EP3551616A1 - Verfahren zur herstellung von 5-(1-phenyl-1h-pyrazol-4-yl)-nicotinamid-derivaten und ähnlicher verbindungen ohne isolierung oder aufreinigung der phenylhydrazin-zwischenstufe - Google Patents

Verfahren zur herstellung von 5-(1-phenyl-1h-pyrazol-4-yl)-nicotinamid-derivaten und ähnlicher verbindungen ohne isolierung oder aufreinigung der phenylhydrazin-zwischenstufe

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Publication number
EP3551616A1
EP3551616A1 EP17823048.8A EP17823048A EP3551616A1 EP 3551616 A1 EP3551616 A1 EP 3551616A1 EP 17823048 A EP17823048 A EP 17823048A EP 3551616 A1 EP3551616 A1 EP 3551616A1
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EP
European Patent Office
Prior art keywords
reaction
compound
formula
halogen
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP17823048.8A
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German (de)
English (en)
French (fr)
Inventor
Florian ERVER
Frank Memmel
Alexander ARLT
Werner Hallenbach
Tobias HARSCHNECK
Christoph SCHOTES
Robert Velten
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Bayer Animal Health GmbH
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Bayer CropScience AG
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Publication of EP3551616A1 publication Critical patent/EP3551616A1/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • Ri is halogen, Ci-C i -alkyl which is optionally substituted by halogen or CN, or by Ci-C i -alkoxy optionally substituted by halogen;
  • R 2 is halogen, C 1 -C -alkyl optionally substituted by halogen or C 1 -C -alkoxy optionally substituted by halogen;
  • R 3 is halogen, C 1 -C -alkyl optionally substituted by halogen or CN or C 1 -C -alkoxy optionally substituted by halogen;
  • R is hydrogen, optionally substituted by halogen or CN substituted Ci-C / i-alkyl or optionally substituted by halogen or CN substituted C3-C6-cycloalkyl;
  • R5 is hydrogen, C 1 -C 18 -alkyl optionally substituted by halogen or CN, or C 3 -C 6 -cycloalkyl optionally substituted by halogen or CN;
  • Ai is or N
  • a 3 is or N;
  • Ri, R2, R3, R4, R5 like and R 1 and R 2 independently of one another are H or C 1 -C 6 -alkyl or R 1 and R 2 together represent a C 1 -C 8 -alkyl bridge (for example - (CH 3) 2 C-C (CH 3) 2) ,
  • A3 is C-halogen
  • A3 is N.
  • a 2 for C (R 7 ) -;
  • a 2 for C (R 7 ); A 3 for N;
  • Ri is halogen, Ci-C i -alkyl which is optionally substituted by halogen, in particular Br, I, Cl or F, or CN, or by C 1 -C -alkoxy which is optionally substituted by halogen;
  • R 2 is halogen-substituted C 1 -C 18 -alkyl or C 1 -C -alkoxy substituted by halogen, in particular Br, I, Cl or F; preferably fluorine-substituted Ci-C / i-alkyl or fluorine-substituted Ci-C / i-alkoxy z.
  • halogen in particular Br, I, Cl or F
  • perfluoro- Ci-C / i-alkyl or perfluoro- Ci-C / i-alkoxy As perfluoro- Ci-C / i-alkyl or perfluoro- Ci-C / i-alkoxy;
  • R 3 is halogen, C 1 -C -alkyl which is optionally substituted by halogen, in particular Br, I, Cl or F, or CN, or by C 1 -C 5 -alkyl optionally substituted by halogen, in particular Br, I, Cl or F, or CN alkoxy;
  • Particularly preferred R2 is difluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1, 2,2,2-tetrafluoroethyl, 1-chloro - 1, 2,2,2-tetrafluoroethyl, 2,2,2-trichloroethyl, 2-chloro-2,2-difluoroethyl, 1, 1 -difluoroethyl, pentafluoroeth
  • R 1 and R 3 independently of one another are H, Br, I, Cl or F, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, chlorodifluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, n- Propoxy, 1-methylethoxy, fluoromethoxy, difluoromethoxy, Chlorodifluoromethoxy, dichloro-fluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy or pentafluoroethoxy.
  • R 1 and R 3 independently of one another are H, chlorine, bromine, fluorine, cyano, methyl, ethyl, difluoromethyl, chlorodifluoromethyl, trifluoromethyl, methoxy, ethoxy, 1-methylethoxy, difluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, Trifluoromethoxy, 2,2,2-trifluoroethoxy or 2-chloro-2,2-difluoroethoxy.
  • Ri and R3 are the substituents described herein, but Ri and R3 are not simultaneously in a compound for H. In other words, when Ri in a compound is H, R3 is one of the other substituents described herein and vice versa.
  • R 1 and R 3 each represent a substituent selected from C 1, Br, C 1 -C 3 -alkyl, halogen-substituted C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy or halogen-substituted C 1 -C 3 -alkoxy.
  • R 1 and R 3 are each Cl, Br, in each case C 1 -C 3 -alkyl, or in each case halogen-substituted C 1 -C 3 -alkyl, such as, for example, As perfluorinated Ci-C3-alkyl (perfluoromethyl, perfluoroethyl or perfluoropropyl).
  • R 1 is perfluorinated C 1 -C 3 -alkyl (for example perfluoromethyl) and R 3 is Cl, Br or F, particularly preferably Cl or Br.
  • R 4 is C 3 -C 6 -cycloalkyl optionally substituted by Cl, Br, I, F or CN
  • R 5 is hydrogen or C 1 -C -alkyl which is optionally substituted by halogen or CN and R 5 is optionally halogen or CN substituted Ci-C i-alkyl or optionally substituted by halogen or CN substituted C3-C6-cycloalkyl.
  • R4 is cyclopropyl, 1 -CN-cyclopropyl and R5 is hydrogen or Ci-C / i-alkyl, such as methyl or ethyl.
  • the invention additionally relates to intermediate (X) and to processes for the preparation of compound (X):
  • the invention relates to intermediates (XI) to (XV), and their preparation.
  • anilines of the formula (a) used as starting materials are known from the literature (for example EP2319830, US2002 / 198399, WO2006137395, WO2009030457, WO2010013567, WO2011009540).
  • anilines 4- (1,1,3,3,3,3-heptafluoropropan-2-yl) -2,6-dimethylaniline
  • Preferred pyrazoles of the formula (d) are
  • the starting materials used to prepare the boranates or boronic acids are either commercially available (for example, 5-bromo-2-chloro-N-cyclopropylnicotinamide, 5-bromo-2-chloro-N-cyclopropyl-N-methylnicotinamide) or can analogously to the rule contained herein getting produced.
  • the following compounds are prepared by the method described herein:
  • the advantage of the present invention is the good handleability of the conversion of a compound of formula (a) into a compound of formula (d). All reaction steps can be carried out in a one-pot reaction.
  • one-pot reaction is understood to mean the conversion of a compound of the formula (a) into a compound of the formula (d) comprising the steps of diazotization of the compound of the formula (a) (reaction 1), reduction of the resulting salt a hydrazine compound of the formula (b) (reaction 2) and cyclization of the resulting compound to compound (d) (reaction 3), wherein at least one of the following conditions is satisfied:
  • reaction volumes in the form of solids, liquids or suspensions, for example in the form of solid, dissolved or suspended reducing agents, or solvents (the same solvent as used before reaction 1 or another solvent) may be added during the reaction sequence
  • solvents the same solvent as used before reaction 1 or another solvent
  • the goal is a reaction sequence without essential / without Substitution of solvent as used in Reaction 1 or active solvent removal as used before Reaction 1.
  • neither the diazonium ion (diazonium salt) resulting from compound (a) nor compound (b) is isolated or purified during the reaction sequence leading to compound (d). It is furthermore preferred that neither the diazonium ion (diazonium salt) resulting from compound (a) nor compound (b) is isolated or purified during the reaction sequence which leads to compound (d), nor is there any essential removal and / or exchange of solvent. z. As the solvent used as before reaction 1.
  • neither the diazonium ion (diazonium salt) resulting from compound (a) nor compound (b) is isolated or purified during the reaction sequence which leads to compound (d), nor is there any essential removal and / or exchange of solvent.
  • the solvent used as before reaction 1 and all reactions 1, 2, and 3 are carried out in the same reaction vessel.
  • the person skilled in the art will choose from the beginning a reaction vessel that can accommodate all volumes for reaction 1, 2 and 3.
  • the reaction sequence be telescoped reactions in one or more vessels, preferably a vessel.
  • purifying in the sense of the present invention refers to the enrichment of a substance (and thus depletion of other substances) to a purity of at least 20% by weight (percent by weight of a substance based on the measured total mass are determined chromatographically (eg HPLC or gas chromatographic or gravimetric), preferably at least 50 wt%, even more preferably at least 75 wt%, eg 90 wt%, 98 wt%) or greater than 99 % wt..
  • chromatographically eg HPLC or gas chromatographic or gravimetric
  • N-arylpyrazoles of the formula (d) are prepared by diazotizing 2,4,6-trisubstituted anilines of the formula (a) with a stoichiometric amount of nitrite, reduced by adding a reducing agent to the corresponding hydrazine intermediate of the formula (b) and then by Adding stoichiometric amounts of 1,1,3,3-tetramethoxypropane (c) is reacted in the presence of a solvent.
  • Suitable nitrites are z. B. alkali or Erdalkalinitrite or ammonium nitrite. Preference is given to LiNO 2 , NaNO 2 , KNO 2 , Mg (NO 2 ) 2 , Ca (NO 2 ) 2 or Ba (NO 2 ) 2 , particularly preferably LiNO 2 NaNO 2 , KNO 2 , very particularly preferably NaNO 2 .
  • Suitable solvents are, for.
  • carboxylic acids such as acetic acid, n-propanoic acid, n-butanoic acid
  • ethers such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane
  • nitriles such as, for example, Acetonitrile
  • Preferred solvents are carboxylic acids.
  • Very particular preference is acetic acid.
  • Suitable reducing agents are, in particular, tin (II) salts (such as tin (II) chloride, tin (II) bromide and tin (II) iodide) and sulfites (such as lithium sulfite, sodium sulfite and potassium sulfite).
  • tin (II) salts such as tin (II) chloride, tin (II) bromide and tin (II) iodide
  • sulfites such as lithium sulfite, sodium sulfite and potassium sulfite
  • the reaction of compounds of formula (a) with nitrite is preferably at an ambient temperature in the range of 0 ° C to 80 ° C, such as in the range of 10 ° C to 60 ° C, more preferably in the range of 20 ° C to 50 ° C (eg, in the range of 20 ° C to 40 ° C) performed.
  • the reduction reaction of compounds of formula (b) with a reducing agent is preferably carried out at an ambient temperature in the range of 0 ° C to 80 ° C, such as in the range of 10 ° C to 60 ° C (e.g., 10 ° C to 35 ° C ° C).
  • the ring closure reaction with 1,1,3,3-tetramethoxypropane is preferably carried out at an ambient temperature in the range of 0 ° C to 80 ° C, more preferably in the range of 10 ° C to 60 ° C, even more preferably in the range of 20 ° C to 50 ° C.
  • all these three reactions are carried out in the range of atmospheric pressure (1013 hPa), z. In the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ⁇ 200 hPa.
  • the reaction time of the compounds of the formula (a) with nitrite is preferably in the range of the metering time of the nitrite in a corresponding acid such as sulfuric acid.
  • the implementation is instantaneous. The skilled person can estimate the dosing time from his experience without any problems. However, preferably at least half an hour, such as in the range of 0.5 h to 3 h, z. 1 h ⁇ 0.5 h.
  • the reaction time of the compounds of formula (b) with a reducing agent is preferably in the range of the metering time of at least 5 min. such as at least 15 minutes, at least 30 minutes. or at least 1 hour.
  • the reaction time of the ring-closing reaction is preferably in the range of 0.05 to 30 hours, more preferably in the range of 0.5 to 20 hours, still more preferably in the range of 2 to 15 hours, such as. In the range of 4 to 8 hours.
  • the compounds of the formula (a) is initially charged in an organic solvent and treated with sodium nitrite, for. B. dissolved in a strong acid such as concentrated sulfuric acid, added. After complete conversion to the reaction mixture, a solution of the reducing agent, for. B. in a strong acid such as concentrated hydrochloric acid or sulfuric acid, preferably hydrochloric acid, added. To Complete conversion of the reaction mixture with 1,1,3,3-tetramethoxypropane is added. Preferably, the reaction mixture is then incubated with good stirring in a temperature range of 15 ° C to 60 ° C, more preferably in a temperature range of 25 ° C to 50 ° C for a period of 4 to 8 hours to complete conversion.
  • a strong acid such as concentrated sulfuric acid
  • a very particularly preferred embodiment of the process according to the invention is the following:
  • the compound of formula (a) is initially charged in acetic acid and mixed with sodium nitrite dissolved in concentrated sulfuric acid. After complete conversion, a solution of stannous chloride in concentrated hydrochloric acid is added to the reaction mixture. After complete conversion, the reaction mixture is treated with 1,1,3,3-tetramethoxypropane. Preferably, the reaction mixture is then incubated with good stirring in a temperature range of 15 ° C to 60 ° C, more preferably in a temperature range of 25 ° C to 50 ° C for a period of 4 to 8 hours to complete conversion.
  • the workup and isolation of the compound of formula (d) may, for. B. by entering the reaction mixture in deionized water.
  • the product can be further extracted into a water-insoluble, organic phase, for.
  • a water-insoluble, organic phase for.
  • the organic phase is washed with an aqueous acid such as 10w% aqueous hydrochloric acid and saturated sodium chloride solution.
  • the solvent can be removed, for. B. are distilled off in vacuo; The residue can be subjected to vacuum distillation at 0.05-0.10 mbar with canned column.
  • the radicals Ri R2 and R3 have the meanings described above.
  • X is z. B. for bromine or iodine.
  • the compounds of structural formula (f) are e.g. the compounds mentioned above as preferred halopyrazoles:
  • halogenating agents are known to those skilled in the art such as bromine, iodine, an inorganic bromine or iodine salt, or an organic bromine or iodine molecule in which the bond of an organic radical to the bromine or iodine is polarized so that the bromine or iodine carrier a partially positive charge is, for example, bromine, iodine, N-bromosuccinimide, N-iodosuccinimide, l, 3-dibromo-5-5-dimethylhydantoin and iodine monochloride.
  • reaction Preference is given to using bromine, iodine and iodosuccinimide. If appropriate, it is advantageous to carry out the reaction in the presence of an oxidizing agent, for example hydrogen peroxide.
  • an oxidizing agent for example hydrogen peroxide.
  • the reaction can be carried out in a wide temperature range. Usually, it is carried out in a temperature range of -78 to 200 ° C, preferably at temperatures between -10 to 150 ° C, such as between 60 ° C and 100 ° C.
  • the reaction can be carried out under elevated as well as reduced pressure.
  • Suitable diluents or solvents for carrying out the processes according to the invention are in principle all organic solvents which are inert under the specific reaction conditions.
  • examples include: halogenated hydrocarbons (eg chlorinated hydrocarbons, such as tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, 1, 2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene), alcohols (eg, methanol, ethanol, isopropanol, butanol), nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile, m-chlor
  • Aliphatic, cycloaliphatic or aromatic hydrocarbons eg pentane, hexane, heptane, octane, nonane and technical hydrocarbons
  • cyclohexane methylcyclohexane
  • petroleum ether ligroin
  • octane benzene, toluene, chlorobenzene, bromobenzene, nitrobenzene, xylene
  • esters eg methyl, Ethyl, butyl, isobutyl acetate, dimethyl, dibutyl, ethylene carbonate
  • Amides e.g., N, N-dimethylformamide, N, N-dipropylformamide, ⁇ , ⁇ -dibutylformamide, N-methyl-pyrrolidine.
  • any solvent which does not affect the reaction such as water
  • aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1, 2-dichloroethane or carbon tetrachloride
  • Esters such as ethyl acetate and butyl acetate
  • Amides such as dimethylformamide and dimethylacetamide, N-methyl-pyrrolidinone
  • Nitriles such as acetonitrile or propionitrile
  • the solvents may be used alone or in combination of 2 or more.
  • the solvent is a nitrile, e.g. For example acetonitrile.
  • the compounds of structural formula (d) are e.g. the compounds mentioned above as preferred pyrazoles, e.g. 1 - [4- (1,1,1,3,3,3,3-Heptafluoropropan-2-yl) -2,6-dimethylphenyl] -1H-pyrazole 1 - [2,6-dichloro-4- (1H) , 1, 1, 2,3,3,3-heptafluoropropan-2-yl) phenyl] -1H-pyrazole 1 - [2-chloro-4- (1,1,2,3,3-heptafluoropropane -2-yl) -6- (trifluoromethyl) phenyl] -1H-pyrazole 1 - [2-chloro-4- (1,1,2,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) phenyl] -1H-pyrazole 1 - [2-chloro-6- (difluoromethoxy)
  • Trifluoromethanesulfonic acid can be used in stoichiometric amounts for activation, but this is not absolutely necessary in the case of the reactions claimed here.
  • the halogenating agent (e) known iodine / bromine donors can be used. Nonlimiting examples are bromine, 1,3,5-tribromo-1, 3,5-triazinane-2,4,6-trione, N-iodosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin; preferred halogenating agents are N -Iodosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin.
  • the carboxylic acid halides can be obtained in a conventional manner by the reaction of a carboxylic acid of structure (g) with suitable halogenating reagents.
  • suitable halogenating reagents for example, inorganic acid halides such as thionyl chloride, thionyl bromide, oxalyl chloride, phosphorus tri- or phosphorus pentahalides can be used for the halogenation reaction, the chlorides being preferred (Houben-Weyl, Methoden der organischen Chemie, Vol. VIII, 4th edition, 1952, G. Thieme Verlag Stuttgart-New York, p. 359, 463 ff.). The reaction can be carried out with or without additional diluent.
  • the compounds of the formula (g) are known and can also be purchased.
  • Preferred compounds of the formula (g) are, for example: 2-chloro-5-bromo-benzoic acid and 2-chloro-5-bromopyridine-3-carboxylic acid.
  • halogenating reagent For 1 mol of the formula (g) 1-10 mol, preferably 1-5 mol halogenating reagent are used.
  • the reaction can be carried out in a wide temperature range. Usually it is carried out in a temperature range of -78 to 200 ° C, preferably at temperatures between -10 to 150 ° C.
  • the reaction can be carried out under elevated as well as reduced pressure. Preferably, however, it is carried out under normal pressure, e.g. in the range of 1013 hPa ⁇ 300 hPa, or in the range of 1013 hPa ⁇ 100 hPa, or in the range of 1013 hPa ⁇ 50 hPa.
  • any solvent which does not affect the reaction can be used.
  • aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1, 2-dichloroethane or carbon tetrachloride
  • Esters such as ethyl acetate and butyl acetate
  • the solvents may be used alone or in combination of 2 or more.
  • the reaction can be carried out without addition of a catalyst.
  • Compounds of formula (h) can be prepared from compounds of formula (k) by reaction with an amine.
  • the reaction can be carried out with or without diluent and with or without the presence of basic reaction auxiliary.
  • Preferred compounds of formula (h) are e.g. 2-Chloro-5-bromo-benzoyl chloride and 2-chloro-5-bromo-pyridine-3-carboxylic acid chloride.
  • the amines used in the reaction are known and can be purchased.
  • cyclopropylamine, 1-cyano-cyclopropylamine, N-methyl-cyclopropylamine and 1-cyano-N-methyl-cyclopropylamine are preferred.
  • As basic reaction auxiliaries for carrying out the process according to the invention it is possible to use all suitable acid binders.
  • alkaline earth or alkali metal compounds eg hydroxides, hydrides, oxides and carbonates of lithium, sodium, Potassium, magnesium, calcium and barium
  • amines especially tertiary amines, (eg triethylamine, trimethylamine, tribenzylamine, triisopropylamine, tributylamine, N, N-dimethylaniline, ⁇ , ⁇ -dimethyl-toluidine, pyridine, 4-pyrrolidinopyridine, 4-dimethyl -amino-pyridine, N-propyl-diisopropylamine, N-ethyl-diisopropylamine, N-methyl-morpholine, N-ethyl-morpholine).
  • the activation of the compounds of the formula (g) and the reaction with amines can also be carried out successively in a one-pot reaction.
  • Compounds of general structure (i) according to the invention are prepared by reacting bromides of general structure (h) in the presence of a suitable catalyst, e.g. B. a palladium catalyst and a suitable base with a Bordonor such. B. bis (pinacolato) diboron or tetrahydroxydiborone
  • a palladium catalyst can be used for this reaction.
  • palladium catalysts Tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, ([1,1'-bis (diphenylphosphino) ferrocene)] - dichloro-palladium (II), ([l, l '-Bis (diphenylphosphino) ferrocene)] - dichloro-palladium (II) dichloromethane complex, (2-dicyclohexylphosphino-2', 4 ', 6'-triisopropyl-1,1'-biphenyl) [2- (2 aminoethyl) phenyl)] palladium (II) chloride, and chloro [(di (l -adamantyl) -N- butylphosphino) -2- (2-a
  • a palladium catalyst e.g. Tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, ([1,1'-bis (diphenylphosphino) ferrocene)] - dichloro-palladium (II) and ([l, l 'bis (diphenylphosphino) ferrocene)] - dichloro-palladium (II) dichloromethane complex.
  • palladium catalyst for example, (2-dicyclohexylphosphino-2 ', 4', 6'-triisopropyl-1, -biphenyl) [2- (2-aminoethyl) phenyl)] palladium (II) chloride, ([l, r-bis (diphenylphosphino) ferrocene)] - dichloro-palladium (II) dichloromethane complex, ([1,1'-bis (diphenylphosphino) ferrocene)] - dichloro-palladium (II) and chloro [(di (l-adamantyl) -N-butylphosphino) -2- (2-aminobiphenyl)] - (cataCXium ® A Pd G2) are used palladium (II).
  • Suitable bases are known to those skilled in the art, e.g. Potassium acetate, sodium acetate, potassium carbonate, cesium carbonate and triethylamine. Preferably, potassium acetate is used.
  • the reaction can be carried out in a wide temperature range. Usually it is carried out in a temperature range of 0 to 200 ° C, preferably at temperatures of 15 to 150 ° C.
  • the reaction can be carried out under elevated as well as reduced pressure. Preferably, however, it is carried out under normal pressure, e.g. in the range of 1013 hPa ⁇ 300 hPa, or in the range of 1013 hPa ⁇ 100 hPa, or in the range of 1013 hPa ⁇ 50 hPa.
  • Suitable diluents or solvents for carrying out the process according to the invention are in principle all organic solvents which are inert under the specific reaction conditions. These can also be used as a mixture. Examples include: 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane, toluene.
  • 1,4-dioxane tetrahydrofuran
  • ethylene glycol dimethyl ether dimethylformamide
  • dimethyl sulfoxide acetonitrile
  • dichloromethane toluene.
  • bis (pinacolato) diboron preference is given to the use of 1,4-dioxane; in the case of the use of tetrahydroxydiborone, preference is given to using methanol.
  • X is z. B. for bromine or iodine.
  • the compounds of structural formula (i) are e.g. the intermediates (XI) to (XV) described above.
  • Compounds of the general structure (I) according to the invention are prepared by reacting halides of the general structure (f) in the presence of a suitable palladium catalyst and a suitable base with a boronic acid derivative of the general structure (i).
  • a suitable palladium catalyst e.g. Tetrakis (triphenylphosphine) palladium (0) and bis (triphenylphosphine) palladium (II) chloride.
  • a suitable palladium catalyst e.g. Tetrakis (triphenylphosphine) palladium (0) and bis (triphenylphosphine) palladium (II) chloride.
  • tetrakis (triphenylphosphine) palladium (0) Preference is given to using tetrakis (triphenylphosphine) palladium (0).
  • Suitable bases are known in the art such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium phosphate.
  • potassium carbonate is used.
  • the reaction can be carried out in a wide temperature range. Usually it is carried out in a temperature range of 0 to 200 ° C, preferably at temperatures of 15 to 150 ° C.
  • the reaction can be carried out under elevated as well as reduced pressure. Preferably, however, it is carried out under normal pressure, e.g. in the range of 1013 hPa ⁇ 300 hPa, or in the range of 1013 hPailOO hPa, or in the range of 1013 hPa ⁇ 50 hPa.
  • Suitable diluents or solvents for carrying out the process according to the invention are in principle all organic solvents which are inert under the specific reaction conditions. These can also be used as a mixture. Examples include: methanol, ethanol, 2-propanol, water, 1,4-dioxane, tetrahydrofuran and dimethylformamide. Preference is given to using 2-propanol.
  • Ci-C4-alkyl which is optionally substituted by halogen (preferably F, Cl, Br or I) or CN, where in the case of Halogen substituted Ci-C4-alkyl one or more than an H up to all H (perhalogenated) may be replaced by a halogen.
  • halogen preferably F, Cl, Br or I
  • CN-substituted Ci-C4-alkyl only one H is preferably replaced by a CN group.
  • Compounds of general structure (Ib) according to the invention may also be prepared by deprotonating secondary amides of general structure (Ia) with a suitable base and then reacting with a suitable electrophile. Alternatively, these compounds can also be prepared according to the method described under 5.
  • the base used is preferably sodium hydride.
  • Suitable electrophiles are e.g. Alkyl halides such as methyl iodide and methyl bromide. Preferably, methyl iodide is used.
  • the reaction can be carried out in a wide temperature range. Usually, it is carried out in a temperature range of -78 ° C to 150 ° C, preferably at temperatures of -40 ° C to 100 ° C.
  • the reaction can be carried out under elevated as well as reduced pressure. However, it is preferably carried out under atmospheric pressure, for example in the range of 1013 hPa ⁇ 300 hPa, or in the range of 1013 hPailOO hPa, or in the range of 1013 hPa ⁇ 50 hPa.
  • Suitable diluents or solvents for carrying out the process according to the invention are in principle all organic solvents which are inert under the specific reaction conditions. These can also be used as a mixture. Examples include: dimethylformamide, acetonitrile, dimethyl sulfoxide, tetrahydrofuran and dichloromethane. Preference is given to using tetrahydrofuran.
  • the residue was partitioned between 146 ml of 10% aqueous NaOH and 146 ml of methyl tert-butyl ether. Undissolved solid was filtered from the residue on the filter washed with 60 ml of 10% aqueous NaOH and 60 ml of methyl tert-butyl ether. Subsequently, the phases were separated, the aqueous phase nachextraiert with 100 ml of methyl tert-butyl ether. The combined organic phases are back-extracted with 60 ml of 10% aqueous sodium hydroxide solution. The combined aqueous phases were then adjusted to pH 1 with ice-bath cooling, at 0-10 ° C.
  • the reaction was then added to 1600 mL of deionized water / ice 1: 1 (v / v) and the product extracted into 1000 mL of isopropyl acetate / n-heptane 1: 1 (v / v). After phase separation, the aqueous phase was back-extracted with 280 ml of isopropyl acetate / n-heptane 1: 1 (v / v) and the combined organic phases were washed with 1 ⁇ 550 ml of 10% strength hydrochloric acid and 2 ⁇ 250 ml of saturated sodium chloride solution.
  • the reaction was then added to 2640 mL deionized water / ice 1: 1 (v / v) and the product extracted into 1760 mL isopropyl acetate / n-heptane 1: 1 (v / v).
  • the aqueous phase was back-extracted with 440 ml of isopropyl acetate / n-heptane 1: 1 (v / v) and the combined organic phases were washed with 1 ⁇ 880 ml of 10% strength hydrochloric acid and 2 ⁇ 440 ml of saturated sodium chloride solution.
  • the mixture was then added to 100 mL of half-concentrated sodium chloride solution and the product extracted into 100 mL of n-heptane.
  • the organic phase was washed with 2 ⁇ 50 ml of 10% strength by weight sodium hydroxide solution and once with 50 ml of 10% strength sodium thiosulfate solution, dried over 1 g of magnesium sulfate, the desiccant was separated by filtration and the solvent was removed in vacuo.
  • Mass detection is done through an Agilent MSD system.
  • Agilent 1100 LC system 50 * 4.6 Zorbax XDB C18 1.8 microm; Eluent A: acetonitrile; Eluent B: water (79 mg ammonium bicarbonate / 1); linear gradient from 10% acetonitrile to 95% acetonitrile in 4.25 min, then 95%> acetonitrile for a further 1.55 min; Oven temperature 55 ° C; Flow: 2.0 mL / min. Mass detection is done through an Agilent MSD system.

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EP17823048.8A 2016-12-08 2017-12-04 Verfahren zur herstellung von 5-(1-phenyl-1h-pyrazol-4-yl)-nicotinamid-derivaten und ähnlicher verbindungen ohne isolierung oder aufreinigung der phenylhydrazin-zwischenstufe Withdrawn EP3551616A1 (de)

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US10981888B2 (en) 2021-04-20
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