Preparation method of chiral phosphine compound

Abstract

The invention relates to a preparation method of a chiral phosphine compound, and belongs to the field of organic synthesis. The preparation method comprises the following steps: under a blue light irradiation condition, carrying out a first reaction on a compound A and a dehalogenation reagent in a first solvent to obtain a compound B; the product obtained by the preparation method provided by the invention is high in yield and high in purity, and the obtained compound B can be applied to asymmetric reduction hydrogenation and other reactions and has excellent yield and ee value. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of chemistry, and particularly relates to a method for preparing a chiral phosphine compound. Background Art

[0002] In the field of organocatalysis, on the one hand, phosphine-centered chiral compounds themselves can participate in catalytic reactions as small molecule catalysts. On the other hand, a large number of commercially available phosphine-centered chiral ligands have provided important support for related fields. In comparison, compared with chiral ligands and catalysts with carbon chiral centers, the phosphine centers of chiral phosphine compounds are often directly connected to metals or substrates, which may have better chiral induction effects. However, relative to such broad applications, its synthetic strategies seem rather inadequate. From the development of the synthesis research of phosphine chiral center compounds at present, its synthetic methods mainly focus on two aspects. Firstly, it is the relatively mature classical synthetic strategies developed in the past, and on the other hand, it is the catalytic asymmetric synthesis strategies that have developed rapidly in recent years.

[0003] The classical synthetic strategies for constructing phosphine-centered chirality mainly rely on relatively inexpensive chiral reagents for chiral induction to generate phosphine-centered chirality, and all such methods require the participation of a dose of chiral reagents. At present, the relatively well-developed classical synthetic strategies for phosphine chiral compounds mainly include chiral resolution, enantioselective derivatization reactions, chiral auxiliary induction and other strategies. Summary of the Invention

[0004] To solve the foregoing technical problems, the present invention provides the following technical solutions.

[0005] In the first aspect, the present invention provides a method for preparing a chiral phosphine compound.

[0006] A method for preparing a chiral phosphine compound, which comprises:

[0007]

[0008] Under the condition of blue light irradiation, compound A reacts with a dehalogenating reagent in a first solvent to obtain compound B;

[0009] Wherein, in compound A and compound B, "*" indicates that the P marked by it is a chiral center with S configuration or R configuration;

[0010] X is F, Cl, Br or I;

[0011] Ar is selected from a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted phenanthrene ring, a substituted or unsubstituted anthracene ring;

[0012] R 1Selected from substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzyl;

[0013] R 2 Selected from substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted styryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl;

[0014] and R 1 is different from R 2

[0015] In some embodiments, the wavelength of the blue light is 430 nm - 490 nm. In some embodiments, the wavelength of the blue light is 430 nm, 440 nm, 450 nm, 460 nm, 470 nm, 480 nm or 490 nm. In some embodiments, the wavelength of the blue light is 435 nm - 445 nm. In some embodiments, the wavelength of the blue light is 440 nm.

[0016] In some embodiments, the carbon on Ar of compound A connected to X is a chiral carbon with S configuration.

[0017] In some embodiments, the 1 substituted or unsubstituted alkyl in R 2 or R 30 is independently selected from substituted or unsubstituted C1-C 1 alkyl. In some embodiments, the 2 substituted or unsubstituted alkyl in R 20 or R 1 is independently selected from substituted or unsubstituted C1-C 2 alkyl. In some embodiments, the 10 substituted or unsubstituted alkyl in R 1 or R 2 is independently selected from substituted or unsubstituted C1-C5 alkyl. In some embodiments, the 1 substituted or unsubstituted alkyl in R 2 or R 10 is independently selected from substituted or unsubstituted groups: C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 ​Alkyl, C 15 Alkyl, C 16 Alkyl, C 17 Alkyl, C 18 Alkyl, C 19 Alkyl, C 20 Alkyl, C 21 Alkyl, C 22 Alkyl, C 23 Alkyl, C 24 Alkyl, C 25 Alkyl, C 26 Alkyl, C 27 Alkyl, C 28 Alkyl, C 29 Alkyl, C 30 Alkyl.

[0018] In some embodiments, the substituted or unsubstituted heteroaryl in said R 1 or R 2 is independently selected from substituted or unsubstituted heteroaryl having 5 to 20 ring atoms. In some embodiments, the substituted or unsubstituted heteroaryl in said R 1 or R 2 is independently selected from substituted or unsubstituted heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms.

[0019] In one embodiment, the heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0020] In some embodiments, the substituted or unsubstituted aryl in said R 2 is independently selected from substituted or unsubstituted aryl having 5 to 20 ring atoms. In some embodiments, the substituted or unsubstituted aryl in said R 2 is independently selected from substituted or unsubstituted aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms.

[0021] In some embodiments, the substituted or unsubstituted alkenyl in said R 2 includes substituted or unsubstituted C2-C 30 alkenyl. In some embodiments, the substituted or unsubstituted alkenyl in said R 2 includes substituted or unsubstituted alkenyl having the following groups: C2 alkenyl, C3 alkenyl, C4 alkenyl, C5 alkenyl, C6 alkenyl, C7 alkenyl, C8 alkenyl, C9 alkenyl, C 10 alkenyl, C 11 alkenyl, C 12 alkenyl, C 13Alkenyl, C 14 Alkenyl, C 15 Alkenyl, C 16 Alkenyl, C 17 Alkenyl, C 18 Alkenyl, C 19 Alkenyl, C 20 Alkenyl, C 21 Alkenyl, C 22 Alkenyl, C 23 Alkenyl, C 24 Alkenyl, C 25 Alkenyl, C 26 Alkenyl, C 27 Alkenyl, C 28 Alkenyl, C 29 Alkenyl, C 30 Alkenyl.

[0022] In some embodiments, the 2 substituted or unsubstituted alkenyl in R contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon-carbon double bonds.

[0023] In some embodiments, the 2 substituted or unsubstituted alkynyl in R includes substituted or unsubstituted C2-C 30 alkynyl. In some embodiments, the 2 substituted or unsubstituted alkynyl in R includes substituted or unsubstituted groups such as: C2 alkynyl, C3 alkynyl, C4 alkynyl, C5 alkynyl, C6 alkynyl, C7 alkynyl, C8 alkynyl, C9 alkynyl, C 10 alkynyl, C 11 alkynyl, C 12 alkynyl, C 13 alkynyl, C 14 alkynyl, C 15 alkynyl, C 16 alkynyl, C 17 alkynyl, C 18 alkynyl, C 19 alkynyl, C 20 alkynyl, C 21 alkynyl, C 22 alkynyl, C 23 alkynyl, C 24 alkynyl, C 25 alkynyl, C 26 alkynyl, C 27 alkynyl, C 28 alkynyl, C 29 alkynyl, C 30 alkynyl.

[0024] In some embodiments, the 2The substituted or unsubstituted alkynyl group described therein contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon-carbon triple bonds.

[0025] In some embodiments, the substitutions in the Ar independently represent that one or more hydrogen atoms are each substituted by at least one of thiophenyl, F, Cl, Br, I, methyl, nitrile group, -COOCH3.

[0026] In some embodiments, the R 1 or R 2 substitutions independently represent that one or more hydrogen atoms are each substituted by at least one of F, Cl, Br, I, cyano group, nitro group, methyl formate group, ethyl acetate group, trifluoromethyl group, methoxy group, phenyl group, ethyl acetate group, aldehyde group, methyl group, tert-butyl group, among others.

[0027] In some embodiments, compound A, compound B, R 1 and R 2 are selected from any one of the following groups:

[0028] (1) R 1 is tert-butyl;

[0029] R 2 is selected from: (1-1) methyl, cyclopentyl, (1-2) phenyl,

[0030] R 3 is selected from F, Cl, Br, I, cyano group, nitro group, methyl formate group, ethyl acetate group, trifluoromethyl group, methoxy group, phenyl group;

[0031] R 4 is selected from F, Cl, Br, I, cyano group, methyl formate group, ethyl acetate group, aldehyde group, trifluoromethyl group, methoxy group, phenyl group;

[0032] R 5 is selected from F, Cl, Br, I, cyano group, methyl formate group, ethyl acetate group, aldehyde group, trifluoromethyl group, methoxy group, phenyl group;

[0033] R 6 is selected from F, Cl, Br, I, cyano group, methyl formate group, ethyl acetate group, aldehyde group, trifluoromethyl group, methoxy group, phenyl group, methyl group, tert-butyl group;

[0034] Compound A is selected from:

[0035]

[0036] Compound B correspondingly is selected from:

[0037]

[0038] (2)R 1 is phenyl;

[0039] R 2 is selected from (2-1) methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane,

[0040] Compound A is selected from:

[0041]

[0042] Compound B correspondingly is selected from:

[0043]

[0044] (3)R 1 is selected from isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

[0045] R 2 is phenyl;

[0046] Compound A is selected from:

[0047]

[0048] Compound B correspondingly is selected from:

[0049]

[0050] In some embodiments, the dehalogenating reagent includes at least one of NaH, SiHCl3, triethylamine, and CuCl. In some preferred embodiments, the dehalogenating reagent is triethylamine.

[0051] In some embodiments, the molar ratio of the feed of compound A to the dehalogenating reagent is 1:1 to 2:1.

[0052] In some embodiments, the reaction temperature of the first reaction is -35°C to 40°C. In some embodiments, the reaction temperature of the first reaction is -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C or 40°C.

[0053] In some embodiments, the first solvent includes at least one of acetonitrile, ethylene glycol dimethyl ether, ethyl acetate, and 1,2-dichloroethane.

[0054] In some embodiments, the method for preparing Compound B further includes performing a first post-treatment after the first reaction.

[0055] In some embodiments, the first post-treatment includes: rotary evaporation of the solvent under reduced pressure and purification.

[0056] In some embodiments, the method for preparing Compound B further includes the preparation of Compound A, and Compound A is prepared according to the preparation method described in the second aspect.

[0057] In some embodiments, Compound A and Compound B are respectively selected from the following groups:

[0058]

[0059]

[0060]

[0061] Second aspect, the present invention provides a method for preparing Compound A. A method for preparing Compound A includes:

[0062]

[0063] In an inert gas or nitrogen atmosphere, Compound C undergoes a second reaction with a halogenating reagent in a second solvent in the presence of a catalyst I, a molecular sieve, and a ligand to obtain Compound A;

[0064] Among them, the meanings of Compound A, R 1 , R 2 are respectively as shown in Group (3) in the preparation method described in the first aspect, and the meanings of "*" and X in Compound A are respectively as shown in "*" and X in Compound A in the preparation method described in the first aspect.

[0065] In some embodiments, R 1 of Compound C and Compound B in the second reaction is tert-butyl, and R 2 of Compound C and Compound B is selected from the R 2 group in Group (1) in the preparation method described in the first aspect, and "*" in the obtained Compound B represents a chiral center where the indicated P is in the S configuration.

[0066] In some embodiments, R 1 of Compound C and Compound B in the second reaction is phenyl, and R 2 of Compound C and Compound B is selected from the R 2 group in Group (2-1) of Group (2) in the preparation method described in the first aspect, and "*" in the obtained Compound B represents a chiral center where the indicated P is in the S configuration.

[0067] In some embodiments, the R of compound C and compound B in the second reaction 1 is selected from the R of group (3) of the preparation method described in the first aspect 1 group, and the R of compound C and compound B 2 is selected from the R of group (3) of the preparation method described in the first aspect 2 group. In the obtained compound B, "*" indicates that the P marked by it is a chiral center with an S configuration.

[0068] In some embodiments, the R of compound C and compound B in the second reaction 1 is phenyl, and the R of compound C and compound B 2 is selected from the R of group (2-2) of group (2) of the preparation method described in the first aspect 2 group. In the obtained compound B, "*" indicates that the P marked by it is a chiral center with an R configuration.

[0069] In some embodiments, the catalyst I includes at least one of CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2, and Zn(OTf)2. In some preferred embodiments, the catalyst I is Cu(OTf)2.

[0070] In some embodiments, the ligand includes

[0071] wherein, R 7 is selected from isopropyl, phenyl, benzyl or tert-butyl. Preferably, R 7 is tert-butyl;

[0072] R 8 is selected from isopropyl, phenyl, benzyl or tert-butyl. Preferably, R 8 is phenyl;

[0073] Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl. Preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl.

[0074] In some embodiments, the second solvent includes one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, methanol, etc. In some preferred embodiments, the second solvent is ethyl acetate.

[0075] In some embodiments, the halogenating reagent includes at least one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-dichloro-5,5-dimethylhydantoin. In some preferred embodiments, the halogenating reagent is 1,3-dichloro-5,5-dimethylhydantoin.

[0076] In some embodiments, the molar ratio of the catalyst I to the compound C in the feeding is 1:100 to 50:100. In some embodiments, the molar ratio of the catalyst I to the compound C in the feeding is 1:100, 5:100, 10:100, 15:100, 20:100, 25:100, 30:100, 35:100, 40:100, 45:100, or 50:100. In some preferred embodiments, the molar ratio of the catalyst I to the compound C in the feeding is 10:100.

[0077] In some embodiments, the molar ratio of the catalyst I to the ligand in the feeding is 1:1 to 1:2. In some embodiments, the molar ratio of the catalyst I to the ligand in the feeding is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2. In some preferred embodiments, the molar ratio of the catalyst I to the ligand in the feeding is 1:1.2.

[0078] In some embodiments, the reaction temperature of the second reaction is -78°C to 25°C. In some embodiments, the reaction temperature of the second reaction is -78°C, -70°C, -60°C, -50°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, or 25°C. In some preferred embodiments, the reaction temperature of the second reaction is -35°C, 0°C, or 25°C;

[0079] In some embodiments, the reaction time of the second reaction is 0.5 - 10 h. In some embodiments, the reaction time of the second reaction is 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, or 10 h. In some preferred embodiments, the reaction time of the second reaction is 0.5 h or 1 h;

[0080] In some embodiments, the method for preparing the compound A further includes performing a second post-treatment after the second reaction.

[0081] In some embodiments, the second post-treatment includes: quenching the reaction, extracting with ethyl acetate, drying the organic phase layer with anhydrous MgSO4, evaporating the solvent, and purification. In some embodiments, the second post-treatment includes: quenching the reaction by adding water, extracting with ethyl acetate, drying the organic phase layer with anhydrous MgSO4, evaporating the solvent, and purification.

[0082] In some embodiments, the particle size of the molecular sieve is 3 Å, 4 Å or 5 Å;

[0083] In some embodiments, the inert gas includes at least one of helium, neon, argon, krypton or xenon.

[0084] In some embodiments, compound A is selected from:

[0085]

[0086] In a third aspect, the present invention provides a method for preparing compound B.

[0087] A method for preparing compound B, which includes preparing compound A according to the preparation method described in the second aspect, and then preparing compound B according to the preparation method described in the first aspect.

[0088] In a fourth aspect, the present invention provides a method for preparing compound B.

[0089] A method for preparing compound B, which includes:

[0090]

[0091] In an inert gas or nitrogen atmosphere, compound C reacts with a halogenating reagent in a third solvent in the presence of catalyst II, a molecular sieve and a ligand to obtain compound B;

[0092] Among them, the meanings of compound B, R 1 , R 2 are as shown in group (1), group (2) or group (3) in the preparation method described in the first aspect, the meaning of X is as shown in the preparation method described in the first aspect, and "*" in compound B indicates that the marked P is a chiral center with R configuration or S configuration.

[0093] In some embodiments, R 1 of compound C and compound B in the third reaction is tert-butyl, and R 2 of compound C and compound B is selected from the R 2 group in group (1) of the preparation method described in the first aspect, and "*" in the obtained compound B indicates that the marked P is a chiral center with R configuration.

[0094] In some embodiments, the R of compound C and compound B in the third reaction 1 is phenyl, and the R of compound C and compound B 2 is selected from the R groups of group (2-1) of group (2) of the preparation method described in the first aspect 2 The "*" in the resulting compound B indicates that the P marked by it is a chiral center with an R configuration.

[0095] In some embodiments, the R of compound C and compound B in the third reaction 1 is selected from the R groups of group (3) of the preparation method described in the first aspect 1 The R of compound C and compound B 2 is selected from the R groups of group (3) of the preparation method described in the first aspect 2 The "*" in the resulting compound B indicates that the P marked by it is a chiral center with an R configuration.

[0096] In some embodiments, the R of compound C and compound B in the third reaction 1 is phenyl, and the R of compound C and compound B 2 is selected from the R groups of group (2-2) of group (2) of the preparation method described in the first aspect 2 The "*" in the resulting compound B indicates that the P marked by it is a chiral center with an S configuration.

[0097] In some embodiments, the particle size of the molecular sieve is 3 Å, 4 Å or 5 Å.

[0098] In some embodiments, the ligand is wherein R 7 is selected from isopropyl, phenyl, benzyl or tert-butyl, and preferably, R 7 is tert-butyl; compound C and compound B are selected from the following groups:

[0099]

[0100]

[0101]

[0102] In some embodiments, the ligand is wherein R 8 is selected from isopropyl, phenyl, benzyl or tert-butyl, and preferably, R 8is phenyl; Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl. Preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl; The compound C and the compound B are selected from the following groups:

[0103]

[0104] In some embodiments, the catalyst II includes at least one of CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2, Zn(OTf)2. In some preferred embodiments, the catalyst II is Cu(OTf)2.

[0105] In some embodiments, the ligand includes

[0106] wherein, R 7 is selected from isopropyl, phenyl, benzyl or tert-butyl. Preferably, R 7 is tert-butyl;

[0107] R 8 is selected from isopropyl, phenyl, benzyl or tert-butyl. Preferably, R 8 is phenyl;

[0108] Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl. Preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl.

[0109] In some embodiments, the third solvent includes one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, methanol, etc. In some preferred embodiments, the second solvent is ethyl acetate;

[0110] In some embodiments, the halogenating agent includes at least one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin. In some preferred embodiments, the halogenating agent is 1,3-dichloro-5,5-dimethylhydantoin.

[0111] In some embodiments, the molar ratio of the catalyst II to the compound C in the feed is 1:100 to 50:100. In some embodiments, the molar ratio of the catalyst II to the compound C in the feed is 1:100, 5:100, 10:100, 15:100, 20:100, 25:100, 30:100, 35:100, 40:100, 45:100 or 50:100. In some preferred embodiments, the molar ratio of the catalyst II to the compound C in the feed is 5:100.

[0112] In some embodiments, the molar ratio of the catalyst II to the ligand in the feed is 1:1 to 1:2. In some embodiments, the molar ratio of the catalyst II to the ligand in the feed is 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2. In some preferred embodiments, the molar ratio of the catalyst II to the ligand in the feed is 1:1.2.

[0113] In some embodiments, the reaction temperature of the third reaction is -78°C to 25°C. In some embodiments, the reaction temperature of the third reaction is -78°C, -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, -40°C, -35°C, -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C or 25°C. In some preferred embodiments, the reaction temperature of the third reaction is -35°C, 0°C or 25°C;

[0114] In some embodiments, the reaction time of the third reaction is 0.5 - 10 h. In some embodiments, the reaction time of the third reaction is 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 7 h, 8 h, 9 h or 10 h. In some preferred embodiments, the reaction time of the third reaction is 0.5 h or 1 h.

[0115] In some embodiments, the method for preparing the compound B further includes performing a third post-treatment after the third reaction.

[0116] In some embodiments, the third post-treatment includes: quenching the reaction, extracting with ethyl acetate, drying the organic phase layer with anhydrous MgSO4, evaporating the solvent, and purifying. In some embodiments, the third post-treatment includes: quenching the reaction with water, extracting with ethyl acetate, drying the organic phase layer with anhydrous MgSO4, evaporating the solvent, and purifying.

[0117] In some embodiments, the inert gas includes at least one of helium, neon, argon, krypton or xenon.

[0118] In a fifth aspect, the present invention provides a compound.

[0119] A compound selected from Compound B or Compound W,

[0120]

[0121] wherein,

[0122] in Compound B or Compound W, "*" represents a chiral center where the indicated P is in the S configuration or the R configuration;

[0123] Ar is selected from a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted phenanthrene ring, a substituted or unsubstituted anthracene ring;

[0124] R 1 is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted benzyl group;

[0125] R 2 is selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted styryl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group;

[0126] and R 1 is different from R 2 ;

[0127] The → in Compound W represents a coordination bond.

[0128] In some embodiments, Compound B, R 1 and R 2 are selected from any one of groups (1), (2), and (3) in the preparation method described in the first aspect; the definitions of Ar, R 1 and R 2 in Compound W are the same as those of Ar, R 1 and R 2 in Compound B, respectively.

[0129] In some embodiments, Compound B is selected from

[0130]

[0131] In some embodiments, Compound W is selected from:

[0132] In a sixth aspect, the present invention provides a method for preparing Compound C.

[0133] A method for preparing a compound C, which comprises:

[0134]

[0135] Under the conditions of nitrogen or an inert atmosphere, compound D undergoes a fourth reaction with compound E in a fourth solvent in the presence of catalyst III and a first base to obtain compound C;

[0136] Wherein, the R 1 、R 2 、and Ar in compound C are respectively selected from any one of groups (1), (2), and (3) in the preparation method described in the first aspect, the R 1 、R 2 and the corresponding Ar in compound B;

[0137] The Y is selected from F, Cl, Br, or I.

[0138] In some embodiments, the catalyst III includes at least one of tetrakis(triphenylphosphine)palladium and cuprous iodide.

[0139] In some embodiments, the first base includes at least one of cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, and sodium phosphate.

[0140] In some embodiments, the fourth solvent includes at least one of toluene, acetonitrile, and N,N-dimethylformamide.

[0141] In some embodiments, the molar ratio of the feed of compound D to compound E is 1.5:1.0 to 1.0:1.0. In some embodiments, the molar ratio of the feed of compound D to compound E is 1.5:1.0, 1.4:1.0, 1.3:1.0, 1.2:1.0, 1.1:1.0, or 1.0:1.0. In some embodiments, the molar ratio of the feed of compound D to compound E is 1.5:1.0.

[0142] In some embodiments, the molar ratio of the feed of catalyst III to compound E is 0.05:1 to 0.1:1.0. In some embodiments, the molar ratio of the feed of catalyst III to compound E is 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, or 0.1:1.0. In some embodiments, the molar ratio of the feed of catalyst III to compound E is 0.1:1.0.

[0143] In some embodiments, the molar ratio of the first base to compound E in the feed is 1.5:1.0 to 1.0:1.0. In some embodiments, the molar ratio of the first base to compound E in the feed is 1.5:1.0, 1.4:1.0, 1.3:1.0, 1.2:1.0, 1.1:1.0 or 1.0:1.0. In some embodiments, the molar ratio of the first base to compound E in the feed is 1.5:1.0.

[0144] In some embodiments, the reaction solvent for the fourth reaction is 100°C - 120°C. In some embodiments, the reaction solvent for the fourth reaction is 100°C, 105°C, 110°C, 115°C or 120°C. In some embodiments, the reaction solvent for the fourth reaction is 110°C;

[0145] In some embodiments, the method for preparing compound C further includes performing a fourth post-treatment after the fourth reaction.

[0146] In some embodiments, the fourth post-treatment includes: quenching the reaction with water, extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

[0147] In some embodiments, compound D, compound E and compound C are selected from the following groups:

[0148]

[0149]

[0150] In a seventh aspect, the present invention provides a method for preparing compound C.

[0151] A method for preparing compound C, which includes:

[0152]

[0153] Under nitrogen or inert atmosphere conditions, compound F is mixed with a second base and a fifth solvent, and then mixed with compound G to undergo a fifth reaction to obtain compound H; or under nitrogen or inert atmosphere conditions, compound F reacts with compound G in a sixth solvent in the presence of a third base, catalyst IV and a ligand to undergo a sixth reaction to obtain compound H;

[0154] Under nitrogen or inert atmosphere conditions, compound H reacts with boron tribromide in a seventh solvent to undergo a seventh reaction to obtain compound C;

[0155] Wherein, R 1 、R 2 are selected from R 1 、R2 ;

[0156] In compounds F, H, and C, the Ar group is selected from the corresponding Ar groups in compound B of group (1), group (2), or group (3) in the preparation method described in the first aspect;

[0157] Z1 is selected from F, Cl, Br, or I.

[0158] In some embodiments, in the fifth reaction, the R 2 groups of compound G and compound H are selected from the R 2 groups of group (2-1) of group (2) in the preparation method described in the first aspect, the Ar group is selected from the corresponding Ar groups in compound B of group (2) in the preparation method described in the first aspect, and the R 1 groups of compound F and compound H in the fifth reaction are phenyl groups.

[0159] In some embodiments, in the fifth reaction, the R 2 groups of compound G and compound H are selected from the R 2 groups of group (1-1) of group (1) in the preparation method described in the first aspect, the Ar group is selected from the corresponding Ar groups in compound B of group (1) in the preparation method described in the first aspect, and the R 1 groups of compound F and compound H in the fifth reaction are tert-butyl groups.

[0160] In some embodiments, in the sixth reaction, the R 2 groups of compound G and compound H are selected from the R 2 groups of group (1-2) of group (1) in the preparation method described in the first aspect, the Ar group is selected from the corresponding Ar groups in compound B of group (1) in the preparation method described in the first aspect, and the R 1 groups of compound F and compound H in the sixth reaction are tert-butyl groups.

[0161] In some embodiments, in the sixth reaction, the R 2 groups of compound G and compound H are selected from the R 2 groups of group (2-2) of group (2) in the preparation method described in the first aspect, the Ar group is selected from the corresponding Ar groups in compound B of group (2) in the preparation method described in the first aspect, and the R 1 groups of compound F and compound H in the sixth reaction are phenyl groups.

[0162] In some embodiments, in the sixth reaction, the R 2 groups of compound G and compound H are selected from the R 2The group, the Ar group is selected from the corresponding Ar group in compound B of group (3) in the preparation method described in the first aspect, and the R of compound F and compound H in the sixth reaction 1 The group is the R of group (3) 1 group.

[0163] In some embodiments, compound F in the fifth reaction is selected from Z1 in compound G in the fifth reaction is selected from Br or iodine, and compound H in the fifth reaction is selected from

[0164] In some embodiments, compound F in the fifth reaction is selected from Z1 in compound G in the fifth reaction is selected from Br or iodine, and compound H in the fifth reaction is selected from

[0165] In some embodiments, compound F in the sixth reaction is selected from Z1 in compound G in the sixth reaction is selected from Br or iodine, and compound H in the sixth reaction is selected from

[0166] In some embodiments, compound F in the sixth reaction is selected from Z1 in compound G in the sixth reaction is selected from Br or iodine, and compound H in the sixth reaction is selected from,

[0167] In some embodiments, compound C is selected from

[0168] In some embodiments, the second base includes at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, and potassium tert-butoxide.

[0169] In some embodiments, the fifth solvent includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile;

[0170] In some embodiments, the ligand in the sixth reaction includes at least one of 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 6,6'-dimethyl-2,2'-bipyridine.

[0171] In some embodiments, the molar ratio of the feed of compound F to the second base is 1:1 to 1:3. In some embodiments, the molar ratio of the feed of compound F to the second base is 1:2.

[0172] In some embodiments, the molar ratio of compound F to compound G in the fifth reaction is independently selected from 1:3 - 1:1. In some embodiments, the molar ratio of compound F to compound G in the fifth reaction is independently selected from 1:2. In some embodiments, the molar ratio of compound F to compound G in the fifth reaction is independently selected from 1:1.5;

[0173] In some embodiments, the reaction temperature of the fifth reaction is 15°C to 35°C. In some embodiments, the reaction temperature of the fifth reaction is 15°C, 20°C, 25°C, 30°C or 35°C.

[0174] In some embodiments, after the fifth reaction is completed, a fifth post-treatment is also carried out, and the fifth post-treatment includes: extracting with water and ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

[0175] In some embodiments, the catalyst IV includes at least one of cuprous iodide, cuprous chloride, and cuprous bromide.

[0176] In some embodiments, the third base includes at least one of cesium carbonate, potassium carbonate, sodium phosphate, and sodium carbonate.

[0177] In some embodiments, the sixth solvent includes at least one of toluene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.

[0178] In some embodiments, the molar ratio of compound F to compound G in the sixth reaction is independently selected from 1:2 - 1:1. In some embodiments, the molar ratio of compound F to compound G in the sixth reaction is independently selected from 1:2. In some embodiments, the molar ratio of compound F to compound G in the sixth reaction is independently selected from 1:1.5.

[0179] In some embodiments, the molar ratio of compound F to the third base is 1:1.5 to 1:1. In some embodiments, the molar ratio of compound F to the third base is 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1 or 1:1. In some preferred embodiments, the molar ratio of compound F to the third base is 1:1.5.

[0180] In some embodiments, the molar ratio of compound F to catalyst IV is 1:0.05 to 1:0.1. In some embodiments, the molar ratio of compound F to catalyst IV is 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09 or 1:0.1.

[0181] In some embodiments, the molar ratio of the compound F to the ligand in the feeding is 1:0.05 to 1:0.1. In some embodiments, the molar ratio of the compound F to the ligand in the feeding is 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09 or 1:0.1. In some embodiments, the molar ratio of the compound F to the ligand in the feeding is 1:0.1.

[0182] In some embodiments, the reaction temperature of the sixth reaction is 100°C to 120°C. In some embodiments, the reaction temperature of the sixth reaction is 100°C, 105°C, 110°C, 115°C or 120°C.

[0183] In some embodiments, after the sixth reaction is completed, a sixth post-treatment is also performed. The sixth post-treatment includes: quenching with water, then extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

[0184] In some embodiments, the seventh solvent includes at least one of dichloromethane and tetrahydrofuran.

[0185] In some embodiments, the molar ratio of the compound H to boron tribromide in the feeding is 1.5:1 to 1:1. In some embodiments, the molar ratio of the compound H to boron tribromide in the feeding is 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1 or 1:1.

[0186] In some embodiments, the reaction temperature of the seventh reaction is -78°C to 0°C. In some embodiments, the reaction temperature of the seventh reaction is -78°C, -70°C, -65°C, -60°C, -55°C, -50°C, -45°C, -40°C, -35°C, -30°C, -25, -20°C, -15°C, -10°C, -5°C or 0°C;

[0187] In some embodiments, after the seventh reaction is completed, a seventh post-treatment is also performed. The seventh post-treatment includes: quenching the reaction with water, adding ethyl acetate for extraction, combining the organic phases, drying, filtering, concentrating, and purifying.

[0188] In some embodiments, the method for preparing the compound C further includes the preparation of the compound F, and the compound F is prepared according to the preparation method described in the eighth aspect.

[0189] In an eighth aspect, the present invention provides a method for preparing a compound F.

[0190] A method for preparing a compound F, which includes:

[0191]

[0192] Step 1: Under the condition of nitrogen or inert atmosphere, compound J is mixed with magnesium chips in the eighth solvent, and then iodine is added to carry out the eighth reaction to obtain compound K;

[0193] Step 2: Compound K and compound L are mixed in the ninth solvent, and then an aqueous sulfuric acid solution is added to carry out the ninth reaction to obtain compound F; alternatively, compound K and compound M are mixed in the tenth solvent to carry out the tenth reaction to obtain compound F.

[0194] In some embodiments, the compound J is selected from The compound K is selected from

[0196] In some embodiments, the compound F is selected from

[0197] In some embodiments, the eighth solvent includes at least one of tetrahydrofuran and 2-methyltetrahydrofuran.

[0198] In some embodiments, the molar ratio of the charged compound J to the magnesium chips is 1:1.2 to 1:1. In some embodiments, the molar ratio of the charged compound J to the magnesium chips is 1:1.2, 1:1.1 or 1:1.

[0199] In some embodiments, the molar ratio of the charged compound J to iodine is 1:0.0005 to 1:0.01. In some embodiments, the molar ratio of the charged compound J to iodine is 1:0.0005, 1:0.0006, 1:0.0007, 1:0.0008, 1:0.0009 or 1:0.001.

[0200] In some embodiments, the reaction temperature of the eighth reaction is 90 °C to 110 °C. In some embodiments, the reaction temperature of the eighth reaction is 90 °C, 95 °C, 100 °C, 105 °C or 110 °C;

[0201] In some embodiments, the ninth solvent includes at least one of tetrahydrofuran and 2-methyltetrahydrofuran.

[0202] In some embodiments, the molar ratio of the charged compound K to compound L is 2:1 to 1:1. In some embodiments, the molar ratio of the charged compound K to compound L is 2:1.

[0203] In some embodiments, the content of sulfuric acid in the aqueous sulfuric acid solution is 10 wt% - 20 wt%. In some embodiments, the content of sulfuric acid in the aqueous sulfuric acid solution is 10 wt%, 15 wt% or 20 wt%.

[0204] In some embodiments, the molar ratio of the compound K to sulfuric acid in the sulfuric acid aqueous solution is from 1:1 to 1:10. In some embodiments, the molar ratio of the compound K to sulfuric acid in the sulfuric acid aqueous solution is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0205] In some embodiments, the reaction temperature of the ninth reaction is from 0 °C to 25 °C. In some embodiments, the reaction temperature of the ninth reaction is 0 °C, 5 °C, 10 °C, 15 °C, 20 °C or 25 °C.

[0206] In some embodiments, after the ninth reaction is completed, a ninth post-treatment is further performed, and the ninth post-treatment includes: extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

[0207] In some embodiments, the tenth solvent includes at least one of tetrahydrofuran and 2-tetrahydrofuran;

[0208] In some embodiments, the molar ratio of the compound K to the compound M in the feed is from 2:1 to 1:1. In some embodiments, the molar ratio of the compound K to the compound M in the feed is 2:1.

[0209] In some embodiments, the reaction temperature of the tenth reaction is from 0 °C to 25 °C. In some embodiments, the reaction temperature of the tenth reaction is 0 °C, 5 °C, 10 °C, 15 °C, 20 °C or 25 °C.

[0210] In some embodiments, after the tenth reaction is completed, a tenth post-treatment is further performed, and the tenth post-treatment includes: quenching with water, then extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

[0211] In a ninth aspect, there is provided an application of the compound B or the compound W according to the fifth aspect, or the compound B obtained by the preparation method according to the first aspect, the third aspect or the fourth aspect.

[0212] An application of the compound B or the compound W according to the fifth aspect, or the compound B obtained by the preparation method according to the first aspect, the third aspect or the fourth aspect in an asymmetric allylation reaction, an asymmetric alkylation reaction or an asymmetric reductive hydrogenation reaction;

[0213] In some embodiments, there is provided an application of the compound W according to the fifth aspect in an asymmetric allylation reaction or an asymmetric alkylation reaction.

[0214] In some embodiments, the asymmetric allylation reaction or the asymmetric alkylation reaction includes:

[0215]

[0216] Compound Q and compound R undergo an asymmetric allylation reaction or an asymmetric alkylation reaction in the eleventh solvent in the presence of a basic reagent, a catalyst, and a chiral ligand to obtain compound S-3; the chiral ligand is compound W described in the fifth aspect, the "*" in compound S-3 represents that the configuration at the indicated position is R configuration or S configuration, and the configuration of compound S-3 is opposite to the configuration of the chiral ligand.

[0217] In some embodiments, the eleventh solvent includes dichloromethane.

[0218] In some embodiments, the basic reagent includes K3PO4.

[0219] In some embodiments, the asymmetric allylation reaction or the asymmetric alkylation reaction is carried out under an inert gas or nitrogen atmosphere.

[0220] In some embodiments, the catalyst includes [Pd(allyl)Cl]2 (dichlorobis(allyl)palladium(II)).

[0221] In some embodiments, the molar ratio of the feed of compound R to compound Q is 2:1 to 1:2. In some embodiments, the molar ratio of the feed of compound Q to compound R is 2:1, 1.5:1, 1:1, 1:1.5, or 1:2.

[0222] In some embodiments, the molar ratio of the feed of the catalyst to compound Q is 0.1:10 to 5:10. In some embodiments, the molar ratio of the feed of the catalyst to compound Q is 0.1:10, 0.5:10, 1:10, 1.5:10, 2:10, 2.5:10, 3:10, 3.5:10, 4:10, 4.5:10, or 5:10.

[0223] In some embodiments, the molar ratio of the feed of the chiral ligand to compound Q is 0.1:10 to 5:10. In some embodiments, the molar ratio of the feed of the chiral ligand to compound Q is 0.1:10, 0.5:10, 1:10, 1.1:10, 1.2:10, 1.3:10, 1.4:10, 1.5:10, 2:10, 2.5:10, 3:10, 3.5:10, 4:10, 4.5:10, or 5:10.

[0224] In some embodiments, the molar ratio of the feed of the basic reagent to compound Q is 2:1 to 1:2. In some embodiments, the molar ratio of the feed of the basic reagent to compound Q is 2:1, 1.5:1, 1:1, 1:1.5, or 1:2.

[0225] In some embodiments, there is provided an application of compound B described in the fifth aspect or compound B prepared by the preparation method described in the first, third or fourth aspect as a chiral ligand in an asymmetric reductive hydrogenation reaction.

[0226] In some embodiments, the asymmetric reductive hydrogenation reaction includes:

[0227]

[0228] Compound T and compound U undergo an asymmetric reductive hydrogenation reaction in a twelfth solvent in the presence of a chiral ligand to obtain compound V-3. The chiral ligand is compound B described in the fifth aspect or compound B prepared by the preparation method described in the first, third or fourth aspect. The "*" in compound V-3 represents that the configuration at the indicated position is R configuration or S configuration, and the configuration of compound V-3 is opposite to that of the chiral ligand.

[0229] In some embodiments, the twelfth solvent includes toluene.

[0230] In some embodiments, the asymmetric reductive hydrogenation reaction is carried out under an inert gas or nitrogen atmosphere.

[0231] In some embodiments, the molar ratio of compound T to compound U in the feed is 1:1 to 1:10. In some embodiments, the molar ratio of compound T to compound U in the feed is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10. In some embodiments, the molar ratio of the chiral ligand to compound T in the feed is 0.5:20 to 1:50. In some embodiments, the molar ratio of the chiral ligand to compound T in the feed is 0.5:20, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45 or 1:50.

[0232] In some embodiments, the asymmetric allylation reaction, asymmetric alkylation reaction or asymmetric reductive hydrogenation reaction is independently selected to be carried out under an inert gas atmosphere and / or nitrogen atmosphere.

[0233] In some embodiments, the inert gas includes at least one of helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe).

[0234] Advantageous Effects

[0235] Compared with the prior art, the present invention has at least one of the following technical effects:

[0236] (1) The compound B provided by the present invention can be used as a ligand in asymmetric reduction hydrogenation reactions, which is beneficial to improving the yield and ee value of the obtained product.

[0237] (2) The compound W provided by the present invention can be used as a ligand in asymmetric alkylation reactions, which is beneficial to improving the yield and ee value of the obtained product.

[0238] (3) Using the method provided by the first aspect, third aspect, fourth aspect, etc. of the present invention to prepare compound B, the obtained product has a high yield and a high ee value, and has excellent technical effects.

[0239] (4) The preparation method of compound B described in the first aspect of the present invention preferably uses at least one of NaH, SiHCl3, triethylamine, and CuCl as a dehalogenating reagent, and more preferably uses triethylamine as a dehalogenating reagent, which is more beneficial to improving the product yield and ee value of compound B, and has unexpected technical effects.

[0240] (5) The preparation method of compound A described in the second aspect of the present invention preferably uses at least one of CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2, and Zn(OTf)2 as a catalyst, and more preferably uses Cu(OTf)2, which is more beneficial to improving the product yield and ee value of compound A, and has unexpected technical effects.

[0241] (6) The preparation method of compound A described in the second aspect of the present invention preferably uses the following ligands, which is more beneficial to improving the product yield and ee value of compound A, and has unexpected technical effects: Among them, R 7 is selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 7 is tert-butyl;

[0242] R 8 is selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 8 is phenyl;

[0243] Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl.

[0244] (7) The preparation method of compound A described in the second aspect of the present invention preferably uses one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, methanol, etc. as the second solvent, and more preferably uses ethyl acetate, which is more beneficial to improving the product yield and ee value of compound A, and has unexpected technical effects.

[0245] (8) The preparation method of compound A described in the second aspect of the present invention preferably uses at least one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-dichloro-5,5-dimethylhydantoin, and more preferably uses 1,3-dichloro-5,5-dimethylhydantoin as the halogenating reagent, which is more conducive to improving the product yield and ee value of compound A and has unexpected technical effects.

[0246] (9) The preparation method of compound B described in the fourth aspect of the present invention preferably uses the following ligands, which is more conducive to improving the product yield and ee value of compound B and has unexpected technical effects:

[0247] Wherein, R 7 is selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 7 is tert-butyl;

[0248] R 8 is selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 8 is phenyl;

[0249] Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl.

[0250] (10) The preparation method of compound B described in the fourth aspect of the present invention preferably uses at least one of CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2, Zn(OTf)2 as catalyst II, and more preferably uses Cu(OTf)2 as catalyst II, which is more conducive to improving the product yield and ee value of the obtained compound B and has unexpected technical effects.

[0251] (11) The preparation method of compound B described in the fourth aspect of the present invention preferably uses one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, methanol, etc. as the second solvent, and more preferably uses ethyl acetate as the second solvent, which is more conducive to improving the product yield and ee value of the obtained compound B and has unexpected technical effects.

[0252] (12) In the preparation method of compound B according to the fourth aspect of the present invention, it is preferred to use at least one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-dichloro-5,5-dimethylhydantoin as the halogenating reagent. More preferably, 1,3-dichloro-5,5-dimethylhydantoin is used, which is more conducive to improving the product yield and ee value of the obtained compound B, and has unexpected technical effects.

[0253] Term Definition

[0254] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings:

[0255] In the present invention, expressions such as "compound (I)" and "the compound represented by formula (I)" refer to the same compound.

[0256] "V / V" represents volume ratio.

[0257] "wt%" represents mass percentage.

[0258] The terms "a plurality of" and "several" mean at least 2, such as 2, 3, 4, or 5, etc.

[0259] In the present invention, the meanings of the atoms in the compound structure: F represents fluorine, Cl represents chlorine, and D represents deuterium.

[0260] The term "and / or" should be understood to mean any one of the optional items or any combination of any two or more of the optional items.

[0261] The terms "optional", "optionally", or "optionally" mean that the subsequent described event or situation may or may not occur. For example, "optionally, the heteroatoms in the heterocycle include at least one selected from nitrogen, oxygen, and sulfur" means that the situation where "the heteroatoms in the heterocycle include at least one selected from nitrogen, oxygen, and sulfur" may or may not exist.

[0262] In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. In particular, it is pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C1-C6 alkyl" particularly refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl independently disclosed.

[0263] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

[0264] "Room temperature" in the present invention refers to ambient temperature, which is from about 10 °C to about 40 °C. In some embodiments, "room temperature" refers to a temperature from about 20 °C to about 30 °C; in other embodiments, "room temperature" refers to a temperature from about 25 °C to about 30 °C; in still other embodiments, "room temperature" refers to 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, etc.

[0265] "Alkyl" is a hydrocarbon containing primary, secondary, tertiary, or cyclic carbon atoms. For example, an alkyl can have 1 to 20 carbon atoms (i.e., C1-C 20alkyl), from 1 to 8 carbon atoms (i.e., C1-C8 alkyl) or from 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 n-octyl (-(CH2)7CH3).

[0266] "Alkenyl" is a hydrocarbon containing a positive, secondary, tertiary or cyclic carbon atom having at least one unsaturated site, i.e., a carbon-carbon sp 2 double bond. For example, alkenyl can have from 2 to 10 carbon atoms (C2-C 10 alkenyl), from 2 to 12 carbon atoms (C2-C 12(alkenyl) or an alkenyl group having 2 to 6 carbon atoms (C2-C6 alkenyl). Among them, the alkenyl group may optionally be substituted by one or more substituents described in the present invention, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0267] "Alkynyl" is a hydrocarbon containing a positive, secondary, tertiary or cyclic carbon atom having at least one unsaturated moiety, i.e., a carbon-carbon sp triple bond. Among them, the alkynyl group may optionally be substituted by one or more substituents described in the present invention. For example, the alkynyl group may have 2 to 10 carbon atoms (C2-C 10 alkynyl), 2 to 12 carbon atoms (C2-C 12 alkynyl) or 2 to 6 carbon atoms (C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH) or the like.

[0268] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbocyclic system containing 6-20 ring atoms, or 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, and each ring system contains a ring composed of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups may include groups derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, etc. and similar groups. The aryl group is optionally substituted by one or more substituents described in the present invention.

[0269] The term "heteroaryl" refers to a monocyclic, bicyclic and tricyclic system containing 5-20 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, and each ring system contains a ring composed of 5-7 atoms and has one or more attachment points connected to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted by one or more substituents described in the present invention. In one embodiment, the heteroaryl composed of 5-20 ring atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0270] Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, 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-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl; also included are the following bicyclics, but in no way limited to these bicyclics: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, 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]pyridyl, and the like.

[0271] The term "substituted" or "substitution" means that one or more hydrogen atoms in the structure are replaced by specific substituents. Unless otherwise indicated, a substituted group can 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, then the substituents can be the same or different at each position.

[0272] The term "unsubstituted" means that the designated group bears no substituents.

[0273] The term "substituted" with respect to alkyl, aryl, arylalkyl, heterocyclic, heteroaryl, carbocyclic, etc., such as "substituted C1-C 10 alkyl", "substituted C6-C 20 aryl", "substituted arylalkyl", "substituted C1-C 20 heterocycle" and "substituted carbocyclic" respectively mean C1-C in which one or more hydrogen atoms are each independently replaced by a non-hydrogen substituent 10 alkyl, C6-C 20 aryl, arylalkyl, C1-C20 Heterocycles, alkylamino, and carbocyclic groups. Unless otherwise indicated, when the term "substituted" is used in connection with a group having two or more moieties capable of substitution, such as arylalkyl, the substituent may be attached to the aryl moiety, the alkyl moiety, or both.

[0274] The term "comprising j - k atoms" or "j - k - membered" means that the cyclic group is composed of j - k ring atoms, which include carbon atoms and / or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non - zero natural number, and k > j; the "j - k" includes j, k, and any natural number between them. For example, "comprising 3 - 8 atoms" or "3 - 8 - membered", "comprising 3 - 6 atoms" or "3 - 6 - membered", "comprising 5 - 10 atoms" or "5 - 10 - membered", "comprising 5 - 6 atoms" or "5 - 6 - membered" mean 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, which include carbon atoms and / or heteroatoms such as O, N, S, P, etc. For another example, piperidinyl is a heterocyclic group or 6 - membered heterocyclic group composed of 6 atoms, while pyridinyl is a heteroaryl group or 6 - membered heteroaryl group composed of 6 atoms.

[0275] The j and k in the terms "j - k", "j - k - membered", or "C j -C k " are each independently any non - zero natural number, and k > j; for example, "1 - 4" means 1, 2, 3, or 4, "4 - 6 - membered" means 4 - membered, 5 - membered, or 6 - membered; "C3 - C6" means C3, C4, C5, or C6. And so on.

[0276] The terms "(alkoxy) - alkylene", "(alkylamino) - alkylene", "(cycloalkyl) - alkylene", "(heterocyclyl) - alkylene", "(aryl) - alkylene", "(heteroaryl) - alkylene" mean that the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each independently attached to the rest of the molecule through an alkylene, where the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkylene all have the meanings described in the present invention. For example, examples of (cycloalkyl) - alkylene include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, etc. For another example, examples of (aryl) - alkylene include, but are not limited to, benzylidene, phenylethylene, phenylpropyl, etc. The (alkoxy) - alkylene, (alkylamino) - alkylene, (cycloalkyl) - alkylene, (heterocyclyl) - alkylene, (aryl) - alkylene, (heteroaryl) - alkylene are each independently optionally substituted by one or more substituents described in the present invention.

[0277] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0278] Whenever a compound described herein is substituted by more than one identical specified group (e.g., "R" or "R 1 "), it should be understood that these groups may be the same or different, i.e., each group is independently selected.

[0279] "V / V" represents a volume ratio.

[0280] The term "inert gas" includes at least one of helium (He), neon (Ne), argon (Ar), krypton (Kr), and xenon (Xe). Detailed implementation mode

[0281] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further elaborate on the present invention.

[0282] The reagents used in the present invention can all be purchased from the market or can be prepared by the methods described in the present invention.

[0283] The wavelength of the blue light used in the following examples is approximately 440 nm.

[0284] EA represents ethyl acetate;

[0285] As used in the present invention, both "equivalent" or "eq" mean that the equivalent refers to the relative molar ratio relationship between reactants. Based on one of the reactants, the amounts of other reactants are expressed as molar ratios relative to this reference reactant. For example, when 1 equivalent (or 1 eq) of compound A reacts with 2 equivalents (or 2 eq) of compound B, it means that the feed molar ratio of compound A to compound B is 1:2.

[0286] It represents a molecular sieve with a particle size of 4 angstroms (i.e., 0.4 nanometers).

[0287] Ligand L1:

[0288] Ligand L2:

[0289] The group "C6H4" represents a benzene ring in which two H atoms are substituted.

[0290] The group "Ph" represents a phenyl group. " t Bu" represents a tert-butyl group; " i Bu" represents an isobutyl group; " i"Pr" or "i-Pr" represents isopropyl; "Me" represents methyl; "Et" represents ethyl; "Bn" represents benzyl.

[0291] NCS represents N-chlorosuccinimide; NBS represents N-bromosuccinimide; NIS represents N-iodosuccinimide; DBDMH represents 1,3-dibromo-5,5-dimethylhydantoin; DCDMH represents 1,3-dichloro-5,5-dimethylhydantoin.

[0292] "p" indicates that two substituents are para-substituted. For example, "p-CO2Me-C6H2" represents "o" indicates that two substituents are ortho-substituted. For example, "o-F–C6H4" represents "m" indicates that two substituents are meta-substituted. For example, "m-CN-C6H4" represents

[0293] I. Preparation of Compound C

[0294] 1. Method 1 (Fourth Reaction):

[0295] Example 1: Preparation of Compound C

[0296]

[0297] Under an argon atmosphere, the corresponding Compound D (5.0 mmol, 1.5 equivalents), Compound E (1.0 equivalent), tetrakis(triphenylphosphine)palladium(0) (0.05 equivalent), and cesium carbonate (1.5 equivalents) were mixed, and 30 mL of anhydrous toluene was added. The mixture was refluxed at 110 °C for 12 hours; the reaction was quenched with water, and the organic phase was extracted with ethyl acetate; the combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain Compound C.

[0298] Compound C shown in Table 1 was prepared using different reactants, and the mass spectra of the products were detected. The structures and mass spectra of the reactants and products are shown in Table 1.

[0299] Table 1: Preparation of Compound C

[0300]

[0301]

[0302] Example 2: Preparation of Compound C

[0303] Compound C in Table 2 was prepared using Compound D and Compound E in Table 2 with reference to the preparation method of Example 1, and the mass spectra of the products were detected. The structures and mass spectra of the reactants and products are shown in Table 2.

[0304] Table 2: Preparation of Compound C

[0305]

[0306] 2. Method 2 (Step 2 is the sixth reaction):

[0307] Example 3: Preparation of Compounds rac-19 and rac-22

[0308]

[0309] Step 1: Under an argon atmosphere, mix Compound J-1 (50 mmol, 1.0 equivalent), activated magnesium turnings (1.0 equivalent, the oxide film on the surface of the magnesium turnings was removed with acid), and 40 mL of anhydrous THF. Then add two grains of elemental iodine (about 0.001 equivalent) to initiate the reaction. The reaction solution changes from brownish-yellow to colorless. Subsequently, add the remaining 1-bromo-2-methoxynaphthalene (50 mmol). Reflux at 90 °C for 2 hours. After the magnesium turnings are consumed, cool the reaction to -78 °C and slowly add a THF solution of tert-butylphosphonous dichloride (0.5 equivalent) to the reaction. Stir for 10 minutes, then transfer the reaction to room temperature. After reacting for 2 hours, add 150 mL of 10 wt% sulfuric acid aqueous solution and continue the reaction for 2 hours. After the reaction is completed, extract the organic phase with ethyl acetate. The combined organic phases are dried over anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain Compound F-1.

[0310] Step 2 (the sixth reaction): Under an argon atmosphere, mix the corresponding Compound G-1 (1.5 equivalents, the group at the R position in Compound G-1), the obtained Compound F-1 (1.0 equivalent), copper(I) iodide (0.1 equivalent), 2,2'-bipyridine (0.1 equivalent), and cesium carbonate (1.5 equivalents). Then add 30 mL of anhydrous toluene and reflux at 110 °C for 12 hours. Quench the reaction with water, then extract the organic phase with ethyl acetate. The combined organic phases are dried over anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain Compound H-1. 2 corresponds to the R of the resulting product 2 at the position of the group

[0311] Step 3: Under an argon atmosphere, mix the obtained Compound H-1 with 20 mL of anhydrous dichloromethane and place it at 0 °C. Slowly add boron tribromide (1.0 equivalent). After reacting for 1 hour, quench the reaction with water, add ethyl acetate to extract the organic phase. The combined organic phases are dried over anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain Compound C-1.

[0312] Compounds rac-19 and rac-22 were prepared using different Compounds G-1 respectively, and the mass spectra of the products were detected.

[0313] (Mass spectrum [M+H] + = 343), (Mass spectrum [M+H] + = 375).

[0314] Example 4: Preparation of Compound C-2

[0315]

[0316] Step 1: Prepare Compound F-1 according to the method of Example 3;

[0317] Step 2 (Sixth reaction): Under an argon atmosphere, mix the corresponding Compound G-2 (7.5 mmol, 1.5 equivalents, the group at the R position in Compound G-2 2 corresponding to the R of the resulting product 2 position), Compound F-1 obtained in Step 1 (5.0 mmol, 1.0 equivalent), copper(I) iodide (0.5 mmol, 0.1 equivalent), 2,2'-bipyridine (0.1 equivalent), cesium carbonate (7.5 mmol, 1.5 equivalents) with 30 mL of anhydrous toluene, reflux at 110 °C for 12 hours; quench the reaction with water, extract the organic phase with ethyl acetate, dry the combined organic phase with anhydrous MgSO4, filter, and concentrate. Purify the residue by silica gel column chromatography to obtain Compound H-1;

[0318] Step 3: Under an argon atmosphere, mix the obtained Compound H-1 with 20 mL of anhydrous dichloromethane, place it at 0 °C, slowly add boron tribromide (1.0 equivalent), quench the reaction with water after 1 hour, extract the organic phase with ethyl acetate, dry the combined organic phase with anhydrous MgSO4, filter, and concentrate. Purify the residue by silica gel column chromatography to obtain Compound C-1.

[0319] Prepare Compound C-2 shown in Table 3 using different Compounds G-2 respectively, detect the mass spectrum of the product, and the structure and mass spectrum results of each product are shown in Table 3.

[0320] Table 3: Preparation of Compound C-2

[0321]

[0322]

[0323]

[0324] Example 5: Preparation of Compound C-3

[0325]

[0326] Step 1: Under an argon atmosphere, 1-bromo-2-methoxynaphthalene (50 mmol, 1.0 equivalent) and activated magnesium turnings (1.0 equivalent) were added to a 500 mL round-bottom flask. 40 mL of anhydrous THF was added, and two grains of elemental iodine (about 0.001 equivalent) were used to initiate the reaction. The reaction solution changed from brown-yellow to colorless. Subsequently, the remaining 1-bromo-2-methoxynaphthalene (50 mmol) was added, and the mixture was refluxed at 110 °C for 2 hours. After the magnesium turnings were consumed, the reaction was placed at 0 °C, and a THF solution of ethyl phenylphosphite (0.5 equivalent) was slowly added to the reaction. After reacting for 2 hours, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO4, filtered, concentrated, and the residue was purified by silica gel column chromatography to obtain compound F-2;

[0327] Step 2 (the sixth reaction): Under an argon atmosphere, the corresponding compound G-3 (7.5 mmol, 1.5 equivalents, the group at the R 2 position corresponding to the obtained product's R 4 position) and compound F-2 (5.0 mmol, 1.0 equivalent), copper(I) iodide (0.5 mmol, 0.1 equivalent), 2,2'-bipyridine (0.1 equivalent), cesium carbonate (7.5 mmol, 1.5 equivalents) were mixed with 30 mL of anhydrous toluene and refluxed at 110 °C for 12 hours; the reaction was quenched with water, and the organic phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO4, filtered, concentrated. The residue was purified by silica gel column chromatography to obtain compound H-2;

[0328] Step 3: Under an argon atmosphere, the obtained compound H-2 was mixed with 20 mL of anhydrous dichloromethane, placed at 0 °C, and boron tribromide (1.0 equivalent) was slowly added. After reacting for 1 hour, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous MgSO4, filtered, concentrated. The residue was purified by silica gel column chromatography to obtain compound C-3.

[0329] Different compounds G-3 and different compounds C-3 (rac-64, rac-68, rac-69, rac-72) were used respectively to detect the mass spectra of the products. The structure and mass spectrometry results of each product are as follows.

[0330] (Mass spectrum [M+H] + = 359), (Mass spectrum [M+H] + = 377), (Mass spectrum [M+H] + = 384), (Mass spectrum [M+H] + = 417).

[0331] 3. Method 3 (Step 2 is the fifth reaction):

[0332] Example 6: Preparation of Compound C-3

[0333]

[0334] Step 1: Prepare Compound F-2 by referring to the method of Example 5.

[0335] Step 2 (fifth reaction): Mix the obtained Compound F-2 (10 mmol) with KOH (20 mmol) and 25 mL of DMSO. After pre-stirring the reaction for 15 min and waiting for the solution to turn dark yellow, add the corresponding alkyl halide (Compound G-2, where the X 1 group can be Br or iodine, Br is used in this example, and the R 4 group in Compound G-2 corresponds to the R 4 group at the corresponding position of the resulting product) (20 mmol), and react for 3 hours. Add water and ethyl acetate to extract the organic phase. The combined organic phases are dried with anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain Compound H-2.

[0336] Step 3: Under an argon atmosphere, mix the obtained Compound H-2 with 20 mL of anhydrous dichloromethane. Place the reaction at 0 °C and slowly add boron tribromide (1.0 equivalent). After reacting for 1 hour, quench the reaction with water. Extract the organic phase with ethyl acetate. The combined organic phases are dried with anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain Compound C-3 (rac-48, rac-51, rac-54, rac-55, rac-56, rac-57 are prepared correspondingly according to different Compound G-2).

[0337] (Mass spectrometry [M+H] + = 339), (Mass spectrometry [M+H] + = 323), (Mass spectrometry [M+H] + = 365), (where the cycloalkyl group is cyclododecyl, mass spectrometry [M+H] + = 435), (Mass spectrometry [M+H] + = 353), (Mass spectrometry [M+H] + = 385).

[0338] Example 7: Preparation of rac-47

[0339]

[0340] Step 1: Prepare compound F-1 according to the method of Example 3;

[0341] Step 2 (the fifth reaction): Mix the obtained compound F-1 (10 mmol) with KOH (20 mmol) and 25 mL of DMSO. After pre-stirring the reaction for 15 min and waiting for the solution to turn dark yellow, add methyl iodide (20 mmol) and react for 3 hours. Add water and ethyl acetate to extract the organic phase. The combined organic phase is dried with anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain compound H-4.

[0342] Step 3: Under an argon atmosphere, mix the obtained compound H-4 with 20 mL of anhydrous dichloromethane. Place the reaction at 0 °C and slowly add boron tribromide (1.0 equivalent). After reacting for 1 hour, quench the reaction with water, extract the organic phase with ethyl acetate. The combined organic phase is dried with anhydrous MgSO4, filtered, and concentrated. The residue is purified by silica gel column chromatography to obtain rac-47.

[0343] (Mass spectrometry [M+H] + = 263).

[0344] II. Preparation of compound B (product 1 and / or product 3): Route 1

[0345] Example 8:

[0346] Step 1:

[0347]

[0348] In an Ar atmosphere, mix Cu(OTf)2 (0.01 mmol), ligand L1 (0.012 mmol), and 2.0 mL of anhydrous ethyl acetate, stir at room temperature for 1 h, then add compound rac-1 (0.20 mmol), 40 mg MS, DCDMH (0.1 mmol), and react at room temperature for 1 h. After the reaction is completed, quench with saturated aqueous sodium sulfite solution, extract the mixture with ethyl acetate, dry the combined organic layer with anhydrous MgSO4, rotary evaporate the solvent under reduced pressure, and purify by column chromatography. The eluent is (petroleum ether:ethyl acetate (V / V) = 5:1 → 1:1) to obtain product (R)-1b-1 (yield 48%, product 1) and (S p ,S)-2b-1 (yield 46%, product 2).

[0349] (R)-1b-1: HPLC conditions: Chiralpak IA column, 98% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.32 min, t r (major) = 7.81 min; = -38.4 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.57 (s, 1H), 7.98 (m, 2H), 7.89 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.55 (m, J = 7.4 Hz, 1H), 7.49 (m, 2H), 7.26 - 7.14 (m, 3H), 7.09 (m, 1H), 1.53 (d, J = 15.4 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 59.24; HRMS Calculated for C 20 H 21 O2P, [M + H] + : 325.1352, found: 325.1357.

[0350] (S p ,S)-2b-1: HPLC conditions: Chiralpak IA column, 96% ee; eluent: hexane / isopropanol = 85 / 15; flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 8.37 min, t r (major) = 9.03 min; = -171.2 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 7.99 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 9.1 Hz, 2H), 7.36 (q, J = 8.4, 7.3 Hz, 2H), 7.16 (m, 3H), 6.99 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.14 (d, J = 9.8 Hz, 1H), 1.35 (d, J = 16.1 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 50.27; HRMS Calculated for C 20 H 20ClO2P,[M+Na] + : 381.0782, found 381.0783.

[0351] Step 2:

[0352]

[0353] In a 5 mL Schlenk tube, add (S p ,S)-2b-1 (0.1 mmol), Et3N (0.3 mmol), 1 mL of acetonitrile, stir at room temperature under blue light for 3 hours. After the reaction is completed, rotary evaporate the solvent under reduced pressure and purify by column chromatography to obtain the corresponding product (S)-1b-1 (yield 97%, product 3).

[0354] (S)-1b-1: HPLC conditions: Chiralpak IA column, 95% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.36 min, t r (major) = 7.96 min; = +30.0 (c = 0.5, CHCl3).

[0355] Example 9:

[0356] Except that the reaction substrate in Step 1 is replaced by the compound rac-1 and the (S p ,S)-2b in Step 2 is replaced by the corresponding product 2 in Table 4, the following compounds are respectively prepared with reference to the preparation method of Example 8, and the results are shown in Table 4.

[0357] Table 4:

[0358]

[0359]

[0360]

[0361]

[0362]

[0363] Separation conditions and structural characterization:

[0364] (R)-1b-25: HPLC conditions: Chiralpak IB column, 97% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; tr (minor)=8.12 min, t r (major)=10.03 min; =-33.6 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.33 (s, 1H), 8.12 (d, J = 5.7 Hz, 2H), 8.08 - 7.98 (m, 2H), 7.88 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.21 - 7.01 (m, 4H), 3.92 (s, 3H), 1.50 (d, J = 15.6 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 58.98; HRMS Calculated for C 22 H 23 O4P, [M+Na] + : 405.1226, found 405.1226。

[0365] (S p ,S)-2b-25: HPLC conditions: Chiralpak IB column, 99% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor)=10.45 min, t r (major)=12.51 min; =-129.6 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.01 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 5.8 Hz, 2H), 7.68 - 7.55 (m, 2H), 7.40 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 9.8 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 6.18 (d, J = 9.8 Hz, 1H), 3.89 (s, 3H), 1.36 (d, J = 16.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 45.89; HRMS Calculated for C 22 H 22 ClO4P, [M+Na] + : 439.0836, found 439.0842。

[0366] (S)-1b-25: HPLC conditions: Chiralpak IB column, 98% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.33 min, t r (minor) = 9.81 min; = +35.6 (c = 0.5, CHCl3).

[0367] (R)-1b-19: HPLC conditions: Chiralpak IA column, 92% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.04 min, t r (major) = 9.05 min; = +32.4 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.4 (s, 1H), 7.9 (m, 2H), 7.7 (d, J = 7.9 Hz, 1H), 7.6 (q, J = 7.1 Hz, 1H), 7.3 (d, J = 8.5 Hz, 1H), 7.3 - 7.1 (m, 5H), 1.5 (d, J = 16.4 Hz, 9H); 19 19F NMR (376 MHz, Chloroform-d): δ -97.83; HRMS Calculated for C 20 H 20 F1O2P1, [M+Na] + : 365.1077, found 365.1086.

[0368] (S p ,S)-2b-19: HPLC conditions: Chiralpak IA column, 89% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 8.5 min, t r (major) = 10.24 min; = -211.2 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 8.01 (d, J = 8.0 Hz, 1H), 7.40 (m, 2H), 7.25 - 7.17 (m, 2H), 6.93 (m, 2H), 6.84 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 6.11 (d, J = 9.9 Hz, 1H), 1.40 (d, J = 17.6 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 45.48; 19 19F NMR (376 MHz, Chloroform-d): δ -63.16; HRMS Calculated for C 20 H 19 FClO2P, [M+Na] + : 399.0687, found 399.0694.

[0369] (S)-1b-19: HPLC conditions: Chiralpak IA column, 87% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 5.91 min, t r (minor) = 8.90 min; = -44.0 (c = 0.5, CHCl3).

[0370] (R)-1b-27: HPLC conditions: Chiralpak IA column, 97% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.40 min, t r (major) = 10.08 min; = -17.2 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.18 (s, 1H), 8.22 (d, J = 10.6 Hz, 1H), 8.20 - 8.11 (t, J = 9.28 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.60 (td, J = 7.8, 2.5 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.18 - 7.05 (m, 3H), 1.50 (d, J = 15.8 Hz, 9H);31 P NMR (162 MHz, Chloroform-d): δ 58.31; HRMS Calculated for C 21 H 20 NO2P, [M+Na] + : 372.1124, found 372.1124.

[0371] (S p ,S)-2b-27: HPLC conditions: Chiralpak IA column, 95% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 11.91 min, t r (major) = 15.82 min; = -282.8 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 8.00 (d, J = 8.0 Hz, 1H), 7.82 (m, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.36 (td, J = 7.8, 2.8 Hz, 1H), 7.28 - 7.22 (m, 1H), 7.14 (d, J = 9.8 Hz, 1H), 6.96 (d, J = 6.4 Hz, 1H), 6.23 (d, J = 9.8 Hz, 1H), 1.35 (d, J = 16.6 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 44.96; HRMS Calculated for C 21 H 19 NClO2P, [M+Na] + : 406.0734, found 406.0730.

[0372] (S)-1b-27: HPLC conditions: Chiralpak IA column, 96% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.16 min, t r (minor) = 10.01 min; = +21.2 (c = 0.5, CHCl3).

[0373] (R)-1b-28: HPLC conditions: Chiralpak IA column, 98% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 8.67 min, t r (major) = 11.92 min; = -59.6 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.34 (s, 1H), 9.99 (s, 1H), 8.47 (d, J = 10.6 Hz, 1H), 8.18 (t, J = 9.2 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.14 - 7.19 (m, 3H), 7.04 - 7.08 (m, 1H), 1.52 (d, J = 15.7 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 58.61; HRMS Calculated for C 21 H 21 O3P, [M+Na] + : 375.1121, found 375.1126.

[0374] (S p ,S)-2b-28: HPLC conditions: Chiralpak IA column, 96% ee; eluent: hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 19.07 min, t r (major) = 23.42 min; = -90.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 9.86 (s, 1H), 8.0 - 8.02 (m, 2H), 7.87 (d, J = 7.2 Hz, 1H), 7.78 (t, J = 8.7 Hz, 1H), 7.37 (q, J = 8.3, 7.6 Hz, 2H), 7.16 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 9.9 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 6.21 (d, J = 9.8 Hz, 1H), 1.38 (d, J = 16.5 Hz, 9H); 31P NMR (162 MHz, Chloroform-d): δ 46.25; HRMS Calculated for C 21 H 20 ClO3P, [M + Na] + : 409.0731, found 409.0932.

[0375] (S)-1b-28: Yield 90%, (S)-1b: HPLC conditions: Chiralpak IA column, 96% ee; Eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.84 min, t r (minor) = 11.44 min; = +51.2 (c = 0.5, CHCl3). [M + Na] + : 375.

[0376] (R)-1b-22: HPLC conditions: Chiralpak IB column, 97% ee; Eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.80 min, t r (major) = 10.13 min; = -48.8 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.61 (s, 1H), 8.55 (d, J = 12.6 Hz, 1H), 7.95 - 7.85 (m, 5H), 7.68 (d, J = 7.9 Hz, 1H), 7.57 (dq, J = 15.0, 7.3, 6.7 Hz, 2H), 7.31 (d, J = 8.6 Hz, 1H), 7.20 (dd, J = 9.0, 3.6 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.00 (t, J = 8.2 Hz, 1H), 1.58 (d, J = 15.4 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 59.29; HRMS Calculated for C 24 H 23 O2P, [M + Na] + : 397.1328, found 397.1332.

[0377] (S p,(S)-2b-22: HPLC conditions: Chiralpak IB column, 91% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 13.81 min, t r (major) = 19.65 min; = -69.2 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.06 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 12.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.67 - 7.64 (m, 1H), 7.55 (q, J = 7.8 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 9.8 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 6.13 (d, J = 9.8 Hz, 1H), 1.42 (d, J = 16.2 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.35; HRMS Calculated for C 24 H 22 Cl1O2P, [M+Na] + : 431.0938, found 431.0936.

[0378] (S)-1b-22: HPLC conditions: Chiralpak IB column, 91% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 7.00 min, t r (minor) = 10.08 min; = +52.4 (c = 0.5, CHCl3).

[0379] (R)-1b-11: HPLC conditions: Chiralpak IB column, 77% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.18 min, t r (major) = 6.91 min; =-16.4 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 14.55 (s, 1H), 8.70 - 8.51 (m, 3H), 8.03 (dd, J = 11.2, 7.0 Hz, 2H), 7.79 (t, J = 7.7 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.62 - 7.46 (m, 3H), 7.35 (t, J = 7.3 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), 1.57 (d, J = 15.3 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 60.74; HRMS Calculated for C 21 H 23 O3P, [M + Na] + : 397.1328, found 397.1330.

[0380] (S p ,S)-2b-11: HPLC conditions: Chiralpak IB column, 91% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 9.62 min, t r (major) = 14.05 min; =-300.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.02 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 7.55 - 7.45 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H), 7.31 - 7.19 (m, 4H), 7.12 (t, J = 9.1 Hz, 2H), 6.95 (t, J = 7.6 Hz, 2H), 1.30 (d, J = 16.1 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 53.07; HRMS Calculated for C 24 H 22 ClO2P, [M + Na] + : 431.0938, found 431.0944.

[0381] (S)-1b-11: HPLC conditions: Chiralpak IB column, 89% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 6.10 min, t r (minor) = 6.73 min; = +21.6 (c = 0.5, CHCl3).

[0382] (R)-1b-9: HPLC conditions: Chiralpak IC column, 89% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 17.05 min, t r (major) = 33.96 min; = +23.2 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.48 (s, 1H), 8.57 (d, J = 3.9 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.97 - 7.86 (m, 2H), 7.57 - 7.53 (m, 1H), 7.51 - 7.42 (m, 3H), 7.36 (dd, J = 9.3, 4.0 Hz, 1H), 6.95 (dd, J = 8.8, 4.2 Hz, 1H), 1.46 (d, J = 15.6 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 58.54; HRMS Calculated for C 19 H 20 N1O2P, [M + H] + : 326.1304, found 326.1310.

[0383] (S p ,S)-2b-9: HPLC conditions: Chiralpak IC column, 86% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 21.96 min, t r (major) = 24.18 min; = -263.2 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 8.38 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.41 - 7.37 (m, 3H), 7.31 - 7.26 (m, 1H), 7.22 - 7.17 (m, 2H), 7.08 (d, J = 10.1 Hz, 1H), 6.30 (d, J = 10.1 Hz, 1H), 1.40 (d, J = 16.5 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.45; HRMS Calculated for C 19 15 19 14N35ClO2P, [M + Na] + : 382.0734, found 382.0734.

[0384] (S)-1b-9: HPLC conditions: Chiralpak IC column, 84% ee; Eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 15.96 min, t r (minor) = 33.10 min; α = -20.0 (c = 0.5, CHCl3).

[0385] (R)-1b-10: HPLC conditions: Chiralpak IA column, 94% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.73 min, t r (major) = 8.87 min; α = +8.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.37 (s, 1H), 8.04 - 7.94 (m, 2H), 7.78 (d, J = 9.0 Hz, 1H), 7.56 - 7.45 (m, 4H), 7.00 (dd, J = 8.9, 3.6 Hz, 1H), 6.80 (dd, J = 8.8, 2.4 Hz, 1H), 6.50 - 6.45 (m, 1H), 3.24 (s, 3H), 1.52 (d, J = 15.3 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 58.32; HRMS Calculated for C21 H 23 O3P, [M+Na] + : 377.1277, found 377.1285.

[0386] (S p , S)-2b-10: HPLC conditions: Chiralpak IC column, 93% ee; Eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 12.43 min, t r (major) = 36.90 min; = -300.0 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ7.58 (s, 1H), 7.49 (t, J = 9.0 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.19 - 7.07 (m, 2H), 6.95 (d, J = 9.8 Hz, 1H), 6.75 - 6.69 (m, 1H), 6.68 - 6.61 (m, 1H), 6.11 (d, J = 9.7 Hz, 1H), 3.88 (s, 3H), 1.38 (d, J = 16.2 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ47.47; HRMS Calculated for C 21 H 22 Cl1O3P, [M+Na] + : 411.0887, found 411.0891.

[0387] (S)-1b-10: HPLC conditions: Chiralpak IA column, 90% ee; Eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 7.40 min, t r (minor) = 8.71 min; = -7.2 (c = 0.5, CHCl3).

[0388] (R)-1b-8: HPLC conditions: Chiralpak IB column, 92% ee; Eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.80 min, t r(major) = 10.02 min; = +43.2 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.53 (s, 1H), 8.02 - 7.93 (m, 2H), 7.92 - 7.85 (m, 2H), 7.60 - 7.53 (m, 1H), 7.52 - 7.47 (m, 2H), 7.36 - 7.33 (m, 2.1 Hz, 1H), 7.29 - 7.25 (m, 2H), 7.23 - 7.14 (m, 2H), 7.09 - 7.02 (m, 1H), 1.52 (d, J = 15.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 59.24; HRMS Calculated for C 24 H 23 O2PS, [M+Na] + : 429.1049, found 429.1049.

[0389] (S p ,S)-2b-8: HPLC conditions: Chiralpak IC column, 95% ee; Eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 18.47 min, t r (major) = 20.68 min; = -38.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.00 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 9.1 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1H), 7.29 - 7.27 (m, 2H), 7.24 - 7.14 (m, 2H), 7.12 - 6.99 (m, 3H), 6.17 (d, J = 9.7 Hz, 1H), 1.39 (d, J = 16.1 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.61; HRMS Calculated for C 24 H 22 O2ClPS, [M+Na] + : 463.0659, found 463.0661.

[0390] (S)-1b-8: HPLC conditions: Chiralpak IB column, 94% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 7.79 min, t r (minor) = 9.66 min; = -42.8 (c = 0.5, CHCl3).

[0391] (R)-1b-15: HPLC conditions: Chiralpak IA column, 99% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.48 min, t r (major) = 8.46 min; = +52.4 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.57 (s, 1H), 8.02 - 7.93 (m, 2H), 7.80 (d, J = 9.0 Hz, 1H), 7.59 - 7.53 (m, 1H), 7.54 - 7.46 (m, 3H), 7.41 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.14 (dd, J = 9.0, 3.5 Hz, 1H), 1.49 (d, J = 15.5 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 58.32; HRMS Calculated for C 20 H 20 BrO2P, [M + H] + : 403.0457, found 403.0462.

[0392] (S p ,S)-2b-15: HPLC conditions: Chiralpak IA column, 96% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.77 min, t r (major) = 8.77 min; = -53.6 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 8.16 (s, 1H), 7.51 (t, J = 9.0 Hz, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.26 - 7.16 (m, 2H), 6.97 (d, J = 9.9 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 6.16 (d, J = 9.8 Hz, 1H), 1.38 (d, J = 16.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.60; HRMS Calculated for C 20 H 19 ClBrO2P, [M+H] + : 437.0068, found 437.0067.

[0393] (S)-1b-15: HPLC conditions: Chiralpak IA column, 94% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 6.36 min, t r (minor) = 8.27 min; = -54.4 (c = 0.5, CHCl3). [M+H] + : 403.0457, found 403.0462.

[0394] (S)-1b-47: HPLC conditions: Chiralpak IB column, 91% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.88 min, t r (major) = 9.69 min; = +22.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.30 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.47 - 7.39 (m, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.10 (dd, J = 9.1, 3.5 Hz, 1H), 2.14 (d, J = 12.1 Hz, 3H), 1.25 (d, J = 15.5 Hz, 9H);31 P NMR (162 MHz, Chloroform-d): δ 65.78; HRMS Calculated for C 15 H 19 O2P, [M + H] + : 263.1196, found 263.1204.

[0395] (R p ,S)-2b-47: HPLC conditions: Chiralpak IA column, 94% ee; Eluent: n-hexane / isopropanol = 75 / 25, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 9.24 min, t r (major) = 18.49 min; = +377.6 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 7.99 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 9.3 Hz, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 6.35 (d, J = 9.8 Hz, 1H), 1.23 (d, J = 16.0 Hz, 9H), 1.13 (d, J = 11.2 Hz, 3H); 31 P NMR (162 MHz, Chloroform-d): δ 58.67; HRMS Calculated for C 15 H 18 ClO2P, [M + H] + : 297.0806, found 297.0814.

[0396] (R)-1b-47: HPLC conditions: Chiralpak IB column, 91% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.02 min, t r (minor) = 10.23 min; = -25.2 (c = 0.5, CHCl3).;

[0397] (S)-1b-41: HPLC conditions: Chiralpak IA column, 88% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; tr (minor) = 7.24 min, t r (major) = 8.39 min; = +24.4 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ13.43 (s, 1H), 7.87 (t, J = 9.4 Hz, 2H), 7.81 - 7.66 (m, 2H), 7.57 (d, J = 5.7 Hz, 2H), 7.49 - 7.36 (m, 4H), 7.34 - 7.21 (m, 2H), 7.20 - 7.15 (m, 1H), 1.34 (d, J = 15.7 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ57.07; HRMS Calculated for C 22 H 23 O2P, [M+Na] + : 373.1379, found 373.1319.

[0398] (R p ,S)-2b-41: HPLC conditions: Chiralpak IB column, 99% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 8.68 min, t r (major) = 10.30 min; = -47.6 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ7.93 (d, J = 7.8 Hz, 1H), 7.46 - 7.42 (m, 3H), 7.24 - 6.99 (m, 7H), 6.32 (d, J = 10.3 Hz, 1H), 5.65 (dd, J = 26.4, 15.0 Hz, 1H), 1.28 (d, J = 16.1 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ45.21; HRMS Calculated for C 22 H 22 ClO2P, [M+Na] + : 407.0938, found 407.0940.

[0399] (R)-1b-41: HPLC conditions: Chiralpak IA column, 98% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 7.56 min, t r (minor) = 8.78 min; = -30.4 (c = 0.5, CHCl3).

[0400] (S)-1b-42: HPLC conditions: Chiralpak IC column, 85% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 9.05 min, t r (major) = 20.86 min; = +48.4 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.33 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.71 - 7.52 (m, 3H), 7.46 - 7.36 (m, 2H), 7.32 - 7.25 (m, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 - 6.90 (m, 4H), 6.59 (dd, J = 23.6, 14.0 Hz, 1H), 1.29 (d, J = 15.3 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 50.80; HRMS Calculated for C 22 H 23 O2P, [M + H] + : 351.1508, found 351.1516.

[0401] (R p ,S)-2b-42: HPLC conditions: Chiralpak IC column, 92% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 10.38 min, t r (major) = 12.16 min; = -532.5 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 7.97 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 9.8 Hz, 1H), 7.32 - 7.25 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 7.16 - 7.08 (m, 2H), 7.00 (d, J = 7.5 Hz, 1H), 6.68 (t, J = 17.3 Hz, 1H), 6.37 (d, J = 9.8 Hz, 1H), 6.26 (dd, J = 29.6, 17.2 Hz, 1H), 1.30 (d, J = 16.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 47.89; HRMS Calculated for C 22 H 22 ClO2P, [M+Na] + : 407.0938, found 407.0940.

[0402] (R)-1b-42: HPLC conditions: Chiralpak IC column, 91% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 9.00 min, t r (minor) = 21.19 min; α = -32.8 (c = 0.5, CHCl3).

[0403] (R)-1b-60: HPLC conditions: Chiralpak IA column, 96% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 5.63 min, t r (major) = 6.71 min; α = -28.8 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 8.56 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.85 - 7.69 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.40 (q, J = 7.0 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 9.7 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 1.38 (d, J = 16.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 58.24; HRMS Calculated for C 22 H 21 O2P, [M+Na] + : 465.1226, found 465.1230;

[0404] (S p ,S)-2b-60: HPLC conditions: Chiralpak IB column, 92% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 10.69 min, t r (major) = 13.56 min; = -186.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.02 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.43 - 7.37 (m, 3H), 7.30 (t, J = 7.7 Hz, 2H), 7.25 - 7.21 (m, 3H), 6.36 (d, J = 9.8 Hz, 1H), 1.37 (d, J = 18.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 34.10; HRMS Calculated for C 22 H 20 ClO2P, [M+K] + : 421.0521, found 421.0520.

[0405] (S)-1b-60: HPLC conditions: Chiralpak IA column, 92% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 5.67 min, t r (minor) = 6.73 min; = +29.6 (c = 0.5, CHCl3).

[0406] (R)-1b-14: HPLC conditions: Chiralpak IB column, 94% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 11.25 min, t r (major) = 8.76 min; = -14.4 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.54 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.51 (ddd, J = 11.6, 8.0, 1.6 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.19 (t, J = 7.1 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.89 (dd, J = 8.1, 2.5 Hz, 1H), 5.99 (d, J = 8.8 Hz, 2H), 1.47 (d, J = 15.4 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 58.93; HRMS Calculated for C 21 H 21 O4P, [M+K] + : 407.0809, found 407.0808;

[0407] (S p ,S)-2b-14: HPLC conditions: Chiralpak IC column, 91% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 23.59 min, t r (major) = 58.08 min; = -198.8 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 7.98 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 9.7 Hz, 1H), 7.06 (t, J = 9.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 9.5 Hz, 1H), 6.64 (dd, J = 7.9, 2.3 Hz, 1H), 6.16 (d, J = 9.7 Hz, 1H), 5.94 (d, J = 7.8 Hz, 2H), 1.34 (d, J = 16.2 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.41; HRMS Calculated for C 21 H 20 ClO4P, [M+Na] + : 425.0680, found 425.0683.

[0408] (S)-1b-14: HPLC conditions: Chiralpak IB column, 90% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 11.96 min t r (minor) = 8.96 min; = +13.6 (c = 0.5, CHCl3).

[0409] (R)-1b-34: HPLC conditions: Chiralpak IB column, 99% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.89 min, t r (major) = 5.39 min; = -70.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.51 (s, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.75 - 7.70 (m, 3H), 7.28 - 7.24 (m, 1H), 7.21 - 7.15 (m, 4H), 7.16 - 7.10 (m, 10H), 7.05 - 7.00 (m, 6H), 1.47 (d, J = 15.3 Hz, 9H); 31P NMR (162 MHz, Chloroform-d): δ 58.62; HRMS Calculated for C 40 H 35 O2P, [M+Na] + : 601.2267, found 601.2262.

[0410] (S p ,S)-2b-34: HPLC conditions: Chiralpak IC column, 84% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 24.92 min, t r (major) = 35.98 min; = -81.6 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 7.98 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.24 - 7.15 (m, 3H), 7.1 - 7.08 m, 9H), 7.02 - 6.89 (m, 8H), 6.88 - 6.82 (m, 2H), 6.08 (d, J = 9.8 Hz, 1H), 1.35 (d, J = 16.2 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 46.61; HRMS Calculated for C 40 H 34 ClO2P, [M+Na] + : 635.1877, found 635.1877.

[0411] (S)-1b-34: HPLC conditions: Chiralpak IB column, 84% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 7.41 min, t r (minor) = 5.07 min; = +118.0 (c = 0.5, CHCl3).

[0412] (R)-1b-35: HPLC conditions: Chiralpak IA column, 96% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r(minor) = 15.22 min, t r (major) = 11.84 min; = -50.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.02 (br, 1H), 8.58 (d, J = 11.1 Hz, 1H), 8.16 - 8.05 (m, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.71 - 7.63 (m, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.21 (dd, J = 9.0, 3.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 1.59 (d, J = 15.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 59.59; HRMS Calculated for C 26 H 23 O3P, [M + H] + : 415.1458, found 415.1457.

[0413] (S p ,S)-2b - 35: HPLC conditions: Chiralpak IA column, 92% ee; Eluent: n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 23.33 min, t r (major) = 25.41 min; = -164.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.13 - 8.01 (m, 2H), 7.86 (d, J = 7.7 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.56 - 7.54 (m, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.43 - 7.33 (m, 3H), 7.11 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 9.8 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.15 (d, J = 9.7 Hz, 1H), 1.43 (d, J = 16.1 Hz, 9H); 31P NMR (162 MHz, Chloroform-d): δ 46.89; HRMS Calculated for C 26 H 22 ClO3P, [M+Na] + : 471.0887, found 471.0894.

[0414] (S)-1b-35: HPLC conditions: Chiralpak IA column, 91% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 15.20 min, t r (minor) = 11.93 min; = +57.2 (c = 0.5, CHCl3).

[0415] (R)-1b-36: HPLC conditions: Chiralpak IA column, 91% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 15.22 min, t r (major) = 11.84 min; = -50.0 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.38 (s, 1H), 8.24 (d, J = 9.5 Hz, 1H), 8.04 (dd, J = 11.0, 7.9 Hz, 1H), 7.89 (d, J = 9.0 Hz, 1H), 7.71 - 7.68 (m, 2H), 7.62 - 7.48 (m, 3H), 7.36 (t, J = 7.3 Hz, 1H), 7.27 - 7.25 (m, 2H), 7.21 - 7.13 (m, 2H), 7.10 (t, J = 7.5 Hz, 1H), 1.52 (d, J = 15.6 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 58.81; HRMS Calculated for C 27 H 23 O3P, [M+Na] + : 449.1277, found 449.1271.

[0416] (S p,(S)-2b-36: HPLC conditions: Chiralpak IA column, 86% ee; eluent: hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 23.33 min, t r (major) = 25.41 min; = -164.8 (c = 0.5, CHCl3). m.p.: 157.5 - 158.4 °C. 1 1H NMR (400 MHz, Chloroform-d): δ 8.13 - 8.01 (m, 2H), 7.86 (d, J = 7.7 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.56 - 7.54 (m, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.43 - 7.33 (m, 3H), 7.11 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 9.8 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.15 (d, J = 9.7 Hz, 1H), 1.43 (d, J = 16.1 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.89; HRMS Calculated for C 26 18 22 H + ClO3P, [M+Na]

[0417] (S)-1b-36: HPLC conditions: Chiralpak IA column, 85% ee; eluent: hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 15.20 min, t r (minor) = 11.93 min; = +57.2 (c = 0.5, CHCl3).

[0418] (R)-1b-37: HPLC conditions: Chiralpak IA column, 98% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 18.24 min, t r (major) = 14.54 min; =-81.6 (c = 0.5, CHCl3). m.p.: 113.2 - 114.4 °C. 1 1H NMR (400 MHz, Chloroform-d): δ 8.56 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.85 - 7.69 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.40 (q, J = 7.0 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 9.7 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 1.38 (d, J = 16.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 58.24; HRMS Calculated for C 27 18 23 H15O4P, [M + Na] + : 465.1226, found 465.1230.

[0419] (S p ,S)-2b-37: HPLC conditions: Chiralpak IA column, 94% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 20.44 min, t r (major) = 16.66 min; =-70.0 (c = 0.5, CHCl3). m.p.: 200.9 - 201.7 °C. 1 1H NMR (400 MHz, Chloroform-d): δ 8.56 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.85 - 7.69 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.40 (q, J = 7.0 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 9.7 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.36 (d, J = 9.5 Hz, 1H), 1.38 (d, J = 16.4 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 47.10; HRMS Calculated for C 27 1822 ClO4P, [M+H] + : 461.1068, found 461.1074,

[0420] (S)-1b-37: HPLC conditions: Chiralpak IA column, 92% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 13.90 min, t r (minor) = 17.84 min; = +116.4 (c = 0.5, CHCl3).

[0421] (S)-1b-39: HPLC conditions: Chiralpak IB column, 96% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 9.50 min, t r (minor) = 7.67 min; = -10.8 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): 13.46 (s, 1H), 8.06 (d, J = 5.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (s, 2H), 7.25 (d, J = 8.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.17 - 7.09 (m, 2H), 1.45 (d, J = 15.8 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 51.86; HRMS Calculated for C 18 H 19 O2P1S1,

[0422] [M+H] + : 331.0916, found 331.0918;

[0423] (S p ,S)-2b-39: HPLC conditions: Chiralpak IC column, 98% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 16.87 min, tr (minor)=14.89 min; =-289.2 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.97 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 6.0, 2.4 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.16 (dt, J = 5.3, 2.9 Hz, 1H), 7.07 - 7.03 (m, 2H), 6.92 (d, J = 7.5 Hz, 1H), 6.17 (d, J = 9.8 Hz, 1H), 1.32 (d, J = 16.7 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 44.52; HRMS Calculated for C 18 H 18 ClO2PS, [M+Na] + : 387.0946, found 387.0349;

[0424] (R)-1b-39: HPLC conditions: Chiralpak IB column, 98% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major)=7.46 min, t r (minor)=9.59 min; =+8.0 (c = 0.5, CHCl3).

[0425] (S)-1b-38: HPLC conditions: Chiralpak IB column, 98% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor)=8.75 min, t r (major)=7.78 min; =+25.2 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.45 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 4.1 Hz, 1H), 7.70 - 7.68 (m, 2H), 7.33 (d, J = 8.5 Hz, 1H), 7.23 - 7.09 (m, 4H), 1.47 (d, J = 16.3 Hz, 9H);31 P NMR (162 MHz, Chloroform-d): δ 52.15; HRMS Calculated for C 18 H 19 O2PS, [M + H] + : 331.0916, found 331.0924.

[0426] (S p ,S)-2b-38: HPLC conditions: Chiralpak IC column, 94% ee; Eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 18.60 min, t r (major) = 20.65 min; = -142.8 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 8.00 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 4.4 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.09 (d, J = 9.8 Hz, 1H), 6.93 (d, J = 7.2 Hz, 2H), 6.22 (d, J = 9.8 Hz, 1H), 1.35 (d, J = 17.1 Hz, 9H); 31 P NMR (162 MHz, Chloroform-d): δ 45.63; HRMS Calculated for C 18 H 18 ClO2PS, [M + Na] + : 387.0346, found 387.0347.

[0427] (R)-1b-38: HPLC conditions: Chiralpak IB column, 94% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.83 min, t r (minor) = 7.66 min; = -29.2 (c = 0.5, CHCl3). -

[0428] (R)-1b-61: HPLC conditions: Chiralpak IB column, 95% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 7.87 min, t r (major) = 6.84 min; = +25.6 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.41 (s, 1H), 7.97 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.25 - 7.18 (m, 2H), 7.13 (dd, J = 9.0, 3.8 Hz, 1H), 6.69 (s, 1H), 1.40 (d, J = 16.2 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 50.90; HRMS Calculated for C 18 H 19 O3P, [M+Na] + : 337.0964, found 337.0962.

[0429] (S p ,S)-2b-61: HPLC conditions: Chiralpak IC column, 99% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 17.59 min, t r (major) = 14.02 min; = -217.2 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.99 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.33 - 7.24 (m, 3H), 7.21 (d, J = 9.9 Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.32 (s, 1H), 6.26 (d, J = 9.8 Hz, 1H), 1.30 (d, J = 16.8 Hz, 9H); 31 31P NMR (162 MHz, Chloroform-d): δ 45.03; HRMS Calculated for C18 H 18 PClO3, [M+Na] + : 371.0574, found 371.0575.

[0430] (S)-1b-61: HPLC conditions: Chiralpak IB column, 98% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 6.80 min, t r (major) = 7.65 min; = -30.4 (c = 0.5, CHCl3).

[0431] III. Preparation Route 2 of Compound B (Product 6, Product 7 and / or Product 8):

[0432] Example 10: Preparation of Compound (S)-2 and Compound (R)-2

[0433] Step 1: Preparation of (S p ,S)-2b-2 and (R p ,S)-2b-2

[0434]

[0435] In an Ar atmosphere, Cu(OTf)2 (3.6 mg, 0.01 mmol), ligand L1 (3.6 mg, 0.012 mmol), and 2.0 mL of anhydrous EA were successively added to a 10.0 mL Schlenk tube and stirred at room temperature for 30 min. Then, rac-2 (0.20 mmol) and 40 mg MS, DCDMH (0.2 mmol) were added, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the solvent was evaporated under reduced pressure and purified by column chromatography. The eluent was (petroleum ether: ethyl acetate = 2:1 (V / V)), and the products (S p ,S)-2b-2 (yield 49%) and (R p ,S)-2b-2 (yield 46%) were obtained.

[0436] (R p ,S)-2b-2: HPLC conditions: Chiralpak IA column, 95% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 10.07 min, t r (major) = 16.49 min; =-472.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.59 - 7.44 (m, 4H), 7.41 - 7.34 (m, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.24 (t, J = 6.7 Hz, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.68 (d, J = 7.9 Hz, 1H), 6.39 (d, J = 9.9 Hz, 1H), 2.93 (h, J = 7.1 Hz, 1H), 1.22 (dd, J = 16.7, 7.1 Hz, 3H), 1.11 (dd, J = 18.3, 7.3 Hz, 3H).; 31 31P NMR (162 MHz, Chloroform-d): δ 49.31; HRMS Calculated for C 19 H 18 ClO2P, [M + H] + : 345.0806, found 345.0815.

[0437] (S p ,S)-2b-2: HPLC conditions: Chiralpak IA column, 97% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 9.46 min, t r (minor) = 13.02 min; =-147.6 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.10 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.32 (q, J = 4.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 7.14 - 7.02 (m, 4H), 6.86 (t, J = 9.3 Hz, 2H), 6.05 (d, J = 9.8 Hz, 1H), 2.71 (pt, J = 10.7, 5.3 Hz, 1H), 1.68 (dd, J = 16.1, 6.8 Hz, 3H), 1.04 (dd, J = 18.4, 7.3 Hz, 3H); 31 31P NMR (162 MHz, Chloroform-d): δ 45.55; HRMS Calculated for C 19 H 18 ClO2P, [M + Na] +: 367.0625, found 367.0623;

[0438] Step 2: Preparation of compound (R)-2

[0439]

[0440] In a 5 mL Schlenk tube, add (R p ,S)-2b-2 (0.1 mmol), Et3N (0.3 mmol), 1 mL of acetonitrile, stir at room temperature under blue light for 3 hours. After the reaction is completed, evaporate the solvent under reduced pressure and purify by column chromatography to obtain the corresponding product (R)-2 (yield 95%, product 6).

[0441] (R)-2: HPLC conditions: Chiralpak IC column, 96% ee; eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 12.87 min, t r (minor) = 26.80 min; = -36.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 13.46 (s, 1H), 7.94 - 7.82 (m, 3H), 7.70 (d, J = 7.4 Hz, 1H), 7.54 - 7.39 (m, 4H), 7.28 - 7.21 (m, 2H), 7.14 (dd, J = 8.8, 3.7 Hz, 1H), 3.10 - 3.02 (m, 1H), 1.54 (dd, J = 16.0, 6.9 Hz, 3H), 1.15 (dd, J = 17.7, 7.2 Hz, 3H); 31 31P NMR (162 MHz, Chloroform-d): δ 55.07; HRMS Calculated for C 19 H 19 O2P1, [M+Na] + : 333.1015, found 333.1025;

[0442] Step 3: Preparation of compound (S)-2

[0443]

[0444] In a 5 mL Schlenk tube, add (S p, (S)-2b-2 (0.1 mmol), Et3N (0.3 mmol), 1 mL of acetonitrile, stirred at room temperature under blue light for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure and purified by column chromatography to obtain the corresponding product (S)-2 (yield 96%, product 7).

[0445] (S)-2: HPLC conditions: Chiralpak IC column, 91% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 12.93 min, t r (major) = 26.56 min; = +36.4 (c = 0.5, CHCl3).

[0446] Example 11:

[0447] Referring to the preparation method of Example 10, rac-2 in Step 1 of Example 10 was replaced with the reaction substrates in Table 5 to prepare products 4 and 5. (R p ,S)-2b-2 in Step 2 of Example 10 was replaced with Product 4 in Table 5 to prepare Product 6; (S p ,S)-2b-2 in Step 3 of Example 10 was replaced with Product 5 in Table 5 to prepare Product 7.

[0448] Table 5:

[0449]

[0450]

[0451] Separation conditions and structure characterization:

[0452] (S p ,S)-51: HPLC conditions: Chiralpak IA column, 97% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 14.56 min, t r (major) = 48.71 min; = -280.8 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 8.02 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.39 (dt, J = 21.4, 7.7 Hz, 2H), 7.20 (td, J = 7.7, 3.0 Hz, 2H), 7.13 - 7.00 (m, 3H), 6.88 (d, J = 9.8 Hz, 1H), 5.85 (d, J = 9.8 Hz, 1H), 3.87 - 3.70 (m, 1H), 3.02 - 2.83 (m, 1H), 2.42 (ddt, J = 15.6, 7.7, 3.7 Hz, 1H), 2.31 - 2.11 (m, 2H), 2.09 - 1.92 (m, 2H); 31 31P NMR (162 MHz, Chloroform-d): δ 40.68; HRMS Calculated for C 20 H 18 ClO2P, [M+K] + : 395.0365, found 395.0362;

[0453] (R p ,S)-51: HPLC conditions: Chiralpak IA column, 76% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 12.02 min, t r (minor) = 19.38 min; = -438.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.49 (d, J = 9.6 Hz, 2H), 7.41 - 7.19 (m, 6H), 7.09 (d, J = 6.2 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 6.33 (d, J = 9.8 Hz, 1H), 3.79 - 3.64 (m, 1H), 2.48 - 2.40 (m, 1H), 2.16 - 1.93 (m, 4H), 1.90 - 1.80 (m, 1H); 31 31P NMR (162 MHz, Chloroform-d): δ 46.92; HRMS Calculated for C 20 H 18 ClO2P, [M+Na] + : 379.0625, found 379.0623;

[0454] (R)-51: HPLC conditions: Chiralpak IC column, 96% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (major) = 12.87 min, t r (minor) = 26.80 min; = -36.8 (c = 0.5, CHCl3).

[0455] (S)-51: HPLC conditions: Chiralpak IC column, 91% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 12.93 min, t r (major) = 26.56 min; = +36.4 (c = 0.5, CHCl3).

[0456] (S p ,S)-54: HPLC conditions: Chiralpak IA column, 90% ee; eluent: hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 20.22 min, t r (major) = 42.52 min; = -166.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.03 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.08 - 6.99 (m, 4H), 6.83 (d, J = 9.9 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.02 (d, J = 9.8 Hz, 1H), 2.88 - 7.73 (m, 1H), 2.59 - 2.46 (m, 1H), 2.10 - 1.94 (m, 1H), 1.87 - 1.75 (m, 1H), 1.69 - 1.42 (m, 8H), 1.33 - 1.23 (m, 1H); 31 31P NMR (162 MHz, Chloroform-d): δ 47.15; HRMS Calculated for C 23 H 24 ClO2P, [M + H] +: 399.1275, found 399.1277;

[0457] (R p ,S)-54: HPLC conditions: Chiralpak IA column, 97% ee; Eluent: n-hexane / isopropanol = 90 / 10, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 18.64 min, t r (minor) = 38.62 min; = -428.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.54 - 7.47 (m, 4H), 7.37 - 7.31 (m, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 9.9 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.05 - 1.95 (m, 1H), 1.92 - 1.82 (m, 1H), 1.72 - 1.63 (m, 2H), 1.59 - 1.46 (m, 6H), 1.44 - 1.37 (m, 2H); 31 31P NMR (162 MHz, Chloroform-d): δ 51.40; HRMS Calculated for C 23 H 24 ClO2P, [M + H] + : 399.1275, found 399.1276;

[0458] (R)-54: HPLC conditions: Chiralpak IA column, 97% ee; Eluent: n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 19.27 min, t r (minor) = 21.13 min; = -52.8 (c = 0.5, CHCl3).

[0459] (S)-54: HPLC conditions: Chiralpak IA column, 88% ee; Eluent: n-hexane / isopropanol = 95 / 5, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 19.21 min, t r(major) = 20.77 min; = +60.8 (c = 0.5, CHCl3).

[0460] (S p ,S)-48: HPLC conditions: Chiralpak IA column, 92% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 9.64 min, t r (major) = 14.24 min; = -252.0 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.06 (d, J = 8.1 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.31 (t, J = 6.3 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.15 - 7.04 (m, 4H), 6.87 (d, J = 9.8 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.06 (d, J = 9.8 Hz, 1H), 2.50 - 2.32 (m, 2H), 2.28 - 2.14 (m, 1H), 1.62 - 1.47 (m, 2H), 1.14 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H); 31 31P NMR (162 MHz, Chloroform-d): δ 45.88; HRMS Calculated for C 21 H 22 ClO2P, [M + H] + : 373.1119, found 373.1120;

[0461] (R p ,S)-48: HPLC conditions: Chiralpak IA column, 94% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 7.89 min, t r (minor) = 13.82 min; = -557.6 (c = 0.5, CHCl3). m.p.: 104.2 - 105.8 °C. 11H NMR (400 MHz, Chloroform-d): δ 7.57 - 7.48 (m, 4H), 7.39 - 7.31 (m, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 8.6 Hz, 1H), 6.40 (d, J = 9.8 Hz, 1H), 2.65 - 2.53 (m, 1H), 1.84 - 1.74 (m, 1H), 1.74 - 1.66 (m, 2H), 1.61 - 1.51 (m, 1H), 0.96 (t, J = 7.4 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H); 31 31P NMR (162 MHz, Chloroform-d): δ 48.68; HRMS Calculated for C 21 H 22 ClO2P, [M + H] + : 373.1119, found 373.1117;

[0462] (R)-48: HPLC conditions: Chiralpak IA column, 94% ee; Eluent: n-Hexane / Isopropanol = 95 / 5, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 13.66 min, t r (minor) = 15.62 min; = -40.4 (c = 0.5, CHCl3).

[0463] (S)-48: HPLC conditions: Chiralpak IA column, 91% ee; Eluent: n-Hexane / Isopropanol = 95 / 5, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 13.75 min, t r (major) = 15.44 min; = +34.0 (c = 0.5, CHCl3).

[0464] (S p ,S)-55: HPLC conditions: Chiralpak IA column, 97% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 9.92 min, t r (major) = 14.32 min; =-306.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.06 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.18 - 7.05 (m, 4H), 6.89 (d, J = 9.9 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 6.05 (d, J = 9.8 Hz, 1H), 2.61 - 2.48 (m, 1H), 2.28 - 2.11 (m, 2H), 1.85 - 1.72 (m, 1H), 1.70 - 1.57 (m, 1H), 1.54 - 1.40 (m, 4H), 1.39 - 1.27 (m, 8H), 1.29 - 1.28 (m, 4H), 1.15 - 1.08 (m, 2H); 31 31P NMR (162 MHz, Chloroform-d): δ 45.56; HRMS Calculated for C 28 H 34 ClO2P, [M + H] + : 469.2058, found 469.2053;

[0465] (R p ,S)-55: HPLC conditions: Chiralpak IA column, 90% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.02 min, t r (minor) = 13.18 min; =-458.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.59 - 7.50 (m, 4H), 7.39 - 7.33 (m, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.42 (d, J = 9.8 Hz, 1H), 2.77 - 2.66 (m, 1H), 1.78 - 1.64 (m, 3H), 1.56 - 1.43 (m, 5H), 1.39 - 1.29 (m, 6H), 1.22 - 1.03 (m, 7H), 0.98 - 0.93 (m, 1H); 31P NMR (162 MHz, Chloroform-d): δ 43.25; HRMS Calculated for C 28 H 34 ClO2P, [M+Na] + : 491.1877, found 491.1874;

[0466] (R)-55: HPLC conditions: Chiralpak IA column, 81% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 8.31 min, t r (minor) = 9.34 min; = -36.8 (c = 0.5, CHCl3).

[0467] (S)-55: HPLC conditions: Chiralpak IA column, 96% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 8.39 min, t r (major) = 9.25 min; = +36.4 (c = 0.5, CHCl3).

[0468] (S p (S)-63: HPLC conditions: Chiralpak IC column, 98% ee; Eluent: n-Hexane / Isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 23.12 min, t r (major) = 55.31 min; = -162.0 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 8.14 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.35 - 7.28 (m, 2H), 7.22 - 7.13 (m, 5H), 7.10 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 9.8 Hz, 1H), 6.00 (d, J = 9.8 Hz, 1H), 3.97 - 3.81 (m, 1H), 3.77 - 3.65 (m, 1H), 3.57 (p, J = 9.0 Hz, 1H), 3.18 - 3.02 (m, 1H), 2.93 - 2.79 (m, 1H); 31 31P NMR (162 MHz, Chloroform-d): δ 51.90; HRMS Calculated for C 25 H 20 ClO2P, [M + H] + : 419.0962, found 419.0963;

[0469] (R p ,S)-63: HPLC conditions: Chiralpak IC column, 94% ee; Eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 28.12 min, t r (minor) = 80.32 min; α = -288.4 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.60 - 7.50 (m, 4H), 7.43 - 7.36 (m, 2H), 7.35 - 7.29 (m, 2H), 7.19 (d, J = 7.0 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.09 - 6.99 (m, 3H), 6.75 (d, J = 6.8 Hz, 1H), 6.45 (d, J = 9.8 Hz, 1H), 3.82 - 3.69 (m, 1H), 3.40 - 3.26 (m, 1H), 3.19 - 3.07 (m, 1H), 3.04 - 2.90 (m, 2H); 31 31P NMR (162 MHz, Chloroform-d): δ 50.06; HRMS Calculated for C 25 H 20ClO2P, [M+H] + : 419.0962, found 419.0965;

[0471] (R)-63: HPLC conditions: Chiralpak IA column, 93% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 53.17 min, t r (minor) = 23.81 min; = -36.8 (c = 0.5, CHCl3).

[0472] (S)-63: HPLC conditions: Chiralpak IA column, 98% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 53.08 min, t r (major) = 23.38 min; = +36.4 (c = 0.5, CHCl3).

[0473] (S p ,S)-56: HPLC conditions: Chiralpak IA column, 93% ee; Eluent: n-hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 20.27 min, t r (major) = 28.87 min; = -176.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 8.11 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 6.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 2H), 7.16 - 7.05 (m, 4H), 6.90 (d, J = 9.9 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 9.8 Hz, 1H), 4.15 - 4.08 (m, 1H), 3.95 - 3.85 (m, 1H), 3.56 (t, J = 11.3 Hz, 1H), 3.46 - 3.33 (m, 1H), 2.82 - 2.65 (m, 2H), 2.37 - 2.25 (m, 1H), 1.89 - 1.76 (m, 1H), 1.32 - 1.24 (m, 1H);31 P NMR (162 MHz, Chloroform-d): δ 41.32; HRMS Calculated for C 21 H 20 ClO3P, [M+H] + : 387.0911, found 387.0905;

[0474] (R p ,S)-56: HPLC conditions: Chiralpak IA column, 98% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 18.70 min, t r (minor) = 28.71 min; = -425.2 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 8.06 (d, J = 8.1 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.34 - 7.27 (m, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.13 - 6.97 (m, 4H), 6.91 - 6.72 (m, 2H), 6.06 (d, J = 9.8 Hz, 1H), 4.12 - 3.99 (m, 1H), 3.91 - 3.78 (m, 1H), 3.52 (t, J = 11.8 Hz, 1H), 3.36 (t, J = 11.6 Hz, 1H), 2.81 - 2.59 (m, 2H), 2.35 - 2.16 (m, 1H), 1.86 - 1.68 (m, 1H), 1.26 - 1.17 (m, 1H); 31 P NMR (162 MHz, Chloroform-d): δ 41.20; HRMS Calculated for C 21 H 20 ClO3P, [M+H] + : 387.0911, found 387.0910;

[0476] (R)-56: HPLC conditions: Chiralpak IA column, 96% ee; Eluent: n-Hexane / Isopropanol = 85 / 15, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (major) = 13.83 min, t r (minor) = 19.16 min; =-8.0 (c = 0.5, CHCl3).

[0477] (S)-56: HPLC conditions: Chiralpak IA column, 93% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor)=14.74 min, t r (major)=18.37 min; =+22.0 (c = 0.5, CHCl3).

[0478] Example 12: Preparation of (S)-1b-64

[0479]

[0480] In an Ar atmosphere, Zn(OTf)2 (3.6 mg, 0.01 mmol), ligand L2 (7.18 mg, 0.012 mmol), and 2.0 mL of anhydrous DME were successively added to a 10.0 mL Schlenk tube and stirred at room temperature for 1 h. Then, compound rac-64 (0.20 mmol) and 40 mg MS, DCDMH (0.1 mmol) were added, and the reaction was carried out at 0 °C for 1 h. After the reaction was completed, the reaction mixture was quenched with a saturated aqueous solution of sodium sulfite, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, the solvent was evaporated under reduced pressure, and the product was purified by column chromatography. The eluent was (petroleum ether: ethyl acetate = 5:1 (V / V)), and the product (S)-1b-64 was obtained (yield 46%, product 8).

[0481] (S)-1b-64: HPLC conditions: Chiralpak IA column, 95% ee; eluent: hexane / isopropanol = 85 / 15, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor)=8.11 min, t r (major)=9.53 min; =+41.6 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 13.37 (s, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 12.5, 7.6 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.50 - 7.35 (m, 4H), 7.32 - 7.24 (m, 2H), 7.24 - 7.15 (m, 3H), 7.07 (t, J = 7.8 Hz, 1H), 2.53 (s, 3H); 31 31P NMR (162 MHz, Chloroform-d): δ 44.61; HRMS Calculated for C 23 H 19 O2P, [M + H] + : 359.1196, found 359.1195.

[0482] Example 13:

[0483] Referring to the preparation method of Example 12, replace the compound rac-64 with the reaction substrate in Table 6 to obtain the product 8.

[0484] Table 6:

[0485]

[0486]

[0487] Separation conditions and structure characterization:

[0488] (S)-1b-68: HPLC conditions: Chiralpak IC column, 99% ee; eluent: hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; temperature = 25 °C, wavelength = 250 nm; t r (minor) = 9.33 min, t r (major) = 11.61 min; = +20.8 (c = 0.5, CHCl3). 1 1H NMR (400 MHz, Chloroform-d): δ 7.96 (d, J = 9.0 Hz, 1H), 7.84 (dd, J = 12.7, 7.6 Hz, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.27 - 7.16 (m, 5H), 7.11 (t, J = 7.6 Hz, 1H), 2.46 (s, 3H);31 PNMR (162 MHz, Chloroform-d): δ 43.3 (d, J = 8.8 Hz); 19 F NMR (376 MHz, Chloroform-d): δ -114.68;

[0489] (R)-1b-69: HPLC conditions: Chiralpak IC column, 99% ee; Eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 15.38 min, t r (major) = 20.83 min; = +244.4 (c = 0.5, CHCl3). 1 H NMR (400 MHz, Chloroform-d): δ 13.02 (s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.83 - 7.73 (m, 3H), 7.73 - 7.59 (m, 8.4 Hz, 3H), 7.56 - 7.48 (m, 2H), 7.37 (dd, J = 8.0, 3.8 Hz, 1H), 7.24 (dd, J = 8.2, 4.1 Hz, 1H), 7.20 (dd, J = 9.0, 4.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 2H), 2.58 (s, 3H); 31 P NMR (162 MHz, Chloroform-d): δ 42.26;

[0490] (S)-1b-72: HPLC conditions: Chiralpak IC column, 99% ee; Eluent: n-hexane / isopropanol = 70 / 30, flow rate = 1.0 mL / min; Temperature = 25 °C, wavelength = 250 nm; t r (minor) = 17.42 min, t r (major) = 24.00 min; = +143.2 (c = 0.5, CHCl3). 11H NMR (400 MHz, Chloroform-d): δ 13.18 (s, 1H), 7.93 (d, J = 9.1 Hz, 2H), 7.85 (d, J = 7.7 Hz, 1H), 7.79 (dd, J = 12.5, 7.6 Hz, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.53 - 7.43 (m, 3H), 7.24 - 7.15 (m, 3H), 7.06 (t, J = 7.8 Hz, 1H), 3.90 (s, 3H), 2.56 (s, 3H); 31 31P NMR (162 MHz, Chloroform-d): δ 44.44;

[0491] IV. Preparation of Compound W:

[0492] Example 14:

[0493]

[0494] Cs2CO3 (146.6 mg, 0.45 mmol), CH3I (85.2 mg, 0.6 mmol), compound (R)-1b-1 (97.2 mg, 0.3 mmol) and 3.0 mL of MeCN were mixed and stirred for 12 h until thin layer chromatography showed the reaction was complete. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (petroleum ether: ethyl acetate (V / V) = 1:1 → 1:2) to obtain compound (R)-1b-1-c. Then, compound rac-1-c (67.6 mg, 0.20 mmol), methyl trifluoromethanesulfonate (28 μL added under argon, 0.24 mmol) and 2 mL of toluene were mixed. The resulting mixture was stirred at 0 °C for 2 h, and then lithium aluminum hydride (0.5 mL, 1.0 mol / L in THF, 0.5 mmol) was added successively at -78 °C. After the reaction was complete, BH3·THF (1.5 mL, 1.0 mol / L, 0.8 mmol) was added and reacted for 2 h. The reaction was quenched with water, and the resulting solution was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and the filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate (V / V) = 200:1 → 100:1) to obtain compound (R)-1b-1-L (61% yield, 97% ee). HRMS Calculated for C 21 H 26 BOP, [M+K] + : 375.1446, found 375.1440.

[0495] Refer to the preparation method of Example 14 above, and prepare Product 9 in Table 7 by replacing the compound (R)-1b-1 with the reaction substrates in Table 7.

[0496] Table 7:

[0497]

[0498] Note: The "→" where P points to B in the above (R)-1b-1-L and each Product 9 represents a coordination bond.

[0499] Similarly, refer to the above method to prepare the corresponding Product 9 of these compounds of (R)-1b-1, (R)-1b-8, (R)-1b-9, (R)-1b-10, (R)-1b-14, (R)-1b-15, (R)-1b-22, (R)-1b-25, (R)-1b-19, (R)-1b-27, (R)-1b-28, (R)-1b-34, (R)-1b-35, (R)-1b-36, (R)-1b-37, (R)-1b-39, (R)-1b-41, (R)-1b-42, (R)-1b-47, (R)-48, (R)-51, (R)-54, (R)-1b-60, (R)-1b-61, (R)-63 respectively.

[0500] V. Application Examples of Compound B and Compound W

[0501] Application Example 1: Asymmetric Allylation Reaction

[0502]

[0503] Under an Ar atmosphere, [Pd(allyl)Cl]2 (0.9 mg, 0.0025 mmol), compound (R)-1-b-1-L (10 mol%) (as a ligand) (3.4 mg, 0.012 mmol), K3PO4 (42.5 mg, 0.2 mmol), compound Q (25.2 mg, 0.1 mmol) and compound R (24.0 mg, 0.15 mmol) were mixed with 2.0 mL of anhydrous CH2Cl2, and stirred at room temperature for 12 h until the reaction was completed. After the reaction was completed, the reaction was quenched with water, the mixture was extracted with ethyl acetate, the combined organic layers were dried over anhydrous MgSO4, the solvent was evaporated under reduced pressure, and purified by column chromatography with an eluent (petroleum ether:ethyl acetate = 10:1 (V / V)) to obtain compound S (62% yield, 54% ee).

[0504] Refer to the method of Application Example 1 above, replace the compound rac-1-L with the ligand in Table 8 in the same molar amount, and examine the yield and ee value of the obtained compound S.

[0505] Table 8:

[0506]

[0507] Referring to the above method and using the products 9 corresponding to the compounds (R)-1b-1, (R)-1b-8, (R)-1b-9, (R)-1b-10, (R)-1b-14, (R)-1b-15, (R)-1b-22, (R)-1b-25, (R)-1b-19, (R)-1b-27, (R)-1b-28, (R)-1b-34, (R)-1b-35, (R)-1b-36, (R)-1b-37, (R)-1b-39, (R)-1b-41, (R)-1b-42, (R)-1b-47, (R)-48, (R)-51, (R)-54, (R)-1b-60, (R)-1b-61, (R)-63 as ligands to prepare compound S, the yields of the obtained compound S are all 47%-80%, and the ee values are 30%-73%.

[0508] Application Example 2: Asymmetric alkylation reaction

[0509]

[0510] Referring to the method of Application Example 1, replacing compound rac-1-L with the same molar amount of (S)-64-L, and performing the remaining operations the same as in Application Example 1, compound S-2 was obtained. The yield of compound S-2 was 66%; the ee value of compound S was 78%.

[0511] Conclusion: It can be seen from the results of Application Example 1 and Application Example 2 that by synthesizing product 9 (compound W) from the compounds included in compound B provided by the present invention and using product 9 (compound W) as a ligand in the asymmetric allylation reaction, it is beneficial to improve the yield and ee value of the obtained product.

[0512] Application Example 3: Application in asymmetric reductive hydrogenation reaction

[0513]

[0514] In an Ar atmosphere, compound (R)-1b-11 (as a ligand) (0.01 mmol) was mixed with 2.0 mL of anhydrous toluene, and then compound T (0.20 mmol) and compound U (0.60 mmol) were added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, it was quenched with dilute hydrochloric acid, the mixture was extracted with ethyl acetate, the combined organic layers were dried over anhydrous MgSO4, the solvent was rotary evaporated under reduced pressure, and purified by column chromatography. The eluent was (petroleum ether:ethyl acetate = 5:1 (V / V)), and compound V was obtained (90% yield, 43% ee).

[0515] Referring to the method of Application Example 3 above, replace the compound (R)-1b-11 with the ligand in Table 9 in the same molar amount, and examine the yield and ee value of the obtained compound V.

[0516] Table 9:

[0517]

[0518] Referring to the above method and using (R)-1b-1, (R)-1b-8, (R)-1b-9, (R)-1b-10, (R)-1b-14, (R)-1b-15, (R)-1b-22, (R)-1b-25, (R)-1b-19, (R)-1b-27, (R)-1b-28, (R)-1b-34, (R)-1b-35, (R)-1b-36, (R)-1b-37, (R)-1b-39, (R)-1b-41, (R)-1b-42, (R)-1b-47, (R)-48, (R)-51, (R)-54, (R)-1b-60, (R)-1b-61, (R)-63 as ligands to prepare compound V, the yield of the obtained compound V is 74%-82%, and the ee value is 46%-76%.

[0519] Application Example 4: Application in Asymmetric Reduction Hydrogenation Reaction

[0520]

[0521] Referring to the method of Application Example 3 above, replace the compound (R)-1b-11 with the same molar amount of (S)-64 to obtain compound V-2. The yield of the obtained compound V-2 is 87%, and the ee value of compound V-2 is 60%.

[0522] Conclusion: From the results of Application Examples 3 and 4 above, it can be seen that the compounds included in compound B provided by the present invention can be used in asymmetric reduction hydrogenation reactions, which is beneficial to improving the yield and ee value of the obtained products.

[0523] In the description of this specification, the description referring to terms such as "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0524] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a chiral phosphine compound, characterized in that, Comprising: Under the condition of blue light irradiation, compound A reacts with a dehalogenating agent in a first solvent to obtain compound B; Wherein, in compound A and compound B, "*" represents a chiral center where the indicated P is in the S configuration or the R configuration; X is F, Cl, Br or I; Ar is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted phenanthrene ring, substituted or unsubstituted anthracene ring; R 1 selected from substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzyl; R 2 selected from substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted styryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; and R 1 is different from R 2 ; Optionally, the carbon on Ar of compound A connected to X is a chiral carbon in the S configuration.

2. The preparation method according to claim 1, wherein compound A, compound B, R 1 and R 2 are selected from any one of the following groups: (1)R 1 is tert-butyl; R 2 Selected from: (1-1) methyl, cyclopentyl, (1-2) phenyl, R 3 selected from F, Cl, Br, I, cyano, nitro, methyl formate group, ethyl acetate group, trifluoromethyl, methoxy, phenyl; R 4 selected from F, Cl, Br, I, cyano, methyl formate, ethyl acetate, aldehyde, trifluoromethyl, methoxy, phenyl; R 5 selected from F, Cl, Br, I, cyano, methyl formate, ethyl acetate, aldehyde, trifluoromethyl, methoxy, phenyl; R 6 selected from F, Cl, Br, I, cyano, methyl formate, ethyl acetate, aldehyde, trifluoromethyl, methoxy, phenyl, methyl, tert-butyl; Compound A is selected from: Compound B correspondingly is selected from: (2)R 1 is phenyl; R 2 selected from (2-1) methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctane, cyclononane, cyclodecane, cycloundecane, cyclododecane, Compound A is selected from: Compound B correspondingly is selected from: (3)R 1 selected from isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 2 is phenyl; Compound A is selected from: Compound B correspondingly is selected from:

3. According to the preparation method described in claim 1, the dehalogenating agent includes at least one of NaH, SiHCl3, triethylamine, CuCl; preferably, the dehalogenating agent is triethylamine; and / or The molar ratio of compound A to the dehalogenating agent in the feed is 1:1 to 2:1; and / or The reaction temperature of the first reaction is -35°C to 40°C; The first solvent includes at least one of acetonitrile, ethylene glycol dimethyl ether, ethyl acetate, 1,2-dichloroethane; and / or Optionally, the preparation method of compound B further includes performing a first post-treatment after the first reaction; and / or The first post-processing includes: Rotary evaporate the solvent under reduced pressure and purify.

4. A method for preparing a compound A, characterized in that, Comprising: In an inert gas or nitrogen atmosphere, compound C reacts with a halogenating agent in a second solvent in the presence of catalyst I, molecular sieve and ligand to obtain compound A; Among them, compound A, R 1 , R 2 have the meanings shown in the (3) group in the preparation method described in claim 2 respectively, and the meanings of "*" and X in compound A are the same as those of "*" and X in compound A in the preparation method described in claim 1; or Optionally, R of compound C and compound B in the second reaction 1 is tert-butyl, and R of compound C and compound B 2 is selected from the R groups in Group (1) of the preparation method according to claim 2 2 ; in the obtained compound B, "*" indicates that the marked P is a chiral center with an S configuration Optionally, R of compound C and compound B in the second reaction 1 is phenyl, and R of compound C and compound B 2 is selected from the R of group (2-1) of group (2) in the preparation method according to claim 2 2 group, and "*" in the resulting compound B indicates that the P marked by it is a chiral center with an S configuration; Optionally, the R of compound C and compound B in the second reaction 1 is selected from the R of group (3) of the preparation method according to claim 2 1 group, and the R of compound C and compound B 2 is selected from the R of group (3) of the preparation method according to claim 2 2 group, and in the resulting compound B, "*" indicates that the P marked by it is a chiral center with an S configuration; Optionally, R of compound C and compound B in the second reaction 1 is phenyl, and R of compound C and compound B 2 is selected from the R of group (2-2) of group (2) in the preparation method according to claim 2 2 group, and "*" in the resulting compound B indicates that the P marked by it is a chiral center with an R configuration.

5. According to the preparation method described in claim 4, catalyst I includes at least one of CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2, Zn(OTf)2; preferably, catalyst I is Cu(OTf)2; and / or The ligand includes Among them, R 7 selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 7 is tert-butyl; R 8 selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 8 is phenyl; Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl, preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl; Optionally, the second solvent includes one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, methanol, etc.; preferably, the second solvent is ethyl acetate; Optionally, the halogenating agent includes at least one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin; preferably, the halogenating agent is 1,3-dichloro-5,5-dimethylhydantoin; Optionally, the molar ratio of catalyst I to compound C in the feed is 1:100 to 50:100; preferably, the molar ratio of catalyst I to compound C in the feed is 10:100; Optionally, the molar ratio of catalyst I to the ligand is 1:1 to 1:2, preferably 1:1.2; Optionally, the reaction temperature of the second reaction is -78°C to 25°C; preferably, it is -35°C, 0°C or 25°C; Optionally, the reaction time of the second reaction is 0.5 - 10 h; preferably, it is 0.5 h or 1 h; Optionally, the method for preparing compound A further includes performing a second post-treatment after the second reaction; Optionally, the second post-treatment includes: quenching the reaction, extracting with ethyl acetate, drying the organic phase layer with anhydrous MgSO4, evaporating the solvent, and purifying; Optionally, the particle size of the molecular sieve is 3 Å, 4 Å, or 5 Å; Optionally, the inert gas includes at least one of helium, neon, argon, krypton, or xenon.

6. A method for preparing compound B, which includes preparing compound A according to the preparation method described in any one of claims 4 - 5, and then preparing compound B according to the preparation method described in any one of claims 1 - 3.

7. A method for preparing compound B, characterized in that, Including: In an inert gas or nitrogen atmosphere, compound C undergoes a third reaction with a halogenating reagent in a third solvent in the presence of catalyst II, a molecular sieve, and a ligand to obtain compound B; Among them, compound B, R 1 , R 2 are as defined in Group (1), Group (2) or Group (3) of the preparation method described in claim 2, X is as defined in the preparation method described in claim 1, and "*" in compound B indicates that the P marked thereby is a chiral center of R configuration or S configuration; Optionally, the particle size of the molecular sieve is 3 Å, 4 Å, or 5 Å; Optionally, R of compound C and compound B in the third reaction 1 is tert-butyl, and R of compound C and compound B 2 is selected from the R 2 groups of group (1) of the preparation method according to claim 2, and "*" in the obtained compound B indicates that the P marked by it is a chiral center with an R configuration; Optionally, R of compound C and compound B in the third reaction 1 is phenyl, and R of compound C and compound B 2 is selected from the R 2 group of group (2-1) of group (2) of the preparation method according to claim 2, and "*" in the resulting compound B indicates that the P marked by it is a chiral center with an R configuration; Optionally, the R of compound C and compound B in the third reaction 1 R selected from group (3) of the preparation method according to claim 2 1 group, the R of compound C and compound B 2 R selected from group (3) of the preparation method according to claim 2 2 group, in the resulting compound B, "*" indicates that the P marked by it is a chiral center with an R configuration; Optionally, R of compound C and compound B in the third reaction 1 is phenyl, and R of compound C and compound B 2 is selected from the R of group (2-2) of group (2) in the preparation method according to claim 2, 2 and in the resulting compound B, "*" indicates that the P marked thereby is a chiral center with an S configuration.

8. According to the preparation method described in claim 7, catalyst II includes at least one of CuCl2, CuBr2, Cu(OTf)2, Cu(OAc)2, Zn(OTf)2; preferably, catalyst II is Cu(OTf)2; and / or The ligand includes Among them, R 7 selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 7 is tert-butyl; R 8 selected from isopropyl, phenyl, benzyl or tert-butyl, preferably, R 8 is phenyl; Ar1 is selected from 4-tert-butylphenyl, 4-adamantylphenyl, 3,5-di-tert-butylphenyl, 4-methylphenyl, 4-trifluoromethylphenyl; preferably, Ar1 is 4-tert-butylphenyl or 4-adamantylphenyl; Optionally, the third solvent includes one or more of toluene, dichloromethane, chloroform, ether, ethyl acetate, THF, acetone, acetonitrile, DMF, methanol, etc.; preferably, the second solvent is ethyl acetate; Optionally, the halogenating reagent includes at least one of N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin; preferably, the halogenating reagent is 1,3-dichloro-5,5-dimethylhydantoin; Optionally, the molar ratio of catalyst II to compound C in the feed is 1:100 - 50:100; preferably, the molar ratio of catalyst II to compound C in the feed is 5:100; Optionally, the molar ratio of catalyst II to the ligand in the feed is 1:1 - 1:2, preferably 1:1.2; Optionally, the reaction temperature of the third reaction is -78 °C to 25 °C; preferably, it is -35 °C, 0 °C, or 25 °C; Optionally, the reaction time of the third reaction is 0.5 - 10 h; preferably, it is 0.5 h or 1 h; Optionally, the method for preparing compound A further includes performing a third post-treatment after the third reaction; Optionally, the third post-treatment includes: quenching the reaction, extracting with ethyl acetate, drying the organic phase layer with anhydrous MgSO4, evaporating the solvent, and purifying; Optionally, the inert gas includes at least one of helium, neon, argon, krypton, or xenon.

9. A compound selected from Compound B or Compound W, wherein, in Compound B or Compound W, "*" represents a chiral center where the P marked thereby is an S configuration or an R configuration; Ar is selected from a substituted or unsubstituted naphthyl group, a substituted or unsubstituted quinolinyl group, a substituted or unsubstituted phenanthrene ring, a substituted or unsubstituted anthracene ring; R 1 selected from substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted benzyl; R 2 selected from substituted or unsubstituted alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted styryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl; and R 1 is different from R 2 ; the → in Compound W represents a coordination bond.

10. The compound according to claim 9, compound B, R 1 and R 2 are selected from any one of groups (1), (2) and (3) in the preparation method according to claim 2; the definitions of Ar, R 1 and R 2 of compound W are the same as those of Ar, R 1 and R 2 of compound B, respectively.

11. A method for preparing a compound C, characterized in that, Comprising: Under nitrogen or an inert atmosphere condition, Compound D undergoes a fourth reaction with Compound E in a fourth solvent in the presence of Catalyst III and a first base to obtain Compound C; Among them, the R 1 , R 2 , and the Ar in compound C respectively correspond to any one of R 1 , R 2 in groups (1), (2), and (3) in the preparation method described in claim 2, and the corresponding Ar in compound B; Y is selected from F, Cl, Br or I; Optionally, Catalyst III includes at least one of tetrakis(triphenylphosphine)palladium and cuprous iodide; Optionally, the first base includes at least one of cesium carbonate, sodium carbonate, potassium carbonate, triethylamine, and sodium phosphate; Optionally, the fourth solvent includes at least one of toluene, acetonitrile, and N,N-dimethylformamide; Optionally, the molar ratio of Compound D to Compound E in the feed is 1.5:1.0 to 1.0:1.0, or is 1.5:1.0; Optionally, the molar ratio of Catalyst III to Compound E in the feed is 0.05:1 to 0.1:1.0, or is 0.1:1.0; Optionally, the molar ratio of the first base to Compound E in the feed is 1.5:1.0 to 1.0:1.0, or is 1.5:1.0; Optionally, the reaction solvent for the fourth reaction is 100 °C to 120 °C, or is 110 °C; Optionally, the preparation method of Compound C further includes a fourth post-treatment after the fourth reaction; Optionally, the fourth post-treatment includes: quenching the reaction with water, extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

12. A method for preparing a compound C, characterized in that, Comprising: Under nitrogen or an inert atmosphere condition, Compound F is mixed with a second base and a fifth solvent, and then mixed with Compound G to undergo a fifth reaction to obtain Compound H; or under nitrogen or an inert atmosphere condition, Compound F undergoes a sixth reaction with Compound G in a sixth solvent in the presence of a third base, Catalyst IV, and a ligand to obtain Compound H; Under nitrogen or an inert atmosphere condition, Compound H reacts with boron tribromide in a seventh solvent to obtain Compound C; Among them, R 1 , R 2 is selected from R 1 , R 2 in Group (1), Group (2) or Group (3) in the preparation method described in Claim 2; The Ar groups in Compound F, Compound H, and Compound C are selected from the corresponding Ar groups in Compound B in Group (1), Group (2), or Group (3) in the preparation method according to Claim 2; Z1 is selected from F, Cl, Br or I; Optionally, in the fifth reaction, the R of the compound G and the compound H 2 group is selected from the R groups of group (2-1) of group (2) in the preparation method according to claim 2, the Ar group is selected from the corresponding Ar group in the compound B of group (2) in the preparation method according to claim 2, and the R of the compound F and the compound H in the fifth reaction 2 group is phenyl; 1 ​ Optionally, in the fifth reaction, the R of the compound G and the compound H 2 group is selected from the R groups of group (1-1) of group (1) in the preparation method according to claim 2, the Ar group is selected from the corresponding Ar group in compound B of group (1) in the preparation method according to claim 2, and the R of compound F and compound H in the fifth reaction 2 group is tert-butyl; 1 ​ Optionally, the R of the compound G and the compound H in the sixth reaction 2 group is selected from the R groups of groups (1-2) of group (1) in the preparation method according to claim 2, the Ar group is selected from the corresponding Ar group in compound B of group (1) in the preparation method according to claim 2, and the R of compound F and compound H in the sixth reaction 2 group is tert-butyl. 1 ​ Optionally, in the sixth reaction, the R of compound G and compound H 2 group is selected from the R groups of group (2-2) of group (2) in the preparation method according to claim 2, the Ar group is selected from the corresponding Ar group in compound B of group (2) in the preparation method according to claim 2, and the R of compound F and compound H in the sixth reaction 2 group is phenyl; 1 ​ Optionally, the R of compound G and compound H in the sixth reaction 2 group is selected from the R groups of group (3) in the preparation method according to claim 2, the Ar group is selected from the corresponding Ar group in compound B of group (3) in the preparation method according to claim 2, and the R of compound F and compound H in the sixth reaction 2 group is the R group of group (3); 1 1 ​​ Optionally, compound F in the fifth reaction is selected from Z1 in compound G in the fifth reaction is selected from Br or iodine, and compound H in the fifth reaction is selected from Optionally, compound F in the fifth reaction is selected from Z1 in compound G in the fifth reaction is selected from Br or iodine, and compound H in the fifth reaction is selected from Optionally, compound F in the sixth reaction is selected from Z1 in compound G in the sixth reaction is selected from Br or iodine, and compound H in the sixth reaction is selected from Optionally, compound F in the sixth reaction is selected from Z1 in compound G in the sixth reaction is selected from Br or iodine, and compound H in the sixth reaction is selected from Optionally, the compound C is selected from Optionally, the compound C is selected from Optionally, the second base includes at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, and potassium tert-butoxide; Optionally, the fifth solvent includes at least one of dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile; Optionally, the ligand in the sixth reaction includes at least one of 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 6,6'-dimethyl-2,2'-bipyridine; Optionally, the molar ratio of Compound F to the second base in the feed is 1:1 to 1:3, or is 1:2; Optionally, the molar ratio of compound F to compound G in the fifth reaction is independently selected from 1:3 to 1:1, or is 1:2, or is 1:1.5; Optionally, the reaction temperature of the fifth reaction is 15°C to 35°C; Optionally, after the fifth reaction, a fifth post-treatment is also carried out, and the fifth post-treatment includes: extracting with water and ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying; Optionally, the catalyst IV includes at least one of cuprous iodide, cuprous chloride, and cuprous bromide; Optionally, the third base includes at least one of cesium carbonate, potassium carbonate, sodium phosphate, and sodium carbonate; Optionally, the sixth solvent includes at least one of toluene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; optionally, the molar ratio of compound F to compound G in the sixth reaction is independently selected from 1:2 - 1:1 or is 1:2, or is 1:1.5; Optionally, the molar ratio of compound F to the third base is 1:1.5 to 1:1, or is 1:1.5; Optionally, the molar ratio of compound F to catalyst IV is 1:0.05 to 1:0.1, or is 1:0.1; Optionally, the molar ratio of compound F to the ligand is 1:0.05 to 1:0.1, or is 1:0.1; Optionally, the reaction temperature of the sixth reaction is 100°C to 120°C, or is 120°C; Optionally, after the sixth reaction, a sixth post-treatment is also carried out, and the sixth post-treatment includes: quenching with water, then extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying; Optionally, the seventh solvent includes at least one of dichloromethane and tetrahydrofuran; Optionally, the molar ratio of compound H to boron tribromide is 1.5:1 to 1:1, or is 1:1; Optionally, the reaction temperature of the seventh reaction is -78°C to 0°C, or is 0°C; Optionally, after the seventh reaction, a seventh post-treatment is also carried out, and the seventh post-treatment includes: quenching the reaction with water, extracting with ethyl acetate, combining the organic phases, drying, filtering, concentrating, and purifying.

13. A method for preparing a compound F, characterized in that, Including: Step 1: Under a nitrogen or inert atmosphere, compound J is mixed with magnesium chips in an eighth solvent, and then iodine is added to carry out an eighth reaction to obtain compound K; Step 2: Compound K and compound L are mixed in a ninth solvent, and then an aqueous sulfuric acid solution is added to carry out a ninth reaction to obtain compound F; or compound K and compound M are mixed in a tenth solvent to carry out a tenth reaction to obtain compound F; Optionally, the eighth solvent includes at least one of tetrahydrofuran and 2-methyltetrahydrofuran; Optionally, the molar ratio of compound J to the magnesium chips is 1:1.2 to 1:1, or is 1:1; Optionally, the molar ratio of compound J to iodine is 1:0.0005 to 1:0.01 or is 1:0.001; Optionally, the reaction temperature of the eighth reaction is 90°C to 110°C, or is 110°C; Optionally, the ninth solvent includes at least one of tetrahydrofuran and 2-methyltetrahydrofuran; Optionally, the molar ratio of the feed of compound K to compound L is 2:1 to 1:1, or is 2:1; Optionally, the content of sulfuric acid in the sulfuric acid aqueous solution is 10 wt% - 20 wt%, or is 10 wt%; Optionally, the molar ratio of the feed of compound K to sulfuric acid in the sulfuric acid aqueous solution is 1:1 to 1:10, or is 1:3; Optionally, the reaction temperature of the ninth reaction is 0°C to 25°C; Optionally, after the ninth reaction is completed, a ninth post-treatment is also carried out, and the ninth post-treatment includes: adding ethyl acetate for extraction, combining the organic phases, drying, filtering, concentrating, and purifying; Optionally, the tenth solvent includes at least one of tetrahydrofuran and 2-tetrahydrofuran; Optionally, the molar ratio of the feed of compound K to compound M is 2:1 to 1:1, or is 2:1; Optionally, the reaction temperature of the tenth reaction is 0°C to 25°C, or is 0°C; Optionally, after the tenth reaction is completed, a tenth post-treatment is also carried out, and the tenth post-treatment includes: quenching with water, then adding ethyl acetate for extraction, combining the organic phases, drying, filtering, concentrating, and purifying.

14. Use of the compound according to claim 9 or the compound B prepared by the preparation method according to any one of claims 1-3, 6-8 in an asymmetric allylation reaction, an asymmetric alkylation reaction, or an asymmetric reductive hydrogenation reaction; Optionally, use of compound W in the compound according to claim 9 in an asymmetric allylation reaction or an asymmetric alkylation reaction; Optionally, use of compound B in the compound according to claim 9 or the compound B prepared by the preparation method according to any one of claims 1-3, 6-8 as a chiral ligand in an asymmetric reductive hydrogenation reaction; Optionally, the asymmetric allylation reaction, the asymmetric alkylation reaction, or the asymmetric reductive hydrogenation reaction is independently selected to be carried out under an inert gas atmosphere and / or a nitrogen atmosphere condition; Optionally, the inert gas includes at least one of helium, neon, argon, krypton, and xenon.

Images