CN113372209B - Synthesis method of megastigmatrienone - Google Patents
Synthesis method of megastigmatrienone Download PDFInfo
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- CN113372209B CN113372209B CN202110734325.2A CN202110734325A CN113372209B CN 113372209 B CN113372209 B CN 113372209B CN 202110734325 A CN202110734325 A CN 202110734325A CN 113372209 B CN113372209 B CN 113372209B
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Abstract
The invention provides a synthesis method of megastigmatrienone, which comprises the following steps: 1) carrying out addition reaction on a compound shown in a formula (I) and alcohol under the action of a catalyst to obtain a compound shown in a formula (II); 2) carrying out reduction reaction on the compound shown in the formula (II) and an ester-based reducing agent to obtain a compound shown in a formula (III); 3) carrying out oxidation reaction on a compound shown in a formula (III) and an oxidant to obtain a compound shown in a formula (IV); 4) carrying out addition reaction on the compound shown in the formula (IV) and an allyl Grignard reagent, and then carrying out dehydration reaction on the compound and an acid to obtain a compound shown in the formula (V); 5) and (3) carrying out isomerization reaction on the compound shown in the formula (V), the ligand, the reducing agent and the additive under the catalysis of cobalt salt to obtain the megastigmatrienone shown in the formula (VI). The synthesis method has the advantages of wide raw materials, mild reaction, simple operation, good yield and high selectivity to megastigmatrienone isomer d.
Description
Technical Field
The invention belongs to the technical field of spices and fine chemical engineering, and particularly relates to a synthesis method of megastigmatrienone.
Background
Megastigmatrienone, also called as tobacco leaf ketone, has the chemical name of 4- (2-butenylidene) -3,5, 5-trimethyl-2-cyclohexene-1-ketone and the CAS (CAS) accession number of 13215-88-8, is an important aroma compound in tobacco, belongs to a carotenoid degradation product, has tobacco fragrance and spicy bottom note, can coordinate with the tobacco fragrance, enhances the tobacco fragrance, improves the smoking taste, harmonizes the smoke, removes miscellaneous gases and reduces irritation, is an indispensable spice in cigarettes, and has important application in the essence and spice industry and the tobacco industry.
Megastigmatrienone was isolated and structurally characterized in 1972 from burley tobacco and greek tobacco and has four isomers, the molecular structural formulas of which are shown below and are respectively named as a, b, c and d according to the order of appearance of peaks on an HP5-ms gas chromatography column or equivalent column. In recent years, researches show that the megastigmatrienone isomer d has the best perfuming effect, can improve the smoke quality, increase the smoke concentration and improve the sensory perception, the perfuming of the megastigmatrienone isomer b has negative effects on the smoke of cigarettes, and the evaluation effects of the megastigmatrienone isomer a and the megastigmatrienone isomer c are general.
Since megastigmatrienone has a very small content in natural plants and cannot meet market demands only by means of extraction from natural products, chemical synthesis is a main source of megastigmatrienone, and the method is mature, for example, Rowland takes dehydroionone as a raw material and sodium borohydride as a reducing agent to reduce the raw material into dehydroionol, then uses dilute sulfuric acid to rearrange in acetone to obtain 3-hydroxy-4, 6, 8-megastigmatrienone, and finally uses active manganese dioxide or chromium trioxide to oxidize to prepare megastigmatrienone; japanese chemist Takazawa takes isophorone as a raw material, adds isophorone into diethyl ether solution containing magnesium, methyl bromide and ferric trichloride to obtain an intermediate product, then adds mixed solution of triethylamine and trimethylchlorosilane in HMPT into the intermediate product, and then condenses the mixed solution with crotonaldehyde under the catalysis of titanium tetrachloride and dehydrates the condensed product to obtain megastigmatrienone; lijun and the like take alpha-ionol acetate as a raw material, oxidize the raw material into 3-oxo-alpha-ionol acetate-intermediate product by air or oxygen under the action of a catalyst, and then carry out thermal cracking reaction, rectification and separation to obtain the final product megastigmatrienone.
In the existing synthesis method, megastigmatrienone exists in the form of isomer mixture, and the megastigmatrienone exists in the form of isomer mixture, so that the selectivity of the isomer d of the megastigmatrienone is poor, the cigarette flavoring effect is not outstanding enough due to the low content of the isomer d in the synthesized megastigmatrienone, and the defects of difficult obtainment of raw materials, expensive reagents, high requirements on reaction conditions, low target products and the like exist.
Therefore, the synthesis method which has the advantages of readily available raw materials, mild reaction conditions, simple operation, good yield and good selectivity for the megastigmatrienone isomer d has important significance and obvious economic value.
Disclosure of Invention
In view of the above-mentioned disadvantages of the prior art, the present invention aims to provide a method for synthesizing megastigmatrienone, which is used to solve the problems of the prior art, such as not easy to obtain raw materials, severe reaction temperature, various reaction steps, long reaction time, low yield, poor selectivity to megastigmatrienone isomer d, etc.
To achieve the above objects and other related objects, the present invention is achieved by the following technical solutions.
One of the objectives of the present invention is to provide a method for synthesizing megastigmatrienone, comprising the following steps:
1) carrying out addition reaction on a compound shown as a formula (I) and alcohol under the action of a catalyst to obtain a compound shown as a formula (II);
2) carrying out reduction reaction on the compound shown in the formula (II) and an ester-based reducing agent to obtain a compound shown in a formula (III);
3) carrying out oxidation reaction on the compound shown in the formula (III) and an oxidant to obtain a compound shown in a formula (IV);
4) carrying out addition reaction on the compound shown in the formula (IV) and an allyl Grignard reagent, and then carrying out dehydration reaction on the compound and an acid to obtain a compound shown in the formula (V);
5) carrying out isomerization reaction on a compound shown as a formula (V), a ligand, a reducing agent and an additive under the catalysis of cobalt salt to obtain megastigmatrienone shown as a formula (VI);
wherein, in the compound shown in the formula (I), R 2 Selected from the group consisting of methyl, ethyl, propyl, and benzyl;
in the compounds of formula (II), formula (III) and formula (IV), R 1 Are all selected from ethyl or propyl.
The wavy line in the compound of the formula (IV) and the megastigmatrienone of the formula (VI) indicates CH in this structural compound 2 -CH 2 The stereo structure of the chemical bond is different, so that the compounds have isomers.
The synthetic route of the present application is as follows:
preferably, in step 1), the alcohol is selected from glycols.
More preferably, the alcohol is selected from ethylene glycol or propylene glycol.
Preferably, in step 1), the catalyst is selected from one or more of toluene sulfonic acid, p-toluene sulfonic acid and pyridine p-toluene sulfonic acid.
More preferably, the catalyst is selected from pyridine p-toluenesulfonic acid. The catalyst is cheap and easy to obtain, low in toxicity, high in efficiency and mild in reaction condition.
Preferably, in the step 1), the mass ratio of the catalyst to the compound shown in the formula (I) is (0.1-0.3): 1.
Preferably, in the step 1), the mass ratio of the alcohol to the compound shown in the formula (I) is (5-30): 1.
Preferably, in the step 1), the temperature of the addition reaction is 40-180 ℃.
More preferably, in the step 1), the temperature of the addition reaction is 100-150 ℃.
Preferably, in step 1), the addition reaction uses an organic solvent as a reaction medium.
More preferably, the reaction medium is selected from toluene.
Preferably, in the step 1), a post-treatment step is further included after the addition reaction, and more preferably, the post-treatment step includes reduced pressure evaporation and separation and purification.
Preferably, in step 2), the ester-based reducing agent is selected from one or more of lithium aluminum hydride, sodium borohydride and sodium hydride.
More preferably, the ester-based reducing agent is selected from lithium aluminum hydride. When the ester-based reducing agent is lithium aluminum hydride, the reduction reaction is more efficient.
Preferably, in the step 2), the mass ratio of the ester-based reducing agent to the compound shown in the formula (II) is (1-4): 1.
Preferably, in the step 2), the temperature of the reduction reaction is 0-70 ℃.
More preferably, the temperature of the reduction reaction is 20-30 ℃.
Preferably, in step 2), the reduction reaction uses an organic solvent as a reaction medium.
More preferably, the reaction medium is tetrahydrofuran.
Preferably, in the step 2), a post-treatment step is further included after the reduction reaction, and more preferably, the post-treatment step includes reduced pressure evaporation and separation and purification.
Preferably, in step 3), the oxidizing agent is selected from one or more of manganese dioxide, potassium permanganate, and pyridinium chlorochromate.
Preferably, in the step 3), the mass ratio of the oxidant to the compound shown in the formula (III) is (5-12): 1.
Preferably, in the step 3), the temperature of the oxidation reaction is 30-90 ℃.
More preferably, the temperature of the oxidation reaction is 40-70 ℃.
Preferably, in step 3), the oxidation reaction uses an organic solvent as a reaction medium.
More preferably, the reaction medium is chosen from dichloromethane.
Preferably, in the step 3), a post-treatment step is further included after the oxidation reaction, and more preferably, the post-treatment step includes reduced pressure evaporation and separation and purification.
Preferably, in step 4), the allyl grignard reagent is selected from allyl magnesium bromide.
Preferably, in the step 4), the mass ratio of the allyl Grignard reagent to the compound represented by the formula (IV) is (1-4): 1.
Preferably, in step 4), the acid is selected from aqueous sulfuric acid. More preferably, the concentration of the sulfuric acid aqueous solution is 1-40 wt%.
Preferably, in the step 4), the temperature of the addition reaction is 0-60 ℃.
Preferably, in step 4), the addition reaction uses an organic solvent as a reaction medium.
More preferably, the reaction medium is selected from tetrahydrofuran.
Preferably, in step 4), the addition reaction further comprises quenching the reaction, specifically, water is used to quench the reaction.
Preferably, in step 4), the dehydration reaction further comprises a post-treatment step, and more preferably, the post-treatment comprises acid neutralization with alkali and separation and purification.
More preferably, the base is selected from sodium bicarbonate.
More preferably, the separation and purification includes extraction, evaporation under reduced pressure and column chromatography separation.
Further preferably, the extraction is performed with ethyl acetate.
Preferably, in step 5), the ligand is selected from one or more of 1, 3-bis (phenylphosphino) propane, 2, 4-bis (phenylphosphino) pentane and 1, 2-bis (phenylphosphino) ethane.
Preferably, in the step 5), the mass ratio of the ligand to the compound shown in the formula (V) is (0.05-0.2): 1.
Preferably, in step 5), the reducing agent is selected from zinc.
Preferably, in the step 5), the mass ratio of the reducing agent to the compound represented by the formula (V) is (0.01-0.3): 1.
Preferably, in step 5), the additive is selected from one or two of zinc iodide and diphenylphosphine hydrogen.
Preferably, in the step 5), the mass ratio of the additive to the compound represented by the formula (V) is (0.1-0.3): 1.
More preferably, when the additive is a mixture of zinc iodide and diphenylphosphine hydrogen, the mass ratio of the zinc iodide to the diphenylphosphine hydrogen is (0.5-2): 1.
Preferably, in step 5), the cobalt salt is selected from one or more of cobalt bromide, cobalt iodide and cobalt chloride.
More preferably, the cobalt salt is selected from cobalt bromide. The application finds that the selectivity of megastigmatrienone isomer d is highest when cobalt bromide is used for catalysis in cobalt salt.
Preferably, in the step 5), the mass ratio of the cobalt salt to the compound represented by the formula (V) is (0.05-0.1): 1.
Preferably, in step 5), the isomerization reaction uses an organic solvent as a reaction medium.
More preferably, the reaction medium is selected from dichloromethane.
Preferably, in the step 5), the temperature of the isomerization reaction is 0-40 ℃.
Preferably, said step 4) or/and said step 5) is carried out in a protective atmosphere selected from nitrogen or an inert gas. The synthesis reaction can be carried out at normal temperature and normal pressure, more preferably in nitrogen or inert gas, and the oxygen-free environment can ensure the normal use of the allyl Grignard reagent and the cobalt salt catalyst, so that the reaction is smoothly carried out, and the yield is improved.
The method comprises the steps of taking a cyclohexenone ester compound as a raw material, taking alcohol as a carbonyl protective agent, obtaining a cyclohexene aldehyde intermediate compound IV through reduction and oxidation conditions, further obtaining a key intermediate V through reactions such as allyl Grignard reagent addition and acid dehydration, and finally promoting isomerization by taking cobalt as a catalyst under a ligand, a reducing agent and an additive to prepare megastigmatrienone.
Compared with the prior art, the invention has the following beneficial effects:
1) the synthesis method has the advantages of wide raw materials, mild reaction, simple operation, high purity of the synthesized megastigmatrienone which can reach more than 98 percent, and high selectivity on the megastigmatrienone isomer d.
2) The synthesis method is designed for the first time independently and successfully realizes the synthesis of megastigmatrienone, the content of the isomer d in the megastigmatrienone synthesized by the method is higher than 61%, and the content ratio of the isomer b to the isomer d is higher than 1: 2.
3) The synthesis method of the application takes the transition metal cobalt salt as the catalyst, the price is cheap and safe, the problems that other catalysts cannot react or the yield is low and the selectivity is poor are solved, and the final step is a column chromatography method, so that the separation is thorough and the yield is high.
4) The synthesis method can obtain high-quality megastigmatrienone, and is applied to cigarette flavoring, and the flavor enhancement effect is very remarkable due to the high proportion of the megastigmatrienone isomer d.
5) The synthesis method is high in operability and easy for industrial application.
Drawings
FIG. 1 shows a nuclear magnetic hydrogen spectrum of megastigmatrienone represented by the formula (VI) obtained in example 1 of the present application.
FIG. 2 shows the nuclear magnetic carbon spectrum of megastigmatrienone represented by the formula (VI) obtained in example 1 of the present application.
FIG. 3 shows a gas chromatogram of megastigmatrienone represented by the formula (VI) obtained in example 1 of the present application.
FIG. 4 shows a gas chromatogram of megastigmatrienone represented by the formula (VI) obtained in example 2 of the present application.
FIG. 5 shows a gas chromatogram of megastigmatrienone represented by the formula (VI) obtained in example 3 of the present application.
Detailed Description
The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure.
Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.
When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.
The application provides a novel synthetic route of megastigmatrienone, and solves the problems that in the synthetic route of megastigmatrienone in the prior art, the selectivity of an isomer d is poor, raw materials are not easy to obtain, reagents are expensive, the requirement on reaction conditions is high, and a target product is low. According to the method, different catalysts of isomerization reaction are tried, metal catalysts such as iron and copper are adopted, but the reaction cannot be carried out and no megastigmatrienone product is generated, and finally, the reaction can be smoothly carried out only under the catalysis of cobalt salt and under the catalysis of a zinc reducing agent and an additive formed by zinc iodide and diphenylphosphine hydrogen, and the content of the obtained megastigmatrienone isomer d is very high and is far higher than that of the megastigmatrienone isomer d reported in the prior art by 10-40%. By adopting the synthesis route, the purity of megastigmatrienone can reach more than 98%, the content of the isomer d in megastigmatrienone is higher than 61%, the content ratio of the isomer b to the isomer d in megastigmatrienone is higher than 1:2, and the flavoring performance of megastigmatrienone in cigarettes is improved.
The specific synthetic method has the following synthetic route:
the method specifically comprises the following steps:
1) carrying out addition reaction on a compound shown as a formula (I) and alcohol under the action of a catalyst to obtain a compound shown as a formula (II);
2) carrying out reduction reaction on the compound shown in the formula (II) and an ester-based reducing agent to obtain a compound shown in a formula (III);
3) carrying out oxidation reaction on a compound shown in a formula (III) and an oxidant to obtain a compound shown in a formula (IV);
4) carrying out addition reaction on the compound shown in the formula (IV) and an allyl Grignard reagent, and then carrying out dehydration reaction on the compound shown in the formula (IV) and an acid to obtain a compound shown in the formula (V);
5) and (3) carrying out isomerization reaction on the compound shown in the formula (V), the ligand, the reducing agent and the additive under the catalysis of cobalt salt to obtain the megastigmatrienone shown in the formula (VI).
In the synthesis step 1) of megastigmatrienone, the applicant screens a plurality of catalysts, and when only the catalyst is toluenesulfonic acid or p-toluenesulfonic acid or pyridine-p-toluenesulfonic acid, the product obtained by the addition reaction of the compound shown in the formula (I) and alcohol is in the proportion range of the application is mainly the compound shown in the formula (II), the yield of the compound shown in the formula (II) is improved by more than 2 times, and the yield of the byproduct is controlled within 10%; in the step 4), after the addition reaction of the allyl-type Grignard reagent, the acid is directly added, so that not only one-step dehydration can be realized, but also an intermediate product is not required to be separated, and meanwhile, the yield of the compound shown in the formula (V) is improved; in step 5), the temperature at which the isomerization is carried out is also critical, too high a temperature leading to a reduction in the yield of megastigmatrienone isomer VI and too low a temperature leading to a reduction in the selectivity towards megastigmatrienone isomer VI.
To further illustrate the above-described synthesis method of the present application and the technical effects achieved by the method, the following examples are further illustrated and described.
Example 1
In this embodiment, the method for synthesizing megastigmatrienone includes the following steps:
1) weighing 2.1g of ethyl cyclohexenoate I and 48g of ethylene glycol in a proper amount of toluene as a medium under the catalysis of 0.42g of pyridine-p-toluenesulfonic acid, stirring at 60 ℃ to perform addition reaction, evaporating the solvent under reduced pressure after the reaction is finished, and separating and purifying to obtain a compound II.
2) Weighing 2g of compound II and 4.1g of lithium aluminum hydride, dissolving in 50mL of tetrahydrofuran, stirring at 25 ℃ for 12h for reduction reaction, evaporating the solvent under reduced pressure after the reaction is finished, and separating and purifying to obtain compound III.
3) Weighing 1.5g of compound III and 15g of manganese dioxide, dissolving in dichloromethane serving as a medium, refluxing and stirring at 60 ℃ for oxidation reaction, evaporating the solvent under reduced pressure after the reaction is finished, and separating and purifying to obtain a compound IV.
4) Under the protection of nitrogen, 0.8g of compound IV and 3g of allyl magnesium bromide are weighed and dissolved in tetrahydrofuran medium, and the mixture is stirred at 0 ℃ to carry out addition reaction; after the reaction is finished, adding 20mL of water to quench the reaction, then slowly dropwise adding 2mL of 30 wt% sulfuric acid aqueous solution into the reaction system, stirring at normal temperature, after the reaction is finished, removing acid by using saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate, evaporating the solvent under reduced pressure, and separating the obtained concentrate by column chromatography to obtain the compound V.
5) Under nitrogen protection, 0.62g of compound V was sequentially charged with 61.8mg of 1, 3-bis (phenylphosphino) propane, 32.7mg of cobalt bromide, 15mg of zinc powder, 100mg of zinc iodide, and 80mg of diphenylphosphine hydride, and then dissolved in an appropriate amount of dichloromethane, followed by stirring at room temperature for 30 min. After reacting for 12h, adding 5mL of water for quenching, then diluting with dichloromethane, collecting an organic phase, removing the solvent under reduced pressure, and carrying out column chromatography separation on the obtained concentrate to obtain the target compound, namely the megastigmatrienone shown in the formula (VI).
In this example, the total yield of megastigmatrienone in the synthesis process was 40.8%.
FIG. 1 is a nuclear magnetic hydrogen spectrum of megastigmatrienone represented by formula (VI) in this example, and FIG. 2 is a nuclear magnetic hydrogen spectrum of megastigmatrienone represented by formula (VI) in this example. As can be seen from FIGS. 1 and 2, the product of this example is megastigmatrienone, and the nuclear magnetic data are consistent with those reported in the literature.
1 H NMR： 1 H NMR(400MHz,CDCl 3 ):δ(ppm)＝6.75(d,J＝1.5Hz,1H),6.46(d,J＝11.6Hz,1H),5.99-5.90(m,1H),5.89(s,1H),2.35(s,2H),2.07(d,J＝0.7Hz,3H),1.87(dd,J＝6.9,1.4Hz,3H),1.33(s,6H)。
13 C NMR： 13 C NMR(100MHz,CDCl 3 ):δ(ppm)＝199.40,155.44,139.93,137.23,132.76,128.74,125.95,54.10,38.46,29.92,22.44,19.06。
FIG. 3 is a gas chromatogram of megastigmatrienone represented by formula (VI) in this example. As can be further seen from fig. 3, the obtained megastigmatrienone actually has 4 isomers, and the content ratio of megastigmatrienone isomer a, megastigmatrienone isomer b, megastigmatrienone isomer c and megastigmatrienone isomer d is 1.494: 11.618: 4.537: 82.351.
example 2
In this embodiment, the method for synthesizing megastigmatrienone includes the following steps:
1) under the catalysis of 0.42g of 4-methylbenzenesulfonic acid, 3.1g of propyl cyclohexenoate and 48g of ethylene glycol are dissolved in a proper amount of toluene, reflux and stirring are carried out at 120 ℃ to carry out addition reaction, after the reaction is finished, the solvent is evaporated under reduced pressure, and the compound II is obtained after separation and purification.
2) Weighing 2g of compound II and 4.1g of lithium aluminum hydride, dissolving in 50mL of tetrahydrofuran, stirring at 25 ℃ for 12h for reduction reaction, after the reaction is finished, evaporating the solvent under reduced pressure, and separating and purifying to obtain compound III.
3) Weighing 1.5g of compound III and 15g of manganese dioxide, dissolving in dichloromethane, refluxing and stirring at 60 ℃ for oxidation reaction, evaporating the solvent under reduced pressure after the reaction is finished, and separating and purifying to obtain a compound IV.
4) Under the protection of nitrogen, 0.8g of compound IV and 3g of allyl magnesium bromide are dissolved in tetrahydrofuran together, and the mixture is stirred at 0 ℃ for addition reaction; after the reaction is finished, adding 20mL of water to quench the reaction, then slowly dropwise adding 2mL of 30 wt% sulfuric acid aqueous solution into the reaction system, stirring at normal temperature, after the reaction is finished, removing acid by using saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate, evaporating the solvent under reduced pressure, and separating the obtained concentrate by column chromatography to obtain the compound V.
5) Under nitrogen protection, 0.62g of compound V was sequentially charged with 61.8mg of 1, 3-bis (phenylphosphino) propane, 32.7mg of cobalt bromide, 15mg of zinc powder, 100mg of zinc iodide, and 80mg of diphenylphosphine hydride, and then dissolved in an appropriate amount of dichloromethane, followed by stirring at room temperature for 30 min. After reacting for 12h, adding 5mL of water for quenching, then diluting with dichloromethane, collecting an organic phase, removing the solvent under reduced pressure, and carrying out column chromatography separation on the obtained concentrate to obtain the target compound, namely the megastigmatrienone shown in the formula (VI).
In this example, the total yield of megastigmatrienone in the synthesis process was 36%.
FIG. 4 is a gas chromatogram of megastigmatrienone represented by the formula (VI) in this example. As can be seen from fig. 4, the content ratio of megastigmatrienone isomer a, megastigmatrienone isomer b, megastigmatrienone isomer c, and megastigmatrienone isomer d was 1.96: 22.74: 2.19: 73.10.
example 3
In this example, the synthesis of megastigmatrienone,
steps 1) to 4) are the same as in example 1, except for step 5).
And step 5): to 0.62g of compound V were added 61.8mg of 1, 3-bis (phenylphosphino) propane, 32.7mg of cobalt bromide, 15mg of zinc powder, 100mg of zinc iodide, and 80mg of diphenylphosphine hydride in this order under nitrogen protection, followed by addition of an appropriate amount of methylene chloride to dissolve them, and the mixture was stirred at 40 ℃ for 30 min. After reacting for 12h, adding 5mL of water for quenching, then diluting with dichloromethane, collecting an organic phase, removing the solvent under reduced pressure, and carrying out column chromatography separation on the obtained concentrate to obtain the target compound, namely the megastigmatrienone shown in the formula (VI).
In this example, the total yield of megastigmatrienone in the synthesis process was 35%.
FIG. 5 is a gas chromatogram of megastigmatrienone represented by the formula (VI) in this example. As can be seen from fig. 5, the content ratio of megastigmatrienone isomer a, megastigmatrienone isomer b, megastigmatrienone isomer c, and megastigmatrienone isomer d was 2.88: 32.45: 3.6: 61.06.
the foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (9)
1. A synthesis method of megastigmatrienone is characterized by comprising the following steps:
1) carrying out addition reaction on a compound shown as a formula (I) and alcohol under the action of a catalyst to obtain a compound shown as a formula (II);
2) carrying out reduction reaction on the compound shown in the formula (II) and an ester-based reducing agent to obtain a compound shown in a formula (III);
3) carrying out oxidation reaction on the compound shown in the formula (III) and an oxidant to obtain a compound shown in a formula (IV);
4) carrying out addition reaction on the compound shown in the formula (IV) and an allyl Grignard reagent, and then carrying out dehydration reaction on the compound and an acid to obtain a compound shown in the formula (V);
5) carrying out isomerization reaction on a compound shown as a formula (V), a ligand, a reducing agent and an additive under the catalysis of cobalt salt to obtain megastigmatrienone shown as a formula (VI);
wherein, in the compound shown in the formula (I), R 2 Selected from the group consisting of methyl, ethyl, propyl, and benzyl;
in the compounds of formula (II), formula (III) and formula (IV), R 1 Are all selected from ethyl or propyl;
in step 4), the acid is selected from aqueous sulfuric acid;
in step 5), the reducing agent is selected from zinc;
in the step 5), the ligand is selected from 1, 3-bis (phenylphosphino) propane;
in the step 5), the additive is a mixture of zinc iodide and diphenylphosphine hydrogen;
in the step 5), the cobalt salt is selected from cobalt bromide;
in the step 5), the mass ratio of the cobalt salt to the compound shown in the formula (V) is (0.05-0.1): 1;
in the step 5), the mass ratio of the ligand to the compound shown in the formula (V) is (0.05-0.2): 1;
in the step 5), the mass ratio of the reducing agent to the compound shown in the formula (V) is (0.01-0.3): 1;
in the step 5), the mass ratio of the additive to the compound shown in the formula (V) is (0.1-0.3): 1;
in the step 5), the temperature of the isomerization reaction is 0-40 ℃;
the step 5) is carried out in a protective atmosphere.
2. The synthesis method according to claim 1, wherein in step 1), the alcohol is selected from diols;
or/and the catalyst is selected from one or two of p-toluenesulfonic acid and pyridine p-toluenesulfonic acid;
or/and the mass ratio of the catalyst to the compound shown in the formula (I) is (0.1-0.3): 1;
or/and the mass ratio of the alcohol to the compound shown in the formula (I) is (5-30) to 1;
or/and the temperature of the addition reaction is 40-180 ℃.
3. The method of claim 2, wherein the alcohol is selected from the group consisting of ethylene glycol and propylene glycol.
4. The method for synthesizing megastigmatrienone as claimed in claim 1, wherein in step 2), the ester-based reducing agent is selected from one or more of lithium aluminum hydride, sodium borohydride and sodium hydride;
or/and the mass ratio of the ester-based reducing agent to the compound shown in the formula (II) is (1-4) to 1;
or/and the temperature of the reduction reaction is 0-70 ℃.
5. The method for synthesizing megastigmatrienone as claimed in claim 1, wherein in step 3), the oxidant is selected from one or more of manganese dioxide and pyridinium chlorochromate;
or/and the mass ratio of the oxidant to the compound shown in the formula (III) is (5-12) to 1;
or/and the temperature of the oxidation reaction is 30-90 ℃.
6. The method of synthesizing megastigmatrienone of claim 1, wherein in step 4), the allyl grignard reagent is selected from allyl magnesium bromide;
and/or the mass ratio of the allyl Grignard reagent to the compound shown in the formula (IV) is (1-4) to 1;
or/and the temperature of the addition reaction is 0-60 ℃.
7. The method for synthesizing megastigmatrienone as claimed in claim 1, wherein the concentration of the aqueous sulfuric acid solution in step 4) is 1-40 wt%.
8. The method for synthesizing megastigmatrienone as claimed in claim 1, wherein the mass ratio of zinc iodide to diphenylphosphine hydrogen is (0.5-2): 1.
9. The method of synthesizing megastigmatrienone as claimed in claim 1, wherein said step 4) is performed in a protective atmosphere selected from nitrogen.
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