HIGHLY EFFICIENT PROCESS FOR THE PREPARATION OF 4-FLUORO-1H-PYRAZOLE OR SALTS THEREOF

Abstract

Highly efficient process for the preparation of 4-Fluoro-1H-pyrazole or salts thereof by reaction of pyrazole with an electrophilic fluorinating reagent is disclosed.

Claims

1. Process for the preparation of 4-Fluoro-1H-pyrazole of formula (I) or salts thereof: ##STR00013## by reaction of pyrazole of formula (II): ##STR00014## with a fluorination reagent wherein said fluorination reagent is an electrophilic fluorination reagent.

2. Process according to the claim 1, wherein the reaction is carried out in presence of a base or an inorganic base.

3. Process according to the claim 2, wherein the inorganic base is NaHCO.sub.3, Na.sub.2CO.sub.3 or Na.sub.3PO.sub.4, KHCO.sub.3, K.sub.2CO.sub.3 or K.sub.3PO.sub.4,

4. Process according to claim 1, wherein the reaction is carried out at a pH value comprised in the range from 6 to 14 or from 6.0 to 8.0.

5. Process according to claim 1, wherein the electrophilic fluorination reagent is Fluorine gas or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III): ##STR00015##

6. Process according to claim 1, wherein the reaction is carried out at a temperature comprised in the range from 20° C. to 80° C. or from 50° C. to 80° C.

7. Process according to the claim 6, wherein the reaction is carried out at a temperature comprised in the range from 50° C. to 80° C. for a reaction time comprised in the range from 5 to 90 hours.

8. Process according to claim 1, wherein the reaction is carried out without the presence of any solvent or wherein the reaction is carried out in pyrazole as means to perform said reaction.

9. Process according to claim 1, wherein the reaction is carried out without the presence of any additional base.

10. Process according to claim 8, wherein the amount of the pyrazole (II) is from 3 to 6 molecular equivalents compared to the compound of formula (III).

11. Process according to claim 8, wherein the reaction is carried out without the presence of any solvent, without the presence of any additional base, and the amount of the pyrazole (II) is from 3 to 6 molecular equivalents compared to the compound of formula (III).

12. Process according to claim 8, wherein the reaction is carried out at a temperature comprised from 60° C. to 70° C., overnight.

13. Process according to claim 1, wherein 4-Fluoro-1H-pyrazole of formula (I) was extracted from the reaction mixture also comprising pyrazole of formula (II) by means of methyl-tert-butyl-ether (MTBE).

14. Process according to claim 13, wherein the extraction of 4-Fluoro-1H-pyrazole of formula (I) with methyl-tert-butyl-ether (MTBE) is carried out at pH=1.8.

15. A method of use of a pyrazole of formula (II): ##STR00016## the method comprising using the pyrazole of formula (II) for the preparation of 4-Fluoro-1H-pyrazole of formula (I) or salts thereof: ##STR00017## in a fluorination reaction of the pyrazole of formula (II).

Description

DESCRIPTION OF EMBODIMENTS

[0021] Object of the present invention is a process for the preparation of 4-Fluoro-1H-pyrazole of formula (I) or salts thereof:

##STR00004##

by reaction of pyrazole of formula (II):

##STR00005##

with a fluorination reagent wherein said fluorination reagent is an electrophilic fluorination reagent.

[0022] The term electrophilic fluorinating reagent means a fluorinating reagent that is electrophilic, i.e. a fluorination reagent having a tendency to attract or acquire electrons.

[0023] It has been indeed surprisingly found that the reaction of 1H-pyrazole with an electrophilic fluorinating reagent provides selectively 4-Fluoro-1H-pyrazole. In other words, in the process of the invention, the electrophilic fluorination of 1H-pyrazole provides selectively 4-Fluoro-1H-pyrazole.

[0024] The electrophilic fluorination clearly differs from standard nucleophilic fluorination reactions, which do not provide at all 4-Fluoro-1H-pyrazole.

[0025] Thus, in the process of the invention, the electrophilic fluorination reaction of 1H-pyrazole provides 4-Fluoro-1H-pyrazole.

[0026] The term salts, includes hydrochloride, hydrobromide, sulphate, bisulphate, etc. of 4-Fluoro-1H-pyrazole, wherein the salt 4-Fluoro-1H-pyrazole hydrochloride is preferred.

[0027] According to an embodiment of the process, the reaction is carried out in presence of a base.

[0028] The term base, includes inorganic bases and organic bases.

[0029] According to a preferred embodiment of the process, the base is an inorganic base, since the inorganic bases provide better conversions compared with organic bases.

[0030] Examples of suitable inorganic bases are alkaline or alkaline hearty salts with weak acids.

[0031] In details, examples of inorganic bases are NaHCO.sub.3, Na.sub.2CO.sub.3 or Na.sub.3PO.sub.4, KHCO.sub.3, K.sub.2CO.sub.3 or K.sub.3PO.sub.4.

[0032] According to a preferred embodiment of the process, the inorganic base is NaHCO.sub.3, Na.sub.2CO.sub.3 or Na.sub.3PO.sub.4, KHCO.sub.3, K.sub.2CO.sub.3 or K.sub.3PO.sub.4.

[0033] According to a more preferred embodiment, the inorganic base is NaHCO.sub.3 since it provides the best and fastest conversions compared with other inorganic bases.

[0034] According to a preferred embodiment of the process, the reaction is carried out at a pH value comprised in the range from 6 to 14 or, more preferably, from 6.0 to 8.0.

[0035] The electrophilic fluorinating reagent can be any fluorination reagent having a tendency to attract or acquire electrons, preferably, the electrophilic fluorination reagent is Fluorine gas or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III):

##STR00006##

III

[0036] More preferably, electrophilic fluorination reagent is 1-chloromethyl fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III) since it does not requires special equipment such as those required for handling fluorine.

[0037] The reaction in the process of the invention can be carried out at a temperature comprised in the range from 20° C. to 80° C. or, preferably, from 50° C. to 80° C.

[0038] Preferably, the reaction is carried out at a temperature comprised in the range from 50° C. to 80° C. for a reaction time comprised in the range from 5 to 90 hours.

[0039] The reaction in the process of the invention can be carried out in an organic solvent, preferably in an organic solvent selected among acetonitrile, dichloromethane and mixtures thereof, more preferably the organic solvent is acetonitrile.

[0040] According to a preferred embodiment of the process, the reaction is carried out in an organic solvent being acetonitrile and in presence of NaHCO.sub.3, since it provides the better and faster conversions, compared with the other inorganic bases and other solvents.

[0041] According to a more preferred embodiment of the process, the electrophilic fluorination reagent is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III) and the reaction is carried out in an organic solvent being acetonitrile and in presence of NaHCO.sub.3.

[0042] According to a preferred embodiment of the process, the reaction is carried out at a temperature comprised in the range from 50° C. to 80° C., the electrophilic fluorination reagent is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III) and the reaction is carried out in an organic solvent and in presence of NaHCO.sub.3, preferably the organic solvent being acetonitrile.

[0043] According to a preferred embodiment of the process, the reaction is carried out at a temperature comprised in the range from 50° C. to 80° C., the electrophilic fluorination reagent is 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III) and the reaction is carried out without the presence of any solvent and in presence of an inorganic base, preferably the inorganic base being NaHCO.sub.3.

[0044] Alternatively and preferably, the reaction in the process of the invention can be carried out without the presence of any solvent, since the reaction can be carried out with pyrazole which is a reactant and liquid compounds, therefore also suitable as means to perform a reaction. Thus, the term “without the presence of any solvent” means only in presence of pyrazole, that acts as a solvent; or, alternatively, means that the reaction is carried out in pyrazole as means to perform said reaction. In such a case, the amount of pyrazole is in excess compared with the electrophilic fluorinating agent. In particular, the amount of pyrazole is comprise between 1 and 50 molecular equivalents compared to the electrophilic fluorinating agent, more preferable, from 2 to 10 molar equivalents, again more preferably from 3 to 6 molecular equivalents compared to the electrophilic fluorinating agent. In such a case, pyrazole acts both as a reactant and as mean or as solvent to perform the reaction.

[0045] Thus, according to a preferred embodiment of the process, the reaction is carried out without the presence of any solvent or the reaction is carried out in pyrazole as means to perform said reaction.

[0046] According to a more preferred embodiment of the process, the reaction is reaction is carried out without the presence of any base, i.e. the reaction is carried out without the addition of any additional base. Indeed, the excess of Pyrazole (II) compared to the compound of formula (III) acts as a base. Thus, the sentence “the reaction is reaction is carried out without the presence of any additional base” means that in the reaction that stoichiometric excess of pyrazole (II), compared to the compound of formula (III), acts as base.

[0047] According to a preferred embodiment of the invention, the amount of the pyrazole (II) is from 3 to 6 molecular equivalents compared to the compound of formula (III), more preferably from 4 to 5 molecular equivalents.

[0048] According to a preferred embodiment, the reaction is carried out without the presence of any solvent, without the presence of any additional base and the amount of the pyrazole (II) is from 3 to 6 molecular equivalents compared to the compound of formula (III), more preferably from 4 to 5 molecular equivalents.

[0049] According to a preferred embodiment, the reaction is carried without the presence of any solvent, without the presence of any additional base and the amount of the pyrazole (II) is from 3 to 6 molecular equivalents compared to the compound of formula (III), at a temperature comprised from 60° C. to 70° C., overnight.

[0050] In the process, the compound 4-Fluoro-1H-pyrazole of formula (I) can be extracted from the reaction mixture also comprising pyrazole of formula (II) by means of methyl-tert-butyl-ether (MTBE). It was indeed found that MTBE is well suitable, differently for other solvents (see example 5) to extract 4-Fluoropyrazole from a mixtures comprising pyrazole.

[0051] Further than MTBE, it was surprisingly found that the compound 4-Fluoro-1H-pyrazole of formula (I) can be extracted from the reaction mixture also comprising pyrazole of formula (II) with methyl-tert-butyl-ether (MTBE), wherein said extraction is carried out at pH=1.8 (see Table in Example 5). At such a specific value of pH, it is possible efficiently separate the compound (I) from the compound (II). Thus, both the combination of MTBE and the pH=1.8 provides a very unexpected effect of a very efficient separation of 4-Fluoro-pyrazole (I) from pyrazole (II). Such a separation is particularly important when the reaction is preformed without any other solvent, i.e. when an excess of pyrazole (II) is used as mean or solvent of the reaction.

[0052] An other object is the use of pyrazole of formula (II):

##STR00007##

for the preparation of 4-Fluoro-1H-pyrazole of formula (I) or salts thereof:

##STR00008##

by means of fluorination reaction of pyrazole of formula (II).

[0053] According to a preferred embodiment, such a use is preferred wherein 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (tetrafluoro borate) of formula (III) is employed as fluorination reagent.

[0054] The skilled in the art of organic chemistry can appreciate as the process of the invention allows a dramatic improvement, in terms of productivity, in the production of 4-Fluoro-1H-pyrazole or salts thereof considering the significant reduction in the number of synthetic steps, considering the fact that the starting material Pyrazole is a common and very cheap commodity and, considering that the industrial scale handling of a cancerogenic substance such as hydrazine is avoided.

EXPERIMENTAL SECTION

[0055] The starting material pyrazole is largely available on the market as well as all the other reagents. For Lab scale, they can be purchased by Sigma Aldrich Company.

Example 1: Preparation of 4-Fluoro-1H-pyrazole

[0056] ##STR00009##

[0057] A 50 mL glass reactor was charged with 1 g of Pyrazole and 15 mL of acetonitrile and 1.04 g of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III), then the mixture was stirred and heated to 65° C. for 1 hour.

[0058] Then 4.16 g of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III) and 0.96 g of NaHCO.sub.3 were added, both in 4 portions every 2 hours, keeping pH=6-7. Every portion comprises 1.04 g of compound of formula (III) and 0.24 g of NaHCO.sub.3.

[0059] After the additions the reaction was continued for other 3 hours (overall reaction time=10 hours), then an In-process-control was performed with the following results: [0060] GC Analysis: Pyrazole (II)=22.7% (A/A %), 4-Fluoropyrazole (I)=68.5% (A/A %); [0061] Assay by HPLC provides 0.676 g of 4-Fluoropyrazole (I), i.e. a non-isolated molar yield of 4-Fluoropyrazole (I) of 53.5%.

Example 2: Preparation of 4-Fluoro-1H-pyrazole

[0062] ##STR00010##

[0063] Example 1 was repeated but at room temperature instead of 65° C.

[0064] After 10 hours of reaction, an in-process-control showed the following results: [0065] GC Analysis: Pyrazole (II)=92.98% (A/A % 4-Fluoropyrazole (I)=6.42% (A/A %).

Example 3: Preparation of 4-Fluoro-1H-pyrazole

[0066] ##STR00011##

[0067] Example 1 was repeated but adding all the reagent at the start of the reaction.

[0068] After 10 hours of reaction an in-process-control showed the following results:

[0069] GC Analysis: Pyrazole (II)=29.62% (A/A %), 4-Fluoropyrazole (I)=59.08% (A/A %).

Example 4: Preparation of 4-Fluoro-1H-pyrazole—Process without Solvent and without Base or without any Additional Base

[0070] ##STR00012##

[0071] 1 L glass reactor was charged with 384 g of pyrazole (II) (4.0 mol. Equivalents compared to the compound (III)) and heated to 75° C. to dissolution.

[0072] Then, the liquid was cooled down to 65° C. and then 500 g of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) of formula (III) were charged on portions.

[0073] The mixture was stirred at 65° C. overnight. An in process control showed that 80% of starting pyrazole was reacted. The reaction was stopped by cooling down the reaction mixture to room temperature.

[0074] When the mixture reached room temperature, 1 L of Methanol was added and then the suspension obtained was filtered to the remove the solid by-product of compound (III).

[0075] The filtrate (solution) was distilled to remove methanol. After the distillation was added dropwise HCl 36% to reach a pH of the mixture of 1.8.

[0076] The solution was then extracted three times with MTBE (the overall amount of MTBE was 12.5 Liters).

[0077] The organic layers where combined and then distilled to remove MTBE by distillation. After that, was charged HCl in MeOH solution (at least a stoichiometric amount of HCl compared to the pyrazole reactant), then distillate again to dryness. The was charged EtOAc for reslurry, and after filtering and drying, 95 g crude solid of 4-Fluoro-1H-pyrazole hydrochloride (abbreviated FPYR.Math.HCl) were obtained, molar yield 54.9%, HPLC purity 89%, pyrazole 9.1%.

Example 4: Preparation of 4-Fluoro-1H-pyrazole—Process without Solvent and without Additional Base—Study of the pH to Extract 4-Fluoro-1H-pyrazole (FPYR) (I) with MTBE

[0078]

TABLE-US-00001 TABLE I pH study for MTBE extraction pH FPYR (I)/pyrazole (II) in MTBE by GC 2.5 1.74:1 2 4.19:1 1.9  5.7:1 1.8 8.86:1 1.7 15.63:1 (low yield)

[0079] Other solvents such as CH.sub.2Cl.sub.2, Isopropyl acetate and sec-Butyl acetate were also tried to extract 4-Fluoro-1H-pyrazole (I) but none was better than MTBE.