CN117285548A

CN117285548A - Sulfur-containing artemisinin dimer, and preparation method and application thereof

Info

Publication number: CN117285548A
Application number: CN202311243606.3A
Authority: CN
Inventors: 李剑峰; 王小婷; 坝德伟; 周启心; 孔迪; 黄陈舟; 王正学; 余开波; 熊伟; 虎文华; 李志强; 王金龙; 李明峰
Original assignee: Shureli Biopharma Co ltd
Current assignee: Shureli Biopharma Co ltd
Priority date: 2022-06-16
Filing date: 2022-06-16
Publication date: 2023-12-26
Also published as: WO2023240920A1; CN115073496A; CN115073496B

Abstract

The invention relates to a sulfur-containing artemisinin dimer, a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry. The chemical structural formula of the sulfur-containing artemisinin dimer is a compound represented by a formula I or pharmaceutically acceptable salt thereof:wherein W is represented as: s, SO and SO ₂ Any one of them; z is expressed as: s, SO ₂ 、O、NR ₁ And CR (CR) ¹ ₂ Any one of them; y is represented as: any one of a single bond, alkyl, aryl, cyclic group, ether, and ammonia; r is R ¹ Expressed as: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether, and ammonia; n and m are each independently selected from: an integer of 0 to 15. The invention also discloses a preparation method of the sulfur-containing artemisinin dimer. The sulfur-containing artemisinin dimer has selective inhibition effect on the growth of human cancer cell lines.

Description

Sulfur-containing artemisinin dimer, and preparation method and application thereof

Technical Field

The invention relates to the technical field of pharmaceutical chemistry, in particular to a sulfur-containing artemisinin dimer, a preparation method and application thereof.

Background

In seventies of the last century, artemisinin is extracted from artemisia annua, and has strong antimalarial effect proved by laboratory and clinic, and a series of derivatives with antimalarial activity, such as dihydroartemisinin, artesunate, artemether, arteether and the like are sequentially synthesized and semisynthesized on the basis of the structure.

After the antimalarial effect of artemisinin drugs has been demonstrated, studies of other biological activities such as against other parasites, anticancer and immunosuppression have also been carried out.

Woredenbag HJ et al report that artemisinin, artemether, arteether, artesunate have a certain cytotoxicity to Ehrlich Ascites cell lines, that 11, 13-dehydroartemisinin (artemesite) has stronger effect, and that the dimer of dihydroartemisinin shows the strongest activity ^[1] 。

In order to find compounds with higher activity, hundreds of artemisinin compounds are synthesized and screened, and particularly, in recent decades, some artemisinin dimers and trimers composed of different connectors are widely reported, wherein a plurality of compounds have strong selective inhibition effect on the growth of human cancer cell lines.

However, sulphur-containing artemisinin dimers have not been reported.

Disclosure of Invention

The invention provides a sulfur-containing artemisinin dimer, a preparation method and application thereof for solving the technical problems.

The technical scheme for solving the technical problems is as follows:

the invention provides a sulfur-containing artemisinin dimer, which is a compound with a chemical structural formula shown as a formula I or pharmaceutically acceptable salt thereof:

Wherein W is represented as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ 、O、NR ₁ And CR (CR) ¹ ₂ Any one of them;

y is represented as: any one of a single bond, alkyl, aryl, cyclic group, ether, and ammonia;

R ¹ expressed as: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether, and ammonia;

n and m are each independently selected from: an integer of 0 to 15.

The beneficial effects of the invention are as follows: the sulfur-containing artemisinin dimer has selective inhibition effect on the growth of human cancer cell lines.

On the basis of the technical scheme, the invention can be improved as follows.

Further, the sulfur-containing artemisinin dimer or a pharmaceutically acceptable salt thereof has a structure of any one of the following:

wherein Y is represented as: any one of a single bond, alkyl, aryl, cyclic group, ether, and ammonia;

n and m are each independently selected from: an integer of 0 to 15.

Further, Y is represented as: single bond, NR ² 、O、S、SO、SO ₂ 、SR ² _x 、PR ² _x C1-C5 heteroalkyl, substituted with 1-5R ² Substituted C1-C5 heteroalkyl, C1-C10 alkyl, substituted with 1-5R ² Substituted C1-C10 alkyl, aryl, substituted with 1-5R ² Substituted aryl, 3-10 membered cyclic group, substituted with 1-5R ² Substituted 3-10 membered cyclic group, 3-10 membered heterocyclic group, substituted 1-5R ² Substituted 3-to 10-membered heterocyclyl, ether and substituted 1-to 5-membered R ² Any one of the substituted ethers;

wherein the R is ² Expressed as: H. f, O, cl, br, I, CN, C1 to C5 alkyl, aryl, cyclic group, ether and ammonia;

x is an integer from 1 to 4;

the aryl is selected from any one of phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolinyl, purinyl and biaryl;

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

The cyclic group comprises a saturated monocyclic group, an unsaturated monocyclic group, a saturated polycyclic group system and an unsaturated polycyclic group system, and the polycyclic group system comprises a spiro ring, a parallel ring, a bridged ring and a linked ring;

the heterocyclyl groups include saturated mono-heterocyclyl groups, unsaturated mono-heterocyclyl groups, saturated multi-heterocyclyl groups, and unsaturated multi-heterocyclyl groups, including spiro, parallel, bridged, and linked rings.

The beneficial effects of adopting the further scheme are as follows: the structure can be enriched as a choice of Y.

Further, R ¹ Expressed as: H. f, cl, br, I, CN, NR ² 、S、SO、SO ₂ 、SR ² x、PR ² x, C1-C5 heteroalkyl, are substituted with 1-5R ² Substituted C1-C5 heteroalkyl, C1-C10 alkyl, substituted with 1-5R ² Substituted C1-C10 alkyl, aryl, substituted with 1-5R ² Substituted aryl, 3-10 membered cyclic group, substituted with 1-5R ² Substituted 3-10 membered cyclic group, 3-10 membered heterocyclic group, substituted 1-5R ² Substituted 3-to 10-membered heterocyclyl, ether and substituted 1-to 5-membered R ² Any one of the substituted ethers;

wherein said R is ² Expressed as: H. f, O, cl, br, I, CN, C1 to C5 alkyl, aryl, cyclic group, ether and ammonia;

x is an integer from 1 to 4;

The cyclic group comprises a saturated cyclic group and an unsaturated cyclic group, and also comprises a single ring system and a multi-ring system, wherein the multi-ring system comprises a spiro ring, a parallel ring, a bridged ring and a linked ring;

Further, the sulfur-containing artemisinin dimer has a structure of any one of the following:

the reaction equation of the preparation method of the sulfur-containing artemisinin dimer is as follows:

wherein W is represented as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ 、O、NR ¹ And CR (CR) ¹ ₂ Any one of the followingSeed;

R ¹ expressed as: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether, and ammonia; n and m are each independently selected from: an integer of 0 to 15;

the acid is selected from: any one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride diethyl etherate, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyl silyl triflate and p-toluenesulfonic acid;

the specific reaction of the above reaction equation is as follows:

as shown in the equation I, the compound of the formula II and the dihydroartemisinin are dispersed in a solvent, and acid is added dropwise for reaction at the temperature of minus 78 ℃ to 25 ℃ to obtain the sulfur-containing artemisinin dimer.

wherein W is represented as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ 、O、NR ₁ And CR (CR) ¹ ₂ Any one of them;

x is expressed as: any one of halogen and halogen-like; the halogen is selected from: F. any one of Cl, br and I; the halogen-like is selected from: any one of methanesulfonyloxy, trifluoromethanesulfonyl, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy and acyloxy;

n and m are each independently selected from: an integer of 0 to 15;

the specific reaction of the above reaction equation is as follows:

as shown in a second equation, the dihydroartemisinin is subjected to a thio-reaction to prepare the thio-dihydroartemisinin shown in a formula III, and the thio-dihydroartemisinin is reacted with a compound shown in a formula IV to obtain the sulfur-containing artemisinin dimer.

wherein W is represented as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ 、O、NR ₁ And CR (CR) ¹ ₂ Any one of them;

TMS is represented by a trimethylsilyl group;

n and m are each independently selected from: an integer of 0 to 15;

the specific reaction of the above reaction equation is as follows:

and as shown in a third equation, dissolving the compound shown in the formula V and dihydroartemisinin in a solvent, and dropwise adding acid at the temperature of-78-25 ℃ for reaction to obtain the sulfur-containing artemisinin dimer.

The preparation method of the sulfur-containing artemisinin dimer is characterized in that the sulfur-containing artemisinin dimer containing low oxidation state sulfur is oxidized by an oxidant in a solvent to obtain the sulfur-containing artemisinin dimer containing high oxidation state sulfur;

the oxidizing agent is selected from: any one of ozone, carbamide peroxide, hydrogen peroxide, hypochlorous acid, hypochlorite, perchloric acid, perchlorate, persulfates, permanganates, dichromates, periodic acid, periodate and peroxy organic acid;

The low oxidation state sulfur is represented as: negative divalent sulfur;

the high oxidation state sulfur is represented as: SO or SO ₂ 。

An application of the sulfur-containing artemisinin dimer in preparing antitumor drugs.

The pathological state of the antitumor drug is cancer, including but not limited to leukemia, lung cancer, liver cancer, breast cancer, colon cancer, gastric cancer, ovarian cancer, cervical cancer and the like

The sulfur-containing artemisinin dimer of the invention can be combined with known anticancer drugs, such as paclitaxel, etoposide, cisplatin and the like.

The sulfur-containing artemisinin dimers of the invention can be used in combination with other cancer therapies, such as radiation therapy and bone marrow transplantation.

Definition and description:

unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings; a particular term or phrase, unless otherwise specified, should not be construed as being ambiguous or clear and should be construed in a generic sense.

When trade names are presented herein, it is intended to refer to the commodity or active ingredient for which it is intended.

The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases.

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

When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solvent. Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts. Wherein the inorganic acid includes, but is 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, phosphorous acid, and the like; organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic 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 the like,

Certain specific compounds of the invention contain both acidic and basic functionalities and thus can be converted to either base or acid addition salts.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: these compounds are prepared via free acid or base formation in water or an organic solvent or a mixture of both, with a stoichiometric amount of the appropriate base or acid.

In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the 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 the present invention.

Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.

Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.

Unless otherwise stated, "(D)" or "(+)" means right-handed, "(L)" or "(-)" means left-handed, "(DL)" or "(±)" means racemic.

Unless otherwise indicated, with solid wedge bondsAnd wedge-shaped dotted bond->Representing the absolute configuration of a solid centre, using straight solid keys +.>And straight dotted bond->Representing the relative configuration of the stereo centers, using wavy lines +.>Indicating that the stereochemical configuration is not defined or fixed or that it is a mixture.

Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The term "substituted" refers to substitution of any one or more of the hydrogen atom Yu Bei substituents on a particular atom, and may include deuterium and variants of hydrogen, provided that the valence 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 substituted. Oxygen substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

When any variable (e.g. R ¹ ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. Thus, for example, if a group is substituted with 0 to 2R ¹ Substituted, the radicals may optionally be substituted by up to two R ¹ Substituted, and R in each case ¹ There are independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

When the number of one linking group is 0, such as- (CR) ¹ ₂ ) ₀ -it is meant that the linking group is a single bond.

When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, and the structure is actually A-B as compared to when L in A-L-B represents a single bond.

When a substituent is absent, this means that the substituent is absent, e.g., C in A-C is absent, which means that the structure is actually A.

When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring. When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary.

Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

The term "C1-C10 alkyl" is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 10 carbon atoms, unless otherwise specified. It may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine).

The term "aryl" in the present invention refers to any functional group or substituent derived from a simple aromatic ring. Including but not limited to phenyl, biphenyl, pyridinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furanyl, indolyl, quinolinyl, purinyl, and the like, the selected aryl group optionally having two C atoms and a main structure- (CR) ¹ ₂ ) _n -are linked, the remaining atoms optionally being substituted by 1 to 5R ¹ Substitution;

the term "3-to 10-membered cyclic group" in the present invention means a saturated or unsaturated cyclic group consisting of 3 to 10 carbon atoms; including monocyclic and polycyclic ring systems, including spiro, fused, bridged and linked rings. In addition to the main structure- (CR) ¹ ₂ ) _n -the remaining atoms, apart from the linking atoms, may optionally be substituted by 1 to 2R ¹ Substitution; unsaturated cyclic refers to a non-aryl group containing 1 to 3 unsaturated bonds.

The term "3-to 10-membered heterocyclic group" in the present invention means a saturated or unsaturated cyclic group consisting of 3 to 10 carbon atoms, 1 to 6 of which are heteroatoms independently selected from O, S and N, and the balance being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S (O) _t T is 1 or 2). It includes monocyclic and polycyclic ring systems, wherein the polycyclic ring systems include spiro, fused, bridged and linked rings. In addition, in the case of the "3-to 10-membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. In addition to the main structure- (CR) ¹ ₂ ) _n The remaining carbon atoms, apart from the linking atoms, optionally being replaced by 1 to 2R ¹ Substitution; unsaturated characterAnd cyclic refers to a non-aryl group containing 1 to 3 unsaturated bonds. The spiro ring shares an atom for two adjacent monocyclic rings; the merging ring is formed by merging more than two single rings, wherein adjacent two atoms on one single ring are shared with adjacent two atoms of the other single ring in the two merged single rings; the bridged ring is a polycyclic structure sharing more than two atoms; the interlink is that atoms on each single ring of more than two single rings are connected by single bond or double bond.

The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The solvent used in the present invention is commercially available. The invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent; 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-oxo-12H-pyrano [4,3-j ]]-1, 2-benzodithiapin-10 (3H) -ol; SDHA-A represents alpha thiodihydroartemisinin, i.e. (3R, 5αS,6R,8αS,9R,10R,12R,12αR) -octahydro-3, 6, 9-trimethyl-3, 12-oxo-12H-pyrano [4,3-j ]]-1, 2-benzodithiine-10 (3H) -thiol; SDHA-B represents beta thiodihydroartemisinin, i.e. (3R, 5αS,6R,8αS,9R,10S,12R,12αR) -octahydro-3, 6, 9-trimethyl-3, 12-oxo-12H-pyrano [4,3-j ]]-1, 2-benzodithiine-10 (3H) -thiol; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide/deuterated dimethylsulfoxide (when nuclear magnetic); EA represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; THF represents tetrahydrofuran; et (Et) ₂ O represents diethyl ether; et (Et) ₃ N represents triethylamine; CCl (CCl) ₄ Represents carbon tetrachloride; CDCl ₃ Represents deuterated chloroform; meOD represents deuterated methanol; DIAD stands for diisopropyl azodicarboxylate; SOCl ₂ Represents thionyl chloride; ts0H represents p-toluenesulfonic acid; liAlH ₄ Represents lithium aluminum hydride; acOH represents acetic acid; DMAP represents 4-dimethylaminopyridine; ac (Ac) ₂ O represents acetic anhydride; naOH represents sodium hydroxide; BF (BF) ₃ ·Et ₂ O represents boron trifluoride diethyl etherate; acSK represents potassium thioacetate; msCl represents methanesulfonyl chloride; naBH ₄ Represents sodium borohydride; cs (cells) ₂ CO ₃ Represents cesium carbonate; k (K) ₂ CO ₃ Represents potassium carbonate; na (Na) ₂ CO ₃ Represents sodium carbonate; DIBAH represents diisobutylaluminum hydride; AIBN represents azobisisobutyronitrile; NBS represents bromosuccinimide; naOCl stands for sodium hypochlorite; TFAA represents trifluoroacetic anhydride; UHP stands for carbamide peroxide.

Compounds are named according to the general naming convention in the art, and commercially available compounds are referred to by the vendor catalog name.

Detailed Description

The principles and features of the present invention are described below with examples given for the purpose of illustration only and are not intended to limit the scope of the invention.

Example 1: preparation of Compound 1

1. Dihydroartemisinin (100.00 g,351.68mmol,1.00 eq) and thioacetic acid (53.53 g,703.35mmol,2.00 eq) were added to 1.2L DCM, cooled to 0deg.C, boron trifluoride diethyl ether (47.7 mL,386.84mmol,1.10 eq) was added dropwise, and after the addition was completed, the reaction was allowed to stir at room temperature for 30min. TCL (20% EA/PE) showed the disappearance of starting material, giving 12.00g SDHA-A1 and 35.50g SDHA-B1, combined in 39% yield.

2. SDHA-A1 (12.00 g,35.04mmol,1.0 eq) was dissolved in 120mL of 95% ethanol, cooled to 0deg.C, 26.3mL of 2M sodium hydroxide solution was added dropwise, and the reaction was stirred at 0deg.C for 1.5h; the reaction solution was poured into 500mL of water, and aqueous citric acid was added dropwise until the system became weakly acidic, to thereby obtain 24.50g of SDHA-A as a white solid, with a yield of 80%.

3. SDHA-B1 (35.00 g,102.20mmol,1.00 eq) was dissolved in 350mL of 95% ethanol, cooled to 0deg.C, 76.7mL of 2M sodium hydroxide solution was added dropwise, and the reaction was stirred at 0deg.C for 1.5h; the reaction solution was poured into 1500mL of water, and aqueous citric acid was added dropwise until the system became weakly acidic, and 8.60g of white solid SDHA-B was obtained by purification, with a yield of 82%.

4. SDHA-A (200 mg,0.67mmol,1.00 eq) or SDHA-A (200 mg,0.67mmol,1.00 eq) and triethylamine (101 mg,1.00mmol,1.50 eq) were added to 2mL of DCM and cooled to 0deg.C; will I ₂ (85 mg,0.33mmol,0.50 eq) was dissolved in 1mL DCM and added dropwise to the reaction, which was stirred at room temperature for 2h. TCL (20% EA/PE) showed disappearance of starting material, purification gave 150mg of Compound 1A in 75% yield; 162mg of compound 1B was obtained in 81% yield.

The nuclear magnetic resonance results of compound 1 are as follows:

compound 1A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 1B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 2: preparation of Compound 2

SDHA-A (500 mg,0.76mmol,1.00 eq) of example 1 and dimercaptomethane (71 mg,0.88mmol,0.50 eq) were added to 10mL of diethyl ether, cooled to 0 ℃, boron trifluoride diethyl ether (250 mg,1.76mmol,1.00 eq) was added dropwise, the reaction stirred at 0 ℃ for 1h and then stirred overnight at room temperature, TCL (20% EA/PE) showed disappearance of starting material, and purification gave 108mg of Compound 2A;

SDHA-B (500 mg,0.76mmol,1.00 eq) from example 1 and dimercaptomethane (71 mg,0.88mmol,0.50 eq) were added to 10mL diethyl ether, cooled to 0deg.C, boron trifluoride diethyl ether (250 mg,1.76mmol,1.00 eq) was added dropwise, the reaction stirred at 0deg.C for 1h and then allowed to stir at room temperature overnight, TCL (20% EA/PE) showed the disappearance of starting material, and purified to give 102mg of Compound 2B.

The nuclear magnetic resonance results of compound 2 were as follows:

compound 2A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 2B: ¹ HNMR(500MHz,CDCl ₃ )δ5.57(s,2H),5.26(d,J＝5.4Hz,2H),3.44(s,2H),3.01(d,J＝7.0Hz,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).

example 3: preparation of Compound 3

As in example 2, starting with 1, 2-ethanedithiol (83 mg,0.88mmol,0.50 eq) produced 196mg of compound 3A and 165mg of compound 3B.

The nuclear magnetic resonance results of the compound 3A and the compound 3B are as follows:

compound 3A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 3B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 4: preparation of Compound 4

As in example 2, 1, 3-propanedithiol (1.00 g,9.24mmol,1.00 eq) was used as starting material to give 1.13g of compound 4A and 2.51g of compound 4B, the combined yields were 61%, and both compound 4A and compound 4B were white solids.

The nuclear magnetic resonance results of compound 4 were as follows:

compound 4A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 4B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 5: preparation of Compound 5

As in example 2, 1, 4-butanedithiol (1.00 g,8.18mmol,1.00 eq) was used as starting material to give 1.08g of compound 5A and 2.33g of compound 5B, the combined yield was 65%, and both compound 5A and compound 5B were white solids.

The nuclear magnetic resonance results of compound 5 were as follows:

compound 5A: ¹ HNMR(600MHz,CDCl ₃ )δ5.28(s,2H),4.53(d,J＝10.7Hz,2H),2.80(dd,J＝12.5,5.3Hz,2H),2.71–2.63(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).

¹³ CNMR(151MHz,CDCl ₃ )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.

compound 5B: ¹ HNMR(600MHz,CDCl ₃ )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).

¹³ CNMR(151MHz,CDCl ₃ )δ104.19,92.25,88.01,86.70,81.17,80.56,80.39,52.71,45.19,37.21,36.44,34.4432.25,32.08,28.97,26.18,24.62,24.37,20.33,14.85.

example 6: preparation of Compound 6

As in example 2, 1, 5-pentanedithiol (1.00 g,7.34mmol,1.00 eq) was used as starting material to give 0.90g of compound 6A, 1.60g of compound 6B and 1.20g of compound 6C, and the combined yields were 75%, compound 6A, compound 6B and compound 6C were all white solids.

The nuclear magnetic resonance results of compound 6 were as follows:

compound 6A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 6B: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 6C: ¹ HNMR(600MHz,CDCl ₃ )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),2.71–2.62(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).

example 7

Preparation of compound 7:

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as in example 2, 1, 6-butanedithiol (1.00 g,6.65mmol,1.00 eq) was used as starting material to give 2.41g of compound 7A and 0.90g of compound 7B, the combined yield was 72%, and both compound 7A and compound 7B were white solids.

The nuclear magnetic resonance results of compound 7 were as follows:

compound 7A: ¹ HNMR(600MHz,CDCl ₃ )δ5.29(d,J＝13.3Hz,2H),4.29(d,J＝9.2Hz,2H),2.32(dt,J＝14.1,8.6Hz,4H),1.96(d,J＝14.4Hz,2H),1.85–1.79(m,2H),1.70(dd,J＝13.5,3.4Hz,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).

compound 7B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 8: preparation of Compound 8

1. 1, 7-heptanediol (1.00 g,7.56mmol,1.00 eq), triethylamine (2.30 g,22.69mmol,3.00 eq) were added to 20mL of dichloromethane, the reaction was cooled to 0 ℃, methanesulfonyl chloride (2.17 g,18.91mmol,2.50 eq) was added dropwise, the reaction was stirred at 0 ℃ for 1h, TLC (5% MeOH/DCM) showed completion of the reaction, 20mL of water was added to the reaction solution, and 2.16g of intermediate 8-1 was obtained by purification;

2. Intermediate 8-1 (2.16 g,7.49mmol,1.00 eq) was added to 25mL of DMF, potassium thioacetate (1.88 g,16.48mmol,2.20 eq) was added, the reaction warmed to 60℃and stirred overnight. TLC (5% EA/PE) showed complete reaction and purification gave 410mg of intermediate 8-2;

3. intermediate 8-2 (400 mg,1.61mmol,1.00 eq) was added to 8mL of 95% ethanol, the reaction was cooled to 0deg.C, 2mL of 2M sodium hydroxide solution was added dropwise, and the reaction was stirred at 0deg.C for 0.5h. TLC (5% EA/PE) showed complete reaction, pH of the reaction solution was adjusted to neutral with 1N hydrochloric acid, and purification gave 250mg of intermediate 8-3 in 95% yield;

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

The nuclear magnetic resonance results of compound 8 were as follows:

compound 8A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 8B: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 9: preparation of Compound 9

As in example 8, 1, 8-octanediol (1.05 g,7.18mmol,1.00 eq) was used as starting material, yielding 180mg of compound 9A, 390mg of compound 9B and 700mg of compound 9C, compound 9A, compound 9B and compound 9C all being colorless oils.

The nuclear magnetic resonance results of compound 9 were as follows:

compound 9A: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

compound 9B: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

compound 9C: ¹ HNMR(500MHz,CDCl ₃ )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,10H),1.53–1.47(m,2H),1.33(m,19H),1.10–1.00(m,1H),1.01–0.88(m,13H).

¹³ CNMR(126MHz,CDCl ₃ )δ104.23,104.16,92.24,88.01,86.72,52.71,51.81,46.07,45.21,37.37,37.20,36.44,36.28,34.45,34.09,32.71,32.08,31.73,29.86,29.70,29.13,28.99,28.87,28.34,26.18,25.96,24.76,24.62,24.37,21.30,20.34,20.25,15.10,14.85.

example 10: preparation of compound 10:

as in example 8, 1, 9-nonanediol (1.00 g,6.24mmol,1.00 eq) was used as starting material to give 667mg of compound 10A, 632mg of compound 10B and 548mg of compound 10C, which were combined in 64% yield, compound 10A, compound 10B and compound 10C as white foam solids.

The nuclear magnetic resonance results of compound 10 were as follows:

compound 10A: ¹ HNMR(500MHz,CDCl ₃ )δ5.29(s,2H),4.52(d,J＝10.6Hz,2H),2.80–2.71(m,2H),2.65–2.59(m,4H),2.36(t,J＝12.6Hz,2H),2.03(t,J＝13.5Hz,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).

¹³ CNMR(126MHz,CDCl ₃ )δ104.25,92.25,80.58,80.40,51.82,46.06,37.39,36.44,34.10,32.06,31.73,29.86,29.38,29.04,28.36,25.95,24.77,21.30,20.25,15.10.

compound 10B: ¹ HNMR(500MHz,CDCl ₃ )δ5.62(s,2H),5.27(d,J＝5.1Hz,2H),3.03(dd,J＝11.4,5.3Hz,2H),2.66(t,J＝6.4Hz,4H),2.37(td,J＝14.0,3.1Hz,2H),2.04(d,J＝14.4Hz,2H),1.95–1.78(m,4H),1.69(t,J＝12.8Hz,4H),1.60(dd,J＝14.9,7.6Hz,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).

¹³ CNMR(126MHz,CDCl ₃ )δ104.18,88.02,86.73,81.20,52.71,45.21,37.21,36.44,34.45,32.72,32.08,29.72,29.38,29.18,28.90,26.19,24.63,24.37,20.35,14.86.

compound 10C: ¹ HNMR(500MHz,CDCl ₃ )δ5.61(s,1H),5.28(s,1H),5.26(d,J＝5.3Hz,1H),4.52(d,J＝10.6Hz,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).

¹³ CNMR(126MHz,CDCl ₃ )δ104.24,104.17,92.25,88.02,86.73,81.20,80.58,80.41,52.72,51.82,46.07,45.21,37.38,37.21,36.44,36.29,34.45,34.10,32.73,32.08,31.73,29.87,29.72,29.40,29.21,29.04,28.90,28.35,26.19,25.96,24.77,24.63,24.37,21.30,20.34,20.25,15.10,14.86.

example 11: preparation of Compound 11:

as in example 8, 1, 10-decanediol (1.00 g,5.74mmol,1.00 eq) was used as starting material, yielding 382mg of compound 11A and 481mg of compound 11B, with a combined yield of 36%, compound 11A and compound 11B both being white solids.

The nuclear magnetic resonance results of compound 11 were as follows:

compound 11A: ¹ HNMR(500MHz,CDCl ₃ )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)

compound 11B: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

Example 12: preparation of Compound 12

1.2, 5-hexanediol (600 mg,5.08mmol,1.00 eq) and triethylamine (3.08 g,30.46mmol,6.00 eq) were added to 25mL of DCM, cooled to 0deg.C, methanesulfonyl chloride (2.33 g,20.31mmol,4.00 eq) was added dropwise, the reaction stirred for 15min and then allowed to stir at room temperature for 1h, TCL (40% EA/PE) showed the starting material disappeared, 50mL of water was added to the reaction, and purification afforded 1.20g of intermediate 12-1 in 86% yield;

2. Intermediate 12-1 (0.50 g,1.82mmol,1.00 eq) and SDHA-A (1.10 g,3.65mmol,3.00 eq) prepared in example 1 were added to 10mL of DMF, potassium carbonate (756 mg,5.47mmol,3.00 eq) was added and the reaction stirred at room temperature for 20h. TCL (15% EA/PE) showed disappearance of starting material, and 30mL of water was added to the reaction, followed by purification to give 510mg of Compound 12A in 41% yield;

3. intermediate 12-1 (0.50 g,1.82mmol,1.00 eq) and SDHA-B (1.10 g,3.65mmol,3.00 eq) from example 1 were added to 10mL of DMF and potassium carbonate (751 mg,5.47mmol,3.00 eq) was added and the reaction stirred at room temperature for 20h. TCL (15% EA/PE) showed the disappearance of starting material, and 30mL of water was added to the reaction, followed by purification to give 560mg of Compound 12B in 45% yield.

The nuclear magnetic resonance results of compound 12 were as follows:

compound 12A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 12B: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 13:

preparation of Compound 13:

13-1 (100 mg,0.31mmol,1.00 eq) and DHA (192 mg,0.68mmol,2.20 eq) were added to 10mL diethyl ether, cooled to 0deg.C, and boron trifluoride diethyl ether (77 mg,0.68mmol,2.20 eq) was added dropwise; stirring the reaction at 0 ℃ for 30min, then moving to room temperature and stirring for 2h; TLC (20% EA/PE) showed complete reaction, quenched with 20mL of saturated sodium bicarbonate solution, separated and purified to give 69mg of compound 13A and 91mg of compound 13B in 61% yield, both compound 13A and compound 13B as white solids.

The nuclear magnetic resonance results of compound 13 were as follows:

compound 13A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 13B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 14: preparation of compound 14:

the preparation process comprises the following steps:

14-1 (0.50 g,2.74mmol,1.00 eq) and dihydroartemisinin (1.72 g,6.03mmol,2.20 eq) were added to 27mL Et ₂ In O, ar was replaced, and the mixture was stirred at-5℃to slowly add boron trifluoride diethyl etherate (0.85 g,6.03mmol,2.20 eq) dropwise, and after the addition was completed, the mixture was allowed to stand at room temperature for 3 hours. The reaction solution was poured into 100mL of saturated sodium bicarbonate solution, quenched, extracted 3 times with 80mL of EA, and purified as a white foam, 0.90g of Compound 14, yield 45%, compound 14 was a white foam.

The nuclear magnetic resonance results of compound 14 were as follows:

¹ HNMR(500MHz,CDCl ₃ )δ5.60(s,2H),5.31(d,J＝4.4Hz,2H),3.80–3.71(m,2H),3.67–3.57(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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 15: preparation of compound 15:

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1. DHA (2.00 g,7.03mmol,1.00 eq) was added to 15mL1, 4-butanediol and 15mL DCM, cooled to 0deg.C, and boron trifluoride etherate (1.05 g,7.39mmol,1.05 eq) was added dropwise; the reaction was stirred at 0deg.C for 30min and then brought to room temperature and stirred for 2h. TLC (20% EA/PE) showed complete reaction, quenched with 100mL of saturated sodium bicarbonate solution, separated and purified to give 2.32g of intermediate 15-1 in 93% yield, intermediate 15-1 as a colorless oily liquid;

2. intermediate 15-1 (2.32 g,8.61mmol,1.0 eq) was dissolved in 50mL of anhydrous dichloromethane, cooled to 0 ℃, triethylamine (1.65 g,16.27mmol,2.50 eq) was added, and after stirring for 10min methylsulfonyl chloride (895 mg,7.81mmol,1.20 eq) was added dropwise; after the addition, the reaction is moved to room temperature and stirred for 2 hours; after the reaction is completed, pouring the reaction solution into 150mL of saturated sodium bicarbonate solution, and fully stirring; purification gave 0.53g of intermediate 15-2 and 2.02g of intermediate 15-3 in 90% yield, intermediate 15-2 and intermediate 16-3 as white solids;

3. 15-2 (200 mg,0.46mmol,1.00 eq) and SDHA-A (139 mg,0.46mmol,1.00 eq) were added to 5mL of DMF, potassium carbonate (128 mg,0.92mmol,2.00 eq) was added and the reaction stirred at room temperature for 20h. TCL (20% EA/PE) showed the disappearance of starting material, giving 163mg of compound 15A in 55% yield.

4. 15-2 (200 mg,0.46mmol,1.00 eq) and SDHA-B (139 mg,0.46mmol,1.00 eq) were added to 5mM LDMF, potassium carbonate (128 mg,0.92mmol,2.00 eq) was added and the reaction stirred at room temperature for 20h. TCL (20% EA/PE) showed the disappearance of starting material, which was purified to yield 143mg of Compound 15C in 49% yield.

5. 15-3 (500 mg,1.15mmol,1.00 eq) and SDHA-A of example 1 (346 mg,1.15mmol,1.00 eq) were added to 10mL of DMF, potassium carbonate (318 mg,2.30mmol,2.00 eq) was added and the reaction stirred at room temperature for 20h. TCL (20% EA/PE) showed the disappearance of starting material, which was purified to yield 465mg of compound 15D in 63% yield.

6. 15-3 (500 mg,1.15mmol,1.00 eq) and SDHA-B of example 1 (346 mg,1.15mmol,1.00 eq) were added to 10mL of DMF and potassium carbonate (318 mg,2.30mmol,2.00 eq) was added and the reaction stirred at room temperature for 20h. TCL (20% EA/PE) showed the disappearance of starting material, giving 432mg of compound 15B in 59% yield.

The nuclear magnetic resonance results of compound 15 were as follows:

compound 15A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 15B: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 15C: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 15D; ¹ HNMR(600MHz,CDCl ₃ )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).

example 16: preparation of Compound 16

As in example 15, starting with 4-aminobutane-1-thiol (174 mg,1.66mmol,0.50 eq) gave 114mg of compound 16A and 131mg of compound 16B, combined yield 23%, compound 16A and compound 16B were both white solids.

The nuclear magnetic resonance results of compound 16 are as follows:

compound 16A:1HNMR (600 MHz, CDCl 3) delta 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, 8.07,6.55Hz, 1H), 2.80 (dd, J=12.5, 5.3Hz, 1H), 2.71-2.61 (m, 2H), 2.59-2.56 (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, 4H), 1.59-1.54 (m, 2H), 1.52-1.30 (m, 12H), 1.24-1.18.08-2.30 (m, 2H), 1.80-1.98.98 (m, 0.95).

Compound 16B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 17: preparation of Compound 17

1. DHA (20.00 g,70.34mmol,1.00 eq) and allyl trimethylchlorosilane (20.09 g,175.84mmol,2.50 eq) are added into 200mL dichloromethane, the reaction is cooled to-50 ℃, boron trifluoride diethyl ether (9.61 g,84.40mmol,1.20 eq) is added dropwise for reaction, and 8.60g intermediate 17-1 is obtained by purification;

2. Intermediate 17-1 (10.00 g,32.42mmol,1.00 eq) was added to 500mL DCM, cooled to-78 ℃, ozone was introduced for 1.5h, the reaction turned blue, the introduction of ozone was stopped, air was continued for 30min, and the solvent was concentrated to remove; into a reaction flask were added 80mL of THF and 20mL of MeOH, cooled to 0deg.C, and NaBH was added in portions ₄ (7.36 g,194.54mmol,6.00 eq) and the reaction was stirred at 0deg.C for 4h and then allowed to stir overnight at room temperature; the reaction was quenched with 50mL of water, separated and purified to give 6.39g of intermediate 17-2;

3. intermediate 17-2 (1.00 g,3.20mmol,1.00 eq) and triethylamine (972 mg,9.60mmol,3.00 eq) were added to 20mL of DCM, the reaction cooled to 0deg.C, methanesulfonyl chloride (440 mg,3.84mmol,1.20 eq) was added dropwise, the reaction stirred at 0deg.C for 2h and then allowed to warm to room temperature overnight, TLC (40% EA/PE) showed complete reaction, and purification afforded 10.05g of intermediate 17-3;

4. intermediate 17-3 (560 mg,1.43mmol,1.00 eq) and potassium thioacetate (246 mg,2.15mmol,1.50 eq) were added to 10mL DMF and the reaction warmed to 60℃and stirred overnight and purified to give 370mg of intermediate 17-4 in 70% yield.

5. Intermediate 17-4 (370 mg,1.00mmol,1.00 eq) was added to 10mLEtOH, cooled to 0deg.C, 0.75mL of 2M sodium hydroxide solution was added dropwise, the reaction was stirred at 0deg.C for 1h, TLC (20% EA/PE) showed completion of the reaction, the reaction solution was neutralized with 2M hydrochloric acid, and purification afforded 300mg of intermediate 17-5 in 91% yield.

6. Intermediate 17-5 (300 mg,0.81mmol,1.00 eq) and DHA (348 mg,1.21mmol,1.50 eq) were added to 20mL diethyl ether, the reaction was cooled to 0deg.C, boron trifluoride diethyl ether (173 mg,1.21mmol,1.50 eq) was added dropwise, the reaction was stirred at 0deg.C for 10min and then gradually warmed to room temperature and stirred for 3h, TLC (20% EA/PE) showed complete reaction, purification afforded 280mg of compound 18 in 52% yield as a white solid.

The nuclear magnetic resonance results of compound 17 were as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )δ103.85,103.82,101.59,98.79,90.63,88.56,81.17,80.04,52.75,51.56,45.43,44.59,37.41,37.37,36.56,36.26,34.85,34.30,32.97,31.17,26.20,25.90,24.79,24.69,24.21,21.99,20.34,20.30,13.09,12.66.

example 18: preparation of Compound 18

1.1, 4-cyclohexanedione (18-1:4.00 g,35.67mmol,1.00 eq) was dissolved in 71mL of methanol and cooled to 0deg.C and NaBH was added in portions ₄ (2.70 g,71.35mmol,2.00 eq) and after addition the reaction was stirred at 0deg.C for 20min, then brought to room temperature and stirred for 1h; TLC (10% MeOH/DCM) showed the starting material disappeared, the reaction was quenched with water and purified to give 3.20g of intermediate 18-1.

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

3. Intermediate 18-2 (3.00 g,11.02mmol,1.00 eq) was dissolved in 55mL DMF and potassium thioacetate (3.77 g,33.05mmol,3.00 eq) was added, the reaction warmed to 80℃and stirred for 3h. TLC (5% EA/PE) showed complete reaction and purification gave 0.90g of intermediate 18-4;

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

5. DHA (284 mg,2.97mmol,2.20 eq) was dissolved in 20mL diethyl ether, cooled to 0deg.C, stirred for 10min, boron trifluoride diethyl ether (514 mg,4.05mmol,3.00 eq) was added dropwise, intermediate 18-5 (200 mg,1.35mmol,1.00 eq) was added after the dropwise addition, and the reaction was stirred at 0deg.C for 10min and then brought to room temperature for 2h. TLC (20% EA/PE) showed complete reaction and purification gave 184mg of compound 18B and 242mg of compound 18C, combined in 47% yield, compound 18B and compound 18C as white solids;

6. 18-3 (1.20 g,4.41mmol,1.00 eq) was dissolved in 40mL of DMF, potassium thioacetate (1.51 g,13.22mmol,3.00 eq) was added, the reaction warmed to 80℃and stirred for 3h. TLC (5% EA/PE) showed complete reaction and purification gave 0.60g of intermediate 18-6;

7. 18-6 (600 mg,2.58mmol,1.00 eq) was dissolved in 25mL of 95% ethanol, cooled to 0℃and 3.9mL of 2M aqueous sodium hydroxide solution was added dropwise, and the reaction was stirred at 0℃for 0.5h. TLC (3% EA/PE) showed complete reaction and purification gave 280mg of intermediate 18-7;

8. DHA (1.05 g,3.71mmol,2.20 eq) was dissolved in 20mL diethyl ether, cooled to 0deg.C, stirred for 10min, boron trifluoride diethyl ether (7197 mg,5.06mmol,3.00 eq) was added dropwise, 18-7 (250 mg,1.69mmol,1.00 eq) was added after the dropwise addition, the reaction was stirred at 0deg.C for 10min and then allowed to stir at room temperature for 2h. TLC (20% ea/PE) showed complete reaction and purification gave 800mg of compound 18A as a white solid in 70% yield.

The nuclear magnetic resonance results of compound 18 were as follows:

compound 18A: ¹ HNMR(600MHz,CDCl ₃ )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),1.59–1.46(m,4H),1.42(t,J＝10.5Hz,6H),1.41–1.16(m,7H),1.07–0.77(m,16H).

compound 18B: ¹ HNMR(600MHz,CDCl ₃ )δ5.62(s,2H),5.35(t,J＝6.0Hz,2H),3.03(dd,J＝12.1,5.1Hz,2H),2.81(s,2H),2.37(td,J＝14.2,3.7Hz,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＝11.3,6.8Hz,3H),0.94-0.88(m,14H).

¹³ CNMR(151MHz,CDCl ₃ )δ104.22,88.07,85.49,81.16,52.67,45.18,43.69,37.18,36.43,34.42,34.14,33.63,32.10,26.20,24.61,24.35,20.33,14.97.

compound 18C: ¹ HNMR(600MHz,CDCl3)δ5.62(s,1H),5.35(d,J＝5.4Hz,1H),5.26(d,J＝6.1Hz,1H),4.61(d,J＝10.8Hz,1H),3.02(dt,J＝17.3,7.9Hz,2H),2.83(t,J＝10.8Hz,1H),2.65–2.54(m,1H),2.37(tt,J＝14.3,3.8Hz,2H),2.26(d,J＝9.4Hz,1H),2.14(dd,J＝10.8,4.9Hz,2H),2.10–1.98(m,3H),1.92–1.84(m,2H),1.78–1.66(m,5H),1.58(dt,J＝13.3,4.0Hz,1H),1.51–1.33(m,16H),1.24(dd,J＝17.9,9.5Hz,3H),1.08–1.00(m,1H),0.94(ddd,J＝18.7,8.8,4.6Hz,12H).

¹³ CNMR(151MHz,CDCl ₃ )δ104.26,104.21,92.13,88.10,85.41,81.16,80.37,79.92,52.67,51.82,46.13,45.20,43.70,40.33,37.37,37.20,36.44,36.28,34.58,34.43,34.07,33.84,33.37,32.09,26.19,25.97,24.77,24.63,24.36,21.28,20.33,20.26,15.28,14.97.

example 19: preparation of Compound 19

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

2. intermediate 19-1 (972 mg,3.36mmol,1.00 eq) was added to 25mL of DMF, potassium thioacetate (1.15 g,10.08mmol,3.00 eq) was added, the reaction warmed to 60℃and stirred overnight. TLC (10% EA/PE) showed complete reaction, purification gave 312mg of intermediate 19-2, 37% yield;

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

4. intermediate 19-3 (154 mg,0.93mmol,1.00 eq) and DHA (580 mg,2.04mmol,2.20 eq) were added to 15mL diethyl ether, cooled to 0deg.C, and boron trifluoride diethyl ether (290 mg,2.04mmol,2.20 eq) was added dropwise; the reaction was stirred at 0deg.C for 30min and then brought to room temperature and stirred for 2h. TLC (20% EA/PE) showed complete reaction and purification gave 164mg of compound 19A and 188mg of compound 19B as white solids, combined in 57% yield, compound 19A and compound 19B as solid.

The nuclear magnetic resonance results of compound 19 were as follows:

compound 19A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 19B: ¹ HNMR(500MHz,CDCl ₃ )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),1.44(s,5H),1.37–1.29(m,2H),1.25-1.01(d,J＝7.3Hz,12H),0.95–0.85(m,8H).

example 20: preparation of Compound 20

As in example 19, using cis-cyclobutanediol (500 mg,5.67mmol,1.00 eq) as starting material, 172mg of compound 20A and 215mg of compound 20B were obtained as white solids, and the combined yields were 55% as white solids, compound 20A and compound 20B.

The nuclear magnetic resonance results of compound 20 were as follows:

compound 20A: ¹ HNMR(500MHz,CDCl ₃ )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).

Compound 20B: ¹ HNMR(500MHz,CDCl ₃ )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,2H),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,5H),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).

example 21: preparation of Compound 21

As in example 19, using cis-cyclooctadiene (500 mg,3.84mmol,1.00 eq) as starting material gave 159mg of compound 21A and 190mg of compound 21B, combined yield 46%, compound 21A and compound 21B were both white solids.

The nuclear magnetic resonance results of compound 21 were as follows:

compound 21A: ¹ HNMR(500MHz,CDCl ₃ )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),2.22–2.13(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).

compound 21B: ¹ HNMR(500MHz,CDCl ₃ )δ5.58(s,1H),5.56(s,1H),5.34–5.20(m,4H),3.04(d,J＝7.0Hz,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).

example 22: preparation of Compound 22

As in example 19, starting material 22 (5.00 g,34.67mmol,1.00 eq) was employed to afford 1.93g of compound 22 in 57% yield as a foamy white solid.

The nuclear magnetic resonance results of compound 22 were as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )δ104.21,104.16,92.22,88.02,87.08,81.17,80.83,80.38,52.69,51.78,46.03,45.19,39.83,38.23,37.99,37.36,37.19,36.43,36.27,35.38,35.32,34.44,34.09,32.75,32.69,32.51,32.36,32.26,32.12,31.73,26.19,25.97,24.76,24.61,24.39,21.30,20.34,20.25,15.08,14.84.

example 23: preparation of Compound 23

As in example 19, starting material 23 (2.00 g,13.87mmol,1.00 eq) gave 210mg of compound 23 in 12% yield, compound 23 as a white foamy solid.

The nuclear magnetic resonance of compound 23 was as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 24: preparation of Compound 24

As in example 19, starting material 24 (1.00 g,6.93mmol,1.00 eq) gave 2.60g of compound 24 in 82% yield as white foamy solid 25.

The nuclear magnetic resonance results of compound 24 are as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 25: preparation of Compound 25

1. Raw material 25 (1.50 g,10.41mmol,1.00 eq) was dissolved in 55mL MeOH and H was slowly added ₂ SO ₄ (4.1 g,41.63mmol,4.00 eq) and after addition the reaction was warmed to reflux and stirred for 3h; cooling the reaction to 0 ℃, adding sodium bicarbonate to adjust the pH to be neutral, and purifying to obtain 1.70g of intermediate 25-1;

2. LiAlH is prepared ₄ (1.45 g,38.33mmol,4.00 eq) was added to 96mL of THF, cooled to 0deg.C and stirred for 10min; intermediate 25-1 (1.65 g,95.83mmol,1.00 eq) was added dropwise to the reaction in 20mL THF, after which time it was allowed to stir at room temperature for 2h; after the reaction is completed, the temperature is reduced to 0 ℃ and 840mg of intermediate 25-2 is obtained after purification;

3. as in example 19, intermediate 25-2 (800 mg,6.89mmol,1.00 eq) was used to give 320mg of compound 25 in 23% yield, compound 25 as a white foamy solid.

The nuclear magnetic resonance results of compound 25 were as follows:

¹ HNMR(600MHz,CDCl ₃ )δ5.63(s,2H),5.28(d,J＝4.3Hz,2H),3.11(d,J＝12.3Hz,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).

¹³ CNMR(151MHz,CDCl ₃ )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.

example 26: preparation of Compound 26

As in example 19, starting material 26 (1.00 g,8.61mmol,1.00 eq) was employed to afford 910mg of compound 26 in 66% yield, compound 26 as a white foamy solid.

The nuclear magnetic resonance results of compound 26 are as follows:

¹ HNMR(500MHz,CH ₃ CN)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).

¹³ CNMR(126MHz,CH ₃ CN)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.

example 27: preparation of Compound 27

1. Methyl triphenylphosphine bromide (41.17 g,115.25mmol,1.20 eq) was added to 400mL THF, argon was replaced, the temperature was reduced to 0 ℃, potassium tert-butoxide (12.93 mg,115.25mmol,1.20 eq) was added in portions, the reaction was stirred at 0℃for 30min, then was stirred at room temperature for 3h, and the reaction was cooled to 0 ℃; raw material 27 (15.00 g,96.04mmol,1.00 eq) was dissolved in 50mL of THF and added dropwise to the reaction, which was stirred at 0 ℃ for 1h and then allowed to stir at room temperature overnight, and purified to give 12.5g of intermediate 27-1;

2. Intermediate 27-1 (10.00 g,64.85mmol,1.00 eq), zn (8.48 g,129.69mmol,2.00 eq) and Cu (OAc) ₂ (1.18 g,6.48mmol,0.10 eq) was added to 300mL diethyl ether, replaced with argon, and stirred at room temperature for 3h; trichloroacetyl chloride (23.58 g,129.69mmol,2.00 eq) was dissolved in 200mL diethyl ether and added dropwise to the reaction, which was stirred overnight at room temperature, and purified to give 10.50g of intermediate 27-2;

3. intermediate 27-2 (10.00 g,37.72mmol,1.00 eq) and Zn (12.33 g,188.59mmol,5.00 eq) were added to 100mL of methanol, ammonium chloride (20.17 g,377.17mmol,10.00 eq) was added in portions with stirring, the reaction was stirred at room temperature for 5h, and purification gave 6.6g of intermediate 27-3;

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

5. will be inAdding intermediate 27-4 (600 mg,3.94mmol,1.00 eq) into 10mL of methanol, cooling to 0 ℃, and adding NaBH in portions ₄ (4478 mg,11.83mmol,3.00 eq) and the reaction stirred at 0deg.C for 3h and then brought to room temperature and stirred for 3h, purification gives 316mg of intermediate 27-5;

6. as in example 19, intermediate 27-5 (300 mg,1.92mmol,1.00 eq) was used to give 57mg of compound 27A and 73mg of compound 27B, and the combined yields were 42% and compound 27A and compound 27B were both white solids.

The nuclear magnetic resonance results of compound 27 were as follows:

compound 27A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 27B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 28: preparation of Compound 28

1. LiAlH is prepared ₄ (403 mg,10.62mmol,2.70 eq) was added to 30ml of THF, cooled to 0deg.C, raw material 28 (1.00 g,3.93mmol,1.00 eq) was dissolved with 9ml of THF and added dropwise to the reaction, the reaction was stirred at 0deg.C for 20min and then moved to room temperature for 12h; TLC (50% EA/PE) showed the starting material disappeared, and purification gave 600mg of intermediate 28-1;

2. intermediate 28-1 (480 mg,4.05mmol,1.00 eq) was dissolved in 20mL toluene, imidazole (820 mg,12.04mmol,2.97 eq), triphenylphosphine (3.16 g,12.04mmol,2.97 eq) and iodine (3.06 g,12.04mmol,2.97 eq) were added sequentially, the reaction warmed to 60℃and stirred for 12h; TLC (40% EA/PE) showed the starting material disappeared, and purification gave 400mg of intermediate 28-2;

3. intermediate 28-2 (400 mg,1.03mmol,1.00 eq) was dissolved in 4ml of LDMF, potassium thioacetate (352 mg,3.08mmol,3.00 eq) was added, and the reaction was warmed to 60℃and stirred for 2h; TLC (40% EA/PE) showed the starting material disappeared, and purification gave 250mg of intermediate 28-3;

4. intermediate 28-3 (150 mg,0.52mmol,1.00 eq) was dissolved in 5mL of 95% ethanol, cooled to 0deg.C, 0.78mL of 2M aqueous sodium hydroxide solution was slowly added dropwise, and the reaction was continued to be stirred at 0deg.C for 15min; TLC (10% EA/PE) showed the starting material disappeared, and purification gave 100mg of intermediate 28-4;

5. Intermediate 28-4 (100 mg,0.49mmol,1.00 eq) and DHA (351 mg,1.24mmol,2.50 eq) were dissolved in 5mL diethyl ether, cooled to 0deg.C, boron trifluoride diethyl ether (210 mg,1.48mmol,3.00 eq) was slowly added dropwise, the reaction was stirred at 0deg.C for 30min and then allowed to stir at room temperature for 2h; TLC (40% EA/PE) showed the starting material disappeared, and purification gave 91mg of compound 28A and 109mg of compound 28B, yield 55%, compound 28A and compound 28B were both white solids.

The nuclear magnetic resonance results of compound 28 are as follows:

compound 28A: ¹ HNMR(600MHz,CDCl ₃ )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＝12.5Hz,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).

compound 28B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 29: preparation of Compound 29

1. LiAlH is prepared ₄ (279 mg,7.35mmol,2.50 eq) was added to 20mL of THF, cooled to 0deg.C, 30-1 (500 mg,2.94mmol,1.00 eq) was dissolved with 9mL of THF and added dropwise to the reaction, the reaction was stirred at 0deg.C for 20min and then allowed to stir at room temperature for 1h, and purification afforded 300mg of intermediate 29-1;

2. intermediate 29-1 (740 mg,5.77mmol,1.00 eq) was dissolved in 58mL DCM, cooled to 0deg.C, imidazole (1.14 g,16.74mmol,2.97 eq), triphenylphosphine (4.39 g,16.74mmol,2.97 eq) and iodine (4.25 g,16.74mmol,2.97 eq) were added sequentially, the reaction was stirred at 0deg.C for 10min and then moved to room temperature for 2h, and purified to give 1.50g intermediate 29-2;

3. Intermediate 29-2 (100 mg,0.29mmol,1.00 eq) was dissolved in 3m LDMF, SDHA-B (168 mg,0.56mmol,1.95 eq) from example 1 and potassium carbonate (79 mg,0.57mmol,2.00 eq) were added sequentially and the reaction stirred at room temperature for 2h to give 102mg of compound 29B in 51% yield and compound 29B as a colourless oily liquid.

4. Intermediate 29-2 (100 mg,0.29mmol,1.00 eq) was dissolved in 3mL of DMF and SDHA-A (168 mg,0.56mmol,1.95 eq) from example 1 and potassium carbonate (79 mg,0.57mmol,2.00 eq) were added sequentially and the reaction stirred at room temperature for 2h to give 104mg of compound 29A in 52% yield as a white solid.

The nuclear magnetic resonance of compound 29 was as follows:

compound 29A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 29B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 30: preparation of Compound 30

1. Raw material 30 (50.00 g,128.10mmol,1.00 eq) and thioacetic acid (12.71 g,166.51mmol,1.30 eq) were dissolved in 650mL DCM, cooled to 0deg.C, boron trifluoride diethyl etherate (29.11 g,204.9mmol,1.60 eq) was slowly added dropwise, after the dropwise addition was completed, the mixture was allowed to stand at room temperature overnight with stirring, and 28.22g of intermediate 30-1 was obtained by purification;

2. adding intermediate 30-1 (18.00 g,44.29mmol,1.00 eq) into 1.5L methanol, cooling to-25 ℃, slowly dropwise adding 97mL of 0.5M sodium methoxide methanol solution, continuously stirring at-25 ℃ for 30min after the dropwise adding, regulating the pH value to be neutral by using cation exchange resin, and purifying to obtain 16.00g intermediate 30-2;

3. DHA (18.73 g,65..87mmol,1.50 eq) was dissolved in 400mL diethyl ether, cooled to 0deg.C, boron trifluoride diethyl ether (12.46 g,87.82mmol,2.00 eq) was added dropwise, then intermediate 30-2 (16.00 g,43.91mmol,1.00 eq) was dissolved in 40mL diethyl ether and added dropwise to the reaction, after the addition was completed the reaction was moved to room temperature and stirred overnight, and 20.15g intermediate 30-3 was obtained by purification;

4. intermediate 30-3 (20.00 g,31.71mmol,1.00 eq) was dissolved in 320mL of methanol, cooled to 0deg.C, sodium methoxide (1.03 g,19.03mmol,0.60 eq) was added, the reaction was stirred at 0deg.C for 10min and then was stirred at room temperature for 2h, the pH of the reaction solution was adjusted to neutral with cation exchange resin, and 13.22g of intermediate 30-4 was obtained by purification;

5. intermediate 30-4 (3.00 g,6.49mmol,1.00 eq) was dissolved in 30mL pyridine, cooled to 0deg.C, and p-toluylcycloacyl chloride (1.36 g,7.13mmol,1.10 eq) and DMAP (79 mg,0.65mmol,0.10 eq) were added, and the reaction was stirred at 0deg.C for 10min and then moved to room temperature for 3h; TLC (5% MeOH/DCM) showed completion of the reaction and purification gave 2.30g of intermediate 30-5;

6. intermediate 30-5 (1.00 g,1.62mmol,1.00 eq) and SDHA-A of example 1 (731 mg,2.43mmol,1.50 eq) were dissolved in 32mL of DMF and potassium carbonate (447 mg,3.24mmol,2.00 eq) was added and the reaction stirred at room temperature overnight to give 160mg of compound 30 as a pale red solid which was purified to yield 13%.

The nuclear magnetic resonance of compound 30 was as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

example 31: preparation of Compound 31

Intermediate 30-4 (50.00 g,128.10mmol,1.00 eq) and thioacetic acid (12.71 g,166.51mmol,1.30 eq) of example 30 were dissolved in 650mL of DCM, cooled to 0deg.C, boron trifluoride diethyl ether (29.11 g,204.9mmol,1.60 eq) was slowly added dropwise, and after the addition was allowed to stir overnight at room temperature, and purified to afford 28.22g of Compound 31 in 54% yield as a white solid.

The nuclear magnetic resonance of compound 31 was as follows:

¹ HNMR(600MHz,CDCl ₃ )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,1H),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).

example 32: preparation of Compound 32

As in example 31, using p-phenylene dithiol (500 mg,3.52mmol,1.00 eq) as the starting material, 423mg of compound 32A, 454mg of compound 32B and 453mg of compound 32C were obtained, and the combined yields were 56%, and compound 32A, compound 32B and compound 32C were all white solids.

The nuclear magnetic resonance results of compound 32 are as follows:

compound 32A: ¹ HNMR(600MHz,CDCl ₃ )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,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).

compound 32B: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 32C: ¹ HNMR(600MHz,CDCl ₃ )δ7.32-7.26(m,4H),5.61(s,1H),5.26(s,1H),5.19(d,J＝5.4Hz,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).

example 33: preparation of Compound 33

As in example 31, using phthalic dithiol (600 mg,4.22mmol,1.00 eq) as starting material, 415mg of compound 33A, 472mg of compound 33B and 363mg of compound 33C were obtained as white solids in 44% yield, compound 33A, compound 33B and compound 33C.

The nuclear magnetic resonance results of compound 33 were as follows:

compound 33A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 33B: ¹ HNMR(600MHz,CDCl ₃ )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),2.06(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).

compound 33C: ¹ HNMR(600MHz,CDCl ₃ )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).

example 34: preparation of Compound 34

1. Raw material 34 (10.00 g,80.51mmol,1.00 eq) and triethylamine (12.22 g,120.77mmol,1.50 eq) were added to 250mL of DCM and acetic anhydride (9.86 g,96.62mmol,1.20 eq) was added and the reaction stirred at room temperature overnight; TCL (3% EA/PE) showed the starting material disappeared and purification gave 11.50g of intermediate 34-1;

2. intermediate 34-1 (11.00 g,66.17mmol,1.00 eq) and NBS (12.96 g,72.79mmol,1.10 eq) were added to 110mL Cl ₄ AIBN (1.09 g,6.62mmol,0.10 eq) was added to replace argon, the reaction was warmed to reflux and stirred under reflux for 3h, and purified to give 12.50g of intermediate 34-2;

3. intermediate 34-2 (2.00 g,8.16mmol,1.00 eq) and potassium thioacetate (1.12 g,9.79mmol,1.20 eq) were added to 25mL of DMF and the reaction stirred at 60℃for 1h; TCL (3% EA/PE) showed the starting material disappeared and purification gave 1.00g of intermediate 34-3;

4. intermediate 34-3 (1.00 g,4.16mmol,1.00 eq) was dissolved in 20mL of 95% ethanol, cooled to 0deg.C, 2N sodium hydroxide (6.2 mL,12.48mmol,3.00 eq) was added dropwise to the reaction, stirred at 0deg.C for 10min and then brought to room temperature for stirring for 1h; TCL (5% EA/PE) showed the starting material disappeared and purification gave 0.50g of intermediate 34-4;

5. Intermediate 34-4 (400 mg,2.70mmol,1.00 eq) and DHA (1.69 g,5.93mmol,2.20 eq) were added to 25mL diethyl ether, cooled to 0deg.C, boron trifluoride diethyl ether (1.15 g,8.09mmol,3.00 eq) was added dropwise, stirred at 0deg.C for 10min and then brought to room temperature for stirring for 2h; TCL (15% EA/PE) showed the starting material disappeared and purification gave 1.1g of compound 34 in 60% yield, compound 34 as a white solid.

The nuclear magnetic resonance results of compound 34 were as follows:

¹ HNMR(600MHz,CDCl ₃ )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(ddd,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).

example 35: preparation of Compound 35

Raw material 35 (100 mg,0.28mmol,1.00 eq) and SDHA-A of example 1 (168 mg,0.56mmol,2.00 eq) were added to 6mL of DMF and potassium carbonate (116 mg,0.84mmol,3.00 eq) was added to react and purify to give 140mg of compound 35A in 71% yield 35A as a white solid.

Raw material 35 (300 mg,0.84mmol,1.00 eq) and SDHA-B of example 1 (503 mg,1.68mmol,2.00 eq) were added to 15mL of DMF and potassium carbonate (348 mg,5.21mmol,3.00 eq) was added to react and purify to give 310mg of compound 35B as a white solid in 52% yield.

The nuclear magnetic resonance of compound 35 was as follows:

compound 35A: ¹ HNMR(600MHz,CDCl ₃ )δ7.30(s,4H),5.25(s,2H),4.40(d,J＝10.7Hz,2H),3.99(d,J＝13.1Hz,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).

¹³ CNMR(151MHz,CDCl ₃ )δ137.12,129.21,104.34,92.32,80.49,79.41,51.83,46.13,37.31,36.30,34.02,32.35,31.89,26.04,24.76,21.24,20.24,14.80.

compound 35B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 36: preparation of Compound 36

1. Raw material 36 (2.00 g,14.48mmol,1.00 eq), triphenylphosphine (7.59 g,28.95mmol,2.00 eq) and imidazole (1.97 g,28.95mmol,2.00 eq) were dissolved in 150mL of DCM, cooled to 0 ℃ and stirred for 10min, iodine (7.35 g,28.95mmol,2.00 eq) was added slowly in portions, and after the addition was completed, the mixture was moved to room temperature and stirred for 1h; TCL (3% EA/PE) showed the disappearance of starting material, yielding 3.70g of intermediate 36-1 by purification;

2. Intermediate 36-1 (300 mg,0.84mmol,1.00 eq) and SDHA-A of example 1 (503 mg,1.68mmol,2.00 eq) were dissolved in 17mL of DMF and potassium carbonate (348 mg,2.51mmol,3.00 eq) was added and the reaction stirred at room temperature for 2h; TCL (10% EA/PE) showed the disappearance of starting material, purification gave 300mg of Compound 36A, 51% yield, compound 36A as a white solid;

3. intermediate 36-1 (300 mg,0.84mmol,1.00 eq) and SDHA-B of example 2 (503 mg,1.68mmol,2.00 eq) were dissolved in 17mL DMF and potassium carbonate (348 mg,2.51mmol,3.00 eq) was added and the reaction stirred at room temperature for 2h; TCL (10% EA/PE) showed the starting material disappeared and purification gave 240mg of Compound 36B in 40% yield, compound 36B as a white solid.

The nuclear magnetic resonance results of compound 36 were as follows:

compound 36A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 36B: ¹ HNMR(600MHz,CDCl ₃ )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).

example 37: preparation of Compound 37

1. Lithium aluminum hydride (2.31 g,60.76mmol,3.00 eq) was dissolved in 100mL of THF, cooled to 0deg.C and stirred for 10min, raw material 37 (3.00 g,20.25mmol,1.00 eq) was dissolved in 20mL of THF and slowly added dropwise to the reaction, which was stirred at 0deg.C for 30min and then allowed to stir at room temperature overnight; TLC (30% EA/PE) showed the starting material disappeared, and purification gave 2.50g of intermediate 37-1;

2. As in example 36, intermediate 37-1 (1.50 g,10.86mmol,1.00 eq) was used to give 140mg of compound 37A and 190mg of compound 37B in 24% yield, both compound 37A and compound 37B as white solids.

The nuclear magnetic resonance of compound 37 was as follows:

compound 37A: ¹ HNMR(600MHz,CDCl ₃ )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＝14.0,3.7Hz,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).

compound 37B: ¹ HNMR(600MHz,CDCl ₃ )δ7.31(dd,J＝5.4,3.5Hz,2H),7.21–7.16(m,2H),5.66(s,2H),5.24(d,J＝5.3Hz,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).

example 38: preparation of Compound 38

As in example 19, starting with starting material 38, 0.70g of compound 38 was obtained in 36% yield, compound 38 was a white foam-like compound.

The nuclear magnetic resonance results of compound 38 are as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 39: preparation of Compound 39

1. LiAlH is carried out under the protection of argon ₄ (351 mg,9.25mmol,2.50 eq) in 22mL THF, cooling to 0deg.C, and charging stock 39 (1.00 g,3.70mmol,1.00 eq)) Dissolving in 15mL of THF, dropwise adding the solution into the reaction, after the completion of dropwise adding, returning the reaction to the temperature of 8 ℃, stirring for 12h, and purifying to obtain 0.70g of intermediate 39-1;

2. as in example 19, intermediate 39-1 (0.70 g,3.27mmol,1.00 eq) was used to give 0.40g of compound 39 in 35% yield as a white foamy solid.

The nuclear magnetic resonance of compound 39 was as follows:

¹ HNMR(500MHz,CDCl ₃ )δ7.52(d,J＝7.7Hz,4H),7.42(d,J＝7.8Hz,4H),5.69(s,2H),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).

example 40: preparation of Compound 40

1. Raw material 40 (1.50 g,6.94mmol,1.00 eq) was dissolved in 30mL MeOH and SOCl was added ₂ (4.13 g,34.69mmol,5.00 eq) and reaction heated to 80℃and stirred for 12h, purification gives 1.69g of intermediate 40-1;

2. As in example 39, intermediate 40-1 (2.20 g,9.01mmoL,1.00 eq) was used to give 0.30g of compound 40A and 0.70g of compound 40B, both compound 40A and compound 40B as white foams.

The nuclear magnetic resonance results of compound 40 were as follows:

compound 40A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 40B: ¹ HNMR(500MHz,CDCl ₃ )δ8.17(s,2H),7.56(s,2H),7.41(s,2H),,5.71(s,2H),5.34(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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 41: preparation of Compound 41

1. Raw material 41 (1.00 g,4.74mmol,1.00 eq) was dissolved in acetic anhydride (8.9 mL,94.73mmol,20.00 eq), replaced with argon, heated to 100deg.C and reacted for 16h, purified to give 0.90g intermediate 41-1;

2. intermediate 41-1 (0.50 g,2.09mmol,1.00 eq) was dissolved in 4mL THF, replaced with argon, cooled to 0deg.C, DIBAH (8.57 mL,8.57mmol,4.10 eq) was then added dropwise, the reaction was allowed to warm to room temperature after 30min at 0deg.C and stirred for 18h, and 100mg of intermediate 41-2 was obtained by purification;

3. intermediate 41-2 (100 mg,0.55mmol,1.00 eq) was dissolved in 3mL of DCM, cooled to 0deg.C, triethylamine (0.22 mL,1.64mmol,3.00 eq) was added dropwise MsCl (0.11 mL,1.36mmol,2.50 eq), the reaction was stirred at 0deg.C for 30min and then allowed to stir at room temperature for 1h, and 150mg of intermediate 41-3 was purified;

4. intermediate 41-3 (180 mg,0.53mmol,1.00 eq) and SDHA-A from example 1 (318 mg,1.06mmol,2.00 eq) were dissolved in 4mL of DMF under argon and K was added ₂ CO ₃ (183 mg,1.33mmol,2.50 eq); the reaction was stirred at room temperature for 3h and purified to give 180mg of compound 41A in 45% yield as a pale yellow solid;

5. intermediate 41-3 (230 mg,0.68mmol,1.00 eq) and SDHA-B of example 1 (407 mg,1.69mmol,2.50 eq) were dissolved in 4mL of DMF under argon and K was added ₂ CO ₃ (234 mg,1.69mmol,2.50 eq); the reaction was stirred at room temperature for 3h and purified to give 243mg of compound 41B, yield 48%, compoundThe material 41B was a pale yellow solid.

The nuclear magnetic resonance results of compound 41 were as follows:

compound 41A: ¹ HNMR(600MHz,CDCl ₃ )δ7.69(d,J＝7.8Hz,1H),7.64(d,J＝7.4Hz,1H),7.32(dd,J＝19.4,12.0Hz,1H),5.27(d,J＝8.4Hz,2H),4.73(d,J＝10.8Hz,1H),4.57(d,J＝10.5Hz,1H),4.48(d,J＝11.0Hz,1H),4.39–4.29(m,2H),4.16(d,J＝13.2Hz,1H),3.16-3.08(m,1H),2.71(s,1H),2.56(d,J＝45.1Hz,2H),2.37(d,J＝13.4Hz,3H),2.20–2.07(m,1H),2.01(d,J＝12.0Hz,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).

compound 41B: ¹ HNMR(500MHz,CDCl ₃ )δ7.72(d,J＝7.8Hz,1H),7.55(d,J＝7.4Hz,1H),7.30(dd,J＝17.3,9.5Hz,1H),5.58(d,J＝7.5Hz,2H),5.30(s,2H),4.36(t,J＝15.8Hz,1H),4.22(d,J＝13.2Hz,1H),4.12(s,2H),3.73(dd,J＝13.9,7.1Hz,1H),3.01(s,2H),2.37(t,J＝14.0Hz,2H),2.04(d,J＝7.1Hz,2H),1.89-1.80(m,2H),1.76(s,2H),1.65(d,J＝17.9Hz,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＝5.6Hz,6H).

¹³ CNMR(126MHz,CDCl ₃ )δ150.70,140.10,134.84,132.06,127.60,123.96,104.26,104.21,88.11,88.02,86.84,86.17,81.07,52.63,44.99,37.21,37.17,36.35,34.36,34.05,32.13,32.03,28.90,26.09,24.60,24.42,20.32,14.61,14.54.

example 42: preparation of Compound 42

As in example 39, starting material 42 (1.00 g,5.10mmol,1.00 eq) gave 414mg of compound 42A and 422mg of compound 42B, combined yield 67% and compound 42A and 42B as white solids.

The nuclear magnetic resonance of compound 42 was as follows:

compound 42A: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

compound 42B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 43: preparation of Compound 43

1. Raw material 43 (500 mg,3.56mmol,1.00 eq) and NBS (1.39 g,7.82mmol,2.20 eq) were added to 20mL Cl ₄ AIBN (58 mg,0.36mmol,0.10 eq) was added to replace argon, the reaction was warmed to reflux and stirred for 16h, and purified to give 864mg of intermediate 43-1;

2. Intermediate 43-1 (300 mg,1.01mmol,1.00 eq) and SDHA-A of example 1 (604 mg,2.02mmol,2.00 eq) were dissolved in 10mL DMF and potassium carbonate (417 mg,3.03mmol,3.00 eq) was added and the reaction stirred at room temperature for 2h to give 460mg of compound 43A which was purified to yield 62% as a white solid;

3. intermediate 43-1 (300 mg,1.01mmol,1.00 eq) and SDHA-B of example 1 (604 mg,2.02mmol,2.00 eq) were dissolved in 10mL DMF and potassium carbonate (417 mg,3.03mmol,3.00 eq) was added and the reaction stirred at room temperature for 2h and purified to give 510mg of compound 43B as a white solid in 69% yield.

The nuclear magnetic resonance of compound 43 was as follows:

compound 43A: ¹ HNMR(600MHz,CDCl ₃ )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).

compound 43B: ¹ HNMR(600MHz,CDCl ₃ )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,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4Hz,6H),0.85(d,J＝7.3Hz,6H).

example 44: preparation of Compound 44

1. Raw material 44 (2.00 g,9.92mmol,1.00 eq) was added to 10mL of SOCl ₂ Dropwise adding a few drops of DMF, heating to 100 ℃ and stirring overnight; concentrating to remove solvent, adding 20mL of DCM, cooling to 0 ℃, dropwise adding 10mL of methanol, stirring the reaction at 0 ℃ for 2h, then moving to room temperature, stirring overnight, and purifying to obtain 2.00g of intermediate 44-1;

2. intermediate 44-1 (1.50 g,6.53mmol,1.00 eq) was added to 100mL absolute ethanol and NaBH was added in portions ₄ (1.24 g,32.66mmol,6.00 eq) and stirred at room temperature overnight and purified to yield 985mg of intermediate 44-2;

3. intermediate 44-2 (0.98 g,5.65mmol,1.00 eq) and triethylamine (2.86 g,28.23mmol,5.00 eq) were added to 20mL of DCM, the reaction was cooled to 0deg.C, methanesulfonyl chloride (1.94 g,16.94mmol,3.00 eq) was added dropwise, the reaction was stirred at 0deg.C for 3h, and 1.80g of intermediate 44-3 was purified;

4. intermediate 44-3 (1.80 g,5.46mmol,1.00 eq) and potassium thioacetate (1.87 mg,16.38mmol,3.00 eq) were added to 30mL DMF and the reaction was warmed to 60℃and stirred overnight, purifying 630mg of intermediate 44-4;

5. intermediate 44-4 (630 mg,2.17mmol,1.00 eq) was added to 20mL EtOH, cooled to 0deg.C, 3.3mL of 2M sodium hydroxide solution was added dropwise, the reaction stirred at 0deg.C for 2h, and purified to give 440mg of intermediate 44-5;

6. intermediate 44-5 (440 mg,2.14mmol,1.00 eq) and DHA (1.22 mg,4.28mmol,2.00 eq) were added to 30mL diethyl ether, the reaction was cooled to 0deg.C, boron trifluoride diethyl ether (608 mg,4.28mmol,2.00 eq) was added dropwise, the reaction was stirred at 0deg.C for 10min and then gradually warmed to room temperature and stirred overnight, and purification afforded 510mg of compound 44A and 590mg of compound 44B, and the combined yield was 70% and compound 44A and compound 44B were both white solids.

The nuclear magnetic resonance of compound 44 is as follows:

compound 44A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 44B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 45: preparation of Compound 45

1. Raw material 45 (1.00 g,7.19mmol,1.00 eq.) was dissolved in 36mL of DCM, cooled to 0 ℃, triethylamine (4.36 g,43.12mmol,6.00 eq.) was added followed by slow dropwise addition of MsCl (3.29 g,28.75mmol,4.00 eq.) and after addition was removed to room temperature and stirred for 2h, and purification gave 1.31g of intermediate 45-1;

2. intermediate 45-1 (200.0 mg,0.677mmol,1.00 eq), SDHA-A of example 1 (447.58 mg,1.49mmol,2.20 eq) and K ₂ CO ₃ (561.57 mg,4.06mmol,6.00 eq) was dissolved in 14ml of LDMF to displace Ar, the reaction was stirred at room temperature for 16h, and 342mg of Compound 45A was purified to give 72% yield, compound 45A as a white foamy solid;

3. will be intermediateBody 45-1 (200.0 mg,0.677mmol,1.00 eq), SDHA-B of example 1 (447.58 mg,1.49mmol,2.20 eq) and K ₂ CO ₃ (561.57 mg,4.06mmol,6.0 eq) was dissolved in 14ml of LDMF to displace Ar, the reaction was stirred at room temperature for 16h, and 365mg of Compound 45B was purified to give 77% yield, compound 45B as a white foamy solid.

The nuclear magnetic resonance of compound 45 was as follows:

compound 45A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 45B: ¹ HNMR(500MHz,CDCl ₃ )δ7.57(t,J＝7.6Hz,1H),7.22(d,J＝7.6Hz,2H),5.65(s,2H),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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 46: preparation of Compound 46

1. Raw material 46 (800 mg,3.28mmol,1.00 eq) was dissolved in 33mL of anhydrous methanol, cooled to 0 ℃, concentrated sulfuric acid (3.27 g,32.76mmol,10.00 eq) was slowly added dropwise under stirring, heated to reflux after the addition was completed and stirred for 16h, and 801mg of intermediate 46-1 was obtained by purification;

2. Intermediate 46-1 (800 mg,2.94mmol,1.00 eq) was dissolved in 30mL absolute ethanol, cooled to 0deg.C and added NaBH in portions with stirring ₄ (1.33 g,35.26mmol,12.00 eq) followed by heating to reflux and stirring for 3h, purification yielded 602mg of intermediateBody 46-2;

3. intermediate 46-2 (600 mg,2.77mmol,1.00 eq) was dissolved in 27mL DCM, cooled to 0deg.C, triethylamine (1.68 g,16.65mmol,6.00 eq) was added followed by slow dropwise addition of MsCl (1.27 g,11.10mmol,4.00 eq), after addition was allowed to stir at room temperature for 2h, and 412mg of intermediate 46-3 was purified;

4. intermediate 46-3 (120 mg,0.32mmol,1.00 eq) and SDHA-A of example 1 (242 mg,0.81mmol,2.50 eq) were dissolved in 6.5mL of DMF and K was added ₂ CO ₃ (267 mg,1.93mmol,6.00 eq) and stirring at room temperature for 16h, purifying to give 151mg of compound 46A, yield 60%, compound 46A as a white foamy solid;

5. intermediate 46-3 (200 mg,0.54mmol,1.00 eq) and SDHA-B of example 1 (403 mg,1.34mmol,2.50 eq) were dissolved in 10.7mL of DMF and K was added ₂ CO ₃ (445 mg,3.22mmol,6.00 eq) and stirred at room temperature for 16h, purified to give 311mg of compound 46B as a white foamy solid in 74% yield.

The nuclear magnetic resonance results of compound 46 are as follows:

compound 46A: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

compound 46B: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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).

example 47: preparation of Compound 47

As in example 46, starting material 47 (1.00 g,5.98mmol,1.00 eq) gave 210mg of compound 47A and 280mg of compound 47B, both compound 47A and compound 47B as white solids;

the nuclear magnetic structure of compound 47 is as follows:

compound 47A: ¹ HNMR(500MHz,CDCl ₃ )δ8.46(d,J＝3.8Hz,1H),7.35(s,1H),7.18(s,1H),5.29(d,J＝15.7Hz,2H),4.59(d,J＝10.7Hz,1H),4.39(d,J＝10.7Hz,1H),4.11(d,J＝13.0Hz,1H),3.97(dd,J＝21.0,13.3Hz,2H),3.78(d,J＝13.4Hz,1H),2.57(s,2H),2.36(t,J＝12.6Hz,2H),2.02(d,J＝14.9Hz,2H),1.88(s,3H),1.67(d,J＝13.3Hz,4H),1.53(s,1H),1.48(d,J＝14.6Hz,2H),1.43(s,6H),1.33(d,J＝10.7Hz,3H),1.28–1.18(m,3H),0.99(d,J＝12.4Hz,2H),0.94(d,J＝5.4Hz,6H),0.81(d,J＝6.2Hz,6H).

¹³ CNMR(126MHz,CDCl ₃ )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.

compound 47B: ¹ HNMR(500MHz,CDCl ₃ )δ8.48(s,1H),7.34(s,1H),7.16(s,1H),5.62(d,J＝11.4Hz,2H),5.35(s,1H),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).

example 48: preparation of Compound 48

1. Dissolving a raw material 48 (0.46 g,2.06mmol,1.00 eq) compound in 21mL of ethanol, cooling to 0 ℃, adding sodium borohydride (935 mg,24.73mmol,12.00 eq), stirring at 0 ℃ for 30min, gradually heating to reflux, stirring for 4h, cooling to room temperature, dropwise adding 5mL of acetone, quenching, and purifying to obtain 100mg of intermediate 48-1;

2. intermediate 48-1 (100 mg,0.72mmol,1.00 eq) was dissolved in 4mL DCM, cooled to 0deg.C, triethylamine (0.6 mL,4.31mmol,6.00 eq) was added, msCl (0.22 mL,2.87mmol,4.00 eq) was added dropwise, the reaction was gradually warmed to room temperature and stirred for 0.5h, and 210mg of intermediate 48-2 was purified;

3. intermediate 48-2 (50 mg,0.17mmol,1.00 eq) and SDHA-A of example 1 (112 mg,0.37mmol,2.20 eq) were added to 2mL of DMF, potassium carbonate (59 mg,0.42mmol,2.50 eq) was added and the reaction stirred at room temperature for 1.5h to give 56mg of compound 48A as a white solid, yield 48%;

4. Intermediate 48-2 (50 mg,0.17mmol,1.00 eq) and SDHA-B of example 1 (112 mg,0.37mmol,2.20 eq) were added to 2mL of exothermic DMF, potassium carbonate (59 mg,0.42mmol,2.50 eq) was added and the reaction stirred at room temperature for 1.5h and purified to give 66mg of compound 48B as a white solid in 55% yield.

The nuclear magnetic resonance results of compound 48 are as follows:

compound 48A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 48B: ¹ HNMR(500MHz,CDCl ₃ )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).

example 49: preparation of Compound 49

As in example 40, starting material 49 (500 mg,2.90mmol,1.00 eq) gave 186mg of compound 49A and 223mg of compound 49B, both compound 49A and compound 49B being foamed white solids.

The nuclear magnetic resonance of compound 49 was as follows:

compound 49A: ¹ HNMR(500MHz,CDCl ₃ )δ7.17(s,2H),5.23(d,J＝7.5Hz,2H),4.37(d,J＝10.8Hz,2H),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).

¹³ CNMR(126MHz,CDCl ₃ )δ137.01,124.20,104.32,92.27,80.49,79.61,51.84,46.14,37.34,36.32,34.03,31.89,26.27,26.07,24.76,21.21,20.25,14.84.

compound 49B: ¹ HNMR(500MHz,CDCl ₃ )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,2H),1.87(s,2H),1.77(d,J＝3.8Hz,2H),1.72–1.64(m,4H),1.62–1.34(m,10H),1.26(dd,J＝11.5,6.4Hz,4H),1.02–0.88(m,8H),0.78(d,J＝7.3Hz,6H).

¹³ CNMR(126MHz,CDCl ₃ )δ136.09,124.79,104.23,88.27,85.13,81.16,52.69,45.07,37.23,36.39,34.42,31.94,29.43,26.17,24.62,24.42,20.36,14.58.

example 50: preparation of Compound 50

1. Raw material 50 (200 mg,1.56mmol,1.00 eq) was dissolved in 10mL of anhydrous dichloromethane, triethylamine (0.8 mL,6.24mmol,4.00 eq) was added, cooled to-20 ℃ and stirred for 10min, methylsulfonyl chloride (0.3 mL,3.9mmol,2.50 eq) was slowly added dropwise, the reaction was stirred for 30min at-20 ℃ and purified to give 380mg of intermediate 50-1;

2. SDHA-A (350 mg,1.16mmol,2.20 eq) of example 1 was dissolved in 5mL anhydrous DMF, anhydrous potassium carbonate (321 mg,1.58mmol,3.00 eq) was added and stirred for 30min; intermediate 50-1 (150 mg,0.53mmol,1.00 eq) was dissolved in 3ml of LDMF and added dropwise to the system, the reaction was stirred at room temperature for 2h, and purification gave 73mg of compound 50A, compound 50A as a white solid, yield 20%;

3. SDHA-B (350 mg,1.16mmol,2.20 eq) from example 1 was dissolved in 5mL anhydrous DMF, anhydrous potassium carbonate (321 mg,1.58mmol,3.00 eq) was added and stirred for 30min; intermediate 50-1 (150 mg,0.53mmol,1.00 eq) was dissolved in 3mL DMF and added dropwise to the system, the reaction stirred at room temperature for 2h, and purification afforded 83mg of Compound 50B as a white solid in 28% yield.

The nuclear magnetic resonance results of compound 50 are as follows:

compound 50A: ¹ HNMR(500MHz,CDCl ₃ )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),1.59–1.55(m,4H),1.51-1.43(m,6H),1.34-1.24(m,6H),1.06–0.79(m,14H).

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.

compound 50B: ¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )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.

example 51: preparation of Compound 51

As in example 40, starting material 41 (1.00 g,5.95mmol,1.00 eq), 312mg of compound 51A and 286mg of compound 51B, both compound 51A and compound 51B were in the form of white foam.

The nuclear magnetic resonance of compound 51 was as follows:

compound 51A: ¹ HNMR(600MHz,CDCl ₃ )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＝11.1,6.6Hz,4H),0.97(dd,J＝33.6,9.4Hz,2H),0.87(d,J＝7.1Hz,6H),0.80(d,J＝7.0Hz,6H).

¹³ CNMR(151MHz,CDCl ₃ )δ153.30,142.00,104.27,92.20,80.50,80.43,51.79,46.12,37.34,36.27,34.04,32.37,32.31,26.01,24.76,21.24,20.24,14.82.

compound 51B: ¹ HNMR(600MHz,CDCl ₃ )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).

¹³ CNMR(151MHz,CDCl ₃ )δ152.70,142.20,104.22,88.11,86.39,81.04,52.62,45.03,37.19,36.35,35.41,34.39,32.06,26.09,24.61,24.44,20.33,14.63.

example 52: preparation of Compound 52

1. Raw material 52 (2.00 g,11.90mmol,1.00 eq) was dissolved in 110mL MeOH and SOCl was slowly added ₂ (7.10 g,59.49mmol,5.00 eq) and after addition, heating to reflux and stirring for 6h, purification yielded 1.74g of intermediate 52-1;

2. intermediate 52-1 (1.70 g,8.67mmol,1.00 eq) was dissolved in 87mL of MeOH/DCM=4:1 mixed solvent, cooled to 0deg.C and stirred for 10min, and NaBH was added slowly in portions ₄ (2.62 g,89.33mmol,8.00 eq) and after addition the reaction was continued with stirring for 4h at 0℃and purification gave 790mg of intermediate 52-2;

3. intermediate 52-2 (650 mg,4.64mmol,1.00 eq) was dissolved in 46mL of anhydrous dichloromethane, cooled to 0deg.C, triethylamine (3.2 mL,23.19mmol,3.00 eq) was added, and after stirring for 10min methylsulfonyl chloride (1.59 g,13.91mmol,2.50 eq) was added dropwise; after the addition, the mixture is moved to room temperature and stirred for 2 hours, and 840mg of intermediate 52-3 is obtained after purification;

4. intermediate 52-3 (840 mg,2.83mmol,1.00 eq) was dissolved in 95mL of DMF and potassium thioacetate (835 mg,8.50mmol,3.00 eq) was added; heating the reaction to 60 ℃ and stirring for 4 hours, naturally cooling the reaction to room temperature, and purifying to obtain 510mg of intermediate 52-4;

5. intermediate 52-4 (570 mg,2.22mmol,1.00 eq) was dissolved in 25mL ethanol, cooled to 0deg.C, and 2.78mL of 2M sodium hydroxide solution was added dropwise; stirring the reaction at 0 ℃ for 1h, and purifying to obtain 320mg of intermediate 52-5;

6. dihydroartemisinin (1.09 g,3.83mmol,2.20 eq) was added to 35mL of anhydrous diethyl ether, stirred well, cooled to 0deg.C and stirred for 10min, intermediate 52-5 (300 mg,1.74mmol,1.00 eq) was dissolved in 10mL of diethyl ether and added dropwise to the reaction, boron trifluoride diethyl ether (742 mg,5.22mmol,3.00 eq) was then added dropwise slowly, the reaction was stirred for 1h at 0deg.C and then allowed to react at room temperature for 4h, and 500mg of compound 52 was purified to give compound 52 as a pale yellow oil in 41% yield.

The nuclear magnetic resonance results of compound 52 are as follows:

¹ HNMR(500MHz,CDCl ₃ )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).

¹³ CNMR(126MHz,CDCl ₃ )δ152.23,143.79,104.27,88.02,86.15,81.06,52.62,45.01,37.19,36.31,35.27,34.38,32.02,26.06,24.61,24.40,20.30,14.60.

example 53: preparation of Compound 53

As in example 40, starting material 53 (1.00 g,5.88mmol,1.00 eq) gave 269mg of compound 53A and 236mg of compound 53B, both compound 53A and compound 53B as white foam.

The nuclear magnetic resonance results of compound 53 were as follows:

compound 53A: ¹ HNMR(500MHz,CDCl ₃ )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).

compound 53B: ¹ HNMR(500MHz,CDCl ₃ )δ7.40(s,1H),5.39(s,1H),5.35(s,1H),4.80(d,J＝10.7Hz,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).

example 54: preparation of Compound 54

Compound 5A (200 mg,0.31mmol,1.00 eq) prepared in example 5 was dissolved in 5mL acetonitrile, naOCl (25 mg,0.34mmol,1.10 eq) was dissolved in 1mL water and slowly added dropwise to the reaction, the reaction was stirred at room temperature for 20min, then quenched with 10mL saturated sodium bisulphite solution and purified to give 93mg of compound 54A as a white solid in 44% yield;

compound 5B (200 mg,0.31mmol,1.00 eq) obtained in example 5 was dissolved in 5mL of acetonitrile; naOCl (25 mg,0.34mmol,1.10 eq) was dissolved in 1mL of water and added slowly dropwise to the reaction, which was stirred at room temperature for 20min, then quenched with 10mL of saturated sodium bisulphite solution and purified to give 84mg of compound 54B as a white solid in 40% yield.

The nuclear magnetic resonance results of compound 54 are as follows:

compound 54A: ¹ HNMR(400MHz,CDCl ₃ )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).

compound 54B: ¹ HNMR(400MHz,CDCl ₃ )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).

Example 55: preparation of Compound 55

The compound 5A (200 mg,0.31mmol,1.00 eq) produced in example 5 and NaCO ₃ (129 mg,1.53mmol,5.00 eq) was added to 20mL acetonitrile and cooled to-40 ℃; TFAA (193 mg,0.92mmol,3.00 eq) was added dropwise to UHP (87 mg,0.92mmol,3.00 eq) in 20mL acetonitrile, stirred at room temperature for 10min and then slowly added dropwise to the reaction, which was stirred at-40℃for 20min and purified to give 145mg of compound 55A in 66% yield;

the compound 5B (200 mg,0.31mmol,1.00 eq) produced in example 5 and NaCO ₃ (129 mg,1.53mmol,5.00 eq) was added to 20mL acetonitrile and cooled to-40 ℃; TFAA (tfAA)(193 mg,0.92mmol,3.00 eq) was added dropwise to UHP (87 mg,0.92mmol,3.00 eq) in 20mL acetonitrile, stirred at room temperature for 10min and then slowly added dropwise to the reaction, which was stirred at-40℃for 20min and purified to give 158mg of compound 55B in 72% yield.

The nuclear magnetic resonance of compound 55 was as follows:

compound 55A: ¹ HNMR(400MHz,CDCl ₃ )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,2H),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).

compound 55B: ¹ HNMR(400MHz,CDCl ₃ )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).

experimental example

Anticancer Activity test of Compounds 1-55

The experimental method comprises the following steps:

inoculating cells: single cell suspension was prepared with culture medium (DMEM or RMPI 1640) containing 10% fetal bovine serum,

3000-15000 cells per well are inoculated into a 96-well plate, the volume of each well is 100ul, and adherent cells are inoculated and cultured in advance for 12-24 hours.

Adding a solution of a compound to be tested: the compound was dissolved in DMSO and the compound was initially screened at a concentration of 40uM with a final volume of 200ul per well, 3 multiplex wells per treatment.

Color development: after culturing at 37 ℃ for 48 hours, the adherent cells discard the culture solution in the wells, and each well is added with 20ul MTS solution and cultivated

100ul of nutrient solution; suspension cells discard 100ul culture supernatant, add 20ul MTS solution per well; 3 blank wells (mixed solution of MTS solution 20ul and culture solution 100 ul) were set, incubation was continued for 2 to 4 hours, and the light absorption value was measured after the reaction was sufficiently performed.

Colorimetric: and selecting 492nm wavelength, reading the light absorption value of each hole by a multifunctional enzyme labeling instrument (MULTISKAN FC), recording the result, and finally taking the average value of 3 times of results.

Positive control compound: two positive compounds of cisplatin (DDP) and Taxol (Taxol) were set up for each experiment.

The results of measuring the inhibition rate of the sulfur-containing artemisinin dimer of the compound 1-55 on tumor cells are shown in the table 1:

table 1: determination of tumor cell inhibition ratio of sulfur-containing artemisinin dimer (n=3)

Table 1, below

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

Continuous table 2

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

Table 3 shows the sequence

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

Reference document:

[1]Woerdenbag,H.J.；Lüers,J.F.J.；van Uden,W.；Pras,N.；Malingré,T.Alfermann,A.W.,Plant Cell,Tissue and Organ Culture,1993,32,247-257.

the foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.

Claims

1. The sulfur-containing artemisinin dimer is characterized in that the chemical structural formula of the sulfur-containing artemisinin dimer is a compound represented by a formula I or pharmaceutically acceptable salt thereof:

wherein W is represented as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ 、O、NR ¹ And CR (CR) ¹ ₂ Any one of them;

y is represented as: single bond, NR ¹ 、O、S、SO、SO ₂ C1-C5 heteroalkyl, substituted with 1-5R ¹ Substituted C1-C5 heteroalkyl, aryl, substituted with 1-5R ¹ Substituted aryl, 3-10 membered cyclic group, substituted with 1-5R ¹ Substituted 3-10 membered cyclic group, 3-10 membered heterocyclic group and substituted 1-5R ¹ Any one of substituted 3-10 membered heterocyclic groups;

R ¹ expressed as: H. f, cl, br, I, NO ₂ 、NO、CN、NR ² _x 、OR ² C1-C5 heteroalkyl, quilt1-5R ² Substituted C1-C5 heteroalkyl, C1-C10 alkyl, substituted with 1-5R ² Any one of substituted C1-C10 alkyl;

wherein the R is ² Expressed as: H. OMe, OEt, me, et, ac, acO, F, cl, br, I, CN, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl;

n and m are each independently selected from: an integer of 0 to 15;

x is selected from integers of 1 to 4;

the aryl is selected from any one of phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolinyl, purinyl and biphenyl;

1 to 6 ring atoms in the 3-10 membered heterocyclic group are independently selected from any one of O, S and N;

the cyclic group comprises a saturated monocyclic group, an unsaturated monocyclic group, a saturated polycyclic group system and an unsaturated polycyclic group system, the polycyclic group system comprises a spiro ring, a parallel ring, a bridged ring and a interlink, and the cyclic group does not comprise an aryl group;

2. The sulfur-containing artemisinin dimer according to claim 1 characterized in that:

w is expressed as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ 、O、NR ¹ And CR (CR) ¹ ₂ Any one of them;

y is represented as: single bond, aryl, and 1-5R ¹ Substituted aryl, 3-10 membered cyclic group, substituted with 1-5R ¹ Any one of substituted 3-10 membered ring groups;

R ¹ expressed as: H. f, cl, br, I, NO ₂ 、NO、CN、OR ² Any one of C1-C10 alkyl;

wherein the R is ² Expressed as: H. me, et, F, cl, br, I, CN, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl;

n and m are each independently selected from: an integer of 0 to 15;

The aryl is selected from any one of phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl and biphenyl;

the cyclic groups include saturated monocyclic groups, unsaturated monocyclic groups, saturated polycyclic groups, and unsaturated polycyclic groups, including spiro, fused, bridged, and bicyclic groups, and the cyclic groups do not include aryl groups.

3. The sulfur-containing artemisinin dimer according to claim 2 which is characterized in that:

w is expressed as: s, SO and SO ₂ Any one of them;

z is expressed as: s, SO ₂ Any one of the following.

4. The sulfur-containing artemisinin dimer of claim 1, wherein the sulfur-containing artemisinin dimer has a structure of any one of:

wherein R is ¹ Y, n, m are as defined in claim 1.

5. The sulfur-containing artemisinin dimer according to any one of claims 1 to 4 wherein,

the sulfur-containing artemisinin dimer has the structure of any one of the following:

6. a process for the preparation of a sulphur-containing artemisinin dimer according to any one of claims 1 to 5 which is characterized by the following reaction scheme:

wherein R is ¹ W, Y, Z, n, m is as defined in any one of claims 1 to 5;

the specific reaction of the above reaction formula is as follows:

as shown in the first reaction formula, dispersing the compound of the formula II and dihydroartemisinin in a solvent, and dripping acid at the temperature of-78-25 ℃ to react to obtain the sulfur-containing artemisinin dimer.

7. A process for the preparation of a sulphur-containing artemisinin dimer according to any one of claims 1 to 5 which is characterized by the following reaction scheme:

wherein R is ¹ W, Y, Z, n, m is as defined in any one of claims 1 to 5;

the specific reaction of the above reaction formula is as follows:

and as shown in a reaction formula II, preparing the dihydroartemisinin into the thiodihydroartemisinin shown in a formula III through a thio reaction, and reacting the thiodihydroartemisinin with a compound shown in a formula IV to obtain the sulfur-containing artemisinin dimer.

8. A process for the preparation of a sulphur-containing artemisinin dimer according to any one of claims 1 to 5 which is characterized by the following reaction scheme:

wherein R is ¹ W, Y, Z, n, m is as defined in any one of claims 1 to 5;

TMS is expressed as: a trimethylsilyl group;

the specific reaction of the above reaction formula is as follows:

and as shown in a reaction formula III, dissolving the compound shown in the formula V and dihydroartemisinin in a solvent, and dropwise adding acid at the temperature of-78-25 ℃ for reaction to obtain the sulfur-containing artemisinin dimer.

9. A method for preparing a sulfur-containing artemisinin dimer according to any one of claims 1 to 5, which is characterized in that the sulfur-containing artemisinin dimer containing low oxidation state sulfur is oxidized by an oxidizing agent in a solvent to obtain the sulfur-containing artemisinin dimer containing high oxidation state sulfur;

The low oxidation state sulfur is represented as: negative divalent sulfur;

the high oxidation state sulfur is represented as: SO or SO ₂ 。

10. Use of a sulphur-containing artemisinin dimer according to any one of claims 1 to 5 for the preparation of an antitumor drug.