阅读说明：本技术 一种(1S,2S,4S)-β-榄香烯的合成方法及其中间体 (Synthesis method of (1S,2S,4S) -beta-elemene and intermediate thereof ) 是由 陈伟 冯准 江崇国 于 2021-09-06 设计创作，主要内容包括：本发明属于药物合成技术领域,公开了一种(1S,2S,4S)-β-榄香烯的合成方法及其中间体。该合成方法以(R)-香芹酮作为起始原料,依次经过加成反应、烷基化反应、羟基保护反应、还原反应、自由基脱氧反应、脱去羟基保护基、氧化反应和烯基化反应,首次合成(1S,2S,4S)-β-榄香烯,其总收率大于8.5％,纯度大于98％。该合成方法反应操作简单,步骤简短,合成效率高；原料(R)-香芹酮便宜易得,生产成本低,适合工业化生产。本发明提供(1S,2S,4S)-β-榄香烯的中间体,能够用于研究(1S,2S,4S)-β-榄香烯的纯度,对其质量的控制具有重要意义。(The invention belongs to the technical field of drug synthesis, and discloses a synthesis method of (1S,2S,4S) -beta-elemene and an intermediate thereof. The synthesis method comprises the steps of taking (R) -carvone as an initial raw material, and sequentially carrying out addition reaction, alkylation reaction, hydroxyl protection reaction, reduction reaction, free radical deoxidation reaction, hydroxyl protecting group removal, oxidation reaction and olefination reaction to synthesize the (1S,2S,4S) -beta-elemene for the first time, wherein the total yield is more than 8.5%, and the purity is more than 98%. The synthesis method has the advantages of simple reaction operation, short steps and high synthesis efficiency; the raw material (R) -carvone is cheap and easy to obtain, the production cost is low, and the method is suitable for industrial production. The invention provides an intermediate of (1S,2S,4S) -beta-elemene, which can be used for researching the purity of the (1S,2S,4S) -beta-elemene and has important significance for controlling the quality of the (1S,2S,4S) -beta-elemene.)

1. A method for synthesizing (1S,2S,4S) -beta-elemene is characterized by comprising the following steps:

(1) under the action of a catalyst, performing addition reaction on (R) -carvone and an isopropenyl Grignard reagent to obtain (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone;

(2) performing alkylation reaction on the (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (1) and an aldehyde group-containing substance under the action of an alkali liquor to obtain (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;

(3) protecting the hydroxyl in the (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (2) to form a protecting group, so as to obtain a compound A;

(4) reducing a ketone group in the compound A prepared in the step (3) into a hydroxyl group under the action of a reducing agent to obtain a compound B;

(5) performing free radical deoxidation reaction on the compound B prepared in the step (4), and then removing the protecting group to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol;

(6) oxidizing ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol prepared in the step (5) under the action of an oxidizing agent to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde;

(7) and (3) carrying out olefination reaction on n-amyl triphenyl phosphonium bromide and ((1R,2S,4S) -1-methyl-2, 4-diisopropenyl cyclohexane) -1-formaldehyde prepared in the step (6) to obtain (1S,2S,4S) -beta-elemene.

2. The synthesis method according to claim 1, wherein in step (1), the catalyst is a copper salt selected from at least one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous trifluoromethanesulfonate, cuprous acetate, cuprous thiophene-2-carboxylate, tetrakis (acetonitrile) copper (I) tetrafluoroborate, tetrakis (acetonitrile) copper (I) hexafluorophosphate or an alkyl copper (I) salt complex.

3. The synthesis method according to claim 1, wherein in step (2), the aldehyde group-containing substance is formaldehyde and/or paraformaldehyde.

4. The method of claim 1, wherein in the step (2), the alkali solution is at least one selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium ethoxide, potassium tert-butoxide, triethylamine, potassium hydride and sodium hydride.

5. The method according to claim 1, wherein in step (3), the protecting group is selected from one of an ester protecting group, a silyl ether protecting group, a benzyl ether protecting group, and an alkoxymethyl ether protecting group.

6. The synthesis method according to claim 1, wherein in the step (4), the reducing agent is at least one selected from sodium borohydride, sodium cyanoborohydride, potassium borohydride, lithium aluminum hydride, diborane, aluminum isopropoxide and metallic sodium.

7. The method of claim 1, wherein in step (6), the oxidizing agent is selected from at least one of pyridinium chlorochromate, pyridinium dichromate, dess-martin oxidizing agent, 2-iodoxybenzoic acid, iodobenzene diacetate/2, 2,6, 6-tetramethylpiperidine oxide, chromium trioxide sulfuric acid solution, chromium oxide-pyridine complex, dimethyl sulfoxide/oxalyl chloride, dimethyl sulfoxide/carbodiimide, dimethyl sulfoxide/sulfur trioxide-pyridine complex, tetrapropylammonium ruthenate/4-methylmorpholine-N-oxide, hypochlorite/2, 2,6, 6-tetramethylpiperidine oxide/bromide, or manganese dioxide.

8. The method of synthesis according to claim 1, comprising the steps of:

(1) under the action of a catalyst, performing addition reaction on (R) -carvone and an isopropenyl Grignard reagent to obtain (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone;

(2) performing alkylation reaction on the (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (1) and an aldehyde group-containing substance under the action of an alkali liquor to obtain (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;

(3) carrying out esterification reaction on the (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (2) and acetic anhydride under the action of alkali liquor to obtain ((1R,4R,6S) -1-methyl-2-ketone-4, 6-diisopropenyl cyclohexane) -1-methyl acetate;

(4) reducing the ((1R,4R,6S) -1-methyl-2-ketone-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester prepared in the step (3) under the action of a reducing agent to obtain ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester;

(5) subjecting the methyl ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate prepared in the step (4) to a radical deoxidation reaction and a hydrolysis reaction to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol;

(6) oxidizing ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol prepared in the step (5) under the action of an oxidizing agent to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde;

(7) and (3) carrying out olefination reaction on n-amyl triphenyl phosphonium bromide and ((1R,2S,4S) -1-methyl-2, 4-diisopropenyl cyclohexane) -1-formaldehyde prepared in the step (6) to obtain (1S,2S,4S) -beta-elemene.

9. An intermediate A for synthesizing (1S,2S,4S) -beta-elemene is characterized in that the structural formula of the intermediate A is shown as a formula (a),

10. an intermediate B for synthesizing (1S,2S,4S) -beta-elemene is characterized in that the structural formula of the intermediate B is shown as a formula (B),

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of (1S,2S,4S) -beta-elemene and an intermediate thereof.

Background

With the change of modern living environment and dietary habits, malignant tumor has developed into one of the major diseases seriously threatening human life and health. Because the traditional tumor therapy (such as radiotherapy and chemotherapy) has large toxic and side effects and is easy to generate drug resistance, the search and development of a new generation of high-efficiency low-toxicity antitumor drugs become the focus of common attention in academia and industry. Among them, natural products derived from nature and having good pharmaceutical potential are one of the important research directions.

Elemene is a sesquiterpenoid natural product existing in various plant volatile oils in nature, named Elemene in English, and has a molecular formula of C₁₅H₂₄. The elemene has a molecular structure containing 3 unsaturated double bonds, and can be classified into alpha-elemene, beta-elemene, gamma-elemene and delta-elemene according to the difference of the positions of the double bonds. Research shows that the four isomers of elemene have certain antitumor activity, but beta-elemene has the strongest pharmacological activity and is also the main antitumor active effective component in elemene antitumor drugs used clinically at present. At present, two dosage forms of beta-elemene injection and oral milk are approved to be used for clinical treatment of hydrothorax, ascites, esophageal cancer, gastric cancer, glioma and brain metastasis. Compared with the traditional antitumor drugs, the beta-elemene has the greatest characteristics of capability of penetrating through a blood brain barrier, small toxic and side effects, capability of improving the immunity of an organism and capability of reversing the drug resistance to other antitumor drugs.

Beta-elemene is further divided into the following two diastereomers according to the stereochemistry of the 4-isopropenyl group: the specific molecular structures of the (1S,2S,4R) -beta-elemene and the (1S,2S,4S) -beta-elemene are shown as the following formula.

At present, the main active ingredients of the clinically used beta-elemene injection and oral milk are (1S,2S,4R) -beta-elemene. However, studies have shown that (1S,2S,4S) - β -elemene has higher antitumor activity and lower toxic and side effects than (1S,2S,4R) - β -elemene.

At present, (1S,2S,4S) -beta-elemene is mainly extracted and separated from traditional Chinese herbal medicine zedoary (also called as curcuma). However, the natural product has low content in the traditional Chinese medicinal materials, the extraction and separation process is complex, the purity of the final product is not easy to control, the yield cannot be ensured, and the source and the clinical application range of the beta-elemene raw material medicine are greatly limited.

Therefore, it is highly desirable to provide a method for synthesizing (1S,2S,4S) - β -elemene, which can prepare (1S,2S,4S) - β -elemene with high purity and easily controllable quality.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a synthesis method of (1S,2S,4S) -beta-elemene, which can prepare the (1S,2S,4S) -beta-elemene with the purity of more than 98 percent and has high production efficiency.

The invention provides a method for synthesizing (1S,2S,4S) -beta-elemene in a first aspect.

Specifically, the synthesis method of (1S,2S,4S) -beta-elemene comprises the following steps:

(1) under the action of a catalyst, performing addition reaction on (R) -carvone and an isopropenyl Grignard reagent to obtain (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone;

(2) performing alkylation reaction on the (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (1) and an aldehyde group-containing substance under the action of an alkali liquor to obtain (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;

(3) protecting the hydroxyl in the (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (2) to form a protecting group, so as to obtain a compound A;

(4) reducing a ketone group in the compound A prepared in the step (3) into a hydroxyl group under the action of a reducing agent to obtain a compound B;

(5) performing free radical deoxidation reaction on the compound B prepared in the step (4), and then removing the protecting group to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol;

(6) oxidizing ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol prepared in the step (5) under the action of an oxidizing agent to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde;

(7) and (3) carrying out olefination reaction on n-amyl triphenyl phosphonium bromide and ((1R,2S,4S) -1-methyl-2, 4-diisopropenyl cyclohexane) -1-formaldehyde prepared in the step (6) to obtain (1S,2S,4S) -beta-elemene.

Preferably, in step (1), the catalyst is a copper salt.

Preferably, the copper salt is at least one selected from the group consisting of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide, cuprous trifluoromethanesulfonate, cuprous acetate, cuprous thiophene-2-carboxylate, tetrakis (acetonitrile) copper (I) tetrafluoroborate, tetrakis (acetonitrile) copper (I) hexafluorophosphate, and alkyl copper (I) salt complexes.

Preferably, in step (1), the isopropenyl grignard reagent is isopropenyl magnesium bromide grignard reagent.

Preferably, in the step (1), the reaction solvent for the addition reaction is selected from at least one of tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, benzene or toluene.

Preferably, in the step (2), the aldehyde group-containing substance is formaldehyde and/or paraformaldehyde.

Preferably, in the step (2), the alkali solution is at least one selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium ethoxide, potassium tert-butoxide, triethylamine, potassium hydride and sodium hydride.

In the step (3), the protecting group is selected from one of ester protecting group, silyl ether protecting group, benzyl ether protecting group or alkoxymethyl ether protecting group.

Preferably, in step (3), the protecting group is formed by reacting (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone prepared in step (2) with a hydroxyl protecting agent.

Preferably, when the protecting group is an ester protecting group, the hydroxyl protecting agent is selected from one of acid, acid anhydride or acid chloride, such as acetic anhydride, acetic acid or acetyl chloride.

Preferably, when the protecting group is a silyl ether protecting group, the hydroxy protecting agent is selected from one of trimethylchlorosilane (TMSCl), triethylchlorosilane (TESCl), triisopropylchlorosilane (tipsccl), tert-butyldimethylchlorosilane (TBSCl), tert-butyldiphenylchlorosilane (TBDPSCl), trimethylsilyl trifluoromethanesulfonate (TMSOTf), triethylsilyl trifluoromethanesulfonate (TESOTf), triisopropylsilyl trifluoromethanesulfonate (tipstotf), tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) or tert-butyldiphenylsilyl trifluoromethanesulfonate (TBDPSOTf).

Preferably, when the protecting group is a benzyl ether protecting group, the hydroxyl protecting agent is selected from benzyl bromide, p-methoxybenzyl bromide, or benzyl chloride.

Preferably, when the protecting group is an alkoxymethyl ether protecting group, the hydroxyl protecting agent is selected from chloromethyl methyl ether (MOMCl) or 2- (trimethylsilyl) ethoxymethyl chloride (SEMCl).

Preferably, in the step (4), the reducing agent is selected from at least one of sodium borohydride, sodium cyanoborohydride, potassium borohydride, lithium aluminum hydride, diborane, aluminum isopropoxide or metallic sodium. When in use, the sodium metal is firstly dissolved in ethanol to form a sodium metal ethanol solution.

Preferably, in step (6), the oxidant is selected from at least one of pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), dess-martin oxidant (DMP), 2-iodoxybenzoic acid (IBX), iodobenzene diacetate/2, 2,6, 6-tetramethylpiperidine oxide (DIB/TEMPO), chromium trioxide sulfuric acid solution (Jones reagent), chromium oxide-pyridine complex (Sarett reagent or Collins reagent), dimethyl sulfoxide/oxalyl chloride, dimethyl sulfoxide/carbodiimide, dimethyl sulfoxide/sulfur trioxide-pyridine complex, tetrapropylammonium ruthenate/4-methylmorpholine-N-oxide (TPAP/NMO), hypochlorite/2, 2,6, 6-tetramethylpiperidine oxide/bromide (sodium bromide, potassium bromide), or manganese dioxide.

Preferably, in step (7), the n-pentyltriphenylphosphonium bromide is prepared by reacting n-butyllithium with triphenylmethylphosphonium bromide.

Preferably, when acetic anhydride is selected as the hydroxyl protecting agent in step (3) to form an ester protecting group, the synthesis method comprises the following steps:

(1) under the action of a catalyst, performing addition reaction on (R) -carvone and an isopropenyl Grignard reagent to obtain (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone;

(2) performing alkylation reaction on the (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (1) and an aldehyde group-containing substance under the action of an alkali liquor to obtain (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;

(3) carrying out esterification reaction on the (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (2) and acetic anhydride under the action of alkali liquor to obtain ((1R,4R,6S) -1-methyl-2-ketone-4, 6-diisopropenyl cyclohexane) -1-methyl acetate;

(4) reducing the ((1R,4R,6S) -1-methyl-2-ketone-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester prepared in the step (3) under the action of a reducing agent to obtain ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester;

(5) subjecting the methyl ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate prepared in the step (4) to a radical deoxidation reaction and a hydrolysis reaction to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol;

(6) oxidizing ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol prepared in the step (5) under the action of an oxidizing agent to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde;

(7) and (3) carrying out olefination reaction on n-amyl triphenyl phosphonium bromide and ((1R,2S,4S) -1-methyl-2, 4-diisopropenyl cyclohexane) -1-formaldehyde prepared in the step (6) to obtain (1S,2S,4S) -beta-elemene.

More specifically, the method for synthesizing (1S,2S,4S) -beta-elemene comprises the following steps:

(1) taking copper salt as a catalyst, taking (R) -carvone as a starting material for reaction, and carrying out 1, 4-Michael addition reaction with an isopropenyl Grignard test to obtain (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone;

(2) under the action of a thermodynamic condition and an alkali liquor, carrying out alpha-alkylation reaction on the (2R,3R,5R) -2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (1) and formaldehyde and/or polyformaldehyde to obtain (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;

(3) carrying out esterification reaction on the (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone prepared in the step (2) and acetic anhydride under the action of alkali liquor to obtain ((1R,4R,6S) -1-methyl-2-ketone-4, 6-diisopropenyl cyclohexane) -1-methyl acetate;

(4) reducing the ((1R,4R,6S) -1-methyl-2-ketone-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester prepared in the step (3) under the action of a reducing agent to obtain ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester;

(5) simultaneously carrying out deoxidation reaction and hydrolysis reaction on the methyl ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate prepared in the step (4) under the classical Buton-Macinton free radical deoxidation reaction condition to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol;

(6) oxidizing ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol prepared in the step (5) under the action of an oxidizing agent to obtain ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde;

(7) reacting n-butyllithium with triphenylphosphine bromide to generate n-pentyltriphenylphosphine bromide, and then carrying out an olefination reaction on the n-pentyltriphenylphosphine bromide and ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde prepared in the step (6) to obtain (1S,2S,4S) -beta-elemene.

In a second aspect, the invention provides an intermediate A for synthesizing (1S,2S,4S) -beta-elemene.

Specifically, the structural formula of the intermediate A is shown as a formula (a), and the intermediate A is ((1R,2S,4S) -1-methyl-2, 4-diisopropenyl cyclohexane) -1-formaldehyde;

the third aspect of the invention provides an intermediate B for synthesizing (1S,2S,4S) -beta-elemene.

Specifically, the structural formula of the intermediate B is shown as a formula (B), and the intermediate B is ((1R,2S,4S) -1-methyl-2, 4-diisopropenyl cyclohexane) -1-methanol;

the above intermediate is generated in the synthesis process of (1S,2S,4S) -beta-elemene, and the residue of the intermediate affects the purity of (1S,2S,4S) -beta-elemene. Therefore, the intermediate can be used for researching the purity of the (1S,2S,4S) -beta-elemene and has important significance for controlling the quality of the (1S,2S,4S) -beta-elemene.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention starts from an initial raw material (R) -carvone, and carries out addition reaction, alkylation reaction, hydroxyl protection reaction, reduction reaction, free radical deoxidation reaction, hydroxyl protecting group removal, oxidation reaction and olefination reaction in sequence to carry out asymmetric total synthesis on (1S,2S,4S) -beta-elemene for the first time, wherein the total yield is more than 8.5 percent, and the purity is more than 98 percent (mass fraction).

(2) The synthesis method provided by the invention has the advantages of simple reaction operation, short steps and high synthesis efficiency; the raw material (R) -carvone is cheap and easy to obtain, the production cost is low, the method is suitable for industrial production, and sufficient sources can be provided for (1S,2S,4S) -beta-elemene.

(3) The invention provides an intermediate of (1S,2S,4S) -beta-elemene, which can be used for researching the purity of the (1S,2S,4S) -beta-elemene and has important significance for controlling the quality of the (1S,2S,4S) -beta-elemene.

Drawings

FIG. 1 is a scheme showing the synthesis of (1S,2S,4S) - β -elemene in example 1;

FIG. 2 is a hydrogen spectrum of (1S,2S,4S) -beta-elemene obtained in example 1.

Detailed Description

In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.

In the following examples, all reactions were carried out under an atmosphere of nitrogen or argon, under anhydrous conditions, unless otherwise specified; the reagents used in the reaction were purchased and used directly (all chemicals were purchased from reagent companies). Tetrahydrofuran and toluene are treated by metal sodium and diphenylethanone under the atmosphere of nitrogen; dichloromethane was treated with calcium hydride under nitrogen atmosphere. Unless otherwise specified, the reaction yields were based on the isolated yields of column chromatography, purchased from Qingdao maritime plant using silica gel (200-300 mesh); a thin-layer chromatography silica gel plate (60F-254) produced by Qingdao ocean chemical engineering with the thickness of 0.25mm is used for reaction detection. All nuclear magnetic resonance spectra are all from Brucker Advance 300(¹H:300MHz,¹³C:75MHz)，Brüker Advance 400(¹H:400MHz, ¹³C:100MHz),Brüker Advance 500(¹H:500MHz,¹³C, 125MHz) measured by an instrument; unless otherwise specified, deuterated chloroform (δ H — 7.26ppm, δ C — 77.16ppm) is generally used as a solvent; the high-resolution mass spectrum is measured by a Brucker Apex IV RTMS instrument; optical rotation values were measured by a Horiba SEPA-300 polarimeter. The following abbreviations are used in explaining multiple splitting: s is singlet, d is double split, t is triple split, q is quadruple split, and m is multiple split.

Example 1

A method for synthesizing (1S,2S,4S) -beta-elemene comprises the following steps:

step 1:

copper iodide (CuI, 12.6g, 66.2mmol, 1.1equiv) was added to tetrahydrofuran (THF, 300.0mL) under an argon atmosphere, followed by the slow addition of isopropenyl magnesium bromide grignard reagent (1.0M, 133.0mL, 133.0mmol, 2.0equiv) at-78 ℃ (dry ice/acetone solid-liquid mixture), the reaction was slowly raised to 0 ℃ and stirring continued at that temperature for 1.0 hour; thereafter, the reaction system was again placed at-78 deg.C, and (R) -carvone (represented by formula 1; 10g, 66.67mmol, 1.0equiv) dissolved in tetrahydrofuran (50.0 mL) was added dropwise and the reaction was stirred at that temperature for 3.0 hours, after which the reaction system was slowly raised to room temperature and the reaction was continued with stirring for 4.0 hours, and finally, saturated aqueous ammonium chloride solution (50.0 mL) was added dropwise to quench the reaction, the aqueous phase was extracted with ethyl acetate (3X 200.0mL), and the resulting organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to flash column chromatography (volume ratio of n-hexane to ethyl acetate from 20:1 to 15:1) to give 8.9g of (2R,3R,5R) -2-methyl-3, 5-diisopropenylcyclohexanone (represented by formula 2; R) as a pale yellow oily liquid in a yield of 70%_f0.45, n-hexane: ethyl acetate 6: 1). Process for preparing (2R,3R,5R) -2-methyl-3, 5-diisopropenylcyclohexanone¹H NMR was as follows:¹H NMR(500MHz,CDCl₃)δ4.93(s,1H),4.80(s,1H),4.73(s,1H),4.52(s,1H),2.71(d,J ＝5.1Hz,1H),2.65(d,J＝4.6Hz,1H),2.62–2.57(m,1H),2.53(m,1H),2.34–2.27(m,1H), 2.03–1.96(m,1H),1.86–1.79(m,1H),1.73(s,3H),1.70(s,3H),1.07(d,J＝6.9Hz,3H)；¹³C NMR(125MHz,CDCl₃)δ213.7,147.5,144.1,112.9,110.6,47.2,46.6,45.1,40.5,32.1,23.9,21.3, 12.1；HRMS(ESI)calcd for C₁₃H₂₁O[M+H]⁺:193.1587；found:193.1589。

step 2:

in an argon atmosphereNext, potassium hydroxide (KOH, 4.6g, 82.1mmol, 2.0equiv) was added to methanol (CH)₂O, 200mL), then (2R,3R,5R) -2-methyl-3, 5-diisopropenylcyclohexanone (8.0g, 41.7mmol, 1.0equiv) dissolved in methanol (MeOH, 10.0mL) was slowly added dropwise at 0 ℃ and the reaction was stirred at that temperature for 1.0 hour, followed by dropwise addition of aqueous formaldehyde (39% in H)₂O, 9.4mL, 125.1mmol, after removal of a portion of the methanol solvent, the aqueous phase was extracted with ethyl acetate (3X 100.0mL), and the resulting organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to flash column chromatography (volume ratio of n-hexane to ethyl acetate from 20:1 to 10:1), and the recovered reaction starting material was subjected to the same experimental operation as described above twice, to finally obtain 4.6g of (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone (represented by formula 3; R) as a pale yellow oily liquid in an overall yield of 50%_f0.35, n-hexane: ethyl acetate 6: 1). Process for preparing (2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone¹H NMR was as follows:¹H NMR(400MHz, CDCl₃)δ4.95(s,1H),4.87(s,1H),4.74(s,1H),4.70(s,1H),3.67(d,J＝11.5Hz,1H),3.43(d,J ＝11.5Hz,1H),2.75–2.69(m,1H),2.69–2.63(m,2H),2.60–2.51(m,1H),2.45(s,1H),2.14(m, 1H),1.84(d,J＝14.3Hz,1H),1.76(s,3H),1.71(s,3H),1.05(s,3H).；¹³C NMR(100MHz,CDCl₃) δ217.2,146.4,144.4,114.8,112.5,66.5,53.7,42.7,42.1,40.4,28.8,24.0,22.1,16.7；HRMS(ESI) calcd for C₁₄H₂₃O₂Na[M+Na]⁺:245.1512；found:245.1512。

and step 3:

(2R,3S,5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone (4.6g, 20.7mmol, 1.0equiv) and triethylamine (TEA, 8.6mL, 62.2mmol, 3.0equiv) were dissolved in 0 ℃ dichloromethane (DCM, 100.0mL) and acetic anhydride (Ac) was added dropwise₂O, 4.0mL, 41.4mmol, 2.0equiv), the reaction was slowly warmed to room temperature and stirred for reaction overnight, after which time the reaction was allowed to proceedThe reaction mixture was filtered through a celite-loaded funnel, concentrated under reduced pressure, and the residue was subjected to flash column chromatography (volume ratio of n-hexane to ethyl acetate was 50:1 to 30:1) to give 4.9g of colorless transparent oily liquid ((1R,4R,6S) -1-methyl-2-one-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester (represented by formula 4; R)_f0.75, n-hexane: ethyl acetate 6: 1). Process for preparing methyl ((1R,4R,6S) -1-methyl-2-one-4, 6-diisopropenylcyclohexane) -1-acetate¹H NMR was as follows:¹H NMR(500MHz,CDCl₃)δ4.92–4.88(m,1H),4.80(s,1H),4.64(s, 1H),4.57(s,1H),4.21(d,J＝10.9Hz,1H),3.96(d,J＝10.9Hz,1H),2.73–2.63(m,2H),2.52(t, J＝5.6Hz,2H),2.02–1.95(m,1H),1.94(s,3H),1.85(m,1H),1.68(s,6H),1.01(s,3H)；¹³C NMR(125MHz,CDCl₃)δ212.5,170.6,146.6,144.0,114.8,111.5,67.1,51.2,44.2,42.4,40.1, 28.9,23.9,21.6,20.7,17.2；HRMS(ESI)calcd for C₁₆H₂₄O₃Na[M+Na]⁺:287.1618；found: 287.1615。

and 4, step 4:

(1R,4R,6S) -1-methyl-2-one-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester (3.0g, 11.3mmol, 1.0equiv) was dissolved in methanol (MeOH, 50.0mL) and sodium borohydride (NaBH) was added at 0 deg.C₄0.86g, 22.6mmol, 2.0equiv), then stirred at that temperature for 1.0 hour, finally quenched dropwise with 3N aqueous hydrochloric acid (15.0 mL), the aqueous phase extracted with ethyl acetate (3 × 50.0mL), the organic phases combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to flash column chromatography (eluent: n-hexane to ethyl acetate, volume ratio of n-hexane to ethyl acetate in elution: 20:1 to 15:1) to obtain 2.7g of methyl ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate (represented by formula 5; R) as a pale yellow oily liquid in a total yield of 90%_f0.40, n-hexane: ethyl acetate 7:1), which is a pair of diastereomers that are difficult to separate by column chromatographyBody (d.r.: 3: 2). Process for preparing methyl ((1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate¹H NMR was as follows:¹H NMR(500MHz,CDCl₃)δ4.90(s,2H), 4.87(s,0.8H),4.85–4.79(m,2.5H),4.73(d,J＝9.9Hz,2H),4.36(d,J＝11.4Hz,1H),4.20(d,J ＝10.9Hz,0.7H),4.00(d,J＝10.9Hz,0.7H),3.76(dd,J＝6.5,3.9Hz,0.7H),3.55(dd,J＝12.0, 3.8Hz,2H),2.71(s,1H),2.61–2.53(m,0.7H),2.43(s,1H),2.41–2.37(m,0.7H),2.30(dd,J＝ 13.4,3.0Hz,1H),2.06(s,3H),2.04(s,2.3H),2.03–1.98(m,1H),1.96–1.81(m,3H),1.80(s, 2H),1.77(s,2H),1.73(s,3H),1.71–1.67(m,1H),1.03(s,2H),0.84(s,3H)；¹³C NMR(125MHz, CDCl₃)δ172.2,171.5,149.45,146.47,146.45,145.48,114.1,114.0,110.7,109.5,73.4,69.0,67.4, 67.3,43.5,42.5,41.9,41.3,38.3,38.1,31.6,30.96,29.7,28.6,24.6,23.2,22.8,22.1,21.1,21.0, 18.2,9.8；HRMS(ESI)calcd for C₁₆H₂₆O₃Na[M+Na]⁺:289.1774；found:289.1772。

and 5:

(1R,4R,6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester (1.5g, 5.64mmol, 1.0equiv) was dissolved in dichloromethane (DCM, 30.0mL), then 4-dimethylaminopyridine (DMAP, 1.37 g, 11.28mmol, 2.0equiv), phenyl thiocarbonate (PHOC (S) Cl, 1.94g, 11.28mmol, 2.0equiv) were added in this order, after the reaction was stirred at room temperature overnight, the reaction mixture was filtered through a celite-loaded filter and concentrated under reduced pressure to obtain a reaction mixture of ((1R,4R,6S) -1-methyl-2-phenylthiocarbamate-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester (represented by formula 6). (1R,4R,6S) -1-methyl-2-phenyl thiocarbamate-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester was directly dissolved in toluene (MeOH, 20.0mL) under an argon atmosphere, heated to reflux, and tributyltin hydride ((n-Bu)₃SnH, 3.30g, 11.28mmol, 2.0equiv) and the radical initiator azobisisobutyronitrile (AIBN, 370mg, 11.28mmol,0.2equiv), the reaction was stirred at that temperature for 8.0 hours, then the reaction system was cooled to room temperature, and potassium hydroxide (KOH, 1.0g) dissolved in methanol (toluene, 30.0mL) was added, the reaction was continued for 2.0 hours with stirring, finally, a saturated aqueous ammonium chloride solution (10.0mL) was added dropwise, the aqueous phase was extracted with ethyl acetate (3 × 30mL), and the resulting organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to flash column chromatography (eluent: n-hexane to ethyl acetate, volume ratio of n-hexane to ethyl acetate in elution: 50:1 to 20:1) to obtain 580mg of white solid ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol (shown in formula 7; R) in two steps with a total yield of 50%_f0.30, n-hexane: ethyl acetate 10: 1). Process for preparing ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol¹H NMR was as follows:¹H NMR(500 MHz,CDCl₃)δ4.88(d,J＝1.3Hz,1H),4.82(s,1H),4.79(s,1H),4.76(d,J＝1.5Hz,1H),3.39– 3.30(m,2H),2.35(s,1H),2.28(dd,J＝10.9,3.7Hz,1H),1.81(m,2H),1.76(s,3H),1.72(s,3H), 1.71–1.62(m,3H),1.56–1.48(m,1H),1.17(dd,J＝9.1,4.1Hz,1H),0.94(s,3H)；¹³C NMR (125MHz,CDCl₃)δ149.2,147.2,112.9,110.5,72.3,44.8,39.0,38.9,31.8,29.9,23.9,23.3,22.5, 17.9；HRMS(ESI)calcd for C₁₄H₂₅O[M+H]⁺:209.1900；found:209.1900。

step 6:

((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol (410mg, 1.97mmol, 1.0equiv) was dissolved in dichloromethane (20.0mL), pyridinium chlorochromate (847mg, 3.94mmol, 2.0equiv) and silica gel for column chromatography (200 mesh, 300 mesh, 800mg) were added at 0 deg.C, after which the reaction was allowed to slowly warm to room temperature and stirred for 3.0 hours. Concentrating the reaction mixture under reduced pressure, and subjecting the residue to flash column chromatography (eluent is n-hexane and ethyl acetate, volume ratio of n-hexane to ethyl acetate in elution is from 80:1 to 50:1) to obtain 314mg of light yellow oil with 75% yieldLiquid ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-carbaldehyde (shown in formula 8; R)_f0.60, n-hexane: ethyl acetate 10: 1). Process for preparing (1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-carbaldehyde¹H NMR was as follows:¹H NMR(400MHz,CDCl₃)δ9.39(s,1H),4.91–4.88(m,1H),4.82(d,J＝1.2Hz,1H),4.77(s,1H), 4.74(s,1H),2.67(dd,J＝7.2,4.8Hz,1H),2.38–2.28(m,1H),1.93–1.84(m,1H),1.74(s,3H), 1.70(s,3H),1.68–1.70(m,4H),1.39(m,1H),1.00(s,3H)；¹³C NMR(100MHz,CDCl₃)δ206.4, 147.9,146.3,113.6,110.1,49.5,42.5,38.5,30.5,29.4,25.4,24.9,21.8,17.1；HRMS(ESI)calcd for C₁₄H₂₃O[M+H]⁺:207.1743；found:207.1742。

and 7:

triphenylphosphine bromide (571mg, 1.60mmol, 2.2equiv) was dissolved in tetrahydrofuran (10.0mL) under an argon atmosphere, and then n-butyllithium solution (1.6M, 0.9mL, 1.46mmol, 2.0equiv) was added dropwise at-78 deg.C, and the reaction was continued at this temperature for 30 minutes with stirring, then slowly warmed to room temperature with stirring, and reacted for 20 minutes to obtain n-pentyltriphenylphosphine bromide. Subsequently, the reaction system was again placed at-78 ℃, ((1R,2S,4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-carbaldehyde (150mg, 0.73mmol, 1.0equiv) dissolved in tetrahydrofuran (2.0 mL) was added dropwise, and after continuing the reaction for 30 minutes with stirring at that temperature, the temperature was slowly raised to room temperature, the reaction was stirred for 30 minutes, and finally, a saturated aqueous ammonium chloride solution (5.0mL) was added dropwise to quench the reaction, the aqueous phase was extracted with ethyl acetate (3 × 20mL), and the resulting organic phases were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to flash column chromatography (eluent: 100% n-hexane) to obtain 121mg of (1S,2S,4S) - β -elemene (represented by formula 9; R) as a colorless transparent liquid in 82% yield_f0.95, 100% n-hexane). Optical rotation value of (1S,2S,4S) - β -elemene:process for preparing (1S,2S,4S) -beta-elemene¹H NMR was as follows:¹H NMR(500MHz,CDCl₃)δ5.82(dd,J＝17.5,11.0Hz,1H),4.93(dd,J＝8.3,1.0Hz,1H), 4.90(s,1H),4.86(d,J＝1.2Hz,1H),4.84(m,1H),4.79(s,1H),4.68(s,1H),2.40–2.32(m,1H), 2.18(m,1H),1.75(s,3H),1.73(s,3H),1.57-1.78(m,5H),1.32(m,1H),1.02(s,3H)；¹³C NMR (125MHz,CDCl₃)δ150.2,148.2,147.9,112.4,110.17,110.15,47.7,39.8,39.1,34.7,30.2,25.5, 24.6,22.30,22.29；HRMS(ESI)calcd for C₁₅H₂₅[M+H]⁺205.1951; 205.1952 hydrogen spectrum of ((1S,2S,4S) -beta-elemene is shown in FIG. 2). The purity of the synthesized (1S,2S,4S) -beta-elemene is 98.89% by High Performance Liquid Chromatography (HPLC) and Gas Chromatography (GC).

The synthetic schemes for steps 1-7 above are shown in FIG. 1. The intermediate A of (1S,2S,4S) -beta-elemene is synthesized in the steps 1-6, and the intermediate B of (1S,2S,4S) -beta-elemene is synthesized in the steps 1-5.

Through a plurality of tests, the purity of the (1S,2S,4S) -beta-elemene prepared by the synthetic method provided by the invention is more than 98.0%, and the research on drug properties such as pharmacology, pharmacodynamics and the like can be met. Compared with (1S,2S,4R) -beta-elemene, the (1S,2S,4S) -beta-elemene has higher antitumor activity and lower toxic and side effects.