CN104892565A - Artificial synthesis method of neomarchantin A - Google Patents
Artificial synthesis method of neomarchantin A Download PDFInfo
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Abstract
The invention relates to an artificial synthesis method of neomarchantin A, which comprises the following step: by using 4-hydroxy-3-methoxybenzaldehyde and methyl parabromobenzoate as initial raw materials, carrying out chemical reaction to finally obtain the neomarchantin A. The method provided by the invention utilizes the artificial synthesis process to obtain the neomarchantin A for the first time and can continuously and abundantly synthesis neomarchantin A, and the overall yield is 18.9%, thereby providing favorable technical supports for subsequent large-scale production of neomarchantin A.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, be specifically related to a kind of preparation method of natural drug compound, particularly relate to the artificial synthesis of new marchantin A.
Background technology
Liverwort has more than 6000 to plant in the whole world, wherein the peculiar kind of China about kind more than 100.Show the research of liverwort activeconstituents, liverwort is the important sources of bioactive natural products.Be separated from liverwort in recent years and obtain a large amount of novel structure and active significant compound, wherein many lead compounds that can be used as new drug research.New marchantin A (Neomarchantin A) is a kind of novel pair of Bibenzyl compound, is obtained first when analyzing the chemical composition slightly splitting marchantia picking up from Leshan sichuan by Natural Medicine Chemistry seminar of Shandong University.Research finds, new marchantin A is given prominence to human lung adenocarcinoma cell line A-549 effect, also has medium cytotoxicity to P-388 leukemia cell line poison.But because the growth cycle of its natural product is relatively long, content is relatively on the low side, isolation technique is complicated, and these factors add the research difficulty to its biology and pharmacological activity aspect, hinder the further investigation and application to this material.
Summary of the invention
the technical problem solved:few for existing natural product new marchantin A amount to obtain; hinder the deficiency existed the further investigation and application aspect of this material; the invention provides a kind of artificial synthesis of new marchantin A; the method can continue, synthesize new marchantin A in large quantities, for the follow-up large-scale production realizing this medicine provides good technical support.
technical scheme:the invention provides the method for the new marchantin A of a kind of preparation newly, the method for starting raw material with 3-methoxy-4-hydroxybenzaldehyde, parabromobenzoic acid methyl esters, finally prepares new marchantin A by chemical reaction, specifically comprises the following steps:
(1) synthesis of compound 1:
1) mixing solutions of 3.9mL DMF and 4.7mL methyl-sulfate is heated 3-5h at 50-60 DEG C, form DMF-DMS adducts;
2) 5g 3-methoxy-4-hydroxybenzaldehyde 30mL methylene dichloride is dissolved, then the propylene glycol of 7.2mL is added, add the above-mentioned DMF-DMS adducts prepared again, 20-30 DEG C of reaction 20-26h, after reaction terminates, under system is placed in ice bath, 6-8mL triethylamine is added in reaction system, by 20-25mL extracted with diethyl ether three times, merge organic layer, with the solution washing containing 5% sodium bisulfite and saturated sodium acetate three times, three times are washed again with saturated sodium-chloride and saturated sodium acetate equal proportion mixed solution, gained organic phase anhydrous sodium sulfate drying, revolve steaming, recrystallization obtains brown crystal, be compound 1,
(2) synthesis of compound 2:
By compound 1 and 3-bromobenzaldehyde with after pyridine stirring and dissolving, add calcium carbonate powders successively again, potassium carbonate powder, cupric oxide powder, backflow after being heated to seethe with excitement, TLC detects to reacting completely, underpressure distillation is except desolventizing, then add methylene chloride leaching, filter, concentrated filtrate, through column chromatography for separation, obtain thick product, last ethyl alcohol recrystallization obtains white powder, be compound 2, wherein compound 1 is 1:(0.95-1.05 with the ratio of 3-bromobenzaldehyde amount of substance), be preferably 1:1.05, calcium carbonate is 1:(1-5 with the ratio of salt of wormwood amount of substance), return time is 15-20h, preferred 18h,
(3) synthesis of compound 3:
3.72g parabromobenzoic acid methyl esters, 2.5g Isovanillin are dissolved in 100mL pyridine, after stirring with mechanical stirrer, then add 3.58g potassium carbonate powder, 0.68g calcium carbonate powders, 0.65g cupric oxide powder successively, reflux 15-20h, TLC detects to reacting completely, underpressure distillation removing solvent pyridine, then adds the leaching of 30ml methylene dichloride, filters, concentrated filtrate, obtain thick product through column chromatography, last ethyl alcohol recrystallization obtains faint yellow solid, is compound 3;
(4) synthesis of compound 4:
3.14g compound 3 is dissolved in 60mL dehydrated alcohol, at 0-5 DEG C, adds 0.17g SODIUM BOROHYDRIDE POWDER, stir 10-20min, then stirred at ambient temperature reacts about 3h, TLC detects to reacting completely, and till adding water to bubble-free generation, stirs 30min, concentrated by rotary evaporation, with dichloromethane extraction, then wash three times with the equal proportion mixing solutions of saturated sodium acetate and saturated sodium-chloride, organic phase anhydrous sodium sulfate drying, solvent evaporated obtains white solid, is compound 4;
(5) synthesis of compound 5:
Put into successively in 100 mL round-bottomed flasks by 2.53g compound 4,3.16 g triphenylphosphine hydrobromate, add 50mL acetonitrile and dissolve, magneton stirs, and is heated to boiling reflux 2h, stop heating, be down to room temperature, concentrating under reduced pressure, through column chromatography for separation, obtain white solid, be compound 5;
(6) synthesis of compound 6:
Be dissolved in 50ml methylene dichloride by 3.6g compound 3,1.7446g compound 5, then add 1.54g salt of wormwood, be preced with-6 catalysis, be heated to boiling reflux 20-24h with 18-, filtrate concentrates, and residuum obtains oily solid through column chromatography for separation, is compound 6;
(7) synthesis of compound 7:
2.0448g compound 6 is dissolved in 40mL ethyl acetate, adds 0.21g Pd/C and 4.5mL triethylamine, pass into hydrogen, stirring at normal temperature 20-24h, TLC detect to reacting completely, and filter, concentrating under reduced pressure, residuum, through column chromatography for separation, obtains pale yellow oil and is compound 7;
(8) synthesis of compound 8:
Successively 1.7834g compound 7,0.18g tetrahydrochysene lithium aluminium are joined in 25mL anhydrous tetrahydro furan, 1-2h is stirred at 0-5 DEG C, after reaction terminates, slowly drip water 10ml, concentrating under reduced pressure, uses 30ml dichloromethane extraction, organic phase washes three times with saturated nacl aqueous solution again, use anhydrous sodium sulfate drying again, solvent evaporated obtains colorless oil, is compound 8;
(9) synthesis of compound 9:
1.3804g compound 8 is dissolved in 60mL ethanol, then adds the water of 2.5ml concentrated hydrochloric acid and 25mL, stirring at room temperature 14h, after completion of the reaction, 6ml saturated sodium bicarbonate solution is dripped to bubble-free, concentrating under reduced pressure, add acetic acid ethyl dissolution, wash three times with sodium bicarbonate and the saturated mixing solutions of sodium-chlor, merge organic phase, do bath by anhydrous sodium sulphate, concentrating under reduced pressure, through column chromatography for separation, obtain colorless oil, be compound 9;
(10) synthesis of compound 10:
0.986g compound 9,0.74g triphenylphosphine hydrobromate are put in 30mL acetonitrile, be heated with stirring to boiling reflux 2h, TLC detects to reacting completely, and is down to room temperature, concentrating under reduced pressure, through column chromatography for separation, obtains white solid, be compound 10;
(11) synthesis of compound 11:
0.86g sodium methylate is joined in 200mL methylene dichloride, delaying after being dissolved with 300 mL methylene dichloride by 1.58g compound 10 drops in the dichloromethane solution of above-mentioned sodium methylate, react 12 h, TLC detects to reacting completely, concentrating under reduced pressure, through column chromatography for separation, obtain white powder, be compound 11;
(12) synthesis of compound 12:
Be dissolved in 20mL ethyl acetate by 0.768g compound 11, add 0.07g Pd/C, pass into hydrogen, stirring at room temperature 24h, TLC detect to filtering after completion of the reaction, filtrate reduced in volume, and residuum obtains white powder through column chromatography for separation, is compound 12;
(13) synthesis of compound 13:
0.7430g compound 12 is dissolved in 30mL methylene dichloride, then at-40 DEG C, instill the 20ml dichloromethane solution of 1.5mL boron tribromide,-10 DEG C time, reacting 12h, TLC detect to reacting complete, at 0-5 DEG C, dripping water 10ml water, with dichloromethane extraction three times, merge organic phase, with anhydrous sodium sulfate drying, evaporate to dryness obtains white powder, be compound 13, described compound 13 is new marchantin A.
TLC detection in described step (2) to the concrete steps reacted completely is: evaporated by the solvent of reaction system with hair drier, dissolve with methylene dichloride again, with the dichloromethane solution point plate of compound 1,3-bromobenzaldehyde, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 1 under action of ultraviolet radiation in observing response system, namely react completely.
TLC detection in described step (3) to the concrete steps reacted completely is: evaporated by the solvent of reaction system with hair drier, dissolve with methylene dichloride again, with the dichloromethane solution point plate of parabromobenzoic acid methyl esters, Isovanillin, chromatographic separation is carried out as moving phase with methylene dichloride, to under action of ultraviolet radiation in observing response system without Isovanillin spot, namely react completely.
TLC detection in described step (4) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 3, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 3 under action of ultraviolet radiation in observing response system, namely react completely.
TLC detection in described step (7) to the concrete steps reacted completely is: with ethyl acetate solution and the reactant mooring points plate of compound 6, chromatographic separation is carried out as moving phase with ethyl acetate and methylene dichloride mixed solution, to the spot without compound 6 under action of ultraviolet radiation in observing response system, namely react completely; Wherein ethyl acetate and methylene chloride volume are than being 1:(0.5-2), preferred 1:1.
TLC detection in described step (10) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 9, chromatographic separation is carried out with ethyl acetate as mobile phase, to the spot without compound 9 under action of ultraviolet radiation in observing response system, namely react completely.
TLC detection in described step (11) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 10, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 10 under action of ultraviolet radiation in observing response system, namely react completely.
TLC detection in described step (12) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 11, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 11 under action of ultraviolet radiation in observing response system, namely react completely.
TLC detection in described step (13) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 12, chromatographic separation is carried out as moving phase with methylene dichloride and ethyl acetate mixtures, to the spot without compound 12 under action of ultraviolet radiation in observing response system, namely react completely; Described methylene dichloride and ethyl acetate volume ratio are 1:(1-5), preferred 1:2.
beneficial effect:the artificial synthesis of new marchantin A provided by the invention, the method is that the method for first passage synthetic prepares new marchantin A, and its overall yield is 18.9%; New marchantin A has stronger restraining effect to human lung carcinoma cell line A549, artificial synthesis of the present invention provides material base for carrying out research further to new marchantin A, also provide foundation for carrying out structural modification transformation to it, discovery and development of new medicine are of great significance.
Accompanying drawing explanation
Fig. 1 is the synthetic schema of new marchantin A of the present invention.
Embodiment
Below by way of concrete embodiment, foregoing of the present invention is described in further detail, but this should be interpreted as any restriction the present invention being protected to theme.All technical schemes realized based on foregoing of the present invention all belong to scope of the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Hereinafter, if not specified, the operation that the present invention carries out carries out under the room temperature condition of this area routine, and described room temperature generally refers to 20 ~ 35 DEG C, preferably 20 ~ 30 DEG C.
embodiment 1
(1) synthesis of compound 1:
1) mixing solutions of 3.9mL DMF and 4.7mL methyl-sulfate is heated 3-5h at 50-60 DEG C, form DMF-DMS adducts;
2) 5g 3-methoxy-4-hydroxybenzaldehyde 30mL methylene dichloride is dissolved, then the propylene glycol of 7.2mL is added, add the above-mentioned DMF-DMS adducts prepared again, 20-30 DEG C of reaction 20-26h, after reaction terminates, under system is placed in ice bath, 6-8mL triethylamine is added in reaction system, by 20-25mL extracted with diethyl ether three times, merge organic layer, with the solution washing containing 5% sodium bisulfite and saturated sodium acetate three times, three times are washed again with saturated sodium-chloride and saturated sodium acetate equal proportion mixed solution, gained organic phase anhydrous sodium sulfate drying, revolve steaming, recrystallization obtains brown crystal, be compound 1, the heavy 5.39g of product, yield is 78%,
(2) synthesis of compound 2:
After 4.24g compound 1,3.84g 3-bromobenzaldehyde, 150mL pyridine stirring and dissolving, then add 4.35g K successively
2cO
3powder, 0.79g calcium carbonate (CaCO
3) powder, 0.78g CuO powder, reflux 15-20h, TLC detects to reacting completely, and decompression distilled, except desolventizing, then adds the leaching of 30ml methylene dichloride, filter, concentrated filtrate, through column chromatography for separation, obtains thick product, last ethyl alcohol recrystallization obtains white powder, be compound 2, product 3.89g, yield is 61%;
(3) synthesis of compound 3:
3.72g parabromobenzoic acid methyl esters, 2.5g Isovanillin are dissolved in 100mL pyridine, after stirring with mechanical stirrer, add 3.58g potassium carbonate powder, 0.68g calcium carbonate powders, 0.65g cupric oxide powder more successively, reflux 15-20h, TLC detects to reacting completely, underpressure distillation removing solvent pyridine, then the leaching of 30ml methylene dichloride is added, filter, concentrated filtrate, obtains thick product through column chromatography, last ethyl alcohol recrystallization obtains faint yellow solid, be compound 3, the heavy 3.25g of product, yield is 69%;
(4) synthesis of compound 4:
3.14g compound 3 is dissolved in 60mL dehydrated alcohol, 0.17g SODIUM BOROHYDRIDE POWDER is added at 0-5 DEG C, stir 10-20min, then stirred at ambient temperature reacts about 3h, TLC detects to reacting completely, till adding water to bubble-free generation, stir 30min, concentrated by rotary evaporation, with dichloromethane extraction, three times are washed again with the equal proportion mixing solutions of saturated sodium acetate and saturated sodium-chloride, organic phase anhydrous sodium sulfate drying, solvent evaporated obtains white solid, is compound 4, the heavy 2.69g of product, yield is 85%;
(5) synthesis of compound 5:
2.53g compound 4,3.16 g triphenylphosphine hydrobromate is put in 100 mL round-bottomed flasks successively, add 50mL acetonitrile to dissolve, magneton stirs, and is heated to boiling reflux 2h, stop heating, be down to room temperature, concentrating under reduced pressure, through column chromatography for separation, obtain white solid, be compound 5, the heavy 5.22g of product, yield is 97%;
(6) synthesis of compound 6:
3.6g compound 3,1.7446g compound 5 are dissolved in 50ml methylene dichloride, then add 1.54g salt of wormwood, be preced with-6 catalysis with 18-, be heated to boiling reflux 20-24h, filtrate concentrates, then obtains oily solid through column chromatography for separation, be compound 6, the heavy 2.6718g of product, productive rate is 84.3%;
(7) synthesis of compound 7:
2.0448g compound 6 is dissolved in 40mL ethyl acetate, add 0.21g Pd/C and 4.5mL triethylamine, pass into hydrogen, stirring at normal temperature 20-24h, TLC detect to reacting completely, filter, concentrating under reduced pressure, residuum, through column chromatography for separation, obtains pale yellow oil and is compound 7, the heavy 1.8834g of product, productive rate is 92%;
(8) synthesis of compound 8:
Successively 1.7834g compound 7,0.18g tetrahydrochysene lithium aluminium are joined in 25mL anhydrous tetrahydro furan, at 0-5 DEG C, stir 1-2h, after reaction terminates, slowly drip water 10ml, concentrating under reduced pressure, use 30ml dichloromethane extraction, organic phase washes three times with saturated nacl aqueous solution again, then uses anhydrous sodium sulfate drying, solvent evaporated obtains colorless oil, be compound 8, the heavy 1.4874g of product, productive rate is 87.7%;
(9) synthesis of compound 9:
1.3804g compound 8 is dissolved in 60mL ethanol, then adds the water of 2.5ml concentrated hydrochloric acid and 25mL, stirring at room temperature 14h, after completion of the reaction, 6ml saturated sodium bicarbonate solution is dripped to bubble-free, concentrating under reduced pressure, add acetic acid ethyl dissolution, wash three times with sodium bicarbonate and the saturated mixing solutions of sodium-chlor, merge organic phase, bath is done, concentrating under reduced pressure, through column chromatography for separation by anhydrous sodium sulphate, obtain colorless oil, be compound 9, product weighs 1. 0560g, and productive rate is 85. 5%;
(10) synthesis of compound 10:
0.986g compound 9,0.74g triphenylphosphine hydrobromate are put in 30mL acetonitrile, be heated with stirring to boiling reflux 2h, TLC detects to reacting completely, and is down to room temperature, concentrating under reduced pressure, through column chromatography for separation, obtains white solid, be compound 10, the heavy 1.6273g of product, productive rate is 98.7%;
(11) synthesis of compound 11:
0.86g sodium methylate is joined in 200mL methylene dichloride, delaying after being dissolved with 300 mL methylene dichloride by 1.58g compound 10 drops in the dichloromethane solution of above-mentioned sodium methylate, react 12 h, TLC detects to reacting completely, and concentrating under reduced pressure, through column chromatography for separation, obtain white powder, be compound 11, product weighs 0.7993 g, and productive rate is about 88.7%;
(12) synthesis of compound 12:
0.768g compound 11 is dissolved in 20mL ethyl acetate, add 0.07g Pd/C, pass into hydrogen, stirring at room temperature 24h, TLC detect to filtering after completion of the reaction, filtrate reduced in volume, residuum obtains white powder through column chromatography for separation, be compound 12, the heavy 0.7545g of product, productive rate is 97. 8%;
(13) synthesis of compound 13:
0.7430g compound 12 is dissolved in 30mL methylene dichloride, at-40 DEG C, then instills the 20ml dichloromethane solution of 1.5mL boron tribromide ,-10 DEG C time, react 12h, TLC detects to reacting complete, drips water 10ml water at 0-5 DEG C, with dichloromethane extraction three times, merge organic phase, with anhydrous sodium sulfate drying, evaporate to dryness obtains white powder, is compound 13, described compound 13, be new marchantin A, the heavy 0.5562g of product, productive rate is 79. 8%.
The structural formula of new marchantin A is detected, obtains following data:
mp：215-216℃；MS[M+H
+]：425，MS[M+NH
4 +]：442；
1HNMR：δ= 7.25(m,1H), 7.15 (d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 2H), 6.94 (s, 1H), 6.89 （d, J = 7.2 Hz, 1H), 6.85 (d, J = 6.6 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.23 (s, 1H), 6.18 (s, 1H), 5.57 (s, 1H), 5.34 (s, 1H), 3.10 (d, J = 10.8 Hz, 4H), 2.51(m, 4H)。
The overall yield of the new marchantin A of synthetic of the present invention is 18.9%.
Claims (9)
1. the artificial synthesis of new marchantin A, is characterized in that the method comprises the following steps:
(1) synthesis of compound 1:
1) mixing solutions of 3.9mL DMF and 4.7mL methyl-sulfate is heated 3-5h at 50-60 DEG C, form DMF-DMS adducts;
2) 5g 3-methoxy-4-hydroxybenzaldehyde 30mL methylene dichloride is dissolved, then the propylene glycol of 7.2mL is added, add the above-mentioned DMF-DMS adducts prepared again, 20-30 DEG C of reaction 20-26h, after reaction terminates, under system is placed in ice bath, 6-8mL triethylamine is added in reaction system, by 20-25mL extracted with diethyl ether three times, merge organic layer, with the solution washing containing 5% sodium bisulfite and saturated sodium acetate three times, three times are washed again with saturated sodium-chloride and saturated sodium acetate equal proportion mixed solution, gained organic phase anhydrous sodium sulfate drying, revolve steaming, recrystallization obtains brown crystal, be compound 1,
(2) synthesis of compound 2:
By compound 1 and 3-bromobenzaldehyde with after pyridine stirring and dissolving, add calcium carbonate powders successively again, potassium carbonate powder, cupric oxide powder, backflow after being heated to seethe with excitement, TLC detects to reacting completely, underpressure distillation is except desolventizing, then add methylene chloride leaching, filter, concentrated filtrate, through column chromatography for separation, obtain thick product, last ethyl alcohol recrystallization obtains white powder, be compound 2, wherein compound 1 is 1:(0.95-1.05 with the ratio of 3-bromobenzaldehyde amount of substance), calcium carbonate is 1:(1-5 with the ratio of salt of wormwood amount of substance), return time is 15-20h,
(3) synthesis of compound 3:
3.72g parabromobenzoic acid methyl esters, 2.5g Isovanillin are dissolved in 100mL pyridine, after stirring with mechanical stirrer, then add 3.58g potassium carbonate powder, 0.68g calcium carbonate powders, 0.65g cupric oxide powder successively, reflux 15-20h, TLC detects to reacting completely, underpressure distillation removing solvent pyridine, then adds the leaching of 30ml methylene dichloride, filters, concentrated filtrate, obtain thick product through column chromatography, last ethyl alcohol recrystallization obtains faint yellow solid, is compound 3;
(4) synthesis of compound 4:
3.14g compound 3 is dissolved in 60mL dehydrated alcohol, at 0-5 DEG C, adds 0.17g SODIUM BOROHYDRIDE POWDER, stir 10-20min, then stirred at ambient temperature reacts about 3h, TLC detects to reacting completely, and till adding water to bubble-free generation, stirs 30min, concentrated by rotary evaporation, with dichloromethane extraction, then wash three times with the equal proportion mixing solutions of saturated sodium acetate and saturated sodium-chloride, organic phase anhydrous sodium sulfate drying, solvent evaporated obtains white solid, is compound 4;
(5) synthesis of compound 5:
Put into successively in 100 mL round-bottomed flasks by 2.53g compound 4,3.16 g triphenylphosphine hydrobromate, add 50mL acetonitrile and dissolve, magneton stirs, and is heated to boiling reflux 2h, stop heating, be down to room temperature, concentrating under reduced pressure, through column chromatography for separation, obtain white solid, be compound 5;
(6) synthesis of compound 6:
Be dissolved in 50ml methylene dichloride by 3.6g compound 3,1.7446g compound 5, then add 1.54g salt of wormwood, be preced with-6 catalysis, be heated to boiling reflux 20-24h with 18-, filtrate concentrates, and residuum obtains oily solid through column chromatography for separation, is compound 6;
(7) synthesis of compound 7:
2.0448g compound 6 is dissolved in 40mL ethyl acetate, adds 0.21g Pd/C and 4.5mL triethylamine, pass into hydrogen, stirring at normal temperature 20-24h, TLC detect to reacting completely, and filter, concentrating under reduced pressure, residuum, through column chromatography for separation, obtains pale yellow oil and is compound 7;
(8) synthesis of compound 8:
Successively 1.7834g compound 7,0.18g tetrahydrochysene lithium aluminium are joined in 25mL anhydrous tetrahydro furan, 1-2h is stirred at 0-5 DEG C, after reaction terminates, slowly drip water 10ml, concentrating under reduced pressure, uses 30ml dichloromethane extraction, organic phase washes three times with saturated nacl aqueous solution again, use anhydrous sodium sulfate drying again, solvent evaporated obtains colorless oil, is compound 8;
(9) synthesis of compound 9:
1.3804g compound 8 is dissolved in 60mL ethanol, then adds the water of 2.5ml concentrated hydrochloric acid and 25mL, stirring at room temperature 14h, after completion of the reaction, 6ml saturated sodium bicarbonate solution is dripped to bubble-free, concentrating under reduced pressure, add acetic acid ethyl dissolution, wash three times with sodium bicarbonate and the saturated mixing solutions of sodium-chlor, merge organic phase, do bath by anhydrous sodium sulphate, concentrating under reduced pressure, through column chromatography for separation, obtain colorless oil, be compound 9;
(10) synthesis of compound 10:
0.986g compound 9,0.74g triphenylphosphine hydrobromate are put in 30mL acetonitrile, be heated with stirring to boiling reflux 2h, TLC detects to reacting completely, and is down to room temperature, concentrating under reduced pressure, through column chromatography for separation, obtains white solid, be compound 10;
(11) synthesis of compound 11:
0.86g sodium methylate is joined in 200mL methylene dichloride, delaying after being dissolved with 300 mL methylene dichloride by 1.58g compound 10 drops in the dichloromethane solution of above-mentioned sodium methylate, react 12 h, TLC detects to reacting completely, concentrating under reduced pressure, through column chromatography for separation, obtain white powder, be compound 11;
(12) synthesis of compound 12:
Be dissolved in 20mL ethyl acetate by 0.768g compound 11, add 0.07g Pd/C, pass into hydrogen, stirring at room temperature 24h, TLC detect to filtering after completion of the reaction, filtrate reduced in volume, and residuum obtains white powder through column chromatography for separation, is compound 12;
(13) synthesis of compound 13:
0.7430g compound 12 is dissolved in 30mL methylene dichloride, then at-40 DEG C, instill the 20ml dichloromethane solution of 1.5mL boron tribromide,-10 DEG C time, reacting 12h, TLC detect to reacting complete, at 0-5 DEG C, dripping water 10ml water, with dichloromethane extraction three times, merge organic phase, with anhydrous sodium sulfate drying, evaporate to dryness obtains white powder, be compound 13, described compound 13 is new marchantin A.
2. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (2) to the concrete steps reacted completely is: evaporated by the solvent of reaction system with hair drier, dissolve with methylene dichloride again, with the dichloromethane solution point plate of compound 1,3-bromobenzaldehyde, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 1 under action of ultraviolet radiation in observing response system, namely react completely.
3. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (3) to the concrete steps reacted completely is: evaporated by the solvent of reaction system with hair drier, dissolve with methylene dichloride again, with the dichloromethane solution point plate of parabromobenzoic acid methyl esters, Isovanillin, chromatographic separation is carried out as moving phase with methylene dichloride, to under action of ultraviolet radiation in observing response system without Isovanillin spot, namely react completely.
4. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (4) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 3, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 3 under action of ultraviolet radiation in observing response system, namely react completely.
5. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (7) to the concrete steps reacted completely is: with ethyl acetate solution and the reactant mooring points plate of compound 6, chromatographic separation is carried out as moving phase with ethyl acetate and methylene dichloride mixed solution, to the spot without compound 6 under action of ultraviolet radiation in observing response system, namely react completely; Wherein ethyl acetate and methylene chloride volume are than being 1:(0.5-2).
6. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (10) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 9, chromatographic separation is carried out with ethyl acetate as mobile phase, to the spot without compound 9 under action of ultraviolet radiation in observing response system, namely react completely.
7. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (11) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 10, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 10 under action of ultraviolet radiation in observing response system, namely react completely.
8. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (12) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 11, chromatographic separation is carried out as moving phase with methylene dichloride, to the spot without compound 11 under action of ultraviolet radiation in observing response system, namely react completely.
9. the artificial synthesis of new marchantin A according to claim 1, it is characterized in that the TLC detection in described step (13) to the concrete steps reacted completely is: with dichloromethane solution and the reactant mooring points plate of compound 12, chromatographic separation is carried out as moving phase with methylene dichloride and ethyl acetate mixtures, to the spot without compound 12 under action of ultraviolet radiation in observing response system, namely react completely; Described methylene dichloride and ethyl acetate volume ratio are 1:(1-5).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| CN111205265A (en) * | 2020-03-02 | 2020-05-29 | 沧州那瑞化学科技有限公司 | Preparation method of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene |
| CN113549046A (en) * | 2021-06-23 | 2021-10-26 | 山东大学 | Bisbecklonin S derivative and preparation method and application thereof |
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| CN102228455A (en) * | 2011-05-05 | 2011-11-02 | 山东大学 | Application of bisbibenzyl compound to preparation of anti-inflammatory medicament |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111205265A (en) * | 2020-03-02 | 2020-05-29 | 沧州那瑞化学科技有限公司 | Preparation method of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene |
| CN111205265B (en) * | 2020-03-02 | 2022-12-02 | 沧州那瑞化学科技有限公司 | Preparation method of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene |
| CN113549046A (en) * | 2021-06-23 | 2021-10-26 | 山东大学 | Bisbecklonin S derivative and preparation method and application thereof |
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