Synthesis of Sulfoximine Compounds with Stereogenic Sulfur Atoms

Abstract

Formula (I) [Formula 1] JPEG2025540262000075.jpg2844, comprising: (A) a compound of formula (II) [Case 2] JPEG2025540262000076.jpg3146, followed by (B) stereoselectively oxidizing a sulfanyl compound of formula (III) [C3] A process is disclosed that comprises the stereospecific iminization of a sulfinyl compound of formula JPEG2025540262000077.jpg2844, wherein the substituents are as defined in claim 1.

Description

[Technical Field]

[0001] The present invention relates to the synthesis of sulfoximine compounds having stereogenic sulfur atoms. [Background technology]

[0002] In recent years, sulfoximines have attracted significant interest from the agrochemical and pharmaceutical industries as isosteres of sulfones and sulfonamides due to their ability to adjust the four substituents and optimize their physicochemical properties (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 a single atom, they can have significantly different properties due to the presence of hydrogen bond donor groups. Consequently, there has been considerable interest in methods for introducing NH-sulfoximines, and several different approaches have recently been developed, as reviewed in Chem. Eur. J. 2021, 27, 17293.

[0003] Unsymmetrical sulfoximines are chiral at sulfur, and therefore it is desirable to be able to prepare them in enantiopure or enantiomerically enriched form to avoid adverse human or environmental health effects resulting from the undesired enantiomer. On a small scale, this can be achieved by separating the enantiomers by chiral chromatography (J. Med. Chem. 2021, 64, 11651). However, for large-scale synthesis, the undesired enantiomer must be discarded, and the separation often requires large volumes of solvent, making this an impractical and wasteful approach. Therefore, there is a need for a method for the enantioselective synthesis of the desired enantiomer.

[0004] An attractive method for the synthesis of enantioenriched sulfoximines is the enantiospecific iminization of enantioenriched sulfoxides, which can be prepared from the corresponding sulfides by various oxidation methods (Chem. Rev. 2020, 120, 4578; reviewed in Chem. Rev. 2010, 110, 4303). Notable such methods include 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 developed highly enantioselective methods using chiral Schiff bases complexed 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), while Maguire's method using a copper catalyst (J. Org. Chem. 2012, 77, 3288) or Jacobsen's method using a manganese catalyst (Tet. Lett. 1992, 33, 7111) often suffer from lower selectivity. More recently, List has disclosed a practical organocatalytic method that avoids metal catalysts but replaces them with highly complex chiral acids (J. Am. Chem. Soc. 2012, 134, 10765; J. Am. Chem. Soc. 2021, 143, 14835). Biocatalysis using engineered enzymes offers an efficient and sustainable option for enantioselective sulfide oxidation (Catalysts, 2018, 8, 624), but the efficiency of such enzymes is highly substrate-dependent, often requiring extensive optimization for a single substrate.

[0005] However, despite the availability of several methods for the synthesis of chiral sulfoxides, the enantioselectivity and yield of many methods for enantioselective sulfoxide synthesis are highly substrate-dependent, especially in the case of heterocyclic substrates, which often hinder metal-catalyzed reactions, and optimization of the oxidation system is often required. This need for individual optimization is exemplified by the titanium-mediated oxidation described in Tet. Assym. 2000, 11, 3819 or the iron-catalyzed enantioselective synthesis of esomeprazole described in ACS Catalysis, 2018, 8, 9738. In both cases, non-obvious modifications to the originally published procedures were crucial to obtain high yields and enantioselectivities on this complex substrate.

[0006] Various methods for the iminization of sulfoxides have also been described. Hypervalent iodine is generally used in combination with a metal catalyst such as rhodium (Org. Lett. 2004, 6, 1305), copper (Tetrahedron Lett. 1998, 39, 4805), iron (Tetrahedron Lett. 1998, 39, 5015), or silver (Org. Lett. 2005, 7, 4983), or without a catalyst, as described by Bull and Luisi (Angew. Chem. Int. Ed. 2016, 51, 7203). The latter method has been used to synthesize the ATR inhibitor selalasertib on a large scale (Org. Process. Res. Dev. 2021, 25, 43). However, hypervalent iodine reagents generate significant halogenated waste, adding cost to the process. Liang's method using NaN3 and Eaton's reagent (Tetrahedron Lett., 2017, 58, 333-337) avoids the use of hypervalent iodine, but is unsuitable for the synthesis of chiral sulfoximines because it results in racemization of the product when starting from an enantiopure sulfoxide starting material, and the use of azides is also large-scale and dangerous. Another alternative reagent is an activated hydroxylamine derivative such as O-mesityl-hydroxylamine (MSH) (Tetrahedron Lett., 1972, 4137; J. Org. Chem., 1974, 39, 2458). However, this reagent is highly unstable and unsuitable for large-scale use. Other hydroxylamine reagents have also been demonstrated, such as nitrobenzotrihydroxylamine triflate in combination with iron (Angew. Chem. Int. Ed 2018, 57, 32) or dinitrophenylhydroxylamine in combination with a rhodium catalyst (Chem. Commun. 2014, 50, 9687).

[0007] The above examples demonstrate that although many methods exist for the synthesis of chiral sulfoxides and their subsequent conversion to sulfoximines, it is not easy to find methods suitable for complex substrates that would be suitable for large-scale use. Summary of the Invention [Problem to be solved by the invention]

[0008] The synthesis of various racemic sulfoximine compounds exhibiting insecticidal activity is described in WO 2019 / 234158. It would be advantageous to be able to prepare these compounds in enantioenriched form, since this would reduce the risk of undesired biological, environmental, or toxicological effects caused by the undesired isomer. However, no known methods exist for producing such sulfoximines enantioselectively. Furthermore, because separation of racemic mixtures by resolution and chromatography is wasteful and inefficient, especially on a large scale, it would be advantageous for this method to involve enantioselective synthesis. However, identifying such enantioselective synthetic methods is difficult for the reasons outlined above. In particular, due to the presence of multiple heteroatoms in the substrate, many metal-catalyzed processes would be expected to be ineffective or provide poor enantioselectivity for such substrates. It is therefore desirable to identify suitable methods for the large-scale enantioselective synthesis of these compounds that are safe, cost-effective, and have minimal environmental impact. [Means for solving the problem]

[0009] The present invention relates to a compound of formula (I) [ka] (In the formula, A1, A2 and A3 are independently CH or N; S* is a stereogenic sulfur atom in the R or S configuration; R1 is cyanoisopropoxy, cyanoisopropyl, or cyanocyclopropyl; R2 is hydrogen or methyl, and R3 is C1-C3 fluoroalkyl. The present invention provides a process for preparing a sulfoximine of formula (I), which comprises: A) Formula (II) [ka] (wherein A1, A2, A3, R1, R2 and R3 are as defined in formula (I)). is stereoselectively oxidized in the presence of an oxidizing agent, in the presence of a chiral catalyst, and optionally in the presence of a suitable carboxylic acid or carboxylate additive, in a suitable solvent (or diluent) to give a sulfanyl compound of formula (III) [ka] wherein A1, A2, A3, R1, R2, R3 and S* are as defined for compounds of formula (I). and forming a sulfinyl compound of the formula: B) reacting a sulfinyl compound of formula (III) with an iminating reagent in a suitable solvent (or diluent) in the presence of a metal catalyst, optionally in the presence of a suitable acid additive, to stereospecifically produce a sulfoximine compound of formula (I); Includes: DETAILED DESCRIPTION OF THE INVENTION

[0010] In one embodiment, S* in formula (I) or formula (III) is a stereogenic sulfur atom in the R or S configuration, and said S* center is in enantiomerically pure or enantiomerically enriched form.

[0011] In another embodiment, the present invention provides a process for preparing enantiomerically enriched sulfoximines of formula (I).

[0012] The ratio of enantiomers produced in the present process can be increased, if desired, by crystallization. Such methods are known to those skilled in the art and include crystallization from an organic solvent, a mixture of organic solvents, or a mixture of organic solvents and water.

[0013] In another preferred embodiment, the present invention provides a process for preparing enantiopure sulfoximines of formula (I).

[0014] Further embodiments of the process of the present invention are provided as follows:

[0015] Process Step (A): In one embodiment of the present invention, process step (A) comprises reacting a compound of formula (II) [ka] (In the formula, A1, A2 and A3 are independently CH or N; R1 is cyanoisopropoxy, cyanoisopropyl, or cyanocyclopropyl; R2 is hydrogen or methyl, and R3 is C1-C3 fluoroalkyl. wherein the sulfanyl compound of formula (II) is oxidized in the presence of an oxidizing agent, in the presence of a metal derivative, in the presence of a chiral ligand, in a suitable solvent (or diluent) and optionally in the presence of a suitable carboxylic acid or carboxylate additive to give a sulfanyl compound of formula (III) [ka] wherein A1, A2, A3, R1, R2 and R3 are as defined for compounds of formula (II), and S* is a stereogenic sulfur atom in the R or S configuration. to produce the sulfinyl compound:

[0016] Examples of suitable and preferred oxidizing agents for step A are 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 sulfanyl compound of formula (II) is in the range of 8:1 to 0.8:1, preferably 5:1 to 1:1, more preferably 3:1 to 1:1.

[0017] Examples of suitable and preferred metal derivatives for Step A are vanadium, titanium, copper, iron, manganese, molybdenum, or zirconium salts. More preferably, the metal derivative in Step A is a vanadium or iron salt. Suitable examples include VOCl2, VO(acac)2, Fe(acac)3, and Fe(acac)2. The amount of metal catalyst used relative to the sulfanyl compound of formula (III) ranges from 0.1 mol% to 200 mol%, preferably from 1 mol% to 10 mol%.

[0018] Examples of suitable and preferred chiral ligands for step A are derivatives of N,N'-bis(salicylidene)ethylenediamine (salen ligands) or are selected from Schiff bases formed from salicylaldehyde derivatives and chiral amines.

[0019] In a preferred embodiment of the present invention, the metal derivative is iron or vanadium, and the chiral ligand is a salicaldehyde derivative and a chiral ligand of formula (IV) [ka] wherein R4 and R5 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, nitro, cyano, C1-C4 alkoxy, C1-C4 haloalkoxy, and optionally substituted aryl. R6 is C1-C6 alkyl, including phenyl, 4-hydroxyphenyl, heteroaryl, hydroxy, sulfhydryl, C1-C6 alkoxy, C1-C6 alkylthio, C(O)OR x , C(O)NR Y R Z , N.R. Y R Z , guanidyl, C3-C6 cycloalkyl, C1-C6 alkyl optionally substituted with optionally substituted aryl. x , R y and R zare independently selected from hydrogen and C1-C6 alkyl. R7 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted aryl or carbonyl group (=O). R6 and R7 can optionally be joined to form a cyclic group. * represents an enantiomerically enriched chiral center of the R or S configuration (where appropriate). Preferably, R4 and R5 are halogen, C1-C4 alkyl, C1-C4 haloalkyl. R6 is C1-C6 alkyl and R7 is hydrogen. More preferably, the chiral ligand is selected from: (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2S)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2R)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2S)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2R)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2R)-2-[(E)-(3,5-di-tertbutyl-phenyl)methyleneamino]-3,3-dimethyl-butan-1-ol (2S)-2-[(E)-(3,5-di-tertbutyl-phenyl)methyleneamino]-3,3-dimethyl-butan-1-ol

[0020] Chiral ligands are used as enantiomerically enriched compounds. The enantiomeric ratio of the ligands is 70:30 to 100:0 [R]:[S] or [S]:[R], preferably 90:10 to 100:0 [R]:[S] or [S]:[R].

[0021] The amount of the ligand used relative to the sulfanyl compound of formula (II) is in the range of 0.01 to 30 mol %, preferably 1 to 15 mol %, and most preferably 2 to 10 mol %.

[0022] Optionally, the ligand can be formed in situ in the reaction by adding an appropriate salicylaldehyde derivative and an appropriate amino alcohol. Alternatively, the ligand can be prepared in a separate step.

[0023] An example of a suitable and preferred additive for step A is a carboxylic acid. Preferably, the additive is benzoic acid, optionally mono-, di-, or tri-substituted with methyl, ethyl, isopropyl, methoxy, or dimethylamino, and optionally in the form of its lithium, sodium, or potassium salt. More preferably, the additive is methoxybenzoic acid or dimethylaminobenzoic acid (optionally in the form of its lithium, sodium, or potassium salt), even more preferably 4-methoxybenzoic acid. The amount of additive used relative to the sulfanyl compound of formula (II) is within the range of 0.01 to 10 mol %, preferably 0.1 to 8 mol %, and most preferably 1 to 5 mol %.

[0024] In a preferred embodiment of Step A, the oxidizing agent is hydrogen peroxide, the metal salt is Fe(acac)3, and the ligand is (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol and the additive is 4-methoxybenzoic acid.

[0025] In another preferred embodiment of step A, the oxidizing agent is hydrogen peroxide, the metal salt is VO(acac)2, and the ligand is (2R)-2-[(E)-(3,5-di-tertbutyl-phenyl)methyleneamino]-3,3-dimethyl-butan-1-ol or (2S)-2-[(E)-(3,5-di-tertbutyl-phenyl)methyleneamino]-3,3-dimethyl-butan-1-ol.

[0026] Examples of suitable and preferred solvents (or diluents) for step A are esters, nitriles, alcohols, ethers and aliphatic, aromatic or halogenated hydrocarbons.

[0027] In particular, examples of suitable and preferred solvents (or diluents) for step A 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-dioxanepentane, hexane, cyclohexane, heptane, dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, xylene, chlorobenzene, fluorobenzene, dichlorobenzene, methoxybenzene, trifluoromethylbenzene, p-cymene, mesitylene, ethylbenzene, isopropylbenzene or mixtures thereof.

[0028] Preferably, the solvent used in process step A 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 mixtures thereof.

[0029] More preferably, the solvent used in process step A is selected from dichloromethane, toluene, xylene, chlorobenzene, methoxybenzene or mixtures thereof.

[0030] Reaction step (A) is advantageously carried out in a temperature range of from about −20° C. to about 50° C., preferably from about −5° C. to about 30° C. In a preferred embodiment, the reaction is carried out in the range of 0° C. to 25° C.

[0031] The ratio of enantiomers produced in Step A is 50.5:49.5 to 100:0 [R]:[S] or [S]:[R]. Preferably, the enantiomeric ratio of the product is 70:30 to 100:0 [R]:[S] or [S]:[R], and even more preferably 90:10 to 100:0 [R]:[S] or [S]:[R]. The enantiomeric ratio of the product can be either lower or higher than the enantiomeric ratio of the chiral ligand used in the reaction.

[0032] The ratio of enantiomers produced in Step A can be increased, if desired, by crystallization. Such methods are known to those skilled in the art and include crystallization from an organic solvent, a mixture of organic solvents, or a mixture of an organic solvent and water.

[0033] A further preferred embodiment of process step (A) of the present invention is as follows.

[0034] Embodiment (A1): Table A-1 provides 12 compounds A-1.001 to A-1.012 of formula II, where A1, A2, A3, R1, R2 and R3 are as defined in Table Y.

[0035] Table A-2 provides 12 compounds A-2.001 to A-2.012 of formula III, where A1, A2, A3, R1, R2 and R3 are as defined in Table Y, and S* is a stereogenic sulfur atom in the R or S configuration.

[0036] [Table 1]

[0037] Embodiment (A1-1): In one aspect of embodiment (A1) of the present invention, step (A) comprises reacting a compound of formula (II) [ka] (In the formula, A1, A2 and A3 are independently CH or N; R1 is cyanoisopropoxy, cyanoisopropyl, or cyanocyclopropyl; R2 is hydrogen or methyl, and R3 is C1-C3 fluoroalkyl. This process comprises the stereoselective oxidation of a sulfanyl compound of formula (III) in the presence of an oxidizing agent, in the presence of a metal derivative, in the presence of a chiral ligand, optionally in the presence of a suitable carboxylic acid or carboxylate additive, optionally in a suitable solvent (or diluent) to give a sulfanyl compound of formula (III) [ka] wherein A1, A2, A3, R1, R2 and R3 are as defined for compounds of formula (II), and S* is a stereogenic sulfur atom in the R or S configuration. with the exception of the process wherein the compound of formula II is Compound A-1.001, the oxidant is hydrogen peroxide, the metal derivative is iron(III) acetylacetonate, the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol, the solvent is toluene, the carboxylic acid additive is 4-methoxybenzoic acid, and the compound of formula III is Compound A-2.001.

[0038] Embodiment (A1-2): In another aspect of embodiment (A1) of invention, step (A) is carried out as described above, except in the process wherein the compound of formula II is Compound A-1.001, the oxidant is hydrogen peroxide (2 equivalents), the metal derivative is iron(III) acetylacetonate (5 mol %), the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (10 mol %), the solvent is toluene, the carboxylic acid additive is 4-methoxybenzoic acid (2.5 mol %), and the compound of formula III is Compound A-2.001.

[0039] Embodiment (A1-3): In another aspect of embodiment (A1) of invention, step (A) is carried out as described above, except for the process wherein the compound of formula II is selected from compounds A-1.001 to A-1.012, the oxidant is hydrogen peroxide (2 equivalents), the metal derivative is iron(III) acetylacetonate (5 mol %), the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (10 mol %), the solvent is toluene, the carboxylic acid additive is 4-methoxybenzoic acid (2.5 mol %), and the compound of formula III is selected from compounds A-2.001 to A-2.012.

[0040] Process Step (B): In one embodiment of the present invention, process step (B) comprises reacting a compound of formula (III) [ka] (In the formula, A1, A2 and A3 are independently CH or N; S* is a stereogenic sulfur atom in the R or S configuration; R1 is cyanoisopropoxy, cyanoisopropyl, or cyanocyclopropyl; R2 is hydrogen or methyl, and R3 is C1-C3 fluoroalkyl. This process involves reacting a compound of formula (III) with an iminating reagent in a suitable solvent (or diluent) in the presence of a metal catalyst, optionally in the presence of a suitable acid additive, to stereospecifically produce a sulfoximine compound of formula (I).

[0041] In one embodiment of the present invention, the iminating reagent used in step B is a compound of formula (V): [ka] wherein R8 is SO2OR9, SO2(R9), C(O)R9, P(O)(R9)2, or optionally substituted aryl. R9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or optionally substituted aryl. Preferably, R8 is 4-nitrobenzoate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, diphenylphosphinate, or 2,4-dinitrophenyl.

[0042] The compound of formula (VII) can be prepared by the reaction of formula (VI) [ka] wherein X is SO2R 10 and R8 is as described for compounds of formula (VII), and R 10 is C1-C6 alkyl, C1-C6 haloalkyl, optionally substituted aryl or OH. Preferably, X is SO2CF3, SO3H or SO2Me.

[0043] Preferably, the iminating reagent is selected from: O-(4-nitrobenzoyl)-hydroxylamine O-(4-Nitrobenzoyl)-hydroxylammonium trifluoromethanesulfonate O-(4-nitrobenzoyl)-hydroxylammonium hydrogen sulfate O-(4-Nitrobenzoyl)-hydroxylammonium methanesulfonate O-(2,4-dinitrophenyl)-hydroxylamine O-(2,4-dinitrophenyl)-hydroxylammonium trifluoromethanesulfonate O-(2,4-dinitrophenyl)-hydroxylammonium hydrogen sulfate O-(2,4-dinitrophenyl)-hydroxylammonium methanesulfonate O-(Methanesulfonyl)-hydroxylamine O-(Methanesulfonyl)-hydroxylammonium trifluoromethanesulfonate O-(methanesulfonyl)-hydroxylammonium hydrogen sulfate O-(Methanesulfonyl)-hydroxylammonium methanesulfonate O-(p-Toluenesulfonyl)-hydroxylamine O-(p-Toluenesulfonyl)-hydroxylammonium trifluoromethanesulfonate O-(p-Toluenesulfonyl)-hydroxylammonium hydrogen sulfate O-(p-Toluenesulfonyl)-hydroxylammonium methanesulfonate Hydroxylamine-O-sulfonic acid

[0044] Even more preferably, the iminating reagent is selected from: O-(4-nitrobenzoyl)-hydroxylamine O-(4-Nitrobenzoyl)-hydroxylammonium trifluoromethanesulfonate O-(4-nitrobenzoyl)-hydroxylammonium hydrogen sulfate O-(4-Nitrobenzoyl)-hydroxylammonium methanesulfonate Hydroxylamine-O-sulfonic acid

[0045] Optionally, the salt of the iminating reagent of formula (VI) can be formed in situ by adding a suitable acid additive (e.g., trifluoromethanesulfonic acid, methanesulfonic acid, sulfuric acid) as an additive to the reaction mixture along with the iminating reagent of formula (V). Alternatively, the iminating reagent of formula (VI) can be added to the reaction mixture as a preformed salt.

[0046] The amount of the iminizing reagent used relative to the sulfinyl compound of formula (III) is within the range of 1:1 to 8:1, preferably 1:1 to 4:1.

[0047] Suitable metal catalysts are complexes of transition metals such as iron, copper, cobalt, manganese, nickel, rhodium, or ruthenium. Preferably, the metal is iron. Examples of suitable and preferred catalysts include iron(II) sulfate, iron(II) chloride, iron(III) chloride, iron(II) acetate, iron(II) trifluoromethanesulfonate, iron(II) acetylacetonate, or iron(III) acetylacetonate, each combined with either 2,2'-bipyridine or 1,10-phenanthroline or iron(II) phthalocyanine (Fe(II) phthalocyanine, FePc). Preferably, the metal catalyst is iron(II) phthalocyanine. The amount of catalyst used relative to the sulfinyl compound of formula (III) is within the range of 0.01 to 10 mol%, preferably 0.1 to 8 mol%, and most preferably 1 to 5 mol%.

[0048] Suitable solvents (or diluents) used in process step B are esters, nitriles, alcohols, ethers, carboxylic acids, amides and water or mixtures thereof.

[0049] Examples of suitable and preferred solvents for use in process step B include acetonitrile, butyronitrile, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, hexafluoroisopropanol, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, acetic acid, propanoic acid, trifluoroacetic acid, dimethylformamide, dimethylacetamide, n-methylpyrrolidinone, water or mixtures thereof.

[0050] Preferably, the solvent used in process step B is acetonitrile, methanol, 2,2,2-trifluoroethanol, hexafluoroisopropanol, dichloromethane, acetic acid, water or mixtures thereof.

[0051] Most preferably, the solvent (or diluent) for Step B is acetonitrile, acetic acid or dichloromethane or a mixture thereof.

[0052] Reaction step (B) is advantageously carried out in a temperature range of from about −20° C. to about 50° C., preferably from about −5° C. to about 30° C. In a preferred embodiment, the reaction is carried out in the range of from 10° C. to 25° C.

[0053] The ratio of enantiomers produced in step B is 50.5:49.5 to 100:0 [R]:[S] or [S]:[R].

[0054] The ratio of enantiomers produced in process step B can be increased, if desired, by crystallization. Such methods are known to those skilled in the art and include crystallization from an organic solvent, a mixture of organic solvents, or a mixture of an organic solvent and water.

[0055] A further preferred embodiment of process step (B) of the present invention is as follows.

[0056] Embodiment (B1): Table B-1 provides 12 compounds B-1.001 to B-1.012 of formula III, where A1, A2, A3, R1, R2 and R3 are as defined in Table Z, and S* is a stereogenic sulfur atom in the R or S configuration.

[0057] [Table 2]

[0058] Embodiment (B1-1): In one aspect of embodiment (B1) of the present invention, step (B) comprises reacting a compound of formula (III) [ka] (In the formula, A1, A2 and A3 are independently CH or N; S* is a stereogenic sulfur atom in the R or S configuration; R1 is cyanoisopropoxy, cyanoisopropyl, or cyanocyclopropyl; R2 is hydrogen or methyl, and R3 is C1-C3 fluoroalkyl. which process comprises reacting a compound of formula (III) with an iminating reagent in a suitable solvent (or diluent) in the presence of a metal catalyst, optionally in the presence of a suitable acid additive, to stereospecifically produce a sulfoximine compound of formula (I), except for the process wherein the compound of formula III is Compound A-2.001, the iminating reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid, the metal catalyst is iron(II) phthalocyanine, the solvent is dichloromethane, and the compound of formula I is Compound B-1.001.

[0059] Embodiment (B1-2): In another aspect of embodiment (A1) of invention, step (B) is carried out as described above, except for the process wherein the compound of formula III is compound A-2.001, the iminizing reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid (2 equivalents), the metal catalyst is iron(II) phthalocyanine (2 mol %), the solvent is dichloromethane, and the compound of formula I is compound B-1.001.

[0060] Embodiment (B1-3): In another aspect of embodiment (B1) of the present invention, step (B) is carried out as described above, except for the process wherein the compound of formula III is selected from compounds A-2.001-A-2.012, the iminizing reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid (2 equivalents), the metal catalyst is iron(II) phthalocyanine (2 mol %), the solvent is dichloromethane, and the compound of formula I is selected from compounds B-1.001-B-1.012.

[0061] Definition: The term "alkyl," as used herein, alone or as part of a chemical group, represents a straight or branched chain hydrocarbon, preferably having from 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-tn methylpropyl, 1-ethylbutyl, and 2 ethylbutyl. Alkyl groups having 1 to 4 carbon atoms are preferred, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl.

[0062] The term "alkenyl", alone or as part of a chemical group, preferably denotes a straight or branched hydrocarbon having 2 to 6 carbon atoms and at least one double bond, such as vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, thenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl Alkenyl groups having 2 to 4 carbon atoms are preferred, such as 2-propenyl, 2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, and 1-ethyl-2-methyl-2-propenyl.

[0063] The term "alkynyl," alone or as part of a chemical group, preferably refers to a straight or branched chain hydrocarbon having 2 to 6 carbon atoms and at least one triple bond, such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pent ... Preference is given to alkynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl and 2,5-hexadiynylalkynyl having 2 to 4 carbon atoms, such as ethynyl, 2-propynyl or 2-butynyl-2-propenyl.

[0064] The term "cycloalkyl", alone or as part of a chemical group, denotes a saturated or partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon, preferably containing 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, 15 bicyclo[2.2.2]octyl or adamantyl.

[0065] The term "heterocyclyl", alone or as part of a chemical group, refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon, preferably containing 3 to 10 carbon atoms, with at least one carbon atom replaced with a heteroatom selected from O, N and S, e.g., tetrahydrofuran, 20 pyrrolidine, tetrahydrothiophene.

[0066] The term "aryl" preferably refers to a monocyclic, bicyclic, or polycyclic aromatic system having 6 to 14, more preferably 6 to 10, ring carbon atoms, such as phenyl, naphthyl, anthryl, or phenanthrenyl, preferably phenyl. "Aryl" also refers to polycyclic systems such as tetrahydronaphthyl, indenyl, indanyl, 25-fluorenyl, and biphenyl. Arylalkyl is an example of a substituted aryl, which can be further substituted with the same or different substituents on both the aryl or alkyl moieties. Benzyl and 1-phenylethyl are examples of such arylalkyls.

[0067] The term "heteroaryl" refers to a heteroaromatic group, i.e., a fully unsaturated aromatic heterocyclic group, which falls within the definition of heterocycle above. "Heteroaryl" has a 5- to 7-membered ring containing 1 to 3, preferably 1 or 2, same or different heteroatoms selected from N, O, and S. Examples of "heteroaryl" are furyl, thienyl, pyrazolyl, imidazolyl, 1,2,3- and 1,2,4-triazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-, 1,3,4-, 1,2,4- and 1,2,5-oxadiazolyl, azepinyl, pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-, 1,2,4- and 1,2,3-triazinyl, 1,2,4-, 1,3,2-, 1,3,6- and 1,2,6-oxazinyl, oxepinyl, thiepinyl, 1,2,4-triazolonyl and 1,2,4-diazepinyl.

[0068] The term "halogen" or "halo" refers to fluoro, chloro, bromo, or iodo, especially fluoro, chloro, or bromo. A chemical group substituted with a halogen, such as haloalkyl, halocycloalkyl, haloalkyloxy, haloalkylsulfanyl, haloalkylsulfinyl, or haloalkylsulfonyl, is substituted with one or up to the maximum number of halogen substituents. When an "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 or different carbon atoms.

[0069] Unless otherwise defined, the term "optionally substituted" means that the group in question can be substituted with from zero to the maximum number of substituents independently selected from the following: halogen, methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopropyl, cyclopropyl, cyclohexyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, trichloromethyl, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, nitro, cyano, hydroxy, sulfhydryl, acetyl, acetoxy, COOH, COOMe, COOEt, CONH, CONHMe, CONMe, amino, methylamino, dimethylamino, phenyl.

[0070] The term "enantiomerically enriched" means that one enantiomer of a compound is present in excess relative to the other enantiomer. This excess is hereinafter referred to as enantiomeric excess or ee. ee can be determined by chiral GC, HPLC or SFC analysis. ee is equal to the difference in the amounts of the enantiomers divided by the sum of the amounts of the enantiomers, and the quotient can be expressed as a percentage after multiplying by 100.

[0071] In one embodiment, the process for preparing sulfoximines of formula (I) comprises the steps of: A1 is CH, A2 is N, A3 is N, R1 is cyanoisopropoxy, R2 is H, and R3 is CF3; and in Step A, the oxidant is hydrogen peroxide (2 equivalents), the metal derivative is iron(III) acetylacetonate (5 mol%), and the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2 -[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (10 mol%), the solvent is toluene, and the carboxylic acid additive is 4-methoxybenzoic acid (2.5 mol%); and in Step B, the iminizing reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid (2 equivalents), the metal catalyst is iron(II) phthalocyanine (2 mol%), and the solvent is dichloromethane.

[0072] In another embodiment, the process for preparing sulfoximines of formula (I) is as follows: A1, A2, N, A3, R1, R2, and R3 are as set forth in Table Z (Nos. 1-12); and in step A, the oxidant is hydrogen peroxide (2 equivalents), the metal derivative is iron(III) acetylacetonate (5 mol%), and the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol.

[0049] The process is carried out as above except that the solvent is S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (10 mol %), the solvent is toluene, and the carboxylic acid additive is 4-methoxybenzoic acid (2.5 mol %), and in Step B, the iminizing reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid (2 equivalents), the metal catalyst is iron(II) phthalocyanine (2 mol %), and the solvent is dichloromethane. [Example]

[0073] The following examples serve to illustrate the invention.

[0074] [Table 3-1]

[0075] [Table 3-2]

[0076] [Table 3-3]

[0077] [Table 4-1]

[0078] [Table 4-2]

[0079] Experimental Procedures and Data: LCMS method: Method 1: Spectra were recorded on a Waters mass spectrometer (ZQ single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative ion, capillary voltage: 3.00 kV, cone range: 30–60 V, extractor voltage: 2.00 V, source temperature: 150 °C, desolvation temperature: 350 °C, cone gas flow rate: 0 L / h, desolvation gas flow rate: 650 L / h, mass range: 100–900 Da) and a Waters Acquity UPLC: binary pump, heated column compartment, and diode array detector. Spectra were recorded on a Waters Acquity UPLC: binary pump, heated column compartment, and diode array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30 × 2.1 mm; Temperature: 60 °C; DAD wavelength range (nm): 210–500; Solvent gradient: A = water + 5% MeOH + 0.05% HCOOH; B = acetonitrile + 0.05% HCOOH; Gradient: 0 min 0% B, 100% A; 1.2–1.5 min 100% B; Flow rate (ml / min) 0.85.

[0080] Method 2: Spectra were recorded on a Waters mass spectrometer (SQD, SQDII single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative ion, capillary: 3.00 kV, cone range: 30 V, extractor: 2.00 V, source temperature: 150 °C, desolvation temperature: 350 °C, cone gas flow: 50 l / h, desolvation gas flow: 650 l / h, mass range: 100–900 Da) and a Waters Acquity UPLC: binary pump, heated column compartment, diode array detector, and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30 × 2.1 mm, temperature: 60 °C, DAD wavelength range (nm): 210–500, solvent gradient: A = water + 5% MeOH + 0.05% HCOOH, B = acetonitrile + 0.05% HCOOH, gradient: 10–100% B in 1.2 min, flow rate (ml / min) 0.85.

[0081] Method 3: Spectra were recorded on a Waters mass spectrometer (SQD, SQDII single quadrupole mass spectrometer) equipped with an electrospray source (polarity: positive or negative ion, capillary: 3.00 kV, cone range: 30 V, extractor voltage: 2.00 V, source temperature: 150 °C, desolvation temperature: 350 °C, cone gas flow: 50 l / h, desolvation gas flow: 650 l / h, mass range: 100–900 Da) and a Waters Acquity UPLC: binary pump, heated column compartment, diode array detector, and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30 × 2.1 mm, temperature: 60 °C, DAD wavelength range (nm): 210–500, solvent gradient: A = water + 5% MeOH + 0.05% HCOOH, B = acetonitrile + 0.05% HCOOH, gradient: 10–100% B in 2.7 min, flow rate (ml / min) 0.85.

[0082] Synthesis of sulfide starting materials: SM-1: Preparation of 2-[[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] This compound was prepared similarly to the method described in WO 2020 / 084075. LCMS (method 1): m / z 422[M+H] + ;Retention time: 1.11 minutes.

[0083] SM-2: Preparation of 2-[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] This compound was prepared similarly to the method described in WO 2018 / 153778. LCMS (method 2): m / z 406[M+H] + ;Retention time: 1.09 minutes.

[0084] SM-3: Preparation of 2-[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] This compound was prepared similarly to the method described in WO 2018 / 153778. LCMS (method 2): m / z 406[M+H] + ;Holding time: 1.02 minutes.

[0085] SM-4: Preparation of 1-[5-ethylsulfanyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile [ka] This compound was prepared similarly to the method described in WO 2019 / 234158. LCMS (method 3): m / z 405[M+H] + ;Holding time: 1.05 minutes.

[0086] SM-5: Preparation of 2-[[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] This compound was prepared similarly to the method described in WO 2020 / 084075. LCMS (method 1): m / z 422[M+H] + ;Holding time: 1.02 minutes.

[0087] Ligand preparation: Ligand (R)-A (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol) [ka] 3,5-Diiodosylacylaldehyde (1.12 g, 3.00 mmol) was dissolved in methanol (6.00 mL), and the resulting orange suspension was stirred at room temperature for 10 min. After that, a solution of (R)-tert-leucinol (473 mg, 3.87 mmol) in methanol (6.00 mL) was added within 2 min. Stirring was continued at room temperature for 2 h, followed by recrystallization. The reaction mixture was heated to 60 °C and stirred for 30 min until a clear solution appeared. Heating was then stopped and the mixture was cooled to 26 °C within 1.5 h. 17 mL of water was added dropwise to the suspension, and the precipitate was filtered through a sintered plate and evaporated to dryness to give the title compound (1.33 g, 2.43 mmol, 81.1%). 1 H NMR(400MHz,CDCl3)δ(ppm)=14.07-15.38(br s,1H),8.10(s,1H),8.01(d,J=1.8Hz,1H),7.52(d,J=1.8Hz,1H),3.98-4.07(dd,1H),3.71-3.75(d,1H),3.09-3.18(dd,1H),2.22-2.78(br s,1H),1.02(s,9H).

[0088] Ligand (S)-A (2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol) [ka] A suspension of 2-hydroxy-3,5-diiodo-benzaldehyde (1.50 g, 4.01 mmol) in methanol (30.0 mL) was degassed with argon, and then a solution of (2S)-2-amino-3,3-dimethyl-butan-1-ol (544 mg, 4.41 mmol) in methanol (2.00 mL) was added, and the reaction mixture was stirred at room temperature overnight. It was then concentrated under reduced pressure, dissolved in ethyl acetate, and washed three times with aqueous ammonium chloride and once with brine. The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product, which was triturated with a few mL of hexane and diethyl ether to give the desired compound (1.90 g, 3.80 mmol, 95.0%). 1 H NMR(400MHz,CDCl3)δ(ppm)=14.83(br s,1H),8.08(s,1H),8.00(d,J=2.2Hz,1H),7.51(d,J=2.2Hz,1H),4.03(dd,J=11.6, 2.2Hz,1H),3.71(dd,J=11.3,9.8Hz,1H),3.12(dd,J=9.4,2.5Hz,1H),2.88-3.08(br s,1H),1.02(s,9H).

[0089] Ligand B (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-dichloro-phenol) [ka] A suspension of 3,5-dichlorosalicylaldehyde (2.75 g, 13.7 mmol) in methanol (25.0 mL) was stirred at room temperature, and then a solution of (R)-tert-leucinol (1.63 g, 13.6 mmol) in methanol (25.0 mL) was added in small portions. The solution was stirred at room temperature for 1 hour, then it was heated to 60 °C for 3.5 h and stirred at 40 °C overnight. The reaction mixture was evaporated to dryness and purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (2.68 g, 8.99 mmol, 65.8%). 1H NMR(400MHz,DMSO-d6)δ(ppm)=15.28(br s,1H),8.51(d,J=5.4Hz,1H),7.60(d,J=2.9Hz,1H),7.54(d,J=2.5Hz,1H),4.8 5(s,1H),3.77-3.86(m,1H),3.39-3.48(m,1H),3.08-3.16(m,1H),0.95(s,9H).

[0090] Ligand C (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-dibromo-phenol) [ka] To a suspension of 3,5-dibromosalicylaldehyde (5.00 g, 17.5 mmol) in methanol (14.0 mL) was added a solution of (R)-tert-leucinol (2.30 g, 19.3 mmol) in methanol (3.50 mL) within 3 min. Exothermic behavior and the formation of a thick suspension were observed, so another portion of methanol (3.50 mL) was added. The reaction mixture was stirred at room temperature for 2 h, then filtered through a sintered plate and rinsed with several small portions of cold methanol. The filter cake was recrystallized by heating in methanol to 60 °C and slowly cooling to room temperature. The precipitate was filtered, washed with cold methanol, and evaporated to give the title compound (1.53 g, 4.04 mmol, 23.1%). 1 H NMR(400MHz,CDCl3)δ(ppm)=14.84(br s,1H),8.13(s,1H),7.61(d,J=2.5Hz,1H),7.27(d,J=2.2Hz,1H),4.02(br s,1H),3.67-3.75(m,1H),3.57(br s, 1H), 3.13 (dd, J=9.4, 2.5Hz, 1H), 1.03 (s, 9H).

[0091] Ligand D (2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-di-tert-butyl-phenol) [ka] To a solution of 3,5-di-tert-butyl-2-hydroxybenzaldehyde (2.00 g, 8.45 mmol) in methanol (84.5 mL) under argon was added a solution of (2S)-2-amino-3,3-dimethyl-butan-1-ol (1.25 g, 10.1 mmol) in methanol (2.00 mL). The reaction mixture was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and extracted three times with water and once with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (3.02 g, 8.01 mmol, 94.8%). LCMS (method 1): m / z 332[M+H] - ;Retention time: 1.37 minutes. 1 H NMR(400MHz,CDCl3)δ ppm 13.22-14.05(br s,1H),8.39(s,1H),7.44(d,J=2.5Hz,1H),7.16(d,J=2.2Hz,1H),3.95(dd,J=11.3,2.9Hz, 1H),3.75-3.79(m,1H),2.95(dd,J=9.4,2.9Hz,1H),1.48(s,9H),1.35(s,9H),1.01(s,9H).

[0092] Preparation of racemic sulfoxides for chiral analytical method development. A racemic sample of the sulfoxide is prepared according to the following general procedure: The sulfide (1 equiv.) is dissolved in acetic acid (5 mL / mmol) and hydrogen peroxide (1.05 equiv., 30% by weight) is added at room temperature. The reaction mixture is stirred at 40 °C for 20 h or until complete consumption of the starting material is observed by LCMS. Aqueous NaHCO3 is added dropwise to the reaction mixture, followed by the addition of ethyl acetate. The phases are separated and the aqueous phase is extracted with another portion of ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered, and evaporated to give the desired sulfoxide. This material is used directly for chiral HPLC method development.

[0093] Preparation of enantiomerically enriched sulfoxides listed in Table 1: Example 1-A: Preparation of enantiomerically enriched 2-[[5-ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] Condition 1-A1 2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methylpropanenitrile (300 mg, 0.680 mmol), iron(III) acetylacetonate (12.2 mg, 0.035 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (37.1 mg, 0.068 mmol), and 4-methoxybenzoic acid (2.6 mg, 0.017 mmol) were dissolved in toluene (2.7 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.139 mL, 1.36 mmol) was added. The reaction was stirred at 0°C for 30 minutes, then warmed to 10°C and stirred overnight, after which it was warmed to room temperature and stirred for an additional 6 hours. The reaction mixture was then poured into a mixture of ethyl acetate and sodium thiosulfate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and 0.5 M aqueous hydrochloric acid, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (224 mg, 0.49 mmol, 73%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.86 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 2.5 Hz, 1H), 8.66 (d, J = 1.5 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H), 4.23 (s, 3H), 3.58-3.48 (m, 1H), 3.12-3.01 (m, 1H), 1.87 (apparent d, J = 2.2 Hz, 6H), 1.27 (t, J = 7.4 Hz, 3H).

[0094] Chiral SFC method SFC:Waters Acquity UPC 2 / QDa PDA detector Waters Acquity UPC 2 Column: Daicel SFC CHIRALPAK® IG, 3 μm, 0.46 cm x 10 cm, 40°C Mobile phase: A:CO2 B:EtOH Isocratic: 20% B in 4.8 min ABPR: 1800 psi Flow rate: 2.0ml / min Detection: 310nm Sample concentration: 1 mg / mL in MeOH / ACN 50 / 50 Injection: 1μL result:

[0095] [Table 5]

[0096] Condition 1-A2 2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (300 mg, 0.681 mmol), iron(III) acetylacetonate (12.3 mg, 0.035 mmol), 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (35.8 mg, 0.071 mmol), and 4-methoxybenzoic acid (2.9 mg, 0.019 mmol) were dissolved in toluene (2.7 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.139 mL, 1.36 mmol) was added. The reaction was stirred at 0°C for 4 hours, then warmed to 10°C and stirred overnight, after which it was warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was then poured into a mixture of ethyl acetate and sodium thiosulfate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and 0.5 M aqueous hydrochloric acid, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (271 mg, 0.59 mmol, 87.3%).

[0097] NMR data similar to Example 1-A1 Chiral SFC method similar to Example 1-A1 result:

[0098] [Table 6]

[0099] Condition 1-A3 2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (200 mg, 0.456 mmol), iron(III) acetylacetonate (1.61 mg, 0.0046 mmol), 2,4-dichloro-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (13.5 mg, 0.046 mmol), and 4-methoxybenzoic acid (1.75 mg, 0.011 mmol) were dissolved in toluene (0.91 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0931 mL, 0.911 mmol) was added. The reaction was stirred at 0 °C for 4 hours, then warmed to room temperature and stirred for an additional 24 hours. The reaction mixture was then poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (146 mg, 0.32 mmol, 70.3%).

[0100] NMR data similar to Example 1-A1 Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IG (4.6 mm x 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% B in 45 min Flow rate: 1.0ml / min Detection: 300nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0101] [Table 7]

[0102] Condition 1-A4 2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (200 mg, 0.456 mmol), iron(III) acetylacetonate (1.61 mg, 0.0046 mmol), 2,4-dibromo-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (17.6 mg, 0.046 mmol), and 4-methoxybenzoic acid (1.75 mg, 0.011 mmol) were dissolved in toluene (0.91 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0931 mL, 0.911 mmol) was added. The reaction was stirred at 0 °C for 4 hours, then warmed to room temperature and stirred for an additional 24 hours. The reaction mixture was then poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (150 mg, 0.33 mmol, 73.0%).

[0103] NMR data similar to Example 1-A1 Chiral HPLC method as in Example 1-A3 result:

[0104] [Table 8]

[0105] Example 2-A Preparation of enantiomerically enriched 2-[5-ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] Condition 2-A1 2-[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methylpropanenitrile (200 mg, 0.459 mmol), iron(III) acetylacetonate (1.62 mg, 0.0046 mmol), 2,4-dichloro-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (13.6 mg, 0.046 mmol), and 4-methoxybenzoic acid (1.76 mg, 0.0115 mmol) were dissolved in toluene (0.92 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0937 mL, 0.918 mmol) was added. The reaction was stirred at room temperature for 19 hours. The reaction mixture was then poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (163 mg, 0.36 mmol, 78.4%). 1H NMR(400MHz,DMSO-d6)δ(ppm)=9.13(d,J=2.35Hz,1H),8.88(d,J=1.53Hz,1H),8.70(d,J=1.53Hz,1H),8.61(d,J= 2.34Hz,1H),4.24(s,3H),3.50-3.59(m,1H),2.99-3.04(m,1H),1.88(s,3H),1.87(s,3H),1.31(t,J=7.43Hz,3H).

[0106] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IG (4.6 mm x 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% B in 40 min Flow rate: 1.0ml / min Detection: 315nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0107] [Table 9]

[0108] Condition 2-A2 2,4-Ditert-butyl-6-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (30.0 mg, 0.0681 mmol) was dissolved in toluene (3.63 mL) and vanadyl acetylacetonate (12.7 mg, 0.0454 mmol) was added at room temperature. The mixture was stirred for 15 minutes, then 2-[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methylpropanenitrile (400 mg, 0.908 mmol) was added, followed by the addition of hydrogen peroxide (30% aqueous solution, 0.232 mL, 2.27 mmol) in four portions over 1 hour. The reaction was stirred at room temperature for 1 hour until the starting material was completely consumed, then added dropwise to a solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (139 mg, 0.33 mmol, 36.3%).

[0109] NMR data similar to Example 2-A1 Chiral HPLC method as in Example 2-A1 result:

[0110] [Table 10]

[0111] Example 3-A Preparation of enantiomerically enriched 2-[5-ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] Condition 3-A1 2-[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methylpropanenitrile (200 mg, 0.469 mmol), iron(III) acetylacetonate (1.66 mg, 0.0047 mmol), 2,4-dibromo-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (18.1 mg, 0.047 mmol), and 4-methoxybenzoic acid (1.80 mg, 0.0117 mmol) were dissolved in toluene (0.94 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0957 mL, 0.937 mmol) was added. The reaction was stirred at room temperature for 19 hours. The reaction mixture was then poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (164 mg, 0.362 mmol, 77.2%). 1H NMR(400MHz,DMSO-d6)δ(ppm)=9.31(s,1H),9.14(d,J=2.34Hz,1H),8.61(d,J=2.35Hz,1H),8.32(s,1H) ),4.33(s,3H),3.50-3.58(m,1H),3.00-3.05(m,1H),1.89(s,3H),1.88(s,3H),1.30(t,J=7.43Hz,3H)

[0112] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IG (4.6 mm x 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% B in 40 min Flow rate: 1.0ml / min Detection: 285nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0113] [Table 11]

[0114] Condition 3-A2 2,4-Ditert-butyl-6-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (57.8 mg, 0.141 mmol) was dissolved in toluene (1.87 mL) and vanadyl acetylacetonate (6.54 mg, 0.0234 mmol) was added at room temperature. The mixture was stirred for 15 minutes, then 2-[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methylpropanenitrile (200 mg, 0.469 mmol) was added, followed by hydrogen peroxide (30% aqueous solution, 0.0957 mL, 0.937 mmol) in one portion. The reaction was stirred at room temperature for 4 hours until the starting material was completely consumed, then added dropwise to a solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (88 mg, 0.209 mmol, 44.6%).

[0115] NMR data similar to Example 3-A1 Chiral HPLC method as in Example 3-A1 result:

[0116] [Table 12]

[0117] Example 4-A Preparation of enantiomerically enriched 1-[5-ethylsulfinyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile [ka] Condition 4-A1 1-[5-Ethylsulfanyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (200 mg, 0.470 mmol), iron(III) acetylacetonate (8.30 mg, 0.0235 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (22.5 mg, 0.047 mmol), and 4-methoxybenzoic acid (1.81 mg, 0.0117 mmol) were dissolved in toluene (0.94 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0960 mL, 0.940 mmol) was added. The reaction was stirred at 0 °C for 5 h and at room temperature for an additional 15 h. Since the starting material was not completely consumed, the reaction mixture was further heated at 40 °C for 21 h. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (73.0 mg, 0.160 mmol, 35.0%). H NMR (400 MHz, chloroform-d) δ (ppm) = 9.09 (d, J = 2.32 Hz, 1H), 8.30 (d, J = 2.20 Hz, 1H), 8.20 (s, 1H), 4.57 (s, 3H), 3.57-3.69 (m, 1H), 2.97-3.0 (m, 1H), 1.97-2.08 (m, 1H), 1.92-2.14 (m, 1H), 1.63-1.79 (m, 2H), 1.45 (t, J = 7.40 Hz, 3H).

[0118] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IC (4.6 mm x 250 mm) 5 μm Mobile phase: A: MTBE B: EtOH-DEA Isocratic: 10% B in 30 min Flow rate: 1.0ml / min Detection: 300nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0119] [Table 13]

[0120] Condition 4-A2 1-[5-Ethylsulfanyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (200 mg, 0.470 mmol), iron(III) acetylacetonate (8.30 mg, 0.0235 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (22.5 mg, 0.047 mmol), and 4-methoxybenzoic acid (1.81 mg, 0.0117 mmol) were dissolved in methoxybenzene (0.94 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0960 mL, 0.940 mmol) was added. The reaction was stirred at 0 °C for 5 h and at room temperature for an additional 15 h. Since the starting material was not completely consumed, the reaction mixture was further heated at 40 °C for 21 h. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (56.0 mg, 0.130 mmol, 28.0%).

[0121] NMR data similar to Example 4-A1 Chiral HPLC method as in Example 4-A1 result

[0122] [Table 14]

[0123] Condition 4-A3 1-[5-Ethylsulfanyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (200 mg, 0.470 mmol), iron(III) acetylacetonate (1.66 mg, 0.00470 mmol), 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (22.5 mg, 0.047 mmol), and 4-methoxybenzoic acid (1.81 mg, 0.0117 mmol) were dissolved in toluene (0.94 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.0960 mL, 0.940 mmol) was added. The reaction was stirred at 0 °C for 5 h and at room temperature for an additional 15 h. Since the starting material was not completely consumed, the reaction mixture was further heated at 40 °C for 21 h. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate and sodium bicarbonate solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (85.0 mg, 0.190 mmol, 41.0%).

[0124] NMR data similar to Example 4-A1 Chiral HPLC method as in Example 4-A1 result

[0125] [Table 15]

[0126] Example 5-A Preparation of enantiomerically enriched 2-[[5-ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] Condition 5-A1 2-[[5-Ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methylpropanenitrile (200 mg, 0.456 mmol), iron(III) acetylacetonate (1.6 mg, 0.005 mmol), 2,4-dibromo-6-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (17.6 mg, 0.046 mmol), and 4-methoxybenzoic acid (1.8 mg, 0.011 mmol) were dissolved in toluene (0.9 mL). The solution was cooled to 0 °C, and hydrogen peroxide (30% aqueous solution, 0.093 mL, 0.911 mmol) was added. The reaction was stirred at room temperature for 15 hours, then poured into a mixture of ethyl acetate and aqueous sodium thiosulfate, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (166 mg, 0.357 mmol, 78.3%). H NMR (400 MHz chloroform-d) δ (ppm) = 9.00 (s, 1H), 8.73 (d, J = 2.69 Hz, 1H), 8.42 (d, J = 2.69 Hz, 1H), 8.11 (s, 1H), 4.39 (s, 3H), 3.64-3.67 (m, 1H), 3.11-3.16 (m, 1H), 1.89 (s, 3H), 1.88 (s, 3H), 1.47 (t, J = 7.46 Hz, 3H).

[0127] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IG (4.6 mm x 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% B in 40 min Flow rate: 1.0ml / min Detection: 290nm Sample concentration: 1 mg / mL in EtOH Injection: 10μL result

[0128] [Table 16]

[0129] Condition 5-A2 2,4-Ditert-butyl-6-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]phenol (56.2 mg, 0.137 mmol) was dissolved in toluene (1.82 mL) and vanadyl acetylacetonate (6.36 mg, 0.0228 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of 2-[[5-ethylsulfanyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methylpropanenitrile (200 mg, 0.456 mmol), followed by the addition of hydrogen peroxide (30% aqueous solution, 0.0931 mL, 0.911 mmol). The reaction mixture was stirred at room temperature for 4 hours, then added dropwise to saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo, and the residue was purified by flash column chromatography (silica, ethyl acetate in cyclohexane) to give the title compound (99.0 mg, 0.226 mmol, 49.7%).

[0130] NMR data similar to Example 5-A1 Chiral HPLC method as in Example 5-A1 result:

[0131] [Table 17]

[0132] Preparation of racemic sulfoximines for chiral analytical method development. A racemic sample of racemic sulfoximine was prepared according to the following general procedure: The racemic sulfoxide was dissolved in dichloromethane, followed by the addition of (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (2.0 equivalents) and iron(II) phthalocyanine (0.02 equivalents) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. Aqueous NaHCO3 was added dropwise, and the reaction mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate and cyclohexane to give the pure sulfoximine. This material was used for chiral HPLC method development.

[0133] Preparation of enantiomerically enriched sulfoximines listed in Table 2: Example 1-B: Preparation of 2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] Condition 1-B1: 2-[[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (250 mg, 0.549 mmol) was dissolved in dichloromethane (1.44 mL) at room temperature under nitrogen. Iron(II) phthalocyanine (6.93 mg, 0.0110 mmol) was added, followed by (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (446 mg, 1.21 mmol). The reaction mixture was stirred at room temperature for 13 hours, then added dropwise to aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate and cyclohexane to give the title compound (200 mg, 0.442 mmol, 80.6%). 1H NMR(400MHz,DMSO-d6)δ(ppm)=8.89(d,J=2.57Hz,1H),8.86(d,J=1.34Hz,1H),8.64(d,J=1.83Hz,1H),8.29(d ,J=2.69Hz,1H),4.57(s,1H),3.73(s,3H),3.58-3.69(m,2H),1.89(s,3H),1.88(s,3H),1.16(t,J=7.34Hz,3H)

[0134] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IC (4.6 mm x 250 mm) 5 μm Mobile phase: A: MTBE B: EtOH Isocratic: 5% B in 10 min Flow rate: 1.0ml / min Detection: 290nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0135] [Table 18]

[0136] Condition 1-B2: 2-[[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (200 mg, 0.439 mmol) was dissolved in acetic acid (1.76 ml) at room temperature under nitrogen. Iron(II) phthalocyanine (5.54 mg, 0.00878 mmol) was added, followed by hydroxylamine-O-sulfonic acid (205 mg, 1.76 mmol). The reaction mixture was stirred at room temperature for 17 hours, then another portion of hydroxylamine-O-sulfonic acid (102 mg, 0.878 mmol) was added, and stirring was continued at room temperature for 2 hours. The reaction mixture was added dropwise to aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (75 mg, 0.166 mmol, 37.8%).

[0137] NMR data similar to Example 1-B1 Chiral HPLC method as in Example 1-B1 result:

[0138] [Table 19]

[0139] Example 2-B: Preparation of 2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] Condition 2-B1: 2-[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (250 mg, 0.575 mmol) was dissolved in dichloromethane (1.51 mL) at room temperature under nitrogen. Iron(II) phthalocyanine (6.61 mg, 0.0115 mmol) was added, followed by (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (467 mg, 1.27 mmol). The reaction mixture was stirred at room temperature for 13 hours, then added dropwise to aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate and cyclohexane to give the title compound (216 mg, 0.495 mmol, 86.0%). 1H NMR(400MHz DMSO-d6)δ(ppm)=9.24(d,J=2.20Hz,1H),8.88(d,J=1.47Hz,1H),8.66(d,J=1.83Hz,1H),8.57(d,J= 2.32Hz,1H),4.3(s,1H),3.74(s,3H),3.61-3.74(m,2H),1.89(s,3H),1.88(s,3H),1.17-1.24(t,3H)

[0140] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IG (4.6 mm x 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% B in 40 min Flow rate: 1.0ml / min Detection: 290nm Sample concentration: 1 mg / mL in EtOH Injection: 2μL result:

[0141] [Table 20]

[0142] Condition 2-B2: 2-[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (200 mg, 0.460 mmol) was dissolved in acetic acid (1.84 ml) at room temperature under nitrogen. Iron(II) phthalocyanine (5.81 mg, 0.00921 mmol) was added, followed by hydroxylamine-O-sulfonic acid (215 mg, 1.84 mmol). The reaction mixture was stirred at room temperature for 17 hours, then another portion of hydroxylamine-O-sulfonic acid (215 mg, 1.84 mmol) was added, and stirring was continued at room temperature for 5 hours. The reaction mixture was added dropwise to aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (80 mg, 0.183 mmol, 39.8%).

[0143] NMR data similar to Example 2-B1 Chiral HPLC method as in Example 2-B1 result:

[0144] [Table 21]

[0145] Condition 2-B3: 2-[5-[(R)-Ethylsulfinyl]-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-b]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (250 mg, 0.576 mmol) was dissolved in acetonitrile (0.230 mL) and acetic acid (0.230 mL) at room temperature under nitrogen. Iron(II) phthalocyanine (7.27 mg, 0.0115 mmol) was added and stirred at room temperature for 60 minutes, then cooled to 0°C. PNBHSO (417 mg, 1.44 mmol) was added and the reaction mixture was stirred at room temperature for 34 hours. Aqueous NaHCO was added dropwise, and the reaction mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (220 mg, 0.504 mmol, 87.6%).

[0146] NMR data similar to Example 2-B1 Chiral HPLC method as in Example 2-B1 result:

[0147] [Table 22]

[0148] Example 3-B: Preparation of 2-[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile [ka] Condition 3-B1: 2-[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (250 mg, 0.564 mmol) was dissolved in dichloromethane (1.48 mL) at room temperature under nitrogen. Iron(II) phthalocyanine (6.47 mg, 0.0113 mmol) was added, followed by (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (458 mg, 1.24 mmol). The reaction mixture was stirred at room temperature for 13 hours, then another portion of (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (458 mg, 1.24 mmol) was added, and stirring was continued at room temperature for 20 hours. Aqueous NaHCO3 was added dropwise, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (146 mg, 0.335 mmol, 59.4%). 1H NMR(400MHz DMSO-d6)δ(ppm)=9.27(s,1H),9.23(d,J=2.20Hz,1H),8.56(d,J=2.20Hz,1H),8.28(s,1H) ,4.55(s,1H),3.82(s,3H),3.49-3.71(m,2H),1.89(s,3H),1.88(s,3H),1.14-1.18(t,3H)

[0149] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IG (4.6 mm x 250 mm) 5 μm Mobile phase: A: n-hexane B: EtOH Isocratic: 30% B in 60 min Flow rate: 1.0ml / min Detection: 270nm Sample concentration: 1 mg / mL in EtOH Injection: 10μL result:

[0150] [Table 23]

[0151] Condition 3-B2: 2-[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (200 mg, 0.451 mmol) was dissolved in acetic acid (1.80 ml) at room temperature under nitrogen. Iron(II) phthalocyanine (5.69 mg, 0.00902 mmol) was added, followed by hydroxylamine-O-sulfonic acid (210 mg, 1.80 mmol). The reaction mixture was stirred at room temperature for 17 hours, then another portion of hydroxylamine-O-sulfonic acid (105 mg, 0.902 mmol) was added, and stirring was continued at room temperature for 2 hours. The reaction mixture was added dropwise to aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (100 mg, 0.229 mmol, 50.8%).

[0152] NMR data similar to Example 3-B1 Chiral HPLC method as in Example 3-B1 result:

[0153] [Table 24]

[0154] Condition 3-B3: Amino 4-nitrobenzoate (261 mg, 1.41 mmol) was dissolved in dichloromethane (2.25 mL) and methanesulfonic acid (135 mg, 1.41 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and then 2-[5-ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]-2-methyl-propanenitrile (250 mg, 0.564 mmol) was added, followed by iron(II) phthalocyanine (6.41 mg, 0.0113 mmol). Stirring was continued at room temperature for 32 hours, and then aqueous NaHCO3 was added dropwise, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (160 mg, 0.367 mmol, 65.1%).

[0155] NMR data similar to Example 3-B1 Chiral HPLC method as in Example 3-B1 result:

[0156] [Table 25]

[0157] Example 4-B: Preparation of 1-[5-(ethylsulfonimidoyl)-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile [ka] Condition 4-B1: 1-[5-Ethylsulfinyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (250 mg, 0.571 mmol) was dissolved in dichloromethane (1.50 mL) at room temperature under nitrogen. Iron(II) phthalocyanine (6.56 mg, 0.0114 mmol) was added, followed by (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (464 mg, 1.26 mmol). The reaction mixture was stirred at room temperature for 20 hours. Aqueous NaHCO3 was added dropwise, and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate and cyclohexane to give the title compound (173 mg, 0.397 mmol, 69.6%). 1H NMR(400MHz,DMSO-d6)δ(ppm)=8.96(d,J=2.20Hz,1H),8.75(s,1H),8.41(d,J=2.32Hz, 1H),4.64(s,1H),3.87(s,3H),3.48-3.65(m,2H),1.88-2.07(m,4H),1.15-1.18(t,3H).

[0158] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IC (4.6 mm x 250 mm) 5 μm Mobile phase: A: MTBE B: EtOH / DEA Isocratic: 10% B in 20 min Flow rate: 1.0ml / min Detection: 270nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0159] [Table 26]

[0160] Condition 4-B2: Amino 2,4-dinitrobenzoate (270 mg, 1.19 mmol) was dissolved in dichloromethane (1.90 mL) under nitrogen at room temperature. Trifluoromethanesulfonic acid (182 mg, 1.19 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. 1-[5-ethylsulfinyl-6-[7-methyl-3-(trifluoromethyl)imidazo[4,5-c]pyridazin-6-yl]-3-pyridyl]cyclopropanecarbonitrile (200 mg, 0.476 mmol) was added, followed by iron(II) phthalocyanine (5.41 mg, 0.00951 mmol). The reaction mixture was stirred at room temperature for 24 hours, then added dropwise to aqueous NaHCO3 and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by chromatography on silica gel with ethyl acetate and cyclohexane to give the title compound (140 mg, 0.322 mmol, 67.6%).

[0161] NMR data similar to Example 4-B1 Chiral HPLC method as in Example 4-B1 result:

[0162] [Table 27]

[0163] Example 5-B: Preparation of 2-[[5-(ethylsulfonimidoyl)-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile [ka] Condition 5-B1: 2-[[5-Ethylsulfinyl-6-[3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridin-2-yl]-3-pyridyl]oxy]-2-methyl-propanenitrile (250 mg, 0.543 mmol) was dissolved in dichloromethane (1.43 mL) at room temperature under nitrogen. Iron(II) phthalocyanine (6.23 mg, 0.0109 mmol) was added, followed by (4-nitrobenzoyl)oxyammonium trifluoromethanesulfonate (441 mg, 1.19 mmol). The reaction mixture was stirred at room temperature for 20 hours, then added dropwise to an aqueous solution of NaHCO and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over NaSO, filtered, and evaporated. The crude product was purified by chromatography on silica gel using ethyl acetate and cyclohexane to give the title compound (185 mg, 0.409 mmol, 75.3%). 1H NMR(400MHz,DMSO-d6)δ(ppm)=9.26(s,1H),8.89(d,J=2.69HZ,1H),8.26-8.29(m,2H),4 .56(s,1H),3.82(s,3H),3.52-3.69(m,2H),1.89(s,3H),1.88(s,3H),1.13-1.17(t,3H).

[0164] Chiral HPLC method: Instrument: Waters Acquity UPLC Column: Chiralpack-IC (4.6 mm x 250 mm) 5 μm Mobile phase: A: MTBE B: EtOH / DEA Isocratic: 8% B in 12 min Flow rate: 1.0ml / min Detection: 274 nm Sample concentration: 1 mg / mL in EtOH Injection: 5μL result:

[0165] [Table 28]

Claims

1. Formula (I) 【Chemistry 1】 (In the formula, A 1 , A 2 and A 3 are independently CH or N; S* is a stereogenic sulfur atom in the R or S configuration; R 1 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl, R 2 is hydrogen or methyl, R 3 is C 1 ~C 3 fluoroalkyl) 1. A process for preparing a compound of formula (I), comprising: (A) Formula (II) 【Chemistry 2】 (In the formula, A 1 , A 2 , A 3 , R 1 , R 2 and R 3 is as defined in formula (I) is stereoselectively oxidized in a suitable solvent (or diluent) in the presence of an oxidizing agent, in the presence of a metal catalyst, in the presence of a chiral ligand, and optionally in the presence of a suitable carboxylic acid or carboxylate additive, to give a sulfanyl compound of formula (III): 【Transformation 3】 (In the formula, A 1 , A 2 , A 3 , R 1 , R 2 and R 3 is as defined in formula (I), S* is a stereogenic sulfur atom in the R or S configuration. and forming a sulfinyl compound of the formula: reacting the sulfinyl compound of formula (III) with an iminating reagent in a suitable solvent (or diluent) in the presence of a catalyst, optionally in the presence of a suitable acid additive, to form the sulfoximine compound of formula (I); Including, however, A 1 is CH, and A 2 is N and A 3 is N and R 1 is cyanoisopropoxy, and R 2 is H, and R 3 is CF 3 and wherein in Step A the oxidizing agent is hydrogen peroxide (2 equivalents), the metal derivative is iron(III) acetylacetonate (5 mol %), the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (10 mol %), the solvent is toluene, and the carboxylic acid additive is 4-methoxybenzoic acid (2.5 mol %); and in Step B the iminizing reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid (2 equivalents), the metal catalyst is iron(II) phthalocyanine (2 mol %), and the solvent is dichloromethane.

2. Formula (II) 【Chemistry 4】 (In the formula, A 1 , A 2 and A 3 are independently CH or N; R 1 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl, R 2 is hydrogen or methyl, and R 3 is C 1 ~C 3 fluoroalkyl) wherein said sulfanyl compound of formula (II) is oxidized in the presence of an oxidizing agent, in the presence of a metal derivative, in the presence of a chiral ligand, in a suitable solvent (or diluent) and optionally in the presence of a suitable carboxylic acid or carboxylate additive to give a sulfanyl compound of formula (III) 【Transformation 5】 (In the formula, A 1 , A 2 , A 3 , R 1 , R 2 and R 3 is as defined for compounds of formula (II), and S* is a stereogenic sulfur atom in the R or S configuration. wherein A is a sulfinyl compound of formula 1 is CH, and A 2 is N and A 3 is N and R 1 is cyanoisopropoxy, and R 2 is H, and R 3 is CF 3 and wherein in Step A the oxidant is hydrogen peroxide (2 equivalents), the metal derivative is iron(III) acetylacetonate (5 mol %), the chiral ligand is 2-[(E)-[(1R)-1-(hydroxymethyl)-2,2-dimethyl-propyl]iminomethyl]-4,6-diiodophenol or 2-[(E)-[(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]iminomethyl]-4,6-diiodophenol (10 mol %), the solvent is toluene, and the carboxylic acid additive is 4-methoxybenzoic acid (2.5 mol %).

3. Formula (III) 【Transformation 6】 (In the formula, A 1 , A 2 and A 3 are independently CH or N; S* is a stereogenic sulfur atom in the R or S configuration; R 1 is cyanoisopropoxy, cyanoisopropyl or cyanocyclopropyl, R 2 is hydrogen or methyl, and R 3 is C 1 ~C 3 fluoroalkyl) by reacting said compound of formula (III) with an iminating reagent in a suitable solvent (or diluent) in the presence of a metal catalyst, optionally in the presence of a suitable acid additive, to give a compound of formula (I) 【Transformation 7】 (In the formula, A 1 , A 2 , A 3 , R 1 , R 2 , R 3 and S* are as defined for compounds of formula (III). wherein A is a substituted or unsubstituted sulfoximine compound; 1 is CH, and A 2 is N and A 3 is N and R 1 is cyanoisopropoxy, and R 2 is H, and R 3 is CF 3 except that the imination reagent is O-(4-nitrobenzoyl)-hydroxylamine triflic acid (2 equivalents), the metal catalyst is iron(II) phthalocyanine (2 mole %), and the solvent is dichloromethane.

4. The oxidizing agent is H 2 O 2 3. The process according to claim 1 or 2, wherein

5. The chiral reagent comprises a metal salt and a compound represented by formula (IV): 【Transformation 8】 (In the formula, R 4 and R 5 is hydrogen, halogen, C 1 ~C 6 Alkyl, C 3 ~C 6 Cycloalkyl, C 1 ~C 6 Haloalkyl, nitro, cyano, C 1 ~C 4 Alkoxy, C 1 ~C 4 haloalkoxy, optionally substituted aryl; R 6 is C 1 ~C 6 Alkyl, including phenyl, 4-hydroxyphenyl, heteroaryl, hydroxy, sulfhydryl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkylthio, C(O)OR x , C(O)NR Y R Z , N.R. Y R Z , guanidyl, C 3 ~C 6 C optionally substituted with cycloalkyl, optionally substituted aryl 1 ~C 6 alkyl, and R x , R y and R z is hydrogen and C 1 ~C 6 alkyl; R 7 is hydrogen, C 1 ~C 6 Alkyl, C 3 ~C 6 cycloalkyl, optionally substituted aryl or carbonyl group (=O), or R 6 and R 7 may be optionally joined to form a cyclic group, and * represents an enantiomerically enriched chiral center in either the R or S configuration (where appropriate).

3. The process according to claim 1 or 2, wherein the metal complex is a metal complex consisting of a ligand of the formula:

6. The ligand of formula (IV) is (2R)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-diiodophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-dibromophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)- 6. The process of claim 5, wherein the methyl group is selected from the group consisting of (3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2S)-2-[(E)-(3,5-dichlorophenyl)methyleneamino]-3,3-dimethyl-butan-1-ol, (2R)-2-[(E)-(3,5-di-tertbutyl-phenyl)methyleneamino]-3,3-dimethyl-butan-1-ol and (2S)-2-[(E)-(3,5-di-tertbutyl-phenyl)methyleneamino]-3,3-dimethyl-butan-1-ol.

7. The metal salt is an iron salt, and preferably the salt is Fe(acac) 3 7. The process according to claim 5 or 6, wherein

8. The metal salt is a vanadium salt, and preferably the salt is VO(acac) 2 7. The process according to claim 5 or 6, wherein

9. 3. The process of claim 1 or 2, wherein the carboxylic acid or carboxylate salt is benzoic acid, mono-, di- or tri-substituted by methyl, ethyl, isopropyl, methoxy or dimethylamino, or benzoic acid, mono-, di- or tri-substituted by methyl, ethyl, isopropyl, methoxy or dimethylamino, in the form of its lithium, sodium or potassium salt.

10. 10. The process of claim 9, wherein the carboxylic acid or carboxylate is selected from methoxybenzoic acid, diaminobenzoic acid, and 4-methoxybenzoic acid.

11. The iminizing reagent is a compound represented by formula (V): 【Chemistry 9】 (In the formula, R 8 is SO 2 OR 9 , S.O. 2 (R 9 ), C(O)R 9 , P(O)(R 9 ) 2 or optionally substituted aryl, preferably R 8 is 4-nitrobenzoate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, diphenylphosphinate or 2,4-dinitrophenyl, R 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or optionally substituted aryl, preferably R 8 is 4-nitrobenzoate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, diphenylphosphinate or 2,4-dinitrophenyl or The iminizing reagent is represented by formula (VI): 【Chemistry 10】 (Wherein, X is SO 2 R 10 and R 8 is as described for compounds of formula (VII), and R 10 is C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, optionally substituted aryl or OH, preferably X is SO 2 CF 3 , S.O. 3 H or SO 2 Me) 4. The process of claim 1 or 3, wherein the compound is a salt of

12. The iminizing reagent may be O-(4-nitrobenzoyl)-hydroxylamine, O-(4-nitrobenzoyl)-hydroxylammonium trifluoromethanesulfonate, O-(4-nitrobenzoyl)-hydroxylammonium hydrogensulfate, O-(4-nitrobenzoyl)-hydroxylammonium methanesulfonate, O-(2,4-dinitrophenyl)-hydroxylamine, O-(2,4-dinitrophenyl)-hydroxylammonium trifluoromethanesulfonate, O-(2,4-dinitrophenyl)-hydroxylammonium hydrogensulfate, O-(2,4-dinitrophenyl)-hydroxylammonium methanesulfonate, O-(methanesulfonyl) 12. The process of claim 11, wherein the hydroxylamine is selected from O-(methanesulfonyl)-hydroxylamine, O-(methanesulfonyl)-hydroxylammonium trifluoromethanesulfonate, O-(methanesulfonyl)-hydroxylammonium hydrogensulfate, O-(methanesulfonyl)-hydroxylammonium methanesulfonate, O-(p-toluenesulfonyl)-hydroxylamine, O-(p-toluenesulfonyl)-hydroxylammonium trifluoromethanesulfonate, O-(p-toluenesulfonyl)-hydroxylammonium hydrogensulfate, O-(p-toluenesulfonyl)-hydroxylammonium methanesulfonate and hydroxylamine-O-sulfonic acid.

13. 3. The process according to claim 1 or 2, wherein the solvent (or diluent) used in step A is selected from esters, nitriles, alcohols, ethers and aliphatic, aromatic or halogenated hydrocarbons.

14. 4. The process according to claim 1 or 3, wherein the solvent (or diluent) used in step B is selected from esters, nitriles, alcohols, ethers, carboxylic acids, amides and water or mixtures thereof.

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