a link of a corresponding residue to the respective superordinate general structure.
  • the process is characterized in that one of R A , R B , R c and R D represents F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN, whereas the remaining 3 substituents represent H.
  • R A represents F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN
  • R B , R c and R D each represent H.
  • R A represents F and R B , R c and R D each represent H.
  • the process is characterized in that (Het)Aryl represents pyridinyl, pyrazolyl, thiazolyl or oxazolyl, each unsubstituted or mono- or independently polysubstituted by one or more substituents selected from the group consisting of OH, F, CI, Br, I, CN, SH, N0 2 , (C C 4 )-alkyl, (C 2 -C frustration)-alkenyl, (C 2 -C 4 )-alkinyl, (d-C 4 )-hydroxyalkyl, (d-d)- cyanoalkyl, (d-d)-alkoxy, (d-C 4 )-thioalkyl, (Ci-C )-haloalkyl, (Ci-C 4 )-thiohaloalkyl, (d-C )-halo- alkoxy, (C C4)-alkyl-S-(C
  • (Het)Aryl represents pyridinyl, pyrazolyl, thiazolyl or oxazolyl, substituted by at least one substituent, selected from optionally substituted aryl or optionally substituted heteroaryl.
  • (Het)Aryl represents a structural element according to sub-formula (SF-1 ), (SF-1), wherein
  • X is N, C(H), C(F), C(CI), C(CH 3 ) or C(CF 3 );
  • R E is H, F, CI, CN, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 , CH 2 CH 3 , CH(CH 3 ) 2 ,
  • R F is H, F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN.
  • SF-2 wherein X is C(F), C(CI) or C(CF 3 ), and R E is CH 3 , CF 3 , C(CH 3 ) 3 or cyclopropyl.
  • the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-3),
  • X is N, C(H), C(F), C(CI), C(CH 3 ) or C(CF 3 );
  • R E is H, F, CI, CN, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 , CH 2 CH 3 , CH(CH 3 ) 2 ,
  • R F is H, F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN.
  • X is N, C(H), C(F), C(CI), C(CH 3 ) or C(CF 3 );
  • Z A is O or S;
  • R E is H, F, CI, CN, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 , CH 2 CH 3 , CH(CH 3 ) 2 ,
  • R F is H, F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN.
  • (Het)Aryl represents a structural element according to sub-formula (SF-6),
  • X is C(F), C(CI) or C(CF 3 ); Z A is O or S; and R E is CH 3 , CF 3 , C(CH 3 ) 3 or cyclopropyl.
  • the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-7),
  • X is N, C(H), C(F), C(CI), C(CH 3 ) or C(CF 3 );
  • Z A is O or S;
  • R E is H, F, CI, CN, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 , CH 2 CH 3 , CH(CH 3 ) 2 ,
  • R F is H, F, CI, CH 3 , CHF 2 , CFH 2 , CF 3 , OCH 3 , OCF 3 , OCFH 2 , OCHF 2 or CN.
  • X is C(F), C(CI) or C(CF 3 ); Z A is O or S; and R E is CH 3 , CF 3 , C(CH 3 ) 3 or cyclopropyl.
  • the process is characterized in that R 2 represents CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 or C(CH 3 ) 3 .
  • R 2 represents CH 3 .
  • R 1 represents 2-propenyl, 1-naphthyl, 4-N0 2 -phenyl or phenyl. More preferably, R 1 represents phenyl.
  • the compound according to (SM-1) will be reacted with a compound according to formula (SM-2) in a molar ratio from about 1 : 2 to 2 : 1 , preferably in a molar ratio of 1 : 1.5 to 1.5 : 1 , more preferably in a molar ratio of 1 : 1.1 to 1.1 : 1 and even more preferably in equimolar ratio.
  • a compound according to formula (SM-2) in a molar ratio from about 1 : 2 to 2 : 1 , preferably in a molar ratio of 1 : 1.5 to 1.5 : 1 , more preferably in a molar ratio of 1 : 1.1 to 1.1 : 1 and even more preferably in equimolar ratio.
  • the process is characterized in that the at least one alkalizing agent of step (A-1) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1 ,4-Diazabicyclo[2.2.2]octan (DABCO).
  • the at least one alkalizing agent of step (A-1) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1 ,4-Diazabicyclo[2.2.2]octan (DABCO).
  • the at least one alkalizing agent of step (A-1) is triethylamine, diisopropylethylamine or 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
  • the at least one alkalizing agent of step (A-1) is triethylamine.
  • the process is characterized in that the reaction medium of step (A-1) is an aprotic solvent, preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethyiether, t-butyl-methylether, diisopropylether, dichloromethane, 1 ,2-dichloroethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, N,N- dimethylformamide, 2-butanone, ,4-dioxane, cyclohexane, hexanes and heptanes.
  • an aprotic solvent preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethyiether, t-butyl-methylether, diisopropylether, dichloromethane, 1 ,2-dichloroethane
  • Hexanes with respect to the present invention relates to a mixture of regioisomeres of hexane, e.g. n- hexane, 2-methylpentane, 3-methylpentane or 2,2-dimethylbutane.
  • Heptanes with respect to the present invention relates to a mixture of regioisomeres of heptane, e.g. n-heptane, 2-methylhexane, 3- methylhexane or 2,2-dimethylpentane.
  • reaction medium of step (A-1 ) being an aprotic solvent is selected from the group consisting of toluene, tetrahydrofuran and dichloromethane.
  • reaction medium of step (A-1 ) being an aprotic solvent is toluene.
  • reaction temperature step (A-1) may vary.
  • the person skilled in the art will be able to choose the appropriate reaction temperatures accordingly.
  • As the stability of the starting materials allows elevated reaction temperatures one may consider such elevated reaction temperatures to increase the turnover and reduce the reaction time without the formation of undesired side products.
  • the reaction temperature may vary between 0°C to 110°C, preferably between 50°C to 110°C, even more preferably around 90°C.
  • the compound according to formula (IM-1), optionally in the form of an addition salt and/or solvate thereof will be reacted with at least one reducing agent in a molar ratio from about 1 : 20 to 1 : 1 , preferably in a molar ratio of 1 : 10 to 1 : 2, more preferably in a molar ratio of 1 : 8 to 1 : 3 and even more preferably in molar ratio of about 1 : 4, whereas the molar ratio relates in each case to the stoichiometric ratio.
  • the process is characterized in that the at least one reducing agent of step (A-2) is selected from the group consisting of
  • AIH(CH 2 CH(CH 3 ) 2 )2 DIBAL-H
  • LiAIH 4 LiBH 4 , NaBH 4 , Ca(BH 4 ) 2
  • the at least one reducing agent of step (A-2) is AIH(CH 2 CH(CH 3 ) 2 ) 2 (DIBAL-H), ), LiAIH , LiBH or UAIH 2 (OC 2 H 4 OCH 3 ) 2 .
  • the at least one reducing agent of step (A-2) is AIH(CH 2 CH(CH 3 ) 2 ) 2 (DIBAL-H).
  • the process is characterized in that the reaction medium of step (A-2) is an aprotic solvent, preferably selected from the group consisting of dimethylsulfoxide, 1 ,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.
  • the reaction medium of step (A-2) is an aprotic solvent, preferably selected from the group consisting of dimethylsulfoxide, 1 ,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.
  • reaction medium of step (A-2) being an aprotic solvent is 1 ,4-dioxane.
  • reaction temperature step (A-2) may vary. The person skilled in the art will be able to choose the appropriate reaction temperatures accordingly.
  • the reaction temperature may vary between -20°C to 50°C, preferably between 0°C to 30°C, even more preferably between 0°C to room temperature (22°C +/- 3°C).
  • the process also includes an additional preceding step (A-0),
  • step (A-0) comprises the reaction of a compound according to formula (SM-3), optionally in the form of an addition salt and/or solvate thereof, with a chloroformiate according to formula (SM-4) in the presence of at least one alkalizing agent in a reaction medium to form the compound according to formula (SM).
  • SM-3 compound according to formula (SM-3)
  • SM-4 chloroformiate according to formula (SM-4)
  • the process is characterized in that the at least one alkalizing agent of step (A-0) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, ⁇ , ⁇ -dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-Diazabicyclo[2.2.2Joctan (DABCO), Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 , LiOH, NaOH, KOH, Mg(OH) 2 and Ca(OH) 2 .
  • the at least one alkalizing agent of step (A-0) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, ⁇ , ⁇ -dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-Diaz
  • the at least one alkalizing agent of step (A-0) is pyridine, Na 2 CO a , K 2 C0 3 or Cs 2 C0 3 . More preferably, the at least one alkalizing agent of step (A-0) is pyridine.
  • the process is characterized in that the reaction medium of step (A-0) is an aprotic solvent, preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethylether, t-butyl-methylether, diisopropylether, dichloromethane, 1 ,2-dichloroethane, cyclohexane, hexanes, heptanes, acetone, dimethylsulfoxide, acetonitrile, ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, ⁇ , ⁇ -diethylacetamide, 1 ,4-dioxane, N- methyl-pyrrolidinone, N-butyl-pyrrolidinone, ethyl acetate and 2-butanone,
  • an aprotic solvent preferably selected from the group consisting of toluene, xylene, tetrahydr
  • reaction medium of step (A-0) being an aprotic solvent is selected from the group consisting of tetrahydrofuran, 2-butanone and acetone.
  • reaction medium of step (A-0) being an aprotic solvent is acetone.
  • reaction temperature step (A-0) may vary. The person skilled in the art will be able to choose the appropriate reaction temperatures accordingly.
  • the reaction temperature may vary between -20°C to 50°C, preferably between 0°C to room temperature (22°C +/- 3°C), even more preferably between 0°C to 10°C and more preferably between 0°C to 5°C.
  • step (A-2) can optionally be further purified in a manner well known to those skilled in the art, for instance in an additional recrystallization step.
  • the process is characterized in that the process further comprises an additional subsequent step (A-3), wherein the step (A-3) comprises the recrystallization of the compound according to general formula (I) obtained from step (A-2) in a recrystallization medium.
  • step (A-3) the compound according to formula (I) obtained from step (A- 2) is dissolved in a suitable medium followed by a precipitation of said compound, preferably by changing the composition of the recrystallization medium by addition of another medium.
  • Suitable recrystallization media for dissolving the compound according to formula (I) obtained from step (A-2) can be determined by the person skilled in the art using preliminary tests.
  • organic solvents selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, iso-propanol and n-butanol; esters such as ethyl acetate, n-propyl acetate, iso-propyl acetate, n-butyl acetate and iso-butyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; ethers such as tert-butyl methyl ether, diethylether, tetrahydrofuran, diisopropylether and 1 ,4-dioxane; nitrites such as acetonitrile; aromatic hydrocarbons such as toluene; chlorinated hydrocarbons such as dichloromethane and chloro
  • step (A-3) after dissolving the compound according to formula (I) obtained from step (A-2) in step (A-3) in a suitable solvent, said compound is precipitated by addition of another medium.
  • the second part of step (A-3) is carried out by the addition of a medium in which the compound of formula (I) is only poorly soluble ("anti-solvent") to the solution obtained in the first part of step (A-3).
  • said medium employed for precipitation of the compound according to formula (I) is selected from the group consisting of water, alcohols, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol, diethyl ether, acetone, and alkyl acetates such as ethyl acetate, more preferably the medium employed for precipitation of the compound according to formula (I) is water.
  • the recrystallization medium of subsequent step (A-3) is an alcohol, selected from methanol, ethanol, n-propanol, iso-propanol and n-butanol which is changed to a mixture of the respective alcohol with water.
  • the recrystallization medium of subsequent step (A-3) is ethanol or a mixture of ethanol, being diluted with water.
  • step (A-3) the compound according to formula (I) obtained after performing step (A-2) is preferably first dissolved in a suitable solvent, preferably in ethanol, at an elevated temperature, preferably at a temperature in the range of from 30°C to 75°C, more preferably at a temperature in the range of from 40°C to 70°C, even more preferably at a temperature in the range of from 50°C to 65°C.
  • a suitable solvent preferably in ethanol
  • the resulting mixture is then cooled, preferably to a temperature in the range of from -5°C to 20°C, more preferably at a temperature in the range of from 0°C to 10°C, followed by addition of the medium employed for precipitation, preferably water, of the compound according to formula (I) at this temperature.
  • the medium employed for precipitation preferably water
  • the resulting mixture of the compound according to formula (I) at this temperature is diluted by the medium employed for precipitation, preferably by water, and then cooled, preferably to a temperature in the range of from -5°C to 20°C, more preferably at a temperature in the range of from 0°C to 10°C, more preferably to about 0°C.
  • Steps (A-3) may be repeated in order to further purify the compound according to formula (I) obtained, if necessary.
  • the steps according to the process according to the present invention can be carried out discontinuously (batchwise) or continuously, preference being given to the discontinuous procedure.
  • reactor for the discontinuous procedure for example, a slurry reactor, and for the continuous procedure a fixed-bed reactor or loop reactor.
  • a compound according to formula (SM-3) (1 equivalent) is dissolved in at least aprotic solvent as reaction medium such as acetone or tetrahydrofuran wherein the reaction medium is preferably employed in an amount by weight that is in the range of from 3 to 60 times higher than the total amount of starting material according to formula (SM-3) by weight and an alkalizing (2 to 3 equivalents), such as pyridine, is added.
  • aprotic solvent such as acetone or tetrahydrofuran
  • the resulting mixture is cooled to a temperature in the range of from -10°C to 0°C and a solution of compound according to formula (SM-4) (1-3 equivalents) in at least aprotic solvent as reaction medium such as acetone or tetrahydrofuran (about 0.5 to 1.5 molar solution) is added over a period of 45 to 90 min.
  • aprotic solvent as reaction medium such as acetone or tetrahydrofuran (about 0.5 to 1.5 molar solution) is added over a period of 45 to 90 min.
  • the resulting mixture is stirred for 1 to 10 h at 0°C to 5°C (reaction time) and then warmed to room temperature.
  • An equal volume of water is added and the resulting mixture is stirred at this temperature for a time of 1 h to 20 h.
  • a precipitate forms which is filtered off and preferably washed with a solvent, preferably with water or methanol.
  • the resulting (SM- 2) is dried under reduced pressure at
  • reaction medium 0.1 to 0.5 molar
  • aprotic solvent such as toluene
  • the alkalizing agent is added (1-3 equivalents, depending on whether SM-2 or SM-3 are employed as salts or as a free base) at room temperature.
  • the resulting mixture is heated slightly below boiling temperature of the solvent (reaction temperature) and stirred for a time that is in the range of from 30 minutes to 20 h (reaction time) at a reaction temperature.
  • An equal volume of water is added and the resulting mixture is stirred while cooling to reaction temperature.
  • a precipitate forms which is filtered off and preferably washed with a solvent, preferably with an aprotic solvent, such as toluene.
  • the resulting (IM-I) is filtered again and the filter cake dried under reduced pressure.
  • a solution of (IM-I) obtained from step (A-1) in a reaction medium (0.1 to 0.5 molar), preferably an aprotic solvent, such as 1 ,4-dioxane is added at 0°C to room temperature.
  • the reaction mixture was stirred at 20-25°C for 90 min to 5 h. After cooling to 0-5°C, water (5-10 v/v-%) was added slowly at 0°C to 10°C.
  • An aqueous solution of sodium hydroxide (3 mol equivalents compared to the reduction agent in water (20-30 v/v- %) is added at 0°C to 10°C.
  • the reaction mixture is stirred at room temperature for 30 min to 20 h.
  • the phases are separated.
  • the organic layer is washed (e.g. with brine) and is dried over an anhydrous magnesium sulfate.
  • the mother liquor is collected and is concentrated under reduced pressure.
  • the crude product is either washed with additional solvent or precipitated by addition of another, less polar.
  • the wet product is dried under reduced pressure at elevated temperatures (e.g. 50°C) for 2 ⁇ *8 h to give (I).
  • step (A-2) To the crude product obtained from step (A-2) is added a solvent such ethanol and the resulting mixture is heated to a temperature in the range of from 50°C to 70°C until the precipitate is completely dissolved at this temperature. Then, a further medium, preferably water (about half of the volume of solvent), is added and the mixture is cooled to a temperature in the range of from -5°C to 10°, and at this temperature the desired product forms, i.e. a compound according to formula (I) in the re- crystallized form, which is filtered and dried at elevated temperatures (e.g. 50°C) under reduced pressure.
  • a solvent such ethanol
  • methyl 4-amino-3-fluoro-benzoate (SM-3-I) (500 g, 2,96 mol) was dissolved in acetone (2,00 I) and pyridine (721 ml, 8,87 mol) was added. The reaction mixture was cooled to 0°C. A solution of phenyl chloroformate (465 ml, 3,70 mol) in acetone (3,00 I) was added at 0-5°C during 45-60 min. The reaction mixture was stirred for 1 h at 0-5°C, upon a white suspension has formed.
  • SM-3-I 4-amino-3-fluoro-benzoate
  • Step A-1 Synthesis of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro- 4-(methoxycarbonyl)-phenyl]-urea
  • the reaction mixture was stirred for 2 h at 80-90°C.
  • Step A-2 Synthesis of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro- 4-(hydroxymethyl)-phenyl]-urea (crude)
  • the reaction mixture was stirred at 20-25°C for 90 min.
  • the mother liquor was concentrated under reduced pressure at 50°C until the solution becomes turbid (about 45 I was distilled off), then toluene (10,0 I) was added at 50°C. After cooling to 20-25°C, the reaction mixture was stirred for 45-60 min and the suspension was filtered over a filter centrifuge (1800 rpm).
  • Step A-3 Synthesis of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro- 4-(hydroxymethyl)-phenyl]-urea
  • aniline 1 is unstable under the reaction conditions and various side products (PGIs) are formed in an uncontrolled manner. Therefore, aniline 1 is not suitable for the controlling the amount of PGIs in the synthesis of compounds of compounds of formula (I).
  • the sum of the amount of methyl 4-amino-3-fluoro-benzoate (S -3-I) prior to step A-2 and the potentially increased amount of [1-(3-chlorophenyl)-3-trifluoromethyl- H-pyrazol- 5-yl]-methan]amine (SM-1-1; free base) during step A-2 represents the maximum amount of all aniline type PGIs without assessment of their individual structure.

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Abstract

The present invention relates to a process for the preparation of certain 1-[(heteroaryl)-methyl]-3-[4- (hydroxymethyl)-phenyl]-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas, in particular certain 1-[(2-aryl-2H-pyrazol-3-yl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas or physiologically acceptable addition salts and/or solvates thereof.

Description

Process for the preparation of 1-[(heteroaryl)-methyl]- or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)- phenyl]-ureas
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of certain 1-[(heteroaryl)-methyl]-3-[4- (hydroxymethyl)-phenyl]-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas, in particular certain 1 -[(2-aryl-2H-pyrazol-3-yl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas or physiologically acceptable addition salts and/or solvates thereof.
BACKGROUND OF THE INVENTION
A class of active ingredients having excellent analgesic effectiveness are 1 -[(heteroaryl)-methyl]-3-[4- (hydroxymethyl)-phenylj-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas, which are inter alia known from WO 2010/127856 A1 and WO 2013/068461 A1.
Compounds that are of great interest for use in the treatment of pain such as acute, visceral, neuropathic, cancer and chronic pain are in particular certain 1 -[(2-aryl-2H-pyrazol-3-yl)-methyl]-3-[4- (hydroxymethyl)-phenyl]-ureas. Two particular compounds that are of great interest for use in the treatment of pain such as acute, visceral, neuropathic, cancer and chronic pain are 1-[[2-(3-chloro- phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea and 1- [[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxylmethyl)-phenyl]-urea.
1-[(heteroaryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)- phenyl]-ureas (I) are conventionally prepared via a multi-step synthesis including an urea formation between an (heteroaryl-arylmethyl)amine X1 and a phenyl 4-(hydroxymethyl)phenylcarbamate X2 or between an phenyl (heteroaryl-arylmethyl)carbamate X3 and a 4-(hydroxymethyl)phenylamine [4- (hydroxymethyl)aniline] X4 as e.g. disclosed by WO 2013/068461 A1 , pages 60 and 63 (scheme 1):
Figure imgf000002_0001
The processes for the preparation of 1-[(heteroaryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas or 1- [(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas according to scheme 1 are, however, not satisfactory and there is a demand for advantageous processes for the preparation of these compounds. In particular, there is a demand for an alternative process that allows for controlling the amount of potentially genotoxic impurities (PGI) during the reaction and in the final product.
The genotoxic impurities guidelines by health authorities such as E (E)A (2006, 2010) and FDA (2008) require the assessment for structural alerts for genotoxicity in the product as well as all possible impurities, intermediates, by-products, residual starting materials and degradation products (potentially genotoxic impurities; PGI). If structural alerts are found and if the impurities cannot be avoided, they have to be limited to an acceptably low level (below the threshold of toxicological concern, TTC) to be considered an acceptable risk. If one or more impurities has a structural alert for genotoxicity, but cannot be controlled below the TTC, then they need to be tested (as individual substances) in conventional genotoxicity tests. The default TTC level is 1.5 pg/day, but has to be lowered if the impurity belongs to one of the chemical classes considered to be particularly potent.
Most aromatic amines (anilines) are metabolized in vivo to the corresponding /V-hydroxyl-amines which are usually regarded to be genotoxic. Therefore, anilines are likely to give structural alerts for genotoxicity when evaluated with software packages such as DEREK or MultiCASE. Therefore, if aromatic amines are present as drug impurities and cannot be controlled below the TTC (either individually or in sum total), they need to be tested in conventional genotoxicity tests.
Most conventional in vitro genotoxicity tests in bacteria and mammalian cells (Ames test) employ an exogenous metabolic activation system to mimic mammalian metabolism. A negative Ames test can overrule a positive structural alert. Aniline itself, however, was negative in a number of different Ames tests with different combinations of strains (see Assmann et al, Mutat. Res. 395 (1997) 139-144), probably due to metabolic reasons. Therefore, standard Ames testing for anilines can result in false negative results, which may result in an even more reduced TTC level. Standard Ames testing is therefore not sufficient for assessing the genotoxic potential of a compound bearing an aniline moiety.
Anilines bearing the 4-hydroxymethyl-substituent, such as 4-(hydroxymethyl)phenylamine X4, have been recognized as key intermediates in the synthesis of (I) either for the direct conversion with phenyl (heteroaryl-/arylmethyl)carbanmates X3 or for the formation of phenyl 4-(hydroxymethyl)phenyl- carbamates X2 to be later converted with (heteroaryl-/arylmethyl)amine X1 .
Figure imgf000003_0001
Besides the genotoxicity alert of 4-(hydroxymethyl)phenylamines X4 itself, which would have to be controlled below the TTC in the final product (I), it was found that in particular 4-(hydroxymethyl)- phenylamines X4 have impaired stability under slightly elevated temperatures. For instance, 3-fluoro- 4-(hydroxymethyl)phenylamine revealed degradation by more than 10% under ethanol-water workup conditions at 50°C. One major degradation product of such decomposition is believed to proceed via the reactive intermediate Y1 which is prone to form dimeric (X5) and even oligomeric and polymeric impurities (X6„) under addition of one or more X4 unit:
Figure imgf000004_0001
Hence, with X5 and X6n being also aromatic amines, a multitude of new potential potential genotoxic impurities (PGI) are formed.
Control of such PGI as a sum below the TTC, however, would still be required, requiring the development of burdensome quantitative detection methodologies for each individual impurity and eventually the quantification of PGI in the final product.
As the quantification of all PGI as well as the genotoxicity testings for each PGI remain a high challenge in the preparation of the compounds (I) according to the known synthetic route, it would be highly desirable to improve said process by suppressing the formation of PGI and/or allow
It is therefore an object of the present invention to provide an alternative process which allows for the preparation of a compound according to formula (I). A further object of the present invention is to provide such a process that has advantages over conventional processes for the preparation of a compound according to formula (I), in particular with respect to influencing the formation of PGI during the process in a targeted manner. A further object of the present invention is to provide a process for the preparation of a compound according to formula (I) that suppresses the formation of PGI. Yet a further object of the present invention is to provide a process for the preparation of a compound according to formula (I) which allows a quantification of formed PGI with reasonable effort.
These objects have been achieved by the subject-matter of the patent claims.
Therefore, a first aspect of the present invention is a process for the preparation of a compound according to formula (I), optionally in the form of a physiologically acceptable addition salt and/or solvate thereof, (Het)Aryl
comprising one step (A-1) and one subsequent step (A-2),
characterized in that
the step (A-1) comprises the reaction of a compound according to formula (S -1 ) with a compound according to formula (SM-2), in each case optionally in the form of an addition salt and/or solvate thereof, in the presence of at least one alkalizing agent in a reaction medium to form a compound according to formula (IM-1),
Figure imgf000005_0001
and
the step (A-2) comprises the reaction of a compound according to formula (IM-1), optionally in the form of an addition salt and/or solvate thereof, with at least one reducing agent in a reaction medium to form a compound according to formula (I):
reducing
agent
(IM-1 )
(I)
wherein in each case
RA, RB, Rc and RD each independently represent H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN;
R1 represents C -4-alkyl, C -alkenyl, halo-C^-alkyl, benzyl, naphthyl or phenyl, wherein said benzyl, naphthyl or phenyl may be mono- or independently polysubstituted by one or more substituents selected from the group consisting of F, CI, Br, I, CN, N02, CN, CH3, CHF2, CFH2,
CF3 or OCH3;
R2 represents C^-alkyl;
and
(Het)aryl represents an optionally substituted aryl or heteroaryl.
It has been surprisingly found that employing certain 4-(alkoxycarbonyl)phenylcarbamates (SM-2) the inventive process allows for the preparation of compounds (I) in multigram quantities. Further, when employing 4-(alkoxycarbonyl)phenylcarbamates (SM-2) in step (A-1 ) of the inventive process, it has been found that the reaction proceeds with the reduced formation of PGI. Even further, due to the improved stability of the intermediates in the process, a clear strategy for assessment of PGI is available. Thus, the inventive process allows for reduced efforts to assess the content of PGI in the final product. DETAILED DESCRIPTION
The compound according to general formula (I) may be present as the free base. The definition of the free base of the compound according to general formula (I) as used herein includes solvates, in particular hydrates, amorphous, co-crystals and crystalline forms, preferably includes solvates, in particular hydrates, co-crystals and crystalline forms. For the purpose of the specification, "free base" means that the compound according to general formula (I) is not present in form of a salt, particularly not in form of an addition salt.
The compound according to general formula (I) may, however, also be present in the form of a physiologically acceptable acid addition salt thereof. The term "physiologically acceptable acid addition salt" comprises in the sense of this invention a salt of at least one compound according to formula (I) and at least one physiologically acceptable acid, preferably in any stoichiometric ratio of the compound according to general formula (I) and the physiologically acceptable acid. The physiologically acid addition salt is in solid form, in particular in a crystalline form, co-crystalline form and/or amorphous form. The physiologically acid addition salt may also include at least one solvent and therefore may also be in the form of a solvate. Physiologically acceptable acids in the sense of this invention are inorganic or organic acids which are physiologically compatible - in particular when used in human beings and/or other mammals.
The term "aryl" for the purpose of this invention represents phenyl, 1-naphthyl or 2-naphthyl, wherein the aryl can be unsubstituted or mono- or polysubstituted.
The term " heteroaryl" for the purpose of this invention represents a cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted; in the case of substitution on the heteroaryl, the substituents can be the same or different and be in any desired and possible position of the heteroaryl. The binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise. It is preferable for the heteroaryl residue to be selected from the group consisting of benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl.
In connection with aromatic moieties such as "aryl" and "heteroaryl", in the context of this invention the term "substituted" is understood as meaning replacement of a hydrogen radical by a substituent selected from the group consisting of OH, F, CI, Br, I, CN, SH, N02l (d-C4)-alkyl, (C2-C4)-alkenyl, (C2- C4)-alkinyl, (C C )-hydroxyalkyl, (C C4)-cyanoalkyl, (CrC4)-alkoxy, (C C4)-thioalkyl, (CrC4)- haloalkyl, (C,-C )-thiohaloalkyl, (CrC4)-haloalkoxy, (d-C4)-alkyl-S-(Ci-C4)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(d-C4)-alkyl, (C3-C7)-heterocycloalkyl, (C3-C7)-heterocycloalkyl-(d-d)-alkyl, NH2, NH(C,-C4)-alkyl, N((d-C4)-alkyl)2, NHCO(C,-C4)-alkyl, NHCOO(d-d)-alkyl, NHC(0)NH2,
NHCONH(d-d)-alkyl, NHCON((d-C4)-alkyl)2, NH((d-d)-alkyl)COO(C,-C4)-alkyl, NH((d-C4)- alkyl)CONH2, NH((C1-C4)-alkyl)CONH(C1-C4)-alkyl, NH((C C4)-alkyl)CON((d-C4)-alkyl)2,
NHS(0)2OH, NHS(0)2(d-C4)-alkyl, NHS(0)20(d-C4)-alkyl, NH-S(0)2NH2, NHS(0)2NH(d-C4)-alkyl, NH-S(0)2N((d-C4)-alkyl)2, NH((d-C4)-alkyl)-S(0)2OH, NH((d-d)-alkyl)S(0)2(d-C4)-alkyl, NH((C C4)-alkyl)-S(0)20(d-C4)-alkyl, NH((d-C4)-alkyl)S(0)2NH2, NH((d-C4)-alkyl)S(0)2NH(d-C4)-alkyl, C02H, CO(C C4)-alkyl, COO(Ci-C4)-alkyl, OCO(Ci-C4)-alkyl, OCOO(d-C4)-alkyl, CONH2l CONH(C C4)-alkyl, CON((C d)-alkyl)2, OCONH(d-C4)-alkyl, OCON((C,-C4)-alkyl)2, OS(0)2(C1-C4)-alkyl, OS(0)2OH, OS(0)2(Ci-C4)-alkoxy, OS(0)2NH2, OS(0)2NH(C1-d)-alkyl, OS(0)2-N((d-C4)-alkyl)2, S(0)(d-d)-alkyl, S(0)2(d-C4)-alkyl, S(0)2OH, S(0)20(d-C4)-alkyl, S(0)2NH2, S(0)2NH(d-d)-alkyl, S(0)2N((d-C4)-alkyl)2, optionally substituted aryl or optionally substituted heteroaryl. If a moiety is substituted with more than 1 substituent, e.g. by 2, 3, 4, or 5 substituents, these substituents may be identical or different. Preferably, the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OH, CN, (d-d)-alkyl, (d-C4)-hydroxyalkyl, (d-C4)-alkoxy, (C3-C6)- cycloalkyl, NH2, NH(d-C4)-alkyl, N((d-C4)-alkyl)2, NHCO(d-C4)-alkyl, NHCONH(d-C4)-alkyl, NHCON((d-d)-alkyl)2, NHS(0)2(CrC4)-alkyl, CONH2, CONH(d-C4)-alkyl, CON((C C4)-alkyl)2, S(0)(d-C4)-alkyl and S(0)2(C1-d)-alkyl.
Unless otherwise specified, the term "d-d-alkyl" ("(d-d)-alkyl") is understood to mean branched and unbranched alkyl groups consisting of 1 to 4 carbon atoms which is optionally mono- or poly- substituted. Examples of d-d-alkyl are methyl, ethyl, n-propyl, 1-methylethyl (2-propyl; isopropyl), n- butyl, 1-methylpropyl (2-butyl), 2-methylpropyl, 1 ,1-dimethylethyl (2-(2-methyl)propyl; tert-butyl). d-C3- alkyl are particularly preferred, in particular methyl, ethyl n-propyl or iso-propyl. Unless otherwise stated, the definitions of propyl and butyl encompass all possible isomeric forms of the individual radicals.
Unless otherwise specified, the term "d-C4-alkoxy" is understood to mean branched and unbranched alkyl groups consisting of 1 to 4 carbon atoms which are linked to the subordinate structure residue via an oxygene atom and which is optionally mono- or polysubstituted. Examples of d-C4-alkoxy are OCH3, OCH2CH3, 0(CH2)2CH3, 0(CH2)3CH3, OCH(CH3)2, OCH2CH(CH3)2, OCH(CH3)(CH2CH3), OC(CH3)3. d-C3-alkoxy are particularly preferred, in particular OCH3, OCH2CH3or OCH(CH3)2.
Unless otherwise specified, a "halo-d. -alkyl" is understood to be a d. -alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably F, CI or Br, particularly preferably F. The halo- d-4-alkyl can be branched or unbranched and optionally mono- or polysubstituted. Preferred halo-d.4- alkyl are CHF2, CH2F, CF3, CH2CH2F, CH2CHF2, CH2CF3. Halo-d-C3-alkyl are more preferred, in particular CHF2l CH2F, CF3, CH2CH2F, CH2CHF2 and CH2CF3. Unless otherwise specified, a "halo-d. 4-alkoxy" is understood to be a C1-4-alkoxy in which at least one hydrogen is exchanged for a halogen atom, preferably F, CI or Br, particularly preferably F. The halo-d.4-alkoxy can be branched or unbranched and optionally mono- or polysubstituted. Preferred halo-C^-alkoxy are OCHF2, OCH2F, OCF3, OCH2CFH2, OCH2CF2H, OCH2CF3. Halo-d.3-alkoxy are preferred, in particular OCHF2, OCH2F, OCF3, OCH2CFH2, OCH2CF2H, OCH2CF3.
Unless otherwise specified, a "hydroxy-C^-alkyl" radical is to be a Ci.4-alkyl in which at least one hydrogen is exchanged for a hydroxyl group. The hydroxy-Ci.4-alkyl can be branched or unbranched and optionally mono- or polysubstituted. hydroxy-C^-alkyl are preferred, in particular CH2OH, CH2CH2OH and CH2CH2CH2OH. Unless otherwise specified, a
Figure imgf000008_0001
is understood to be a C1-4-alkyl in which at least one hydrogen is exchanged for a cyano group. The
Figure imgf000008_0002
can be branched or unbranched and optionally mono- or polysubstituted. Cyano-C^-alkyl are preferred, in particular CH2CN, CH2CH2CN and CH2CH2CH2CN. Unless otherwise specified, a "C^-alkoxy-C^- alkyl" is understood to be a C -4-alkyl in which at least one hydrogen is exchanged for Ci.4-alkoxy. The Ci.4-alkoxy-Ci.4-alkyl can be branched or unbranched and optionally mono- or polysubstituted. C^- alkoxy-C^-alkyl are preferred, in particular CH2OCH3, CH2CH2OCH3, CH2CH2CH2OCH3,
CH2OCH2CH3 and CH2OCH(CH3)2.
Unless otherwise specified, a
Figure imgf000008_0003
alkoxy" each is understood to be a Ci_ -alkoxy in which at least one hydrogen is exchanged for a hydroxyl, a cyano or a C,.4-alkoxy. The hydroxy-C^-alkoxy, cyano-C^-alkoxy and C,.4-alkoxy-Ci.4- alkoxy can be branched or unbranched and optionally mono- or polysubstituted. Preferred hydroxy-C^ 4-alkoxy are OCH2CH2OH and OCH2CH2CH2OH. Preferred cyano-C^-alkoxy are OCH2CN, OCH2CH2CN and OCH2CH2CH2CN. Preferred C^-alkoxy-C alkoxy are OCH2CH2OCH3,
OCH2CH2CH2OCH3, OCH(CH3)OCH3, OCH2CH2OCH2CH3 and OCH2CH2OCH(CH3)2.
The term "C3.B-cycloalkyl" means for the purposes of this invention cyclic aliphatic hydrocarbons containing 3, 4, 5 or 6 carbon atoms, wherein the hydrocarbons in each case can be unsubstituted or mono- or polysubstituted. The C3.6-cycloalkyl can be bound to the respective superordinate general structure via any desired and possible ring member of the C3.6-cycloalkyl. The C3.6-cycloalkyl can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloalkyl, heterocycloalkyl, aryl or heteroaryl residues. Preferred C3.6-cyclo- alkyls are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, in particular cyclopropyl.
The terms "C3-7-heterocycloalkyl" mean for the purposes of this invention heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members, in which in each case at least one, if appropriate also two, three or four carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of 0, S, S(=0), S(=0)2, N, NH and NiC^-alky!) such as N(CH3), wherein the ring members can be unsubstituted or mono- or polysubstituted. The C3.7-heterocycloalkyl can also be condensed with further saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloalkyl, heterocycloalkyl, aryl or heteroaryl residues. The C3.7-heterocycloalkyl may be bound to the superordinate general structure via any possible ring member of the heterocycloalkyl if not indicated otherwise.
Within the scope of the present invention, the symbol used in the formulae or part structures denotes a link of a corresponding residue to the respective superordinate general structure.
In one embodiment of the first aspect of the present invention, the process is characterized in that one of RA, RB, Rc and RD represents F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN, whereas the remaining 3 substituents represent H.
Preferably, RA represents F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN, and RB, Rc and RD each represent H.
More preferably, RA represents F and RB, Rc and RD each represent H.
In one embodiment of the first aspect of the present invention, the process is characterized in that (Het)Aryl represents pyridinyl, pyrazolyl, thiazolyl or oxazolyl, each unsubstituted or mono- or independently polysubstituted by one or more substituents selected from the group consisting of OH, F, CI, Br, I, CN, SH, N02, (C C4)-alkyl, (C2-C„)-alkenyl, (C2-C4)-alkinyl, (d-C4)-hydroxyalkyl, (d-d)- cyanoalkyl, (d-d)-alkoxy, (d-C4)-thioalkyl, (Ci-C )-haloalkyl, (Ci-C4)-thiohaloalkyl, (d-C )-halo- alkoxy, (C C4)-alkyl-S-(CrC4)-alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(d-C4)-alkyl, (C3-C7)- heterocycloalkyl, (C3-C7)-heterocycloalkyl-(C1-C )-alkyl, NH2, NH(C1-C4)-alkyl, N((C C4)-alkyl)2) NHCO(C C4)-alkyl, NHCOO(C C4)-alkyl, NHC(0)NH2, NHCONH(d-C4)-alkyl, NHCON((d-C4)- alkyl)2, NH((d-C4)-alkyl)C00(d-C4)-alkyl, NH((C C4)-alkyl)CONH2, NH((d-C4)-alkyl)C0NH(d-C4)- alkyl, NH((C C4)-alkyl)CON((d-C4)-alkyl)2, NHS(0)2OH, NHS(0)2(d-C4)-alkyl, NHS(0)20(C C4)- alkyl, NH-S(0)2NH2, NHS(0)2NH(d-C4)-alkyl, NH-S(0)2N((C1-C4)-alkyl)2, NH((d-C4)-alkyl)-S(0)2OH, NH((d-C4)-alkyl)S(0)2(d-C4)-alkyl, NH((Ci-C4)-alkyl)-S(0)20(d-C4)-alkyl, NH((C C4)-alkyl)- S(0)2NH2, NH((C1-C4)-alkyl)S(0)2NH(C1-C4)-alkyl, C02H, CO(C C4)-alkyl, COO(d-C4)-alkyl, OCO(d-C4)-alkyl, OCOO(Ci-C4)-alkyl, CONH2, CONH(C C4)-alkyl, CON((C C4)-alkyl)2, OCONH(d- C4)-alkyl, OCON((d-C4)-alkyl)2, 0S(0)2(C C4)-alkyl, OS(0)2OH, OS(0)2(d-C4)-alkoxy, 0S(0)2NH2, OS(0)2NH(d-C4)-alkyl, OS(0)2-N((d-C4)-alkyl)2l S(0)(C C4)-alkyl, S(0)2(C1-C4)-alkyl, S(0)2OH, S(0)20(C C4)-alkyl, S(0)2NH2, S(0)2NH(d-C4)-alkyl, S(0)2N((C C4)-alkyl)2, optionally substituted aryl or optionally substituted heteroaryl.
Preferably, (Het)Aryl represents pyridinyl, pyrazolyl, thiazolyl or oxazolyl, substituted by at least one substituent, selected from optionally substituted aryl or optionally substituted heteroaryl.
More preferably, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-1 ),
Figure imgf000010_0001
(SF-1), wherein
X is N, C(H), C(F), C(CI), C(CH3) or C(CF3);
RE is H, F, CI, CN, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2, CH2CH3, CH(CH3)2,
C(CH3)3 or cyclopropyl; and
RF is H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN.
Particularly preferred, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-2),
Figure imgf000010_0002
(SF-2), wherein X is C(F), C(CI) or C(CF3), and RE is CH3, CF3, C(CH3)3 or cyclopropyl.
In another preferred embodiment of the first aspect of the present invention, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-3),
Figure imgf000010_0003
(SF-3), wherein
X is N, C(H), C(F), C(CI), C(CH3) or C(CF3);
RE is H, F, CI, CN, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2, CH2CH3, CH(CH3)2,
C(CH3)3or cyclopropyl; and
RF is H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN.
Particularly preferred, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-4),
Figure imgf000010_0004
(SF-4), wherein X is C(F), C(CI) or C(CF3); and RE is CH3, CF3, C(CH3)3 or cyclopropyl. In another preferred embodiment of the first aspect of the present invention, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-5),
Figure imgf000011_0001
(SF-5), wherein
X is N, C(H), C(F), C(CI), C(CH3) or C(CF3); ZA is O or S;
RE is H, F, CI, CN, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2, CH2CH3, CH(CH3)2,
C(CH3)3 or cyclopropyl; and
RF is H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN.
Particularly preferred, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-6),
Figure imgf000011_0002
wherein X is C(F), C(CI) or C(CF3); ZA is O or S; and RE is CH3, CF3, C(CH3)3 or cyclopropyl.
In another preferred embodiment of the first aspect of the present invention, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-7),
Figure imgf000011_0003
-7), wherein
X is N, C(H), C(F), C(CI), C(CH3) or C(CF3); ZA is O or S;
RE is H, F, CI, CN, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2, CH2CH3, CH(CH3)2,
C(CH3)3or cyclopropyl; and
RF is H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN.
Particularly preferred, the process is characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-8),
Figure imgf000012_0001
wherein X is C(F), C(CI) or C(CF3); ZA is O or S; and RE is CH3, CF3, C(CH3)3 or cyclopropyl.
In yet another more preferred embodiment of the first aspect of the present invention, the process is characterized in that the compound according to formula (I) is
Figure imgf000012_0002
namely 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxyl- methyl)-phenyl]-urea, or is
Figure imgf000012_0003
namely 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxylmethyl)- phenyl]-urea,
in each case optionally in the form of a physiologically acceptable addition salt and/or solvate thereof.
In yet another embodiment of the first aspect of the present invention, the process is characterized in that R2 represents CH3, CH2CH3, CH(CH3)2 or C(CH3)3.
Preferably, R2 represents CH3.
In another embodiment of the first aspect of the present invention, the process is characterized in that R represents CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2CF3l CH2CH=CH2 (allyl), C(CH3)=CH2 (2- propenyl), 1-naphthyl, 2-naphthyl, 4-N02-phenyl or phenyl.
Preferably, R1 represents 2-propenyl, 1-naphthyl, 4-N02-phenyl or phenyl. More preferably, R1 represents phenyl.
In the step (A-1 ) of the process according to the present invention, the compound according to (SM-1) will be reacted with a compound according to formula (SM-2) in a molar ratio from about 1 : 2 to 2 : 1 , preferably in a molar ratio of 1 : 1.5 to 1.5 : 1 , more preferably in a molar ratio of 1 : 1.1 to 1.1 : 1 and even more preferably in equimolar ratio.
In another embodiment of the first aspect of the present invention, the process is characterized in that the at least one alkalizing agent of step (A-1) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1 ,4-Diazabicyclo[2.2.2]octan (DABCO).
Preferably, the at least one alkalizing agent of step (A-1) is triethylamine, diisopropylethylamine or 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
More preferably, the at least one alkalizing agent of step (A-1) is triethylamine.
In another embodiment of the first aspect of the present invention, the process is characterized in that the reaction medium of step (A-1) is an aprotic solvent, preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethyiether, t-butyl-methylether, diisopropylether, dichloromethane, 1 ,2-dichloroethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, N,N- dimethylformamide, 2-butanone, ,4-dioxane, cyclohexane, hexanes and heptanes.
Hexanes with respect to the present invention relates to a mixture of regioisomeres of hexane, e.g. n- hexane, 2-methylpentane, 3-methylpentane or 2,2-dimethylbutane. Heptanes with respect to the present invention relates to a mixture of regioisomeres of heptane, e.g. n-heptane, 2-methylhexane, 3- methylhexane or 2,2-dimethylpentane.
Preferably, the reaction medium of step (A-1 ) being an aprotic solvent is selected from the group consisting of toluene, tetrahydrofuran and dichloromethane.
More preferably, the reaction medium of step (A-1 ) being an aprotic solvent is toluene.
Depending on the type of the reaction medium, the reaction temperature step (A-1) may vary. The person skilled in the art will be able to choose the appropriate reaction temperatures accordingly. As the stability of the starting materials allows elevated reaction temperatures, one may consider such elevated reaction temperatures to increase the turnover and reduce the reaction time without the formation of undesired side products.
For instance, if the reaction medium of step (A-1) is toluene, the reaction temperature may vary between 0°C to 110°C, preferably between 50°C to 110°C, even more preferably around 90°C.
In the step (A-2) of the process according to the present invention, the compound according to formula (IM-1), optionally in the form of an addition salt and/or solvate thereof, will be reacted with at least one reducing agent in a molar ratio from about 1 : 20 to 1 : 1 , preferably in a molar ratio of 1 : 10 to 1 : 2, more preferably in a molar ratio of 1 : 8 to 1 : 3 and even more preferably in molar ratio of about 1 : 4, whereas the molar ratio relates in each case to the stoichiometric ratio.
In another embodiment of the first aspect of the present invention, the process is characterized in that the at least one reducing agent of step (A-2) is selected from the group consisting of
AIH(CH2CH(CH3)2)2 (DIBAL-H), LiAIH4, LiBH4, NaBH4, Ca(BH4)2, LiBH[CH(CH3)CH2CH3]3,
LiBH[CH(CH3)CH(CH3)2]3, NaBH[CH(CH3)CH2CH3)]3l KBH[CH(CH3)CH2CH3l3, LiAIH[OC(CH3)3]3 and LiAIH2(OC2H4OCH3)2.
Preferably, the at least one reducing agent of step (A-2) is AIH(CH2CH(CH3)2)2 (DIBAL-H), ), LiAIH , LiBH or UAIH2(OC2H4OCH3)2.
More preferably, the at least one reducing agent of step (A-2) is AIH(CH2CH(CH3)2)2 (DIBAL-H).
In another embodiment of the first aspect of the present invention, the process is characterized in that the reaction medium of step (A-2) is an aprotic solvent, preferably selected from the group consisting of dimethylsulfoxide, 1 ,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene.
More preferably, the reaction medium of step (A-2) being an aprotic solvent is 1 ,4-dioxane.
Depending on the type of the reaction medium, the reaction temperature step (A-2) may vary. The person skilled in the art will be able to choose the appropriate reaction temperatures accordingly.
For instance, if the reaction medium of step (A-2) is 1 ,4-dioxane, the reaction temperature may vary between -20°C to 50°C, preferably between 0°C to 30°C, even more preferably between 0°C to room temperature (22°C +/- 3°C).
In another embodiment of the first aspect of the present invention, the process also includes an additional preceding step (A-0),
wherein the step (A-0) comprises the reaction of a compound according to formula (SM-3), optionally in the form of an addition salt and/or solvate thereof, with a chloroformiate according to formula (SM-4) in the presence of at least one alkalizing agent in a reaction medium to form the compound according to formula (SM
Figure imgf000014_0001
(SM-4) (SM-3) (SM-2) wherein RA, RB, Rc and RD, R and R2 are defined as above. In another embodiment of the first aspect of the present invention, the process is characterized in that the at least one alkalizing agent of step (A-0) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, Ν,Ν-dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-Diazabicyclo[2.2.2Joctan (DABCO), Na2C03, K2C03, Cs2C03, LiOH, NaOH, KOH, Mg(OH)2 and Ca(OH)2.
Preferably, the at least one alkalizing agent of step (A-0) is pyridine, Na2COa, K2C03 or Cs2C03. More preferably, the at least one alkalizing agent of step (A-0) is pyridine.
In another embodiment of the first aspect of the present invention, the process is characterized in that the reaction medium of step (A-0) is an aprotic solvent, preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethylether, t-butyl-methylether, diisopropylether, dichloromethane, 1 ,2-dichloroethane, cyclohexane, hexanes, heptanes, acetone, dimethylsulfoxide, acetonitrile, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, Ν,Ν-diethylacetamide, 1 ,4-dioxane, N- methyl-pyrrolidinone, N-butyl-pyrrolidinone, ethyl acetate and 2-butanone,
Preferably, the reaction medium of step (A-0) being an aprotic solvent is selected from the group consisting of tetrahydrofuran, 2-butanone and acetone.
More preferably, the reaction medium of step (A-0) being an aprotic solvent is acetone.
Depending on the type of the reaction medium, the reaction temperature step (A-0) may vary. The person skilled in the art will be able to choose the appropriate reaction temperatures accordingly.
For instance, if the reaction medium of step (A-0) is acetone, the reaction temperature may vary between -20°C to 50°C, preferably between 0°C to room temperature (22°C +/- 3°C), even more preferably between 0°C to 10°C and more preferably between 0°C to 5°C.
An advantage of applying the preceding step (A-0) in the process according to the present invention is given by the fact the compound according to formula (SM-3),
Figure imgf000015_0001
(SM-3) jS |ess prone to decomposition.
In particular, due to the structure of compound (SM-3), the decomposition to an intermediate of type Y1 and so the formation of dimeric or even unspecified oligo- and polymeric aromatic amines (to be regarded as PGI) can be excluded. Therefore, the amount of PGI in the final product firstly will be reduced and secondly will precisely be determined as originating only from the residual amount of (S -3), hence not exceeding this amount.
The compound according to formula (I) obtained from step (A-2) can optionally be further purified in a manner well known to those skilled in the art, for instance in an additional recrystallization step.
In another embodiment of the first aspect of the present invention, the process is characterized in that the process further comprises an additional subsequent step (A-3), wherein the step (A-3) comprises the recrystallization of the compound according to general formula (I) obtained from step (A-2) in a recrystallization medium.
Hence, in the recrystallization step (A-3) the compound according to formula (I) obtained from step (A- 2) is dissolved in a suitable medium followed by a precipitation of said compound, preferably by changing the composition of the recrystallization medium by addition of another medium.
Suitable recrystallization media for dissolving the compound according to formula (I) obtained from step (A-2) can be determined by the person skilled in the art using preliminary tests.
Conventional recrystallization media known to persons skilled in the art may be used, in particular organic solvents selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, iso-propanol and n-butanol; esters such as ethyl acetate, n-propyl acetate, iso-propyl acetate, n-butyl acetate and iso-butyl acetate; ketones such as acetone, 2-butanone, pentan-2-one, pentan-3-one, hexan-2-one and hexan-3-one; ethers such as tert-butyl methyl ether, diethylether, tetrahydrofuran, diisopropylether and 1 ,4-dioxane; nitrites such as acetonitrile; aromatic hydrocarbons such as toluene; chlorinated hydrocarbons such as dichloromethane and chloroform; and also dimethylsulfoxide, N,N- dimethylformamide, N,N-dimethylacetamide, Ν,Ν-diethylacetamide, N-methyl-pyrrolidinone, N-butyl- pyrrolidinone and mixtures thereof.
Preferably, however, after dissolving the compound according to formula (I) obtained from step (A-2) in step (A-3) in a suitable solvent, said compound is precipitated by addition of another medium.
In a preferred embodiment, the second part of step (A-3) is carried out by the addition of a medium in which the compound of formula (I) is only poorly soluble ("anti-solvent") to the solution obtained in the first part of step (A-3).
Preferably, said medium employed for precipitation of the compound according to formula (I) is selected from the group consisting of water, alcohols, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol and isopropanol, diethyl ether, acetone, and alkyl acetates such as ethyl acetate, more preferably the medium employed for precipitation of the compound according to formula (I) is water. Preferably, the recrystallization medium of subsequent step (A-3) is an alcohol, selected from methanol, ethanol, n-propanol, iso-propanol and n-butanol which is changed to a mixture of the respective alcohol with water.
More preferably, the recrystallization medium of subsequent step (A-3) is ethanol or a mixture of ethanol, being diluted with water.
In case step (A-3) is performed, the compound according to formula (I) obtained after performing step (A-2) is preferably first dissolved in a suitable solvent, preferably in ethanol, at an elevated temperature, preferably at a temperature in the range of from 30°C to 75°C, more preferably at a temperature in the range of from 40°C to 70°C, even more preferably at a temperature in the range of from 50°C to 65°C.
In one embodiment, the resulting mixture is then cooled, preferably to a temperature in the range of from -5°C to 20°C, more preferably at a temperature in the range of from 0°C to 10°C, followed by addition of the medium employed for precipitation, preferably water, of the compound according to formula (I) at this temperature.
In another, preferred embodiment, the resulting mixture of the compound according to formula (I) at this temperature is diluted by the medium employed for precipitation, preferably by water, and then cooled, preferably to a temperature in the range of from -5°C to 20°C, more preferably at a temperature in the range of from 0°C to 10°C, more preferably to about 0°C.
Steps (A-3) may be repeated in order to further purify the compound according to formula (I) obtained, if necessary.
The steps according to the process according to the present invention can be carried out discontinuously (batchwise) or continuously, preference being given to the discontinuous procedure.
There come into consideration as the reactor for the discontinuous procedure, for example, a slurry reactor, and for the continuous procedure a fixed-bed reactor or loop reactor.
EXAMPLES
The following examples further illustrate the invention but are not to be construed as limiting its scope.
General procedure:
Step (A-0)
A compound according to formula (SM-3) (1 equivalent) is dissolved in at least aprotic solvent as reaction medium such as acetone or tetrahydrofuran wherein the reaction medium is preferably employed in an amount by weight that is in the range of from 3 to 60 times higher than the total amount of starting material according to formula (SM-3) by weight and an alkalizing (2 to 3 equivalents), such as pyridine, is added. The resulting mixture is cooled to a temperature in the range of from -10°C to 0°C and a solution of compound according to formula (SM-4) (1-3 equivalents) in at least aprotic solvent as reaction medium such as acetone or tetrahydrofuran (about 0.5 to 1.5 molar solution) is added over a period of 45 to 90 min. The resulting mixture is stirred for 1 to 10 h at 0°C to 5°C (reaction time) and then warmed to room temperature. An equal volume of water is added and the resulting mixture is stirred at this temperature for a time of 1 h to 20 h. A precipitate forms which is filtered off and preferably washed with a solvent, preferably with water or methanol. The resulting (SM- 2) is dried under reduced pressure at 50°C.
Step (A-1)
To a mixture of (S -2) obtained from step (A-0) and (SM-1) (equimolar ratio up to 1.5 : 1 to 1 : 1.5) in a reaction medium (0.1 to 0.5 molar), preferably an aprotic solvent, such as toluene, the alkalizing agent is added (1-3 equivalents, depending on whether SM-2 or SM-3 are employed as salts or as a free base) at room temperature. The resulting mixture is heated slightly below boiling temperature of the solvent (reaction temperature) and stirred for a time that is in the range of from 30 minutes to 20 h (reaction time) at a reaction temperature. An equal volume of water is added and the resulting mixture is stirred while cooling to reaction temperature. A precipitate forms which is filtered off and preferably washed with a solvent, preferably with an aprotic solvent, such as toluene. The resulting (IM-I) is filtered again and the filter cake dried under reduced pressure.
Step (A-2)
To a mixture of the reduction agent (3-4 molar equivalents) in an aprotic solvent, a solution of (IM-I) obtained from step (A-1) in a reaction medium (0.1 to 0.5 molar), preferably an aprotic solvent, such as 1 ,4-dioxane is added at 0°C to room temperature. The reaction mixture was stirred at 20-25°C for 90 min to 5 h. After cooling to 0-5°C, water (5-10 v/v-%) was added slowly at 0°C to 10°C. An aqueous solution of sodium hydroxide (3 mol equivalents compared to the reduction agent in water (20-30 v/v- %) is added at 0°C to 10°C. The reaction mixture is stirred at room temperature for 30 min to 20 h. The phases are separated. The organic layer is washed (e.g. with brine) and is dried over an anhydrous magnesium sulfate. The mother liquor is collected and is concentrated under reduced pressure. The crude product is either washed with additional solvent or precipitated by addition of another, less polar. The wet product is dried under reduced pressure at elevated temperatures (e.g. 50°C) for 2^*8 h to give (I).
Step (A-3)
To the crude product obtained from step (A-2) is added a solvent such ethanol and the resulting mixture is heated to a temperature in the range of from 50°C to 70°C until the precipitate is completely dissolved at this temperature. Then, a further medium, preferably water (about half of the volume of solvent), is added and the mixture is cooled to a temperature in the range of from -5°C to 10°, and at this temperature the desired product forms, i.e. a compound according to formula (I) in the re- crystallized form, which is filtered and dried at elevated temperatures (e.g. 50°C) under reduced pressure.
1. Example according to the invention
Step A-0 - Synthesis of 0-phenyl-W-[3-fluoro-4-methoxycarbonylphenyl] carbamate
st ep A-0
Figure imgf000019_0001
.
(SM-3-I) (SM-2-I)
In an inert (N2) 20 I reactor vessel, methyl 4-amino-3-fluoro-benzoate (SM-3-I) (500 g, 2,96 mol) was dissolved in acetone (2,00 I) and pyridine (721 ml, 8,87 mol) was added. The reaction mixture was cooled to 0°C. A solution of phenyl chloroformate (465 ml, 3,70 mol) in acetone (3,00 I) was added at 0-5°C during 45-60 min. The reaction mixture was stirred for 1 h at 0-5°C, upon a white suspension has formed.
After warming up to 20-25 °C, water (7,65 I) was added and the reaction mixture was stirred for 60 min. The suspension was filtered and the filter cake was washed well with water (27,8 I). The wet product was dried under vacuum for 16-40 h at 50°C to give 0-phenyl-/V-[3-fluoro-4- methoxycarbonylphenyl] carbamate (S -2-I) (861 g, 2,98 mol, 101 %) as a light beige solid.
Step A-1 - Synthesis of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro- 4-(methoxycarbonyl)-phenyl]-urea
step A-1
Figure imgf000019_0002
In an inert (N2) 100 I reactor vessel, 0-phenyl-/V-[3-fluoro-4-methoxycarbonylphenyl] carbamate (SM- 2-I) (2,40 kg, 8,30 mol) and [1 -(3-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-methan]amine hydrochloride (S -1-1) (WO2013/068461 , p 69; 2,60 kg, 8,30 mol) was suspended in toluene (50,0 I). Triethylamine (3,47 I, 24,9 mol) was added at 20-25°C and the reaction mixture was heated to 80- 90°C, upon a clear, brown solution has formed.
The reaction mixture was stirred for 2 h at 80-90°C.
Water (56,0 I) was added continuously during 45 min while the reaction mixture was cooled down to 20-25°C. The suspension was filtered over a filter centrifuge (1800 rpm, 45 min). The wet solid was transferred to a 100 I reactor vessel and toluene (34,0 I) was added. The suspension was stirred at 30- 35°C for 12-18 h. After cooling to 20-25°C, the suspension was filtered over a filter centrifuge (1800 rpm, 45 min).The wet product was dried under vacuum for 20-30 h to give 1-[[2-(3-chlorophenyl)-5- (trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(methoxycarbonyl)-phenyl]-urea (IM-1-1) (3,37 kg, 7, 16 mol, 86%) as a white, crystalline solid.
Step A-2 - Synthesis of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro- 4-(hydroxymethyl)-phenyl]-urea (crude)
Figure imgf000020_0001
(IM-1 -1) (1-1) crude
In an inert (N2) 100 I reactor vessel, diisobutylaluminium hydride in toluene (25 %w/w, 14,9 kg, 26,2 mol) was cooled to 0-5°C. A solution of 1 -[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]- methyl]-3-[3-fluoro-4-(methoxycarbonyl)-phenyl]-urea (IM-1 -1) (3,00 kg, 6,37 mol) in 1 ,4-dioxane (51 ,6 I) was added at 0-20°C during 45 min.
[Note: The solution of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4- (methoxycarbonyl)-phenyl]-urea (IM-1 -1) in 1,4-dioxane was prepared at 50°C]
The reaction mixture was stirred at 20-25°C for 90 min.
After cooling to 0-5°C, water (5,00 I) was added slowly at 0-6°C. Then, a solution of sodium hydroxide (aq., 6 mol/l, 15,0 I, 90,0 mol) was added slowly at 0-6°C and the reaction mixture was thereafter stirred at 20-25°C for 30 min. The organic layer was separated, washed twice with a solution of sodium chloride (aq., sat, 21 ,0 I) and dried 30 min on magnesium sulfate (5 kg). The magnesium sulfate was filtered of using a pressure filter und the filter cake was washed with toluene (5 I). The mother liquor was concentrated under reduced pressure at 50°C until the solution becomes turbid (about 45 I was distilled off), then toluene (10,0 I) was added at 50°C. After cooling to 20-25°C, the reaction mixture was stirred for 45-60 min and the suspension was filtered over a filter centrifuge (1800 rpm). The wet product was dried under vacuum at 50°C for 16-24 h to give 1 -[[2-(3- chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea (l-l) (crude) (2,37 kg, 5,35 mol, 84%) as a white, crystalline solid.
Step A-3 - Synthesis of 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro- 4-(hydroxymethyl)-phenyl]-urea
Figure imgf000020_0002
(l-l) crude
(l-l) In an inert (N2) 100 I reactor vessel, 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]- 3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea (l-l) (crude) (2,37 kg, 5,35 mol) was added to ethanol (15,0 I) and the suspension was heated to 60°C. After a clear solution was formed, water (7,5 I) was added and the solution was cooled to 0-5°C during 60 min, upon which a white suspension has formed. After further stirring for 60 min at 0-5°C, the suspension was filtered over a filter centrifuge (1800 rpm, 5 min) and the filter cake was dried under vacuum at 50°C for 12-20 h to give (l-l) (2,21 kg, 4,99 mol, 93%) as a white, crystalline solid.
2. Comparative example
The formation for the PGIs of the present process has been assessed in comparison with the synthesis (l-l) as described in WO 2013/068461 A1 , pages 60 and 63. hydroxymethyl)phenylamine:
Figure imgf000021_0001
To 544 mg 3-fluoro-4-(hydroxymethyl)phenylamine (aniline 1) was added 17,4 ml ethanol and 4,35 ml water. The mixture was heated to 50°C for 1 h and thereafter the solvent was evaporated.
The purity of the compound and formation of side-products (SP 1- SP 7) belonging to dimeric (X5) and even oligomeric and polymeric impurities (X6n) was assessed by HPLC (254 nm).
Figure imgf000021_0002
Aniline 1 is unstable under the reaction conditions and various side products (PGIs) are formed in an uncontrolled manner. Therefore, aniline 1 is not suitable for the controlling the amount of PGIs in the synthesis of compounds of compounds of formula (I).
2.2 Assay of anilines according to the present invention.
To assess the content of anilines according to inventive process, the following background considerations are taken into account: a) The content of methyl 4-amino-3-fluoro-benzoate (SM-3-I) is assessed prior to step A-2. b) The content of [1-(3-chlorophenyl)-3-trifluoromethyl-1 H-pyrazol-5-yl]-methan]amine (SM- -1; free base) is assessed prior and after step A-2. The difference would correspond to the degradation of the starting material or the product. As the degradation of starting material or product results in equimolar amounts of aniline and pyrazole, the amount of pyrazole represents the amount of anilines (monomeric or polymeric) formed from this degradation. Therefore, the sum of the amount of methyl 4-amino-3-fluoro-benzoate (S -3-I) prior to step A-2 and the potentially increased amount of [1-(3-chlorophenyl)-3-trifluoromethyl- H-pyrazol- 5-yl]-methan]amine (SM-1-1; free base) during step A-2 represents the maximum amount of all aniline type PGIs without assessment of their individual structure.
The results are given below:
Figure imgf000022_0001
Figure imgf000022_0002
Figure imgf000022_0003
The obtained data for 3 individually preformed processes (batch 1 , batch 2, batch 3) demonstrate that
(a) only little amounts of aniline are present prior to step A-2 (22 - 29 ppm) and
(b) no pyrazole (SM-1-1; free base), and hence no aniline, is formed during the step A-2 (reduction).
Therefore, it is evident that the process according to the present invention is more suitable to avoid the formation of PGIs than the previously known route.

Claims

Patent claims:
1. A process for the preparation of a compound according to formula (I), optionally in the form of a physiologically acceptable addition salt and/or solvate thereof,
comprising one step (A-1) and one subsequent step (A-2),
characterized in that
the step (A-1) comprises the reaction of a compound according to formula (SM- ) with a compound according to formula (SM-2), in each case optionally in the form of an addition salt salt and/or solvate thereof, in the presence of at least one alkalizing agent in a reaction medium to form a compound according to formula (IM-1),
Figure imgf000023_0002
and
the step (A-2) comprises the reaction of a compound according to formula (IM-1 ), optionally in the form of an addition salt and/or solvate thereof, with at least one reducing agent in a reaction medium to form a compound according to formula (I):
reducing
agent
(IM-1 ) __f „. (
wherein in each case
RA, RB, Rc and RD each independently represent H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN;
R represents C^-alkyl, C2.4-alkenyl, halo-C1-4-alkyl, benzyl, naphthyl or phenyl, wherein said benzyl, naphthyl or phenyl may be mono- or independently polysubstituted by one or more substituents selected from the group consisting of F, CI, Br, I, CN, N02, CN, CH3, CHF2, CFH2,
CF3 or OCH3;
R2 represents C^-alkyl;
and
(Het)aryl represents an optionally substituted aryl or heteroaryl.
The process according to claim 1 , characterized in that in the compound according to formula (I), RA represents F and RB, Rc and RD each represent H.
3. The process according to claim 1 or 2, characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-1),
Figure imgf000024_0001
SF-1),
wherein
X is N, C(H), C(F), C(CI), C(CH3) or C(CF3);
RE is H, F, CI, CN, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2, CH2CH3,
CH(CH3)2, C(CH3)3or cyclopropyl; and
RF is H, F, CI, CH3, CHF2, CFH2, CF3, OCH3, OCF3, OCFH2, OCHF2 or CN.
4. The process according to any of the preceding claims, characterized in that (Het)Aryl represents a structural element according to sub-formula (SF-2),
Figure imgf000024_0002
(SF-2), wherein
X is C(F), C(CI) or C(CF3), and RE is CH3, CF3, C(CH3)3 or cyclopropyl.
5. The process according to any of the preceding claims, characterized in that R2 represents CH3, CH2CH3, CH(CH3)2 or C(CH3)3,
preferably R2 represents CH3.
6. The process according to any of the preceding claims, characterized in that R1 represents CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2CF3, C(CH3)=CH2 (2-propenyl), 1-naphthyl, 2-naphthyl, 4-N02- phenyl or phenyl,
preferably R1 represents phenyl.
7. The process according to any of the preceding claims, characterized in that the at least one alkalizing agent of step (A-1 ) is selected from the group consisting of triethylamine, diisopropyl- ethylamine, pyridine, N,N-dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1 ,4-Diazabicyclo[2.2.2]octan (DABCO),
preferably the at least one alkalizing agent of step (A-1) is triethylamine.
8. The process according to any of the preceding claims, characterized in that the reaction
medium of step (A-1) is an aprotic solvent, preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethylether, t-butyl-methylether, diisopropyl- ether, dichloromethane, 1 ,2-dichloroethane, 2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, Ν,Ν-dimethylformamide, 2-butanone, 1 ,4-dioxane, cyclohexane, hexanes and heptanes,
preferably the reaction medium of step (A-1) is toluene.
9. The process according to any of the preceding claims, characterized in that the at least one reducing agent of step (A-2) is selected from the group consisting of AIH(CH2CH(CH3)2)2
(DIBAL-H), UAIH4, L1BH4, NaBH4, Ca(BH4)2, LiBH[CH(CH3)CH2CH3]3, LiBH[CH(CH3)CH(CH3)2]3, NaBH[CH(CH3)CH2CH3)]3, KBH[CH(CH3)CH2CH3]3, LiAIH[OC(CH3)3]3 and LiAIH2(OC2H4OCH3)2, - preferably the at least one reducing agent of step (A-2) is AIH(CH2CH(CH3)2)2 (DIBAL-H).
10. The process according to any of the preceding claims, characterized in that the reaction
medium of step (A-2) is an aprotic solvent, preferably selected from the group consisting of dimethylsulfoxide, 1 ,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and toluene, preferably the reaction medium of step (A-2) is 1 ,4-dioxane.
11. The process according to any of the preceding claims, characterized in that the process further comprises an additional preceding step (A-0),
wherein
the step (A-0) comprises the reaction of a compound according to formula (SM-3), optionally in the form of an addition salt and/or solvate thereof, with a chloroformiate according to formula (SM-4) in the presence of at least one alkalizing agent in a reaction medium to form the compound according to formula (S -2),
Figure imgf000025_0001
(SM-4) (SM-3) (SM-2)
wherein R , RB, Rc and RD, R and R2 are defined as above.
12. The process according to claim 11 , characterized in that the at least one alkalizing agent of step (A-0) is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, Ν,Ν-dimethylaminopyridine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-Diazabi- cyclo[2.2.2]octan (DABCO), Na2C03, 2C03, Cs2C03, LiOH, NaOH, KOH, Mg(OH)2 and
Ca(OH)2,
preferably the at least one alkalizing agent of step (A-0) is pyridine.
13. The process according to any of the preceding claims, characterized in that the reaction
medium of step (A-0) is an aprotic solvent, preferably selected from the group consisting of toluene, xylene, tetrahydrofuran, petroleum ether, diethylether, t-butyl-methylether, diisopropyl- ether, dichloromethane, 1 ,2-dichloroethane, cyclohexane, hexanes, heptanes, acetone, dimethylsulfoxide, acetonitrile, N,N-dimethylformamide, Ν,Ν-dimethylacetamide, N,N-diethyl- acetamide,1 ,4-dioxane, N-methyl-pyrrolidinone, N-butyl-pyrrolidinone, ethyl acetate and 2- butanone,
preferably the reaction medium of step (A-0) is acetone.
14. The process according to any of the preceding claims, characterized in that the process further comprises an additional subsequent step (A-3), wherein the step (A-3) comprises the recrystallization of the compound according to general formula (I) obtained from step (A-2) in a recrystallization medium, preferably the recrystallization medium of subsequent step (A-3) is ethanol or ethanol, being diluted with water.
15. The process according to any of the preceding claims, characterized in that the compound according to formula (I) is
Figure imgf000026_0001
namely 1-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-
(hydroxymethyl)-phenyl]-urea,
Figure imgf000026_0002
namely 1-[[5-tert-butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxyl- methyl)-phenyl]-urea,
in each case optionally in the form of a physiologically acceptable addition salt and/or solvate thereof.
PCT/EP2015/002552 2014-12-19 2015-12-18 Process for the preparation of 1-[(heteroaryl)-methyl]- or 1-[(aryl)-methyl]-3-[4-(hydroxymethyl)-phenyl]-ureas WO2016096140A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120258946A1 (en) * 2009-05-07 2012-10-11 Gruenenthal Gmbh Substituted Phenylureas and Phenylamides as Vanilloid Receptor Ligands
WO2013068461A1 (en) * 2011-11-09 2013-05-16 Grünenthal GmbH Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an o-containing group as vanilloid receptor ligands

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120258946A1 (en) * 2009-05-07 2012-10-11 Gruenenthal Gmbh Substituted Phenylureas and Phenylamides as Vanilloid Receptor Ligands
WO2013068461A1 (en) * 2011-11-09 2013-05-16 Grünenthal GmbH Substituted pyrazolyl-based carboxamide and urea derivatives bearing a phenyl moiety substituted with an o-containing group as vanilloid receptor ligands

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