Efficient process for the preparation of 4-fluoro-1h-pyrazole or salts thereof

Abstract

The objective of this invention is to provide an efficient method for preparing 4-fluoro-1H-pyrazole or its salts by reacting pyrazole with an electrophilic fluorinating agent.

Description

Technical Field

[0001] This invention relates to small molecules, particularly 4-fluoro-1H-pyrazole or its salts, and efficient methods for their preparation.

[0002] 4-Fluoro-1H-pyrazole or its salts are currently used as starting materials for the synthesis of many organometallic compounds or small organic molecules, including active or potentially active pharmaceutical compounds. Background Technology

[0003] The compound 4-fluoro-1H-pyrazole or its salt has the following chemical formula (I):

[0004]

[0005] It also has the chemical name 4-fluopyrazole and CAS RN 35277-02-2.

[0006] 4-Fluoro-1H-pyrazole, also known as 4-fluoropyrazole, is currently prepared by synthetic methods that include many synthetic steps, such as those disclosed in Example 28 of WO2013043624, wherein the compound is prepared in three steps starting from a compound containing a fluorine atom, with the final step being hydrazine cyclization.

[0007] A similar method was previously disclosed in Justus Liebigs Annalen Chemie (1975), (3), 470-483, in which 4-fluoro-1H-pyrazole was prepared by cyclizing 2-fluoromalondialdehyde with hydrazine.

[0008] Shi, Xifeng et al. disclosed a method for preparing 4-fluoropyrazole in Tetrahedron Letters (1995), 36(9), 1527-30. The method starts with a trifluoroenylammonium compound, which reacts with diethylamine and then reacts with hydrazine to convert it into the final compound.

[0009] Therefore, by examining the literature, it appears clear that 4-fluoro-1H-pyrazole is always prepared by cyclization of a compound containing a fluorine atom, wherein the cyclization is carried out with hydrazine or a salt thereof.

[0010] However, all of the methods described have the following drawbacks: the length of the synthetic route, i.e., the number of synthetic steps, and the use of hydrazine, which is known to be a carcinogen.

[0011] International patent application WO2017214634 discloses an active pharmaceutical ingredient having the following formula:

[0012]

[0013] And its derivatives containing the 4-fluopyrazole moiety. In particular, the above-mentioned compounds, as well as compounds numbered 1007, 1017, 1020, 1022, 1023, 1024, 1029, 1041, and 1046 described in WO2017214634 (all of which have the 4-fluopyrazole moiety), are indicated as selective androgen receptor degrader (SARS) ligands.

[0014] International patent application WO2021173731 discloses a compound with the following formula:

[0015]

[0016] Other compounds, indicated by numbers 2, 9, 11, 12, and 17 (all of which have a 4-fluopyrazole moiety), have been identified as selective androgen receptor covalent antagonists (SARCAS).

[0017] Therefore, the compound 4-fluopyrazole prepared according to the method of the present invention can be used in the supply chain involved in the preparation of, for example, the SARS or SARCAS compounds described above. Invention Overview

[0019] Therefore, in view of the above-mentioned prior art methods, the problem solved by the present invention is to provide a method for preparing 4-fluoro-1H-pyrazole or a salt thereof, said method simultaneously allowing:

[0020] - Avoid using hydrazine.

[0021] -The compound is prepared from a chemical commodity using only one chemical reaction, thus providing a direct and efficient method for preparing 4-fluoro-1H-pyrazole or its salts.

[0022] The method of the present invention solves this problem because it selectively provides 4-fluoro-1H-pyrazole starting from pyrazole using only one chemical reaction, without using hydrazine.

[0023] In fact, it is obvious that starting with pyrazole and directly fluorinating it may potentially produce other substances, such as the isomer 3-fluoropyrazole or other impurities such as 3,4-difluoropyrazole. Therefore, there is always a significant potential problem related to the selectivity of the reaction for those skilled in the art of synthetic organic chemistry.

[0024] However, the method of the present invention also overcomes the potential selectivity problem, providing a method for selectively and directly obtaining 4-fluoro-1H-pyrazole or its salts from chemical commodities such as pyrazole.

[0025] As an additional advantage, acidic conditions are desired, as the presence of hydrofluoric acid (even in small amounts) is still harmful to the reactor due to its highly corrosive nature. Therefore, according to embodiments of the method of the invention, the reaction is carried out at a pH in the range of 6.0 to 8.0.

[0026] Furthermore, since the method of the present invention is the first to use pyrazole for the preparation of 4-fluoro-pyrazole, another objective is the use of pyrazole for the preparation of 4-fluoro-1H-pyrazole or its salts by fluorination of pyrazole of formula (II).

[0027] Description of the implementation plan

[0028] The object of this invention is a method for preparing 4-fluoro-1H-pyrazole of formula (I) or a salt thereof by reacting pyrazole of formula (II) with a fluorinating agent:

[0029]

[0030] The fluorinating agent mentioned therein is an electrophilic fluorinating agent.

[0031] The term electrophilic fluorinating agent refers to an electrophilic fluorinating agent, that is, a fluorinating agent that has the tendency to attract or gain electrons.

[0032] It was surprisingly found that the reaction of 1H-pyrazole with an electrophilic fluorinating agent selectively yields 4-fluoro-1H-pyrazole. In other words, in the method of the present invention, the electrophilic fluorination of 1H-pyrazole selectively yields 4-fluoro-1H-pyrazole.

[0033] Electrophilic fluorination is distinctly different from standard nucleophilic fluorination, which does not provide 4-fluoro-1H-pyrazole at all.

[0034] Therefore, in the method of the present invention, the electrophilic fluorination reaction of 1H-pyrazole provides 4-fluoro-1H-pyrazole.

[0035] The term salt includes hydrochloride, hydrobromide, sulfate, hydrogen sulfate, etc. of 4-fluoro-1H-pyrazole, with 4-fluoro-1H-pyrazole hydrochloride being preferred.

[0036] According to the implementation scheme of this method, the reaction is carried out in the presence of a base.

[0037] The term "base" includes both inorganic and organic bases.

[0038] According to a preferred embodiment of this method, the base is an inorganic base because inorganic bases provide better conversion compared to organic bases.

[0039] Suitable examples of inorganic bases are alkaline or alkalinehearty salts formed with weak acids.

[0040] In detail, examples of inorganic bases are NaHCO3, Na2CO3 or Na3PO4, KHCO3, K2CO3 or K3PO4.

[0041] According to a preferred embodiment of this method, the inorganic base is NaHCO3, Na2CO3 or Na3PO4, KHCO3, K2CO3 or K3PO4.

[0042] According to a more preferred embodiment, the inorganic base is NaHCO3, because NaHCO3 provides the best and fastest conversion compared to other inorganic bases.

[0043] According to a preferred embodiment of this method, the reaction is carried out at a pH value in the range of 6 to 14, or more preferably 6.0 to 8.0.

[0044] The electrophilic fluorinating agent can be any fluorinating agent with a tendency to attract or gain electrons. Preferably, the electrophilic fluorinating agent is fluorine gas or 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III).

[0045]

[0046] More preferably, the electrophilic fluorinating agent is 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III), because it does not require special equipment, such as equipment required for handling fluorine.

[0047] The reaction in the method of the present invention can be carried out at a temperature in the range of 20°C to 80°C, or preferably 50°C to 80°C.

[0048] Preferably, the reaction is carried out at a temperature in the range of 50°C to 80°C for a duration in the range of 5 to 90 hours.

[0049] The reaction in the method of the present invention can be carried out in an organic solvent, preferably in an organic solvent selected from acetonitrile, dichloromethane and mixtures thereof, and more preferably in an organic solvent selected from acetonitrile.

[0050] According to a preferred embodiment of this method, the reaction is carried out in an organic solvent, acetonitrile, and in the presence of NaHCO3, because it provides a better and faster conversion compared to other inorganic bases and other solvents.

[0051] According to a more preferred embodiment of the method, the electrophilic fluorinating agent is 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III), and the reaction is carried out in an organic solvent of acetonitrile and in the presence of NaHCO3.

[0052] According to a preferred embodiment of the method, the reaction is carried out at a temperature in the range of 50°C to 80°C, the electrophilic fluorinating agent is 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III), and the reaction is carried out in an organic solvent and in the presence of NaHCO3, preferably acetonitrile.

[0053] According to a preferred embodiment of this method, the reaction is carried out at a temperature in the range of 50°C to 80°C, the electrophilic fluorinating agent is 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III), and the reaction is carried out in the absence of any solvent and in the presence of an inorganic base, preferably NaHCO3.

[0054] Alternatively and preferably, the reaction in the method of the present invention can be carried out in the absence of any solvent, since the reaction can be carried out with pyrazole, which is both a reactant and a liquid compound, and is therefore also suitable as a tool for carrying out the reaction. Thus, the term "in the absence of any solvent" means that only pyrazole is present, which acts as a solvent; or alternatively, it means that the reaction is carried out in pyrazole, which serves as a tool for carrying out the reaction. In this case, the amount of pyrazole is in excess relative to the electrophilic fluorinating agent. In particular, the amount of pyrazole is 1 to 50 molar equivalents relative to the electrophilic fluorinating agent, more preferably 2 to 10 molar equivalents, and even more preferably 3 to 6 molar equivalents relative to the electrophilic fluorinating agent. In this case, pyrazole acts both as a reactant and as a tool for carrying out the reaction, or as a solvent for carrying out the reaction.

[0055] Therefore, according to a preferred embodiment of the method, the reaction is carried out in the absence of any solvent, or the reaction is carried out in pyrazole, which serves as the tool for carrying out the reaction.

[0056] According to a more preferred embodiment of this method, the reaction is carried out in the absence of any base, i.e., the reaction is carried out without the addition of any additional base. In fact, pyrazole (II) in excess relative to the compound of formula (III) acts as a base. Therefore, the sentence "the reaction is carried out in the absence of any additional base" means that in this reaction, pyrazole (II) in stoichiometric excess relative to the compound of formula (III) acts as a base.

[0057] According to a preferred embodiment of the invention, the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III), more preferably 4 to 5 molar equivalents.

[0058] According to a preferred embodiment, the reaction is carried out in the absence of any solvent or any additional base, and the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III), more preferably 4 to 5 molar equivalents.

[0059] According to a preferred embodiment, the reaction is carried out in the absence of any solvent or additional base, and the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III), and the reaction is carried out overnight at a temperature of 60°C to 70°C.

[0060] In this method, the compound 4-fluoro-1H-pyrazole of formula (I) can be extracted from a reaction mixture that also contains pyrazole of formula (II) using methyl tert-butyl ether (MTBE). Indeed, it has been found that, unlike other solvents, MTBE is well-suited for extracting 4-fluoropyrazole from mixtures containing pyrazole (see Example 5).

[0061] Surprisingly, going further than MTBE, it was found that the compound 4-fluoro-1H-pyrazole of formula (I) could be extracted from a reaction mixture containing pyrazole of formula (II) using methyl tert-butyl ether (MTBE), wherein the extraction was carried out at pH = 1.8 (see the table in Example 5). At this specific pH, compound (I) could be effectively separated from compound (II). Thus, the combination of MTBE and pH = 1.8 provided a very unexpectedly effective separation of 4-fluoro-pyrazole (I) from pyrazole (II). This separation is particularly important when the reaction is carried out without any other solvent, i.e., when an excess of pyrazole (II) is used as a tool or solvent for the reaction.

[0062] Another objective is the use of pyrazole of formula (II) for the preparation of 4-fluoro-1H-pyrazole of formula (I) or its salts by fluorination of pyrazole of formula (II):

[0063]

[0064] According to a preferred embodiment, the use of 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III) as a fluorinating agent is preferred.

[0065] Those skilled in the art of organic chemistry will understand that the method of the present invention significantly improves the productivity of the production of 4-fluoro-1H-pyrazole or its salts: this is due to the significant reduction in the number of synthetic steps, the fact that the starting material pyrazole is a common and very inexpensive commodity, and the avoidance of industrial-scale handling of carcinogenic substances such as hydrazine.

[0066] Experimental Section

[0067] The starting material pyrazole and all other reagents are readily available on the market. For laboratory-scale applications, they can be purchased from Sigma Aldrich Company.

[0068] Example 1 Preparation of 4-fluoro-1H-pyrazole.

[0069]

[0070] 1 g of pyrazole, 15 mL of acetonitrile, and 1.04 g of 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III) were loaded into a 50 mL glass reactor. The mixture was then stirred and heated to 65 °C for 1 hour.

[0071] Then add 4.16 g of 1-chloromethyl-4-fluoro-1,4-diazazonium-bis[2.2.2]octanebis(tetrafluoroborate) of formula (III) and 0.96 g of NaHCO3, both added in four portions every 2 hours, maintaining pH 6-7. Each portion contains 1.04 g of the compound of formula (III) and 0.24 g of NaHCO3.

[0072] After the addition, the reaction continued for another 3 hours (total reaction time = 10 hours), followed by in-process control, with the following results:

[0073] -GC analysis: Pyrazole (II) = 22.7% (A / A%), 4-Fluoropyrazole (I) = 68.5% (A / A%);

[0074] - HPLC analysis yielded 0.676 g of 4-fluopyrazole (I), representing an unseparated molar yield of 53.5% for 4-fluopyrazole (I).

[0075] Example 2 Preparation of 4-fluoro-1H-pyrazole.

[0076]

[0077] Repeat Example 1, but at room temperature instead of 65°C.

[0078] After 10 hours of reaction, the process control showed the following results:

[0079] -GC analysis: Pyrazole (II) = 92.98% (A / A%), 4-Fluoropyrazole (I) = 6.42% (A / A%).

[0080] Example 3 Preparation of 4-fluoro-1H-pyrazole.

[0081]

[0082] Repeat Example 1, but add all reagents at the start of the reaction.

[0083] After 10 hours of reaction, the process control showed the following results:

[0084] GC analysis: Pyrazole (II) = 29.62% (A / A%), 4-Fluoropyrazole (I) = 59.08% (A / A%).

[0085] Example 4 Preparation of 4-fluoro-1H-pyrazole – A solvent-free and base-free method or one without any additional base.

[0086]

[0087] 384 g of pyrazole (II) (4.0 molar equivalents relative to compound (III)) was charged into a 1 L glass reactor and heated to 75 °C to dissolve.

[0088] Then, the liquid was cooled to 65°C, and then 500g of 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III) was added in batches.

[0089] The mixture was stirred overnight at 65°C. Process controls showed that 80% of the initial pyrazole had reacted. The reaction was stopped by cooling the reaction mixture to room temperature.

[0090] When the mixture reaches room temperature, 1 L of methanol is added, and the resulting suspension is then filtered to remove solid byproducts of compound (III).

[0091] Distill the filtrate (solution) to remove methanol. After distillation, add 36% HCl dropwise to bring the pH of the mixture to 1.8.

[0092] The solution was then extracted three times with MTBE (the total amount of MTBE was 12.5 liters).

[0093] The organic layers were combined and then distilled to remove MTBE by distillation. Afterwards, a solution of HCl in MeOH (at least stoichiometric amounts of HCl relative to the pyrazole reactants) was added, and the mixture was distilled again until dry. EtOAc was added for reslurrying, and after filtration and drying, 95 g of crude solid 4-fluoro-1H-pyrazole hydrochloride (abbreviated FPYR.HCl) was obtained, with a molar yield of 54.9%, HPLC purity of 89%, and pyrazole content of 9.1%.

[0094] Example 5 Preparation of 4-fluoro-1H-pyrazole—A solvent-free and base-free method—pH study of extraction of 4-fluoro-1H-pyrazole (FPYR)(I) with MTBE

[0095] Table I: pH studies used for MTBE extraction

[0096]

[0097] Other solvents, such as CH2Cl2, isopropyl acetate, and sec-butyl acetate, were also tried to extract 4-fluoro-1H-pyrazole (I), but none were superior to MTBE.

Claims

1. A method for preparing 4-fluoro-1H-pyrazole of formula (I) or a salt thereof by reacting pyrazole of formula (II) with a fluorinating agent: The fluorinating agent mentioned above is an electrophilic fluorinating agent. The reaction is carried out in the absence of any solvent, or the reaction is carried out in pyrazole, which serves as the instrument for carrying out the reaction. The 4-fluoro-1H-pyrazole of formula (I) was extracted from the reaction mixture containing pyrazole of formula (II) by means of methyl tert-butyl ether (MTBE). The extraction of 4-fluoro-1H-pyrazole of formula (I) with methyl tert-butyl ether (MTBE) was carried out at pH 1.

8.

2. The method according to claim 1, wherein the reaction is carried out in the presence of a base.

3. The method according to claim 2, wherein the alkali is NaHCO3, Na2CO3 or Na3PO4, KHCO3, K2CO3 or K3PO4.

4. The method of claim 1, wherein the reaction is carried out at a pH value in the range of 6 to 14.

5. The method according to claim 1, wherein the electrophilic fluorinating agent is fluorine gas or 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III): 。 6. The method according to claim 4, wherein the electrophilic fluorinating agent is fluorine gas or 1-chloromethyl-4-fluoro-1,4-diazamonite-bis(2.2.2)octanebis(tetrafluoroborate) of formula (III): 。 7. The method according to claim 1 or claim 6, wherein the reaction is carried out at a temperature in the range of 20°C to 80°C.

8. The method of claim 4, wherein the reaction is carried out at a temperature in the range of 20°C to 80°C.

9. The method of claim 5, wherein the reaction is carried out at a temperature in the range of 20°C to 80°C.

10. The method of claim 7, wherein the reaction is carried out at a temperature in the range of 50°C to 80°C for a duration in the range of 5 to 90 hours.

11. The method according to claim 8 or 9, wherein the reaction is carried out at a temperature in the range of 50°C to 80°C for a duration in the range of 5 to 90 hours.

12. The method according to any one of claims 1, 6 and 8 to 10, wherein the reaction is carried out in the absence of any additional base.

13. The method of claim 4, wherein the reaction is carried out in the absence of any additional base.

14. The method of claim 5, wherein the reaction is carried out in the absence of any additional base.

15. The method of claim 7, wherein the reaction is carried out in the absence of any additional base.

16. The method of claim 11, wherein the reaction is carried out in the absence of any additional base.

17. The method according to any one of claims 13 to 16, wherein the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III).

18. The method of claim 12, wherein the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III).

19. The method according to any one of claims 13 to 16 and 18, wherein the reaction is carried out in the absence of any solvent and any additional base, and the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III).

20. The method of claim 12, wherein the reaction is carried out in the absence of any solvent or any additional base, and the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III).

21. The method of claim 17, wherein the reaction is carried out in the absence of any solvent or any additional base, and the amount of pyrazole (II) is 3 to 6 molar equivalents relative to the compound of formula (III).

22. The method according to any one of claims 13 to 16, 18 and 20 to 21, wherein the reaction is carried out overnight at a temperature of 60°C to 70°C.

23. The method of claim 12, wherein the reaction is carried out overnight at a temperature of 60°C to 70°C.

24. The method of claim 17, wherein the reaction is carried out overnight at a temperature of 60°C to 70°C.

25. The method of claim 19, wherein the reaction is carried out overnight at a temperature of 60°C to 70°C.

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