CN110776516A - Method for synthesizing natural product cephalotaxine - Google Patents
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Abstract
The invention discloses a method for synthesizing a natural product cephalotaxine. The technical scheme aims at providing a brand-new synthetic route: taking cyclopentadienyl sodium as an initial raw material, and finally realizing the formal synthesis of the natural product cephalotaxine by taking hydroboration oxidation reaction, iodine ion induced N heterocyclic ring construction reaction, palladium catalyzed coupling ring closure reaction and the like as key reaction steps in the synthesis process. The synthesis route has unique and novel design, mild conditions, high speed, relatively few side reactions and simple and convenient operation in the reaction process, utilizes conventional chemical reagents in the route, has cheap and easily obtained raw materials, and can greatly reduce the synthesis cost.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and further relates to a synthesis method of a key intermediate of a compound with anticancer activity, in particular to a synthesis method of a natural product cephalotaxine.
Background
The cephalotaxine compound is an alkaloid extracted from cephalotaxus plants, and a large number of clinical tests show that the cephalotaxine compound has good antitumor activity, and particularly homoharringtonine and cephalotaxtonine in the cephalotaxus compounds are already applied to clinical treatment of diseases. The cephalotaxine itself does not show obvious pharmacological activity, but its derivatives such as cephalotaxine and homoharringtonine have good anti-leukemia and other malignant tumor activities. The unique five-membered fused ring structure and strong pharmacological activity attract a plurality of scholars to carry out total synthesis research on the novel five-membered fused ring structure. Paudler et al first isolated harringtonine and cephalotaxine from cephalotaxus and cephalotaxus japonica. Their structures were determined by Powell et al in 1969. The structure is shown in the following formula 10:
for this natural product, The chemical Synthesis methods reported in The literature are mainly The research papers entitled Total Synthesis of (+ -) -Cephalotaxine published in 1972 by ① Weinred et al, The research papers entitled Enantioselective high efficiency Synthesis of (-) -Cephalotaxine Using Two Palladium-catalyst Transformations published 1999 by ② Tietz et al, The research papers entitled Stereoselective Synthesis of (-) -Cephalotaxine and C-7Alkylated Synthesis published in 2004 by ③ Royer et al, The research papers entitled Stereoselective Synthesis of (-) -Cephalotaxine and C-7Alkylated Synthesis published by JOC in 2004, The research papers entitled Strailability-recovery of N-video-2-Synthesis of (-) -Synthesis of (-) -Tokytopathy published in 2006 by ④ Gin et al, The research papers entitled "Strailability-reaction of N-recovery of Synthesis-2-Synthesis of Synthesis-Synthesis of (-) -Tokytopathy and The research papers published in 2006 by No. ④ Gi et al, ((+) -Centrol Synthesis of synthesized Tokytopathy and Synthesis of (+) -Synthesis of The same)A research paper entitled Short Synthesis of (-) -Cepalotaxine Using pharmaceutical Cascade in OL 2008, ⑦ Hayes et al in 2008, a research paper entitled A Formal Synthesis of (-) -Cepalotaxine in OL, ⑧ Honghua et al in 2015, a research paper entitled Stereolyticus in N Iminium Ion Cyclization, a Development of Effect Synthesis of (+ -) -Cepalotaxine in OL ⑨ Srivari et al in 2016, a research paper entitled Formal Total Synthesis of (+ -) -Cepalotaxine and Congenerants ViaAryne Insertion in OL ⑩, and a research paper entitled library of calcium Synthesis of (+ -) -Cepalotaxine and Congenerants ViaAryne Insertion in OL ⑩, and a research paper entitled "Ca 2+ Au 3 + C in OL in 2017]A research article on amino with peptidyl Esters, Total Synthesis of Cephalotaxine and Cephalozolamine H;
peter et al published 2018 a research paper entitled FormalSynthesis of ent-Cepalotaxine Using a One-dot Parham-Aldol Sequence on JOC;
sanghe et al published 2019 a research paper entitled Total Synthesis and structural Election of (-) -Cephalozolamine G on OL.
The conventional synthetic routes have the disadvantages of long route, harsh conditions, low construction efficiency and high synthetic cost, and further research on the cephalotaxine is severely restricted, so that a simple and efficient cephalotaxine synthetic route is urgently needed.
Disclosure of Invention
The invention aims to provide a synthetic method of a natural product cephalotaxine aiming at the technical defects of the prior art, and aims to solve the technical problems of long route and high synthetic cost of the conventional synthetic method of the cephalotaxine in the prior art.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
the synthesis process of natural cephalotaxine includes the following steps:
1) in a tetrahydrofuran solvent environment, carrying out electrophilic addition reaction on a compound (cyclopentadienyl sodium) shown in a formula 1 and a compound shown in a formula 2 at-78 ℃ to obtain a compound shown in a formula 3;
2) dissolving the compound of formula 3 in tetrahydrofuran at normal temperature, adding disubstituted borane at 0 ℃ to perform hydroboration reaction, adding TMAO at normal temperature, heating to 90 ℃ to perform oxidation reaction to obtain a compound of formula 4;
3) dissolving the compound shown in the formula 4 in dichloromethane, and performing hydroxyl protection by using a MOMCl-DIPEA system at 0 ℃ to obtain a compound shown in the formula 5;
4) dissolving the compound shown in the formula 5 in dichloromethane, and then carrying out ester reduction reaction with diisobutylaluminum hydride at-78 ℃ to obtain a compound shown in the formula 6;
5) dissolving a compound shown in a formula 6 in methanol, dropwise adding a compound shown in a formula 7 into the methanol, reacting for 4 hours at normal temperature, cooling to 0 ℃, adding sodium borohydride into the solution, and carrying out an aldehyde-amine condensation reduction reaction at 0 ℃ for 4 hours to obtain a compound shown in a formula 8;
6) dissolving the compound shown in the formula 8 in dichloromethane, then dropwise adding LDA into the dichloromethane at 0 ℃, adding NIS into the mixture after 30min, and reacting for 2h to obtain a compound shown in the formula 9;
7) dissolving a compound shown in a formula 9 in 1, 4-dioxane, refluxing for 1.5 hours at 100 ℃ by taking tetrakis (triphenylphosphine) palladium as a catalyst and cesium carbonate as an alkali source to obtain a compound 10, namely the cephalotaxine;
preferably, step 1) comprises: adding a compound of formula 2 into a tetrahydrofuran solution of a compound of formula 1 at-78 ℃ under the protection of nitrogen, reacting for 3 hours, changing the solution from clear to turbid, and separating and purifying to obtain the compound of formula 3.
Preferably, the disubstituted borane in step 2) is prepared by the following method: under the protection of nitrogen, borane is dissolved in tetrahydrofuran, 2-methyl-2-butene is added into the tetrahydrofuran at the temperature of minus 20 ℃, and after 5min, the mixture reacts for 2h at the temperature of 0 ℃ to obtain disubstituted borane.
Preferably, step 2) comprises: dissolving the compound shown in the formula 3 in tetrahydrofuran, dropwise adding disubstituted borane into the tetrahydrofuran at 0 ℃, reacting for 1 hour, heating to normal temperature, adding TMAO, and heating and refluxing for 4 hours at 90 ℃ to obtain the compound shown in the formula 4.
Preferably, step 3) comprises: dissolving the compound of the formula 4 in dichloromethane, protecting hydroxyl by using a MOMCl-DIPEA system at 0 ℃, and reacting overnight to obtain the compound of the formula 5.
Preferably, step 4) comprises: dissolving the compound shown in the formula 5 in dichloromethane, and carrying out ester reduction reaction with diisobutylaluminum hydride at-78 ℃ to obtain the compound shown in the formula 6.
Preferably, step 5) comprises: under the protection of nitrogen, dissolving a compound shown in a formula 6 in methanol, adding a compound shown in a formula 7 into a reaction system, and reacting for 4 hours at room temperature; then adding sodium borohydride in ice bath, keeping the temperature for reaction for 4 hours, and carrying out aldehyde-amine condensation reduction reaction to obtain the compound shown in the formula 8.
Preferably, in step 6), an iodide ion-induced N-heterocycle building reaction occurs under the conditions: dissolving the compound shown in the formula 8 in dichloromethane, dropwise adding LDA at 0 ℃, adding NIS after 30min, moving to room temperature and reacting for 2h to obtain the compound shown in the formula 9.
Preferably, in step 7) a palladium-catalysed coupling ring closure reaction takes place under the following conditions: under the protection of nitrogen, dissolving the compound shown in the formula 9 in 1, 4-dioxane, carrying out ultrasonic degassing, adding palladium tetrakis (triphenylphosphine) and cesium carbonate, and heating and refluxing at 100 ℃ to obtain the compound shown in the formula 10, namely the cephalotaxine.
In step 1) of the invention: under the protection of nitrogen, dissolving the compound 2 in THF, transferring to-78 ℃, dissolving the compound 1 in THF, then slowly dripping into a reaction system, reacting for 3 hours at-78 ℃, filtering by silica gel after the temperature in the mixed reaction system is raised to room temperature, and separating and purifying the filtrate to obtain the compound 3.
In step 2) of the invention: under the protection of nitrogen, borane tetrahydrofuran complex is dissolved in THF, the temperature is changed to-20 ℃, 2-methyl-2-butylene is slowly dropped into a reaction system, the temperature is raised to 0 ℃ after 10 minutes, and the reaction is carried out for 2 hours, thus obtaining the disubstituted borane. Dissolving the compound 3 in THF, slowly dripping prepared disubstituted borane into a new reaction system at 0 ℃ for reacting for 1 hour, then moving to room temperature for reacting for 1 hour, adding TMAO into the reaction system, heating and refluxing for 4 hours, and stirring the solution vigorously during refluxing. Filtering with diatomite, and separating and purifying the filtrate to obtain the compound 4.
In step 3) of the present invention: under the protection of nitrogen, the compound 4 is dissolved in dichloromethane under the protection of nitrogen, N, N-diisopropylethylamine is slowly added into a reaction system at 0 ℃, chloromethyl methyl ether is slowly dripped into the reaction system after 0.5 hour (ensuring that no large amount of white smoke exists in the reaction system during dripping), and the reaction is carried out at 0 ℃ overnight. Quenching with water, extracting with dichloromethane, concentrating, separating and purifying to obtain compound 5.
In step 4) of the present invention: under the protection of nitrogen, dissolving the compound 5 in dichloromethane, slowly dripping diisobutyl aluminum hydride into a reaction system at-78 ℃, reacting for 0.5 hour, adding methanol and sodium potassium tartrate for quenching, stirring at room temperature for 1-2 hours for layering, extracting with dichloromethane, concentrating under reduced pressure, separating and purifying to obtain the compound 6.
In step 5) of the invention: under the protection of nitrogen, compound 6 was dissolved in methanol, and compound 7 was slowly added to the reaction system, and stirred at this temperature for 4 hours. Cooling to 0 ℃, adding sodium borohydride, continuing stirring for 4 hours under the ice bath condition, then adding 2.5M sodium hydroxide solution for alkalization, raising the mixed system to room temperature, adding dichloromethane for extraction, concentrating under reduced pressure, separating and purifying to obtain the compound 8.
Step 6) of the invention: under the protection of nitrogen, dissolving the compound 8 in dichloromethane, slowly dropwise adding LDA into a reaction system at 0 ℃, reacting for 0.5 hour, adding NIS into the reaction system, reacting for 2 hours at 0 ℃, quenching with sodium thiosulfate, extracting with dichloromethane, concentrating, separating and purifying to obtain the compound 9.
Step 7) of the invention: under the protection of nitrogen, the compound 9 is dissolved in 1.4-dioxane, ultrasonic degassing is carried out at normal temperature, tetrakis (triphenylphosphine) palladium and cesium carbonate are added, heating reflux is carried out at 100 ℃, and reaction is carried out for one hour, thus obtaining the compound 10.
The invention discloses a method for synthesizing a natural product cephalotaxine. The technical scheme aims at providing a brand-new synthetic route: taking cyclopentadienyl sodium as an initial raw material, and finally realizing the formal synthesis of the natural product cephalotaxine by taking hydroboration oxidation reaction, iodine ion induced N heterocyclic ring construction reaction, palladium catalyzed coupling ring closure reaction and the like as key reaction steps in the synthesis process. The synthesis route has unique and novel design, mild conditions, high speed, relatively few side reactions and simple and convenient operation in the reaction process, utilizes conventional chemical reagents in the route, has cheap and easily obtained raw materials, and can greatly reduce the synthesis cost.
The beneficial effects of the invention are reflected in the following aspects:
1. the design of the whole synthesis route is unique and novel, the single selective synthesis of the cephalotaxine obtained by theory is realized, the speed is high, the side reaction is relatively less, and the product yield is high;
2. the conventional chemical reagent is utilized in the route, the raw materials and the reagent are cheap and easy to obtain, and the production cost can be greatly reduced;
3. the synthesis route has simple and reasonable design, simple and convenient operation process, mild reaction conditions in the reaction process, less linear steps and suitability for industrial preparation.
Drawings
FIG. 1 is a reaction scheme of the synthesis method of the present invention.
Detailed Description
Hereinafter, specific embodiments of the present invention will be described in detail. Well-known structures or functions may not be described in detail in the following embodiments in order to avoid unnecessarily obscuring the details. Approximating language, as used herein in the following examples, may be applied to identify quantitative representations that could permissibly vary in number without resulting in a change in the basic function. Unless defined otherwise, technical and scientific terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
1. Synthesizing a compound 3; under the protection of nitrogen, compound 2(3.67g, 22mmol, 1.1eq) is dissolved in 22mL of dry THF, compound 1(1.76g, 20mmol, 1.0eq) is dissolved in 67mL of dry THF at-78 ℃, then the solution is slowly dropped into the reaction system, after the TLC detection reaction is completed, the reaction system is warmed to room temperature, silica gel is used for filtration, filter residue is washed by dichloromethane (3X 25mL), the filtrate is decompressed and distilled, the product is separated and purified by column chromatography (ethyl acetate: petroleum ether 1:100), and finally the eluent is concentrated to obtain compound 3(2.5851 g). Yield: 85 percent.
2. Synthesis of Compound 4: borane-tetrahydrofuran complex (15.78ml, 1M, 1.2eq) was dissolved in 32ml of dry THF under nitrogen protection, 2-methyl-2-butene (2.213g, 2.4eq) was slowly added dropwise to the reaction system at-20 deg.C, and after 10 minutes, the temperature was raised to 0 deg.C for 2 hours. Dissolving compound 3(2g, 13.15mmol, 1eq) in 53ml of dry THF, slowly dropping borane reagent reacted for 2 hours at 0 ℃ into the reaction system, reacting for 1 hour at 0 ℃, heating to room temperature, reacting for 1 hour, then adding TMAO (8.769g, 6eq) into the mixed system, heating and refluxing, stirring vigorously in the reaction system, cooling to room temperature after TLC detection reaction is completed, filtering with diatomite, washing filter residue with diethyl ether (3X 20ml), distilling the filtrate under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1:3), and finally concentrating the eluent to obtain compound 4(2.01 g). Yield: 90 percent.
3. Synthesis of Compound 5: compound 4(1g, 5.88mmol, 1eq) was dissolved in 30ml of dichloromethane under nitrogen protection, N, N-diisopropylethylamine (23.5mmol, 4eq) was slowly added to the reaction system at 0 ℃ for 0.5 hour, chloromethyl methyl ether (23.5mmol, 4eq) was slowly added dropwise to the reaction system (to ensure that no significant amount of white smoke was present in the reaction system) and reacted at 0 ℃ overnight. Quenched with 20ml of water, extracted with dichloromethane (3X 15ml), the organic phases were combined and washed once with saturated NaCl solution and anhydrous Na was added
2SO
4Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1:6), and concentrating the eluate to obtain compound 5(1.04 g). Yield: 82.5 percent.
4. Synthesis of Compound 6: dissolving a compound 5(1g, 4.67mmol, 1eq) in 24mL of dry dichloromethane solution under the protection of nitrogen at room temperature, cooling the solution to-78 ℃, after the temperature is stabilized, dropwise adding diisobutylaluminum hydride DIBAL-H (7mmol, 1.5M, 1.5eq), after dropwise adding, allowing the reaction system to continue to react at-78 ℃ for 30 minutes, monitoring by TLC, adding 10mL of methanol to quench, adding 30mL of saturated potassium sodium potassium tartrate solution, heating the mixed system to room temperature, stirring for 1-2 hours, filtering with kieselguhr when the system is obviously layered, extracting the filtrate with dichloromethane (3X 15mL), combining the obtained organic phases, washing with saturated NaCl solution once, adding anhydrous Na
2SO4 was dried, filtered to remove solid impurities, distilled under reduced pressure, and the product was isolated and purified by column chromatography (ethyl acetate: petroleum ether 1:7), and finally the eluate was concentrated to give compound 6(0.731 g). Yield: 85 percent.
5. Synthesis of Compound 8: under nitrogen protection, compound 6(1.87g, 10.15mmol, 1eq) was dissolved in 11mL of methanol, and then compound 7(1.44mL, 1eq) was slowly added dropwise to the reaction mixture, followed by stirring at this temperature for 4 hours. Then the system is put in ice water bath to be cooled to 0 ℃, and sodium borohydride NaBH is added
4(1.15g, 3eq) at this temperature for 4 hours, then 5mL of 2.5M sodium hydroxide solution was added, dichloromethane (3X 15mL) was added for extraction, all organic phases were combined, part of the solvent was removed by concentration under reduced pressure, the organic phases were combined, anhydrous MgSO was added
4Drying, filtration to remove solid impurities, distillation under reduced pressure, and separation and purification by column chromatography (dichloromethane: methanol ═ 50:1) gave compound 8(2.54 g). Yield: 72 percent.
6. Synthesis of compound 9: under the protection of nitrogen, compound 8(1g, 2.88mmol,1eq) is dissolved in 15mL dichloromethane, LDA (3.16mmol, 1.1eq) is slowly added into the reaction system at 0 ℃, NIS (1.3g, 2eq) is added after 30 minutes, the reaction is carried out for 2 hours, after TLC detection reaction is finished, saturated sodium thiosulfate solution (5mL) is used for quenching, dichloromethane extraction (3X 10mL) is carried out, organic phases are combined, and anhydrous Na is added
2SO4 was dried, filtered to remove solid impurities, distilled under reduced pressure, separated by column chromatography (ethyl acetate: petroleum ether: 1:10) and purified to give compound 9(0.423 g). Yield: 32 percent.
7. Synthesis of compound 10: dissolving compound 9(0.1g, 0.3177mmol, 1eq) in 1mL of 1.4-dioxane solution under the protection of nitrogen at room temperature, then carrying out ultrasonic degassing, then adding tetrakis (triphenylphosphine) palladium (0.025g, 0.1eq) and cesium carbonate (0.20g, 2eq), heating and refluxing at 100 ℃, reacting for one hour, reducing to room temperature after TLC monitoring reaction is finished, quenching with 1N hydrochloric acid solution, adding dichloromethane (3X 15mL) into a mixed system for extraction, combining obtained organic phases, adding anhydrous MgSO, adding anhydrous magnesium chloride, stirring
4Drying, filtering to remove solid impurities, distilling under reduced pressure, separating and purifying the product by column chromatography (ethyl acetate: petroleum ether 1:5), and finally concentrating the eluate to obtain the compound of formula 10 (0.05g) in yield: 50 percent.
The embodiments of the present invention have been described in detail, but the description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention. Any modification, equivalent replacement, and improvement made within the scope of the application of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The method for synthesizing the natural product cephalotaxine is characterized by comprising the following steps:
1) in a tetrahydrofuran solvent environment, carrying out electrophilic addition reaction on the compound shown in the formula 1 and the compound shown in the formula 2 at-78 ℃ to obtain a compound shown in the formula 3;
2) dissolving the compound of formula 3 in tetrahydrofuran at normal temperature, adding disubstituted borane at 0 ℃ to perform hydroboration reaction, adding TMAO at normal temperature, heating to 90 ℃ to perform oxidation reaction to obtain a compound of formula 4;
3) dissolving the compound shown in the formula 4 in dichloromethane, and performing hydroxyl protection by using a MOMCl-DIPEA system at 0 ℃ to obtain a compound shown in the formula 5;
4) dissolving the compound shown in the formula 5 in dichloromethane, and then carrying out ester reduction reaction with diisobutylaluminum hydride at-78 ℃ to obtain a compound shown in the formula 6;
5) dissolving a compound shown in a formula 6 in methanol, dropwise adding a compound shown in a formula 7 into the methanol, reacting for 4 hours at normal temperature, cooling to 0 ℃, adding sodium borohydride into the solution, and carrying out an aldehyde-amine condensation reduction reaction at 0 ℃ for 4 hours to obtain a compound shown in a formula 8;
6) dissolving the compound shown in the formula 8 in dichloromethane, then dropwise adding LDA into the dichloromethane at 0 ℃, adding NIS into the mixture after 30min, and reacting for 2h to obtain a compound shown in the formula 9;
7) dissolving a compound shown in a formula 9 in 1, 4-dioxane, refluxing for 1.5 hours at 100 ℃ by taking tetrakis (triphenylphosphine) palladium as a catalyst and cesium carbonate as an alkali source to obtain a compound 10, namely the cephalotaxine;
2. the method for synthesizing the natural product cephalotaxine according to claim 1, wherein the step 1) comprises: adding a compound of formula 2 into a tetrahydrofuran solution of a compound of formula 1 at-78 ℃ under the protection of nitrogen, reacting for 3 hours, changing the solution from clear to turbid, and separating and purifying to obtain the compound of formula 3.
3. The method for synthesizing the natural product cephalotaxine according to claim 1, characterized in that the disubstituted borane in step 2) is prepared by the following method: under the protection of nitrogen, borane is dissolved in tetrahydrofuran, 2-methyl-2-butene is added into the tetrahydrofuran at the temperature of minus 20 ℃, and after 5min, the mixture reacts for 2h at the temperature of 0 ℃ to obtain disubstituted borane.
4. The method for synthesizing the natural product cephalotaxine according to claim 1, wherein the step 2) comprises: dissolving the compound shown in the formula 3 in tetrahydrofuran, dropwise adding disubstituted borane into the tetrahydrofuran at 0 ℃, reacting for 1 hour, heating to normal temperature, adding TMAO, and heating and refluxing for 4 hours at 90 ℃ to obtain the compound shown in the formula 4.
5. The method for synthesizing the natural product cephalotaxine according to claim 1, wherein the step 3) comprises: dissolving the compound of the formula 4 in dichloromethane, protecting hydroxyl by using a MOMCl-DIPEA system at 0 ℃, and reacting overnight to obtain the compound of the formula 5.
6. The method for synthesizing the natural product cephalotaxine according to claim 1, wherein the step 4) comprises: dissolving the compound shown in the formula 5 in dichloromethane, and carrying out ester reduction reaction with diisobutylaluminum hydride at-78 ℃ to obtain the compound shown in the formula 6.
7. The method for synthesizing the natural product cephalotaxine according to claim 1, wherein the step 5) comprises: under the protection of nitrogen, dissolving a compound shown in a formula 6 in methanol, adding a compound shown in a formula 7 into a reaction system, and reacting for 4 hours at room temperature; then adding sodium borohydride in ice bath, keeping the temperature for reaction for 4 hours, and carrying out aldehyde-amine condensation reduction reaction to obtain the compound shown in the formula 8.
8. The method for synthesizing cephalotaxine as a natural product according to claim 1, wherein the construction reaction of N heterocycle induced by iodide ion in step 6) is carried out under the following conditions: dissolving the compound shown in the formula 8 in dichloromethane, dropwise adding LDA at 0 ℃, adding NIS after 30min, moving to room temperature and reacting for 2h to obtain the compound shown in the formula 9.
9. The method of claim 1, wherein the step 7) comprises a palladium-catalyzed coupling-ring closure reaction under the following conditions: under the protection of nitrogen, dissolving the compound shown in the formula 9 in 1, 4-dioxane, carrying out ultrasonic degassing, adding palladium tetrakis (triphenylphosphine) and cesium carbonate, and heating and refluxing at 100 ℃ to obtain the compound shown in the formula 10, namely the cephalotaxine.
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Citations (3)
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|---|---|---|---|---|
| WO2009148654A2 (en) * | 2008-03-03 | 2009-12-10 | Sloan-Kettering Institute For Cancer Research | Cephalotaxus esters, methods of synthesis, and uses thereof |
| CN104045645A (en) * | 2014-05-26 | 2014-09-17 | 河北科技大学 | Synthetic method of harringtonine C-ring intermediate |
| CN109776506A (en) * | 2017-11-14 | 2019-05-21 | 中国科学院上海有机化学研究所 | A kind of synthetic method and its intermediate of chirality (-)-cephalotaxine |
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2019
- 2019-11-27 CN CN201911177458.3A patent/CN110776516A/en active Pending
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| WO2009148654A2 (en) * | 2008-03-03 | 2009-12-10 | Sloan-Kettering Institute For Cancer Research | Cephalotaxus esters, methods of synthesis, and uses thereof |
| CN104045645A (en) * | 2014-05-26 | 2014-09-17 | 河北科技大学 | Synthetic method of harringtonine C-ring intermediate |
| CN109776506A (en) * | 2017-11-14 | 2019-05-21 | 中国科学院上海有机化学研究所 | A kind of synthetic method and its intermediate of chirality (-)-cephalotaxine |
Non-Patent Citations (2)
| Title |
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| 蔡仲军: "三尖杉碱全合成研究的新进展", 《有机化学》 * |
| 陈洋等: "天然三尖杉碱((-)-Cephalotaxine)的不对称全合成研究", 《有机化学》 * |
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