CN113788734B - Synthesis method of (1S, 2S, 4S) -beta-elemene and intermediate thereof - Google Patents
Synthesis method of (1S, 2S, 4S) -beta-elemene and intermediate thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of drug synthesis, and discloses a method for synthesizing (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 (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.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing (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 anti-tumor 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 C 15 H 24 . 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. Researches show that the four isomers of elemene have certain antitumor activity, but the beta-elemene has the strongest pharmacological activity and is also the most main antitumor active effective component in elemene antitumor medicaments 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 (1S, 2S, 4R) -beta-elemene and (1S, 2S, 4S) -beta-elemene are shown in the following formulas.
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 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 turmeric). 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 produce (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 method for synthesizing (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 method for synthesizing (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 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) Subjecting the compound B prepared in the step (4) to free radical deoxidation reaction, 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 (1S, 2S, 4S) -beta-elemene is obtained by performing 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).
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 at least one selected from 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 a hydroxyl protecting agent with (2R, 3S, 5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone prepared in step (2).
Preferably, when the protecting group is an ester protecting group, the hydroxyl protecting agent is selected from one of 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 oxidizing agent is selected from at least one of pyridinium chlorochromate (PCC), pyridinium Dichromate (PDC), dess-martin oxidizing agent (DMP), 2-iodoxybenzoic acid (IBX), iodobenzene diacetate/2, 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, 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 alkali liquor to obtain (2R, 3S, 5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;
(3) Carrying out esterification reaction on (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 ((1R, 4R, 6S) -1-methyl-2-keto-4, 6-diisopropenylcyclohexane) -1-methyl acetate 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-methyl acetate;
(5) Subjecting the methyl ((1R, 4R, 6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate prepared in step (4) to radical deoxidation and hydrolysis 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 (1) performing olefination reaction on n-amyl triphenyl phosphorus 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 an initial raw material of the reaction, and carrying out 1, 4-Michael addition reaction with isopropenyl Grignard reaction to obtain (2R, 3R, 5R) -2-methyl-3, 5-diisopropenyl cyclohexanone;
(2) 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 under the action of a thermodynamic condition and an alkali liquor to obtain (2R, 3S, 5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;
(3) Carrying out esterification reaction on (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-keto-4, 6-diisopropenylcyclohexane) -1-methyl acetate 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-methyl acetate;
(5) (1R, 4R, 6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester prepared in step (4) is subjected to simultaneous deoxygenation and hydrolysis under classical Buton-Maicony radical deoxygenation reaction conditions to give ((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) N-butyllithium and triphenylphosphine bromide are reacted to generate n-pentyltriphenylphosphonium bromide, and then the n-pentyltriphenylphosphonium bromide and ((1R, 2S, 4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-formaldehyde prepared in the step (6) are subjected to an olefination reaction to obtain (1S, 2S, 4S) -beta-elemene.
The invention provides an intermediate A for synthesizing (1S, 2S, 4S) -beta-elemene in a second aspect.
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-diisopropenylcyclohexane) -1-formaldehyde;
in a third aspect, 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-diisopropenylcyclohexane) -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 (1S, 2S, 4S) -beta-elemene and has important significance for controlling the quality of (1S, 2S, 4S) -beta-elemene.
Compared with the prior art, the invention has the following beneficial effects:
(1) The method 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 (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 (1S, 2S, 4S) -beta-elemene and has important significance for controlling the quality of (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 a nitrogen or argon atmosphere in the absence of water, unless otherwise indicated; 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 works using silica gel (200-300 mesh); a thin-layer chromatography silica gel plate (60F-254) produced by Qingdao ocean chemical industry with the thickness of 0.25mm is used for reaction detection. All nuclear magnetic resonance spectra were determined by Bruker Advance 300 ( 1 H:300MHz, 13 C:75MHz)，Brüker Advance 400( 1 H:400MHz, 13 C:100MHz),Brüker Advance 500( 1 H:500MHz, 13 C, 125 MHz) measured by an instrument; deuterated chloroform (δ H =7.26ppm, δ C =77.16 ppm) is generally used as a solvent, unless otherwise specified; the high-resolution mass spectrum is measured by a Brker 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 = singlet, d = double split, t = triple split, q = quadruple split, m = multiple split.
Example 1
A method for synthesizing (1S, 2S, 4S) -beta-elemene comprises the following steps:
step 1:
cuprous iodide (CuI, 12.6g,66.2mmol, 1.1equiv) was added to tetrahydrofuran (THF, 300.0 mL) under an argon atmosphere, followed by streaking at-78 deg.CIsopropenyl magnesium bromide grignard reagent (1.0M, 133.0mL,133.0mmol, 2.0equiv) was slowly added under the condition (dry ice/acetone solid-liquid mixture), the reaction system was slowly raised to 0 ℃ and the reaction was continuously stirred at the 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, then the reaction system was slowly raised to room temperature to continue the reaction with stirring for 4.0 hours, and finally, a saturated aqueous ammonium chloride solution (50.0 mL) was added dropwise to quench the reaction, the aqueous phase was extracted with ethyl acetate (3X 200.0 mL), 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 to 15: 1) to give 8.9g of a pale yellow oily liquid (2R, 3R, 5R) -2-methyl-3, 5-diisopropenylcyclohexanone (represented by formula 2; R f =0.45, n-hexane: ethyl acetate = 6). Process for preparing (2R, 3R, 5R) -2-methyl-3, 5-diisopropenylcyclohexanone 1 H NMR was as follows: 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 C 13 H 21 O[M+H] + :193.1587；found:193.1589。
step 2:
potassium hydroxide (KOH, 4.6g,82.1mmol,2.0 equiv) was added to methanol (CH) under an argon atmosphere 2 O, 200 mL), then (2r, 3r, 5r) -2-methyl-3, 5-diisopropenylcyclohexanone (8.0g, 41.7mmol, 1.0equiv) dissolved in methanol (MeOH, 10.0 mL) was slowly dropped under the condition of 0 ℃ and the reaction was stirred at that temperature for 1.0 hour, followed by dropwise addition of aqueous formaldehydeLiquid (39%) 2 O,9.4mL,125.1mmol, after removing part of the methanol solvent, the aqueous phase was extracted with ethyl acetate (3X 100.0 mL), 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 to 10 f =0.35, n-hexane: ethyl acetate = 6). Process for preparing (2R, 3S, 5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone 1 H NMR was as follows: 1 H NMR(400MHz, CDCl 3 )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).； 13 C NMR(100MHz,CDCl 3 ) 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 C 14 H 23 O 2 Na[M+Na] + :245.1512；found:245.1512。
and step 3:
(2R, 3S, 5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenylcyclohexanone (4.6 g,20.7mmol, 1.0equiv) and triethylamine (TEA, 8.6mL,62.2mmol, 3.0equiv) were dissolved in dichloromethane (DCM, 100.0 mL) at 0 ℃ and acetic anhydride (Ac) was added dropwise 2 O,4.0ml,41.4mmol, 2.0equiv), the reaction system was slowly raised to room temperature and stirred to react overnight, after which the reaction mixture was filtered using a celite-loaded sand-core funnel, concentrated under reduced pressure, and the residue was subjected to flash column chromatography (the volume ratio of n-hexane to ethyl acetate was varied from 50; r is f =0.75, n-hexane: ethyl acetate = 6). Process for producing methyl ((1R, 4R, 6S) -1-methyl-2-one-4, 6-diisopropenylcyclohexane) -1-acetate 1 H NMR was as follows: 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 C 16 H 24 O 3 Na[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 (3.0 g,11.3mmol,1.0 equiv) was dissolved in methanol (MeOH, 50.0 mL) and sodium borohydride (NaBH) was added at 0 deg.C 4 0.86g, 22.6mmol,2.0 equiv), followed by stirring at that temperature for 1.0 hour, finally, dropwise addition of 3N aqueous hydrochloric acid (15.0 mL) to quench the reaction, extraction of the aqueous phase with ethyl acetate (3X 50.0 mL), combination of the resulting organic phases and drying over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to flash column chromatography (eluent was n-hexane and ethyl acetate, and the volume ratio of n-hexane to ethyl acetate in elution was from 20 to 15 f =0.40, n-hexane: ethyl acetate = 7) which is a pair of diastereomers that are difficult to separate by column chromatography (d.r. = 3. Process for producing methyl ((1R, 4R, 6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate 1 H NMR was as follows: 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz, CDCl 3 )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 C 16 H 26 O 3 Na[M+Na] + :289.1774；found:289.1772。
and 5:
((1R, 4R, 6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester (1.5 g,5.64mmol,1.0 equiv) was dissolved in dichloromethane (DCM, 30.0 mL), after which 4-dimethylaminopyridine (DMAP, 1.37 g,11.28mmol, 2.0equiv), phenyl thiocarbohydrochloride (PHOC (S) Cl,1.94g,11.28mmol, 2.0equiv) were added in this order, the reaction was stirred overnight at room temperature, then the reaction mixture was filtered using a celite-loaded sand core funnel and concentrated under reduced pressure to give a reaction mixture of ((1R, 4R, 6S) -1-methyl-2-phenylthiocarbamate-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester (shown in formula 6). ((1R, 4R, 6S) -1-methyl-2-phenylthiocarbamate-4, 6-diisopropenylcyclohexane) -1-acetic acid methyl ester was directly dissolved in toluene (MeOH, 20.0 mL) under an argon atmosphere, heated to reflux, and tributyltin hydride ((n-Bu) 3 SnH, 3.30g,11.28mmol,2.0 equiv) and a radical initiator azobisisobutyronitrile (AIBN, 370mg,11.28mmol, 0.2 equiv), stirred at that temperature for 8.0 hours, then the temperature of the reaction system was lowered to room temperature, and potassium hydroxide (KOH, 1.0 g) dissolved in methanol (toluene, 30.0 mL) was added, the reaction was continued with stirring for 2.0 hours, finally a saturated aqueous ammonium chloride solution (10.0 mL) was added dropwise, the aqueous phase was extracted with ethyl acetate (3X 30 mL), the resulting organic phases were combined, and anhydrous sulfur was used to separate the organic phase from the aqueous phase, followed by filtration, and filtrationAnd (5) drying the sodium salt. After concentration under reduced pressure, the residue was separated by flash column chromatography (eluent was n-hexane and ethyl acetate, the volume ratio of n-hexane to ethyl acetate in elution was from =50 to 20 f =0.30, n-hexane: ethyl acetate = 10). Process for preparation of ((1R, 2S, 4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-methanol 1 H NMR was as follows: 1 H NMR(500 MHz,CDCl 3 )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)； 13 C NMR (125MHz,CDCl 3 )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 C 14 H 25 O[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 methylene chloride (20.0 mL), pyridinium chlorochromate (847 mg,3.94mmol, 2.0 equiv) and silica gel for column chromatography (200-300 mesh, 800 mg) were added at 0 ℃, and then the reaction was slowly warmed to room temperature and stirred for 3.0 hours. After the reaction mixture was directly concentrated under reduced pressure, the residue was subjected to flash column chromatography (eluent: n-hexane and ethyl acetate, volume ratio of n-hexane to ethyl acetate in elution: from 80 to 50: 1) to obtain 314mg of pale yellow oily liquid ((1r, 2s, 4s) -1-methyl-2, 4-diisopropenylcyclohexane) -1-carbaldehyde (shown in formula 8; R f =0.60, n-hexane: ethyl acetate = 10). Process for producing ((1R, 2S, 4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-carbaldehyde 1 H NMR was as follows: 1 H NMR(400MHz,CDCl 3 )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)； 13 C NMR(100MHz,CDCl 3 )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 C 14 H 23 O[M+H] + :207.1743；found:207.1742。
and 7:
triphenylphosphine bromide (571mg, 1.60mmol, 2.2equiv) was dissolved in tetrahydrofuran (10.0 mL) under an argon atmosphere, and then an n-butyllithium solution (1.6M, 0.9mL,1.46mmol, 2.0 equiv) was added dropwise at-78 deg.C, and the reaction was continued for 30 minutes with stirring at that temperature, then slowly warmed to room temperature, and stirred for 20 minutes to obtain n-pentyltriphenylphosphine bromide. The reaction system was then placed again at-78 deg.C, ((1R, 2S, 4S) -1-methyl-2, 4-diisopropenylcyclohexane) -1-carbaldehyde (150mg, 0.73mmol,1.0 equiv) dissolved in tetrahydrofuran (2.0 mL) was added dropwise, and after continuing the reaction at that temperature for 30 minutes with stirring, the reaction was slowly warmed to room temperature with stirring for 30 minutes, and finally the reaction was quenched by dropwise addition of saturated aqueous ammonium chloride (5.0 mL), the aqueous phase was extracted with ethyl acetate (3X 20 mL), 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 colorless transparent liquid (1S, 2S, 4S) -beta-elemene (represented by formula 9; R) f =0.95, 100% n-hexane). Optical rotation value of (1s, 2s, 4s) - β -elemene:
process for preparation of (1S, 2S, 4S) -beta-elemene 1 H NMR was as follows: 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR (125MHz,CDCl 3 )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 C 15 H 25 [M+H] + 205.1951; the hydrogen spectrum of found:205.1952 ((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, (1S, 2S, 4S) -beta-elemene has higher antitumor activity and lower toxic and side effects.
Claims (7)
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 a substance containing aldehyde group under the action of 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) Subjecting the compound B prepared in the step (4) to radical deoxidation reaction, 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) Performing 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;
in the step (2), the aldehyde group-containing substance is formaldehyde and/or paraformaldehyde.
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 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.
4. 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.
5. 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.
6. 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, 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, 6-tetramethylpiperidine oxide/bromide, or manganese dioxide.
7. 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 alkali liquor to obtain (2R, 3S, 5R) -2-hydroxymethyl-2-methyl-3, 5-diisopropenyl cyclohexanone;
(3) Carrying out esterification reaction on (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 ((1R, 4R, 6S) -1-methyl-2-keto-4, 6-diisopropenylcyclohexane) -1-methyl acetate 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-methyl acetate;
(5) Subjecting the methyl ((1R, 4R, 6S) -1-methyl-2-hydroxy-4, 6-diisopropenylcyclohexane) -1-acetate prepared in step (4) to radical deoxidation and hydrolysis 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 (1) performing olefination reaction on n-amyl triphenyl phosphorus 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.
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| Benito Iglesias, D.等.Synthesis of trans-β-Elemene.《European Journal of Organic Chemistry》.2018,第35卷P4926-4932. * |
| Gold-Catalyzed Enantio- and Diastereoselective Syntheses of Left Fragments of Azadirachtin/Meliacarpin-Type Limonoids;Shi Hang，等;《Journal of Organic Chemistry》;20160205;第81卷(第3期);P751-771 * |
| Synthesis of trans-β-Elemene;Benito Iglesias, D.等;《European Journal of Organic Chemistry》;20180829;第35卷;P4926-4932 * |
| Unusual radical 6-endo cyclization to carbocyclic-ENA and elucidation of its solution conformation by 600 MHz NMR and ab initio calculations;Zhou, Chuanzheng 等;《Organic & Biomolecular Chemistry》;20081231;第6卷(第24期);P4627-4633 * |
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