Ligand, catalyst, chiral alcohol and synthesis method of chiral alcohol

Abstract

The invention relates to a ligand, a catalyst, chiral alcohol and a synthesis method thereof, and belongs to the technical field of chemical synthesis. The ligand is shown as the result of the ligand A. The catalyst is formed by complexing the ligand A and a transition metal precursor. The catalyst is used for preparing chiral alcohol. The chiral alcohol prepared by catalysis of the catalyst has the advantages of high product yield, high ee value, low cost and the like. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a pentadentate ligand, a catalyst, a chiral alcohol and a synthesis method thereof. Background Art

[0002] Chiral alcohols and their derivatives are widely present in natural products, bioactive molecules and clinical drug molecules (or their key intermediates). In recent years, the enantioselective synthesis of chiral cyclic alcohols has developed rapidly. It has a good application value in the field of asymmetric catalysis. However, many existing asymmetric hydrogenation methods for synthesizing chiral alcohols are limited by the difficulty of catalyst synthesis, high catalytic cost, low catalytic efficiency and other limitations, which violate the concept of green economy.

[0003] Chiral alcohols and their derivatives are widely present in natural products and bioactive molecules, such as cannabidiol, Sakuranetin, and Myristinin A. In addition, chiral alcohols and their derivatives are present in many drugs (or their intermediates), such as Faropenem medoxomil and Larotrectinib. Therefore, chiral alcohols have important uses in the field of medicinal chemistry.

[0004] Although some important progress has been made in the synthesis of chiral alcohols, it is still very important to develop more practical, efficient, and asymmetric synthesis methods with higher product yields and enantioselectivities. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0006] In a first aspect, the present invention provides a ligand.

[0007] A ligand having a structure as shown in Ligand A or its enantiomer or diastereomer:

[0008]

[0009] Among them, R 7 Selected from

[0010] In the structural formula of the ligand, tBu represents tert-butyl, Cy represents cyclohexyl, R 6 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic aryl;

[0011] Each of the R 6 are independently selected from substituted or unsubstituted C6-C 20 Aryl (e.g., C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, C11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20 aryl) or a substituted or unsubstituted 6-20 membered heterocyclic aryl (e.g., a substituted or unsubstituted 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered heterocyclic aryl).

[0012] In some embodiments, each of the R 6 and substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted phenanthrenyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted biphenyl, or substituted or unsubstituted heteroaryl: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl 1,2,3-oxadiazolyl, 1,2,3-thiazolyl, 1,3-thiazolyl, 2,4-thiazolyl, 3,5-thiazolyl, pyridazinyl ... , 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzo[d][1,3]dioxetane, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl) 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl.

[0013] In some embodiments, each of the R6 The heteroaryl group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0014] In some embodiments, each of the R 6 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl, C 10 Straight chain alkyl), C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl, C 10 branched alkyl), fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -NR 19 R 20 、-S-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -S-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight-chain alkyl) substituted; said R 19 , R 20 Each independently selected from C1-C 10Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl) or C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 In some preferred embodiments, each of the R 6 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl), C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 branched alkyl).

[0015] In some embodiments, the ligand includes ligand B or an enantiomer or diastereomer thereof, ligand C or an enantiomer or diastereomer thereof, ligand D or an enantiomer or diastereomer thereof, ligand E or an enantiomer or diastereomer thereof, ligand H or an enantiomer or diastereomer thereof, ligand J or an enantiomer or diastereomer thereof, ligand K or an enantiomer or diastereomer thereof, ligand L or an enantiomer or diastereomer thereof:

[0016]

[0017] Among them, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from R 6 .

[0018] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic aryl.

[0019] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from substituted or unsubstituted C6-C 20 Aryl (e.g., C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20 aryl) or a substituted or unsubstituted 6-20 membered heterocyclic aryl (e.g., a substituted or unsubstituted 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered heterocyclic aryl).

[0020] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl, C 10 Straight chain alkyl), C3-C 10Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl, C 10 branched alkyl), fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -NR 19 R 20 、-S-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -S-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight-chain alkyl) substituted; said R 19 , R 20 Each independently selected from C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl) or C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 branched alkyl).

[0021] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11, each of the R 12 , each of the R 13 , each of the R 14 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl) or C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 branched alkyl).

[0022] In some embodiments, any of the aforementioned substituted or unsubstituted C3-C 10 The branched alkyl groups are independently selected from the following substituted or unsubstituted groups: isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,3-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl, 4,4-dimethylhexyl, C9 branched alkyl groups and C10 branched alkyl groups. 10 of branched chain alkyl.

[0023] In some embodiments, the ligand includes at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1d or its enantiomer or diastereomer, ligand 1e or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, ligand 1h or its enantiomer or diastereomer:

[0024]

[0025] In some preferred embodiments, the ligand is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, and ligand 1h or its enantiomer or diastereomer.

[0026] In some more preferred embodiments, the ligand is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, and ligand 1g or its enantiomer or diastereomer.

[0027] In a second aspect, the present invention provides a catalyst.

[0028] A catalyst, which is obtained by complexing a transition metal precursor with the ligand described in the first aspect; the transition metal precursor is at least one of [Ru(C6H6)Cl2]2, [Ru(p-cymene)Cl2]2, [Ru(p-cymene)l2]2 or Ru(Me-allyl)2(COD).

[0029] In some embodiments, the method for preparing the catalyst includes: mixing the ligand and the transition metal precursor in a solvent, performing a complex reaction, and obtaining the catalyst.

[0030] In some embodiments, the solvent includes at least one of a mixed solvent of toluene and methanol, a mixed solvent of toluene and ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and tetrahydrofuran.

[0031] In some embodiments, the volume ratio of the mixed solvent of toluene and methanol is 1:2-2:1. In some embodiments, the volume ratio of the mixed solvent of toluene and methanol is 1:1.

[0032] In some embodiments, the volume ratio of the mixed solvent of toluene and ethanol is 1:2-2:1. In some embodiments, the volume ratio of the mixed solvent of toluene and ethanol is 1:1.

[0033] In some embodiments, the temperature of the complexation reaction is 20° C.-130° C. In some embodiments, the temperature of the complexation reaction is 20° C., 30° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., 100° C., 110° C., 120 or 130° C. In some embodiments, the temperature of the complexation reaction is 100° C.

[0034] In some embodiments, the reaction time of the complex reaction is 2 hours to 10 hours. In some embodiments, the reaction time of the complex reaction is 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours. In some embodiments, the reaction time of the complex reaction is 3 hours.

[0035] In some embodiments, the molar ratio of the transition metal precursor to the ligand in the complex reaction is 0.5:1.00-0.5:1.50. In some embodiments, the molar ratio of the transition metal precursor to the ligand in the complex reaction is 0.5:1.05, 0.5:1.10, 0.5:1.15, 0.5:1.20, 0.5:1.25, 0.5:1.30, 0.5:1.35, 0.5:1.40, 0.5:1.45 or 0.5:1.50. In some embodiments, the molar ratio of the transition metal precursor to the ligand in the complex reaction is 0.5:1.05.

[0036] In some embodiments, 0.25-1.0 mmol of the transition metal precursor is added per 1 ml of the solvent in the complex reaction. In some embodiments, 0.25 mmol, 0.3 mmol, 0.4 mmol, 0.5 mmol, 0.6 mmol, 0.7 mmol, 0.8 mmol, 0.9 mmol or 1.0 mmol of the transition metal precursor is added per 1 ml of the solvent in the complex reaction. In some embodiments, 0.5 mmol of the transition metal precursor is added per 1 ml of the solvent in the complex reaction.

[0037] In some embodiments, the method for preparing the catalyst further comprises performing a first post-treatment after the complexation reaction is completed, and the first post-treatment comprises: removing the solvent.

[0038] In some embodiments, removing the solvent in the first post-treatment comprises volatilizing the solvent or removing the solvent by rotary evaporation; or removing the solvent in the first post-treatment comprises adding purified water to precipitate solids, filtering and then drying.

[0039] In a third aspect, the present invention provides a method for synthesizing a chiral alcohol compound represented by formula II.

[0040] A method for synthesizing a chiral alcohol compound represented by formula II, comprising:

[0041]

[0042] In the presence of the catalyst of the second aspect, the compound represented by formula I reacts with hydrogen to obtain the chiral alcohol compound represented by formula II;

[0043] in,

[0044] Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 1 is selected from substituted or unsubstituted alkyl groups.

[0045] In some embodiments, the reaction is carried out in an alcohol solvent.

[0046] In some preferred embodiments, the alcohol solvent is selected from at least one of methanol, ethanol, tert-butanol, and isopropanol.

[0047] In some more preferred embodiments, the alcohol solvent is isopropanol.

[0048] In some embodiments, Ar is selected from substituted or unsubstituted C6-C 20 Aryl (e.g., substituted or unsubstituted: C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20 aryl) or a substituted or unsubstituted 6-20 membered heterocyclic aryl (e.g., a substituted or unsubstituted 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered heterocyclic aryl).

[0049] In some embodiments, the Ar is independently selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted tetrahydronaphthyl, substituted or unsubstituted phenanthrenyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted biphenyl, or substituted or unsubstituted heteroaryl: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2 -oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is in no way limited to these bicyclic rings: benzo[d][1,3]dioxetyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl), imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl.

[0050] In some embodiments, the heteroaryl group in Ar comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0051] In some embodiments, the R 1 Selected from substituted or unsubstituted C1-C 10 Straight chain alkyl (e.g., substituted or unsubstituted C1 straight chain alkyl, substituted or unsubstituted C2 straight chain alkyl, substituted or unsubstituted C3 straight chain alkyl, substituted or unsubstituted C4 straight chain alkyl, substituted or unsubstituted C5 straight chain alkyl, substituted or unsubstituted C6 straight chain alkyl, substituted or unsubstituted C7 straight chain alkyl, substituted or unsubstituted C8 straight chain alkyl, substituted or unsubstituted C9 straight chain alkyl or substituted or unsubstituted C 10 Straight chain alkyl), substituted or unsubstituted C3-C 10branched alkyl (e.g., substituted or unsubstituted C3 branched alkyl, substituted or unsubstituted C4 branched alkyl, substituted or unsubstituted C5 branched alkyl, substituted or unsubstituted C6 branched alkyl, substituted or unsubstituted C7 branched alkyl, substituted or unsubstituted C8 branched alkyl, substituted or unsubstituted C9 branched alkyl or substituted or unsubstituted C 10 branched alkyl), substituted or unsubstituted C3-C 10 Cycloalkyl (e.g., substituted or unsubstituted C3 cycloalkyl, substituted or unsubstituted C4 cycloalkyl, substituted or unsubstituted C5 cycloalkyl, substituted or unsubstituted C6 cycloalkyl, substituted or unsubstituted C7 cycloalkyl, substituted or unsubstituted C8 cycloalkyl, substituted or unsubstituted C9 cycloalkyl or substituted or unsubstituted C 10 cycloalkyl).

[0052] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from R 6 .

[0053] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 6 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from substituted or unsubstituted C6-C 20 Aryl (e.g., substituted or unsubstituted: C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20aryl) or a substituted or unsubstituted 6-20 membered heterocyclic aryl (e.g., a substituted or unsubstituted 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19- or 20-membered heterocyclic aryl).

[0054] In some embodiments, the substitution in the substituted aryl in Ar means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl, C 10 Straight chain alkyl), C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl, C 10 branched alkyl), fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -NR 15 R 16 、-S-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -S-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight-chain alkyl) substituted; said R 15 , R 16 Each independently selected from C1-C 10Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl) or C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 branched chain alkyl).

[0055] In some embodiments, the R 1 The substituted C1-C 10 Straight chain alkyl, substituted C3-C 10 Branched alkyl, substituted C3-C 10 The substitution in the cycloalkyl group is independently that at least one hydrogen atom is replaced by fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -NR 17 R 18 、-S-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -S-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight-chain alkyl) substituted; said R 17 , R 18 Each independently selected from C1-C 10Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl) or C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 branched alkyl).

[0056] In some embodiments, the R 1 Selected from unsubstituted C1-C 10 Straight chain alkyl, unsubstituted C3-C 10 Branched alkyl, unsubstituted C3-C 10 Cycloalkyl.

[0057] In some embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 6 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl, C 10 Straight chain alkyl), C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl, C 10 branched alkyl), fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl) (C3-C 10The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -NR 19 R 20 、-S-(C3-C 10 Branched alkyl) (C3-C 10 The branched alkyl group may be a C3 branched alkyl group, a C4 branched alkyl group, a C5 branched alkyl group, a C6 branched alkyl group, a C7 branched alkyl group, a C8 branched alkyl group, a C9 branched alkyl group or a C 10 Branched alkyl), -S-(C1-C 10 Straight chain alkyl) (wherein C1-C 10 The straight chain alkyl group may be a C1 straight chain alkyl group, a C2 straight chain alkyl group, a C3 straight chain alkyl group, a C4 straight chain alkyl group, a C5 straight chain alkyl group, a C6 straight chain alkyl group, a C7 straight chain alkyl group, a C8 straight chain alkyl group, a C9 straight chain alkyl group or a C 10 Straight-chain alkyl) substituted; said R 19 , R 20 Each independently selected from C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl or C 10 Straight chain alkyl) or C3-C 10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl or C 10 branched chain alkyl).

[0058] In some preferred embodiments, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 6 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl (e.g., C1 straight chain alkyl, C2 straight chain alkyl, C3 straight chain alkyl, C4 straight chain alkyl, C5 straight chain alkyl, C6 straight chain alkyl, C7 straight chain alkyl, C8 straight chain alkyl, C9 straight chain alkyl, C 10 Straight chain alkyl), C3-C10 Branched alkyl (e.g., C3 branched alkyl, C4 branched alkyl, C5 branched alkyl, C6 branched alkyl, C7 branched alkyl, C8 branched alkyl, C9 branched alkyl, C 10 branched alkyl).

[0059] In some embodiments, any of the aforementioned substituted or unsubstituted C3-C 10 The branched alkyl groups are independently selected from the following substituted or unsubstituted groups: isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 2,2-dimethylhexyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,3-dimethylhexyl, 3,4-dimethylhexyl, 3,5-dimethylhexyl, 4,4-dimethylhexyl, C9 branched alkyl groups and C10 branched alkyl groups. 10 of branched chain alkyl.

[0060] In some embodiments, the ligand in the catalyst includes at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1d or its enantiomer or diastereomer, ligand 1e or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, ligand 1h or its enantiomer or diastereomer:

[0061]

[0062] In some preferred embodiments, the ligand in the catalyst is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, and ligand 1h or its enantiomer or diastereomer.

[0063] In some more preferred embodiments, the ligand in the catalyst is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, and ligand 1g or its enantiomer or diastereomer.

[0064] In some embodiments, the compound represented by Formula I includes at least one of Compound I-1 to Compound I-20:

[0065]

[0066] In some embodiments, the chiral alcohol compound of Formula II includes at least one of compounds II-1 to II-20:

[0067]

[0068] In some embodiments, the reaction to obtain the chiral alcohol compound of Formula II is carried out in the presence of a basic reagent.

[0069] In some embodiments, the alkaline reagent includes at least one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and cesium carbonate.

[0070] In some embodiments, the alkaline agent is at least one of sodium tert-butoxide and potassium tert-butoxide.

[0071] In some embodiments, the molar ratio of the alkaline agent to the compound of formula I is 1.0:100.0-3.0:100.0. In some embodiments, the molar ratio of the alkaline agent to the compound of formula I is 1.0:100.0, 1.5:100.0, 2.0:100.0, 2.5:100.0 or 3.0:100.0.

[0072] In some embodiments, the reaction to obtain the chiral alcohol compound of Formula II is carried out in the absence of oxygen.

[0073] In some embodiments, the reaction to obtain the chiral alcohol compound of Formula II is carried out under a reaction atmosphere containing nitrogen or an inert gas.

[0074] In some embodiments, the ratio of the volume of nitrogen or inert gas to the volume of hydrogen in the reaction to obtain the chiral alcohol compound of formula II is 0:100.0-10.0:90.0. In some embodiments, the ratio of the volume of nitrogen or inert gas to the volume of hydrogen in the reaction to obtain the chiral alcohol compound of formula II is 0:100.0, 1.0:99.0, 2.0:98.0, 3.0:97.0, 4.0:96.0, 5.0:95.0, 6.0:94.0, 7.0:93.0, 8.0:92.0, 9.0:91.0 or 10.0:90.0.

[0075] In some embodiments, the hydrogen pressure in the reaction to obtain the chiral alcohol compound of formula II is 10 atm-70 atm. In some embodiments, the hydrogen pressure in the reaction to obtain the chiral alcohol compound of formula II is 10 atm, 15 atm, 20 atm, 25 atm, 30 atm, 35 atm, 40 atm, 45 atm, 50 atm, 55 atm, 60 atm, 65 atm or 70 atm.

[0076] In some embodiments, the inert gas includes at least one of helium, neon, argon, krypton, and xenon.

[0077] In some embodiments, the molar ratio of the catalyst to the compound of formula I in the reaction of obtaining the chiral alcohol compound of formula II is 0.001:1.000-0.010:1.000. In some embodiments, the molar ratio of the catalyst to the compound of formula I in the reaction of obtaining the chiral alcohol compound of formula II is 0.001:1.000, 0.002:1.000, 0.003:1.000, 0.004:1.000, 0.005:1.000, 0.006:1.000, 0.007:1.000, 0.008:1.000, 0.009:1.000 or 0.010:1.000.

[0078] In some embodiments, the reaction temperature of the reaction to obtain the chiral alcohol compound of formula II is 15° C.-150° C. In some embodiments, the reaction temperature of the reaction to obtain the chiral alcohol compound of formula II is 15° C., 20° C., 25° C., 30° C., 35° C., 40° C., 45° C., 50° C., 55° C., 60° C., 65° C., 70° C., 75° C., 80° C., 85° C., 90° C., 95° C., 100° C., 105° C., 110° C., 115° C., 120° C., 125° C., 130° C., 135° C., 140° C., 145° C., or 150° C.

[0079] In some embodiments, the reaction time of the reaction to obtain the chiral alcohol compound of formula II is 5 hours to 24 hours. In some embodiments, the reaction time of the reaction to obtain the chiral alcohol compound of formula II is 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours.

[0080] In some embodiments, the synthesis method for obtaining the chiral alcohol compound of formula II also includes performing a second post-treatment after the reaction is completed; the second post-treatment includes: releasing hydrogen, adding ethyl acetate to dilute, adding water to quench, separating the organic phase and the aqueous phase, washing the aqueous phase with ethyl acetate, combining the organic phases, drying the combined organic phases, spinning the solvent to dryness, and purifying.

[0081] Beneficial Effects

[0082] Compared with the prior art, a certain embodiment of the present invention has at least one of the following beneficial effects:

[0083] (1) Compared with other solvents, using isopropanol as a solvent is more conducive to improving the yield and ee value of the obtained product.

[0084] (2) Compared with other alkaline reagents, the use of sodium tert-butoxide or potassium tert-butoxide is more conducive to improving the yield and ee value of the obtained product.

[0085] (3) Compared with other catalysts, the use of catalyst 2a, catalyst 2b, catalyst 2c, catalyst 2f, catalyst 2g or catalyst 2h is more conducive to improving the yield and ee value of the obtained product; among them, catalyst 2b, catalyst 2f, catalyst 2g or catalyst 2h is preferred.

[0086] (4) Compared with using a complex of iridium metal and a ligand as a catalyst, using a complex of ruthenium metal and a ligand provided by the present invention as a catalyst is more conducive to improving the product yield and ee value of the chiral alcohol represented by formula II.

[0087] (5) Compared with the ferrocene ligand, which has only one -P(R 6 )2 substituent, using the ferrocene structure with two -P(R 6 )2 substituent, is more conducive to improving the catalytic activity of the catalyst for the reaction of preparing the chiral alcohol shown in formula II from the compound shown in formula I.

[0088] (6) Compared with using the complex of [Ir(COD)Cl]2 and ligand L9 as a catalyst, using the catalyst provided by the present invention is more conducive to improving the product yield and ee value of the chiral alcohol represented by formula II.

[0089] (7) The catalyst provided by the present invention has low cost, high catalytic activity, can catalyze a variety of substrates, and has unexpected technical effects.

[0090] (8) The catalyst provided by the present invention has high catalytic activity, and still has excellent catalytic activity when the feed molar ratio of the catalyst to the compound represented by the formula I is as low as 0.001:1.000.

[0091] Terminology

[0092] In the present invention, "room temperature" refers to ambient temperature, which may be 10°C-40°C, or 20°C-30°C; in some embodiments, it is 22°C-28°C; in some embodiments, it is 24°C-26°C; in some embodiments, it is 25°C.

[0093] In the above text of the present invention, regardless of whether the words "about" or "approximately" are used, all the numbers disclosed herein are approximate values. Based on the disclosed numbers, the value of each number may vary by less than ±10% or reasonable differences considered by those skilled in the art, such as ±1%, ±2%, ±3%, ±4% or ±5%.

[0094] The terms "optional", "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur.

[0095] 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.

[0096] The "C1-C 10 "Includes C1-C 10 Any integer point value in, such as C1, C2, C3, C4, C5, C6, C7, C8, C9, or C 10 . "C6-C 12 ”, “C3-C 10 ”, “C3-C 12 ”, “C4-C 12 ”, “C3-C 10 ”, “C6-C 20 " and so on, that is, "C6-C 12 "Includes C6-C 12 Any integer point value in, such as C6, C7, C8, C9, C 10 , C 11 , C 12 .

[0097] "Alkyl" is a hydrocarbon containing normal carbon atoms, secondary carbon atoms, tertiary carbon atoms, or ring carbon atoms. For example, an alkyl group can have 1 to 10 carbon atoms (i.e., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, or C 10alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH (CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 or octyl (-(CH2)7CH3).

[0098] An "alkenyl group" is a group containing at least one unsaturated site, i.e., a carbon-carbon sp 2 For example, an alkenyl group can have 2 to 10 carbon atoms (C2-C 10 alkenyl), 2 to 12 carbon atoms (C2-C 12 alkenyl, such as C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, C6 alkenyl, C7 alkenyl, C8 alkenyl, C9 alkenyl, C 10 Alkenyl, C 11 Alkenyl or C 12Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH), allyl (-CHCH=CH), cyclopentenyl (-C5H7) and 5-hexenyl (-CHCHCHCHCH=CH), propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl or pentadecenyl, etc.

[0099] "Alkynyl" is a hydrocarbon containing a positive, secondary, tertiary, or cyclic carbon atom with at least one unsaturated site, i.e., a carbon-carbon sp triple bond. For example, an alkynyl group can have 2 to 10 carbon atoms (C2-C 10 Alkynyl), 2 to 12 carbon atoms (C2-C 12 Alkynyl, for example C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl, C6 alkynyl, C7 alkynyl, C8 alkynyl, C9 alkynyl, C 10 Alkynyl, C 11 Alkynyl or C 12 Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C=CH), propargyl (-CH2C=CH), or the like.

[0100] The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Bicyclic or tricyclic ring systems may include fused rings, bridged rings and spirocyclic rings. Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In one embodiment, the carbocyclyl contains 3-10 carbon atoms, such as C 3- C 10 In another embodiment, the carbocyclic group contains 3-8 carbon atoms, such as C 3- C8 carbocyclyl; In another embodiment, the carbocyclyl contains 3-6 carbon atoms, such as C 3- In another embodiment, the monocyclic carbocyclic group contains 4-8 carbon atoms, such as C 4- C8 monocyclic carbocyclic group; In another embodiment, the monocyclic carbocyclic group contains 4-6 carbon atoms, such as C 4-C6 monocyclic carbocyclic radical.The example of carbocyclic radical group further comprises, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.Described carbocyclic radical group is optionally substituted by one or more substituents described in the present invention. The example of carbocyclyl group further includes, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.When the structure clearly needs a linking group, the Markush variable listed for the group should be understood as a linking group.For example, if the structure needs a linking group and the Markush group definition for the variable lists "carbocyclyl", it should be understood that the subcarbocyclyl group connected by the "carbocyclyl" representative.

[0101] "Aryl" means an aromatic hydrocarbon group derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms (e.g., C6 aryl, C7 aryl, C8 aryl, C9 aryl, C 10 Aryl, C 11 Aryl, C 12 Aryl, C 13 Aryl, C 14 Aryl, C 15 Aryl, C 16 Aryl, C 17 Aryl, C 18 Aryl, C 19 Aryl or C 20 The aryl group may be 6 to 14 carbon atoms or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from benzene (e.g., phenyl), substituted benzene, naphthyl, anthracenyl, tetrahydronaphthyl, phenanthrenyl, fluorenyl or biphenyl or the like.

[0102] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 3-20 ring atoms, 4-20 ring atoms, or 5-15 ring atoms, or 6-10 ring atoms, or 9 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and at least one aromatic ring contains one or more heteroatoms, wherein each ring system contains 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle", "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a heteroaryl composed of 5-20 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In some embodiments, heteroaryl is a heteroaryl composed of 5-12 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 5-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In other embodiments, heteroaryl is a bicyclic heteroaryl consisting of 9-10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In other embodiments, heteroaryl is a heteroaryl consisting of 9 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. In other embodiments, heteroaryl is a monocyclic heteroaryl consisting of 5-6 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, sulfur and oxygen. And the heteroaryl can be substituted or unsubstituted, and the aryl group can be independently and optionally substituted by one or more substituents described in the present invention.

[0103] Examples of heteroaromatic rings include, but are not limited to, the following monocyclic heteroaryl groups: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazin ...1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodiazolyl, 1,3,4-thiodia 3,5-triazinyl, oxadiazolyl, thiadiazolyl, triazinyl, etc.; also include the following bicyclic heteroaryl, but are by no means limited to these bicyclic: benzo[d][1,3]dioxetane, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), benzopyrazolyl, benzopyrrolyl, benzoxazolyl 1,3-benzodioxolyl, benzisoxazolyl, isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo[1,2-a]pyridinyl, pyrazol[1,5-a]pyridinyl, pyrazol[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0104] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In one embodiment, the cycloalkyl contains 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms); in another embodiment, the cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0105] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0106] The term "substituted" refers to alkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, "substituted C1-C 10 Alkyl", "substituted C6-C 20 Aryl", "substituted arylalkyl", "substituted C1-C 20 "Heterocycle" and "substituted carbocyclyl" refer to C1-C2- 10 Alkyl, C6-C 20 Aryl, Arylalkyl, C1-C 20 Heterocyclic, carbocyclic. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be the same or different at each position.

[0107] The term "unsubstituted" means that the designated group bears no substituents.

[0108] The term "jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k, and any natural number between the two. For example, "3-8 atoms" or "3-8-membered", "3-6 atoms" or "3-6-membered", "5-10 atoms" or "5-10-membered", "5-6 atoms" or "5-6-membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For another example, piperidinyl is a 6-atom heterocyclic group or a 6-membered heterocyclic group, and pyridinyl is a 6-atom heteroaryl group or a 6-membered heteroaryl group.

[0109] The term "jk pieces", "jk yuan" or "C j -C k " wherein j and k are independently any non-zero natural numbers, 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.

[0110] "Heterocycle" or "heterocyclyl" include by way of example and are not limited to those described in: Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28 and J. Am. Chem. Soc. (1960) 82:5566. In a particular embodiment of the invention, "heterocycle" includes "carbocycle" as defined herein, in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by heteroatoms (e.g., O, N or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyl groups include, for example, heterocycles substituted with any of the substituents disclosed herein including carbonyl.

[0111] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-8 ring atoms (1-7 carbon atoms and 1-4 heteroatoms selected from N, O, P or S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2); in another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-6 ring atoms (1-5 carbon atoms and 1-4 heteroatoms selected from N, O, P or S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7-12 ring atoms (1-11 carbon atoms and 1-4 heteroatoms selected from N, O, P or S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2). The heterocyclyl groups are optionally substituted by one or more substituents described herein.

[0112] The ring atoms of the heterocyclic group can be carbon groups or heteroatom groups. Wherein, the -CH2- group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group is optionally substituted by one or more substituents described herein.

[0113] The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 20 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur or oxygen atom.

[0114] Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidinyl), thiazolyl, tetrahydrothiophenyl, thiooxytetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthyl, indolyl, indolene, quinolyl, isoquinolyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenolic flavinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl pyridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatoacyl, and bis-tetrahydrofuranyl.

[0115] The term "V / V" means volume ratio.

[0116] The term "wt%" means percent by mass.

[0117] "Me" means methyl; "Et" means ethyl; "Ph" means phenyl; t "Bu" means tert-butyl; i Pr" or "i-Pr" means isopropyl; n "Pr" or "n-Pr" means n-propyl; n "Hex" or "n-Hex" means n-hexyl; "n-C4H9" means n-butyl; "n-C5H 11 " represents n-pentyl; "n-C6H 13" represents n-hexyl; "-OAc" represents acetoxy (i.e., CH3COO-); "n-butyl" represents n-butyl; "n-amyl" represents n-pentyl; "OBz" represents benzoyl; and "Cy" represents cyclohexyl. [Ru(C6H6)Cl2]2 represents dichlorophenylruthenium (II) dimer. [Ru(p-cymene)Cl2]2 represents dichloro(p-methylisopropylbenzene)ruthenium (II) dimer. [Ru(p-cymene)l2]2 represents diiodo(p-methylisopropylbenzene)ruthenium (II) dimer. Ru(Me-allyl)2(COD) represents bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium (II).

[0118] The term "equiv" or "eq" means equivalent. If a substance in the reaction is positioned at 1.0 equiv, the molar ratio of each substance is the equivalent ratio.

[0119] The term "M" means mol / L.

[0120] The term "atm" means standard atmospheric pressure; for example, "10 atm" means 10 times standard atmospheric pressure.

[0121] The term "ee value" means enantiomeric excess.

[0122] As used herein, the term "treatment" refers to clinical intervention intended to alter the natural course of a disease in the individual being treated. Desired therapeutic effects include, but are not limited to, preventing the onset or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating the disease state, and alleviating or improving prognosis.

[0123] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means 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 may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0124] In this application, "composition" can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical art. All methods include the step of combining the active ingredient with a carrier that constitutes one or more accessory ingredients. Usually, the composition is prepared by uniformly and thoroughly combining the active compound with a liquid carrier, a finely divided solid carrier, or both.

[0125] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used throughout this article, "each... and... are independently", "... and... are each independently", and "... and... are respectively independently" are interchangeable and should be understood in a broad sense, which can 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. DETAILED DESCRIPTION

[0126] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0127] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention or by conventional methods in the art.

[0128] Example 1: Preparation of Compound M

[0129]

[0130] Preparation method:

[0131] Reaction 1-1:

[0132] 1) Under N2 protection, (R)-Ugi's amine (50 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and n-BuLi (n-butyl lithium) (28 mL, 2.2 M) was added dropwise at 0°C. After the addition was completed, the temperature was raised to room temperature and reacted for 1 hour to obtain reaction solution 1.

[0133] 2) Anhydrous tetramethylethylenediamine (TMEDA) (60 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and n-BuLi (30 mL, 2.2 M) was added dropwise at 0°C. After the addition was completed, the mixture was kept warm for 0.5 hours to obtain reaction solution 2. The reaction solution 2 was then aspirated with a syringe and added dropwise to the reaction solution 1 in 1) at 0°C. After the addition was completed, the mixture was heated to room temperature for 5 hours to obtain reaction solution 3.

[0134] 3) At 0°C, add phosphine trichloride (130 mmol) to the reaction solution 2) in step 2. After the addition, raise the temperature to room temperature and react for 12 h. Add 2-naphthylmagnesium bromide (i.e. R6 -MgBr) tetrahydrofuran solution (1.0 M, 150 ml) was added and reacted at room temperature for 5 hours to obtain reaction solution 4.

[0135] After the reaction was completed, saturated ammonium chloride was added dropwise to the reaction solution 4 at 0° C. The solution was separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined and concentrated, slurried with ethanol, filtered, and dried to obtain a crude compound which was directly used for the next step of reaction.

[0136] Reaction 1-2: Under N2 protection, 10 g of the crude compound obtained in reaction 1-1 was dissolved in 10 mL of acetic anhydride, and the temperature was raised to 100°C for reaction for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and allowed to stand for crystallization. The mixture was filtered, the filter cake was washed with petroleum ether, and vacuum dried to obtain dark red crystalline compound M, which was directly subjected to the next step of reaction.

[0137] Example 2: Preparation of Compound N

[0138]

[0139] Preparation method:

[0140] Reaction 2-1: 1) Under N2 protection, (R)-Ugi's amine (50 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL), and n-BuLi (28 mL, 2.2 M) was added dropwise at 0°C. After the addition was completed, the mixture was heated to room temperature and reacted for 1 hour to obtain reaction solution 5.

[0141] 2) Dissolve anhydrous tetramethylethylenediamine (TMEDA) (60 mmol) in anhydrous tetrahydrofuran (10 mL), cool to 0°C, and drop n-BuLi (30 mL, 2.2 M). After the addition is complete, keep warm and react for 0.5 hours to obtain reaction solution 6. Then, the above reaction solution 6 is sucked out with a syringe, and added dropwise to the reaction solution in 1) at 0°C. After the addition is complete, heat to room temperature and react for 5 hours to obtain reaction solution 7.

[0142] 3) At 0°C, add phosphine trichloride (130 mmol) to the reaction solution 7 in 2), and after adding, raise the temperature to room temperature and react for 12 h; add 3,5-di-tert-butylphenylmagnesium bromide (i.e. R 6 -MgBr) tetrahydrofuran solution (1.0 M, 150 ml) was added and reacted at room temperature for 5 hours to obtain reaction solution 8.

[0143] After the reaction was completed, saturated ammonium chloride was added dropwise to the reaction solution at 0° C. to quench. After separation, the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined and concentrated, slurried with ethanol, filtered, and dried to obtain a crude product for direct next step reaction.

[0144] Reaction 2-2: Under N2 protection, 10 g of the crude product obtained in reaction 2-1 was dissolved in 10 mL of acetic anhydride, and the temperature was raised to 100°C for reaction for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and allowed to stand for crystallization. The mixture was filtered, the filter cake was washed with petroleum ether, and vacuum dried to obtain dark red crystalline compound N, which was directly subjected to the next step of reaction.

[0145] Example 3: Preparation of ligand

[0146]

[0147] General preparation method: Compound O (1.0 eq), compound P (3.0 eq) and triethylamine (3.0 eq) were mixed in methanol, reacted at 80° C. for 10 h, the reaction solution was concentrated, and then column chromatography was performed to obtain compound A (ligand A).

[0148] According to the general preparation method of Example 3, ligands 1b, 1c, 1d, 1e, 1f, 1c and 1d were prepared respectively. g , Ligand 1h:

[0149] (1) Preparation of ligand 1b: R 6 is phenyl, compound P is Ligand 1b is

[0150]

[0151] Ligand 1b characterization data:

[0152] [α]D20=-283.50(c=1.0,CH2Cl2).

[0153] 1H NMR (400MHz, CDCl3) δ7.49-7.42(m,3H),7.36-7.33(m,3H),7.27-7.24(m,12H),7.19-7.16(m,2H),4.37(s,2H),4.20-3.99(m,4H),3.81(d,J=1 3.9Hz,1H),3.64(dd,J=14.3,5.5Hz,3H),3.52-3.38(m,1H),2.96(d,J=17.4Hz,1H),2.74(d,J=17.4Hz,1H),1.30(d,J=6.7Hz,3H),0.86(s,9H).

[0154] 13C NMR (151MHz, CDCl3) δ173.7,139.5,138.9,138.5,136.4,134.9,134.8133.6,133.5,133.3,133.2,132.5,132.4129.4,128.7128.6,1 28.5,128.5128.3,128.3128.3128.2128.297.1,75.4,75.073.9,73.473.0,72.571.6,71.3,63.2,60.0,51.3,48.5,33.4,27.0,19.4.

[0155] 31 P NMR(162MHz, CDCl3)δ-17.97(s),-25.43(s).

[0156] HRMS(ESI)Calcd for C 44 H 48 FeN2O2P2[M+H] + :755.2613,Found:755.2610.

[0157] (2) Preparation of ligand 1c: R 6 is phenyl, compound P is Ligand 1c is Characterization data of ligand 1c:

[0158] 1 H NMR (600MHz, CDCl3) δ7.39(t,J=7.6Hz,2H),7.22-7.13(m,13H),7.11-7.05(m,5H),4.40(s,1H),4.28(s,1H),4.15(d,J=5.8Hz,1H),4.03(d,J= 13.2Hz,2H),3.83(s,1H),3.60(s,1H),3.49(d,J=11.3Hz,1H),3.39(s, 1H),3.25-3.03(m,1H),2.20(s,1H),1.23(d,J=6.0Hz,3H),0.47(s,9H).

[0159] 13C NMR (151MHz, CDCl3) δ140.2,140.2,139.4,139.3,138.5,138.4,137.2,137.1,135.4,135.2,133.8,133.7,13 3.2,133.1,132.2,132.1,99.1,76.5,75.8,75.0,74.2,72.8,72.63,71.3,63.1,62.2,49.8,33.2,27.1,19.0.

[0160] 31 P NMR(243MHz, CDCl3)δ-17.63(s),-25.33(s).

[0161] (3) Preparation of ligand 1d: R in compound O 6 is phenyl, compound P is Ligand 1d is

[0162] Ligand 1d characterization data:

[0163] 1 H NMR(600MHz, CDCl3)δ7.38(s,2H),7.30-7.15(m,13H),7.11(s,3H),7.05(s, 2H),6.98(s,2H),6.73(s,1H),6.31(s,1H),4.41(s,1H),4.33(s,1H),4.18(s ,1H),4.09(s,2H),4.06(s,1H),3.92(s,1H),3.89(s,1H),3.62(s,1H),3.52( s,1H),2.77(d,J=16.4Hz,1H),2.67(d,J=18.2Hz,1H),1.36(d,J=4.8Hz,3H).

[0164] 13 C NMR (151MHz, CDCl3) δ142.2,140.7,139.9,139.8,139.1,139.1,138.5,138.4 ,137.0,136.9,135.3,135.1,133.7,133.6,133.4,133.2,132.4,132.3,129. 4,128.7,128.6,128.6,128.3,128.2,127.6,126.7,125.4,123.6,75.3,75.2,74.9,74.8,73.8,73.3,73.2,72.8,72.3,71.9,71.7,71.5,64.9,51.4,51.3.

[0165] 31 P NMR(243MHz, CDCl3)δ-17.81(s),-26.28(s).

[0166] (4) Preparation of ligand 1f: Compound O is compound N, and compound P is Ligand 1f is

[0167] Characterization data of ligand 1f: MS (ESI): 1203.8 [M+H] +.

[0168] (5) Preparation of ligand 1g: Compound O is compound M, and compound P is Ligand 1g is

[0169] Characterization data of ligand 1g: MS (ESI): 955.3 [M+H] +.

[0170] (6) Preparation of ligand 1h: R in compound O 6 is phenyl, compound P is Ligand 1h

[0171] Characterization data of ligand 1h: MS (ESI): 781.3 [M+H] +.

[0172] Example 4: Preparation of ligand

[0173]

[0174] General preparation method: Compound Q (1.0 eq), compound R (3.0 eq) and triethylamine (3.0 eq) were mixed in methanol, reacted at 80°C for 10 h, the reaction solution was concentrated, and then column chromatography was performed to obtain compound S (ligand).

[0175] According to the general preparation method of Example 4 above, ligand 1a and ligand 1e were prepared respectively:

[0176] (1) Preparation of ligand 1a: Compound R is Ligand 1a is Characterization data of ligand 1a: [α] D 20 =+288.60 (c=1.0, CH2Cl2).

[0177] 1H NMR (600MHz, CDCl3) δ7.48-7.44(m,3H),7.38-7.30(m,3H),7.28-7.24(m,12H), 7.21-7.15(m,2H),4.38(s,2H),4.11(d,J=11.5Hz,3H),4.02(s,1H),3.77(d,J= 11.2Hz,1H),3.65(t,J=7.5Hz,3H),3.50-3.29(m,1H),2.93(d,J=17.5Hz,1H),2 .73(d,J=17.5Hz,1H),1.29(d,J=6.7Hz,3H),1.25(t,J=7.1Hz,1H),0.91(s,9H).

[0178] 13 C NMR (151MHz, CDCl3) δ173.9,139.6,139.5,139.0,138.9,138.4,136.5,134.9134.7,133.6,133.5,133.3,133.2,132.5,132.4,129.4, 128.7,128.5,128.3,128.2,128.1,97.175.6,75.0,73.9,73.3,73.0,72.5,71.6,71.2,63.6,60.2,51.2,48.0,33.4,27.0,19.2,14.2.

[0179] 31 P NMR(243MHz, CDCl3)δ-17.97(s),-25.62(s).

[0180] HRMS(ESI)Calcd for C 44 H 48 FeN2O2P2[M+H] + :755.2613,Found:755.2606.

[0181] (2) Preparation of ligand 1e: Compound R is Ligand 1e is Ligand 1e characterization data:

[0182] 1H NMR (600MHz, CDCl3) δ7.40 (t, J = 6.7Hz, 2H), 7.18-7.12 (m, 13H), 7.06-6.97 (m, 7H),6.89(t,J=7.0Hz,1H),6.63(d,J=7.4Hz,1H),4.38(s,1H),4.33(s,2H),4. 11(s,2H),4.06(d,J=13.3Hz,1H),3.90(s,1H),3.83(s,1H),3.65(s,1H),3.46 (s,1H),2.70(d,J=16.1Hz,1H),2.56(d,J=16.1Hz,1H),1.41(d,J=6.4Hz,3H).

[0183] 13 C NMR (151MHz, CDCl3) δ142.9,141.2,140.0,139.9,139.3,139.2,138.7,138 .6,137.6,137.5,135.3,135.2,133.8,133.6,133.5,133.4,132.5,132.4,1 29.4,128.8,128.6,128.3,128.2,127.7,126.5,125.4,123.8,98.7,76.8,75.6,75.5,74.4,73.3,73.273.0,72.6,72.5,71.4,62.6,50.9,39.1,21.3.

[0184] 31 P NMR(243MHz, CDCl3)δ-17.67(s),-24.90(s).

[0185] Example 5: Preparation of Catalyst

[0186] General method: Separately take the ligand (0.105 mmol) and [Ru(C6H6)Cl2]2 (0.05 mmol) and mix them with solvent N,N-dimethylformamide (2.0 mL), stir at 90°C for 3.0 hours, and then remove the solvent by rotary evaporation to obtain the catalyst.

[0187] Take ligand 1a, ligand 1b, ligand 1c, ligand 1d, ligand 1e, ligand 1f, ligand 1g, and ligand 1h as ligands respectively, and prepare catalyst 2a (corresponding to ligand 1a as ligand), catalyst 2b (corresponding to ligand 1b as ligand), catalyst 2c (corresponding to ligand 1c as ligand), catalyst 2d (corresponding to ligand 1d as ligand), catalyst 2e (corresponding to ligand 1e as ligand), catalyst 2f (corresponding to ligand 1f as ligand), catalyst 2g (corresponding to ligand 1g as ligand), and catalyst 2h (corresponding to ligand 1h as ligand) according to the general method of Example 5.

[0188] The characterization data of each catalyst are shown in Table 1.

[0189] Table 1: Characterization data of each catalyst

[0190]

[0191]

[0192] Example 6: Investigation of the preparation of chiral alcohols

[0193]

[0194] (1) Investigation of solvents

[0195] Under nitrogen atmosphere, 2.0 mmol of the compound represented by formula I-1 and catalyst 2a (2.0×10 -3 mmol) and alkaline reagent (0.02mmol, see Table 2) were mixed with 2.0mL of solvent (preliminary vacuum deoxygenation treatment, see Table 2), and then transferred to a pressure autoclave, under the reaction atmosphere of 99%vol hydrogen and 1% nitrogen, the hydrogen pressure was set to 10atm, and the reaction was carried out at a temperature of 25°C for 20h, followed by slow release of hydrogen, addition of 4.0mL of ethyl acetate for dilution, quenching with 8.0mL of water, separation of the organic phase, washing the aqueous phase twice with 2.0mL of ethyl acetate, and then combining the organic phases, drying with anhydrous sodium sulfate, and spinning the solvent to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the chiral alcohol shown in Formula II-1. The results are shown in Table 2.

[0196] Table 2: Investigation of solvents

[0197] test catalyst Solvents Alkaline reagents Yield (%) ee(%) 1 2a i-PrOH Potassium tert-butoxide 99 -83 2 2a MeOH Potassium tert-butoxide 0 - 3 2a THF Potassium tert-butoxide 0 - 4 2a Dioxane Potassium tert-butoxide 0 -

[0198] (2) Investigation of alkaline reagents

[0199] Under nitrogen atmosphere, 2.0 mmol of the compound represented by formula I-1 and catalyst 2a (2.0×10 -3mmol) and alkaline reagent (0.02mmol, see Table 3) were mixed with 2.0mL of solvent (preliminary vacuum deoxygenation treatment, see Table 3), and then transferred to a pressure autoclave, under the reaction atmosphere of 99%vol hydrogen and 1% nitrogen, the hydrogen pressure was set to 10atm, and the reaction was carried out at a temperature of 25°C for 20h, followed by slow release of hydrogen, addition of 4.0mL of ethyl acetate for dilution, quenching with 8.0mL of water, separation of the organic phase, washing the aqueous phase twice with 2.0mL of ethyl acetate, and then combining the organic phases, drying with anhydrous sodium sulfate, and spinning the solvent to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the chiral alcohol shown in Formula II-1. The results are shown in Table 3.

[0200] Table 3: Investigation of alkaline reagents

[0201]

[0202] (3) Investigation of catalyst

[0203] Under nitrogen atmosphere, 2.0 mmol of the compound represented by formula I-1 and a catalyst (2.0×10 -3 mmol, see Table 4) and alkaline reagent (0.02mmol, see Table 4) were mixed with 2.0mL of solvent (preliminary vacuum deoxygenation treatment, see Table 4), and then transferred to a pressure autoclave, under the reaction atmosphere of 99% vol hydrogen and 1% nitrogen, the hydrogen pressure was set to 10atm, and the reaction was carried out at a temperature of 25°C for 20h, followed by slow release of hydrogen, addition of 4.0mL of ethyl acetate for dilution, quenching with 8.0mL of water, separation of the organic phase, washing the aqueous phase twice with 2.0mL of ethyl acetate, and then combining the organic phases, drying with anhydrous sodium sulfate, and spinning the solvent to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the chiral alcohol shown in formula II-1. The results are shown in Table 4.

[0204] Table 4: Investigation of catalysts

[0205]

[0206]

[0207] Conclusion: From the results in Tables 2-4, we can see that:

[0208] (1) Compared with other solvents, using isopropanol as a solvent is more conducive to improving the yield and ee value of the obtained product.

[0209] (2) Compared with other alkaline reagents, the use of sodium tert-butoxide or potassium tert-butoxide is more conducive to improving the yield and ee value of the obtained product.

[0210] (3) Compared with other catalysts, the use of catalyst 2a, catalyst 2b, catalyst 2c, catalyst 2f, catalyst 2g or catalyst 2h is more conducive to improving the yield and ee value of the obtained product; among them, catalyst 2b, catalyst 2f, catalyst 2g or catalyst 2h is preferred.

[0211] Example 7: Preparation of chiral alcohols II-1 to II-20

[0212]

[0213] General synthesis method: Under an inert gas atmosphere, 2.0 mmol of the compound shown in formula I, catalyst 2b (0.002 mmol) and sodium tert-butoxide (0.02 mmol) are mixed with 2.0 mL of isopropanol (preliminarily vacuum deoxygenated), and then transferred to a pressure autoclave. Under a reaction atmosphere of 99% vol hydrogen and 1% nitrogen, the hydrogen pressure is set to 10 atm, and the reaction is carried out at a temperature of 25°C for 20 h. Subsequently, the hydrogen is slowly released, 4.0 mL of ethyl acetate is added for dilution, and the mixture is quenched with 8.0 mL of water. The organic phase is separated, and the aqueous phase is washed twice with 2.0 mL of ethyl acetate. The organic phases are then combined, dried over anhydrous sodium sulfate, and the solvent is spin-dried to obtain a crude product, which is subsequently separated and purified by column chromatography to obtain a chiral alcohol shown in formula II.

[0214] The general synthesis method of Example 7 was used, and different compounds of Formula I were used according to the target product. The remaining operations were the same as the general synthesis method of Example 7 to prepare chiral alcohols of Formula II-1 to Formula II-20. The yields and ee values ​​of the obtained products are shown in Table 5:

[0215]

[0216] The characterization data of each chiral alcohol are shown in Table 5.

[0217] Table 5: Characterization data, yield and ee value results

[0218]

[0219]

[0220] Example 8: Preparation of chiral alcohols II-1 to II-20

[0221] The amount of catalyst 2b in Example 7 was changed to 0.0002 mmol, and the remaining operations were the same as Example 7 to prepare chiral alcohols represented by formula II-1 to formula II-20. The yields and ee values ​​of the obtained products are shown in Table 6.

[0222] Table 6: Yield and ee value results

[0223] Chiral alcohol Yield ee value Formula II-1 99％ 95％ Formula II-2 97％ 92％ Formula II-3 97％ 94％ Formula II-4 98％ 92％ Formula II-5 98％ 93％ Formula II-6 97％ 91％ Formula II-7 97％ 88％ Formula II-8 98％ 94％ Formula II-9 96％ 90％ Formula II-10 96％ 89％ Formula II-11 97％ 91％ Formula II-12 99％ 86％ Formula II-13 98％ 87％ Formula II-14 98％ 86％ Formula II-15 97％ 85％ Formula II-16 96％ 96％ Formula II-17 98％ 95％ Formula II-18 98％ 87％ Formula II-19 97％ 95％ Formula II-20 99％ 97％

[0224] Conclusion: The catalyst provided by the present invention has high catalytic activity, and still has excellent catalytic activity when the feed molar ratio of the catalyst to the substrate is as low as 0.001:1.000.

[0225] Comparative Example 1: Complex of iridium metal and ligand as catalyst

[0226] Preparation of catalyst 3: Ligand 1b (1.05 mmol) and [Ir(COD)Cl]2 (0.05 mmol) were mixed with solvent N,N-dimethylformamide (2.0 mL) respectively, stirred at 90°C for 3.0 hours, and then the solvent was removed by rotary evaporation to obtain catalyst 3.

[0227] Preparation of chiral alcohols: Referring to the “General Synthesis Method” of Example 7, catalyst 2b was replaced with catalyst 3 of Comparative Example 1 to prepare chiral alcohols of formula II-1 to formula II-20, respectively. The product yields and ee values ​​are shown in Table 7.

[0228] Table 7: Catalytic activity results of catalyst 3

[0229]

[0230]

[0231] Conclusion: Compared with using a complex of iridium metal and a ligand as a catalyst, using a complex of ruthenium metal and a ligand provided by the present invention as a catalyst is more conducive to improving the product yield and ee value of the chiral alcohol represented by formula II.

[0232] Comparative Example 2: Investigation of functional groups in ligands

[0233] Preparation of catalyst: Take ligand L9 (1.05 mmol) and [Ru(C6H6)Cl2]2 (0.05 mmol) and mix them with solvent N,N-dimethylformamide (2.0 mL), stir at 90°C for 3.0 hours, and then remove the solvent by rotary evaporation to obtain catalyst 4.

[0234] Preparation of chiral alcohols: Referring to the “General Synthesis Method” of Example 7, catalyst 2b was replaced with catalyst 4 of Comparative Example 2 to prepare chiral alcohols of formula II-1 to formula II-20, respectively. The product yields and ee values ​​are shown in Table 8.

[0235] The structure of ligand L9:

[0236] Table 8: Catalytic activity results of catalyst 4

[0237]

[0238] Conclusion: Compared with the ferrocene with ligand, there is only one -P(R 6 )2 substituent, using the ferrocene structure with two -P(R 6 )2 substituted ligands are used to prepare catalysts, which is more conducive to improving the catalytic activity of the catalyst for the reaction of preparing chiral alcohols shown in formula II from compounds shown in formula I. Comparative Example 3: Complexes of iridium metal and ligands as catalysts (refer to f-phamidol-L9 in CN114874134B)

[0239]

[0240] In an argon atmosphere, [Ir(COD)Cl]2(3.8*10 -3 mmol) and ligand L9 (8.4*10 -3 mmol) was dissolved in 4mL isopropanol and stirred for 3 hours at room temperature to obtain an orange clear catalyst solution (catalyst 5 solution). 200uL of the orange solution was taken with a microsyringe and added to a mixed system of the compound (3.82mmol), isopropanol (4mL) and potassium tert-butoxide (4.3mg, 0.038mmol) shown in Formula I. The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 50atm hydrogen was filled and reacted at 60°C for 24 hours. After the reaction was completed, the gas in the autoclave was slowly released and concentrated under reduced pressure to obtain a chiral alcohol shown in Formula II.

[0241] Chiral alcohols of formula II-1 to formula II-20 were prepared respectively according to the method of the above comparative example 3. The product yields and ee values ​​are shown in Table 9.

[0242] Table 9: Catalytic activity results of f-phamidol-L9

[0243] Chiral alcohol Yield (%) ee value (%) Formula II-1 99 -81 Formula II-2 99 -83 Formula II-3 97 -82 Formula II-4 98 -80 Formula II-5 99 -81 Formula II-6 97 -83 Formula II-7 96 -79 Formula II-8 98 -82 Formula II-9 97 -83 Formula II-10 98 -84 Formula II-11 96 -85 Formula II-12 95 -83 Formula II-13 97 -79 Formula II-14 98 -75 Formula II-15 99 -77 Formula II-16 98 -82 Formula II-17 99 -83 Formula II-18 97 -80 Formula II-19 98 -86 Formula II-20 99 -84

[0244] Conclusion: Compared with using the complex of [Ir(COD)Cl]2 and ligand L9 as a catalyst, the catalyst provided by the present invention is more conducive to improving the product yield and ee value of the chiral alcohol represented by formula II.

[0245] Test Example 1: Catalyst Storage Stability Study

[0246] Preparation of Catalyst 5: [Ir(COD)Cl]2(3.8*10 -3 mmol) and ligand L9 (8.4*10 - 3 mmol) was dissolved in 4 mL of isopropanol and stirred at room temperature for 3 hours to obtain an orange clear catalyst solution (catalyst 5 solution), and then the solvent was removed by rotary evaporation to obtain catalyst 5.

[0247] Study on the storage stability of catalysts: Catalyst 2b, catalyst 2f, catalyst 2g, catalyst 3, catalyst 4, catalyst 5 solution, and catalyst 5 were sealed and placed under accelerated conditions (40°C, 75% RH) for 0 days and 6 months, respectively. After being taken out, formula II-1 was prepared according to the method of Example 7. The results are shown in Table 10.

[0248] Table 10: Catalyst storage stability study

[0249]

[0250] Conclusion: The catalyst provided by the present invention has good stability under accelerated conditions and has unexpected technical effects.

[0251] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A ligand, characterized in that The structure of the ligand is shown as ligand A or its enantiomer or diastereomer: Among them, R 7 Selected from In the structural formula of the ligand, tBu represents tert-butyl, Cy represents cyclohexyl, R 6 is selected from substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic aryl; Each of the R 6 are independently selected from substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 6- to 20-membered heterocyclic aromatic group.

2. The ligand according to claim 1, wherein each of said R 6 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl, C3-C 10 Branched alkyl, fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl), -NR 19 R 20 、-S-(C3-C 10 Branched alkyl), -S-(C1-C 10 Straight-chain alkyl) substituted; said R 19 , R 20 Each independently selected from C1-C 10 Straight chain alkyl or C3-C 10 Branched chain alkyl; Preferably, each of the R 6 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl, C3-C 10 Substituted with branched alkyl groups; Optionally, the ligand comprises ligand B or an enantiomer or diastereomer thereof, ligand C or an enantiomer or diastereomer thereof, ligand D or an enantiomer or diastereomer thereof, ligand E or an enantiomer or diastereomer thereof, ligand H or an enantiomer or diastereomer thereof, ligand J or an enantiomer or diastereomer thereof, ligand K or an enantiomer or diastereomer thereof, ligand L or an enantiomer or diastereomer thereof: in, Each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from R 6 .

3. The ligand according to any one of claims 1 to 2, wherein the ligand comprises at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1d or its enantiomer or diastereomer, ligand 1e or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, ligand 1h or its enantiomer or diastereomer: Preferably, the ligand is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, ligand 1h or its enantiomer or diastereomer; More preferably, the ligand is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, and ligand 1g or its enantiomer or diastereomer.

4. A catalyst, characterized in that The catalyst is obtained by complexing a transition metal precursor with the ligand described in any one of claims 1 to 3; the transition metal precursor is at least one of [Ru(C6H6)Cl2]2, [Ru(p-cymene)Cl2]2, [Ru(p-cymene)l2]2 or Ru(Me-allyl)2(COD); Optionally, the preparation method of the catalyst comprises: mixing the ligand and the transition metal precursor in a solvent, performing a complexation reaction, and obtaining the catalyst; Optionally, the solvent includes at least one of a mixed solvent of toluene and methanol, a mixed solvent of toluene and ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and tetrahydrofuran; Optionally, the volume ratio of the mixed solvent of toluene and methanol is 1:2-2:1 or 1:1; Optionally, the volume ratio of the mixed solvent of toluene and ethanol is 1:2-2:1 or 1:1; Optionally, the temperature of the complexation reaction is 20°C-130°C or 100°C; Optionally, the reaction time of the complex reaction is 2 hours to 10 hours or 3 hours; Optionally, the molar ratio of the transition metal precursor to the ligand in the complex reaction is 0.5:1.00-0.5:1.50 or 0.5:1.05; Optionally, in the complexation reaction, 0.25-1.0 mmol or 0.5 mmol of the transition metal precursor is added per 1 ml of the solvent; Optionally, the method for preparing the catalyst further comprises performing a first post-treatment after the complexation reaction is completed, wherein the first post-treatment comprises: removing the solvent; Optionally, removing the solvent in the first post-treatment comprises volatilizing the solvent or removing the solvent by rotary evaporation; or removing the solvent in the first post-treatment comprises adding purified water to precipitate solids, filtering and then drying.

5. A method for synthesizing a chiral alcohol compound represented by formula II, characterized in that: include: In the presence of the catalyst of claim 4, the compound of formula I reacts with hydrogen to obtain the chiral alcohol compound of formula II; in, Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, R 1 is selected from substituted or unsubstituted alkyl groups.

6. The synthesis method according to claim 5, wherein the reaction is carried out in an alcohol solvent; Preferably, the alcohol solvent is selected from at least one of methanol, ethanol, tert-butyl alcohol and isopropanol; More preferably, the alcohol solvent is isopropanol.

7. The synthesis method according to any one of claims 5 to 6, wherein Ar is selected from substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 6- to 20-membered heterocyclic aromatic group; and / or The R 1 Selected from substituted or unsubstituted C1-C 10 Straight chain alkyl, substituted or unsubstituted C3-C 10 Branched alkyl, substituted or unsubstituted C3-C 10 Cycloalkyl; and / or Each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 are independently selected from R 6 ; and / or Each of the R 6 are independently selected from substituted or unsubstituted C6-C 20 Aryl or substituted or unsubstituted 6- to 20-membered heterocyclic aromatic group.

8. The synthesis method according to any one of claims 5 to 7, wherein the substitution in the substituted aryl in Ar means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl, C3-C 10 Branched alkyl, fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl), -NR 15 R 16 、-S-(C3-C 10 branched alkyl) substituted; said R 15 , R 16 Each independently selected from C1-C 10 Straight chain alkyl or C3-C 10 branched alkyl; and / or The R 1 The substituted C1-C 10 Straight chain alkyl, substituted C3-C 10 Branched alkyl, substituted C3-C 10 The substitution in the cycloalkyl group is independently that at least one hydrogen atom is replaced by fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl), -NR 17 R 18 、-S-(C3-C 10 Branched alkyl), -S-(C1-C 10 Straight-chain alkyl) substituted; said R 17 , R 18 Each independently selected from C1-C 10 Straight chain alkyl or C3-C 10 branched alkyl; and / or The R 1 Selected from unsubstituted C1-C 10 Straight chain alkyl, unsubstituted C3-C 10 Branched alkyl, unsubstituted C3-C 10 Cycloalkyl; and / or Each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 6 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl, C3-C 10 Branched alkyl, fluorine, chlorine, bromine, iodine, -O-(C1-C 10 Straight chain alkyl), -O-(C3-C 10 Branched alkyl), -NR 19 R 20 、-S-(C3-C 10 Branched alkyl), -S-(C1-C 10 Straight-chain alkyl) substituted; said R 19 , R 20 Each independently selected from C1-C 10 Straight chain alkyl or C3-C 10 Branched chain alkyl; Preferably, each of the R 2 , each of the R 3 , each of the R 4 , each of the R 5 , each of the R 6 , each of the R 11 , each of the R 12 , each of the R 13 , each of the R 14 The substituted C6-C 20 The substitution in the aryl or substituted 6- to 20-membered heterocyclic aryl group independently means that at least one hydrogen atom is replaced by a C1-C 10 Straight chain alkyl, C3-C 10 Substituted with branched alkyl groups; Optionally, the ligand in the catalyst includes at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1d or its enantiomer or diastereomer, ligand 1e or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, ligand 1h or its enantiomer or diastereomer: Preferably, the ligand in the catalyst is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1c or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, ligand 1g or its enantiomer or diastereomer, ligand 1h or its enantiomer or diastereomer; More preferably, the ligand in the catalyst is at least one of ligand 1a or its enantiomer or diastereomer, ligand 1b or its enantiomer or diastereomer, ligand 1f or its enantiomer or diastereomer, and ligand 1g or its enantiomer or diastereomer.

9. The synthesis method according to any one of claims 5 to 8, wherein the compound represented by formula I comprises at least one of compounds I-1 to I-20: ； and / or The chiral alcohol compound of formula II includes at least one of compounds II-1 to II-20:

10. The synthesis method according to any one of claims 5 to 9, wherein the reaction to obtain the chiral alcohol compound of formula II is carried out in the presence of an alkaline reagent; Optionally, the alkaline reagent includes at least one of sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, and cesium carbonate; and / or Preferably, the alkaline agent is at least one of sodium tert-butoxide and potassium tert-butoxide; and / or Optionally, the molar ratio of the alkaline agent to the compound of formula I is 1.0:100.0-3.0:100.0; and / or Optionally, the reaction to obtain the chiral alcohol compound of formula II is carried out in the absence of oxygen; and / or Optionally, the reaction to obtain the chiral alcohol compound of formula II is carried out under a reaction atmosphere containing nitrogen or an inert gas; and / or Optionally, the ratio of the volume of nitrogen or inert gas to the volume of hydrogen in the reaction to obtain the chiral alcohol compound of formula II is 0:100.0-10.0:90.0; and / or Optionally, the hydrogen pressure in the reaction to obtain the chiral alcohol compound of formula II is 10 atm-70 atm; and / or Optionally, the inert gas comprises at least one of helium, neon, argon, krypton and xenon; and / or Optionally, in the reaction of obtaining the chiral alcohol compound of formula II, the molar ratio of the catalyst to the compound of formula I is 0.001:1.000-0.010:1.000; and / or Optionally, the reaction temperature of the reaction to obtain the chiral alcohol compound of formula II is 15° C.-150° C.; and / or Optionally, the reaction time of the reaction to obtain the chiral alcohol compound of formula II is 5 hours to 24 hours; and / or Optionally, the synthesis method for obtaining the chiral alcohol compound of formula II further comprises performing a second post-treatment after the reaction is completed; the second post-treatment comprises: Hydrogen was released, ethyl acetate was added to dilute, water was added to quench, the organic phase and the aqueous phase were separated, the aqueous phase was washed with ethyl acetate, the organic phases were combined, the combined organic phases were dried, the solvent was spin-dried, and the reaction was purified.

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