EP1904425A1 - Verfahren zur herstellung von mono- oder difluorierten kohlenwasserstoffverbindungen - Google Patents

Verfahren zur herstellung von mono- oder difluorierten kohlenwasserstoffverbindungen

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Publication number
EP1904425A1
EP1904425A1 EP06778821A EP06778821A EP1904425A1 EP 1904425 A1 EP1904425 A1 EP 1904425A1 EP 06778821 A EP06778821 A EP 06778821A EP 06778821 A EP06778821 A EP 06778821A EP 1904425 A1 EP1904425 A1 EP 1904425A1
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EP
European Patent Office
Prior art keywords
group
saturated
formula
fluoride
process according
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EP06778821A
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English (en)
French (fr)
Inventor
Laurent Saint-Jalmes
Daniel Uguen
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Centre National de la Recherche Scientifique CNRS
Rhodia Chimie SAS
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Centre National de la Recherche Scientifique CNRS
Rhodia Chimie SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/18—Preparation of halogenated hydrocarbons by replacement by halogens of oxygen atoms of carbonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C19/00—Acyclic saturated compounds containing halogen atoms
    • C07C19/08—Acyclic saturated compounds containing halogen atoms containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
    • C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
    • C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
    • C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
    • C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • 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
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • the present invention relates to a process for the preparation of mono- or difluorinated hydrocarbon compounds.
  • Fluorinated compounds are generally difficult to access.
  • the reactivity of the fluorine is such that it is difficult or impossible to directly obtain the fluorinated derivatives.
  • fluorinated derivative One of the most widely used techniques for producing the fluorinated derivative is to react a halogenated derivative, generally chlorinated, to exchange the halogen with a mineral fluorine, generally an alkali metal fluoride, most often of high atomic weight.
  • a halogenated derivative generally chlorinated
  • a mineral fluorine generally an alkali metal fluoride
  • the fluoride used is potassium fluoride which constitutes a satisfactory economic compromise.
  • reaction requires reagents such as alkali metal fluorides such as potassium fluoride which are made relatively expensive by the specifications they must meet to be suitable for this type of synthesis; they must be very pure, dry and in a suitable physical form.
  • alkali metal fluorides such as potassium fluoride
  • Reagents such as liquid hydrofluoric acid or diluted by aprotic dipolar solvents are also used.
  • hydrofluoric acid is a too powerful reagent and often leads to unwanted polymerization reactions or tars.
  • alkyl represents an alkyl or cycloalkyl group.
  • alkyl is intended to mean a linear or branched hydrocarbon-based chain containing from 1 to 6 carbon atoms and preferably from 1 to 4 carbon atoms.
  • Examples of preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl.
  • cycloalkyl is meant a cyclic, monocyclic hydrocarbon group comprising from 3 to 7 carbon atoms, preferably from 5 to 6 carbon atoms.
  • group Ro could have another meaning, for example, benzyl but from an economic point of view, there is no point in having a complicated group R 0 .
  • C 1 -C 4 alkyl groups are preferred and more particularly the methyl group.
  • the fluorination is carried out using the fluorinating reagent of an alcohol or a carbonyl compound, aldehyde or ketone.
  • a first embodiment of the invention consists in preparing a monofluorinated compound from a corresponding hydroxyl compound (alcohol).
  • Another variant of the invention consists in preparing a gifluorinated compound from a carbonyl compound.
  • a fluorination reagent comprising the unit having the formula (F) is involved.
  • a preferred reagent is to use 1-alkyl- or 1-cycloalkyl-2-fluoropyridinium but the invention also contemplates the case where said unit is included in a polycyclic structure such as for example the pyridinium ring is attached to a ring having 5 or 6 carbon atoms, saturated, unsaturated or aromatic.
  • 1-alkyl- or 1-cycloalkyl-2-fluoroquinolinium may be mentioned.
  • the invention does not exclude the presence of one or more (at most 4) substituents on one or more rings of the reagent, in particular on the pyridinium ring.
  • alkyl or alkoxy groups having from 1 to 4 carbon atoms, a halogen atom (F, Cl, Br, I) or an electron-withdrawing group, for example nitro, carboxylate. alkyl having 1 to 4 atoms.
  • the fluorinated reagent can be prepared in situ by using, associated with a source of fluoride, a halogen reagent comprising a pyridinium unit corresponding to the following formula:
  • X represents a halogen atom of higher rank than fluorine, preferably chlorine, bromine or iodine,
  • - Ro represents an alkyl or cycloalkyl group.
  • the nitrogen atom is quaternized.
  • the counter-ion associated with it and symbolized by Y " results from the process for preparing said unit, and is preferably a halide, a sulphonate group or a carboxylate group.
  • halides mention may be made of fluoride, chloride, bromide or iodide.
  • the sulphonate group it can be represented by the formula R a S ⁇ 3 " in which R a is a hydrocarbon group.
  • R a is a hydrocarbon group of any kind.
  • R a is of a simple nature, and more particularly represents a linear or branched alkyl group having 1 to 4 carbon atoms, preferably a methyl or ethyl group but it may also represent for example a phenyl or tolyl group or a trifluoromethyl group.
  • the preferred group is a triflate group which corresponds to a group R a representing a trifluoromethyl group.
  • Y " may also be a carboxylate group which may be represented by the formula R b CO 2 " wherein R b is a hydrocarbon group.
  • R b is not critical, but it is economically desirable for R b to be an alkyl group having 1 to 4 carbon atoms, preferably a methyl group.
  • fluorination reagents used preferentially in the process of the invention, mention may be made in particular of:
  • the amount of fluorination reagent used is expressed relative to the amount of substrate, alcohol or carbonyl compound. It is preferably at least equal to the stoichiometric amount. It is such that the ratio between the number of moles of fluorination reagent and the number of moles of substrate varies most often between 1 and 3 and is preferably between 1, 5 and 2.
  • an alcohol or a carbonyl compound is reacted with the fluorination reagent of the invention, in the presence of a base and in an organic medium.
  • R 1 - OH (I) in said formula (I): - Ri represents a hydrocarbon group having from 1 to 30 carbon atoms, which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic cycloaliphatic group; a saturated or unsaturated, linear or branched, aliphatic group carrying a cyclic substituent.
  • the alcohol which is involved in the process of the invention corresponds to formula (I) in which R 1 represents a linear or branched, saturated or unsaturated acyclic aliphatic group.
  • R 1 represents an alkyl, alkenyl, alkadienyl, alkynyl, linear or branched group preferably having from 1 to 30 carbon atoms.
  • the hydrocarbon chain can be optionally:
  • R 2 represents hydrogen or an alkyl group preferably a methyl or ethyl group, and / or carrier of one of the following substituents:
  • acyclic, saturated or unsaturated, linear or branched aliphatic residue may optionally carry a cyclic substituent.
  • ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.
  • the acyclic aliphatic residue may be linked to the ring by a valency bond or by one of the following groups:
  • R 1 can also represent a carbocyclic group saturated or comprising 1 or 2 unsaturations in the ring, generally having 3 to 7 carbon atoms, preferably 6 carbon atoms in the ring.
  • R 1 groups include cyclohexyl or cyclohexenyl.
  • the invention also includes the case where the ring may carry one or more substituents insofar as they do not interfere with the process of the invention. Mention may in particular be made of alkyl or alkoxy groups having from 1 to 4 carbon atoms. The process is easily carried out with most alcohols.
  • alcohols More specific examples include:
  • lower aliphatic alcohols having from 1 to 5 carbon atoms such as, for example, methanol, ethanol, trifluoroethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, dry alcohol, butyl alcohol, tert-butyl alcohol, pentanol, isopentyl alcohol, dry-pentyl alcohol and tert-pentyl alcohol, ethylene glycol monoethyl ether, methyl lactate, isobutyl lactate, methyl D-lactate, isobutyl D-lactate,
  • higher aliphatic alcohols having at least 6 and up to about 20 carbon atoms such as, for example, hexanol, heptanol, isoheptyl alcohol, octanol, isooctyl alcohol, ethyl- 2 hexanol, sec-octyl alcohol, tert-octyl alcohol, nonanol, isononyl alcohol, decanol, dodecanol, tetradecanol, octadecanol, hexadecanol, oleyl alcohol, alcohol eicosylic, diethylene glycol monoethyl ether.
  • cycloaliphatic alcohols having from 3 to about 20 carbon atoms, such as, for example, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, cycloheptanol, cyclooctanol, cyclododecanol, tripropylcyclohexanol, methylcyclohexanol and methylcycloheptanol, cyclopenten-ol, cyclohexen-ol,
  • an aliphatic alcohol bearing an aromatic group having from 7 to about 20 carbon atoms such as, for example, benzyl alcohol, phenethyl alcohol, phenylpropyl alcohol, phenyloctadecyl alcohol and naphthyl decyl alcohol.
  • polyols in particular polyoxyethylene glycols such as, for example, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol and glycerol.
  • the aliphatic or cycloaliphatic alcohols preferably primary or secondary aliphatic alcohols having 1 to 4 carbon atoms, are preferably used in the process of the invention.
  • a variant of the process of the invention consists in using a terpene alcohol and more particularly a terpene alcohol of formula (Ia):
  • - T represents the remainder of a terpene alcohol having a number of carbon atoms multiple of 5.
  • pene is intended to mean oligomers derived from isoprene.
  • the alcohol used has the general formula (Ia) in which the residue T represents a hydrocarbon group having from 5 to 40 carbon atoms and more particularly a linear or branched, saturated or unsaturated aliphatic group; a cycloaliphatic, saturated, unsaturated or aromatic, monocyclic or polycyclic group, comprising rings having from 3 to 8 carbon atoms.
  • a cycloaliphatic, monocyclic, saturated or unsaturated terpene alcohol, or aromatic a cycloaliphatic, monocyclic, saturated or unsaturated terpene alcohol, or aromatic
  • a polycyclic cycloaliphatic terpene alcohol comprising at least two carbocycles, saturated and / or unsaturated.
  • the number of carbon atoms varies between 5 and 40 carbon atoms.
  • residue T there may be mentioned groups comprising 8 carbon atoms, saturated or having a double bond, and bearing two methyl groups, preferably in position 3 and 7.
  • the number of carbon atoms in the ring can vary widely from 3 to 8 carbon atoms, but is preferably 5 or 6 carbon atoms.
  • the carbocycle may be saturated or comprising 1 or 2 unsaturations in the ring, preferably 1 to 2 double bonds which are most often in position ⁇ of the oxygen atom.
  • the aromatic ring is usually a benzene ring.
  • the compound may also be polycyclic, preferably bicyclic which means that at least two rings have two carbon atoms in common.
  • the number of carbon atoms in each ring varies between 3 and 6: the total number of carbon atoms is preferably equal to 7.
  • substituents are one or more alkyl groups, preferably three methyl groups, a methylene group (corresponding to an exocyclic bond), an alkenyl group, preferably an isopropenyl group.
  • terpenic alcohols examples include:
  • aromatic cycloaliphatic terpene alcohols such as:
  • the preferred alcohols are as follows:
  • Carbonyl compound May intervene in the process of the invention, as substrates, an aldehyde or a ketone (or dione) corresponding to one of the general formulas:
  • R 3 , R 4 and R 5 which may be identical or different, represent a hydrocarbon group comprising from 1 to 40 carbon atoms, which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a sequence of the aforementioned groups,
  • the groups R 4 and R 5 may be bonded together to form a ring comprising 5 or 6 atoms,
  • the groups R 4 and R 5 do not comprise any hydrogen atoms on the carbon atom in position ⁇ with respect to the carbonyl group.
  • R 4 is identical to R 5 and asymmetric ketones or diones if R 4 is different from R 5 .
  • R 3 , R 4 and R 5 represent a hydrocarbon group having from 1 to 20 carbon atoms which may be a saturated or unsaturated, linear or branched acyclic aliphatic group; a saturated, unsaturated or aromatic, monocyclic or polycyclic carbocyclic or heterocyclic group; a saturated or unsaturated, linear or branched, aliphatic group carrying a cyclic substituent.
  • R 3 , R 4 and R 5 preferably represent a linear or branched saturated acyclic aliphatic group preferably having from 1 to 12 carbon atoms, and even more preferably from 1 to 4 carbon atoms.
  • the invention does not exclude the presence of unsaturation on the hydrocarbon chain such as one or more double bonds which may or may not be conjugated, or a triple bond.
  • the hydrocarbon chain may be optionally interrupted by a heteroatom (for example, oxygen or sulfur) or by a functional group to the extent that it does not react and there may be mentioned in particular a group such as in particular -CO-.
  • the hydrocarbon chain may optionally carry one or more substituents (for example, halogen, ester) insofar as they do not interfere with the ketone reaction.
  • the acyclic aliphatic group, saturated or unsaturated, linear or branched may optionally carry a cyclic substituent.
  • ring is meant a carbocyclic or heterocyclic ring, saturated, unsaturated or aromatic.
  • the acyclic aliphatic group may be linked to the ring by a valence bond, a heteroatom or a functional group such as oxy, carbonyl, carboxy, sulphonyl, etc.
  • cyclic substituents it is possible to envisage cycloaliphatic, aromatic or heterocyclic, in particular cycloaliphatic, substituents comprising 6 ring carbon atoms or benzenes, these cyclic substituents being themselves optionally carrying any substituent insofar as they do not do not interfere with the reactions involved in the process of the invention.
  • alkyl or alkoxy groups having 1 to 4 carbon atoms may be mentioned.
  • cycloalkylalkyl groups for example cyclohexylalkyl or aralkyl groups having 7 to 12 carbon atoms, in particular benzyl or phenylethyl, are more particularly targeted.
  • R 3 , R 4 and R 5 may also represent a saturated or unsaturated carbocyclic group preferably having 5 or 6 carbon atoms. carbon in the cycle; a heterocyclic group, saturated or unsaturated, in particular containing 5 or 6 atoms in the ring, including 1 or 2 heteroatoms such as nitrogen, sulfur and oxygen atoms; an aromatic or monocyclic aromatic carbocyclic or heterocyclic group, preferably phenyl, pyridyl, pyrazolyl, imidazolyl or polycyclic fused or unsubstituted, preferably naphthyl.
  • R 3 , R 4 and R 5 comprises a ring
  • this ring may also be substituted.
  • the nature of the substituent can be any as long as it does not interfere with the main reaction.
  • the number of substituents is generally at most 4 per cycle but most often equal to 1 or 2.
  • R 3 preferably represents a linear or branched alkyl group having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms or a phenyl group.
  • the groups R 4 and R 5 do not comprise hydrogen atoms on the carbon atom in position ⁇ with respect to the carbonyl group.
  • the carbon atoms in position ⁇ with respect to the carbonyl group are tertiary carbon atoms.
  • An example of a tertiary carbon atom may be represented by the formula (R 6 ) (R 7) (Re) C - in which R 6 , R 7 and R 8 represent, in particular, a halogen atom, preferably an atom fluorine; a linear or branched alkyl group having 1 to 6 carbon atoms; the groups R 6 , R 7 and R 8 can also form a ring, for example a phenyl group optionally included in a polycyclic structure, for example of the naphthalenic type.
  • the groups R 4 and R 5 may be bonded together to form a ring comprising 5 or 6 atoms: the carbon atoms located in the ⁇ position on either side of the carbonyl group [ formula (III)] or carbonyl groups [formula (IV)] being tertiary which means that they are either substituted (as mentioned above) or included in an unsaturated or aromatic ring having 5 or 6 atoms, preferably a benzene ring.
  • ketones that can be used in the process of the invention, there may be mentioned more particularly:
  • alcohols and carbonyl compounds used in the process of the invention are given below: 1-decanol, 1-decanol, isopropyl mandelate, anisaldehyde, terephthaldehyde , phenanthrene-9,10-dione.
  • Base Optionally intervenes in the process of the invention, a base whose function is to trap the leaving group which is a hydracid.
  • the characteristic of the base is that it has a pka at least greater than or equal to 4, preferably between 5 and 14, and more preferably between 7 and 11. "
  • the pKa is defined as the ionic dissociation constant of the acid pair. / base, when water is used as a solvent.
  • Another characteristic of the base is that it is preferable that it be soluble in an organic medium.
  • mineral bases such as carbonates, hydrogencarbonates, phosphates, hydrogen phosphates of alkali metals, preferably of sodium, of potassium, of cesium or of alkaline earth metals preferably calcium, barium or magnesium.
  • Organic bases such as tertiary amines and more particularly triethylamine, tri-n-propylamine, tri-n-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine and N, N-diethylcyclohexylamine are also suitable.
  • pyridine 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, N- [7-butylpiperidine, 1,2-dimethylpiperidine, N-methylpyrrolidine, 1,2-dimethylpyrrolidine.
  • triethylamine is preferably chosen.
  • the amount of base used expressed relative to the pyridinium salt is at least equal to the stoichiometric amount. More preferentially, it is such that the ratio between the number of moles of pyridinium salt and the number of moles of base preferably varies between 1 and 3 and even more preferably between 1, 5 and 2.
  • the fluoride is introduced into the medium in the form of salt (s).
  • salt such as hydrofluoric acid; salts such as, for example, potassium fluoride or ammonium fluoride.
  • quaternary ammonium fluorides preferably tetraalkylammonium fluorides, and more particularly tetrapropylammonium, tetrabutylammonium; tetraalkylammonium hydrogenodifluoride, preferably ammonium hydrogen difluoride.
  • TBAT tetrabutylammonium fluoride
  • the amount of fluoride source used expressed relative to the oxygenated substrate is at least equal to the stoichiometric amount. More preferably, it is such that the ratio of the number of moles of fluoride. and the number of moles of substrate (alcohol or ketone) preferably varies between 1 and 3 and even more preferably between 1, 5 and 2.
  • reaction is generally conducted in the presence of a reaction solvent.
  • a solvent is chosen which is inert under the reaction conditions.
  • solvents that are suitable for the present invention, mention may be made preferably of aprotic polar solvents such as dimethylsulfoxide, sulfolane or linear or cyclic carboxamides, such as ⁇ /, ⁇ -dimethylacetamide (DMAC), ⁇ /, ⁇ -diethylacetamide, dimethylformamide (DMF), diethylformamide; the alpha or aromatic nitriles, preferably acetonitrile, propionitrile, butanenitrile, isobutanenitrile, pentanenitrile, 2-methylglutaronitrile, adiponitrile, benzonitrile, tolunitrile, malonitrile, 1,4-benzonitrile.
  • aprotic polar solvents such as dimethylsulfoxide, sulfolane or linear or cyclic carboxamides, such as ⁇ /, ⁇ -dimethylacetamide (DMAC), ⁇ /, ⁇ -diethylace
  • less polar organic solvents suitable for the invention mention may in particular be made of halogenated or non-halogenated aliphatic, cycloaliphatic or aromatic hydrocarbons; ether-oxides. It is also possible to use aliphatic and cycloaliphatic hydrocarbons, more particularly paraffins, such as, in particular, hexane, heptane, octane, isooctane, nonane, decane, undecane, tetradecane and ether.
  • paraffins such as, in particular, hexane, heptane, octane, isooctane, nonane, decane, undecane, tetradecane and ether.
  • aromatic hydrocarbons such as, in particular, benzene, toluene, xylenes, ethylbenzene, diethylbenzenes, trimethylbenzenes, cumene, pseudocumene, petroleum fractions consisting of a mixture of alkylbenzenes, especially the Solvesso® type cuts.
  • perchlorinated hydrocarbons such as in particular tetrachlorethylene, hexachloroethane; partially chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2,2-tetrachloroethane, pentachloroethane, trichlorethylene, 1-chlorobutane, 1,2-dichlorobutane; monochlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene or mixtures of different chlorobenzenes.
  • perchlorinated hydrocarbons such as in particular tetrachlorethylene, hexachloroethane
  • partially chlorinated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane
  • Dichloromethane or chloroform is preferably chosen.
  • solvents examples include aliphatic, cycloaliphatic or aromatic ether-oxides and, more particularly, diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl tertiobutyl ether, dipentyl ether, diisopentyl ether, ethylene glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol dimethyl ether (or 1,5-dimethoxy-3-oxapentane), dioxane, tetrahydrofuran.
  • diethyl ether dipropyl ether, diisopropyl ether, dibutyl ether, methyl tertiobutyl ether, dipentyl ether, diisopentyl ether, ethylene glycol dimethyl ether (or 1,2-dimethoxyethane), diethylene glycol dimethyl ether (or 1,5-dimethoxy-3-oxapentane),
  • the amount of organic solvent used is chosen in a preferential manner such that the weight concentration of the starting substrate in the solvent is between 5 and 40%, preferably between 10 and 20%.
  • the reaction is generally carried out at a temperature of between 0 ° C. and 140 ° C., preferably between 80 ° C. and 100 ° C.
  • the fluorination reaction is generally carried out under atmospheric pressure, but preferably under a controlled atmosphere of inert gases. It is possible to establish an atmosphere of rare gases, preferably argon, but it is more economical to use nitrogen. A pressure slightly above or below atmospheric pressure may be suitable.
  • reaction is simple to implement.
  • the order of implementation of the reagents is not critical.
  • a preferred alternative is to charge the substrate, the solvent and the fluorinating agent and then the base and heat to the desired temperature.
  • the duration of the reaction is very variable. It can go from 1 to 24 hours and is preferably between 8 and 15 hours.
  • the fluorinated product is recovered by implementing the usual techniques of a person skilled in the art.
  • water is added to solubilize the salts in aqueous phase and an immiscible solvent, for example, dichloroethane, toluene or monochlorobenzene to recover the fluorinated compound obtained in the organic phase.
  • an immiscible solvent for example, dichloroethane, toluene or monochlorobenzene to recover the fluorinated compound obtained in the organic phase.
  • the fluorinated compound is recovered by conventional separation methods, for example by distillation or by crystallization in a suitable solvent, in particular an ether such as isopropyl ether or an alcohol such as methanol, ethanol or isopropanol.
  • a suitable solvent in particular an ether such as isopropyl ether or an alcohol such as methanol, ethanol or isopropanol.
  • the fluorination reagents according to the invention comprising the units (F) or (Fi) can be prepared in a conventional manner. Reference can be made in particular to the work of P. H. Gross et al, [J. Org.
  • One way of accessing said reagents is to perform an alkylation reaction of a 2-halopyridine which may be represented by the following formula:
  • X1 represents a fluorine, chlorine, bromine or iodine atom.
  • alkylating agents it is possible to use alkyl halides, preferably having a low carbon C 1 -C 4 condensation and preferably methyl iodide or bromide.
  • a sulphonic acid or carboxylic acid halide which may be represented by the following formulas: R 3 SO 3 X 2 (VI) and R b CO 2 X 2 (VII) in which R a and R b have the meaning given above and X 2 represents a halogen atom, chlorine, bromine or iodine.
  • the 2-halopyridine is reacted with an alkylating agent as mentioned above.
  • the alkylating agent is in slight excess, the molar ratio between the alkylating agent and 2-halopyridine advantageously varies between 1, 1 and 1, 2.
  • the temperature of the alkylation reaction is generally between 0 ° C. and 80 ° C., preferably between 20 ° C. and 50 ° C.
  • the reaction is conducted in the presence of an inert organic solvent under the reaction conditions.
  • solvents that may be mentioned include aliphatic or aromatic hydrocarbons, halogenated or otherwise, or nitriles.
  • Dichloromethane, chlorobenzene and toluene are preferred.
  • the precipitate is recovered by conventional solid / liquid separation techniques, preferably by filtration.
  • the precipitate may be washed, preferably with the aid of the organic solvent used in the reaction, and the solvent is removed by evaporation.
  • 1-cycloalkyl-2-fluoropyridinium from a reagent comprising another halogen, for example a 1-alkyl- or 1-cycloalkyl-2-chloropyridinium by performing the exchange of chlorine with a fluorine atom, using an alkali metal fluoride, preferably sodium or potassium.
  • the starting reagent is suspended in an organic solvent such as, for example, acetonitrile, and then the alkali metal fluoride is added in powder form in an amount ranging from stoichiometric to excess amount, for example %.
  • the alkali metal chloride formed is separated by conventional solid / liquid separation techniques, preferably by filtration.
  • the fluorinated reagent is then recovered.
  • Examples of embodiments of the invention given below are given by way of non-limiting illustration.
  • the yield defined in the examples corresponds to the ratio between the number of moles of product formed and the number of moles of substrate involved.
  • Examples A to K relate to the preparation of the fluorination reagent and the following examples, their use for preparing monofluorinated compounds (Examples 1 to 5) or di- or polyfluorinated compounds (Examples 6 to 8).
  • Hot toluene (15 ml) is then added before the mixture cools and crystallizes. The whole is left stirring for 10 minutes and the mixture is allowed to rise to room temperature.
  • the crystallized bottom phase is recovered.
  • the product is in the form of a white solid and is obtained with a yield of 88% (5.4 g).
  • the NMR characteristics are as follows:
  • the precipitate is then filtered on B ⁇ chner.
  • the traces of solvent are removed by evaporation under reduced pressure of about 20 mm of mercury.
  • the product is in the form of a white solid and is obtained with a yield of 99%.
  • the mixture is refluxed with magnetic stirring overnight. During the reaction appears a second yellow phase which crystallizes at room temperature.
  • the precipitate is then filtered on B ⁇ chner.
  • Example D Preparation of 2-fluoro-N-methylpyridinium tosylate from 2-chloro N-methylpyridinium tosylate
  • the potassium chloride is filtered on B ⁇ chner after cooling the solution.
  • the filtrate is concentrated under reduced pressure of approximately 20 mm of mercury and then redissolved in 100 ml of dichloromethane.
  • the mixture is filtered again which eliminates excess potassium fluoride.
  • the filtrate is again concentrated under reduced pressure of about 20 mm Hg.
  • the recovered solid is then triturated in methyl-t-butyl ether for one hour and then the mixture is filtered.
  • the product is in the form of a yellow solid and is obtained with a yield of 90%.
  • the mixture is stirred magnetically at room temperature for one hour.
  • the precipitate is then filtered on B ⁇ chner.
  • the traces of solvent are removed by evaporation under reduced pressure of about 20 mm of mercury.
  • the product is in the form of a white solid and is obtained with a yield of 99%.
  • 2-chloro-N-methylpyridinium triflate (2.7 g, 10 mmol) is dissolved in 15 ml of acetonitrile.
  • potassium fluoride "spray dried" (0.64 g, 11 mmol, 1.1 eq) previously dried under reduced pressure of about 20 mm of mercury when hot.
  • the potassium chloride is filtered on B ⁇ chner after cooling the solution.
  • the filtrate is concentrated under reduced pressure of approximately 20 mm of mercury and then redissolved in 100 ml of dichloromethane.
  • the solid is again filtered and dried under reduced pressure of 20 mm Hg.
  • the product is in the form of a white solid and is obtained with a yield of 99%.
  • 2-fluoro-N-methylpyridinium triflate (10 mmol) is dissolved in a minimum of acetonitrile (5 ml).
  • the solid is then dried under reduced pressure of about 20 mm Hg.
  • the whole is left stirring for 8 hours at room temperature.
  • the precipitated white solid is then filtered and washed with toluene. It is then dried under reduced pressure of approximately 20 mm of mercury.
  • the quinolinium salt is obtained with a yield of 95%.
  • the NMR characteristics are as follows:
  • the residue is purified by chromatography on a silica column (eluent: petroleum ether).
  • the mixture is refluxed with chloroform for 5 hours. It is then hydrolysed with 2 ml of water and neutralized with a saturated aqueous solution of sodium monohydrogen carbonate.
  • the extraction is carried out with 4 times 5 ml of petroleum ether.
  • the tetrabutylammonium hydrogen difluoride (280 mg, 1 mmol) is dried under reduced pressure of 1 mm of mercury at 100 ° C. for one hour. After cooling, triethylamine (0.07 ml, 1 mmol) is added.
  • the mixture is refluxed with chloroform overnight. It is then hydrolysed with 2 ml of water and neutralized with a saturated aqueous solution of sodium monohydrogen carbonate. The extraction is carried out with 4 times 5 ml of ethyl ether.
  • the mixture is refluxed with chloroform for three hours. It is then hydrolyzed with 5 ml of water. The extraction is carried out with 3 times 5 ml of ethyl ether. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of approximately 20 mm of mercury.
  • the tetrabutylammonium hydrogen difluoride (280 mg, 1 mmol) is dried under reduced pressure of 1 mm of mercury at 100 ° C. for 12 hours.
  • tetrabutylammonium hydrogenodifluoride monohydrate (3 g, 10 mmol, 3.3 eq).
  • the latter is heated at 100 ° C. in an oil bath under reduced pressure of 1 mm of mercury for one hour.
  • 1-methyl-2-fluoropyridinium tosylate (2.8 g, 10 mmol, 3.3 eq) is introduced followed by anisaldehyde (408 mg, 3 mmol) and triethylamine (1, 4 ml, 10 mmol, 3.3 eq).
  • the organic phase is dried over magnesium sulfate. After filtration, the solvent is evaporated under reduced pressure of approximately 20 mm of mercury.
  • 1-Difluoromethyl-4-methoxybenzene is in the form of a slightly yellow oil (278 mg, 1.76 mmol, 59%).
  • the recovered anisaldehyde is a white solid (100 mg, 0.73 mmol, 24%).
  • the NMR characteristics are as follows:
  • the whole is heated at 80 ° C. for 6 hours.
  • the extraction is carried out with 3 times 5 ml of ethyl ether.
  • the organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure of approximately 20 mm of mercury.
  • the residue is purified by chromatography on a silica column (eluent: gradient of dichloromethane in petroleum ether).
  • the tetrabutylammonium hydrogen difluoride (2.8 g, 10 mmol) is dried under reduced pressure of 1 mm Hg at 100 ° C. for 1 hour.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)
EP06778821A 2005-07-19 2006-07-07 Verfahren zur herstellung von mono- oder difluorierten kohlenwasserstoffverbindungen Withdrawn EP1904425A1 (de)

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FR0507651A FR2888845B1 (fr) 2005-07-19 2005-07-19 Procede de preparation de composes hydrocarbones mono- ou difluores
PCT/FR2006/001648 WO2007010111A1 (fr) 2005-07-19 2006-07-07 Procede de preparation de composes hydrocarbones mono-ou difluores

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JP5415789B2 (ja) * 2009-03-09 2014-02-12 学校法人 名城大学 フルオラス縮合剤、フッ素成分の分離方法
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BR112018072548B1 (pt) * 2016-05-02 2022-05-17 Dow Global Technologies Llc Método para fluoração aromática
CN106083539B (zh) * 2016-06-15 2018-10-23 郑州泰基鸿诺医药股份有限公司 一种单氟甲氧基或单氟氘代甲氧基类化合物的合成方法
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FR2888845A1 (fr) 2007-01-26
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CN101203472A (zh) 2008-06-18
US20090234151A1 (en) 2009-09-17

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