WO2019224174A1 - Process for producing 2-(fluoroalkyl)nicotinic acids - Google Patents

Process for producing 2-(fluoroalkyl)nicotinic acids Download PDF

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WO2019224174A1
WO2019224174A1 PCT/EP2019/063049 EP2019063049W WO2019224174A1 WO 2019224174 A1 WO2019224174 A1 WO 2019224174A1 EP 2019063049 W EP2019063049 W EP 2019063049W WO 2019224174 A1 WO2019224174 A1 WO 2019224174A1
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formula
compound
process according
steps
temperature
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PCT/EP2019/063049
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French (fr)
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Florian ERVER
Dirk Brohm
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Bayer Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

Definitions

  • the present invention relates to a method for preparing a 2-(fluoroalkyl)nicotinic acid derivative.
  • fungicidal indanyl carboxamides can be produced via the coupling of a 4-aminoindane derivative with an activated 2-(fluoroalkyl)nicotinic acid derivative by linking the primary amino group of the former with the activated carboxyl group of the latter (coupling reaction).
  • a 4-aminoindane derivative, but also an activated heterocyclic acid that shall be linked to the 4-aminoindane derivative are important intermediates in the synthesis of fungicidal indanyl carboxamides.
  • WO 2015/197530 discloses a three-step process for the preparation of 2-(fluoroalkyl)nicotinic acid derivatives in which in a first step, a formamide is activated to a corresponding Vilsmeier-Haack reagent (i.e. a Vilsmeier salt) by reacting the formamide with an activating agent such as SOCL, POCI 3 , oxalylchloride or phosgene. From this, a cyclization precursor is synthesized by condensing the Vilsmeier salt with a vinylether and a P-fluoroalkyl-P-ketoester derivative, optionally in the presence of a diluent.
  • a formamide is activated to a corresponding Vilsmeier-Haack reagent (i.e. a Vilsmeier salt) by reacting the formamide with an activating agent such as SOCL, POCI 3 , oxalylchloride or phosgene.
  • the cyclization precursor can be obtained by reacting a P-fluoroalkyl-P-ketoester derivative with a b-aminoalkyl substituted a,b-unsaturated aldehyde in the presence of a suitable acid or dehydrating agent and optionally in the presence of a diluent.
  • suitable acids are HC1, HBr, HF, H2SO4, KHSO4, AcOH, trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, methansulfonic acid, trifluoromethansulfonic acid, polyphosphoric acid, phosphoric acid.
  • Suitable dehydrating agents may be for example carboxylic or sulfonic acid anhydrides, e.g. acetic anhydride.
  • the obtained cyclization precursor is cyclocondensated to a nicotinic ester(further referred to as the ester), optionally in the presence of a diluent with ammonia as a gas or with ammonia dissolved in a suitable solvent, e.g. in water as ammonium hydroxide.
  • the thus obtained ester is saponified for example in the presence of sodium hydroxide (NaOH), yielding finally the desired 2-(fluoroaLkyl)nicotinic acid derivative.
  • the cyclization precursor is an intermediate which displays some lability against humidity and more important acidic moisture.
  • the 2-(fhioroalkyl)nicotinic acid derivative obtainable by this desired method should preferably in this case be obtained in high yield and high purity.
  • the desired method should enable the desired target compounds to be obtained without the need for complex purification methods.
  • the process according to the invention avoids the isolation of intermediary compounds such as the cyclization precursor and the ester which maximizes the overall space-time -yield of the desired 2-(fluoroalkyl)nicotinic acid derivative.
  • the process according to the invention can be conducted as a telescoping synthesis, i.e. it is workable as a sequential one-pot synthesis with reagents added to a reactor one at a time, wherein minimal work-up procedures are performed during the process leading to this improved space-time-yield. Minimal work-up procedures are e.g. separation and/or washing steps and/or removal of solvents and/or reagents via distillation. Concluding, the process according to the invention allows the production of a 2-(fhioroalkyl)nicotinic acid derivative in high yields with at the same time reduced amounts of waste.
  • the process according to the invention allows the production of a 2-(fhioroalkyl)nicotinic acid derivative in high yields and high purity by avoiding at the same time loss of intermediary compounds due to degradation.
  • the present invention provides a process for the preparation of a compound of the formula (I)
  • R 1 represents methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2- difluoroethyl and pentafluoroethyl;
  • X represents halogen
  • R 2 , R 3 and X 2 represent a C1-C6 alkyl group; characterized in that the steps (a) to (e) are performed as a telescoping synthesis, wherein the compounds of the formulae (Ha), (Ilia), (V) and (VI) are not isolated before obtaining the compound of the formula (I).
  • Preferred, particularly preferred and most preferred definitions of the residues R 1 , R 2 , R 3 , X and X 2 listed in the herein-defined formulae (I)- (VI)) are elucidated below.
  • R 1 represents methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2- difluoroethyl and pentafluoroethyl;
  • R 2 represents methyl or ethyl
  • R 3 represents butyl
  • X represents fluorine
  • X 2 represents methyl or ethyl It is particularly preferable when in each case:
  • R 1 represents difluoromethyl and trifluoromethyl
  • R 2 represents ethyl
  • R 3 represents butyl
  • X represents fluorine
  • X 2 represents ethyl
  • R 1 represents difluoromethyl
  • R 2 represents ethyl
  • R 3 represents butyl
  • X represents fluorine
  • X 2 represents ethyl
  • Halogen fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine and most preferably chlorine.
  • Alkyl saturated, straight-chain or branched hydrocarbyl radical having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C 6 -alkyl such as methyl, ethyl, propyl (n- propyl), 1 -methylethyl (iso-propyl), butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), l ,l-dimethylethyl (tert-butyl), pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 - ethylpropyl, l ,l -dimethylpropyl, l,2-dimethylpropyl, hexyl, l-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylp
  • said group is a C1 -C4- alkyl group, e.g. a methyl, ethyl, propyl, 1 -methylethyl (isopropyl), butyl, 1 -methylpropyl (sec-butyl), 2- methylpropyl (iso-butyl) or l,l-dimethylethyl (tert-butyl) group.
  • a C1 -C4- alkyl group e.g. a methyl, ethyl, propyl, 1 -methylethyl (isopropyl), butyl, 1 -methylpropyl (sec-butyl), 2- methylpropyl (iso-butyl) or l,l-dimethylethyl (tert-butyl) group.
  • an activated hydroxyl group shall mean that the hydroxyl forms together with the adjacent carbonyl an ester which spontaneously reacts with an amino group.
  • Common activated esters include p- nitrophenyl, pentafluorophenyl, succinimido esters or phosphorous anhydrides
  • telescoping synthesis is defined as a sequence of different chemical transformations which ultimately leads to the isolation of a product and runs through several different intermediates whose isolation is omitted in order to maximize the space-time-yield of the process.
  • Minimal downstreaming operations such as liquid-liquid extraction and distillation may be implemented between the chemical transformations in order to remove substances not being compatible with the follow-up chemistry.
  • Step (a) the compound of the formula (II) is activated via an activating agent, generating a compound of the formula (Ila) which is a Vilsmeyer salt. This is achieved by addition of an activating reagent to the diluted or undiluted compound of the formula (II) at a suitable temperature.
  • the activating agent in step (a) is an dehydroxyhalogenating agent.
  • the activating agent in step (a) is selected from phosgene (COCb), oxalyl chloride ( (COCl)2 ), cyanuric chloride, SOCl 2 , SO2CI2, PCI3, PCls, POCl 3 , PBr 3 , SOBr 2 and S0 2 Br 2 .
  • the activating agent is selected from COCI2, (COCl SOCI2, S0 2 Cl 2 and POCI3.
  • the activating agent is COCI2 or (COCl)2.
  • the compound of the formula (II) is ,V,/V-d i c t h y 1 fo r m a m i d c and the activating agent is (COCl) 2 .
  • the amount of the employed activating agent may be varied over a wide range but is preferably in the range of from 1 to 3 molar equivalents and particularly preferably of from 1 to 1,5 molar equivalents, based on the total amount of the compound of the formula (II).
  • the activating reagent is added to the diluted or undiluted compound of the formula (II) in stoichiometric amounts.
  • the activating reagent is (COCl)22
  • it is added to the diluted or undiluted compound of the formula (II) in stoichiometric amounts.
  • the activating reagent is COCb
  • 1,5 molar equivalents are added to the diluted or undiluted compound of the formula (II).
  • step (a) can be conducted in the presence of one or more of the following solvents: ethers such as tetrahydrofuran (THF) or 2-methyltetrahydrofuran, dioxane, diethyl ether, diglyme, methyl tert-butyl ether
  • solvents such as tetrahydrofuran (THF) or 2-methyltetrahydrofuran, dioxane, diethyl ether, diglyme, methyl tert-butyl ether
  • MTBE tert- amyl methyl ether
  • TAME tert- amyl methyl ether
  • 2-methyl-THF 2-methyl-THF
  • nitriles such as acetonitrile (ACN) or butyronitrile
  • esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate
  • halohydrocarbons and halogenated aromatic hydrocarbons particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, trifluorobenzene, l ,2-dichloroethane, chlorobenzene,
  • the solvent is selected from dichloromethane and 2-methyltetrahydrofuran.
  • the solvent is dichloromethane.
  • step (a) of the process according to the invention is carried out at a temperature in the range of from -25°C to 25°C.
  • the process is carried out at a temperature in the range of from -lO°C to 25°C.
  • the process is carried out at a temperature in the range of from -5°C to l5°C.
  • the compound of the formula (Ila) obtained via step (a) is generally reacted with a compound of the formula (III).
  • the compound of the formula (Ila) is condensated with the compound of the formula (III) to obtain the compound of the formula (Ilia).
  • the amount of the employed compound of the formula (III) may be varied over a wide range.
  • 2 to 3 molar equivalents of the compound of the formula (III) are employed in step (b), based on the total amount of the compound of the formula (IV) employed in step (c).
  • step (b) of the process according to the invention is carried out at a temperature in the range of from -25°C to 25°C.
  • step (b) of the process according to the invention is carried out at a temperature in the range of from -10°C to 25 °C.
  • step (b) of the process according to the invention is carried out at a temperature in the range of from -5°C to 15°C.
  • the compound of the formula (III) employed in step (b) is n-butylvinylether.
  • T o obtain the compound of the formula (V) via step (c)
  • the compound of the formula (Ilia) obtained via step (b) is generally reacted with the compound of the formula (IV) in the presence of a base and a solvent at a suitable temperature.
  • the compound of the formula (IV) is reacted with the compound of the formula (Ilia) in stoichiometric amounts.
  • Suitable bases are all customary organic bases. These preferably include Tri-n-butylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamin (DIPEA), N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2- methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl- 2-methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, l,4-diazabicyclo[2.2.2]-octane (DABCO), l ,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or l,
  • the base used in step (c) is triethylamine.
  • the amount of the employed base may be varied over a wide range but is preferably in the range of from 3 to 4 molar equivalents based on the total amount of the compound of the formula (IV) employed in step (c). Particularly preferably, 3 molar equivalents of the base are employed in step (c) based on the total amount of the compound of the formula (IV) employed in step (c).
  • Step (c) is preferably conducted in one or more of the solvents listed in the general solvent definition of step (a).
  • the solvent is selected from dichloromethane and 2-methyltetrahydrofuran.
  • the solvent is dichloromethane.
  • step (c) of the process according to the invention is carried out at a temperature in the range of from -25°C to 25°C.
  • step (c) of the process according to the invention is carried out at a temperature in the range of from -10°C to 25°C.
  • step (c) of the process according to the invention is carried out at a temperature in the range of from -5°C to 15°C.
  • the compound of the formula (IV) employed in step (c) is ethyl 4,4-difluoro-3-oxo-butanoate and the base is triethylamine.
  • the compound of the formula (V) obtained via step (c) is generally reacted with an ammonia source in the presence of a solvent at a suitable temperature.
  • the compound of the formula (V) is cyclized in the presence of an ammonia source and a solvent at a suitable temperature to obtain the compound of the formula (VI).
  • the amount of the employed ammonia source may be varied over a wide range but is preferably in the range of from 2,5 to 5 molar equivalents based on the total amount of the compound of the formula (IV) employed in step (c).
  • step (d) can be conducted in the presence of one or more of the following ammonia sources: aqueous ammonia, ammonia as a gas, ammonium hydroxide or with ammonium salts, wherein the ammonium salt is selected from ammonium halides and ammonium carboxylates, such as ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium formate, ammonium acetate and mixtures thereof.
  • ammonia sources aqueous ammonia, ammonia as a gas, ammonium hydroxide or with ammonium salts, wherein the ammonium salt is selected from ammonium halides and ammonium carboxylates, such as ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium formate, ammonium acetate and mixtures thereof.
  • the ammonia source is selected from aqueous ammonia, ammonium hydroxide, ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium formate, ammonium acetate and mixtures thereof.
  • the ammonia source is selected from aqueous ammonia, ammonium gas, ammonium hydroxide and ammonium acetate.
  • ammonia source is ammonium hydroxide
  • step (d) can be conducted in a water-miscible organic solvent.
  • the solvent used in step (d) is one or more of the following solvents: tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-propanol, 1 ,4-dioxan, acetone, dimethoxyethane, furfuryl alcohol, ethylene glycol, triethyleneglycol, 1 ,3 -propanediol, 1,5-pentanediol, propylene glycol, glycerol, 1 ,2-butanediol, 1,3-butanediol, 1 ,4-butanediol, 2 -butoxy ethanol, diethanolamine, methyl diethanolamine, diethylenetriamine, pyridine or dimethylsulfoxide and mixtures thereof.
  • solvents tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-propanol, 1 ,4-
  • the solvent used in step (d) is ethanol.
  • step (d) of the process according to the invention is carried out at a temperature in the range of from 25°C to 150°C.
  • step (d) of the process according to the invention is carried out at a temperature in the range of from 25°C to 100°C.
  • step (d) of the process according to the invention is carried out at a temperature in the range of from 55°C to 90°C.
  • the compound of the formula (VI) obtained via step (d) is generally reacted with a base in the presence of a solvent at a suitable temperature.
  • the compound of the formula (VI) is hydrolyzed in the presence of a base and a solvent at a suitable temperature to obtain the compound of the formula (I).
  • step (e) can be conducted in the presence of one or more of the following bases: alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate (Na2C03), potassium carbonate (K2CO3), calcium carbonate, caesium carbonate (CS2CO3), sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride (NaH), potassium hydride or calcium hydride, lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH) or calcium hydroxide, n- butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide (NaOMe),
  • bases
  • KOtBu basic organic nitrogen compounds
  • basic organic nitrogen compounds for example trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamin, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N- dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6- dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl-2-methylpyridine, 4-dimethylaminopyridine, N- methylpiperidine, l ,4-diazabicyclo[2.2.2]-octane (DABCO), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or 1 ,8-diazabicyclo[5.
  • the base is selected from Na 2 C0 3 , K 2 CO 3 , CS 2 CO 3 , LiOH, NaOH, KOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof.
  • the base used in step (e) is selected from LiOH, NaOH, KOH and mixtures thereof. More preferably, the base used in step (e) is NaOH.
  • the amount of the employed base may be varied over a wide range but is preferably in the range of from 5,5 to 8 molar equivalents based on the total amount of the compound of the formula (IV) employed in step (c). Particularly preferably, 5,5 molar equivalents of the base are employed in step (e) based on the total amount of the compound of the formula (IV) employed in step (c).
  • step (e) of the process according to the invention is carried out at a temperature in the range of from 25°C to 150°C.
  • step (e) of the process according to the invention is carried out at a temperature in the range of from 25°C to 100°C. More preferably, step (e) of the process according to the invention is carried out at a temperature in the range of from 55°C to 90°C.
  • the steps (a), (b) and (c) of the process according to the invention are conducted in the presence of an aprotic organic solvent.
  • the steps (a), (b) and (c) of the process according to the invention are conducted in haloalkanes and ethers as solvents.
  • the steps (a), (b) and (c) of the process according to the invention are conducted in dichloromethane and 2-methyltetrahydrofuran as solvents.
  • the steps (a), (b) and (c) of the process according to the invention are conducted in dichloromethane as solvent.
  • the steps (d) and (e) of the process according to the invention are conducted in the presence of a water miscible organic solvent.
  • the steps (d) and (e) of the process according to the invention are conducted in the presence of alcohols and ethers. More preferably, the steps (d) and (e) of the process according to the invention are conducted in ethanol, isopropanol and tetrahydrofuran.
  • the steps (d) and (e) of the process according to the invention are conducted in ethanol.
  • the steps (a), (b) and (c) of the process according to the invention are conducted in the presence of dichloromethane and the steps (d) and (e) are conducted in the presence of ethanol.
  • the steps (a), (b) and (c) of the process according to the invention are carried out at a temperature in the range of from -25°C to 25°C and the steps (d) and (e) of the process according to the invention are carried out at a temperature in the range of from 25°C to l50°C.
  • the steps (a), (b) and (c) of the process according to the invention are carried out at a temperature in the range of from -lO°C to 25°C and the steps (d) and (e) of the process according to the invention are carried out at a temperature in the range of from 25°C to l00°C.
  • the steps (a), (b) and (c) of the process according to the invention are carried out at a temperature in the range of from -5°C to l5°C and the steps (d) and (e) of the process according to the invention are carried out at a temperature in the range of from 55°C to 90°C.
  • the present invention further relates to a process for producing a compound of the formula (VIII)
  • R 4 represents (Ci-C alkyl
  • R 5 represents hydrogen or (C i-Cx)alkyl
  • R 6 represents hydrogen or (C i-Cx)alkyl
  • R 7 represents hydrogen, halogen, (Ci-C Oalkyl or (Ci-C haloalkyl; comprising the steps (a) to (e) as defined above and further comprising step (f), wherein the compound of the formula (I) is reacted with a compound of the formula (VII)
  • step (f) The reaction according to step (f) and also how to obtain a compound of the formula (VII) is in principle known from e.g. WO 2014/095675 A1 and WO 2015/197530 A2.
  • R 4 represents methyl or n-propyl
  • R 5 and R 6 represent methyl
  • R 7 represents hydrogen or fluorine.
  • R 4 represents methyl or n-propyl
  • R 5 and R 6 represent methyl
  • R 7 represents hydrogen
  • R 4 represents n-propyl
  • R 5 and R 6 represent methyl; R 7 represents hydrogen.
  • R 4 , R 5 and R 6 represent methyl
  • R 7 represents hydrogen

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a method for preparing a 2-(fluoroalkyl)nicotinic acid derivative of the formula (I) in which the substituent R1 has the definition as specified in the description.

Description

Process for producing 2-(fluoroalkyl)nicotinic acids
The present invention relates to a method for preparing a 2-(fluoroalkyl)nicotinic acid derivative.
It is known that various pyrazole indanyl carboxamides have fungicidal activity (e.g. WO 1992/12970, WO 2012/065947, J. Org. Chem. 1995, 60, 1626 and WO 2012/084812). It is also known that various pyridine indanyl carboxamides have fungicidal activity (e.g. EP-A 0256503; JP-A 1117864; J. Pesticide Sci. 1993, 18, 245-251 ; WO 2014/095675; WO 2015/197530).
In addition, it is known that some benzoyl indanyl amides have fungicidal activity (WO 2010/109301).
Very generally, fungicidal indanyl carboxamides can be produced via the coupling of a 4-aminoindane derivative with an activated 2-(fluoroalkyl)nicotinic acid derivative by linking the primary amino group of the former with the activated carboxyl group of the latter (coupling reaction). Concluding, a 4-aminoindane derivative, but also an activated heterocyclic acid that shall be linked to the 4-aminoindane derivative, are important intermediates in the synthesis of fungicidal indanyl carboxamides.
Chemical syntheses of 2-(fluoroalkyl)nicotinic acid derivatives have been described e.g. in Chemical Communications (Chem. Commun., 2008, 4207-4209), Organic Letters (Org. Lett., 2008, 1835-1837) and WO 2015/197530.
In particular, WO 2015/197530 discloses a three-step process for the preparation of 2-(fluoroalkyl)nicotinic acid derivatives in which in a first step, a formamide is activated to a corresponding Vilsmeier-Haack reagent (i.e. a Vilsmeier salt) by reacting the formamide with an activating agent such as SOCL, POCI3, oxalylchloride or phosgene. From this, a cyclization precursor is synthesized by condensing the Vilsmeier salt with a vinylether and a P-fluoroalkyl-P-ketoester derivative, optionally in the presence of a diluent.
Alternatively, the cyclization precursor can be obtained by reacting a P-fluoroalkyl-P-ketoester derivative with a b-aminoalkyl substituted a,b-unsaturated aldehyde in the presence of a suitable acid or dehydrating agent and optionally in the presence of a diluent. Suitable acids are HC1, HBr, HF, H2SO4, KHSO4, AcOH, trifluoroacetic acid, p-toluenesulfonic acid, camphorsulfonic acid, methansulfonic acid, trifluoromethansulfonic acid, polyphosphoric acid, phosphoric acid. Suitable dehydrating agents may be for example carboxylic or sulfonic acid anhydrides, e.g. acetic anhydride.
In a second step, the obtained cyclization precursor is cyclocondensated to a nicotinic ester(further referred to as the ester), optionally in the presence of a diluent with ammonia as a gas or with ammonia dissolved in a suitable solvent, e.g. in water as ammonium hydroxide. Thirdly, the thus obtained ester is saponified for example in the presence of sodium hydroxide (NaOH), yielding finally the desired 2-(fluoroaLkyl)nicotinic acid derivative.
However, all three steps of the known process need to be conducted independently from each other in individual reaction vessels with intermediary purification of the intermediates (i.e. the cyclization precursor and the ester) before obtaining the final product which is a 2-(fluoroalkyl)nicotinic acid derivative, resulting firstly in a high energy requirement and in a suboptimal space-time yield since the intermediary purification steps require time. Furthermore, since three isolations are carried out, consequently three mother liquors are formed, resulting in a high amount of waste that needs to be disposed.
Additionally, the cyclization precursor is an intermediate which displays some lability against humidity and more important acidic moisture.
With regard to the disadvantages outlined above, there is a demand for a simplified method that can be carried out industrially and economically for the general preparation of a 2-(fhioroalkyl)nicotinic acid derivative. The 2-(fhioroalkyl)nicotinic acid derivative obtainable by this desired method should preferably in this case be obtained in high yield and high purity. In particular, the desired method should enable the desired target compounds to be obtained without the need for complex purification methods.
The hereinbelow-described process according to the invention achieves these objects.
The process according to the invention avoids the isolation of intermediary compounds such as the cyclization precursor and the ester which maximizes the overall space-time -yield of the desired 2-(fluoroalkyl)nicotinic acid derivative. In particular, the process according to the invention can be conducted as a telescoping synthesis, i.e. it is workable as a sequential one-pot synthesis with reagents added to a reactor one at a time, wherein minimal work-up procedures are performed during the process leading to this improved space-time-yield. Minimal work-up procedures are e.g. separation and/or washing steps and/or removal of solvents and/or reagents via distillation. Concluding, the process according to the invention allows the production of a 2-(fhioroalkyl)nicotinic acid derivative in high yields with at the same time reduced amounts of waste.
In particular, during the process according to the invention the isolation of the cyclization precursor which exhibits lability against humidity and acidic moisture can be avoided and instead the cyclization precursor can be cyclized directly to the ester without the need of intermediary purification. Therefore, the process according to the invention allows the production of a 2-(fhioroalkyl)nicotinic acid derivative in high yields and high purity by avoiding at the same time loss of intermediary compounds due to degradation.
The present invention provides a process for the preparation of a compound of the formula (I)
Figure imgf000004_0001
comprising the steps (a) to (e):
(a) a compound of the formula (II)
Figure imgf000004_0002
is reacted with an activating agent in the presence of a solvent to obtain a compound of the formula (Ila)
Figure imgf000004_0003
(b) the compound of the formula (Ila) is reacted with a compound of the formula (III)
Figure imgf000004_0004
to obtain a compound of the formula (Ilia)
Figure imgf000004_0005
(c) the compound of the formula (Ilia) is reacted in the presence of a base with a compound of the formula (IV)
Figure imgf000005_0001
to obtain a compound of the formula (V)
Figure imgf000005_0002
(d) cyclizing the compound of the formula (V) to obtain a compound of the formula (VI)
Figure imgf000005_0003
(e) hydrolyzing the compound of the formula (VI) to obtain the compound of the formula (I); wherein in formulae (I), (II), (Ila), (III), (Ilia), (IV), (V) and (VI) (further referred to as formulae (I)- (VI)) R1 represents methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2- difluoroethyl and pentafluoroethyl;
X represents halogen; and
R2, R3 and X2 represent a C1-C6 alkyl group; characterized in that the steps (a) to (e) are performed as a telescoping synthesis, wherein the compounds of the formulae (Ha), (Ilia), (V) and (VI) are not isolated before obtaining the compound of the formula (I). Preferred, particularly preferred and most preferred definitions of the residues R1, R2, R3, X and X2 listed in the herein-defined formulae (I)- (VI)) are elucidated below.
It is preferable when in each case:
R1 represents methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2- difluoroethyl and pentafluoroethyl;
R2 represents methyl or ethyl;
R3 represents butyl;
X represents fluorine;
X2 represents methyl or ethyl It is particularly preferable when in each case:
R1 represents difluoromethyl and trifluoromethyl;
R2 represents ethyl;
R3 represents butyl;
X represents fluorine; X2 represents ethyl.
It is more preferable when in each case:
R1 represents difluoromethyl;
R2 represents ethyl;
R3 represents butyl; X represents fluorine;
X2 represents ethyl.
Unless otherwise stated, the following definitions apply for the substituents and residues used throughout this specification and claims: Halogen: fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine and most preferably chlorine.
Alkyl: saturated, straight-chain or branched hydrocarbyl radical having 1 to 8, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, for example (but not limited to) Ci-C6-alkyl such as methyl, ethyl, propyl (n- propyl), 1 -methylethyl (iso-propyl), butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), l ,l-dimethylethyl (tert-butyl), pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 - ethylpropyl, l ,l -dimethylpropyl, l,2-dimethylpropyl, hexyl, l-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, l,l-dimethylbutyl, 1 ,2-dimethylbutyl, l,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, l,l,2-trimethylpropyl, 1 ,2,2- trimethylpropyl, 1 -ethyl- 1 -methylpropyl and 1 -ethyl-2-methylpropyl. Particularly, said group is a C1 -C4- alkyl group, e.g. a methyl, ethyl, propyl, 1 -methylethyl (isopropyl), butyl, 1 -methylpropyl (sec-butyl), 2- methylpropyl (iso-butyl) or l,l-dimethylethyl (tert-butyl) group.
Generally, an activated hydroxyl group shall mean that the hydroxyl forms together with the adjacent carbonyl an ester which spontaneously reacts with an amino group. Common activated esters include p- nitrophenyl, pentafluorophenyl, succinimido esters or phosphorous anhydrides
The "crossed line" representation of the C-C double bond in formula (V) reflects the possible E/Z stereochemistry of this bond.
The term telescoping synthesis is defined as a sequence of different chemical transformations which ultimately leads to the isolation of a product and runs through several different intermediates whose isolation is omitted in order to maximize the space-time-yield of the process. Minimal downstreaming operations such as liquid-liquid extraction and distillation may be implemented between the chemical transformations in order to remove substances not being compatible with the follow-up chemistry.
Detailed description of the process
The process according to the invention can be conducted as shown in scheme (1):
Figure imgf000008_0001
In scheme 1 the substituents R1, R2, R3, X and X2 of the formulae (I)-(VI) each have the general, preferred, particularly preferred, more preferred or most preferred meanings which have already been defined for these substituents in connection with the description of the compounds of the formulae (I)- (VI). The process shown in scheme 1 is the process according to the invention when conducted as a telescoping synthesis. This means, the process is worked as a sequential one-pot synthesis with reagents added to a reactor one at a time and wherein minimal work-up procedures are performed during the process.
The starting materials, i.e. compounds of the formulae (II), (III) and (IV) are commercially available.
Step (a) In step (a) the compound of the formula (II) is activated via an activating agent, generating a compound of the formula (Ila) which is a Vilsmeyer salt. This is achieved by addition of an activating reagent to the diluted or undiluted compound of the formula (II) at a suitable temperature.
Preferably, the activating agent in step (a) is an dehydroxyhalogenating agent. Preferably, the activating agent in step (a) is selected from phosgene (COCb), oxalyl chloride ( (COCl)2 ), cyanuric chloride, SOCl2, SO2CI2, PCI3, PCls, POCl3, PBr3, SOBr2 and S02Br2.
Particularly preferably, the activating agent is selected from COCI2, (COCl SOCI2, S02Cl2and POCI3.
More preferably, the activating agent is COCI2 or (COCl)2. Most preferable, the compound of the formula (II) is ,V,/V-d i c t h y 1 fo r m a m i d c and the activating agent is (COCl)2.
The amount of the employed activating agent may be varied over a wide range but is preferably in the range of from 1 to 3 molar equivalents and particularly preferably of from 1 to 1,5 molar equivalents, based on the total amount of the compound of the formula (II). Also preferably, the activating reagent is added to the diluted or undiluted compound of the formula (II) in stoichiometric amounts. Preferably, if the activating reagent is (COCl)2, it is added to the diluted or undiluted compound of the formula (II) in stoichiometric amounts. Preferably, if the activating reagent is COCb, 1,5 molar equivalents are added to the diluted or undiluted compound of the formula (II).
Generally, step (a) can be conducted in the presence of one or more of the following solvents: ethers such as tetrahydrofuran (THF) or 2-methyltetrahydrofuran, dioxane, diethyl ether, diglyme, methyl tert-butyl ether
(MTBE), tert- amyl methyl ether (TAME), dimethyl ether, 2-methyl-THF; nitriles such as acetonitrile (ACN) or butyronitrile; esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate; halohydrocarbons and halogenated aromatic hydrocarbons, particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, trifluorobenzene, l ,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1 ,2-dichlorobenzene, chlorotoluene, trichlorobenzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane and water. It is also possible to use solvent mixtures.
Preferably, the solvent is selected from dichloromethane and 2-methyltetrahydrofuran. Particularly preferably, the solvent is dichloromethane.
Preferably, step (a) of the process according to the invention is carried out at a temperature in the range of from -25°C to 25°C.
Particularly preferably, the process is carried out at a temperature in the range of from -lO°C to 25°C.
More preferably, the process is carried out at a temperature in the range of from -5°C to l5°C. Step (b)
To obtain a compound of the formula (Ilia) via step (b), the compound of the formula (Ila) obtained via step (a) is generally reacted with a compound of the formula (III). Preferably, the compound of the formula (Ila) is condensated with the compound of the formula (III) to obtain the compound of the formula (Ilia). The amount of the employed compound of the formula (III) may be varied over a wide range. Preferably, 2 to 3 molar equivalents of the compound of the formula (III) are employed in step (b), based on the total amount of the compound of the formula (IV) employed in step (c). Particularly preferably, 2 molar equivalents of the compound of the formula (III) are employed, based on the total amount of the compound of the formula (IV) employed in step (c). Preferably, step (b) of the process according to the invention is carried out at a temperature in the range of from -25°C to 25°C.
Particularly preferably, step (b) of the process according to the invention is carried out at a temperature in the range of from -10°C to 25 °C.
More preferably, step (b) of the process according to the invention is carried out at a temperature in the range of from -5°C to 15°C.
Preferably, the compound of the formula (III) employed in step (b) is n-butylvinylether.
Step (c)
T o obtain the compound of the formula (V) via step (c), the compound of the formula (Ilia) obtained via step (b) is generally reacted with the compound of the formula (IV) in the presence of a base and a solvent at a suitable temperature.
Preferably, the compound of the formula (IV) is reacted with the compound of the formula (Ilia) in stoichiometric amounts.
Suitable bases are all customary organic bases. These preferably include Tri-n-butylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamin (DIPEA), N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N-dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2- methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl- 2-methylpyridine, 4-dimethylaminopyridine, N-methylpiperidine, l,4-diazabicyclo[2.2.2]-octane (DABCO), l ,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or l,8-diazabicyclo[5.4.0]-undec-7-ene (DBU). Particularly preferably, the base used in step (c) is selected from triethylamine, diisopropylethylamin, N- methylmorpholine, tri-n-butylamine.
More preferably, the base used in step (c) is triethylamine.
The amount of the employed base may be varied over a wide range but is preferably in the range of from 3 to 4 molar equivalents based on the total amount of the compound of the formula (IV) employed in step (c). Particularly preferably, 3 molar equivalents of the base are employed in step (c) based on the total amount of the compound of the formula (IV) employed in step (c).
Step (c) is preferably conducted in one or more of the solvents listed in the general solvent definition of step (a). Preferably, the solvent is selected from dichloromethane and 2-methyltetrahydrofuran.
Particularly preferably, the solvent is dichloromethane.
Preferably, step (c) of the process according to the invention is carried out at a temperature in the range of from -25°C to 25°C.
Particularly preferably, step (c) of the process according to the invention is carried out at a temperature in the range of from -10°C to 25°C.
More preferably, step (c) of the process according to the invention is carried out at a temperature in the range of from -5°C to 15°C.
Preferably, the compound of the formula (IV) employed in step (c) is ethyl 4,4-difluoro-3-oxo-butanoate and the base is triethylamine. Step (d)
T o obtain the compound of the formula (VI) via step (d), the compound of the formula (V) obtained via step (c) is generally reacted with an ammonia source in the presence of a solvent at a suitable temperature. Preferably, the compound of the formula (V) is cyclized in the presence of an ammonia source and a solvent at a suitable temperature to obtain the compound of the formula (VI). The amount of the employed ammonia source may be varied over a wide range but is preferably in the range of from 2,5 to 5 molar equivalents based on the total amount of the compound of the formula (IV) employed in step (c). Particularly preferably, 2,5 molar equivalents of the ammonia source are employed in step (d) based on the total amount of the compound of the formula (IV) employed in step (c). Generally, step (d) can be conducted in the presence of one or more of the following ammonia sources: aqueous ammonia, ammonia as a gas, ammonium hydroxide or with ammonium salts, wherein the ammonium salt is selected from ammonium halides and ammonium carboxylates, such as ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium formate, ammonium acetate and mixtures thereof.
Preferably, the ammonia source is selected from aqueous ammonia, ammonium hydroxide, ammonium fluoride, ammonium chloride, ammonium bromide, ammonium iodide, ammonium formate, ammonium acetate and mixtures thereof.
Particularly preferably, the ammonia source is selected from aqueous ammonia, ammonium gas, ammonium hydroxide and ammonium acetate.
More preferred, the ammonia source is ammonium hydroxide
Generally, step (d) can be conducted in a water-miscible organic solvent.
Preferably, the solvent used in step (d) is one or more of the following solvents: tetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-propanol, 1 ,4-dioxan, acetone, dimethoxyethane, furfuryl alcohol, ethylene glycol, triethyleneglycol, 1 ,3 -propanediol, 1,5-pentanediol, propylene glycol, glycerol, 1 ,2-butanediol, 1,3-butanediol, 1 ,4-butanediol, 2 -butoxy ethanol, diethanolamine, methyl diethanolamine, diethylenetriamine, pyridine or dimethylsulfoxide and mixtures thereof.
Particularly preferably, the solvent used in step (d) is ethanol.
Preferably, step (d) of the process according to the invention is carried out at a temperature in the range of from 25°C to 150°C.
Particularly preferably, step (d) of the process according to the invention is carried out at a temperature in the range of from 25°C to 100°C.
More preferably, step (d) of the process according to the invention is carried out at a temperature in the range of from 55°C to 90°C. Step (e)
T o obtain the compound of the formula (I) via step (e), the compound of the formula (VI) obtained via step (d) is generally reacted with a base in the presence of a solvent at a suitable temperature. Preferably, the compound of the formula (VI) is hydrolyzed in the presence of a base and a solvent at a suitable temperature to obtain the compound of the formula (I).
Generally, step (e) can be conducted in the presence of one or more of the following bases: alkaline earth metal acetates, amides, carbonates, hydrogencarbonates, hydrides, hydroxides or alkoxides, for example sodium acetate, potassium acetate or calcium acetate, lithium amide, sodium amide, potassium amide or calcium amide, sodium carbonate (Na2C03), potassium carbonate (K2CO3), calcium carbonate, caesium carbonate (CS2CO3), sodium hydrogencarbonate, potassium hydrogencarbonate or calcium hydrogencarbonate, lithium hydride, sodium hydride (NaH), potassium hydride or calcium hydride, lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH) or calcium hydroxide, n- butyllithium, sec-butyllithium, tert-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium methoxide (NaOMe), ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide or potassium methoxide (KOMe), ethoxide, n- or i-propoxide, n-, i-, s- or t-butoxide (e.g. KOtBu); and also basic organic nitrogen compounds, for example trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamin, N,N-dimethylcyclohexylamine, dicyclohexylamine, ethyldicyclohexylamine, N,N- dimethylaniline, N,N-dimethylbenzylamine, pyridine, 2-methyl-, 3-methyl-, 4-methyl-, 2,4-dimethyl-, 2,6- dimethyl-, 3,4-dimethyl- and 3,5-dimethylpyridine, 5-ethyl-2-methylpyridine, 4-dimethylaminopyridine, N- methylpiperidine, l ,4-diazabicyclo[2.2.2]-octane (DABCO), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]-undec-7-ene (DBU).
Preferably the base is selected from Na2C03, K2CO3, CS2CO3, LiOH, NaOH, KOH, NaOMe, KOMe, KOtBu, NaH and mixtures thereof.
Particularly preferably, the base used in step (e) is selected from LiOH, NaOH, KOH and mixtures thereof. More preferably, the base used in step (e) is NaOH.
The amount of the employed base may be varied over a wide range but is preferably in the range of from 5,5 to 8 molar equivalents based on the total amount of the compound of the formula (IV) employed in step (c). Particularly preferably, 5,5 molar equivalents of the base are employed in step (e) based on the total amount of the compound of the formula (IV) employed in step (c).
Preferably, step (e) of the process according to the invention is carried out at a temperature in the range of from 25°C to 150°C.
Particularly preferably, step (e) of the process according to the invention is carried out at a temperature in the range of from 25°C to 100°C. More preferably, step (e) of the process according to the invention is carried out at a temperature in the range of from 55°C to 90°C.
Preferably, the steps (a), (b) and (c) of the process according to the invention are conducted in the presence of an aprotic organic solvent. Particularly preferably, the steps (a), (b) and (c) of the process according to the invention are conducted in haloalkanes and ethers as solvents.
More preferably, the steps (a), (b) and (c) of the process according to the invention are conducted in dichloromethane and 2-methyltetrahydrofuran as solvents.
Most preferably, the steps (a), (b) and (c) of the process according to the invention are conducted in dichloromethane as solvent.
Preferably, the steps (d) and (e) of the process according to the invention are conducted in the presence of a water miscible organic solvent.
Particularly preferably, the steps (d) and (e) of the process according to the invention are conducted in the presence of alcohols and ethers. More preferably, the steps (d) and (e) of the process according to the invention are conducted in ethanol, isopropanol and tetrahydrofuran.
Most preferably, the steps (d) and (e) of the process according to the invention are conducted in ethanol.
Preferably, the steps (a), (b) and (c) of the process according to the invention are conducted in the presence of dichloromethane and the steps (d) and (e) are conducted in the presence of ethanol. Preferably, the steps (a), (b) and (c) of the process according to the invention are carried out at a temperature in the range of from -25°C to 25°C and the steps (d) and (e) of the process according to the invention are carried out at a temperature in the range of from 25°C to l50°C.
Particularly preferably, the steps (a), (b) and (c) of the process according to the invention are carried out at a temperature in the range of from -lO°C to 25°C and the steps (d) and (e) of the process according to the invention are carried out at a temperature in the range of from 25°C to l00°C.
More preferably, the steps (a), (b) and (c) of the process according to the invention are carried out at a temperature in the range of from -5°C to l5°C and the steps (d) and (e) of the process according to the invention are carried out at a temperature in the range of from 55°C to 90°C. The present invention further relates to a process for producing a compound of the formula (VIII)
Figure imgf000015_0001
wherein in formula (VIII) the substituent R1 has the general, preferred, particularly preferred, more preferred or most preferred meaning which have already been defined for this substituent in connection with the description of the compounds of the formulae (I)-(VI) as defined above, and wherein in formula (VIII)
R4 represents (Ci-C alkyl;
R5 represents hydrogen or (C i-Cx)alkyl;
R6 represents hydrogen or (C i-Cx)alkyl;
R7 represents hydrogen, halogen, (Ci-C Oalkyl or (Ci-C haloalkyl; comprising the steps (a) to (e) as defined above and further comprising step (f), wherein the compound of the formula (I) is reacted with a compound of the formula (VII)
Figure imgf000015_0002
to obtain the compound of the formula (VIII). The reaction according to step (f) and also how to obtain a compound of the formula (VII) is in principle known from e.g. WO 2014/095675 A1 and WO 2015/197530 A2.
It is also preferable when in each case in formula (VIII):
R4 represents methyl or n-propyl; R5 and R6 represent methyl;
R7 represents hydrogen or fluorine.
It is particularly preferable when in each case:
R4 represents methyl or n-propyl; R5 and R6 represent methyl;
R7 represents hydrogen.
It is most preferable when in each case:
R4 represents n-propyl;
R5 and R6 represent methyl; R7 represents hydrogen.
It is also most preferable when in each case:
R4, R5 and R6 represent methyl;
R7 represents hydrogen.
The present invention is elucidated in detail by the example which follows, although the example should not be interpreted in such a manner that it restricts the invention.
Preparation example
Example (a): Preparation of 2-(difluoromethyl)pyridine-3-carboxylic acid
Figure imgf000017_0001
To a 4000 mL four-necked round-bottomed flask equipped with a reflux condenser, a dropping funnel with pressure equalizer, a mechanical stirrer and a thermometer, were placed 134 g (1.325 mol, 1.1 eq) of NN- diethylformamide in 500 mL of dichloromethane. The solution was cooled to 0°C. Afterwards 0.183 g (1.444 mol, 1.2 eq) of oxalyl chloride were dosed over 1 h, followed by 1 h of post-stirring. To the yellow solution was then dosed 241 g (2.408 mol, 2.0 eq) of n-butylvinylether over 1 h at 0°C. The yellow solution turned into an orange suspension. The mixture was stirred at this temperature for further 3 h to become a red-orange solution. To this solution was dosed 364 g (3.600 mol, 3.0 eq) of triethylamine over 1 h, keeping the internal temperature below 5°C. The solution was then stirred further for 1 h and became orange-brown in color. To this solution was then dosed 200 g (1.204 mol, 1.0 eq) of ethyl 4,4-difluoro-3-oxo-butanoate within 1 h so that an internal temperature of 10°C was not exceeded. A dark-brown suspension formed which was allowed to warm up to 22°C and was stirred at this temperature for 1 h. Afterwards 1000 mL of ethanol was added in one portion. This was followed by atmospheric distillation of dichloromethane to reach an internal temperature of 73°C. By this 700 g of distillate was removed from the reaction vessel. Afterwards 228 mL (3.010 mol, 2.5 eq) of aqueous ammonia (25 w%) was dosed over 45 min to the dark reaction solution at an internal temperature of 70-78°C. After 30 min of additional post-stirring time at this temperature 348 mL (6.623 mol, 5.5 eq) of aqueous sodium hydroxide (50 w%) was dosed to the reaction solution within 2 h. After further 0.5 h post-stirring time full conversion was achieved. The reaction mixture was now concentrated at 40°C down to 5 mbar to leave 554 g of a dark-brown oil. This residue was dissolved in 1000 mL of deion. water at 40°C. The pH of this solution was measured 8.2. To the solution was added 50 g of active charcoal. To the suspension was then added 7.0 g of glacial acetic acid to adjust the pH to 4-6. After 1 h of stirring at 25°C the suspension was fdtered. The filtrate was then cooled to 10°C and 100 mL of cone aqueous HC1 (37 w%) were dosed in to decrease the pH to a level of pH 2-3 for product precipitation. The orange suspension was then filtered and the solid was washed with 2 x 500 mL of deion. water. Afterwards the filter cake was dried at 60°C, 65 mbar for 16 h to leave 176 g (95% purity, 0.965 mol, 80% yield) of a beige solid. ¾-NMR (400 MHz; DMSO-d6) d = 13.93 (bs, 1H), 8.87 (d, J = 4.0 Hz, 1H), 8.34 (d, J= 8.0 Hz, 1H), 7.71 (dd, J= 4.0, 8.0 Hz, 1H), 7.52 (t, J= 56 Hz, 1H).

Claims

Claims:
1. Process for the preparation of a compound of the formula (I)
Figure imgf000018_0001
comprising the steps (a) to (e): (a) a compound of the formula (II)
Figure imgf000018_0002
is reacted with an activating agent in the presence of a solvent to obtain a compound of the formula (Ila)
Figure imgf000018_0003
Figure imgf000018_0004
(b) the compound of the formula (Ila) is reacted with a compound of the formula (III)
Figure imgf000018_0005
to obtain a compound of the formula (Ilia)
Figure imgf000019_0001
(c) the compound of the formula (Ilia) is reacted in the presence of a base with a compound of the formula (IV)
Figure imgf000019_0002
to obtain a compound of the formula (V)
Figure imgf000019_0003
(d) cyclizing the compound of the formula (V) to obtain a compound of the formula (VI)
Figure imgf000019_0004
(e) hydrolyzing the compound of the formula (VI) to obtain the compound of the formula (I); wherein in formulae (I), (II), (Ila), (III), (Ilia), (IV), (V) and (VI)
R1 represents methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2 -trifluoroethyl, 2,2- difluoroethyl and pentafluoroethyl; X represents halogen; and
R2, R3 and X2 represent a C1-C6 alkyl group; characterized in that the steps (a) to (e) are performed as a telescoping synthesis, wherein the compounds of the formulae (Ila), (Ilia), (V) and (VI) are not isolated before obtaining the compound of the formula (I).
2. The process according to claim 1 , wherein R1 is difluoromethyl, R2 is ethyl, R3 is butyl, X represents fluorine and X2 is ethyl.
3. The process according to one og the claims 1 or 2, wherein the activating agent in step (a) is a dehydroxyhalogenating agent, selected from the group consisting of oxalyl chloride and phosgene. 4. The process according to one of the claims 1 to 3, wherein the solvent used in step (a) is selected from the group consisting of dichloromethane and 2-methyltetrahydrofuran.
5. The process according to one of the claims 1 to 4, wherein the base used in step (c) is selected from the group consisting of triethylamine, diisopropylethylamin , N-methylmorpholine, tri-n-butylamine.
6. The process according to claim 5, wherein the base used in step (c) is triethylamine. 7. The process according to one of the claims 1 to 6, wherein the steps (d) and/or (e) are conducted in the presence of a solvent and/or an ammonia source and/or a base.
The process according to claim 7, wherein the solvent used in steps (d) and (e) is ethanol.
9. The process according to claim 7 and 8, wherein the ammonia source used in step (d) is selected from the group consisting of aqueous ammonia, gaseous ammonia and ammonium acetate. 10. The process according to one of the claims 7 to 9, wherein the base used in step (e) is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate.
11. The process according to claim 10, wherein the base used in step (e) is selected from the group consisting of sodium hydroxide, lithium hydroxide and potassium hydroxide. 12. The process according to one of the claims 9 to 11 , wherein the base used in step (e) is sodium hydroxide.
13. The process according to one of the claims 1 to 12, wherein the steps (a), (b) and (c) are carried out at a temperature in the range of from -25°C to 25°C and/or the steps (d) and (e) are carried out at a temperature in the range of from 25°C to l50°C.
14. The process according to claim 13, wherein the steps (a), (b) and (c) are carried out at a temperature in the range of from -lO°C to 25°C and/or the steps (d) and (e) are carried out at a temperature in the range of from 25°C to l00°C.
15. Process for the preparation of a compound of the formula (VIII)
Figure imgf000021_0001
wherein in formula (VIII) the substituent R1 has the meaning as defined in any one of the claims 1 or 2; and wherein
R4 represents (Ci-C alkyl;
R5 represents hydrogen or (C i-Cx)alkyl;
R6 represents hydrogen or (C i-Cx)alkyl;
R7 represents hydrogen, halogen, (Ci-C Oalkyl or (Ci-C haloalkyl comprising the process according to one of the claims 1 to 14 and further comprising step (f), wherein the compound of the formula (I) is reacted with a compound of the formula (VII)
Figure imgf000021_0002
to obtain the compound of the formula (VIII).
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