Ligand, catalyst and application thereof in synthesis of 2-pyridinol

Abstract

The invention discloses a ligand, a catalyst and application of the catalyst in synthesis of 2-pyridinol, and belongs to the technical field of chemical synthesis. The structure of the ligand or the stereoisomer, the enantiomer and the diastereoisomer thereof is shown as a formula (I). The catalyst is prepared from a transition metal precursor and a ligand as shown in the formula (I). The catalyst is used for synthesizing 2-pyridinol. The 2-pyridinol prepared by adopting the catalyst has the advantages of high yield, high product enantioselectivity, low cost and the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of organic chemical synthesis, and in particular to a ligand, a catalyst and application thereof in the synthesis of 2-pyridinol, in particular to the synthesis of 2-pyridine chiral alcohol. Background Art

[0002] Chiral alcohols, especially those with heteroaromatic rings, are important intermediates in the pharmaceutical industry and are typically obtained by chemical or bioreductive reduction of ketones. In recent years, the enantioselective synthesis of pyridine-containing chiral alcohols has developed rapidly. However, many existing asymmetric hydrogenation methods for synthesizing pyridine-containing chiral alcohols have been limited by difficulties in catalyst synthesis, high catalyst costs, and low catalytic efficiency, hindering their development.

[0003] Chiral 2-pyridyl alcohols and their derivatives are present in many drugs (or their intermediates), such as bepotastine besilate tablets, carbinoxamine maleate, mefloquine, etc. Therefore, chiral 2-pyridyl alcohols have important uses in the field of medicinal chemistry.

[0004] Metal-catalyzed asymmetric hydrogenation of prochiral ketones is an attractive method for synthesizing chiral secondary alcohols. However, due to the coordination effect of pyridine, the asymmetric hydrogenation of 2-pyridones remains a challenging task. Although iridium and rhodium-catalyzed reactions have made some progress in this field (e.g., CN114478362A, CN109824579B, and literature (Organic Letters (2015), 17(17), 4144-4147)), the high price of Ir / Rh makes their practicality poor; while ruthenium-catalyzed methods are relatively low-cost, they still face the problem of low enantiomeric excess (ee value).

[0005] Therefore, it is necessary to develop a new ligand and a new ruthenium catalyst and use it in the hydrogenation reaction of 2-pyridone to improve practicality. Summary of the Invention

[0006] To achieve the above objectives, the present invention provides a ligand, a catalyst and their use in the synthesis of 2-pyridinol. The ligand and catalyst are used in the synthesis reaction of pyridinol and have the advantages of mild conditions, easy operation and high product enantioselectivity.

[0007] In a first aspect, the present invention provides a ligand or a stereoisomer, enantiomer, or diastereomer thereof, the structure of which is as follows:

[0008]

[0009] R 1 、R 2 and R 3are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0010] R 4 At least one selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, alkyl-COOH, -SO3H, alkyl-SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl;

[0011] R 1 、R 2 and R 3 The aryl and heteroaryl groups are further optionally substituted independently by the same or different substituents R 5 Single or multiple substitutions; the substituent R 5 It is hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, alkyl-COOH, -SO3H, alkyl-SO3H, alkyl-C(=O)-, amide, alkyl-COOalkyl, haloalkyl, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl.

[0012] Furthermore, R 1 、R 2 and R 3 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl or C 1-12 Heteroaryl.

[0013] Furthermore, R 1 、R 2 and R 3 Each is independently selected from hydrogen, tert-butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or thiazolyl.

[0014] Furthermore, R 4 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6 Alkyl-SO3H, C 1-6 Alkyl-C(=O)-, -CONH2, -C 1-6 Alkyl-COOC 1-6Alkyl, C 1-6 Halogenated alkyl, C 6-12 Aryl-C(=O)-, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-6 Heteroaryl or C 1-6 At least one of the alkyl groups.

[0015] Furthermore, the R 4 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-4 Alkyl-COOH, -SO3H, -CON(R 5 )2. -C 1-4 Alkyl-COOC 1-4 Alkyl, C 1-4 At least one of a haloalkyl group (e.g., -CF3, -CH2CF3), a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a cyclobutyl group, a cyclopropyl group, a cyclohexyl group, a cyclopentyl group, and a phenyl group.

[0016] Furthermore, R 5 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6 Alkyl-SO3H, C 1-6 Alkyl-C(=O)-, -CONH2, -C 1-6 Alkyl-COOC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-12 Aryl-C(=O)-, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-6 Heteroaryl or C 1-6 At least one of the alkyl groups.

[0017] Furthermore, R 5 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-4 Alkyl-COOH, -SO3H, -CONH2, -C 1-4 Alkyl-COOC 1-4 Alkyl, C 1-4At least one of a haloalkyl group (e.g., -CF3, -CH2CF3), a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a cyclobutyl group, a cyclopropyl group, a cyclohexyl group, a cyclopentyl group, and a phenyl group.

[0018] Furthermore, the ligand is selected from one of the following structures:

[0019] In the structural formula of the ligand, Ph represents a phenyl group. In the present application, the ligand represented by formula (1a) is abbreviated as f-PPNNPhos.

[0020] In a second aspect, the present invention provides a method for preparing a ligand represented by formula (I), the specific steps of which are as follows:

[0021]

[0022] The compound of formula (II), the compound of formula (III) and an alkaline reagent react in an alcohol solvent to prepare a ligand represented by formula (I);

[0023] Among them, R 1 、R 2 、R 3 、R 4 Has the definition as described in the present invention.

[0024] Furthermore, the alcohol solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, and tert-butanol.

[0025] Furthermore, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:1 to 1:5, preferably 1:1, 1:2, 1:3, 1:4, or 1:5.

[0026] Furthermore, the alkaline reagent is selected from at least one of cesium carbonate, potassium carbonate, sodium hydride, sodium amide, butyl lithium, lithium tert-butoxide, lithium diisopropylamide, sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate, diethylamine, ethylenediamine, potassium phosphate, sodium carbonate, sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine and N,N-diisopropylethylamine.

[0027] Furthermore, the molar ratio of the compound of formula (II) to the alkaline reagent is 1:1 to 1:5, preferably 1:1, 1:2, 1:3, 1:4, or 1:5.

[0028] Furthermore, the reaction time is 6 to 12 hours, preferably 6 hours, 8 hours, 10 hours, 11 hours, or 12 hours.

[0029] Furthermore, the reaction temperature is 60-100°C, preferably 60°C, 70°C, 80°C, 90°C, or 100°C.

[0030] In a third aspect, the present invention provides a catalyst prepared from a transition metal precursor and the ligand of the present invention.

[0031] Furthermore, the transition metal precursor is selected from at least one of (DMSO)4RuCl2, [Ru(C6H6)Cl2]2, [Ru(C6H6)I2]2, [Ru(p-cymene)Cl2]2, [Ru(p-cymene)I2]2 or Ru(Me-allyl)2(COD).

[0032] Furthermore, the specific preparation process of the catalyst includes: mixing the transition metal precursor and the ligand in a first solvent, heating and stirring, and concentrating under reduced pressure to obtain the catalyst.

[0033] Furthermore, the first solvent is at least one of N,N-dimethylformamide and N,N-dimethylacetamide.

[0034] Furthermore, the stirring reaction time is 2 to 10 hours, preferably 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, or 10 hours.

[0035] Furthermore, the stirring reaction temperature is 60-100°C, preferably 60°C, 70°C, 80°C, 90°C, or 100°C.

[0036] Furthermore, the molar ratio of the transition metal precursor to the ligand is 1:1 to 1:2.5, preferably 1:1, 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5.

[0037] In a fourth aspect, the present invention provides a method for synthesizing 2-pyridinol represented by formula (V), the specific steps of which are as follows:

[0038]

[0039] The compound represented by formula (IV) and hydrogen are used as raw materials, and the catalyst of the present invention is used to undergo an asymmetric hydrogenation reaction in the presence of a base additive and a second solvent to produce the compound represented by formula (V);

[0040] R 6 is selected from hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl, R 6 further optionally each independently substituted by the same or different substituents R 7 monosubstituted or polysubstituted;

[0041] n is selected from 0, 1, 2, 3 or 4;

[0042] The R 7 and R 8 each independently hydrogen, -F, -Cl, -Br, -I, -CN, hydroxy, -COOH, alkyl-COOH, alkyl-OC(=O)-, amido, alkyl-COOalkyl, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, or alkyl;

[0043] or 2 R 8 Together with the attached carbon atoms, they may form an aromatic ring.

[0044] Furthermore, the R 6 Selected from hydrogen, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-6 Heteroaryl or C 1-6 alkyl.

[0045] Furthermore, the R 7 and R 8 Each independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, hydroxyl, -COOH, C 1-6 Alkyl-COOH, C 1-6 Alkyl-OC(=O)-, -CONH2, -C 1-6 Alkyl-COOC 1-6 Alkyl, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-6 Heteroaryl or C 1-6 alkyl;

[0046] or 2 R 8 Together with the carbon atoms connected to it, it can form C 6-12 Aromatic ring.

[0047] Furthermore, the R 6 It is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, and the like.

[0048] Furthermore, the R 7 and R 8 Each independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, hydroxyl, -COOH, C 1-4 Alkyl-COOH, C 1-4 Alkyl-OC(=O)-, -CONH2, -C 1-4 Alkyl-COOC1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy (e.g., methoxy), methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, phenyl, etc.;

[0049] or 2 R 8 Together with the attached carbon atoms, they can form a benzene ring, e.g. 2 Rs in 8 Can form with attached carbon atoms Other similar situations can be analogized.

[0050] Furthermore, the compound represented by formula (IV) is selected from one of the following structures:

[0051]

[0052] Furthermore, the compound represented by formula (V) is selected from one of the following structures:

[0053]

[0054] Furthermore, the second solvent is an aprotic solvent, selected from at least one of diethyl ether, methyl tert-butyl ether, toluene, and o-xylene.

[0055] Furthermore, the base additive is a strong organic base selected from at least one of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), and TBD (tri-n-butylamine). It is understood that within the scope of the present invention, other basic compounds that can form strong base conditions may also be used.

[0056] Furthermore, the molar ratio of the compound represented by formula (IV) and the base additive is 1:1 to 1:3, preferably 1:1, 1:1.05, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, and 1:3.

[0057] Furthermore, the pressure of the hydrogen is 10-70 atm, preferably 10 atm, 20 atm, 30 atm, 40 atm, 50 atm, 60 atm, or 70 atm.

[0058] Furthermore, the molar ratio of the catalyst to the compound represented by formula (IV) is 0.001:1 to 0.05:1, preferably 0.001:1 to 0.03:1, 0.001:1, 0.005:1, 0.008:1, 0.02:1, 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1, 0.05:1.

[0059] Furthermore, the temperature of the asymmetric reaction is 15-150°C, preferably 15°C, 50°C, 80°C, 100°C, 120°C, or 150°C.

[0060] Furthermore, the asymmetric reaction time is 5-24°C, preferably 5h, 10h, 15h, 20h, or 24h.

[0061] Furthermore, the asymmetric hydrogenation reaction is carried out in an oxygen-free environment.

[0062] Furthermore, the oxygen-free environment is an inert gas atmosphere.

[0063] Furthermore, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon. Preferably, the inert gas is nitrogen.

[0064] It should be noted that the main purpose of introducing inert gas into the reaction system in this application is to form an oxygen-free environment. If an oxygen-free environment can be ensured, inert gas can also be omitted. In one implementation of the present application, even if inert gas is used, most of the entire reaction environment is still hydrogen, for example, more than 99% is hydrogen and the rest is inert gas.

[0065] This application uses the ligand represented by formula 1a (hereinafter referred to as: f-PPNNPhos) and the transition metal precursor [Ru(C6H6)Cl2]2 to prepare a catalyst complex (chiral Ru / f-PPNNPhos complex); the catalyst complex is used to efficiently asymmetric catalytic hydrogenate the compound represented by formula (IV) (for example, an alkyl aromatic ketone compound) to synthesize the compound represented by formula (V) (for example, a chiral alcohol derivative). The obtained product has high yield, high catalytic efficiency, high enantiomeric selectivity, and high optical purity, and can be used as an intermediate for a variety of biologically active compounds.

[0066] Beneficial effects:

[0067] Compared with other Ir or Rh catalysts, the catalyst obtained by complexing the ligand provided in this application with a transition metal precursor is a tetradentate ligand catalyst (such as Ru / f-PPNNPhos), which is simple and easy to synthesize, has high catalytic efficiency, and the raw materials are cheap and easily available, with low cost and high practicality.

[0068] In the synthesis method of 2-pyridinol of the present application, a simple and easy-to-synthesize tetradentate ligand catalyst (such as Ru / f-PPNNPhos) is used, a cheap and readily available 2-pyridyl ketone compound (i.e., the compound represented by formula (IV)) is used as a substrate, and hydrogen, a green energy source, is used as a hydrogen source. In accordance with the concept of green development, a chiral alcohol compound is chemically selectively synthesized, and the chiral alcohol can be synthesized in a one-step reaction. The synthesis steps are simple and easy to operate, which can better meet the large-scale production of chiral alcohols.

[0069] Furthermore, the catalyst prepared herein is used in a method for synthesizing 2-pyridine chiral alcohols, resulting in high catalytic efficiency, high yield, and high product enantioselectivity (for example, in one embodiment of the present invention, the reaction yield is as high as 100% and the enantioselectivity is as high as 99%). The catalyst provided herein facilitates the synthesis of chiral alcohols with higher purity, thereby enabling further synthesis of bioactive substances, such as drug molecules, with improved efficiency and quality.

[0070] It can be understood that the key to this application is the use of a chiral complex (such as Ru / f-PPNNPhos) to efficiently catalyze the asymmetric hydrogenation reduction of alkyl aryl ketone compounds to synthesize chiral alcohols represented by structural formula (V), which provides a new scheme for the synthesis of chiral alcohols; as for the use of the synthesized chiral alcohols, reference can be made to the existing technology, for example, they can be used as intermediates for various drug molecules.

[0071] Terminology

[0072] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0073] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0074] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0075] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0076] In the following disclosure, all numerical values ​​disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15%, or 20%. Whenever a number having a value of N is disclosed, any number having a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15%, or N+ / -20% is expressly disclosed, where "+ / -" means plus or minus.

[0077] In this application, for example, "Formula (I)", "Formula (II)", etc., are only used to distinguish the objects described and do not have any order or technical meaning. In this application, the description of a numerical range includes the endpoints and any value within the range, for example, "1-10" can include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0078] In the chemical formulae of the present application, Ar represents an aryl group or a heterocyclic aryl group, such as an unsubstituted phenyl group, a phenyl group in which at least one hydrogen is substituted, a five-membered heterocycle, or a heterocycle with more than five members; tBu- represents a tert-butyl group.

[0079] The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon radical containing 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted with one or more substituents described herein. Unless otherwise specified, an alkyl radical contains 1-20 carbon atoms. In one embodiment, the alkyl radical contains 1-12 carbon atoms; in another embodiment, the alkyl radical contains 1-6 carbon atoms; in yet another embodiment, the alkyl radical contains 1-4 carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl. When alkyl is a linking group and "alkyl" is listed for the Markush group definition, "alkyl" refers to the linking alkylene radical. The term "alkylene" refers to a saturated, divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated, linear or branched hydrocarbon radical. Examples of alkylene radicals include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)CH2-, and the like. The "alkyl" in "alkyl-COOH", "alkyl-COOalkyl", "alkyl-SO3H" and the like mentioned herein has the definition as described in the present invention, and the same applies to other groups.

[0080] As used herein, "alkoxy," "alkylthio," and "heteroalkyl" refer to groups in which some of the carbon atoms in an alkyl group are replaced by different heteroatoms (e.g., O, N, S, Si, or P), wherein the alkyl moiety has the meaning described herein. The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P), such as alkoxy, alkylamino, and the like. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0081] The term "haloalkyl" refers to an alkyl group substituted with F, Cl, Br or I, wherein the alkyl portion has the meaning as defined herein, for example, -CH2Cl, -CF3, -CH2CF3, -CH2CCl3, etc.

[0082] The terms "heterocycle" or "heterocyclyl" are used interchangeably and refer to a monovalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system of 3 to 12 ring atoms, containing at least one carbon atom and one, two or three heteroatoms selected from O, N and S, including monoheterocyclyl, bridged heterocyclyl, paraheterocyclyl and spiroheterocyclyl. Unless otherwise specified, the heterocyclyl group may be a carbon group or a nitrogen group, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide, and the nitrogen atom of the ring may be optionally oxidized to an N-oxide. The heterocycle may be monocyclic or bicyclic; in particular, the bicyclic ring system may be a paraheterobicyclic, spiroheterobicyclic or bridged heterobicyclic. In some embodiments, the heterocyclyl group contains 4-7 ring atoms, that is, it represents a 4-7 membered heterocyclyl group; examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, etc. Examples of heterocyclic groups include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolane, oxathiophenyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl, oxepanyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl. "Cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent refer to a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

[0083] Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryls. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linker. The term "arylene" refers to a divalent aryl group, wherein aryl has the definition as described herein.

[0084] Heteroaryl groups may include groups such as pyrrole, pyridine, imidazole, pyrazole, thiazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), etc. The term "heteroarylene" refers to a divalent heteroaryl group, wherein heteroaryl has the definition as described herein.

[0085] Cycloalkyl refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which may be fully saturated or contain one or more degrees of unsaturation, but may not have an aromatic ring. In one embodiment, the cycloalkyl group contains 3-6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. 4-7 Cycloalkyl refers to a cycloalkyl group having 4 to 7 ring atoms. 3-6 Cycloalkyl refers to a cycloalkyl group having 3 to 6 ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.

[0086] In the present invention, The positions of the bonds can be combined at any reasonable position on the ring, which can be expressed as Etc.; and so on.

[0087] The elements referred to in the structures of the present invention are elements including all isotopes thereof, and exemplary isotopes in the compounds of the present invention include isotopes of hydrogen (H), carbon (C), nitrogen (N), oxygen (O), phosphorus (P), sulfur (S), fluorine (F), chlorine (Cl) and bromine (Br), such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F, 37 Cl, Br 81 That is, hydrogen (H) includes 1 H. 2 H. 3 H; Carbon (C) includes 12 C. 13 C. 14 C; Nitrogen (N) includes 14 N. 15 N; oxygen (O) includes 16 O. 17 O; Phosphorus (P) includes 30 P. 31 P.32 P; sulfur (S) includes 32 S. 33 S. 34 S. 36 S; Fluorine (F) includes 18 F. 17 F; Chlorine (Cl) includes 35 Cl, 37 Cl; bromine (Br) including Br 79 Br 81 .

[0088] In the present invention, similar terms such as "jk pieces", "jk yuan" or "C j -C k "The j and k in it are each independently any non-zero natural number, and k>j; for example, "1-4" means 1, 2, 3 or 4, "4-6 yuan" means 4 yuan, 5 yuan or 6 yuan; "C3-C6" means C3, C4, C5 or C6. And so on.

[0089] In the present invention, "room temperature" refers to ambient temperature, which may be 10°C-40°C, 20°C-30°C, and preferably 25°C.

[0090] The terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur. The term "and / or" should be understood to mean any one of the optional items or a combination of any two or more of the optional items.

[0091] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “each ... and ... are independently,” “... and ... are each independently,” and “... and ... are respectively independently,” are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0092] "Stereoisomers" refer to compounds with the same chemical structure but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formulas described herein are within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein may include enriched isotopes of one or more different atoms.

[0093] Stereochemical definitions and conventions used herein generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994.

[0094] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Figure 1 This is the carbon NMR spectrum of ligand 1a prepared in the ligand preparation example.

[0096] Figure 2 This is the carbon NMR spectrum of ligand 1a prepared in the ligand preparation example.

[0097] Figure 3 This is the nuclear magnetic resonance phosphorus spectrum of ligand 1a prepared in the ligand preparation example.

[0098] Figure 4 This is the carbon NMR spectrum of ligand 1c prepared in the ligand preparation example.

[0099] Figure 5 This is the carbon NMR spectrum of ligand 1c prepared in the ligand preparation example.

[0100] Figure 6 This is the nuclear magnetic resonance phosphorus spectrum of ligand 1c prepared in the ligand preparation example.

[0101] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the chiral alcohol II-1 prepared in Example 2.

[0102] Figure 8 This is the carbon NMR spectrum of the chiral alcohol II-1 prepared in Example 2.

[0103] Figure 9 This is the hydrogen nuclear magnetic resonance spectrum of the chiral alcohol II-2 prepared in Example 2.

[0104] Figure 10 This is the carbon NMR spectrum of the chiral alcohol II-2 prepared in Example 2.

[0105] Figure 11 This is the nuclear magnetic resonance fluorine spectrum of the chiral alcohol II-2 prepared in Example 2.

[0106] Figure 12 This is the hydrogen nuclear magnetic resonance spectrum of the chiral alcohol II-10 prepared in Example 2.

[0107] Figure 13 This is the carbon NMR spectrum of the chiral alcohol II-10 prepared in Example 2. DETAILED DESCRIPTION

[0108] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0109] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0110] Ligand Preparation Example

[0111]

[0112] General method: Mix the compound of formula (II) (1 mmol), the compound of formula (III) (3 mmol), triethylamine (3 mmol), and methanol (2.0 mL), stir at 80°C for 10 hours, and evaporate under reduced pressure to obtain the ligand represented by formula (I). The specific structures of each ligand are shown in Table 1 below:

[0113] Table 1 Specific structure of ligand preparation example

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120] Catalyst Preparation Example

[0121] General Method: Combine the transition metal precursor (25 mg, 0.05 mmol), the ligand (82 mg, 0.105 mmol), and N,N-dimethylformamide (2.0 mL) and stir at 90°C for 3 hours to obtain a clear, reddish-brown solution, the catalyst solution. Rotary evaporate the solvent from the catalyst solution to obtain the crude catalyst.

[0122] Other catalysts were prepared by referring to the general method steps of Catalyst Preparation Example 1, as described in Table 2 below:

[0123] Table 2 Specific conditions of each substance in the catalyst preparation example

[0124]

[0125] The characterization data of each catalyst are shown in Table 3 below:

[0126] Table 3 Characterization data of each catalyst

[0127]

[0128]

[0129] Application Example 1

[0130] (1) Investigation of the solvent used in the reaction

[0131]

[0132] General method: Under nitrogen atmosphere, 0.1 mmol of the compound represented by formula I-1 and catalyst 2a (3.0×10 -3 mmol) and an alkaline reagent (0.01 mmol, see Table 4) were mixed with 0.4 mL of a solvent (previously vacuum-deoxygenated, see Table 4) and then transferred to an autoclave. Under a reaction atmosphere of 99% vol hydrogen and 1% nitrogen, the hydrogen pressure was set to 50 atm and the reaction was carried out at 25°C for 10 h. Subsequently, the hydrogen was slowly released, 4.0 mL of ethyl acetate was added for dilution, and the reaction was quenched with 8.0 mL of water. The organic phase was separated, and the aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were then combined and dried over anhydrous sodium sulfate. The solvent was then spin-dried to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the chiral alcohol represented by Formula II-1. The results are shown in Table 4.

[0133] Table 4: Investigation of solvents

[0134] test catalyst solvent Alkaline reagents Yield (%) ee(%) 1 2a i-PrOH t-BuOK 90 66 2 2a THF t-BuOK 99 64 3 2a o-xylene t-BuOK 99 70 4 2a DCM t-BuOK 90 68 5 2a MTBE t-BuOK 99 78

[0135] From the results in Table 4 above, it can be seen that the yield of the product obtained using MTBE (methyl tert-butyl ether), THF and o-xylene (1,2-xylene) as solvents is the highest, but the ee value of the product obtained using the aprotic solvent MTBE is higher.

[0136] (2) Investigation of alkaline reagents

[0137] Under nitrogen atmosphere, 0.1 mmol of the compound represented by formula I-1 and catalyst 2a (3.0×10 -3 mmol) and an alkaline reagent (0.01 mmol, see Table 5) were mixed with 0.4 mL of a solvent (the solvent was previously vacuum-deoxygenated, see Table 5) and then transferred to an autoclave. Under a reaction atmosphere of 99% hydrogen and 1% nitrogen (volume percentage), the hydrogen pressure was set to 50 atm, and the reaction was carried out at a temperature of 25°C for 10 hours. Subsequently, the hydrogen was slowly released, 4.0 mL of ethyl acetate was added for dilution, and the reaction was quenched with 8.0 mL of water. The organic phase was separated, and the aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were then combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain a crude product. The crude product was subsequently separated and purified by column chromatography to obtain the chiral alcohol represented by Formula II-1. The results are shown in Table 5.

[0138] Table 5: Investigation of alkaline reagents

[0139] test catalyst solvent Alkaline reagents Yield (%) ee(%) 1 2a MTBE DBN 99 94 2 2a MTBE <![CDATA[Cs2CO3]]> 99 87 3 2a MTBE t-BuOK 99 78 4 2a MTBE DBU 99 91 5 2a MTBE TMG 0 -

[0140] As can be seen from Table 5 above, the yield and ee value of the product obtained by using an organic base (such as DBN, DBU) are both higher, and the use of an organic base is more conducive to improving the yield and ee value of the product.

[0141] (3) Investigation of catalyst

[0142] Under nitrogen atmosphere, 0.1 mmol of the compound represented by formula I-1 and catalyst 2a (3.0×10 -3 mmol) and an alkaline reagent (0.1 mmol, see Table 6) were mixed with 0.4 mL of a solvent (previously vacuum-deoxygenated, see Table 6) and then transferred to an autoclave. Under a reaction atmosphere of 99% hydrogen and 1% nitrogen (volume percentage), the hydrogen pressure was set to 50 atm, and the reaction was carried out at a temperature of 25°C for 10 hours. Subsequently, the hydrogen was slowly released, 4.0 mL of ethyl acetate was added for dilution, and the reaction was quenched with 8.0 mL of water. The organic phase was separated, and the aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were then combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain a crude product. The crude product was subsequently separated and purified by column chromatography to obtain the chiral alcohol represented by Formula II-1. The results are shown in Table 6.

[0143] Table 6: Catalyst investigation

[0144]

[0145]

[0146] It can be seen from Table 6 above that the use of catalyst 2a, catalyst 2c, catalyst 2e, catalyst 2g or catalyst 2h is more conducive to improving the yield and ee value of the obtained product; among them, catalyst 2a and catalyst 2c are preferred.

[0147] Application Example 2

[0148] The chiral alcohol represented by structural formula (V) was prepared by using the optimal experimental conditions screened by (1)-(3).

[0149]

[0150] General method: Under nitrogen atmosphere, 0.1 mmol of 2-pyridyl ketone derivative of compound (IV) was added to a hydrogenation bottle, and then catalyst 2a (Ru / f-PPNNPhos complex) (2.7 mg, 1.0×10 -2 mmol), DBN (12.4 mg, 0.1 mmol), methyl tert-butyl ether 0.4 mL, and then transferred to a pressure autoclave. The inert gas in the reaction chamber was nitrogen, and more than 99% of the reaction atmosphere was hydrogen. The hydrogen pressure was set to 50 atm, and the reaction was carried out at 25°C for 10 h. Subsequently, the hydrogen was slowly released, 4.0 mL of ethyl acetate was added for dilution, and the mixture was quenched with 8.0 mL of water. The organic phase was separated, and the aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were then combined and dried over anhydrous sodium sulfate. The solvent was spin-dried to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain a clean compound represented by formula (V).

[0151] pass 1 H NMR and 13 The structure of the hydrogenated product is determined by C NMR spectroscopy, the ee value (enantioselectivity) of the product is determined by HPLC (high performance liquid chromatography), the yield is analyzed by hydrogen nuclear magnetic resonance spectroscopy, and the optical rotation value of the product is determined using a polarimeter. The structure of the compound represented by formula (V) can be:

[0152]

[0153] This example specifically synthesized chiral alcohols II-1 to II-12. The structures of the products, their yields, and enantioselectivities are shown in Table 7 below:

[0154] Table 7: Structures of each product and their yields and enantioselectivity results

[0155] Chiral alcohols Yield (%) ee(%) Characterization data Formula II-1 99 94 <![CDATA[[α] D 20 =+0.8(c=0.5,CH3CH2OH)]]> Formula II-2 99 94 <![CDATA[[α] D 20 =-0.7(c=0.5,CH3CH2OH)]]> Formula II-3 99 91 <![CDATA[[α] D 20 =17.3(c=0.5,CH3CH2OH)]]> Formula II-4 99 94 <![CDATA[[α] D 20 =11.4(c=0.5,CH3CH2OH)]]> Formula II-5 99 95 <![CDATA[[α] D 20 =16.8(c=0.5,CH3CH2OH)]]> Formula II-6 100 96 <![CDATA[[α] D 20 =-25.9(c=1.0,CH2Cl2)]]> Formula II-7 100 99 <![CDATA[[α] D 22 =-20.4(c=0.5,CHCl3)]]> Formula II-8 100 99 <![CDATA[[α] D 22 =-31.3(c=1.0,CH2Cl2)]]> Formula II-9 100 97 <![CDATA[[α] D 22 =-3.8(c=1.0,CH2Cl2)]]> Formula II-10 100 96 <![CDATA[[α] D 22 =-30.2(c=1.0,CH2Cl2) <!-- 19 -->]]> Formula II-11 100 99 <![CDATA[[α] D 25 =-119.5(c=1.17,CHCl3)]]> Formula II-12 100 97 <![CDATA[[α] D 25 =-6.2(c=0.52,CHCl3)]]> Formula II-13 100 93 <![CDATA[[α] D 20 =-28.4(c=0.5,CH3CH2OH)]]> Formula II-14 100 99 <![CDATA[[α] D 20 =-5.0(c=1.0,CH2Cl2)]]> Formula II-15 99 97 <![CDATA[[α] D 20 =-24(c=1.0,CH2Cl2)]]> Formula II-16 99 92 <![CDATA[[α] D 20 =-14.2(c=1.0,CH2Cl2)]]> Formula II-17 99 93 <![CDATA[[α] D 20 =-9.2(c=1.0,CH2Cl2).]]> Formula II-18 100 99 <![CDATA[[α] D 20 =-40.8(c=1.0,CH2Cl2)]]> Formula II-19 99 93 <![CDATA[[α] D 20 =-60.3(c=1.0,CH2Cl2)]]> Formula II-20 99 93 <![CDATA[[α] D 20 =14.0(c=1.0,CH2Cl2)]]>

[0156] The specific synthesis steps of some products and their product structures, yields and enantioselectivity detection and analysis data are schematically listed in this example, as follows:

[0157] Under an inert gas atmosphere, 0.1 mmol of the 2-pyridyl ketone derivative of compound I-1 was added to the hydrogenation bottle, and then the catalyst Ru / f-PPNNPhos complex (2.7 mg, 3.0×10 -3 mmol), DBN (12.4 mg, 0.1 mmol), methyl tert-butyl ether 0.4 mL, and then transferred to a pressure autoclave. The inert gas in the reaction chamber was nitrogen, and more than 99% of the reaction atmosphere was hydrogen. The hydrogen pressure was set to 50 atm, and the reaction was carried out at 25°C for 10 h. Subsequently, the hydrogen was slowly released, 4.0 mL of ethyl acetate was added for dilution, and the mixture was quenched with 8.0 mL of water. The organic phase was separated, and the aqueous phase was washed twice with 2.0 mL of ethyl acetate. The organic phases were then combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain a clean chiral alcohol represented by structural formula II-1.

[0158] Chiral alcohol represented by II-1 Colorless oil, 18.3 mg, 99% yield, 94% ee; [α] D 20 = -127 (c = 1.0, CH2Cl2). Enantiomeric excess (ee) was determined by chiral high-performance liquid chromatography (HPLC) (Chiralpak ID column, n-hexane / isopropanol (v / v) = 95:5, flow rate 1.0 mL / min, detection wavelength λ = 254 nm, temperature 25°C). Retention time: tR(major) = 15.994 min for the major component, tR(minor) = 21.435 min for the minor component.

[0159] 1 H NMR (600MHz, CDCl3) δ8.48(d,J=4.6Hz,1H),7.54(t,J=7.7Hz,1H),7.30(d,J=7.3Hz,2H),7.2 6(t,J=7.5Hz,2H),7.21-7.17(m,1H),7.15-7.10(m,1H),7.08(d,J=7.9Hz,1H),5.68(s,1H). 13 C NMR (151MHz, CDCl3) δ160.9,147.8,143.2,136.9,128.6,127.9,127.1,122.5,121.4,75.0.

[0160] The chiral alcohol shown in II-2 was prepared according to the same general method. Colorless oil, 99% yield, 20.1 mg; 94% ee; [α] D 20 =-0.7 (c = 0.5, CH3CH2OH).

[0161] Enantiomeric excess (ee) was determined by chiral high performance liquid chromatography (HPLC) (Chiralpak ID column, n-hexane / isopropanol (v / v) = 95:5, flow rate 1.0 mL / min, detection wavelength λ = 254 nm, temperature 25°C). Retention time: tR(major) = 15.462 min for the major component, tR(minor) = 19.504 min for the minor component.

[0162] 1 H NMR(600MHz, CDCl3)δ8.46(d,J=4.6Hz,1H),7.54(t,J=7.0Hz,1H),7.32-7.22(m, 2H),7.16-7.09(m,1H),7.05(d,J=7.9Hz,1H),6.93(t,J=8.7Hz,2H),5.65(s,1H). 13 CNMR (151MHz, CDCl3) δ162.4 (d, J = 246.1Hz), 160.7, 147.9, 139.0 (d, J = 3.0Hz), 137.0, 128.7 (d, J = 8.4Hz), 122.5, 121.2, 115.4 (d, J = 21.6Hz), 74.3. 19 F NMR(565MHz, CDCl3)δ-114.67(s).

[0163] Prepare the chiral alcohol shown in II-10 according to the general method Colorless oil, 17.27 mg, 100% yield, 96% ee.

[0164] [α] D 22 =-30.2 (c = 1.0, CH2Cl2).

[0165] Enantiomeric excess (ee) was determined by chiral high performance liquid chromatography (HPLC) (Chiralpak ID column, n-hexane / isopropanol 95:5 volume ratio, flow rate 1.0 mL / min, detection wavelength λ = 254 nm, temperature 25°C). Retention time: The retention time of the major component was tR(major) = 27.943 min, and the retention time of the minor component was tR(minor) = 36.528 min.

[0166] 1H NMR (400MHz, CDCl3) δ9.19 (s, 1H), 7.95 (d, J = 8.2Hz, 1H), 7.80 (d, J = 8.3Hz, 1H), 7.7 0-7.65(m,2H),7.57(t,J=7.5Hz,1H),5.07(q,J=6.5Hz,1H),1.61(d,J=6.5Hz,3H).

[0167] 13 C NMR (151MHz, CDCl3) δ156.9,151.6,136.4,130.6,127.8,127.6,126.9,126.6,115.6,69.5,24.1.

[0168] The synthesis method of the embodiment of the present invention has the advantages of cheap and readily available raw materials, simple operation steps, high catalytic efficiency, high yield, and high product enantioselectivity.

[0169] Comparative Example 1:

[0170] Chiral alcohols were prepared by referring to the general method of Example 2. Catalyst 2a prepared in this application was replaced with catalyst 2b in patent CN119462781A to prepare chiral alcohols II-1 to II-20. The product yields and ee values ​​are shown in Table 8:

[0171] Table 8 Product situation of comparative example 1

[0172] Chiral alcohols Yield (%) ee(%) Chiral alcohols Yield (%) ee(%) Formula II-1 90 75 Formula II-11 84 70 Formula II-2 85 76 Formula II-12 87 79 Formula II-3 89 65 Formula II-13 90 72 Formula II-4 91 69 Formula II-14 79 75 Formula II-5 86 81 Formula II-15 78 79 Formula II-6 84 73 Formula II-16 77 77 Formula II-7 83 79 Formula II-17 91 75 Formula II-8 87 80 Formula II-18 87 69 Formula II-9 89 65 Formula II-19 88 73 Formula II-10 92 69 Formula II-20 89 65

[0173] Comparing the results in Table 7 and Table 8, it can be seen that using the complex of Ru metal and ligand 1a provided by the present invention as catalyst 2a is more conducive to improving the yield and ee value of 2-pyridine chiral alcohol.

[0174] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A ligand or a stereoisomer, enantiomer or diastereomer thereof, characterized in that: Its structure is as follows (I): R 1 、R 2 and R 3 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R 4 At least one selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxy, -COOH, -alkyl-COOH, -SO3H, alkyl-SO3H, alkyl-C(=O)-, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl; R 1 、R 2 and R 3 The aryl and heteroaryl groups are further optionally substituted independently by the same or different substituents R 5 Single or multiple substitutions; the substituent R 5 It is hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, alkyl-COOH, -SO3H, alkyl-SO3H, alkyl-C(=O)-, amide, alkyl-COOalkyl, haloalkyl, aryl-C(=O)-, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl.

2. The ligand according to claim 1 or its stereoisomers, enantiomers, diastereomers, characterized in that: R 1 、R 2 and R 3 are each independently selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl or C 1-12 heteroaryl; More preferably, R 1 、R 2 and R 3 Each is independently selected from hydrogen, tert-butyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or thiazolyl.

3. The ligand according to claim 1 or its stereoisomers, enantiomers, diastereomers, characterized in that: R 4 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6 Alkyl-SO3H, C 1-6 Alkyl-C(=O)-, -CONH2, -C 1-6 Alkyl-COOC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-12 Aryl-C(=O)-, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-6 Heteroaryl or C 1-6 At least one of the alkyl groups; More preferably, the R 4 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-4 Alkyl-COOH, -SO3H, -CON(R 5 )2. -C 1-4 Alkyl-COOC 1-4 Alkyl, C 1-4 At least one of haloalkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl, cyclopropyl, cyclohexyl, cyclopentyl, and phenyl.

4. The ligand according to claim 1 or its stereoisomers, enantiomers, diastereomers, characterized in that: R 5 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-6 Alkyl-COOH, -SO3H, C 1-6 Alkyl-SO3H, C 1-6 Alkyl-C(=O)-, -CONH2, -C 1-6 Alkyl-COOC 1-6 Alkyl, C 1-6 Halogenated alkyl, C 6-12 Aryl-C(=O)-, amino, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, C 2-6 Heterocyclic group, C 6-12 Aryl, C 1-6 Heteroaryl or C 1-6 At least one of the alkyl groups; Furthermore, R 5 Selected from hydrogen, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, hydroxyl, -COOH, C 1-4 Alkyl-COOH, -SO3H, -CONH2, -C 1-4 Alkyl-COOC 1-4 Alkyl, C 1-4 At least one of a haloalkyl group (e.g., -CF3, -CH2CF3), a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a tert-butyl group, a cyclobutyl group, a cyclopropyl group, a cyclohexyl group, a cyclopentyl group, and a phenyl group.

5. The ligand according to any one of claims 1 to 4, or a stereoisomer, enantiomer or diastereomer thereof, characterized in that: The ligand is selected from one of the following structures 6. A method for preparing the ligand represented by formula (I) according to claim 1, characterized in that: The specific steps are as follows: The compound of formula (II), the compound of formula (III) and an alkaline reagent react in an alcohol solvent to prepare a ligand represented by formula (I).

7. The preparation method according to claim 1, characterized in that: The alcohol solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, and tert-butanol; Further preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:1 to 1:

5. Further preferably, the alkaline reagent is selected from at least one of cesium carbonate, potassium carbonate, sodium hydride, sodium amide, butyl lithium, lithium tert-butoxide, lithium diisopropylamide, sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate, diethylamine, ethylenediamine, potassium phosphate, sodium carbonate, sodium phosphate, potassium hydroxide, sodium hydroxide, lithium hydroxide, triethylamine and N,N-diisopropylethylamine; Further preferably, the molar ratio of the compound of formula (II) to the alkaline reagent is 1:1 to 1:5; Further preferably, the reaction time is 6 to 12 hours; More preferably, the reaction temperature is 60-100°C.

8. A catalyst, characterized in that Prepared from a transition metal precursor and the ligand according to any one of claims 1 to 5 or the ligand prepared by the method according to any one of claims 6 to 7; Further preferably, the transition metal precursor is selected from at least one of (DMSO)4RuCl2, [Ru(C6H6)Cl2]2, [Ru(C6H6)I2]2, [Ru(p-cymene)Cl2]2, [Ru(p-cymene)I2]2 or Ru(Me-allyl)2(COD); Further preferably, the specific preparation process of the catalyst includes: mixing the transition metal precursor and the ligand in a first solvent, heating and stirring, and concentrating under reduced pressure to obtain the catalyst; Further preferably, the first solvent is at least one of N,N-dimethylformamide and N,N-dimethylacetamide; Further preferably, the stirring reaction time is 2 to 10 hours; Further preferably, the stirring reaction temperature is 60-100°C; More preferably, the molar ratio of the transition metal precursor to the ligand is 1:1 to 1:2.

5.

9. A method for synthesizing 2-pyridinol represented by formula (V), characterized in that: The specific steps are as follows: The compound represented by formula (IV) and hydrogen are used as raw materials, and the catalyst described in claim 8 is used to undergo an asymmetric hydrogenation reaction in the presence of a base additive and a second solvent to produce the compound represented by formula (V); R 6 is selected from hydrogen, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl, R 6 further optionally each independently substituted with the same or different substituents R 7 Monosubstituted or polysubstituted; n is selected from 0, 1, 2, 3 or 4; The R 7 and R 8 Each is independently hydrogen, -F, -Cl, -Br, -I, -CN, hydroxy, -COOH, alkyl-COOH, alkyl-OC(=O)-, amide, -alkyl-COOalkyl, amino, nitro, alkoxy, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl or alkyl; or 2 R 8 Together with the attached carbon atoms, they may form an aromatic ring.

10. The synthesis method according to claim 9, characterized in that: The compound represented by formula (IV) is selected from one of the following structures: And / or, the compound represented by formula (V) is selected from one of the following structures: Further preferably, the second solvent is an aprotic solvent, selected from at least one of diethyl ether, methyl tert-butyl ether, toluene, and o-xylene; Further preferably, the base additive is selected from at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,5,7-triazabicyclo[4.4.0]decene-5-ene (TBD); Further preferably, the molar ratio of the compound represented by formula (IV) to the base additive is 1:1 to 1:3; Further preferably, the pressure of the hydrogen is 10-70 atm; Further preferably, the molar ratio of the catalyst to the compound represented by formula (IV) is 0.001:1 to 0.05:1; Further preferably, the temperature of the asymmetric reaction is 15 to 150°C, preferably 15°C, 50°C, 80°C, 100°C, 120°C, or 150°C; further preferably, the time of the asymmetric reaction is 5 to 24°C; further preferably, the asymmetric hydrogenation reaction is carried out in an inert gas atmosphere.

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