Chiral 3-sulfinylbenzoic acids

Abstract

The present invention relates to chiral 3-sulfinylbenzoic acids of absolute configuration as specified by formulae (IR) and (IS) as precursors for the production of herbicidal compounds, in which X, Z and R' represent groups such as alkyl, cycloalkyl, halogenalkyl and halogen. [Formula 1] TIFF2024526285000014.tif30143

Description

[Technical field]

[0001] The present invention relates to chiral 3-sulfinylbenzoic acids, their uses, and processes for the preparation of chiral N-(1,2,5-oxadiazol-3-yl)-, N-(1,3,4-oxadiazol-2-yl)-, N-(tetrazol-5-yl)- and N-(triazol-5-yl)phenylcarboxamides. [Background technology]

[0002] WO2021 / 078174A1 discloses herbicidally active chiral N-(1,2,5-oxadiazol-3-yl)-, N-(1,3,4-oxadiazol-2-yl)-, N-(tetrazol-5-yl)- and N-(triazol-5-yl)phenylcarboxamides. EP21162218 similarly discloses herbicidally active chiral N-(1,3,4-oxadiazol-2-yl)phenylcarboxamides. The herbicidally active chiral compounds described therein have a chiral sulfinyl group at the 3-position of the phenyl ring. These compounds are prepared in a complex manner by enantiomeric separation of N-(1,2,5-oxadiazol-3-yl)-, N-(1,3,4-oxadiazol-2-yl)-, N-(tetrazol-5-yl)- and N-(triazol-5-yl)phenylcarboxamides. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2021 / 078174A1 [Patent Document 2] EP21162218 Summary of the Invention [Problem to be solved by the invention]

[0004] The object of the present invention was to overcome the drawbacks known from the prior art. [Means for solving the problem]

[0005] The present invention provides chiral 3-sulfinylbenzoic acids of the respective absolute configurations given in formulae (IR) and (IS). [ka] wherein the substituents are defined as follows: R' is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkyl-O-(C1-C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C6)-alkyl, X is halogen, (C1-C6)-alkyl, halo-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, OR a , S(O) n R b or (C1-C6)-alkyl-OR a and Z is halogen, (C1-C6)-alkyl, halo-(C1-C6)-alkyl, (C3-C6)-cycloalkyl or S(O) n R b and R a is (C1-C6)-alkyl or (C3-C6)-cycloalkyl, R b is (C1-C6)-alkyl or (C3-C6)-cycloalkyl, n is 0, 1 or 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The compounds of the present invention are compounds of general formula (IS) in the S configuration, with the proviso that R' has a lower priority than the phenyl ring according to the Cahn-Ingold-Prelog rules. This is true, for example, of compounds of general formula (I) where R' is methyl or cyclopropyl. Further compounds of the present invention are compounds of general formula (I) in the R configuration, with the proviso that R' has a higher priority than the phenyl ring according to the Cahn-Ingold-Prelog rules. This is true, for example, of compounds of general formula (I) where R' is methoxymethyl.

[0007] In formulae (IR) and (IS) and all subsequent formulae, alkyl groups having more than two carbon atoms may be linear or branched. Alkyl groups are, for example, methyl, ethyl, n-propyl or isopropyl, n-, iso-, t- or 2-butyl, pentyl, hexyl, such as n-hexyl, isohexyl and 1,3-dimethylbutyl. Cycloalkyl is a carbocyclic saturated ring system having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Halogen-substituted alkyl means linear or branched alkyl groups in which some or all of the hydrogen atoms in these groups may be substituted with halogen atoms, such as C1-C2-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl.

[0008] Halogen represents fluorine, chlorine, bromine or iodine.

[0009] If a group is polysubstituted with a radical, this should be understood to mean that the group is substituted with one or more identical or different groups selected from the mentioned groups.

[0010] Preferred are: X is F, Cl, Br, methyl, ethyl, i-Pr, c-Pr, OMe, SMe, SEt, CHOMe or CF; R' is methyl, ethyl, c-Pr, CH2-cPr, CH2CH2OMe, c-Pr, CH2-cPr or CH2CH2OMe; Compounds of general formula (IR) and (IS) where Z is F, Cl, Br, I, methyl, ethyl, c-Pr, i-Pr, SMe, S(O)Me, S(O)2Me, S(O)2Et, CF3, C2F5 or CHF2.

[0011] Particularly preferred are X is F, Cl, Br, methyl, ethyl, c-Pr, OMe, SMe, SEt, CHOMe or CF; R' is Me, Et, c-Pr, CH2-cPr or CH2CH2OMe; Compounds of general formula (IR) and (IS) where Z is Cl, Br, methyl, ethyl, c-Pr, i-Pr, S(O)2Me, S(O)2Et, CF3, C2F5 or CHF2.

[0012] Very particularly preferred are X is Cl or methyl; R' is methyl or c-Pr; Compounds of general formula (IR) and (IS) where Z is CF3 or CHF2.

[0013] In all formulas specified below, the substituents and symbols have the same meaning as set forth in formulas (IR) and (IS) unless otherwise defined: OMe means O-methyl; SMe means S-methyl; SEt means S-ethyl; CHOMe means CHO-methyl; i-Pr means isopropyl; c-Pr means cyclopropyl.

[0014] The compounds of general formula (IR) and (IS) of the present invention can be prepared, for example, from the respective racemates (I-rac) by the methods described below, which processes likewise form part of the subject matter of the present invention.

[0015] The racemic compound (I-rac) and its preparation are basically known, for example from WO2021 / 078174A1 and WO2012 / 126932A1. The racemic compound (I-rac) is reacted with an enantiomerically pure amine of general formula (II). Under suitable conditions, only one of the two possible diastereomeric salts (III-dR) and (III-dS) crystallizes and can be separated for further workup. The other diastereomeric salt can be isolated from the mother liquor. [ka] Crystallization can be carried out in various suitable solvents or solvent mixtures using methanol, methanol / water (1:1-10:1), ethanol / water (1:1-10:1), isopropanol, preferably isopropanol / water (range 1:1-10:1), acetone / water (1:1-20:1), ethyl acetate, THF, THF / water (3:1-20:1) or toluene. The obtained salt crystals are separated from the mother liquor by filtration using known methods, washed with the solvent or solvent mixture used and dried under reduced pressure. In a further reaction step, the isolated diastereomeric compounds of general formula (III-dR) or (III-dS) are then mixed with water at temperatures between 0°C and 20°C, optionally in the presence of an organic solvent such as methanol, ethanol, isopropanol, THF, acetone, and mixed with a strong acid such as HCl or H2SO4 to a pH of 1-2. The enantiomerically pure compounds of general formula (IR) or (IS) precipitate and are separated from the mother liquor by filtration, washed and dried in vacuum.

[0016] The compound of formula (I-rac) and the amine of formula (II) are typically used in equimolar amounts. This step is usually carried out at room temperature.

[0017] Suitable chiral amines are the numerous commercially available amines of formula (II), for example R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, R 2 is hydroxymethyl, phenyl, or 4-methylphenyl.

[0018] For example, amines of formula (II) below are very suitable: (S)-(-)-α,4-Dimethylbenzylamine (CAS number 27298-98-2). (R)-(-)-3-Methyl-2-phenylbutylamine (CAS number 67152-35-6). (S)-(+)-2-Amino-3-methyl-1-butanol (CAS number 2026-48-4).

[0019] Preferred is (S)-(-)-α,4-dimethylbenzylamine (CAS number 27298-98-2).

[0020] The 3-sulfinylbenzoic acids of formula (IR) and (IS) of the present invention are generally obtained in the above process with an enantiomeric excess (ee) of at least 94%, and often even at least 99%.

[0021] 3-Sulfinylbenzoic acids of formulae (IR) and (IS) in enantiomeric excess of at least 94% are preferred. 3-Sulfinylbenzoic acids of formulae (IR) and (IS) in enantiomeric excess of at least 99% are especially preferred.

[0022] The 3-sulfinylbenzoic acids of the general formula (IS) according to the invention are particularly well suited for the preparation of the herbicidally active compounds described in EP 2 1162 218.

[0023] The present invention therefore further provides a 2-amino-1,3,4-oxadiazole of general formula (III) which is reacted with a 3-sulfinylbenzoic acid of general formula (IS) of the present invention to produce a 3-sulfinylbenzoic acid of formula (I * 2. A process for preparing an N-(1,3,4-oxadiazol-2-yl)phenylcarboxamide having the absolute configuration provided in [ka] That, a) in the presence of an activating agent (activator) from the group consisting of thionyl chloride, phosgene, diphosgene, mesyl chloride, tosyl chloride, POCl3, PCl5, oxalyl chloride and C1-C8-alkyl-OC(O)Cl, and b) General formula (IV): [ka] In the presence of a base Do it with and c) the substituents are as defined below: R is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, methoxymethyl or methoxyethyl, R' is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkyl-O-(C1-C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C6)-alkyl, X is halogen, (C1-C6)-alkyl, halo-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, OR 1 , S(O) n R 2 or (C1-C6)-alkyl-OR 1 and Z is halogen, (C1-C6)-alkyl, halo-(C1-C6)-alkyl, (C3-C6)-cycloalkyl or S(O). n R 2 and R 1 is (C1-C6)-alkyl or (C3-C6)-cycloalkyl, R2 is (C1-C6)-alkyl or (C3-C6)-cycloalkyl, R 5 C1-C 12 - alkyl or phenyl, The method is provided wherein n is 0, 1 or 2.

[0024] The 3-sulfinylbenzoic acids of the general formula (IR) according to the invention are particularly well suited for the preparation of the herbicidally active compounds described in WO2021 / 078174A1.

[0025] Therefore, the present invention further relates to a compound of the formula (I) by reacting a 2-amino-1,3,4-oxadiazole of the formula (V) with a 3-sulfinylbenzoic acid of the formula (IR) of the present invention. ** 2. A process for preparing an N-(1,3,4-oxadiazol-2-yl)phenylcarboxamide having the absolute configuration provided in [ka] That, a) in the presence of an activating agent (activator) from the group consisting of thionyl chloride, phosgene, diphosgene, mesyl chloride, tosyl chloride, POCl3, PCl5, oxalyl chloride and C1-C8-alkyl-OC(O)Cl, and b) General formula (IV): [ka] In the presence of a base Do it with and c) the substituents are as defined below: R is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, methoxymethyl or methoxyethyl, R' is (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C1-C6)-alkyl-O-(C1-C6)-alkyl or (C3-C6)-cycloalkyl-(C1-C6)-alkyl, X is halogen, (C1-C6)-alkyl, halo-(C1-C6)-alkyl, (C3-C6)-cycloalkyl, OR 1 , S(O) n R 2 or (C1-C6)-alkyl-OR 1 and Z is halogen, (C1-C6)-alkyl, halo-(C1-C6)-alkyl, (C3-C6)-cycloalkyl or S(O). n R 2 and R 1 is (C1-C6)-alkyl or (C3-C6)-cycloalkyl, R 2 is (C1-C6)-alkyl or (C3-C6)-cycloalkyl, R 5 C1-C 12 - alkyl or phenyl, The method is provided wherein n is 0, 1 or 2.

[0026] The compound of formula (I) is prepared by converting the compound of formula (V) and (IS) into * ) from a compound of formula (V) and (IR) ** In the above two methods for preparing compounds of formula (I), the groups are preferably as follows: R is hydrogen or methyl; X is F, Cl, Br, methyl, ethyl, i-Pr, c-Pr, OMe, SMe, SEt, CHOMe or CF; R' is methyl, ethyl, c-Pr, CH2-cPr, CH2CH2OMe, c-Pr, CH2-cPr or CH2CH2OMe; Z is F, Cl, Br, I, methyl, ethyl, c-Pr, i-Pr, SMe, S(O)Me, S(O)2Me, S(O)2Et, CF3, C2F5 or CHF2; More preferably: R is hydrogen or methyl; X is F, Cl, Br, methyl, ethyl, c-Pr, OMe, SMe, SEt, CHOMe or CF; R' is Me, Et, c-Pr, CH2-cPr or CH2CH2OMe; Z is Cl, Br, methyl, ethyl, c-Pr, i-Pr, S(O)2Me, S(O)2Et, CF3, C2F5 or CHF2; Very particularly, R is hydrogen or methyl; X is Cl or methyl; R' is methyl or c-Pr; Z is CF3 or CHF2.

[0027] The compound of formula (I) is prepared by converting the compound of formula (V) and (IS) into * ) from a compound of formula (V) and (IR) ** In the above two processes for preparing the compound of formula (V) and (IS) or (V) and (IR), the compounds of formula (V) and (IS) or (V) and (IR) are typically used in a molar ratio of 0.8 to 1.5. The compound of formula (V) is preferably used in a 10% excess relative to the compound of formula (IS) or (IR).

[0028] The activator and the compound of formula (IS) or (IR) are typically used in a molar ratio of 0.5 to 3, preferably 1 to 2, more preferably 1.2 to 1.9.

[0029] The activating agent used is preferably thionyl chloride, phosgene or diphosgene, more preferably thionyl chloride.

[0030] The base of formula (IV) and the compound of formula (IS) or (IR) are typically used in a molar ratio of 0.5 to 10, preferably 1 to 3, more preferably 1 to 2.5.

[0031] Formula (I * ) and (I **The above two processes of the invention for preparing the compound of formula (I) are carried out in a solvent. Suitable solvents are inert organic solvents, preferably aliphatic, cycloaliphatic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene and decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane and trichloroethane; esters, such as ethyl acetate and isopropyl acetate; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane. and anisole; ketones such as acetone, butanone, methyl isobutyl ketone and cyclohexanone; nitriles such as acetonitrile, propionitrile, n- or isobutyronitrile and benzonitrile; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone and hexamethylphosphoramide; pyridines such as 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,3-dimethylpyridine, 2-methyl-5-ethylpyridine, 2,6-dimethylpyridine, 2,4-dimethylpyridine, 3,4-dimethylpyridine and 2,4,6-trimethylpyridine. Mixtures of the abovementioned solvents are also suitable.

[0032] The solvent used is preferably tetrahydrofuran, acetonitrile, 3-methylpyridine or 2-methyl-5-ethylpyridine, particularly preferably 3-methylpyridine.

[0033] These methods are typically carried out within a temperature range of -5°C to 50°C, preferably 0°C to 25°C.

[0034] These methods are typically carried out in such a manner that the activating agent is slowly added dropwise, or in the case of phosgene, introduced, under stirring, to the compounds of formulae (III), (IS) and (IV) initially in the solvent. The progress of the reaction can be monitored by HPLC. The reaction usually proceeds to completion after 10-20 hours.

[0035] After the reaction is complete, the reaction mixture is cooled, and the product usually precipitates essentially quantitatively. Alternatively, the reaction mixture can be diluted with a polar solvent, such as water or an alcohol, such as isopropanol. * ) or (I ** The reaction product of formula (IV) is obtained in high purity and can be further purified if necessary. It is particularly advantageous to add water to the reaction mixture over a period of 3 to 6 hours at a temperature of 20 to 35° C. This gives the product in a form that can be rapidly filtered. After treatment of the mother liquor with sodium hydroxide solution, the base of formula (IV) can be recovered to an extent of about 95%. EXAMPLES

[0036] The following examples illustrate the invention. Example 1 Preparation of 2-chloro-3-[(S)-methylsulfinyl]-4-(trifluoromethyl)benzoic acid Step 1: Preparation of 2-chloro-3-[(S,R)-methylsulfinyl]-4-(trifluoromethyl)benzoic acid In a stirred 3 liter jacketed reactor, first 1 liter of glacial acetic acid is added, then 0.2 kg of 2-chloro-3-methylsulfanyl-4-(trifluoromethyl)benzoic acid. The turbid mixture is heated to 60 °C and at that temperature a 35% aqueous hydrogen peroxide solution is added dropwise within 130 minutes and stirred for 21 hours at an internal temperature of 70 °C. The mixture is cooled to 20 °C and 100 mL of 39% sodium hydrogen sulfite solution is added dropwise. The mixture is concentrated on a rotary evaporator to a residual volume of about 20%. The residue is taken up in 1 liter of water and made alkaline with 120 mL of 45% sodium hydroxide solution (pH 13-14). The aqueous solution is then washed with dichloromethane and the removed aqueous phase is cooled to 5 °C and acidified with 280 mL of 32% hydrochloric acid. The product precipitates as an oil and crystallizes after a few minutes. The solid is filtered by cold filtration on a suction filter, washed with water and dried. 194 g of a beige solid are obtained. HPLC(H3PO4):logP=0.96; Mass spectrometry: 287.0(M+H) + , 328.1 (M+H+CH3CN) + , 573.0(2M+H) + ; 1 H NMR [DMSO-D6]: 14.2 (br s, 1H), 7.96-8.00 (m, 2H), 3.14 (s, 3H).

[0037] Step 2: Preparation of 2-chloro-3-[(S,R)-methylsulfinyl]-4-(trifluoromethyl)benzoic acid 2-Chloro-3-[(S)-methylsulfinyl]-4-(trifluoromethyl)benzoate[(1S)-1-(p-tolyl)ethyl]ammonium In an inactivated, stirred jacketed reactor, 1.06 kg of racemic 2-chloro-3-[(S,R)-methylsulfinyl]-4-(trifluoromethyl)benzoic acid are dissolved in 20 liters of acetone and heated to 55 ° C. Under gentle reflux, 519.4 g of (S)-(-)-α,4-dimethylbenzylamine are added dropwise within 4 hours and the resulting suspension is stirred overnight at 52 ° C. The mixture is gradually cooled to 20 ° C within 6 hours. The suspension is filtered through a suction filter. The filter cake is then washed with acetone and then dried under reduced pressure at 40 ° C. This leaves 637 g of colorless crystals. HPLC(H3PO4):logP=0.50 / 1.00; Mass Spectrometry: 119.0 (Amine-M+H) + , 286.9(acid-M+H) + ;Chiral HPLC 95.1% ee; 1 H NMR [DMSO-D6]:8.23 (br s, 3H), 7.70-7.71 (m, 1H), 7.45-7.46 (m, 1H), 7.35-7.36 (m, 2H), 7.22-7.23 (m, 2H), 4.35 (q, 1H), 3.07 (s, 3H), 2.31 (s, 3H), 1.47 (d, 3H).

[0038] Step 3: Preparation of 2-chloro-3-[(S)-methylsulfinyl]-4-(trifluoromethyl)benzoic acid A stirred jacketed reactor is first charged with 4.9 liters of ice water and 636 g of the salt from stage 2 are suspended therein. A total of 0.55 liters of concentrated hydrochloric acid solution is then added dropwise, maintaining the temperature at 0°C-5°C. The suspension is gradually warmed to room temperature and stirring is continued overnight. The suspension is then filtered through a suction filter. The filter cake is washed with 3 liters of distilled water and then dried at 50°C under reduced pressure. This leaves 408.5 g of colorless crystals. HPLC(H3PO4):logP=1.00; Mass spectrometry: 286.9(M+H) + ;Chiral HPLC 98.0% ee; 1H NMR [DMSO-D6]:14.2 (br s, 1H) 7.96-7.99 (m, 2H), 3.14 (s, 3H).

[0039] Example 2: Preparation of 2-chloro-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-[((S)-methylsulfinyl)]-4-(trifluoromethyl)benzamide 28.6 g (0.1 mol) of 2-chloro-3-[(S)-methylsulfinyl]-4-(trifluoromethyl)benzoic acid, 11 g (0.11 mol) of 2-amino-5-methyl-1,3,4-oxadiazole and 28.7 g (0.35 mol) of N-methylimidazole are dissolved in 200 mL of acetonitrile and stirred for 30 minutes. After cooling to 5°C, 18.9 g (0.16 mol) of thionyl chloride are added dropwise over 60 minutes so that the temperature remains between 5°C and 10°C. Then, the mixture is stirred at 20°C for another 15 hours. The solvent is removed under reduced pressure and water is added to the oily residue at 40°C. The product precipitates and, after filtration, is washed with cold hydrochloric acid and water. After drying, 33.7 g (92%) of 2-chloro-N-(5-methyl-1,3,4-oxadiazol-2-yl)-3-[((S)-methylsulfinyl)]-4-(trifluoromethyl)benzamide of melting point 220° C. are obtained. Optical rotation: (-)-69° (MeOH).

Claims

1. Chiral 3-sulfinylbenzoic acid of the individual absolute configurations given by formulas (I-R) and (I-S). 【Chemical 1】 [Wherein the substituents are defined as follows; R′ is (C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl, (C １ -C ６ ) -Alkyl-O-(C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl-(C １ -C ６ )-alkyl, and X is halogen, (C １ -C ６ )-alkyl, halo-(C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl, OR ａ , S(O) ｎ R ｂ or (C １ -C ６ )-alkyl-OR ａ wherein Z is halogen, (C １ -C ６ )-alkyl, halo-(C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl or S(O) ｎ R ｂ wherein R ａ is (C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl, R ｂ is (C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl, n is 0, 1 or 2. ]

2. X is F, Cl, Br, methyl, ethyl, i-Pr, c-Pr, OMe, SMe, SEt, CH ２ OMe or CF ３ and R′ is methyl, ethyl, c-Pr, CH ２ -cPr, CH ２ CH ２ OMe, c-Pr, CH ２ -cPr or CH ２ CH ２ OMe, and Z is F, Cl, Br, I, methyl, ethyl, c-Pr, i-Pr, SMe, S(O)Me, S(O) ２ Me, S(O) ２ Et, CF ３ , C ２ F ５ or CHF ２ and the 3-sulfinylbenzoic acid according to claim 1

3. X is F, Cl, Br, methyl, ethyl, c-Pr, OMe, SMe, SEt, CH ２ OMe or CF ３ and R′ is Me, Et, c-Pr, CH ２ -cPr or CH ２ CH ２ OMe, and Z is Cl, Br, methyl, ethyl, c-Pr, i-Pr, S(O) ２ Me, S(O) ２ Et, CF ３ , C ２ F ５ or CHF ２ and the 3-sulfinylbenzoic acid according to claim 1 or 2

4. X is Cl or methyl, R' is methyl or c-Pr, Z is CF ３ or CHF ２ The 3-sulfinylbenzoic acid according to claim 1, wherein the Z is CF or CHF.

5. The 3-sulfinylbenzoic acid according to claim 1, having at least 94% enantiomeric excess (ee).

6. The 3-sulfinylbenzoic acid according to claim 5, having at least 99% enantiomeric excess (ee).

7. a) Reacting a racemic compound of formula (I-rac) with an enantiomerically pure amine of general formula (II), b) Filtering, purifying, and liberating one of the two crystallized diastereomeric salts (III-dr) or (III-ds) by adding water and an acid to obtain the 3-sulfinylbenzoic acid of formula (I-R) or (I-S), c) Liberating the other diastereomeric salt from the mother liquor of step a) by adding water and an acid to obtain the 3-sulfinylbenzoic acid of formula (I-R) or (I-S), d) In formula (II), R １ is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, and R ２ The method for producing 3-sulfinylbenzoic acid according to claim 1, wherein R is hydroxymethyl, phenyl, or 4-methylphenyl. 【Chemical 2】

8. By reacting a 2-amino-1,3,4-oxadiazole of general formula (V) with a 3-sulfinylbenzoic acid of general formula (I-S) of the present invention, an N-(1,3,4-oxadiazol-2-yl)phenylcarboxamide having the absolute configuration provided by formula (I ＊ ) is a method for producing, [Chemical Formula 3] Doing it, a) in the presence of an activating reagent (activator) selected from the group consisting of thionyl chloride, phosgene, diphosgene, mesyl chloride, tosyl chloride, POCl ３ , PCl ５ , oxalyl chloride and C １ -C ８ -alkyl-OC(O)Cl, and b) In the presence of a base of general formula (IV): 【Chemical Formula 4】 And Doing it, And c) The substituents are as defined below, namely R is hydrogen, (C １ -C ６ ), -alkyl, (C ３ -C ７ ), -cycloalkyl, methoxymethyl or methoxyethyl, R′ is (C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl, (C １ -C ６ )-alkyl-O-(C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl-(C １ -C ６ )-alkyl, and X is halogen, (C １ -C ６ )-alkyl, halo-(C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl, OR １ , S(O) ｎ R ２ or (C １ -C ６ )-alkyl-OR １ and Z is halogen, (C １ -C ６ )-alkyl, halo-(C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl or S(O) ｎ R ２ and R １ is (C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl, R ２ is (C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl, R ５ is C １ -C １２ -alkyl or phenyl, and A method in which n is 0, 1 or 2.

9. By reacting 2-amino-1,3,4-oxadiazole of general formula (V) with 3-sulfinylbenzoic acid of general formula (I-R) of the present invention, N-(1,3,4-oxadiazol-2-yl)phenylcarboxamide having the absolute configuration provided by formula (I ＊＊ ) is a method for producing a compound, [Chemical Formula 5] Doing it, a) in the presence of an activating reagent (activator) selected from the group consisting of thionyl chloride, phosgene, diphosgene, mesyl chloride, tosyl chloride, POCl ３ , PCl ５ , oxalyl chloride and C １ -C ８ -alkyl-OC(O)Cl, and b) In the presence of a base of general formula (IV): 【Chemical Formula 6】 And Doing it, c) The substituents are as defined below, namely R is hydrogen, (C １ -C ６ )-alkyl, (C ３ -C ７ )-cycloalkyl, methoxymethyl or methoxyethyl; R' is (C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl, (C １ -C ６ )-alkyl-O-(C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl-(C １ -C ６ )-alkyl, X is halogen, (C １ -C ６ )-alkyl, halo-(C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl, OR １ , S(O) ｎ R ２ or (C １ -C ６ )-alkyl-OR １ and Z is halogen, (C １ -C ６ )-alkyl, halo-(C １ -C ６ )-alkyl, (C ３ -C ６ )-cycloalkyl or S(O) ｎ R ２ and is R １ is (C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl, R ２ is (C １ -C ６ )-alkyl or (C ３ -C ６ )-cycloalkyl, R ５ is C １ -C １２ -alkyl or phenyl, and A method in which n is 0, 1 or 2.

10. R is hydrogen or methyl, X is F, Cl, Br, methyl, ethyl, i-Pr, c-Pr, OMe, SMe, SEt, CH ２ OMe or CF ３ and R′ is methyl, ethyl, c-Pr, CH ２ -cPr, CH ２ CH ２ OMe, c-Pr, CH ２ -cPr or CH ２ CH ２ OMe, and Z is F, Cl, Br, I, methyl, ethyl, c-Pr, i-Pr, SMe, S(O)Me, S(O) ２ Me, S(O) ２ Et, CF ３ , C ２ F ５ or CHF ２ The method according to claim 8 or 9, wherein it is so.

11. R is hydrogen or methyl, X is F, Cl, Br, methyl, ethyl, c-Pr, OMe, SMe, SEt, CH ２ OMe or CF ３ and R′ is Me, Et, c - Pr, CH ２ -cPr or CH ２ CH ２ OMe, and Z is Cl, Br, methyl, ethyl, c-Pr, i-Pr, S(O) ２ Me, S(O) ２ Et, CF ３ , C ２ F ５ or CHF ２ The method according to claim 8 or 9, wherein it is so.

12. R is hydrogen or methyl, X is Cl or methyl, R' is methyl or c-Pr, Z is CF ３ or CHF ２ The method according to claim 8 or 9, wherein

13. The method according to claim 8 or 9, wherein the compounds of formula (V) and (I-S) or (V) and (I-R) are used in a molar ratio of 0.8 to 1.

5.

14. wherein the activator is selected from the group consisting of thionyl chloride, phosgene, diphosgene, mesyl chloride, tosyl chloride, POCl ３ , PCl ５ , oxalyl chloride and C １ -C ８ -alkyl-OCOCl, and the activator and the compound of formula (I-S) or (I-R) are used in a molar ratio of 1 to 2, the method according to claim 8 or 9.

15. The method according to claim 8 or 9, wherein the activator is selected from the group consisting of thionyl chloride, phosgene and diphosgene.

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