Method for preparing chiral pentavalent phosphorus center and intermediate thereof from phosphorus oxychloride

Abstract

The invention discloses a method for preparing a chiral pentavalent phosphorus center and an intermediate thereof from phosphorus oxychloride, and particularly provides a preparation method of a compound as shown in a formula II, which comprises the following steps: S1, in a solvent, under the action of alkali, carrying out reaction on phosphorus oxychloride and a compound as shown in a formula D1 to obtain a mixture a; and S2, mixing a catalyst and a compound as shown in the formula D2 with the mixture a, and reacting to obtain a compound as shown in a formula II. Through an iterative assembly strategy catalyzed by an organic base, construction of a series of different types of pentavalent phosphorus stereo centers and intermediates thereof is efficiently completed, and the yield is good. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a chiral pentavalent phosphorus center and an intermediate thereof by using phosphorus oxychloride. Background Art

[0002] Fully heteroatom-substituted chiral pentavalent phosphorus fragments are widely present in the structures of natural products, pharmaceutical molecules, pesticides, and organic catalysts. For example, the drug molecules sofosbuvir, remdesivir, stampidine, and acelarin all contain this type of skeleton. Currently, the construction of fully heteroatom-substituted pentavalent phosphorus centers mainly relies on the resolution of racemic substrates and the control of chiral reagents or cofactors. The preparation of this type of skeleton via catalytic asymmetric synthesis has many synthetic advantages, but the known effective systems are relatively limited. In 2017, DiRocco et al. developed a dynamic kinetic asymmetric transformation method based on pentavalent phosphorus precursors (Science 2017, 356, 426–430). The same strategy has also been used in other studies (Adv. Synth. Catal. 2019, 361, 3729-3732; Angew. Chem. Int. Ed. 2020, 59, 20814-20819; J. Org. Chem. 2021, 86, 4977-4985; J. Am. Chem. Soc. 2024, 146, 31339–31347.). In 2021, Miller et al. developed a synthetic approach based on trivalent phosphorus asymmetric transformation tandem oxidation (Science 2021, 371, 702–707). Recently, there have been reports on the realization of pentavalent phosphorus centers by two consecutive stereoselective substitutions (J.Am.Chem.Soc.2025,147,11010; J.Am.Chem.Soc.2025,147,13566–13576.). However, this article points out that when the EtOP(O)Cl2 substrate is used for two consecutive stereoselective substitutions to prepare the chiral pentavalent phosphorus center, the transformation cannot proceed and no product is obtained. This also shows that these published works still face many problems, such as the complex structure of the required substrates and low universality, which can usually only be used for the preparation of special types of pentavalent phosphorus centers. Therefore, starting from simple and readily available raw materials, it is of great scientific value and practical significance to develop a universal and highly universal synthetic strategy to achieve the construction of related pentavalent phosphorus centers. Summary of the Invention

[0003] This invention addresses the current scarcity of asymmetric catalytic methods for preparing fully heteroatom-substituted chiral pentavalent phosphorus centers. By developing a universal catalytic asymmetric synthesis strategy based on inexpensive phosphorus oxychloride as a starting material, this method utilizes an organic base-catalyzed iterative assembly strategy to efficiently construct a range of different pentavalent phosphorus stereocenters and their intermediates in excellent yields.

[0004] The present invention provides a method for preparing a compound represented by Formula II, comprising the following steps:

[0005] S1: In a solvent, under the action of a base, phosphorus oxychloride and a compound represented by formula D1 react to obtain a mixture a;

[0006] S2: mixing the catalyst and the compound represented by formula D2 with the mixture a and reacting them to obtain a compound represented by formula II;

[0007]

[0008] The catalyst is a compound as shown in formula C-1,

[0009]

[0010] in,

[0011] X is a methylene group or a single bond;

[0012] R 1 H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-1 replace;

[0013] When X is a single bond, R 1 Not for H;

[0014] R 1-1 are independently halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, -OC 1-12 Alkyl, -O-halogenated C 1-12Alkyl, -C(O)OC 1-12 Alkyl, C 2-12 Alkenyl, C 6-10 Aryl and 5-12 membered heteroaryl;

[0015] R 2 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-10 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-2 replace;

[0016] R 1-2 are independently halogen, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -SC 1-12 Alkyl, -OC 1-12 Alkyl, -C 0-12 Alkylene-C(O)OC 1-12 Alkyl, C 6-10 Aryl, -OC 6-10 Aryl, 5-12 membered heteroaryl or NR a R b , the C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -SC 1-12 Alkyl, OC 1-12 Alkyl, -C 0-12 Alkylene-C(O)OC 1-12 Alkyl, C 6-10 Aryl, -OC 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-1-1 replace;

[0017] R 1-1-1 are independently halogen, nitro, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl or -NR a R b ;

[0018] R a and R b Independently H, C 1-12 Alkyl or -C(O)OC 1-12 alkyl;

[0019] The heteroatom species in the 3-12 membered heterocycloalkyl group and the 5-12 membered heteroaryl group are independently one, two or three selected from N, O and S, and the number of the heteroatoms is independently one, two or three.

[0020] In one embodiment, X is methylene, R 1 H, C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl or C 6-10 Aryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl and C 6-10 Aryl is optionally substituted independently by one or more R 1-1 replace.

[0021] In one embodiment, the compound represented by formula D1 is any one of the following compounds:

[0022]

[0023] In one embodiment, in steps S1 and S2, the reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere.

[0024] In one embodiment, in step S1, the solvent is a halogenated alkane solvent.

[0025] In one embodiment, in step S1, the halogenated alkane solvent is selected from one or both of chloroform and dichloromethane. For example, the halogenated alkane solvent consists of chloroform and dichloromethane.

[0026] In one embodiment, in step S1, the halogenated alkane solvent consists of chloroform and dichloromethane, and the volume ratio of chloroform to dichloromethane is (0.1-10):1, for example (1-7):1, and for example 2:1.

[0027] In one embodiment, in step S1, the ratio of the molar number of phosphorus oxychloride to the volume of the solvent is (0.01-10) mmol:1 mL, for example (0.05-1) mmol:1 mL, and for example 0.15 mmol:1 mL.

[0028] In one embodiment, in step S1, the molar ratio of the compound represented by formula D1 to the phosphorus oxychloride is (0.1-5):1, for example (1-3):1, and for example 1:1.

[0029] In one embodiment, in step S1, the base is an organic base, such as triethylamine or 2-tert-butyl-1,1,3,3-tetramethylguanidine.

[0030] In one embodiment, in step S1, the molar ratio of the base to the phosphorus oxychloride is (0.1-5):1, for example (1-3):1, and for example 1.1:1 or 1.4:1.

[0031] In one embodiment, the reaction system further includes an additive, which may be a molecular sieve, such as Molecular sieve or molecular sieve.

[0032] In one embodiment, the mass ratio of the additive to the phosphorus oxychloride is (1-10):1, for example (1-3):1, and for example 1.3:1 or 1.8:1.

[0033] In one embodiment, the reaction temperature is -80°C to 0°C, such as -80°C to -40°C, such as -60°C.

[0034] The progress of the reaction is monitored by conventional monitoring methods in the art (such as TLC or LC-MS), and the disappearance or no-reaction of the phosphorus oxychloride is regarded as the end point of the reaction; in one embodiment, the reaction time is 1-15 hours, for example, 12 hours.

[0035] In one embodiment, S1 includes the following steps: adding a mixed solution of the compound represented by formula D1, the base and part of the solvent to a mixed solution of phosphorus oxychloride and part of the solvent at -80°C to 0°C and reacting to obtain a mixture a.

[0036] In one embodiment, S1 includes the following steps: adding a mixed solution of the compound represented by formula D1, the base and part of the solvent to a mixed solution of phosphorus oxychloride, the molecular sieve and part of the solvent at -80°C to 0°C and reacting to obtain a mixture a.

[0037] In one scheme, R 2 C 1-12 Alkyl, C 2-12 Alkenyl, C 6-10 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-2 replace.

[0038] In one embodiment, the compound represented by formula D2 is any one of the following compounds:

[0039]

[0040]

[0041] In one embodiment, in step S2, the catalyst and the compound represented by formula D2 are mixed with the mixture a in the form of a solution or together in the form of a mixed solution to react; preferably, the solvent in the solution and the mixed solution is a halogenated alkane solvent, more preferably, the halogenated alkane solvent is selected from one or both of chloroform and dichloromethane, for example, consisting of chloroform and dichloromethane;

[0042] Preferably, the solvent consists of chloroform and dichloromethane, and the volume ratio of chloroform to dichloromethane is (0.1-10):1, for example (1-7):1, and for example 2:1;

[0043] Or, the ratio of the molar number of the compound represented by Formula D2 to the volume of the solvent is (0.01-10) mmol:1 mL, for example (0.01-1) mmol:1 mL, for example 0.4 mmol:1 mL or 1 mmol:1 mL;

[0044] Alternatively, the ratio of the molar number of the catalyst to the volume of the solvent is (0.01-10) mmol:1 mL, for example (0.01-1) mmol:1 mL, for example 0.04 mmol:1 mL or 0.11 mmol:1 mL.

[0045] In one embodiment, in step S2, the molar ratio of the compound represented by formula D2 to the phosphorus oxychloride is (0.9-5):1, for example (0.9-3):1, and for example 0.9:1.

[0046] In one embodiment, in step S2, the molar ratio of the catalyst to the phosphorus oxychloride is (0.01-0.5):1, for example (0.01-0.3):1, and for example 0.09:1.

[0047] In one embodiment, in step S2, the reaction system further includes a base E. Preferably, the base E is an organic base, such as triethylamine or 2-tert-butyl-1,1,3,3-tetramethylguanidine.

[0048] In one embodiment, in step S2, the molar ratio of the base E to the phosphorus oxychloride is (0.1-5):1, for example (0.9-3):1, and for example 0.9:1 or 1.1:1.

[0049] In one embodiment, in step S2, the temperature of the mixing and the reaction are independently -80°C to 0°C, such as -80°C to -40°C, such as -80°C to -60°C.

[0050] In one embodiment, step S2 includes the following steps: adding a mixed solution of the catalyst, base E and the compound represented by formula D2 to the mixture a for reaction to obtain the compound represented by formula II.

[0051] In one embodiment, step S2 includes the following steps: adding a mixed solution of the catalyst, base E and the compound represented by formula D2 to the mixture a at -80°C to 0°C to react to obtain a compound represented by formula II.

[0052] The progress of the reaction is monitored by conventional monitoring methods in the art (e.g., TLC or LC-MS), and the reaction endpoint is when the compound represented by Formula D2 disappears or no longer reacts. In one embodiment, the reaction time is 1-15 hours, for example, 12 hours.

[0053] In step S2, after the reaction is completed, conventional post-treatment in the art is further included. In one embodiment, the post-treatment includes the following steps: removing the solvent and purifying. The purification is column chromatography purification, and the eluent for the column chromatography can be a mixed solvent of petroleum ether and ethyl acetate.

[0054] In one embodiment, in step S2, the mixture obtained after the reaction is completed is directly used in the next reaction without post-treatment.

[0055] In one embodiment, the compound represented by formula II is a compound represented by formula II':

[0056]

[0057] In one embodiment, the compound represented by Formula II is any one of the following compounds:

[0058]

[0059]

[0060] Preferably, the compound represented by formula II is any one of the following compounds:

[0061]

[0062]

[0063] The present invention provides a compound as shown in Formula II, wherein the compound as shown in Formula II is any of the following compounds:

[0064]

[0065]

[0066] The present invention provides a method for preparing a compound as shown in Formula I, comprising the following steps S3:

[0067]

[0068] In a solvent, under the action of a base, the compound represented by Formula II' and the nucleophilic reagent represented by Formula A1, A2 or A3 undergo a reaction as shown above to obtain a compound represented by Formula I.

[0069] in,

[0070] R 3 and R 4 Independently H, -NR c R d 、C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-12 membered heteroaryl or The C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-3 replace;

[0071] Or, R 3 、R 4 Together with the nitrogen atom to which it is attached, it forms a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally substituted by one or more R 1-4 Substitution, the type of heteroatoms in the 3-12 membered heterocyclic group optionally further includes one, two or three selected from N, O and S, and the number of heteroatoms in the 3-12 membered heterocyclic group is 1, 2, 3 or 4;

[0072] R 1-3 are independently hydroxy, halogen, cyano, nitro, C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, -OC 0-6 Alkylene-C6-10 Aryl, 5-12 membered heteroaryl or -NR c R d , the C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-1-2 replace;

[0073] R 1-1-2 are independently hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)O-CH2-C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl or -NR c R d , the C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)O-CH2-C 6-10 Aryl, -O-CH2-C 6-10 Aryl and C 6-10 Aryl is optionally substituted independently by one or more R 1-1-1-1 replace;

[0074] R 1-1-1-1 Independently C 6-10 Aryl or

[0075] R c and R d Independently H, C 1-12 Alkyl, C 6-10 Aryl, -C(O)OC 1-12 Alkyl or -C(O)O-CH2-C 6-10 aryl;

[0076] R 1-4 Independently C 6-10 aryl;

[0077] R s is H or Na;

[0078] Y is -N(R 4 )-, O or S;

[0079] The types of heteroatoms in the 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl groups are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0080] X, R 1 and R 2 The definition of is as described in any of the previous schemes.

[0081] In one embodiment, in the compound shown in Formula A1, R 3 and R 4 Not H at the same time.

[0082] In one embodiment, in the compound shown in Formula A1, R 4 H, C 1-12 Alkyl or C 2-12 Alkenyl, the C 1-12 Alkyl and C 2-12 Alkenyl is optionally substituted independently by one or more R 1-3 preferably, R 1-3 Independently C 6-10 Aryl or -C(O)OC 1-12 alkyl.

[0083] In one embodiment, in the compound shown in Formula A1, R 3 for -NR c R d 、C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl or C 6-10 Aryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl or C 6-10 Aryl is optionally substituted independently by one or more R 1-3 preferably, R 1-3 are independently hydroxyl, C 1-12 Alkyl, C 3-12 Cycloalkyl, -OC 1-12 Alkyl, -C 6-10 Aryl, -C(O)OC 1-12 Alkyl or -OC 0-6 Alkylene-C 6-10 Aryl.

[0084] In one embodiment, the compound represented by formula A1 is any one of the following compounds:

[0085]

[0086]

[0087] In one embodiment, in the compound shown in formula A2, R 3 C 1-12 Alkyl, C 6-10 Aryl, 5-12 membered heteroaryl or The C 1-12 Alkyl, C 6-10 Aryl, 5-12 membered heteroaryl are independently optionally substituted with one or more R 1-3 replace;

[0088] Preferably, R 1-3 are independently halogen, cyano, nitro, C 1-12 Alkyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, -OC 0-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl or -NR c R d , 1-12 Alkyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, -OC 0-6 Alkylene-C 6-10 Aryl and C 6-10 Aryl is optionally substituted independently by one or more R 1-1-2 replace;

[0089] Preferably, R 1-1-2 are independently hydroxyl, C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)O-CH2-C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl or -NR c R d .

[0090] In one embodiment, the compound represented by formula A2 is any one of the following compounds:

[0091]

[0092]

[0093] In one embodiment, the compound shown in formula A3, R 3 C 6-10 Aryl, the C 6-10 The aryl group is optionally substituted with one or more R 1-3 preferably, R 1-3 are independently halogen or -OC 1-12 alkyl.

[0094] In one embodiment, the compound represented by formula A3 is any one of the following compounds:

[0095]

[0096] In one embodiment, the compound as shown in Formula I is any of the following compounds:

[0097]

[0098]

[0099]

[0100]

[0101]

[0102] In one embodiment, in step S3, the solvent is an ether solvent or a halogenated alkane solvent.

[0103] In one embodiment, in step S3, the ether solvent is tetrahydrofuran; the halogenated alkane solvent can be selected from one or both of dichloromethane and chloroform, for example, the halogenated alkane solvent is chloroform or consists of chloroform and dichloromethane.

[0104] In one embodiment, in step S3, the halogenated alkane solvent is composed of chloroform and dichloromethane, and the volume ratio of chloroform to dichloromethane is (0.1-10):1, for example (1-7):1, and for example 2:1.

[0105] In one embodiment, in step S3, the ratio of the molar number of the compound represented by Formula II to the volume of the solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, for example 0.1 mmol:1 mL, 0.2 mmol:1 mL or 0.24 mmol:1 mL.

[0106] In one embodiment, in step S3, the molar ratio of the nucleophile to the compound of formula II is (0.1-5):1, for example (0.8-3):1, and for example 0.8:1, 1:1, 1.2:1 or 1.5:1.

[0107] In one embodiment, in step S3, the base is an organic base, such as triethylamine or 2-tert-butyl-1,1,3,3-tetramethylguanidine.

[0108] In one embodiment, in step S3, the molar ratio of the base to the compound of formula II is (0.1-5):1, for example (0.8-3):1, and for example 0.8:1, 0.9:1, 1:1 or 2:1.

[0109] In one embodiment, in step S3, the reaction system further includes an additive, which may be a molecular sieve, for example Molecular sieve or molecular sieve.

[0110] In one embodiment, in step S3, the mass ratio of the additive to the compound represented by formula II is (0.1-10):1, for example (0.1-3):1, and for example 0.7:1 or 1:1.

[0111] In one embodiment, in step S3, the reaction temperature is 0-40°C, such as 20-35°C, and for example 30°C.

[0112] In one embodiment, step S3 includes the following steps: first mixing the base, the nucleophilic reagent and the solvent, and then adding the compound represented by formula II to react to obtain the compound represented by formula I to react.

[0113] In one embodiment, step S3 includes the following steps: first mixing the base, the additive, the nucleophilic reagent and the solvent, and then adding the compound represented by formula II to react to obtain the compound represented by formula I for reaction.

[0114] The progress of the reaction is monitored by conventional monitoring methods in the art (e.g., TLC or LC-MS), and the reaction endpoint is the disappearance or no-reaction of the compound represented by Formula II. In one embodiment, the reaction time is 1-15 hours, for example, 6 hours or 12 hours.

[0115] After the reaction is completed, conventional post-treatment in the art is also performed. In one embodiment, the post-treatment includes the following steps: removing the solvent and purifying. The purification is column chromatography purification, and the eluent of the column chromatography can be a mixed solvent of petroleum ether and ethyl acetate.

[0116] In one embodiment, the method for preparing the compound of formula I also includes a method for preparing the compound of formula II, which comprises the following steps:

[0117] S1: In a solvent, under the action of a base, phosphorus oxychloride and a compound represented by formula D1 react to obtain a mixture a;

[0118] S2: mixing a solution of a catalyst and a compound represented by formula D2 with the mixture a and reacting the mixture to obtain a compound represented by formula II;

[0119]

[0120] The catalyst is a compound as shown in formula C-1,

[0121]

[0122] X, R 1 and R 2 The definition of is as described in any of the previous schemes. The operation and conditions of the preparation method of the compound shown in Formula II can also be as described in any of the previous schemes.

[0123] Unless otherwise specified, the terms used in this invention have the following meanings:

[0124] In the present invention, the temperature is 0-40°C, such as 20-35°C, and another example is 30°C.

[0125] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0126] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is bonded to the parent moiety through a single bond.

[0127] If a linking group is represented as a "single bond", the structures on both sides of the linking group are directly connected by a single bond, for example -ABC-, when B is a single bond, -ABC- is -AC-.

[0128] The terms "halogen and halo" refer to fluorine, chlorine, bromine or iodine.

[0129] The term "alkyl (e.g. C1-C 12 )" refers to a straight or branched chain alkyl group having the specified number of carbon atoms. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0130] The term "alkylene (e.g., C1-C6 alkylene)" refers to a substituent formed by eliminating two hydrogen atoms from a saturated straight-chain or branched alkane. The two hydrogen atoms eliminated may be on the same carbon atom or on different carbon atoms (e.g., the two hydrogen atoms eliminated may be on carbon atoms at both ends). References to alkylene include: methylene, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH2-CH3)-, -C(CH3)2-, -CH2-CH(CH3)-, -CH2-CH2-CH2-CH2-, -CH2-CH2-CH(CH2)-, -CH2-CH(CH2-CH2)-, -CH(CH2-CH2-CH2)-.

[0131] The term "alkoxy" refers to a group R X -O-, where R X is an alkyl group as defined above.

[0132] The term "alkenyl (e.g. C2-C 12 "Alkenyl)" refers to a straight-chain or branched alkene with a specified number of carbon atoms, containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds may be internal or terminal. Examples of alkene include vinyl, allyl, Methylvinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2-propenyl, hexenyl, wait.

[0133] The term "alkynyl" refers to a straight or branched hydrocarbon group (e.g., C2-C 12 The one or more carbon-carbon triple bonds may be internal or terminal, for example, a propynyl group with an internal triple bond. or a propynyl group with a triple bond at the terminal end wait.

[0134] The term "cycloalkyl" refers to a monovalent saturated cyclic alkyl group having a specified number of ring carbon atoms, preferably a monovalent saturated cyclic alkyl group having 3 to 12 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclodecyl,

[0135] The term "cycloalkenyl" refers to a monovalent partially saturated cyclic alkyl group having a specified number of ring carbon atoms and containing one or more olefinic bonds, preferably a monovalent partially saturated cyclic alkyl group having 3 to 12 ring carbon atoms, such as cyclohexenyl. Cycloheptenyl

[0136] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (1, 2, or 3 of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. For example, azetidinyl Tetrahydropyrrolyl Tetrahydrofuranyl, morpholinyl Piperidinyl Piperazinyl Azacycloheptyl wait

[0137] The term "heterocyclyl" refers to a saturated or partially saturated cyclic group having a specified number of ring atoms (e.g., 3-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (1, 2, or 3 of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring. When it is a saturated cyclic group, its definition is the same as that of the above-mentioned heterocycloalkyl. When it is a partially saturated cyclic group, it means that at least one ring in the heteroalkyl group also contains one or more double bonds or triple bonds, and the partially saturated heterocyclyl that does not have aromaticity is connected to other fragments in the molecule through the ring that does not have aromaticity. Heterocyclyl includes but is not limited to

[0138] The term "aryl" refers to a radical having the specified number of carbon atoms (e.g., C 6-10 ) is a cyclic group consisting only of carbon atoms, which is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The aryl group is connected to other fragments in the molecule through the aromatic ring. Aryl groups include but are not limited to phenyl, naphthyl, wait.

[0139] The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing a specified number of ring atoms (e.g., 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S), and at least one ring is aromatic (in accordance with Huckel's rule). Heteroaryl is connected to other fragments in the molecule through an aromatic ring. Heteroaryl includes, but is not limited to, pyridyl Pyrimidinyl

[0140] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0141] The reagents and raw materials used in the present invention are commercially available.

[0142] The positive advances of this invention lie in its proposed novel synthetic strategy for preparing fully heteroatom-substituted pentavalent phosphorus centers. Using inexpensive phosphorus oxychloride as a raw material, and through sequential, iterative substitution with different nucleophiles under organic base catalysis, a wide range of fully heteroatom-substituted chiral pentavalent phosphorus compounds and their intermediates can be efficiently prepared. This method offers advantages such as simplicity, versatility, inexpensive raw materials, and mild synthetic conditions. DETAILED DESCRIPTION

[0143] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0144] In the following examples, chloroform-d refers to deuterated chloroform (CDCl3).

[0145] Example 1: Compound 5a

[0146]

[0147] Under nitrogen protection, add Molecular sieves (60 mg), phosphorus oxychloride 1 (34 mg, 0.22 mmol), and dry DCM / CHCl3 (1.0 mL, v / v = 1 / 2) were added. The reaction was placed at -60°C, and then methanol 2a (0.22 mmol), triethylamine (30 mg, 0.30 mmol), and DCM / CHCl3 (0.50 mL, v / v = 1 / 2) were added to the reaction solution. The reaction was continued at this temperature for 12 hours. The reaction was then placed at -80°C, and catalyst C-1 (5.0 mg, 0.020 mmol), benzyl alcohol 3a (0.20 mmol), triethylamine (20 mg, 0.20 mmol), and DCM / CHCl3 (0.50 mL, v / v = 1 / 2) were added to the reaction solution. The reaction was continued at this temperature for 12 hours. The reaction mixture was then allowed to cool to room temperature. Phenylethylamine 4a (0.26 mmol), triethylamine (20 mg, 0.20 mmol), and DCM / CHCl (0.50 mL, v / v = 1 / 2) were then added to the reaction mixture. The reaction was continued at room temperature for 6 hours. After completion of the reaction, the mixture was concentrated and purified by flash column chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford product 5a.

[0148] Yellow oil, yield 81%, column chromatography (petroleum ether / ethyl acetate = 2 / 1), [α] D 25 +2.0(c 1.0,CHCl3)for 94%ee; 1H NMR(400MHz,chloroform-d)δ7.31–7.21(m,5H),7.21–7.16(m,2H),7.12–7.01(m,3H),4.98–4. 78(m,2H),3.56(d,J=11.2,1.8Hz,3H),3.12–2.98(m,2H),2.82–2.68(m,1H),2.67–2.60(m,2H). 13 C NMR(126MHz,chloroform-d)δ138.6,136.5(d,J=7.3Hz),132.1(d,J=10.3Hz),128.9,128.8(d, J=7.2Hz), 128.3, 127.7, 126.5, 67.8 (d, J=5.0Hz), 53.0 (d, J=5.7Hz), 42.6, 37.8 (d, J=6.1Hz). 31 P NMR(162MHz,chloroform-d))δ6.92(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 21 O3NP ⊕ 306.1257, found 306.1254. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 20% isopropanol in n-hexane as the mobile phase, and a flow rate of 1.0 mL / min. The retention times for the two structures were 10.2 min (major) and 10.8 min (minor). Using the corresponding starting materials, following the reaction conditions and procedures described in Example 1, the following compounds 5b-5am were prepared.

[0149] Example 2: Compound 5b

[0150]

[0151] Compound 5b, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 71%, [α] D 25 +4.2 (c1.0, CHCl3) for 92% ee. 1 H NMR(400MHz,chloroform-d)δ7.44–7.26(m,5H),5.10–4.99(m,2H),3.73(d,J=11.2Hz,3H),2 .90–2.84(m,1H),2.78–2.68(m,2H),0.99–0.88(m,1H),0.50–0.43(m,2H),0.14–0.11(m,2H).13 CNMR(126MHz,chloroform-d)δ136.5(d,J=7.3Hz),128.5,128.3,127.7,67.8(d,J=4.8Hz),53.1(d,J=5.7Hz),46.5,12.7(d,J=7.5Hz),3.3(d,J=2.6Hz). 31 P NMR(162MHz,chloroform-d))δ10.29(s).HRMS(ESI):[M+H] ⊕ calcd for C 12 H 19 O3NP ⊕ 256.1100, found 256.1097. HPLC results: IF-H chiral column, detection at 25°C, 210 nm wavelength, 4% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 38.9 min (minor) and 42.7 min (major).

[0152] Example 3: Compound 5c

[0153]

[0154] Compound 5c, yellow oil, column chromatography (petroleum ether / ethyl acetate = 4 / 1), yield 64%, [α] D 25 +5.7(c1.0,CHCl3)for 93%ee; 1 H NMR(500MHz,Chloroform-d)δ7.43–7.26(m,5H),5.11–4.95(m,2H),3.72(d,J=11.2Hz,3H),2.9 3–2.79(m,2H),2.78–2.65(m,1H),1.52–1.38(m,2H),1.33–1.22(m,6H),0.87(t,J=6.7Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 136.6 (d, J = 7.8Hz), 128.6, 128.3, 127.8, 67.8 (d, J = 5.0Hz), 53.1 (d, J = 5.6Hz), 41.5, 31.7 (d, J = 6.0Hz), 31.4, 26.3, 22.6, 14.1. 31 P NMR(162MHz,chloroform-d)δ10.72(s).HRMS(ESI):[M+H] ⊕ calcd for C14 H 25 O3NP ⊕ 286.1569, found 286.1567. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 5% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 14.2 min (minor) and 15.0 min (major).

[0155] Example 4: Compound 5d

[0156]

[0157] Compound 5d, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 92%, [α] D 25 +3.9(c1.0,CHCl3)for 93%ee; 1 H NMR(500MHz,chloroform-d)δ7.43–7.27(m,5H),5.10–4.99(m,2H),3.72(d,J=11 .2Hz,3H),3.41–3.35(m,2H),3.32(s,3H),3.24–3.15(m,1H),3.10–3.00(m,2H). 13 C NMR (126MHz, chloroform-d) δ 136.5 (d, J = 7.4Hz), 128.5, 128.3, 127.7, 72.5 (d, J = 5.8Hz), 67.8 (d, J = 4.9Hz), 58.7, 53.1 (d, J = 5.6Hz), 41.0. 31 P NMR(162MHz,chloroform-d)δ10.67(s).HRMS(ESI):[M+H] ⊕ calcd for C 11 H 19 O4NP ⊕ 260.1048, found 260.1046. HPLC results: AD-H chiral column, detection conditions: 25 degrees, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two configurations were 11.5 min (minor) and 12.1 min (major).

[0158] Example 5: Compound 5e

[0159]

[0160] Compound 5e, white solid, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 77%, [α] D 25 +8.6(c1.0,CHCl3)for 94%ee; 1 H NMR(500MHz,chloroform-d)δ7.44–7.27(m,5H),5.10–4.96(m,2H),3.71(d,J=11.3Hz,3H),3.01–2.88(m,1H),2 .84–2.72(m,1H),1.97–1.79(m,2H),1.73–1.60(m,2H),1.59–1.50(m,1H),1.32–1.21(m,2H),1.19–1.06(m,3H). 13 C NMR (126MHz, chloroform-d) δ 136.6 (d, J = 7.7Hz), 128.5, 128.2 127.6, 67.7 (d, J = 5.0Hz), 53.0 (d, J = 5.8Hz), 50.6, 35.6 (d, J = 4.6Hz), 25.3, 25.0. 31 P NMR(162MHz,chloroform-d))δ9.82(s).HRMS(ESI):[M+H] ⊕ calcd for C 14 H 23 O3NP ⊕ 284.1413, found 284.1410. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 5% isopropanol in n-hexane mobile phase, flow rate 0.8 mL / min. The retention times of the two structures were 15.9 min (minor) and 17.4 min (major).

[0161] Example 6: Compound 5f

[0162]

[0163] Compound 5f, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 67%, [α] D 25 -1.1(c 1.0,CHCl3)for 93%ee; 1H NMR(400MHz,chloroform-d)δ7.45–7.15(m,6H),6.92–6.73(m,3H),5.09–4.9 4(m,2H),4.09–3.98(m,2H),3.75(s,3H),3.71(d,J=11.2Hz,3H),3.27(s,1H). 13 C NMR (126MHz, CDCl3) δ159.8, 141.1 (d, J = 6.1Hz), 136.4 (d, J = 7.3Hz), 129.7, 128.6, 128. 4,127.8,119.5,112.9(d,J=18.2Hz),68.0(d,J=5.1Hz),55.2,53.3(d,J=5.4Hz),45.3. 31 P NMR(162MHz,chloroform-d))δ9.99(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 21 O4NP ⊕ 322.1206, found 322.1203. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 12.1 min (minor) and 12.9 min (major).

[0164] Example 7: Compound 5g

[0165]

[0166] Compound 5g, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 67%, [α] D 25 +0.5(c1.0,CHCl3)for 93%ee; 1 H NMR(400MHz,chloroform-d)δ7.40–7.25(m,5H),7.09–7.02(m,2H),6.86–6.77(m,2H),4.98(dd,2H) ),3.77(s,3H),3.67(d,J=11.3Hz,3H),3.16–3.04(m,2H),2.78–2.71(m,1H),2.67(t,J=6.8Hz,2H). 13C NMR(126MHz, CDCl3)δ158.3,136.5(d,J=7.3Hz),130.5,129.8,128.6,128.3,127 .8,114.0,67.8(d,J=4.8Hz),55.29,53.1(d,J=5.6Hz),42.8,36.9(d,J=6.1Hz). 31 P NMR(162MHz,chloroform-d))δ10.47(s).HRMS(ESI):[M+H] ⊕ calcd for C 17 H 23 O4NP ⊕ 336.1363, found 336.1359. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 18.5 min (major) and 19.6 min (minor).

[0167] Example 8: Compound 5h

[0168]

[0169] Compound 5h, white solid, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 63%, [α] D 25 +6.1(c1.0,CHCl3)for 94%ee; 1 H NMR(500MHz,chloroform-d)δ7.44–7.26(m,5H),5.23–4.87(m,2H),3.71(d,J=11.3H z,3H),2.65(d,J=8.1Hz,1H),2.04(s,1H),1.80(d,J=3.0Hz,6H),1.67–1.56(m,6H). 13 C NMR (126MHz, chloroform-d) δ 136.7 (d, J = 7.9Hz), 128.5, 128.2, 127.7, 67.7 (d, J = 5.1Hz), 53.0 (d, J = 5.8Hz), 51.0, 44.3 (d, J = 4.4Hz), 36.0, 29.7. 31 PNMR(162MHz,chloroform-d)δ8.58(s).HRMS(ESI):[M+H] ⊕ calcd for C 18 H 27 NO3P⊕ 336.1725, found 336.1723. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 1% isopropanol in n-hexane as the mobile phase, and a flow rate of 1.0 mL / min. The retention times of the two structures were 13.8 min (major) and 15.0 min (minor).

[0170] Example 9: Compound 5i

[0171]

[0172] Compound 5i, white solid, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 78%, [α] D 25 -34.3(c1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.33–7.17(m,8H),7.13–7.05(m,2H),4.92–4.58(m,2H),4.34–4.24(m,1H),3 .66(d,J=11.2Hz,3H,major),3.58(t,J=10.4Hz,1H),3.45(d,J=11.2Hz,0H,minor),1.43(d,J=6.8Hz,3H). 13 C NMR (126MHz, CDCl3) δ145.1 (d, J = 4.5Hz), 136.3 (d, J = 8.3Hz), 128.6, 128.4, 128.1, 127.6, 127.1, 125.8, 67.6 (d, J = 4.9Hz), 53.1 (d, J = 5.5Hz), 52.0, 25.3 (d, J = 6.4Hz). 31 P NMR(162MHz,chloroform-d)δ8.95(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 21 O3NP ⊕ 306.1256,found306.1254.

[0173] Example 10: Compound 5j

[0174]

[0175] Compound 5j, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 71%, [α] D 25-1.1(c1.0,CHCl3). 1 H NMR(400MHz,chloroform-d)δ7.44–7.22(m,10H),5.13–4.96(m,2H),4.24(d,J=9.9Hz,2H),3.73(d,J=11.2Hz,3H),3.04–2.91(m,2H),1.04(t,J=7.1Hz,3H). 13 CNMR(101MHz, CDCl3)δ138.0(d,J=3.8Hz),136.7(d,J=8.0Hz),128.5,128.5,128.3,12 8.2, 127.7, 127.4, 67.8 (d, J = 5.5Hz), 53.2, 48.6 (d, J = 5.1Hz), 39.5 (d, J = 4.1Hz), 13.3. 31 P NMR(162MHz,chloroform-d))δ11.68(s).HRMS(ESI):[M+H] ⊕ calcd for C 17 H 23 NO3P ⊕ 320.1414, found 320.1410. HPLC results: IF-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 13.6 min (minor) and 15.2 min (major).

[0176] Example 11: Compound 5k

[0177]

[0178] Compound 5k, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 61%, [α] D 25 -3.9(c1.0,CHCl3)for 94%ee; 1 H NMR(500MHz,chloroform-d)δ7.56–7.12(m,15H),5.23–4.95(m,2H),4.23–3.99(m,4H),3.75(d,J=11.2Hz,3H). 13C NMR(126MHz,chloroform-d)δ137.3(d,J=2.6Hz),136.6(d,J=8.0Hz),128.7,128.6, 128.5, 128.3, 127.8, 127.5, 68.1 (d, J = 5.4Hz), 53.4 (d, J = 6.0Hz), 48.4 (d, J = 4.9Hz). 31 P NMR(162MHz,chloroform-d))δ11.31(s).HRMS(ESI):[M+H] ⊕ calcd for C 22 H 25 O3NP ⊕ 382.1568, found 382.1567. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 19.5 min (minor) and 21.6 min (major).

[0179] Example 12: Compound 51

[0180]

[0181] Compound 51, yellow oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 53%, [α] D 25 +2.1(c1.0,CHCl3)for 93%ee; 1 H NMR(500MHz,Chloroform-d)δ7.43–7.25(m,5H),5.09–4.90(m,2H),3.68(d,J=11.2Hz,3H) ,3.04–2.90(m,4H),1.55–1.39(m,4H),1.28(dt,J=15.0,7.3Hz,4H),0.90(t,J=7.4Hz,6H). 13 C NMR (126MHz, chloroform-d) δ 136.8 (d, J = 8.1Hz), 128.5, 128.1, 127.6, 67.5 (d, J = 5.2Hz), 52.9 (d, J = 5.7Hz), 45.5 (d, J = 4.1Hz), 30.8 (d, J = 2.1Hz), 20.1, 13.9. 31 P NMR(162MHz,chloroform-d)δ11.34(s).HRMS(ESI):[M+H] ⊕ calcdfor C16 H 29 O3NP ⊕ 314.1882, found 314.1880. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 8.7 min (minor) and 9.9 min (major).

[0182] Example 13: Compound 5m

[0183]

[0184] Compound 5m, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 67%, [α] D 25 -4.2(c1.0,CHCl3)for 93%ee; 1 H NMR(500MHz,chloroform-d)δ7.33–7.08(m,7H),6.85–6.70(m,3H),4.98–4.86(m ,2H),3.61(d,J=11.2Hz,3H),3.15(dt,J=7.3,4.9Hz,4H),2.94(q,J=4.8Hz,4H). 13 C NMR(126MHz,chloroform-d)δ151.4,136.4(d,J=6.9Hz),129.2,128.6,128.4,127.9,12 0.3, 116.6, 68.1 (d, J = 5.3Hz), 53.2 (d, J = 6.0Hz), 49.7 (d, J = 5.5Hz), 44.4 (d, J = 2.1Hz). 31 P NMR(162MHz,chloroform-d))δ9.64(s).HRMS(ESI):[M+H] ⊕ calcdfor C 18 H 24 O3N2P ⊕ 347.1522, found 347.1519. HPLC results: IF-H chiral column, detection at 25°C, 210 nm wavelength, 4% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 50.8 min (major) and 54.0 min (minor).

[0185] Example 14: Compound 5n

[0186]

[0187] Compound 5n, yellow oil, column chromatography (petroleum ether / ethyl acetate = 4 / 1), yield 67%, [α] D 25 +1.2(c1.0,CHCl3)for 94%ee; 1 H NMR(500MHz,chloroform-d)δ7.37–7.04(m,3H),5.05–4.72(m,1H),3.59(d,J=11.2Hz,1H),3.17–2.91(m,2H),1.60–1.51(m,2H),1.50–1.42(m,2H). 13 CNMR (126MHz, CDCl3) δ 136.7 (d, J = 7.8Hz), 128.5, 128.1, 127.6, 67.6 (d, J = 5.1Hz), 52.9 (d, J = 5.8Hz), 47.4 (d, J = 4.1Hz), 30.1 (d, J = 4.0Hz), 26.9. 31 P NMR(162MHz,chloroform-d))δ11.82(s).HRMS(ESI):[M+H] ⊕ calcd for C 14 H 23 O3NP ⊕ 284.1413, found 284.1410. HPLC results: ID-H chiral column, detection at 25°C, 210 nm wavelength, 1% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 7.6 min (minor) and 7.9 min (major).

[0188] Example 15: Compound 5o

[0189]

[0190] Compound 5o, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 83%, [α] D 25 -4.2(c1.0,CHCl3)for 94%ee, 1 H NMR(400MHz,chloroform-d)δ7.46–7.24(m,5H),5.10–4.96(m,2H),3.78–3.67(m,3H),3.21–3.11(m,4H),1.84–1.74(m,4H). 13C NMR (126MHz, chloroform-d) δ 136.8 (d, J = 7.1Hz), 128.5, 128.3, 127.8, 67.7 (d, J = 5.1Hz), 53.0 (d, J = 5.7Hz), 46.8 (d, J = 4.8Hz), 26.3 (d, J = 9.4Hz). 31 P NMR(162MHz,chloroform-d)δ9.73(s).HRMS(ESI):[M+H] ⊕ calcd for C 12 H 19 O3NP ⊕ 256.1101, found 256.1097. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 8% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 20.9 min (major) and 23.3 min (minor).

[0191] Example 16: Compound 5p

[0192]

[0193] Compound 5p, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 58%, [α] D 25 +9.4(c1.0,CHCl3)for 90%ee; 1 H NMR(500MHz,chloroform-d)δ7.43–7.20(m,10H),7.00–6.73(m,4H),6.34(d,J=9.4Hz,1H),5.14–5.03(m,1H),5.01–4.89(m,3H),3.74(d,J=11.6Hz,3H). 13 C NMR (126MHz, CDCl3) δ154.1,137.2,135.9,132.9,128.6,128.6,128.4,128.0,128 .0,127.5,119.2(d,J=6.8Hz),115.7,70.4,68.2(d,J=4.1Hz),53.2(d,J=5.4Hz). 31 P NMR(162MHz,chloroform-d)δ4.98(s).HRMS(ESI):[M+H] ⊕ calcd for C 21 H 23 O4NP ⊕384.1362, found 384.1359. HPLC results: IF-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 14.3 min (major) and 16.0 min (minor).

[0194] Example 17: Compound 5q

[0195]

[0196] Compound 5q, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 52%, [α] D 25 +5.6(c1.0,CHCl3)for 90%ee; 1 H NMR(500MHz,chloroform-d)δ7.30–7.18(m,7H),6.95–6.90(m,2H),6.54(d,J=9.7Hz,1H),5.15–4.95(m,2H),3.75(d,J=11.5Hz,3H),1.25(s,9H). 13 CNMR(126MHz,chloroform-d)δ144.6,136.8,135.9(d,J=8.0Hz),128.5,128.4,12 8.0, 126.1, 117.3 (d, J = 7.2Hz), 68.2 (d, J = 4.4Hz), 53.3 (d, J = 5.1Hz), 34.1, 31.5. 31 P NMR(162MHz,chloroform-d)δ4.60(s).HRMS(ESI):[M+H] ⊕ calcd for C 18 H 25 O3NP ⊕ 334.1568, found 334.1567. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 6.7 min (major) and 7.2 min (minor).

[0197] Example 18: Compound 5r

[0198]

[0199] Compound 5r, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 53%, [α] D 25 -1.3(c1.0,CHCl3)for 94%ee; 1 H NMR(400MHz,chloroform-d)δ7.40–7.28(m,3H),7.17(d,J=8.9Hz,1H),6.83(d,J=8.6 Hz,1H),5.11–4.97(m,2H),3.78(s,2H),3.72(d,J=11.3Hz,2H),3.10(d,J=9.0Hz,2H). 13 C NMR(126MHz,chloroform-d)δ156.9,136.9(d,J=4.2Hz),136.3(d,J=7.7Hz),128.5,128.3,12 7.9, 125.6 (d, J = 3.8Hz), 114.3, 68.2 (d, J = 5.2Hz), 55.5, 53.3 (d, J = 5.9Hz), 38.1 (d, J = 5.4Hz). 31 P NMR(162MHz,chloroform-d))δ7.98(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 21 O4NP ⊕ 322.1204, found 322.1203. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 11.0 min (major) and 12.1 min (minor).

[0200] Example 19: Compound 5s

[0201]

[0202] Compound 5s, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 71%, [α] D 25 -9.2(c1.0,CHCl3)for 92%ee; 1H NMR(500MHz,chloroform-d)δ7.39–7.28(m,5H),7.19–7.05(m,3H),6.86(t,J=7.4Hz,1H),5 .16–4.97(m,2H),3.84(td,J=9.2,3.4Hz,2H),3.76(d,J=11.4Hz,3H),3.03(t,J=8.7Hz,2H). 13 C NMR(126MHz,chloroform-d)δ144.5(d,J=6.4Hz),135.9(d,J=7.3Hz),131.1(d,J=12.5Hz),128.5,128.4,128 .03,127.5,124.8,121.3,112.4,68.3(d,J=4.8Hz),53.2(d,J=5.4Hz),49.2(d,J=4.6Hz),28.9(d,J=6.9Hz). 31 PNMR(162MHz,chloroform-d))δ3.74(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 19 O3NP ⊕ 304.1100, found 304.1097. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 20% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 11.8 min (major) and 12.9 min (minor).

[0203] Example 20: Compound 5t

[0204]

[0205] Compound 5t, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 64%, [α] D 25 +3.4(c1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.39–7.23(m,7H),7.22–7.19(m,3H),4.95–4.8 4(m,2H),3.47(d,J=11.2Hz,4H),3.37(s,1H),2.93–2.69(m,2H),1.26(s,1H). 13C NMR(126MHz, CDCl3)δ138.4,136.3(d,J=6.6Hz),129.6,128.6,128.5,128.3,12 7.7, 126.5, 68.1 (d, J = 5.2Hz), 65.2, 55.5, 53.1 (d, J = 5.6Hz), 39.4 (d, J = 6.0Hz). 31 PNMR(162MHz,chloroform-d)δ9.94(s).HRMS(ESI):[M+H] ⊕ calcd for C 17 H 23 NO4P ⊕ 336.1362, found 336.1359.

[0206] Example 21: Compound 5u

[0207]

[0208] Compound 5u, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 70%, [α] D 25 +13.7(c 1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.33–7.14(m,5H),4.98–4.85(m,2H),3.81–3.66(m,2H),3.60(d, J=11.2Hz,3H),3.54–3.40(m,1H),2.90–2.77(m,1H),2.69–2.55(m,1H),1.02(d,J=6.3Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 136.3 (d, J = 7.6Hz), 128.6, 128.4, 127.9, 68.1 (d, J = 5.2Hz), 67.7 (d, J = 5.6Hz), 53.3 (d, J = 5.6Hz), 48.9, 20.3. 31 P NMR(162MHz,chloroform-d))δ11.76(s).HRMS(ESI):[M+H] ⊕ calcd for C 11 H 19 O4NP ⊕ 260.1048,found 260.1046.

[0209] Example 22: Compound 5v

[0210]

[0211] Compound 5v, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 61%, [α] D 25 +9.0(c1.0,CHCl3)for 15:1dr; 1 H NMR(500MHz,chloroform-d)δ7.31–7.18(m,5H),4.99–4.87(m,2H),3.84–3.75(m,1H),3.63(d,J=11.2 Hz,3H),3.57(s,6H),3.48(t,J=10.2Hz,1H),2.43–2.25(m,2H),2.05–1.95(m,1H),1.89–1.76(m,1H). 13 C NMR(126MHz,chloroform-d)δ173.28(d,J=5.1Hz),173.1,136.2(d,J=7.7Hz),128.5,128. 3,127.7,68.1(d,J=5.0Hz),53.5,53.4(d,J=5.8Hz),52.4,51.7,29.6,29.2(d,J=5.8Hz). 31 P NMR(162MHz,chloroform-d))δ9.03(s).HRMS(ESI):[M+H] ⊕ calcd for C 15 H 23 O7NP ⊕ 360.1210,found360.1207.

[0212] Example 23: Compound 5w

[0213]

[0214] Compound 5w, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 58%, [α] D 25 +9.0(c1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.31–7.14(m,5H),5.00–4.89(m,2H),4.09–3.97(m,1H),3.76–3.66(m,1H),3.65–3.51(m,9H),2.85–2.58(m,2H). 13C NMR(126MHz, CDCl3)δ172.1(d,J=6.9Hz),171.1,136.3(d,J=7.7Hz),128.6,128.4, 127.9, 68.25 (d, J = 5.0Hz), 53.4 (d, J = 5.6Hz), 52.8, 52.0, 50.9, 38.4 (d, J = 3.8Hz). 31 P NMR(162MHz,chloroform-d))δ8.88(s).HRMS(ESI):[M+H] ⊕ calcd for C 14 H 21 7NJ ⊕ 368.0873,found 368.0870.

[0215] Example 24: Compound 5x

[0216]

[0217] Compound 5x, light red solid, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 59%, [α] D 25 +6.5(c1.0,CHCl3)for90%ee; 1 H NMR(500MHz,chloroform-d)δ7.26(s,5H),7.13(t,J=7.8Hz,2H),6.84–6.75(m,3H ),5.30(s,1H),5.16(d,J=33.7Hz,1H),5.06–4.96(m,2H),3.67(d,J=11.2Hz,3H). 13 C NMR (126MHz, chloroform-d) δ148.3 (d, J = 4.4Hz), 136.1 (d, J = 6.7Hz), 129.2, 128.6, 128.5, 128.0, 121.1, 113.1, 68.8 (d, J = 5.4Hz), 54.0 (d, J = 5.9Hz). 31 P NMR(162MHz,chloroform-d))δ7.0(s).HRMS(ESI):[M+H] ⊕ calcd for C 14 H 18 O3N2P ⊕293.1051, found 293.1050. HPLC results: IF-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 20.9 min (major) and 22.1 min (minor).

[0218] Example 25: Compound 5y

[0219]

[0220] Compound 5y, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 58%, [α] D 25 +8.5(c1.0,CHCl3)for 91%ee, 1 H NMR(400MHz,chloroform-d)δ7.44–7.19(m,2H),7.08–6.77(m,3H),4.39–4.24(m,2H),4.23–4.09(m,2H),3.69(d,J=11.2Hz,3H),3.0 6–2.88(m,1H),2.80–2.64(m,1H),1.91(d,J=12.1Hz,2H),1.72–1.59(m,2H),1.58–1.47(m,1H),1.35–1.23(m,2H),1.18–1.03(m,3H). 13 C NMR (126MHz, chloroform-d) δ158.5, 129.5, 121.2, 114.6, 67.0 (d, J = 7.2Hz), 64.5 (d, J = 5.0Hz), 53.1 (d, J = 5.6Hz), 50.6, 35.7 (d, J = 4.1Hz), 25.4, 25.0. 31 P NMR(162MHz,chloroform-d)δ9.93(s).HRMS(ESI):[M+H] ⊕ calcdfor C 15 H 25 O4NP ⊕ 313.1516, found 314.1516. HPLC results: AD-H chiral column, detection at 25°C, 254 nm wavelength, 20% isopropanol in n-hexane as the mobile phase, and a flow rate of 1.0 mL / min. The retention times of the two structures were 6.2 min (major) and 6.8 min (minor).

[0221] Example 26: Compound 5z

[0222]

[0223] Compound 5z, white solid, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 58%, [α] D 25 +5.5(c1.0,CHCl3)for 94%ee, 1 H NMR(500MHz,chloroform-d)δ7.37(t,J=8.4,5.4Hz,2H),7.05(t,J=8.5Hz,2H),5.08–4.86(m,2H),3.71(d,J=11.2Hz,3H) ,2.94(s,1H),2.73(t,1H),1.97–1.81(m,2H),1.75–1.63(m,2H),1.60–1.50(m,1H),1.30–1.23(m,2H),1.19–1.06(m,3H). 13 C NMR(126MHz,chloroform-d)δ162.7(d,J=246.7Hz),132.0(d,J=2.7Hz),129.7(d,J=8.3Hz),128.5(d,J= 12.0Hz), 115.5 (d, J = 21.6Hz), 67.1 (d, J = 5.1Hz), 53.0 (d, J = 5.7Hz), 50.7, 35.7 (d, J = 4.1Hz), 25.3, 25.0. 31 P NMR(162MHz,chloroform-d)δ9.71(s). 19 F NMR(376MHz,chloroform-d)δ-113.81.HRMS(ESI):[M+H] ⊕ calcd for C 14 H 22 O3NFP ⊕ 302.1318, found 302.1316. HPLC results: ID-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 11.7 min (major) and 12.3 min (minor).

[0224] Example 27: Compound 5aa

[0225]

[0226] Compound 5aa, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 55%, [α] D 25 -33.9(c 1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.35–7.27(m,4H),7.28–7.22(m,1H),5.77–5.61(m,1H),5.00–4. 90(m,2H),4.37–4.25(m,1H),3.95–3.82(m,1H),3.74–3.64(m,4H),3.22(t,J=10.3Hz,1H),2.01

[0227] –1.91(m,2H),1.64–1.52(m,2H),1.51–1.43(m,3H). 13 C NMR(101MHz,chloroform-d)δ145.1(d,J=4.1Hz),137.5,128.6,127.2,125.8,115.2,6 5.6(d,J=5.1Hz), 53.0(d,J=5.4Hz), 51.5, 29.6, 29.3(d,J=7.7Hz), 25.4(d,J=6.5Hz). 31 P NMR(162MHz,chloroform-d)δ9.28(s).HRMS(ESI):[M+H] ⊕ calcd for C 14 H 23 O3NP ⊕ 284.1412,found284.1410.

[0228] Example 28: Compound 5ab

[0229]

[0230] Compound 5ab, yellow oil, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 58%, [α] D 25 -18.9(c 2.0,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ7.34–7.19(m,5H),4.33–4.22(m,1H),3.95–3.87(m,1H),3.73–3.60(m,4H),3.42–3.3 2(m,1H),1.86(s,3H),1.67–1.51(m,6H),1.46(d,J=6.8Hz,3H),1.34(s,6H),1.28–1.24(m,1H),1.20–1.13(m,1H). 13 C NMR(126MHz,chloroform-d)δ145.2(d,J=4.4Hz),128.5,127.1,125.8,62.7(d,J=5.2Hz),5 2.9(d,J=5.5Hz),51.4,43.9(d,J=7.4Hz),42.4,37.0,31.5,28.5,25.5(d,J=6.3Hz),14.2. 31 P NMR(162MHz,chloroform-d)δ8.94(s).HRMS(ESI):[M+H] ⊕ calcd for C 21 H 33 O3NP ⊕ 378.2195, found 378.2193.

[0231] Example 29: Compound 5ac

[0232]

[0233] Compound 5ac, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 58%, [α] D 25 +18.2(c1.0,CHCl3)for 88%ee; 1 H NMR(500MHz,chloroform-d)δ7.37–7.24(m,7H),7.23–7.19(m,2H),7.15(t,J=7.4Hz,1H),4.19–4.12(m,2H),3.77(d,J=11.4Hz,3H),3.54–3.44(m,1H). 13 C NMR (126MHz, chloroform-d) δ151.0, 150.9, 139.2 (d, J = 6.4Hz), 129.7, 128.6, 127.5, 127.4, 124.8, 120.2 (d, J = 4.8Hz), 53.5 (d, J = 5.6Hz), 45.5.31 P NMR(162MHz,chloroform-d)δ5.45(s).HRMS(ESI):[M+H] ⊕ calcd for C 15 H 17 O3NP ⊕ 278.0944, found 278.0941. HPLC conditions: IF-H chiral column; wavelength: 210 nm, 25°C; mobile phase: 15% isopropanol in n-hexane; flow rate: 1.0 mL / min; retention time: 10.9 min (major), 11.7 min (minor).

[0234] Example 30: Compound 5ad

[0235]

[0236] Compound 5ad, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 58%, [α] D 25 -27.4(c 1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.43–7.31(m,5H),5.05(dd,J=7.8,1.8Hz,2H),4.96(s,1H),4.71(dd,J=5.9,1.0Hz,1H),4.57(d,J=6.0Hz,1H),4 .40–4.32(m,1H),4.02–3.96(m,2H),3.40–3.35(m,2H),3.30(d,J=13.6 Hz,6H),3.23–3.14(m,1H),3.12–3.01(m,2H),1.48(s,3H),1.31(s,3H). 13 C NMR(126MHz,chloroform-d)δ136.4(d,J=7.2Hz),128.5,128.3,127.8,112.4,109.3,85.0,84.9(d,J =8.7Hz), 81.6, 72.4 (d, J = 6.0Hz), 68.0 (d, J = 5.1Hz), 66.1 (d, J = 5.7Hz), 58.7, 54.9, 41.1, 26.4, 24.9. 31 P NMR(162MHz,chloroform-d)δ9.48(s).HRMS(ESI):[M+H] ⊕ calcd for C 19 H 31O8NP ⊕ 432.1785, found 432.1782.

[0237] Example 31: Compound 5ae

[0238]

[0239] Compound 5ae, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 57%, [α] D 25 -29.4(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.37–7.29(m,4H),7.26–7.22(m,1H),4.37–4.28(m, 1H),3.84(dq,J=13.5,6.9Hz,1H),3.80–3.73(m,2H),3.66(d,J=7.7Hz,4H),3.12( t,J=9.9Hz,1H),2.24(tt,J=12.3,3.7Hz,1H),2.05–1.97(m,2H),1.89–1.81(m,2H ),1.71–1.58(m,1H),1.55–1.37(m,7H),1.06–0.92(m,2H),0.81(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ176.3,145.1(d,J=4.6Hz),128.5,127.2,125.8,70.8(d,J=5.7Hz),67.8(d,J=5. 3Hz), 51.6, 51.5, 43.2, 37.7 (d, J = 7.6Hz), 28.4 (d, J = 2.5Hz), 28.3, 25.4 (d, J = 6.5Hz), 23.5 (d, J = 7.5Hz), 10.0. 31 P NMR(162MHz,chloroform-d)δ7.85(s).

[0240] Example 32: Compound 5af

[0241]

[0242] Compound 5af, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 47%, [α] D 25 +23.0(c1.0,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ7.37(d,J=4.4Hz,3H),7.35–7.24(m,4H),7.22(t,J=7. 3Hz,1H),7.14(d,J=7.4Hz,2H),5.75(s,1H),5.06–4.91(m,2H),4.71(d,J=12.2Hz,2H ),4.41–4.26(m,2H),3.24–3.07(m,2H),2.74(t,J=6.8Hz,2H),2.69–2.60(m,1H),2.2 0–2.02(m,4H),2.00–1.90(m,1H),1.88–1.80(m,1H),1.73(s,3H),1.52–1.40(m,1H). 13 C NMR (126 MHz, chloroform-d) δ 149.7, 138.7, 129.0, 128.7, 128.6, 128.3, 127.8, 126.6, 125.7, 108.9, 70.4, 67.8 (d, J = 4.9 Hz), 42.7, 40.9, 37.9 (d, J = 5.9 Hz), 30.5, 27.3, 26.1, 20.8 (the two aromatic carbon signals were not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ9.25(s).HRMS(ESI):[M+Na] ⊕ calcd for C 25 H 33 O3NNaP ⊕ 448.2016,found448.2012.

[0243] Example 33: Compound 5ag

[0244]

[0245] Compound 5ag, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 62%, [α] D 25 +1.8(c 1.0,CHCl3)for89%ee; 1 H NMR(500MHz,chloroform-d)δ7.46–7.14(m,10H),5.10–4.96(m,2H),4.23(d,J=10.1Hz,2H),4.17–4.05(m,2H), 13C NMR(126MHz,chloroform-d)δ156.2,137.8(d,J=3.6Hz),136.4(d,J=7.6Hz),128.5(d,J=10.5Hz),128.3,128.0(d,J=56.0Hz),127 .4,79.5,67.9(d,J=5.3Hz),67.2(d,J=5.7Hz),64.4,48.6(d,J=5.2Hz),39.6(d,J=3.8Hz),28.9(d,J=7.8Hz),28.40,28.37,13.3. 31 P NMR(162MHz,chloroform-d)δ10.73(s).HRMS(ESI):[M+Na] ⊕ calcd for C 25 H 36 O5N2NaP ⊕ 497.2181, found 497.2176. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 1% isopropanol in n-hexane as the mobile phase, and a flow rate of 1.0 mL / min. The retention times of the two structures were 19.1 min (major) and 23.9 min (minor).

[0246] Example 34: Compound 5ah

[0247]

[0248] Compound 5ah, white solid, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 51%, [α] D 25 +1.2(c1.0,CHCl3)for 15:1dr, 1 H NMR(500MHz,chloroform-d)δ7.83(s,1H),7.55(dd,J=69.3,8.5Hz,2H),7.35–7.23(m,8H),7.2 0–7.16(m,2H),5.15–4.84(m,2H),4.63–4.55(m,1H),3.81–3.74(m,1H),1.51(d,J=6.9Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 144.4, 130.8 (d, J = 3.3Hz), 128.7, 128.5, 128.5, 127.8, 127.4, 125.8, 121.4, 68.9 (d, J = 5.1Hz), 52.0, 25.2 (d, J = 6.9Hz).31 P NMR(162MHz,chloroform-d)δ2.77(s). 19 F NMR(376MHz,chloroform-d)δ-62.72–-63.37(m).HRMS(ESI):[M+H] ⊕ calcd for C 22 H 21 O3NBrF3P ⊕ 514.0395,found 514.0389.

[0249] Example 35: Compound 5ai

[0250]

[0251] Compound 5ai, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 71%, [α] D 25 +15.4(c1.0,CHCl3)for 84%ee; 1 H NMR(400MHz,chloroform-d)δ7.42–7.34(m,2H),7.23–7.18(m,1H),3.84(d,J=11.4Hz,3H),3.06–2.95(m,1H),2.69(dd,J=12.4,5.8Hz,3H),1.27(s,9H). 13 C NMR (101MHz, chloroform-d) δ 148.9, 144.5 (d, J = 6.0Hz), 127.5, 124.9, 124.7 (d, J = 7.0Hz), 120.9 (d, J = 2.2Hz), 53.7 (d, J = 5.7Hz), 34.6, 31.3, 27.8. 31 P NMR (162 MHz, chloroform-d) δ 7.0 (s). HPLC results: Detection was performed on an AD-H chiral column at 25°C, 210 nm wavelength, a mobile phase consisting of 15% isopropanol in n-hexane, and a flow rate of 1.0 mL / min. The retention times of the two structures were 5.4 min (major) and 7.0 min (minor).

[0252] Example 36: Compound 5aj

[0253]

[0254] Compound 5aj, known substance, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 71%, [α] D25 +9.18(c 2.0,CHCl3)for 82%ee; 1 H NMR(400MHz,chloroform-d)δ7.15–7.02(m,3H),4.22–4.10(m,2H),3.45(tddd,J=8.0,6.4,4.8,1 .6Hz,1H),2.91(d,J=10.7Hz,1H),2.42(s,2H),2.32(s,3H),1.39–1.31(m,3H),1.22–1.10(m,7H). 31 P NMR (162 MHz, chloroform-d) δ 3.5 (s). HPLC results: AD-H chiral column, detection conditions: 25 degrees, 210 nm wavelength, mobile phase: 15% isopropanol in n-hexane, flow rate: 1.0 mL / min. Two configurations were obtained with retention times of 6.6 min (major) and 7.1 min (minor). Comparison with known standards confirmed that compound 5aj has the configuration shown in the above formula.

[0255] Example 37: Compound 5ak

[0256]

[0257] Compound 5ak, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 59%. [α] D 25 +1.8(c1.0,CHCl3)for 87%ee; 1 H NMR(400MHz,chloroform-d)δ5.99(s,1H),3.78(d,J=11.4Hz,3H),3.59–3.48(m,4H) ,3.30–3.20(m,1H),2.68(dd,J=13.2,5.8Hz,3H),2.25(s,3H),1.14(t,J=7.0Hz,6H). 13 C NMR (101MHz, chloroform-d) δ 170.6, 165.0 (d, J = 6.2Hz), 160.7, 95.7 (d, J = 6.9Hz), 53.3 (d, J = 5.6Hz), 41.9, 27.6, 24.4, 13.0 (one alkyl carbon signal was not observed because of overlapping). 31P NMR (162 MHz, chloroform-d) δ 6.8 (s). HPLC results: Using an AD-H chiral column, detection was performed at 25°C, 254 nm wavelength, with a mobile phase consisting of 10% isopropanol in n-hexane at a flow rate of 1.0 mL / min. The retention times of the two structures were 6.5 min (major) and 6.9 min (minor).

[0258] Example 38: Compound 5a1

[0259]

[0260] Compound 5a1, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 60%. [α] D 25 -0.20(c 1.0,CHCl3)for 88%ee; 1 H NMR(500MHz,chloroform-d)δ7.85(d,J=8.4Hz,1H),7.14(s,1H),7.02(d,J=8.4Hz,1H),6.06–5.92(m,1H),5.90–5.79(m,1H),5.36(d, J=17.1Hz,1H),5.25(dd,J=13.8,7.5Hz,2H),5.16–5.03(m,3H),4.62–4.48(m,2H),3.97(s,3H),3.62–3.52(m,2H),3.15–3.06(m,1H). 13 C NMR(126MHz,chloroform-d)δ153.2,143.6(d,J=7.5Hz),139.0,135.7(d,J=5.8Hz),132.7(d,J =7.2Hz), 126.0, 118.6, 118.1, 115.8, 112.1, 67.2 (d, J = 5.0Hz), 66.6 (d, J = 4.7Hz), 56.6, 43.8. 31 P NMR(162MHz,chloroform-d)δ9.31(s).HRMS(ESI):[M+Na] ⊕ calcd for C 14 H 19 O6N2PNa ⊕365.0869, found 365.0873. HPLC results: IF-H chiral column, detection at 10°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 10.9 min (major) and 11.7 min (minor).

[0261] Example 39: Compound 5am

[0262]

[0263] Compound 5am, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 45%, [ α] D 25 -3.7(c1.0,CHCl3)for 82%ee; 1 H NMR(500MHz,chloroform-d)δ7.24(dd,J=46.6,8.5Hz,4H),6.04–5.88(m,1H),5.72–5.60(m,1H),5.34(d ,J=17.0Hz,1H),5.28–5.13(m,3H),4.74–4.59(m,2H),3.99–3.90(m,1H),3.84–3.72(m,3H),3.70(s,3H). 13 C NMR(126MHz,chloroform-d)δ170.8(d,J=2.5Hz),149.6(d,J=6.3Hz),133.1(d,J=2.4Hz),132.6(d,J=7.9Hz), 130.1, 129.6, 121.7 (d, J = 5.0Hz), 119.4, 118.1, 67.6 (d, J = 4.8Hz), 52.1, 49.8 (d, J = 3.7Hz), 46.7 (d, J = 5.9Hz). 31 P NMR(162MHz,chloroform-d)δ4.74(s).HRMS(ESI):[M+H] ⊕ calcd for C 15 H 20 5NJ ⊕ 360.0758, found 360.0762. HPLC results: AD-AD chiral column, detection at 40°C, 219 nm wavelength, 5% isopropanol in n-hexane mobile phase, flow rate 0.9 mL / min. The retention times of the two structures were 43.0 min (major) and 45.9 min (minor).

[0264] Example 40: Compound 6a

[0265]

[0266] Under nitrogen protection, add Molecular sieves (1.0 g), phosphorus oxychloride 1 (0.80 g, 5.3 mmol), and dry DCM / CHCl3 (30 mL, v / v = 1 / 2) were added. The reaction mixture was placed at -60°C, and propanol (5.3 mmol), triethylamine (0.60 g, 6.0 mmol), and DCM / CHCl3 (5.0 mL, v / v = 1 / 2) were added to the reaction mixture. The reaction was continued at this temperature for 12 hours. The reaction mixture was then placed at -80°C, and catalyst C-1 (0.13 g, 0.50 mmol), benzyl alcohol 3a (5.0 mmol), triethylamine (0.60 g, 6.0 mmol), and DCM / CHCl3 (5.0 mL, v / v = 1 / 2) were added to the reaction mixture. The reaction was continued at this temperature for 12 hours. The reaction mixture was then returned to room temperature, concentrated, and flash column chromatography was performed to obtain product 6a.

[0267] Colorless oil, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 65%, [α] D 25 +6.3(c 1.0,CHCl3)for 95%ee; 1 H NMR(400MHz,chloroform-d)δ7.44–7.31(m,5H),5.26–5.14(m,2H),4.16(dq,J=8.4,6.4Hz,2H),1.79–1.70(m,2H),0.97(t,J=7.4Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 134.5 (d, J = 8.2Hz), 129.1, 128.8, 128.2, 71.5 (d, J = 7.4Hz), 70.8 (d, J = 6.6Hz), 23.3 (d, J = 8.0Hz), 9.9. 31 P NMR(162MHz,chloroform-d)δ4.89(s).HRMS(ESI):[M+Na] ⊕ calcd for C 10 H 14 ClO3PNa ⊕271.0265, found 271.0261. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 7.3 min (minor) and 7.7 min (major).

[0268] Using the corresponding raw materials and referring to the reaction conditions and operation methods in Example 40, the following compounds 6b-6j were prepared.

[0269] Example 41: Compound 6b

[0270]

[0271] Compound 6b, colorless oil, column chromatography (petroleum ether / ethyl acetate = 8 / 1), yield 90%, [α] D 25 +4.2(c1.0,CHCl3)for 94%ee; 1 H NMR(500MHz,chloroform-d)δ7.33–7.24(m,5H),5.16–5.02(m,2H),3.77(d,J=13.8Hz,3H). 13 C NMR (126MHz, chloroform-d) δ134.3 (d, J = 8.2Hz), 129.2, 128.8, 128.3, 71.0 (d, J = 6.5Hz), 55.7 (d, J = 7.3Hz). 31 P NMR(162MHz,chloroform-d)δ6.3(s).HRMS(ESI):[M+H] ⊕ calcd for C8H 11 ClO3P ⊕ 221.0129, found 221.0128. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 5% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 15.5 min (minor) and 16.1 min (major).

[0272] Example 42: Compound 6c

[0273]

[0274] Compound 6c, colorless oil, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 74%, [α] D 25-21.0(c 2.0,CHCl3)for 89%ee; 1 H NMR(400MHz,chloroform-d)δ7.49–7.14(m,5H),4.49–4.33(m,2H),1.52–1.41(m,3H). 13 CNMR(101MHz,chloroform-d)δ149.8(d,J=8.7Hz),130.0,126.19,120.4(d,J=5.2Hz),66.8(d,J=7.2Hz),15.8(d,J=8.0Hz). 31 P NMR(162MHz,chloroform-d)δ-0.36(s).HRMS(ESI):[M+Na] ⊕ calcd for C8H 10 ClO3PNa ⊕ 220.9954, found 220.9948. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane as the mobile phase, and a flow rate of 1.0 mL / min. The retention times of the two structures were 8.7 min (major) and 8.9 min (minor).

[0275] Example 43: Compound 6d

[0276]

[0277] Compound 6d, yellow oil, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 73%, [α] D 25 +3.1(c2.0,CHCl3)for 97%ee; 1 H NMR(400MHz,chloroform-d)δ7.30–7.23(m,2H),7.21–7.12(m,3H),4.25–4.11(m,2H),3.85(d,J=13.8Hz,3H),2.71(t,J=7.6Hz,2H),2.03(p,J=6.5Hz,2H). 13 C NMR (126MHz, chloroform-d) δ140.2, 128.3, 128.2, 126.0, 68.8 (d, J = 7.2Hz), 55.2 (d, J = 6.9Hz), 31.2, 31.14, 31.08. 31 P NMR(162MHz,chloroform-d)δ5.6(s).HRMS(ESI):[M+H]⊕ calcd for C 10 H 15 O3PCl ⊕ 249.0442, found 249.0441. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 7.7 min (major) and 13.0 min (minor).

[0278] Example 44: Compound 6e

[0279]

[0280] Compound 6e, yellow oil, column chromatography (petroleum ether / ethyl acetate = 15 / 1), yield 71%, [α] D 25 +6.0(c2.0,CHCl3)for 93%ee; 1 H NMR (400MHz, chloroform-d) δ7.35–7.07(m,7H),7.01(t,J=8.6Hz,2H),5.17–5.01(m,2H),4.20–4.05(m,2H),2.65(t,J=7.6Hz,2H),2.02–1.92(m,2H). 13 C NMR(126MHz,chloroform-d)δ163.1(d,J=248.4Hz),140.4,130.4,130.4,128.54,128.45, 126.2, 115.8 (d, J = 21.8Hz), 70.1 (d, J = 6.4Hz), 69.1 (d, J = 7.3Hz), 31.4, 31.3 (d, J = 8.0Hz). 31 P NMR(162MHz,chloroform-d)δ4.8(s). 19 F NMR(376MHz,chloroform-d)δ-112.0.HRMS(ESI):[M+H] ⊕ calcd for C 16 H 18 3PCI ⊕ 343.0661, found 343.0657. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 9.3 min (minor) and 9.8 min (major).

[0281] Example 45: Compound 6f

[0282]

[0283] Compound 6f, colorless oil, column chromatography (petroleum ether / ethyl acetate = 8 / 1), yield 78%, [α] D 25 -18.0(c2.0,CHCl3)for 87%ee; 1 H NMR(500MHz,chloroform-d)δ7.36–7.10(m,4H),4.29(dt,J=14.3,6.4Hz,2H),3.70(s,3H),3.62(s,2H),1.87–1.74(m,2H),1.02(t,J=7.3Hz,3H). 13 CNMR(126MHz,chloroform-d)δ171.6,δ148.9(d,J=8.9Hz),132.0,130.8,120.49,120.45,72.1(d,J=7.6Hz),52.2,40.36,23.3(d,J=8.0Hz),9.9. 31 P NMR(162MHz,chloroform-d)δ-0.23(s).HRMS(ESI):[M+Na] ⊕ calcd for C 12 H 16 O5PClNa ⊕ 329.0316, found 329.0318. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 15.4 min (major) and 16.0 min (minor).

[0284] Example 46: Compound 6g

[0285]

[0286] Compound 6g, colorless oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 77%, [α] D 25 +12.2(c2.0,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ7.11–6.92(m,4H),5.35–5.15(m,1H),4.32(p,J=7.5Hz,1H),4.13–4.01(m,2H),3.97–3 .88(m,2H),2.87(dp,J=47.7,7.1Hz,2H),1.65–1.54(m,2H),1.23–1.16(m,9H),1.04–0.98(m,3H),0.84–0.77(m,3H). 13 CNMR(126MHz,chloroform-d)δ171.2,154.7,148.3(d,J=8.5Hz),134.3,130.4,11 9.7,79.1,71.6(d,J=7.7Hz),60.8,54.1,37.1,27.8,22.8(d,J=7.8Hz),13.6,9.4. 31 P NMR(162MHz,chloroform-d)δ-0.40(s).HRMS(ESI):[M+Na] ⊕ calcd for C 19 H 29 O7PClNa ⊕ 472.1262, found 472.1267.

[0287] Example 47: Compound 6h

[0288]

[0289] Compound 6h, colorless oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 73%, [α] D 25 -27.5(c1.0,CHCl3)for 15:1dr; 1 H NMR(500MHz,chloroform-d)δ7.46–7.38(m,5H),5.34–5.19(m,2H),5.00(s,1H),4.71(d,J=5.9H z,1H),4.63–4.59(m,1H),4.39(s,1H),4.24–4.09(m,2H),3.33(s,3H),1.50(s,3H),1.34(s,3H). 13 C NMR (126MHz, chloroform-d) 31 P NMR(162MHz,chloroform-d)δ4.8(s).HRMS(ESI):[M+H] ⊕calcd for C 16 H 23 7PCl ⊕ 393.0864,found 393.0860.

[0290] Example 48: Compound 6i

[0291]

[0292] Compound 6i, colorless oil, column chromatography (petroleum ether / ethyl acetate = 15 / 1), yield 76%, [α] D 25 +0.57(c2.0,CHCl3); 1 HNMR(500MHz,chloroform-d)δ7.28(q,J=7.2Hz,2H),7.20(t,J=7.9Hz,3H),4.27–4.08(m,4H ),2.74(t,J=7.6Hz,2H),2.05(p,J=6.6Hz,2H),1.76(h,J=7.1Hz,2H),0.99(t,J=7.4Hz,3H). 13 C NMR (101MHz, chloroform-d) δ140.5, 128.5, 128.4, 126.2, 71.2 (d, J = 7.3Hz), 68.8 (d, J = 7.3Hz), 31.4 (d, J = 8.0Hz), 23.2 (d, J = 7.9Hz), 9.9. 31 P NMR(162MHz,chloroform-d)δ4.77(s).HRMS(ESI):[M+H] ⊕ calcd for C 12 H 19 O3PCl ⊕ 277.0755,found 277.0750.

[0293] Example 49: Compound 6j

[0294]

[0295] Compound 6j, colorless oil, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 78% yield, [α] D 25 +0.01(c 1.0,CHCl3); 1H NMR(400MHz,chloroform-d)δ7.40–7.09(m,5H),4.47–4.28(m,2H),4.28–4.09(m,2H),3.03(t,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H). 13 C NMR (101MHz, chloroform-d) δ136.2, 128.8, 128.5, 126.8, 69.5 (d, J = 7.3Hz), 65.8 (d, J = 7.0Hz), 36.1 (d, J = 7.9Hz), 15.5 (d, J = 7.7Hz). 31 P NMR(162MHz,chloroform-d)δ4.3(s).HRMS(ESI):[M+H] ⊕ calcd for C 10 H 15 ClO3P ⊕ 249.0442,found 249.0438.

[0296] Example 50: Compound 8a

[0297]

[0298] Under nitrogen protection, add Molecular sieves (60 mg), ammonium carbamate 7 (16 mg, 0.20 mmol), triethylamine (40 mg, 0.40 mmol), and dry tetrahydrofuran (1.0 mL) were added. The reaction was stirred at room temperature for 5 minutes. Compound 6f (0.20 mmol) was then added to the reaction, and the reaction was continued at room temperature for 12 hours. The reaction solution was then concentrated and flash column chromatography was performed to obtain product 8a.

[0299] Yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 73%, [α] D 25 -7.5(c 2.0,CHCl3)for 84%ee; 1 H NMR(500MHz,chloroform-d)δ7.39–7.11(m,7H),7.03(t,J=8.0Hz,2H),5.00(d,J=7.6H z, 2H), 4.03 (q, J = 6.1Hz, 2H), 3.20 (s, 2H), 2.68 (t, J = 7.4Hz, 2H), 1.97 (p, J = 6.8Hz, 2H). 13C NMR(126MHz,chloroform-d)δ162.7(d,J=247.0Hz)141.1,132.4(d,J=3.3Hz),132.3(d,J=3.1Hz),129.8(d, J=8.4Hz), 128.5, 126.1, 115.5 (d, J=21.7Hz), 67.3 (d, J=5.1Hz), 66.0 (d, J=5.6Hz), 31.8 (d, J=7.3Hz), 31.7. 31 P NMR(162MHz,chloroform-d)δ10.0(s). 19 F NMR(376MHz,chloroform-d)δ-113.5.HRMS(ESI):[M+H] ⊕ calcd for C 16 H 20 O3PNF ⊕ 324.1159, found 324.1162. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 13.9 min (major) and 14.5 min (minor).

[0300] Using the corresponding raw materials 6d, 6a, and 6h, and referring to the reaction conditions and operation methods in Example 50, the following compounds 8b-8e were prepared.

[0301] Example 51: Compound 8b

[0302]

[0303] Compound 8b, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 81%, [α] D 25 +7.4(c1.0,CHCl3)for 94.5:5.5er; 1 H NMR(500MHz,chloroform-d)δ7.32–7.23(m,2H),7.22–7.13(m,3H),4.03(d,J=6.5Hz, 2H), 3.73 (d, J = 11.2Hz, 3H), 3.16 (s, 2H), 2.71 (d, J = 7.7Hz, 2H), 1.99 (p, J = 6.8Hz, 2H). 13C NMR (126MHz, chloroform-d) δ141.1, 128.4, 126.0, 65.8 (d, J = 5.5Hz), 53.1 (d, J = 5.5Hz), 31.9 (d, J = 7.2Hz), 31.8. 31 PNMR(162MHz,chloroform-d)δ11.1(s).HRMS(ESI):[M+H] ⊕ calcd for C 10 H 17 O3PN ⊕ 230.0941, found 230.0943. HPLC results: AD-H chiral column, detection conditions: 25 degrees, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two configurations were 9.0 min (minor) and 9.9 min (major).

[0304] Example 52: Compound 8c

[0305]

[0306] Compound 8c, yellow oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 86%, [α] D 25 +6.0(c1.0,CHCl3)for 92%ee. 1 H NMR (500MHz, chloroform-d) δ7.45–7.27(m,5H),5.06(d,J=7.5Hz,2H),3.98(q,J=6.7Hz,2H),3.21(s,2H),1.65(h,J=7.1Hz,2H),0.91(t,J=7.4Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 135.4 (d, J = 7.6Hz), 127.5, 127.3, 126.8, 67.2 (d, J = 43.7Hz), 22.6 (d, J = 7.3Hz), 9.0. 31 P NMR(162MHz,chloroform-d)δ12.2(s).HRMS(ESI):[M+Na] ⊕ calcd for C 11 H 17 O4PNa ⊕267.0757, found 267.0761. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 14.6 min (minor) and 15.2 min (major).

[0307] Example 53: Compound 8d

[0308]

[0309] Compound 8d, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 93%, [α] D 25 -25.1(c2.0,CHCl3)for 10:1dr; 1 H NMR(400MHz,chloroform-d)δ7.40–7.27(m,5H),5.05(d,J=7.9Hz,2H),4.94(s,1H),4.68(d,J=6.0Hz,1H),4.54(d,J =5.8Hz,1H),4.34(t,J=6.9Hz,1H),4.05–3.90(m,2H),3.27(s,3H),3.22(d,J=5.2Hz,2H),1.45(s,3H),1.29(s,3H). 13 CNMR(126MHz,chloroform-d)δ136.3(d,J=7.4Hz),128.6,128.4,127.9,112.5,109.4, 85.0,84.9(d,J=8.5Hz),81.5,68.2(d,J=5.1Hz),66.3(d,J=5.6Hz),55.0,26.4,24.9. 31 P NMR(162MHz,chloroform-d)δ10.8(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 25 O7P ⊕ 374.1363, found 374.1360.

[0310] Example 54: Compound 10a

[0311]

[0312] Under nitrogen protection, add Molecular sieves (30 mg), compound 9a (0.15 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 34 mg, 0.20 mmol), and dry chloroform (1.0 mL) were added. The reaction was stirred at room temperature for 5 minutes. Compound 6g (0.10 mmol) was then added to the reaction, and the reaction was continued at 30°C for 12 hours. The reaction solution was then concentrated and flash column chromatography was performed to obtain product 10a.

[0313] Yellow oil, yield 61%, [α] D 25 +28.8(c 1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.34–7.23(m,5H),7.09(s,4H),5.02(d,J=8.3Hz,1H),4.54(q,J=6.7Hz,1H),4.17–3.98 (m,6H),3.06(qd,J=14.0,5.8Hz,2H),1.69(h,J=7.2Hz,2H),1.43(s,9H),1.22(t,J=7.1Hz,3H),0.94(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ171.7,155.1,149.3(d,J=7.4Hz),137.0(d,J=5.9Hz),133.3,130.6,129.0,128.7,127.8 ,120.6(d,J=4.8Hz),80.0,69.7(d,J=6.7Hz),61.4,54.4,37.7,35.3(d,J=3.7Hz),28.3,23.5(d,J=7.4Hz),14.2,10.0. 31 P NMR(162MHz,chloroform-d)δ24.0(s).HRMS(ESI):[M+Na] ⊕ calcd for C 25 H 34 O7PNSNa ⊕ 564.1686, found 546.1685.

[0314] Using the corresponding raw materials 6g, 6c, and 6f, and referring to the reaction conditions and operation methods in Example 54, the following compounds 10b-10d were prepared.

[0315] Example 55: Compound 10b

[0316]

[0317] Compound 10b, yellow oil, column chromatography (petroleum ether / ethyl acetate = 4 / 1), yield 56%, [α] D 25 +37.2(c1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.15–6.99(m,5H),6.95(s,1H),6.79(d,J=8.3Hz,1H),5.02(d,J=7.9Hz,1H),4.50(d,J=6.7Hz,1H),4.20– 4.05(m,4H),3.85(s,3H),3.79(s,3H),3.12–2.84(m,2H),1.69(h,J=6.9Hz,2H),1.39(s,9H),1.21–1.18(m,3H),0.91(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ171.7,155.1,150.3(d,J=3.5Hz),149.5(d,J=7.8Hz),149.2(d,J=2.2Hz),133.2,130.6,128.3(d,J=6.0Hz),120.3(d,J=5.0 Hz),117.8(d,J=4.2Hz),115.7(d,J=7.7Hz),111.6,80.0,70.2(d,J=7.2Hz), 61.4, 58.3, 56.0, 55.9, 54.4, 37.6, 28.3, 23.6 (d, J = 7.2Hz), 18.4, 14.1, 10.0. 31 P NMR(162MHz,chloroform-d)δ23.2(s).HRMS(ESI):[M+Na] ⊕ calcd for C 27 H 38 O9PNSNa ⊕ 606.1897,found 606.1896.

[0318] Example 56: Compound 10c

[0319]

[0320] Compound 10c, yellow oil, column chromatography (petroleum ether / ethyl acetate = 10 / 1), yield 72%, [α] D 25 +17.8(c 1.0,CHCl3)for89%ee; 1H NMR (400MHz, chloroform-d) δ7.54–7.43(m,2H),7.33(t,J=7.7Hz,2H),7.22–7.15(m,3H),7.03(t,J=8.4Hz,2H),4.36–4.24(m,2H),1.36(t,J=7.1Hz,3H). 13 C NMR(126MHz,chloroform-d)162.6(d,J=7.4Hz),150.4(d,J=8.1Hz),137.2(dd,J=8.3,5.1Hz),129.8,1 25.4, 120.4 (d, J = 5.1Hz), 116.8 (d, J = 2.4Hz), 116.6 (d, J = 2.4Hz), 64.9 (d, J = 7.6Hz), 16.1 (d, J = 7.0Hz). 31 P NMR (162MHz, chloroform-d) δ18.7 (d, J = 5.7Hz). 19 F NMR(376MHz,chloroform-d)δ-111.1(d,J=2.5Hz).HRMS(ESI):[M+H] ⊕ calcd for C 18 H 22 O5PS ⊕ 313.0458, found 313.0457. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 10% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 19.5 min (minor) and 20.5 min (major).

[0321] Example 57: Compound 10d

[0322]

[0323] Compound 10d, yellow oil, column chromatography (petroleum ether / ethyl acetate = 8 / 1), yield 72%, [α] D 25 +7.3(c1.0,CHCl3)for 84%ee; 1H NMR(400MHz,chloroform-d)δ7.52(d,J=6.8Hz,2H),7.40–7.29(m,3H),7.23(d,J=8.1Hz,2H),7.11(d ,J=7.9Hz,2H),4.22–4.12(m,2H),3.69(s,3H),3.60(s,2H),1.75–1.66(m,2H),0.92(t,J=7.3Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 171.8, 149.6 (d, J = 8.2Hz), 135.0 (d, J = 5.4Hz), 131.0 (d, J = 1.4Hz), 130.6, 129.5 (d, J = 2. 7Hz), 129.4 (d, J = 2.9Hz), 125.8 (d, J = 7.5Hz), 120.60, 120.56, 70.3 (d, J = 6.9Hz), 52.2, 40.5, 23.6 (d, J = 7.3Hz), 10.0. 31 P NMR(162MHz,chloroform-d)δ19.4(s).HRMS(ESI):[M+Na] ⊕ calcd for C 18 H 21 5PSNa ⊕ 403.0740, found 403.0738. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 45.3 min (minor) and 55.0 min (major).

[0324] Example 58: Compound 11a

[0325]

[0326] Under nitrogen protection, add Molecular sieves (30 mg), fluoroethanol (0.10 mmol), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG, 17 mg, 0.10 mmol), and dry chloroform (0.50 mL) were added. The reaction was stirred at room temperature for 5 minutes. Compound 6a (0.12 mmol) was then added to the reaction, and the reaction was continued at 30°C for 12 hours. The reaction solution was then concentrated and flash column chromatography was performed to obtain product 11a.

[0327] Colorless oil, column chromatography (petroleum ether / ethyl acetate = 6 / 1), yield 67%, [α] D25 +0.29(c 1.0,CHCl3)for 90%ee; 1 H NMR(500MHz,chloroform-d)δ7.4-7.3(m,5H),5.08(d,J=8.2Hz,2H),4.61-4.49(m,2H ),4.29–4.15(m,2H),3.99(q,J=6.7Hz,2H),1.70–1.63(m,2H),0.93(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ135.8(d,J=6.7Hz),128.66,128.64,128.0,82.0(dd,J=172.4,7 .1Hz), 69.7(d,J=6.2Hz), 69.4(d,J=5.6Hz), 66.3(dd,J=20.6,5.5Hz), 23.5(d,J=7.0Hz), 9.9. 31 P NMR(162MHz,chloroform-d)δ-0.99(s). 19 FNMR(376MHz,chloroform-d)δ-194.5–-195.3(m).HRMS(ESI):[M+H] ⊕ calcd for C 12 H 19 O4FP ⊕ 277.1000, found 277.1004. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 5% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 20.8 min (minor) and 21.9 min (major).

[0328] Using the corresponding raw materials 6a, 6b, 6g, 6i, and 6j, and referring to the reaction conditions and operation methods in Example 58, the following compounds 11b-11ad were prepared.

[0329] Example 59: Compound 11b

[0330]

[0331] Compound 11b, colorless oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 71%, [α] D 25 +0.40(c3.0,CHCl3)for94%ee; 1H NMR(500MHz,chloroform-d)δ7.39–7.28(m,8H),7.14–7.05(m,2H),7.03–6.94(m,4H ),5.07–4.96(m,4H),3.95(q,J=6.8Hz,2H),1.68–1.59(m,2H),0.90(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ157.6,156.9,137.9(d,J=7.0Hz),135.9(d,J=6.8Hz),130.0,129.9,128.62,128.57,128. 0,123.6,122.4,119.1,118.7,117.9,69.5(d,J=6.2Hz),69.2(d,J=5.6Hz),68.6(d,J=5.5Hz),23.5(d,J=7.1Hz),10.0. 31 P NMR(162MHz,chloroform-d)δ-0.86(s).HRMS(ESI):[M] ⊕ calcd for C 23 H 26 O5P ⊕ 413.1512, found 413.1518. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 5.9 min (minor) and 9.6 min (major).

[0332] Example 60: Compound 11c

[0333]

[0334] Compound 11c, colorless oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 52%, [α] D 25 -4.2(c0.5,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.44–7.29(m,5H),5.07(d,J=8.0Hz,2H),4.03–3.90(m,4H),3.51(h,J =5.8Hz,1H),3.36(d,J=4.4Hz,3H),1.66(h,J=6.7Hz,2H),1.13(t,J=5.2Hz,3H),0.97–0.88(m,3H).13 C NMR(126MHz,chloroform-d)δ136.1(d,J=6.7Hz),128.6,128.5,127.9,75.4(d,J=7.4Hz),6 9.9(d,J=6.0Hz),69.5(d,J=6.1Hz),69.2(d,J=5.6Hz),56.9,23.6(d,J=7.1Hz),16.0,10.0. 31 P NMR(162MHz,chloroform-d)δ-1.27(s).HRMS(ESI):[M+H] ⊕ calcd for C 14 H 24 O5P ⊕ 303.1356,found303.1354.

[0335] Example 61: Compound 11d

[0336]

[0337] Compound 11d, colorless oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 68%, [α] D 25 +30.9(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.49–7.29(m,5H),5.07(d,J=7.9Hz,2H),4.25–3.70(m,8H),3 .55–3.38(m,2H),3.19–2.90(m,1H),1.70–1.61(m,2H),1.45(s,9H),0.92(t,J=7.2Hz,3H). 13 C NMR(126MHz,chloroform-d)δ154.6,136.0(d,J=6.7Hz),128.6,128.6,128.0,80.5,69.6(d,J=6.2Hz),69.3 (d,J=5.4Hz),66.7(d,J=5.4Hz),65.6(d,J=2.4Hz),63.1(d,J=5.9Hz),28.4,28.4,23.6(d,J=6.9Hz),10.0. 31 PNMRδ-0.87(s).HRMS(ESI):[M+H] ⊕ calcd for C 20 H 33 O7NP ⊕430.1989,found430.1993.

[0338] Example 62: Compound 11e

[0339]

[0340] Compound 11e, colorless oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 51%, [α] D 25 +0.81(c 1.0,CHCl3)for90%ee; 1 H NMR(400MHz,chloroform-d)δ7.41–7.29(m,5H),5.05(d,J=8.7Hz,2H),4.11–4.04(m,2H),3.94(d,J=7.1 Hz,4H),3.72(d,J=6.6Hz,1H),3.66–3.63(m,2H),1.68–1.61(m,2H),1.40(s,9H),0.91(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ135.8(d,J=7.0Hz),132.1(d,J=9.4Hz),128.6,128.0,79.5,79.3,69.6(d,J= 6.2Hz), 69.4 (d, J = 6.0Hz), 68.5 (d, J = 5.6Hz), 30.5, 28.7 (d, J = 7.4Hz), 28.4, 28.3, 23.5 (d, J = 7.2Hz), 9.9. 31 P NMR(162MHz,chloroform-d)δ-0.80(s).HRMS(ESI):[M+Na] ⊕ calcd for C 19 H 30 O6NPNa ⊕ 422.1703, found 422.1708. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 30.9 min (minor) and 33.0 min (major).

[0341] Example 63: Compound 11f

[0342]

[0343] Compound 11f, colorless oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 85%, [α] D 25 -5.9(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.39-7.31(m,5H),5.05(d,J=8.7Hz,2H),3.95(q,J=7.4Hz,3H),3.88(t,J=7.6Hz,1H),3.46( s,2H),3.29(s,1H),3.06(s,1H),2.47(p,J=7.3Hz,1H),1.92(s,1H),1.70-1.59(m,3H),1.43(s,9H),0.91(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ154.4,135.9(d,J=7.5Hz),128.7,128.6,127.9,79.3,69.5(d,J=6.1Hz),69.3(d,J=5.6 Hz), 68.4, 48.0 (d, J = 60.0Hz), 45.0 (d, J = 31.9Hz), 39.3, 38.4, 28.5, 27.9 (d, J = 7.3Hz), 27.1, 23.6 (d, J = 7.0Hz), 10.0. 31 P NMR(162MHz,chloroform-d)δ-0.88(s).HRMS(ESI):[M+H] ⊕ calcd for C 22 H 33 O6NP ⊕ 414.2040,found 414.2040.

[0344] Example 64: Compound 11g

[0345]

[0346] Compound 11g, colorless oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 79%, [α] D 25 -0.87(c 2.0,CHCl3)for 89%ee; 1H NMR(500MHz,chloroform-d)δ7.60–7.54(m,4H),7.44(q,J=7.5Hz,3H),7.38-7.30(m,7H),5.11(dd,J=8.1, 3.8Hz, 2H), 5.06 (dd, J=8.1, 2.7Hz, 2H), 3.98 (q, J=6.7Hz, 2H), 1.65 (q, J=7.2Hz, 2H), 0.91 (t, J=7.4Hz, 3H). 13 C NMR(126MHz,chloroform-d)δ141.6,140.6,136.5(d,J=6.7Hz),135.9(d,J=7.0Hz),129.0,128.8,128.6,128.5,127.9, 127.5, 127.3, 127.2, 126.8, 126.7, 69.5 (d, J = 6.1Hz), 69.24 (d, J = 5.8Hz), 69.18 (d, J = 5.8Hz), 23.6 (d, J = 7.2Hz), 10.0. 31 P NMR(162MHz,chloroform-d)δ-0.69(s).HRMS(ESI):[M+Na] ⊕ calcd for C 23 H 25 O4PNa ⊕ 419.1383, found 419.1386. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 17.9 min (major) and 20.0 min (minor).

[0347] Example 65: Compound 11h

[0348]

[0349] Compound 11h, colorless oil, column chromatography (petroleum ether / ethyl acetate = 15 / 1), yield 79%, [α] D 25 -1.87(c 1.0,CHCl3)for95%ee; 1H NMR(500MHz,chloroform-d)δ7.43–7.30(m,5H),5.06(d,J=8.2Hz,2H),4.06(p,J=6.8Hz,2H),3.96(qd,J=6 .7,3.5Hz,2H),1.92(s,3H),1.72–1.64(m,5H),1.63–1.56(m,3H),1.50–1.42(m,8H),0.93(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ136.1(d,J=6.6Hz),128.6,128.5,127.9,69.3(d,J=6.2Hz),69.0(d,J=5.8Hz),64.3( d,J=6.0Hz),58.6,47.2,44.0(d,J=6.9Hz),42.7,42.5,37.1,37.0,31.9,31.7,28.7,28.5,23.6(d,J=7.2Hz),10.0. 31 P NMR(162MHz,chloroform-d)δ-0.68(s).HRMS(ESI):[M+H] ⊕ calcd for C 22 H 34 O4P ⊕ 393.2189, found 393.2190. HPLC results: ID-H chiral column, detection conditions: 10 degrees, 210 nm wavelength, 2% isopropanol in n-hexane mobile phase, flow rate 0.7 mL / min. Two configurations were obtained with retention times of 47.3 min (minor) and 48.5 min (major).

[0350] Example 66: Compound 11i

[0351]

[0352] Compound 11i, colorless oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 44%, [α] D 25 +9.7(c1.0,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ7.45–7.28(m,5H),5.06(d,J=8.1Hz,2H),4.32(s,1H),4.03–3.92(m,5H),2.76–2.65(m,1H),2.12–2.03(m ,1H),1.78–1.69(m,1H),1.69–1.62(m,2H),1.59–1.55(m,2H),1.54–1.48(m,2H),1.48–1.43(m,2H),1.43(s,9H),0.92(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ154.9,136.1(d,J=5.1Hz),128.6,128.5,127.9,79.4,69.4(d,J=6.0Hz),69.1(d ,J=5.4Hz),65.5(d,J=3.5Hz),47.5,38.8,30.6(d,J=3.9Hz),28.7,28.4,25.5,23.6(d,J=7.4Hz),19.0,10.0. 31 P NMR(162MHz,chloroform-d)δ-0.82(s).HRMS(ESI):[M+H] ⊕ calcd for C 22 H 37 O6NP ⊕ 442.2353,found442.2355.

[0353] Example 67: Compound 11j

[0354]

[0355] Compound 11j, colorless oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 87%, [α] D 25 +10.6(c1.0,CHCl3)for 13:1dr; 1 H NMR(500MHz,chloroform-d)δ7.40–7.14(m,15H),5.27(d,J=8.6Hz,1H),5.08–4.97(m, 4H), 4.11–3.83 (m, 5H), 2.92–2.75 (m, 2H), 1.64 (p, J = 7.0Hz, 2H), 0.91 (t, J = 7.4Hz, 3H). 13C NMR(126MHz,chloroform-d)δ155.8,137.0,136.4,135.8(d,J=6.3Hz),129.4,128.7,128.63,128.57,128.5,128.1,128.04,1 28.00,126.8,69.7(d,J=6.1Hz),69.5(d,J=5.6Hz),67.6(d,J=5.6Hz),66.7,52.3(d,J=7.0Hz),37.2,23.6(d,J=7.0Hz),10.0. 31 P NMR(162MHz,chloroform-d)δ-0.47.HRMS(ESI):[M+H] ⊕ calcdfor C 27 H 33 O6NP ⊕ 498.2040,found 498.2040.

[0356] Example 68: Compound 11k

[0357]

[0358] Compound 11k, colorless oil, column chromatography (petroleum ether / ethyl acetate = 2 / 1), yield 85%, [α] D 25 -10.3(c 1.0,CHCl3)for 14:1dr; 1 H NMR(500MHz,chloroform-d)δ7.43–7.31(m,5H),5.08–5.00(m,2H),4.69(dd,J=21.8,9.9Hz,1H),4.05(ddd,J=9.6,5.4,3.7Hz,1H) ,3.96(q,J=6.7Hz,3H),3.60(ddd,J=10.7,7.0,3.6Hz,1H),1.65(h,J=7.1Hz,2H),1.43(d,J=11.2Hz,9H),0.91(d,J=20.2Hz,12H). 13 C NMR(126MHz,chloroform-d)δ156.0,136.0(d,J=6.2Hz),128.65,128.60,128.0,79.2,69.5(d,J=6.2H z), 69.3 (d, J = 5.7Hz), 67.1 (d, J = 6.0Hz), 58.0 (d, J = 7.3Hz), 34.1, 28.4, 26.8, 23.6 (d, J = 7.1Hz), 10.0. 31P NMR(162MHz,chloroform-d)δ-0.67(s).HRMS(ESI):[M+H] ⊕ calcd for C 21 H 37 O6NP ⊕ 430.2353,found430.2353.

[0359] Example 69: Compound 111

[0360]

[0361] Compound 111, colorless oil, column chromatography (petroleum ether / ethyl acetate = 8 / 1), yield 60%. [α] D 25 -19.9(c 1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.43–7.27(m,5H),5.31–5.24(m,1H),5.05(d,J=8.1Hz,2H),4.04–3.91(m,4H),2.37–2.27(m,3H),2.23–2.1 2(m,2H),2.08–2.03(m,1H),2.02–1.95(m,1H),1.73–1.58(m,2H),1.25(s,3H),1.12(d,J=8.4Hz,1H),0.92(t,J=7.4Hz,3H),0.80(s,3H). 13 C NMR(126MHz,chloroform-d)δ143.4,136.2(d,J=6.8Hz),128.6,128.5,127.9,119.2,69.4(d,J=6.2Hz),69.1(d,J =5.5Hz), 65.9 (d, J = 6.1Hz), 45.7, 40.7, 38.1, 37.7 (d, J = 7.0Hz), 31.6, 31.4, 26.3, 23.6 (d, J = 6.9Hz), 21.2, 10.0. 31 P NMR(162MHz,chloroform-d)δ-0.88(s).HRMS(ESI):[M+H] ⊕ calcd for C 21 H 32 O4P ⊕ 379.2033,found 379.2033.

[0362] Example 70: Compound 11m

[0363]

[0364] Compound 11m, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 85%, [α] D 25 -13.7(c 1.0,CHCl3)for90%ee; 1 H NMR(500MHz,chloroform-d)δ7.40–7.31(m,5H),6.72–6.66(m,2H),6.63(dt,J=8.7,1.7Hz,1H),5 .95(s,2H),5.19–5.09(m,2H),4.05(q,J=6.8Hz,2H),1.67(q,J=7.1Hz,2H),0.92(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ148.1,145.0(d,J=7.3Hz),144.8,135.6(d,J=6.9Hz),128.7,128.6,128.0,112. 5(d,J=4.8Hz),108.0,102.6(d,J=5.1Hz),101.7,70.2(d,J=6.3Hz),69.9(d,J=5.9Hz),23.5(d,J=7.0Hz),9.9. 31 P NMR(162MHz,chloroform-d)δ-5.70(s).HRMS(ESI):[M+H] ⊕ calcdfor C 17 H 20 O6P ⊕ 351.0992, found 351.0998. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 16.1 min (major) and 18.5 min (minor).

[0365] Example 71: Compound 11n

[0366]

[0367] Compound 11n, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 85%, [α] D 25 -9.9(c1.0,CHCl3)for 89%ee; 1H NMR(500MHz,chloroform-d)δ7.43–7.30(m,5H),7.25–7.12(m,1H),6.95–6.79(m,2H),5.19(qt,J=12.5,7. 6Hz,2H),4.11(dq,J=13.4,6.3Hz,2H),3.88–3.73(m,3H),1.76–1.63(m,2H),0.94(dt,J=14.4,6.5Hz,3H). 13 C NMR(126MHz,chloroform-d)δ151.3,138.6,135.8,130.8,128.6,127.9,122.22,122. 20,120.5,113.3,70.3(d,J=6.3Hz),69.8(d,J=5.5Hz),56.1,23.5(d,J=7.2Hz),9.9. 31 PNMR(162MHz,chloroform-d)δ-5.84(s).HRMS(ESI):[M+H] ⊕ calcd for C 17 H 21 ClO5P ⊕ 371.0810, found 371.0823. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 19.9 min (major) and 23.0 min (minor).

[0368] Example 72: Compound 11o

[0369]

[0370] Compound 11o, yellow oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 63%, [α] D 25 -0.52(c 1.0,CHCl3)for97.5:2.5er; 1 H NMR(500MHz,chloroform-d)δ7.52–7.17(m,14H),4.85(ddd,J=47.3,11.8,7.8Hz, 2H), 3.78 (p, J=6.8, 6.4Hz, 2H), 1.50 (p, J=7.1Hz, 2H), 0.80 (td, J=7.4, 1.4Hz, 3H). 13C NMR(126MHz,chloroform-d)δ147.6(d,J=7.5Hz),137.5,135.7(d,J=7.5Hz),133.7(d,J=6.3Hz),131.2,129.6,128.7,12 8.5,128.4,128.1,127.7,127.4,125.3,120.6(d,J=2.3Hz),70.0(d,J=6.6Hz),69.5(d,J=5.9Hz),23.4(d,J=7.4Hz),9.8. 31 P NMR(162MHz,chloroform-d)δ-6.75(s).HRMS(ESI):[M+H] ⊕ calcd for C 22 H 24 O4P ⊕ 383.1407, found 383.1420. HPLC results: AD-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 8.9 min (major) and 9.9 min (minor).

[0371] Example 73: Compound 11p

[0372]

[0373] Compound 11p, yellow oil, column chromatography (petroleum ether / ethyl acetate = 4 / 1), yield 76%, [α] D 25 -4.8(c1.0,CHCl3)for 93%ee; 1 H NMR(500MHz,chloroform-d)δ8.23(d,J=6.0Hz,1H),7.65(q,J=7.4Hz,1H),7.37–7.24(m,5H),7.07(q,J=7.0Hz,1 H),6.93(t,J=7.4Hz,1H),5.24(t,J=7.4Hz,2H),4.13(p,J=6.7Hz,2H),1.70–1.61(m,2H),0.88(q,J=7.2Hz,3H). 13C NMR(126MHz,chloroform-d)δ157.6(d,J=5.6Hz),147.9,140.0,135.8(d,J=7.3Hz),128.6,128.5 ,128.0,120.7,113.3(d,J=7.2Hz),70.4(d,J=6.3Hz),70.0(d,J=5.6Hz),23.5(d,J=7.3Hz),9.9. 31 P NMR(162MHz,chloroform-d)δ-7.16(s).HRMS(ESI):[M+H] ⊕ calcd for C 15 H 19 O4NP ⊕ 308.1046, found 308.1055. HPLC results: AD-H chiral column, detection conditions: 25 degrees, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 13.5 min (minor) and 15.7 min (major).

[0374] Example 74: Compound 11q

[0375]

[0376] Compound 11q, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 78%, [α] D 25 +9.1(c1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.34(d,J=2.7Hz,5H),7.07(dd,J=9.1,1.3Hz,2H),6.82–6.76(m,2H),5.18–5.07(m,2H),4.6 9(q,J=6.8Hz,1H),4.04(q,J=6.8Hz,2H),3.74(s,3H),1.65(q,J=7.4Hz,2H),1.59(d,J=6.8Hz,3H),0.90(t,J=7.4Hz,3H). 13C NMR(126MHz,chloroform-d)δ172.5,154.6,145.0(d,J=7.2Hz),135.6(d,J=6.8Hz),128.6,127.99, 121.1,121.0,116.1,73.1,70.1(d,J=6.3Hz),69.8(d,J=5.9Hz),52.3,23.5(d,J=6.8Hz),18.6,9.9. 31 P NMR(162MHz,chloroform-d)δ-5.78(s).HRMS(ESI):[M+H] ⊕ calcd for C 20 H 26 O7P ⊕ 409.1411, found 409.1425.

[0377] Example 75: Compound 11r

[0378]

[0379] Compound 11r, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 89%, [α] D 25 +12.1(c 1.0,CHCl3)for11:1dr; 1 H NMR(500MHz,chloroform-d)δ7.34(s,5H),7.14–7.03(m,4H),5.12(qt,J=8.3,6.0Hz,2H),4.99(d,J=8.5Hz,1H),4.51(q,J=6.8Hz,1H),4.17–4.0 9(m,3H),4.04(q,J=6.9Hz,2H),3.04(qd,J=13.8,5.7Hz,2H),1.65(h,J= 7.1Hz, 2H), 1.40 (s, 9H), 1.21 (td, J=7.2, 1.5Hz, 3H), 0.96–0.83 (m, 3H). 13 C NMR(126MHz,chloroform-d)δ171.6,155.1,149.7(d,J=8.8Hz),135.5(d,J=6.9Hz),132.9,130.5,128.6,128.5,127.9 ,119.9(d,J=4.9Hz),79.9,70.1(d,J=6.4Hz),69.8(d,J=5.8Hz),61.4,54.4,37.5,28.2,23.5(d,J=7.1Hz),14.1,9.9.31 P NMR(162MHz,chloroform-d)δ-6.22(s).HRMS(ESI):[M+H] ⊕ calcd for C 26 H 37 O8NP ⊕ 522.2251, found 522.2270.

[0380] Example 76: Compound 11s

[0381]

[0382] Compound 11s, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 72%. [α] D 25 -0.42(c 1.0,CHCl3)for18:1dr; 1 H NMR(500MHz,chloroform-d)δ7.39–7.28(m,16H),7.01(d,J=8.2Hz,2H),6.91(d,J=8.3Hz,2H),5.23(d,J=8.2Hz,1H),5.15(q,J=10.4,9.1Hz, 3H),5.09(s,3H),4.67(q,J=7.0,6.4Hz,1H),4.05(q,J=6.8Hz,2H),3.07(qd,J=14.2,5.8Hz,2H),1.66(h,J=7.1Hz,2H),0.91(t,J=7.4Hz,3H). 13 CNMR (126 MHz, chloroform-d) δ 171.1, 155.6, 149.8 (d, J = 6.3 Hz), 136.2, 135.6 (d, J = 6.8 Hz), 135.0, 132.3, 130.6, 128.7, 128.69, 128.66, 128.60, 128.3, 128.3, 128.0, 120.12, 120.08, 70.2 (d, J = 6.4 Hz), 69.8 (d, J = 5.7 Hz), 67.4, 67.0, 54.7, 37.3, 23.5 (d, J = 6.9 Hz), 9.9 (one aromatic carbon signal was not observed due to overlap). 31 PNMR(162MHz,chloroform-d)δ–6.21(s).HRMS(ESI):[M+H] ⊕ calcd for C 34 H 37 O8NP ⊕618.2251,found618.2275.

[0383] Example 77: Compound 11t

[0384]

[0385] Compound 11t, yellow oil, column chromatography (petroleum ether / ethyl acetate = 15 / 1), yield 84%, [α] D 25 -10.7(c 1.0,CHCl3)for94%ee; 1 H NMR(500MHz,chloroform-d)δ7.44–7.24(m,5H),7.16–7.02(m,4H),5.20–5.06(m,2H),4.12–4.00(m,2H),2.42(dt,J=15.4,11.9Hz ,1H),1.84(t,J=11.5Hz,4H),1.72–1.58(m,2H),1.46–1.33(m,3H),1.33–1.14(m,14H),1.03(q,J=11.4Hz,3H),0.94–0.82(m,6H). 13 C NMR(126MHz,chloroform-d)δ148.6(d,J=7.0Hz),144.6,135.7(d,J=6.9Hz),128.6,128.5,128.0,127.9,119.7(d,J=4.9Hz),7 0.1(d,J=6.4Hz),69.7(d,J=5.6Hz),44.0,37.4,37.3,34.4,33.6,31.9,30.0,29.4,27.0,23.5(d,J=7.1Hz),22.8,14.2,10.0. 31 P NMR(162MHz,chloroform-d)δ-5.89(s).HRMS(ESI):[M+H] ⊕ calcd for C 29 H 44 O4P ⊕ 487.2972, found 487.2989.HPLC analysis: Chiracel AD-H column; detected at 210nm, 25℃; 15% i PrOH in n-hexane; flow=1.0mL / min; Retention time: 6.4min (major), 7.0min (minor).

[0386] Example 78: Compound 11u

[0387]

[0388] Compound 11u, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 63%. [α] D 25 -30.5(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.62(s,1H),7.49–7.44(m,2H),7.41(qd,J=9.6,8.6,3.9Hz,5H),7.34–7.25(m,6H) ,7.17(d,J=8.8Hz,2H),7.10–7.04(m,2H),6.96(d,J=8.6Hz,2H),5.25–5.14(m,2H),4.68(d,J=11.9Hz,1H),4.45( d,J=12.0Hz,1H),4.24(ddd,J=11.0,7.0,3.9Hz,1H),4.11(q,J=6.8Hz,2H),3.85(p,J=6.4Hz,1H),3.37(ddd,J=38 .4,7.3,4.2Hz,8H),2.03–1.81(m,2H),1.73(h,J=7.1Hz,2H),1.32(d,J=6.3Hz,3H),0.95(dt,J=19.2,7.4Hz,6H). 13 C NMR (126 MHz, chloroform-d) δ 153.2, 138.8, 135.7, 133.9, 128.6, 128.3, 128.0, 127.6, 127.4, 126.3, 123.5, 120.8, 120.7, 117.8, 116.9, 75.9, 70.9, 70.2 (d, J = 6.5 Hz), 69.8 (d, J = 5.6 Hz), 61.3, 50.0, 49.3, 23.6 (d, J = 6.9 Hz), 21.8, 16.5, 10.8, 10.0 (the three aromatic carbon signals were not observed due to overlap). 1 PNMR(162MHz,chloroform-d)δ-5.59(s).HRMS(ESI):[M+H] ⊕ calcd for C 40 H 49 O6N5P ⊕ 726.3415, found 726.3443.

[0389] Example 79: Compound 11v

[0390]

[0391] Compound 11v, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 87%, [α] D 25 +6.3(c1.0,CHCl3)for 17:1dr; 1 H NMR(400MHz,chloroform-d)δ7.97–7.88(m,4H),7.78(d,J=9.0Hz,2H),7.49–7.42(m,2H),7.36–7.29(m,4H),7.27–7.20(m ,6H),7.12–7.01(m,4H),4.72–4.63(m,2H),4.55–4.46(m,2H),3.35–3.25(m,4H),1.20–1.09(m,4H),0.53(t,J=7.4Hz,6H). 13 C NMR(126MHz,chloroform-d)δ146.8(d,J=6.1Hz),135.6(d,J=7.2Hz),133.6,130.9,130.2,128.44,128.37,128.0,127.8, 127.1, 126.2, 125.5, 121.7 (d, J = 8.7Hz), 119.3 (d, J = 1.9Hz), 69.8 (d, J = 6.8Hz), 69.5 (d, J = 6.5Hz), 23.1 (d, J = 7.1Hz), 9.6. 31 PNMR(162MHz,chloroform-d)δ29.2(s).HRMS(ESI):[M+H] ⊕ calcd for C 38 H 39 N3O7P2 ⊕ 711.2258,found711.2259.

[0392] Example 80: Compound 11w

[0393]

[0394] Compound 11w, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1.5 / 1), yield 74%, [α] D 25 +26.0(c 1.0,CHCl3)for>20:1dr; 1H NMR(400MHz,chloroform-d)δ7.12–7.05(m,4H),5.00(d,J=8.2Hz,1H),4.49(q,J=6.5Hz,1H),4.16–4.02(m,4H),3.8 1(d,J=11.3Hz,3H),3.09–2.95(m,2H),1.74–1.62(m,2H),1.38(s,9H),1.19(t,J=7.2Hz,3H),0.91(t,J=7.4Hz,3H). 13 CNMR(126MHz,chloroform-d)δ171.6,155.0,149.7(d,J=6.5Hz),132.9,130.6,119.8(d,J=5.0Hz) ,79.8,70.1(d,J=6.5Hz),61.3,54.7(d,J=6.2Hz),54.4,37.5,28.2,23.5(d,J=6.8Hz),14.1,9.9. 31 P NMR(162MHz,chloroform-d)δ-5.15(s).HRMS(ESI):[M+Na] ⊕ calcdfor C 20 H 32 NO8PNa ⊕ 468.1758, found 468.1765.

[0395] Example 81: Compound 11x

[0396]

[0397] Compound 11x, yellow oil, column chromatography (petroleum ether / ethyl acetate = 1 / 1), yield 73%, [α] D 25 -67.0(c 1.0,CHCl3)for 13:1dr; 1H NMR(500MHz,chloroform-d)δ11.13–10.91(m,1H),7.45–7.26(m,7H),6.64(s,1H),5.89(d, J=2.0Hz,1H),5.65(dd,J=8.2,2.2Hz,1H),5.19(qd,J=11.8,8.6Hz,2H),4.43(t,J=2.8Hz,2 H),4.25(dt,J=6.7,3.0Hz,1H),4.19–4.10(m,3H),4.08–4.01(m,1H),2.60(h,J=7.0Hz,1H) ,1.75(h,J=7.0Hz,2H),1.27(t,J=7.0Hz,1H),1.23(d,J=7.0Hz,6H),0.97(t,J=7.4Hz,3H). 13 C NMR(126MHz,chloroform-d)δ176.5,150.9(d,J=11.7Hz),150.0,135.4(d,J=6.4Hz),132.2,128.6,128.4,128.1,96.0,9 0.0,81.6,74.5,70.5(d,J=6.0Hz),70.0(d,J=5.6Hz),69.3,62.8,34.0,29.7,23.5(d,J=6.7Hz),19.0(d,J=5.3Hz),9.9. 31 P NMR(162MHz,chloroform-d)δ-0.58(s).HRMS(ESI):[M+H] ⊕ calcd for C 23 H 33 O 10 N3P ⊕ 542.1898, found 542.1920.

[0398] Example 83: Compound 11y

[0399]

[0400] Compound 11y, yellow oil, column chromatography (petroleum ether / ethyl acetate = 4 / 1), yield 80%. [α] D 25 -4.5(c1.0,CHCl3)for 95%ee; 1H NMR(500MHz,chloroform-d)δ7.39–7.17(m,9H),4.27–4.12(m,4H),2.78(t,J=7.7Hz,2H),2. 53(d,J=5.2Hz,3H),2.07(q,J=7.1Hz,2H),1.79(h,J=7.1,6.6Hz,2H),1.03(t,J=7.4Hz,3H). 13 CNMR(101MHz,chloroform-d)δ148.7(d,J=7.0Hz),140.9,134.7,128.5,128.50,126.2,120.6,12 0.6, 70.2 (d, J = 6.2Hz), 67.7 (d, J = 6.2Hz), 31.9 (d, J = 6.8Hz), 31.6, 23.7 (d, J = 6.9Hz), 16.7, 10.0. 31 P NMR(162MHz,chloroform-d)δ-5.99(s).HRMS(ESI):[M+H] ⊕ calcd for C 19 H 26 O4PS ⊕ 381.1284, found 381.1289. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 24.0 min (minor) and 24.9 min (major).

[0401] Example 84: Compound 11z

[0402]

[0403] Compound 11z, yellow oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 93%, [α] D 25 -19.8(c 1.0,CHCl3)for 90%ee; 1 H NMR(500MHz,chloroform-d)δ7.66–7.61(m,2H),7.39(s,5H),7.29–7.25(m,2H),5.20(dd,J=9.2,1.5Hz,2H),3.85(d,J=11.5Hz,3H). 13C NMR (126MHz, chloroform-d) δ153.8, 134.0, 129.0, 128.7, 128.2, 120.9 (d, J = 5.7Hz), 118.1, 109.0, 70.5 (d, J = 6.2Hz), 55.1 (d, J = 6.3Hz). 31 P NMR(162MHz,chloroform-d)δ-5.79(s).HRMS(ESI):[M+H] ⊕ calcd for C 15 H 15 O4NP ⊕ 304.0733, found 304.0738. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 29.6 min (minor) and 30.6 min (major).

[0404] Example 85: Compound 11aa

[0405]

[0406] Compound 11aa, yellow oil, column chromatography (petroleum ether / ethyl acetate = 3 / 1), yield 91%, [α] D 25 -6.8(c 1.0,CHCl3)for 95%ee; 1 H NMR(500MHz,chloroform-d)δ7.38–7.26(m,6H),6.73(s,1H),4.54(qd,J=7.3,4.5Hz,2H),4.33(p,J =7.4Hz, 2H), 3.18 (p, J = 6.9Hz, 1H), 3.12 (t, J = 7.1Hz, 2H), 2.54 (s, 3H), 1.40 (dd, J = 20.4, 6.9Hz, 9H). 13 C NMR(126MHz,chloroform-d)δ175.7,170.1,164.2(d,J=4.8Hz),136.8,129.0,128.5,126.7,106.0( d, J=6.5Hz), 69.0 (d, J=6.2Hz), 65.0 (d, J=6.0Hz), 37.3, 36.6 (d, J=7.2Hz), 24.2, 21.5, 16.1, 16.0. 31PNMR(162MHz,chloroform-d)δ-8.08(s).HRMS(ESI):[M+H] ⊕ calcd for C 18 H 26 O4N2P ⊕ 365.1625, found 365.1630. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 8.9 min (major) and 9.8 min (minor).

[0407] Example 86: Compound 11ab

[0408]

[0409] Compound 11ab, yellow oil, column chromatography (petroleum ether / ethyl acetate = 4 / 1), yield 97%, [α] D 25 -10.9(c 1.0,CHCl3)for96%ee; 1 H NMR(500MHz,chloroform-d)δ8.17(d,J=8.7Hz,2H),7.24(ddd,J=28.8,18.6,7.4Hz,7H),4.3 8(qq,J=6.5,3.2Hz,2H), 4.17(p,J=7.4Hz,2H), 3.02(t,J=6.8Hz,2H), 1.33(t,J=7.1Hz,3H). 13 CNMR(126MHz,chloroform-d)δ155.4(d,J=6.4Hz),144.5,136.6,129.0,128.6,126.9,125.6,1 20.4(d,J=5.4Hz), 69.1(d,J=6.4Hz), 65.2(d,J=6.1Hz), 36.5(d,J=7.3Hz), 16.0(d,J=6.6Hz). 31 P NMR(162MHz,chloroform-d)δ-7.33(s).HRMS(ESI):[M+H] ⊕ calcd for C 16 H 19 O6NP ⊕352.0945, found 352.0948. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 25.8 min (major) and 27.0 min (minor).

[0410] Example 87: Compound 11ac

[0411]

[0412] Compound 11ac, yellow oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 75%, [α] D 25 -5.1(c 1.0,CHCl3)for 91%ee; 1 H NMR(500MHz,chloroform-d)δ7.88(s,1H),7.39–7.27(m,5H),4.63–4.42(m,2H) ),4.40–4.22(m,2H),3.12(dp,J=16.2,8.8,8.2Hz,2H),1.43(q,J=7.2Hz,3H). 13 C NMR (126MHz, chloroform-d) δ150.6 (d, J = 6.0Hz), 144.0, 141.2, 136.8, 129.0, 128.5, 126.8, 126. 7,119.3(d,J=8.7Hz), 69.7(d,J=6.0Hz), 65.8(d,J=6.0Hz), 36.6(d,J=7.0Hz), 16.0(d,J=6.9Hz). 31 P NMR(162MHz,chloroform-d)δ-8.19(s).HRMS(ESI):[M+H] ⊕ calcd for C 15 H 16 Cl3O4NP ⊕ 409.9877, found 409.9883. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 15% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 17.0 min (major) and 19.7 min (minor).

[0413] Example 88: Compound 11ad

[0414]

[0415] Compound 11ad, yellow oil, column chromatography (petroleum ether / ethyl acetate = 5 / 1), yield 91%, [α] D 25 +5.8(c1.0,CHCl3)for 92%ee; 1 H NMR(500MHz,chloroform-d)δ7.43–7.31(m,5H),5.08(d,J=8.2Hz,2H),3.98(qd,J=6 .8,2.4Hz,2H),3.73(d,J=11.2Hz,3H),1.68(h,J=7.1Hz,2H),0.94(t,J=7.4Hz,3H). 13 C NMR (126MHz, chloroform-d) δ 136.0 (d, J = 6.5Hz), 128.63, 128.57, 128.0, 69.5 (d, J = 6.0Hz), 69.2 (d, J = 5.5Hz), 54.2 (d, J = 6.2Hz), 23.6 (d, J = 7.2Hz), 10.0. 31 P NMR(162MHz,chloroform-d)δ0.34(s).HRMS(ESI):[M+Na] ⊕ calcd for C 11 H 17 O4PNa ⊕ 267.0762, found 267.0765. HPLC results: IG-H chiral column, detection at 25°C, 210 nm wavelength, 5% isopropanol in n-hexane mobile phase, flow rate 1.0 mL / min. The retention times of the two structures were 24.9 min (major) and 26.1 min (minor).

Claims

1. A method for preparing a compound as shown in formula II, characterized in that: It includes the following steps: S1: In a solvent, under the action of a base, phosphorus oxychloride and a compound represented by formula D1 react to obtain a mixture a; S2: mixing the catalyst and the compound represented by formula D2 with the mixture a and reacting them to obtain a compound represented by formula II; The catalyst is a compound as shown in formula C-1, in, X is a methylene group or a single bond; R 1 H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-1 replace; When X is a single bond, R 1 Not for H; R 1-1 are independently halogen, C 1-12 Alkyl, halogenated C 1-12 Alkyl, -OC 1-12 Alkyl, -O-halogenated C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, C 2-12 Alkenyl, C 6-10 Aryl or 5-12 membered heteroaryl; R 2 C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-10 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-2 replace; R 1-2 are independently halogen, C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -SC 1-12 Alkyl, -OC 1-12 Alkyl, -C 0-12 Alkylene-C(O)OC 1-12 Alkyl, C 6-10 Aryl, -OC 6-10 Aryl, 5-12 membered heteroaryl or NR a R b , the C 1-12 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, -SC 1-12 Alkyl, OC 1-12 Alkyl, -C 0-12 Alkylene-C(O)OC 1-12 Alkyl, C 6-10 Aryl, -OC 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-1-1 replace; R 1-1-1 are independently halogen, nitro, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl or -NR a R b ; R a and R b Independently H, C 1-12 Alkyl or -C(O)OC 1-12 alkyl; The heteroatom species in the 3-12 membered heterocycloalkyl group and the 5-12 membered heteroaryl group are independently one, two or three selected from N, O and S, and the number of the heteroatoms is independently one, two or three.

2. The method for preparing the compound of formula II according to claim 1, wherein Step S1 satisfies one or more of the following conditions: (1) X is methylene, R 1 H, C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl or C 6-10 Aryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 Cycloalkenyl and C 6-10 Aryl is optionally substituted independently by one or more R 1-1 replace; Preferably, the compound represented by formula D1 is any one of the following compounds: (2) The reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere; (3) The solvent is a halogenated alkane solvent; the halogenated alkane solvent is selected from one or both of chloroform and dichloromethane, for example, the halogenated alkane solvent consists of chloroform and dichloromethane; preferably, the volume ratio of chloroform to dichloromethane is (0.1-10):1, for example (1-7):1, and for example 2:1; (4) The ratio of the molar number of phosphorus oxychloride to the volume of the solvent is (0.01-10) mmol:1 mL, for example (0.05-1) mmol:1 mL, and for example 0.15 mmol:1 mL; (5) The molar ratio of the compound represented by formula D1 to the phosphorus oxychloride is (0.1-5):1, for example (1-3):1, and for example 1:1; (6) The base is an organic base, such as triethylamine or 2-tert-butyl-1,1,3,3-tetramethylguanidine; (7) The molar ratio of the base to the phosphorus oxychloride is (0.1-5):1, for example (1-3):1, and for example 1.1:1 or 1.4:1; (8) The reaction system also includes an additive, which can be a molecular sieve, such as Molecular sieve or Molecular sieves; Preferably, the mass ratio of the additive to the phosphorus oxychloride is (1-10):1, for example (1-3):1, and for example 1.3:1 or 1.8:1; (9) The reaction temperature is -80°C to 0°C, for example -80°C to -40°C, for example -60°C; (10) S1 comprises the following steps: adding a mixed solution of the compound represented by formula D1, the base and a portion of the solvent to a mixed solution of phosphorus oxychloride and a portion of the solvent at -80°C to 0°C and reacting to obtain a mixture a; Preferably, S1 comprises the following steps: adding a mixed solution of the compound represented by formula D1, the base and part of the solvent to a mixed solution of phosphorus oxychloride, the molecular sieve and part of the solvent at -80°C to 0°C and reacting to obtain a mixture a.

3. The method for preparing the compound of formula II according to claim 1, wherein Step S2 satisfies one or more of the following conditions: (1)R 2 C 1-12 Alkyl, C 2-12 Alkenyl, C 6-10 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-2 replace; Preferably, the compound represented by formula D2 is any one of the following compounds: (2) The catalyst and the compound represented by Formula D2 are each mixed with the mixture a in the form of a solution or together in the form of a mixed solution and then reacted; preferably, the solvent in the solution and the mixed solution is a halogenated alkane solvent, more preferably, the halogenated alkane solvent is selected from one or both of chloroform and dichloromethane, for example, consisting of chloroform and dichloromethane; (3) The molar ratio of the compound represented by formula D2 to the phosphorus oxychloride is (0.9-5):1, for example (0.9-3):1, and for example 0.9:1; (4) The molar ratio of the catalyst to the phosphorus oxychloride is (0.01-0.5):1, for example (0.01-0.3):1, and another example is 0.09:1 (5) The reaction system further includes a base E. Preferably, the base E is an organic base, such as triethylamine or 2-tert-butyl-1,1,3,3-tetramethylguanidine; (6) the temperature of the mixing and the reacting are independently -80°C to 0°C, such as -80°C to -40°C, such as -80°C to -60°C; (7) Step S2 comprises the following steps: adding a mixed solution of the catalyst, base E and the compound represented by formula D2 to the mixture a for reaction to obtain the compound represented by formula II; (8) The reaction further comprises post-treatment, which comprises the following steps: solvent removal and purification, wherein the purification may be column chromatography purification, and the eluent for the column chromatography may be a mixed solvent of petroleum ether and ethyl acetate; alternatively, the mixture obtained after the reaction is directly used in the next reaction without post-treatment; (9) The compound represented by formula II is a compound represented by formula II':

4. The method for preparing the compound of formula II according to claim 3, wherein: Step S2 satisfies one or more of the following conditions: (1) The solvent consists of chloroform and dichloromethane, and the volume ratio of chloroform to dichloromethane is (0.1-10):1, for example (1-7):1, and for example 2:1; (2) The ratio of the molar number of the compound represented by Formula D2 to the volume of the solvent is (0.01-10) mmol:1 mL, for example (0.01-1) mmol:1 mL, for example 0.4 mmol:1 mL or 1 mmol:1 mL; (3) The ratio of the number of moles of the catalyst to the volume of the solvent is (0.01-10) mmol:1 mL, for example (0.01-1) mmol:1 mL, for example 0.04 mmol:1 mL or 0.1 mmol:1 mL; (4) The molar ratio of the base E to the phosphorus oxychloride is (0.1-5):1, for example (0.9-3):1, and further for example 0.9:1 or 1.1:1; (5) Step S2 comprises the following steps: adding a mixed solution of the catalyst, base E, and the compound represented by formula D2 to the mixture a at -80°C to 0°C to react to obtain the compound represented by formula II; (6) The compound represented by formula II is any one of the following compounds: Preferably, the compound represented by formula II is any one of the following compounds:

5. A compound as shown in formula II, wherein the compound as shown in formula II is any one of the following compounds:

6. A method for preparing a compound as shown in formula I, characterized in that: It includes the following steps S3: In a solvent, under the action of a base, the compound represented by Formula II' and the nucleophilic reagent represented by Formula A1, A2 or A3 undergo a reaction as shown above to obtain a compound represented by Formula I. in, R 3 and R 4 Independently H, -NR c R d , C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, 5-12 membered heteroaryl or The C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-3 replace; Or, R 3 、R 4 Together with the nitrogen atom to which it is attached, it forms a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally substituted by one or more R 1-4 Substitution, the type of heteroatoms in the 3-12 membered heterocyclic group optionally further includes one, two or three selected from N, O and S, and the number of heteroatoms in the 3-12 membered heterocyclic group is 1, 2, 3 or 4; R 1-3 are independently hydroxy, halogen, cyano, nitro, C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl, 5-12 membered heteroaryl or -NR c R d , the C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl and 5-12 membered heteroaryl are independently optionally substituted by one or more R 1-1-2 replace; R 1-1-2 are independently hydroxyl, C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)O-CH2-C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl or -NR c R d , the C 1-12 Alkyl, -OC 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)O-CH2-C 6-10 Aryl, -O-CH2-C 6-10 Aryl and C 6-10 Aryl is optionally substituted independently by one or more R 1-1-1-1 replace; R 1-1-1-1 Independently C 6-10 Aryl or R c and R d Independently H, C 1-12 Alkyl, C 6-10 Aryl, -C(O)OC 1-12 Alkyl or -C(O)O-CH2-C 6-10 aryl; R 1-4 Independently C 6-10 aryl; R s is H or Na; Y is -N(R 4 )-, O or S; The types of heteroatoms in the 3-12 membered heterocycloalkyl and 5-12 membered heteroaryl groups are independently one, two or three selected from N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; X, R 1 As defined in claim 1 or 2, R 2 The definition as claimed in claim 1 or 3.

7. The method for preparing the compound of formula I according to claim 6, wherein: It meets one or more of the following conditions: (1) In the compound represented by formula A1, R 3 and R 4 Not at the same time H; Preferably, R 4 H, C 1-12 Alkyl or C 2-12 Alkenyl, the C 1-12 Alkyl and C 2-12 Alkenyl is optionally substituted independently by one or more R 1-3 preferably, R 1-3 Independently C 6-10 Aryl or -C(O)OC 1-12 alkyl; and / or, R 3 for -NR c R d 、C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl or C 6-10 Aryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 3-12 Cycloalkyl or C 6-10 Aryl is optionally substituted independently by one or more R 1-3 preferably, R 1-3 are independently hydroxyl, C 1-12 Alkyl, C 3-12 Cycloalkyl, -OC 1-12 Alkyl, -C 6-10 Aryl, -C(O)OC 1-12 Alkyl or -OC 0-6 Alkylene-C 6-10 aryl; More preferably, the compound represented by formula A1 is any one of the following compounds: (2) In the compound represented by formula A2, R 3 C 1-12 Alkyl, C 6-10 Aryl, 5-12 membered heteroaryl or The C 1-12 Alkyl, C 6-10 Aryl, 5-12 membered heteroaryl are independently optionally substituted with one or more R 1-3 replace; Preferably, R 1-3 are independently halogen, cyano, nitro, C 1-12 Alkyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, -OC 0-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl or -NR c R d , 1-12 Alkyl, -OC 1-12 Alkyl, -SC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, 3-12 membered heterocycloalkyl, -OC 0-6 Alkylene-C 6-10 Aryl and C 6-10 Aryl is optionally substituted independently by one or more R 1-1-2 replace; More preferably, R 1-1-2 are independently hydroxyl, C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -C(O)O-CH2-C 6-10 Aryl, -OC 0-6 Alkylene-C 6-10 Aryl, C 6-10 Aryl or -NR c R d ; More preferably, the compound represented by formula A2 is any one of the following compounds: (3) In the compound represented by formula A3, R 3 C 6-10 Aryl, the C 6-10 The aryl group is optionally substituted with one or more R 1-3 preferably, R 1-3 are independently halogen or -OC 1-12 Alkyl; more preferably, The compound represented by formula A3 is any of the following compounds:

8. The method for preparing the compound of formula I according to claim 7, wherein: The compound shown in formula I is any of the following compounds:

9. The method for preparing the compound of formula I according to any one of claims 6 to 8, wherein: It meets one or more of the following conditions: (1) The solvent is an ether solvent or a halogenated alkane solvent; preferably, the ether solvent is tetrahydrofuran; the halogenated alkane solvent can be selected from one or both of chloroform and dichloromethane, for example, the halogenated alkane solvent is chloroform or consists of chloroform and dichloromethane; more preferably, the volume ratio of chloroform to dichloromethane is (0.1-10):1, for example (1-7):1, and for example 2:1; (2) The ratio of the molar number of the compound represented by Formula II to the volume of the solvent is (0.01-1) mmol:1 mL, for example (0.05-0.5) mmol:1 mL, for example 0.1 mmol:1 mL, 0.2 mmol:1 mL or 0.24 mmol:1 mL; (3) The molar ratio of the nucleophile to the compound of Formula II is (0.1-5):1, for example (0.8-3):1, and further for example 0.8:1, 1:1, 1.2:1 or 1.5:1; (4) The base is an organic base, such as triethylamine or 2-tert-butyl-1,1,3,3-tetramethylguanidine; (5) The molar ratio of the base to the compound of Formula II is (0.1-5):1, for example (0.8-3):1, and for example 0.8:1, 0.9:1, 1:1 or 2:1; (6) The reaction system also includes an additive, which can be a molecular sieve, such as Molecular sieve or Molecular sieves; Preferably, the mass ratio of the additive to the compound represented by formula II is (0.1-10):1, for example (0.1-3):1, and for example 0.7:1 or 1:1; (7) The reaction temperature is 0-40°C, for example 20-35°C, and for example 30°C; (8) Step S3 comprises the following steps: first mixing the base, the nucleophilic reagent, and the solvent, and then adding the compound represented by Formula II to react to obtain the compound represented by Formula I; Preferably, step S3 comprises the following steps: first mixing the base, the additive, the nucleophilic reagent and the solvent, and then adding the compound represented by formula II to react to obtain the compound represented by formula I to react; (9) After the reaction is completed, post-treatment is also included, and the post-treatment includes the following steps: removing the solvent and purification, and the purification is column chromatography purification, and the eluent of the column chromatography can be a mixed solvent of petroleum ether and ethyl acetate.

10. The method for preparing the compound of formula I according to claim 6, wherein: The method for preparing the compound of formula I also includes a method for preparing the compound of formula II, which comprises the following steps: S1: In a solvent, under the action of a base, phosphorus oxychloride and a compound represented by formula D1 react to obtain a mixture a; S2: mixing a solution of a catalyst and a compound represented by formula D2 with the mixture a and reacting the mixture to obtain a compound represented by formula II; The catalyst is a compound as shown in formula C-1, X and R 1 As defined in claim 1 or 2, R 2 The definition is as described in claim 1 or 3; the operation and conditions of the preparation method of the compound shown in formula II can also be as described in claim 2 or 3.

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