WO2012163896A1

WO2012163896A1 - Method for the preparation of a fluoro-methylpyrazole compound in carboxylic acid or derivative form

Info

Publication number: WO2012163896A1
Application number: PCT/EP2012/060004
Authority: WO
Inventors: Olivier Buisine
Original assignee: Rhodia Operations
Priority date: 2011-06-01
Filing date: 2012-05-29
Publication date: 2012-12-06
Also published as: FR2975992B1; FR2975992A1

Abstract

The invention relates to a method for the preparation of a fluoro-methylpyrazole compound in the carboxylic acid form or derivative forms thereof, comprising the reaction, in an aqueous medium or anhydrous medium, of a salt providing a fluoride anion and a halogeno-methylpyrazole compound containing at least one halogen atom different from the fluorine atom.

Description

PROCESS FOR PREPARING A COMPOUND

FLUOROMETHYLPYRAZOLE IN CARBOXYLIC ACID FORM OR

DERIVED

The present invention relates to a process for preparing a fluoromethylpyrazole compound whose pyrazole ring is substituted in the 4-position by a carboxylic acid function or a function derived from said acid. More specifically, the invention relates to a process for preparing said compounds according to a halogen exchange reaction.

The manufacture of difluoromethylpyrazole compounds by the action of methylhydrazine on a type 2 derivative ethyloxymethylene-4,4-difluoro-3-oxobutyrate ethyl has already been described in US Patent 5,093,347. The direct fluorination of ethyl 3-dichloromethyl-1-methyl-4-pyrazolecarboxylate by the HF-Et ₃ N complex under microwave irradiation has also been described in Tetrahedron Letters (2009), 50 (26), 3665-3668. . The production of these fluoromethylpyrazole compounds according to the known methods has the particular disadvantage of requiring conditions which are not suitable for use in an industrial environment.

The fluoromethylpyrazole compounds whose pyrazole ring is substituted at the 4-position by a carboxylic acid function or a function derived from said acid are of great interest in pharmaceutical and agrochemical applications. Also to overcome the aforementioned drawbacks and facilitate the production of this class of fluoromethylpyrazole compounds, the present invention proposes the implementation of an innovative alternative method.

The object of the present invention is a process for preparing a fluoromethylpyrazole compound of formula (I)

(I) in which R 'represents a hydroxyl group OH, a group OR where R is chosen from an alkyl moiety and a cycloalkyl moiety, an OMe group wherein Me is a metal cation, an amide group or a halogen atom Z,

Q represents a hydrogen atom, a halogen atom or an OH hydroxyl group,

P represents an alkyl group or an aryl group,

X represents a chlorine and / or bromine atom

with 0≤n <3 and 0≤m <3 with n + m <3, n and m being integers,

said process comprising the reaction, in anhydrous medium in the presence of a polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, sulfolane, dimethylimidazolidinone, formamide and ionic liquids, of at least one salt providing at least one fluoride anion and at least one halomethylpyrazole compound of formula (II) containing at least one halogen atom X selected from chlorine, bromine and the mixture of chlorine and bromine

(II) where R ', Q, P and X have the same definition as that given for the formula (I), with 0≤ n <3 and 1 ≤ i≤ 3 with 0 <n + i≤ 3 and i is strictly greater than m.

According to the process according to the invention, the halomethylpyrazole compound of formula (II) containing at least one halogen atom X different from the fluorine atom is subjected to an exchange reaction between the said (s) halogen atoms X and fluorine introduced by a fluoride anion. According to the invention, said halogen atom X is chosen from chlorine, bromine and the mixture of chlorine and bromine.

The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, may be in acid form such that the radical R 'present in the COR' function carried by the heterocycle in position 4 is a hydroxyl group (R '= OH). The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, may be in esterified form such that the radical R 'present in the COR' function carried by the heterocycle in the 4-position, is a group OR wherein R is selected from an alkyl moiety and a cycloalkyl moiety. In esterified form, the hydrogen atom present in the acid form of the compound of formula (II) is replaced by an alkyl moiety or a cycloalkyl moiety. In the context of the invention, the term "alkyl", a linear or branched hydrocarbon chain having 1 to 15 carbon atoms and preferably 1 or 2 to 10 carbon atoms. Preferably, said alkyl moiety R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl. More preferably, said alkyl moiety R is selected from methyl, ethyl, propyl and butyl and even more preferably, said alkyl moiety R is selected from methyl and ethyl. Cycloalkyl means a cyclic hydrocarbon group, preferably monocyclic, comprising from 3 to 8 carbon atoms. Said cycloalkyl moiety R is preferably cyclopentyl or cyclohexyl, most preferably cyclohexyl. According to the invention, one or more hydrogen atoms present in the fragment R selected from said alkyl moiety and said cycloalkyl moiety as defined above can be replaced by a substituent ( for example a halogen, especially a fluorine atom), insofar as it does not interfere with obtaining the desired compound of formula (I). According to this embodiment, the fragment R may represent a fluorinated or perfluorinated alkyl group comprising from 1 to 10 carbon atoms and from 1 to 21 fluorine atoms, preferably from 3 to 21 fluorine atoms.

The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, may also be in salified form such that the radical R 'present in the COR' function carried by the heterocycle in the 4-position, is an OMe group where Me is a metal cation. In salified form, the hydrogen atom present in the acid form of the compound of formula (II) is replaced by a metal cation. Said metal cation is preferably a cation of a mono- or divalent metal. There may be mentioned more particularly an alkali metal or alkaline earth metal cation. As more specific examples of salts, there may be mentioned alkali metal cations, preferably lithium, sodium, potassium or cesium; alkaline earth metal cations, preferably magnesium, calcium, barium. In the aforementioned list, the preferred metal cations are sodium or potassium cations.

The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, can also be in amide form such that the radical R 'present in the COR' function carried by the heterocycle in position 4 is preferably, a group -NH ₂ , -NHR ₁ or -NR 1 R 1 'where R 1 and R 1' are alkyl moieties having the same meaning as that given for the fragment R described above for the esterified form of the halomethyl pyrazole compound of formula (II) . Preferably, R1 and R1 'are chosen from methyl, ethyl, propyl and butyl.

The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, may also be in a form such that the radical R 'present in the COR' function carried by the heterocycle in position 4 is consisting of a halogen atom Z selected from chlorine, bromine and fluorine. According to the invention, the presence of said halogen Z atom does not interfere with obtaining the compound of formula (I) desired.

The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, has a substituent Q in position 5 on the heterocycle. Said substituent Q represents a hydrogen atom, a halogen atom or an OH hydroxyl group. Preferably, said substituent Q is a hydrogen atom, a fluorine atom or an OH hydroxyl group.

The halomethylpyrazole compound of formula (II), used as a reagent in the preparation process according to the invention, has a substituent P in connection with the nitrogen atom in position 1 on the heterocycle. Said substituent P represents an alkyl group or an aryl group. When P is an alkyl group, P is a hydrocarbon chain preferably having 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms. More particularly, P is a methyl group or an ethyl group. When P is an aryl group, P is preferably a phenyl -C6H _{5 group} . According to the process of the invention, the at least one halogen atom (s) present in the compound of formula (II) is (are) one or more chlorine atoms or one or more bromine atoms. again a mixture of chlorine and bromine atoms. In a preferred manner, all the halogen atoms X are chlorine atoms. The compound of formula (II) has from 1 to 3 halogen atoms (i = 1, 2 or 3). Advantageously, the compound of formula (II) is chosen such that i = 2 and n = 1 or i = 3 and n = 0. According to the method of the invention, the substituent CH _n XiF _(3- ni ₎ placed in position 3 on the heterocycle has up to 2 hydrogen atoms (n = 0, 1 or 2) and up to 2 fluorine atoms so that n + 1 is strictly positive. Advantageously, when i = 2 and n = 1 or i = 3 and n = 0, said substituent CH _n XiF ( _3- ni) is devoid of the presence of fluorine.

More preferably, the halomethylpyrazole compound of formula (II) is such that it is chosen from compounds for which

R '= OH; Q = H; P = CH ₃ ; X = Cl; n = 1; i = 2.

R '= OH; Q = H; P = CH ₃ ; X = Cl; n = 0; i = 3.

R '= OC ₂ H ₅ or R' = OCH ₃ ; Q = H; P = CH ₃ ; X = Cl; n = 1; i = 2.

R = OC2H5 or R '= OCH _3; Q = H; P = CH ₃ ; X = Cl; n = 0; i = 3.

R '= OMe with Me = Na or K; Q = H; P = CH ₃ ; X = Cl; n = 1; i = 2.

R '= OMe with Me = Na or K; Q = H; P = CH ₃ ; X = Cl; n = 0; In the process according to the invention, said halomethylpyrazole compound of formula (II) reacts with at least one salt providing a fluoride anion so that an exchange reaction between the chlorine atom (s) and / or bromine (X = Cl and / or Br) present in the compound of formula (II) and the fluorine atom (s) introduced by said fluoride anion is established to conduct in the production of the fluoromethylpyrazole compound of formula (I). According to the process of the invention, the chlorine and / or bromine atom (s), preferably the chlorine atom (s), present in the compound of formula (II) is are) exchanged with at least one fluorine atom such that the fluoromethylpyrazole compound of formula (I) contains more fluorine atoms than the compound of formula (II) (i> m). The nature of said salt providing at least said fluoride anion may be varied in nature. Advantageously, said salt is chosen from metal fluorides, onium fluorides and mixtures thereof. Said metal fluorides, advantageously employed as salts providing fluoride anions in the process according to the invention, are preferably fluorides in which the metal cations belong to groups IA, MA and MB of the periodic table of elements. As examples of suitable cations for carrying out the process of the invention, mention may be made more particularly of Group IA cations, lithium, sodium, potassium and cesium, among the cations of the MA group. , magnesium and calcium, and among the cations of the MB group, zinc. Among the above-mentioned salts, potassium fluoride and sodium fluoride are preferably chosen.

The invention does not exclude the use of double salts such as double fluorides of aluminum and sodium or potassium and sodium or potassium fluosilicates.

Said onium fluorides, advantageously employed as salts providing fluoride anions in the process according to the invention, are preferably chosen from ammonium fluorides, phosphonium fluorides, imidazolium fluorides and pyridinium fluorides, taken alone. or in mixture.

Ammonium fluorides and phosphonium fluorides are salts whose cation corresponds in particular to the following formula (III):

in which :

- W represents N or P,

- R ₂ , R 3, F¾, and R ₅ , identical or different represent:

. a linear or branched alkyl group having 1 to 16 carbon atoms and optionally substituted by one or more heteroatoms or phenyl, hydroxyl, halogen, nitro, alkoxy or alkoxycarbonyl groups, the alkoxy groups having 1 to 4 carbon atoms; a linear or branched alkenyl group having 2 to 12 carbon atoms;

an aryl group having 6 to 10 carbon atoms, optionally substituted by one or more heteroatoms or alkyl groups having 1 to 4 carbon atoms, alkoxy, alkoxycarbonyl, alkoxy group having 1 to 4 carbon atoms, or halogen.

Ammonium fluorides and phosphonium fluorides, preferably used for carrying out the process according to the invention, have a cation which corresponds to formula (III) in which W is a nitrogen or phosphorus atom and R _2, R3, R4 and R _5, identical or different, are selected from an alkyl group, linear or branched, having 1 to 4 carbon atoms and benzyl.

By way of more specific examples, mention may be made of tetrabutylammonium, methyltri (n-butyl) ammonium, N-methyl-N, N, N-trioctylammonium, trimethylphenylphosphonium, tetrabutylphosphonium, methyltri (n-butyl) fluorides. ) phosphonium, methyltri (isobutyl) phosphonium, diisobutyl-n-octylmethylphosphonium. Tetrabutylammonium fluoride (R ₂ = R 3 = R ₄ = R 5 = butyl and W = N) and tetrabutylphosphonium fluoride (R ₂ = R 3 = R ₄ = R ₅ = butyl and W = P) are preferably chosen.

Imidazolium fluorides and pyridinium fluorides are salts providing fluoride anions and whose cation respectively corresponds to formula (IV) or formula (V) below:

(IV) (V) in which:

the group R ₆ represents an alkyl group having from 1 to 20 carbon atoms,

the group R ₇ represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms,

the group R ₈ represents an alkyl group having from 1 to 4 carbon atoms, the group Rg represents an alkyl group having from 1 to 6 carbon atoms.

Among the cations corresponding to formulas (IV) and (V), the cations 1-alkyl-2,3-dimethylimidazolium (R 6 = C 1 -C 20 alkyl, R 7 = R 5 = methyl), 1-alkyl-3-methylimidazolium (R 6 = C 1 -C 20 alkyl, R 7 = H, R 5 = methyl) and 1-alkylpyridinium (R ₉ = C 1 -C 6 alkyl) are preferred.

As more specific examples of imidazolium fluorides, mention may be made of 1-alkyl-2,3-dimethylimidazolium fluorides such as 1-ethyl-2,3-dimethylimidazolium fluoride, 1-butyl-2,3-dimethylimidazolium fluoride. 1-hexyl-2,3-dimethylimidazolium; 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 1-hexyl-2,3-dimethylimidazolium; 1-alkyl-3-methylimidazolium fluorides, such as 1-ethyl-3-methylimidazolium fluoride, 1-hexyl-3-methylimidazolium, 1-octyl-3-methylimidazolium fluoride, 1-decyl-3-methylimidazolium fluoride, 1-dodecyl-3-methylimidazolium, 1-tetradecyl-3-methylimidazolium, 1-hexadecyl-3-methylimidazolium, 1-octadecyl-3-methylimidazolium; 1-butyl-3-methylimidazolium hexafluorophosphate, 1-hexyl-3-methylimidazolium, 1-octyl-3-methylimidazolium; 1-butyl-3-methylimidazolium tetrafluoroborate, 1-hexyl-3-methylimidazolium. The preferred imidazolium fluorides are 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium tetrafluoroborate. As more specific examples of pyridinium fluorides, mention may be made of 1-alkylpyridinium salts such as 1-ethylpyridinium fluoride, 1-butylpyridinium fluoride, 1-hexylpyridinium fluoride; 1-butylpyridinium hexafluorophosphate, 1-hexylpyridinium; 1-butylpyridinium tetrafluoroborate, 1-hexylpyridinium.

The invention does not exclude the use of the halogenated precursors of said fluorides of ionium, chloride or bromide, the corresponding fluorides can be formed in situ, by reaction with a metal fluoride as defined above, preferably potassium fluoride. .

The process according to the invention is advantageously carried out using a mixture of the various salts defined above which provide a fluoride anion. In particular, it is advantageous to use a mixture of a metal fluoride, such as potassium fluoride, and an onium fluoride as defined above. In this case, the amount of onium fluoride may represent from 1 to 10 mol%, expressed relative to the halogenethylpyrazole compound of formula (II). According to the process according to the invention, the reaction of at least said salt providing a fluoride anion and at least said halomethylpyrazole compound of formula (II) containing at least one halogen atom X selected from chlorine, bromine and the mixture of chlorine and bromine is used in an anhydrous medium.

The reaction between said salt providing at least one fluoride anion and said compound of formula (II), called the exchange reaction, is carried out in the presence of a polar aprotic solvent which is chosen from DMF (dimethylformadide), DMSO (dimethylsulfoxide). ), sulfolane, DMI (dimethylimidazolidinone), formamide. Ionic liquids are also advantageous for use as a polar aprotic solvent. Said polar aprotic solvent contains a water content of less than 1% by weight, preferably less than 1000 ppm. It is very advantageously without water.

According to the process according to the invention, the amount of halomethylpyrazole compound of formula (II) employed in the anhydrous reaction medium comprising said salt and said compound of formula (II) is such that the mass concentration of said halomethylpyrazole compound is between 1 and 50 % by weight, preferably between 20 and 40% by weight, relative to the total weight of said polar aprotic solvent.

The reagents used, namely at least said salt providing at least one fluoride anion and at least said halomethylpyrazole compound of formula (II), are used in a proportion such that 1 to 20 molar equivalents of fluoride anions are (are) used. per halogen atom X, preferably 1 to 2 molar equivalents.

According to the process of the invention, the reaction between said salt providing at least one fluoride anion and said compound of formula (II), called the exchange reaction, is carried out at a temperature of between 150 and 400 ° C., preferably between 200 ° C and 400 ° C, even more preferably between 250 and 300 ° C.

Said exchange reaction is carried out under atmospheric pressure or under autogenous pressure of the reagents, preferably under autogenous pressure of the reactants.

The exchange reaction is generally carried out 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. The reagents can be introduced in any order according to different variants but some are preferred. In particular, a preferred embodiment consists in introducing the halomethylpyrazole compound of formula (II), pure or present in solution into said polar aprotic solvent, on a suspension of at least one salt bringing at least said fluoride anion into said solvent, said suspension having been previously heated to the selected temperature between 150 and 400 ° C. The heating of the reaction mixture is maintained for a time varying between 2 and 20 hours, preferably between 2 and 10 hours.

After maintaining the reaction medium, at the selected temperature, at the end of the reaction, the fluoromethylpyrazole compound of formula (I) is obtained, preferably in acid form, esterified or salified according to the form used of the compound of formula (II). Said fluoromethylpyrazole compound of formula (I) has a number of fluorine atoms, present in the CH _n XmF fragment (3 _-n -m), greater than that present in the CH _n moiety XiF ( _3- _n- ) carried by the halomethylpyrazole compound of formula (II).

The compound of formula (I) is recovered from the reaction mixture, according to all conventional techniques known to those skilled in the art, for example by liquid-liquid extraction or crystallization after filtration of salts (excess fluorides).

The process according to the invention is advantageously carried out in an apparatus capable of resisting corrosion of the anhydrous reaction mixture. For this purpose, materials are chosen for the part in contact with the corrosion-resistant reaction medium such as alloys based on molybdenum, chromium, cobalt, iron, copper, manganese, titanium, zirconium, aluminum, carbon and tungsten sold under HASTELLOY ^® brands or alloys of nickel, chromium, iron, manganese with added copper and / or molybdenum sold under the name INCONEL ^® and more particularly alloys HASTELLOY C 276 or INCONEL 600, 625 or 718. It is also possible to choose steels stainless steels, such as austenitic steels [Robert H. Perry et al., Perry's Chemical Engineers' Handbook, Sixth Edition (1984), pp. 23-44]. and more particularly 304, 304 L, 316 or 316 L stainless steels. A steel having a nickel content of at most 22% by weight, preferably between 6 and 20%, and more preferably between 8 and 20%, is used. and 14%. The 304 and 304 L steels have a nickel content ranging between 8 and 12% and the 316 and 316 L steels have a nickel content ranging between 10 and 14%. 316L steels are more particularly chosen. As other materials which may be suitable for being in contact with the anhydrous reaction medium, mention may also be made of graphite derivatives. The method of the invention can be implemented continuously or discontinuously.

An exemplary embodiment of the invention given for illustrative and non-limiting purposes is given below. In this example, the yield obtained, which corresponds to the ratio between the number of moles of the fluoromethylpyrazole compound in esterified form and the number of moles of the chloromethylpyrazole compound in esterified form, is defined.

Example 1

In a 100 mL autoclave equipped with a Rushton turbine, a suspension of anhydrous potassium fluoride (13.9 g, 0.24 mol, [H ₂ O] = 590 ppm) in sulfolane (57 g, 0.48 mol) is brought to a temperature of 250 ° C. Ethyl 3- (dichloromethyl) -1-methyl-β-pyrazole-4-carboxylate (14.22 g, 60 mmol) is added at this temperature for a period of 2 hours and agitation is maintained. for an additional 5 hours. The temperature is then brought back to ambient temperature and the reactor is decompressed. The reaction medium is diluted with water (m = 200 mL) and extracted with ethyl acetate (V = 200 mL). The organic phase is recovered and the extraction is repeated twice. The organic phases are then combined and concentrated by evaporation under vacuum (P = 300mbar). After evaporation, 5 g of an oil containing 78% by weight of ethyl 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylate are obtained. The yield of the fluorination reaction is 32%.

Claims

1. Process for preparing a fluoromethylpyrazole compound of formula (I)

(I) in which:

R 'represents a hydroxyl group OH, a group OR where R is chosen from an alkyl moiety and a cycloalkyl moiety, an OMe group wherein Me is a metal cation, an amide group or a halogen atom Z,

Q represents a hydrogen atom, a halogen atom or an OH hydroxyl group,

P represents an alkyl group or an aryl group,

X represents a chlorine and / or bromine atom

with 0≤n <3 and 0≤m <3 with n + m <3, n and m being integers

2. Preparation process according to claim 1 wherein said alkyl moiety R present in the group OR is selected from methyl, ethyl, propyl and butyl.

3. Preparation process according to claim 1 or claim 2 wherein said metal cation Me present in the OMe group is an alkali metal or alkaline earth metal cation.

4. Preparation process according to one of claims 1 to 3 wherein said substituent P is a methyl group or an ethyl group.

5. Preparation process according to one of claims 1 to 4 wherein all the halogen atoms X are chlorine atoms.

6. Preparation process according to one of claims 1 to 5 wherein said compound of formula (II) is chosen such that i = 2 and n = 1 or i = 3 and n = 0.

7. Preparation process according to claim 6 wherein said substituent CH _n XIE (3 _-n- _i) is devoid of the presence of fluorine.

8. Preparation process according to one of claims 1 to 7 wherein said salt is selected from metal fluorides, onium fluorides and mixtures thereof.

9. Preparation process according to one of claims 1 to 8 wherein said salt is potassium fluoride or sodium fluoride.

10. Preparation process according to claim 8 wherein said onium fluorides are selected from ammonium fluorides, phosphonium fluorides, imidazolium fluorides and pyridinium fluorides, alone or in admixture.

1 1. Preparation process according to one of claims 1 to 10 wherein said reaction is conducted in an anhydrous medium in the presence of a polar aprotic solvent containing a water content of less than 1% by weight.

12. Preparation process according to one of claims 1 to 1 1 wherein the amount of halomethylpyrazole compound of formula (II) engaged in the anhydrous reaction medium comprising said salt and said compound of formula (II) is such that the mass concentration of said halomethylpyrazole compound is between 1 and 50% by weight.

13. Preparation process according to one of claims 1 to 12 wherein said salt providing at least one fluoride anion and said halomethylpyrazole compound of formula (II) are used in a proportion such that 1 to 20 molar equivalents of fluoride anions is (are) implemented by halogen atom X.

14. Preparation process according to one of claims 1 to 13 such that said reaction is carried out at a temperature between 150 and 400 ° C.