Preparation method and application of chiral pentavalent phosphorus center

Abstract

The invention discloses a preparation method and application of a chiral pentavalent phosphorus center. Specifically, the invention provides a preparation method of a compound IV, which comprises the following steps: step 1, reacting a compound I with a compound II in a solvent in the presence of alkali and an imidazole chiral catalyst; 2, in a solvent, the product obtained in the step 1 reacts with a compound III, and a compound IV is prepared. Through an iterative substitution strategy catalyzed by the organic base, construction of a series of different pentavalent phosphorus three-dimensional centers is efficiently completed, and the method is wide in substrate adaptability and can be applied to simplified synthesis of ProTide active molecule derivatives and pesticide molecules. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a preparation method and application of a chiral pentavalent phosphorus center. Background Art

[0002] Fully heteroatom-substituted chiral pentavalent phosphorus fragments are widely present in structures such as natural products and drug molecules. For example, the genetic materials DNA and RNA in living organisms contain a large number of such phosphorus centers. Drug molecules such as Sofosbuvir, Remdesivir, Stampidine and Acelarin also contain such skeletons. Therefore, the construction of fully heteroatom-substituted pentavalent phosphorus centers has always been a hot topic and difficulty in research. At present, only two strategies have been reported for preparing such skeletons by catalytic asymmetric synthesis. The first one is the dynamic kinetic asymmetric transformation method catalyzed by bisimidazole chiral organic bases by DiRocco et al. in 2017 (Science 2017,356,426–430). The same strategy has also been used in some other studies (Adv. Synth. Catal. 2019, 361, 3729-3732; Angew. Chem. Int. Ed. 2020, 59, 20814-20819; J. Org. Chem. 2021, 86, 4977-4985). The second type is the asymmetric substitution tandem oxidation idea catalyzed by chiral phosphoric acid developed by Miller et al. in 2021 (Science 2021, 371, 702–707). The above works all use a single substitution process, and the structure of the required substrate is complex and not highly universal. At the same time, the reaction is also limited to the construction of special types of pentavalent phosphorus oxygen chiral compounds. Therefore, the development of new and universal synthetic strategies to achieve the construction of relevant pentavalent phosphorus centers is of great scientific value and practical significance. Summary of the invention

[0003] The technical problem to be solved by the present invention is to overcome the defects of the prior art in the method of preparing a fully heteroatom-substituted chiral pentavalent phosphorus center by an asymmetric catalytic method. The present invention provides a preparation method and application of a chiral pentavalent phosphorus center. The present invention efficiently completes the construction of a series of different pentavalent phosphorus stereocenters through an iterative substitution strategy catalyzed by an organic base, has a wide substrate adaptability and can be applied to the streamlined synthesis of ProTide-type active molecular derivatives and pesticide molecules.

[0004] The present invention provides a method for preparing compound IV, which comprises the following steps:

[0005] Step 1, reacting compounds I and II in a solvent in the presence of a base and an imidazole chiral catalyst;

[0006] Step 2, reacting the product obtained in step 1 with compound III in a solvent to prepare compound IV;

[0007]

[0008] Among them, R 1 C6-C 10 or 1, 2 or 3 R 1-1 Substituted C6-C 10 The aromatic group;

[0009] R 1-1 is independently halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 1a Substituted C1-C6 alkyl, 1, 2 or 3 R 1b Substituted C1-C6 alkoxy or -S-C1-C6 alkyl;

[0010] R 1a and R 1b are each independently halogen, nitro or hydroxy;

[0011] R 2 is C3-C6 cycloalkyl, 1, 2 or 3 R 2-1 Substituted C3-C6 cycloalkyl, C1-C6 alkyl, 1, 2 or 3 R 2-2 Substituted C1-C6 alkyl, C2-C6 alkenyl, 1, 2 or 3 R 2-3 Substituted C2-C6 alkenyl, C2-C6 alkynyl, 1, 2 or 3 R 2-4 Substituted C2-C6 alkynyl, C1-C6 alkoxy, 1, 2 or 3 R 2-5 Substituted C1-C6 alkoxy, C6-C 10 or 1, 2 or 3 R 2-6 Substituted C6-C 10 The aromatic group;

[0012] R 2-1 and R 2-6 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano or nitro;

[0013] R 2-2 , R 2-3 , R 2-4 and R 2-5 Each is independently -C(=O)OR 2a , C3-C6 cycloalkyl, 1, 2 or 3 R 2bSubstituted C3-C6 cycloalkyl, "a 3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", 1, 2 or 3 R 2c Substituted "3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", C6-C 10 aryl, 1, 2 or 3 R 2d Substituted C6-C 10 aryl, "a 5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", 1, 2 or 3 R 2e Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl group with 1 or more heteroatoms", "3-10 membered heterocycloalkenyl group with 1 or more heteroatoms", "substituted with 1, 2 or 3 R 2f Substituted "3-10 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms";

[0014] R 2a are independently C1-C6 alkyl;

[0015] R 2b , R 2c , R 2d and R 2e Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, nitro, "a 5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms", 1, 2 or 3 R 2b-1 Substituted "5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms";

[0016] R 2b-1 Each is independently halogen, nitro, cyano, C1-C6 alkyl or C1-C6 alkoxy;

[0017] R 2f Each independently represents a "5-10 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", 2f-1 Substituted "heteroatoms selected from one, two or three of N, O and S, with one or more heteroatoms, 5-10 membered heterocycloalkenyl", "heteroatoms selected from one, two or three of N, O and S, with one or more heteroatoms, 3-10 membered heterocycloalkyl", 1, 2 or 3 R 2f-2Substituted "3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", C6-C 10 or 1, 2 or 3 R 2f-3 Substituted C6-C 10 The aromatic group;

[0018] R 2f-1 , R 2f-2 and R 2f-3 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, hydroxyl or oxo;

[0019] X is -NR 3 R 4 、-SR 5 OR 6 ;

[0020] R 3 and R 4 are each independently hydrogen, C1-C6 alkyl, 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 3-2 Substituted C1-C6 alkoxy, C3-C6 cycloalkyl, 1, 2 or 3 R 3-3 Substituted C3-C6 cycloalkyl, C6-C 10 aryl, 1, 2 or 3 R 3-4 Substituted C6-C 10 The aromatic group;

[0021] or R 3 and R 4 The nitrogen connected thereto forms a "3-10 membered heterocycloalkyl group with one, two or three heteroatoms selected from N, O and S" or is replaced by one, two or three R 3-5 Substituted "3-10 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms";

[0022] R 3-1 and R 3-2 Each is independently -C(=O)OR 3a , C3-C6 cycloalkyl, 1, 2 or 3 R 3b Substituted C3-C6 cycloalkyl, C6-C 10 or 1, 2 or 3 R 3c Substituted C6-C 10 The aromatic group;

[0023] R 3aare independently C1-C6 alkyl;

[0024] R 3b and R 3c Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano or nitro;

[0025] R 3-3 , R 3-4 and R 3-5 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano or nitro;

[0026] R 5 and R 6 are each independently hydrogen, C1-C6 alkyl, 1, 2 or 3 R 5-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 5-2 Substituted C1-C6 alkoxy, C3-C6 cycloalkyl, 1, 2 or 3 R 5-3 Substituted C3-C6 cycloalkyl, C6-C 10 or 1, 2 or 3 R 5-4 Substituted C6-C 10 The aromatic group;

[0027] R 5-1 and R 5-2 are each independently halogen or hydroxy;

[0028] R 5-3 and R 5-4 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano or nitro.

[0029] In certain preferred embodiments of the present invention, certain groups in the compounds shown in Formula I, II, III or IV are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention").

[0030] In a certain embodiment of the present invention, each of the C6-C 10 Aryl and substituted C6-C 10 The C6-C 10 The aryl groups of are independently phenyl or naphthyl; for example, phenyl.

[0031] In one embodiment of the present invention, each halogen is independently fluorine, chlorine, bromine or iodine; for example, bromine or chlorine.

[0032] In a certain embodiment of the present invention, the C3-C6 cycloalkyl group and the C3-C6 cycloalkyl group in the substituted C3-C6 cycloalkyl group are independently cyclopropyl, cyclopentyl or cyclohexyl.

[0033] In a certain embodiment of the present invention, the C1-C6 alkyl group and the C1-C6 alkyl group in the substituted C1-C6 alkyl group are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; for example, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

[0034] In one embodiment of the present invention, the C2-C6 alkenyl and substituted C2-C6 alkenyl are independently

[0035] In one embodiment of the present invention, the C2-C6 alkynyl group and the substituted C2-C6 alkynyl group are independently C2-C4 alkynyl groups; for example,

[0036] In a certain embodiment of the present invention, the C1-C6 alkoxy group and the C1-C6 alkoxy group in the substituted C1-C6 alkoxy group are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example, methoxy.

[0037] In one embodiment of the present invention, R 2-2 In the 3-10 membered heterocycloalkyl and substituted 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is an 8 membered heterocycloalkyl having oxygen as the heteroatom and 3 heteroatoms; for example,

[0038] In one embodiment of the present invention, R 3 and R 4 In the 3-10 membered heterocycloalkyl and substituted 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl having one or two heteroatoms selected from N and O; for example,

[0039]

[0040] In one embodiment of the present invention, the 5-10 membered heteroaryl group and the substituted 5-10 membered heteroaryl group are 9-membered heteroaryl groups with N as the heteroatom and 4 heteroatoms; for example,

[0041] In one embodiment of the present invention, the 3-10 membered heterocycloalkenyl and substituted 3-10 membered heterocycloalkenyl are 5-6 membered heterocycloalkenyl with 1 or 2 heteroatoms, for example,

[0042] In one embodiment of the present invention, R 1 C6-C10 or 1, 2 or 3 R 1-1 Substituted C6-C 10 The aromatic group.

[0043] In one embodiment of the present invention, R 1-1 For halogen, nitro, Or C1-C6 alkyl.

[0044] In one embodiment of the present invention, R 2 is C3-C6 cycloalkyl, C1-C6 alkyl, 1, 2 or 3 R 2-2 Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 or 1, 2 or 3 R 2-6 Substituted C6-C 10 The aromatic group.

[0045] In one embodiment of the present invention, R 2-6 are independently C1-C6 alkyl.

[0046] In one embodiment of the present invention, R 2-2 are independently -C(=O)OR 2a , 1, 2 or 3 R 2c Substituted "3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", C6-C 10 aryl, 1, 2 or 3 R 2d Substituted C6-C 10 aryl, 1, 2 or 3 R 2f The substituted "3- to 10-membered heterocycloalkenyl group having one, two or three heteroatoms selected from the group consisting of N, O and S, and having one or more heteroatoms".

[0047] In one embodiment of the present invention, R 2c and R 2d Each independently represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or 1, 2 or 3 R 2b-1 The substituted "5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms".

[0048] In one embodiment of the present invention, R 2b-1 are each independently halogen.

[0049] In one embodiment of the present invention, R 2f Each independently is 1, 2 or 3 R 2f-1The substituted "5- to 10-membered heterocycloalkenyl group having one, two or three heteroatoms selected from the group consisting of N, O and S, and having one or more heteroatoms".

[0050] In one embodiment of the present invention, R 2f-1 Each is independently a C1-C6 alkyl group or an oxo group.

[0051] In one embodiment of the present invention, X is -NR 3 R 4 or -SR 5 .

[0052] In one embodiment of the present invention, R 3 and R 4 are each independently hydrogen, C1-C6 alkyl, 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 or 1, 2 or 3 R 3-4 Substituted C6-C 10 The aromatic group;

[0053] or R 3 and R 4 The nitrogen connected thereto forms a "3-10 membered heterocycloalkyl group in which the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of the heteroatoms is 1 or more".

[0054] In one embodiment of the present invention, R 3-1 and R 3-2 Each is independently -C(=O)OR 3a , C3-C6 cycloalkyl or 1, 2 or 3 R 3c Substituted C6-C 10 The aromatic group.

[0055] In one embodiment of the present invention, R 3c are independently C1-C6 alkoxy.

[0056] In one embodiment of the present invention, R 3-4 are independently C1-C6 alkyl.

[0057] In one embodiment of the present invention, R 5 For 1, 2 or 3 R 5-4 Substituted C6-C 10 The aromatic group.

[0058] R 5-4 Each is independently a C1-C6 alkyl group or a C1-C6 alkoxy group.

[0059] In one embodiment of the present invention, R 1 for

[0060] In one embodiment of the present invention, R 2 for

[0061] In one embodiment of the present invention, R 3 for

[0062] In one embodiment of the present invention, R 4 is hydrogen, methyl or In one embodiment of the present invention, R 3 and R 4 The nitrogen attached to it forms In one embodiment of the present invention, R 5 for In one embodiment of the present invention, compound I is

[0063] In a certain embodiment of the present invention, compound II is

[0064] In a certain embodiment of the present invention, compound III is

[0065]

[0066] In a certain embodiment of the present invention, compound IV is

[0067]

[0068]

[0069] In one embodiment of the present invention, in step 1, the base is an organic base; preferably a tertiary amine organic base; for example, triethylamine.

[0070] In a certain embodiment of the present invention, in step 1, the imidazole chiral organic base is

[0071] In one embodiment of the present invention, in steps 1 and 2, the solvent is one or more halogenated alkane solvents; preferably two; for example, dichloromethane and chloroform.

[0072] In a certain embodiment of the present invention, in steps 1 and 2, the volume ratio of the dichloromethane to the chloroform can be 1:(5-8); preferably 1:7.

[0073] In one embodiment of the present invention, in step 1, the molar ratio of the compound II to the compound I is 1:(0.8-1.2); for example, 1:1.1.

[0074] In one embodiment of the present invention, the molar ratio of compound II in step 1 to compound III in step 2 is 1:(3-5); for example, 1:4.

[0075] In one embodiment of the present invention, in step 1, the molar ratio of the compound II to the imidazole chiral organic base is 1:(0.08-0.12); for example, 1:0.1.

[0076] In one embodiment of the present invention, in step 1, the molar ratio of the compound II to the base is 1:(1.2-1.8); for example, 1:1.5.

[0077] In one embodiment of the present invention, in step 1, the molar volume ratio of the compound II to the solvent is 1 mmol:(8-12) mL; for example, 1 mmol:10 mL.

[0078] In one embodiment of the present invention, in step 1 and step 2, the reaction temperature is (-60°C)-(-100°C); for example, -80°C.

[0079] In one embodiment of the present invention, in step 1, the reaction time is 36 h-60 h; for example, 48 h.

[0080] In one embodiment of the present invention, in step 1, the reaction further comprises a molecular sieve; for example, Molecular sieve.

[0081] In one embodiment of the present invention, in step 2, the molar volume ratio of the compound III to the solvent is 8 mmol:(4-8) mL; for example, 8 mmol:5 mL.

[0082] In one embodiment of the present invention, in step 2, the reaction time is 8-16 hours; for example, 12 hours.

[0083] In one embodiment of the present invention, step 2 further comprises the following post-treatment steps: returning to room temperature, concentrating and column chromatography; for example, returning to room temperature and concentrating.

[0084] In one embodiment of the present invention, the reaction raw materials of the preparation method of the compound IV are the solvent, the base, the imidazole chiral organic base, the compound I, the compound II and the compound III.

[0085] The present invention provides a method for preparing compound VI, which comprises the following steps: in a solvent, t In the presence of BuMgCl, compound IV and V react to prepare compound VI;

[0086]

[0087] Among them, R 1 , R 2 and X are defined as described in any embodiment of the present invention;

[0088] R 7 is C1-C6 alkyl, 1, 2 or 3 R 7-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 7-2 Substituted C1-C6 alkoxy, C2-C6 alkenyl, 1, 2 or 3 R 7-3 Substituted C2-C6 alkenyl, C2-C6 alkynyl, 1, 2 or 3 R 7-4 Substituted C2-C6 alkynyl, C6-C 10 or 1, 2 or 3 R 7-5 Substituted C6-C 10 The aromatic group;

[0089] R 7-1 , R 7-2 , R 7-3 and R 7-4 Each independently is C6-C 10 or 1, 2 or 3 R 7a Substituted C6-C 10 The aromatic group;

[0090] R 7-5 Each is independently a C1-C6 alkyl group;

[0091] R 7a Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, hydroxyl, oxo, C6-C 10 or 1, 2 or 3 R 7a-1 Substituted C6-C 10 The aromatic group;

[0092] R 7a-1 Each is independently a C1-C6 alkyl group.

[0093] In one embodiment of the present invention, R 1 For 1, 2 or 3 R 1-1 Substituted C6-C 10 The aromatic group.

[0094] In one embodiment of the present invention, R 1-1 For nitro.

[0095] In one embodiment of the present invention, R 2 is C3-C6 cycloalkyl, 1, 2 or 3 R 2-2 Substituted C1-C6 alkyl or C2-C6 alkenyl.

[0096] In one embodiment of the present invention, X is -NR 3 R 4 .

[0097] In one embodiment of the present invention, R 2-2 Each independently is 1, 2 or 3 R 2c The substituted "heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 or more 3-10 membered heterocycloalkyl" or 1, 2 or 3 R 2d Substituted C6-C 10 The aromatic group.

[0098] In one embodiment of the present invention, R 2c Each is independently a C1-C6 alkoxy group.

[0099] In one embodiment of the present invention, R 2d Each is independently a C1-C6 alkoxy group.

[0100] In one embodiment of the present invention, R 7 is C1-C6 alkyl, 1, 2 or 3 R 7-1 Substituted C1-C6 alkyl, 1, 2 or 3 R 7-3 Substituted C2-C6 alkenyl, 1, 2 or 3 R 7-4 Substituted C2-C6 alkynyl or 1, 2 or 3 R 7-5 Substituted C6-C 10 The aromatic group.

[0101] In one embodiment of the present invention, R 7-1 Each independently is C6-C 10 or 1, 2 or 3 R 7a Substituted C6-C 10 The aromatic group.

[0102] In one embodiment of the present invention, R 7-3Each independently is C6-C 10 or 1, 2 or 3 R 7a Substituted C6-C 10 The aromatic group.

[0103] In one embodiment of the present invention, R 7-4 Each independently is C6-C 10 The aromatic group.

[0104] In one embodiment of the present invention, R 7a Each independently is a C1-C6 alkyl, a C1-C6 alkoxy or a C6-C 10 The aromatic group.

[0105] In one embodiment of the present invention, R 1 for

[0106] In one embodiment of the present invention, R 2 for

[0107] In one embodiment of the present invention, R 3 and R 4 The nitrogen attached to it forms

[0108] In one embodiment of the present invention, R 7 for

[0109] In a certain embodiment of the present invention, compound IV is

[0110] In one embodiment of the present invention, compound V is BnOH,

[0111] In one embodiment of the present invention, compound VI is

[0112]

[0113] In one embodiment of the present invention, in the method for preparing compound VI, the solvent is an organic solvent; preferably an ether solvent; for example, tetrahydrofuran.

[0114] In a certain embodiment of the present invention, in the method for preparing compound VI, the molar ratio of compound IV to compound V is 1:(2-6); for example, 1:4.

[0115] In one embodiment of the present invention, in the method for preparing compound VI, the compound IV and thet The molar ratio of BuMgCl is 1:(2-6); for example, 1:4.

[0116] In a certain embodiment of the present invention, in the method for preparing compound VI, the molar volume ratio of compound IV to the solvent is 1 mmol:(10-16) mL; for example, 1 mmol:12 mL.

[0117] In a certain embodiment of the present invention, in the method for preparing compound VI, the reaction temperature is 15°C-35°C; preferably 20°C-30°C.

[0118] In a certain embodiment of the present invention, in the method for preparing compound VI, the reaction time is 20 min-60 min, preferably 30 min.

[0119] In a certain embodiment of the present invention, in the method for preparing compound VI, the reaction further comprises the following post-treatment steps: quenching, extraction, concentration and column chromatography separation; the quenching may be quenching with water; the extraction may be extraction with ethyl acetate.

[0120] In one embodiment of the present invention, in the preparation method of compound VI, the raw materials of the reaction are the solvent, t BuMgCl, the compound IV and the compound V.

[0121] In a certain embodiment of the present invention, the preparation method of compound VI also includes the preparation method of compound IV, and the preparation method of compound IV is as described in any embodiment of the present invention.

[0122] The present invention provides a method for preparing compound VIII, which comprises the following steps:

[0123] Step (1): Preparation method of compound IV,

[0124]

[0125] The preparation method of compound IV is as described in any scheme of the present invention;

[0126] Step (2): Compound IV and Compound VII are reacted in a solvent in the presence of an acid to prepare Compound VIII;

[0127]

[0128] Among them, compound R 1 , R 2 and X are defined as described in any embodiment of the present invention;

[0129] R 8 It is a C1-C6 alkyl group.

[0130] In one embodiment of the present invention, R 1 For 1, 2 or 3 R 1-1 Substituted C6-C 10 The aromatic group.

[0131] In one embodiment of the present invention, R 2 It is a C3-C6 cycloalkyl group.

[0132] In one embodiment of the present invention, R 8 It is a C1-C6 alkyl group.

[0133] In one embodiment of the present invention, R 2 for

[0134] In one embodiment of the present invention, R 3 and R 4 The nitrogen attached to it forms

[0135] In one embodiment of the present invention, R 8 Methyl or

[0136] In a certain embodiment of the present invention, compound IV is

[0137] In one embodiment of the present invention, compound VII is methanol or

[0138] In one embodiment of the present invention, compound VIII is

[0139] In one embodiment of the present invention, in step (2), the solvent is a mixed organic solvent; preferably a mixed solvent of an alcohol solvent and an alkane solvent; the alcohol solvent may be methanol; and the alkane solvent may be dichloromethane.

[0140] In one embodiment of the present invention, in step (2), the volume ratio of the alcohol solvent to the alkane solvent is 1:(0.8-1.5); for example, 1:1.

[0141] In one embodiment of the present invention, in step (2), the acid is an organic acid; preferably a fluorine-containing organic acid, for example, trifluoromethanesulfonic acid.

[0142] In a certain embodiment of the present invention, in step (2), the molar volume ratio of the compound IV and the compound VII is 1:(10-120); preferably 1:74 or 1:100.

[0143] In a certain embodiment of the present invention, in step (2), the molar ratio of the compound IV to the acid is 1:(2-5); preferably 1:3.

[0144] In one embodiment of the present invention, in step (2), the reaction temperature is 40-60°C, preferably 50°C.

[0145] In a certain embodiment of the present invention, in step (2), the reaction time is 20-24 hours, preferably 22 hours.

[0146] In one embodiment of the present invention, the preparation method of step (2) further comprises the following post-treatment steps: concentration and column chromatography.

[0147] The present invention provides a method for preparing compound IX, which comprises the following steps:

[0148] Step (1): Preparation method of compound IV:

[0149]

[0150] The preparation method of compound IV is as described in any scheme of the present invention;

[0151] Step (3): Compound IV is reacted in a solvent in the presence of a base to prepare Compound IX;

[0152]

[0153] Among them, R 2 , R 3 and R 4 The definition of is as described in any embodiment of the present invention.

[0154] In one embodiment of the present invention, R 2 It is a C1-C6 alkyl group or a C3-C6 cycloalkyl group.

[0155] In one embodiment of the present invention, R 2 for

[0156] In a certain embodiment of the present invention, compound IV is

[0157] In a certain embodiment of the present invention, compound IX is

[0158] In one embodiment of the present invention, in step (3), the solvent is an organic solvent; preferably an ether solvent, for example, tetrahydrofuran.

[0159] In one embodiment of the present invention, in step (3), the base is an organic base; for example, an organic lithium metal base; preferably phenyllithium.

[0160] In one embodiment of the present invention, in step (3), the molar ratio of compound IV to base is 1:(3-5); preferably 1:4.3.

[0161] In one embodiment of the present invention, in step (3), the molar volume ratio of compound IV to solvent is 1 mmol:(3-7) mL; for example, 1 mmol:5 mL.

[0162] In one embodiment of the present invention, in step (3), the reaction temperature is 15-40°C; preferably 20-30°C.

[0163] In a certain embodiment of the present invention, in step (3), the reaction time is 25-45 hours, preferably 33 hours.

[0164] In one embodiment of the present invention, the preparation method of step (3) further comprises the following post-treatment steps: quenching, extraction, concentration and column chromatography separation; the quenching may be quenching with water; the extraction may be extraction with ethyl acetate.

[0165] The present invention provides the following compounds:

[0166]

[0167]

[0168]

[0169] Terminology

[0170] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0171] The "-" at the end of a group means that the group is connected to the rest of the molecule through this site; It means that the structural fragment is connected to the rest of the molecule through this site, for example, It refers to the methoxy group.

[0172] The term "plurality" means 1, 2 or 3.

[0173] The term "oxo" is =0.

[0174] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0175] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (eg, C1-C6). Alkyl groups include, but are not limited to, methyl groups.

[0176] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of two to six carbon atoms (eg, C2-C6 alkenyl) having at least one site of unsaturation, ie, a carbon-carbon sp2 double bond.

[0177] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon group of two to six carbon atoms (eg, C2-C6 alkynyl) having at least one site of unsaturation, ie, a carbon-carbon sp triple bond.

[0178] The term "alkoxy" refers to a group R Z -O-, where R Z is an alkyl group as defined above.

[0179] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms, having a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0180] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-10 yuan, 3-6 yuan), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified heteroatom species (one or more of N, O and S), which is a monocyclic, bridged or spirocyclic ring, and each ring is saturated. A bridged ring refers to a polycyclic ring that shares two or more atoms between monocyclic rings. Spirocyclic rings refer to polycyclic rings that share one atom between monocyclic rings. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, etc.

[0181] The term "heterocycloalkenyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (one, two, or three of N, O, and S), which is a monocyclic, bridged, or spirocyclic unsaturated alkyl group. The heterocycloalkenyl group is attached to the rest of the molecule through a carbon atom or a heteroatom.

[0182] The term "aryl" refers to a radical having a specified number of carbon atoms (e.g., C6-C 10 ) is a cyclic group consisting only of carbon atoms, which is monocyclic or polycyclic, and each ring is aromatic (conforming to Huckel's rule). Aromatic rings include but are not limited to phenyl, naphthyl, etc.

[0183] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom species (one, two, or three of N, O, and S), which is monocyclic or polycyclic, and each ring is aromatic (in accordance with Huckel's rule). The heteroaryl is connected to the rest of the molecule through a carbon atom or a heteroatom; the heteroaryl is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms. Heteroaryl includes, but is not limited to, furan ring, pyrrole ring, thiophene ring, pyrazole ring, imidazole ring, oxazole ring, thiazole ring, pyridine ring, pyrimidine ring, indole ring, benzopyrrole ring, etc.

[0184] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0185] The reagents and raw materials used in the present invention are commercially available.

[0186] The positive progress of the present invention is that the present invention provides a preparation method and application of a chiral pentavalent phosphorus center. The present invention efficiently completes the construction of a series of different pentavalent phosphorus stereocenters through an iterative substitution strategy catalyzed by an organic base, has a wide substrate adaptability and can be applied to the streamlined synthesis of ProTide-type active molecular derivatives and pesticide molecules. BRIEF DESCRIPTION OF THE DRAWINGS

[0187] Figure 1 : Single crystal structure of compound 4t. DETAILED DESCRIPTION

[0188] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0189] Example 1: Compound 4a

[0190]

[0191] Under nitrogen protection, phosphorus oxychloride 1a (0.22 mmol) was added to a Shrek tube. Molecular sieves (80 mg) and dry DCM / CHCl3 (0.80 mL, v / v = 1 / 7). Then, at minus 80 degrees, catalyst C-1 (5.1 mg, 0.020 mmol) and cyclohexanol 2a (0.20 mmol) in DCM / CHCl3 (0.80 mL, v / v = 1 / 7) solution, as well as triethylamine (31 mg, 0.30 mmol) in DCM / CHCl3 (0.40 mL, v / v = 1 / 7) solution were added. After reacting at minus 80 degrees for 48 hours, cyclopentaneamine 3a (0.80 mmol) in DCM / CHCl3 (0.50 mL, v / v = 1 / 7) solution was added to the reaction solution. The reaction was continued to stir at minus 80 degrees for 12 hours. After the reaction was completed, the mixture was returned to room temperature, concentrated, and separated by column chromatography to obtain pure compound 4a.

[0192] Compound 4a, colorless oil, 84% yield, [α] D 25 -2.0(c 0.50,CHCl3)for 97:3er; 1 H NMR(500MHz,chloroform-d)δ7.41(d,J=8.5Hz,2H),7.12(d,J=8.4Hz,2H),4.49–4.39(m,1H),3.67–3.50( m,1H),2.76(t,J=10.3Hz,1H),2.02–1.82(m,4H),1.79–1.61(m,4H),1.61–1.44(m,5H),1.44–1.26(m,5H). 13 C NMR (126 MHz, chloroform-d) δ 150.5 (d, J = 6.8 Hz), 132.5, 122.1 (d, J = 5.0 Hz), 117.2, 53.7, 35.0 (d, J = 6.3 Hz), 34.9 (d, J = 6.3 Hz), 33.6 (d, J = 4.5 Hz), 33.4 (d, J = 4.0 Hz), 25.2, 23.63, 23.57, 23.19, 23.16 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ2.69(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 26 BrNO3P ⊕402.0828, found 402.0825. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25°C, 20% iPrOH in n-hexane; flow rate = 1.0 mL / min; retention time: 7.5 min (a small amount), 8.4 min (mainly)

[0193] Using the corresponding raw materials and referring to the reaction conditions and operation methods in Example 1, the following compounds 4b-4ar were prepared.

[0194] The reactants of each example are shown in Table 1 below:

[0195] Table 1

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202] Example 2: Compound 4b

[0203]

[0204] Compound 4b, yellow oil, yield 55%, [α] D 25 +1.6(c 0.50,CHCl3)for 97:3er; 1 H NMR(400MHz,chloroform-d)δ7.48–7.40(m,2H),7.19–7.11(m,2H),4.50–4.39(m,1H),3.55–3.41(m,1H),2.60(t,J=10 .3Hz,1H),1.96(t,J=14.5Hz,2H),1.81–1.68(m,2H),1.62–1.46(m,3H),1.43–1.29(m,3H),1.17(dd,J=8.8,6.5Hz,6H). 13C NMR(126MHz,chloroform-d)δ150.5(d,J=6.8Hz),132.5,122.1(d,J=5.0Hz),117.2, 44.26,33.6(d,J=4.5Hz),33.4(d,J=4.1Hz),25.32,25.27,25.22,25.20,23.6,23.5. 31 P NMR(162MHz,chloroform-d)δ2.43(s).HRMS(ESI):[M+H] ⊕ Calculate for C 15 H 24 BrNO3P ⊕ 376.0672, found 376.0668.HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 25℃, 10% iPrOH in n-hexane; flow rate = 1.0mL / min; retention time: 9.2min (small amount), 11.4min (mainly).

[0205] Example 3: Compound 4c

[0206]

[0207] Compound 4c, colorless oil, yield 90%, [α] D 25 -1.4(c 1.0,CHCl3)for 97:3er; 1 H NMR(400MHz,chloroform-d)δ7.45–7.37(m,2H),7.33–7.27(m,2H),7.25–7.20(m,1H),7.17–7.12(m,2H),7.12–7.06(m,2H),4.4 7–4.36(m,1H),3.29–3.19(m,2H),2.80–2.70(m,3H),1.98–1.85(m,2H),1.79–1.66(m,2H),1.56–1.45(m,3H),1.40–1.26(m,3H). 13C NMR(101MHz,chloroform-d)δ149.7(d,J=7.3Hz),138.1,132.8,128.9(d,J=8.3Hz),126.8,122.1(d,J=4.9Hz),118.1, 109.7, 78.3 (d, J = 5.8Hz), 42.9, 37.7 (d, J = 6.3Hz), 33.4 (d, J = 4.1Hz), 33.2 (d, J = 3.8Hz), 25.0, 23.5 (d, J = 6.1Hz), 20.6. 31 P NMR(162MHz,chloroform-d)δ3.35(s).HRMS(ESI):[M+H] ⊕ Calculate for C 20 H 26 BrNO3P ⊕ 438.0828, found 438.0825. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 8.7 min (small amount), 11.1 min (mainly).

[0208] Example 4: Compound 4d

[0209]

[0210] Compound 4d, yellow oil, yield 69%, [α] D 25 +2.2(c 1.0,CHCl3)for 97:3er; 1 H NMR(400MHz,chloroform-d)δ7.42(d,J=8.8Hz,2H),7.13(d,J=8.8Hz,2H),4.48–4.42(m,1H),2.88–2.78(m,2H), 2.23–1.88(m,2H),1.62–1.44(m,4H),1.41–1.17(m,4H),1.01–0.85(m,1H),0.50–0.40(m,2H),0.16–0.13(m,2H). 13C NMR(101MHz,chloroform-d)δ150.4(d,J=6.7Hz),132.5,122.1(d,J=5.1Hz),117.3,76.9(d ,J=5.9Hz),46.8,33.5(d,J=4.6Hz),33.4(d,J=3.8Hz),25.2,23.63,23.57,12.6,12.5,3.4. 31 P NMR(162MHz,chloroform-d)δ3.16(s).HRMS(ESI):[M+H] ⊕ Calculate for C 16 H 24 BrNO3P ⊕ 388.0672, found388.0672. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 7.8 min (small amount), 8.8 min (mainly).

[0211] Example 5: Compound 4e

[0212]

[0213] Compound 4e, colorless oil, yield 89%, [α] D 25 -3.8(c 0.50,CHCl3)for 94:6er; 1 H NMR(500MHz,chloroform-d)δ7.43–7.38(m,2H),7.14–7.08(m,2H),4.00–3.94(m,1H),3.61–3.50(m,1H),3.09–3.02(m ,1H),1.95–1.79(m,2H),1.69–1.58(m,2H),1.58–1.46(m,2H),1.42–1.28(m,2H),0.90–0.78(m,2H),0.69–0.59(m,2H). 13 C NMR(126MHz,chloroform-d)δ150.3(d,J=6.5Hz),132.6,122.0(d,J=5.1Hz),117.4,53.7(d,J=1.1Hz),5 1.0(d,J=5.3Hz), 34.9(d,J=5.3Hz), 34.8(d,J=5.3Hz), 23.12, 23.10, 5.7(d,J=4.7Hz), 5.6(d,J=5.0Hz).31 P NMR(162MHz,chloroform-d)δ3.70(s).HRMS(ESI):[M+H] ⊕ Calculate for C 14 H 20 BrNO3P ⊕ 360.0359, found 360.0356.HPLC analysis: Chiracel AD-H column;

[0214] Detection conditions: 210 nm, 25 °C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 7.5 min (small amount), 8.2 min (mainly)

[0216] Example 6: Compound 4f

[0217]

[0218] Compound 4f, colorless oil, yield 82%, [α] D 25 -5.9(c 1.0,CHCl3)for 95:5er; 1 H NMR(500MHz,chloroform-d)δ7.46–7.35(m,2H),7.16–7.08(m,2H),4.77–4.67(m,1H),3.63–3.52(m,1 H),2.83(t,J=10.3Hz,1H),1.94–1.83(m,2H),1.70–1.59(m,2H),1.59–1.46(m,2H),1.42–1.27(m,8H). 13 C NMR(126MHz,chloroform-d)δ150.5(d,J=6.6Hz),132.5,122.1(d,J=5.1Hz),117.3,72.1(d,J=5.8Hz),53 .7(d,J=1.1Hz),34.94(d,J=4.0Hz),34.90(d,J=3.8Hz),23.9(d,J=5.2Hz),23.8(d,J=4.8Hz),23.2,23.1. 31 P NMR(162MHz,chloroform-d)δ2.65(s).HRMS(ESI):[M+H] ⊕ Calculate for C 14 H 22 BrNO3P ⊕362.0515, found 362.0511. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 6.1 min (a small amount), 6.8 min (mainly).

[0219] Example 7: Compound 4g

[0220]

[0221] Compound 4g, yellow solid, melting point 63.4-67.5℃. Yield 67%, [α] D 25 -0.5(c 1.0,CHCl3)for97:3er; 1 H NMR(500MHz,chloroform-d)δ7.39(d,J=8.3Hz,2H),7.11(d,J=8.4Hz,2H),4.67–4.52(m,1H),3.61–3.49(m,1H),2. 92(t,J=10.6Hz,1H),2.04–1.91(m,2H),1.91–1.71(m,4H),1.70–1.57(m,4H),1.57–1.46(m,6H),1.45–1.27(m,4H). 13 C NMR(126MHz,chloroform-d)δ150.5(d,J=6.6Hz),132.4,122.1(d,J=5.0Hz),117.2,79.4(d,J=6.2Hz),53.7,35.7(d ,J=4.7Hz),35.5(d,J=4.1Hz),34.9(d,J=6.6Hz),34.8(d,J=6.6Hz),28.0,23.2(d,J=4.7Hz),22.2(d,J=11.9Hz)(one alkyl carbon signal was not observed because of overlapping). 31 P NMR(162MHz,chloroform-d)δ2.69(s).HRMS(ESI):[M+H] ⊕ Calculate for C 18 H 28 BrNO3P ⊕416.0985, found 416.0979. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25 ° C, 5% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 25.1 min (a small amount), 27.2 min (mainly).

[0222] Example 8: Compound 4h

[0223]

[0224] Compound 4h, yellow oil, yield 49%, [α] D 25 +1.3(c 1.0,CHCl3)for>20:1dr; 1 H NMR(400MHz,chloroform-d)δ7.46–7.35(m,2H),7.16–7.05(m,2H),5.85–5.61 (m,1H),5.09–5.06(m,1H),5.05–5.02(m,1H),4.67–4.55(m,1H),3.86–3.75(m, 1H),3.69(s,3H),3.42(t,J=10.4Hz,1H),2.48–2.18(m,2H),1.79–1.72(m,1H), 1.49–1.36(m,1H),1.32(d,J=6.3Hz,3H),1.19–1.06(m,1H),0.92–0.84(m,6H). 13 C NMR(101MHz,chloroform-d)δ173.1,150.2(d,J=6.7Hz),133.0,132.5,122.1(d,J=5.0Hz),118.3,117.5, 75.2(d,J=4.6Hz),59.0,52.1,41.7(d,J=5.1Hz),39.3(d,J=5.9Hz),24.8,21.1(d,J=3.5Hz),15.3,11.5. 31 P NMR(162MHz,chloroform-d)δ1.9(s).HRMS(ESI):[M+H] ⊕ Calculate for C 18 H 28 BrNO5P ⊕ 448.0883, found 448.0877.

[0225] Example 9: Compound 4i

[0226]

[0227] Compound 4i, yellow oil, yield 68%, [α] D 25 +1.1(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.45–7.37(m,2H),7.22(t,J=7.9Hz,1H),7.11–7.07(m,2H),6.88–6.85(m,1H),6.84–6.78( m,2H),5.24–5.13(m,1H),4.26–4.13(m,2H),3.77(s,3H),3.30–3.20(m,1H),2.56(d,J=2.1Hz,1H),1.57(d,J=6.7Hz,3H). 13 C NMR(126MHz,chloroform-d)δ159.9,149.9(d,J=6.7Hz),140.5(d,J=7.3Hz),132.6,129.7,122.2(d,J=5.0Hz),11 9.7, 117.8 (d, J = 1.4Hz), 113.2, 112.9, 82.0 (d, J = 5.5Hz), 74.4, 63.5 (d, J = 4.5Hz), 55.2, 45.6, 23.3 (d, J = 5.8Hz). 31 P NMR(162MHz,chloroform-d)δ3.37(s).HRMS(ESI):[M+H] ⊕ Calculate for C 18 H 20 BrNO4P ⊕ 424.0308, found 424.0302.

[0228] Example 10: Compound 4j

[0229]

[0230] Compound 4j, colorless oil, yield 78%, [α] D 25 +1.6(c 0.50,CHCl3)for>20:1dr; 1H NMR(400MHz,chloroform-d)δ7.44–7.38(m,2H),7.13–7.07(m,2H),4.48–4.38(m,1H),4.05–3.93(m,1H),3.71(s,3H),3.63(s,3H),3. 54(t,J=10.1Hz,1H),2.47–2.29(m,2H),2.15–2.04(m,1H),1.96–1.83(m,4H),1.72–1.65(m,1H),1.56–1.40(m,3H),1.38–1.25(m,3H). 13 CNMR (101MHz, chloroform-d) δ173.09, 173.05, 150.1 (d, J = 6.7Hz), 132.6, 122.1, 122.1, 117.6, 53.8, 52.6, 51.8, 33.4 (d, J = 4.6Hz), 33.2 (d, J = 4.0Hz), 29.43, 29.38, 25.1, 23.5, 23.4 (due to overlap, the signal of one of the alkyl carbons was not observed). 31 P NMR(162MHz,chloroform-d)δ3.07(s).HRMS(ESI):[M+H] ⊕ Calculate for C 19 H 28 BrNO7P ⊕ 492.0781, found 492.0773.

[0231] Example 11: Compound 4k

[0232]

[0233] Compound 4k, yellow oil, yield 52%, [α] D 25 +1.0(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.42(d,J=8.8Hz,2H),7.16–7.10(m,2H),5.01–4.90(m,1H),3.73(s,3H),3.68–3.59(m,1H) ),3.10–2.94(m,1H),1.97–1.83(m,2H),1.71–1.61(m,2H),1.58(d,J=6.9Hz,3H),1.56–1.48(m,2H),1.44–1.28(m,2H). 13C NMR(126MHz,chloroform-d)δ171.2(d,J=5.1Hz),150.1(d,J=6.8Hz),132.6,122.1(d,J=5.2Hz),117. 6,71.4(d,J=5.4Hz),53.8,52.5,34.9(d,J=5.7Hz),34.8(d,J=5.8Hz),23.2,23.1,19.5(d,J=5.4Hz). 31 P NMR(162MHz,chloroform-d)δ2.66(s).HRMS(ESI):[M+H] ⊕ Calculate for C 15 H 22 BrNO5P ⊕ 406.0413, found 406.0409.

[0234] Example 12: Compound 41

[0235]

[0236] Compound 4l, colorless oil, yield 64%, [α] D 25 -1.4(c 1.0,CHCl3)for 13:1dr; 1 H NMR(500MHz,chloroform-d)δ7.41(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),7.05(d,J=8.2Hz,2H),6.82(d,J=8.2Hz,2H),5.0 4–4.76(m,1H),3.78(s,3H),3.73(s,3H),3.32–3.14(m,2H),3.06–2.98(m,1H),2.71(t,J=6.9Hz,2H),1.55(d,J=6.9Hz,3H). 13 C NMR(126MHz,chloroform-d)δ170.1(d,J=5.4Hz),157.5,149.0,131.6,129.2,128.9,121.1(d,J= 5.0Hz), 116.8, 113.2, 70.5 (d, J = 5.5Hz), 54.4, 51.5, 42.0, 35.8 (d, J = 6.2Hz), 18.5 (d, J = 5.2Hz). 31 P NMR(162MHz,chloroform-d)δ3.34(s).HRMS(ESI):[M+H] ⊕ Calculate for C19 H 24 BrNO6P ⊕ 472.0519, found 472.0513.

[0237] Example 13: Compound 4m

[0238]

[0239] Compound 4m, colorless oil, yield 92%, [α] D 25 -12.6(c 0.50,CHCl3)for 15:1dr; 1 H NMR(500MHz,chloroform-d)δ7.39(d,J=8.5Hz,2H),7.08(d,J=8.3Hz,2H),5.05–4.92(m,J=6.4Hz,1H),4.81–4.69(m,1H),3.95–3.83(m,1H),3 .63(t,J=10.2Hz,1H),2.35–2.22(m,2H),2.20–2.08(m,2H),1.76–1.62 (m,1H),1.56–1.41(m,1H),1.32(d,J=7.0Hz,3H),1.21(q,J=5.3Hz,6H). 13 C NMR (126 MHz, chloroform-d) δ 172.9 (d, J = 7.7 Hz), 150.0 (d, J = 6.6 Hz), 132.6, 122.0 (d, J = 5.1 Hz), 117.5, 70.9 (d, J = 7.4 Hz), 69.2, 50.3, 31.8 (d, J = 4.8 Hz), 31.6 (d, J = 5.7 Hz), 21.7 (d, J = 9.1 Hz), 21.1 (d, J = 4.7 Hz), 12.6 (the signal of one of the alkyl carbons was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ0.49(s).HRMS(ESI):[M+H] ⊕ Calculate for C 16 H 24 BrNO5P ⊕ 420.0570, found 420.0566.

[0240] Example 14: Compound 4n

[0241]

[0242] Compound 4n, yellow oil, yield 71%, [α] D 25 -9.9(c 0.50,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.41(d,J=8.4Hz,2H),7.11(d,J=8.4Hz,2H),5.07–4.98(h,J=6.5Hz,1H),4.98–4.92(m,1H),3.96–3.8 6(m,1H),3.53(t,J=10.3Hz,1H),1.90–1.76(m,4H),1.75–1.65(m,2H),1.64–1.51(m,2H),1.35(d,J=7.1Hz,3H),1.28–1.20(m,6H). 13 CNMR(126MHz,chloroform-d)δ173.1(d,J=7.6Hz),150.2(d,J=6.6Hz),132.6,122.12(d,J=5.0Hz),117.5,81. 2(d,J=6.0Hz),69.3,50.4,34.00(d,J=4.2Hz),33.96(d,J=5.1Hz),23.1,23.0,21.8,21.7,21.2(d,J=4.7Hz). 31 P NMR(162MHz,chloroform-d)δ1.43(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 26 BrNO5P ⊕ 434.0726, found 434.0720.

[0243] Example 15: Compound 4o

[0244]

[0245] Compound 4o, colorless oil, yield 65%, [α] D 25 +1.2(c 0.50,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ7.42(d,J=8.4Hz,2H),7.13(d,J=8.4Hz,2H),5.06–4.91(m,2H),4.04–3.94 (m,1H),3.79–3.74(m,1H),3.73(s,3H),1.55(d,J=6.9Hz,3H),1.37(d,J=7.0Hz,3H),1.27–1.21(m,6H). 13 CNMR(126MHz,chloroform-d)δ172.9(d,J=8.3Hz),171.0(d,J=5.0Hz),149.9(d,J=6.8Hz),132.6,122.1(d,J=5.0Hz), 117.9 (d, J = 1.7Hz), 71.7 (d, J = 5.5Hz), 69.4, 52.6, 50.4 (d, J = 1.7Hz), 21.8, 21.7, 21.1 (d, J = 4.4Hz), 19.3 (d, J = 5.5Hz). 31 P NMR(162MHz,chloroform-d)δ1.32(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 16 H 23 BrNO7PNa ⊕ 474.0288, found 474.0289.

[0246] Example 16: Compound 4p

[0247]

[0248] Compound 4p, yellow oil, yield 81%, [α] D 25 +8.5(c 1.0,CHCl3)for 95:5er; 1 H NMR(400MHz,MeOH-d4)δ7.50–7.43(m,2H),7.32–7.26(m,2H),7.25–7.19(m,3H),7.07–7. 00(m,2H),4.37–4.15(m,2H),3.18–3.04(m,4H),2.98(t,J=6.5Hz,2H),1.83–1.75(m,4H). 13CNMR(126MHz,chloroform-d)δ150.3(d,J=6.8Hz),137.4,132.6,129.1,128.5,126.7,121.9(d , J=5.0Hz), 117.3, 67.2 (d, J=5.7Hz), 46.9 (d, J=4.9Hz), 36.8 (d, J=7.2Hz), 26.3 (d, J=9.3Hz). 31 P NMR(162MHz,chloroform-d)δ3.04(s).HRMS(ESI):[M+H] ⊕ calcdfor C 18 H 22 BrNO3P⊕410.0515, found 410.0512.HPLC analysis: Chiracel AD-H column; detected at 210nm, 25℃; 20% i PrOH in n-hexane; flow=1.0mL / min; Retention time: 9.1min (minor), 10.7min (major).

[0249] Example 17: Compound 4q

[0250]

[0251] Compound 4q, yellow oil, yield 80%, [α] D 25 -13.8(c 1.0,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.37–7.31(m,2H),7.24–7.16(m,5H),7.16–7.09(m,3H),7.09–7.01(m,4H), 4.14(d,J=9.5Hz,2H),4.10–3.96(m,2H),2.61(t,J=8.0Hz,2H),2.51(d,J=10.0Hz,3H),1.97–1.88(m,2H). 13C NMR(101MHz,chloroform-d)δ150.2(d,J=6.6Hz),140.9,137.2(d,J=4.5Hz),132.6,128.51,128.48,128.4,128.2,127. 5,126.08,122.2(d,J=4.9Hz),117.6,66.3(d,J=6.0Hz),53.1(d,J=5.0Hz),33.2(d,J=3.8Hz),31.9(d,J=7.0Hz),31.7. 31 P NMR(162MHz,chloroform-d)δ6.00(s).HRMS(ESI):[M+H] ⊕ Calculate for C 23 H 26 BrNO3P ⊕ 474.0828, found 474.0828.HPLC analysis: Chiracel AD-H column; detected at210nm, 25℃; 20% i PrOH in n-hexane; flow=1.0mL / min; Retention time: 13.3min (major), 18.9min (minor).

[0252] Example 18: Compound 4r

[0253]

[0254] Compound 4r, colorless oil, yield 82%, [α] D 25 +7.8(c 0.50,CHCl3)for 96:4er; 1 H NMR(500MHz,chloroform-d)δ7.45–7.40(m,2H),7.12–7.07(m,2H),4.99–4.90(m,1H),3.6 3–3.57(m,4H),3.23–3.12(m,4H),1.90–1.76(m,5H),1.76–1.65(m,2H),1.65–1.54(m,2H). 13CNMR(126MHz,chloroform-d)δ150.2(d,J=6.9Hz),132.6,122.0(d,J=4.9Hz),117.5 ,81.1(d,J=6.1Hz), 66.9(d,J=5.6Hz), 44.7, 34.0(d,J=4.8Hz), 23.0(d,J=16.9Hz). 31 P NMR(162MHz,chloroform-d)δ2.21(s).HRMS(ESI):[M+H] ⊕ Calculate for C 15 H 22 BrNO4P ⊕ 390.0464, found 390.0462.HPLC analysis: Chiracel AD-H column;

[0255] Detection conditions: 210 nm, 25 °C, 15% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 11.2 min (small amount), 12.1 min (mainly).

[0256] Example 19: Compound 4s

[0257]

[0258] Compound 4s, colorless oil, yield 85%, [α] D 25 +11.3(c 1.0,CHCl3)for 94:6er; 1 H NMR (400MHz, DMSO-d6) δ7.50(d,J=7.7Hz,2H),7.31–7.15(m,8H),7.13(d,J=7.4Hz,2H),7.06(d,J=8.3Hz, 2H),5.60–5.41(m,1H),4.19–3.96(m,2H),3.01–2.91(m,2H),2.89(t,J=7.3Hz,2H),2.63(t,J=7.1Hz,2H). 13C NMR (126 MHz, chloroform-d) δ 150.1 (d, J = 6.7 Hz), 138.3, 137.3, 132.6, 129.1, 128.9, 128.7, 128.6, 126.8 (d, J = 6.4 Hz), 122.1 (d, J = 4.8 Hz), 117.6, 67.4 (d, J = 5.7 Hz), 42.7, 37.7 (d, J = 6.0 Hz), 36.8 (d, J = 7.2 Hz) (the signal of one of the aromatic carbons was not observed due to overlap). 31 P NMR(162MHz,DMSO-d6)δ5.21(s).HRMS(ESI):[M+H] ⊕ Calculate for C 12 H 24 BrNO3P ⊕ 460.0672, found 460.0668. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane; flow rate = 1.0 mL / min; retention time: 11.0 min (small amount), 15.0 min (mainly).

[0259] Example 20: Compound 4t

[0260]

[0261] Compound 4t, yellow solid, melting point 58.3–59.3°C. Yield 75%, [α] D 25 +14.7(c 0.50,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.46–7.31(m,7H),7.31–7.18(m,3H),7.08(t,J=7.9 Hz,4H),5.12–4.99(m,2H),3.27–3.14(m,2H),3.03(s,1H),2.71(t,J=6.8Hz,2H). 13 C NMR(101MHz,chloroform-d)δ150.1(d,J=6.7Hz),138.3,136.0(d,J=7.1Hz),132.6,128.9,128.71, 128.65, 128.5, 127.9, 126.7, 122.1 (d, J = 4.9Hz), 117.6, 68.5 (d, J = 5.3Hz), 42.8, 37.6 (d, J = 6.2Hz). 31P NMR(162MHz,chloroform-d)δ4.49(s).HRMS(ESI):[M+H] ⊕ Calculate for C 21 H 22 BrNO3P ⊕ 446.0515, found 446.0510.HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 25℃, 20% iPrOH in n-hexane solution; flow rate = 1.0mL / min; retention time: 13.0min (small amount), 16.3min (mainly).

[0262] Single crystal preparation method: Compound 4t was dissolved in a mixed solution of n-hexane / dichloromethane (10 / 1) and the corresponding single crystal was grown by slow evaporation.

[0263] Single crystal structure (4t) see Figure 1 , the configuration is S:

[0264] Table 2 Crystal data and structure refinement for 4t.

[0265]

[0266]

[0267] Example 21: Compound 4u

[0268]

[0269] Compound 4u, yellow oil, yield 83%, [α] D 25 -6.3(c 1.0,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.44–7.36(m,2H),7.13–7.06(m,2H),4.20–4.02(m,2 H),3.19–3.05(m,4H),1.58–1.50(m,2H),1.50–1.42(m,4H),1.33(t,J=7.1Hz,3H). 13C NMR (126MHz, chloroform-d) δ 150.4 (d, J = 6.7Hz), 132.5, 122.0 (d, J = 5.1Hz), 117.2, 63.0 (d, J = 5.7Hz), 45.5 (d, J = 2.4Hz), 25.89, 25.86, 24.3, 16.2, 16.1. 31 P NMR(162MHz,chloroform-d)δ4.18(s).HRMS(ESI):[M+H] ⊕ Calculate for C 13 H 20 BrNO3P ⊕ 348.0359, found 348.0357.HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 25℃, 10% iPrOH in n-hexane solution; flow rate = 1.0mL / min; retention time: 17.4min (small amount), 18.5min (mainly).

[0270] Example 22: Compound 4v

[0271]

[0272] Compound 4v, yellow oil, yield 83%, [α] D 25 +15.9(c 0.50,CHCl3)for 94:6er; 1 H NMR(400MHz,chloroform-d)δ7.39(d,J=8.4Hz,2H),7.33–7.23(m,3H),7.22–7.16(m,2H),7.06(d,J=8.3Hz,2H),4.36–4.20(m,2H),3.53 –3.37(m,1H),2.99(t,J=6.9Hz,2H),2.80(t,J=10.5Hz,1H),1.90–1.74(m,3H),1.68–1.56(m,2H),1.56–1.44(m,2H),1.35–1.22(m,2H). 13C NMR (126 MHz, chloroform-d) δ 150.3 (d, J = 7.0 Hz), 137.4, 132.6, 129.1, 128.6, 126.7, 122.1 (d, J = 4.9 Hz), 117.4, 67.3 (d, J = 5.8 Hz), 53.6, 36.8 (d, J = 7.3 Hz), 34.9 (d, J = 5.6 Hz), 34.8 (d, J = 5.6 Hz), 23.1 (the signal of one alkyl carbon was not observed due to overlap). 31 PNMR(162MHz,chloroform-d)δ3.54(s).HRMS(ESI):[M+H] ⊕ Calculate for C 19 H 24 BrNO3P ⊕ 424.0672, found 424.0670. HPLC analysis: Chiracel OD-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 5.8 min (main), 7.7 min (small).

[0273] Example 23: Compound 4w

[0274]

[0275] Compound 4w, white solid, melting point 79.8–82.3°C. Yield 65%, [α] D 25 -53.1(c 1.0,CHCl3)for 98:2er; 1 H NMR(500MHz,chloroform-d)δ8.10(d,J=8.9Hz,2H),7.32–7.27(m,3H),7.09–6.98(m,4H),5. 20–5.01(m,1H),2.07–1.98(m,1H),1.93–1.83(m,2H),1.82–1.67(m,3H),1.67–1.53(m,2H). 13 C NMR(126MHz,chloroform-d)δ155.4(d,J=5.8Hz),144.6,138.9,129.4,125.6,122.4,121.0(d,J= 5.1Hz), 117.7 (d, J = 7.7Hz), 82.4 (d, J = 5.6Hz), 34.0 (d, J = 4.7Hz), 33.8 (d, J = 5.5Hz), 23.0, 22.9. 31P NMR(162MHz,chloroform-d)δ-3.31(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 17 H 19 N2O5PNa ⊕ 385.0924, found 385.0919. HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 25℃, 20% iPrOH in n-hexane solution; flow rate = 1.0mL / min; retention time: 17.3min (small amount), 18.8min (mainly).

[0276] Example 24: Compound 4x

[0277]

[0278] Compound 4x, yellow oil, yield 59%, [α] D 25 +3.0(c 1.0,CHCl3)for 95:5er; 1 H NMR(500MHz,chloroform-d)δ7.32(t,J=8.0Hz,2H),7.21(d,J=7.9Hz,2H),7.14(t,J=7.5Hz,1H),4.59–4.25(m,1H), 3.59(t,J=4.3Hz,4H),3.30–3.12(m,4H),2.02–1.87(m,2H),1.79–1.65(m,2H),1.63–1.45(m,3H),1.42–1.18(m,3H). 13 C NMR(126MHz,chloroform-d)δ151.1(d,J=7.1Hz),129.6,124.6,120.2(d,J=5.0Hz),66 .9(d,J=5.7Hz),44.8,33.5(d,J=4.4Hz),33.3(d,J=4.2Hz),25.2,23.6(d,J=10.5Hz). 31 P NMR(162MHz,chloroform-d)δ2.16(s).HRMS(ESI):[M+H] ⊕ Calculate for C 16 H 25 NO4P ⊕326.1516, found326.1513.HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25°C, 15% iPrOH in n-hexane; flow rate = 1.0 mL / min; retention time: 17.5 min (small amount), 18.4 min (mainly).

[0279] Example 25: Compound 4y

[0280]

[0281] Compound 4y, colorless oil, yield 79%, [α] D 25 -2.5(c 1.0,CHCl3)for 95:5er; 1 H NMR(500MHz,chloroform-d)δ7.29(t,J=7.8Hz,2H),7.21(d,J=8.0Hz,2H),7.10(t,J=7.3Hz,1H),4.49–4.36(m,1H) ,3.30–3.13(m,4H),2.00–1.89(m,2H),1.83–1.66(m,6H),1.58–1.45(m,3H),1.38–1.27(m,2H),1.27–1.17(m,1H). 13 C NMR (126 MHz, chloroform-d) δ 151.4 (d, J = 6.7 Hz), 129.5, 124.3, 120.2 (d, J = 5.0 Hz), 76.4 (d, J = 6.0 Hz), 47.1 (d, J = 4.7 Hz), 33.6 (d, J = 4.3 Hz), 33.4 (d, J = 4.3 Hz), 26.4, 26.3, 25.3, 23.73, 23.66 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ2.21(s).HRMS(ESI):[M+H] ⊕ Calculate for C 16 H 25 NO3P ⊕ 310.1567, found 310.1566. HPLC analysis: Chiracel IF-H column; detection conditions: 210 nm, 25 ° C, 8% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 16.0 min (main), 17.4 min (small amount).

[0282] Example 26: Compound 4z

[0283]

[0284] Compound 4z, colorless oil, yield 54%, [α] D 25 -0.80(c 0.50,CHCl3)for 95:5er; 1 H NMR(400MHz,chloroform-d)δ7.30(t,J=7.8Hz,2H),7.21(d,J=8.0Hz,2H),7.11(t,J=7.3Hz,1H),4.46–4. 35(m,1H),3.21–3.06(m,4H),2.00–1.89(m,2H),1.79–1.64(m,2H),1.60–1.42(m,9H),1.40–1.24(m,3H). 13 C NMR (126 MHz, chloroform-d) δ 151.4 (d, J = 7.1 Hz), 129.5, 124.3, 120.3 (d, J = 5.0 Hz), 76.3 (d, J = 6.0 Hz), 45.6 (d, J = 2.2 Hz), 33.5 (d, J = 4.4 Hz), 33.4 (d, J = 4.2 Hz), 25.89, 25.85, 25.3, 24.4, 23.7, 23.6 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ3.31(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 27 NO3P ⊕ 324.1723, found 324.1722. HPLC analysis: Chiracel IE-H column; detection conditions: 210 nm, 25 ° C, 10% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 23.0 min (main), 24.7 min (small amount).

[0285] Example 27: Compound 4aa

[0286]

[0287] Compound 4aa, colorless oil, yield 59%, [α] D 25 -8.6(c 1.0,CHCl3)for 95:5er; 1H NMR(500MHz,chloroform-d)δ7.35–7.21(m,9H),7.15(t,J=7.3Hz,1H),4.53–4.43 (m,1H),4.30–4.17(m,2H),2.59(d,J=10.0Hz,3H),2.03–1.88(m,2H),1.79–1.66(m 2H), 1.62–1.46(m, 3H), 1.40–1.27(m, 3H). 13 C NMR(126MHz,chloroform-d)δ151.3(d,J=6.9Hz),137.6(d,J=4.6Hz),129.6,128.4,128.2,127.4,124.5,120.4(d,J=5 .0Hz),76.7(d,J=6.1Hz),53.2(d,J=4.8Hz),33.5(d,J=4.6Hz),33.3(d,J=4.4Hz),33.3(d,J=3.7Hz),25.2,23.7,23.6. 31 P NMR(162MHz,chloroform-d)δ4.90(s).HRMS(ESI):[M+H] ⊕ Calculate for C 20 H 27 NO3P ⊕ 360.1723, found 360.1721. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 17.3 min (main), 18.8 min (small amount).

[0288] Example 28: Compound 4ab

[0289]

[0290] Compound 4ab, colorless oil, yield 50%, [α] D 25 -6.2(c 0.50,CHCl3)for 94:6er; 1H NMR(500MHz,chloroform-d)δ7.28(t,J=7.9Hz,2H),7.22(d,J=8.1Hz,2H),7.09(t,J=7.3Hz,1H),4. 77–4.64(m,1H),3.26–3.17(m,4H),1.80–1.70(m,4H),1.34(d,J=6.3Hz,3H),1.31(d,J=6.2Hz,3H). 13 C NMR (126 MHz, chloroform-d) δ 150.7 (d, J = 6.7 Hz), 128.9, 123.7, 119.5 (d, J = 5.0 Hz), 70.8 (d, J = 5.7 Hz), 46.4 (d, J = 5.0 Hz), 25.7, 25.6, 23.2 (d, J = 4.9 Hz), 23.1 (d, J = 4.9 Hz) (the signal of one of the alkyl carbons was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ1.90(s).HRMS(ESI):[M+H] ⊕ Calculate for C 13 H 21 NO3P ⊕ 270.1254, found 270.1252. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 20 ° C, 5% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 29.0 min (main), 30.8 min (small).

[0291] Example 29: Compound 4ac

[0292]

[0293] Compound 4ac, colorless oil, yield 81%, [α] D 25 +12.7(c 0.50,CHCl3)for 92:8er; 1H NMR(500MHz,chloroform-d)δ7.33–7.27(m,4H),7.25–7.16(m,5H),7.14(t,J=7.4Hz,1H),4.37–4.21(m,2H),3.54–3.44(m,1 H),3.00(t,J=6.9Hz,2H),2.69(t,J=10.4Hz,1H),1.87–1.75(m,3H),1.66–1.56(m,2H),1.55–1.44(m,2H),1.35–1.23(m,2H). 13 C NMR (126 MHz, chloroform-d) δ 151.1 (d, J = 6.5 Hz), 137.5, 129.6, 129.1, 128.5, 126.7, 124.5, 120.3 (d, J = 5.0 Hz), 67.2 (d, J = 5.7 Hz), 53.6, 36.8 (d, J = 7.3 Hz), 34.9 (d, J = 5.6 Hz), 34.7 (d, J = 5.9 Hz), 23.1 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ3.59(s).HRMS(ESI):[M+H] ⊕ Calculate for C 19 H 25 NO3P ⊕ 346.1567, found346.1569.HPLC analysis: Chiracel OD-H column; detected at 210nm, 25℃; 20% i PrOHin n-hexane; flow=1.0mL / min; Retention time: 5.3min (major), 8.7min (minor).

[0294] Example 30: Compound 4ad

[0295]

[0296] Compound 4ad, yellow oil, yield 80%, [α] D 25 +9.0(c 1.0,CHCl3)for 94:6er; 1H NMR (500MHz, methanol-d4) δ7.43–7.31(m,7H),7.20–7.14(m,2H),5.10(d,J=9.0Hz,2H),3.22–3.11(m,4H),1.81–1.72(m,4H). 13 C NMR(126MHz,chloroform-d)δ149.8(d,J=6.5Hz),136.3(d,J=6.8Hz),129.8,129.7,128.6, 128.5, 128.0, 121.5 (d, J = 5.0Hz), 68.4 (d, J = 5.1Hz), 47.0 (d, J = 4.9Hz), 26.3 (d, J = 9.6Hz). 31 P NMR(162MHz,chloroform-d)δ3.30(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 20 ClNO3P ⊕ 352.0864, ​​found 352.0865. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25 ° C, 10% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 17.2 min (a small amount), 21.8 min (mainly).

[0297] Example 31: Compound 4ae

[0298]

[0299] Compound 4ae, yellow oil, yield 84%, [α] D 25 +6.1(c 1.0,CHCl3)for 99:1er; 1 H NMR(500MHz,chloroform-d)δ8.19(d,J=9.1Hz,2H),7.35(d,J=9.0Hz,2H),4.54–4.33(m,1H),3.28–3.18(m,4H), 1.96–1.89(m,2H),1.86–1.77(m,4H),1.76–1.65(m,2H),1.58–1.44(m,3H),1.37–1.26(m,2H),1.26–1.17(m,1H). 13C NMR (101 MHz, chloroform-d) δ 156.6 (d, J = 6.4 Hz), 144.1, 125.5, 120.6 (d, J = 5.4 Hz), 47.1 (d, J = 5.0 Hz), 33.5 (d, J = 4.4 Hz), 33.4 (d, J = 4.5 Hz), 26.4, 26.3, 25.1, 23.62, 26.55 (due to overlap, the signals of two alkyl carbons were not observed). 31 P NMR(162MHz,chloroform-d)δ-6.77(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 16 H 23 N2O5PNa ⊕ 377.1237, found 377.1241. HPLC analysis: Chiracel IF-H column; detection conditions: 210 nm, 25°C, 20% iPrOH in n-hexane; flow rate = 1.0 mL / min; retention time: 15.4 min (small amount), 12.7 min (mainly).

[0300] Example 32: Compound 4af

[0301]

[0302] Compound 4af, yellow oil, yield 88%, [α] D 25 +13.0(c 1.0,CHCl3)for 96:4er; 1 H NMR(500MHz,chloroform-d)δ8.22–8.14(m,2H),7.32–7.23(m,5H),7.23–7.19(m,2H),4.37– 4.22(m,2H),3.15–3.03(m,4H),3.01(t,J=6.9Hz,2H),1.59–1.51(m,2H),1.47–1.42(m,4H). 13 C NMR (126 MHz, chloroform-d) δ 156.3 (d, J = 6.7 Hz), 144.2, 137.2, 129.1, 128.6, 126.8, 125.6, 120.6 (d, J = 5.5 Hz), 67.5 (d, J = 5.9 Hz), 45.5 (d, J = 2.3 Hz), 36.7 (d, J = 7.5 Hz), 25.89, 25.86, 24.2 (the signal of one alkyl carbon was not observed due to overlap). 31PNMR(162MHz,chloroform-d)δ3.65(s).HRMS(ESI):[M+H] ⊕ Calculate for C 19 H 24 N2O5P ⊕ 391.1419, found 391.1419. HPLC analysis: Chiracel IF-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 15.7 min (a small amount), 18.0 min (mainly).

[0303] Example 33: Compound 4ag

[0304]

[0305] Compound 4ag, yellow oil, yield 95%, [α] D 25 +4.4(c 1.0,CHCl3)for 97:3er; 1 H NMR(500MHz,chloroform-d)δ8.26–8.18(m,2H),7.38–7.32(m,2H),7.09–7.02(m,2H),6.86–6.79(m,2H),4.18–4.06( m,2H),3.78(s,3H),3.67–3.56(m,4H),3.26–3.15(m,4H),2.58(t,J=7.3Hz,2H),1.76–1.69(m,2H),1.69–1.61(m,2H). 13 C NMR(126MHz,chloroform-d)δ157.9,156.0(d,J=6.6Hz),144.4,133.8,129.3,125.7,120 .6(d,J=5.3Hz),113.8,67.5(d,J=6.1Hz),66.9,66.8,55.3,44.7,34.3,29.7,29.6,27.5. 31 P NMR(162MHz,chloroform-d)δ2.80(s).HRMS(ESI):[M+H] ⊕ Calculate for C 21 H 28 N2O7P ⊕451.1629, found 451.1632. HPLC analysis: Chiracel IE-H column; detection conditions: 210 nm, 15 ° C, 15% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 87.5 min (a small amount), 80.6 min (mainly).

[0306] Example 34: Compound 4ah

[0307]

[0308] Compound 4ah, colorless oil, yield 91%, [α] D 25 +0.90(c 0.50,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ8.24–8.18(m,2H),7.40–7.34(m,2H),5.80–5.69(m,1H),5.12–5.02(m,2H),4.69– 4.59(m,1H),3.29–3.20(m,4H),2.46–2.39(m,1H),2.38–2.31(m,1H),1.89–1.78(m,4H),1.36(d,J=6.2Hz,3H). 13 C NMR(126MHz,chloroform-d)δ156.5(d,J=6.4Hz),144.1,133.1,125.6,120.5(d,J=5.5Hz) ,118.3,74.9(d,J=6.0Hz),47.1(d,J=4.9Hz),41.8(d,J=5.9Hz),26.3,26.3,21.21,21.18. 31 PNMR(162MHz,chloroform-d)δ1.54(s).HRMS(ESI):[M+H] ⊕ Calculate for C 15 H 22 N2O5P ⊕ 341.1261, found 341.1261.

[0309] Example 35: Compound 4ai

[0310]

[0311] Compound 4ai, yellow oil, yield 70%, [α] D 25-8.8(c 1.0,CHCl3)for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ8.26–8.17(m,2H),7.40–7.33(m,2H),5.00–4.90(m,1H),4.18–4.04(m,2H),3.20–3.09(m,4H),2.75(dd,J=15.5,6.8 Hz,1H),2.53(ddd,J=15.4,6.0,1.8 Hz,1H),1.60–1.51(m,2H),1.50–1.43(m,7H),1.22(t,J=7.1 Hz,3H). 13 C NMR(126MHz,chloroform-d)δ169.9,156.3(d,J=6.5 Hz),144.2,125.6,120.6(d,J=5.7 Hz),72.0(d,J=6.0 Hz),60.7,45.5,42.5(d,J=6.7 Hz),25.8,25.7,24.2,21.74,21.71,14.2. 31 P NMR(162 MHz,chloroform-d)δ2.12(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 26 N2O7P ⊕ 401.1472, found 401.1471.

[0312] Example 36: Compound 4aj

[0313]

[0314] Compound 4aj, yellow oil, yield 77%, [α] D 25 -33.7(c 1.0,CHCl3)for>20:1 dr; 1 H NMR(500 MHz,chloroform-d)δ8.26–8.18(m,2H),7.41–7.33(m,2H),4.96(s,1H),4.67(d,J=6.0 Hz,1H),4.58(d,J=5.9 Hz,1H),4.35(dd,J=8.6,6.0 Hz,1H),4.13–4.01(m,2H),3.31(s,3H),3.29–3.22(m,4H),1.89–1.81(m,4H),1.47(s,3H),1.30(s,3H).13 C NMR(126MHz,chloroform-d)δ156.1(d,J=6.3 Hz),144.4,125.6,120.6(d,J=5.4 Hz),112.6,109.3,85.0,84.9,84.8,81.6,66.6(d,J=5.8 Hz), 55.1, 47.1 (d, J = 4.9 Hz), 26.39, 26.35, 26.27, 24.9. 31 P NMR(162 MHz,chloroform-d)δ2.70(s).HRMS(ESI):[M+H] ⊕ calcdforC 19 H 28 N2O9P ⊕ 459.1527, found 459.1527.

[0315] Example 37: Compound 4ak

[0316]

[0317] Compound 4ak, yellow oil, yield 50%, [α] D 25 -12.0(c 1.0,CHCl3)for 93:7er; 1 H NMR (500 MHz, chloroform-d) δ7.41 (dd, J=8.2, 1.9 Hz, 2H), 7.31 (t, J=7.9 Hz,2H),7.22–7.04(m,5H),4.76–4.53(m,1H),2.35(s,3H),1.99–1.86(m,2H),1.75–1.67(m,2H),1.60–1.46(m,3H),1.38–1.24(m,3H). 13 C NMR (126 MHz, chloroform-d) δ150.7 (d, J = 8.4 Hz), 139.5 (d, J = 3.4 Hz), 135.0 (d, J = 5.3 Hz), 130.2 (d, J = 2.4 Hz), 129.7, 125.2, 122.4 (d, J = 7.4 Hz), 120.6 (d, J = 4.8 Hz), 79.1 (d, J = 7.5 Hz), 33.4 (d, J = 3.5 Hz), 33.3 (d, J = 4.9 Hz), 25.1, 23.54, 23.49, 21.3. 31P NMR(162 MHz,chloroform-d)δ18.26(s).HRMS(ESI):[M+Na] ⊕ calcdfor C 19 H 23 NaO3PS ⊕ 385.0998, found 385.0998. HPLC analysis: Chiracel AD-H column; detection conditions: 210 nm, 25°C, 20% iPrOH in n-hexane; flow rate = 1.0 mL / min; retention time: 21.3 min (small amount), 18.6 min (mainly).

[0318] Example 38: Compound 4al

[0319]

[0320] Compound 4al, yellow oil, yield 72%, [α] D 25 -28.7(c 1.0,CHCl3)for 95:5er; 1 H NMR(500MHz,chloroform-d)δ8.21(d,J=9.1Hz,2H),7.38(dd,J=8.2,2.0Hz,2H),7.30(d,J=8.4Hz,2H),7.15(d,J=7.9Hz, 2H),4.80–4.61(m,1H),2.36(d,J=1.8Hz,3H),2.01–1.92(m,2H),1.79–1.69(m,2H),1.62–1.49(m,3H),1.40–1.26(m,3H). 13 C NMR(126MHz,chloroform-d)δ155.5(d,J=7.8Hz),144.7,140.1,135.1(d,J=5.3Hz),130.4(d,J=2.7Hz),125.6,121.4 (d,J=7.8Hz),121.1(d,J=5.5Hz),80.0(d,J=7.6Hz),33.5(d,J=3.6Hz),33.3(d,J=5.1Hz),25.0,23.53,23.48,21.3. 31 P NMR(162MHz,chloroform-d)δ18.43(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 19 H 22 NNaO5PS ⊕430.0849, found 430.0851. HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 25℃, 20% iPrOH in n-hexane; flow rate = 1.0mL / min; retention time: 49.6min (small amount), 24.3min (mainly).

[0321] Example 39: Compound 4am

[0322]

[0323] Compound 4am, yellow oil, yield 49%, [α] D 25 -27.9(c 1.0,CHCl3)for 95:5er; 1 H NMR(500MHz,chloroform-d)δ7.47–7.34(m,4H),7.11–7.00(m,2H),6.86(d,J=8.7Hz,2H),4.96–4.84(m,1H),3.81(s,3H),1.35(dd,J=6.1,1.9Hz,6H). 13 C NMR(126MHz,chloroform-d)δ160.8(d,J=3.0Hz),149.8(d,J=8.1Hz),136.7(d,J=5.0Hz),132.6,122.3(d,J=5.2Hz),11 8.1(d,J=1.5Hz), 115.6(d,J=7.7Hz), 115.1(d,J=2.5Hz), 74.7(d,J=7.3Hz), 55.5, 23.9(d,J=4.2Hz), 23.7(d,J=5.7Hz). 31 P NMR(162MHz,chloroform-d)δ18.66(s).HRMS(ESI):[M+H] ⊕ Calculate for C 16 H 19 BrO4PS ⊕ 416.9920, found 416.9920. HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 25℃, 20% iPrOH in n-hexane solution; flow rate = 1.0mL / min; retention time: 28.3min (small amount), 20.3min (mainly).

[0324] Example 40: Compound 4an

[0325]

[0326] Compound 4an, colorless oil, yield 61%, [α] D 25 -4.5(c 1.0,CHCl3)for 17:1dr; 1 H NMR(500MHz,chloroform-d)δ8.74(s,1H),8.32(s,1H),7.23–7.18(m,2H),7.12–7.06(m, 2H),6.16(d,J=2.5Hz,1H),5.33(dd,J=6.3,2.6Hz,1H),5.03(dd,J=6.3,3.0Hz,1H),4.51 –4.49(m,1H),4.38–4.31(m,1H),4.26–4.19(m,1H),3.54(dd,J=10.0,4.3Hz,2H),1.94–1 .84(m,1H),1.60(s,3H),1.37–1.34(m,12H),0.77(d,J=6.8Hz,3H),0.68(d,J=6.9Hz,3H). 13 C NMR(126MHz,chloroform-d)δ171.4(d,J=4.5Hz),152.2,151.5,150.9,149.0(d,J=6.7Hz),144.3,132.4,130.3,129.6,121.5(d,J= 4.9Hz), 114.9, 91.6, 85.4 (d, J = 8.0Hz), 84.2, 82.1, 81.2, 66.3 (d, J = 5.3Hz), 60.2, 32.1 (d, J = 5.8Hz), 27.9, 27.1, 25.3, 18.8, 17.0. 31 P NMR(162MHz,chloroform-d)δ4.13(s).HRMS(ESI):[M+H] ⊕ Calculate for C 28 H 37 Cl2N5O8P ⊕ 672.1751, found 672.1756.

[0327] Example 41: Compound 4ao

[0328]

[0329] Compound 4ao, colorless oil, yield 46%, [α] D 25 -9.6(c 1.0,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ8.74(s,1H),8.32(s,1H),7.37(d,J=8.5Hz,2H), 7.04(d,J=8.4Hz,2H),6.17(d,J=2.5Hz,1H),5.34(dd,J=6.3,2.5Hz,1H),5.03( dd,J=6.3,3.1Hz,1H),4.49(q,J=4.3Hz,1H),4.37–4.28(m,1H),4.26–4.19(m, 1H), 3.78–3.69 (m, 2H), 1.60 (s, 3H), 1.38–1.35 (m, 12H), 1.20 (d, J = 5.3Hz, 3H). 13 C NMR(126MHz,chloroform-d)δ172.3(d,J=7.8Hz),152.2,151.5,151.0,149.6(d,J=6.4Hz),144.3,132.7,132.4,122.0(d,J=4 .9Hz), 118.0, 115.0, 91.4, 85.4 (d, J = 7.9Hz), 84.2, 82.3, 81.2, 66.2 (d, J = 5.2Hz), 50.7, 27.9, 27.2, 25.3, 21.1 (d, J = 4.7Hz). 31 P NMR(162MHz,chloroform-d)δ2.86(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 26 H 32 BrClN5O8PNa ⊕ 710.0753, found 710.0760.

[0330] Example 42: Compound 4ap

[0331]

[0332] Compound 4ap, white solid, melting point 119.4–122.6°C. Yield 40%, [α] D 25 -9.8(c 1.0,CHCl3)for 15:1dr; 1HNMR(500MHz,chloroform-d)δ8.19(d,J=9.2Hz,2H),7.34(d,J=9.0Hz,2H),7.17–7. 14(m,1H),7.07–7.02(m,1H),6.33–6.27(m,1H),5.99–5.90(m,1H),5.05–4.98(m,1H) ,4.36–4.29(m,1H),4.28–4.20(m,1H),3.71–3.57(m,2H),3.32(s,3H),2.06–1.97(m, 1H), 1.86 (d, J = 1.2Hz, 3H), 1.39 (s, 9H), 0.88 (d, J = 6.9Hz, 3H), 0.80 (d, J = 6.9Hz, 3H). 13 C NMR(126MHz,chloroform-d)δ171.4(d,J=4.6Hz),163.6,155.4(d,J=6.3Hz),151.6,144.6,133.4,-132.8,127.8,-125.7,1 20.7(d,J=5.4Hz),110.5,90.8,84.4(d,J=8.3Hz),82.5,67.8(d,J=5.6Hz),60.3,32.1(d,J=5.7Hz),28.0,18.9,17.1,13.3. 31 P NMR(162MHz,chloroform-d)δ3.54(s).HRMS(ESI):[M+H] ⊕ Calculate for C 26 H 35 N4O 10 PNa ⊕ 617.1983, found 617.1982.

[0333] Example 43: Compound 4aq

[0334]

[0335] Compound 4aq, colorless oil, yield 61% yield, [α] D 25 +2.8(c 1.0,CHCl3)for>20:1dr; 1HNMR(500MHz,chloroform-d)δ8.78(s,1H),8.30(s,1H),8.20–8.16(m,2H),7.35–7.30(m,2H), 6.19(d,J=2.4Hz,1H),5.39(dd,J=6.3,2.4Hz,1H),5.09(dd,J=6.3,3.3Hz,1H),4.53(q,J=4.2H z,1H),4.45–4.38(m,1H),4.32–4.25(m,1H),3.61–3.56(m,1H),3.51(t,J=10.2Hz,1H),1.99–1 .88(m,1H),1.62(s,3H),1.38(s,3H),1.37(s,9H),0.79(d,J=6.8Hz,3H),0.69(d,J=6.8Hz,3H). 13 C NMR(126MHz,chloroform-d)δ171.3(d,J=4.5Hz),155.4(d,J=6.0Hz),152.2,151.5,150.8,144.5,144.4,132.4,125.6,120.7(d,J= 5.4Hz),115.1,91.4,85.5(d,J=7.9Hz),84.2,82.4,81.1,66.6(d,J=5.4Hz),60.3,31.9(d,J=6.0Hz),27.9,27.1,25.3,18.9,16.9. 31 P NMR(162MHz,chloroform-d)δ3.87(s).HRMS(ESI):[M+H] ⊕ Calculate for C 28 H 37 ClN6O 10 P ⊕ 683.1992, found 683.1996.

[0336] Example 44: Compound 4ar ((S)-Fenamiphos)

[0337]

[0338] Compound 4ar ((S)-Fenamiphos), white solid, yield 58%, [α] D 25 -7.4(c 1.0,CHCl3)for 91:9er; 1H NMR(500MHz,chloroform-d)δ7.11(d,J=8.3Hz,1H),7.06(d,J=7.7Hz,2H),4.20–4.11(m,2H),3.51– 3.40(m,1H),2.60(t,J=10.3Hz,1H),2.42(s,3H),2.32(s,3H),1.36–1.32(m,3H),1.18–1.12(m,6H). 13 CNMR(126MHz,chloroform-d)δ148.8(d,J=6.9Hz),137.9,133.2,126.8,121.7(d,J=5.0Hz),118.2(d,J= 4.8Hz), 63.0 (d, J = 5.6Hz), 44.2, 25.33 (d, J = 5.1Hz), 25.29 (d, J = 5.7Hz), 20.2, 16.3 (d, J = 7.1Hz), 16.1. 31 PNMR (162MHz, chloroform-d) δ3.61(s).HPLC analysis: Chiracel AD-H column; detection conditions: 210nm, 15℃, 3% iPrOH in n-hexane solution; flow rate = 0.8mL / min; retention time: 38.7min (small amount), 42.9min (mainly).

[0339] Example 45: Compound 5a

[0340]

[0341] Under nitrogen protection, add alcohol 2b (0.40 mmol) and tetrahydrofuran (0.50 mL) to a dry Shrek tube. Place the reaction mixture at zero degrees and add t BuMgCl (0.40 mmol, 1 M in THF). The reaction was stirred for 30 minutes. Then, a solution of pentavalent phosphorus substrate 4m (0.10 mmol) in tetrahydrofuran (0.70 mL) was added to the reaction. Stirring was continued at room temperature for 30 hours. After the reaction was completed, water was added to quench, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain pure product 5a.

[0342] Compound 5a, colorless oil, yield 90%, [α] D 25 -1.3(c 1.0,CHCl3)for 99:1er; 1H NMR(500MHz,chloroform-d)δ7.40–7.32(m,4H),7.32–7.27(m,1H),5.06–4.92(m,2H),4.36–4.28(m ,1H),3.20–3.08(m,4H),1.99–1.87(m,2H),1.81–1.66(m,6H),1.52–1.43(m,3H),1.38–1.26(m,3H). 13 C NMR (126 MHz, chloroform-d) δ 137.1 (d, J = 7.3 Hz), 128.5, 128.1, 127.7, 75.7 (d, J = 5.7 Hz), 67.4 (d, J = 5.2 Hz), 46.8 (d, J = 4.8 Hz), 33.62 (d, J = 5.0 Hz), 33.58 (d, J = 4.6 Hz), 26.3, 26.2, 25.3, 23.74, 23.70 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.23(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 27 NO3P ⊕ 324.1723, found 324.1722. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 10.2 min (small amount), 9.5 min (mainly).

[0343] Using the corresponding raw materials and referring to the reaction conditions and operation methods in Example 45, the following compounds 5b-5k were prepared.

[0344] The reactants of each example are shown in Table 2 below:

[0345] Table 2

[0346]

[0347]

[0348] Example 46: Compound 5b

[0349]

[0350] Compound 5b, yellow oil, yield 76%, [α] D 25-1.5(c 1.0,CHCl3)for 99:1er; 1 H NMR(500MHz,chloroform-d)δ7.31–7.25(m,2H),7.22–7.16(m,3H),4.34–4.26(m,1H),4.03–3.91(m,2H),3.23–3.14(m,4H),2.7 5–2.67(m,2H),2.02–1.88(m,4H),1.86–1.78(m,4H),1.77–1.69(m,2H),1.55–1.45(m,3H),1.38–1.28(m,2H),1.29–1.17(m,1H). 13 C NMR (126 MHz, chloroform-d) δ 141.4, 128.5, 128.4, 126.0, 75.5 (d, J = 5.5 Hz), 65.1 (d, J = 5.8 Hz), 46.8 (d, J = 4.6 Hz), 33.6 (d, J = 4.4 Hz), 32.1, 32.0, 31.9, 26.4, 26.3, 25.3, 23.74, 23.70 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.24(s).HRMS(ESI):[M+H] ⊕ Calculate for C 19 H 31 NO3P ⊕ 352.2036, found 352.2037. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 5% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 33.5 min (a small amount), 31.9 min (mainly).

[0351] Example 47: Compound 5c

[0352]

[0353] Compound 5c, colorless oil, yield 69% yield, [α] D 25 -1.0(c 0.50,CHCl3)for 99:1er; 1HNMR(500MHz,chloroform-d)δ7.62–7.55(m,4H),7.49–7.40(m,4H),7.35(t,J=7.4Hz,1H),5.10–4.98(m,2H),4.39–4.30(m,1H),3 .22–3.13(m,4H),2.05–1.89(m,2H),1.82–1.76(m,4H),1.76–1.69(m,2H),1.57–1.46(m,3H),1.38–1.28(m,2H),1.27–1.17(m,1H). 13 C NMR (126 MHz, chloroform-d) δ 141.0, 140.8, 136.1 (d, J = 7.3 Hz), 128.8, 128.2, 127.4, 127.2, 127.1, 75.7 (d, J = 5.2 Hz), 67.2 (d, J = 5.2 Hz), 46.9 (d, J = 4.7 Hz), 33.64 (d, J = 4.1 Hz), 33.61 (d, J = 4.1 Hz), 26.34, 26.27, 25.3, 23.8, 23.7 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.26(s).HRMS(ESI):[M+H] ⊕ Calculate for C 23 H 31 NO3P ⊕ 400.2036, found 400.2038. HPLC analysis: Chiracel IE-H column; detection conditions: 210 nm, 25 ° C, 7% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 71.4 min (a small amount), 66.0 min (mainly).

[0354] Example 48: Compound 5d

[0355]

[0356] Compound 5d, yellow oil, yield 64%, [α] D 25 -1.1(c 0.50,CHCl3)for 99:1er; 1H NMR(500MHz,chloroform-d)δ7.11–7.04(m,2H),6.84–6.78(m,2H),4.32–4.22(m,1H),4.01–3.88(m,2H),3.78(s,3H),3.20–3.10(m,4H),2.61–2 .53(m,2H),1.99–1.86(m,2H),1.84–1.76(m,4H),1.75–1.69(m,2H),1.6 9–1.64(m,4H),1.54–1.41(m,3H),1.36–1.26(m,2H),1.25–1.16(m,1H). 13 C NMR (126 MHz, chloroform-d) δ 157.8, 134.3, 129.3, 113.8, 75.4 (d, J = 5.0 Hz), 65.7 (d, J = 5.8 Hz), 55.3, 46.9 (d, J = 4.6 Hz), 34.5, 33.7 (d, J = 4.3 Hz), 30.0, 29.9, 27.7, 26.4, 26.3, 25.3, 23.80, 23.77 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.23(s).HRMS(ESI):[M+H] ⊕ Calculate for C 21 H 35 NO4P ⊕ 396.2298, found 396.2298. HPLC analysis: Chiracel IE-H column; detection conditions: 210nm, 20℃, 5% iPrOH in n-hexane solution; flow rate = 0.7mL / min; retention time: 48.0min (small amount), 46.8min (mainly).

[0357] Example 49: Compound 5e

[0358]

[0359] Compound 5e, yellow oil, yield 60%, [α] D 25 +2.2(c 0.50,CHCl3)for 99:1er; 1H NMR(500MHz,chloroform-d)δ7.89–7.79(m,4H),7.55–7.43(m,3H),5.22–5.10(m,2H),4.40–4.31(m,1H),3.2 3–3.12(m,4H),2.02–1.91(m,2H),1.80–1.67(m,6H),1.58–1.46(m,3H),1.37–1.27(m,2H),1.24–1.17(m,1H). 13 CNMR (126MHz, chloroform-d) δ134.5 (d, J = 7.3 Hz), 133.2, 133.1, 128.3, 128.0, 127.8, 126.6, 126.3, 126.2, 125.6, 75.8 (d, J = 5.9 Hz), 67.7 (d, J = 5.3 Hz), 46.9 (d, J = 4.8 Hz), 33.7 (d, J = 4.1 Hz), 33.6 (d, J = 3.9 Hz), 26.34, 26.27, 25.3, 23.8, 23.7 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.32(s).HRMS(ESI):[M+H] ⊕ Calculate for C 21 H 29 NO3P ⊕ 374.1880, found 374.1882. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 14.3 min (small amount), 13.2 min (mainly).

[0360] Example 50: Compound 5f

[0361]

[0362] Compound 5f, yellow oil, yield 63%, [α] D 25 -2.4(c 1.0,CHCl3)for 99:1er(100%es); 1H NMR(500MHz,chloroform-d)δ7.77(t,J=9.0Hz,3H),7.67(s,1H),7.57(d,J=8.6Hz,1H ),7.49–7.35(m,2H),6.58(d,J=15.7Hz,1H),6.39–6.31(m,1H),4.36–4.27(m,1H),4. 11–3.97(m,2H),3.25–3.15(m,4H),2.38(q,J=7.2Hz,2H),2.03–1.85(m,4H),1.85–1. 78(m,4H),1.77–1.69(m,2H),1.53–1.45(m,2H),1.38–1.28(m,3H),1.24–1.16(m,1H). 13 CNMR (126MHz, chloroform-d) δ135.1, 133.7, 132.8, 130.8, 130.0, 128.1, 127.9, 127.7, 126.2, 125.6, 125.5, 123.5, 75.6 (d, J = 5.3 Hz), 65.3 (d, J = 5.8 Hz), 46.9 (d, J = 4.6 Hz), 33.7 (d, J = 4.3 Hz), 30.2, 30.1, 29.3, 26.4, 26.3, 25.3, 23.79, 23.76 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.26(s).HRMS(ESI):[M+H] ⊕ Calculate for C 25 H 35 NO3P ⊕ 428.2349, found 428.2352. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 12.7 min (small amount), 13.9 min (mainly).

[0363] Example 51: Compound 5g

[0364]

[0365] Compound 5g, yellow oil, yield 74%, [α] D 25 -1.3(c 1.0,CHCl3)for 98:2er; 1H NMR(500MHz,chloroform-d)δ7.42–7.37(m,1H),7.18–7.09(m,3H),6.60(d,J=15.7Hz,1H),6.12–6.04(m,1H),4.35–4.26(m,1H),4.09–3.93(m,2H),3 .26–3.11(m,4H),2.38–2.28(m,5H),2.01–1.89(m,2H),1.89–1.80(m,6H), 1.77–1.69(m,2H),1.55–1.42(m,3H),1.37–1.27(m,2H),1.24–1.16(m,1H). 13 C NMR (126 MHz, chloroform-d) δ 136.7, 135.0, 130.9, 130.2, 128.5, 127.0, 126.0, 125.5, 75.5 (d, J = 5.0 Hz), 65.3 (d, J = 5.7 Hz), 46.9 (d, J = 4.6 Hz), 33.6 (d, J = 3.9 Hz), 30.3, 30.2, 29.5, 26.4, 26.3, 25.3, 23.80, 23.75, 19.9 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ7.26(s).HRMS(ESI):[M+H] ⊕ Calculate for C 22 H 35 NO3P ⊕ 392.2349, found 392.2350. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 8.4 min (a small amount), 9.3 min (mainly).

[0366] Example 52: Compound 5h

[0367]

[0368] Compound 5h, colorless oil, yield 58%, [α] D 25 -0.20(c 0.50,CHCl3)for 99:1er; 1H NMR(500MHz,chloroform-d)δ7.42–7.35(m,2H),7.31–7.27(m,3H),4.37–4.28(m,1H),4.19–4.05(m,2H),3.22(s,4H),2.80 (t,J=6.9Hz,2H),1.96(dd,J=33.4,12.4Hz,2H),1.88–1.78(m,4H),1.77–1.69(m,2H),1.57–1.44(m,3H),1.37–1.27(m,3H). 13 C NMR(126MHz,chloroform-d)δ131.7,128.3,128.0,123.5,85.6,82.1,75.8(d,J=5.8Hz),63.9(d,J=5.6Hz ), 46.9 (d, J = 4.6Hz), 33.7 (d, J = 4.3Hz), 33.6 (d, J = 4.2Hz), 26.42, 26.35, 25.3, 23.80, 23.77, 21.8, 21.7. 31 P NMR(162MHz,chloroform-d)δ7.03(s).HRMS(ESI):[M+H] ⊕ Calculate for C 20 H 29 NO3P ⊕ 362.1880, found 362.1885. HPLC analysis: Chiracel IG-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 8.9 min (small amount), 8.3 min (mainly).

[0369] Example 53: Compound 5i

[0370]

[0371] Compound 5i, yellow oil, yield 80%, the reaction uses compound 4ag as raw material, [α] D 25 +1.9(c 0.50,CHCl3)for 96:4er; 1H NMR(500MHz,chloroform-d)δ7.40–7.30(m,5H),7.10–7.05(m,2H),6.85–6.79(m,2H),5.07–4.95(m,2H),4. 07–3.94(m,2H),3.78(s,3H),3.62–3.49(m,4H),3.14–3.00(m,4H),2.58(t,J=7.0Hz,2H),1.74–1.57(m,5H). 13 C NMR(126MHz,chloroform-d)δ157.8,136.5(d,J=6.8Hz),134.1,129.3,128.6,128.4,127.9,1 13.8, 68.0 (d, J = 5.5Hz), 67.0 (d, J = 5.8Hz), 66.52, 66.47, 55.3, 44.6, 34.4, 29.9, 29.8, 27.6. 31 P NMR(162MHz,chloroform-d)δ8.09(s).HRMS(ESI):[M+H] ⊕ Calculate for C 22 H 31 NO5P ⊕ 420.1934, found 420.1937. HPLC analysis: Chiracel IF-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 14.1 min (small amount), 13.0 min (mainly).

[0372] Example 54: Compound 5j

[0373]

[0374] Compound 5j, yellow oil, yield 81%, the reaction uses compound 4ah as raw material, [α] D 25 +9.4(c 1.0,CHCl3)for>20:1dr; 1H NMR(500MHz,chloroform-d)δ7.31–7.26(m,2H),7.24–7.19(m,3H),5.81–5.71(m,1H),5.12–5.02(m,2H),4.49–4.39(m,1H),4.21–4.14(m,1H),4.13–4 .05(m,1H),3.16–3.09(m,2H),3.09–3.02(m,2H),2.97(t,J=7.1Hz,2H),2.4 2–2.33(m,1H),2.32–2.23(m,1H),1.81–1.71(m,4H),1.27(d,J=6.2Hz,3H). 13 C NMR(126MHz,chloroform-d)δ137.8,133.8,129.1,128.5,126.6,117.8,73.3(d,J=6.0Hz),66. 4(d,J=5.8Hz), 46.8(d,J=4.6Hz), 42.0(d,J=5.7Hz), 37.0,36.9,26.3,26.3,21.3(d,J=3.5Hz). 31 P NMR(162MHz,chloroform-d)δ7.18(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 27 NO3P ⊕ 324.1723, found 324.1723.

[0375] Example 55: Compound 5k

[0376]

[0377] Compound 5k, yellow oil, yield 82%, the reaction uses compound 4aj as raw material, [α] D 25 -24.4(c0.50,CHCl3)

[0378] for>20:1dr; 1 H NMR(500MHz,chloroform-d)δ7.62–7.57(m,2H),7.54(d,J=8.2Hz,2H),7.46–7.38

[0379] (m,4H),7.37–7.30(m,1H),6.45(d,J=15.8Hz,1H),6.29–6.21(m,1H),4.97(s,1H),4.72(d,J=5.9Hz,1H),4.59(d,J=5.9Hz,1H),4. 40–4.34(m,1H),4.14–3.89(m,4H),3.31(s,3H),3.25–3.18(m,4H),2.37–2.32(m,2H),1.92–1.80(m,6H),1.48(s,3H),1.32(s,3H). 13 C NMR (126 MHz, chloroform-d) δ 140.8, 139.8, 136.6, 130.3, 129.5, 128.8, 127.3, 126.9, 126.4, 112.5, 109.3, 85.12, 85.06, 81.8, 65.9 (d, J = 5.6 Hz), 65.7 (d, J = 5.6 Hz), 55.0, 46.9 (d, J = 4.5 Hz), 30.1 (d, J = 7.0 Hz), 29.2, 26.5, 26.4, 26.3, 25.0 (one of the carbon signals was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ8.10(s).HRMS(ESI):[M+H] ⊕ Calculate for C 30 H 41 NO7P ⊕ 558.2615, found 558.2621.

[0380] Example 56: Compound 6a

[0381]

[0382] In a Shrek tube, pentavalent phosphorus 4m (0.10 mmol) and methanol (7.4 mmol, 0.30 mL) were added in sequence, and then a solution of trifluoromethanesulfonic acid (45 mg, 0.30 mmol) dissolved in methanol (0.15 mL) and dichloromethane (0.15 mL) was added at zero degree.

[0383] The reaction solution was stirred at 50°C for 22 hours. Subsequently, the reaction solution was directly concentrated and separated by column chromatography to obtain pure product 6a.

[0384] Compound 6a, yellow oil, yield 74%, [α] D 25 -7.2(c1.0,CHCl3)for99:1er; 1HNMR(500MHz,chloroform-d)δ8.29–8.19(m,2H),7.42–7.34(m,2H),4.59–4.46(m,1H),3.87(dd ,J=11.9,1.9Hz,3H),2.03–1.85(m,2H),1.81–1.65(m,2H),1.63–1.47(m,3H),1.42–1.22(m,3H). 13 C NMR (126 MHz, chloroform-d) δ 155.7 (d, J = 6.5 Hz), 144.7, 125.7, 120.6 (d, J = 5.4 Hz), 79.5 (d, J = 6.4 Hz), 55.0 (d, J = 6.2 Hz), 33.3 (d, J = 4.5 Hz), 33.2 (d, J = 4.6 Hz), 25.0, 23.5 (the signal of one alkyl carbon was not observed due to overlap). 31 P NMR(162MHz,chloroform-d)δ-6.78(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 13 H 18 NO6PNa ⊕ 338.0764, found 338.0759. HPLC analysis: Chiracel IF-H column; detection conditions: 210 nm, 25 ° C, 20% iPrOH in n-hexane solution; flow rate = 1.0 mL / min; retention time: 11.3 min (a small amount), 12.2 min (mainly).

[0385] Using the corresponding raw materials and referring to the reaction conditions and operation methods in Example 56, the following compound 6b was prepared.

[0386] Example 57: Compound 6b; the starting material is

[0387]

[0388] Compound 6b, yellow oil, yield 42%, [α] D 25 -1.2(c 0.50,CHCl3)for 95:5er; 1HNMR(500MHz,chloroform-d)δ8.24(d,J=8.7Hz,2H),7.37(d,J=8.7Hz,2H),4.57–4.45(m,1H),4.22–4.10 (m,2H),2.01–1.85(m,2H),1.72–1.63(m,3H),1.63–1.46(m,4H),1.45–1.27(m,5H),0.92(t,J=7.5Hz,3H). 13 C NMR(126MHz,chloroform-d)δ155.8(d,J=6.4Hz),144.6,125.7,120.6(d,J=5.6Hz),79.2 ,68.7(d,J=6.5Hz),33.3(dd,J=11.9,4.6Hz),32.2(d,J=6.9Hz),25.0,23.5,18.7,13.6. 31 P NMR(162MHz,chloroform-d)δ-7.79(s).HRMS(ESI):[M+Na] ⊕ Calculate for C 16 H 24 NO6PNa ⊕ 380.1233, found 380.1230.HPLC analysis: Chiracel ID-H column; detection conditions: 210nm, 25℃, 20% iPrOH in n-hexane solution; flow rate = 1.0mL / min; retention time: 11.3min (small amount), 10.5min (mainly).

[0389] Example 58: Compound 7a

[0390]

[0391] Under nitrogen protection, phenyl lithium (0.30 mmol, 0.30 mL, 1 M in Et2O) was added to a Shrek tube and placed at zero degrees. Compound 4i (0.070 mmol) in THF (0.35 mL) was then added to the reaction. The reaction was stirred at room temperature for 33 hours. After completion, the reaction was quenched with water, extracted with ethyl acetate three times, concentrated, and separated by column chromatography to obtain pure product 7a.

[0392] Compound 7a, yellow oil, yield 58%, [α] D 25 -22.6(c 1.0,CHCl3)for 94:6er(100%es); 1H NMR(500MHz,chloroform-d)δ10.91(s,1H),7.41–7.35(m,1H),7.35–7.27(m,1H),6.97–6.92(m,1H),6.90–6.84(m,1H), 4.66–4.48(m,1H),3.28–3.21(m,2H),3.20–3.12(m,2H),1.89–1.75(m,4H),1.38(d,J=6.2Hz,3H),1.19(d,J=6.2Hz,3H). 13 C NMR(126MHz,chloroform-d)δ162.0(d,J=6.6Hz),134.1(d,J=2.5Hz),131.3(d,J=6.5Hz),119.1(d,J=12.9Hz),117.6 (d,J=10.9Hz),112.0(d,J=161.7Hz),70.6(d,J=4.8Hz),46.4(d,J=5.1Hz),26.3(d,J=8.6Hz),24.3,24.2,23.8,23.7. 31 P NMR(162MHz,chloroform-d)δ25.36(s).HRMS(ESI):[M+H] ⊕ Calculate for C 13 H 21 NO3P ⊕ 270.1254, found 270.1253. HPLC analysis: Chiracel IG-H column; detection conditions: 210nm, 25℃, 10% iPrOH in n-hexane solution; flow rate = 1.0mL / min; retention time: 17.2min (small amount), 21.8min (mainly).

[0393] detected at 210nm,25℃; 8% i PrOH in n-hexane; flow=1.0mL / min; Retentiontime:17.1min(major),

[0394] 18.1min(minor).

[0395] Using the corresponding raw materials and referring to the reaction conditions and operation methods in Example 58, the following compound 7b was prepared.

[0396] Example 59: Compound 7b; the starting material is

[0397]

[0398] Compound 7b, yellow oil, yield 56%, [α] D 25 -16.6(c 1.0,CHCl3)for 95:5er; 1 H NMR(500MHz,chloroform-d)δ10.74(s,1H),7.37(t,J=7.7Hz,1H),7.29(ddd,J=13.8,7.7,1.8Hz,1H),6.93(dd,J=8.4,5.8Hz,1H),6.89–6.83(m,1H),4 .38–4.28(m,1H),3.19–3.00(m,4H),2.01–1.91(m,1H),1.80–1.69(m,2H), 1.69–1.59(m,2H),1.59–1.39(m,8H),1.38–1,29(m,1H),1.29–1.20(m,2H). 13 C NMR(126MHz,chloroform-d)δ161.8(d,J=6.4Hz),134.0(d,J=2.5Hz),131.2(d,J=6.5Hz),119.1(d,J=13.1Hz),117.5(d,J=11.0Hz ),112.4(d,J=162.8Hz),75.5(d,J=5.3Hz),45.0(d,J=2.7Hz),33.8(d,J=3.9Hz),33.42,33.38,26.0,25.9,25.2,24.5,23.6,23.5. 31 P NMR(162MHz,chloroform-d)δ24.73(s).HRMS(ESI):[M+H] ⊕ Calculate for C 17 H 27 NO3P ⊕ 324.1723, found 324.1722.HPLC analysis:ChiracelIE-H column; detected at 210nm, 25℃; 20% i PrOH in n-hexane; flow=1.0mL / min; Retention time: 14.2min (major), 15.8min (minor).

[0399] Example 60: One-pot preparation of compound 5a

[0400]

[0401] Under nitrogen protection, phosphorus oxychloride 1a (0.22 mmol) was added to a Shrek tube. Molecular sieves (80 mg) and dry DCM / CHCl3 (0.80 mL, v / v = 1 / 7). Then, catalyst C-1 (5.1 mg, 0.020 mmol) and cyclohexanol 2a (0.20 mmol) in DCM / CHCl3 (0.80 mL, v / v = 1 / 7) solution and triethylamine (31 mg, 0.30 mmol) in DCM / CHCl3 (0.40 mL, v / v = 1 / 7) solution were added at -80 degrees Celsius. After reacting at -80 degrees Celsius for 48 hours, cyclopentaneamine 3a (0.80 mmol) in DCM / CHCl3 (0.50 mL, v / v = 1 / 7) solution was added to the reaction solution. The reaction was stirred at -80 degrees Celsius for 12 hours. After the reaction was completed, the temperature was restored to room temperature and concentrated to obtain a crude sample intermediate. Under nitrogen protection, add alcohol 2b (0.80 mmol) and tetrahydrofuran (1.0 mL) to a dry Shrek tube. Place the reaction mixture at zero degrees and add t BuMgCl (0.80 mmol, 1 M in THF). The reaction was stirred for 30 minutes. Then, the reaction solution in the Shrek tube was transferred to the above-concentrated tetrahydrofuran solution of the intermediate prepared, and stirred for 30 hours at room temperature. After the reaction was completed, water was added to quench, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain pure product 5a (52% yield, 34 mg, 98.5:1.5er).

Claims

1. A method for preparing compound IV, characterized in that: It comprises the following steps: Step 1, reacting compounds I and II in a solvent in the presence of a base and an imidazole chiral catalyst; Step 2, reacting the product obtained in step 1 with compound III in a solvent to prepare compound IV; Among them, R 1 C6-C 10 or 1, 2 or 3 R 1-1 Substituted C6-C 10 The aromatic group; R 1-1 is independently halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 1a Substituted C1-C6 alkyl, 1, 2 or 3 R 1b Substituted C1-C6 alkoxy or -S-C1-C6 alkyl; R 1a and R 1b are each independently halogen, nitro or hydroxy; R 2 is C3-C6 cycloalkyl, 1, 2 or 3 R 2-1 Substituted C3-C6 cycloalkyl, C1-C6 alkyl, 1, 2 or 3 R 2-2 Substituted C1-C6 alkyl, C2-C6 alkenyl, 1, 2 or 3 R 2-3 Substituted C2-C6 alkenyl, C2-C6 alkynyl, 1, 2 or 3 R 2-4 Substituted C2-C6 alkynyl, C1-C6 alkoxy, 1, 2 or 3 R 2-5 Substituted C1-C6 alkoxy, C6-C 10 or 1, 2 or 3 R 2-6 Substituted C6-C 10 The aromatic group; R 2-1 and R 2-6 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano or nitro; R 2-2 , R 2-3 , R 2-4 and R 2-5 Each is independently -C(=O)OR 2a , C3-C6 cycloalkyl, 1, 2 or 3 R 2b Substituted C3-C6 cycloalkyl, "a 3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", 1, 2 or 3 R 2c Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1 or more heteroatoms, 3-10 membered heterocycloalkyl", C6-C 10 aryl, 1, 2 or 3 R 2d Substituted C6-C 10 aryl, "a 5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", 1, 2 or 3 R 2e Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaryl with 1 or more heteroatoms", "3-10 membered heterocycloalkenyl with 1 or more heteroatoms", 1, 2 or 3 R 2f Substituted "3-10 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms"; R 2a are independently C1-C6 alkyl; R 2b , R 2c , R 2d and R 2e Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano, nitro, "a 5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms", 1, 2 or 3 R 2b-1 Substituted "5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms"; R 2b-1 Each is independently halogen, nitro, cyano, C1-C6 alkyl or C1-C6 alkoxy; R 2f Each independently represents a "5-10 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms", 2f-1 Substituted "heteroatoms selected from one, two or three of N, O and S, with one or more heteroatoms, 5-10 membered heterocycloalkenyl", "heteroatoms selected from one, two or three of N, O and S, with one or more heteroatoms, 3-10 membered heterocycloalkyl", 1, 2 or 3 R 2f-2 Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1 or more heteroatoms, 3-10 membered heterocycloalkyl", C6-C 10 or 1, 2 or 3 R 2f-3 Substituted C6-C 10 The aromatic group; R 2f-1 , R 2f-2 and R 2f-3 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, hydroxyl or oxo; X is -NR 3 R 4 、-SR 5 OR 6 ; R 3 and R 4 are each independently hydrogen, C1-C6 alkyl, 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 3-2 Substituted C1-C6 alkoxy, C3-C6 cycloalkyl, 1, 2 or 3 R 3-3 Substituted C3-C6 cycloalkyl, C6-C 10 aryl, 1, 2 or 3 R 3-4 Substituted C6-C 10 The aromatic group; or R 3 and R 4 The nitrogen connected thereto forms a "3-10 membered heterocycloalkyl group in which the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1 or more" or is replaced by 1, 2 or 3 R 3-5 Substituted "3-10 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S, with one or more heteroatoms"; R 3-1 and R 3-2 Each is independently -C(=O)OR 3a , C3-C6 cycloalkyl, 1, 2 or 3 R 3b Substituted C3-C6 cycloalkyl, C6-C 10 or 1, 2 or 3 R 3c Substituted C6-C 10 The aromatic group; R 3a are independently C1-C6 alkyl; R 3b and R 3c Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano or nitro; R 3-3 , R 3-4 and R 3-5 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, cyano or nitro; R 5 and R 6 are each independently hydrogen, C1-C6 alkyl, 1, 2 or 3 R 5-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 5-2 Substituted C1-C6 alkoxy, C3-C6 cycloalkyl, 1, 2 or 3 R 5-3 Substituted C3-C6 cycloalkyl, C6-C 10 or 1, 2 or 3 R 5-4 Substituted C6-C 10 The aromatic group; R 5-1 and R 5-2 are each independently halogen or hydroxy; R 5-3 and R 5-4 Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano or nitro.

2. The method for preparing compound IV according to claim 1, characterized in that: It meets one or more of the following conditions; (1) Each of the C6-C 10 Aryl and substituted C6-C 10 The C6-C 10 The aryl groups of are independently phenyl or naphthyl; for example, phenyl; (2) Each of the halogens is independently fluorine, chlorine, bromine or iodine; for example, bromine or chlorine; (3) The C3-C6 cycloalkyl group and the substituted C3-C6 cycloalkyl group are independently cyclopropyl, cyclopentyl or cyclohexyl; (4) The C1-C6 alkyl group and the substituted C1-C6 alkyl group are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl or sec-butyl; for example, methyl, ethyl, n-propyl, isopropyl or tert-butyl; (5) The C2-C6 alkenyl groups and substituted C2-C6 alkenyl groups are independently (6) The C2-C6 alkynyl group in each of the C2-C6 alkynyl groups and substituted C2-C6 alkynyl groups is independently a C2-C4 alkynyl group; for example, (7) The C1-C6 alkoxy group and the substituted C1-C6 alkoxy group in each of the C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example, methoxy; (8)R 2-2 In the 3-10 membered heterocycloalkyl and the substituted 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is an 8 membered heterocycloalkyl having oxygen as the heteroatom and 3 heteroatoms; for example, (9)R 3 and R 4 In the 3-10 membered heterocycloalkyl and substituted 3-10 membered heterocycloalkyl, the 3-10 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl having one or two heteroatoms selected from N and O; for example, (10) In each of the 5-10 membered heteroaryl groups and substituted 5-10 membered heteroaryl groups, the 5-10 membered heteroaryl group is a 9 membered heteroaryl group having 4 heteroatoms and a nitrogen atom as the heteroatom; for example, (11) In each of the 3-10 membered heterocycloalkenyl and substituted 3-10 membered heterocycloalkenyl, the 3-10 membered heterocycloalkenyl is a 5-6 membered heterocycloalkenyl having a heteroatom of N or O and 1 or 2 heteroatoms; for example, (12) In step 1, the base is an organic base; preferably a tertiary amine organic base; for example, triethylamine; (13) In step 1, the imidazole chiral catalyst is (14) In steps 1 and 2, the solvent is one or more halogenated alkane solvents; preferably two; for example, dichloromethane and chloroform; preferably, the volume ratio of the dichloromethane to the chloroform is 1:(5-8); preferably 1:7; (15) In step 1, the molar ratio of compound II to compound I is 1:(0.8-1.2); for example, 1:1.1; (16) The molar ratio of the compound II in step 1 to the compound III in step 2 is 1:(3-5); for example, 1:4; (17) In step 1, the molar ratio of the compound II to the imidazole chiral catalyst is 1:(0.08-0.12); for example, 1:0.1; (18) In step 1, the molar ratio of the compound II to the base is 1:(1.2-1.8); for example, 1:1.5; (19) In step 1, the molar volume ratio of the compound II to the solvent is 1 mmol:(8-12) mL; for example, 1 mmol:10 mL; (20) In step 1 and step 2, the reaction temperature is (-60°C) to (-100°C); for example, -80°C; (21) In step 1, the reaction time is 36 h-60 h; for example, 48 h; (22) In step 1, the reaction further comprises a molecular sieve; for example, Molecular sieves; (23) In step 2, the molar volume ratio of the compound III to the solvent is 8 mmol:(4-8) mL; for example, 8 mmol:5 mL; (24) In step 2, the reaction time is 8-16 h; for example, 12 h; (25) Step 2 further comprises the following post-treatment steps: returning to room temperature, concentrating, and column chromatography; for example, returning to room temperature and concentrating; and (26) The reaction raw materials of the preparation method of the compound IV are the solvent, the base, the imidazole chiral catalyst, the compound I, the compound II and the compound III.

3. The method for preparing compound IV according to claim 1, characterized in that: It meets one or more of the following conditions; (1)R 1 C6-C 10 or 1, 2 or 3 R 1-1 Substituted C6-C 10 for example, (2)R 1-1 For halogen, nitro, or C1-C6 alkyl; (3)R 2 is C3-C6 cycloalkyl, C1-C6 alkyl, 1, 2 or 3 R 2-2 Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 or 1, 2 or 3 R 2-6 Substituted C6-C 10 for example, (4)R 2-6 are independently C1-C6 alkyl; (5)R 2-2 are independently -C(=O)OR 2a , 1, 2 or 3 R 2c Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, with 1 or more heteroatoms, 3-10 membered heterocycloalkyl", C6-C 10 aryl, 1, 2 or 3 R 2d Substituted C6-C 10 aryl, 1, 2 or 3 R 2f Substituted "3-10 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms"; (6)R 2c and R 2d Each independently represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or 1, 2 or 3 R 2b-1 Substituted "5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms"; (7)R 2b-1 are each independently a halogen; (8)R 2f Each independently is 1, 2 or 3 R 2f-1 Substituted "5-10 membered heterocycloalkenyl group having one, two or three heteroatoms selected from N, O and S, and having one or more heteroatoms"; (9)R 2f-1 Each is independently a C1-C6 alkyl or an oxo group; (10) X is -NR 3 R 4 or -SR 5 ; (11)R 3 and R 4 are each independently hydrogen, C1-C6 alkyl, 1, 2 or 3 R 3-1 Substituted C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 or 1, 2 or 3 R 3-4 Substituted C6-C 10 The aromatic group; or R 3 and R 4 The nitrogen connected thereto forms a "3-10 membered heterocycloalkyl group in which the heteroatom is selected from 1, 2 or 3 of N, O and S, and the number of the heteroatom is 1 or more"; Preferably, R 3 for R 4 is hydrogen, methyl or Or, R 3 and R 4 The nitrogen attached to it forms (12)R 3-1 and R 3-2 Each is independently -C(=O)OR 3a , C3-C6 cycloalkyl or 1, 2 or 3 R 3c Substituted C6-C 10 The aromatic group; (13)R 3c are independently C1-C6 alkoxy; (14)R 3-4 are independently C1-C6 alkyl; (15)R 5 For 1, 2 or 3 R 5-4 Substituted C6-C 10 for example, and (16)R 5-4 Each is independently a C1-C6 alkyl group or a C1-C6 alkoxy group.

4. The method for preparing compound IV according to claim 1, characterized in that: It meets one or more of the following conditions; (1) Compound I is (2) Compound II is (3) Compound III is (4) Compound IV is 5. A method for preparing compound VI, characterized in that: The method comprises the following steps, in a solvent, t In the presence of BuMgCl, compound IV and V react to prepare compound VI; Among them, R 1 , R 2 and X is defined as in any one of claims 1 to 4; R 7 is C1-C6 alkyl, 1, 2 or 3 R 7-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, 1, 2 or 3 R 7-2 Substituted C1-C6 alkoxy, C2-C6 alkenyl, 1, 2 or 3 R 7-3 Substituted C2-C6 alkenyl, C2-C6 alkynyl, 1, 2 or 3 R 7-4 Substituted C2-C6 alkynyl, C6-C 10 or 1, 2 or 3 R 7-5 Substituted C6-C 10 The aromatic group; R 7-1 , R 7-2 , R 7-3 and R 7-4 Each independently is C6-C 10 or 1, 2 or 3 R 7a Substituted C6-C 10 The aromatic group; R 7-5 Each is independently a C1-C6 alkyl group; R 7a Each is independently C1-C6 alkyl, C1-C6 alkoxy, halogen, nitro, cyano, hydroxyl, oxo, C6-C 10 or 1, 2 or 3 R 7a-1 Substituted C6-C 10 The aromatic group; R 7a-1 Each is independently a C1-C6 alkyl group; Preferably, the method for preparing compound VI satisfies one or more of the following conditions: (1)R 1 For 1, 2 or 3 R 1-1 Substituted C6-C 10 for example, (2)R 1-1 for nitro; (3)R 2 is C3-C6 cycloalkyl, 1, 2 or 3 R 2-2 Substituted C1-C6 alkyl or C2-C6 alkenyl; for example, (4) X is -NR 3 R 4 Preferably, R 3 and R 4 The nitrogen attached to it forms (5)R 2-2 Each independently is 1, 2 or 3 R 2c Substituted "heteroatoms selected from 1, 2 or 3 of N, O and S, 3-10 membered heterocycloalkyl with 1 or more heteroatoms" or 1, 2 or 3 R 2d Substituted C6-C 10 The aromatic group; (6)R 2c Each is independently a C1-C6 alkoxy group; (7)R 2d Each is independently a C1-C6 alkoxy group; (8)R 7 is C1-C6 alkyl, 1, 2 or 3 R 7-1 Substituted C1-C6 alkyl, 1, 2 or 3 R 7-3 Substituted C2-C6 alkenyl, 1, 2 or 3 R 7-4 Substituted C2-C6 alkynyl or 1, 2 or 3 R 7-5 Substituted C6-C 10 for example, (9)R 7-1 Each independently is C6-C 10 or 1, 2 or 3 R 7a Substituted C6-C 10 The aromatic group; (10)R 7-3 Each independently is C6-C 10 or 1, 2 or 3 R 7a Substituted C6-C 10 The aromatic group; (11)R 7-4 Each independently is C6-C 10 The aromatic group; (12)R 7a Each independently is a C1-C6 alkyl, a C1-C6 alkoxy or a C6-C 10 The aromatic group; (13) In the method for preparing compound VI, the solvent is an organic solvent; preferably an ether solvent; for example, tetrahydrofuran; (14) In the method for preparing compound VI, the molar ratio of compound IV to compound V is 1:(2-6); for example, 1:4; (15) In the method for preparing compound VI, the compound IV and the t The molar ratio of BuMgCl is 1:(2-6); for example, 1:4; (16) In the preparation method of compound VI, the molar volume ratio of compound IV to the solvent is 1 mmol:(10-16) mL; for example, 1 mmol:12 mL; (17) In the method for preparing compound VI, the reaction temperature is 15°C-35°C; preferably 20°C-30°C; (18) In the preparation method of compound VI, the reaction time is 20 min-60 min; preferably 30 min; (19) In the method for preparing compound VI, the reaction further comprises the following post-treatment steps: quenching, extraction, concentration and column chromatography separation; the quenching can be quenching with water; the extraction can be extraction with ethyl acetate; (21) In the preparation method of compound VI, the raw materials of the reaction are the solvent, t BuMgCl, the compound IV and the compound V; and (22) The method for preparing compound VI also includes a method for preparing compound IV, wherein the method for preparing compound IV is as described in any one of claims 1 to 4.

6. The method for preparing compound VI according to claim 5, characterized in that: It meets one or more of the following conditions; (1) Compound IV is (2) Compound V is BnOH, (3) Compound VI is 7. A method for preparing compound VIII, characterized in that: It includes the following steps: Step (1): Preparation method of compound IV, The preparation method of compound IV is as described in any one of claims 1 to 4; Step (2): Compound IV and Compound VII are reacted in a solvent in the presence of an acid to prepare Compound VIII; Among them, compound R 1 , R 2 and X is defined as in any one of claims 1 to 6; R 8 is a C1-C6 alkyl group; Preferably, the method for preparing compound VIII satisfies one or more of the following conditions: (1)R 1 For 1, 2 or 3 R 1-1 Substituted C6-C 10 for example, (2)R 2 is a C3-C6 cycloalkyl group; (3)R 3 and R 4 The nitrogen attached to it forms (4)R 8 is C1-C6 alkyl; for example, methyl or (5) In step (2), the solvent is a mixed organic solvent; preferably a mixed solvent of an alcohol solvent and an alkane solvent; the alcohol solvent may be methanol; the alkane solvent may be dichloromethane; (6) In step (2), the volume ratio of the alcohol solvent to the alkane solvent is 1:(0.8-1.5); for example, 1:1; (7) In step (2), the acid is an organic acid; preferably a fluorine-containing organic acid, for example, trifluoromethanesulfonic acid; (8) In step (2), the molar volume ratio of compound IV to compound VII is 1:(10-120); preferably 1:74 or 1:100; (9) In step (2), the molar ratio of compound IV to the acid is 1:(2-5); preferably 1:3; (10) In step (2), the reaction temperature is 40-60°C, preferably 50°C; (11) In step (2), the reaction time is 20-24 h; preferably 22 h; and (12) The preparation method of step (2) further comprises the following post-treatment steps: concentration and column chromatography.

8. The method for preparing compound VIII according to claim 7, characterized in that: It meets one or more of the following conditions; (1) Compound IV is (2) Compound VII is methanol or and (3) Compound VIII is 9. A method for preparing compound IX, characterized in that: It includes the following steps: Step (1): Preparation method of compound IV: The preparation method of compound IV is as described in any one of claims 1 to 4; Step (3): Compound IV is reacted in a solvent in the presence of a base to prepare Compound IX; Among them, R 2 and X is defined as in any one of claims 1 to 4; Preferably, in the preparation method of compound IX, R 2 is a C1-C6 alkyl group or a C3-C6 cycloalkyl group; for example, 10. The method for preparing compound IX according to claim 9, characterized in that: It meets one or more of the following conditions; (1) Compound IV is (2) Compound IX is (3) In step (3), the solvent is an organic solvent; preferably an ether solvent, for example, tetrahydrofuran; (4) In step (3), the base is an organic base; for example, an organic lithium metal base; preferably phenyllithium; (5) In step (3), the molar ratio of compound IV to base is 1:(3-5); preferably 1:4.3; (6) In step (3), the molar volume ratio of compound IV to solvent is 1 mmol:(3-7) mL; for example, 1 mmol:5 mL; (7) In step (3), the reaction temperature is 15-40°C; preferably 20-30°C; (8) In step (3), the reaction time is 25-45 h; preferably 33 h; and (9) The preparation method of step (3) further comprises the following post-treatment steps: quenching, extraction, concentration and column chromatography separation; the quenching may be quenching with water; the extraction may be extraction with ethyl acetate.

11. A compound as shown below:

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