WO2016020403A1 - Préparation d'un dérivé d'acide benzoïque et son utilisation pour la préparation de suvorexant - Google Patents

Préparation d'un dérivé d'acide benzoïque et son utilisation pour la préparation de suvorexant Download PDF

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WO2016020403A1
WO2016020403A1 PCT/EP2015/067993 EP2015067993W WO2016020403A1 WO 2016020403 A1 WO2016020403 A1 WO 2016020403A1 EP 2015067993 W EP2015067993 W EP 2015067993W WO 2016020403 A1 WO2016020403 A1 WO 2016020403A1
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compound
formula
group
alkyl
ppm
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PCT/EP2015/067993
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Kathrin HÖFERL-PRANTZ
Roland Barth
Frank Richter
Borut ZUPANCIC
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Sandoz Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a process for the preparation of a compound of formula 1)
  • the present invention relates further to a compound obtained or obtainable by said method and to a compound of formula (1) as such. Further, the present invention relates to use of the compound of formula (1) for the preparation of Suvorexant employing the compound of formula (1).
  • Orexin is a neurotransmitter that regulates wakefulness and appetite.
  • Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness.
  • Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behavior disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprol
  • HIV HIV
  • post-chemotherapy pain post-stroke pain
  • post-operative pain neuralgia
  • conditions associated with visceral pain such as irritable bowel syndrome, and angina
  • migraine urinary bladder incontinence, e.g. urge incontinence
  • tolerance to narcotics or withdrawal from narcotics sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome
  • neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism- amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction.
  • orexin receptor antagonists are capable of influencing at least some of the above described pathological conditions.
  • orexin receptor antagonists capable of promoting sleep in animals and humans are described in the art.
  • One example for such an orexin receptor antagonist is [(7R)-4-(5-chloro-l,3-benzoxazol-2-yl)-7-methyl-l,4- diazepan-l-yl][5-methyl-2-(2H-l ,2,3-triazole-2-yl)phenyl]methanone which has the structure according to Formula XI)
  • the synthesis of Suvorexant is based on the synthesis of the three main building blocks, i.e. the diazapane ring, the benzoxazole ring as well as the triazole building block. These building blocks are coupled to each other to give the desired product.
  • the triazole building block is usually coupled in the form of an acid or an acid chloride to the diazepane ring. Such a synthesis is e.g. described in WO2008069997 and in Cox et al, J. Med. Chem. 2010, 53: 5320.
  • 2-iodo.5.methylbenzoic acid is converted in the presence of a copper catalyst and triazole to give 5-methyl-2-(2H-l,2,3-triazole- 2yl)benzoic acid.
  • this building block is coupled as acid or acid chloride to the diazapene ring and the resulting compound is then, after a deprotection step, coupled to the oxazole ring.
  • the 2-iodo.5.methylbenzoic acid is a comparatively costly starting material which renders the process disadvantageous.
  • regioisomer may be formed since the triazole may be coupled via any one of the present NH groups. These regioisomer need to be separated via column chromatography, which is difficult, and thus renders the process disadvantageous for industrial scale.
  • R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, and wherein the process comprises
  • halogen in the context of E is denote to mean a halogen residue, i.e. in particular -CI, -Br or -I.
  • the present invention relates to a process for the preparation of a compound of formula A) or a pharmaceutically acceptable salt or solvate thereof
  • R 1 is selected from the group consisting of H, PG 1 and R A , with R A being
  • PG 1 is a suitable protecting group and wherein n is 0 or 1, the process comprising
  • R la is selected from the group consisting of H, PG 1 , and R A , with R A being
  • PG 1 is a suitable protecting group and wherein R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H, (iii) optionally converting the R la into R 1 if R 1 and R la differ from each other, to give the compound of formula (A), preferably (Al *).
  • the present invention relates to a compound obtained or obtainable by any of the above described method, and to a com ound of formula (1)
  • R a , R b , R c and R d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl, -NR 6 R 7 , -SR and -N0 2 , wherein R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH.
  • the present invention also relates to a process for the preparation of a compound of formula A) or a pharmaceutically acceptable salt or solvate thereof
  • PG 1 is a suitable protecting group and wherein n is 0 or 1, the process comprising
  • the compound comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the regioisomeric side product havin the structure:
  • R la is selected from the group consisting of H, PG 1 and R A , with R A being
  • PG 1 is a suitable protecting group and wherein R la may be the same or may differ from R 1 and, wherein in case n is 0, R la is preferably not H,
  • the present invention relates to a process for the preparation of a compound of formula (1) as well as to a compound obtained or obtainable by said method and to a com ound of formula (1) as such
  • R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group
  • R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group.
  • alkyl relates to non-branched alkyl residues and branched alkyl residues.
  • the term also encompasses alkyl groups which are further substituted by one or more suitable substituents.
  • substituted alkyl as used in this context of the present invention preferably refers to alkyl groups being substituted in any position by one or more substituents, preferably by 1, 2, 3, 4, 5 or 6 substituents, more preferably by 1, 2, or 3 substituents. If two or more substituents are present, each substituent may be the same or may be different from the at least one other substituent. There are in general no limitations as to the substituent.
  • the substituents may be, for example, selected from the group consisting of aryl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino, acylamino, including alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, nitro, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, s
  • cycloalkyl refers to alkyl groups which form a ring, such as a 5-membered, 6-membered or 7-membered ring, e.g. cyclopentyl or cyclohexyl.
  • aryl refers to, but is not limited to, optionally suitably substituted 5- and 6-membered single-ring aromatic groups as well as optionally suitably substituted multicyclic groups, for example bicyclic or tricyclic aryl groups.
  • aryl thus includes, for example, optionally substituted phenyl groups or optionally suitably substituted naphthyl groups.
  • Aryl groups can also be fused or bridged with alicyclic or heterocycloalkyl rings which are not aromatic so as to form a polycycle, e.g. benzodioxolyl or tetraline.
  • heteroaryl as used within the meaning of the present invention includes optionally suitably substituted 5- and 6-membered single-ring aromatic groups as well as substituted or unsubstituted multicyclic aryl groups, for example tricyclic or bicyclic aryl groups, comprising one or more, preferably from 1 to 4, such as 1, 2, 3 or 4, heteroatoms, wherein in case the aryl residue comprises more than 1 heteroatom, the heteroatoms may be the same or different.
  • heteroaryl groups including from 1 to 4 heteroatoms are, for example, benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenylyl, napthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, or indolizinyl.
  • optionally substituted aryl and the term “optionally substituted heteroaryl” as used in the context of the present invention describes moieties having substituents replacing a hydrogen on one or more atoms, e.g. C or N, of an aryl or heteroaryl moiety. Again, there are in general no limitations as to the substituent.
  • the substituents may be, for example, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino, acylamino, including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido, amidino, nitro, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfmyl, sulfonate, sul
  • compound (1) comprises less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm, more preferably 0 ppm, of a regioisomeric side product having the structure:
  • Residues R a , R b , and R d are preferably, independently of each other, H or alkyl.
  • residues R a , R b , and R d are H.
  • the present invention also relates to the preparation of a compound of formula (1), as described above, and a compound obtainable or obtained by said process as well as to the compound as such the compound having the structure
  • the present invention relates to the processes for the preparation of a compound of formula (A) and a compound of formula (A) obtained or obtainable by said processes, as described above, wherein in step (i), a com ound having the structure
  • Residue R c is preferably H or alkyl, more preferably selected from the group consisting of H, methyl, ethyl, propyl and butyl, more preferably H or methyl, most preferably methyl.
  • the present invention also relates to the preparation of a compound of formula (1), as described above, and a compound obtainable or obtained by said process as well as to the compound as such the compound havin the structure
  • the present invention relates to the processes for the preparation of a compound of formula (A) and a compound of formula (A) obtained or obtainable by said processes, as described above, wherein in step (i), a com ound having the structure
  • residues R a , R b , and R d are H and residue R c is -CH 3 , the compound of formula (1) thus having the structure (la)
  • E is an electrophilic group.
  • electrophilic group means any functional group attached to the phenyl ring that can accept a pair of electrons.
  • R 5 is not OH.
  • leaving group as used in this context of the present invention is denoted to mean a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage upon reaction with a nucleophile, such as with an amine group of the diazepane building block.
  • leaving groups are, inter alia, halogens, sulfonic esters (such as, inter alia, the mesyl and tosyl grou or any one of the following groups
  • the present invention relates to a compound obtained or obtainable by the above described method the compound havin the structure (1)
  • the present invention relates to a compound obtained or obtainable by the above described method the compound havin the structure (la)
  • the present invention relates to a compound obtained or obtainable by the above described method, wherein the com ound has the structure
  • the compound of formula (II) has the structure
  • residues R a , R b , and R d are preferably, independently of each other, H or alkyl.
  • Residue R c is preferably alkyl, more preferably methyl.
  • step (b) the compound of formula (II), preferably of formula (Ila), is reacted with an organolithium reagent in an aprotic solvent to give an intermediate compound of formula (III)
  • the reaction may be carried out in any suitable aprotic solvent known to those skilled in the art.
  • the reaction is carried out in an organic aprotic solvent selected from the group consisting of diethylether, Tetrahydrofuran, 2-methyltetrahydrofuran, hexane, pentane, cyclopentane, cyclohexane, heptane, toluene and mixtures of two or more thereof.
  • diethylether is used as solvent.
  • the organolithium reagent is preferably selected from the group consisting of n-butyllithium, sec-butyllithium, tert-butyllithium, isopropyllithium, more preferably the reagent is n-butyllithium.
  • the reaction is carried out at a temperature in the range of from -85 °C to - 20 °C, more preferably in the range of from -85 °C to -50°C more preferably in the range of from -80 °C to -60°C.
  • the temperature may be varied or held essentially constant.
  • the mol equivalents of the organolithium compound to compound of formula (II) is preferably in the range of from 0.8 to 4, more preferably in the range of from 0.9 to 2.5, more preferably 0.95 to 1.1.
  • the compound of formula (II) when providing the reaction mixture to be reacted in (b), the compound of formula (II) is first admixed with at least a portion of a suitable solvent and is preferably cooled to the temperature range mentioned above.
  • the organolithium reagent is then added which, for example, can be employed as mixture with at least a portion of the solvent or as such.
  • Compound (II) is preferably allowed to react with the organolithium reagent for a time in the range of from 10 min to 3 h, more preferably in the range of from 10 min to 2 h, more preferably in the range of from 10 min to 1 h. Compound (II) is then preferably reacted, without any intermediate purification step, in step (c).
  • Step (c) Step (c) of the invention comprises the reacting of the intermediate compound of formula (III) with an electrophile E* thereby forming, optionally after at least one further step, the compound of formula (1) comprising the electrophilic group E.
  • Electrophile is a reagent attracted to electrons. Electrophiles are positively charged or neutral species having vacant orbitals that are attracted to an electron rich centre. An electrophile participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.
  • X is X being a halogen (residue), a sulfonic ester (such as, inter alia, the mes l and tosyl group) or any one of the following groups
  • Z is preferably-N(CH 3 ) 2 , or -R 5 with R5 being preferably -O-alkyl, i.e. Z is preferably - N(CH 3 ) 2 or -O-AlkyL .
  • E* is selected from the group consisting of C0 2 , carbonates, formiates, formamides, halogens, preferably E* is an alkylformiate or an alkylcarbonate or C0 2 , more preferably E* is selected from the group consisting of C0 2 , ethylcarbonate, methylcarbonate, ethylformiate and methylformiate.
  • the reaction is carried out in the same aprotic solvent used in step (c).
  • the solvent is preferably selected from the group consisting of diethylether, Tetrahydrofuran, 2-methyltetrahydrofuran, hexane, pentane, cyclopentane, cyclohexane, heptane, toluene and mixtures of two or more thereof.
  • diethylether is used as solvent.
  • step (c) and step (b) are carried out in one pot.
  • the reaction is carried out at a temperature in the range of from -85 °C to -20 C, more preferably in the range of from -85 °C to -50 °C , more preferably in the range of from -80 °C to -60 .
  • the temperature may be varied or held essentially constant.
  • halogen in the context of E* is denoted to mean a halogen molecule, i.e. in particular Cl 2 , Br 2 or I 2 .
  • E is a halogen residue
  • E* is preferably a halogen.
  • the compound of formula (III) is preferably reacted with Cl 2 , I 2 or Br 2 , more preferably with Cl 2 or I 2 to give the compound of formula (1) with E being a halogen residue, in particular -CI or -I.
  • E* is preferably C0 2 .
  • the compound of formula (III) is preferably reacted with C0 2 to give the compound of formula (1) with E being -COOH.
  • E* is thus preferably an alkylcarbonate, more preferably methylcarbonate or ethylcarbonate.
  • This compound may further be transformed to E being -COOH via oxidation if desired.
  • E is CN
  • E* is preferably C0 2 .
  • the compound of formula (III) is preferably reacted with C0 2 give an intermediate compound comprising a carboxylic acid and the carboxylic acid is then transformed in at least one further step to give the compound of formula (1).
  • the group -CO(NH 2 ) may be obtained e.g. by activation of the -COOH group and subsequent reaction with ammonia.
  • the dehydration may e.g. be carried out by reaction with cyanuric chloride.
  • compound (1) may be isolated or may be directly further processed to give the compound of formula (A). If such isolation is carried out, this may be carried out by any method known to those skilled in the art. Such isolation may comprise one or more stages wherein preferably at least one stage comprises a purification, such as an extraction and/or a precipitation and/or filtration.
  • a purification such as an extraction and/or a precipitation and/or filtration.
  • Compound (II), preferably compound (Ila), may be provided by any suitable method known to those skilled in the art.
  • step (a) comprises
  • step (a) comprises
  • compound (II) has the structure Ila)
  • step (a) compound (Ila) is provided, wherein this provision comprises providing a compound of formula (IVa) or a salt thereof
  • step (a) comprises
  • the present invention also relates to the preparation of a compound of formula (A), as described above, and a compound obtainable or obtained by said process as well as to the compound as such, wherein the provision of compound (la) in step (i) comprises
  • the compound of formula (IV) has the structure
  • the compound (IV) in (al) is provided in the form of a salt, preferably the HC1 salt.
  • the compound (IV) has the structure
  • step (a2) the compound of formula (IV), preferably (Iva) is reacted with glyoxal.
  • the reaction in step (a2) is carried out in the presence of a copper salt, preferably Cu(OTf) 2 .
  • a copper salt preferably Cu(OTf) 2 .
  • first compound (V), preferably compound (Va) is prepared which is optionally isolated and thereafter, compound (V), preferably (Va), is transformed, in the presence of Cu(OTf) 2 , to compound (II).
  • step (a2) preferably comprises
  • step (a2) of step (a) comprises
  • step (i) transforming the compound of formula (V), preferably (Va), in the presence of a copper salt, preferably Cu(OTf) 2 to give the compound of formula (II), preferably (II a).
  • a copper salt preferably Cu(OTf) 2
  • the present invention also relates to the preparation of a compound of formula (A), as described above, and a compound obtainable or obtained by said process as well as to the compound as such, wherein the provision of compound (la) in step (i) comprises
  • the present invention also relates to a compound of formula (V), preferably (Va), as such as well as to a compound of formula (V), preferably (Va), obtained by a method comprising the steps (a2.1) and (a.2.2).
  • reaction in step (a2) may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction in (a2.1) is carried out in an acidic solvent, preferably in acidic acid.
  • the reaction in (a2.1) is carried out at a temperature in the range of from 25°C to 80°C, more preferably in the range of from 40°C to 60°C. During the reaction, the temperature may be varied or held essentially constant.
  • the sequence of mixing the components of the reaction mixture is not subject to specific restrictions.
  • the compound of formula (IV), preferably (IVa) is first admixed with at least a portion of the solvent and, to the resulting mixture, glyoxal is added which, for example, can be employed as mixture with at least a portion of the solvent or as such.
  • the isolation in step (a2.2) may be carried out by any method known to those skilled in the art.
  • Such isolation may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like.
  • Preferably compound (V) is precipitated and filtered off.
  • the mol equivalents of the copper salt, preferably Cu(OTf) 2 , to compound of formula (V) is preferably in the range of from 0 to 0.1, more preferably in the range of from 0.01 to 0.03.
  • PG is a suitable protecting group and wherein n is 0 or.
  • the compound (A) has, e.g., the structure (Aa) or (Ab)
  • the present invention also relates to a method, as described above, and to a compound obtained or obtainable by said method, wherein the compound (A) has the
  • R 1 is selected from the group consisting of H, PG 1 and R A , with being
  • PG 1 is a suitable protecting group.
  • compound (A) is preferably selected from the group consisting of
  • suitable protecting group as used herein is denoted to encompass any amino protecting group.
  • protecting group refers to a chemical moiety that can be selectively attached to and removed from a particular chemically reactive functional group in a molecule to prevent it from participating in undesired chemical reactions. The protecting group will vary depending on reaction conditions to be employed and the presence of additional reactive or protecting groups in the molecule. It is understood that the term “amino protecting group” is a chemical moiety being attached to a former amino group. After removal of the protecting group, the free amine is regained.
  • Representative protecting groups for amino groups are well known to those skilled in the art and are described, for example, in T. W. Greene and G. M.
  • amino-protecting group preferably includes both acyclic as well as cyclic protecting groups.
  • a “cyclic protecting group” is a group which, together with the N to which it is bound, forms a cyclic group.
  • Preferred protecting groups for PG 1 include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldi- methylsilyl and triisopropylsilyl.
  • carbamates such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and
  • Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the like. More preferably, PG 1 is selected from the group consisting of Benzyl, t-butyloxycarbonyl (Boc), Cbz, PNZ, Alloc, Trifluoroacetate and Phthalimide, more preferably PG 1 is a Boc group or a Cbz group, more preferably Boc.
  • compound (A) is preferably selected from the group consisting of
  • a bond shown as " in any one of the compounds shown herein is denoted to represent a single bond, wherein the resulting structure including the bond encompasses the isolated S isomer, the isolated R isomer, as well as mixtures of the S and R isomer.
  • the present invention also relates to methods for the preparation of a compound (A), as described above, and a compound obtained or obtainable by any of these processes, wherein the compound has a structure selected from
  • compound (A) is (A*) and is selected from the group consisting of
  • R 1 is selected from the roup consisting of H,
  • R la is selected from the group consisting of H, PG 1 and R A , with R A being
  • R la is a suitable protecting group. It is to be understood that R la may be different from R 1 or may be the same
  • R la is selected from the group consisting of H,
  • R a is H or — 0 s
  • R la is H.
  • Step (i) The compound of formula (la) may be provided by any method known to those skilled in the art.
  • the compound (la) is thus provided by a method comprising the steps (a) to (c) as mentioned above.
  • step (i) comprises
  • the compound (la) obtained or obtainable by the above described method preferably comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the regioisomeric side product
  • E is not COOH and not CI, preferably not COOH and not a halogen.
  • step (i) compound (la) is provided wherein X is not CI and E is not COOH.
  • step (i) compound (la) is provided wherein compound (la) comprises less than 1000 ppm, more preferably less than 100 ppm, preferably less than 10 ppm, more preferably 0 ppm, of the re ioisomeric side product
  • step (ii) the compound of formula (la) is reacted, i.e. coupled with the compound of formula (Al)
  • R la is PG 1 , and wherein n is preferably 0, wherein R la is selected from the group consisting of H, PG 1 , and R A , with R A being
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H.
  • the coupling is preferably carried out in the presence of a suitable base, preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methylimidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), N- methylpiperidine, N-methylpyrrolidine, 2,6-lutidine, collidine, pyridine, 4- dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • a suitable base preferably an organic base, most preferably an amino group comprising base, most preferably a base selected from the group consisting of diisopropylamine (DIEA), triethylamine (TEA), N-methylmorpholine, N-methylimidazole, l,4-diazabicy
  • the reaction is carried out in an organic solvent, such as N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile, acetone, dimethyl acetamide (DMA), dimethyl formamide (DMF), formamide, tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, tert.-butyl methyl ether (MTBE), dichloromethane (DCM), chloroform, tetrachloromethane and mixtures of two or more thereof. More preferably, the reaction is carried out in dichloromethane.
  • NMP N-methyl pyrrolidone
  • DMSO dimethyl sulfoxide
  • DMA dimethyl formamide
  • THF tetrahydrofuran
  • THF tetrahydrofuran
  • MTBE tert.-butyl methyl ether
  • DCM dichloromethane
  • chloroform tetrachlor
  • the temperature of the coupling reaction is preferably in the range of from 0 to 100 °C, more preferably in the range of from 5 to 50 °C, and especially preferably in the range of from 15 to 30 °C. During the course of the reaction, the temperature may be varied, preferably in the above given ranges, or held essentially constant.
  • compound (la) preferably readily reacts with the NH group of compound (Al), optionally in the presence of a suitable base as mentioned above without the need to add a catalyst or a coupling reagent.
  • activating agents such as EtMgBr or A1C1 3 may be added.
  • a coupling reagent is required in order to react compound (la) and (Al) with each other.
  • Such coupling reagents include, but are not limited to, oxalyl chloride, HATU (0-(7-azabenzotriazole-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate); HO At (l-hydroxy-7-azabenzotriazole), HBTU (0-benzotriazole-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate); TBTU (2-(lH-benzotriazole-l-yl)-l,l,3,3- tetramethyluronium hexafluorophosphate); TFFH (N,N',N",N"-tetramethyluronium-2- fluoro-hexafluorophosphate); BOP (benzotriazo
  • EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, CDC (1- cyclohexyl-3-(2-morpholinoethyl)carbodiimide), Pyclop, T3P, CDI, Mukayama's reagent, HODhbt, HAPyU, TAPipU, TPTU, TSTU, TNTU, TOTU, BroP, PyBroP, BOI, TOO, NEPIS, BBC, BDMP, BOMI, AOP, BDP, PyAOP, TDBTU, BOP-Cl, CIP, DEPBT, Dpp- Cl, EEDQ, FDPP, HOTT, TOTT, PyCloP.
  • reaction with (Al) is preferably carried out in the presence of an oxidizing agent, in particular in the presence of tBuOOH .
  • reaction with (Al) is preferably carried out in the in the presence of a basic organometallic reagent, preferably an alkylaluminum or a Grignard reagent, more preferably a Grignard reagent, in particular in the presence of EtMgBr
  • step (iii) R la is converted into R 1 if R 1 and R la differ from each other. Thus, it is to be understood that R la may be different from R 1 or may be the same. In case R 1 differs from R la , step (iii) is carried out. In case R 1 is equal to R la , step (iii) is omitted.
  • step (ii) corresponds to the compound (A), in case R la is equal to R 1 .
  • step (ii) is transformed in step (iii) to give the compound of formula (A) wherein this transformation may be carried out in one or in multiple steps.
  • (A) is (Ax)
  • R la is H, PG 1 or R A , with R A bein
  • step (ii) in case n in compound Al is 1 and n in compound Ax is 0,
  • step (iiia) removing the protecting group PG 1 in case R la is PG 1 and reacting the compound of step (ii) with
  • X* is a leaving group, preferably CI, or by (iiib) reacting the compound of step (ii) with
  • X* is a leaving group, preferably CI, in case R la is H,
  • step (iii) is omitted.
  • the process preferably comprises:
  • R la is PG 1 and wherein the compound of step (ii) is reduced in case n in Ay is 0 and n in compound Al is 1.
  • (A) is (Az)
  • the process preferably comprises:
  • R la is H, PG 1
  • step (iii) is omitted.
  • (A) has the structure
  • the process preferably comprises
  • R la is R A , with R A bein
  • the process preferably comprises
  • R la is PG 1 or H, and optionally reducing the compound of step (ii) in case n in compound Al is 1,
  • step (iiia) removing the protecting group PG 1 in case R 1 is PG 1 and reacting the compound of step (ii) with
  • X* is a leaving group, preferably CI, or by
  • X* is a leaving group, preferably CI, in case R 1 is H,
  • step (ii) the compound is reduced in case in compound (A) n is 0 and in compound (Al) n is 1.
  • reduction may also be carried out in step (iii).
  • a reduction of the carbonyl group is carried out.
  • the reduction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE (methyl-tert-butyl ether), DIPET (diisopropylether), toluene, acetonitrile, CH 2 CI 2 and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE (methyl-tert-butyl ether), DIPET (diisopropylether), toluene, acetonitrile, CH 2 CI 2 and mixtures of two or more thereof.
  • the reduction is carried out at a temperature in the range of from -20 °C to 110 °C.
  • the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 , LiBH 4 and H 2 in the presence of transition metals, wherein the transition metal is preferably selected from the group consisting of IR, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co.
  • the reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 and LiBH 4 , more preferably the reducing agent is NaBH 4 , NaCNBH 3 or NaBH(OAc) 3, more preferably NaBH 4 .
  • leaving group in the context of compound (XII) is denoted to encompass any group that departs upon reaction of compound (XII) with an amine.
  • Preferred leaving groups are -CI, -S, -SMe, -SEt or -Br, in particular -CI or -Br.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of dichloromethane, DMF, DMSO, NMP (N-methyl pyrrolidone), methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile, tetrametyhlharnstoff (tetramethylurea), dimethylacetamid, EtOAc, iPrOAc, hexan, cyclohexan, heptan and mixtures of two or more thereof.
  • a solvent selected from the group consisting of dichloromethane, DMF, DMSO, NMP (N-methyl pyrrolidone), methanol, ethanol, propan
  • the reaction is carried out at a temperature in the range of from 0 to 110 ° C, more preferably in the range of from 20 to 80 °C, more preferably in the range of from 40 to 80 °C, more preferably at room temperature.
  • the temperature may be varied or held essentially constant.
  • the compounds are preferably allowed to react for a time in the range of from 10 min to 72 h, more preferably in the range of from 30 min to 24 h, more preferably in the range of from 1 h to 12 h.
  • reaction mixture obtained is subjected to a suitable work-up, such as an isolation of the respective compound.
  • working up may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like.
  • purification such as an extraction and/or a precipitation and/or filtration and/or chromatography or the like.
  • some reactions may be carried out with the crude intermediate products or even in situ.
  • the compound of formula (Al) may be provided by any method known to those skilled in the art.
  • compound (Al) is provided by a process comprising
  • R E is selected from the group consisting of H, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl and heterocycloalkyl, more preferably wherein R E is alkyl, more preferably wherein R E is methyl, ethyl or propyl, more preferably wherein R E is methyl, and wherein R la is selected from the group consisting of H, PG 1 , and R A , with R A being
  • R a is a protecting group PG a
  • R la is selected from the roup consisting of H, and
  • R la is H or
  • R la is H.
  • PG 2a is a suitable protecting group.
  • Preferred protecting groups for PG 2a include, but are not limited to, carbamates, such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Alloc (allyloxycarbonyl), methyl and ethyl carbamates; trityl, benzyl, benzylidene, tosyl and the like; cyclic imide derivatives, such as succinimide and phthalimide; amides, such as formyl, (un)substituted acetyl, and benzoyl; and trialkyl silyl groups, such as t-butyldimethylsilyl and triisopropylsilyl.
  • carbamates such as Boc (t-butyloxycarbonyl, Cbz (carboxybenzyl), Fmoc (fluorenylmethyloxycarbonyl), Al
  • Particularly preferred amino-protecting groups include Boc, Cbz, Fmoc, benzyl, acetyl, benzoyl, trityl and the like.
  • PG 2a is a Boc group or a Cbz group, more preferably Cbz.
  • R E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably R E is alkyl, more preferably R E is methyl, ethyl or propyl, more preferably R E methyl.
  • step (bb) of the process of the invention the compound of formula (XX) is reacted with a base and optionally subsequently reduced to give after step (cc) the compound (A). Upon reaction with the base, the 7-membered ring is formed ("cyclization reaction").
  • the reaction may be carried out in any suitable solvent known to those skilled in the art.
  • the cyclization reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of R E -OH, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof, with R E being as described above and below, preferably wherein R E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl.
  • the solvent has the structure R E -OH, with R E being as described above and below, preferably wherein R E is selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R E is alkyl, more preferably wherein R E is methyl, ethyl or propyl, more preferably wherein R E is methyl.
  • the cyclization is carried out at a temperature in the range of from -20 to 80 °C, more preferably in the range of from 0 to 50°C, more preferably in the range of from 20 to 30 °C. During the reaction, the temperature may be varied or held essentially constant.
  • a base selected from the group consisting of NaOR E , sodium- tert.butoxide, potassium-tert.butoxide, NaNH2, DBU (l,8-Diazabicycloundec-7-ene), Tetramethylguanidine, Na-CH 2 S(0)CH 3 and mixtures of two or more thereof is employed, with R E being selected from the group consisting of alkyl, aryl, alkylaryl, heteroaryl cycloalkyl and heterocycloalkyl, more preferably wherein R E is alkyl, more preferably wherein R E is methyl, ethyl or propyl, more preferably wherein R E is methyl.
  • the base is thus sodium methanolate.
  • the weight ratio of base to compound of formula (XX) is preferably in the range of from 0 to 8, more preferably in the range of from 1 to 5.
  • the sequence of mixing the components of the reaction mixture is not subject to specific restrictions.
  • the compound of formula (XX) is first admixed with at least a portion of a suitable solvent and, to the resulting mixture, the base is added which, for example, can be employed as mixture with at least a portion of the solvent or as such.
  • Compound (XX) is preferably allowed to react with the base for a time in the range of from 0 to 24, more preferably in the range of from 0 to 5, more preferably in the range of from 0 to 3.
  • step (bb) the compound of formula (XX) is reacted with a base to give, optionally after further steps, the compound (Al). In this case, no additional reduction step is necessary. Directly upon reaction with the base, the 7-membered ring of compound (Al) is formed ("cyclization reaction").
  • step (bb) the compound of formula (XX) is reacted with a base which is thereafter or in step (cc) reduced to give, after step (cc) and optionally after further steps, the compound (Al).
  • a reduction of the carbonyl group is thus carried out.
  • compound may be isolated or may be directly reduced in situ to give the compound of formula (XX). If such isolation is carried out, this may be carried out by any method known to those skilled in the art.
  • isolation may comprise one or more stages wherein preferably at least one stage comprises purification, such as an extraction and/or a precipitation and/or filtration.
  • the protecting group PG 2a may be removed.
  • the way of removing the protecting group PG 2a depends on the protecting group used. Suitable methods are known to those skilled in the art.
  • the removal of PG 2a is carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably, the protecting group is removed with Pd/C.
  • the removal of group PG 2a may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, iPrOH, nPrOH, EtOAc, iPrOAc and mixtures of two or more thereof.
  • the removal of group PG 2a is carried out at a temperature in the range of from 0 °C to 100 °C, more preferably in the range of from 10 °C to 70 °C, more preferably at room temperature 20 °C to 50 °C, more preferably at room temperature.
  • the reaction is preferably carried out at a pressure in the range of from 1 to 4 bar, more preferably, 1.0 to 2.5 bar.
  • the compound is preferably allowed to react for a time in the range of from 10 min to 180 min, more preferably in the range of from 20 to 120 min, more preferably in the range of from 30 to 60 min.
  • the reduction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitrile, CH 2 CI 2 and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, nPrOH, i-PrOH, THF, 2-MeTHF, MTBE, DIPET, toluene, acetonitrile, CH 2 CI 2 and mixtures of two or more thereof.
  • step (cl) is carried out at a temperature in the range of from -20 °C to 110 °C.
  • the compound is reduced by reaction with a reducing agent selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 , LiBH 4 and H 2 in the presence of transition metals, wherein the transition metal is preferably selected from the group consisting of IR, Pt, Fe, Rh, Pd, Re, Ru, Ni and Co.
  • the reducing agent is selected from the group consisting of NaBH 4 , NaCNBH 3 , NaBH(OAc) 3 , LiAlH 4 and LiBH 4 , more preferably the reducing agent is NaBH 4 , NaCNBH 3 or NaBH(OAc) 3, more preferably NaBH 4 .
  • Compound (XX) preferably has either the structure
  • step (aa) compound (XX) is provided in the correct stereochemistr , i.e. as compound (XX*)
  • step (bb) This compound is then employed in step (bb) instead of the racemic mixture consisting of (XX*) and (XX**) shown above.
  • step (bb) in case compound (XX) consists of a racemic mixture, in step (bb), in the cyclization reaction of compound (XX), a compound (Al) consisting of a racemic mixture is obtained.
  • a chiral resolution of (Al) is carried out.
  • the racemic mixture in this case consists of the com ounds (Al *) and (Al **)
  • the compound (Al) contains from 20 to 75 % % by weight of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **).
  • the mixture comprising (Al *) and (Al **) is resolved by chiral resolution.
  • (II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) contains at least than 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),
  • single stereoisomer of a chiral acid in this context is denoted to mean that the chiral acid comprises less than 1 % by weight, preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no impurities of respective other stereoisomers of the chiral acid, based on the total weight of the chiral acid.
  • step (I) upon addition of the chiral acid in a suitable solvent, a chiral acid salt (T*) of at least part of the compound of formula (XX) is formed, and at least part of this chiral acid salt (T*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent.
  • a chiral acid salt (T*) of at least part of the compound of formula (XX) is formed, and at least part of this chiral acid salt (T*) formed is precipitated, preferably crystallized, thereby obtaining a mixture comprising the precipitated, preferably crystallized, tartaric acid salt (T) and the solvent.
  • the chiral acid is preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, preferably Dibenzoyl tartaric acid.
  • the process thus comprises
  • (II) preferably separating the precipitated, preferably crystallized, chiral acid salt (T) of the compound of formula (Al) from the mixture obtained in (I), wherein the chiral acid salt (T) of the compound of formula (Al) contains at least 80 % by weight of the chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al),
  • the present invention also relates to a process, as described above, and a compound obtained or obtainable by the above described method the method comprising
  • a chiral acid salt preferably a tartaric acid salt, (T*) of at least part of the compound of formula (Al) by treating the compound of formula (Al) with a single stereoisomer of a chiral acid, preferably of a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, in a suitable solvent, and precipitating, preferably crystallizing, at least part of the salt (T*) formed, thereby obtaining a mixture comprising the precipitated, preferably crystallized, salt (T) and the solvent,
  • the compound of formula (Al) employed in (I) contains of from 40 to 60 % by weight of the compound of formula (Al *) based on the total weight of the sum of (Al *) and (Al **).
  • step (b) at least part of the compound of formula (Al) obtained in the cyclization reaction is transformed into the corresponding chiral acid salt, preferably tartaric acid salt, (T*).
  • the chiral acid salt (T*) contains the chiral acid salt of the compound of formula (Al *), e.g. in an amount in the range of from 1 to 80 % by weight, such as in the range of from 10 to 70 % by weight, or in the range of from 30 to 60 % by weight, or in the range of from 45 to 55 % by weight, based on the total amount of the chiral acid salt (T*).
  • At least part of (T*) is precipitated, preferably crystallized.
  • This is preferably achieved by contacting (treating) the compound of formula (Al) in a suitable solvent with the chiral acid. Thereby, a mixture comprising the crystallized chiral acid salt (T) of the compound of formula (Al *) and the solvent is formed.
  • the precipitated, preferably crystallized, tartaric acid salt (T) of the compound of formula (Al) contains at least 80 % by weight of chiral acid salt of the compound of formula (Al *) based on the total weight of the chiral acid salt of the compound of formula (Al).
  • the mixture obtained in step (I) may comprise further compounds, in particular non crystalline forms of the compound of formula (Al) and salts thereof.
  • the mixture obtained in step (I) comprises non-crystalline forms of the compound of formula (Al **) and chiral acids salts thereof.
  • the chiral acid salt (T*) of the compound of formula (Al) is denoted to encompass all chiral acid salts of compound (Al) formed in step (I) including the chiral acid salt (T) which precipitates as well as all chiral acid salts formed which remain dissolved.
  • the chiral acid salt (T*) may comprise a mixture of chiral acid salts of compounds of formula (Al *) and (Al **).
  • step (I) and (II) thus a chiral resolution of the stereoisomers (Al *) and (Al **) is carried out.
  • any suitable organic solvent in which the compound of formula (Al) is sufficiently soluble may be used.
  • the solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH 2 CI 2 , ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.
  • the suitable solvent comprises acetone or methanol, more preferably the suitable solvent is acetone or methanol.
  • step (I) a further solvent may be added in order to precipitate, preferably crystallize, the chiral acid salt (T).
  • the mixture obtained in step (I) preferably additionally comprises said further solvent.
  • This further solvent may be added prior to, together with or after the addition of the chiral acid to the compound of formula (Al).
  • the compound of formula (Al) is dissolved in the suitable solvent mentioned above and a mixture, preferably a solution of the chiral acid, in a further solvent is added to the solution, wherein the further solvent and the suitable solvent may be the same or may be different.
  • the further solvent is selected from the group consisting of EtOH, i-PrOH, nPrOH, acetone, toluene, MTBE, CH 2 CI 2 , ethyl acetate, acetone, isopropanol, methanol, water, formic acid ethyl ester, isopropyl acetate, propyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, methylisobutylketone, toluene, hexane, cyclohexane, heptane and mixtures of two or more thereof.
  • the suitable solvent comprises acetone or methanol, more preferably the further solvent is acetone or methanol.
  • the present invention also relates to a process for the preparation of a chiral acid salt (T) of a compound of formula (Al), as described above, and a chiral acid salt (T) of the compound of formula (Al), obtained or obtainable by said process, wherein step (I) comprises dissolving the compound of formula (Al) in the suitable solvent and adding a solution of the chiral acid dissolved in a further solvent to the solution, wherein the further solvent and the suitable solvent are preferably the same, more preferably acetone or methanol.
  • the compound of formula (Al) is dissolved in the suitable solvent and the mixture is heated to a temperature in the range of from 20 to 80 °C, more preferably to a temperature in the range of from 30 to 60 °C more preferably to a temperature in the range of from 30 to 50 °C, more preferably to a temperature in the range of from 30 to 40 °C, prior to the addition of the tartaric acid.
  • the temperature may be varied, constantly or stepwise, or held essentially constant.
  • the mixture is heated until a clear solution of the compound of formula (Al) in the suitable solvent is obtained.
  • the mixture is afterwards cooled to room temperature.
  • the precipitation, preferably the crystallizing, in step (I) is preferably carried out at a temperature in the range of from 0 to 60 °C, wherein the temperature is preferably continuously or stepwise decreased.
  • the chiral acid may thus e.g. be added to a solution of the compound of formula (Al) in the suitable solvent which has been previously heated or which has been previously heated and afterwards cooled to a specific temperature, or which has not been previously heated.
  • the mixture may again be heated or alternatively be cooled, or the temperature may be held constant.
  • the mixture is cooled to a temperature in the range of from 0 to 50 °C, more preferably to a temperature in the range of from 0 to 40 °C, more preferably to a temperature in the range of from 10 to 30 °C.
  • the mixture obtained in step (I) consists of the chiral acid salt (T), optionally the unreacted chiral acid derivative, optionally the unreacted compound of formula (Al), optionally the further chiral acid salts (salt (T*) minus the amount of precipitated chiral acid salt (T)), the suitable solvent and optionally the further suitable solvent.
  • step (II) of the process of the invention the chiral acid salt (T) is separated from the mixture obtained in step (I).
  • the separation may be carried out by any suitable method known to those skilled in the art.
  • the separating in step (II) is carried out by centrifugation or filtration, preferably filtration.
  • the separated salt may be subjected to a further treatment such as an after-treatment such as a purification step and/or lyophilization.
  • the obtained chiral acid salt (T) of the compound of formula (Al) contains at least 85 % by weight, more preferably at least 95 % by weight, more preferably at least 96 % by weight, more preferably at least 97 % by weight, more preferably at least 98 % by weight, more preferably at least 99 % by weight, more preferably at least 99,5 % by weight, more preferably at least 99,9 % by weight, of the tartaric salt of the compound of formula (Al *), based on the total weight of chiral acid salt of the compound of formula (Al), i.e. based on the sum of (Al **) and (Al *). More preferably, the chiral acid salt (T) of the compound of formula (Al) consists of the chiral acid salt of the compound of formula (Al *).
  • compound (Al) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the chiral acid is preferably or a di-toluoyl tartaric acid, more preferably L-di- toluoyl tartaric acid (LTTA).
  • LTTA L-di- toluoyl tartaric acid
  • R 1 H and the chiral acid is L-di-toluoyl tartaric acid.
  • the suitable solvent is preferably methanol.
  • Al consist of a mixture of
  • the chiral acid is preferably a di-benzoyl tartaric acid, more preferably D-di- benzoyl tartaric acid (DBTA).
  • DBTA D-di- benzoyl tartaric acid
  • R 1 Cbz and the chiral acid is D-di- benzoyl tartaric acid.
  • the suitable solvent is preferably acetone.
  • the compound of formula (XX) may be provided by any suitable method known to those skilled in the art.
  • compound (XX) provided in step (a) according to the invention comprises
  • R laa is H, PG 1 , R A or PG laa and wherein R 2a is PG 2a , and wherein PG laa and PG : are, independently of each other, suitable protecting groups,
  • the resent invention is further directed to a compound of formula (1)
  • R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH.
  • the heteroaryl is an unsubstituted heteroaryl or alternatively, regarding R 6 or R 7 being heteroaryl, it is preferred that the heteroaryl, is selected from the group consisting of benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenylyl, napthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, de
  • R a , R b , R c and R d are independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, carbonyl, alkoxy, hydroxyl, -NR 6 R 7 , -SR and -N0 2 , wherein R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl and heterocycloalkyl.
  • X it is referred that X is selected from the group consisting of
  • R c it is preferred that it is alkyl, more preferably methyl.
  • R a , R b and R d it is preferred that they are H.
  • a preferred compound according to the present invention is he compound of structure (la)
  • X is selected from the group consisting of
  • the present invention relates to a com ound having the structure
  • the compound of formula (1) or of formula (la) contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.
  • the compound of formula (XX) provided in step (aa) has either the structure (XX*) or consists of a mixture of (XX*) and (XX**).
  • step (aa) the compound of formula (XX*) is provided, thus the "isolated isomer” with R configuration.
  • isolated isomer in this context is denoted to mean that the compound of formula (XX*) comprises less than 1 % by weight of compound (XX**), preferably less than 0.5 % by weight, more preferably less than 0.1 % by weight, more preferably less than 0.05 % by weight, more preferably less than 0.01 % by weight, more preferably essentially no, more preferably no compound of formula (XX**) based on the total weight of (XX*) and (XX**).
  • step (a) the provision preferably either comprises a chiral resolution step or an enantioselective reaction step, such as enantioselective reduction of the double bond present in compound (Va).
  • the chiral resolution may be carried out by any suitable method known to those skilled in the art, such as resolution by crystallization or by chiral chromatography, such as chiral HPLC.
  • the chiral resolution during step (aa) is carried out by crystallization employing an optical pure resolving agent, preferably an optical pure chiral acid.
  • the chiral acid is tartaric acid or a tartaric acid derivative selected from the group consisting of Ditoluoyl tartaric acid, Dibenzoyl tartaric acid, Dianisoyl tartaric acid, Dibenzoyl tartaric acid mono(dimethylamide) and a mixture of two or more thereof, more preferably, the chiral acid is tartaric.
  • step (aa3) may be carried out in a stereoselective or in a non- stereoselective manner.
  • the reduction may be carried out by any suitable manner known to those skilled in the art.
  • a metal catalyst and hydrogen is used.
  • the metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh and mixtures of two or more thereof.
  • the metal catalyst is preferably selected from the group consisting of a catalyst comprising Pd, Fe, Ir, Rh, and mixtures of two or more thereof.
  • the catalyst comprises Fe and/or Rh.
  • the reaction is preferably carried out at a hydrogen pressure in the range of from 1 to 25 bar, more preferably, 2.5 to 10 bar. During the reaction, the pressure may be varied or held essentially constant.
  • the reaction is carried out at a temperature in the range of from 10 to 100 °C, more preferably in the range of from 20 to 60 °C, more preferably at 25 to 40 C.
  • the temperature may be varied or held essentially constant.
  • the reaction may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • the solvent is methanol or TFE.
  • the catalyst is a palladium catalyst, more preferably Pd/C.
  • the reaction is preferably carried out in a non- stereoselective manner.
  • non-stereoselective manner is denoted to mean that a racemic mixture of compounds (XX*) and (XX**) is obtained.
  • the present invention also relates to a process, as described above, wherein step (aa) comprises the steps (aal) to (aa4), as described above, and wherein in step (aa3), the compound is reduced with Pd/C.
  • step (aa4) is carried out.
  • step (aa4) comprises one or multiple steps, such a deprotection step and/or a protection step and/or a coupling step with a compound of formula (XII) as described above
  • the removal is preferably carried out under acidic conditions. More preferably, the removal is carried out with HC1 or TFA.
  • the removal of such protecting groups may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluene, acetonitrile and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s
  • the removal is carried out at a temperature in the range of from 0 to 40 °C, more preferably in the range of from 10 to 30 °C, more preferably at room temperature.
  • the temperature may be varied or held essentially constant.
  • the removal is preferably carried out under reductive conditions. More preferably, the removal is carried out with hydrogen and a metal catalyst, preferably a palladium catalyst, more preferably the protecting group is removed with Pd/C.
  • a metal catalyst preferably a palladium catalyst
  • the protecting group is removed with Pd/C.
  • the removal of such a protecting group may be carried out in any suitable solvent known to those skilled in the art.
  • the reaction is carried out in an organic solvent, more preferably in a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, methyltertbutylether, diethylether, diisopropylether, toluol, acetonitrile, EtOAc, iPrOAc, hexane, cyclohexane, heptane, dimethylacetamid and mixtures of two or more thereof.
  • a solvent selected from the group consisting of methanol, ethanol, trifluoroethanol (TFE), dichloromethane, DMF, DMSO, NMP, methanol, ethanol, propanol,
  • the removal is carried out at a temperature in the range of from 0 to 60 °C, more preferably in the range of from 10 to 50 °C, more preferably at room temperature.
  • the temperature may be varied or held essentially constant.
  • the reaction is preferably carried out at a pressure in the range of from 1 to 3 bar, more preferably, 1.5 to 2.5 bar.
  • the compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound is useful in a method of antagonizing orexin receptor activity.
  • the present invention also describes the compound of formula (IX) obtained or obtainable by the above-described process or a pharmaceutical composition comprising this compound for use as antagonists of orexin receptor activity, in particular for use in treating, preventing, ameliorating, controlling or reducing the risk of a variety of neurological and psychiatric disorders associated with orexin receptors, in particular for enhancing the quality of sleep; augmenting sleep maintenance; increasing REM sleep; increasing stage 2 sleep; decreasing fragmentation of sleep patterns; treating insomnia; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling depression; treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; or treating, controlling, ameliorating or reducing the risk of schizophrenia, in a ma
  • the compound of formula (IX) obtained or obtainable by the above described process or a pharmaceutical composition comprising this compound is used for treating or preventing a sleep disorder, in particular for enhancing the quality of sleep or for treating insomnia in a mammalian patient, in particular for treating or controlling obesity in a mammalian patient.
  • treatment refers to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such a disease or disorder.
  • R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group
  • step (a) comprises
  • step (a2) is carried out in the presence of a copper salt, preferably Cu(OTf) 2 .
  • R 1 is selected from the group consisting of H, PG 1 and R A , with R A being
  • PG 1 is a suitable protecting group and wherein n is 0 or 1, the process comprising
  • the compound comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H,
  • the compound comprises less than 1000 ppm, more preferably less than 100 ppm of the regioisomeric side product
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H,
  • PG 1 is a suitable protecting group and wherein n is 0 or 1, the process comprising
  • R la is selected from the group consisting of H, PG 1 and R A , with R A being
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H,
  • step (i) comprises
  • step (iv) reacting the com ound of step (iii) with
  • X* is a leaving group, preferably CI
  • X is referabl selected from the group consisting of
  • R 1 A with R A being preferably — ' ⁇ ,
  • step (ii) optionally reducing the compound of step (ii) in case n is 1 ,
  • step (a) of step (i) comprises (al) providing a compound of formula (IVa) or a salt thereof,
  • a compound of formula (1) obtained or obtainable by a process according to any one of embodiments 1 to 14, preferably wherein the compound contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.
  • a compound of formula (1) obtained or obtainable by a process according to any one of embodiments 1 to 14, preferably wherein the compound contains less than 1000 ppm, more preferably less than 100 ppm, more preferably less than 10 ppm regioisomeric compounds as impurities.
  • R a , R b , R c and R d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, halogen, carbonyl, alkoxy, hydroxyl,— NR 6 R 7 , -SR and -N0 2 , wherein R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl and heterocycloalkyl, and wherein E is an electrophilic group, with the proviso that E is not COOH,
  • heteroaryl is preferably a unsubstituted heteroaryl or
  • heteroaryl is preferably selected from the group consisting of benzodioxolyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyridazinyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, methylenedioxyphenylyl, napthyridinyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, deazapurinyl, or indolizinyl.
  • R a , R b , R c and R d are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl, carbonyl, alkoxy, hydroxyl, - NR 6 R 7 , -SR and -N0 2 , wherein R 6 and R 7 are, independently of each other, selected from the group consisting of H, alkyl, aryl, cycloalkyl and heterocycloalkyl.
  • R 1 is selected from the group consisting of H, PG 1 and R A , with R ⁇ being
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H,
  • R la is PG 1
  • X* is a leaving group, preferably CI
  • R 1 is R A , with R A bein
  • R 1 is selected from the group consisting of H, PG 1 and R A , with R A being
  • PG 1 is a suitable protecting group and wherein n is 0 or 1, the process comprising
  • R la is selected from the group consisting of H, PG 1 and R A , with R A being
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H,
  • R la is PG 1
  • X* is a leaving group, preferably CI
  • X is preferabl selected from the group consisting of
  • R 1 is R A , with R A being
  • R 1 is selected from the group consisting of H, PG 1 and R A , with R A being preferably ⁇ — ⁇ ' ⁇ >*- ,
  • PG 1 is a suitable protecting group and wherein n is 0 or 1, the process comprising
  • R la is selected from the group consisting of H, PG 1 and R A , with R A being
  • R la may be the same or may differ from R 1 , and wherein in case n is 0, R la is preferably not H,
  • X* is a leaving group, preferably CI
  • X is referabl selected from the group consisting of
  • R 1 is R A , with R A bein
  • p-tolylhydrazine hydrochloride 80 g, 504.22 mmol was dissolved in acetic acid (700 mL, 60 %) at slightly elevated temperatures (50 °C).
  • glyoxal 27 g, 40 % in water, 186.37 mmol was diluted with acetic acid (200 mL, 60 %).
  • the warm p-tolylhydrazine hydrochloride was added slowly and the solution turned dark red. After 3 h, a suspension formed which was cooled to 10 °C and filtered. The residue was washed with ethyl acetate and dried under vacuum at 50 °C to give 47.03 g (70 %>).
  • the glyoxal imine (60 g, 225.3 mmol) and Cu(OTf) 2 (1.2 g, 3.64 mmol) were heated under reflux in toluene (500 mL) for 4h. Toluene was removed and the residue was dissolved in ethyl acetate (300 mL) and washed with a saturated K 2 CO 3 solution (2x75 mL). The organic solution was dried with Na 2 S0 4 and MsOH (14.6 mL, 225.3 mmol) was added and cooled to 0 °C to remove p-toluidine. After filtration, the organic solvent was evaporated and the residue (54 g) was purified by vacuum distillation (92 °C bp, 7 mbar) to get 30.1 g (82 %) of white crystalline product.
  • the aldehyde (50 mg, 0.267 mmol) was added to a solution of NaH 2 P0 4 (96 mg, 0.8 mmol) of tBuOH (0.5 mL) and water (0.5 mL). 2-methyl-2-butene (0.45 mL, 5.34 mmol) was added followed by NaC10 2 (72.5 mg, 0.8 mmol). After 18 h, ethyl acetate and a saturated NH 4 C1 solution were added. Layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over Na 2 S0 4 and the solvent was removed under reduced pressure.
  • the bromine solution was carefully added to the organometallics solution, followed by stirring at -65° C for 1.5 h. Now, the reaction was quenched using a 5 % sodium thiosulfate solution (150 mL) and the mixture was allowed to warm to ambient temperature. The organic layer was washed with sodium thiosulfate solution (5 wt.-%) and brine and dried over anhydrous sodium sulfate.
  • KMn0 4 (96 mg, 0.607 mmol) was dissolved in a 2 : 1 CH 3 CN : water mixture (2.5 mL), then tetrabutylammonium bromide (10 mg) was added and heated to 55 °C. A solution of the imine (100 mg, 0.303 mmol) in CH 3 CN (1.5 mL) was added over 2 h and stirring was continued for 18 h. The reaction was cooled to room temperature, the solids were filtered off and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and saturated NaHC0 3 solution. Layers were separated and the organic layer was extracted repeatedly with saturated NaHC0 3 solution. The organic layer was dried over Na 2 S0 4 and the solvent was removed under reduced pressure.
  • the aldehyde (lg, 5.34mmol) and Boc-ethylenediamine (873 mg, 5.34 mmol) were dissolved in toluene (60 mL) and MS 4 A was added. Toluene (50 mL) was removed by distillation and a second toluene portion (50 mL) added and azeotropically distilled again. The mixture was filtered over Celite and the solvent removed in vacuum. The product crystallized upon standing and was used without further purification.
  • a screw-cap vial equipped with magnetic stirrer bar was charged with 2-(2-iodo-4- methylphenyl)-2H-l,2,3-triazole (100 mg, 0.35 mmol, 1 equiv), Cu(OAc) 2 (12 mg, 0.07 mmol, 0.2 equiv), triphenyl phosphine oxide (39 mg, 0.14 mmol, 0.4 equiv), Ag 2 0 (81 mg, 0.35 mmol, 1.0 equiv) and acetonitrile (1.2 mL).
  • the vial was capped and the resulting mixture was stirred at 120 °C overnight.
  • the conversion to 5-methyl-2-(2H- 1,2,3- triazole-2-yl)benzonitrile was 20 % as determined by RP-HPLC.
  • reaction mixture was evaporated to dryness under reduced pressure and purified by column chromatography (Si0 2 , cyclohexane/ethyl acetate 9 : 1), yielding perfluorophenyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (2.5 g, 72 %) as a colorless powder.
  • a screw-cap vial equipped with a magnetic stirrer was charged with toluene (0.2 mL), ethyl 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzoate (50 mg, 0.22 mmol, 1.0 equiv) and the respective amine (0.32 mmol, 1.5 equiv).
  • To this mixture was added powdered 4 A MS (15 mg) and A1C1 3 (43 mg, 0.32 mmol, 1.5 equiv).
  • the vial was capped, placed in a sand bath and heated to 120°C. After stirring for 7 h at 120 °C, the conversion to the corresponding amide was determined by RP-HPLC using previously isolated material as reference.
  • a screw-cap vial equipped with a magnetic stirrer bar was charged with dry acetonitrile (2.6 mL) and 5-methyl-2-(2H-l,2,3-triazole-2-yl)benzaldehyde (150 mg, 0.8 mmol, 1.0 equiv).
  • To the clear, orange solution was added the respective amine (1.04 mmol, 1.3 equiv) and a iert-butyl hydroperoxide solution (70 wt-% in H 2 0, 1.04 mmol, 1.3 equiv).
  • the reaction mixture was heated to 100 °C and the progress of the reaction was monitored by RP-HPLC using previously isolated material as reference.

Abstract

La présente invention concerne un procédé pour la préparation d'un composé de formule (1), selon lequel le procédé est fondé sur l'utilisation d'un réactif organolithium et dans lequel Ra, Rb, Rc et Rd sont, indépendamment les uns des autres, choisis dans le groupe constitué par H, alkyle, aryle, cycloalkyle, hétéroalkyle, hétéroaryle, hétérocycloalkyle, halogène, carbonyle, alcoxy, hydroxyle, -NR6R7, -SR et -NO2, R6 et R7 étant, indépendamment l'un de l'autre, choisis dans le groupe constitué par H, alkyle, aryle, cycloalkyle, hétéroalkyle, hétéroaryle et hétérocycloalkyle, et dans lequel E est un groupe électrophile. La présente invention se rapporte en outre à un composé obtenu ou pouvant être obtenu par ledit procédé et un composé de formule (1) en tant que tel. En outre, la présente invention concerne l'utilisation du composé de formule (1) pour la préparation de suvorexant.
PCT/EP2015/067993 2014-08-04 2015-08-04 Préparation d'un dérivé d'acide benzoïque et son utilisation pour la préparation de suvorexant WO2016020403A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573294A (zh) * 2017-09-19 2018-01-12 四川大学 5‑甲基‑2‑(2h‑1,2,3‑***‑2‑基)苯甲酸的合成方法
WO2018202689A1 (fr) 2017-05-03 2018-11-08 Idorsia Pharmaceuticals Ltd Préparation de dérivés de l'acide 2-([1,2,3]triazol-2-yl)-benzoïque

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008069997A1 (fr) * 2006-12-01 2008-06-12 Merck & Co., Inc. Antagonistes des récepteurs de l'orexine sous forme de composés de diazépane substitués
US7491819B1 (en) * 2004-05-28 2009-02-17 Bristol-Myers Squibb Company N-[4-Fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide as an HIV integrase inhibitor
WO2009136995A2 (fr) * 2008-04-16 2009-11-12 Portola Pharmaceuticals, Inc. Inhibiteurs de la syk protéine kinase
WO2011050198A1 (fr) * 2009-10-23 2011-04-28 Janssen Pharmaceutica Nv Octahydropyrrolo[3,4-c]pyrroles disubstitués en tant que modulateurs de récepteur d'orexine
WO2012148553A1 (fr) * 2011-03-03 2012-11-01 Merck Sharp & Dohme Corp. Procédé de préparation d'un antagoniste des récepteurs des orexines

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7491819B1 (en) * 2004-05-28 2009-02-17 Bristol-Myers Squibb Company N-[4-Fluorophenyl)methyl]-4,6,7,9-tetrahydro-3-hydroxy-9,9-dimethyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide as an HIV integrase inhibitor
WO2008069997A1 (fr) * 2006-12-01 2008-06-12 Merck & Co., Inc. Antagonistes des récepteurs de l'orexine sous forme de composés de diazépane substitués
WO2009136995A2 (fr) * 2008-04-16 2009-11-12 Portola Pharmaceuticals, Inc. Inhibiteurs de la syk protéine kinase
WO2011050198A1 (fr) * 2009-10-23 2011-04-28 Janssen Pharmaceutica Nv Octahydropyrrolo[3,4-c]pyrroles disubstitués en tant que modulateurs de récepteur d'orexine
WO2012148553A1 (fr) * 2011-03-03 2012-11-01 Merck Sharp & Dohme Corp. Procédé de préparation d'un antagoniste des récepteurs des orexines

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CARL A. BAXTER ET AL: "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 15, no. 2, 18 March 2011 (2011-03-18), pages 367 - 375, XP055127210, ISSN: 1083-6160, DOI: 10.1021/op1002853 *
CHRISTOPHER D. COX ET AL.: "Conformational analysis of N,N-disubstituted-1,4-diazepane orexin receptor antagonists and implications for receptor binding", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, 2009, GBOXFORD, pages 2997 - 3001, XP002736230, ISSN: 0960-894X *
M.E.K. CARTOON ET AL.: "Lithiation reactions of 1-(2'-bromophenyl)pyrrole and related compounds", JOURNAL OF ORGANOMETALLIC CHEMISTRY, vol. 212, 1981, pages 1 - 9, XP002736232 *
QINGSHAN TIAN ET AL.: "Regioselective halogenation of 2-substituted-1,2,3-triazoles via sp2 C-H activation", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 11, 2013, pages 7830 - 7833, XP002736231 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018202689A1 (fr) 2017-05-03 2018-11-08 Idorsia Pharmaceuticals Ltd Préparation de dérivés de l'acide 2-([1,2,3]triazol-2-yl)-benzoïque
US11124488B2 (en) 2017-05-03 2021-09-21 Idorsia Pharmaceuticals Ltd Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
CN107573294A (zh) * 2017-09-19 2018-01-12 四川大学 5‑甲基‑2‑(2h‑1,2,3‑***‑2‑基)苯甲酸的合成方法

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