Synthesis of enantio-enriched 2-cyanopyridyl sulfoxide

Abstract

Equation (I) [Formula 1] JPEG2026519167000049.jpg34161 (wherein R1 and R2 are as defined herein) A process for preparing enantioconcentrated pyridine compounds is provided.

Description

[Technical Field]

[0001] This invention relates to the synthesis of enantioenriched sulfoxide compounds as intermediates for the enantioselective preparation of sulfoximines. [Background technology]

[0002] In recent years, sulfoximines have attracted considerable interest from the agrochemical and pharmaceutical industries as isosteres of sulfones and sulfonamides because their physicochemical properties can be optimized by adjusting their four substituents (J.Med.Chem.2020,63,14243,Eur.J.Med.Chem.2021,209,112885). N-unsubstituted sulfoximines are particularly interesting because, although they differ from sulfones by only one atom, they can have significantly different properties due to the presence of hydrogen bond donors. Consequently, there has been great interest in methods for introducing NH-sulfoximines, and several different approaches have recently been developed, as outlined in Chem.Eur.J.2021,27,17293. A particularly preferred method for larger-scale synthesis is the enantiospecific iron-catalyzed iminolation of the enantioenriched sulfoxide with the amino 4-nitrobenzoate (Angew. Chem. Int. Ed. 2018, 57, 324).

[0003] Enantioenriched sulfoxides can be prepared from the corresponding sulfides by various oxidation methods (see Chem. Rev. 2020, 120, 4578; Chem. Rev. 2010, 110, 4303; Pitchen Philippe et al, Tetrahedron Letters, 1 January 1984, pp. 1049-1052 for an overview). A notable method is the titanium-mediated oxidation of kagan using a tartaric acid ligand (J. Am. Chem. Soc. 1984, 106, 8188). A catalytic version of this protocol has been developed to avoid the use of stoichiometric titanium (Synlett. 1996, 404). Bolm has developed highly enantioselective methods using chiral Schiff bases compounded with either vanadium (Angew. Chem. Int. Ed. 1996, 34, 2640) or iron (Chem. Eur. J, 2005, 11, 1086, Angew. Chem. Int. Ed. 2004, 43, 4225). Related methods include those of Maguire (J. Org. Chem. 2012, 77, 3288) using copper catalysts or Jacobsen (Tet. Lett. 1992, 33, 7111) using manganese catalysts, but these often suffer from low selectivity. More recently, List has disclosed a practical organocatalytic method that avoids metal catalysts and replaces them with highly complex chiral acids (J.Am.Chem.Soc.2012,134,10765,J.Am.Chem.Soc.2021,143,14835). Biocatalysis using artificial enzymes offers an efficient and sustainable alternative for enantioselective sulfide oxidation (Catalysts,2018,8,624), however, the efficiency of such enzymes is highly substrate-dependent and often requires extensive optimization for a single substrate.

[0004] Despite the availability of several methods for chiral sulfoxide synthesis, the enantioselectivity and yield of many methods for enantioselective sulfoxide synthesis are highly substrate-dependent, particularly in the case of complex heterocyclic substrates that can inhibit metal-catalyzed reactions, often requiring optimization of the oxidation system. This need for individual optimization is exemplified by the enantioselective synthesis of esomeprazole using titanium-mediated oxidation, as described in Tet.Assym.2000,11,3819, or iron catalysts, as described in ACS Catalysis,2018,8,9738. In both cases, non-trivial modifications to the initially published procedures were crucial for obtaining high yields and enantioselectivity on these complex substrates. Thus, while numerous methods exist for the synthesis of chiral sulfoxides, finding a method suitable for large-scale applications on complex substrates is not easy.

[0005] The synthesis of various enantioenriched sulfoximine compounds exhibiting insecticidal activity is described in International Publication No. 2022 / 253841. The later stages of the synthetic strategy consist of enantioselective oxidation of sulfides followed by enantiospecific iron-catalyzed imination, as shown in Scheme 1 as one specific example (see the patent application mentioned above for details). Scheme 1 [ka]

[0006] This is a viable strategy for the synthesis of enantioenriched sulfoximines, but the oxidation efficiency decreases when large substituents are present in the ortho position relative to the sulfide, so each skeleton must be optimized separately. It is advantageous to introduce the stereocenter on the sulfur at an earlier stage in a simpler substrate. [Overview of the Initiative] [Means for solving the problem]

[0007] The present invention describes a strategy that starts from a thio derivative of formula (II), generates a sulfoxide of formula (I) after stereoselective oxidation, which can then be synthesized into an enantioconcentrated sulfoxide of formula (III). These can then be converted into enantioconcentrated sulfoximines as described above. Scheme 2

Chemical formula

[0008] R1 is hydrogen, halogen, C1-C6-haloalkyl, C1-C6-cyanoalkyl, C1-C6-cyanoalkoxy, C3-C6-cyanocycloalkyl or optionally substituted aryl, R2 is C1-C4 alkyl, R3 is C1-C4 alkyl, G1 and G2 are independently CH or N.

[0009] Several methods for synthesizing a compound of formula (I) into a compound of formula (III) can be envisioned. As shown in Scheme 3 for a specific example, a particularly preferred approach consists of the selective hydrolysis of the nitrile at the 2-position of pyridine, first performing basic hydrolysis and then nitrosating the primary amide. Then, the acid thus generated is coupled with a functionalized aminopyridine derivative, and the resulting product is cyclized under acidic conditions to obtain the desired sulfoxide. This series of reactions will be described in more detail in the experimental part of the present invention. Scheme 3

Chemical formula

[0010] The present invention relates to formula (I)

Chemical formula

[0011] In one embodiment, the present invention includes oxidizing a sulfanyl compound of formula (II) in the presence of an oxidizing agent, a metal derivative, a chiral ligand (such as a reagent or catalyst), a suitable solvent (or diluent), and optionally a suitable acid additive.

[0012] Suitable and preferred oxidizing agents include inorganic peroxides such as hydrogen peroxide or organic peroxides such as tert-butyl hydroperoxide. Preferably, the oxidizing agent is hydrogen peroxide. The ratio of the oxidizing agent used to the sulfanil compound of formula (II) is in the range of 8:1 to 0.8:1, preferably 5:1 to 1:1, and more preferably 3:1 to 1:1.

[0013] Suitable and preferred metal derivatives include vanadium salts and iron salts. Preferably, iron salts are used. Suitable examples include, but are not limited to, VOCl2, VO(acac)2, Fe(acac)3, and Fe(acac)2. Compared to the sulfanil compound of formula (II), the amount of metal catalyst used is in the range of 0.1 mol% to 50 mol%, preferably in the range of 0.5 mol% to 10 mol%.

[0014] Suitable and preferred chiral ligands are selected from Schiff bases formed from salicylaldehyde derivatives and chiral amines.

[0015] In a preferred embodiment of the present invention, the metal derivative is iron, and the chiral ligand is a salicylaldehyde derivative and formula (IV) [ka] (In the formula, R4 is a halogen, * (where appropriate, represents an enantioenriched chiral center in either the R or S configuration.) It is a Schiff base formed from a chiral amino alcohol represented by a compound. Preferably, R4 is chloro, iodine, or bromo.

[0016] Chiral ligands are used as enantio-enriched compounds. The enantiomeric ratio of the ligand is 80:20 to 100:0 [R]:[S] or [S]:[R], preferably 90:10 to 100:0 [R]:[S] or [S]:[R].

[0017] The amount of ligand used relative to the sulfanyl compound of formula (II) is in the range of 0.1 to 30 mol%, preferably 1 to 15 mol%, and most preferably 2 to 10 mol%.

[0018] Optionally, ligands may be formed in situ during the reaction by adding a suitable salicylaldehyde derivative and a suitable amino alcohol. Alternatively, ligands may be prepared in a separate step.

[0019] Examples of suitable and preferred additives are carboxylic acids. Preferably, the additive is benzoic acid, which may optionally be monosubstituted, disubstituted, or trisubstituted with methyl, ethyl, isopropyl, methoxy, or dimethylamino, and may optionally be in the form of a lithium salt, sodium salt, or potassium salt. More preferably, the additive is methoxybenzoic acid or dimethylaminobenzoic acid (optionally in the form of a lithium salt, sodium salt, or potassium salt), and even more preferably 4-methoxybenzoic acid. The amount of additive used relative to the sulfanil compound of formula (II) is in the range of 0.1 to 10 mol%, most preferably 0.5 to 5 mol%.

[0020] In the most preferred embodiment, the oxidizing agent is hydrogen peroxide, the metal salt is Fe(acac)3, and the ligand is selected from the following: (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2S)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2R)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2S)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2R)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethylbutan-1-ol The additive is 4-methoxybenzoic acid.

[0021] Suitable and preferred solvents (or diluents) include, but are not limited to, esters, nitriles, alcohols, ethers, and aliphatic, aromatic, or halogenated hydrocarbons. Examples include ethyl acetate, isopropyl acetate, acetonitrile, butyronitrile, ethanol, methanol, isopropanol, n-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, t-butyl methyl ether, diethyl ether, 1,4-dioxampentane, hexane, cyclohexane, heptane, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, or mixtures thereof.

[0022] Preferably, the solvent is an aromatic or halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, or a mixture thereof.

[0023] More preferably, the solvent is selected from dichloromethane, toluene, xylene, chlorobenzene, methoxybenzene, or a mixture thereof.

[0024] The enantiomer ratio of the generated product is [R]:[S] or [S]:[R] in the range of 50.5:49.5 to 100:0. Preferably, the enantiomer ratio of the product is [R]:[S] or [S]:[R] in the range of 70:30 to 100:0, and more preferably [R]:[S] or [S]:[R] in the range of 90:10 to 100:0. The enantiomer ratio of the product may be lower or higher than the enantiomer ratio of the chiral ligand used in the reaction.

[0025] The ratio of the resulting enantiomers can be increased by crystallization as needed. Such methods are known to those skilled in the art and include crystallization from organic solvents, mixtures of organic solvents, or mixtures of organic solvents and water.

[0026] X-ray crystal structure analysis (see Example 8) has demonstrated that a chiral ligand of formula (IV) rich in the R enantiomer provides an enantio-enriched sulfoxide of formula (I) rich in the R enantiomer. Similarly, a chiral ligand of formula (IV) rich in the S enantiomer yields an enantio-enriched sulfoxide of formula (I) rich in the S enantiomer. [Brief explanation of the drawing]

[0027] [Figure 1] The unit cell was determined to be orthorhombic (space group P212121), and its structure contained one molecule within the crystal-asymmetric unit (thin bar representation with chirality labeled, generated with the Flare software package). [Modes for carrying out the invention]

[0028] Definition: When used herein alone or as part of a chemical group, the term "alkyl" preferably refers to a linear or branched hydrocarbon having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylpropyl, 1,3-dimethylbutyl, 1,4-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, and 2-ethylbutyl. Alkyl alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, or t-butyl.

[0029] The term "aryl" refers to monocyclic, bicyclic, or polycyclic aromatic systems having preferably 6 to 14, more preferably 6 to 10 ring carbon atoms, such as phenyl, naphthyl, anthryl, phenantrenyl, preferably phenyl. "Aryl" also refers to polycyclic systems, such as tetrahydronaphthyl, indenyl, indanyl, fluorenyl, and biphenyl. Arylalkyls are examples of substituted aryls, which can be further substituted with the same or different substituents in both the aryl and alkyl moieties. Benzyl and 1-phenylethyl are examples of such arylalkyls.

[0030] The term "halogen" or "halo" refers to fluoro, chloro, bromo, or iodine, particularly fluoro, chloro, or bromo. Chemical groups substituted with halogens, such as haloalkyl, halocycloalkyl, haloalkyloxy, haloalkylsulfanyl, haloalkylsulfinyl, or haloalkylsulfonyl, are substituted with halogens up to one or the maximum number of substituents. When "alkyl," "alkenyl," or "alkynyl" is substituted with a halogen, the halogen atoms may be the same or different, and may be bonded to the same carbon atom or different carbon atoms.

[0031] Unless otherwise defined, the term “arbitrarily substituted” means that the group in question may be substituted with zero to a maximum number of substituents of groups independently selected from the following: halogen, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclohexyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, nitro, cyano, hydroxy, sulfhydryl, acetyl, acetoxy, COOH, COOMe, COOEt, CONH2, CONHMe, CONMe2, amino, methylamino, dimethylamino, phenyl.

[0032] The term "enantiomerically concentrated" means that one enantiomer of a compound is present in excess compared to the other enantiomer. This excess is hereafter referred to as enantiomerically excess or ee. ee can be measured by chiral GC, HPLC, or SFC analysis. ee is equal to the difference in the amount of enantiomers divided by the total amount of enantiomers, and this quotient can be expressed as a percentage by multiplying it by 100.

[0033] If the compound of formula (II) is not commercially available, it was synthesized according to the synthetic method described below. Other combinations of substituents not specifically illustrated can be synthesized by similar methods well known to those skilled in the art.

[0034] As described in International Publication No. 2018095795, R1 is Br and R2 is ethyl. As described in International Publication No. 2014104407, R1 is CF3 and R2 is ethyl. As described in International Publication No. 2022074214, R1 is cyanocyclopropyl and R2 is ethyl.

[0035] As shown in Scheme 4, R1 is cyanoisopropoxy and R2 is ethyl. Scheme 4 [ka]

[0036] A pre-prepared acid chloride was reacted with aqueous ammonia to obtain a primary amide, which was then dehydrated with trifluoroacetic anhydride (TFAA) to obtain the compound of formula (II) with this substitution pattern.

[0037] As shown in Scheme 5, R1 is 3-fluorophenyl and R2 is methyl. Scheme 5 [ka]

[0038] The chloro derivative prepared as described in International Publication No. 2016118858 was reacted with sodium methylthiolate to obtain the compound of formula (II) with this substitution pattern.

[0039] As shown in Scheme 6, R1 is cyanoisopropyl and R2 is ethyl. Scheme 6 [ka]

[0040] A primary amide prepared as described in International Publication No. 2021175959 was dehydrated to obtain a 2-cyanopyridine derivative. In the second step, the coupling product obtained by a coupling reaction with ethyl cyanoacetate in the presence of a base was decarboxylated in acetic acid using sodium chloride. Finally, a double methylation reaction using either methyl iodide or dimethyl sulfate yielded the compound of formula (II) having this substitution pattern.

[0041] Specific preferred embodiments of the present invention are provided as described below.

[0042] Embodiment 1 provides a process for preparing an enantiomerically concentrated sulfoxide of formula (I) as defined above.

[0043] Embodiment 2 provides a process for preparing a compound of formula (I), comprising stereoselectively oxidizing a sulfanil compound of formula (II) in a suitable solvent (or diluent), in the presence of an oxidizing agent, in the presence of a chiral reagent or catalyst, and optionally in the presence of a suitable additive, to produce a compound of formula (I) as defined above.

[0044] Embodiment 3 provides preferred alternatives to the oxidizing agents, metal derivatives, chiral ligands, solvents (or diluents), and acid additives used in the processes of Embodiments 1 and 2, and in any combination thereof, as described above.

[0045] With respect to Embodiments 1 to 3, the preferred values ​​of R1 and R2 for any combination thereof are as shown below.

[0046] Preferably, R1 is hydrogen, a halogen, a C1-C6 haloalkyl, a C1-C6 cyanoalkyl, a C1-C6 cyanoalkoxy, a C3-C6 cyanocycloalkyl, or an optionally substituted aryl.

[0047] More preferably, R1 is hydrogen, halogen, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 cyanoalkoxy, C3-C4 cyanocycloalkyl, or optionally substituted aryl.

[0048] Most preferably, R1 is hydrogen, halogen, trifluoromethyl, cyanoisopropoxy, cyanoisopropyl, cyanocyclopropyl, or optionally substituted phenyl. Preferably, the optionally substituted phenyl is phenyl or halophenyl.

[0049] Preferably, R2 is a C1-C4 alkyl group, more preferably R2 is methyl or ethyl, and most preferably R2 is ethyl. [Examples]

[0050] The following examples illustrate the present invention.

[0051] Experimental procedure and data: Synthesis of sulfide starting materials: Example 1: Preparation of 5-(1-cyano-1-methylethoxy)-3-ethylsulfanylpyridine-2-carboxamide [ka] A few drops of DMF were added to a suspension of 5-(1-cyano-1-methylethoxy)-3-ethylsulfanylpyridine-2-carboxylic acid (1.00 g, 98% purity, 3.68 mmol) in ethyl acetate (9.0 mL). Then, oxalyl chloride (0.360 mL, 4.05 mmol) was added dropwise at room temperature over 2 hours. The acid chloride solution thus prepared was slowly added to a two-phase mixture of sodium bicarbonate (0.372 g, 4.42 mmol), water (2.7 mL), ethyl acetate (2.5 mL), and aqueous ammonium hydroxide solution (4.31 g, 36.9 mmol), and cooled to 0°C. After addition, the reaction mixture was stirred at ambient temperature for a further 1 hour. The phases were separated, and the aqueous layer was extracted with phenylethylamine. The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the title compound (1.00 g, 83% purity, 85% yield) as a brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.18(d,J=2.3Hz,1H),7.99(s,1H),7.54(m,2H),2.89(q,J=7.3Hz,2H),1.77(s,6H),1.27(t,J=7.3Hz,3H).

[0052] Example 2: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carbonitride [ka] A solution of 5-(1-cyano-1-methylethoxy)-3-ethylsulfanylpyridine-2-carboxamide (10.0 g, 87.5% purity, 33.0 mmol) and Et3N (18 mL, 80.42 mmol) in THF (100 mL) was to be added dropwise with trifluoroacetic anhydride (14.1 mL, 132 mmol) over 15 minutes at 0°C. After the addition was complete, the reaction mixture was warmed to room temperature. After stirring for 1 hour, water and saturated sodium bicarbonate were slowly added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (8.98 g, 82% purity, 90% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.38(d,J=2.4Hz,1H),7.74(d,J=2.4Hz,1H),3.20(q,J=7.3Hz,2H),1.81(s,6H),1.29(t,J=7.3Hz,3H).

[0053] Example 3: Preparation of 5-(3-fluorophenyl)-3-methylsulfanylpyridine-2-carbonitride [ka] Sodium methanethiolate (2.6 g, 35.2 mmol) was added to a solution of 3-chloro-5-(3-fluorophenyl)pyridine-2-carbonitrile (3.47 g, 94.5% purity, 14.1 mmol) in tetrahydrofuran (17 mL). The reaction mixture was stirred at 60°C for 2 hours, then cooled to ambient temperature and quenched with ice water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using ethyl acetate and cyclohexane as eluates to obtain the title compound (2.60 g, 94% purity, 71% yield) as a brown solid. 1H NMR(400MHz,DMSO-d6)δ 8.83(d,J=2.0Hz,1H),8.13(d,J=1.83Hz,1H),7.78-7.83(m,1H),7.73(d,J=7.5Hz,1H),7.56-7.63(m,1H),7.35(d,J=2.6Hz,1H),2.74(s,3H)

[0054] Example 4: Preparation of 5-chloro-3-ethylsulfanylpyridine-2-carbonitride [ka] To a solution of 5-chloro-3-ethylsulfanylpyridine-2-carboxamide (15.0 g, 97% purity, 67.0 mmol) and Et3N (23.5 mL, 167.5 mmol) in dry THF (255 mL), trifluoroacetic anhydride (11.3 mL, 80.4 mmol) was added over 15 minutes while maintaining the internal temperature below 5°C. The reaction mixture was warmed to room temperature and stirred for a further 2 hours. Most of the THF was evaporated under reduced pressure, and water (45 mL) was slowly added. The resulting brown precipitate was filtered and washed on the filter with cold water. The precipitate was dissolved in acetone (60 mL), and the solution was slowly added to water (150 mL) while vigorously stirring. The resulting light brown precipitate was filtered and dried under reduced pressure to obtain the title compound (13.25 g, 97% purity, 97% yield). 1 H NMR(400MHz,CDCl3)δ 8.38(d,J=2.1Hz,1H),7.66(d,J=2.1Hz,1H),3.07(q,J=7.3Hz,2H),1.41(t,J=7.4Hz,3H).

[0055] Example 5: Preparation of 2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl)acetate [ka] A solution of 5-chloro-3-ethylsulfanylpyridine-2-carbonitrile (20.0 g, 97% purity, 97.6 mmol) in dry DMF (100 mL) was mixed with powdered potassium carbonate (34.4 g, 244 mmol). The resulting suspension was then heated to 100 °C, and ethyl cyanoethyl (15.9 mL, 146 mmol) was added over 1 hour. After completely consuming the starting material, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and the precipitate (inorganic salt) was filtered off. The filtrate was neutralized with 2N aqueous HCl, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na₂SO₄, and evaporated under reduced pressure. Using ethyl acetate and cyclohexane as eluents, the crude residue was purified by silica gel chromatography to obtain the title compound (19.12 g, 95.5% purity, 87% yield) as a gray solid. 1 H NMR(400MHz,CD3CN)δ 8.50(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H),5.21(s,1H),4.23(q,J=7.1H z,2H),3.14(q,J=7.4Hz,2H),1.34(t,J=7.3Hz,3H),1.24(t,J=7.1Hz,3H).

[0056] Example 6: Preparation of 5-(cyanomethyl)-3-ethylsulfanylpyridine-2-carbonitride [ka] A solution of ethyl 2-cyano-2-(6-cyano-5-ethylsulfanyl-3-pyridyl)acetate (10.00 g, 95% purity, 34.51 mmol) in a mixture of acetic acid (44 mL) and water (22.5 mL) was added with sodium chloride (5.07 g, 86.3 mmol). Then, the reaction mixture was stirred at 100 °C until the starting material was completely consumed. The reaction mixture was cooled to ambient temperature and cold water (100 mL) was added. Then, the resulting mixture was neutralized by adding solid sodium hydrogen carbonate little by little with vigorous stirring, and the neutralized solution was extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was dissolved in acetone (20 mL) and slowly added to water (100 mL) at 0 °C with vigorous stirring. The resulting grayish-white precipitate was filtered off, washed with water (50 mL) on the filter, and dried under reduced pressure to obtain the title compound as a grayish-white powder (7.17 g, 93% purity, 95% yield). 1 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 1.7 Hz, 1H), 4.21 (s, 2H), 3.18 (q, J = 7.3 Hz, 2H), 1.30 (t, J = 7.3 Hz, 3H).

[0057] Example 7: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-ethylsulfanyl-pyridine-2-carbonitrile

Chemical formula

[0058] Preparation of racemic sulfoxides for the development of chiral analytical methods: Racemic samples of sulfoxides were prepared according to the following general procedure. One equivalent of sulfide was dissolved in acetic acid (5 mL / mmol) at room temperature, and hydrogen peroxide (1.05 equivalents, 30% by mass) was added. The reaction mixture was stirred at 40°C for 20 hours, or until it was confirmed by LC-MS that the starting material had been completely consumed. An aqueous solution of NaHCO3 was added dropwise to the reaction mixture, followed by the addition of ethyl acetate. The phases were separated, and the aqueous phase was extracted with further ethyl acetate. The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and evaporated to obtain the desired sulfoxide. This substance was used directly for the development of the chiral HPLC method.

[0059] Preparation of enantioconcentrated sulfoxides: Example 8: Preparation of 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-bromo-3-ethylsulfanylpyridine-2-carbonitride (2.157 g, 93% purity, 8.25 mmol) in anisole (8.3 mL), (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol) (0.235 g, 97% purity, 0.602 mmol), 4-methoxybenzoic acid (43 mg, 0.28 mmol), and Fe(acac)3 (0.277 g, 0.0784 mmol) were added. The resulting dark red solution was cooled to 10°C, and 30% H2O2 water (1.35 mL, 13.2 mmol) was added. The resulting two-phase mixture was stirred at 10°C for 22 hours. At this stage (complete conversion of the starting materials), the reaction was quenched by adding crushed ice (4 g) and 40% NaHSO3 aqueous solution (2.6 mL). After warming to ambient temperature, the mixture was diluted with toluene (8 mL) and treated with 1 M H2SO4 aqueous solution (0.83 mL). After stirring for 30 minutes, the phases were separated and the organic phase was washed with NaHCO3 aqueous solution (8 mL) and saturated brine (8 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain the crude product. Quantitative NMR analysis using 1,3,5-trimethoxybenzene as an internal standard showed a 91% chemical yield to the desired 5-bromo-3-[(R)-ethylsulfinyl]pyridine-2-carbonitride. The crude product was purified by reverse-phase HPLC (MeCN / water / 0.1% formic acid mobile phase) to obtain the title compound (1.63 g, >99% purity, >99.5% ee, 76% isolation yield) as a white powder. 1 H NMR(400MHz,CDCl3)δ 1.32(t,J=7.45Hz,3H),2.99(dq,J=14.0,7.2Hz,1H),3.15-3.36(m,1H),8.50(d,J=2.2Hz,1H),8.85(d,J=2.2Hz,1H)

[0060] Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector2 Column: Daicel SFC CHIRALPAK(registered trademark) IC, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A: CO2 B: IPA Gradient: B from 20% to 60% over 2 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 240nm Sample concentration: 1 mg / mL in ACN Injection volume: 2μL

[0061] result: [Table 1]

[0062] For X-ray data analysis, a single crystal grown from diisopropyl ether was selected. The mounted crystal sample measured 0.4 mm × 0.3 mm × 0.3 mm and was a colorless prism. Data acquisition was performed at 293 K using a Rigaku Oxford Diffraction Supernova diffractometer. The unit cell was determined to be orthorhombic (space group P212121), and its structure contained one molecule within the crystal asymmetric unit (Figure 1, thin bar representation with chirality labeled. Figure 1 was generated with the Flare software package). The stereochemistry was clearly determined to be R isomer, and the Flack parameter was 0.02 + / - 0.03. Crystallographic data are summarized in Table 1, and the selected geometric parameters are listed in Table 2.

[0063] [Table 2-1]

[0064] [Table 2-2]

[0065] [Table 3]

[0066] Example 9a: Preparation of 5-(1-cyanocyclopropyl)-3-[(S)-ethylsulfinyl]pyridine-2-carbonitrile [ka] A solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitride (241.5 mg, 95% purity, 1.00 mmol), Fe(acac)3 (17.5 mg, 0.0500 mmol), 4-methoxybenzoic acid (3.8 mg, 0.0250 mmol), and 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (48.8 mg, 97% purity, 0.100 mmol) in PhMe (4.0 mL) was to be mixed with 30% H2O2 water (0.20 mL, 2.00 mmol) at ambient temperature. After vigorous stirring for 2.5 hours, the reaction mixture was poured into siRNA (23 mL) and quenched by adding 1.0 M Na2S2O3 (2.4 mL). The phases were separated, and the organic phase was washed with 1.0 M HCl (2.3 mL) and NaHCO3 aqueous solution. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by reverse-phase HPLC (water / MeCN / 0.1% formic acid mobile phase) to obtain the title compound (234 mg, 97% ee, 95% yield) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 8.77(d,J=2.3Hz,1H),8.18(d,J=2.3Hz,1H),3.26(dq,J=13.6,7.3Hz,1H ),3.04(dq,J=13.6,7.3Hz,1H),2.09-1.79(m,4H),1.12(t,J=7.4Hz,3H); 13 C NMR(101MHz,d6-DMSO)δ=165.7,146.0,144.4,142.8,136.0,131.1,121.2,48.9,19.2,12.0,6.3

[0067] Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK (registered trademark) IA, 3□m, 0.3cm × 10cm, 40℃ Mobile phase: A: CO2 B: IPA Gradient: B ratio increases from 20% to 60% over 1.8 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: DAD 210~500nm Sample preparation: Dissolve in MeOH Injection volume: 2μL

[0068] result: [Table 4]

[0069] Example 9b: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] Using a syringe pump, 30% H2O2 water (0.23 ml, 2.11 mmol) was added over 1 hour at 0°C to a solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitrile (237.0 mg, 97% purity, 1.00 mmol), Fe(acac)3 (3.6 mg, 0.0101 mmol), 4-methoxybenzoic acid (3.8 mg, 0.0251 mmol), and 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dichlorophenol (32.8 mg, 98% purity, 0.110 mmol) in PhOMe (1.0 mL). The resulting reaction mixture was stirred at the same temperature for a further 20 hours. The reaction mixture was poured into toluene (23 mL) and quenched by adding 1.0 M NaHSO3 (2.4 mL). The phases were separated, and the organic phase was washed with 1.0 M HCl (2.3 mL) and aqueous NaHCO3 solution. The organic phase was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was purified by reverse-phase HPLC (water / MeCN / 0.1% formic acid mobile phase) to obtain the title compound (230 mg, >99.5% ee, 93% yield) as a white powder.

[0070] Chiral SFC method: Same as Example 2a result: [Table 5]

[0071] Example 9c: Preparation of 5-(1-cyanocyclopropyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] Using a syringe pump, 30% H2O2 water (7.8 ml, 76.3 mmol) was added over 2 hours at 10°C to a solution of 5-(1-cyanocyclopropyl)-3-ethylsulfanylpyridine-2-carbonitride (10.61 g, 98% purity, 45.5 mmol), Fe(acac)3 (0.153 g, 0.432 mmol), 4-methoxybenzoic acid (0.234 g, 1.54 mmol), and 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol (1.281 g, 97% purity, 3.30 mmol) in anisole (46 mL). The resulting reaction mixture was vigorously stirred at the same temperature for a further 22 hours. The reaction was quenched by adding 10.6 mL of 40% NaHSO3 aqueous solution and diluted with anisole (53 mL). The phases were separated, and the organic phase was washed with 21 mL of 1 M H2SO4, 21 mL of saturated NaHCO3 aqueous solution, and 21 mL of saturated brine. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (water / MeCN as mobile phase) to obtain the title compound (10.44 g, >99.5% ee, 93% yield) as a white powder.

[0072] Chiral SFC method: SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C Mobile phase: A: CO2 B: IPA Gradient: B increased from 5% to 20% over 9.8 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 238nm Sample preparation: 1 mg / mL in ACN Injection volume: 2μL

[0073] result: [Table 6]

[0074] Example 10: Preparation of 5-(1-cyano-1-methyl-ethoxy)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] A solution of 5-(1-cyano-1-methyl-ethoxy)-3-ethylsulfanylpyridine-2-carbonitrile (2.00 g, 82% purity, 6.64 mmol), iron(III) acetylacetonate (46.9 mg, 0.133 mmol), 2,4-dichloro-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (0.602 g, 1.99 mmol), and p-anisic acid (51 mg, 0.332 mmol) was mixed in toluene (13 mL) and 30% H2O2 water (1.36 ml, 50.1 mmol) was added over 1 hour at ambient temperature. The reaction mixture was stirred for a further 5 hours and then quenched by adding saturated sodium thiosulfate solution at 0°C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound. The crude material was purified by silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (1.55 g, 89% purity, >99.5% ee, 79% yield). 1 H NMR(400MHz,DMSO-d6)δ 8.71(d,J=2.6Hz,1H)8.02(d,J=2.75Hz,1H)3.28-3.33(m,1H)2.96-3.02(m,1H),1.84(s,6H),1.09(t,J=7.3Hz,3H)

[0075] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IA (4.6mm x 250mm) 5μm Mobile phase: A: TBME B: IPA Isocratic: 20% of B over 13 minutes Flow rate: 1.0ml / min Detection: 240nm Sample preparation: 1 mg / mL in EtOH Injection volume: 2μL

[0076] result: [Table 7]

[0077] Example 11: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(1-cyano-1-methyl-ethyl)-3-ethylsulfanylpyridine-2-carbonitrile (6.00 g, 96.5% purity, 25.0 mmol), iron(III) acetylacetonate (0.177 g, 0.5 mmol), and 2,4-dibromo-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (1.47 g, 3.75 mmol) in toluene (90 mL), 30% hydrogen peroxide solution (2.0 equivalents, 50.1 mmol) was added dropwise over 1 hour at 0°C. The reaction mixture was stirred at 24°C for 2 hours, and then quenched by adding saturated Na2S2O3 at 0°C. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude substance was purified by column chromatography using cyclohexane and ethyl acetate as eluents to obtain the title compound (5.48 g, 91% purity, 97% ee, 81% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.10(d,J=2.3Hz,1H),8.35(d,J=2.3Hz,1H),3.28(m,1H),3.04(m,1H),1.82(d,J=1.9Hz,6H),1.12(t,J=7.3Hz,3H)

[0078] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IC (4.6mm x 250mm) 5μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% of B in 30 minutes Flow rate: 1.0ml / min Detection: 225nm Sample preparation: 1 mg / mL in EtOH Injection volume: 2μL

[0079] result: [Table 8]

[0080] Example 12: Preparation of 5-(3-fluorophenyl)-3-[(R)-methylsulfinyl]pyridine-2-carbonitrile [ka] To a solution of 5-(3-fluorophenyl)-3-methylsulfanylpyridine-2-carbonitride (0.800 g, 90% purity, 2.95 mmol), iron(III) acetylacetonate (10.4 mg, 0.0295 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (0.213 g, 0.442 mmol), and p-anisic acid (11.3 mg, 0.0737 mmol) in toluene (6.0 mL), 30% H2O2 water (0.6 ml, 5.9 mmol) was added dropwise over 15 minutes, and the reaction mixture was stirred for a further 1 hour. The reaction mixture was quenched with saturated sodium thiosulfate, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The title compound (0.73 g, 94% purity, 97% ee, 89% yield) was obtained by purification using silica gel chromatography with cyclohexane and ethyl acetate as eluents. 1 H NMR(400MHz,DMSO-d6)δ 9.29(d,J=2.1Hz,1H),8.64(d,J=2.1Hz,1H),7.89(m,1H),7.80(d,J=7.8Hz,1H),7.64(m,1H),7.41(m,1H),3.04(s,3H)

[0081] Methods of chiral analysis: Chiral HPLC: Waters, Acquisition, and Pulse Controlled Calculation (UPLC) Column: Chiralpack-IA (4.6mm x 250mm) 5μm Mobile phase: A: TBME B: IPA Isocratic: 30% of B over 30 minutes Flow rate: 1.0ml / min Detection: 225nm Sample preparation: 1 mg / mL in EtOH Injection volume: 2μL

[0082] result: [Table 9]

[0083] Example 13: Preparation of 3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile [ka] A solution of 3-ethylsulfanylpyridine-2-carbonitride (182.0 mg, 90% purity, 1.00 mmol), Fe(acac)3 (3.4 mg, 0.0095 mmol), 4-methoxybenzoic acid (5.3 mg, 0.034 mmol), and 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol (28.5 mg, 0.073 mmol) in PhOMe (1 mL) was prepared. The resulting deep red solution was cooled to 10°C, and 30% H2O2 water (163 μL, 1.60 mmol) was slowly added. The resulting two-phase mixture was stirred at 10°C for 22 hours. The reaction was quenched by cooling to 0°C and adding 40% NaHSO3 aqueous solution (0.315 mL, 1.60 mmol). After warming to ambient temperature, the mixture was diluted with toluene (10 mL), and concentrated H₂SO₄ (50 μl) was added to acidify the mixture. After stirring for 30 minutes, the phases were separated, and the aqueous layer was extracted again with toluene (15 mL). The combined organic layers were washed with saturated NaHCO₃ aqueous solution (8 mL) and saturated brine (8 mL). The organic layers were dried over anhydrous MgSO₄ and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (cyclohexane / toluene 100:0~0:100) to obtain the title compound (112 mg, 95% purity, 94% ee, 59% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ 1.31(t,J=7.3Hz,3H)2.88-3.07(m,1H)3.15-3.33(m,1H)7.80(dd,J=8.0,4.7Hz,1H)8.40(dd,J=8.2,1.6Hz,1H)8.83(dd,J=4.7,1.4Hz,1H)

[0084] Chiral SFC method SFC: Waters Acquity UPC2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK® IA, 3 μm, 0.3 cm × 10 cm, 40°C Mobile phase: A:CO2 B:MeOH Isocratic: 5% of B in 5 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 260nm Sample concentration: 1 mg / mL in MeOH Injection volume: 1μL

[0085] result: [Table 10]

[0086] Example 14: Preparation of 3-[(R)-ethylsulfinyl]-5-(trifluoromethyl)pyridine-2-carbonitrile [ka] To a solution of 3-ethylsulfanyl-3-(trifluoromethyl)pyridine-2-carbonitrile (0.237 g, 98% purity, 1.00 mmol) in anisole (1.0 mL), (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-dibromophenol) (28.5 mg, 97% purity, 0.073 mmol), 4-methoxybenzoic acid (5.3 mg, 0.034 mmol), and Fe(acac)3 (3.4 mg, 0.010 mmol) were added. The resulting dark red solution was cooled to 10°C, and 30% H2O2 water (0.136 mL, 1.6 mmol) was added. The resulting two-phase mixture was stirred at 10°C for 22 hours. At this stage (complete transformation of the starting materials), the reaction was quenched by adding crushed ice (4 g) and 40% NaHSO3 aqueous solution (0.30 mL). After warming to ambient temperature, the mixture was diluted with HCl (10 mL) and treated with concentrated H2SO4 (50 μL). After stirring for 30 minutes, the phases were separated, and the aqueous layer was extracted again with HCl (15 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (8 mL) and saturated brine (8 mL). The organic layers were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (cyclohexane / HCl 100:0 to 60:40) to obtain the title compound (127 mg, 98% purity, >99% ee, 50% yield) as a colorless solid. 1 H NMR(400MHz,CDCl3)δ 1.27-1.40(m,3H),2.95-3.09(m,1H),3.21-3.37(m,1H)8.65(d,J=1.45Hz,1H),9.06(d,J=1.09Hz,1H) 19 F NMR(377MHz,CDCl3)δ -62.80(s,3F)

[0087] Chiral SFC method SFC: Waters Acquity UPC 2 / QDa Waters Acquity UPC PDA Detector 2 Column: Daicel SFC CHIRALPAK(registered trademark) IC, 3μm, 0.3cm × 10cm, 40℃ Mobile phase: A:CO2 B:MeOH Isocratic: 3% of B in 2 minutes ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 270nm Sample concentration: 1 mg / mL in MeOH Injection volume: 1μL

[0088] result: [Table 11]

[0089] Further synthetic treatment of enantioenriched sulfoxides This section demonstrates the further functionalization of a specific enantioenriched sulfoxide to an agriculturally important intermediate (Scheme 3).

[0090] Example 15: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carboxamide [ka] A suspension of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carbonitrile (3.2 g, 91% purity, 11.81 mmol) in tert-butanol (32 mL) was heated to 60°C, and potassium hydroxide (2.34 g, 35.4 mmol) was added to the resulting solution. The resulting reaction mixture was stirred at 60°C for 1.5 hours. The reaction mixture was cooled to room temperature and quenched with 2N HCl aqueous solution until the pH was approximately 7. The reaction mixture was then extracted with toluene, dried over anhydrous sodium 2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel column chromatography using toluene / cyclohexane as the eluate to obtain the title compound (1.80 g, 93% purity, 53% yield) as a grayish-white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.91(d,J=2.3Hz,1H),8.50(d,J=2.3Hz,1H),8.43(br s,1H),8.05(br s,1H),3.21-3.28(m,1H),2.77-2.80(m,1H),1.81(s,6H),1.08(t,J=7.4Hz,3H).

[0091] Example 16: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carboxylic acid [ka] To a solution of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carboxamide (0.490 g, 93% purity, 1.72 mmol) in AcOH (5.15 mL), tert-butyl nitrite (0.69 ml, 5.15 mmol) was added at room temperature. The reaction mixture was then heated at 70 °C for 5 hours. The reaction mixture was then cooled to ambient temperature and evaporated under reduced pressure. The crude residue was evaporated using toluene to remove residual acetic acid, and the mixture was dried under high vacuum to obtain the title compound (0.470 g, 86% purity, 89% yield) as a semi-solid, which was used in the next step without further purification. 1 H NMR(400MHz,CD3CN)δ 8.89(d,J=2.2Hz,1H),8.59(s,1H),6.83(br s,1H),3.12-3.33(m,1H),2.79-2.89(m,1H),1.84(s,3H),1.83(s,3H),1.17(t,J=7.4Hz,3H).

[0092] Example 17: Preparation of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-N-[2-(methylamino)-5-(trifluoromethyl)-3-pyridyl]pyridine-2-carboxamide [ka] A solution of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]pyridine-2-carboxylic acid (440 mg, 86% purity, 1.43 mmol) in a mixture of pyridine (1.3 mL) and ethyl acetate (0.9 mL) was added to a solution of 1-propanephosphonic anhydride (2.2 mL, 3.57 mmol, 50% w / w) in ethyl acetate at room temperature, and the mixture was stirred for 10 minutes. Then, N2-methyl-5-(trifluoromethyl)pyridine-2,3-diamine (344 mg, 1.71 mmol) was added, and the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was then cooled to ambient temperature and diluted with cold water. The resulting mixture was extracted with ethyl acetate, the combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate / cyclohexane as the eluent to obtain the title compound (220 mg, 91% purity, 32% yield) as a light brown solid. 1 H NMR(400MHz,CD3CN)δ 9.58(s,1H),8.90(d,J=2.2Hz,1H),8.62(d,J=2.2Hz,1H),8.35(s,1H),7.74(d,J=2.2Hz,1H),5.82(br s,1H),3.21-3.31(m,1H),2.93(d,J=4.0Hz,3H),2.82-2.86(m,1H),1.84(s,3H),1.83(s,3H),1.17(t,J=8.0Hz,3H).

[0093] Example 18: Preparation of 2-[5-[(R)-ethylsulfinyl]-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] A solution of 5-(1-cyano-1-methyl-ethyl)-3-[(R)-ethylsulfinyl]-N-[2-(methylamino)-5-(trifluoromethyl)-3-pyridyl]pyridin-2-carboxamide (200 mg, 91% purity, 0.414 mmol) in acetic acid (1.4 mL) was heated at 110°C for 2 hours. After completely consuming the starting material, the reaction mixture was evaporated under reduced pressure. Using ethyl acetate / cyclohexane as the eluate, the crude material was purified by silica gel chromatography to obtain the title compound as a brown solid (130 mg, 97% purity, 72% yield). 1 H NMR(400MHz,CD3CN)δ 9.01(d,J=2.4Hz,1H),8.82(d,J=1.2Hz,1H),8.64(d,J=2.4Hz,1H),8.47(d,J=1.6Hz,1H)4.27 (s,3H),3.56-3.62(m,1H),2.98-3.03(m,1H),1.88(s,3H),1.87(s,3H),1.37(t,J=7.4Hz,3H).

Claims

1. Equation (I) 【Chemistry 1】 (In the formula, S * This is a stereogenic sulfur atom with an R or S stereoconfiguration, R 1 is hydrogen, halogen, C 1 to C 6 -haloalkyl, C 1 to C 6 -cyanoalkyl, C 1 to C 6 -cyanoalkoxy, C 3 to C 6 -cyanocycloalkyl or optionally substituted aryl, and R 2 C 1 ~C 4 (It is alkyl.) A process for preparing an enantiomerically concentrated sulfoxide of formula (II) 【Chemistry 2】 (In the formula, R 1 and R 2 (This is as defined for the compound of formula (I).) A process for preparing the sulfinyl compound of formula (I) by stereoselectively oxidizing the sulfinyl compound in a suitable solvent (or diluent) in the presence of an oxidizing agent, a metal derivative, a chiral ligand, or optionally a suitable acid additive, to produce the sulfinyl compound of formula (I).

2. R 1 is hydrogen, halogen, C 1 ~C 4 - Haloalkyl, C 1 ~C 4 -Cyanoalkyl, C 1 ~C 4 -Cyanalkoxy, C 3 ~C 4 - The process according to claim 1, wherein the compound is a cyanocycloalkyl or an optionally substituted aryl.

3. R 1 The process according to claim 1, wherein is hydrogen, halogen, trifluoromethyl, cyanoisopropoxy, cyanoisopropyl, cyanocyclopropyl, or optionally substituted phenyl.

4. R 2 is methyl or ethyl, preferably R 2 The process according to claim 1, wherein is ethyl.

5. The process according to any one of claims 1 to 4, wherein the oxidizing agent is an inorganic peroxide.

6. The process according to any one of claims 1 to 5, wherein the oxidizing agent is an organic peroxide.

7. The process according to claim 5 or 6, wherein the ratio of the oxidizing agent used to the sulfanil compound of formula (II) is in the range of 8:1 to 0.8:

1.

8. The process according to any one of claims 1 to 7, wherein the metal derivative is selected from vanadium salts and iron salts.

9. The process according to any one of claims 1 to 8, wherein the chiral ligand is selected from a Schiff base formed from a salicylaldehyde derivative and a chiral amine.

10. The metal derivative is iron, and the chiral ligand is a salicylaldehyde derivative and formula (IV) 【Transformation 3】 (In the formula, R 4 It is a halogen, * (This represents an enantioenriched chiral center in either the R or S configuration.) The process according to any one of claims 1 to 9, wherein the Schiff base is formed from a chiral amino alcohol represented by the compound.

11. The process according to any one of claims 1 to 10, wherein the additive is benzoic acid, which may optionally be monosubstituted, disubstituted, or trisubstituted with methyl, ethyl, isopropyl, methoxy, or dimethylamino, and may optionally be in the form of a lithium salt, sodium salt, or potassium salt.

12. The oxidizing agent is hydrogen peroxide, The aforementioned metal salt is Fe(acac) 3 And, The ligands are (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2S)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2R)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, ( Selected from (2S)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, (2R)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethylbutan-1-ol and (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethylbutan-1-ol, and The process according to any one of claims 1 to 11, wherein the additive is 4-methoxybenzoic acid.

13. The process according to any one of claims 1 to 12, wherein the solvent (or diluent) is selected from esters, nitriles, alcohols, ethers, and aliphatic, aromatic, or halogenated hydrocarbons and mixtures thereof.

14. The process according to claim 13, wherein the solvent is an aromatic or halogenated hydrocarbon selected from dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene, and mixtures thereof.

15. Formula I: 【Chemistry 4】 (In the formula, S * This is a stereogenic sulfur atom with an R or S stereoconfiguration, R 1 is hydrogen, halogen, C 1 ~C 6 - Haloalkyl, C 1 ~C 6 -Cyanoalkyl, C 1 ~C 6 -Cyanalkoxy, C 3 ~C 6 -Cyanocycloalkyl or optionally substituted aryl, and R 2 C 1 ~C 4 (It is alkyl.) A compound of [unclear].

16. S * The compound according to claim 15, wherein is a stereogenic sulfur atom having an R configuration.

17. S * The compound according to claim 15, wherein is a stereogenic sulfur atom having an S configuration.

18. R 1 R is hydrogen, halogen, trifluoromethyl, cyanoisopropoxy, cyanoisopropyl, cyanocyclopropyl, or optionally substituted phenyl. 2 is C 1 ~C 4 Alkyl, more preferably R 2 is methyl or ethyl, most preferably R 2 The compound according to any one of claims 15 to 17, wherein is ethyl.

19. Formula (II) 【Transformation 5】 (In the formula, R 1 is hydrogen, halogen, C 1 ~C 6 - Haloalkyl, C 1 ~C 6 -Cyanoalkyl, C 1 ~C 6 -Cyanalkoxy, C 3 ~C 6 -Cyanocycloalkyl or optionally substituted aryl, and R 2 C 1 ~C 4 (It is alkyl.) A compound of [unclear].

20. R 1 R is hydrogen, halogen, trifluoromethyl, cyanoisopropoxy, cyanoisopropyl, cyanocyclopropyl, or optionally substituted phenyl. 2 The compound according to claim 19, wherein is methyl or ethyl.

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