Sulfur-containing artemisinin dimer, preparation method and application thereof

Abstract

The present application relates to a kind of sulfur-containing artemisinin dimers, its preparation method and application, belong to the technical field of pharmaceutical chemistry.The chemical structural formula of the sulfur-containing artemisinin dimers is as the compound represented in formula I or its pharmaceutically acceptable salt: wherein, W is any one of S, SO and SO2;Z is any one of S, SO, SO2, O, NR1 and CR 1 2;Y is any one of single bond, alkyl, aryl, ring group, ether and ammonia;R 1 It is any one of hydrogen, halogen, alkyl, aryl, ring group, ether and ammonia;n and m are each independently selected from the integer of 0-15.The preparation method of the sulfur-containing artemisinin dimers is disclosed.The sulfur-containing artemisinin dimers of the present application have selective inhibitory effect on the growth of human cancer cell strains.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a sulfur-containing artemisinin dimer, its preparation method, and its application. Background Technology

[0002] In the 1970s, artemisinin was extracted from Artemisia annua, and its strong antimalarial effect was confirmed in the laboratory and clinical practice. Based on this structure, a series of derivatives with antimalarial activity were subsequently synthesized or semi-synthesized, such as dihydroartemisinin, artesunate, artemether, and artesyl ether.

[0003] After the antimalarial effects of artemisinin-based drugs were confirmed, research on other biological activities, such as antiparasitic effects, anticancer effects, and immunosuppression, was also carried out.

[0004] Woerdenbag HJ et al. reported that artemisinin, artemether, artesunate, and artesunate have certain cytotoxic effects on Ehrlich Ascites cell lines, with 11,13-dehydroartemisinin showing stronger activity, and the dimer of dihydroartemisinin exhibiting the strongest activity. [1] .

[0005] In search of compounds with higher activity, hundreds of artemisinin-like compounds have been synthesized and screened. In particular, in the last decade, a large number of artemisinin dimers and trimers composed of different linkers have been reported, many of which have strong selective inhibitory effects on the growth of human cancer cell lines.

[0006] However, no reports have been found on sulfur-containing artemisinin dimers. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a sulfur-containing artemisinin dimer, its preparation method, and its application.

[0008] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0009] This invention provides a sulfur-containing artemisinin dimer, the chemical structure of which is a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein, W represents any one of S, SO and SO2;

[0012] Z is represented as: S, SO, SO2, O, NR1, and CR 1 Any one of 2;

[0013] Y represents any one of the following: single bond, alkyl, aryl, cycloyl, ether and ammonia;

[0014] R 1 It is represented as any one of hydrogen, halogen, alkyl, aryl, cycloyl, ether, and ammonia;

[0015] n and m are each independently selected from integers from 0 to 15.

[0016] The beneficial effect of the present invention is that the sulfur-containing artemisinin dimer of the present invention has a selective inhibitory effect on the growth of human cancer cell lines.

[0017] Based on the above technical solution, the present invention can be further improved as follows.

[0018] Furthermore, the sulfur-containing artemisinin dimer or a pharmaceutically acceptable salt of the sulfur-containing artemisinin dimer has any of the following structures:

[0019]

[0020]

[0021]

[0022] Wherein, Y represents any one of the following: single bond, alkyl, aryl, cycloyl, ether and ammonia;

[0023] R 1 It is represented as any one of hydrogen, halogen, alkyl, aryl, cycloyl, ether, and ammonia;

[0024] n and m are each independently selected from integers from 0 to 15.

[0025] Furthermore, Y is represented as: single bond, NR 2 O, S, SO, SO2, SR 2 x PR 2 x C1-C5 heteroalkyl groups, with 1-5 R groups 2 Substituted C1–C5 heteroalkyl, C1–C10 alkyl, with 1–5 R 2 Substituted C1-C10 alkyl, aryl, with 1-5 R 2 Substituted aryl, 3-10 membered cycloalgides, with 1-5 R groups 2 Substituted 3-10 membered cyclic groups, 3-10 membered heterocyclic groups, and substituted with 1-5 R groups 2 Substituted 3- to 10-membered heterocyclic groups, ethers, and those with 1 to 5 R groups 2 Any one of the substituted ethers;

[0026] Wherein, the R2 It is represented as any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cycloyl, ether and ammonia;

[0027] The x is selected from integers from 1 to 4;

[0028] The aryl group is selected from any one of phenyl, pyridyl, pyrazinyl, pyridazinyl, thiophenyl, thiazolyl, naphthyl, pyrroleyl, furanyl, indolyl, quinolinyl, purinyl, and biaryl;

[0029] The 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.

[0030] The cyclic group includes saturated monocyclic groups, unsaturated monocyclic groups, saturated polycyclic group systems, and unsaturated polycyclic group systems. The polycyclic group system includes spiro rings, fused rings, bridged rings, and interlocking rings.

[0031] The heterocyclic group includes saturated monoheterocyclic groups, unsaturated monoheterocyclic groups, saturated polyheterocyclic group systems, and unsaturated polyheterocyclic group systems. The polyheterocyclic group system includes spirocyclic, fused ring, bridged ring, and fused ring.

[0032] The beneficial effect of adopting the above-mentioned further scheme is that it can enrich the structure of Y.

[0033] Furthermore, R 1 Represented as: H, F, Cl, Br, I, CN, NR 2 S, SO, SO2, SR 2 x、PR 2 x, C1-C5 heteroalkyl, surrounded by 1-5 R 2 Substituted C1–C5 heteroalkyl, C1–C10 alkyl, with 1–5 R 2 Substituted C1-C10 alkyl, aryl, with 1-5 R 2 Substituted aryl, 3-10 membered cycloalgides, with 1-5 R groups 2 Substituted 3-10 membered cyclic groups, 3-10 membered heterocyclic groups, and substituted with 1-5 R groups 2 Substituted 3- to 10-membered heterocyclic groups, ethers, and those with 1 to 5 R groups 2 Any one of the substituted ethers;

[0034] Wherein R 2 It is represented as any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cycloyl, ether and ammonia;

[0035] The x is selected from integers from 1 to 4;

[0036] The aryl group is selected from any one of phenyl, pyridyl, pyrazinyl, pyridazinyl, thiophenyl, thiazolyl, naphthyl, pyrroleyl, furanyl, indolyl, quinolinyl, purinyl, and biaryl;

[0037] The 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.

[0038] The cyclic groups include saturated cyclic groups and unsaturated cyclic groups, and also include monocyclic and polycyclic systems. The polycyclic systems include spirocyclic, fused ring, bridged ring and interlocking ring.

[0039] The heterocyclic group includes saturated monoheterocyclic groups, unsaturated monoheterocyclic groups, saturated polyheterocyclic group systems, and unsaturated polyheterocyclic group systems. The polyheterocyclic group system includes spirocyclic, fused ring, bridged ring, and fused ring.

[0040] Furthermore, the sulfur-containing artemisinin dimer has any of the following structures:

[0041]

[0042]

[0043]

[0044]

[0045] A method for preparing the above-mentioned sulfur-containing artemisinin dimer, the reaction equation of which is as follows:

[0046]

[0047] Wherein, W represents any one of S, SO and SO2;

[0048] Z is represented as: S, SO, SO2, O, NR 1 and CR 1 Any one of 2;

[0049] Y represents any one of the following: single bond, alkyl, aryl, cycloyl, ether and ammonia;

[0050] R 1 It is represented as: any one of hydrogen, halogen, alkyl, aryl, cycloyl, ether and ammonia; n and m are each independently selected from: integers from 0 to 15;

[0051] The acid is selected from any one of the following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride diethyl ether complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethylsilyl trifluoromethanesulfonate, and p-toluenesulfonic acid;

[0052] The specific reactions in the above reaction equations are as follows:

[0053] As shown in Equation 1, the compound of Formula II and dihydroartemisinin are dispersed in a solvent, and acid is added dropwise at -78℃ to 25℃ to carry out the reaction, thereby obtaining sulfur-containing artemisinin dimers.

[0054] A method for preparing the above-mentioned sulfur-containing artemisinin dimer, the reaction equation of which is as follows:

[0055]

[0056] Wherein, W represents any one of S, SO and SO2;

[0057] Z is represented as: S, SO, SO2, O, NR1, and CR 1 Any one of 2;

[0058] Y represents any one of the following: single bond, alkyl, aryl, cycloyl, ether and ammonia;

[0059] R 1 It is represented as any one of hydrogen, halogen, alkyl, aryl, cycloyl, ether, and ammonia;

[0060] X represents any one of halogens and halogen-like substances; the halogen is selected from any one of F, Cl, Br, and I; the halogen-like substance is selected from any one of methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and acyloxy.

[0061] n and m are each independently selected from integers from 0 to 15;

[0062] The specific reactions in the above reaction equations are as follows:

[0063] As shown in Equation 2, the thiodihydroartemisinin shown in Formula 3 is prepared by the thioreaction of dihydroartemisinin. The thiodihydroartemisinin is then reacted with the compound shown in Formula 4 to obtain the sulfur-containing artemisinin dimer.

[0064] A method for preparing the above-mentioned sulfur-containing artemisinin dimer, the reaction equation of which is as follows:

[0065]

[0066] Wherein, W represents any one of S, SO and SO2;

[0067] Z is represented as: S, SO, SO2, O, NR1, and CR 1 Any one of 2;

[0068] Y represents any one of the following: single bond, alkyl, aryl, cycloyl, ether and ammonia;

[0069] R1 It is represented as any one of hydrogen, halogen, alkyl, aryl, cycloyl, ether, and ammonia;

[0070] TMS stands for trimethylsilyl group;

[0071] n and m are each independently selected from integers from 0 to 15;

[0072] The acid is selected from any one of the following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride diethyl ether complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethylsilyl trifluoromethanesulfonate, and p-toluenesulfonic acid;

[0073] The specific reactions in the above reaction equations are as follows:

[0074] As shown in Equation 3, the compound shown in Formula V and dihydroartemisinin are dissolved in a solvent, and acid is added dropwise at -78℃ to 25℃ to react and obtain sulfur-containing artemisinin dimers.

[0075] A method for preparing the above-mentioned sulfur-containing artemisinin dimer, characterized in that, in a solvent, the sulfur-containing artemisinin dimer containing low-oxidation-state sulfur is oxidized with an oxidant to obtain the sulfur-containing artemisinin dimer containing high-oxidation-state sulfur.

[0076] The oxidant is selected from any one of the following: ozone, urea peroxide, hydrogen peroxide, hypochlorous acid, hypochlorite, perchloric acid, perchlorate, persulfate, persulfate, permanganate, dichromate, periodic acid, periodate, and peroxy organic acids;

[0077] The low oxidation state sulfur is referred to as: divalent sulfur;

[0078] The high oxidation state sulfur is represented as SO or SO2.

[0079] Application of the above-mentioned sulfur-containing artemisinin dimer in the preparation of antitumor drugs.

[0080] This antitumor drug is used for cancer, including but not limited to leukemia, lung cancer, liver cancer, breast cancer, colon cancer, stomach cancer, ovarian cancer, and cervical cancer.

[0081] The sulfur-containing artemisinin dimer described above can be used in combination with known anticancer drugs, such as paclitaxel, etoposide, and cisplatin.

[0082] The sulfur-containing artemisinin dimer described in this invention can be used in combination with other cancer therapies, such as radiotherapy and bone marrow transplantation.

[0083] Definitions and explanations:

[0084] Unless otherwise stated, the following terms and phrases used in this invention are intended to have the following meanings; a particular term or phrase should not be considered uncertain or unclear without a specific definition, but should be understood in its ordinary sense.

[0085] When a product name appears in this article, it is intended to refer to the product or active ingredient to which it is used.

[0086] The term “pharmaceutically acceptable” as used in this article refers to compounds, materials, compositions, and / or dosage forms that, to the extent of sound medical judgment, are suitable for tissue contact in humans or animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0087] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound with a relatively nontoxic acid or base, which is a compound with specific substituents discovered in the present invention.

[0088] When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amine, magnesium salts, or similar salts.

[0089] When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in a solvent with a sufficient amount of acid in their neutral form. Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, sulfurous acid, and phosphorous acid; organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, butenedioic acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, amino acids, glucuronic acid, and similar acids.

[0090] Certain compounds of the present invention contain acidic and basic functional groups, and can thus be converted into salts of either base or acid addition.

[0091] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof, via a free acid or base.

[0092] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described in this invention readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0093] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0094] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0095] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0096] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0097] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0098] Unless otherwise stated, "(D)" or "(+)" indicates right-handed rotation, "(L)" or "(-)" indicates left-handed rotation, and "(DL)" or "(±)" indicates racemic rotation.

[0099] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. This indicates that the stereochemical configuration is uncertain or not fixed, or that it is a mixture.

[0100] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0101] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0102] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0103] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0104] When any variable (e.g., R) 1 When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is surrounded by 0 to 2 R... 1 If replaced, the group may optionally be replaced by at most two R groups.1 Replaced, and R in each case 1 Each has its own independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds.

[0105] When the number of a linker group is 0, for example -(CR) 1 2) 0- indicates that the linking group is a single bond.

[0106] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALB represents a single bond, it means that the structure is actually AB.

[0107] When a substituent is vacant, it means that the substituent does not exist. For example, if C is vacant in AC, it means that the structure is actually A.

[0108] When the listed substituents do not specify which atom they are attached to the substituted group, they can be bonded to any of their atoms. For example, a pyridinium group, as a substituent, can be attached to the substituted group via any carbon atom on the pyridine ring. When the listed linking groups do not specify their attachment direction, the attachment direction is arbitrary.

[0109] The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0110] Unless otherwise specified, the term "C1-C10 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 10 carbon atoms. It can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine).

[0111] In this invention, the term "aryl" refers to any functional group or substituent derived from a simple aromatic ring. This includes, but is not limited to, phenyl, biphenyl, pyridyl, pyrazinyl, pyridazinyl, thiopheneyl, thiazolyl, naphthyl, pyrroleyl, furanyl, indoleyl, quinolinyl, purineyl, etc. The selected aryl group may optionally have two carbon atoms that are -(CR) in the main structure. 1 2) n - Connected, the remaining atoms can be arbitrarily connected by 1 to 5 R atoms. 1 replace;

[0112] In this invention, the term "3-10 membered cyclic group" refers to a saturated or unsaturated cyclic group composed of 3 to 10 carbon atoms; this includes monocyclic and polycyclic systems, with polycyclic systems including spirocyclic, fused, bridged, and linked rings. (Except for -(CR) in the main structure) 1 2) n - Apart from the connected atoms, the remaining atoms can be arbitrarily coupled with 1 to 2 R atoms. 1Substitution; unsaturated cyclic groups refer to non-aryl groups containing 1 to 3 unsaturated bonds.

[0113] In this invention, the term "3- to 10-membered heterocyclic group" refers to a saturated or unsaturated cyclic group composed of 3 to 10 carbon atoms, wherein 1 to 6 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O)). t ,t is 1 or 2). It includes monocyclic and polycyclic systems, with polycyclic systems including spirocyclic, fused, bridged, and linked rings. Furthermore, regarding this "3- to 10-membered heterocyclic group," the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. Except for the -(CR) group in the main structure... 1 2) n - Apart from the bonded atoms, the remaining carbon atoms can be optionally bonded by 1 to 2 R atoms. 1 Substitution; unsaturated cyclic group refers to a non-aryl group containing 1 to 3 unsaturated bonds. The spirocyclic ring is two adjacent monocyclic rings sharing one atom; the fused ring is two or more monocyclic rings fused together, in which two adjacent atoms of one monocyclic ring are shared with two adjacent atoms of the other monocyclic ring; the bridged ring is a polycyclic structure sharing two or more atoms; the linked ring is two or more monocyclic rings, each with one atom connected by a single or double bond.

[0114] The structures of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art.

[0115] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0116] The solvents used in this invention are commercially available. The following abbreviations are used in this invention: aq represents water; eq represents equivalent amount; M or N represents L / mol or mL / mmol; DHA represents dihydroartemisinin, i.e., (3R,5αS,6R,8αS,9R,10S,12R,12αR)-octahydro-3,6,9-trimethyl-3,12-bridgedoxy-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)-ol; SDHA-A represents α-thiodihydroartemisinin, i.e., (3R,5αS,6R,8αS,9R,10R,12R,12αR)-octahydro-3,6,9-trimethyl-3,12-bridgedoxy-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)-ol; αR)-octahydro-3,6,9-trimethyl-3,12-bridgedoxy-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)-thiol; SDHA-B represents β-thiodihydroartemisinin, i.e. (3R,5αS,6R,8αS,9R,10S,12R,12αR)-octahydro-3,6,9-trimethyl-3,12-bridgedoxy-12H-pyrano[4,3-j]-1,2-benzodithiapine-10(3H)-thiol; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-Dimethylformamide; DMSO represents dimethyl sulfoxide / deuterated dimethyl sulfoxide (for NMR); EA represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; THF represents tetrahydrofuran; Et2O represents diethyl ether; Et3N represents triethylamine; CCl4 represents carbon tetrachloride; CDCl3 represents deuterated chloroform; MeOD represents deuterated methanol; DIAD represents diisopropyl azodicarboxylate; SOCl2 represents thionyl chloride; TsOH represents p-toluenesulfonic acid; LiAlH4 represents lithium aluminum hydride; AcOH represents acetic acid; DMAP represents... 4-Dimethylaminopyridine; Ac2O represents acetic anhydride; NaOH represents sodium hydroxide; BF3·Et2O represents boron trifluoride ether; AcSK represents potassium thioacetate; MsCl represents methanesulfonyl chloride; NaBH4 represents sodium borohydride; Cs2CO3 represents cesium carbonate; K2CO3 represents potassium carbonate; Na2CO3 represents sodium carbonate; DIBAH represents diisobutylaluminum hydride; AIBN represents azobisisobutyronitrile; NBS represents brominated succinimide; NaOCl represents sodium hypochlorite; TFAA represents trifluoroacetic anhydride; UHP represents urea peroxide.

[0117] Compounds are named in accordance with conventional naming principles in the field, and commercially available compounds are named according to the supplier's catalog. Detailed Implementation

[0118] The principles and features of the present invention are described below. The examples given are only for explaining the present invention and are not intended to limit the scope of the present invention.

[0119] Example 1: Preparation of Compound 1

[0120]

[0121] 1. Dihydroartemisinin (100.00 g, 351.68 mmol, 1.00 eq) and thioacetic acid (53.53 g, 703.35 mmol, 2.00 eq) were added to 1.2 L of DCM. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether (47.7 mL, 386.84 mmol, 1.10 eq) was added dropwise. After the addition was complete, the reaction mixture was moved to room temperature and stirred for 30 min. TCL (20% EA / PE) showed that the starting material disappeared. The purified product was 12.00 g of SDHA-A1 and 35.50 g of SDHA-B1, with a combined yield of 39%.

[0122] 2. Dissolve SDHA-A1 (12.00 g, 35.04 mmol, 1.0 eq) in 120 mL of 95% ethanol, cool to 0 °C, add 26.3 mL of 2M sodium hydroxide solution dropwise, and stir the reaction at 0 °C for 1.5 h. Pour the reaction solution into 500 mL of water, add citric acid aqueous solution dropwise until the system is weakly acidic, and purify to obtain 24.50 g of white solid SDHA-A, yield 80%.

[0123] 3. Dissolve SDHA-B1 (35.00 g, 102.20 mmol, 1.00 eq) in 350 mL of 95% ethanol, cool to 0 °C, add 76.7 mL of 2M sodium hydroxide solution dropwise, and stir the reaction at 0 °C for 1.5 h. Pour the reaction solution into 1500 mL of water, add citric acid aqueous solution dropwise until the system is weakly acidic, and purify to obtain 8.60 g of white solid SDHA-B, yield 82%.

[0124] 4. SDHA-A (200 mg, 0.67 mmol, 1.00 eq) or SDHA-A (200 mg, 0.67 mmol, 1.00 eq) and triethylamine (101 mg, 1.00 mmol, 1.50 eq) were added to 2 mL of DCM and cooled to 0 °C. I2 (85 mg, 0.33 mmol, 0.50 eq) was dissolved in 1 mL of DCM and added dropwise to the reaction mixture. The reaction was stirred at room temperature for 2 h. TCL (20% EA / PE) showed that the starting material disappeared. After purification, 150 mg of compound 1A was obtained, with a yield of 75%; 162 mg of compound 1B was obtained, with a yield of 81%.

[0125] The NMR results for compound 1 are as follows:

[0126] Compound 1A: 1HNMR(500MHz, CDCl3)δ5.29(s,2H),4.73(d,J=10.8Hz,2H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.04–1.97(m,2H),1.90–1.83(m,2H),1. 73(d,J=3.9Hz,2H),1.69–1.61(m,3H),1.48–1.44(m,1H),1.42–1.39(m,7H),1.36(d,J=3.4Hz,1H),1.29–1.22(m,5H),0.97-0.91(m,15H).

[0127] Compound 1B: 1 HNMR(500MHz, CDCl3)δ5.56(s,2H),5.25(d,J=5.3Hz,2H),3.04(d,J=7.0Hz,2H),2 .36(d,J=3.8Hz,2H),2.05(s,2H),1.91–1.84(m,2H),1.76–1.66(m,4H),1.57(d,J =3.0Hz,1H),1.50(dd,J=7.0,4.9Hz,3H),1.44(s,5H),1.37(d,J=3.6Hz,1H),1.25 (d,J=5.9Hz,7H),1.01(d,J=7.3Hz,5H),0.95(d,J=6.4Hz,6H),0.88–0.85(m,2H).

[0128] Example 2: Preparation of Compound 2

[0129]

[0130] SDHA-A (500 mg, 0.76 mmol, 1.00 eq) and dimercaptomethane (71 mg, 0.88 mmol, 0.50 eq) from Example 1 were added to 10 mL of diethyl ether. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether (250 mg, 1.76 mmol, 1.00 eq) was added dropwise. The reaction was stirred at 0 °C for 1 h and then moved to room temperature and stirred overnight. TCL (20% EA / PE) showed that the starting material disappeared. After purification, 108 mg of compound 2A was obtained.

[0131] SDHA-B (500 mg, 0.76 mmol, 1.00 eq) and dimercaptomethane (71 mg, 0.88 mmol, 0.50 eq) from Example 1 were added to 10 mL of diethyl ether. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether (250 mg, 1.76 mmol, 1.00 eq) was added dropwise. The reaction was stirred at 0 °C for 1 h and then moved to room temperature and stirred overnight. TCL (20% EA / PE) showed that the starting material disappeared. After purification, 102 mg of compound 2B was obtained.

[0132] The NMR results for compound 2 are as follows:

[0133] Compound 2A: 1 HNMR(500MHz, CDCl3)δ5.30(s,2H),4.72(d,J=10.6Hz,2H),3.43(s,2H),2.77–2.63(m,2H),2.41–2.30(m,2H),2.14–1.99( m,2H),1.90–1.83(m,2H),1.76-1.71(m,2H),1.69–1.61(m,3H),1.48-1.36(m,9H),1.30–1.21(m,5H),0.97-0.84(m,15H).

[0134] Compound 2B: 1 HNMR(500MHz, CDCl3)δ5.57(s,2H),5.26(d,J=5.4Hz,2H),3.44(s,2H),3.01(d,J=7.0H z,2H),2.31(d,J=3.8Hz,2H),2.06(s,2H),1.90–1.84(m,2H),1.75–1.67(m,4H),1.56( d,J=3.0Hz,1H),1.51(dd,J=7.0,4.9Hz,3H),1.44-1.40(m,5H),1.38(d,J=3.6Hz,1H), 1.22(d,J=5.8Hz,7H),1.01(d,J=7.0Hz,5H),0.97(d,J=6.6Hz,6H),0.90–0.85(m,2H).

[0135] Example 3: Preparation of Compound 3

[0136]

[0137] As in Example 2, 1,2-ethylenedithiol (83 mg, 0.88 mmol, 0.50 eq) was used as the raw material to prepare 196 mg of compound 3A and 165 mg of compound 3B.

[0138] The NMR results for compounds 3A and 3B are as follows:

[0139] Compound 3A: 1 HNMR(500MHz, CDCl3)δ5.30(s,2H),4.72(d,J=10.6Hz,2H),2.75–2.67(m,6H),2.41–2.32(m,2H),2.03–1.97(m,2H),1.90–1.83(m,2H),1. 72(d,J=3.9Hz,2H),1.69–1.63(m,3H),1.48–1.43(m,1H),1.41–1.39(m,7H),1.37(d,J=3.4Hz,1H),1.28–1.22(m,5H),0.96-0.91(m,15H).

[0140] Compound 3B: 1 HNMR(500MHz, CDCl3)δ5.57(s,2H),5.24(d,J=5.3Hz,2H),3.04(d,J=7.0Hz,2H),2.71– 2.68(m,4H),2.37(d,J=3.8Hz,2H),2.05(s,2H),1.90–1.84(m,2H),1.74–1.68(m,4H), 1.57(d,J=3.0Hz,1H),1.51(dd,J=7.0,4.9Hz,3H),1.43(s,5H),1.38(d,J=3.6Hz,1H), 1.25(d,J=5.9Hz,7H),1.00(d,J=7.3Hz,5H),0.94(d,J=6.4Hz,6H),0.88–0.85(m,2H).

[0141] Example 4: Preparation of Compound 4

[0142]

[0143] As in Example 2, 1,3-propanedithiol (1.00 g, 9.24 mmol, 1.00 eq) was used as the starting material to obtain 1.13 g of compound 4A and 2.51 g of compound 4B, with a combined yield of 61%. Both compounds 4A and 4B were white solids.

[0144] The NMR results for compound 4 are as follows:

[0145] Compound 4A: 1HNMR (600MHz, CDCl3) δ5.27 (s, 2H), 4.54 (d, J = 10.7Hz, 2H), 2.96–2.86 (m, 2H), 2.80–2.68(m,2H),2.64–2.55(m,2H),2.35(td,J=14.0,3.9Hz,2H),2.08–1.98 (m,4H),1.91–1.83(m,2H),1.76–1.67(m,4H),1.58(m,2H),1.51–1.29(m,12H) ,1.24(m,2H),1.07–0.98(m,2H),0.95(d,J=6.3Hz,6H),0.92(d,J=7.1Hz,6H).

[0146] Compound 4B: 1 HNMR(600MHz, CDCl3)δ5.61(s,2H),5.28–5.23(m,2H),3.03(dd,J=12.0,5.2Hz,2H),2.83–2.72(m,4H),2.37(m,2H),2.07– 1.93(m,4H),1.91–1.78(m,4H),1.75–1.63(m,6H),1.55–1.47(m,4H),1.47–1.37(m,8H),1.25(m,2H),1.00–0.90(m,12H).

[0147] Example 5: Preparation of Compound 5

[0148]

[0149] As in Example 2, the starting material was 1,4-butanedithiol (1.00 g, 8.18 mmol, 1.00 eq) to obtain 1.08 g of compound 5A and 2.33 g of compound 5B, with a combined yield of 65%. Both compounds 5A and 5B were white solids.

[0150] The NMR results for compound 5 are as follows:

[0151] Compound 5A: 1HNMR (600MHz, CDCl3) δ5.28 (s, 2H), 4.53 (d, J = 10.7Hz, 2H), 2.80 (dd, J = 12.5, 5.3Hz, 2H), 2.71–2.6 3(m,2H),2.59(ddd,J=11.0,9.3,5.8Hz,2H),2.36(td,J=14.0,3.8Hz,2H),2.01(d,J=14.2Hz,2H),1 .91–1.83(m,2H),1.82–1.75(m,4H),1.74–1.68(m,4H),1.58(dt,J=13.5,4.0Hz,2H),1.52–1.30(m, 12H),1.24(dt,J=11.3,6.9Hz,2H),1.08–0.98(m,2H),0.95(d,J=6.3Hz,6H),0.92(d,J=7.1Hz,6H).

[0152] 13 CNMR (151MHz, CDCl3) δ104.26,92.25,80.51,80.41,51.83,46.09,37.37,36.30,34.10,31.83,29.10,28.03,26.00,24.77,21.31,20.26,15.10.

[0153] Compound 5B: 1 HNMR(600MHz, CDCl3)δ5.61(s,2H),5.27(d,J=5.2Hz,2H),3.07–2.99(m,2H),2.69(m,4H),2.37(td,J=14.1,3.6Hz,2H),2.04(dd, J=14.6,2.9Hz,2H),1.92–1.79(m,4H),1.77–1.63(m,8H),1.55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.90(m,12H).

[0154] 13 CNMR(151MHz,CDCl3)δ104.19,92.25,88.01,86.70,81.17,80.56,80.39,52.71,4 5.19,37.21,36.44,34.4432.25,32.08,28.97,26.18,24.62,24.37,20.33,14.85.

[0155] Example 6: Preparation of Compound 6

[0156]

[0157] As in Example 2, 1,5-pentanedithiol (1.00 g, 7.34 mmol, 1.00 eq) was used as the starting material to obtain 0.90 g of compound 6A, 1.60 g of compound 6B and 1.20 g of compound 6C, with a combined yield of 75%. Compounds 6A, 6B and 6C were all white solids.

[0158] The NMR results for compound 6 are as follows:

[0159] Compound 6A: 1 HNMR(600MHz, CDCl3)δ5.30(s,2H),4.51(d,J=10.7Hz,2H),2.88–2.83(m,2H),2.71–2.62(m,4H),2.39-2.34(m,2H),2.18–2.03(m,2H),1.91– 1.83(m,4H),1.74–1.68(m,4H),1.65-1.62(m,4H),1.56–1.46(m,6H), 1.43(s,6H),1.38–1.33(m,2H),1.29–1.21(m,2H),1.08–0.90(m,14H).

[0160] Compound 6B: 1 HNMR (600MHz, CDCl3) δ5.61 (s, 2H), 5.27 (d, J = 5.3Hz, 2H), 3.08–2.98 (m, 2H), 2. 71–2.62(m,4H),2.37(td,J=14.1,3.8Hz,2H),2.08–1.98(m,2H),1.92–1.77(m, 4H),1.69(ddd,J=10.7,7.3,4.0Hz,4H),1.63–1.59(m,5H),1.56–1.46(m,7H),1 .44(s,6H),1.40(dd,J=6.3,3.3Hz,2H),1.29–1.21(m,2H),0.98–0.93(m,12H).

[0161] Compound 6C: 1HNMR(600MHz, CDCl3)δ5.61(s,1H),5.31(s,1H),5.28(d,J=5.4Hz,1H),4.50(d,J=10.6Hz,2H),3.07–2.97(m,1H),2.88–2.82(m,1H),2.71–2.6 2(m,4H),2.37-2.28(m,2H),2.07–1.78(m,6H),1.68–1.60(m,9H),1.56 –1.46(m,7H),1.44-1.38(m,8H),1.29–1.21(m,2H),1.08–0.94(m,12H).

[0162] Example 7

[0163] Preparation of compound 7:

[0164]

[0165] As in Example 2, 1,6-butanedithiol (1.00 g, 6.65 mmol, 1.00 eq) was used as the starting material to obtain 2.41 g of compound 7A and 0.90 g of compound 7B, with a combined yield of 72%. Both compounds 7A and 7B were white solids.

[0166] The NMR results for compound 7 are as follows:

[0167] Compound 7A: 1 HNMR(600MHz, CDCl3) δ5.29(d,J=13.3Hz,2H),4.29(d,J=9.2Hz,2H),2.32(dt,J=1 4.1,8.6Hz,4H),1.96(d,J=14.4Hz,2H),1.85–1.79(m,2H),1.70(dd,J=13.5,3.4H z,2H),1.62(dd,J=13.3,2.7Hz,2H),1.50–1.41(m,4H),1.38(s,6H),1.30–1.09(m ,10H),0.95(dd,J=20.1,7.6Hz,2H),0.89(d,J=6.2Hz,6H),0.81(d,J=7.1Hz,6H).

[0168] Compound 7B: 1HNMR(600MHz, CDCl3)δ5.61(s,2H),5.27(d,J=5.3Hz,2H),3.03(dd,J=12.2,5.2Hz,2H),2.67(m,4H),2.37(td,J=14.1,3.8Hz,2H),2.08–2.02(m,2H ),1.93–1.79(m,4H),1.75–1.66(m,4H),1.62(s,4H),1.52(m,5H),1.44(s ,6H),1.42–1.35(m,7H),1.25(td,J=11.6,6.7Hz,2H),0.99–0.92(m,12H).

[0169] Example 8: Preparation of Compound 8

[0170]

[0171] 1. 1,7-Heptanediol (1.00 g, 7.56 mmol, 1.00 eq) and triethylamine (2.30 g, 22.69 mmol, 3.00 eq) were added to 20 mL of dichloromethane. The reaction was cooled to 0 °C, and methanesulfonyl chloride (2.17 g, 18.91 mmol, 2.50 eq) was added dropwise. The reaction was stirred at 0 °C for 1 h. TLC (5% MeOH / DCM) showed that the reaction was complete. 20 mL of water was added to the reaction solution, and the mixture was purified to obtain 2.16 g of intermediate 8-1.

[0172] 2. Intermediate 8-1 (2.16 g, 7.49 mmol, 1.00 eq) was added to 25 mL of DMF, followed by potassium thioacetate (1.88 g, 16.48 mmol, 2.20 eq). The reaction was heated to 60 °C and stirred overnight. TLC (5% EA / PE) showed that the reaction was complete, and 410 mg of intermediate 8-2 was obtained after purification.

[0173] 3. Intermediate 8-2 (400 mg, 1.61 mmol, 1.00 eq) was added to 8 mL of 95% ethanol. The reaction mixture was cooled to 0 °C, and 2 mL of 2M sodium hydroxide solution was added dropwise. The reaction was stirred at 0 °C for 0.5 h. TLC (5% EA / PE) showed that the reaction was complete. The pH of the reaction solution was adjusted to neutral with 1N hydrochloric acid, and 250 mg of intermediate 8-3 was obtained after purification, with a yield of 95%.

[0174] 4. Intermediate 8-3 (210 mg, 1.28 mmol, 1.00 eq) and DHA (727 mg, 2.56 mmol, 2.00 eq) were added to 15 mL of diethyl ether. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether (320 mg, 2.81 mmol, 2.20 eq) was added dropwise. The reaction was stirred at 0 °C for 30 min, then cooled to room temperature and stirred for 2 h. TLC (20% EA / PE) showed that the reaction was complete. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution. The mixture was separated and purified to give 172 mg of compound 8A and 190 mg of compound 8B, with a yield of 48%. Both compounds 8A and 8B were white solids.

[0175] The NMR results for compound 8 are as follows:

[0176] Compound 8A: 1 HNMR (500MHz, CDCl3) δ5.27(s,2H),4.52(d,J=10.7Hz,2H),2.76(d,J=7.0Hz,2H),2.61(d,J=11.7Hz,2H),2.37(m, 2H),2.03(m,2H),1.82(d,J=10.5Hz,4H),1.76–1.58(m,6H),1.50(m,4H),1.46–1.19(m,20H),1.01–0.81(m,14H).

[0177] Compound 8B: 1 HNMR (500MHz, CDCl3) δ5.61 (s, 2H), 5.26 (d, J = 5.0Hz, 2H), 3.03 (d, J = 5.8Hz, 2H), 2.66 (s, 4H), 2.37 (t, J = 14.1Hz, 2H), 2.04 (d, J = 14 .7Hz,2H),1.84(dd,J=26.4,11.8Hz,4H),1.74–1.65(m,5H),1.52(dd,J=27.8,15.5Hz,4H),1.46–1.22(m,19H),0.99–0.85(m,14H).

[0178] 13 CNMR (126MHz, CDCl3) δ104.21,88.03,86.75,52.71,45.20,37.21,36.43,34.44,32.09,29.64,26.19,24.37,20.34,14.86.

[0179] Example 9: Preparation of Compound 9

[0180]

[0181] As in Example 8, 1,8-octanediol (1.05 g, 7.18 mmol, 1.00 eq) was used as the raw material to obtain 180 mg of compound 9A, 390 mg of compound 9B and 700 mg of compound 9C. Compounds 9A, 9B and 9C are all colorless oily substances.

[0182] The NMR results for compound 9 are as follows:

[0183] Compound 9A: 1 HNMR(500MHz, CDCl3)δ5.31(s,2H),4.52(d,J=10.7Hz,2H),2.79–2.68(m,2H),2.73–2.54(m,4H),2.37(dd,J=19.4,8 .5Hz,2H),2.01(d,J=14.1Hz,2H),1.87(dd,J=8.5,5.1Hz,2H),1.77–1.54(m,12H),1.51–1.18(m,20H),0.98(m,14H).

[0184] 13 CNMR (126MHz, CDCl3) δ104.24,92.25,80.58,80.40,51.82,46.07,37.37,36.29 ,34.10,31.74,29.86,29.15,29.02,28.38,25.97,24.76,21.30,20.25,15.10.

[0185] Compound 9B: 1 HNMR (500MHz, CDCl3) δ5.61 (s, 2H), 5.26 (d, J = 4.8Hz, 2H), 3.03 (d, J = 6.2Hz, 2H), 2.74–2.58(m,4H),2.38(dd,J=19.5,8.2Hz,2H),2.04(d,J=14.3Hz,2H),1.85(dd, J=25.8,12.3Hz,4H),1.70(dd,J=19.7,7.8Hz,5H),1.60(td,J=14.2,6.9Hz,5H),1 .50(t,J=14.9Hz,4H),1.44(s,6H),1.37(s,6H),1.33–1.21(m,6H),0.95(m,14H).

[0186] 13CNMR (126MHz, CDCl3) δ104.16,88.01,86.73,52.71,45.21,37.21,36.43,34 .45,32.71,32.08,29.69,29.10,28.83,26.18,24.63,24.37,20.34,14.85.

[0187] Compound 9C: 1 HNMR (500MHz, CDCl3) δ5.61 (s, 1H), 5.28 (s, 1H), 5.26 (d, J = 5.0Hz, 1H), 4.52 ( d,J=10.7Hz,1H),3.03(d,J=6.3Hz,1H),2.83–2.73(m,1H),2.75–2.54(m,4H) ,2.37(t,J=13.5Hz,2H),2.03(t,J=14.0Hz,2H),1.85(m,3H),1.77–1.55(m,1 0H),1.53–1.47(m,2H),1.33(m,19H),1.10–1.00(m,1H),1.01–0.88(m,13H).

[0188] 13 CNMR (126MHz, CDCl3) δ104.23,104.16,92.24,88.01,86.72,52.71,51.81,46.07,45.21,37.37,37.20,36.44,36.28,34.45,34.09,3 2.71,32.08,31.73,29.86,29.70,29.13,28.99,28.87,28.34,26.18,25.96,24.76,24.62,24.37,21.30,20.34,20.25,15.10,14.85.

[0189] Example 10: Preparation of compound 10:

[0190]

[0191] As in Example 8, 1,9-nonanediol (1.00 g, 6.24 mmol, 1.00 eq) was used as the raw material to obtain 667 mg of compound 10A, 632 mg of compound 10B and 548 mg of compound 10C, with a combined yield of 64%. Compounds 10A, 10B and 10C were all white foamy solids.

[0192] The NMR results for compound 10 are as follows:

[0193] Compound 10A:1 1H NMR (500 MHz, CDCl3) δ 5.29 (s, 2H), 4.52 (d, J = 10.6 Hz, 2H), 2.80–2.71 (m, 2H), 2.65–2.59 (m, 4H), 2.36 (t, J = 12.6 Hz, 2H), 2.03 (t, J = 13.5 Hz, 2H), 1.93–1.78 (m, 4H), 1.75–1.54 (m, 8H), 1.50–1.46 (m, 4H), 1.48–1.37 (m, 12H), 1.28 (s, 8H), 1.08–1.00 (m, 2H), 0.96–0.92 (m, 12H).

[0194] 13 13C NMR (126 MHz, CDCl3) δ 104.25, 92.25, 80.58, 80.40, 51.82, 46.06, 37.39, 36.44, 34.10, 32.06, 31.73, 29.86, 29.38, 29.04, 28.36, 25.95, 24.77, 21.30, 20.25, 15.10.

[0195] Compound 10B: 1 1H NMR (500 MHz, CDCl3) δ 5.62 (s, 2H), 5.27 (d, J = 5.1 Hz, 2H), 3.03 (dd, J = 11.4, 5.3 Hz, 2H), 2.66 (t, J = 6.4 Hz, 4H), 2.37 (td, J = 14.0, 3.1 Hz, 2H), 2.04 (d, J = 14.4 Hz, 2H), 1.95–1.78 (m, 4H), 1.69 (t, J = 12.8 Hz, 4H), 1.60 (dd, J = 14.9, 7.6 Hz, 4H), 1.55–1.46 (m, 4H), 1.44 (s, 6H), 1.39–1.36 (m, 6H), 1.32–1.23 (m, 8H), 0.96–0.90 (m, 14H).

[0196] 13 13C NMR (126 MHz, CDCl3) δ 104.18, 88.02, 86.73, 81.20, 52.71, 45.21, 37.21, 36.44, 34.45, 32.72, 32.08, 29.72, 29.38, 29.18, 28.90, 26.19, 24.63, 24.37, 20.35, 14.86.

[0197] Compound 10C: 1HNMR (500MHz, CDCl3) δ5.61 (s, 1H), 5.28 (s, 1H), 5.26 (d, J = 5.3Hz, 1H), 4.52 (d, J = 1 0.6Hz,1H),3.03(s,1H),2.81–2.72(m,1H),2.66–2.60(m,4H),2.36(t,J=13.1Hz,2H ),2.03(t,J=13.1Hz,2H),1.93–1.78(m,3H),1.75–1.54(m,10H),1.50(dd,J=17.2, 8.4Hz,3H),1.48–1.37(m,12H),1.28(s,8H),1.08–1.00(m,1H),0.96–0.92(m,13H).

[0198] 13 CNMR (126MHz, CDCl3) δ104.24,104.17,92.25,88.02,86.73,81.20,80.58 ,80.41,52.72,51.82,46.07,45.21,37.38,37.21,36.44,36.29,34.45,3 4.10,32.73,32.08,31.73,29.87,29.72,29.40,29.21,29.04,28.90,28. 35,26.19,25.96,24.77,24.63,24.37,21.30,20.34,20.25,15.10,14.86.

[0199] Example 11: Preparation of compound 11:

[0200]

[0201] As in Example 8, 1,10-decanediol (1.00 g, 5.74 mmol, 1.00 eq) was used as the starting material to obtain 382 mg of compound 11A and 481 mg of compound 11B, with a combined yield of 36%. Both compounds 11A and 11B were white solids.

[0202] The NMR results for compound 11 are as follows:

[0203] Compound 11A: 1HNMR(500MHz, CDCl3)δ5.26(s,2H),4.52(d,J=10.7Hz,2H),2.81–2.71(m,2H),2.61(d,J=11.4Hz,2H),2.37(t,J=13.7Hz,2H),2.03(t,J =14.6Hz,2H),1.88–1.79(m,4H),1.77–1.54(m,5H),1.50(t,J=12.9Hz,4H),1.44-1.37(m,16H),1.27-1.24(m,11H),1.01-0.83(m,14H)

[0204] Compound 11B: 1 HNMR(500MHz, CDCl3)δ5.62(s,2H),5.27(d,J=5.1Hz,2H),3.03(d,J=5.5Hz,2H), 2.66(t,J=6.9Hz,4H),2.35(dd,J=9.0,4.6Hz,2H),2.07–1.98(m,2H),1.84(td,J =13.9,3.4Hz,4H),1.69(t,J=14.1Hz,4H),1.61(dd,J=14.1,7.5Hz,5H),1.50(dd ,J=17.0,8.3Hz,4H),1.40(d,J=34.2Hz,11H),1.27(s,10H),1.06-0.86(m,14H).

[0205] 13 CNMR (126MHz, CDCl3) δ104.18,88.02,86.73,81.20,52.72,45.21,37.21,36.44,34 .45,32.72,32.08,29.73,29.45,29.23,28.92,26.19,24.63,24.37,20.34,14.86.

[0206] Example 12: Preparation of Compound 12

[0207]

[0208] 1. 2,5-Hexanediol (600 mg, 5.08 mmol, 1.00 eq) and triethylamine (3.08 g, 30.46 mmol, 6.00 eq) were added to 25 mL of DCM, cooled to 0 °C, and methanesulfonyl chloride (2.33 g, 20.31 mmol, 4.00 eq) was added dropwise. The reaction was stirred for 15 min and then moved to room temperature and stirred for 1 h. The TCL (40% EA / PE) showed that the starting material disappeared. 50 mL of water was added to the reaction, and the mixture was purified to obtain 1.20 g of intermediate 12-1, with a yield of 86%.

[0209] 2. Intermediate 12-1 (0.50 g, 1.82 mmol, 1.00 eq) and SDHA-A (1.10 g, 3.65 mmol, 3.00 eq) prepared in Example 1 were added to 10 mL of DMF, and potassium carbonate (756 mg, 5.47 mmol, 3.00 eq) was added. The reaction was stirred at room temperature for 20 h. TCL (15% EA / PE) showed that the starting material disappeared. 30 mL of water was added to the reaction mixture, and the mixture was purified to give 510 mg of compound 12A, with a yield of 41%.

[0210] 3. Intermediate 12-1 (0.50 g, 1.82 mmol, 1.00 eq) and SDHA-B prepared in Example 1 (1.10 g, 3.65 mmol, 3.00 eq) were added to 10 mL of DMF, along with potassium carbonate (756 mg, 5.47 mmol, 3.00 eq). The reaction mixture was stirred at room temperature for 20 h. TCL (15% EA / PE) showed the starting material had disappeared. 30 mL of water was added to the reaction mixture, and purification yielded 560 mg of compound 12B, with a yield of 45%.

[0211] The NMR results for compound 12 are as follows:

[0212] Compound 12A: 1 HNMR(500MHz, CDCl3)δ5.26(s,2H),4.52(d,J=10.6Hz,2H),3.11–2.96(m,2H),2.45-2.36( m,2H),2.07(t,J=14.9Hz,2H),1.89-1.65(m,12H),1.59–1.23(m,22H),1.03–0.86(m,14H).

[0213] Compound 12B: 1HNMR(500MHz, CDCl3)δ5.61(s,2H),5.33(d,J=5.2Hz,2H),3.10–2.97(m,2H),2.40-2.35(m ,2H),2.02(t,J=14.9Hz,2H),1.86–1.63(m,13H),1.57–1.23(m,21H),1.06–0.84(m,14H).

[0214] 13 CNMR (126MHz, CDCl3) δ104.17,92.15,88.06,84.85,81.18,80.58,80.40,52.73,45.25 ,40.81,37.22,36.45,34.47,34.22,32.10,26.16,24.63,24.42,21.64,20.33,14.93.

[0215] Example 13:

[0216] Preparation of compound 13:

[0217]

[0218] 13-1 (100 mg, 0.31 mmol, 1.00 eq) and DHA (192 mg, 0.68 mmol, 2.20 eq) were added to 10 mL of diethyl ether, cooled to 0 °C, and boron trifluoride diethyl ether (77 mg, 0.68 mmol, 2.20 eq) was added dropwise. The reaction was stirred at 0 °C for 30 min and then moved to room temperature and stirred for 2 h. TLC (20% EA / PE) showed that the reaction was complete. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution, separated, and purified to give 69 mg of compound 13A and 91 mg of compound 13B, with a yield of 61%. Both compounds 13A and 13B were white solids.

[0219] The NMR results for compound 13 are as follows:

[0220] Compound 13A: 1 HNMR (500MHz, CDCl3) δ5.61 (s, 2H), 5.26 (d, J = 5.2Hz, 2H), 3.05-3.18 (m, 2H), 2.67 (s, 6H), 2.37 (t, J = 13.8Hz, 2H), 2.04 (d, J = 12 .2Hz,2H),1.89–1.80(m,4H),1.74–1.58(m,13H),1.57(s,6H),1.50(t,J=12.4Hz,4H),1.45–1.22(m,27H),0.98–0.88(m,14H).

[0221] Compound 13B: 1 HNMR (500MHz, CDCl3) δ5.26 (s, 2H), 4.36 (d, J = 10.6Hz, 2H), 2.88-2.85 (m, 2H), 2.67 (s, 2H), 2.38 (t, J = 13.8Hz, 2H), 2.05 (d, J = 12. 2Hz,2H),1.84(d,J=14.4Hz,4H),1.74–1.58(m,13H),1.57(s,6H),1.50(t,J=12.4Hz,4H),1.45–1.22(m,23H),0.98–0.88(m,12H).

[0222] Example 14: Preparation of compound 14:

[0223]

[0224] Preparation process:

[0225] Compound 14-1 (0.50 g, 2.74 mmol, 1.00 eq) and dihydroartemisinin (1.72 g, 6.03 mmol, 2.20 eq) were added to 27 mL of Et₂O to replace Ar. The mixture was stirred at -5 °C, and boron trifluoride diethyl ether (0.85 g, 6.03 mmol, 2.20 eq) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 h. The reaction solution was quenched in 100 mL of saturated sodium bicarbonate solution and extracted three times with 80 mL of EA to purify 0.90 g of white foamy compound 14, with a yield of 45%. Compound 14 was a white foam.

[0226] The NMR results for compound 14 are as follows:

[0227] 1 HNMR (500MHz, CDCl3) δ5.60 (s, 2H), 5.31 (d, J = 4.4Hz, 2H), 3.80–3.71 (m, 2H), 3.67–3.5 7(m,6H),3.03(d,J=4.8Hz,2H),2.92(dd,J=13.4,6.6Hz,2H),2.83(dd,J=12.9,6.7Hz, 2H), 2.37 (t, J=13.9Hz, 2H), 2.04 (d, J=14.5Hz, 2H), 1.94–1.76 (m, 4H), 1.68 (dd, J=28. 1,12.9Hz,6H),1.51–1.48(m,4H),1.43(s,6H),1.32–1.19(m,4H),0.96–0.86(m,12H).

[0228] 13CNMR (126MHz, CDCl3) δ104.21,87.95,87.25,81.17,70.86,70.24,52.67,45.12,37.21,36.40,34.42,32.18,26.16,24.63,24.37,20.36,14.85.

[0229] Example 15: Preparation of compound 15:

[0230]

[0231]

[0232] 1. DHA (2.00 g, 7.03 mmol, 1.00 eq) was added to 15 mL of 1,4-butanediol and 15 mL of DCM. The mixture was cooled to 0 °C, and boron trifluoride ether (1.05 g, 7.39 mmol, 1.05 eq) was added dropwise. The reaction was stirred at 0 °C for 30 min, then moved to room temperature and stirred for 2 h. TLC (20% EA / PE) showed that the reaction was complete. The reaction was quenched with 100 mL of saturated sodium bicarbonate solution. The mixture was separated and purified to give 2.32 g of intermediate 15-1, with a yield of 93%. Intermediate 15-1 was a colorless oily liquid.

[0233] 2. Intermediate 15-1 (2.32 g, 8.61 mmol, 1.0 eq) was dissolved in 50 mL of anhydrous dichloromethane, cooled to 0 °C, and triethylamine (1.65 g, 16.27 mmol, 2.50 eq) was added. After stirring for 10 min, methanesulfonyl chloride (895 mg, 7.81 mmol, 1.20 eq) was added dropwise. After the addition was complete, the reaction mixture was moved to room temperature and stirred for 2 h. After the reaction was completed, the reaction solution was poured into 150 mL of saturated sodium bicarbonate solution and stirred thoroughly. The solution was purified to obtain 0.53 g of intermediate 15-2 and 2.02 g of intermediate 15-3, with a yield of 90%. Both intermediate 15-2 and intermediate 15-3 were white solids.

[0234] 3. 15-2 (200 mg, 0.46 mmol, 1.00 eq) and SDHA-A (139 mg, 0.46 mmol, 1.00 eq) were added to 5 mL of DMF, followed by potassium carbonate (128 mg, 0.92 mmol, 2.00 eq). The reaction mixture was stirred at room temperature for 20 h. TCL (20% EA / PE) showed the starting material disappeared. Purification yielded 163 mg of compound 15A, with a yield of 55%.

[0235] 4. 15-2 (200 mg, 0.46 mmol, 1.00 eq) and SDHA-B (139 mg, 0.46 mmol, 1.00 eq) were added to 5 mL of LDM, followed by potassium carbonate (128 mg, 0.92 mmol, 2.00 eq). The reaction mixture was stirred at room temperature for 20 h. TCL (20% EA / PE) showed the starting material disappeared. Purification yielded 143 mg of compound 15C, with a yield of 49%.

[0236] 5. 15-3 (500 mg, 1.15 mmol, 1.00 eq) and SDHA-A (346 mg, 1.15 mmol, 1.00 eq) from Example 1 were added to 10 mL of DMF, followed by potassium carbonate (318 mg, 2.30 mmol, 2.00 eq). The reaction mixture was stirred at room temperature for 20 h. TCL (20% EA / PE) showed the starting material disappeared, and the product was purified to yield 465 mg of compound 15D, with a yield of 63%.

[0237] 6. 15-3 (500 mg, 1.15 mmol, 1.00 eq) and SDHA-B (346 mg, 1.15 mmol, 1.00 eq) from Example 1 were added to 10 mL of DMF, along with potassium carbonate (318 mg, 2.30 mmol, 2.00 eq). The reaction mixture was stirred at room temperature for 20 h. TCL (20% EA / PE) showed the starting material disappeared, and purification yielded 432 mg of compound 15B, with a yield of 59%.

[0238] The NMR results for compound 15 are as follows:

[0239] Compound 15A: 1 HNMR(600MHz, CDCl3)δ5.38(s,1H),5.34(s,1H),4.52(d,J=10.7Hz,1H),4.42(d,J=9.2Hz,1H),3.87-3.85(m,1H),3.40-3.37(m,1H),2.83–2.78 (m,1H),2.71–2.66(m,2H),2.64-2.56(m,2H),2.37–2.24(m,2H),2.13-2 .02(m,2H),1.95–1.60(m,11H),1.58–1.12(m,14H),1.05–0.81(m,14H).

[0240] Compound 15B: 1HNMR(600MHz, CDCl3)δ5.61(s,1.0H),5.39(s,1H),5.26(d,J=5.3Hz,1H),4.79(d,J=3.0Hz,1H),3.87-3.85(m,1H),3.40-3.37(m,1H),3.04–3.02 (m,1H),2.72–2.65(m,2H),2.65-2.56(m,2H),2.37–2.24(m,2H),2.13-2 .04(m,2H),1.93–1.58(m,11H),1.53–1.18(m,14H),1.02–0.81(m,14H).

[0241] Compound 15C: 1 HNMR(600MHz, CDCl3)δ5.61(s,1.0H),5.34(s,1H),5.26(d,J=5.3Hz,1H),4.42(d,J=9.2Hz,1H),3.88-3.86(m,1H),3.41-3.38(m,1H),3.04–3.02 (m,1H),2.72–2.66(m,2H),2.64-2.55(m,2H),2.37–2.28(m,2H),2.15-2 .03(m,2H),1.94–1.59(m,11H),1.53–1.18(m,14H),1.01–0.81(m,14H).

[0242] Compound 15D; 1 HNMR(600MHz, CDCl3)δ5.39(s,1H),5.28(s,1H),4.79(d,J=3.0Hz,1H),4.52(d,J=10.7Hz,1H),3.87-3.85(m,1H),3.40-3.37(m,1H),2.83–2.78 (m,1H),2.71–2.66(m,2H),2.64-2.56(m,2H),2.37–2.24(m,2H),2.13-2 .02(m,2H),1.95–1.60(m,11H),1.58–1.12(m,14H),1.05–0.81(m,14H).

[0243] Example 16: Preparation of Compound 16

[0244]

[0245] As in Example 15, the starting material was 4-aminobutane-1-thiol (174 mg, 1.66 mmol, 0.50 eq), yielding 114 mg of compound 16A and 131 mg of compound 16B, with a combined yield of 23%. Both compounds 16A and 16B were white solids.

[0246] The NMR results for compound 16 are as follows:

[0247] Compound 16A: ¹H NMR (600 MHz, CDCl₃) δ 5.31 (s, ¹H), 5.28 (s, ¹H), 4.53 (d, J = 10.7 Hz, ¹H), 4.13 (d, J = 9.8 Hz, ¹H), 2.95 (ddd, J = 11.4, 8.07, 6.55 Hz, ¹H), 2.80 (dd, J = 12.5, 5.3 Hz, ¹H), 2.71–2.61 (m, 2H), 2.59–2.5 6(m,2H),2.36–2.30(m,2H),2.07–2.01(m,2H),1.91–1.83(m,2H),1.83–1.75(m,4H),1.73–1.66(m,4 H),1.59–1.54(m,2H),1.52–1.30(m,12H),1.24-1.18(m,2H),1.08–0.98(m,2H),0.95–0.89(m,12H).

[0248] Compound 16B: 1 HNMR (600MHz, CDCl3) δ5.61(s,1H),5.59(s,1H),5.27(d,J=5.2Hz,1H),5.20(d,J=4.6Hz,1H),3.07–2.99(m,2H),2.69–2.60(m,4H),2.37-2. 31(m,2H),2.08–2.01(m,2H),1.94–1.79(m,4H),1.75–1.61(m,8H),1. 55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.86(m,12H).

[0249] Example 17: Preparation of Compound 17

[0250]

[0251] 1. DHA (20.00 g, 70.34 mmol, 1.00 eq) and allyltrimethylchlorosilane (20.09 g, 175.84 mmol, 2.50 eq) were added to 200 mL of dichloromethane. The reaction was cooled to -50 °C, and boron trifluoride diethyl ether (9.61 g, 84.40 mmol, 1.20 eq) was added dropwise. The reaction was purified to obtain 8.60 g of intermediate 17-1.

[0252] 2. Intermediate 17-1 (10.00 g, 32.42 mmol, 1.00 eq) was added to 500 mL of DCM, cooled to -78 °C, and ozone was bubbled through for 1.5 h. The reaction solution turned blue. The ozone bubbling was stopped, and air was bubbled through for 30 min. The solvent was then concentrated to remove the solvent. 80 mL of THF and 20 mL of MeOH were added to the reaction flask, and the temperature was lowered to 0 °C. NaBH4 (7.36 g, 194.54 mmol, 6.00 eq) was added in portions. The reaction was stirred at 0 °C for 4 h and then moved to room temperature and stirred overnight. The reaction was quenched with 50 mL of water, separated, and purified to obtain 6.39 g of intermediate 17-2.

[0253] 3. Intermediate 17-2 (1.00 g, 3.20 mmol, 1.00 eq) and triethylamine (972 mg, 9.60 mmol, 3.00 eq) were added to 20 mL of DCM. The reaction was cooled to 0 °C, and methanesulfonyl chloride (440 mg, 3.84 mmol, 1.20 eq) was added dropwise. The reaction was stirred at 0 °C for 2 h and then moved to room temperature overnight. TLC (40% EA / PE) showed that the reaction was complete. 10.05 g of intermediate 17-3 was obtained after purification.

[0254] 4. Intermediate 17-3 (560 mg, 1.43 mmol, 1.00 eq) and potassium thioacetate (246 mg, 2.15 mmol, 1.50 eq) were added to 10 mL of DMF. The reaction was heated to 60 °C and stirred overnight. After purification, 370 mg of intermediate 17-4 was obtained, with a yield of 70%.

[0255] 5. Intermediate 17-4 (370 mg, 1.00 mmol, 1.00 eq) was added to 10 mL of LEtOH, cooled to 0 °C, and 0.75 mL of 2 M sodium hydroxide solution was added dropwise. The reaction was stirred at 0 °C for 1 h. TLC (20% EA / PE) showed that the reaction was complete. The reaction solution was adjusted to neutral with 2 M hydrochloric acid and purified to obtain 300 mg of intermediate 17-5, with a yield of 91%.

[0256] 6. Intermediate 17-5 (300 mg, 0.81 mmol, 1.00 eq) and DHA (346 mg, 1.21 mmol, 1.50 eq) were added to 20 mL of diethyl ether. The reaction was cooled to 0 °C, and boron trifluoride diethyl ether (173 mg, 1.21 mmol, 1.50 eq) was added dropwise. The reaction was stirred at 0 °C for 10 min and then gradually raised to room temperature and stirred for 3 h. TLC (20% EA / PE) showed that the reaction was complete. 280 mg of compound 18 was obtained after purification, with a yield of 52%. Compound 17 was a white solid.

[0257] The NMR results for compound 17 are as follows:

[0258] 1 HNMR(500MHz,CDCl3)δ5.79(s,1H),5.41(s,1H),5.01(s,1H),4.73(d,J=9.2Hz,1H),2.63(s,1H),2.44(s,1H),2.35(t,J=13.7Hz,2H),2 .02(t,J=13.9Hz,3H),1.87(d,J=14.9Hz,3H),1.70(dd,J=35.7,14.2Hz,4H),1.56–1.42(m,7H),1.39–1.22(m,11H),0.96–0.85(m,14H).

[0259] 13 CNMR (126MHz, CDCl3) δ103.85,103.82,101.59,98.79,90.63,88.56,81.17,80.04,52.75,51.56,45.43,44.59,37.41,3 7.37,36.56,36.26,34.85,34.30,32.97,31.17,26.20,25.90,24.79,24.69,24.21,21.99,20.34,20.30,13.09,12.66.

[0260] Example 18: Preparation of Compound 18

[0261]

[0262] 1. Dissolve 1,4-cyclohexanedione (18-1: 4.00 g, 35.67 mmol, 1.00 eq) in 71 mL of methanol, cool to 0 °C, and add NaBH4 (2.70 g, 71.35 mmol, 2.00 eq) in portions. After the addition is complete, stir the reaction at 0 °C for 20 min, then move to room temperature and stir for 1 h. TLC (10% MeOH / DCM) shows that the starting material has disappeared. Quench the reaction with water and purify to obtain 3.20 g of intermediate 18-1.

[0263] 2. Intermediate 18-1 (3.00 g, 25.83 mmol, 1.00 eq) and triethylamine (6.53 g, 64.57 mmol, 2.50 eq) were added to 50 mL of DCM. The reaction was cooled to 0 °C, and methanesulfonyl chloride (6.51 g, 56.82 mmol, 2.20 eq) was slowly added dropwise. The reaction was stirred at 0 °C for 10 min and then moved to room temperature and stirred for 1 h. TLC (2.5% MeOH / DCM) showed that the starting material disappeared. The reaction was quenched with ice water, and the product was purified to obtain 2.08 g of intermediate 18-2 and 1.12 g of intermediate 18-3.

[0264] 3. Intermediate 18-2 (3.00 g, 11.02 mmol, 1.00 eq) was dissolved in 55 mL of DMF, and potassium thioacetate (3.77 g, 33.05 mmol, 3.00 eq) was added. The reaction was heated to 80 °C and stirred for 3 h. TLC (5% EA / PE) showed that the reaction was complete, and 0.90 g of intermediate 18-4 was obtained after purification.

[0265] 4. Intermediate 18-4 (900 mg, 3.87 mmol, 1.00 eq) was dissolved in 25 mL of 95% EtOH, cooled to 0 °C, and 5.8 mL of 2M sodium hydroxide aqueous solution was added dropwise. The reaction was stirred at 0 °C for 0.5 h. TLC (3% EA / PE) showed that the reaction was complete. 100 mL of water was added to the reaction mixture, and the pH was adjusted to 3-4 with 1M hydrochloric acid. The mixture was purified to obtain 500 mg of intermediate 18-5.

[0266] 5. DHA (844 mg, 2.97 mmol, 2.20 eq) was dissolved in 20 mL of diethyl ether, cooled to 0 °C, and stirred for 10 min. Boron trifluoride diethyl ether (574 mg, 4.05 mmol, 3.00 eq) was added dropwise. After the addition was complete, intermediate 18-5 (200 mg, 1.35 mmol, 1.00 eq) was added. The reaction was stirred at 0 °C for 10 min, then moved to room temperature and stirred for 2 h. TLC (20% EA / PE) showed that the reaction was complete. Purification yielded 184 mg of compound 18B and 242 mg of compound 18C, with a combined yield of 47%. Both compounds 18B and 18C were white solids.

[0267] 6. Dissolve 18-3 (1.20 g, 4.41 mmol, 1.00 eq) in 40 mL of DMF, add potassium thioacetate (1.51 g, 13.22 mmol, 3.00 eq), heat the reaction to 80 °C and stir for 3 h. TLC (5% EA / PE) showed that the reaction was complete, and 0.60 g of intermediate 18-6 was obtained after purification.

[0268] 7. Dissolve 18-6 (600 mg, 2.58 mmol, 1.00 eq) in 25 mL of 95% ethanol, cool to 0 °C, and add 3.9 mL of 2M sodium hydroxide aqueous solution dropwise. Stir the reaction at 0 °C for 0.5 h. TLC (3% EA / PE) showed that the reaction was complete, and 280 mg of intermediate 18-7 was obtained after purification.

[0269] 8. DHA (1.05 g, 3.71 mmol, 2.20 eq) was dissolved in 20 mL of diethyl ether, cooled to 0 °C, and stirred for 10 min. Boron trifluoride diethyl ether (717 mg, 5.06 mmol, 3.00 eq) was added dropwise. After the addition was complete, 18-7 (250 mg, 1.69 mmol, 1.00 eq) was added. The reaction was stirred at 0 °C for 10 min, then moved to room temperature and stirred for 2 h. TLC (20% EA / PE) showed that the reaction was complete. Purification yielded 800 mg of compound 18A as a white solid, with a yield of 70%. Compound 18A was a white solid.

[0270] The NMR results for compound 18 are as follows:

[0271] Compound 18A: 1 HNMR(600MHz, CDCl3)δ5.61(s,1H),5.39(s,1H),5.31(d,J=6.0Hz,1H),4.79– 4.72(m,1H),3.24(s,1H),2.99(s,1H),2.69–2.57(m,1H),2.43–2.26(m,3H), 2.04(ddd,J=14.3,7.7,4.6Hz,2H),1.94–1.75(m,6H),1.74–1.62(m,3H),1.5 9–1.46(m,4H),1.42(t,J=10.5Hz,6H),1.41–1.16(m,7H),1.07–0.77(m,16H).

[0272] Compound 18B: 11H NMR (600 MHz, CDCl3) δ 5.62 (s, 2H), 5.35 (t, J = 6.0 Hz, 2H), 3.03 (dd, J = 12.1, 5.1 Hz, 2H), 2.81 (s, 2H), 2.37 (td, J = 14.2, 3.7 Hz, 2H), 2.17–2.12 (m, 4H), 2.08–2.02 (m, 2H), 1.91–1.85 (m, 2H), 1.80–1.72 (m, 2H), 1.68–1.66 (m, 4H), 1.51–1.34 (m, 15H), 1.25 (td, J = 11.3, 6.8 Hz, 3H), 0.94 - 0.88 (m, 14H).

[0273] 13 13C NMR (151 MHz, CDCl3) δ 104.22, 88.07, 85.49, 81.16, 52.67, 45.18, 43.69, 37.18, 36.43, 34.42, 34.14, 33.63, 32.10, 26.20, 24.61, 24.35, 20.33, 14.97.

[0274] Compound 18C: 1 1H NMR (600 MHz, CDCl3) δ 5.62 (s, 1H), 5.35 (d, J = 5.4 Hz, 1H), 5.26 (d, J = 6.1 Hz, 1H), 4.61 (d, J = 10.8 Hz, 1H), 3.02 (dt, J = 17.3, 7.9 Hz, 2H), 2.83 (t, J = 10.8 Hz, 1H), 2.65–2.54 (m, 1H), 2.37 (tt, J = 14.3, 3.8 Hz, 2H), 2.26 (d, J = 9.4 Hz, 1H), 2.14 (dd, J = 10.8, 4.9 Hz, 2H), 2.10–1.98 (m, 3H), 1.92–1.84 (m, 2H), 1.78–1.66 (m, 5H), 1.58 (dt, J = 13.3, 4.0 Hz, 1H), 1.51–1.33 (m, 16H), 1.24 (dd, J = 17.9, 9.5 Hz, 3H), 1.08–1.00 (m, 1H), 0.94 (ddd, J = 18.7, 8.8, 4.6 Hz, 12H).

[0275] 13CNMR(151MHz, CDCl3)δ104.26,104.21,92.13,88.10,85.41,81.16,80.37,79.92,52.67,51.82,46.13,45.20,43.70,40.33,37.37,3 7.20,36.44,36.28,34.58,34.43,34.07,33.84,33.37,32.09,26.19,25.97,24.77,24.63,24.36,21.28,20.33,20.26,15.28,14.97.

[0276] Example 19: Preparation of Compound 19

[0277]

[0278] 1. Cis-1,3-cyclopentanediol (500 mg, 3.73 mmol, 1.00 eq) and triethylamine (1.88 g, 18.63 mmol, 5.00 eq) were added to 10 mL of dichloromethane. The reaction was cooled to 0 °C, and methanesulfonyl chloride (1.28 g, 11.18 mmol, 3.00 eq) was added dropwise. The reaction was stirred at 0 °C for 1 h. TLC (5% MeOH / DCM) showed that the reaction was complete. 976 mg of intermediate 19-1 was obtained after purification.

[0279] 2. Intermediate 19-1 (972 mg, 3.36 mmol, 1.00 eq) was added to 25 mL of DMF, followed by potassium thioacetate (1.15 g, 10.08 mmol, 3.00 eq). The reaction was heated to 60 °C and stirred overnight. TLC (10% EA / PE) showed that the reaction was complete. Purification yielded 312 mg of intermediate 19-2, with a yield of 37%.

[0280] 3. Intermediate 19-2 (300 mg, 1.20 mmol, 1.00 eq) was added to 10 mL of 95% ethanol. The reaction was cooled to 0 °C, and 1.5 mL of 2 M sodium hydroxide solution was added dropwise. The reaction was stirred at 0 °C for 0.5 h. TLC (10% EA / PE) showed that the reaction was complete. The pH of the reaction solution was adjusted to neutral with 1 N HCl, and 154 mg of intermediate 19-3 was obtained after purification.

[0281] 4. Intermediate 19-3 (154 mg, 0.93 mmol, 1.00 eq) and DHA (580 mg, 2.04 mmol, 2.20 eq) were added to 15 mL of diethyl ether. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether (290 mg, 2.04 mmol, 2.20 eq) was added dropwise. The reaction was stirred at 0 °C for 30 min, then cooled to room temperature and stirred for 2 h. TLC (20% EA / PE) showed that the reaction was complete. Purification yielded 164 mg of compound 19A and 188 mg of compound 19B as white solids, with a combined yield of 57%. Both compounds 19A and 19B were terephthalic solids.

[0282] The NMR results for compound 19 are as follows:

[0283] Compound 19A: 1 HNMR(500MHz, CDCl3)δ5.27(s,2H),4.56(d,J=10.7Hz,2H),4.01-3.96(m,2H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.05–1.97(m,3H),1 .90–1.83(m,2H),1.73(d,J=3.9Hz,2H),1.69–1.59(m,5H),1.58–1.50(m,2H),1.48–1.39(m,8H),1.36-1.22(m,7H),0.97-0.90(m,15H).

[0284] Compound 19B: 1 HNMR (500MHz, CDCl3) δ5.58 (s, 2H), 5.26 (d, J = 5.3Hz, 2H), 4.01-3.96 (m, 2H) ,3.04(d,J=7.0Hz,2H),2.36(d,J=3.8Hz,2H),2.08-2.03(s,3H),1.91–1.84( m,2H),1.76–1.69(m,6H),1.65-1.55(m,3H),1.51(dd,J=7.0,4.9Hz,3H),1.4 4(s,5H),1.37–1.29(m,2H),1.25-1.01(d,J=7.3Hz,12H),0.95–0.85(m,8H).

[0285] Example 20: Preparation of Compound 20

[0286]

[0287] As in Example 19, the starting material was cis-cyclobutanediol (500 mg, 5.67 mmol, 1.00 eq), yielding 172 mg of compound 20A (white solid) and 215 mg of compound 20B, with a combined yield of 55%. Both compounds 20A and 20B were white solids.

[0288] The NMR results for compound 20 are as follows:

[0289] Compound 20A: 1 HNMR (500MHz, CDCl3) δ5.27 (s, 2H), 4.53 (d, J = 10.8Hz, 2H), 4.42-4.38 (m, 2H),2.73–2.60(m,4H),2.38–2.30(m,4H),2.05–1.97(m,2H),1.91–1.83( m,2H),1.74(d,J=3.9Hz,2H),1.69–1.62(m,3H),1.48–1.44(m,1H),1.43– 1.38(m,7H),1.36(d,J=3.4Hz,1H),1.28–1.21(m,6H),0.98-0.90(m,14H).

[0290] Compound 20B: 1 HNMR(500MHz, CDCl3)δ5.56(s,2H),5.25(d,J=5.3Hz,2H),4.42–4.38(m,2H),3.04( d,J=7.1Hz,2H),2.68–2.60(m,2H),2.36–2.29(m,4H),2.04(s,2H),1.92–1.86(m,2 H),1.77–1.66(m,4H),1.56(d,J=3.0Hz,1H),1.51(dd,J=7.0,4.9Hz,3H),1.46(s,5 H),1.38(d,J=3.6Hz,1H),1.28–1.20(m,7H),1.04-1.00(m,6H),0.94–0.85(m,7H).

[0291] Example 21: Preparation of compound 21

[0292]

[0293] As in Example 19, the starting material was cis-cyclooctanediol (500 mg, 3.84 mmol, 1.00 eq), yielding 159 mg of compound 21A and 190 mg of compound 21B, with a combined yield of 46%. Both compounds 21A and 21B were white solids.

[0294] The NMR results for compound 21 are as follows:

[0295] Compound 21A: 1 HNMR (500MHz, CDCl3) δ5.33–5.24(m,4H),4.53(d,J=10.8Hz,1H),4.51(d,J=10.8Hz,1H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.2 2–2.13(m,2H),2.13–2.05(m,2H),2.04–1.97(m,2H),1.90–1.61(m,13H),1.48–1.32(m,9H),1.29–1.22(m,6H),0.97-0.91(m,14H).

[0296] Compound 21B: 1 HNMR(500MHz, CDCl3)δ5.58(s,1H),5.56(s,1H),5.34–5.20(m,4H),3.04(d,J=7.0H z,2H),2.36(d,J=3.8Hz,2H),2.22–2.13(m,2H),2.10-2.05(m,4H),1.91–1.84(m,6H) ),1.80–1.66(m,6H),1.57(d,J=3.0Hz,1H),1.50(dd,J=7.0,4.9Hz,3H),1.44(s,5H) ,1.37(d,J=3.6Hz,1H),1.25-1.20(m,7H),1.01(d,J=7.3Hz,6H),0.95-0.85(m,7H).

[0297] Example 22: Preparation of compound 22

[0298]

[0299] As in Example 19, the raw material was prepared by using raw material 22 (5.00 g, 34.67 mmol, 1.00 eq) to obtain 1.93 g of compound 22, with a yield of 57%. Compound 22 was a foamy white solid.

[0300] The NMR results for compound 22 are as follows:

[0301] 1HNMR(500MHz, CDCl3)δ5.57(s,1H),5.24–5.20(m,2H),4.46(d,J=10.6Hz,1H),2.99(s,1H),2.66–2.45(m,5H),2.34(t ,J=13.5Hz,2H),2.05–1.76(m,9H),1.66(t,J=14.2Hz,4H),1.58–1.26(m,15H),1.26–1.17(m,2H),1.02–0.84(m,18H).

[0302] 13 CNMR (126MHz, CDCl3) δ104.21,104.16,92.22,88.02,87.08,81.17,80.83,80 .38,52.69,51.78,46.03,45.19,39.83,38.23,37.99,37.36,37.19,36.43,3 6.27,35.38,35.32,34.44,34.09,32.75,32.69,32.51,32.36,32.26,32.12,31.73,26.19,25.97,24.76,24.61,24.39,21.30,20.34,20.25,15.08,14.84.

[0303] Example 23: Preparation of compound 23

[0304]

[0305] As in Example 19, using raw material 23 (2.00 g, 13.87 mmol, 1.00 eq), 210 mg of compound 23 was obtained, with a yield of 12%. Compound 23 was a white foamy solid.

[0306] The NMR results for compound 23 are as follows:

[0307] 1 HNMR(500MHz, CDCl3)δ5.58(s,2H),5.22(d,J=4.5Hz,2H),3.03(d,J=11.8Hz,4H),2.60–2.51(m,2H),2.36(t,J=13.8Hz,2H),2.03(d,J=12 .9Hz,2H),1.86(d,J=9.8Hz,7H),1.73–1.64(m,6H),1.51(dd,J=31.7,11.4Hz,6H),1.42(m,9H),1.23-1.16(m,6H),0.95(d,J=3.0Hz,12H).

[0308] 13 CNMR (126MHz, CDCl3) δ104.16,88.04,87.78,81.19,52.71,45.22,41.28,37.78 ,37.21,36.45,34.46,32.27,31.37,26.18,25.70,24.62,24.44,20.35,14.89.

[0309] Example 24: Preparation of compound 24

[0310]

[0311] As in Example 19, using raw material 24 (1.00 g, 6.93 mmol, 1.00 eq), 2.60 g of compound 24 was obtained with a yield of 82%. Compound 24 was a white foamy solid 25.

[0312] The NMR results for compound 24 are as follows:

[0313] 1 HNMR(500MHz, CDCl3)δ5.60(s,2H),5.24(d,J=5.7Hz,2H),3.02(d,J=4.8Hz,2H),2.74–2.71(m,2H),2.64–2.54(m,2H),2. 36(t,J=13.9Hz,2H),2.04(d,J=14.4Hz,2H),1.97–1.80(m,6H),1.72–1.69(m6H),1.58–1.20(m,18H),0.96–0.90(m,16H).

[0314] 13 CNMR(126MHz, CDCl3)δ104.14,88.06,88.01,87.27,81.15,81.12,52.70,45.20,39.38,38.63,37.20,37.18 ,36.44,34.46,34.11,32.20,32.13,28.18,28.12,26.17,26.15,24.61,24.58,24.43,24.40,20.35,14.88.

[0315] Example 25: Preparation of Compound 25

[0316]

[0317] 1. Dissolve raw material 25 (1.50 g, 10.41 mmol, 1.00 eq) in 55 mL of MeOH, and slowly add H2SO4 (4.1 g, 41.63 mmol, 4.00 eq). After the addition is complete, heat the reaction mixture to reflux and stir for 3 h. Cool the reaction mixture to 0 °C, add sodium bicarbonate to adjust the pH to neutral, and purify to obtain 1.70 g of intermediate 25-1.

[0318] 2. LiAlH4 (1.45 g, 38.33 mmol, 4.00 eq) was added to 96 mL of THF, cooled to 0 °C and stirred for 10 min; intermediate 25-1 (1.65 g, 95.83 mmol, 1.00 eq) was dissolved in 20 mL of THF and added dropwise to the reaction mixture. After the addition was complete, the mixture was moved to room temperature and stirred for 2 h; after the reaction was completed, the reaction mixture was cooled to 0 °C and purified to obtain 840 mg of intermediate 25-2.

[0319] 3. As in Example 19, using intermediate 25-2 (800 mg, 6.89 mmol, 1.00 eq), 320 mg of compound 25 was obtained, with a yield of 23%. Compound 25 was a white foamy solid.

[0320] The NMR results for compound 25 are as follows:

[0321] 1 HNMR (600MHz, CDCl3) δ5.63 (s, 2H), 5.28 (d, J = 4.3Hz, 2H), 3.11 (d, J = 12.3H z,2H),3.01(s,2H),2.86(d,J=12.5Hz,2H),2.35(d,J=13.8Hz,2H),2.03(d, J=14.0Hz,2H),1.88(d,J=12.3Hz,9H),1.73–1.65(m,4H),1.50(dd,J=22.3, 14.2Hz, 4H), 1.43 (s, 6H), 1.23 (dd, J=25.9, 8.9Hz, 4H), 1.01–0.88 (m, 15H).

[0322] 13 CNMR(151MHz,CDCl3)δ104.15,88.04,87.97,81.21,52.70,45.21,42.49,42 .41,37.17,36.45,34.46,32.33,31.14,26.22,24.62,24.44,20.37,14.96.

[0323] Example 26: Preparation of Compound 26

[0324]

[0325] As in Example 19, the raw material used was raw material 26 (1.00 g, 8.61 mmol, 1.00 eq) to obtain 910 mg of compound 26, with a yield of 66%. Compound 26 was a white foamy solid.

[0326] The NMR results for compound 26 are as follows:

[0327] 1 HNMR(500MHz,CH3CN)δ5.52(m,2H),5.13(m,2H),3.08–2.47(m,10H),2.49–2.25( m,2H),1.97(m,4H),1.90–1.57(m,10H),1.58–1.17(m,14H),0.98-0.94(m,12H).

[0328] 13 CNMR(126MHz,CH3CN)δ104.18,92.18,88.05,88.01,87.41,86.79,81.16,52.70,46.06,45.19,37.35,37 .19,36.87,36.44,34.44,34.18,34.06,32.21,32.09,26.18,24.62,24.38,24.30,20.33,20.25,14.89.

[0329] Example 27: Preparation of Compound 27

[0330]

[0331] 1. Methyltriphenylphosphine bromide (41.17 g, 115.25 mmol, 1.20 eq) was added to 400 mL of THF, purged with argon, and cooled to 0 °C. Potassium tert-butoxide (12.93 mg, 115.25 mmol, 1.20 eq) was added in portions. The reaction was stirred at 0 °C for 30 min, then moved to room temperature and stirred for 3 h. The reaction was cooled to 0 °C. Starting material 27 (15.00 g, 96.04 mmol, 1.00 eq) was dissolved in 50 mL of THF and added dropwise to the reaction mixture. The reaction was stirred at 0 °C for 1 h, then moved to room temperature and stirred overnight. The purified product was 12.5 g of intermediate 27-1.

[0332] 2. Intermediate 27-1 (10.00 g, 64.85 mmol, 1.00 eq), Zn (8.48 g, 129.69 mmol, 2.00 eq), and Cu(OAc)2 (1.18 g, 6.48 mmol, 0.10 eq) were added to 300 mL of diethyl ether, purged with argon, and stirred at room temperature for 3 h. Trichloroacetyl chloride (23.58 g, 129.69 mmol, 2.00 eq) was dissolved in 200 mL of diethyl ether and added dropwise to the reaction mixture. The reaction was stirred overnight at room temperature, and the mixture was purified to obtain 10.50 g of intermediate 27-2.

[0333] 3. Intermediate 27-2 (10.00 g, 37.72 mmol, 1.00 eq) and Zn (12.33 g, 188.59 mmol, 5.00 eq) were added to 100 mL of methanol. Ammonium chloride (20.17 g, 377.17 mmol, 10.00 eq) was added in portions with stirring. The reaction was stirred at room temperature for 5 h. After purification, 6.6 g of intermediate 27-3 was obtained.

[0334] 4. Intermediate 27-3 (2.20 g, 11.21 mmol, 1.00 eq) was added to 30 mL of 6N hydrochloric acid and stirred at room temperature for 3 h to purify and obtain 1.66 g of intermediate 27-4;

[0335] 5. Intermediate 27-4 (600 mg, 3.94 mmol, 1.00 eq) was added to 10 mL of methanol, cooled to 0 °C, and NaBH4 (448 mg, 11.83 mmol, 3.00 eq) was added in portions. The reaction was stirred at 0 °C for 3 h and then moved to room temperature and stirred for 3 h. The mixture was purified to obtain 316 mg of intermediate 27-5.

[0336] 6. As in Example 19, using intermediate 27-5 (300 mg, 1.92 mmol, 1.00 eq), 57 mg of compound 27A and 73 mg of compound 27B were obtained, with a combined yield of 42%. Both compounds 27A and 27B were white solids.

[0337] The NMR results for compound 27 are as follows:

[0338] Compound 27A: 1HNMR(500MHz, CDCl3)δ5.29(s,2H),4.73(d,J=10.8Hz,2H),4.20–4.09(m,1H),3.48(s,1H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.23( s,1H),2.07(s,1H),2.04–1.97(m,2H),1.90–1.83(m,2H),1.7–1.61(m,11H),1.48–1.39(m,8H),1.36–1.22(m,10H),0.97-0.91(m,15H).

[0339] Compound 27B: 1 HNMR(500MHz, CDCl3)δ5.56(s,2H),5.25(d,J=5.3Hz,2H),4.20–4.09(m,1H),3.48( s,1H),3.04(d,J=7.0Hz,2H),2.36(d,J=3.8Hz,2H),2.23(s,1H),2.09–2.04(m,3H) ,1.91–1.84(m,2H),1.76–1.57(m,11H),1.51(dd,J=7.0,4.9Hz,3H),1.44(s,5H),1 .37-1.25(m,12H),1.01(d,J=7.3Hz,5H),0.96(d,J=6.4Hz,6H),0.89–0.85(m,2H).

[0340] Example 28: Preparation of compound 28

[0341]

[0342] 1. LiAlH4 (403 mg, 10.62 mmol, 2.70 eq) was added to 30 mL of THF and cooled to 0 °C. The starting material 28 (1.00 g, 3.93 mmol, 1.00 eq) was dissolved in 9 mL of THF and added dropwise to the reaction mixture. The reaction was stirred at 0 °C for 20 min and then moved to room temperature and stirred for 12 h. TLC (50% EA / PE) showed that the starting material disappeared, and 600 mg of intermediate 28-1 was obtained after purification.

[0343] 2. Intermediate 28-1 (690 mg, 4.05 mmol, 1.00 eq) was dissolved in 20 mL of toluene, and imidazole (820 mg, 12.04 mmol, 2.97 eq), triphenylphosphine (3.16 g, 12.04 mmol, 2.97 eq), and iodine (3.06 g, 12.04 mmol, 2.97 eq) were added sequentially. The reaction was heated to 60 °C and stirred for 12 h. TLC (40% EA / PE) showed that the starting material disappeared, and 400 mg of intermediate 28-2 was obtained after purification.

[0344] 3. Intermediate 28-2 (400 mg, 1.03 mmol, 1.00 eq) was dissolved in 4 mL of LDM, and potassium thioacetate (352 mg, 3.08 mmol, 3.00 eq) was added. The reaction was heated to 60 °C and stirred for 2 h. TLC (40% EA / PE) showed that the starting material disappeared, and 250 mg of intermediate 28-3 was obtained after purification.

[0345] 4. Dissolve intermediate 28-3 (150 mg, 0.52 mmol, 1.00 eq) in 5 mL of 95% ethanol, cool to 0 °C, and slowly add 0.78 mL of 2 M sodium hydroxide aqueous solution. Continue stirring at 0 °C for 15 min. TLC (10% EA / PE) showed that the starting material disappeared, and 100 mg of intermediate 28-4 was obtained after purification.

[0346] 5. Intermediate 28-4 (100 mg, 0.49 mmol, 1.00 eq) and DHA (351 mg, 1.24 mmol, 2.50 eq) were dissolved in 5 mL of diethyl ether. The mixture was cooled to 0 °C, and boron trifluoride diethyl ether (210 mg, 1.48 mmol, 3.00 eq) was slowly added dropwise. The reaction was stirred at 0 °C for 30 min and then moved to room temperature and stirred for 2 h. TLC (40% EA / PE) showed that the starting material disappeared. After purification, 91 mg of compound 28A and 109 mg of compound 28B were obtained, with a yield of 55%. Both compounds 28A and 28B were white solids.

[0347] The NMR results for compound 28 are as follows:

[0348] Compound 28A: 1HNMR (600MHz, CDCl3) δ5.58(s,2H),5.16(d,J=5.2Hz,2H),3.01(d,J=7.0Hz,2H),2.64(d,J=12.5Hz,2H),2.57(d,J=6.8Hz,1H),2.45(d,J=12.5 Hz,2H),2.40–2.31(m,2H),2.06-2.02(m,2H),1.90–1.83(m,4H),1.73– 1.67(m,4H),1.58–1.33(m,21H),1.27–1.20(m,4H),1.00–0.85(m,14H).

[0349] Compound 28B: 1 HNMR(600MHz, CDCl3)δ5.25(s,2H),4.49–4.43(d,J=10.7Hz,2H),3.04-2.98( m,2H),2.63(d,J=12.0Hz,2H),2.58(d,J=7.0Hz,1H),2.46(d,J=12.4Hz,2H), 2.41–2.30(m,2H),2.04-2.00(m,2H),1.93–1.85(m,4H),1.72-1.66(m,4H),1 .58–1.33(m,22H),1.25-1.20(m,3H),1.15-1.04(m,2H),1.00–0.85(m,12H).

[0350] Example 29: Preparation of compound 29

[0351]

[0352] 1. LiAlH4 (279 mg, 7.35 mmol, 2.50 eq) was added to 20 mL of THF and cooled to 0 °C. 30-1 (500 mg, 2.94 mmol, 1.00 eq) was dissolved in 9 mL of THF and added dropwise to the reaction mixture. The reaction was stirred at 0 °C for 20 min and then moved to room temperature and stirred for 1 h. 300 mg of intermediate 29-1 was obtained after purification.

[0353] 2. Intermediate 29-1 (740 mg, 5.77 mmol, 1.00 eq) was dissolved in 58 mL of DCM and cooled to 0 °C. Imidazole (1.14 g, 16.74 mmol, 2.97 eq), triphenylphosphine (4.39 g, 16.74 mmol, 2.97 eq), and iodine (4.25 g, 16.74 mmol, 2.97 eq) were added sequentially. The reaction was stirred at 0 °C for 10 min and then moved to room temperature and stirred for 2 h. The mixture was purified to obtain 1.50 g of intermediate 29-2.

[0354] 3. Intermediate 29-2 (100 mg, 0.29 mmol, 1.00 eq) was dissolved in 3 mL of LDMF, and SDHA-B (168 mg, 0.56 mmol, 1.95 eq) and potassium carbonate (79 mg, 0.57 mmol, 2.00 eq) from Example 1 were added sequentially. The reaction was stirred at room temperature for 2 h, and 102 mg of compound 29B was obtained after purification (51% yield). Compound 29B was a colorless oily liquid.

[0355] 4. Intermediate 29-2 (100 mg, 0.29 mmol, 1.00 eq) was dissolved in 3 mL of DMF, and SDHA-A (168 mg, 0.56 mmol, 1.95 eq) and potassium carbonate (79 mg, 0.57 mmol, 2.00 eq) from Example 1 were added sequentially. The reaction was stirred at room temperature for 2 h, and 104 mg of compound 29A was obtained after purification, with a yield of 52%. Compound 29A was a white solid.

[0356] The NMR results for compound 29 are as follows:

[0357] Compound 29A: 1 HNMR (600MHz, CDCl3) δ5.18(s,2H),4.46(d,J=10.7Hz,2H),2.86(d,J=13.2Hz,2H),2.73(d ,J=13.3Hz,2H),2.51–2.41(m,2H),2.29(td,J=14.1,3.9Hz,2H),1.97–1.90(m,2H),1.83–1 .76(m,2H),1.69–1.58(m,7H),1.50(dt,J=13.3,4.0Hz,2H),1.45–1.33(m,10H),1.31–1.22 (m,5H),1.21–1.14(m,2H),1.01–0.92(m,2H),0.89(d,J=6.3Hz,6H),0.85(d,J=7.2Hz,6H).

[0358] Compound 29B: 1HNMR (600MHz, CDCl3) δ5.60 (s, 2H), 5.22 (d, J = 5.6Hz, 2H), 3.03–3.01 (m, 2H), 2.85 (d, J = 14.3Hz, 2H), 2.74d, J = 12.3Hz, 2H), 2. 36(td,J=14.1,4.0Hz,2H),1.84–1.72(m,2H),1.70–1.58(m,13H),1.50–1.33(m,12H),1.25–1.23(m,3H),0.98–0.94(m,14H).

[0359] Example 30: Preparation of compound 30

[0360]

[0361] 1. Dissolve raw material 30 (50.00 g, 128.10 mmol, 1.00 eq) and thioacetic acid (12.71 g, 166.51 mmol, 1.30 eq) in 650 mL of DCM, cool to 0 °C, and slowly add boron trifluoride diethyl ether (29.11 g, 204.9 mmol, 1.60 eq). After the addition is complete, move to room temperature and stir overnight. Purify to obtain 28.22 g of intermediate 30-1.

[0362] 2. Add intermediate 30-1 (18.00 g, 44.29 mmol, 1.00 eq) to 1.5 L of methanol, cool to -25 °C, and slowly add 97 mL of 0.5 M sodium methoxide methanol solution. After the addition is complete, continue stirring at -25 °C for 30 min. Adjust the pH of the reaction to neutral using a cation exchange resin and purify to obtain 16.00 g of intermediate 30-2.

[0363] 3. Dissolve DHA (18.73 g, 65.87 mmol, 1.50 eq) in 400 mL of diethyl ether, cool to 0 °C, and add boron trifluoride diethyl ether (12.46 g, 87.82 mmol, 2.00 eq) dropwise. Then dissolve intermediate 30-2 (16.00 g, 43.91 mmol, 1.00 eq) in 40 mL of diethyl ether and add it dropwise to the reaction. After the addition is complete, move the reaction to room temperature and stir overnight. Purify to obtain 20.15 g of intermediate 30-3.

[0364] 4. Dissolve intermediate 30-3 (20.00 g, 31.71 mmol, 1.00 eq) in 320 mL of methanol, cool to 0 °C, add sodium methoxide (1.03 g, 19.03 mmol, 0.60 eq), stir the reaction at 0 °C for 10 min, then move to room temperature and stir for 2 h. Adjust the pH of the reaction solution to neutral using a cation exchange resin, and purify to obtain 13.22 g of intermediate 30-4;

[0365] 5. Intermediate 30-4 (3.00 g, 6.49 mmol, 1.00 eq) was dissolved in 30 mL of pyridine, cooled to 0 °C, and p-toluenecycloyl chloride (1.36 g, 7.13 mmol, 1.10 eq) and DMAP (79 mg, 0.65 mmol, 0.10 eq) were added. The reaction was stirred at 0 °C for 10 min and then moved to room temperature and stirred for 3 h. TLC (5% MeOH / DCM) showed that the reaction was complete, and 2.30 g of intermediate 30-5 was obtained after purification.

[0366] 6. Intermediate 30-5 (1.00 g, 1.62 mmol, 1.00 eq) and SDHA-A (731 mg, 2.43 mmol, 1.50 eq) from Example 1 were dissolved in 32 mL of DMF, and potassium carbonate (448 mg, 3.24 mmol, 2.00 eq) was added. The reaction was stirred overnight at room temperature, and the mixture was purified to give 160 mg of compound 30, with a yield of 13%. Compound 30 was a pale red solid.

[0367] The NMR results for compound 30 are as follows:

[0368] 1 HNMR (500MHz, CDCl3) δ5.69(d,J=5.2Hz,1H),5.61(s,1H),5.37(s,1H),4.51(d,J=10.7Hz,1H),4.35(d,J=9.5Hz,1H),4. 15(d,J=4.4Hz,1H),4.02(td,J=9.2,4.7Hz,1H),3.83(t,J=8.7Hz,1H),3.59(dd,J=17.1,8.8Hz,2H),3.20(d,J=13.0Hz, 1H),3.04(dd,J=6.6,2.8Hz,3H),2.97(s,1H),2.60(d,J=10.8Hz,1H),2.36(t,J=14.0Hz,2H),2.08–1.99(m,2H),1.96–1 .84(m,2H),1.79–1.57(m,6H),1.55–1.31(m,12H),1.26(tt,J=11.8,6.1Hz,3H),1.09–1.01(m,1H),1.00–0.90(m,12H).

[0369] Example 31: Preparation of compound 31

[0370]

[0371] Intermediate 30-4 (50.00 g, 128.10 mmol, 1.00 eq) from Example 30 and thioacetic acid (12.71 g, 166.51 mmol, 1.30 eq) were dissolved in 650 mL of DCM, cooled to 0 °C, and boron trifluoride diethyl ether (29.11 g, 204.9 mmol, 1.60 eq) was slowly added dropwise. After the addition was complete, the mixture was moved to room temperature and stirred overnight. The mixture was purified to give 28.22 g of compound 31, with a yield of 54%. Compound 31 was a white solid.

[0372] The NMR results for compound 31 are as follows:

[0373] 1 HNMR (600MHz, CDCl3) δ6.34(d,J=3.5Hz,1H),5.48(t,J=9.9Hz,1H),5.15(t,J=9.8Hz,1H),5.11(dd,J=10.3,3.6Hz,1 H),4.28(dd,J=12.3,3.7Hz,1H),4.14–4.07(m,2H),2.19(s,3H),2.10(s,3H),2.05(s,3H),2.04(s,3H),2.03(s,3H).

[0374] Example 32: Preparation of compound 32

[0375]

[0376] As in Example 31, p-benzene dithiophenol (500 mg, 3.52 mmol, 1.00 eq) was used as the raw material to obtain 423 mg of compound 32A, 454 mg of compound 32B and 453 mg of compound 32C, with a combined yield of 56%. Compounds 32A, 32B and 32C were all white solids.

[0377] The NMR results for compound 32 are as follows:

[0378] Compound 32A: 1HNMR (600MHz, CDCl3) δ7.30 (s, 4H), 5.25 (s, 2H), 4.40 (d, J = 10.7Hz, 2H), 2.66 –2.53(m,2H),2.38(td,J=14.1,3.9Hz,2H),2.09–2.00(m,2H),1.94–1.84(m,2 H),1.70–1.59(m,4H),1.58–1.48(m,4H),1.47(s,6H),1.37–1.28(m,2H),1.28 –1.21(m,4H),1.03–0.96(m,2H),0.95(d,J=6.3Hz,6H),0.80(d,J=7.2Hz,6H).

[0379] Compound 32B: 1 HNMR(600MHz, CDCl3)δ7.27(d,J=9.0Hz,4H),5.66(s,2H),5.18(d,J=5.4Hz,2H),2 .98(dd,J=12.2,5.1Hz,2H),2.40–2.36(m,2H),2.12–2.01(m,2H),1.90–1.87(m,2H ),1.85–1.74(m,2H),1.71–1.64(m,4H),1.62–1.47(m,4H),1.46(s,6H),1.44–1.35 (m,3H),1.25(td,J=11.6,6.6Hz,3H),0.95(d,J=6.4Hz,6H),0.82(d,J=7.3Hz,6H).

[0380] Compound 32C: 1 HNMR (600MHz, CDCl3) δ7.32-7.26 (m, 4H), 5.61 (s, 1H), 5.26 (s, 1H), 5.19 (d, J = 5.4 Hz,1H),4.40(d,J=10.7Hz,1H),2.97(d,J=5.1Hz,1H),2.66–2.53(m,1H),2.39-2. 30(m,2H),2.12–2.01(m,2H),1.94–1.88(m,2H),1.85–1.78(m,1H),1.70–1.59(m, 4H),1.58–1.47(s,9H),1.37–1.21(m,7H),1.03–0.96(m,1H),0.95-0.80(m,12H).

[0381] Example 33: Preparation of compound 33

[0382]

[0383] As in Example 31, the raw material used was o-benzyldithiophenol (600 mg, 4.22 mmol, 1.00 eq), yielding 415 mg of compound 33A, 472 mg of compound 33B, and 363 mg of compound 33C in a yield of 44%. Compounds 33A, 33B, and 33C were all white solids.

[0384] The NMR results for compound 33 are as follows:

[0385] Compound 33A: 1 HNMR (600MHz, CDCl3) δ7.31 (s, 1H), 7.26-7.22 (m, 3H), 5.30 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 2.61 (s, 2H), 2.38 (d, J = 3.6Hz ,2H),2.03(d,J=14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H),0.95(d,J=6.3Hz,6H),0.82(d,J=7.1Hz,6H).

[0386] Compound 33B: 1 HNMR(600MHz, CDCl3)δ7.34(s,1H),7.24-7.21(m,3H),5.66(s,2H),5.21(d, J=5.3Hz,2H),2.99(dd,J=12.0,5.2Hz,2H),2.38(td,J=14.0,3.7Hz,2H),2.0 6(d,J=15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36(m,12H ),1.25(td,J=11.6,6.7Hz,4H),0.95(d,J=6.4Hz,6H),0.85(d,J=7.3Hz,6H).

[0387] Compound 33C: 1HNMR (600MHz, CDCl3) δ7.32 (s, 1H), 7.26-7.22 (m, 3H), 5.66 (s, 1H), 5.30 (s, 1H), 5.21 (d, J = 5.3Hz, 1H), 4.42 (d, J = 10.7Hz, 1H), 2.99 (dd, J = 12. 0,5.2Hz,1H),2.61(s,1H),2.40-2.36(m,2H),2.06–2.01(m,2H),1.94- 1.86(m,4H),1.71-1.64(m,2H),1.59–0.99(m,18H),0.95-0.82(m,12H).

[0388] Example 34: Preparation of compound 34

[0389]

[0390] 1. Add starting material 34 (10.00 g, 80.51 mmol, 1.00 eq) and triethylamine (12.22 g, 120.77 mmol, 1.50 eq) to 250 mL of DCM, add acetic anhydride (9.86 g, 96.62 mmol, 1.20 eq), and stir the reaction overnight at room temperature; TCL (3% EA / PE) showed that the starting material disappeared, and 11.50 g of intermediate 34-1 was obtained after purification;

[0391] 2. Intermediate 34-1 (11.00 g, 66.17 mmol, 1.00 eq) and NBS (12.96 g, 72.79 mmol, 1.10 eq) were added to 110 mL of CCl4, and AIBN (1.09 g, 6.62 mmol, 0.10 eq) was added to replace the argon gas. The reaction was heated to reflux and stirred under reflux for 3 h. The purified product was 12.50 g of intermediate 34-2.

[0392] 3. Intermediate 34-2 (2.00 g, 8.16 mmol, 1.00 eq) and potassium thioacetate (1.12 g, 9.79 mmol, 1.20 eq) were added to 25 mL of DMF, and the reaction was stirred at 60 °C for 1 h. TCL (3% EA / PE) showed that the starting material disappeared, and 1.00 g of intermediate 34-3 was obtained after purification.

[0393] 4. Dissolve intermediate 34-3 (1.00 g, 4.16 mmol, 1.00 eq) in 20 mL of 95% ethanol, cool to 0 °C, add 2N sodium hydroxide (6.2 mL, 12.48 mmol, 3.00 eq) dropwise to the reaction, stir at 0 °C for 10 min, then move to room temperature and stir for 1 h; TCL (5% EA / PE) showed that the starting material disappeared, and 0.50 g of intermediate 34-4 was obtained after purification;

[0394] 5. Intermediate 34-4 (400 mg, 2.70 mmol, 1.00 eq) and DHA (1.69 g, 5.93 mmol, 2.20 eq) were added to 25 mL of diethyl ether, cooled to 0 °C, and boron trifluoride diethyl ether (1.15 g, 8.09 mmol, 3.00 eq) was added dropwise. The mixture was stirred at 0 °C for 10 min and then moved to room temperature and stirred for 2 h. TCL (15% EA / PE) showed that the starting material disappeared. After purification, 1.1 g of compound 34 was obtained with a yield of 60%. Compound 34 was a white solid.

[0395] The NMR results for compound 34 are as follows:

[0396] 1 HNMR (600MHz, CDCl3) δ7.47(d,J=8.2Hz,2H),7.27(d,J=8.3Hz,2H),5.73(s,1H),5.65(s,1H),5.53( d,J=5.3Hz,1H),5.19(d,J=5.4Hz,1H),3.84(d,J=5.2Hz,2H),3.05(dd,J=72.7,7.1Hz,2H),2.38(dd d,J=14.2,9.1,4.0Hz,2H),2.06(d,J=14.4Hz,2H),1.94–1.86(m,2H),1.85–1.64(m,6H),1.56–1.21 (m,16H),1.05(d,J=7.3Hz,3H),0.98(d,J=6.3Hz,3H),0.95(d,J=6.4Hz,3H),0.84(d,J=7.3Hz,3H).

[0397] Example 35: Preparation of compound 35

[0398]

[0399] The starting material 35 (100 mg, 0.28 mmol, 1.00 eq) and SDHA-A from Example 1 (168 mg, 0.56 mmol, 2.00 eq) were added to 6 mL of DMF, and potassium carbonate (116 mg, 0.84 mmol, 3.00 eq) was added to react. After purification, 140 mg of compound 35A was obtained with a yield of 71%. 35A was a white solid.

[0400] The starting material 35 (300 mg, 0.84 mmol, 1.00 eq) and SDHA-B from Example 1 (503 mg, 1.68 mmol, 2.00 eq) were added to 15 mL of DMF, and potassium carbonate (348 mg, 5.21 mmol, 3.00 eq) was added to react. After purification, 310 mg of compound 35B was obtained, with a yield of 52%. Compound 35B was a white solid.

[0401] The NMR results for compound 35 are as follows:

[0402] Compound 35A: 1 HNMR (600MHz, CDCl3) δ7.30 (s, 4H), 5.25 (s, 2H), 4.40 (d, J = 10.7Hz, 2H), 3.99 (d, J = 13.1H z,2H),3.85(d,J=13.1Hz,2H),2.66–2.53(m,2H),2.38(td,J=14.1,3.9Hz,2H),2.09–2.00 (m,2H),1.94–1.84(m,2H),1.70–1.59(m,4H),1.58–1.48(m,4H),1.47(s,6H),1.37–1.28( m,2H),1.28–1.21(m,4H),1.03–0.96(m,2H),0.95(d,J=6.3Hz,6H),0.80(d,J=7.2Hz,6H).

[0403] 13 CNMR(151MHz,CDCl3)δ137.12,129.21,104.34,92.32,80.49,79.41,51.83,4 6.13,37.31,36.30,34.02,32.35,31.89,26.04,24.76,21.24,20.24,14.80.

[0404] Compound 35B: 1HNMR(600MHz, CDCl3) δ7.27(d,J=9.0Hz,4H),5.66(s,2H),5.18(d,J=5.4Hz,2H),3.85(s,4H) ,2.98(dd,J=12.2,5.1Hz,2H),2.38(td,J=14.1,3.9Hz,2H),2.12–2.01(m,2H),1.88(ddd,J= 13.4,6.5,3.3Hz,2H),1.85–1.74(m,2H),1.71–1.64(m,4H),1.62–1.47(m,4H),1.46(s,6H), 1.44–1.35(m,3H),1.25(td,J=11.6,6.6Hz,3H),0.95(d,J=6.4Hz,6H),0.82(d,J=7.3Hz,6H).

[0405] Example 36: Preparation of compound 36

[0406]

[0407] 1. The starting material 36 (2.00 g, 14.48 mmol, 1.00 eq), triphenylphosphine (7.59 g, 28.95 mmol, 2.00 eq), and imidazole (1.97 g, 28.95 mmol, 2.00 eq) were dissolved in 150 mL of DCM, cooled to 0 °C, and stirred for 10 min. Iodine (7.35 g, 28.95 mmol, 2.00 eq) was slowly added in portions. After the addition was complete, the mixture was moved to room temperature and stirred for 1 h. TCL (3% EA / PE) showed that the starting material disappeared. The purified product was 3.70 g of intermediate 36-1.

[0408] 2. Intermediate 36-1 (300 mg, 0.84 mmol, 1.00 eq) and SDHA-A (503 mg, 1.68 mmol, 2.00 eq) from Example 1 were dissolved in 17 mL of DMF, and potassium carbonate (348 mg, 2.51 mmol, 3.00 eq) was added. The reaction was stirred at room temperature for 2 h. TCL (10% EA / PE) showed that the starting material disappeared. After purification, 300 mg of compound 36A was obtained, with a yield of 51%. Compound 36A was a white solid.

[0409] 3. Intermediate 36-1 (300 mg, 0.84 mmol, 1.00 eq) and SDHA-B (503 mg, 1.68 mmol, 2.00 eq) from Example 2 were dissolved in 17 mL of DMF, and potassium carbonate (348 mg, 2.51 mmol, 3.00 eq) was added. The reaction was stirred at room temperature for 2 h. TCL (10% EA / PE) showed that the starting material disappeared. After purification, 240 mg of compound 36B was obtained with a yield of 40%. Compound 36B was a white solid.

[0410] The NMR results for compound 36 are as follows:

[0411] Compound 36A: 1 HNMR (600MHz, CDCl3) δ7.31 (s, 1H), 7.26-7.22 (m, 3H), 5.30 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 3.98 (d, J = 12.8Hz, 2H), 3.86 (d, J = 12.8Hz, 2H), 2.61 ( s,2H),2.38(d,J=3.6Hz,2H),2.03(d,J=14.8Hz,2H),1.87(m,2H),1.65( m,4H),1.59–0.99(m,18H),0.95(d,J=6.3Hz,6H),0.82(d,J=7.1Hz,6H).

[0412] Compound 36B: 1 HNMR (600MHz, CDCl3) δ7.34 (s, 1H), 7.24-7.21 (m, 3H), 5.66 (s, 2H), 5.21 (d, J = 5.3Hz ,2H),3.86(dd,J=27.3,13.0Hz,4H),2.99(dd,J=12.0,5.2Hz,2H),2.38(td,J=14.0, 3.7Hz,2H),2.06(d,J=15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36 (m,12H),1.25(td,J=11.6,6.7Hz,4H),0.95(d,J=6.4Hz,6H),0.85(d,J=7.3Hz,6H).

[0413] Example 37: Preparation of compound 37

[0414]

[0415] 1. Lithium aluminum hydride (2.31 g, 60.76 mmol, 3.00 eq) was dissolved in 100 mL of THF, cooled to 0 °C and stirred for 10 min. The starting material 37 (3.00 g, 20.25 mmol, 1.00 eq) was dissolved in 20 mL of THF and slowly added dropwise to the reaction mixture. The reaction was stirred at 0 °C for 30 min and then moved to room temperature and stirred overnight. TLC (30% EA / PE) showed that the starting material disappeared, and 2.50 g of intermediate 37-1 was obtained after purification.

[0416] 2. As in Example 36, using intermediate 37-1 (1.50 g, 10.86 mmol, 1.00 eq), 140 mg of compound 37A and 190 mg of compound 37B were obtained, with a yield of 24%. Both compounds 37A and 37B were white solids.

[0417] The NMR results for compound 37 are as follows:

[0418] Compound 37A: 1 HNMR (600MHz, CDCl3) δ7.33 (dd, J=5.3, 3.6Hz, 2H), 7.18 (dd, J=5.5, 3.4Hz, 2H), 5.25 ( d,J=8.5Hz,2H),4.43(d,J=10.7Hz,2H),4.10(m,4H),2.68–2.52(m,2H),2.38(td,J=1 4.0,3.7Hz,2H),2.02(s,2H),1.92–1.83(m,2H),1.69–1.60(m,4H),1.57–1.38(m,10H ),1.35–1.19(m,8H),1.04–0.96(m,2H),0.95(d,J=6.3Hz,6H),0.81(d,J=7.2Hz,6H).

[0419] Compound 37B: 1HNMR(600MHz, CDCl3)δ7.31(dd,J=5.4,3.5Hz,2H),7.21–7.16(m,2H),5.66(s,2H),5.24(d,J=5.3 Hz,2H),4.15–4.07(m,2H),3.98(d,J=13.1Hz,2H),2.99(dd,J=12.2,5.1Hz,2H),2.38(td,J=14.1, 3.9Hz,2H),2.09–2.03(m,2H),1.93–1.85(m,2H),1.80(qd,J=13.9,3.8Hz,2H),1.70–1.61(m,4H) ,1.58–1.44(m,10H),1.41–1.33(m,2H),1.22(m,4H),0.95(d,J=6.4Hz,6H),0.81(d,J=7.3Hz,6H).

[0420] Example 38: Preparation of compound 38

[0421]

[0422] As in Example 19, raw material 38 was used to obtain 0.70g of compound 38, with a yield of 36%. Compound 38 was a white foamy compound.

[0423] The NMR results for compound 38 are as follows:

[0424] 1 HNMR (500MHz, CDCl3) δ5.52(s,2H),5.40(d,J=4.8Hz,2H),3.94(q,J=13.2Hz,4H),3.04(d,J=5.6Hz,2H),2.36(t,J=13.3Hz,2H) ,2.04(d,J=14.3Hz,2H),1.86(s,2H),1.69(dd,J=33.2,13.3Hz,6H),1.54–1.31(m,12H),1.29–1.18(m,2H),0.98–0.82(m,14H).

[0425] 13 CNMR (126MHz, CDCl3) δ104.25,87.96,87.12,81.00,52.62,44.98,37.18,36.32,34.37,32.15,26.03,24.51,23.58,20.29,14.58.

[0426] Example 39: Preparation of compound 39

[0427]

[0428] 1. Under argon protection, LiAlH4 (351 mg, 9.25 mmol, 2.50 eq) was dispersed in 22 mL of THF and cooled to 0 °C. The starting material 39 (1.00 g, 3.70 mmol, 1.00 eq) was dissolved in 15 mL of THF and added dropwise to the reaction. After the addition was complete, the reaction was warmed back to 8 °C and stirred for 12 h. The purified product was 0.70 g of intermediate 39-1.

[0429] 2. As in Example 19, using intermediate 39-1 (0.70 g, 3.27 mmol, 1.00 eq), 0.40 g of compound 39 was obtained with a yield of 35%. Compound 39 was a white foamy solid.

[0430] The NMR results for compound 39 are as follows:

[0431] 1 HNMR(500MHz, CDCl3) δ7.52(d,J=7.7Hz,4H),7.42(d,J=7.8Hz,4H),5.69(s,2 H),5.25(d,J=4.3Hz,2H),3.92(s,4H),3.00(s,2H),2.39(t,J=12.8Hz,2H),2 .07(d,J=15.2Hz,2H),1.83-1.71(m,4H),1.68(t,J=13.4Hz,4H),1.56–1.44( m,8H),1.40(s,2H),1.26(d,J=5.3Hz,4H),0.96(m,8H),0.86(d,J=7.1Hz,6H).

[0432] Example 40: Preparation of Compound 40

[0433]

[0434] 1. Dissolve raw material 40 (1.50 g, 6.94 mmol, 1.00 eq) in 30 mL of MeOH, add SOCl2 (4.13 g, 34.69 mmol, 5.00 eq), heat the reaction to 80 °C and stir for 12 h, and purify to obtain 1.69 g of intermediate 40-1;

[0435] 2. As in Example 39, intermediate 40-1 (2.20 g, 9.01 mmol, 1.00 eq) was used to obtain 0.30 g of compound 40A and 0.70 g of compound 40B. Both compound 40A and compound 40B were white foamy.

[0436] The NMR results for compound 40 are as follows:

[0437] Compound 40A: 1 HNMR(500MHz, CDCl3)δ8.34–8.21(m,2H),7.55(d,J=3.0Hz,2H),7.39(s,2H), 5.32(s,2H),4.47(d,J=11.8Hz,2H),4.47(d,J=11.8Hz,4H),4.32(d,J=12.8Hz ,2H),2.70(s,2H),2.41(t,J=13.8Hz,2H),2.06(d,J=14.4Hz,2H),1.89(s,2H) ,1.72–1.46(m,12H),1.26-1.21(m,6H),1.01-0.95(m,7H),0.93–0.65(m,7H).

[0438] Compound 40B: 1 HNMR(500MHz, CDCl3)δ8.17(s,2H),7.56(s,2H),7.41(s,2H),,5.71(s,2H),5.3 4(s,2H),4.39(d,J=13.0Hz,2H),4.24(d,J=12.9Hz,2H),3.01(s,2H),2.39(t,J= 13.6Hz,2H),2.09(d,J=14.1Hz,2H),1.88(s,2H),1.84–1.71(m,2H),1.69–1.42 (m,14H),1.37(s,2H),1.25(d,J=6.1Hz,2H),0.91(m,8H),0.77(d,J=6.8Hz,6H).

[0439] 13 CNMR(126MHz, CDCl3)δ133.42,133.42,131.99,127.04,125.88,124.95,104.29,88.27,85.97 ,81.25,52.69,45.10,37.17,36.42,34.37,34.04,32.04,26.23,24.65,24.43,20.35,14.63.

[0440] Example 41: Preparation of compound 41

[0441]

[0442] 1. Dissolve raw material 41 (1.00 g, 4.74 mmol, 1.00 eq) in acetic anhydride (8.9 mL, 94.73 mmol, 20.00 eq), replace with argon gas, heat to 100 °C and react for 16 h, and purify to obtain 0.90 g intermediate 41-1;

[0443] 2. Dissolve intermediate 41-1 (0.50 g, 2.09 mmol, 1.00 eq) in 4 mL of THF, replace with argon gas, cool to 0 °C, and then add DIBAH (8.57 mL, 8.57 mmol, 4.10 eq) dropwise. After reacting at 0 °C for 30 min, the temperature is raised to room temperature and stirred for 18 h. The resulting product is purified to obtain 100 mg of intermediate 41-2.

[0444] 3. Dissolve intermediate 41-2 (100 mg, 0.55 mmol, 1.00 eq) in 3 mL of DCM, cool to 0 °C, add triethylamine (0.22 mL, 1.64 mmol, 3.00 eq), and add MsCl (0.11 mL, 1.36 mmol, 2.50 eq) dropwise. Stir the reaction at 0 °C for 30 min, then return to room temperature and stir for 1 h. Purify to obtain 150 mg of intermediate 41-3.

[0445] 4. Under argon protection, intermediate 41-3 (180 mg, 0.53 mmol, 1.00 eq) and SDHA-A (318 mg, 1.06 mmol, 2.00 eq) from Example 1 were dissolved in 4 mL of DMF, and K2CO3 (183 mg, 1.33 mmol, 2.50 eq) was added. The reaction was stirred at room temperature for 3 h, and purified to give 180 mg of compound 41A, with a yield of 45%. Compound 41A was a pale yellow solid.

[0446] 5. Under argon protection, intermediate 41-3 (230 mg, 0.68 mmol, 1.00 eq) and SDHA-B (407 mg, 1.69 mmol, 2.50 eq) from Example 1 were dissolved in 4 mL of DMF, and K2CO3 (234 mg, 1.69 mmol, 2.50 eq) was added. The reaction was stirred at room temperature for 3 h, and the mixture was purified to give 243 mg of compound 41B, with a yield of 48%. Compound 41B was a pale yellow solid.

[0447] The NMR results for compound 41 are as follows:

[0448] Compound 41A: 1HNMR (600 MHz, CDCl3) δ 7.69 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.32 (dd, J = 19.4, 12.0 Hz, 1H), 5.27 (d, J = 8.4 Hz, 2H), 4.73 (d, J = 10.8 Hz, 1H), 4.57 (d, J = 10.5 Hz, 1H), 4.48 (d, J = 11.0 Hz, 1H), 4.39–4.29 (m, 2H), 4.16 (d, J = 13.2 Hz, 1H), 3.16 - 3.08 (m, 1H), 2.71 (s, 1H), 2.56 (d, J = 45.1 Hz, 2H), 2.37 (d, J = 13.4 Hz, 3H), 2.20–2.07 (m, 1H), 2.01 (d, J = 12.0 Hz, 3H), 1.88 (s, 3H), 1.67 (s, 2H), 1.57 - 1.44 (m, 9H), 1.25 (s, 2H), 0.99 - 0.83 (m, 15H).

[0449] Compound 41B: 1 HNMR (500 MHz, CDCl3) δ 7.72 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.30 (dd, J = 17.3, 9.5 Hz, 1H), 5.58 (d, J = 7.5 Hz, 2H), 5.30 (s, 2H), 4.36 (t, J = 15.8 Hz, 1H), 4.22 (d, J = 13.2 Hz, 1H), 4.12 (s, 2H), 3.73 (dd, J = 13.9, 7.1 Hz, 1H), 3.01 (s, 2H), 2.37 (t, J = 14.0 Hz, 2H), 2.04 (d, J = 7.1 Hz, 2H), 1.89 - 1.80 (m, 2H), 1.76 (s, 2H), 1.65 (d, J = 17.9 Hz, 5H), 1.49 - 1.44 (m, 8H), 1.37 (s, 2H), 1.30–1.18 (m, 4H), 0.95 (s, 6H), 0.88 (d, J = 5.6 Hz, 6H).

[0450] 13CNMR(126MHz, CDCl3)δ150.70,140.10,134.84,132.06,127.60,123.96,104.26,104.21,88.11,88.02,86.84,86.17,8 1.07,52.63,44.99,37.21,37.17,36.35,34.36,34.05,32.13,32.03,28.90,26.09,24.60,24.42,20.32,14.61,14.54.

[0451] Example 42: Preparation of compound 42

[0452]

[0453] As in Example 39, using raw material 42 (1.00 g, 5.10 mmol, 1.00 eq), 414 mg of compound 42A and 422 mg of compound 42B were obtained, with a combined yield of 67%. Both compounds 42A and 42B were white solids.

[0454] The NMR results for compound 42 are as follows:

[0455] Compound 42A: 1 HNMR (500MHz, CDCl3) δ6.91(s,1H),6.80(s,2H),5.30(s,2H),4.45(d,J=10.7Hz,2H),3.95(d,J=12.8Hz,2H),3.85(d,J=12.8Hz,2H),3.80(s ,3H),2.65–2.56(m,2H),2.38-2.27(m,2H),2.03-1.96(m,3H),1.92–1 .84(m,3H),1.71–1.40(m,12H),1.28-1.13(m,6H),1.05–0.79(m,14H).

[0456] 13 CNMR (126MHz, CDCl3) δ159.85,139.81,122.54,113.33,104.31,92.34,80.50,79.58,55.30,51. 86,46.17,37.26,36.32,35.43,34.06,32.82,31.96,26.04,24.73,21.24,20.27,14.86,14.13.

[0457] Compound 42B: 1HNMR (500MHz, CDCl3) δ6.94 (s, 1H), 6.82 (s, 2H), 5.66 (s, 2H), 5.26 (d, J = 5.1Hz, 2H), 3.93 (d, J = 12.6Hz, 2H), 3.83 (d, J = 12.4Hz, 2H), 3.80 (s, 3H),2.02–2.97(m,2H),2.41–2.35(m,2H),2.08–1.99(m,3H),1.90–1. 85(m,3H),1.70–1.40(m,12H),1.26-1.15(m,6H),0.95–0.93(m,14H).

[0458] Example 43: Preparation of compound 43

[0459]

[0460] 1. Add raw material 43 (500 mg, 3.56 mmol, 1.00 eq) and NBS (1.39 g, 7.82 mmol, 2.20 eq) to 20 mL of CCl4, add AIBN (58 mg, 0.36 mmol, 0.10 eq), replace argon gas, heat the reaction to reflux and stir for 16 h, and purify to obtain 864 mg of intermediate 43-1;

[0461] 2. Intermediate 43-1 (300 mg, 1.01 mmol, 1.00 eq) and SDHA-A (604 mg, 2.02 mmol, 2.00 eq) from Example 1 were dissolved in 10 mL of DMF, and potassium carbonate (417 mg, 3.03 mmol, 3.00 eq) was added. The reaction was stirred at room temperature for 2 h, and 460 mg of compound 43A was obtained after purification, with a yield of 62%. Compound 43A was a white solid.

[0462] 3. Intermediate 43-1 (300 mg, 1.01 mmol, 1.00 eq) and SDHA-B (604 mg, 2.02 mmol, 2.00 eq) from Example 1 were dissolved in 10 mL of DMF, and potassium carbonate (417 mg, 3.03 mmol, 3.00 eq) was added. The reaction was stirred at room temperature for 2 h, and 510 mg of compound 43B was purified to obtain 69% yield. Compound 43B was a white solid.

[0463] The NMR results for compound 43 are as follows:

[0464] Compound 43A: 1HNMR (600MHz, CDCl3) δ7.34 (s, 2H), 7.32 (s, 1H), 5.30 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 4.40 (s, 4H), 2.61 (s, 2H), 2.38 (d, J = 3. 6Hz,2H),2.03(d,J=14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H),0.95(d,J=6.3Hz,6H),0.82(d,J=7.1Hz,6H).

[0465] Compound 43B: 1 HNMR (600MHz, CDCl3) δ7.34 (s, 2H), 7.31 (s, 1H), 5.66 (s, 2H), 5.21 (d, J = 5.3Hz ,2H),4.42(s,4H),,2.99(dd,J=12.0,5.2Hz,2H),2.38(td,J=14.0,3.7Hz,2H) ,2.06(d,J=15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36(m,1 2H), 1.25 (td, J=11.6, 6.7Hz, 4H), 0.95 (d, J=6.4Hz, 6H), 0.85 (d, J=7.3Hz, 6H).

[0466] Example 44: Preparation of compound 44

[0467]

[0468] 1. Add raw material 44 (2.00 g, 9.92 mmol, 1.00 eq) to 10 mL of SOCl2, add a few drops of DMF, heat to 100 °C and stir overnight; concentrate to remove solvent, add 20 mL of DCM, cool to 0 °C, add 10 mL of methanol, stir the reaction at 0 °C for 2 h, then move to room temperature and stir overnight, and purify to obtain 2.00 g of intermediate 44-1;

[0469] 2. Intermediate 44-1 (1.50 g, 6.53 mmol, 1.00 eq) was added to 100 mL of anhydrous ethanol, and NaBH4 (1.24 g, 32.66 mmol, 6.00 eq) was added in portions. The reaction was stirred overnight at room temperature, and 985 mg of intermediate 44-2 was obtained after purification.

[0470] 3. Intermediate 44-2 (0.98 g, 5.65 mmol, 1.00 eq) and triethylamine (2.86 g, 28.23 mmol, 5.00 eq) were added to 20 mL of DCM. The reaction was cooled to 0 °C, and methanesulfonyl chloride (1.94 g, 16.94 mmol, 3.00 eq) was added dropwise. The reaction was stirred at 0 °C for 3 h, and 1.80 g of intermediate 44-3 was obtained after purification.

[0471] 4. Intermediate 44-3 (1.80 g, 5.46 mmol, 1.00 eq) and potassium thioacetate (1.87 mg, 16.38 mmol, 3.00 eq) were added to 30 mL of DMF, the reaction was heated to 60 °C and stirred overnight, and 630 mg of intermediate 44-4 was obtained after purification.

[0472] 5. Add intermediate 44-4 (630 mg, 2.17 mmol, 1.00 eq) to 20 mL of EtOH, cool to 0 °C, add 3.3 mL of 2 M sodium hydroxide solution dropwise, stir the reaction at 0 °C for 2 h, and purify to obtain 440 mg of intermediate 44-5;

[0473] 6. Intermediate 44-5 (440 mg, 2.14 mmol, 1.00 eq) and DHA (1.22 mg, 4.28 mmol, 2.00 eq) were added to 30 mL of diethyl ether. The reaction was cooled to 0 °C, and boron trifluoride diethyl ether (608 mg, 4.28 mmol, 2.00 eq) was added dropwise. The reaction was stirred at 0 °C for 10 min and then gradually raised to room temperature and stirred overnight. The mixture was purified to obtain 510 mg of compound 44A and 590 mg of compound 44B. The combined yield was 70%. Both compounds 44A and 44B were white solids.

[0474] The NMR results for compound 44 are as follows:

[0475] Compound 44A: 1 HNMR (500MHz, CDCl3) δ7.23 (s, 2H), 5.29 (s, 2H), 4.52 (d, J = 10.7Hz, 2H), 4.05 (d, J = 13.4Hz, 2H), 3.93 (d, J = 13.3Hz, 2H), 3.05 (d,J=5.2Hz,2H),2.34(t,J=14.0Hz,2H),2.07(d,J=14.6Hz,2H),1.93–1.65(m,10H),1.61–1.31(m,11H),1.08–0.85(m,14H).

[0476] Compound 44B: 1HNMR (500MHz, CDCl3) δ7.23(s,2H),5.65(s,2H),5.37(d,J=4.8Hz,2H),4.03(d,J=13.4Hz,2H),3.97(d,J=13.3Hz,2H),3.00(d,J=5.2Hz,2H) ,2.35(t,J=14.0Hz,2H),2.05(d,J=14.6Hz,2H),1.93–1.63(m,10H),1.60–1.35(m,11H),1.25(dd,J=17.8,11.2Hz,2H),0.98–0.84(m,12H).

[0477] Example 45: Preparation of compound 45

[0478]

[0479] 1. Dissolve raw material 45 (1.00 g, 7.19 mmol, 1.00 eq.) in 36 mL of DCM, cool to 0 °C, add triethylamine (4.36 g, 43.12 mmol, 6.00 eq.), then slowly add MsCl (3.29 g, 28.75 mmol, 4.00 eq.) dropwise. After the addition is complete, move to room temperature and stir for 2 h. Purify to obtain 1.31 g of intermediate 45-1;

[0480] 2. Intermediate 45-1 (200.0 mg, 0.677 mmol, 1.00 eq), SDHA-A (447.58 mg, 1.49 mmol, 2.20 eq) from Example 1, and K2CO3 (561.57 mg, 4.06 mmol, 6.00 eq) were dissolved in 14 mL of LDMF, Ar was replaced, the reaction was stirred at room temperature for 16 h, and 342 mg of compound 45A was purified, with a yield of 72%. Compound 45A was a white foamy solid.

[0481] 3. Intermediate 45-1 (200.0 mg, 0.677 mmol, 1.00 eq), SDHA-B (447.58 mg, 1.49 mmol, 2.20 eq) from Example 1, and K2CO3 (561.57 mg, 4.06 mmol, 6.0 eq) were dissolved in 14 mL of LDMF to replace Ar. The reaction was stirred at room temperature for 16 h, and purified to obtain 365 mg of compound 45B, with a yield of 77%. Compound 45B was a white foamy solid.

[0482] The NMR results for compound 45 are as follows:

[0483] Compound 45A: 1HNMR (500MHz, CDCl3) δ7.58(t,J=7.6Hz,1H),7.23(d,J=7.6Hz,2H),5.29(s,2H),4.52(d,J=10.7Hz,2H),4.05(d,J=13.4Hz,2H),3.91(d,J=13 .3Hz,2H),3.05(d,J=5.2Hz,2H),2.33(t,J=14.0Hz,2H),2.07(d,J=14.6Hz,2H),1.93–1.62(m,10H),1.61–1.31(m,12H),1.08–0.83(m,14H).

[0484] Compound 45B: 1 HNMR(500MHz, CDCl3)δ7.57(t,J=7.6Hz,1H),7.22(d,J=7.6Hz,2H),5.65(s,2 H),5.37(d,J=4.8Hz,2H),4.03(d,J=13.4Hz,2H),3.96(d,J=13.3Hz,2H),3.01 (d,J=5.2Hz,2H),2.37(t,J=14.0Hz,2H),2.05(d,J=14.6Hz,2H),1.93–1.62(m ,10H),1.60–1.35(m,12H),1.25(dd,J=17.8,11.2Hz,2H),0.98–0.83(m,12H).

[0485] 13 CNMR (126MHz, CDCl3) δ158.15,136.99,121.42,104.20,88.14,85.94,81.20,52. 71,45.14,38.09,37.18,36.41,34.44,32.06,26.15,24.63,24.44,20.34,14.63.

[0486] Example 46: Preparation of Compound 46

[0487]

[0488] 1. Dissolve raw material 46 (800 mg, 3.28 mmol, 1.00 eq) in 33 mL of anhydrous methanol, cool to 0 °C, and slowly add concentrated sulfuric acid (3.27 g, 32.76 mmol, 10.00 eq) dropwise while stirring. After the addition is complete, heat to reflux and stir for 16 h to obtain 801 mg of intermediate 46-1.

[0489] 2. Dissolve intermediate 46-1 (800 mg, 2.94 mmol, 1.00 eq) in 30 mL of anhydrous ethanol, cool to 0 °C, and add NaBH4 (1.33 g, 35.26 mmol, 12.00 eq) in portions with stirring. Then heat the reaction to reflux and stir for 3 h. After purification, 602 mg of intermediate 46-2 was obtained.

[0490] 3. Dissolve intermediate 46-2 (600 mg, 2.77 mmol, 1.00 eq) in 27 mL of DCM, cool to 0 °C, add triethylamine (1.68 g, 16.65 mmol, 6.00 eq), then slowly add MsCl (1.27 g, 11.10 mmol, 4.00 eq). After the addition is complete, move to room temperature and stir for 2 h to purify and obtain 412 mg of intermediate 46-3.

[0491] 4. Intermediate 46-3 (120 mg, 0.32 mmol, 1.00 eq) and SDHA-A (242 mg, 0.81 mmol, 2.50 eq) from Example 1 were dissolved in 6.5 mL of DMF, and K2CO3 (267 mg, 1.93 mmol, 6.00 eq) was added. The reaction was stirred at room temperature for 16 h, and 151 mg of compound 46A was obtained after purification, with a yield of 60%. Compound 46A was a white foamy solid.

[0492] 5. Intermediate 46-3 (200 mg, 0.54 mmol, 1.00 eq) and SDHA-B (403 mg, 1.34 mmol, 2.50 eq) from Example 1 were dissolved in 10.7 mL of DMF, and K2CO3 (445 mg, 3.22 mmol, 6.00 eq) was added. The reaction was stirred at room temperature for 16 h, and 311 mg of compound 46B was obtained after purification, with a yield of 74%. Compound 46B was a white foamy solid.

[0493] The NMR results for compound 46 are as follows:

[0494] Compound 46A: 1 HNMR (500MHz, CDCl3) δ8.61 (s, 2H), 8.36 (s, 2H), 7.39 (s, 2H), 5.34 (s, 2H), 4.47 (d, J = 10.4Hz, 2H), 4.09 (d, J = 13.2Hz, 2H), 3.89 (d, J = 13. 1Hz,2H),2.62(s,2H),2.39(t,J=13.6Hz,2H),2.04(d,J=13.1Hz,2H),1.88(s,2H),1.78(s,2H),1.73–1.18(m,18H),1.06–0.77(m,14H).

[0495] 13 CNMR(126MHz, CDCl3)δ156.24,149.34,148.93,124.26,121.76,104.40,100.00,92.33,80.49 ,79.47,51.76,46.07,37.32,36.27,33.97,32.00,31.72,26.00,24.77,21.26,20.24,14.76.

[0496] Compound 46B: 1 HNMR(500MHz,CDCl3)δ8.61(d,J=3.5Hz,2H),8.38(s,2H),7.34(s,2H),5.64(s,2H),5.22(s,2H),3.93(q,J=13.5Hz,4H),3.01(s,2H ),2.37(t,J=13.7Hz,2H),2.06(d,J=12.5Hz,2H),1.96–1.63(m,10H),1.60–1.34(m,10H),1.25(d,J=6.4Hz,2H),1.04–0.80(m,14H).

[0497] 13 CNMR(126MHz, CDCl3)δ149.32(s),148.42(s),124.21(s),121.67(s),104.29(s),88.15(s),85.68(s),81.12(s),52.66( s),45.01(s),37.20(s),36.36(s),35.21(s),34.38(s),31.95(s),26.13(s),24.61(s),24.44(s),20.33(s),14.58(s).

[0498] Example 47: Preparation of Compound 47

[0499]

[0500] As in Example 46, using raw material 47 (1.00 g, 5.98 mmol, 1.00 eq), 210 mg of compound 47A and 280 mg of compound 47B were obtained, both of which are white solids;

[0501] The NMR structure of compound 47 is as follows:

[0502] Compound 47A: 11H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 3.8 Hz, 1H), 7.35 (s, 1H), 7.18 (s, 1H), 5.29 (d, J = 15.7 Hz, 2H), 4.59 (d, J = 10.7 Hz, 1H), 4.39 (d, J = 10.7 Hz, 1H), 4.11 (d, J = 13.0 Hz, 1H), 3.97 (dd, J = 21.0, 13.3 Hz, 2H), 3.78 (d, J = 13.4 Hz, 1H), 2.57 (s, 2H), 2.36 (t, J = 12.6 Hz, 2H), 2.02 (d, J = 14.9 Hz, 2H), 1.88 (s, 3H), 1.67 (d, J = 13.3 Hz, 4H), 1.53 (s, 1H), 1.48 (d, J = 14.6 Hz, 2H), 1.43 (s, 6H), 1.33 (d, J = 10.7 Hz, 3H), 1.28–1.18 (m, 3H), 0.99 (d, J = 12.4 Hz, 2H), 0.94 (d, J = 5.4 Hz, 6H), 0.81 (d, J = 6.2 Hz, 6H).

[0503] 13 13C NMR (126 MHz, CDCl3) δ 158.42, 149.76, 148.06, 123.70, 122.40, 104.31, 104.23, 88.16, 88.12, 86.16, 85.75, 81.20, 81.12, 53.21, 52.68, 45.10, 44.98, 38.40, 37.20, 37.14, 36.35, 34.99, 34.41, 34.36, 32.08, 31.95, 26.14, 24.62, 24.41, 20.33, 14.66, 14.58.

[0504] Compound 47B: 1HNMR (500MHz, CDCl3) δ8.48 (s, 1H), 7.34 (s, 1H), 7.16 (s, 1H), 5.62 (d, J = 11.4Hz, 2H), 5.35 (s, 1 H),5.17(d,J=4.3Hz,1H),4.00(s,2H),3.81(dd,J=29.8,13.6Hz,2H),3.00(s,2H),2.36(t,J=13 .8Hz,2H),2.05(d,J=12.5Hz,2H),1.87(s,3H),1.82–1.74(m,2H),1.68(d,J=16.1Hz,4H),1.48 (d,J=12.2Hz,4H),1.44(s,5H),1.39(s,2H),1.24(s,2H),0.99–0.90(m,8H),0.89–0.82(m,6H).

[0505] 13 CNMR(126MHz, CDCl3)δ158.42,149.76,148.06,123.70,122.40,104.31,104.23,88.16,88.12,86.16,85.75,81.20,81.12,53.21 ,52.68,45.10,44.98,38.40,37.20,37.14,36.35,34.99,34.41,34.36,32.08,31.95,26.14,24.62,24.41,20.33,14.66,14.58.

[0506] Example 48: Preparation of Compound 48

[0507]

[0508] 1. The starting material 48 (0.46 g, 2.06 mmol, 1.00 eq) was dissolved in 21 mL of ethanol, cooled to 0 °C, and sodium borohydride (935 mg, 24.73 mmol, 12.00 eq) was added. The reaction was stirred at 0 °C for 30 min, then gradually heated to reflux and stirred for 4 h. After the reaction was cooled to room temperature, 5 mL of acetone was added dropwise to quench the reaction. The purified product was 100 mg of intermediate 48-1.

[0509] 2. Dissolve intermediate 48-1 (100 mg, 0.72 mmol, 1.00 eq) in 4 mL of DCM, cool to 0 °C, add triethylamine (0.6 mL, 4.31 mmol, 6.00 eq), then add MsCl (0.22 mL, 2.87 mmol, 4.00 eq). Gradually heat the reaction to room temperature and stir for 0.5 h. Purify to obtain 210 mg of intermediate 48-2.

[0510] 3. Intermediate 48-2 (50 mg, 0.17 mmol, 1.00 eq) and SDHA-A (112 mg, 0.37 mmol, 2.20 eq) from Example 1 were added to 2 mL of DMF, and potassium carbonate (59 mg, 0.42 mmol, 2.50 eq) was added. The reaction was stirred at room temperature for 1.5 h, and 56 mg of compound 48A was obtained after purification. Compound 48A was a white solid with a yield of 48%.

[0511] 4. Intermediate 48-2 (50 mg, 0.17 mmol, 1.00 eq) and SDHA-B from Example 1 (112 mg, 0.37 mmol, 2.20 eq) were added to 2 mL of heating DMF, and potassium carbonate (59 mg, 0.42 mmol, 2.50 eq) was added. The reaction was stirred at room temperature for 1.5 h, and 66 mg of compound 48B was obtained after purification. Compound 48B was a white solid with a yield of 55%.

[0512] The NMR results for compound 48 are as follows:

[0513] Compound 48A: 1 HNMR(500MHz, CDCl3)δ8.43(s,2H),7.71(s,1H),5.33(s,2H),4.42(d,J=10.7Hz,2H),4.14–4.06(m,4H),3.01(d, J=5.2Hz,2H),2.35–2.31(m,2H),2.11-2.02(m,2H),1.91–1.65(m,10H),1.62–1.31(m,12H),1.09–0.83(m,14H).

[0514] Compound 48B: 1 HNMR (500MHz, CDCl3) δ8.43(s,2H),7.71(s,1H),5.61(s,2H),5.23(d,J=5.4Hz,2H),4.05(d,J=13.4Hz,2H),3.98(d,J=13.3Hz,2H),3.01 –2.96(m,2H),2.37-3.31(m,2H),2.05(d,J=14.6Hz,2H),1.93–1.62(m,10H),1.60–1.35(m,12H),1.25–1.13(m,2H),0.98–0.83(m,12H).

[0515] Example 49: Preparation of Compound 49

[0516]

[0517] As in Example 40, raw material 49 (500 mg, 2.90 mmol, 1.00 eq) was used to obtain 186 mg of compound 49A and 223 mg of compound 49B. Both compound 49A and compound 49B are foamy white solids.

[0518] The NMR results for compound 49 are as follows:

[0519] Compound 49A: 1 HNMR(500MHz, CDCl3)δ7.17(s,2H),5.23(d,J=7.5Hz,2H),4.37(d,J=10.8Hz,2 H),4.07(d,J=13.8Hz,2H),4.00(d,J=13.8Hz,2H),2.64–2.55(m,2H),2.37(td, J=14.0,3.9Hz,2H),2.06–1.98(m,2H),1.91–1.84(m,2H),1.72–1.59(m,4H),1 .56–1.41(m,10H),1.36–1.15(m,6H),1.05–0.92(m,8H),0.80(d,J=7.2Hz,6H).

[0520] 13 CNMR (126MHz, CDCl3) δ137.01,124.20,104.32,92.27,80.49,79.61,51.84,4 6.14,37.34,36.32,34.03,31.89,26.27,26.07,24.76,21.21,20.25,14.84.

[0521] Compound 49B: 1 HNMR (500MHz, CDCl3) δ7.17 (s, 2H), 5.63 (s, 2H), 5.15 (d, J = 5.3Hz, 2H), 3. 96(s,4H),3.01–2.93(m,2H),2.37(td,J=14.1,3.8Hz,2H),2.09–2.01(m,2 H),1.87(s,2H),1.77(d,J=3.8Hz,2H),1.72–1.64(m,4H),1.62–1.34(m,10 H),1.26(dd,J=11.5,6.4Hz,4H),1.02–0.88(m,8H),0.78(d,J=7.3Hz,6H).

[0522] 13CNMR(126MHz,CDCl3)δ136.09,124.79,104.23,88.27,85.13,81.16,52.69,4 5.07,37.23,36.39,34.42,31.94,29.43,26.17,24.62,24.42,20.36,14.58.

[0523] Example 50: Preparation of Compound 50

[0524]

[0525] 1. Dissolve raw material 50 (200 mg, 1.56 mmol, 1.00 eq) in 10 mL of anhydrous dichloromethane, add triethylamine (0.8 mL, 6.24 mmol, 4.00 eq), cool to -20 °C and stir for 10 min, slowly add methanesulfonyl chloride (0.3 mL, 3.9 mmol, 2.50 eq), stir the reaction at -20 °C for 30 min, and purify to obtain 380 mg of intermediate 50-1;

[0526] 2. SDHA-A (350 mg, 1.16 mmol, 2.20 eq) from Example 1 was dissolved in 5 mL of anhydrous DMF, and anhydrous potassium carbonate (321 mg, 1.58 mmol, 3.00 eq) was added. The mixture was stirred for 30 min. Intermediate 50-1 (150 mg, 0.53 mmol, 1.00 eq) was dissolved in 3 mL of DMF and added dropwise to the system. The reaction was stirred at room temperature for 2 h. After purification, 73 mg of compound 50A was obtained. Compound 50A was a white solid with a yield of 20%.

[0527] 3. SDHA-B (350 mg, 1.16 mmol, 2.20 eq) from Example 1 was dissolved in 5 mL of anhydrous DMF, and anhydrous potassium carbonate (321 mg, 1.58 mmol, 3.00 eq) was added. The mixture was stirred for 30 min. Intermediate 50-1 (150 mg, 0.53 mmol, 1.00 eq) was dissolved in 3 mL of DMF and added dropwise to the system. The reaction was stirred at room temperature for 2 h. After purification, 83 mg of compound 50B was obtained. Compound 50B was a white solid with a yield of 28%.

[0528] The NMR results for compound 50 are as follows:

[0529] Compound 50A: 1HNMR (500MHz, CDCl3) δ6.11(s,2H),5.29(s,2H),4.56(d,J=10.7Hz,2H),4.02(d,J=14.6Hz,2H),3.82(d,J=14.5Hz,2H),2.60(s,2H),2.37(t,J=13. 7Hz,2H),2.02(d,J=14.0Hz,2H),1.87(s,2H),1.68(t,J=13.2Hz,4H),1.5 9–1.55(m,4H),1.51-1.43(m,6H),1.34-1.24(m,6H),1.06–0.79(m,14H).

[0530] 13 CNMR (126MHz, CDCl3) δ151.51,108.31,104.34,100.09,92.42,80.52,79.75,51. 85,46.17,37.31,36.31,34.05,32.04,26.03,25.20,24.75,21.26,20.26,14.81.

[0531] Compound 50B: 1 HNMR(500MHz, CDCl3)δ6.13(s,2H),5.62(s,2H),5.30(d,J=4.7Hz,2H),3.90(d,J=14.7Hz,2H),3.78(d,J=14.6Hz,2H),3.02(s,2H), 2.37(t,J=14.1Hz,2H),2.05(d,J=14.6Hz,2H),1.87(s,2H),1.84–1.63(m,8H),1.65–1.31(m,10H),1.26(s,4H),0.96–0.85(m,12H).

[0532] 13 CNMR (126MHz, CDCl3) δ151.01,108.65,104.24,100.00,88.21,85.65,81.18,52. 70,45.09,37.20,36.39,34.41,32.02,28.30,26.16,24.62,24.39,20.34,14.62.

[0533] Example 51: Preparation of compound 51

[0534]

[0535] As in Example 40, the raw materials used were raw material 41 (1.00 g, 5.95 mmol, 1.00 eq), 312 mg of compound 51A and 286 mg of compound 51B, both of which were white foam.

[0536] The NMR results for compound 51 are as follows:

[0537] Compound 51A: 1 HNMR (600MHz, CDCl3) δ8.35 (s, 2H), 5.25 (s, 2H), 4.66 (d, J = 10.7Hz, 2H), 4.26 (s, 4H), 2.56 (s,2H),2.37-2.32(m,2H),1.99(d,J=14.3Hz,2H),1.87-1.82(s,2H),1.75(s,2H),1.67(t, J=15.1Hz,4H),1.55(d,J=13.2Hz,2H),1.48-1.38(m,4H),1.36-1.30(m,4H),1.23(dd,J=1 1.1, 6.6Hz, 4H), 0.97 (dd, J = 33.6, 9.4Hz, 2H), 0.87 (d, J = 7.1Hz, 6H), 0.80 (d, J = 7.0Hz, 6H).

[0538] 13 CNMR(151MHz,CDCl3)δ153.30,142.00,104.27,92.20,80.50,80.43,51.79,4 6.12,37.34,36.27,34.04,32.37,32.31,26.01,24.76,21.24,20.24,14.82.

[0539] Compound 51B: 1 HNMR (600MHz, CDCl3) δ8.37 (s, 2H), 5.56 (s, 2H), 5.46 (d, J = 4.8Hz, 2H), 4.21 ( d,J=13.7Hz,2H),4.14(d,J=13.6Hz,2H),3.01(d,J=5.3Hz,2H),2.35(t,J=13 .8Hz,2H),2.02(d,J=14.7Hz,2H),1.87–1.75(m,4H),1.71–1.62(m,4H),1.49 (t,J=16.7Hz,4H),1.43–1.35(m,8H),1.25–1.20(m,2H),0.95–0.82(m,14H).

[0540] 13CNMR(151MHz,CDCl3)δ152.70,142.20,104.22,88.11,86.39,81.04,52.62,4 5.03,37.19,36.35,35.41,34.39,32.06,26.09,24.61,24.44,20.33,14.63.

[0541] Example 52: Preparation of compound 52

[0542]

[0543] 1. Dissolve raw material 52 (2.00 g, 11.90 mmol, 1.00 eq) in 110 mL of MeOH, slowly add SOCl2 (7.10 g, 59.49 mmol, 5.00 eq), heat to reflux and stir for 6 h, and purify to obtain 1.74 g of intermediate 52-1;

[0544] 2. Intermediate 52-1 (1.70 g, 8.67 mmol, 1.00 eq) was dissolved in 87 mL of a mixed solvent of MeOH / DCM = 4:1. The mixture was cooled to 0 °C and stirred for 10 min. NaBH4 (2.62 g, 89.33 mmol, 8.00 eq) was slowly added in portions. After the addition was complete, the reaction was continued to be stirred at 0 °C for 4 h. The mixture was purified to obtain 790 mg of intermediate 52-2.

[0545] 3. Intermediate 52-2 (650 mg, 4.64 mmol, 1.00 eq) was dissolved in 46 mL of anhydrous dichloromethane and cooled to 0 °C. Triethylamine (3.2 mL, 23.19 mmol, 3.00 eq) was added, and the mixture was stirred for 10 min. Then, methanesulfonyl chloride (1.59 g, 13.91 mmol, 2.50 eq) was added dropwise. After the addition was complete, the mixture was moved to room temperature and stirred for 2 h. The resulting product was purified to obtain 840 mg of intermediate 52-3.

[0546] 4. Dissolve intermediate 52-3 (840 mg, 2.83 mmol, 1.00 eq) in 95 mL of DMF, add potassium thioacetate (835 mg, 8.50 mmol, 3.00 eq); heat the reaction to 60 °C and stir for 4 h, then allow the reaction to cool naturally to room temperature, and purify to obtain 510 mg of intermediate 52-4;

[0547] 5. Dissolve intermediate 52-4 (570 mg, 2.22 mmol, 1.00 eq) in 25 mL of ethanol, cool to 0 °C, and add 2.78 mL of 2 M sodium hydroxide solution dropwise; stir the reaction at 0 °C for 1 h, and purify to obtain 320 mg of intermediate 52-5;

[0548] 6. Dihydroartemisinin (1.09 g, 3.83 mmol, 2.20 eq) was added to 35 mL of anhydrous diethyl ether and stirred thoroughly. The mixture was cooled to 0 °C and stirred for 10 min. Intermediate 52-5 (300 mg, 1.74 mmol, 1.00 eq) was dissolved in 10 mL of diethyl ether and added dropwise to the reaction mixture. Then, boron trifluoride diethyl ether (742 mg, 5.22 mmol, 3.00 eq) was slowly added dropwise. The reaction was stirred at 0 °C for 1 h and then moved to room temperature for 4 h. After purification, 500 mg of compound 52 was obtained. Compound 52 was a light yellow oil with a yield of 41%.

[0549] The NMR results for compound 52 are as follows:

[0550] 1 HNMR (500MHz, CDCl3) δ8.56 (s, 2H), 5.55 (s, 2H), 5.35 (d, J = 4.3Hz, 2H), 4.05 (d, J = 13.8Hz, 2H), 3.96 (d, J = 13.8Hz, 2H), 3.01(d,J=4.3Hz,2H),2.44–2.28(m,2H),2.06(t,J=20.4Hz,2H),1.76(m,8H),1.56–1.16(m,14H),1.00–0.77(m,14H).

[0551] 13 CNMR (126MHz, CDCl3) δ152.23,143.79,104.27,88.02,86.15,81.06,52.62,4 5.01,37.19,36.31,35.27,34.38,32.02,26.06,24.61,24.40,20.30,14.60.

[0552] Example 53: Preparation of compound 53

[0553]

[0554] As in Example 40, raw material 53 (1.00 g, 5.88 mmol, 1.00 eq) was used to obtain 269 mg of compound 53A and 236 mg of compound 53B, both of which were white foam.

[0555] The NMR results for compound 53 are as follows:

[0556] Compound 53A: 1HNMR (500MHz, CDCl3) δ7.36 (s, 1H), 5.66 (s, 1H), 5.60 (s, 1H), 5.32 (d, J = 5.3Hz ,1H),5.22(d,J=5.3Hz,1H),4.05–3.84(m,4H),3.64(s,3H),2.99(td,J=12.4,6 .5Hz,2H),2.39-2.33(m,2H),2.05-1.97(m,4H),1.89(dd,J=23.9,11.1Hz,4H) ,1.76-1.68(m,4H),1.57–1.35(m,12H),1.32–1.20(m,2H),0.98–0.81(m,12H).

[0557] Compound 53B: 1 HNMR(500MHz, CDCl3)δ7.40(s,1H),5.39(s,1H),5.35(s,1H),4.80(d,J=1 0.7Hz,1H),4.56(d,J=10.5Hz,1H),3.14-3.80(m,4H),3.67(s,3H),2.58(s ,2H),2.37(t,J=13.3Hz,2H),2.06–1.90(m,8H),1.73–1.60(m,4H),1.56(d ,J=13.5Hz,2H),1.52–1.39(m,8H),1.28-1.20(m,2H),1.10–0.79(m,14H).

[0558] Example 54: Preparation of compound 54

[0559]

[0560] Compound 5A (200 mg, 0.31 mmol, 1.00 eq) obtained in Example 5 was dissolved in 5 mL of acetonitrile. NaOCl (25 mg, 0.34 mmol, 1.10 eq) was dissolved in 1 mL of water and slowly added dropwise to the reaction. The reaction was stirred at room temperature for 20 min and then quenched with 10 mL of saturated sodium bisulfite solution. After purification, 93 mg of compound 54A was obtained. Compound 54A was a white solid with a yield of 44%.

[0561] Compound 5B (200 mg, 0.31 mmol, 1.00 eq) obtained in Example 5 was dissolved in 5 mL of acetonitrile; NaOCl (25 mg, 0.34 mmol, 1.10 eq) was dissolved in 1 mL of water and slowly added dropwise to the reaction. The reaction was stirred at room temperature for 20 min and then quenched with 10 mL of saturated sodium bisulfite solution. After purification, 84 mg of compound 54B was obtained. Compound 54B was a white solid with a yield of 40%.

[0562] The NMR results for compound 54 are as follows:

[0563] Compound 54A: 1 HNMR(400MHz, CDCl3)δ5.28(s,2H),4.44(d,J=10.6Hz,2H),3.11–3.05(m, 4H),2.80–2.76(m,2H),2.36-2.30(m,2H),2.01(d,J=14.4Hz,2H),1.91–1 .83(m,2H),1.83–1.75(m,4H),1.75–1.68(m,4H),1.60-1.56(m,2H),1.51 –1.32(m,12H),1.26–1.20(m,2H),1.08–0.98(m,2H),0.95-0.92(m,12H).

[0564] Compound 54B: 1 HNMR(400MHz, CDCl3)δ5.84(s,2H),5.13(d,J=5.8Hz,2H),3.19–3.11(m,2H),3.09–2.97(m,4H),2.37–2.30(m,2H),2.04–2 .00(m,2H),1.94–1.79(m,4H),1.77–1.60(m,8H),1.55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.90(m,12H).

[0565] Example 55: Preparation of compound 55

[0566]

[0567] Compound 5A (200 mg, 0.31 mmol, 1.00 eq) obtained in Example 5 and NaCO3 (129 mg, 1.53 mmol, 5.00 eq) were added to 20 mL of acetonitrile and cooled to -40 °C. TFAA (193 mg, 0.92 mmol, 3.00 eq) was added dropwise to 20 mL of acetonitrile containing UHP (87 mg, 0.92 mmol, 3.00 eq). After stirring at room temperature for 10 min, the mixture was slowly added dropwise to the reaction mixture. The reaction was stirred at -40 °C for 20 min, and 145 mg of compound 55A was obtained after purification, with a yield of 66%.

[0568] Compound 5B (200 mg, 0.31 mmol, 1.00 eq) obtained in Example 5 and NaCO3 (129 mg, 1.53 mmol, 5.00 eq) were added to 20 mL of acetonitrile and cooled to -40 °C. TFAA (193 mg, 0.92 mmol, 3.00 eq) was added dropwise to 20 mL of acetonitrile containing UHP (87 mg, 0.92 mmol, 3.00 eq). After stirring at room temperature for 10 min, the TFAA was slowly added dropwise to the reaction mixture. The reaction was stirred at -40 °C for 20 min, and 158 mg of compound 55B was obtained after purification, with a yield of 72%.

[0569] The NMR results for compound 55 are as follows:

[0570] Compound 55A: 1 HNMR(400MHz, CDCl3)δ5.37(s,2H),4.38(d,J=10.8Hz,2H),3.20–3.16(m,2H),3.11–3.07(m, 2H),2.87–2.83(m,2H),2.36(td,J=14.0,3.8Hz,2H),2.02(d,J=14.2Hz,2H),1.90–1.83(m,2 H),1.82–1.75(m,4H),1.74–1.68(m,4H),1.59(dt,J=13.5,4.0Hz,2H),1.52–1.30(m,12H),1 .22(dt,J=11.3,6.9Hz,2H),1.09–0.98(m,2H),0.96(d,J=6.3Hz,6H),0.93(d,J=7.1Hz,6H).

[0571] Compound 55B: 1HNMR(400MHz, CDCl3)δ5.90(s,2H),5.08(d,J=6.6Hz,2H),3.23–3.19(m,2H),3.18–3.10(m,4H),2.37(td,J=14.1,3.6Hz,2H),2.04(dd, J=14.6,2.9Hz,2H),1.92–1.79(m,4H),1.77–1.63(m,8H),1.55–1.48(m,4H),1.44–1.34(m,10H),1.27–1.24(m,2H),0.99–0.91(m,12H).

[0572] Experimental Example

[0573] Anticancer activity test of compounds 1-55

[0574] Experimental methods:

[0575] Cell seeding: Prepare a single-cell suspension using culture medium (DMEM or RMPI1640) containing 10% fetal bovine serum.

[0576] Seed 3,000 to 15,000 cells per well in a 96-well plate, with a volume of 100 μL per well. Adherent cells were seeded and cultured 12 to 24 hours in advance.

[0577] Add the solution of the compound to be tested: Dissolve the compound in DMSO, and screen the compound at a concentration of 40 μM. The final volume of each well is 200 μL, and each treatment has 3 replicates.

[0578] Color development: After incubation at 37°C for 48 hours, discard the culture medium in the wells of adherent cells, and add 20 μL of MTS solution and culture medium to each well.

[0579] Add 100 μL of culture medium; discard 100 μL of culture supernatant to each well of suspended cells, and add 20 μL of MTS solution to each well; set up 3 blank replicates (a mixture of 20 μL of MTS solution and 100 μL of culture medium), and continue incubation for 2-4 hours to allow the reaction to proceed fully before measuring the absorbance.

[0580] Colorimetric analysis: Select a wavelength of 492nm, use a multi-functional microplate reader (MULTISKAN FC) to read the absorbance values ​​of each well, record the results, and finally take the average of the three results.

[0581] Positive control compounds: Two positive compounds, cisplatin (DDP) and paclitaxel (Taxol), were included in each experiment.

[0582] The results of the determination of the inhibitory rate of the sulfur-containing artemisinin dimer of compound 1-55 on tumor cells are shown in Table 1:

[0583] Table 1: Results of the inhibition rate of sulfur-containing artemisinin dimers on tumor cells (n=3)

[0584]

[0585] Continued from Table 1

[0586] 9A 40 99.12 68.12 98.06 74.32 95.36 9B 40 98.62 71.05 98.99 70.56 94.26 9C 40 97.23 69.73 99.01 71.23 97.36 10A 40 99.18 70.10 98.89 74.44 98.26 10B 40 99.40 62.53 98.76 71.56 99.12 10C 40 99.10 66.75 99.01 70.56 92.14 11A 40 98.99 71.26 98.99 73.96 94.99 11B 40 98.76 75.21 99.01 70.89 96.65 12A 40 99.86 68.62 99.65 78.16 95.12 12B 40 99.45 67.59 99.46 72.89 96.89 13A 40 98.69 70.12 99.01 70.19 95.21 13B 40 97.49 78.15 99.36 68.59 92.12 14 40 98.99 56.99 98.16 74.12 95.06 15A 40 98.77 62.15 98.76 70.19 97.23 15B 40 98.52 59.15 98.76 64.59 95.69 15C 40 98.64 64.13 98.93 67.89 95.01 15D 40 98.57 60.12 98.83 63.21 96.06 16A 40 97.49 46.21 98.88 65.23 97.23 16B 40 98.56 52.21 98.97 59.99 96.56 17 40 98.49 40.15 98.69 46.98 95.23 18A 40 99.89 84.12 99.86 85.26 99.23 18B 40 99.76 86.15 99.87 79.59 98.12 18C 40 99.59 72.22 99.69 78.44 98.65 19A 40 99.12 80.06 99.56 80.19 97.12 19B 40 99.35 82.19 99.42 75.26 98.13 20A 40 99.46 79.08 99.16 76.29 97.69 20B 40 99.01 75.24 99.43 74.10 95.89 21A 40 99.04 79.23 99.56 78.23 97.66 21B 40 99.06 75.16 99.28 70.19 96.58 22 40 99.28 77.19 99.16 80.12 98.72 23 40 99.56 68.99 99.46 76.69 95.68 24 40 99.28 71.00 99.59 77.26 96.56 25 40 99.69 80.04 99.59 78.26 96.66 26 40 99.82 81.26 99.42 77.18 97.26 27A 40 97.99 79.08 99.01 74.12 95.94 27B 40 98.05 70.13 98.89 71.11 94.28

[0587] Continued from Table 2

[0588] 28A 40 98.29 73.25 98.89 75.29 96.56 28B 40 98.89 78.16 99.01 78.18 94.25 29A 40 98.49 69.99 98.76 74.29 98.11 29B 40 98.99 75.06 99.02 70.13 95.26 30 40 99.01 68.05 98.79 54.12 96.48 31 40 98.56 59.97 98.42 43.16 95.26 32A 40 98.89 71.15 99.53 77.16 98.26 32B 40 99.01 69.46 99.01 80.12 96.35 32C 40 98.79 59.86 99.26 76.15 97.69 33A 40 98.96 66.18 99.42 76.18 94.06 33B 40 98.26 69.72 99.25 72.01 95.38 33C 40 99.64 71.08 99.38 74.59 94.69 34 40 98.78 68.45 99.32 71.25 95.69 35A 40 99.05 69.17 99.58 79.16 94.23 35B 40 99.00 70.12 99.62 72.08 96.89 36A 40 99.52 53.18 99.68 80.16 94.86 36B 40 99.01 60.15 99.56 75.26 96.38 37A 40 99.71 56.15 99.65 69.25 97.01 37B 40 99.06 62.56 99.26 62.15 96.49 38 40 99.86 76.26 99.87 80.69 94.29 39 40 98.26 46.23 98.46 68.72 95.86 40A 40 98.86 75.68 98.69 74.16 97.16 40B 40 98.10 74.12 99.27 72.18 96.59 41A 40 98.89 74.59 99.23 69.12 94.16 41B 40 98.59 69.12 99.51 58.12 95.35 42A 40 99.01 79.18 99.28 77.16 94.65 42B 40 99.00 80.12 99.08 70.59 95.12 43A 40 99.49 65.89 99.66 70.16 96.04 43B 40 98.89 69.99 99.16 68.16 94.65 44A 40 99.28 72.59 99.76 75.59 96.85 44B 40 99.06 76.18 99.59 70.45 94.26 45A 40 99.76 62.12 99.58 69.88 94.65 45B 40 99.41 66.36 99.86 63.47 97.01 46A 40 98.99 78.29 99.01 70.18 95.09 46B 40 98.69 61.18 98.69 76.28 94.44 47A 40 98.46 69.28 98.99 68.78 95.68

[0589] Continued from Table 3

[0590] 47B 40 98.86 71.03 98.69 70.03 94.38 48A 40 99.56 75.66 99.05 74.28 96.66 48B 40 99.08 64.25 98.99 71.11 93.21 49A 40 99.76 66.95 99.56 70.12 94.12 49B 40 99.48 64.12 99.15 62.15 92.99 50A 40 99.50 59.28 99.52 67.79 94.35 50B 40 99.01 62.18 99.27 59.98 95.12 51A 40 99.01 71.29 99.69 70.11 95.32 51B 40 98.76 65.28 99.42 68.12 92.31 52 40 98.89 56.48 99.46 70.45 95.12 53A 40 98.99 62.15 99.59 78.82 94.44 53B 40 98.21 42.13 99.50 74.65 95.12 54A 40 98.86 35.26 98.21 66.28 91.12 54B 40 98.01 43.15 99.01 69.75 92.18 55A 40 98.79 31.86 98.06 58.42 90.86 55B 40 99.01 46.15 99.06 45.16 89.99

[0591] Reference documents:

[0592] [1] Woerdenbag, HJ; Lüers, JFJ; van Uden, W.; Pras, N.; Malingré, T. Alfermann, AW, Plant Cell, Tissue and Organ Culture, 1993, 32, 247-257.

[0593] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A sulfur-containing artemisinin dimer, characterized in that, The sulfur-containing artemisinin dimer has any of the following structures: in, Y represents: single bond, aryl, with 1 to 5 R groups. 2 Substituted aryl, 3-10 membered cycloalgides, with 1-5 R groups 2 Any one of the 3- to 10-membered ring groups that are substituted; R 1 Represented as: H, F, Cl, Br, I, CN, OR 2 Any one of C1 to C10 alkyl groups; The R 2 Represented as: any one of H, F, Cl, Br, I, CN, or C1 to C5 alkyl groups; n and m are each independently selected from integers from 0 to 15; The aryl group is selected from any one of phenyl, pyridyl, pyrazinyl, pyridazinyl, thiophenyl, thiazolyl, naphthyl, pyrroleyl, furanyl, and biphenyl; The cyclic group is selected from saturated monocyclic groups, unsaturated monocyclic groups, saturated polycyclic systems, and unsaturated polycyclic systems. The polycyclic systems include spirocyclic, fused, bridged, and linked rings. The cyclic group is not aryl. The condition is that compounds with CAS Registry Numbers 1803240-76-7, 171012-20-7, 171231-03-1, and 1026475-31-9 are not included.

2. A sulfur-containing artemisinin dimer, characterized in that, The sulfur-containing artemisinin dimer has any of the following structures:

3. A method for preparing the sulfur-containing artemisinin dimer according to claim 1 or 2, characterized in that, The reaction formula is as follows: Among them, R 1 Y, n, m are as defined in any one of claims 1 or 2; W is denoted as S; Z is denoted as S, O, and NR. 1 Any one of them; The acid is selected from any one of the following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride diethyl ether complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethylsilyl trifluoromethanesulfonate, and p-toluenesulfonic acid; The specific reactions described in the above reaction formula are as follows: As shown in reaction formula 1, the compound of formula II and dihydroartemisinin are dispersed in a solvent, and acid is added dropwise at -78℃ to 25℃ to carry out the reaction, thereby obtaining sulfur-containing artemisinin dimers.

4. A method for preparing the sulfur-containing artemisinin dimer according to claim 1 or 2, characterized in that, The reaction formula is as follows: Among them, R 1 Y, n, m are defined as in any one of claims 1 or 2; in formula I, W represents S; Z represents S; X represents any one of halogens and halogen-like substances; the halogen is selected from any one of F, Cl, Br, and I; the halogen-like substance is selected from any one of methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, and acyloxy. The specific reactions described in the above reaction formula are as follows: As shown in reaction formula 2, dihydroartemisinin is prepared into thiodihydroartemisinin as shown in formula 3 by thioreaction. The thiodihydroartemisinin is then reacted with the compound shown in formula 4 to obtain sulfur-containing artemisinin dimers.

5. A method for preparing the sulfur-containing artemisinin dimer according to claim 1 or 2, characterized in that, The reaction formula is as follows: Among them, R 1 Y, n, m are defined as in any one of claims 1 or 2; in formulas I and V, W represents S; Z represents CH2; TMS stands for trimethylsilyl group; The acid is selected from any one of the following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride diethyl ether complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethylsilyl trifluoromethanesulfonate, and p-toluenesulfonic acid; The specific reactions described in the above reaction formula are as follows: As shown in Equation 3, the compound shown in Formula V and dihydroartemisinin are dissolved in a solvent, and acid is added dropwise at -78℃ to 25℃ to react and obtain sulfur-containing artemisinin dimers.

6. A method for preparing the sulfur-containing artemisinin dimer according to claim 1 or 2, characterized in that, In a solvent, the sulfur-containing artemisinin dimer with low oxidation state sulfur is oxidized with an oxidizing agent to obtain the sulfur-containing artemisinin dimer with high oxidation state sulfur. The oxidant is selected from any one of the following: ozone, urea peroxide, hydrogen peroxide, hypochlorous acid, hypochlorite, perchloric acid, perchlorate, persulfate, persulfate, permanganate, dichromate, periodic acid, periodate, and peroxy organic acids; The low oxidation state sulfur is referred to as: divalent sulfur; The high oxidation state sulfur is represented as SO or SO2.

7. The use of the sulfur-containing artemisinin dimer as described in claim 1 or 2 in the preparation of antitumor drugs.

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