Synthesis method of intermediate for preparing cephalotaxine
阅读说明：本技术 一种用于制备三尖杉碱的中间体的合成方法 (Synthesis method of intermediate for preparing cephalotaxine ) 是由 王晓季 肖和盛 张雪松 王建新 陈新 郭文彬 黄双平 李琳 于 2019-11-27 设计创作，主要内容包括：本发明公开了一种用于制备三尖杉碱的中间体的合成方法。该技术方案以环戊二烯基钠和3-溴丙酸甲酯为起始原料,经亲核加成、硼氢化氧化、羟基保护、还原、氧化和还原氨化6步反应合成了N-2-(3,4-亚甲二氧基苯乙基)-3-(4-甲氧基甲基-1-环戊烯基-1-丙基)胺。作为该中间体的一条全新合成路线,本发明反应条件温和、操作简单、原材料廉价易得,而且具有较高的反应收率,经试验验证表明,该方法总收率可达到33.4％。综上所述,本发明不仅填补了N-2-(3,4-亚甲二氧基苯乙基)-3-(4-甲氧基甲基-1-环戊烯基-1-丙基)胺合成方法的技术空白,而且在成本、收率、反应条件等方面具有突出的技术优势。(The invention discloses a synthetic method of an intermediate for preparing cephalotaxine. The technical scheme takes cyclopentadienyl sodium and methyl 3-bromopropionate as initial raw materials, and N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine is synthesized through 6 steps of reactions of nucleophilic addition, hydroboration oxidation, hydroxyl protection, reduction, oxidation and reductive amination. As a brand new synthesis route of the intermediate, the method has the advantages of mild reaction conditions, simple operation, cheap and easily-obtained raw materials and higher reaction yield, and the total yield of the method can reach 33.4 percent as shown by experimental verification. In conclusion, the method not only fills up the technical blank of the synthetic method of the N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine, but also has outstanding technical advantages in the aspects of cost, yield, reaction conditions and the like.)
1. A synthetic method for preparing an intermediate of cephalotaxine, which is characterized by comprising the following steps:
1) in the tetrahydrofuran solvent environment, performing electrophilic addition reaction on cyclopentadienyl sodium and 3-bromomethyl propionate at the temperature of minus 78 ℃ to obtain a compound shown in a formula 1;
2) dissolving the compound shown in the formula 1 in tetrahydrofuran at normal temperature, adding disubstituted borane into the tetrahydrofuran at 0 ℃ to perform hydroboration reaction, adding TMAO into the tetrahydrofuran at normal temperature, and heating the mixture to 90 ℃ to perform oxidation reaction to obtain a compound shown in the formula 2;
3) dissolving the compound shown in the formula 2 in dichloromethane, and performing hydroxyl protection by using a MOMCl-DIPEA system at 0 ℃ to obtain a compound shown in the formula 3;
4) dissolving the compound shown in the formula 3 in dichloromethane, and then reacting with diisopropylaluminum hydride at 0 ℃ to obtain a compound shown in a formula 4;
5) dissolving the compound shown in the formula 4 in dichloromethane, adding dessimutan oxidant and anhydrous sodium bicarbonate into the dichloromethane at 0 ℃, and then heating the mixture to room temperature to react to obtain a compound shown in the formula 5;
6) dissolving the compound shown in the formula 5 in methanol, adding 3, 4-methylenedioxyphenethylamine, reacting for 4h at normal temperature, cooling to 0 ℃, adding sodium borohydride, and performing an aldehyde-amine condensation reduction reaction at 0 ℃ to obtain a compound shown in the formula 6, namely N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine;
2. the method of synthesis according to claim 1, wherein step 1) comprises: adding methyl 3-bromopropionate and tetrahydrofuran into a container, starting stirring, and cooling to-78 ℃; under the protection of nitrogen, dropwise adding cyclopentadienyl sodium, stirring for 3h at-78 ℃, adding dichloromethane into the container, and monitoring the reaction by thin-layer chromatography; after the reaction is finished, heating to room temperature; filtering with diatomite, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound shown in the formula 1.
3. The method of synthesis according to claim 1, wherein step 2) comprises: under the protection of nitrogen, adding borane dimethyl sulfide complex and tetrahydrofuran into a container, cooling to 0 ℃, dropwise adding 2-methyl-2-butene into the container, stirring for 2h at 0 ℃, dropwise adding a compound shown in the formula 1 into the container, stirring for 1h at 0 ℃, heating to normal temperature, stirring for 2h, evaporating solvent tetrahydrofuran under reduced pressure, and adding toluene; adding trimethylamine oxide dihydrate into the mixture, heating and refluxing the mixture, reacting the mixture for 2 hours, and monitoring the reaction by thin-layer chromatography; after the reaction is finished, cooling, adding a saturated ammonium chloride solution, stirring for 1h, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound shown in the formula 2.
4. The method of synthesis according to claim 1, wherein step 3) comprises: adding a compound of formula 2 and dichloromethane to a vessel under nitrogen protection; cooling to 0 ℃, dropwise adding N, N-diisopropylethylamine, stirring for 15mim after the addition, dropwise adding chloromethyl methyl ether, stirring for 10mim after the addition, heating to room temperature, and monitoring the reaction by thin-layer chromatography; after the reaction is finished, adding water for quenching; extracting with dichloromethane, mixing organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound of the formula 3.
5. The method of synthesis according to claim 1, wherein step 4) comprises: adding the compound of formula 3 and dichloromethane into a container under the protection of nitrogen, cooling to 0 ℃, dropwise adding diisopropylaluminum hydride, stirring at 0 ℃, and monitoring the reaction by thin-layer chromatography; after the reaction is finished, dropwise adding methanol into the mixture at 0 ℃ until no bubbles are generated, then dropwise adding a saturated solution of potassium sodium tartrate with the same volume as that of the methanol used in the step 4), heating to room temperature, and stirring until the solution is layered; filtering with diatomite, and drying with anhydrous sodium sulfate; filtering, decompressing and concentrating the solvent, and separating and purifying the crude product by silica gel column chromatography to obtain the compound of the formula 4.
6. The method of synthesis according to claim 1, wherein step 5) comprises: under the protection of nitrogen, adding the compound of formula 4 and dichloromethane into a container, cooling to 0 ℃, sequentially adding dessimutan oxidant and anhydrous sodium bicarbonate, heating to room temperature, and monitoring the reaction by thin-layer chromatography; after the reaction, quenching the mixture by water, extracting the mixture by dichloromethane, combining organic phases, washing the organic phases by saturated saline solution, and drying the organic phases by anhydrous sodium sulfate; filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound of the formula 5.
7. The method of synthesis according to claim 1, wherein step 6) comprises: under the protection of nitrogen, adding a compound of a formula 5, 3, 4-methylenedioxyphenethylamine and methanol into a container, stirring for 4 hours at normal temperature, cooling to 0 ℃, adding sodium borohydride in batches, stirring at 0 ℃, and monitoring the reaction by thin-layer chromatography; after the reaction is finished, quenching the mixture by using a sodium hydroxide solution, extracting the mixture by using dichloromethane, and drying the mixture by using anhydrous magnesium sulfate; filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound shown in the formula 6, namely N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine.
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of an intermediate for preparing cephalotaxine.
Background
The cephalotaxine is the mother nucleus of natural anticancer product cephalotaxine compound, and its derivatives cephalotaxine and homoharringtonine have strong anticancer activity, and can be clinically used for treating acute and chronic leukemia, lupus erythematosus and other diseases, and its action mechanism mainly has the functions of inhibiting protein gene expression, inducing cell apoptosis and cell differentiation. N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine is a key intermediate for synthesizing cephalotaxine, and the synthesis research of the intermediate provides a brand new synthesis strategy for the full synthesis research of the cephalotaxine, and has important significance.
The literature reports on the synthesis method of N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine, and the currently reported synthesis method of the derivative of N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine uses expensive metal catalysts in the synthesis process, and specific reaction conditions are not given in the article. Therefore, it is necessary to develop a new synthetic route for the key intermediate.
Disclosure of Invention
The invention aims to provide a synthesis method of an intermediate for preparing cephalotaxine aiming at overcoming the technical defects in the prior art, and aims to solve the technical problem that the method for synthesizing N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine is lacked in the prior art.
The invention also aims to solve the technical problem of ensuring that the synthesis method of the compound has low cost, mild condition, simple and convenient operation and high yield.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
a synthetic method for an intermediate used for preparing cephalotaxine, comprising the following steps:
1) in the tetrahydrofuran solvent environment, performing electrophilic addition reaction on cyclopentadienyl sodium and 3-bromomethyl propionate at the temperature of minus 78 ℃ to obtain a compound shown in a formula 1;
2) dissolving the compound shown in the formula 1 in tetrahydrofuran at normal temperature, adding disubstituted borane into the tetrahydrofuran at 0 ℃ to perform hydroboration reaction, adding TMAO into the tetrahydrofuran at normal temperature, and heating the mixture to 90 ℃ to perform oxidation reaction to obtain a compound shown in the
3) dissolving the compound shown in the
4) dissolving the compound shown in the formula 3 in dichloromethane, and then reacting with diisopropylaluminum hydride at 0 ℃ to obtain a compound shown in a formula 4;
5) dissolving the compound shown in the formula 4 in dichloromethane, adding dessimutan oxidant and anhydrous sodium bicarbonate into the dichloromethane at 0 ℃, and then heating the mixture to room temperature to react to obtain a compound shown in the
6) dissolving the compound shown in the
preferably, step 1) comprises: adding methyl 3-bromopropionate (shown as the following formula 8) and tetrahydrofuran into a container, starting stirring, and cooling to-78 ℃; under the protection of nitrogen, dropwise adding sodium cyclopentadienyl (shown as the following formula 7), stirring at-78 deg.C for 3h, adding dichloromethane into the container, and monitoring the reaction by thin layer chromatography; after the reaction is finished, heating to room temperature; filtering with diatomite, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound shown in the formula 1.
Preferably, step 2) comprises: under the protection of nitrogen, adding borane dimethyl sulfide complex and tetrahydrofuran into a container, cooling to 0 ℃, dropwise adding 2-methyl-2-butene into the container, stirring for 2h at 0 ℃, dropwise adding a compound shown in the formula 1 into the container, stirring for 1h at 0 ℃, heating to normal temperature, stirring for 2h, evaporating solvent tetrahydrofuran under reduced pressure, and adding toluene; adding trimethylamine oxide dihydrate (TMAO, shown in the following formula 9), heating under reflux, reacting for 2h, and monitoring the reaction by thin layer chromatography; after the reaction is finished, cooling, adding a saturated ammonium chloride solution, stirring for 1h, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound shown in the
Preferably, step 3) comprises: adding a compound of
Preferably, step 4) comprises: adding the compound of formula 3 and dichloromethane into a container under the protection of nitrogen, cooling to 0 ℃, dropwise adding diisopropylaluminum hydride, stirring at 0 ℃, and monitoring the reaction by thin-layer chromatography; after the reaction is finished, dropwise adding methanol into the mixture at 0 ℃ until no bubbles are generated, then dropwise adding a saturated solution of potassium sodium tartrate with the same volume as that of the methanol used in the step 4), heating to room temperature, and stirring until the solution is layered; filtering with diatomite, and drying with anhydrous sodium sulfate; filtering, decompressing and concentrating the solvent, and separating and purifying the crude product by silica gel column chromatography to obtain the compound of the formula 4.
Preferably, step 5) comprises: under the protection of nitrogen, adding the compound of formula 4 and dichloromethane into a container, cooling to 0 ℃, sequentially adding dessimutan oxidant and anhydrous sodium bicarbonate, heating to room temperature, and monitoring the reaction by thin-layer chromatography; after the reaction, quenching the mixture by water, extracting the mixture by dichloromethane, combining organic phases, washing the organic phases by saturated saline solution, and drying the organic phases by anhydrous sodium sulfate; filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain the compound of the
Preferably, step 6) comprises: under the protection of nitrogen, adding a compound of a
The invention discloses a synthetic method of an intermediate for preparing cephalotaxine. The technical scheme takes cyclopentadienyl sodium and methyl 3-bromopropionate as initial raw materials, and N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine is synthesized through 6 steps of reactions of nucleophilic addition, hydroboration oxidation, hydroxyl protection, reduction, oxidation and reductive amination. As a brand new synthesis route of the intermediate, the method has the advantages of mild reaction conditions, simple operation, cheap and easily-obtained raw materials and higher reaction yield, and the total yield of the method can reach 33.4 percent as shown by experimental verification. In conclusion, the method not only fills up the technical blank of the synthetic method of the N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine, but also has outstanding technical advantages in the aspects of cost, yield, reaction conditions and the like.
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. Primary reagents and instruments
Sodium cyclopentadienyl, trimethylamine oxide dihydrate (TMAO), analytically pure, largeway technologies ltd; methyl 3-bromopropionate, borane dimethylsulfide complex, 2-methyl-2-butene, N-Diisopropylethylamine (DIPEA), diisobutylaluminum hydride (DIBAl-H), 3, 4-methylenedioxyphenethylamine, tetrahydrofuran, deslmatine oxidant (DMP), analytical purity, sahn chemical technology (shanghai) ltd; dichloromethane, methanol, analytically pure, west longa science ltd; sodium borohydride, chloromethyl methyl ether (MOMCl), analytically pure, shandong west asia chemical company, ltd. Model AC-P400 NMR spectrometer, Bruker, Germany.
2. Experimental procedure
2.1 Synthesis of methyl 1, 3-cyclopentadienylpropionate (Compound of formula 1)
A1000 mL round bottom flask was charged with 33.4g (0.2mol) of methyl 3-bromopropionate and 290mL of tetrahydrofuran, stirred and cooled to-78 ℃. Under nitrogen, 17.62g (0.2mol) of cyclopentadienyl sodium was slowly added dropwise, and after stirring at-78 ℃ for 3 hours, 100mL of dichloromethane was added to the round-bottomed flask, and the reaction was monitored by TLC (thin layer chromatography). After the reaction, the temperature is raised to room temperature. Filtering with diatomite, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain 22.87g of a product, namely a light yellow liquid, wherein the yield is as follows: 75.2 percent. 1H NMR(400MHz,CDCl 3),δ6.45～6.39(m,1H),6.27(d,J＝5.3Hz,1H),6.19(s,1H),3.69(s,3H),2.99～2.88(m,2H),2.77(t,J＝7.5Hz,2H),2.63～2.54(m,2H)。
2.2 Synthesis of methyl 3- (4-hydroxy-1-cyclopentenyl) propionate (Compound of formula 2)
Under the protection of nitrogen, 3.00g (0.04mol) of borane dimethyl sulfide complex and 160mL of tetrahydrofuran are added into a clean and dry 500mL round bottom flask, the temperature is reduced to 0 ℃, 5.54g (0.079mol) of 2-methyl-2-butene is slowly dropped into the flask and added, after stirring for 2h at 0 ℃, 5g (0.033mol) of the compound of formula 1 is slowly dropped into the flask and stirred for 1h at 0 ℃, the temperature is raised to the normal temperature and stirred for 2h, the solvent tetrahydrofuran is distilled off under reduced pressure, and 130mL of toluene is added. The mixture was transferred to a clean and dry 1000mL three-necked round-bottomed flask, and 21.93g (0.197mol) of trimethylamine oxide dihydrate was added, followed by heating under reflux for 2 hours and monitoring the reaction by TLC (thin layer chromatography). After the reaction, the reaction mixture was cooled, 30mL of a saturated ammonium chloride solution was added, the mixture was stirred for 1 hour, extracted with ethyl acetate (3X 25mL), and the organic phases were combined, washed with a saturated brine (1X 50mL), and dried over anhydrous sodium sulfate. Filtering, concentrating under reduced pressureAnd (3) condensing the solvent, and separating and purifying the crude product by silica gel column chromatography to obtain 4.89g of a product, colorless liquid, yield: 87.5 percent. 1H NMR(400MHz,CDCl 3),δ5.32(s,1H),4.48(d,J＝6.1Hz,1H),3.67(s,3H),2.70～2.55(m,2H),2.52～2.44(m,2H),2.41(d,J＝7.2Hz,2H),2.30(dd,J＝23.6Hz,J＝15.4Hz,2H),2.20(s,1H)。
2.3 Synthesis of methyl 3- (4-methoxymethyl-1-cyclopentenyl) propionate (Compound of formula 3)
Under nitrogen, 4.89g (0.029mol) of the compound of
2.4 Synthesis of 3- (4-methoxymethyl-1-cyclopentenyl) propanol (Compound of formula 4)
5g (0.023mol) of the compound of formula 3 and 120mL of dichloromethane were added to a clean dry 500mL round bottom flask under nitrogen, cooled to 0 deg.C, 18.68mL (0.028mol, 1.5M) of diisopropylaluminum hydride was slowly added dropwise, stirred at 0 deg.C, and the reaction was monitored by TLC (thin layer chromatography). After the reaction is finished, slowly dripping methanol at 0 ℃ until no bubbles are generated, then dripping saturated solution of potassium sodium tartrate with the same volume as the methanol, heating to room temperature, and stirring until the solution is layered. Filtered through celite and dried over anhydrous sodium sulfate. Filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain 3.92g of a product, a colorless liquid, and the yield: 90.2 percent. 1H NMR(400MHz,CDCl 3),δ5.33(s,1H),4.64(s,2H),4.40(tt,J＝6.5,J＝3.1Hz,1H),3.64(t,J＝6.4Hz,2H),3.36(s,3H),2.57(ddd,J＝23.3,J＝16.7,J＝6.5Hz,2H),2.34(t,J＝17.4Hz,2H),2.15(t,J＝7.2Hz,2H),1.77～1.68(m,2H).
2.5 Synthesis of 3- (4-methoxymethyl-1-cyclopentenyl) propanal (Compound of formula 5)
Under nitrogen protection, 3.92g (0.021mol) of the compound of formula 4 and 110mL of dichloromethane are added into a clean and dry 250mL round bottom flask, the temperature is reduced to 0 ℃, 10.72g (0.025mol) of dessimidine oxidant and 6.19g (0.074mol) of anhydrous sodium bicarbonate are sequentially added, the temperature is raised to room temperature after the addition, and the reaction is monitored by TLC (thin layer chromatography). After the reaction was completed, the reaction mixture was quenched with water, extracted with dichloromethane (3X 25mL), and the organic phases were combined, washed with saturated brine (1X 50mL), and dried over anhydrous sodium sulfate. Filtering, concentrating the solvent under reduced pressure, and separating and purifying the crude product by silica gel column chromatography to obtain 3.7g of a product, a colorless liquid, and the yield: 95.4 percent. 1H NMR(400MHz,CDCl 3),δ9.77(d,J＝1.4Hz,1H),5.31(s,1H),4.64(s,2H),4.41(dq,J＝10.0,J＝3.3Hz,1H),3.36(s,3H),2.61(d,J＝7.4Hz,2H),2.55(dd,J＝19.0,J＝4.1Hz,2H),2.43～2.36(m,3H),2.31(d,J＝16.7Hz,2H).
2.6 Synthesis of N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine (Compound of formula 6)
Under nitrogen protection, 3.5g (0.019mol) of the compound of
3. Conclusion
In this example, cyclopentadienyl sodium and methyl 3-bromopropionate are used as starting materials, and a target compound, N-2- (3, 4-methylenedioxyphenethyl) -3- (4-methoxymethyl-1-cyclopentenyl-1-propyl) amine, is synthesized through 6 steps of reaction, with a total yield of 33.4%. The method has the advantages of mild reaction conditions, simple operation, cheap and easily-obtained raw materials and higher total reaction yield.
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.
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