US20100256390A1 - Processes for the preparation of pyrazoles - Google Patents

Processes for the preparation of pyrazoles Download PDF

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Publication number
US20100256390A1
US20100256390A1 US12/665,738 US66573808A US2010256390A1 US 20100256390 A1 US20100256390 A1 US 20100256390A1 US 66573808 A US66573808 A US 66573808A US 2010256390 A1 US2010256390 A1 US 2010256390A1
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formula
compound
hal
reaction
process according
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Martin Charles Bowden
Brian David Gott
David Anthony Jackson
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Syngenta Ltd
Syngenta Crop Protection LLC
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Syngenta Ltd
Syngenta Crop Protection LLC
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    • 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
    • C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/76—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • 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
    • 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
    • C07D231/14—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel processes for the production of 3-halomethyl-1-methyl-1H-pyrazoles, which are useful as intermediates in the production of fungicides.
  • 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid and 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid are valuable intermediates in the preparation of pyrazolyl carboxanilide fungicides, as described, for example, in WO 03/070705 and WO 03/074491.
  • the aim of the present invention is therefore to provide novel processes for the production of key intermediates in the synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid and 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid that makes it possible to prepare said acids with high regioselectivity (in respect to the two nitrogen atoms of the pyrazole ring), in high yields and good quality in an economically advantageous and easily handled way.
  • the invention relates to a process for the preparation of a compound of formula (I)
  • Hal and Hal′ are independently Cl or F, and R 1 is H, Cl or F, comprising the steps of
  • R 2 is C1-6 alkyl
  • Hal, Hal′ and R 1 are as defined above, and
  • the invention provides a process for the preparation of a compound of formula (VI)
  • Hal, Hal′ and R 1 are as defined above and R 3 is selected from H and C1-6 alkyl comprising reacting a hydrazide of formula (XXIII)
  • Hal, Hal′ and R 1 are as defined above,
  • R3 is as defined above.
  • the invention provides a process for the preparation of a compound of formula (VI)
  • Hal, Hal′ and R 1 are as defined above and R 3 is selected from H and C1-6 alkyl comprising reacting a compound of formula (XXV)
  • Hal, Hal′, R 1 and R 3 are as defined above with chloramine.
  • the invention relates to a compound of formula X
  • the invention relates to a compound of formula VIII
  • the invention relates to a compound of formula VII
  • step i) of the reaction according to a first embodiment of the invention a compound of formula (II) reacts with an enol ether of formula (III) to give a 4-alkoxy-3-en-2-one of formula (IV) (Scheme 1)
  • leaving group refers to a moiety that can be displaced by enol ether (III) to form a carbon-carbon bond present in compound (IV).
  • Preferred leaving groups are halogens. A more preferred leaving group is chlorine.
  • R 2 is ethyl
  • reaction of compound (II) with the enol ether (III) may take place in a suitable solvent. Alternatively, and preferably, the reaction takes place in the absence of a solvent.
  • Preferred solvents are toluene, hexane, dichloromethane and diethylether.
  • the reaction is conducted under an inert atmosphere. More preferably, the reaction is conducted under a nitrogen atmosphere. Preferably, the reaction proceeds with purge to help remove volatile co-products.
  • the reaction takes place in the presence of a base.
  • bases are pyridine, alkyl pyridines or trialkylamines.
  • the reaction occurs in the absence of base.
  • the enol ether (III) is present in excess relative to the compound (II). More preferably, the enol ether is present in an amount of between 1.1 and 10 equivalents relative to the amount of compound (II) on a molar basis. More preferably, the enol ether is present in an amount of between 1.2 and 5 equivalents relative to the amount of compound (II) on a molar basis. More preferably, the enol ether is present in an amount of between 1.5 and 2.5 equivalents relative to the amount of compound (II) on a molar basis. More preferably, the enol ether is present in an amount of about 2 equivalents relative to the amount of compound (II) on a molar basis.
  • the enol ether (III) is added to the compound (II). More preferably, the enol ether (III) is added to the compound (II) over at least 1 hour. More preferably, the enol ether (III) is added to the compound (II) over at least 4 hours. More preferably, the enol ether (III) is added to the compound (II) over about 8 hours.
  • the reaction is cooled during the addition of the enol ether (III) to the compound (II).
  • the reaction is cooled to between ⁇ 20 and ⁇ 40° C. during the addition of the enol ether (III) to the compound (II).
  • the reaction is allowed to continue for at least 1 hour. More preferably, the reaction is allowed to continue for at least 6 hours. More preferably, the reaction is allowed to continue for at least 8 hours.
  • reaction mixture may be necessary or desirable to isolate the 4-alkoxy-3-en-2-one of formula (IV), if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2 nd Edition ), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.
  • step ii) of the reaction according to a first embodiment of the invention a 4-alkoxy-3-en-2-one of formula (IV) reacts with methyl hydrazine to give a 3-halomethyl-1-methyl-1H-pyrazole (I) (Scheme 2).
  • reaction of compound (IV) with methyl hydrazine preferably takes place in a suitable solvent. Alternatively the reaction takes place in the absence of a solvent.
  • Preferred solvents are xylene, toluene, mesitylene, tert-butyl benzene, chlorobenzene, 1,2-dichlorobenzene, tetrahydrofuran, diethyl ether and hexane.
  • a more preferred solvent is tetrahydrofuran.
  • methyl hydrazine is used in an amount of 0.7 to 1.3 equivalents relative to the amount of 4-alkoxy-3-en-2-one of formula (IV).
  • the methyl hydrazine is added to the 4-alkoxy-3-en-2-one of formula (IV).
  • both the methyl hydrazine and the 4-alkoxy-3-en-2-one of formula (IV) are both dissolved in solvent. Addition preferably takes place over a period of between 5 minutes and 10 hours, more preferably over about 5 hours.
  • the reaction is preferably held at between 0 to 50° C., more preferably at between 35 to 45° C.
  • reaction mixture may be necessary or desirable to isolate the pyrazole (I), if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2 nd Edition ), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.
  • Suitable techniques include recrystallization, distillation, and chromatography.
  • pyrazole (I) is subjected to a halogenation step to convert it to 4-halopyrazole of formula (V) (Scheme 3)
  • the halogenation reaction is conducted in a solvent.
  • a preferred solvent is carbon tetrachloride.
  • the reaction is conducted under an inert atmosphere. More preferably, the reaction is conducted under a nitrogen atmosphere. Preferably, the reaction proceeds with purge to help remove volatile co-products.
  • X is Br.
  • a preferred halogenating agents are elemental bromine (Br 2 ), N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin. More preferably, the halogenating agent is Br 2 in the presence of an iron compound, preferably iron powder.
  • the halogentating agent is used in excess relative to pyrazole (I). More preferably, the halogentating agent is used in amount of 1.5 to 5 equivalents relative to pyrazole (I) on a molar basis.
  • the reaction is allowed to continue for at least 1 hour. More preferably, the reaction is allowed to continue for from 1 to 48 hours. More preferably, the reaction is allowed to continue for from 1 to 5 hours.
  • 4-halopyrazole (V) is subjected to a carbonylation step to convert it to 4-carboxypyrazole of formula (VI) (Scheme 4)
  • R 3 is H or C1-6 alkyl.
  • R 3 is Ethyl or H.
  • Reagent R 3 OH is preferably present in excess relative to 4-halopyrazole (V), preferably in an amount of from 100 to 150 equivalents relative to the amount of (V) on a molar basis.
  • Carbon monoxide is preferably used in excess relative to the amount of (V).
  • the reaction takes place in the presence of a palladium catalyst.
  • the palladium catalyst is preferably a palladium (II) or palladium (0) catalyst.
  • Preferred catalysts are tris(triphenylphosphine) palladium (II) chloride, bis(triphenylphosphine) palladium (II) chloride, and tetrakis(triphenylphosphine)palladium(0).
  • a preferred catalyst is tris(triphenylphosphine) palladium (II) chloride.
  • the palladium catalyst is used in an amount of between 0.01 and 0.5 equivalents relative to the amount of 4-halopyrazole (V), more preferably between 0.1 and 0.3 equivalents.
  • triphenylphosphine is added to the reaction, preferably in an amount of 0.5 to 0.7 equivalents.
  • the reaction is conducted at a temperature of from 50 to 200° C., more preferably at a temperature of from 100 to 150° C.
  • bases are nitrogen-containing organic bases, preferably tertiary amines, more preferably trialkylamines, preferably trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine.
  • Alternative preferred bases are N,N-dimethylaniline or N-methylmorpholine, piperidine, pyrrolidine, alkali metal or alkaline earth metal alcoholates, preferably lithium, sodium or potassium alcoholates, preferably methanolates, ethanolates or butanolates, or inorganic bases, preferably hydroxides, more preferably NaOH or KOH, or hydrides, preferably NaH.
  • tertiary amines preferably trialkylamines, more preferably trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine.
  • Triethylamine is very highly preferred.
  • Suitable amounts of base for that reaction are, for example, from 1 to 10 equivalents, especially from 4 to 6 equivalents.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 36 hours, more preferably 1 to 18 hours.
  • the reaction according to the invention is carried out typically at elevated pressure, preferably 1 to 20 bar, more preferably 10 to 15 bar.
  • an optional further step comprises hydrolyzing the group R 3 to a compound (VI) wherein R 3 is hydrogen, or a salt form thereof (Scheme 5).
  • R 3 is C1-6 alkyl
  • Hydrolysis can be effected under either acid or basic conditions. If basic conditions are employed, generally a salt form of 4-carboxypyrazole (VI) is obtained. A further step of acidification to convert the salt to the free acid may be employed.
  • Preferred bases for the hydrolysis reaction are metal hydroxides and metal carbonates. More preferred bases are alkali metal hydroxides. Still more preferred are sodium, potassium and lithium hydroxide. Most preferred is sodium hydroxide.
  • the base is used in excess relative to 4-carboxypyrazole (VI). More preferably, between 1 and 5 equivalents of base are used. Still more preferably, between 1 and 3 equivalents of base are used.
  • water is present in excess.
  • a co-solvent is present.
  • a preferred co-solvent is ethanol.
  • the hydrolysis preferably takes place at between 0 and 200° C., more preferably at between 50 and 150° C.
  • the free acid (VI) may be liberated by treatment with acid.
  • Preferred acids are mineral acids, preferably hydrochloric or sulphuric acid. Most preferred is hydrochloric acid.
  • mineral acids or organic acids may be used. Preferred are mineral acids. More preferred are hydrochloric and sulphuric acid. Most preferred is hydrochloric acid.
  • At least 0.01 equivalents of acid relative to the amount of (VI) on a molar basis are employed, more preferably between 0.01 and 5 equivalents, still more preferably 1 to 5 equivalents.
  • acid hydrolysis occurs at a temperature of between 40 and 100° C.
  • the reaction sequence includes a halogen exchange step.
  • halogen exchange refers to a reaction wherein halogen atoms of one element are exchanged for halogen atoms of a second, different element.
  • chlorine atoms are exchanged for fluorine atoms.
  • Halogen exchange may be conducted at any suitable step of the reaction sequence.
  • halogen exchange is effected on 3-dichloromethyl-1-methyl-1H-pyrazole (VII) to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbaldehyde (VIII) (Scheme 6).
  • halogen exchange is effected on 4-bromo-3-dichloromethyl-1-methyl-1H-pyrazole (IX) to give 4-bromo-3-fluoromethyl-1-methyl-1H -pyrazole (X) (Scheme 7).
  • halogen exchange is effected on 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate (XI) or a salt form thereof to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate (XII) (Scheme 8).
  • Halogen exchange may be conducted under a variety of conditions. Preferably, halogen exchange is conducted in the presence of a source of F ⁇ ions.
  • Preferred reagents are AgF, KF, HgF 2 , Bu 4 N + HF 2 ⁇ , BrF 3 , Et 3 N.2HF, Et 3 N.3HF and HF plus SbF 3 .
  • a very highly preferred reagent is Et 3 N.3HF.
  • the halogen exchange reaction is optionally conducted in a solvent. Alternatively, and preferably, the reaction is conducted under solvent-free conditions.
  • the reaction is held at between 0 and 250° C. More preferably, the reaction is held at between 50 and 200° C. More preferably, the reaction is held at between 125 and 175° C. Most preferably, the reaction is held at about 150° C.
  • Suitable techniques include recrystallization, distillation, and chromatography.
  • the reaction takes place in a solvent.
  • Dimethylformamide is preferred.
  • the reaction occurs under acid catalysis.
  • p-Toluene sulphonic acid is preferred.
  • 4-carboxypyrazole (VI) may be hydrolysed to the free acid or a salt form thereof as outlined above.
  • the enamine (XXV) is reacted with a base prior to reaction with chloramine.
  • a preferred base is sodium hydride.
  • the reaction takes place in a solvent.
  • solvents are diethyl ether, tetrahydrofuran and mixtures thereof.
  • 4-carboxypyrazole (VI) may be hydrolysed to the free acid or a salt form thereof as outlined above.
  • Hal, Hal′ and R 1 are all fluorine.
  • Hal and Hal′ are fluorine and R 1 is hydrogen.
  • Hal and Hal′ are both chlorine, and R 1 is hydrogen.
  • the present invention relates to a process for the production of a compound of formula XIII
  • R 1 is C 1 -C 6 alkyl, to form a compound of formula XV
  • R 1 is as defined above;
  • R 2 is C 1 -C 6 alkyl
  • single compounds of formula (III), such as compounds of formula (III), wherein R 1 is ethyl, can be used or mixtures thereof.
  • An example of such a mixture are compounds of formula (III), wherein in R 1 is methyl, mixed with compounds of formula (III), wherein R 1 is ethyl.
  • R 1 is ethyl.
  • the reaction according to the invention is preferably carried out in a temperature range of from ⁇ 40° C. to 0° C., especially from ⁇ 40° C. to ⁇ 20° C.
  • the reaction can be carried out in the presence or absence of a base.
  • bases include pyridine, alkyl pyridines or trialkylamines.
  • the reaction can be carried out without solvent or in an inert solvent.
  • Preferred inert solvents are, for example, toluene, hexane, dichloromethane or diethylether.
  • the reaction is carried out without a solvent.
  • the compound of formula (III) for example ethylenol ether
  • the compound of formula (III) can be used in equimolar amounts, in sub-equimolar amounts or in excess relative to compounds of formula XIV, preferably the compound of formula (III) is used in excess, more preferably in an 1.5-fold to 3-fold excess.
  • the reaction according to the invention may be carried out in a dry inert gas atmosphere.
  • nitrogen can be used as inert gas.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours.
  • the reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at normal pressure.
  • the reaction according to the invention is preferably carried out in a temperature range of from 0° C. to 50° C., especially from 10° C. to 25° C.
  • the reaction is conveniently carried out in an inert solvent.
  • inert solvents are, for example, xylene, toluene, mesitylene, tert-butyl benzene, chlorobenzene, 1,2-dichlorobenzene, tetrahydrofuran, diethyl ether and hexane, preferably tetrahydrofuran.
  • methylhydrazine in the reaction according to the invention, can be used in equimolar amounts, in sub-equimolar amounts or in excess relative to compounds of formula XV, preferably methylhydrazine is used in equimolar amounts.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours, more preferably 1 to 5 hours.
  • the reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at normal pressure.
  • the fluorination according to the invention is preferably carried out in a temperature range of from 100° C. to 200° C., especially from 140° C. to 160° C.
  • the preferred fluorinating agent is tris(hydrogen fluoride)-triethylamine.
  • the fluorinating agent is typically used in excess relative to compounds of formula VII, preferably in a 2-fold to 5-fold excess.
  • the fluorination can be carried out without solvent or in an inert solvent.
  • Preferred inert solvents are, for example, acetonitrile, chloroform, carbon tetrachloride and dichloromethane. Use of excess tris(hydrogen fluoride)-triethylamine, which then acts as solvent is preferred.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours, more preferably 1 to 5 hours.
  • the reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at elevated pressure.
  • the bromination according to the invention is preferably carried out in a temperature range of from 0° C. to 100° C., preferably from 20° C. to 40° C.
  • reaction is conveniently carried out in an inert solvent.
  • a preferred inert solvent is, for example, carbon tetrachloride.
  • Preferred brominating agents are, for example, bromine in the presence of an iron catalyst, N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin; preferably bromine in the presence of an iron catalyst.
  • brominating agent is bromine in the presence of an iron catalyst
  • said bromine is typically used in excess relative to compounds of formula VIII, preferably in a 1.5-fold to 5-fold excess; and said iron catalyst is used typically in the form of iron powder and in the range of from 0.1 to 1 equivalents relative to compounds of formula VIII, especially from 0.3 to 0.8 equivalents.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours, more preferably 1 to 5 hours.
  • the reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at normal pressure.
  • the preferred C 1 -C 6 alkanol is ethanol; but also mixtures C 1 -C 6 alkanols can be used, such as a mixture of methanol/ethanol.
  • the reaction according to the invention is preferably carried out in a temperature range of from 50° C. to 200° C., especially from 100° C. to 150° C.
  • the reaction is conveniently carried out in a large excess of the C 1 -C 6 alkanol, such as a 100-fold to 150-fold excess, which then acts as solvent.
  • a large excess of the C 1 -C 6 alkanol such as a 100-fold to 150-fold excess, which then acts as solvent.
  • ethanol is used.
  • a large excess of carbon monoxide is used.
  • a suitable palladium catalyst is tris(triphenylphosphonium)palladium(II)chloride.
  • Said palladium catalyst is used generally in the range of from 0.1 to 0.5 equivalents relative to compounds of formula X, especially from 0.1 to 0.3 equivalents. If tris(triphenylphosphonium)palladium(II)chloride is used as palladium catalyst, then generally triphenyl phosphine is also added to the reaction mixture in amounts of from 0.5 to 0.7 equivalents relative to compounds of formula X.
  • Suitable bases are, for example, nitrogen-containing organic bases, such as, for example, tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine, N,N-dimethylaniline or N-methylmorpholine, piperidine, pyrrolidine, alkali metal or alkaline earth metal alcoholates, such as, for example, lithium, sodium or potassium alcoholates, especially methanolates, ethanolates or butanolates, or inorganic bases, such as hydroxides, e.g.
  • Bases to which preference is given are tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine, especially triethylamine.
  • Suitable amounts of base for that reaction are, for example, from 1 to 10 equivalents, especially from 4 to 6 equivalents.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 36 hours, more preferably 1 to 18 hours.
  • the reaction according to the invention is carried out typically at elevated pressure, such as 1 to 20 bar, preferably 10 to 15 bar.
  • Process step b6) the saponification of compounds of formula (XII) to form the compound of formula (XIII), can be carried out as described under step b6.1) (alkaline saponification) or under step b6.2) (acidic saponification).
  • Step b6.1) can be divided into two sub-steps: i) the formation of the anion of the compound of formula (XIII) (“the anion”) by adding a base and ii) the formation of the compound of formula (I) (“the free acid”) by later adding an acid.
  • hydroxide base is used to form the anion, then NaOH or KOH, especially NaOH, is preferred.
  • a suitable amount of hydroxide base is, for example, at least one equivalent relative to compounds of formula (XII), preferably from 1 to 5 equivalents; more preferably from 1 to 3 equivalents.
  • inorganic bases such as hydroxides, for example LiOH, NaOH or KOH, or carbonates, for example sodium carbonate, are preferred.
  • hydroxides for example LiOH, NaOH or KOH
  • carbonates for example sodium carbonate
  • at least one equivalent of water and at least one equivalent of the base relative to compounds of formula (XII) are used.
  • the formation of the anion can be carried out in an inert solvent, such as ethanol.
  • the formation of the anion is preferably carried out in a temperature range of from 0° C. to 200° C.
  • the reaction time for anion formation is generally from 1 to 48 hours, preferably from 1 to 18 hours.
  • Said anion formation can be carried out at normal, elevated or reduced pressure, preferably at normal pressure.
  • Suitable acids are inorganic acids, such as hydrochloric acid or sulfuric acid; or organic acids, such as formic acid, acetic acid or propionic acid. Preference is given to inorganic acids and special preference is given to hydrochloric acid.
  • the acid is added in a temperature range of from 50° C. to 95° C.
  • the reaction time for formation of the free acid is generally from 1 to 48 hours, preferably from 1 to 18 hours.
  • Said free acid formation can be carried out at normal, elevated or reduced pressure, preferably at normal pressure.
  • the acid used in step b6.2) is typically an inorganic acid, such as hydrochloric acid or sulfuric acid; or an organic acid, such as formic acid, acetic acid or propionic acid.
  • aqueous solutions of the acid are used in step b6.2).
  • a preferable amount of water is at least one equivalent relative to compounds of formula (XII).
  • a preferable amount of acid is at least 0.01 equivalents relative to compounds of formula (XII), more preferably from 0.01 to 5 equivalents; even more preferably from 1 to 5 equivalents.
  • the formation of the free acid is preferably carried out in a temperature range of from 40° C. to 100° C.
  • the reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours.
  • Said free acid formation can be carried out at normal, elevated or reduced pressure, preferably at normal pressure.
  • the second embodiment of the present invention makes it possible to produce compounds of formula I in a high yield, with a high degree of regioselectivity and at low cost.
  • the compounds of formula (X), (VII) and (VIII) are valuable intermediates for the preparation of compounds of formula (XIII) and were developed specifically for the present process according to the invention.
  • the present invention accordingly relates also to those compounds.
  • steps b1), b2), b3), b4) and b5) are performed as described above.
  • R 1 and R 2 stands for C 1 -C 6 alkyl and TREAT HF means tris(hydrogen fluoride)-triethylamine.
  • the invention includes, in separate embodiments, the following multi-step processes, which involve:
  • Dichloroacetyl chloride (114.9 g, compound of formula XIV) was charged to a clean/oven dried 250 ml 3-necked flask fitted with nitrogen feed, syringe feed, thermometer and a PTFE coated magnetic stirrer.
  • the reactor was vented via a cold finger condenser and water condenser to follow.
  • a caustic scrubber system was connected to the vent from the water condenser system.
  • the agitation was provided by a magnetic stirrer/hotplate fitted with a drykold acetone bath.
  • the cold finger condenser was filled with the same cooling mixture.
  • the reactor contents were agitated and the contents cooled to ⁇ 40° C. with a gentle nitrogen purge applied to the reactor.
  • 1,1-Dichloro-4-ethoxy-but-3-en-2-one (0.99 g, compound of formula XVI) was dissolved in tetrahydrofuran (12.5 ml) in a clean/dry 50 ml 3-necked flask fitted with thermometer, condenser and syringe feed system. The top of the condenser was back pressured with a gentle flow of nitrogen. The reactor contents were agitated and heated to 40° C. then the N-methyl hydrazine (0.26 g) was dissolved in tetrahydrofuran (25 ml) and the resultant solution syringe pump fed into the reactor over a 5 hour period. The reaction mixture was agitated overnight under nitrogen to complete.
  • Formaldehyde (7.4 g) was charged to the reactor and the mixture agitated for 30 minutes at room temperature accompanied by a small exotherm reaction. 1 g Pt/C was added and washed in with methanol (20 ml). The Parr reactor was sealed, purged with nitrogen three times, purged with hydrogen three times (all to 200 psi) and then pressurized up to 200 psi with hydrogen. Agitation and external heating were applied to heat the reaction to 50° C. The reactor was held under these conditions for 3 h and then allowed to cool. The system was purged three times with nitrogen to 200 psi. The contents were removed and filtered. The solvent was removed under vacuum, filtered and concentrated under vacuo. The compound of formula XX was obtained in the form of an orange oil (9.1 g). Yield 40% total isomers and 36% of the desired isomer. The product was analysed by GC, GCMS and NMR ( 1 H and 19 F).
  • a 25 ml reaction tube was fitted with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere.
  • Dimethylformamide (10 g), ethyl propargylate (0.14 g), the compound of formula XX (0.24 g) and p-toluene sulphonic acid (0.028 g) were charged to the reaction tube.
  • the mixture was stirred at 50° C. overnight, 80° C. overnight and then 110° C. overnight to give the desired product (compound of formula XVII).
  • the compound of formula (I) can be formed from the compound of formula (V) via step b6) as described above.
  • the compound of formula (XVII) can be formed from the compound of formula (XX) via the methology described in comparative example C5 above.
  • the compound of formula (XII) can be formed from the compound of formula (XVII) via step b6) as described above.
  • a 100 ml conical flask was fitted with a magnetic stirrer and thermometer. Diethyl ether (31 ml) and ammonium chloride (0.91 g) were charged to the flask. The mixture was cooled to ⁇ 10° C. and aqueous ammonia solution (1.7 g) was added. Sodium hypochlorite (14.3 g) solution was charged over 10 minutes to the vigorously stirred solution at ⁇ 10° C., and the reaction was then stirred at ⁇ 10° C. for 0.5 hr. The organic layer was separated, washed with brine, dried over CaCl 2 for 1 hr at ⁇ 15° C. The desired chloramine was generated as a 3% chloramine solution in diethylether.
  • This tetrahydrofuran solution was added slowly to the chloramine/diethylether-solution described above (6.22 mmol, 5.0 eq) at ⁇ 15° C. The reaction was stirred at ⁇ 15° C. for 1 h and then allowed to warm to ambient temperature. A new solution of chloramine in diethylether (2.7% strength) was prepared as described above. Additional sodium hydride dispersion (0.20 g, 4.96mmol, 4.0 eq) and chloramine (new solution) (10.4 g, 5.46 mmol, 4.4 eq) were added and the reaction was stirred for 1 h at ambient temperature.
  • the compound of formula (XIII) can be formed from the compound of formula (XVII) via step b6) as described above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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US20130237710A1 (en) * 2008-09-30 2013-09-12 Solvay Sa Process for the synthesis of halogenated cyclic compounds
US10239841B2 (en) 2015-03-26 2019-03-26 AGC Inc. Method for producing pyrazole derivative

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GB0908435D0 (en) * 2009-05-15 2009-06-24 Syngenta Ltd Processes
WO2012025469A1 (en) * 2010-08-24 2012-03-01 Solvay Sa Improved process for the preparation of esters of 1-h-pyrazole-4-carboxylic acids
FR2975992B1 (fr) * 2011-06-01 2013-11-08 Rhodia Operations Procede de preparation d'un compose fluoromethylpyrazole sous forme acide carboxylique ou derivee
FR2975990B1 (fr) * 2011-06-01 2013-05-24 Rhodia Operations Procede de preparation d'un compose organique fluore
MX348274B (es) * 2012-05-14 2017-06-02 Bayer Cropscience Ag Procedimiento de preparacion de cloruros de 1-alquil-3-fluoroalqui l-1h-pirazol-4-carbonilo.
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WO2015059067A1 (de) 2013-10-23 2015-04-30 Bayer Cropscience Ag Verfahren zur herstellung von halogenketonen
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CN111303035A (zh) * 2020-03-18 2020-06-19 徐州圣元化工有限公司 一种3-(二氟甲基)-1-甲基-1h-吡唑-4-羧酸的制备方法
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US20110009642A1 (en) * 2008-02-25 2011-01-13 Bayer Cropscience Ag Method for the Regioselective Synthesis of 1-Alkyl-3-haloalkyl-pyrazole-4-carboxylic Acid Derivatives
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US20130237710A1 (en) * 2008-09-30 2013-09-12 Solvay Sa Process for the synthesis of halogenated cyclic compounds
US8981115B2 (en) * 2008-09-30 2015-03-17 Solvay Sa Process for the synthesis of halogenated cyclic compounds
US10239841B2 (en) 2015-03-26 2019-03-26 AGC Inc. Method for producing pyrazole derivative

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