PROCESSES FOR THE PREPARATION OF PYRAZOLES

The present invention relates to novel processes for the production of 3-halomethyl-1-methyl-1H-pyrazoles, which are useful as intermediates in the production of fungicides.

3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid and 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid are valuable intermediates in the preparation of pyrazolyl carboxanilide fungicides, as described, for example, in WO 03/070705 and WO 03/074491.

The aim of the present invention is therefore to provide novel processes for the production of key intermediates in the synthesis of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid and 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid that makes it possible to prepare said acids with high regioselectivity (in respect to the two nitrogen atoms of the pyrazole ring), in high yields and good quality in an economically advantageous and easily handled way.

SUMMARY OF THE INVENTION

According to a first aspect, the invention relates to a process for the preparation of a compound of formula (I)

wherein Hal and Hal′ are independently Cl or F, and R¹is H, Cl or F, comprising the steps of

i) reacting a compound of formula (II)

wherein Hal, Hal′ and R¹are as defined above, and LG is a leaving group, with an enol ether of formula (III)

wherein R²is C1-6 alkyl,

to give a compound of formula (IV)

wherein Hal, Hal′ and R¹are as defined above, and

ii) reacting the compound of formula (IV) with methylhydrazine to give a pyrazole of formula (I).

According to a second aspect, the invention provides a process for the preparation of a compound of formula (VI)

wherein Hal, Hal′ and R¹are as defined above and R³is selected from H and C1-6 alkyl comprising reacting a hydrazide of formula (XXIII)

wherein Hal, Hal′ and R¹are as defined above,

with an alkyl propargylate of formula (XXIV)

wherein R3 is as defined above.

According to a third aspect, the invention provides a process for the preparation of a compound of formula (VI)

wherein Hal, Hal′ and R¹are as defined above and R³is selected from H and C1-6 alkyl comprising reacting a compound of formula (XXV)

wherein Hal, Hal′, R¹and R³are as defined above with chloramine.

According to a fourth aspect, the invention relates to a compound of formula X

According to a fifth aspect, the invention relates to a compound of formula VIII

According to a sixth aspect, the invention relates to a compound of formula VII

DETAILED DESCRIPTION OF THE INVENTION

In step i) of the reaction according to a first embodiment of the invention, a compound of formula (II) reacts with an enol ether of formula (III) to give a 4-alkoxy-3-en-2-one of formula (IV) (Scheme 1)

As used herein, the term “leaving group” refers to a moiety that can be displaced by enol ether (III) to form a carbon-carbon bond present in compound (IV). Preferred leaving groups are halogens. A more preferred leaving group is chlorine.

Preferably, R²is ethyl.

The reaction of compound (II) with the enol ether (III) may take place in a suitable solvent. Alternatively, and preferably, the reaction takes place in the absence of a solvent.

Preferred solvents are toluene, hexane, dichloromethane and diethylether.

Preferably, the reaction is conducted under an inert atmosphere. More preferably, the reaction is conducted under a nitrogen atmosphere. Preferably, the reaction proceeds with purge to help remove volatile co-products.

In one embodiment, the reaction takes place in the presence of a base. Preferred bases are pyridine, alkyl pyridines or trialkylamines. Preferably, however, the reaction occurs in the absence of base.

Preferably, the enol ether (III) is present in excess relative to the compound (II). More preferably, the enol ether is present in an amount of between 1.1 and 10 equivalents relative to the amount of compound (II) on a molar basis. More preferably, the enol ether is present in an amount of between 1.2 and 5 equivalents relative to the amount of compound (II) on a molar basis. More preferably, the enol ether is present in an amount of between 1.5 and 2.5 equivalents relative to the amount of compound (II) on a molar basis. More preferably, the enol ether is present in an amount of about 2 equivalents relative to the amount of compound (II) on a molar basis.

Preferably, the enol ether (III) is added to the compound (II). More preferably, the enol ether (III) is added to the compound (II) over at least 1 hour. More preferably, the enol ether (III) is added to the compound (II) over at least 4 hours. More preferably, the enol ether (III) is added to the compound (II) over about 8 hours.

Preferably, the reaction is cooled during the addition of the enol ether (III) to the compound (II). Preferably, the reaction is cooled to between −20 and −40° C. during the addition of the enol ether (III) to the compound (II).

Subsequent to the addition of the enol ether (III) to the compound (II), the reaction is allowed to continue. The skilled person will be aware that it may be advantageous to monitor the course of the reaction. Suitable techniques are set out in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999, and include for example thin layer chromatography, gas chromatography, and high performance liquid chromatography (HPLC).

Preferably, the reaction is allowed to continue for at least 1 hour. More preferably, the reaction is allowed to continue for at least 6 hours. More preferably, the reaction is allowed to continue for at least 8 hours.

The skilled person will be aware that work up of the reaction mixture may be necessary or desirable to isolate the 4-alkoxy-3-en-2-one of formula (IV), if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.

The skilled person will also be aware of purification techniques suitable for purifying the 4-alkoxy-3-en-2-one of formula (IV). Suitable techniques include recrystallization, distillation, and chromatography.

In some embodiments of the invention, however, purification of (IV) is unnecessary, and the crude (IV) may be used directly in the next step.

In step ii) of the reaction according to a first embodiment of the invention, a 4-alkoxy-3-en-2-one of formula (IV) reacts with methyl hydrazine to give a 3-halomethyl-1-methyl-1H-pyrazole (I) (Scheme 2).

The reaction of compound (IV) with methyl hydrazine preferably takes place in a suitable solvent. Alternatively the reaction takes place in the absence of a solvent.

Preferred solvents are xylene, toluene, mesitylene, tert-butyl benzene, chlorobenzene, 1,2-dichlorobenzene, tetrahydrofuran, diethyl ether and hexane. A more preferred solvent is tetrahydrofuran.

Preferably, methyl hydrazine is used in an amount of 0.7 to 1.3 equivalents relative to the amount of 4-alkoxy-3-en-2-one of formula (IV).

Preferably, the methyl hydrazine is added to the 4-alkoxy-3-en-2-one of formula (IV). Preferably, both the methyl hydrazine and the 4-alkoxy-3-en-2-one of formula (IV) are both dissolved in solvent. Addition preferably takes place over a period of between 5 minutes and 10 hours, more preferably over about 5 hours.

The reaction is preferably held at between 0 to 50° C., more preferably at between 35 to 45° C.

The skilled person will be aware that it may be advantageous to monitor the course of the reaction. Suitable techniques are set out in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999, and include for example thin layer chromatography, gas chromatography, and high performance liquid chromatography (HPLC).

The skilled person will be aware that work up of the reaction mixture may be necessary or desirable to isolate the pyrazole (I), if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.

The skilled person will also be aware of purification techniques suitable for purifying the pyrazole (I). Suitable techniques include recrystallization, distillation, and chromatography.

In some embodiments of the invention, however, purification of (I) is unnecessary, and the crude (I) may be used directly in the next step.

Halogenation

According to one embodiment, pyrazole (I) is subjected to a halogenation step to convert it to 4-halopyrazole of formula (V) (Scheme 3)

wherein X is a halogen.

Many suitable reaction conditions exist for the halogenation of aromatic compounds. Suitable methods are disclosed for example in Advanced Organic Chemistry, J. March, John Wiley and Sons, 1992, pages 531 to 534.

Preferably, the halogenation reaction is conducted in a solvent. A preferred solvent is carbon tetrachloride.

Preferably, X is Br. In this embodiment, a preferred halogenating agents are elemental bromine (Br₂), N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin. More preferably, the halogenating agent is Br₂in the presence of an iron compound, preferably iron powder.

Preferably, the halogentating agent is used in excess relative to pyrazole (I). More preferably, the halogentating agent is used in amount of 1.5 to 5 equivalents relative to pyrazole (I) on a molar basis.

Preferably, the reaction is allowed to continue for at least 1 hour. More preferably, the reaction is allowed to continue for from 1 to 48 hours. More preferably, the reaction is allowed to continue for from 1 to 5 hours.

The skilled person will be aware that work up of the reaction mixture may be necessary or desirable to isolate the 4-halopyrazole (V), if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.

The skilled person will also be aware of purification techniques suitable for purifying the 4-halopyrazole (V). Suitable techniques include recrystallization, distillation, and chromatography.

In some embodiments of the invention, however, purification of (V) is unnecessary, and the crude (V) may be used directly in the next step.

Carbonylation

According to one embodiment, 4-halopyrazole (V) is subjected to a carbonylation step to convert it to 4-carboxypyrazole of formula (VI) (Scheme 4)

wherein R³is H or C1-6 alkyl.

Preferably, R³is Ethyl or H. Reagent R³OH is preferably present in excess relative to 4-halopyrazole (V), preferably in an amount of from 100 to 150 equivalents relative to the amount of (V) on a molar basis.

Carbon monoxide is preferably used in excess relative to the amount of (V).

Preferably, the reaction takes place in the presence of a palladium catalyst. The palladium catalyst is preferably a palladium (II) or palladium (0) catalyst. Preferred catalysts are tris(triphenylphosphine) palladium (II) chloride, bis(triphenylphosphine) palladium (II) chloride, and tetrakis(triphenylphosphine)palladium(0). A preferred catalyst is tris(triphenylphosphine) palladium (II) chloride. Preferably, the palladium catalyst is used in an amount of between 0.01 and 0.5 equivalents relative to the amount of 4-halopyrazole (V), more preferably between 0.1 and 0.3 equivalents.

Preferably, additional triphenylphosphine is added to the reaction, preferably in an amount of 0.5 to 0.7 equivalents.

Preferably, the reaction is conducted at a temperature of from 50 to 200° C., more preferably at a temperature of from 100 to 150° C.

The reaction is preferably carried out in the presence of a base. Preferred bases are nitrogen-containing organic bases, preferably tertiary amines, more preferably trialkylamines, preferably trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine. Alternative preferred bases are N,N-dimethylaniline or N-methylmorpholine, piperidine, pyrrolidine, alkali metal or alkaline earth metal alcoholates, preferably lithium, sodium or potassium alcoholates, preferably methanolates, ethanolates or butanolates, or inorganic bases, preferably hydroxides, more preferably NaOH or KOH, or hydrides, preferably NaH.

Very preferred bases to which preference is given are tertiary amines, preferably trialkylamines, more preferably trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine. Triethylamine is very highly preferred.

Suitable amounts of base for that reaction are, for example, from 1 to 10 equivalents, especially from 4 to 6 equivalents.

The reaction time is generally from 1 to 48 hours, preferably from 1 to 36 hours, more preferably 1 to 18 hours.

The reaction according to the invention is carried out typically at elevated pressure, preferably 1 to 20 bar, more preferably 10 to 15 bar.

The skilled person will be aware that work up of the reaction mixture may be necessary or desirable to isolate the 4-carboxypyrazole (VI), if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.

The skilled person will also be aware of purification techniques suitable for purifying the 4-carboxypyrazole (VI). Suitable techniques include recrystallization, distillation, and chromatography.

In some embodiments of the invention, however, purification of (VI) is unnecessary, and the crude (VI) may be used directly in the next step.

Hydrolysis

In embodiments of the invention wherein R³is other than hydrogen in 4-carboxypyrazole (VI), an optional further step comprises hydrolyzing the group R³to a compound (VI) wherein R³is hydrogen, or a salt form thereof (Scheme 5).

wherein R³is C1-6 alkyl

The skilled person will be aware of many suitable methods for the hydrolysis of esters to carboxylic acids. Some exemplary conditions are detailed in Advanced Organic Chemistry, J. March, John Wiley and Sons, 1992, pages 378 to 383.

Hydrolysis can be effected under either acid or basic conditions. If basic conditions are employed, generally a salt form of 4-carboxypyrazole (VI) is obtained. A further step of acidification to convert the salt to the free acid may be employed.

Preferred bases for the hydrolysis reaction are metal hydroxides and metal carbonates. More preferred bases are alkali metal hydroxides. Still more preferred are sodium, potassium and lithium hydroxide. Most preferred is sodium hydroxide.

Preferably, the base is used in excess relative to 4-carboxypyrazole (VI). More preferably, between 1 and 5 equivalents of base are used. Still more preferably, between 1 and 3 equivalents of base are used.

Suitably, water is present in excess. Preferably, a co-solvent is present. A preferred co-solvent is ethanol.

The hydrolysis preferably takes place at between 0 and 200° C., more preferably at between 50 and 150° C.

After the hydrolysis reaction is complete, the free acid (VI) may be liberated by treatment with acid. Preferred acids are mineral acids, preferably hydrochloric or sulphuric acid. Most preferred is hydrochloric acid.

If hydrolysis is effected under acid conditions, mineral acids or organic acids may be used. Preferred are mineral acids. More preferred are hydrochloric and sulphuric acid. Most preferred is hydrochloric acid.

Preferably, at least 0.01 equivalents of acid relative to the amount of (VI) on a molar basis are employed, more preferably between 0.01 and 5 equivalents, still more preferably 1 to 5 equivalents.

Preferably, acid hydrolysis occurs at a temperature of between 40 and 100° C.

The skilled person will also be aware of purification techniques suitable for purifying the 4-carboxypyrazole (VI). Suitable techniques include recrystallization, distillation, and chromatography.

Halogen Exchange.

In one embodiment of the invention, the reaction sequence includes a halogen exchange step.

The term “halogen exchange”, as used herein, refers to a reaction wherein halogen atoms of one element are exchanged for halogen atoms of a second, different element. Preferably, chlorine atoms are exchanged for fluorine atoms.

Halogen exchange may be conducted at any suitable step of the reaction sequence.

In a preferred embodiment, halogen exchange is effected on 3-dichloromethyl-1-methyl-1H-pyrazole (VII) to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbaldehyde (VIII) (Scheme 6).

In an alternative embodiment, halogen exchange is effected on 4-bromo-3-dichloromethyl-1-methyl-1H-pyrazole (IX) to give 4-bromo-3-fluoromethyl-1-methyl-1H -pyrazole (X) (Scheme 7).

In an alternative embodiment, halogen exchange is effected on 3-dichloromethyl-1-methyl-1H-pyrazole-4-carboxylate (XI) or a salt form thereof to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate (XII) (Scheme 8).

Halogen exchange may be conducted under a variety of conditions. Preferably, halogen exchange is conducted in the presence of a source of F⁻ ions. Preferred reagents are AgF, KF, HgF₂, Bu₄N⁺ HF²⁻, BrF₃, Et₃N.2HF, Et₃N.3HF and HF plus SbF₃. A very highly preferred reagent is Et₃N.3HF.

The halogen exchange reaction is optionally conducted in a solvent. Alternatively, and preferably, the reaction is conducted under solvent-free conditions.

Preferably, the reaction is held at between 0 and 250° C. More preferably, the reaction is held at between 50 and 200° C. More preferably, the reaction is held at between 125 and 175° C. Most preferably, the reaction is held at about 150° C.

Again, the skilled person will be aware of techniques for monitoring the course of the halogen exchange reaction in order to judge when it is complete. HPLC is particularly useful in this context.

The skilled person will be aware that work up of the reaction mixture may be necessary or desirable to isolate the product of the halogen exchange reaction, if isolation is intended. Suitable work up procedures are described for example in Experimental Organic Chemistry standard and microscale (2nd Edition), L. M. Harwood, C. J. Moody, and J. M. Percy, Blackwell Scientific, 1999.

The skilled person will also be aware of purification techniques suitable for purifying the reaction product. Suitable techniques include recrystallization, distillation, and chromatography.

Second Embodiment

In the second embodiment of the invention, hydrazide (XXIII) reacts with propargylate (XXIV) to give 4-carboxypyrazole (VI) (Scheme 9)

Preferably, the reaction takes place in a solvent. Dimethylformamide is preferred.

Preferably, the reaction occurs under acid catalysis. p-Toluene sulphonic acid is preferred.

4-carboxypyrazole (VI) may be hydrolysed to the free acid or a salt form thereof as outlined above.

Third Embodiment

In the third embodiment of the invention, enamine (XXV) reacts with chloramine to give 4-carboxypyrazole (VI) (Scheme 10)

Preferably, the enamine (XXV) is reacted with a base prior to reaction with chloramine. A preferred base is sodium hydride.

Preferably, the reaction takes place in a solvent. Preferred solvents are diethyl ether, tetrahydrofuran and mixtures thereof.

4-carboxypyrazole (VI) may be hydrolysed to the free acid or a salt form thereof as outlined above.

Preferred Embodiments

In a preferred embodiment, Hal, Hal′ and R¹are all fluorine.

In another preferred embodiment, Hal and Hal′ are fluorine and R¹is hydrogen.

In another preferred embodiment, Hal and Hal′ are both chlorine, and R¹is hydrogen.

In a preferred embodiment, the present invention relates to a process for the production of a compound of formula XIII

which comprises

b1) reacting a compound of formula XIV (dichloroacetyl chloride)

with a compound of formula III

wherein R₁is C₁-C₆alkyl, to form a compound of formula XV

wherein R₁is as defined above;

b2) converting that compound with methylhydrazine into a compound of formula VII (3-dichloromethyl-1-methyl-1H-pyrazole)

b3) fluorinating that compound with a fluorinating agent into a compound of formula VIII (3-difluoromethyl-1-methyl-1H-pyrazole)

b4) brominating that compound with a brominating agent into a compound of formula X (4-bromo-3-difluoromethyl-1-methyl-1H-pyrazole)

b5) converting that compound with carbon monoxide and a C₁-C₆alkanol in the presence of a palladium catalyst into a compound of formula XII

wherein R₂is C₁-C₆alkyl; and

b6) saponifying that compound leading to the formation of the compound of formula (XIII) by

b6.1) adding a hydroxide base or water in the presence of a base to form the anion of the compound of formula (XIII) and then adding an acid to form the compound of formula (XIII); or

b6.2) adding water in the presence of an acid to form the compound of formula (XIII).

Process Step b1):

In process step b1) single compounds of formula (III), such as compounds of formula (III), wherein R₁is ethyl, can be used or mixtures thereof. An example of such a mixture are compounds of formula (III), wherein in R₁is methyl, mixed with compounds of formula (III), wherein R₁is ethyl. In preferred compounds of formula (III), R₁is ethyl.

The reaction according to the invention is preferably carried out in a temperature range of from −40° C. to 0° C., especially from −40° C. to −20° C.

The reaction can be carried out in the presence or absence of a base. Preferred bases include pyridine, alkyl pyridines or trialkylamines.

The reaction can be carried out without solvent or in an inert solvent. Preferred inert solvents are, for example, toluene, hexane, dichloromethane or diethylether. Preferably, the reaction is carried out without a solvent.

In the reaction according to the invention, the compound of formula (III), for example ethylenol ether, can be used in equimolar amounts, in sub-equimolar amounts or in excess relative to compounds of formula XIV, preferably the compound of formula (III) is used in excess, more preferably in an 1.5-fold to 3-fold excess.

The reaction according to the invention may be carried out in a dry inert gas atmosphere. For example, nitrogen can be used as inert gas.

The reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours.

The reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at normal pressure.

Process Step b2):

The reaction according to the invention is preferably carried out in a temperature range of from 0° C. to 50° C., especially from 10° C. to 25° C.

The reaction is conveniently carried out in an inert solvent. Preferred inert solvents are, for example, xylene, toluene, mesitylene, tert-butyl benzene, chlorobenzene, 1,2-dichlorobenzene, tetrahydrofuran, diethyl ether and hexane, preferably tetrahydrofuran.

In the reaction according to the invention, methylhydrazine can be used in equimolar amounts, in sub-equimolar amounts or in excess relative to compounds of formula XV, preferably methylhydrazine is used in equimolar amounts.

The reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours, more preferably 1 to 5 hours.

The reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at normal pressure.

Process Step b3):

The fluorination according to the invention is preferably carried out in a temperature range of from 100° C. to 200° C., especially from 140° C. to 160° C.

The preferred fluorinating agent is tris(hydrogen fluoride)-triethylamine. The fluorinating agent is typically used in excess relative to compounds of formula VII, preferably in a 2-fold to 5-fold excess.

The fluorination can be carried out without solvent or in an inert solvent. Preferred inert solvents are, for example, acetonitrile, chloroform, carbon tetrachloride and dichloromethane. Use of excess tris(hydrogen fluoride)-triethylamine, which then acts as solvent is preferred.

The reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours, more preferably 1 to 5 hours.

The reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at elevated pressure.

Process Step b4):

The bromination according to the invention is preferably carried out in a temperature range of from 0° C. to 100° C., preferably from 20° C. to 40° C.

The reaction is conveniently carried out in an inert solvent. A preferred inert solvent is, for example, carbon tetrachloride.

Preferred brominating agents are, for example, bromine in the presence of an iron catalyst, N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin; preferably bromine in the presence of an iron catalyst.

In case the brominating agent is bromine in the presence of an iron catalyst, said bromine is typically used in excess relative to compounds of formula VIII, preferably in a 1.5-fold to 5-fold excess; and said iron catalyst is used typically in the form of iron powder and in the range of from 0.1 to 1 equivalents relative to compounds of formula VIII, especially from 0.3 to 0.8 equivalents.

The reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours, more preferably 1 to 5 hours.

The reaction according to the invention can be carried out at normal, elevated or reduced pressure. In one embodiment of the invention the reaction is carried out at normal pressure.

Process Step b5):

For process step b5) the preferred C₁-C₆alkanol is ethanol; but also mixtures C₁-C₆alkanols can be used, such as a mixture of methanol/ethanol.

The reaction according to the invention is preferably carried out in a temperature range of from 50° C. to 200° C., especially from 100° C. to 150° C.

The reaction is conveniently carried out in a large excess of the C₁-C₆alkanol, such as a 100-fold to 150-fold excess, which then acts as solvent. Typically ethanol is used. Typically also a large excess of carbon monoxide is used.

A suitable palladium catalyst is tris(triphenylphosphonium)palladium(II)chloride. Said palladium catalyst is used generally in the range of from 0.1 to 0.5 equivalents relative to compounds of formula X, especially from 0.1 to 0.3 equivalents. If tris(triphenylphosphonium)palladium(II)chloride is used as palladium catalyst, then generally triphenyl phosphine is also added to the reaction mixture in amounts of from 0.5 to 0.7 equivalents relative to compounds of formula X.

The reaction is carried out preferably in the presence of a base. Suitable bases are, for example, nitrogen-containing organic bases, such as, for example, tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine, N,N-dimethylaniline or N-methylmorpholine, piperidine, pyrrolidine, alkali metal or alkaline earth metal alcoholates, such as, for example, lithium, sodium or potassium alcoholates, especially methanolates, ethanolates or butanolates, or inorganic bases, such as hydroxides, e.g. NaOH or KOH, or hydrides, such as, for example, NaH. Bases to which preference is given are tertiary amines, such as trialkylamines, e.g. trimethylamine, triethylamine, diisopropylethylamine (Hünig's Base), or tri-n-butylamine, especially triethylamine. Suitable amounts of base for that reaction are, for example, from 1 to 10 equivalents, especially from 4 to 6 equivalents.

The reaction time is generally from 1 to 48 hours, preferably from 1 to 36 hours, more preferably 1 to 18 hours.

The reaction according to the invention is carried out typically at elevated pressure, such as 1 to 20 bar, preferably 10 to 15 bar.

Process Step b6):

Process step b6), the saponification of compounds of formula (XII) to form the compound of formula (XIII), can be carried out as described under step b6.1) (alkaline saponification) or under step b6.2) (acidic saponification).

Process Step b6.1):

Step b6.1) can be divided into two sub-steps: i) the formation of the anion of the compound of formula (XIII) (“the anion”) by adding a base and ii) the formation of the compound of formula (I) (“the free acid”) by later adding an acid.

If a hydroxide base is used to form the anion, then NaOH or KOH, especially NaOH, is preferred. A suitable amount of hydroxide base is, for example, at least one equivalent relative to compounds of formula (XII), preferably from 1 to 5 equivalents; more preferably from 1 to 3 equivalents.

If water in the presence of a base is used to form the anion, then inorganic bases, such as hydroxides, for example LiOH, NaOH or KOH, or carbonates, for example sodium carbonate, are preferred. In one embodiment, at least one equivalent of water and at least one equivalent of the base relative to compounds of formula (XII) are used.

The formation of the anion can be carried out in an inert solvent, such as ethanol.

The formation of the anion is preferably carried out in a temperature range of from 0° C. to 200° C. The reaction time for anion formation is generally from 1 to 48 hours, preferably from 1 to 18 hours. Said anion formation can be carried out at normal, elevated or reduced pressure, preferably at normal pressure.

After formation of the anion, an acid is added to form the compound of formula (XIII).

Suitable acids are inorganic acids, such as hydrochloric acid or sulfuric acid; or organic acids, such as formic acid, acetic acid or propionic acid. Preference is given to inorganic acids and special preference is given to hydrochloric acid.

In one embodiment of the invention, the acid is added in a temperature range of from 50° C. to 95° C. The reaction time for formation of the free acid is generally from 1 to 48 hours, preferably from 1 to 18 hours. Said free acid formation can be carried out at normal, elevated or reduced pressure, preferably at normal pressure.

Process Step b6.2):

In process step b6.2) the compound of formula (XIII) (“the free acid”) is formed directly by acidic saponification.

The acid used in step b6.2) is typically an inorganic acid, such as hydrochloric acid or sulfuric acid; or an organic acid, such as formic acid, acetic acid or propionic acid.

Preference is given to inorganic acids and special preference is given to hydrochloric acid.

Typically, aqueous solutions of the acid are used in step b6.2).

A preferable amount of water is at least one equivalent relative to compounds of formula (XII).

A preferable amount of acid is at least 0.01 equivalents relative to compounds of formula (XII), more preferably from 0.01 to 5 equivalents; even more preferably from 1 to 5 equivalents.

The formation of the free acid is preferably carried out in a temperature range of from 40° C. to 100° C. The reaction time is generally from 1 to 48 hours, preferably from 1 to 18 hours. Said free acid formation can be carried out at normal, elevated or reduced pressure, preferably at normal pressure.

Also the second embodiment of the present invention makes it possible to produce compounds of formula I in a high yield, with a high degree of regioselectivity and at low cost.

The compounds of formula (X), (VII) and (VIII) are valuable intermediates for the preparation of compounds of formula (XIII) and were developed specifically for the present process according to the invention. The present invention accordingly relates also to those compounds.

Further aspects of the second embodiment are the following five individual processes:

1) A process for the production of a compound of formula (XII), which comprises b1) reacting a compound of formula (XIV) with a compound of formula (III) to form the compound of formula (XV).

2) A process for the production of a compound of formula (VII), which comprises b2) converting a compound of formula (XV) with methylhydrazine into the compound of formula (VII).

3) A process for the production of a compound of formula (VIII), which comprises b3) fluorinating a compound of formula (VII) with a fluorinating agent into the compound of formula (VIII).

4) A process for the production of a compound of formula (X), which comprises b4) brominating a compound of formula (VIII) with bromine in the presence of an iron catalyst into the compound of formula (X).

5) A process for the production of a compound of formula (XII), which comprises b5) converting a compound of formula (X) with carbon monoxide and a C₁-C₆alkanole in the presence of a palladium catalyst into the compound of formula (XII).

In all five aspects above, the process steps, e.g. steps b1), b2), b3), b4) and b5) are performed as described above.

For convenience, the foregoing reactions—and further reactions, descriptions for which will follow—are summarized in scheme 9 below. In scheme 1, R₁and R₂stands for C₁-C₆alkyl and TREAT HF means tris(hydrogen fluoride)-triethylamine.

As already discussed above, the invention includes, in separate embodiments, the following multi-step processes, which involve:

(1) the formation of (XV) from (XIV);

(2) the formation of (VII) from (XV);

(3) the formation of (VIII) from (VII);

(4) the formation of (X) from (VIII);

(5) the formation of (XII) from (X)

(6) the formation of (XII) from (XXII)

(7) the formation of (XII) from (XX)

The following non-limiting examples illustrate the invention in more detail. All following %-values are (w/w)-values unless noted otherwise.

EXAMPLES
Example 1
Preparation of 1,1-Dichloro-4-ethoxy but-3-en-2-one (XVI)

Dichloroacetyl chloride (114.9 g, compound of formula XIV) was charged to a clean/oven dried 250 ml 3-necked flask fitted with nitrogen feed, syringe feed, thermometer and a PTFE coated magnetic stirrer. The reactor was vented via a cold finger condenser and water condenser to follow. A caustic scrubber system was connected to the vent from the water condenser system. The agitation was provided by a magnetic stirrer/hotplate fitted with a drykold acetone bath. The cold finger condenser was filled with the same cooling mixture. The reactor contents were agitated and the contents cooled to <−40° C. with a gentle nitrogen purge applied to the reactor. Ethylenol ether (113.0 g) was charged to the reactor over ˜8 hrs maintaining at −20 to −40° C. throughout. The reaction mixture was then agitated overnight allowing it to self heat to room temperature. The following day the reaction mass was black and more viscous then before. The reaction mass was analyzed by GC/GCMS and shown to have effectively completed. The reactor contents were then agitated under nitrogen whilst samples were removed for Kugelrohr distillation. A total mass of 164.4 g of black liquor was obtained. The yield estimate at this stage for the product (compound of formula IX) was 48% (based on GC area % analysis) with a further potential 15% from the chlorinated intermediate present which had not dehydrochlorinated. Several distillations were carried out obtaining up to 63% recovery of the product with strengths of ˜97% by GC area %. Main fraction was obtained at 137.5° C. and 8 mbar. The product was analysed by GC, GCMS and NMR (¹H).

GCMS: 35, 43, 48, 53, 61, 71, 76, 83, 91, 99, 109, 119, 182 (M⁺)

¹H NMR (CDCl₃): 1.40(t, 3H, CH₃CH₂O—), 4.08(q, 2H, CH₃CH₂O—), 5.83(s, 1H, CHCl2—), 6.01(d, 1H, —CO—CH═CH), 7.80(d, 1H, —CH═CH—O—)

Example 2
Preparation of 3-dichloromethyl-1-methyl-1H-pyrazole (VII)

1,1-Dichloro-4-ethoxy-but-3-en-2-one (0.99 g, compound of formula XVI) was dissolved in tetrahydrofuran (12.5 ml) in a clean/dry 50 ml 3-necked flask fitted with thermometer, condenser and syringe feed system. The top of the condenser was back pressured with a gentle flow of nitrogen. The reactor contents were agitated and heated to 40° C. then the N-methyl hydrazine (0.26 g) was dissolved in tetrahydrofuran (25 ml) and the resultant solution syringe pump fed into the reactor over a 5 hour period. The reaction mixture was agitated overnight under nitrogen to complete. The mixture was allowed to self cool over this period. A yellow/orange solution was obtained. The product solution was concentrated under vacuo and the resultant oil taken up in dichloromethane. The product solution was then washed with water, separated, dried over anhydrous magnesium sulphate and concentrated under vacuo again to give the product in form of a red oil (0.7 g ˜83% yield). The reaction was followed by gas chromatography throughout to assess the extent of reaction. Distillation and separation of the desired product (compound of formula VII) from its isomer is possible—distillation with a Kugelrohr enabled separation of the isomers—the target 1,3-isomer was predominantly obtained at 77° C. and 3 mbar. The unwanted 1,5-isomer was predominantly obtained at 89° C. and 4 mbar. The product was analyzed by GC, GCMS and NMR (¹H).

GCMS: 35, 43, 48, 53, 61, 71, 76, 83, 91, 99, 109, 119, 182 (M⁺)

¹H NMR (CDCl₃): 4.03 (s, 3H, CH₃N), 6.82 (s, 1H, CHCl₂), 6.41 (d, 1H, N—CH═CH—), 7.39 (d, 1H, N—CH═CH—)

For the isomer:

¹H NMR (CDCl₃): 3.88 (s, 3H, CH₃N), 6.80 (s, 1H, CHCl₂), 6.50 (d, 1H, N—CH═CH—), 7.34 (d, 1H, N—CH═CH—)

Example 3
Preparation of 3-difluoromethyl-1-methyl-1H-pyrazole (VIII)

15.4 g (94 mmol) of the compound of formula VII was charged to a clean dry Monel 100 ml pressure reactor followed by 56 g (342 mmol) tris(hydrogen fluoride)-triethylamine by syringe. The system was sealed up and agitated whilst heating the contents to 150° C. After achieving the target temperature the reaction mass was held on temperature for a further 4 hours. External cooling was then applied to cool the reactor/contents to room temperature before the reaction mass was quenched. Quenching was effected by drowning out the reactor contents (black liquid) into water (100 ml). The quenched reaction mass was then extracted with methyl-t-butyl ether (3×25 ml). After separating the organic phases were washed with brine and the organic layer was dried with magnesium sulphate, filtered and concentrated under vacuo to give the compound of formula VIII in the form of a yellow/orange oil (6.3 gm, ˜51% yield on GC area %). The product was analysed by GC, GCMS and NMR (¹H, ¹³C and ¹⁹F).

GCMS: 38, 42, 51, 81, 113, 117, 132 (M⁺)

For the desired product: ¹H NMR (CDCl₃): 3.90 (s, 3H, CH₃N), 6.44 (d, 1H, N—CH═CH), 6.68 (t, 1H, CHF₂), 7.37 (d, 1H, N—CH═CH); ¹⁹F NMR (CDCl₂): −111.72 (d, CHF₂)

For the isomer: ¹H NMR (CDCl₂): 3.97 (s, 3H, CH₃N), 6.45 (d, 1H, N—CH═CH), 6.74 (t, 1H, CHF₂), 7.44 (d, 1H, N—CH═CH); ¹⁹F NMR (CDCl₃): −113.11 (d, CHF₂)

Example 4
Preparation of 4-Bromo-3-difluoromethyl-1-methyl-1H-pyrazole (X)

1.7 g (30 mmol) iron powder was added to 6.1 g (57 mmol) of the compound of formula VIII in a 250 ml 3-necked round bottom flask fitted with condenser (which was vented to a caustic scrubber system), thermometer and syringe pump feed. The first charge of carbon tetrachloride (25 ml) was made to the flask and the flask contents agitated. Bromine (6.8 g) was dissolved in further carbon tetrachloride (35 ml). Coolant was applied to the condenser, and the bromine solution was fed to the reactor over 1 hr. During the addition the temperature of the reaction rose to −29° C. GC analysis showed that the reaction was incomplete. A second charge of bromine (8.6 g) in carbon tetrachloride (25 ml) was then made to the reactor over a further 1 hr and the reaction mass was allowed to stand overnight. GC analysis showed that the reaction wasn't complete but additional impurities were forming at significant levels. The reaction mass was therefore quenched by treating with sodium bisulphite solution (100 ml)—a small exotherm occurred to 26° C. and the system was decolourised. The two phases were separated and the organic phase was then washed with further sodium bisulphite solution (50 ml). The organic phase was separated from the aqueous phase and dried over magnesium sulphate. The solvent was removed by distillation to give an orange oil (7.5 gm ˜77% yield on actual weight and GC area % strength). The oil was distilled on a kugelrohr short path distillation system at 50 to 96° C. (9 to 6 mbar). The compound of formula X was obtained in the form of a yellow oil over 88 to 96° C. (7 mbar). The main fraction from the distillation was 5.97 g (80% recovery or 62% through yield). Crude and distilled products were analysed by GC, GCMS and NMR (¹H and ¹⁹F).

GCMS: 42, 51, 69, 80, 88, 104, 118, 131, 159, 191, 197, 210 (M⁺)

¹H NMR (CDCl₃): 3.91 (s, 3H, CH₃N), 6.67 (t, 1H, CHF₂), 7.44 (s, 1H, N—CH═C—Br)

¹⁹F NMR (CDCl₃): −114.41(d, CHF₂)

Example 5
Preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-caboxylic acid ethyl ester (XVII)

0.43 g 4-Bromo-3-difluoromethyl-1-methyl-1H-pyrazole (X), 10 g ethanol, 1 g triethylamine, 0.11 g tris(triphenylphosphonium)palladium(II)chloride and 0.12 g triphenyl phosphine were charged to a 50 ml glass miniclave reactor fitted with a 10 bar bursting disc, thermometer and gas feed. The system was pre-purged with carbon monoxide six times up to 7 bar—venting off slowly each time and agitating throughout. Finally the reactor was pressurized up to 6 bar. The system was agitated whilst heating up to 150° C. and the pressure maintained at 6-7 bar by venting as necessary. When the mixture had stabilized on temperature, and pressure, it was agitated overnight under these conditions. GC analysis showed the reaction to be incomplete, so a second charge of catalyst (0.06 g tris-triphenylphosphine palladium (II) chloride and 0.14 g triphenylphosphine) was added to the reactor. The reaction was agitated at 150° C. for a further 5 hr then cooled to ambient temperature. The product was not isolated but compared to reference material by HPLC, GC and GCMS. Analysis via GC area % of the reaction mixture suggested a conversion of 60%.

Example 6
Preparation of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (XIII)

0.31 g 4-Bromo-3-difluoromethyl-1-methyl-1H-pyrazole, 0.82 g water, 9 g N-methylpyrrolidinone, 1 g triethylamine, 0.06 g tris(triphenylphosphonium)palladium(II)chloride and 0.12 g triphenyl phosphine were charged to a 50 ml glass miniclave reactor fitted with a 10 bar bursting disc, thermometer and gas feed. The system was pre-purged with carbon monoxide six times up to 7 bar—venting off slowly each time and agitating throughout. Finally the reactor was pressurized up to 6 bar. The system was agitated whilst heating up to 150° C. and the pressure maintained at 6-7 bar by venting as necessary. When the mixture had stabilized on temperature, and pressure, it was agitated overnight under these conditions. The following day the system was cooled, vented and the reactor contents evaporated as far as possible on a rotary evaporator. The resultant oil was quenched with an aqueous base and extracted with 3×25 ml of ether. The combined ether extracts were washed with brine, dried over magnesium sulphate and concentrated under vacuo to yield a red/brown oil (0.5 g). The aqueous base extracts were acidified and back extracted with 3×25 ml of ether. The extracts were combined, dried over magnesium sulphate and concentrated under vacuo. Derivatized GC analysis showed that the desired 1,3-pyrazole isomer (compound of formula XIII) was present in virtually all phases obtained from the work-up (HPLC analysis). Most of the product, and its isomer, were present in the ether extract from the initial base wash. The product was not isolated but compared to reference material by HPLC, derivatized GC and GCMS.

Preparation of (XIII) from (XVIII) via (XIX), (XX) and (XVII):

Example C4
Preparation of (XX) from (XVIII) via (XIX):

Hydrazine hydrate (4.62 g) was charged to a 3-necked round bottomed flask. The flask was fitted with a thermometer, condenser and syringe feed. The system was back pressured on the condenser outlet with a nitrogen purge/bubbler. Methanol (75 ml) was charged to the reactor and the mixture agitated under nitrogen. Methyldifluoroacetate (10.2 g, compound of formula XVIII) was dissolved in methanol (17 ml) and fed, by syringe, into the reactor over 75 minutes. The resultant mixture was transferred to a 300 ml Hastelloy Parr reactor. Formaldehyde (7.4 g) was charged to the reactor and the mixture agitated for 30 minutes at room temperature accompanied by a small exotherm reaction. 1 g Pt/C was added and washed in with methanol (20 ml). The Parr reactor was sealed, purged with nitrogen three times, purged with hydrogen three times (all to 200 psi) and then pressurized up to 200 psi with hydrogen. Agitation and external heating were applied to heat the reaction to 50° C. The reactor was held under these conditions for 3 h and then allowed to cool. The system was purged three times with nitrogen to 200 psi. The contents were removed and filtered. The solvent was removed under vacuum, filtered and concentrated under vacuo. The compound of formula XX was obtained in the form of an orange oil (9.1 g). Yield 40% total isomers and 36% of the desired isomer. The product was analysed by GC, GCMS and NMR (¹H and ¹⁹F).

GCMS: 45, 51, 60, 75, 79, 96, 124 (M⁺)

For the desired product: ¹H NMR (CDCl₃): 2.67 (s, 3H, CH₃N), 5.95 (t, 1H, CHF₂);

¹⁹F NMR (CDCl₃): −127.92 (d, CHF₂)

For the isomer: ¹H NMR (CDCl₃): 2.59 (s, 3H, CH₃N), 5.92 (t, 1H, CHF₂); ¹⁹F NMR (CDCl₃): −127.94 (d, CHF₂)

Example C5
Preparation of (XVII) from (XX)

A 25 ml reaction tube was fitted with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere. Dimethylformamide (10 g), ethyl propargylate (0.14 g), the compound of formula XX (0.24 g) and p-toluene sulphonic acid (0.028 g) were charged to the reaction tube. The mixture was stirred at 50° C. overnight, 80° C. overnight and then 110° C. overnight to give the desired product (compound of formula XVII).

MS: 42, 43, 112, 132, 140, 159, 176, 204 (M⁺)

¹H NMR (CDCl₃): 1.35 (t, 3H, CH₃CH₂), 3.97 (s, 3H, NCH₃), 4.32 (q, 2H, CH₃CH₂O), 7.25 (t, 1H, CHF₂), 7.90 (S, 1H, ArH)

The compound of formula (I) can be formed from the compound of formula (V) via step b6) as described above.

Preparation of (XIII) from (XVIII) via (XX) and (V):

Example C6
Direct Preparation of (XX) from (XVIII)

A 3-neck 250 ml round bottomed flask was fitted with a magnetic stirrer, thermometer and nitrogen atmosphere. Tetrahydrofuran (120 ml), methyl difluoroacetate (compound of formula XVIII; 4 g) and methylhydrazine (1.65 g) were charged, and the mixture stirred at ambient temperature for 4 h. Further methyl hydrazine (0.38 g) was added and the mixture stirred for a further 3 h at ambient temperature. The desired product (compound of formula XX) was formed as a 3:1 mixture with its N-regioisomer and was isolated by concentration in vacuo.

MS: 45, 51, 60, 75, 79, 96, 124 (M⁺)

¹H NMR (CDCl₃): 2.67 (s, 3H, CH₃N), 5.95 (t, 1H, CHF₂)

The compound of formula (XVII) can be formed from the compound of formula (XX) via the methology described in comparative example C5 above. The compound of formula (XII) can be formed from the compound of formula (XVII) via step b6) as described above.

Preparation of (XIII) from (XXI) via (XXII), (XXIII) and (XVII):

Example C7
Preparation of (XXII from (XXI)

A 3-neck 50 ml round bottomed flask was fitted with a magnetic stirrer, thermometer, and nitrogen atmosphere. Dichloromethane (36 ml) and the compound of formula XXI (5.0 g) were charged to the reactor and the resulting solution cooled to 0° C. Methylamine (4.20 g) was added over 0.25 h, maintaining the temperature below 5° C., and the reaction stirred at ambient temperature for 1.5 h. Concentration in vacuo gave a yellow solid, which was washed with isohexane (60 ml, 20 ml). The compound of formula XXII was obtained as an off-white solid (86% yield).

MS: 42,43, 55, 84, 112, 128, 156, 162, 207 (M⁺)

¹H NMR (CDCl₃): 1.32 (t, 3H, CH₃CH₂), 3.25 (d, 3H, NHCH₃), 4.23 (q, 2H, CH₃CH₂O), 6.88 (t, 1H, CHF₂), 8.10 (d, 1H, C═CH), 10.83 (br s, 1H, ═CH—NH—CH₃)

Example C8
Preparation of (XVII) from (XXII) via XXIII)

a) Preparation of Chloramine:

A 100 ml conical flask was fitted with a magnetic stirrer and thermometer. Diethyl ether (31 ml) and ammonium chloride (0.91 g) were charged to the flask. The mixture was cooled to −10° C. and aqueous ammonia solution (1.7 g) was added. Sodium hypochlorite (14.3 g) solution was charged over 10 minutes to the vigorously stirred solution at −10° C., and the reaction was then stirred at −10° C. for 0.5 hr. The organic layer was separated, washed with brine, dried over CaCl₂for 1 hr at −15° C. The desired chloramine was generated as a 3% chloramine solution in diethylether.

b) Preparation of the Compound of Formula XVII via the Compound of Formula XXIII:

A 3-neck round bottomed flask was fitted with a magnetic stirrer, thermometer and nitrogen atmosphere. Sodium hydride in mineral oil (0.28 g, 6.82 mmol, 5.5 eq) was charged to the reactor. The obtained paste was triturated with isohexane (2×10 ml) to remove the mineral oil, then tetrahydrofuran (25 ml) and 0.26 g of the compound of formula XXII (prepared as described in comparative example 7) were added. The mixture was stirred at ambient temperature for 0.5 h to give a clear solution. This tetrahydrofuran solution was added slowly to the chloramine/diethylether-solution described above (6.22 mmol, 5.0 eq) at −15° C. The reaction was stirred at −15° C. for 1 h and then allowed to warm to ambient temperature. A new solution of chloramine in diethylether (2.7% strength) was prepared as described above. Additional sodium hydride dispersion (0.20 g, 4.96mmol, 4.0 eq) and chloramine (new solution) (10.4 g, 5.46 mmol, 4.4 eq) were added and the reaction was stirred for 1 h at ambient temperature. A final charge of sodium hydride dispersion (0.22 g, 5.46 mmol, 4.4 eq) and chloramine (10.7 g, 5.58 mmol, 4.5 eq) was added to the reactor. The reaction was stirred at ambient temperature overnight to give the desired compound of formula XVII.

MS: 42, 43, 112, 132, 140, 159, 176, 204 (M⁺)

¹H NMR (CDCl₃): 1.35 (t, 3H, CH₃CH₂), 3.97 (s, 3H, NCH₃), 4.32 (q, 2H, CH₃CH₂O), 7.25 (t, 1H, CHF₂), 7.90 (S, 1H, ArH)

The compound of formula (XIII) can be formed from the compound of formula (XVII) via step b6) as described above.

PROCESSES FOR THE PREPARATION OF PYRAZOLES

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