Synthetic method of alpha-fully substituted large steric hindrance aldehyde

Abstract

The invention relates to a synthesis method of alpha-full-substituted large steric hindrance aldehyde. The invention provides a preparation method of a compound B. The preparation method comprises the following step: reacting a compound as shown in a formula I with a compound A to generate the compound B. The synthesis method is simple to operate, free of transition metal catalysis and additives, atom-economical and environment-friendly; good reactivity and relatively high yield are achieved; the reaction post-treatment is simple, and large-scale production can be realized.

Description

Technical Field

[0001] This invention relates to a method for synthesizing α-fully substituted sterically hindered aldehydes. Background Technology

[0002] Aldehyde α-fully substituted sterically hindered aldehydes are aldehydes in which the α-carbon (the tertiary carbon center substituted with oxygen, nitrogen, or sulfur at the α-position) is entirely replaced by a sterically hindered group. The aldehyde group is a key pharmacodynamic group, widely found in anti-infective and antitumor drugs. However, despite their inherent reactivity conferring therapeutic activity, metabolic instability and the risk of off-target effects due to covalent binding limit the application of these compounds in the pharmaceutical field. In drug design, introducing steric hindrance at the α-position through methyl substitution can effectively suppress off-target interactions while preserving therapeutic function. J. Med. Chem 2020, 63 , 14357). Meanwhile, the literature ( J. Am. Chem. Soc. 2025, 147 The journal 31662 disclosed sterically hindered aldehydes, including tertiary aldehydes and quaternary aldehydes with alkyl substitutions, which are commonly found in pharmaceuticals, such as the antitumor drug guanosine and diterpenoids used as appetite suppressants. Although sterically hindered aldehydes have pharmacological relevance, there is a lack of universally applicable methods for the direct synthesis of these structures, limiting their exploration and application in drug discovery. Furthermore, the aldehyde group, as a very basic organic functional group, allows for efficient conversion of products into other high-value products through classical reduction, oxidation, and reductive amination methods.

[0003] Currently, the methods for preparing α-fully substituted sterically hindered aldehydes mainly fall into two categories: the first is the α-functionalization of aldehydes, including enamine activation, Brønsted base activation, metal catalysis, and enamine-metal dual catalytic activation, etc. Molecules 2023, 28 , 2694); the second is the radical hydroformylation of olefins ( J. Am. Chem. Soc. 2025, 147 (31662). However, the former method involves high catalyst usage for enamine catalysis, poor compatibility of the dual-catalysis system, and some reactions rely on toxic reagents or expensive metals and ligands. The latter method requires light and catalysts to initiate free radical processes to promote the reaction, resulting in poor atom economy and environmental unfriendliness. Furthermore, both methods significantly reduce yields or make synthesis difficult when synthesizing aldehydes substituted with α-sterically hindered groups (such as adamantyl). Therefore, the development of efficient, environmentally friendly, and substrate-wide synthetic methods is urgently needed. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the shortcomings of existing technologies in synthesizing aldehydes with significantly reduced yields or difficulty in synthesis when α-substituted with large sterically hindered groups. Therefore, this invention provides a method for synthesizing α-fully substituted sterically hindered aldehydes. This method is simple to operate, requires no transition metal catalysis, requires no additives, is atom-economical and environmentally friendly; it exhibits good reactivity and high yield; and it is simple to process after the reaction and can be scaled up for production.

[0005] The present invention solves the above-mentioned technical problems through the following technical solution: The present invention provides a method for preparing compound B, which includes the following steps: reacting a compound as shown in Formula I with compound A to generate compound B; ; When compound A is XN3, compound B is compound B-1. ; When compound A is HR 3 When compound B is compound B-2 ; When compound A is PhSY, compound B is compound B-3. ; X is either Na or K; Y is Na or K; R 1 C 1-10 Alkyl, C 5-16 cycloalkyl, with one or more R 1-1 Replacement C 1-10 Alkyl, or, by one or more R 1-2 Replacement C 5-16 cycloalkyl; R 2 C 5-16 cycloalkyl, C 3-12 cycloalkyl-C 6-12 aryl, with one or more R 2-1 Replacement C 1-10 Alkyl, or, by one or more R 2-2 Replacement C 5-16 cycloalkyl; R 1-1 and R 2-1 Each independently is C 6-12 Aryl; R 1-2 and R 2-2 Each is independently a halogen or C 1-6 alkyl; Or R 1 and R 2 Together with the carbon atom it is attached to, they form a C5-24 cycloalkyl, or, by one or more R a Replacement C 5-24 cycloalkyl; R a Independently for C 1-10 Alkyl or C 1-10 Alkoxy; R 3 C 1-6 Alkoxy, 5-16 membered heterocyclic alkyl, with one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2 -NR 3-3 R 3-4 Or 5-16-membered heteroaryl; the 5-16-membered heterocyclic alkyl group and the group with one or more R 3-1 In the 5-16-membered heterocyclic alkyl group that replaces the heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; in the 5-16-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 3-1 Independently 5-16 membered heteroaryl, or by one or more R 3-1-1 Substituted 5-16 heteroaryl groups; the 5-16 heteroaryl group and the group substituted with one or more R groups 3-1-1 In the substituted 5-16 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 3-2 It is a 5-16 membered heteroaryl group, or is composed of one or more R groups. 3-2-1 Substituted 5-16 heteroaryl groups; the 5-16 heteroaryl group and the group substituted with one or more R groups 3-2-1 In the substituted 5-16 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 3-1-1 and R 3-2-1 Each independently is C 1-6 Alkyl or oxo (=O); R 3-3 For H or C 1-6 alkyl; R 3-4 for ; L 1 For -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 1One or both of the -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- mentioned above are optionally represented by -X. 1 -replace; X 1 -O-, -S-, or -CHR 3-4-1 -; R 3-4-1 C 6-12 aryl, or, by one or more R 3-4-1-1 Replacement C 6-12 Aryl; Ring A is C 6-12 aryl, or, by one or more R 3-4-2 Replacement C 6-12 Aryl; R 3-4-1-1 and R 3-4-2 Each independently constitutes a halogen, C 1-6 Alkyl groups, or C groups substituted with one or more halogens 1-6 alkyl.

[0006] In one embodiment, certain groups in the compound are defined as follows, and other groups are defined as in any embodiment of the present invention (hereinafter referred to as "in one embodiment").

[0007] In one scheme, the C 1-10 Alkyl group is C 1-8 Alkyl; preferably C 1-4 Alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or heptyl; and for example, methyl or heptyl.

[0008] In one scheme, the C 5-16 Cycloalkyl group is C 5-12 cycloalkyl; preferably C 5-6 Monocycloalkyl or C 8-12 Bridged cycloalkyl groups; for example or .

[0009] In one scheme, the C 3-12 cycloalkyl-C 6-12 The aryl group is C 3-6 cycloalkyl-C 6-12 Aryl; preferably C 5-6 cycloalkyl-C 6-10 Aryl, for example .

[0010] In one scheme, the C 6-12 The aryl group is either phenyl or naphthyl.

[0011] In one embodiment, the halogen is fluorine, chlorine, bromine, or iodine.

[0012] In one scheme, the C 5-24 Cycloalkyl group is C 5-17 Monocycloalkyl or C 8-20 cycloalkyl; for example , or .

[0013] In one scheme, the C 1-10 The alkoxy group is C 1-6 Alkoxy; preferably methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy or ethoxy.

[0014] In one scheme, the C 1-6 The alkoxy group is C 1-4 Alkyl group; preferably methoxy, ethoxy, propoxy, isopropoxy or n-butoxy; for example methoxy or ethoxy.

[0015] In one scheme, the C 1-6 Alkyl group is C 1-4 Alkyl; preferably methyl, ethyl, propyl, isopropyl or n-butyl; for example, methyl.

[0016] In one embodiment, the 5-16 membered heterocyclic alkyl group is a 5-12 membered heterocyclic alkyl group; preferably a 5-6 membered heterocyclic alkyl group, wherein the heteroatom in the 5-16 membered heterocyclic alkyl group is preferably one or both of N and O, and the number of heteroatoms is preferably 1 or 2; for example .

[0017] In one embodiment, the 5-16-membered heteroaryl group is a 5-12-membered heteroaryl group; preferably a 5-10-membered heteroaryl group, wherein the heteroatom in the 5-16-membered heteroaryl group is preferably one or both of N and O, and the number of heteroatoms is preferably 1 or 2; for example or .

[0018] In a certain scheme, X is N.

[0019] In one particular scheme, Y is K.

[0020] In one particular scheme, R 1 C 1-10 Alkyl or C 5-16 Cycloalkyl.

[0021] In one particular scheme, R 2 C 5-16 cycloalkyl, C 3-12 cycloalkyl-C6-12 aryl, or, by one or more R 2-1 Replacement C 1-10 alkyl.

[0022] In one particular scheme, R 2-1 Independently for C 6-12 Aryl.

[0023] In one particular scheme, R 1 and R 2 Together with the carbon atom it is attached to, they form a group consisting of one or more R atoms. a Replacement C 5-24 Cycloalkyl.

[0024] In one particular scheme, R 3 C 1-6 Alkyl group, by one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2 or -NR 3-3 R 3-4 .

[0025] In one particular scheme, R 3-1 It is independently a 5-16 aryl heteroaryl group.

[0026] In one particular scheme, R 3-2 For one or more R 3-2-1 Substituted 5-16 heteroaryl groups.

[0027] In one particular scheme, R 3-3 C 1-6 alkyl.

[0028] In one of the schemes, L 1 It is -(CH2)4-, L 1 The two -CH2- groups in -(CH2)4- described above are optionally replaced by -X 1 -replace.

[0029] In one of the plans, X 1 -O- or -CHR 3-4-1 -

[0030] In one particular scheme, R 3-4-1 C 6-12 Aryl.

[0031] In a certain scheme, ring A is bounded by one or more R... 3-4-2 Replacement C 6-12 Aryl; In one particular scheme, R 3-4-2 Independently for C substituted with one or more halogens 1-6 alkyl.

[0032] In one particular scheme, R 1 Methyl, ethyl or .

[0033] In one particular scheme, R 2 for , , or .

[0034] In one particular scheme, R 1 and R 2 Together , or .

[0035] In one particular scheme, R 3 for , , or .

[0036] In a certain scheme, the compound shown in Formula I is any of the following compounds: , , , , , , or .

[0037] In one embodiment, compound A is any of the following compounds: NaN3, PhSK, EtOH, , or .

[0038] In one embodiment, compound B-1 is any of the following compounds: , , , , , , or .

[0039] In one embodiment, compound B-2 is any of the following compounds: , , or .

[0040] In one embodiment, compound B-3 is... .

[0041] In one embodiment, the reaction is carried out in the presence of a solvent.

[0042] The solvent can be a conventional solvent in the art. In one embodiment, the solvent is one or more of amide solvents, alcohol solvents, and nitrile solvents. The preferred amide solvent is DMF; The preferred alcohol solvent is ethanol; The preferred nitrile solvent is acetonitrile.

[0043] In one embodiment, when compound A is XN3, the solvent is an amide solvent.

[0044] In one embodiment, when compound A is PhSY, the solvent is an alcohol solvent.

[0045] In one embodiment, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.01-0.3) mol / L; preferably (0.01-0.2) mol / L.

[0046] In one embodiment, when compound A is XN3, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.02-0.2) mol / L; for example, 0.02 mol / L, 0.04 mol / L, 0.08 mol / L, or 0.2 mol / L.

[0047] In one embodiment, when compound A is PhSY, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.01-0.04) mol / L; for example, 0.02 mol / L.

[0048] In one embodiment, when compound A is HR 3 R 3 It is a 5-16 membered heterocyclic alkyl group, surrounded by one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2 -NR 3-3 R 3-4 When the compound is a 5-16 member heteroaryl group, the solvent is a nitrile solvent; preferably, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.02-0.06) mol / L; for example, 0.028 mol / L, 0.032 mol / L or 0.04 mol / L.

[0049] In one embodiment, the molar ratio of the compound shown in Formula I to compound A is 1:(0.8-4); preferably 1:(1-3); for example, 1:1.2, 1:1.25, 1:1.3, 1:1.6, 1:1.8 or 1:2.5.

[0050] In one embodiment, when compound A is HR 3 R 3 C 1-6 When alkoxy is involved, the solvent in the reaction is used in the form of compound A; preferably, the molar volume ratio of the compound as shown in Formula I to compound A is (0.02-0.05) mol / L; for example, 0.04 mol / L.

[0051] In one embodiment, the reaction temperature is 60~120℃; preferably 70~110℃; for example 80℃ or 100℃.

[0052] The reaction process can be monitored using conventional testing methods in the art (such as TLC, HPLC, GC, or NMR), and the reaction endpoint is generally defined as when the compound shown in Formula I no longer reacts. In one embodiment, the reaction time is 2-24 hours, for example, 3 hours, 12 hours, or 16 hours.

[0053] In one embodiment, when compound A is XN3, the preparation method is method 1, which includes the following steps: reacting compound A as shown in formula I with compound A in the amide solvent to obtain compound B-1.

[0054] In one embodiment, the reactants of method 1 are the amide solvent, the compound as shown in formula I, and compound A.

[0055] In one scheme, when compound A is HR 3 When the solvent is a nitrile solvent, the reaction is carried out under alkaline conditions.

[0056] The alkaline reagent is preferably an alkali metal carbonate, such as K2CO3 or Cs2CO3.

[0057] Preferably, the molar ratio of the compound as shown in Formula I to the basic reagent is 1:(0.8-3); more preferably 1:(1-2); for example, 1:1.25, 1:1.6 or 1:1.8.

[0058] In one embodiment, when compound A is HR 3 R 3 It is a 5-16 membered heterocyclic alkyl group, surrounded by one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2-NR 3-3 R 3-4 When the compound is a 5-16 member heteroaryl group, the preparation method is method 2, which includes the following steps: reacting the compound shown in Formula I with compound A in the nitrile solvent and in the presence of the alkaline reagent to obtain compound B-2.

[0059] In one embodiment, the reactants of method 2 are the nitrile solvent, the basic reagent, the compound as shown in Formula I, and compound A.

[0060] In one embodiment, when compound A is HR 3 R 3 C 1-6 When alkoxy is involved, the preparation method is method 3, which includes the following steps: reacting the compound shown in Formula I with compound A to obtain compound B-2.

[0061] In one embodiment, the reactants of method 3 are the compound shown in Formula I and compound A.

[0062] In one embodiment, when compound A is PhSY, the preparation method is method 4, which includes the following steps: reacting compound A as shown in formula I with compound B in the alcohol solvent to obtain compound B-3.

[0063] In one embodiment, the reactants of method 4 are the alcohol solvent, the compound as shown in Formula I, and compound A.

[0064] In one embodiment, when compound B is compound B-1, the reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled (to room temperature), an ester solvent (e.g., ethyl acetate) and water are added for extraction (preferably three times), washing (e.g., washing with saturated brine), drying (e.g., drying with anhydrous sodium sulfate), filtration, concentration of the obtained organic phase, and column chromatography (e.g., using petroleum ether and ethyl acetate as the eluent) to obtain compound B-1.

[0065] In one embodiment, when compound B is compound B-2 or compound B-3, the reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled (to room temperature) and concentrated, and the crude product is subjected to column chromatography (e.g., the elution solvent is petroleum ether and ethyl acetate) to obtain compound B-2 or compound B-3.

[0066] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0067] The reagents and raw materials used in this invention are all commercially available.

[0068] The positive and progressive effects of this invention are as follows: the synthesis method of this invention is simple to operate, requires no transition metal catalysis, requires no additives, is atom-economical and environmentally friendly; it has good reactivity and high yield; the post-reaction processing is simple and can be scaled up for production.

[0069] the term

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0071] In this article, the chemical structural formula Indicates the connection location.

[0072] In chemical structures, wedge-shaped solid lines are used ( ) and wedge-shaped dashed key ( ) represents the absolute configuration of a solid center, key " " "No configuration is specified, meaning that if configurational isomerism exists in the chemical structure, the bond..." " "can be " "or" , or both contain " "and" "Two configurations (e.g., " "and" The ratio is 1:1.

[0073] The term "one or more" refers to one, two, or three.

[0074] The term "halogen" is F, Cl, Br, or I, for example, F.

[0075] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C1-4, C1-6, C1-C8, C1-C). 10 Alkyl groups are straight-chain or branched alkyl groups. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0076] The term "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C15, C25, C35, C45, C5 ... 3-6 C3-C 12 C5-C 16 Or C5-C 24 Rings can be saturated monocyclic or polycyclic rings composed solely of carbon atoms. When polycyclic, they can be connected by fused rings or bridged rings. For example... or wait.

[0077] The term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-). 12 Or C6- 10 ), a cyclic aromatic group consisting only of carbon atoms, which can be monocyclic or polycyclic (e.g., when it is bicyclic, each ring satisfies Hückel's rule). Examples of aryl groups include, but are not limited to, phenyl or naphthyl.

[0078] The term "cycloalkylaryl" refers to a group formed by the fusion of a cycloalkyl group and an aryl group (sharing two adjacent carbon atoms), where "cycloalkyl" and "aryl" are as described above.

[0079] The term "alkoxy group" refers to an alkoxy group having a specified number of carbon atoms (e.g., C1-4, C1-6, or C1-4). 1-10 Alkoxy groups are straight-chain or branched alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0080] The term "heterocyclic alkyl" refers to a saturated cyclic group having heteroatoms, which can be monocyclic or polycyclic, preferably containing one, two, or three 5-16 membered (e.g., 5-12 or 5-6 membered) saturated groups independently selected from N, O, and S cyclic heteroatoms. Examples of heterocyclic alkyl groups are: .

[0081] The term "heteroaryl" refers to a cyclic aromatic group containing heteroatoms, which can be monocyclic or polycyclic (e.g., when it is bicyclic or tricyclic, at least one ring satisfies Hückel's rule). Preferably, it contains 1-3 heteroaryl groups (5-16, 5-12, or 5-10) that are independently selected from N, O, and S. It has, but is not limited to, […]. or . Detailed Implementation

[0082] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0083] Example 1

[0084] 1. Synthesis of α-azido, α-adamantylbutanal

[0085] Procedure: Weigh fluorinated epoxy 1 (44 mg, 0.2 mmol) into a 25 mL round-bottom flask, add 5 mL DMF and sodium azide (16 mg, 0.25 mmol), heat to 100 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL ethyl acetate, extract three times with 10 mL water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain target product 2 (47 mg, 95% yield).

[0086] 1 H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 2.19–2.08 (m, 1H), 2.06–1.96 (m, 3H), 1.85–1.75 (m, 4H), 1.72–1.60 (m, 9H), 0.91 (t, J = 7.4 Hz, 3H). 13 CNMR (126 MHz, CDCl3) δ 202.3, 79.0, 42.6, 37.2, 36.7, 28.4, 21.4, 8.6. HRMS(FI, m / z) calcd for C 14 H 22 ON3[M+H] + : 248.1757, found: 248.1754.

[0087] Example 2

[0088] 2. Synthesis of α-azido, α-adamantylpropionaldehyde

[0089] Procedure: Weigh 80 mg (0.4 mmol) of fluorinated epoxy 3 into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (32 mg, 0.5 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, extract three times with 10 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 4 (82 mg, 93% yield).

[0090] 1H NMR (600 MHz, CDCl3) δ 9.67 (s, 1H), 2.03–1.98 (m, 3H), 1.77–1.73 (m, 3H), 1.72–1.68 (m, 3H), 1.64–1.60 (m, 6H), 1.35 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 201.4, 75.2, 40.1, 36.8, 36.8, 28.4, 12.7. HRMS (FI) calcd forC 13 H 20 ON3[M+H] + : 234.1601, found: 234.1595.

[0091] Gram-scale reaction procedure: Weigh 1.05 g (5 mmol) of fluorinated epoxy 3 into a 250 mL round-bottom flask, add 25 mL of DMF and sodium azide (390 mg, 6 mmol), heat to 80 °C and stir for 20 hours. After the reaction is complete, cool to room temperature, add 30 mL of ethyl acetate, extract three times with 40 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 4 (820 mg, 70% yield).

[0092] Example 3

[0093] Synthesis of α-azide, α,α-dicyclohexylacetaldehyde

[0094] Procedure: Weigh 45 mg (0.2 mmol) of fluorinated epoxy 5 into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, extract three times with 10 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 6 (43 mg, 86% yield).

[0095] 1H NMR (500 MHz, CDCl3) δ 9.51 (s, 1H), 1.99–1.89 (m, 2H), 1.88–1.73 (m, 6H), 1.70–1.64 (m, 2H), 1.62–1.55 (m, 2H), 1.32–1.18 (m, 6H), 1.18–1.10(m, 2H), 1.10–1.04 (m, 2H). 13 C NMR (126 MHz, CDCl3) δ 202.4, 78.1, 41.7,28.0, 27.0, 26.6, 26.5, 26.3. HRMS (FI, m / z) calcd for C 14 H 24 ON3[M+H] + :250.1914, found: 250.1912.

[0096] Example 4

[0097] Synthesis of (1-azido-2-heptylcyclopentyl)methane

[0098] Procedure: Weigh fluorinated epoxy 7 (43 mg, 0.2 mmol) into a 25 mL round-bottom flask, add 5 mL DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL ethyl acetate, extract three times with 10 mL water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to obtain the target product 8 (47 mg, 99% yield, dr = 1.8:1.0).

[0099] 1 H NMR (500 MHz, CDCl3) δ 9.57 (s, 0.35H), 9.47 (s, 0.65H), 2.21–1.98(m, 3H), 1.97–1.76 (m, 3H), 1.55–1.44 (m, 1H), 1.36–1.15 (m, 12H), 0.86 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3) isomer1: δ 199.8, 79.8, 47.9, 33.1,31.9, 30.8, 29.9, 29.3, 29.2, 28.8, 22.8, 22.6, 14.2; isomer2: δ 200.1, 78.4,50.7, 32.7, 31.9, 31.4, 30.1, 29.7, 29.2, 28.8, 23.0, 22.8, 14.2. HRMS (FI,m / z) calcd for C 13 H 23 ON[M-N2]: 209.1774, found: 209.1768.

[0100] Example 5

[0101] Synthesis of 2-azido-2-(2,3-dihydro-1H-inden-2-yl)propionaldehyde

[0102] Procedure: Weigh 38 mg (0.2 mmol) of fluorinated epoxy 9 into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, extract three times with 10 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 100:1) to obtain the target product 10 (43 mg, 99% yield).

[0103] 1 H NMR (600 MHz, CDCl3) δ 9.59 (s, 1H), 7.24–7.12 (m, 4H), 3.09–2.92 (m, 4H), 2.89–2.81 (m, 1H), 1.48 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 199.0,141.8, 141.3, 126.8, 126.7, 124.5, 124.5, 71.3, 44.5, 33.8, 33.6, 17.2. HRMS(FI, m / z) calcd for C 12 H 13 ON3: 215.1053, found: 215.1052.

[0104] Example 6

[0105] Synthesis of [(1S,3aS,3bR,5aS,7R,9aS,9bS,9S,11aS)-7-azido-1-methoxy-9,9a,11a-trimethylhexadecyl-1H-cyclopentano[1,2-a]phenanthrene-7-yl]methanealdehyde

[0106] Procedure: Weigh 35 mg (0.1 mmol) of fluorinated epoxy 11 into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, and extract three times with 10 mL of water. Wash with saturated brine, dry to anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target product 12 (20 mg, 54% yield, dr > 20:1).

[0107] 1 H NMR (500 MHz, CDCl3) δ 9.37 (s, 1H), 3.33 (s, 3H), 3.22 (t, J = 8.3Hz, 1H), 2.08 (dd, J = 15.0, 5.7 Hz, 1H), 2.03–1.95 (m, 1H), 1.91–1.86 (m,1H), 1.85–1.78 (m, 1H), 1.68–1.62 (m, 2H), 1.60–1.53 (m, 2H), 1.48–1.38 (m,4H), 1.34–1.27 (m, 2H), 1.24–1.14 (m, 4H), 1.10 (d, J = 7.4 Hz, 3H), 1.00–0.82 (m, 6H), 0.74 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 198.5, 90.8, 69.4,58.0, 51.4, 48.4, 43.1, 38.0, 37.7, 35.4, 34.5, 32.9, 31.8, 31.1, 30.0, 28.3,27.7, 23.4, 20.1, 14.9, 14.3, 11.8.

[0108] Example 7

[0109] Synthesis of (1-azido-3-methylcyclopentadecanyl)methanealdehyde

[0110] Procedure: Weigh 51 mg (0.2 mmol) of fluorinated epoxy 13 into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, extract three times with 10 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 14 (52 mg, 93% yield, dr = 1.3:1).

[0111] 1 H NMR (600 MHz, CDCl3) δ 9.47 (s, 0.44H), 9.45 (s, 0.56H), 1.80–1.59 (m, 4H), 1.52–1.16 (m, 23H), 0.99 (d, J = 6.6 Hz, 1.7H), 0.83 (d, J = 6.4 Hz, 1.3H). 13 C NMR (151 MHz, CDCl3) δ 199.0, 198.8, 71.9, 71.4, 39.7, 37.8, 36.9,35.9, 32.0, 30.2, 27.5, 27.4, 27.3, 27.2, 27.1, 27.1, HRMS (FI, m / z) calcd for C 17 H 31 ON[M-N2]: 265.2400, found: 265.2397.

[0112] Example 8

[0113] Synthesis of 2-(phenylthio)-2-adamantylpropionaldehyde

[0114] Procedure: Weigh 20 mg (0.1 mmol) of fluorinated epoxy 3 into a 25 mL round-bottom flask, add 5 mL of ethanol and potassium thiophene (19 mg, 0.13 mmol), heat to 80 °C and stir for 3 hours. After the reaction is complete, cool to room temperature and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 15 (28 mg, 98% yield).

[0115] 1 H NMR (600 MHz, CDCl3) δ 9.79 (s, 1H), 7.30–7.15 (m, 5H), 2.00–1.95 (m, 3H), 1.96–1.90 (m, 3H), 1.74–1.69 (m, 3H), 1.63 (q, J = 12.3 Hz, 6H), 0.92 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 196.4, 137.8, 129.8, 129.4, 129.0,67.1, 38.8, 37.7, 37.0, 28.7, 13.9. HRMS (FI, m / z) calcd for C 19 H 24 OS:300.1542, found: 300.1540.

[0116] Example 9

[0117] Synthesis of 2-azido-2-methyl-4-phenylbutanal

[0118] Procedure: Weigh 36 mg (0.2 mmol) of fluorinated epoxy 16 into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, extract three times with 10 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 17 (40 mg, 99% yield).

[0119] 1H NMR (500 MHz, CDCl3) δ 9.45 (s, 1H), 7.32–7.27 (m, 2H), 7.23–7.15 (m, 3H), 2.77–2.68 (m, 1H), 2.64–2.56 (m, 1H), 2.09–2.03 (m, 1H), 1.97–1.89(m, 1H), 1.44 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 199.0, 140.7, 128.8, 128.5,126.5, 69.4, 37.7,30.0, 19.2. HRMS (FI, m / z) calcd for C 11 H 13 ON3: 203.1053, found: 203.1051.

[0120] Example 10

[0121] Synthesis of 2-ethoxy-2-methyl-4-phenylbutanal

[0122] Procedure: Weigh 36 mg (0.2 mmol) of fluoroepoxide 16 into a 25 mL round-bottom flask, add 5 mL of ethanol, heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 18 (40 mg, 97% yield).

[0123] 1 H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.33–7.07 (m, 5H), 3.58–3.36 (m, 2H), 2.81–2.49 (m, 2H), 2.02–1.81 (m, 2H), 1.29–1.18 (m, 6H). 13 C NMR (126MHz, CDCl3) δ 205.5, 141.8, 128.6, 128.4, 126.1, 82.1, 59.5, 36.9, 29.4,18.5, 16.1. HRMS (EI Positive, m / z) calcd for C 13 H 18 O2Na [M+Na] + : 229.1199, found: 229.1197.

[0124] Example 11

[0125] Synthesis of 2-methyl-4-phenyl-2-[4-(pyridin-2-yl)piperazin-1-yl]butyraldehyde

[0126] Procedure: Weigh fluorinated epoxy 16 (25 mg, 0.14 mmol) into a 25 mL round-bottom flask, dissolve it in 5 mL of acetonitrile, then add 19 (41 mg, 0.25 mmol) and K2CO3 (35 mg, 0.25 mmol) sequentially. Heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain the target product 20 (37 mg, 82% yield).

[0127] 1 H NMR (500 MHz, CDCl3) δ 9.62 (s, 1H), 8.25–8.17 (m, 1H), 7.52–7.46 (m, 1H), 7.31–7.26 (m, 2H), 7.23–7.14 (m, 3H), 6.68–6.61 (m, 2H), 3.66–3.52(m, 4H), 2.81–2.75 (m, 2H), 2.70–2.63 (m, 1H), 2.61–2.52 (m, 3H), 2.00–1.86(m, 2H), 1.16 (s, 3H). 13 C NMR (126 MHz, CDCl3) δ 205.6, 159.6, 148.1, 141.9,137.6, 128.6, 128.3, 126.2, 113.6, 107.2, 67.7, 46.5, 46.0, 36.7, 30.1, 13.1.HRMS (ESI Positive, m / z) calcd for C 20 H 26 ON3 [M+H] + : 324.2070, found: 324.2074.

[0128] Example 12

[0129] Synthesis of {3-methyl-1-[(4-methyl-2-oxomylidene-6-yl)thio]cyclopentadecanyl}methane

[0130] Procedure: Weigh fluorinated epoxy 13 (42 mg, 0.16 mmol) into a 25 mL round-bottom flask, dissolve it in 5 mL of acetonitrile, then add 13 (48 mg, 0.25 mmol) and Cs₂CO₃ (82 mg, 0.25 mmol) sequentially. Heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain the target product 16 (46 mg, 67% yield, dr = 2.3:1.0).

[0131] 1 H NMR (500 MHz, CDCl3) δ 9.33 (s, 0.31H), 9.24 (s, 0.69H), 7.52–7.47(m, 1H), 7.34 (d, J = 1.7 Hz, 0.7 H), 7.33 (d, J = 1.7 Hz, 0.3H), 7.24–7.18(m, 1H), 6.31 (d, J = 1.5 Hz) + 6.30 (d, J = 1.5 Hz),1H, 2.41 (s, 3H), 1.82–1.57 (m, 6H), 1.41–1.22 (m, 21H), 0.99 (d, J = 6.5 Hz, 2.1H), 0.77 (d, J =6.0 Hz, 0.9H). 13C NMR (126 MHz, CDCl3) mixture: δ 194.4, 194.3, 160.2, 160.2,153.0, 151.7, 134.6, 133.9, 132.2, 131.6, 124.8, 124.7, 124.6, 124.2, 120.8,120.5, 116.0, 115.9, 77.3, 77.0, 76.8, 65.4, 64.8, 39.9, 37.2, 36.4, 34.8,29.7, 29.5, 28.0, 27.9, 27.3, 27.2, 27.1, 26.9, HRMS (ESI) Positive, m / z) calcd for C 27 H 39 O3S [M+H] + : 443.2614, found:443.2612.

[0132] Example 13

[0133] Synthesis of 2-methyl-2-[methyl(3-phenyl-3-{[4-(trifluoromethyl)phenyl]oxy}propyl)amino]-4-phenylbutanal

[0134] Procedure: Weigh fluorinated epoxy 16 (33 mg, 0.2 mmol) into a 25 mL round-bottom flask, dissolve it in 5 mL of acetonitrile, then add 23 (77 mg, 0.25 mmol) and K2CO3 (35 mg, 0.25 mmol) sequentially. Heat to 80 °C and stir for 12 hours. After the reaction is complete, cool to room temperature and rotary evaporate to obtain the crude product. Separate by 200-300 mesh silica gel column chromatography (petroleum ether / ethyl acetate = 9:1) to obtain the target product 24 (52 mg, 61% yield, dr = 1.3:1.0).

[0135] 1 H NMR (500 MHz, CDCl3) δ 9.43 (s, 0.43H), 9.36 (s, 0.57H), 7.42 (d, J = 8.4 Hz) + 7.37 (d, J= 8.5 Hz), 2H, 7.35–7.29 (m, 4H), 7.28–7.20 (m, 3H),7.20–7.15 (m, 1H), 7.10 (d, J = 7.5 Hz, 1.14H), 7.03 (d, J = 7.4 Hz, 0.86H),6.88 (d, J = 8.4 Hz) + 6.85 (d, J = 8.6 Hz), 2H, 5.40 (dd, J = 9.6, 3.7 Hz) +5.34 (dd, J = 9.2, 3.7 Hz), 1H, 2.90–2.78 (m, 0.43H), 2.63–2.53 (m, 1.57H),2.50–2.37 (m, 2H), 2.31 (s) + 2.29 (s), 3H, 2.17–2.01 (m, 2H), 1.91–1.73 (m,2H), 1.09 (s) + 1.07 (s), 3H. 13 C NMR (126 MHz, CDCl3) mixture: δ 206.1,205.4, 160.6, 160.6, 142.0, 141.9, 141.5, 141.4, 129.0, 128.6, 128.6, 128.3,128.3, 128.0, 128.0, 127.0 (q, J = 3.8 Hz), 126.9 (q, J = 3.8 Hz), 126.2,126.1, 125.9, 125.8, 115.7, δ 124.5 (q, J = 271.1 Hz), 122.9 (q, J = 32.6Hz), 122.8 (q, J = 32.6 Hz), 115.8, 77.6, 77.4, 68.8, 68.6, 48.4, 47.5, 38.0,38.0, 37.6, 36.5, 35.5, 34.5, 30.2, 30.1, 13.3, 12.8. 19 F NMR (376 MHz, CDCl3)δ -61.5, -61.6. HRMS (FI, m / z) calcd for C 28H 31 NO2F3 [M+H] + : 470.2301, found:470.2295.

[0136] Comparative Example 1:

[0137] Procedure: Weigh 45 mg (0.2 mmol) of fluorinated epoxy into a 25 mL round-bottom flask, add 5 mL of DMF and sodium azide (16 mg, 0.25 mmol), heat to 80 °C and stir for 18 hours. After the reaction is complete, cool to room temperature, add 10 mL of ethyl acetate, extract three times with 10 mL of water, wash with saturated brine, dry with anhydrous sodium sulfate, filter, collect the solution phase, and rotary evaporate to obtain the crude product. The NMR yield ratio of A and B was determined to be 1:0.75.

[0138] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for preparing compound B, characterized in that, It includes the following steps: reacting the compound shown in Formula I with compound A to generate compound B; ； When compound A is XN3, compound B is compound B-1. ; When compound A is HR 3 When compound B is compound B-2 ; When compound A is PhSY, compound B is compound B-3. ; X is either Na or K; Y is Na or K; R 1 C 1-10 Alkyl, C 5-16 cycloalkyl, with one or more R 1-1 Replacement C 1-10 Alkyl, or, by one or more R 1-2 Replacement C 5-16 cycloalkyl; R 2 C 5-16 cycloalkyl, C 3-12 cycloalkyl-C 6-12 aryl, with one or more R 2-1 Replacement C 1-10 Alkyl, or, by one or more R 2-2 Replacement C 5-16 cycloalkyl; R 1-1 and R 2-1 Each independently is C 6-12 Aryl; R 1-2 and R 2-2 Each is independently a halogen or C 1-6 alkyl; Or R 1 and R 2 Together with the carbon atom it is attached to, they form a C 5-24 cycloalkyl, or, by one or more R a Replacement C 5-24 cycloalkyl; R a Independently for C 1-10 Alkyl or C 1-10 Alkoxy; R 3 C 1-6 Alkoxy, 5-16 membered heterocyclic alkyl, with one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2 -NR 3-3 R 3-4 Or 5-16-membered heteroaryl; the 5-16-membered heterocyclic alkyl group and the group with one or more R 3-1 In the 5-16-membered heterocyclic alkyl group that replaces the heterocyclic alkyl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; in the 5-16-membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 3-1 Independently 5-16 membered heteroaryl, or by one or more R 3-1-1 Substituted 5-16 heteroaryl groups; the 5-16 heteroaryl group and the group substituted with one or more R groups 3-1-1 In the substituted 5-16 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 3-2 It is a 5-16 membered heteroaryl group, or is composed of one or more R groups. 3-2-1 Substituted 5-16 heteroaryl groups; the 5-16 heteroaryl group and the group substituted with one or more R groups 3-2-1 In the substituted 5-16 heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. R 3-1-1 and R 3-2-1 Each independently is C 1-6 Alkyl or oxo; R 3-3 For H or C 1-6 alkyl; R 3-4 for ; L 1 For -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-, L 1 One or both of the -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- and -(CH2)6- mentioned above are optionally represented by -X. 1 -replace; X 1 -O-, -S-, or -CHR 3-4-1 -; R 3-4-1 C 6-12 aryl, or with one or more R 3-4-1-1 Replacement C 6-12 Aryl; Ring A is C 6-12 aryl, or with one or more R 3-4-2 Replacement C 6-12 Aryl; R 3-4-1-1 and R 3-4-2 Each independently constitutes a halogen, C 1-6 Alkyl groups, or C groups substituted with one or more halogens 1-6 alkyl.

2. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The C 1-10 Alkyl group is C 1-8 Alkyl; preferably C 1-4 Alkyl groups; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or heptyl; and for example, methyl or heptyl. (2) The C 5-16 Cycloalkyl group is C 5-12 cycloalkyl; preferably C 5-6 Monocycloalkyl or C 8-12 Bridged cycloalkyl groups; for example or ; (3) The C 3-12 cycloalkyl-C 6-12 The aryl group is C 3-6 cycloalkyl-C 6-12 Aryl; preferably C 5-6 cycloalkyl-C 6-10 Aryl, for example ; (4) The C 6-12 The aryl group is phenyl or naphthyl; (5) The halogen is fluorine, chlorine, bromine or iodine; (6) The C mentioned 5-24 Cycloalkyl group is C 5-17 Monocycloalkyl or C 8-20 cycloalkyl; for example , or ; (7) The C 1-10 The alkoxy group is C 1-6 Alkyl group; preferably methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy or ethoxy. (8) The C 1-6 The alkoxy group is C 1-4 Alkyl group; preferably methoxy, ethoxy, propoxy, isopropoxy, or n-butoxy; for example, methoxy or ethoxy. (9) The C 1-6 Alkyl group is C 1-4 Alkyl; preferably methyl, ethyl, propyl, isopropyl, or n-butyl; for example, methyl; (10) The 5-16 membered heterocyclic alkyl group is a 5-12 membered heterocyclic alkyl group; preferably a 5-6 membered heterocyclic alkyl group, wherein the heteroatom in the 5-16 membered heterocyclic alkyl group is preferably one or both of N and O, and the number of heteroatoms is preferably 1 or 2; for example ; (11) The 5-16-membered heteroaryl group is a 5-12-membered heteroaryl group; preferably a 5-10-membered heteroaryl group, wherein the heteroatom in the 5-16-membered heteroaryl group is preferably one or two of N and O, and the number of heteroatoms is preferably 1 or 2; for example or .

3. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) R 1 Methyl, ethyl or ; (2) R 2 for , , or ; (3) R 1 and R 2 Together , or ; (4) R 3 for , , or .

4. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The compound shown in Formula I is any of the following compounds: , , , , , , or ; (2) Compound A is any of the following compounds: NaN3, PhSK, EtOH, , or ; (3) The compound B-1 is any of the following compounds: , , , , , , or ; (4) The compound B-2 is any of the following compounds: , , or ; (5) The compound B-3 is .

5. The preparation method according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The reaction is carried out in the presence of a solvent; (2) The molar ratio of the compound shown in Formula I to the compound A is 1:(0.8-4); preferably 1:(1-3); for example 1:1.2, 1:1.25, 1:1.3, 1:1.6, 1:1.8 or 1:2.5; (3) The reaction temperature is 60~120℃; (4) When compound B is compound B-1, the reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled, ester solvent and water are added for extraction, washing, drying, filtering, the obtained organic phase is concentrated, and the obtained crude product is subjected to column chromatography to obtain compound B-1. (5) When compound B is compound B-2 or compound B-3, the reaction further includes the following post-processing steps: after the reaction is completed, the reaction solution is cooled and concentrated, and the crude product is subjected to column chromatography to obtain compound B-2 or compound B-3.

6. The preparation method according to claim 5, characterized in that, It satisfies one or more of the following conditions: (1) When the reaction is carried out in the presence of a solvent, the solvent is one or more of amide solvents, alcohol solvents and nitrile solvents; The preferred amide solvent is DMF; The preferred alcohol solvent is ethanol; The preferred nitrile solvent is acetonitrile; (2) When the reaction is carried out in the presence of a solvent, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.01-0.3) mol / L; preferably (0.01-0.2) mol / L; (3) The reaction temperature is 70~110℃.

7. The preparation method according to claim 5, characterized in that, When compound A is HR 3 R 3 C 1-6 When alkoxy is involved, the solvent in the reaction is used in the form of compound A; preferably, the molar volume ratio of the compound as shown in Formula I to compound A is (0.02-0.05) mol / L; for example, 0.04 mol / L.

8. The preparation method according to claim 6, characterized in that, It satisfies one or more of the following conditions: (1) When the compound A is XN3, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.02-0.2) mol / L; for example, 0.02 mol / L, 0.04 mol / L, 0.08 mol / L or 0.2 mol / L; (2) When compound A is PhSY, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.01-0.04) mol / L; for example, 0.02 mol / L; (3) When compound A is HR 3 R 3 It is a 5-16 membered heterocyclic alkyl group, surrounded by one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2 -NR 3-3 R 3-4 When the compound is a 5-16 member heteroaryl group, the molar volume ratio of the compound as shown in Formula I to the solvent is (0.02-0.06) mol / L; for example, 0.028 mol / L, 0.032 mol / L, or 0.04 mol / L. (4) The reaction temperature is 80℃ or 100℃.

9. The preparation method according to claim 6, characterized in that, It satisfies one or more of the following conditions: (1) When the compound A is XN3, the preparation method is method 1, which includes the following steps: reacting the compound as shown in Formula I with compound A in the amide solvent to obtain the compound B-1; (2) When compound A is HR 3 R 3 It is a 5-16 membered heterocyclic alkyl group, surrounded by one or more R 3-1 Substituted 5-16 membered heterocyclic alkyl groups, -SR 3-2 -NR 3-3 R 3-4 When the compound is a 5-16 member heteroaryl group, the preparation method is method 2, which includes the following steps: in the nitrile solvent, in the presence of an alkaline reagent, the compound shown in Formula I is reacted with compound A to obtain compound B-2; The alkaline reagent is preferably an alkali metal carbonate, such as K2CO3 or Cs2CO3; Preferably, the molar ratio of the compound of Formula I to the basic reagent is 1:(0.8-3); more preferably 1:(1-2); for example, 1:1.25, 1:1.6 or 1:1.8; (3) When compound A is HR 3 R 3 C 1-6 When alkoxy is involved, the preparation method is method 3, which includes the following steps: reacting the compound shown in formula I with compound A to obtain compound B-2; (4) When the compound A is PhSY, the preparation method is method 4, which includes the following steps: reacting the compound shown in Formula I with compound A in the alcohol solvent to obtain the compound B-3.

10. The preparation method according to claim 9, characterized in that, It satisfies one or more of the following conditions: (1) The reactants in Method 1 are the amide solvent, the compound as shown in Formula I, and compound A; (2) The reactants in method 2 are the nitrile solvent, the basic reagent, the compound as shown in formula I, and compound A; (3) The reactants of method 3 are the compound shown in formula I and compound A; (4) The reactants of method 4 are the alcohol solvent, the compound as shown in formula I and compound A.

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