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WO2021259852A1 - Procédé de préparation de dérivés de 5-(alcoxycarbonyle)-et de 5- (carboxamide)-1-aryl-1,2,4-triazole - Google Patents

Procédé de préparation de dérivés de 5-(alcoxycarbonyle)-et de 5- (carboxamide)-1-aryl-1,2,4-triazole Download PDF

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WO2021259852A1
WO2021259852A1 PCT/EP2021/066815 EP2021066815W WO2021259852A1 WO 2021259852 A1 WO2021259852 A1 WO 2021259852A1 EP 2021066815 W EP2021066815 W EP 2021066815W WO 2021259852 A1 WO2021259852 A1 WO 2021259852A1
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general formula
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trifluoromethyl
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Nicolas GUIMOND
Guido Becker
Hendricus Nicolaas Sebastiaan VAN DER HAAS
Reinerus Gerardus Gieling
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present application relates to a novel and improved process for preparing 5- (hydroxyalkyl)-, 5 -(alkoxy carbonyl)- and 5 -(carboxamide)- 1 -aryl- 1,2, 4-triazole derivatives of the general formulas (XXI), (III) and (IV) in which Ar 1 represents a phenyl group, which is optionally substituted with one or more halogen atoms, R 1 represents a (Ci-Cz -alkyl group, which is optionally substituted with one or more substituents selected from a fluorine atom, hydroxy and oxo, R 2 represents a (Ci-C -alkoxycarbonyl group, and Ar 2 represents a phenyl group or a 5- or 6-membered heteroaryl group attached via a ring carbon atom having one or two ring heteroatoms selected from a nitrogen atom and a sulfur atom, wherein any phenyl group and any 5- or 6- membered heteroaryl group are each
  • Compounds of the formula (IV) as disclosed in WO 2017/191102-A1 and WO 2017/191107- Al, are highly potent and selective antagonists of the Via receptor and can be used as agents for prophylaxis and/or treatment of cardiovascular disorders and renal disorders, for example acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud’s syndrome and dysmenorrhea.
  • acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud’s syndrome and dysmenorrhea.
  • Scheme 1 and 2 below show the process for preparing the substituted 1,2,4-triazole derivatives according to WO 2011/104322.
  • the target compounds of the formula (I) are prepared in the gram range in 4 stages using a linear synthesis with an overall yield of 3- 48% of theory.
  • Scheme 3 below shows the process for preparing the compounds of the formula (IV) according to WO 2017/191102, WO 2017/191105 and WO 2017/191107 (see WO 2017/191102, page 13-23, claim 4, examples therein; WO 2017/191105, page 17-30, claim 5, examples therein; WO 2017/191107, page 14-24, claim 4, examples therein) .
  • R/S is converted by reaction with sodium methoxide to methyl 2- ⁇ 3-(4-chlorophenyl)-5-oxo- 4-[3 ,3 ,3 -trifluoro-2-hydroxypropyl] -4,5 -dihydro- 177- 1 ,2,4-triazol- 1 -yl ⁇ ethanimidate (XI- R/S).
  • the 1,2,4-triazole ring is then formed via a one-pot three-component cyclization reaction, wherein the imino ester compound (XI-R/S) reacts with methyl chlorooxoacetate (XII) and a substituted arylhydrazine compound (XIII), and the methyl 3-( ⁇ 3-(4- chlorophenyl)-5 -oxo-4-[3 ,3 ,3 -trifluoro-2-hydroxypropyl] -4,5 -dihydro- 1H- 1 ,2,4-triazol- 1 - yl ⁇ methyl)-l-(aryl)-lH-l,2,4-triazole-5-carboxylate (III-A) is obtained.
  • the subsequent aminolysis of the methyl ester group affords the target compounds of the formula (IV-A).
  • the new inventive process may further be applied to 5 -(hydroxyethyl)-l -aryl- 1,2,4- triazole derivatives of the general formula (XXI)
  • Pecavaptan which is 5-(4-chlorophenyl)-2-( ⁇ l-(3-chlorophenyl)-5-[(lS)-l-hydroxyethyl]- lH-l,2,4-triazol-3-yl ⁇ methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H- l,2,4-triazol-3-one and is disclosed as example 79 of WO 2016/071212-A1, corresponds to the compound of formula (XXI-l-S-S) and is a highly potent dual vasopressin receptor antagonist (Via and V2).
  • R 1A , R 1B hydrogen, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy and trifluoromethoxy; a) Na2C03, methyl isobutyl ketone; b) sodium methoxide, MeOH, c) 1.
  • XII- A DIPEA, toluene/THF, 2.
  • XIII DIPEA, THF; d) NaOH, MeOH; Compound numbering according to WO 2017/191104]
  • transformations are conducted by customary methods familiar to the person skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of metal organyls (e.g. Grignard compounds or lithium organyls), oxidation and reduction reactions, hydrogenation, halogenation (e.g. fluorination, bromination), dehalogenation, animation, alkylation and acylation, the formation of carboxylic esters, carboxamides and sulphonamides, ester cleavage and hydrolysis, and the introduction and removal of temporary protecting groups or other reactions known to those skilled in the art.
  • reactions such as nucleophilic or electrophilic substitution reactions, transition metal-mediated coupling reactions, preparation and addition reactions of metal organyls (e.g. Grignard compounds or lithium organyls), oxidation and reduction reactions, hydrogenation, halogenation (e.g. fluorination, bromination), dehalogenation, animation, alkylation and acylation
  • Suitable protecting groups and reagents and reaction conditions for the introduction and detachment thereof are known to those skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts; "Protective Groups in Organic Synthesis 3rd Edition, Wiley 1999). Specific examples are cited in the text passages which follow.
  • the methyl ester compound (III-l-S) may then be converted to the free amide (IV-l-S) in an aminolysis reaction (Step 2).
  • Other 5 -(alkoxy carbonyl)- 1 -aryl- 1,2,4- triazole derivatives (III) and their corresponding 5 -(carboxamide) analogues (IV) may be prepared by an analogous procedure.
  • Scheme 7 Process according to the invention for preparing the compounds of the formula (XXI-l-S/S) .
  • a hydroxy-protected form of (XXII-l-S) may be employed as a coupling partner. After the coupling reaction, the protection group may then be cleaved by reaction with a suitable deprotection reagent.
  • Other 5 -(hydroxyalkyl)-l -aryl- 1,2, 4-triazole derivatives (XXI) may be prepared by an analogous procedure.
  • the starting compound of the formula (II-l-S) described in Synthesis Schemes 6 and 7 as well as the starting compound of the formula (II-2) can be prepared according to Synthesis Scheme 8 below, proceeding from starting compounds that are commercially available or known to the person skilled in the art:
  • the starting substances of the formula (II) are described in WO 2010/105770 (see Schemes 4 and 5; Examples 1A, 2A, 3A, 4A and 158A therein) and WO 2011/104322 (see Scheme 1; Examples 1A, 2A, 3 A, 4A and 5 A therein).
  • the compounds of the formula (II) are obtained by reacting 4-chlorobenzohydrazide (XIV) with ethyl 2-isocyanatoacetate (XV) to give ethyl N-( ⁇ 2-[(4-chlorophenyl)carbonyl]hydrazinyl ⁇ carbonyl)glycinate (XVI).
  • the compound of formula (1-1) is obtained by reacting ethyl lH-l,2,4-triazole-3-carboxylate (V-l) with 2-bromo-3-(trifluoromethyl)pyridine (VI-1) under basic conditions in an aromatic nucleophilic substitution reaction.
  • the compound of formula (XXII-l-S) may be obtained by reacting ethyl lH-l,2,4-triazole-3- carboxylate (V-l) with (3-chlorophenyl)boronic acid (XXIII-1) in the presence of a copper source under Chan-Lam reaction conditions.
  • the resulting ethyl l-(3-chlorophenyl)-l,2,4- triazole-3-carboxylate (XXIV-1) can then be reduced to the corresponding [l-(3- chlorophenyl)-l,2,4-triazol-3-yl]methanol (XXV-1) and the alcohol funtionality can be protected with s suitable protecting group (e.g.
  • the methyl ketone is then reduced to the ( l.Y)- 1 -hydroxyethyl group in a ruthenium -catalyzed asymmetric reduction reaction or via reduction with sodium borohydride followed by enzymatic resolution.
  • the hydroxymethyl function of (XXVIII-l-S) may then be converted to the corresponding bromide using phosphorus tribromide analogous to the reaction conditions described above in scheme 9 for the synthesis of (IX-1). It may be beneficial to protect the secondary alcohol of the hydroxyethyl group e.g. by reaction with acetyl chloride before subjecting to the deoxybromination conditions.
  • the acetyl group may thereafter be cleaved under standard deprotection conditions, e.g.
  • Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention (for example, cf. S . M. Berge etai, "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).
  • the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the inventive compounds also include salts of customary bases, preferred examples being alkali metal salts (e.g.
  • alkaline earth metal salts e.g. calcium salts and magnesium salts
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, preferred examples being ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.
  • alkaline earth metal salts e.g. calcium salts and magnesium salts
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, preferred examples being ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicycl
  • Solvates in the context of the invention are described as those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water.
  • the 3,3,3-trifluoro-2-oxopropyl derivatives (substituent definition in R 1 ) according to the invention (ketone form) may also be present in the 3,3,3-trifluoro-2,2- dihydroxypropyl form ( hydrate form) (see Scheme 11 below); both forms are expressly embraced by the present invention.
  • the compounds of the formula (I- A), (III-A), (IV-A), (VII-A) (XXI-A), (XXI-B) and (XXII-A) are each a subset of the compounds of formula (I), (III), (IV), (VII), (XXI) and (XXII) as defined by the respective R group definitions.
  • the compounds of the formula (1-1- S), (II-l-S) and the like are assigned here to an (5) configuration of the stereocentre, and the compounds of the formula (I-l-R), (II-l-R) and the like are each assigned to an (R) configuration of the stereocentre.
  • the definitions of the compounds of the formula (II-l- R/S), (III-l-R/S) as well as (IV-l-R/S) shall encompass both enantiomeric forms.
  • the compound of the formula (XXI-l-S/S) and the like are assigned here to an (.V)/(.V) configuration of the stereocentres.
  • the definition of the compounds of the formula (XXI-1- R/R/S/S) shall encompass all diastereomeric forms.
  • the present invention encompasses all the tautomeric forms.
  • the present invention provides a method of preparing a compound of general formula (III), or the salts thereof, the solvates thereof or the solvates of the salts thereof, said method comprising the step [A] of allowing an intermediate compound of general formula (II) : in which Ar 1 represents a phenyl group, which is optionally substituted with one or more halogen atoms, in particular a chlorine atom, and in which R 1 represents a (Ci-Cz -alkyl group, which is optionally substituted with one or more substituents selected from a fluorine atom, hydroxy and oxo, in particular R 1 represents a group of the formula in which #' represents the point of attachment to the nitrogen atom, to react in the presence of a suitable solvent and a base with an intermediate compound of general formula (I): in which X is a leaving group, preferably chloride, bromide or iodide, R 2 represents a (C1-C4)- alkoxycarbonyl group, in particular
  • R ' in which # 2 represents the point of attachment to the nitrogen atom, R 3A represents a group selected from a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl and -C( 0)NH 2 , R 3B represents a group selected from a chlorine atom, trifluoromethyl, and ethoxycarbonyl, thereby giving a compound of general formula (III-A) :
  • the present invention provides a method of preparing a compound of general formula (III) or (XXI), or the salts thereof, the solvates thereof or the solvates of the salts thereof, said method comprising the step [A] of allowing an intermediate compound of general formula (II) : (P), in which Ar 1 represents a phenyl group, which is optionally substituted with one or more halogen atoms, in particular a chlorine atom, and in which R 1 represents a (Ci-Cz -alkyl group, which is optionally substituted with one or more substituents selected from a fluorine atom, hydroxy and oxo, in particular R 1 represents a group of the formula in which #' represents the point of attachment to the nitrogen atom, to react in the presence of a suitable solvent and a base with an intermediate compound of general formula (I) or (XXII): in which X is a leaving group, preferably chloride, bromide or iodide, R 2 represents a (C
  • XXII-B in which X is a leaving group, preferably chloride or bromide, and R 5 represents hydrogen or a protecting group (PG), preferably acetyl, thereby giving a compound of general formula (XXI-C) : in which R 5 has the definition given above.
  • R 5 represents a protecting group (PG), preferably acetyl
  • PG protecting group
  • a suitable deprotection agent preferably a base
  • the present invention further provides a method of preparing methyl 5-(bromomethyl)-2-[3- (trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate of formula (1-1), or the salts thereof, the solvates thereof or the solvates of the salts thereof, said method comprising the step [C] of allowing a compound of general formula (V):
  • the method of preparing methyl 5- (bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate of formula (I- 1) is conducted as a one-pot reaction in the presence of a suitable solvent, wherein the intermediate compounds (VII-A) and (VIII-1) are converted without isolation from the reaction mixture, i.e. in solution.
  • Such a one-pot method is especially advantageous for an industrial scale synthesis, since it is possible in this way to avoid additional workup steps as (chromatographic) purification of intermediates is not necessary, and a high overall yield for the process is achieved..
  • the present invention further provides a compound of the general formula (I) in which R 2 , Ar 2 and X are as defined above.
  • the compound is methyl 5-(bromomethyl)- 2-[3-(trifhioromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate (1-1)
  • the present invention further provides the use of a compound of the general formula (I) for preparation of a compound of the general formula (III).
  • the present invention further provides a compound of the general formula (XXII) in which R 5 , R 6 , Ar 3 and X are as defined above.
  • the present invention further provides the use of a compound of the general formula (XXII) for preparation of a compound of the general formula (XXI).
  • the present invention further provides a compound of the general formula (VII- A):
  • the present invention further provides [l-[3-(trifhioromethyl)-2-pyridyl]-l,2,4-triazol-3- yl]methanol (VIII-1) of formula
  • the present invention further provides 2-[3-(Bromomethyl)-l,2,4-triazol-l-yl]-3- (trifluoromethyl)pyridine (IX- 1) of formula Step GA1:
  • Suitable bases for process step [A] are the standard inorganic or organic bases, for example and with preference alkali metal carbonates such as sodium carbonate, potassium carbonate or caesium carbonate, alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, alkali metal phosphate such as sodium phosphate or potassium phosphate or organic amines such as N,N- diisopropylethylamine (DIPEA), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- Diazabicyclo[4.3.0]non-5-ene (DBN)
  • Solvents used may be inert solvents, for example acetonitrile, methyl isobutyl ketone, dioxane, dimethylformamide, dimethylacetamide, isopropyl acetate, N-methylpyrrolidinone, dimethyl sulphoxide or sulpholane. If appropriate, these process steps can advantageously be conducted with addition of alkylation catalysts, for example lithium bromide, sodium iodide, tetra-u-butylammonium iodide, tetra- u-butylam monium bromide, benzyltriethylammonium chloride.
  • alkylation catalysts for example lithium bromide, sodium iodide, tetra-u-butylammonium iodide, tetra- u-butylam monium bromide, benzyltriethylammonium chloride.
  • the reactions are effected generally within a temperature range from +20°C to +100°C, preferably at +30°C to +70°C.
  • the reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.
  • Step 1B1 The aminolysis reaction [B-l] (III) — » (IV) is usually carried out in a solution of ammonia.
  • Suitable ammonia solutions for this step are saturated ammonia solutions, in particular a solution of ammonia in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or water or a mixture thereof.
  • a methanolic ammonia solution is used.
  • the reaction is preferably performed directly in the ammonia solution in the absence of any further reaction solvent. This step is generally carried out at a temperature in the range of +20°C to +120°C, preferably at room temperature.
  • Concomitant microwave irradiation may have a beneficial effect in this reaction as well at a temperature in the range of +60°C to +150°C, preferably at +120°C.
  • the reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.
  • Suitable bases for process step [C]: (V) + (VI) — » (VII) are the standard inorganic or organic bases, for example and with preference alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate or caesium fluoride, alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide, alkali metal phosphate such as sodium phosphate or potassium phosphate.
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate or caesium fluoride
  • alkali metal alkoxides such as sodium tert-butoxide or potassium tert-butoxide
  • alkali metal phosphate such as sodium phosphate or potassium phosphate.
  • Solvents used may be inert solvents, for example acetonitrile, methyl isobutyl ketone, dioxane, dimethylformamide, dimethylacetamide, isopropyl acetate, N-methylpyrrolidinone, dimethyl sulphoxide, tetrahydrofiiran or sulpholane.
  • phase-transfer catalysts for example te t ra- « -b uty 1 am m o n i um iodide, te t ra- « -b uty 1 am m o n i um bromide, benzyltriethylammonium chloride, tetrabutylammonium fluoride or crown ethers such as 18- crown-6.
  • the reactions are effected generally within a temperature range from +60°C to +120°C, preferably at +80°C to +110°C.
  • the reaction can be performed at standard, elevated or reduced pressure (e.g. from 0.5 to 5 bar); in general, standard pressure is employed.
  • the reduction can be performed using hydride sources such as sodium borohydride, lithium borohydride, diisobutylaluminium hydride, lithium aluminium hydride, diborane or its complex with inert solvents.
  • the preferred reducing agent is sodium borohydride.
  • solvent a series of solvents that are compatible with reducing agents are possible to use. The preferred ones are alcohols like methanol, ethanol, or isopropanol, ethers such as diethyl ether, tetrahydrofiiran or 1,4-dioxane, or other polar solvents such as acetonitrile, propionitrile, dimethylacetamide, dimethylformamide or water. Mixtures of mentioned solvents are also appropriate.
  • the most preferred solvent is methanol, or a combination of methanol and propionitrile.
  • the deoxybromination can be performed using typical bromination agents such as phosphorus tribromide, thionyl bromide, or combination of triphenyl phosphine and an electrophilic bromide source such as carbon tetrabromide, hexabromoacetone, N-b ro m os lice i n i m i de or N- bromosaccharin.
  • typical solvents are, for example, dichloromethane, dichloroethane, dioxane, tetrahydrofuran, toluene, acetonitrile, dimethylformamide, ethyl acetate, acetone, methyl isobutylketone or dimethyl carbonate.
  • the preferred conditions are using phosphorus tribromide as reagent and dichloromethane as solvent.
  • the reactions are effected generally within a temperature range from -20°C to +50°C, preferably at 0°C to +30°C.
  • Step 1F1 Process step (IX) — » (I)
  • Suitable bases for this process step are, for example, lithium hexamethyldisilane, lithium diisopropyl amide, lithium tetramethylpiperidine, tert-butyl lithium, sec-butyl lithium, n-butyl lithium, sodium hemamethyldisilane, potassium hexamethyldisilane, Grignard reagents such as isopropyl magnesium chloride or isopropyl magnesium bromide.
  • Typical solvents are, for example, dioxane, tetrahydrofuran, 2-methyl-tetrahydrofuran, toluene, acetonitrile, dimethyl carbonate.
  • Typical reagents are, for example, dimethyl carbonate, methyl cyanoformate or methyl chloroformate. Preference is given to using methyl chloroformate.
  • the reactions are effected generally within a temperature range from -78°C to +50°C, preferably at -10°C to +30°C.
  • the compounds of the formula (1-1) may alternatively also be prepared from compounds of the formula (XVIII) and (VI-1) that are known from the literature in 3 steps (Scheme 12):
  • the coupling step (V) + (XXIII) (XXIV) is typically carried out under Chan-Lam coupling" conditions; see, for instance, D. M. T. Chan et al., Tetrahedron Lett. 44 (19), 3863- 3865 (2003); J. X. Qiao and P. Y. S. Lam, Synthesis, 829-856 (2011); K. S. Rao and T.-S. Wu, Tetrahedron 68, 7735-7754 (2012); Org. Biomol. Chem., 16 (46), 8984 - 8988 (2016)].
  • the reduction step (XXIV) (XXV) can be performed under typical conditions as described above for reaction step [D]
  • Introduction of the protective group (PG 1 ) (XXV) -> (XXVI) can be carried out by customary methods known from the literature [see, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999]
  • Typical reaction conditions for the acylation (XXVI) (XXVII) are e.g. in Hoffmann-La Roche US 5,438,052 A. .
  • the asymmetric reduction of (XXVII) ⁇ (XXVIII) is typically performed with the aid of an asymmetric transition metal catalys, for example and preferably a ruthenium complex, e.g. Eur. J. Med. Chem, 162, 80-108, (2019).
  • Typical reaction conditions and reagents for the deoxybromination reaction from (XXVIII) -> (XXII) are those listed above for reaction step [E] .
  • the compounds according to the invention have valuable pharmacological properties and can be used for prevention and/or treatment of various disorders and disease-related conditions in humans and animals. Possible target indications are listed by way of example and with preference in WO 2017/191102-A1 , pages 24 to 27 for compounds of the formula (IV) as well as in WO 2016/071212-A1, pages 16 to 19 for compounds of the formula (XXI).
  • Suitable combination active ingredients and dosage forms are listed by way of example and with preference in WO 2017/191102-A1, pages 28 to 39 for compounds of the formula (IV) as well as in WO 2016/071212-A1, pages 19 to 25 for compounds of the formula (XXI)..
  • Purity figures are generally based on corresponding peak integrations in the HPLC chromatogram, but may additionally also have been determined with the aid of the 'H NMR spectrum. If no purity is indicated, the purity is generally 100% according to automated peak integration in the LC/MS chromatogram, or the purity has not been determined explicitly.
  • the 'H NMR data of selected examples are stated in the form of 'H NMR peak lists. For each signal peak, first the d value in ppm and then the signal intensity in round brackets are listed. The d value/signal intensity number pairs for different signal peaks are listed with separation from one another by commas.
  • the peak list for an example therefore takes the following form: di (intensityi), 6 2 (intensity2), , d ⁇ (intensity i), ... , d h (intensity n ).
  • the intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities in comparison with other signals. In the case of broad signals, several peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum.
  • the lists of the 'H NMR peaks are similar to the conventional 'H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation. In addition, like conventional 'H NMR printouts, they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities.
  • the peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of > 90%). Such stereoisomers and/or impurities may be typical of the particular preparation process. Their peaks can thus help in identifying reproduction of our preparation process with reference to "by-product fingerprints".
  • An expert calculating the peaks of the target compounds by known methods can, if required, isolate the peaks of the target compounds, optionally using additional intensity filters. This isolation would be similar to the peak picking in question in conventional 'H NMR interpretation.
  • Ethyl lH-l,2,4-triazole-3-carboxylate (V-l) (7.49 g, 53.1 mmol, 1.2 eq.), 18-crown-6 (2.81 g, 10.6 mmol, 0.24 eq.), potassium bicarbonate (5.32 g, 53.1 mmol, 1.2 eq.) and potassium carbonate (7.34 g, 53.1 mmol, 1.2 eq.) were sequentially added to the mixture at room temperature. The resulting suspension was then heated at reflux under argon for 46 hours. It was then cooled to room temperature before being added over 15 min to 100 mL of a 1 M aqueous potassium phosphate buffer solution (pH 7).
  • Ethyl l-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate (21.9 g, 76.5 mmol) was dissolved in EtOH (130 mL) at room temperature. To this solution was added sodium borohydride (2.89 g, 76.5 mmol, 1.0 eq.) and the mixture was allowed to stir at room temperature for one hour before another portion of sodium borohydride (2.89 g, 76.5 mmol, 1.0 eq.) was added.
  • reaction mixture was then stirred for 16 hours before being added onto 255 mL of an aqueous solution of dipotassium dihydrogen phosphate (80:20 (v:v) saturated aqueous solution : water). Without performing a phase separation, the organic volatiles were evaporated under reduced pressure. The resulting mixture was then extracted 4 times with 100 mL methyl tert-butyl ether. The combined organic layers were then evaporated under reduced pressure to afford 15.5 g (83%) of the title compound.
  • methyl lH-l,2,4-triazole-3-carboxylate (VII-2) (100 g, 787 mmol) was suspended in ethanol (1.5 L) and then sodium ethylate (95%, 56.4 g, 787 mmol) was added in one portion to the mixture.
  • the resulting suspension was then heated under reflux for 7.5 hours (jacket @ 90°C).
  • the jacket temperature was then adjusted to 100 °C and 350g EtOH were distilled off.
  • 1000 mL propionitrile were then added to the reactor and ethanol was distilled off at 175 mbar until constant boiling point.
  • Propionitrile 500 mL was added each time the mixture reached the limit of stirrability.
  • the jacket temperature was reduced to -10 °C and a pre-cooled (5°C) 50 wt% solution of acetaldehyde in ethanol (798 mL, 7.87 mol) was very slowly added while keeping the internal temperature of the reaction mixture under 8°C. [CAUTION! This quench is very exothermic!]
  • the reaction mixture was then added onto this buffer and the organic solvents were distilled off at a pressure of 175 mbar until constant boiling temperature.
  • Dichloromethane 500 mL was then added to the resulting mixture and the phases were separated.
  • the aqueous phase was extracted once more with dichloromethane (500 mL) and the combined organic extracts were evaporated under reduced pressure. The residue obtained was taken up in 1.1 L dichloromethane and cooled to 5°C. Phosphorus tribromide (142 g, 524 mmol, 0.8 eq.) was then slowly added to the mixture within 20 min. [The temperature reached a maximum of 11°C upon addition.] 1 h after the addition, the reaction mixture was allowed to reach room temperature and stir for another 16 h. A saturated aqueous solution of potassium dihydrogen phosphate (1 L) was then slowly added while stirring and the resulting biphasic mixture was filtered over Celite.
  • the heterogeneous mixture was heated at 55 °C to obtain a solution. 110 mL water was then slowly added at this temperature and the solution was cooled to 0°C within 300 minutes. Seeding crystals were added when the temperature reached 51 °C. The resulting suspension was filtered and the solid was dried under vacuum at 40 °C for 16 hours. The title compound was obtained as a solid (35.7 g, 75 % yield).
  • methyl 5- (bromomethyl)-2-[3-(trifluoromethyl)-2-pyridyl]-l,2,4-triazole-3-carboxylate (1-1) (1.433 kg, 3.93 mol) was dissolved in acetone (2.5 kg) and added within 10 min to the reactor at reflux. The mixture was stirred at reflux for 90 min before being rapidly cooled down to room temperature. MtBE (10.7 kg) and 29.6 kg of a 4 wt.% aqueous sodium bicarbonate solution was added to the mixture. The mixture was stirred for 10 min and the phases were then separated.
  • the organic phase was then washed twice with 14.6 kg of a 2.6 wt.% aqueous sodium chloride solution, once with a 7 wt% hydrochloric acid solution, and once with a 13 wt.% aqueous sodium chloride solution.
  • the resulting organic phase was then filtered over 1- 2 cm layer of diatomaceous earth and washed three times with 2.5 kg MtBE.
  • the resulting product-containing solution (18 L), was evaporated down to 6 L under reduced pressure.
  • the mixture was transferred to a 6 L glass reactor and the solvent was distilled off under atmospheric pressure until the stirring limit. Diisopropyl ether (2 L) was then added and distilled off. This step was repeated until a constant boiling point of 68.5 °C.
  • Diisopropyl ether was then added up to a volume of 6 L and the mixture was heated to 40 °C.
  • Acetone 600 mL was then added, which resulted in a homogenous red-brown solution. Seeding crystals of the product were then added and the mixture was allowed to stir at 40 °C for 24 hours.
  • the solid product was then collected by filtration and washed with 600 mL of an diisopropyl ether : Acetone 9: 1 (v:v) mixture. The product was dried under vacuum in an oven at 40 °C for 16 hours to afford 1.50 kg (80 %) of the title compound.

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Abstract

La présente invention concerne un procédé nouveau et amélioré de préparation de dérivés de 5-(alcoxycarbonyl)-et 5-(carboxamide)-1-aryl-1,2,4-triazole représentés par les formules générales (III) et (IV), dans lesquelles Ar1 représente un groupe phényle, qui est éventuellement substitué par un ou plusieurs atomes d'halogène, R1 représente un groupe alkyle en C1-C4, qui est éventuellement substitué par un ou plusieurs substituants sélectionnés parmi un atome de fluor, un hydroxy et un oxo, R2 représente un groupe alcoxycarbonyle en C1-C4, et Ar2 représente un groupe phényle ou un groupe hétéroaryle à 5 ou 6 chaînons lié par l'intermédiaire d'un atome de carbone cyclique ayant un ou deux hétéroatomes cycliques sélectionnés parmi un atome d'azote et un atome de soufre, tout groupe phényle et tout groupe hétéroaryle à 5 ou 6 chaînons étant chacun éventuellement substitués, de manière identique ou différente, avec un ou deux groupes sélectionnés parmi un atome d'halogène, un nitro, un cyano, un alkyle en C1-C4, un alcoxy en C1-C4, un alkylsulfanyle en C1-C4, un alcoxycarbonyle en C1-C4, un aminocarbonyle, -C(=O)N(H)CH3, - S(=O)2CH3, et -S(=O)2NH2, ledit groupe alkyle en C1-C4, ledit groupe alcoxy en C1-C4 et ledit groupe alkylsulfanyle en C1-C4 sont chacun éventuellement substitués par jusqu'à trois atomes de fluor. L'invention concerne également de nouveaux précurseurs pour la préparation de ces dérivés
PCT/EP2021/066815 2020-06-25 2021-06-21 Procédé de préparation de dérivés de 5-(alcoxycarbonyle)-et de 5- (carboxamide)-1-aryl-1,2,4-triazole Ceased WO2021259852A1 (fr)

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