Production method for fluorinated thio group–containing aryl compound

Abstract

The present invention provides a production method for an aryl compound that contains a thio group that is substituted with at least one fluorine atom. The present invention is a production method for a fluorinated thio group–containing aryl compound that involves synthesizing a fluorinated thio group–containing aryl compound in which at least one fluorine atom has been introduced into a thio group from a thio group–containing aryl compound represented by general formula (1) (in which A1 is a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group, and R1 is a trityl group, a methoxymethyl group, or a benzoyl group) by means of an oxidation fluorination reaction that uses trichloroisocyanuric acid, an alkali metal fluoride, and potassium bis(trifluoromethanesulfonyl)imide, methanol, or trifluoroacetic acid.

Description

Method for producing fluorinated thio-containing aryl compounds

[0001] The present invention relates to a method for producing a fluorinated thio group-containing aryl compound in which the sulfur atom of a thio group bonded to an aryl group is substituted with at least one fluorine atom. This application claims priority to Japanese Patent Application No. 2023-207314 filed on December 7, 2023, and Japanese Patent Application No. 2024-065778 filed on April 15, 2024, the contents of which are incorporated herein by reference.

[0002] Fluorine atoms have a high electronegativity and are as small as hydrogen atoms. This characteristic allows fluorine atoms to bond stably with many atoms, and organic compounds into which fluorine has been introduced tend to have improved heat resistance, chemical resistance, light resistance, water resistance, etc. compared to before the introduction of fluorine. Fluorination of organic compounds allows the synthesis of useful organic compounds, and therefore a variety of fluorinating agents have been developed.

[0003] In recent years, compounds containing sulfur-fluorine bonds have been particularly expected to be useful. For example, pentafluorosulfanyl (SF ５ The CF group is relatively large in size, has high electron-withdrawing ability, is excellent in hydrolysis stability, and has improved lipophilicity, making it a "super trifluoromethyl (CF)" with excellent properties. ３ ) group. Meanwhile, sulfuric acid fluoride, a compound having a sulfur-fluorine bond, has attracted attention as a compound capable of performing a next-generation click reaction called SuFEx (sulfur-fluoride exchange) (Non-Patent Document 1). Similarly, compounds having a sulfur-fluorine bond are expected to be compounds capable of performing SuFEx. However, it is difficult to introduce a group having a sulfur-fluorine bond into existing compounds, and for this reason, despite its great appeal, its application to pharmaceuticals and the like has not progressed very well.

[0004] science fiction ５ There are various methods for synthesizing compounds in which fluorine is introduced into an aryl group such as a phenyl group. ２ ) (Patent Document 1), and a method of directly fluorinating aryl disulfides using chlorine gas (Cl２ ) and potassium fluoride to fluorinate aryl disulfides to give aryl tetrafluorosulfanyl chlorides (Ar-SF ４ After obtaining zinc fluoride (ZnF ２ ) or the like to give arylsulfa pentafluorides (Ar-SF ５ ) (Patent Document 2). ２ As a method using the above-mentioned aryl compound, there is a method for synthesizing a pentafluorosulfanyl group-containing aryl compound from a thioaryl compound in a single step by using silver (II) fluoride and a tetraalkylammonium halide (Patent Document 3).

[0005] JP-T-10-507206 A JP-T-2010-522213 A International Publication No. 2022 / 186304

[0006] Dong et al., Angewandte Chemie International Edition, 2014, vol.53(36), p.9430-9448.

[0007] An object of the present invention is to provide a method for producing an aryl compound containing a thio group substituted with at least one fluorine atom.

[0008] The present inventors have reported that, among the thio groups introduced into aryl or heteroaryl groups, thio groups substituted with a trityl group, a methoxymethyl group, or a benzoyl group can be converted into thio groups by the reaction of trichloroisocyanuric acid (TCICA) (CAS No.: 87-90-1), an alkali metal fluoride, and potassium bis(trifluoromethanesulfonyl)imide (KNTf ２ The present inventors have found that by using a combination of fluorine-containing aryl compounds containing thio groups substituted with at least one fluorine atom in a fluorine-containing aryl group, fluorine-containing aryl compounds containing thio groups substituted with at least one fluorine atom can be efficiently fluorinated under relatively mild conditions.

[0009] That is, the present invention is as follows: [1] A compound represented by the following general formula (1) is obtained by an oxidative fluorination reaction using trichloroisocyanuric acid and an alkali metal fluoride.

[0010]

[0011] [In the formula, A １ is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; R １ [2] A method for producing a fluorinated thio group-containing aryl compound according to the above item [1], wherein the oxidative fluorination reaction is further carried out using potassium bis(trifluoromethanesulfonyl)imide, methanol, or trifluoroacetic acid. [3] A method for producing a fluorinated thio group-containing aryl compound according to the above item [1], wherein the thio group-containing aryl compound represented by the above general formula (1) is synthesized from a fluorinated thio group-containing aryl compound represented by the following general formula (2) using trichloroisocyanuric acid, an alkali metal fluoride, and potassium bis(trifluoromethanesulfonyl)imide:

[0012]

[0013] [In the formula, A １ represents A in general formula (1). １ [4] A method for producing a fluorinated thio group-containing aryl compound according to the above [1] or [2], wherein a fluorinated thio group-containing aryl compound represented by the following general formula (3) is synthesized from the thio group-containing aryl compound represented by the above general formula (1) using trichloroisocyanuric acid, an alkali metal fluoride, and methanol:

[0014]

[0015] [In the formula, A １ represents A in general formula (1). １[5] A method for producing a fluorinated thio group-containing aryl compound according to the above [1], wherein a fluorinated thio group-containing aryl compound represented by the following general formula (4) is synthesized from the thio group-containing aryl compound represented by the above general formula (1) using trichloroisocyanuric acid, an alkali metal fluoride, and trifluoroacetic acid:

[0016]

[0017] [In the formula, A １ represents A in general formula (1). １ [6] A method for producing a fluorinated thio group-containing aryl compound according to the above [1], wherein a fluorinated thio group-containing aryl compound represented by the following general formula (5) is synthesized from the thio group-containing aryl compound represented by the above general formula (1) using trichloroisocyanuric acid, an alkali metal fluoride, and trifluoroacetic acid:

[0018]

[0019] [In the formula, A １ represents A in general formula (1). １ [7] The method for producing a fluorinated thio group-containing aryl compound according to any one of [1] to [6], wherein the alkali metal fluoride is at least one selected from the group consisting of cesium fluoride and potassium fluoride. [8] The method for producing a fluorinated thio group-containing aryl compound according to any one of [1] to [6], wherein the R １ [9] The method for producing a fluorinated thio group-containing aryl compound according to any one of [1] to [7] above, wherein A is a trityl group. １an unsubstituted aryl group, an aryl group having one or more substituents selected from the group consisting of a halogen atom, an alkyl group, a fluorinated alkyl group, an alkenyl group, an aryl group, a heteroaryl group, an alkoxy group, a hydroxy group, a carboxy group, an acyl group, a cyano group, a fluorinated formyl group, an amino group, a nitro group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyrazolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a 1,3-dioxolanyl group, a tetrahydrothiophenyl group, a 1,2-oxathiolanyl group, a morpholinyl group, and a tetrahydropyranyl group, an unsubstituted heteroaryl group, or

[0022] A method for producing a fluorinated thio group-containing aryl compound according to any one of [1] to [8] above, wherein the heteroaryl group has one or more substituents selected from the group consisting of a halogen atom, an alkyl group, a fluorinated alkyl group, an alkenyl group, an aryl group, a heteroaryl group, an alkoxy group, a hydroxy group, a carboxy group, an acyl group, a cyano group, a fluorinated formyl group, an amino group, a nitro group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyrazolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a 1,3-dioxolanyl group, a tetrahydrothiophenyl group, a 1,2-oxathiolanyl group, a morpholinyl group, and a tetrahydropyranyl group.

[10] A method for producing a fluorinated thio group-containing aryl compound according to any one of [1] to [9] above, wherein the oxidative fluorination reaction is carried out at 0 to 80°C.

[11] A method for producing a fluorinated thio group-containing aryl compound according to any one of [1] to

[10] above, wherein the oxidative fluorination reaction is carried out in an aprotic polar solvent.

[0020] According to the method of the present invention, aryl compounds containing a thio group substituted with at least one fluorine atom can be efficiently synthesized from various aryl compounds under relatively mild conditions.

[0021] In the present invention and the present specification, "C ｐ１－ｐ２ " (p1 and p2 are positive integers satisfying p1<p2) means that the group has p1 to p2 carbon atoms.

[0022] In the present invention and the present specification, "C １－６The "alkyl group" is an alkyl group having 1 to 6 carbon atoms, and may be a straight chain, a branched chain, or a ring. １－６ Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, and a cyclohexyl group.

[0023] In the present invention and the present specification, "C １－６ The "alkoxy group" is a C １－６ A group in which an oxygen atom is bonded to the bonding terminal of an alkyl group. １－６ The alkoxy group may be a straight chain or a branched chain. １－６ Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.

[0024] In the present invention and the present specification, "C ２－６ The term "alkenyl group" refers to an alkyl group having 2 to 6 carbon atoms in which at least one carbon-carbon bond is unsaturated. ２－６ The alkenyl group may be a straight chain or a branched chain, or may be a ring. ２－６ Examples of the alkenyl group include a vinyl group, an allyl group, a butenyl group, a pentenyl group, a hexenyl group, and a cyclohexenyl group.

[0025] In the present invention and the present specification, "C ２－７ An "acyl group" is an acyl group in which the hydrocarbon group moiety obtained by removing the carbonyl group is C １－６ Alkyl group, C ２－６ The term "acyl group" refers to a group that is an alkenyl group, a 5- or 6-membered aryl group, or a 5- or 6-membered heteroaryl group. The hydrocarbon group portion of the acyl group may be linear or branched. ２－７ Examples of the acyl group include a formyl group, an acetyl group, a propanoyl group, a propenoyl group, and a benzoyl group.

[0026] In the present invention and this specification, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. The term "halogen atom other than a fluorine atom" refers to a chlorine atom, a bromine atom, or an iodine atom. Preferred examples of "halogen atoms other than a fluorine atom" include a chlorine atom or a bromine atom, with a chlorine atom being particularly preferred.

[0027] In the following description, "compound (n)" means a compound represented by formula (n).

[0028] <Method for Producing Fluorinated Thio Group-Containing Aryl Compound> The method for producing a fluorinated thio group-containing aryl compound according to the present invention is a method for synthesizing a fluorinated thio group-containing aryl compound having at least one fluorine atom introduced into the thio group from a thio group-containing aryl compound represented by the following general formula (1) by an oxidative fluorination reaction using TCICA and an alkali metal fluoride. The method for producing a fluorinated thio group-containing aryl compound according to the present invention further comprises the step of: ２ , methanol, or TFA.

[0029]

[0030] In general formula (1), R １ is a trityl group, a methoxymethyl group, or a benzoyl group.

[0031] In general formula (1), A １ is an aryl group which may have a substituent or a heteroaryl group which may have a substituent. In the present invention and this specification, the term "aryl group which may have a substituent" includes both an unsubstituted aryl group and an aryl group which has at least one substituent. Similarly, the term "heteroaryl group which may have a substituent" includes both an unsubstituted heteroaryl group and a heteroaryl group which has at least one substituent.

[0032] A １ The aryl group and heteroaryl group of the formula (I) may be any group as long as the ring structure to which S is bonded has aromaticity, and may be a group having a condensed ring of an aryl ring or heteroaryl ring and a non-aromatic ring.１ The aryl group may be a monovalent group of a benzdioxane ring in which a benzene ring and a dioxane ring are condensed.

[0033] A １ When A is an aryl group which may have a substituent, the aryl group is not particularly limited, and examples thereof include fused ring groups of aromatic rings such as a phenyl group, a naphthyl group, and an anthryl group; and fused ring groups of an aromatic ring and a non-aromatic ring such as a 9-fluorenyl group, a dibenzofuranyl group, a benzodioxolanyl group, a chromenyl group, a carbazolyl group, a fluorenyl group, and a phenoxazinyl group. １ When is a heteroaryl group which may have a substituent, the heteroaryl group is not particularly limited, and examples thereof include heteroaryl groups having a nitrogen atom such as a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazolyl group, a quinolyl group, an isoquinolyl group, a pyrrolyl group, an imidazolyl group, an indolyl group, a quinazolinyl group, a quinoxalinyl group, and a phenazinyl group; heteroaryl groups having an oxygen atom such as a furyl group and a benzofuryl group; heteroaryl groups having a sulfur atom such as a thienyl group, a benzothienyl group, and a benzothiophenyl group; heteroaryl groups having a nitrogen atom and a sulfur atom such as a thiazolyl group, a benzothiazolyl group, an isothiazolyl group, a benzoisothiazolyl group, a thiazinyl group, and a benzothiazinyl group; and heteroaryl groups having a nitrogen atom and an oxygen atom such as an oxazolyl group, a benzoxazolyl group, an isoxazolyl group, a benzoisoxazolyl group, and a benzodioxazolyl group. １ As the heteroaryl group, a heteroaryl group having a nitrogen or oxygen atom is more preferred, and a heteroaryl group having a nitrogen atom is even more preferred, for reasons of reactivity.

[0034] A "substituted aryl group" is a group in which one or more, preferably 1 to 3, of the hydrogen atoms bonded to the carbon atoms of the aryl group have been substituted with other functional groups. Similarly, a "substituted heteroaryl group" is a group in which one or more, preferably 1 to 3, of the hydrogen atoms bonded to the carbon atoms of the heteroaryl group have been substituted with other functional groups. When a heteroaryl group has two or more substituents, the substituents may be the same or different.

[0035] A １ The substituents on the aryl group or heteroaryl group are not particularly limited as long as they do not inhibit the thiotritylation of the halogen atom in the halogenated aryl compound (1). Examples of the substituents include halogen atoms, alkyl groups, fluorinated alkyl groups, alkenyl groups, alkoxy groups, aryl groups, heteroaryl groups, acyl groups, hydroxy groups, carboxy groups, cyano groups, fluorinated formyl groups (-C(=O)F), amino groups, nitro groups, and non-aromatic heterocyclic groups. The alkyl groups include C １－６ The alkyl group is preferred, and the alkenyl group is C ２－６ The alkyl group is preferred, and the alkoxy group is C １－６ Alkoxy groups are preferred, and C ２－７ An acyl group is preferred. The fluorinated alkyl group is C １－６ A group in which one or more hydrogen atoms of an alkyl group are substituted with fluorine atoms is preferred, and a fully fluorinated C group in which all hydrogen atoms are substituted with fluorine atoms is preferred. １－６ An alkyl group is more preferred, and a trifluoromethyl group is particularly preferred. １ Examples of the non-aromatic heterocyclic group include the same groups as those exemplified as the aryl group and heteroaryl group of the formula (1), and a phenyl group or a pyridyl group is preferred. Examples of the non-aromatic heterocyclic group include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyrazolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a 1,3-dioxolanyl group, a tetrahydrothiophenyl group, a 1,2-oxathiolanyl group, a morpholinyl group, and a tetrahydropyranyl group. １Regarding the position of the substituent on the aryl group or heteroaryl group, from the viewpoint of reactivity, it is preferable that there is no substituent at at least one ortho-position relative to the sulfur atom, and it is preferable that there is no substituent at both ortho-positions. That is, the substituent is preferably located at the meta-position or the para-position.

[0036] A １ When the substituent of the aryl group or heteroaryl group is an alkyl group, an alkenyl group, an alkoxy group, an aryl group, a heteroaryl group, an acyl group, or an amino group, these substituents may further have a substituent. Examples of the substituent include the same groups as those described above. For example, A １ As for the C １－６ It may be an aryl group having an alkyl group as a substituent, and may be a C １－６ It may be an aryl group having an alkyl group as a substituent. １ The aryl group may be an aryl group having an unsubstituted amino group as a substituent, or an aryl group having an amino group as a substituent in which one or two hydrogen atoms are substituted with a phenyl group.

[0037] A １ The substituents on the aryl and heteroaryl groups may be protected with protecting groups. Groups commonly used in organic synthesis can be used as appropriate as the protecting groups. For example, when the substituent is an amino group, the two hydrogen atoms of the amino group can be substituted with a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an allyloxycarbonyl group, a trifluoroacetyl group, a phthaloyl group, a p-toluenesulfonyl group, or a 2-nitrobenzenesulfonyl group before the amino group is subjected to the thiotritylation reaction. Similarly, when the substituent is a carboxy group, the hydrogen atoms of the carboxy group can be substituted with a benzyl group or a tert-butyl group.

[0038] A １When is an optionally substituted heteroaryl group, the heteroatom in the heteroaryl group may also be protected with a protecting group. Examples of such protecting groups include the same groups as those described above.

[0039] In the present invention, the thio group-containing aryl compound (1) is １ However, an optionally substituted phenyl group, an optionally substituted benzodioxazolyl group, an optionally substituted benzodiisolanyl group, an optionally substituted dibenzofuranyl group, an optionally substituted indolyl group, an optionally substituted quinoxalinyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidinyl group, or an optionally substituted furanyl group is preferred. When these groups have a substituent, an optionally substituted C １－６ alkyl group, optionally substituted C １－６ an alkoxy group, an optionally substituted C ２－７ It is preferably a group having 1 to 3 substituents selected from the group consisting of an acyl group, a halogen atom, an amino group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, a piperazinyl group which may have a substituent, and a cyano group.

[0040] The alkali metal fluoride used as the fluorinating agent in the present invention may be, for example, any of lithium fluoride (LiF), sodium fluoride (NaF), potassium fluoride (KF), rubidium fluoride (RbF), cesium fluoride (CsF), and francium fluoride (FrF). From the viewpoints of reactivity and ease of handling, however, it is preferably one or more selected from the group consisting of KF, RbF, and CsF, and more preferably one or more selected from the group consisting of KF and CsF.

[0041] Fluorinating agents include TCICA, alkali metal fluorides, and KNTf ２ When A is used in combination with A, a fluorinated thio group-containing aryl compound represented by the following general formula (2) is synthesized from the thio group-containing aryl compound (1). １represents A in general formula (1). １ is the same as:

[0042]

[0043] When TCICA, an alkali metal fluoride, and methanol are used in combination as a fluorinating agent, a fluorinated thio group-containing aryl compound represented by the following general formula (3) is synthesized from the thio group-containing aryl compound (1). １ represents A in general formula (1). １ is the same as:

[0044]

[0045] When TCICA, an alkali metal fluoride, and TFA are used in combination as a fluorinating agent, a fluorinated thio group-containing aryl compound represented by the following general formula (4) is synthesized from the thio group-containing aryl compound (1). １ represents A in general formula (1). １ is the same as:

[0046]

[0047] When TCICA, an alkali metal fluoride, and TFA are used in combination as a fluorinating agent, a fluorinated thio group-containing aryl compound represented by the following general formula (5) is synthesized from the thio group-containing aryl compound (1). １ represents A in general formula (1). １ is the same as:

[0048]

[0049] The amount of TCICA added to the reaction system may be at least a stoichiometric amount. From the viewpoints of reaction efficiency and cost, the amount of TCICA used in the oxidative fluorination reaction is preferably 1 to 20 equivalents, more preferably 1 to 10 equivalents, of the thio group-containing aryl compound (1).

[0050] The amount of alkali metal fluoride added to the reaction system is not particularly limited, but from the viewpoint of reaction efficiency, it is preferably 5 equivalents or more, more preferably 8 equivalents or more, and even more preferably 10 equivalents or more, of the thio group-containing aryl compound (1). From the viewpoint of cost, the amount of alkali metal fluoride used in the oxidative fluorination reaction is preferably 100 equivalents or less, more preferably 50 equivalents or less, even more preferably 30 equivalents or less, and even more preferably 20 equivalents or less, of the thio group-containing aryl compound (1).

[0051] KNTf added to the reaction system ２ The amounts of KNTf, methanol, and TFA may be stoichiometric or greater. ２ The amounts of methanol and TFA used are preferably 0.1 to 5 equivalents, more preferably 0.5 to 5 equivalents, and even more preferably 1 to 5 equivalents, based on the amount of the thio group-containing aryl compound (1).

[0052] The oxidative fluorination reaction can be carried out in a solvent inert to the reaction. The inert solvent is not particularly limited, but an aprotic polar solvent is preferred. Examples of the aprotic polar solvent include acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane (DCM), and diethyl ether. The solvent used in the reaction may be a mixed solvent of two or more solvents.

[0053] The oxidative fluorination reaction is carried out by mixing the thio group-containing aryl compound (1), TCICA, and an alkali metal fluoride in a reaction solvent, and reacting the resulting mixture at an appropriate temperature for an appropriate time. ２A reaction solution obtained by mixing the above with methanol or TFA is reacted at an appropriate temperature for an appropriate time. The oxidative fluorination reaction proceeds under mild conditions. For example, the reaction temperature is not particularly limited as long as the reaction solvent is in a liquid state. The reaction can be carried out at a temperature of −40 to 130°C, preferably 0 to 80°C, or at room temperature (0 to 30°C). For example, the reaction time can be 1 to 48 hours, preferably 3 to 36 hours, and more preferably 6 to 24 hours. Furthermore, for example, the oxidative fluorination reaction can be carried out at room temperature for less than 1 hour to obtain the desired fluorinated thio group-containing aryl compound in essentially quantitative yield.

[0054] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0055] Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Dry and degassed solvents were used in all reactions under argon. All reported yields refer to spectroscopically and chromatographically pure compounds unless otherwise specified.

[0056] １９ F nuclear magnetic resonance (NMR) spectra were measured at ambient temperature using an NMR spectrometer (JEOL, JNM-ECZ400S) or an NMR spectrometer (JEOL, ECZ500R) unless otherwise specified. The solvents used and their respective measurement frequencies are indicated for each experiment. Resonance multiplicities are expressed as s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), m (multiplet), and br (broad). Unless otherwise specified, all spectra were broadband decoupled.

[0057] [Production Example 1] Typical Production Method A for Synthesizing Tetrafluorosulfanyl Group-Containing Aryl Compounds

[0058]

[0059] ​In a glove box under argon atmosphere, a glass vial was charged with a magnetic stir bar, aryl trityl sulfide (0.1 mmol), trichloroisocyanuric acid (TCICA, 0.5 mmol, 5 equivalents), CsF (1.0 mmol, 10 equivalents), and potassium bis(trifluoromethanesulfonyl)imide (KNTf ２ , 0.1 mmol, 1.0 equivalent) was placed in the reaction mixture. MeCN (1 mL, 0.1 M) was added to the mixture in the vial with vigorous stirring. The vial was then sealed with a screw cap, and the reaction solution in the vial was stirred at room temperature for 24 hours in a glove box. After the reaction, 1,4-bis(trifluoromethyl)benzene (15.5 μL, 0.1 mmol) was added to the reaction mixture as an internal standard (1 equivalent), and the precipitate in the reaction mixture was removed by syringe filtration. １９ For F NMR measurements, 0.3 mL of the filtrate and 0.3 mL of CD ３ NMR samples were prepared using CN.

[0060] [Production Example 2] Typical Production Method B for Synthesizing Tetrafluorosulfanyl Group-Containing Aryl Compounds

[0061]

[0062] In a glove box under an argon atmosphere, a glass vial was charged with a magnetic stir bar, a methoxymethyl aryl sulfide (0.2 mmol), TCICA (1.0 mmol, 5 equiv.), CsF (2.0 mmol, 10 equiv.), and KNTf ２ (0.2 mmol, 1.0 equivalent) was placed in the reaction mixture. MeCN (2 mL, 0.1 M) was added to the mixture in the vial with vigorous stirring. The vial was then sealed with a screw cap, and the reaction solution in the vial was stirred at room temperature for 24 hours in a glove box. After the reaction, 1,4-bis(trifluoromethyl)benzene (31 μL, 0.1 mmol) was added to the reaction mixture as an internal standard (1 equivalent), and the precipitate in the reaction mixture was removed by syringe filtration. １９ For F NMR measurements, 0.3 mL of the filtrate and 0.3 mL of CD ３ NMR samples were prepared using CN.

[0063] [Production Example 3] Typical Production Method C for Synthesizing Tetrafluorosulfanyl Group-Containing Aryl Compounds

[0064]

[0065] In a glove box under an argon atmosphere, a glass vial was charged with a magnetic stir bar, aryl thiobenzoate (0.1 mmol), TCICA (0.2 mmol, 5 equivalents), CsF (1.0 mmol, 10 equivalents), and KNTf ２ (0.1 mmol, 1.0 equivalent) was placed in the reaction mixture. MeCN (1 mL, 0.1 M) was added to the mixture in the vial with vigorous stirring. The vial was then sealed with a screw cap, and the reaction solution in the vial was stirred at room temperature for 24 hours in a glove box. After the reaction, 1,4-bis(trifluoromethyl)benzene (15.5 μL, 0.1 mmol) was added to the reaction mixture as an internal standard (1 equivalent), and the precipitate in the reaction mixture was removed by syringe filtration. １９ For F NMR measurements, 0.3 mL of the filtrate and 0.3 mL of CD ３ NMR samples were prepared using CN.

[0066] [Production Example 4] Typical Production Method D for Synthesizing Monofluorosulfonyl Group-Containing Aryl Compounds

[0067]

[0068] In a glove box under an argon atmosphere, a glass vial was charged with a magnetic stir bar, aryl trityl sulfide (0.1 mmol), TCICA (0.5 mmol, 5 equivalents), and CsF (1.0 mmol, 10 equivalents). To the mixture in the vial, MeCN (1 mL, 0.1 M) was added with vigorous stirring, followed by the addition of a MeOH / MeCN solution (0.2 mL of a 1 M solution of MeOH in MeCN). The vial was then sealed with a screw cap, and the reaction mixture in the vial was stirred at room temperature for 24 hours in a glove box. After the reaction, 1,4-bis(trifluoromethyl)benzene (15.5 μL, 0.1 mmol) was added as an internal standard (1 equivalent) to the reaction mixture, and the solids in the reaction mixture were removed by syringe filtration. １９For F NMR measurements, 0.3 mL of the filtrate and 0.3 mL of CD ３ NMR samples were prepared using CN.

[0069] [Production Example 5] Typical Production Method E for Synthesizing Trifluorosulfinyl Group-Containing Aryl Compounds

[0070]

[0071] In a glove box under an argon atmosphere, a glass vial was charged with a magnetic stir bar, aryl trityl sulfide (0.1 mmol), TCICA (0.9 mmol, 9 equivalents), and CsF (1.6 mmol, 16 equivalents). To the mixture in the vial, MeCN (1 mL, 0.1 M) was added with vigorous stirring, followed by the addition of a TFA / MeCN solution (0.2 mL of a solution in which TFA was dissolved in MeCN to a concentration of 0.1 M). The vial was then sealed with a screw cap, and the reaction solution in the vial was stirred at room temperature for 24 hours in a glove box. After the reaction, 1,4-bis(trifluoromethyl)benzene (15.5 μL, 0.1 mmol) was added as an internal standard (1 equivalent) to the reaction mixture, and the solids in the reaction mixture were removed by syringe filtration. １９ For F NMR measurements, 0.3 mL of the filtrate and 0.3 mL of CD ３ NMR samples were prepared using CN.

[0072] Example 1 4-(trans-4'-propylcyclohexyl)phenyltetrafluoro-λ ６ -sulfanyl chloride was synthesized from 1-[(trityl)thio]-4-(trans-4'-propylcyclohexyl)benzene (0.1 mmol, 47.7 mg) according to Preparation Method A described in Preparation Example 1. １９ The yield, as determined by F NMR, was 80%.

[0073]

[0074] 19 F NMR (376 MHz, CD3CN) δ 137.7 (s).

[0075] Example 2 4-Fluorophenyltetrafluoro-λ６ -sulfanyl chloride was synthesized from 4-fluorophenyltrityl sulfide (0.1 mmol, 37.1 mg) according to Preparation A described in Preparation 1. １９ The yield, as determined by F NMR, was 73%.

[0076]

[0077] 19 F NMR (376 MHz, CD3CN)δ 137.3 (s).

[0078] Example 3 4'-Bromo-[1,1'-biphenyl]-4-tetrafluoro-λ ６ -sulfanyl chloride was synthesized from 4-bromo-4'-[(trityl)thio]-1,1'biphenyl (0.1 mmol, 50.8 mg) according to Preparation A described in Preparation 1. １９ The yield, as determined by F NMR, was 50%.

[0079]

[0080] 19 F NMR (376 MHz, CD3CN)δ 137.1 (s).

[0081] Example 4 4'-chloro-[1,1'-biphenyl]-4-tetrafluoro-λ ６ -sulfanyl chloride was synthesized from 4-chloro-4'-[(trityl)thio]-1,1'biphenyl (0.1 mmol, 46.3 mg) according to Preparation A described in Preparation 1. １９ The yield, as determined by F NMR, was 60%.

[0082]

[0083] 19 F NMR (376 MHz, CD3CN)δ 137.2 (s).

[0084] [Example 5] 1,3-diphenyl-5-tetrafluoro-λ ６-sulfanyl chloride was synthesized from 5'-[(trityl)thio]-m-terphenyl (0.1 mmol, 50.5 mg) according to Preparation A described in Preparation Example 1. １９ The yield as determined by F NMR was 9%.

[0085]

[0086] 19 F NMR (376 MHz, CD3CN)δ 137.0 (s).

[0087] [Example 6] Phenyltetrafluoro-λ ６ -sulfanyl chloride was synthesized from phenyltrityl sulfide (0.1 mmol, 35.3 mg) according to Preparation A described in Preparation Example 1. １９ The yield as determined by F NMR was 68%.

[0088] Phenyltetrafluoro-λ ６ -sulfanyl chloride could also be prepared from phenylmethoxymethyl sulfide (0.1 mmol, 15.4 mg) according to Preparation B described in Preparation 2. １９ The yield, as determined by F NMR, was 39%.

[0089]

[0090] 19 F NMR (376 MHz, CD3CN)δ 136.6 (s).

[0091] [Example 7] 4-cyanophenyltetrafluoro-λ ６ -sulfanyl chloride was synthesized from 4-cyanophenyl thiobenzoate (0.1 mmol, 23.9 mg) according to Preparation C described in Preparation 3. １９ The yield, as determined by F NMR, was 72%.

[0092]

[0093] 19 F NMR (376 MHz, CD3CN)δ 134.6 (s).

[0094] [Example 8] 4'-propyl-[1,1'-biphenyl]-4-tetrafluoro-λ ６ -sulfanyl chloride was synthesized from 4'-propyl-[1,1'-biphenyl]-4-thiobenzoate (0.1 mmol, 33.3 mg) according to Preparation C described in Preparation 3. １９ The yield as determined by F NMR was 51%.

[0095]

[0096] 19 F NMR (376 MHz, CD3CN)δ 137.4 (s).

[0097] Example 9 2-(ethylcarboxyl)benzofuranyl-5-tetrafluoro-λ ６ -sulfanyl chloride was synthesized from 5-(benzoylthio)-2-(ethylcarboxyl)benzofuran (0.1 mmol, 32.6 mg) according to Preparation C described in Preparation 3. １９ The yield, as determined by F NMR, was 8%.

[0098]

[0099] 19 F NMR (376 MHz, CD3CN)δ 139.0 (s).

[0100] [Example 10] 3-chloro-4-iodophenyltetrafluoro-λ ６ -sulfanyl chloride was synthesized from 3-chloro-4-iodophenylthiobenzoate (0.1 mmol, 37.5 mg) according to Preparation C described in Preparation 3. １９ The yield, as determined by F NMR, was 15%.

[0101]

[0102] 19 F NMR (376 MHz, CD3CN)δ 134.6 (s).

[0103] Example 11 4-(trans-4'-propylcyclohexyl)phenylsulfonyl fluoride was synthesized from 1-[(trityl)thio]-4-(trans-4'-propylcyclohexyl)benzene (0.1 mmol, 47.7 mg) according to Preparation Method D described in Preparation Example 4. １９ The yield, as determined by F NMR, was 85%.

[0104]

[0105] 19 F NMR (376 MHz, CD3CN) δ 65.1 (s).

[0106] Example 12 4-Fluorophenylsulfonyl fluoride was synthesized from 4-fluorophenyltrityl sulfide (0.1 mmol, 37.1 mg) according to Preparation D described in Preparation Example 4. １９ The yield as determined by F NMR was 83%.

[0107]

[0108] 19 F NMR (376 MHz, CD3CN)δ 66.4(s,1F), -100.2(s,1F).

[0109] Example 13 4'-Bromo-[1,1'-biphenyl]-4-sulfonyl fluoride was synthesized from 4-bromo-4'-[(trityl)thio]-1,1'biphenyl (0.1 mmol, 50.8 mg) according to Preparation D described in Preparation Example 4. １９ The yield as determined by F NMR was 84%.

[0110]

[0111] 19 F NMR (376 MHz, CD3CN)δ 65.1 (s).

[0112] Example 14 4'-Chloro-[1,1'-biphenyl]-4-sulfonyl fluoride was synthesized from 4-chloro-4'-[(trityl)thio]-1,1'biphenyl (0.1 mmol, 46.3 mg) according to Preparation D described in Preparation Example 4.１９ The yield, as determined by F NMR, was 77%.

[0113]

[0114] 19 F NMR (376 MHz, CD3CN)δ 65.1 (s).

[0115] Example 15 1,3-Diphenylbenzene-5-sulfonyl fluoride was synthesized from 5'-[(trityl)thio]-m-terphenyl (0.1 mmol, 50.5 mg) according to Preparation D described in Preparation Example 4. １９ The yield as determined by F NMR was 51%.

[0116]

[0117] 19 F NMR (376 MHz, CD3CN)δ 64.5 (s).

[0118] Example 16 4-(trans-4'-propylcyclohexyl)phenylsulfur trifluoroxide was synthesized from 1-[(trityl)thio]-4-(trans-4'-propylcyclohexyl)benzene (0.1 mmol, 47.7 mg) according to Production Method E described in Production Example 5. １９ The yield, as determined by F NMR, was 75%.

[0119]

[0120] 19 F NMR (376 MHz, CD3CN) δ 99.4 (d, 2 J FF = 156.8 Hz, 2F), 65.5 (t, 2 J FF = 156.9 Hz, 1F).

[0121] Example 17 4-Fluorophenylsulfur trifluoride was synthesized from 4-fluorophenyltrityl sulfide (0.1 mmol, 37.1 mg) according to Preparation E described in Preparation Example 5. １９ The yield, as determined by F NMR, was 65%.

[0122]

[0123] 19 F NMR (376 MHz, CD3CN) δ 100.3 (d, 2 J FF = 158.4 Hz, 2F), 66.6 (t, 2 J FF = 158.2 Hz, 1F).

[0124] Example 18 4'-Bromo-[1,1'-biphenyl]-4-sulfur trifluoroxide was synthesized from 4-bromo-4'-[(trityl)thio]-1,1'biphenyl (0.1 mmol, 50.8 mg) according to Preparation E described in Preparation Example 5. １９ The yield, as determined by F NMR, was 73%.

[0125]

[0126] 19 F NMR (376 MHz, CD3CN) δ 100.1 (d, 2 J FF = 158.1 Hz, 2F), 65.8 (t, 2 J FF = 158.1 Hz, 1F).

[0127] Example 19 4′-Bromo-[1,1′-biphenyl]-4-sulfur trifluoroxide was synthesized from 4-bromophenyltrityl sulfide (0.1 mmol, 43.1 mg) according to Preparation E described in Preparation Example 5. １９ The yield, as determined by F NMR, was 65%.

[0128]

[0129] 19 F NMR (376 MHz, CD3CN) δ 100.6 (d, 2 J FF = 159.4 Hz, 2F), 66.0 (t, 2 J FF = 159.4 Hz, 1F).

[0130] Example 20 4-Chlorophenylsulfur trifluoride was synthesized from 4-chlorophenyltrityl sulfide (0.1 mmol, 38.7 mg) according to Preparation E described in Preparation Example 5. １９ The yield, as determined by F NMR, was 80%.

[0131]

[0132] 19 F NMR (376 MHz, CD3CN) δ 100.5 (d, 2 J FF = 159.2 Hz, 2F), 66.1 (t, 2 J FF = 159.2 Hz, 1F).

[0133] [Production Example 6] Typical Production Method F for Synthesizing Sulfinyl Fluoride Group-Containing Aryl Compounds

[0134]

[0135] In a glove box under an argon atmosphere, a glass vial was charged with a magnetic stir bar, aryltrityl sulfide (0.1 mmol), TCICA (0.2 mmol, 2 equivalents), and CsF (5 mmol, 5 equivalents). MeCN (1 mL, 0.1 M) was added to the mixture in the vial while vigorously stirring. The vial was then sealed with a screw cap, and the reaction solution in the vial was stirred at room temperature for 3 hours in a glove box. TFA (0.1 mmol, 2 equivalents) was then added to the reaction solution, followed by further stirring at room temperature for 4 hours. After the reaction, 1,4-bis(trifluoromethyl)benzene (15.5 μL, 0.1 mmol) was added to the reaction mixture as an internal standard (1 equivalent), and the solids in the reaction mixture were removed by syringe filtration. １９ For F NMR measurements, 0.3 mL of the filtrate and 0.3 mL of CD ３ NMR samples were prepared using CN.

[0136] Example 21 4-(trans-4'-propylcyclohexyl)phenylsulfinyl fluoride was synthesized from 1-[(trityl)thio]-4-(trans-4'-propylcyclohexyl)benzene (0.1 mmol, 47.7 mg) according to Preparation F described in Preparation Example 6. １９ The yield as determined by F NMR was 64%.

[0137]

[0138] 19 F NMR (376 MHz, CD3CN) δ 8.7 (s).

[0139] Example 22 5-{2-ethoxy-5-sulfinylfluoride-phenyl}-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one was synthesized from 5-{2-ethoxy-5-[(trityl)thio]-phenyl}-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one (0.1 mmol, 58.7 mg) according to Preparation F described in Preparation 6. １９ The yield, as determined by F NMR, was 11%.

[0140]

[0141] 19 F NMR (376 MHz, CD3CN) δ 10.7 (s).

[0142] Example 23 4-Benzoylbenzenesulfonyl fluoride was synthesized from 4-[(trityl)thio]benzophenone (0.1 mmol, 45.6 mg) according to Preparation F described in Preparation Example 6. １９ The yield, as determined by F NMR, was 73%.

[0143]

[0144] 19 F NMR (376 MHz, CD3CN) δ 64.5 (s).

[0145] [Example 24] 4-benzoylbenzene-1-tetrafluoro-λ ６-sulfanyl chloride was synthesized from 4-[(trityl)thio]benzophenone (0.1 mmol, 45.6 mg) according to Preparation A described in Preparation 1. １９ The yield, as determined by F NMR, was 76%.

[0146]

[0147] 19 F NMR (376 MHz, CD3CN) δ 135.7 (s).

[0148] Example 25 4-Benzoylbenzene-1-sulfur trifluoroxide was synthesized from 4-[(trityl)thio]benzophenone (0.1 mmol, 45.6 mg) according to Preparation Method E described in Preparation Example 5. １９ The yield as determined by F NMR was 83%.

[0149]

[0150] 19 F NMR (376 MHz, CD3CN) δ 101.5 (d, 2 J FF = 159.8 Hz, 2F), 64.8 (t, 2 J FF = 159.8 Hz, 1F).

[0151] Example 26 5-{2-ethoxy-5-sulfurtrifluoroxide-phenyl}-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one was synthesized from 5-{2-ethoxy-5-[(trityl)thio]-phenyl}-1-methyl-3-propyl-6H-pyrazolo[4,3-d]pyrimidin-7-one (0.1 mmol, 58.7 mg) according to Preparation E described in Preparation 5. １９ The yield as determined by F NMR was 51%.

[0152]

[0153] 19 F NMR (376 MHz, CD3CN) δ 97.1 (dd, 2 J FF= 157.4, 28.5 Hz, 2F), 68.2 (t, 2 J FF = 157.3 Hz, 1F).

[0154] Example 27 Methyl 4-(fluorosulfonyl)benzoate was synthesized from methyl 4-[(trityl)thio]benzoate (0.1 mmol, 41.1 mg) according to Preparation E described in Preparation Example 5. １９ The yield as determined by F NMR was 84%.

[0155]

[0156] 19 F NMR (376 MHz, CD3CN) δ 101.71 (d, 2 J FF = 160.1 Hz, 2F), 64.6 (t, 2 J FF = 160.1 Hz, 1F).

[0157] [Example 28] 2-Fluoropyridine-5-tetrafluoro-λ ６ -sulfanyl chloride was synthesized from 2-fluoro-5-[(trityl)thio]pyridine (0.1 mmol, 37.2 mg) according to Preparation A described in Preparation 1. １９ The yield, as determined by F NMR, was 30%.

[0158]

[0159] 19 F NMR (376 MHz, CD3CN) δ 138.4 (s).

[0160] [Example 29] 2-Fluoropyridine-4-tetrafluoro-λ ６ -sulfanyl chloride was synthesized from 2-fluoro-4-[(trityl)thio]pyridine (0.1 mmol, 37.2 mg) according to Preparation A described in Preparation 1. １９ The yield, as determined by F NMR, was 34%.

[0161]

[0162] 19 F NMR (376 MHz, CD3CN) δ 132.3 (s).

[0163] Example 30 N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-sulfonylfluoridequinazolin-4-amine was synthesized from N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-[(trityl)thio]quinazolin-4-amine (0.1 mmol, 65.4 mg) according to Preparation D described in Preparation 4. １９ The yield as determined by F NMR was 51%.

[0164]

[0165] 19 F NMR (376 MHz, CD3CN) δ 65.0 (s).

[0166] Example 31 2-Benzyloxypyrimidine-5-sulfonyl fluoride was synthesized from 2-benzyloxy-5-[(trityl)thio]pyrimidine (0.1 mmol, 46.1 mg) according to Preparation D described in Preparation Example 4. １９ The yield, as determined by F NMR, was 17%.

[0167]

[0168] 19 F NMR (376 MHz, CD3CN) δ 68.5 (s).

[0169] Example 32 2,4-Dimethoxypyrimidine-5-sulfonyl fluoride was synthesized from 2,4-dimethoxy-5-[(trityl)thio]pyrimidine (0.1 mmol, 41.5 mg) according to Preparation D described in Preparation 4. １９ The yield, as determined by F NMR, was 19%.

[0170]

[0171] 19 F NMR (376 MHz, CD3CN) δ 61.4 (s).

[0172] The present invention provides a production method that enables the synthesis of a compound having a fluorinated thio group introduced therein by an oxidative fluorination reaction under relatively mild conditions. The compound having a fluorinated thio group introduced therein can undergo SuFEx, which is attracting attention as a next-generation click reaction, and is expected to be useful as a pharmaceutical. Therefore, the present invention is useful for the synthesis of pharmaceuticals.

Claims

1. A compound represented by the following general formula (1) is obtained by an oxidative fluorination reaction using trichloroisocyanuric acid, an alkali metal fluoride, potassium bis(trifluoromethanesulfonyl)imide, methanol, or trifluoroacetic acid. [In the formula, A １ is an unsubstituted aryl group, a substituted aryl group, an unsubstituted heteroaryl group, or a substituted heteroaryl group; R １ wherein R is a trityl group, a methoxymethyl group, or a benzoyl group, to synthesize a fluorinated thio group-containing aryl compound in which at least one fluorine atom has been introduced into the thio group.

2. Using trichloroisocyanuric acid, an alkali metal fluoride, and potassium bis(trifluoromethanesulfonyl)imide, a thio group-containing aryl compound represented by the general formula (1) is converted into a thio group-containing aryl compound represented by the following general formula (2): [In the formula, A １ is A in general formula (1). １ The method for producing a fluorinated thio group-containing aryl compound according to claim 1 , further comprising synthesizing a fluorinated thio group-containing aryl compound represented by the formula:

3. Using trichloroisocyanuric acid, an alkali metal fluoride, and methanol, a thio group-containing aryl compound represented by the general formula (1) is converted into a thio group-containing aryl compound represented by the following general formula (3): [In the formula, A １ is A in general formula (1). １ The method for producing a fluorinated thio group-containing aryl compound according to claim 1 , further comprising synthesizing a fluorinated thio group-containing aryl compound represented by the formula:

4. Using trichloroisocyanuric acid, an alkali metal fluoride, and trifluoroacetic acid, a thio group-containing aryl compound represented by the general formula (1) is converted into a thio group-containing aryl compound represented by the following general formula (4): [In the formula, A １ is A in general formula (1). １ The method for producing a fluorinated thio group-containing aryl compound according to claim 1 , further comprising synthesizing a fluorinated thio group-containing aryl compound represented by the formula:

5. Using trichloroisocyanuric acid, an alkali metal fluoride, and trifluoroacetic acid, a thio group-containing aryl compound represented by the general formula (1) is converted into a thio group-containing aryl compound represented by the following general formula (5): [In the formula, A １ is A in general formula (1). １ The method for producing a fluorinated thio group-containing aryl compound according to claim 1 , further comprising synthesizing a fluorinated thio group-containing aryl compound represented by the formula:

6. The method for producing a fluorinated thio group-containing aryl compound according to claim 1, wherein the alkali metal fluoride is at least one selected from the group consisting of cesium fluoride and potassium fluoride.

7. The above R １ The method for producing a fluorinated thio group-containing aryl compound according to claim 1, wherein is a trityl group.

8. Section A above １ an unsubstituted aryl group, an aryl group having one or more substituents selected from the group consisting of a halogen atom, an alkyl group, a fluorinated alkyl group, an alkenyl group, an aryl group, a heteroaryl group, an alkoxy group, a hydroxy group, a carboxy group, an acyl group, a cyano group, a fluorinated formyl group, an amino group, a nitro group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyrazolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a 1,3-dioxolanyl group, a tetrahydrothiophenyl group, a 1,2-oxathiolanyl group, a morpholinyl group, and a tetrahydropyranyl group, an unsubstituted heteroaryl group, or The method for producing a fluorinated thio group-containing aryl compound according to claim 1, wherein the heteroaryl group has one or more substituents selected from the group consisting of a halogen atom, an alkyl group, a fluorinated alkyl group, an alkenyl group, an aryl group, a heteroaryl group, an alkoxy group, a hydroxy group, a carboxy group, an acyl group, a cyano group, a fluorinated formyl group, an amino group, a nitro group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a pyrazolidinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a 1,3-dioxolanyl group, a tetrahydrothiophenyl group, a 1,2-oxathiolanyl group, a morpholinyl group, and a tetrahydropyranyl group.

9. The method for producing a fluorinated thio group-containing aryl compound according to any one of claims 1 to 8, wherein the oxidative fluorination reaction is carried out at 0 to 80°C.

10. The method for producing a fluorinated thio group-containing aryl compound according to any one of claims 1 to 8, wherein the oxidative fluorination reaction is carried out in an aprotic polar solvent.

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