CN107032973A - The preparation method of the geranyl p-benzoquinone derivative of 2 methoxyl group 5 and Scabellone B - Google Patents
The preparation method of the geranyl p-benzoquinone derivative of 2 methoxyl group 5 and Scabellone B Download PDFInfo
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- CN107032973A CN107032973A CN201710448213.4A CN201710448213A CN107032973A CN 107032973 A CN107032973 A CN 107032973A CN 201710448213 A CN201710448213 A CN 201710448213A CN 107032973 A CN107032973 A CN 107032973A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
Abstract
The invention discloses a kind of preparation method of the geranyl p-benzoquinone derivative of 2 methoxyl group 5, this method is achieved by the steps of：Step 1, prepare the halogen trimethylsilylbenzene of 1,2,4 trimethoxy of intermediate product 3；Step 2, prepare the geranyl benzene of 1,2,4 trimethoxy of intermediate product 6；Step 3, prepare object.The invention discloses a kind of Scabellone B preparation method.The present invention is by with 1,2,4 trimethoxy-benzenes are raw material, smoothly realize under the conditions of conventional organic solvent, one step is aoxidized by ammonium ceric nitrate and obtains the geranyl p-benzoquinone derivative (coupled product) of 2 methoxyl group 5, again by having synthesized Scabellone B from the condition such as different classes of nitrogenous organic base and the their own consumption of control so that Scabellone B yield is improved, so as to be had laid a good foundation for a large amount of industrialized productions of the compound.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives
Preparation method；Relate further specifically to a kind of Scabellone B preparation method.
Background technology
Ascidian biology in Aplidium category, which is found it, can provide a variety of natural productions with important biomolecule activity
Thing and it is well-known.Its architectural feature is mainly quinones or hydroquinones, and Scabellones just belongs to a class therein and naturally produced
Thing；This species of Aplidiumscabellone are Michaelsen seminars and nineteen twenty-four finds, 2011 by
From it, by Scabellones, this class Separation of Natural Products is come out for BrentR.Copp seminars, and this kind of natural products is shown pair
The good inhibitory action of the respiratory burst of the neutrophil cell of human body.And Scabellone B have good antimalarial biological
Activity；
At present to the ScabelloneA-C existing report of synthesis, this report is shown in a Publication about Document：
(Susanna T.S.Chan, A.Norrie Pearce, Ana H.Januario, Michael J.Page,
Marcel Kaiser, Rene J.Mc Laughlin, Jacquie L.Harper, Victoria L.Webb, David
Barker, and Brent R.Copp*Anti-inflammatory and Antimalarial Meroterpenoids
From the NewZealand Ascidian Aplidium Scabellone J.Org.Chem.2011,76 (21),
pp9151–9156；Susanna T.S.Chan, Michael A.Pullar, Iman M.K halil, Emmanuelle
Allouche, David Barker, Brent R.Copp*Bio-inspired dimerisation of prenylated
quinones directed towards the synthesis of the meroterpenoid natural
Products, the scabellones TetrahedronLetters56,2015, Pages1486-1488).
The synthesis strategy of this report：First, with 2,4- dimethoxy benzaldehydes be initiation material, by Baeyer-
Villiger oxidation reactions obtain 2,4- syringol, then obtain 2- spiceleafs under conditions of sodium hydride with geranyl bromide
Base -4,6- syringol, is oxidized to quinone by ammonium ceric nitrate and obtains 2- geranyl -6- first by hydrosulfurous acid sodium reduction again
Oxy-1,4- hydroquinones.
2nd, obtain after monomer 2- geranyls -6- methoxyl groups-Isosorbide-5-Nitrae-hydroquinones, dissolved in pyridine, in the ginseng of oxygen
With lower room temperature reaction 30min, Scabellone A (11%), Scabellone B (3%) can be obtained, but do not synthesize
Scabellone C。
Although this report be to Scabellone A, Scabellone B it is fully synthetic first, for synthesis step
Some cumbersome and gross production rates are less than 2%, and the synthesis compound Scabellone C failed, so still existing not
Foot.
But inventor just finds out, first prepare and tied with Scabellone A, Scabellone B, Scabellone C
The close monomer diquinone of structure, then further prepared respectively by monomer diquinone Scabellone A, Scabellone B,
Scabellone C。
The content of the invention
In view of this, it is a primary object of the present invention to supply a kind of system of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives
Preparation Method, the problem of solving preparation process very complicated in the prior art；It is a kind of that the main object of the present invention also resides in offer
Scabellone B preparation method, the problem of solving complex operation step, low yield in the prior art.
To reach above-mentioned purpose, the technical proposal of the invention is realized in this way：A kind of 2- methoxyl groups -5- geranyls are to benzene
The preparation method of quinone derivative, this method is achieved by the steps of：
Step 1,1,2,4- trimethoxy-benzene is dissolved in tetrahydrofuran, the lower tetramethylethylenediamine that adds of stirring simultaneously cools
To -10~0 DEG C, add after n-BuLi, 1~2h of reaction, add trim,ethylchlorosilane, react 20~40min, afterwards,
It is quenched, extracted, being dried and column chromatography for separation, 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene is made；
Step 2, made from step 11,2,4- trimethoxy -3- trimethyls silicon substrate-benzene is dissolved in tetrahydrofuran, stirred
Lower addition tetramethylethylenediamine is simultaneously cooled to -75~-80 DEG C, adds n-BuLi, is warming up to -10~0 DEG C of 1~2h of reaction,
Geranyl bromide is added, 0.5~1.5h is reacted, afterwards, is quenched, extracted, dried and column chromatography for separation, being made 1,2,4- tri-
Methoxyl group -6- geranyls-benzene；
Step 3, made from step 21,2,4- trimethoxy -6- geranyls-benzene is dissolved in acetonitrile and 0~-40 are cooled to
DEG C, then ammonium ceric nitrate is dissolved in 2~4ml water, ceric ammonium nitrate solution is made, and ceric ammonium nitrate solution is added 1,2,4- tri-
In methoxyl group -6- geranyls-benzole soln, 3~8min is reacted, afterwards, is quenched, extracted, dried and column chromatography for separation, is made
A kind of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives.
Preferably, in the step 1, described 1,2,4- trimethoxy-benzenes, tetramethylethylenediamine, n-BuLi and trimethyl
Mol ratio between chlorosilane is 1：(1.5~2.5)：(1~1.5)：(1.5~2).
Preferably, in the step 2, described 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene, tetramethylethylenediamine, just
The mol ratio of butyl lithium and geranyl bromide is 1：(2~2.5)：(1~1.5)：(1.5~2).
Preferably, in the step 3, described 1,2,4- trimethoxy -6- geranyls-benzene and ammonium ceric nitrate mole are 1：
(4~5).
What another technical scheme of the present invention was realized in：A kind of Scabellone B preparation method, this method
Specially：
2- methoxyl groups -5- geranyl p-benzoquinone derivatives described above are dissolved in organic solvent, added nitrogenous organic
Alkali, 0.5~6h is stirred at 0~60 DEG C, and saturated ammonium chloride is quenched, and is extracted, is washed, drying, being used column chromatography after drying, is made
Scabellone B。
Preferably, the organic solvent is the one or more in dichloromethane, methanol, pyridine.
Preferably, the nitrogenous organic base is 2,6- lutidines, 4- picolines, one kind in triethylamine or many
Kind.
Preferably, the 2- methoxyl groups -5- geranyls p-benzoquinone derivative and the mol ratio of nitrogenous organic base are 1：(4
~6).
Compared with prior art, the present invention has by, for raw material, smoothly being realized with 1,2,4- trimethoxy-benzene conventional
Under machine solvent condition, a step is aoxidized by ammonium ceric nitrate and obtains 2- methoxyl group -5- geranyls p-benzoquinone derivatives (coupled product),
Again by having synthesized Scabellone B from the condition such as different classes of nitrogenous organic base and the their own consumption of control,
So that Scabellone B yield is improved, so as to establish good base for a large amount of industrialized productions of the compound
Plinth.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the products therefrom of the embodiment of the present invention 1；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of the products therefrom of the embodiment of the present invention 11.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, it is right below in conjunction with drawings and Examples
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.
The invention provides a kind of preparation method of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives, its reaction structure formula
It is as follows：
In reaction structure formula：Alkali 1,2 is metal hydride, metal alkyl alkali, metal alkyl alkali.We have tried out positive fourth
The final n-BuLi yield of base lithium, tert-butyl lithium, sodium hydride is higher thus select n-BuLi, and add after alkali can shape for raw material
Into white suspension, so adding the ability that hydrogen is pulled out in tetramethylethylenediamine (TMEDA) enhancing；Oxidant is ammonium ceric nitrate (CAN).
This method is achieved by the steps of：
Step 1,1,2,4- trimethoxy-benzene (compound 1) is dissolved in tetrahydrofuran, stirring is lower to add tetramethyl second two
Amine is simultaneously cooled to -10~0 DEG C, adds after n-BuLi, 1~2h of reaction, adds trim,ethylchlorosilane, and reaction 20~
40min, afterwards, is quenched, is extracted, being dried and column chromatography for separation, 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene is made
(compound 2)；
Wherein, 1,2,4- trimethoxy-benzenes (compound 1), tetramethylethylenediamine, n-BuLi and trim,ethylchlorosilane it
Between mol ratio be 1：(1.5~2.5)：(1~1.5)：(1.5~2)；
Step 2, made from step 11,2,4- trimethoxy -3- trimethyls silicon substrate-benzene (compound 2) is dissolved in tetrahydrochysene furan
In muttering, stir and descend to add tetramethylethylenediamine and be cooled to -75~-80 DEG C, add n-BuLi, be warming up to -10~0 DEG C instead
1~2h is answered, geranyl bromide is added, 0.5~1.5h is reacted, afterwards, is quenched, extracted, dried and column chromatography for separation, is made
1,2,4- trimethoxy -6- geranyls-benzene (compound 3)；
Wherein, 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene (compound 2), tetramethylethylenediamine, n-BuLi and
The mol ratio of geranyl bromide is 1：(2~2.5)：(1~1.5)：(1.5~2)；
Step 3, made from step 21,2,4- trimethoxy -6- geranyls-benzene (compound 3) is dissolved in acetonitrile and dropped
Temperature is dissolved in 2~4ml water to 0~-40 DEG C, then by ammonium ceric nitrate, ceric ammonium nitrate solution is made, and ceric ammonium nitrate solution is added
Enter in 1,2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, react 3~8min, afterwards, be quenched, extracted, done
Dry and column chromatography for separation, is made 2- methoxyl group -5- geranyls p-benzoquinone derivatives (compound 4)；
Wherein, the mol ratio of 1,2,4- trimethoxy -6- geranyls-benzene (compound 3) and oxidant is 1：(4~5).
Wherein, 2- methoxyl groups -5- geranyls p-benzoquinone derivative can be also named as：6,6'-bis ((Z) -3,7-
Dimethylocta-2,6-dienyl) -4,4'-dimethoxy-1,1'-bi (cyclohexa-3,6-diene) -2,2', 5,
5'-tetraone, and following 6,6'-bis (3,7-dimethylocta-2,6-dienyl) -4,4'-dimethoxy-1,
1'-bi (cyclohexa-3,6-diene) -2,2', 5,5'-tetraone are replaced with compound 4.
Present invention also offers a kind of Scabellone B preparation method, its reaction structure formula difference is as follows：
In reaction structure formula：Alkali 3 is the one or more in 2,6- lutidines, 4- picolines, triethylamine.
Wherein, Scabellone B preparation method is specially：
Scabellone B preparation method is specially：
Above-mentioned compound 4 is dissolved in organic solvent, adds and 0.5~6h is stirred at nitrogenous organic base, 0~60 DEG C,
Saturated ammonium chloride is quenched, and extracts, washs, drying, being used column chromatography after drying, Scabellone B are made.
Wherein, organic solvent is the one or more in dichloromethane, methanol, pyridine；Nitrogenous organic base is 2,6- bis-
One or more in picoline, 4- picolines, triethylamine；Compound 4 and the mol ratio of nitrogenous organic base are 1：(4
~6).
Compared with prior art, the present invention has by, for raw material, smoothly being realized with 1,2,4- trimethoxy-benzene conventional
Under machine solvent condition, a step is aoxidized by ammonium ceric nitrate and obtains compound 4 (2- methoxyl group -5- geranyl p-benzoquinone derivatives,
It is entitled：6,6'-bis (3,7-dimethylocta-2,6-dienyl) -4,4'-dimethoxy-1,1'-bi (cyclohexa-
3,6-diene) -2,2', 5,5'-tetraone), then by from different classes of nitrogenous organic base and control each of which
The condition such as consumption synthesized Scabellone B so that Scabellone B yield is improved, so as to be the chemical combination
A large amount of industrialized productions of thing are had laid a good foundation.
The preparation method of compound 4, this method is achieved by the steps of：
Embodiment 1
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 47.6mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 28.5mmol n-BuLis are added dropwise, instead
Answer after 1.5 hours, 35.7mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 30min, saturated ammonium chloride is quenched, ethyl acetate
Extraction three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50), make
Obtain 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene (compound 2), yield 96%；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 8.32mmol tetramethylethylenediamines and is cooled to -75~-80 DEG C, then
5.5mmol n-BuLis are added, 0 DEG C of reaction 1.5h is warming up to, adds 6.24mmol geranyl bromides, stirring reaction 1h, saturation
Ammonium chloride is quenched, and ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure petroleum ether) is used column chromatography after being spin-dried for,
Column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, (the change of 1,2,4- trimethoxy -6- geranyls-benzene is obtained
Compound 3), unreacted product, which is dissolved at 30ml ethyl acetate, 0 DEG C, adds 10.4mmol KI and 14.56mmol tetramethyls second two
Amine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and adds anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 72%；
Step 3, the trimethoxy -6- geranyls of 0.65mmol 1,2,4--benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is to -30 DEG C, then 2.29mmol ammonium ceric nitrates are dissolved in 2ml water, ceric ammonium nitrate solution is made, and ceric ammonium nitrate solution is added
Enter in 1,2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, react 5min, ethyl acetate extraction, saturated aqueous common salt
Wash 3 times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：10), it is made
Compound 4, yield is 40%.
Embodiment 2
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 47.6mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 28.5mmol n-BuLis are added dropwise, instead
Answer after 1.5 hours, 35.7mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 30min, saturated ammonium chloride is quenched, ethyl acetate
Extraction three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50), make
Obtain 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene (compound 2), yield 96%；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 8.32mmol tetramethylethylenediamines and is cooled to -75~-80 DEG C, then
5.5mmol n-BuLis are added, 0 DEG C of reaction 1.5h is warming up to, adds 6.24mmol geranyl bromides, stirring reaction 1h, saturation
Ammonium chloride is quenched, and ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure petroleum ether) is used column chromatography after being spin-dried for,
Column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, (the change of 1,2,4- trimethoxy -6- geranyls-benzene is obtained
Compound 3), unreacted product, which is dissolved at 30ml ethyl acetate, 0 DEG C, adds 10.4mmol KI and 14.56mmol tetramethyls second two
Amine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and adds anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 72%；
Step 3, the trimethoxy -6- geranyls of 0.65mmol 1,2,4--benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is dissolved in 4ml water to 0 DEG C, then by 2.29mmol ammonium ceric nitrates, and ceric ammonium nitrate solution is made, and oxidizing agent solution is added into 1,
In 2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, 5min, ethyl acetate extraction, saturated common salt washing 3 are reacted
Time, anhydrous sodium sulfate drying is added, (volume ratio of ethyl acetate and petroleum ether is 1 through column chromatography for separation：10) compound, is made
4, yield is 25%.
Embodiment 3
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 47.6mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 28.5mmol n-BuLis are added dropwise, instead
Answer after 1.5 hours, 35.7mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 30min, saturated ammonium chloride is quenched, ethyl acetate
Extraction three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50), make
Obtain 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene (compound 2), yield 96%；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 8.32mmol tetramethylethylenediamines and is cooled to -- and 75~-80 DEG C, then
5.5mmol n-BuLis are added, 0 DEG C of reaction 1.5h is warming up to, adds 6.24mmol geranyl bromides, stirring reaction 1h, saturation
Ammonium chloride is quenched, and ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure petroleum ether) is used column chromatography after being spin-dried for,
Column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, (the change of 1,2,4- trimethoxy -6- geranyls-benzene is obtained
Compound 3), unreacted product, which is dissolved at 30ml ethyl acetate, 0 DEG C, adds 10.4mmol KI and 14.56mmol tetramethyls second two
Amine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and adds anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 72%；
Step 3, the trimethoxy -6- geranyls of 0.65mmol 1,2,4--benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is dissolved in 2ml water to 0 DEG C, then by 2.29mmol ammonium ceric nitrates, and ceric ammonium nitrate solution is made, and oxidizing agent solution is added into 1,
In 2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, 5min, ethyl acetate extraction, saturated common salt washing 3 are reacted
Time, anhydrous sodium sulfate drying is added, (volume ratio of ethyl acetate and petroleum ether is 1 through column chromatography for separation：10) compound, is made
4, yield is 30%.
Embodiment 4
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 35.7mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 23.8mmol n-BuLis are added dropwise, instead
Answer after 1.5 hours, 42.84mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 30min, saturated ammonium chloride is quenched, acetic acid second
Ester extract three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50),
1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene (compound 2), yield 80% is made；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 9.15mmol tetramethylethylenediamines and is cooled to -75~-80 DEG C, then
4.16mmol n-BuLis are added, 0 DEG C of reaction 1.5h is warming up to, adds 7.07mmol geranyl bromides, stirring reaction 1h, saturation
Ammonium chloride is quenched, and ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure petroleum ether) is used column chromatography after being spin-dried for,
Column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, (the change of 1,2,4- trimethoxy -6- geranyls-benzene is obtained
Compound 3), unreacted product, which is dissolved at 30ml ethyl acetate, 0 DEG C, adds 10.4mmol KI and 14.56mmol tetramethyls second two
Amine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and adds anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 60%；
Step 3, by 0.65mmol1,2,4- trimethoxy -6- geranyls-benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is dissolved in 2ml water to 0 DEG C, then by 2.6mmol ammonium ceric nitrates, and ceric ammonium nitrate solution is made, and oxidizing agent solution is added into 1,
In 2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, 5min, ethyl acetate extraction, saturated common salt washing 3 are reacted
Time, anhydrous sodium sulfate drying is added, (volume ratio of ethyl acetate and petroleum ether is 1 through column chromatography for separation：10) compound, is made
4, yield is 20%.
Embodiment 5
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 59.5mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 35.7mmol n-BuLis are added dropwise, instead
Answer after 1.5 hours, 47.6mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 30min, saturated ammonium chloride is quenched, ethyl acetate
Extraction three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50), make
Obtain 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene (compound 2), yield 85%；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 10.4mmol tetramethylethylenediamines and is cooled to -75~-80 DEG C, then
6.24mmol n-BuLis are added, 0 DEG C of reaction 1.5h is warming up to, adds 8.32mmol geranyl bromides, stirring reaction 1h, saturation
Ammonium chloride is quenched, and ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure petroleum ether) is used column chromatography after being spin-dried for,
Column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, (the change of 1,2,4- trimethoxy -6- geranyls-benzene is obtained
Compound 3), unreacted product, which is dissolved at 30ml ethyl acetate, 0 DEG C, adds 10.4mmol KI and 14.56mmol tetramethyls second two
Amine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and adds anhydrous slufuric acid
Sodium is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 55%；
Step 3, by 0.65mmol1,2,4- trimethoxy -6- geranyls-benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is dissolved in 2ml water to 0 DEG C, then by 3.25mmol ammonium ceric nitrates, and ceric ammonium nitrate solution is made, and oxidizing agent solution is added into 1,
In 2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, 5min, ethyl acetate extraction, saturated common salt washing 3 are reacted
Time, anhydrous sodium sulfate drying is added, (volume ratio of ethyl acetate and petroleum ether is 1 through column chromatography for separation：10) compound, is made
4, yield is 22%.
Embodiment 6
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 47.6mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 28.5mmol n-BuLis are added dropwise, instead
Answer after 1 hour, 35.7mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 20min, saturated ammonium chloride is quenched, ethyl acetate extraction
Take three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50), it is made
1,2,4- trimethoxy -3- trimethyls silicon substrate-benzene (compound 2), yield 92%；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 8.32mmol tetramethylethylenediamines and is cooled to -75~-80 DEG C, then
5.5mmol n-BuLis are added, -10 DEG C of reaction 1h are warming up to, 6.24mmol geranyl bromides are added, stirring reaction 0.5h satisfies
It is quenched with ammonium chloride, ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure oil is used column chromatography after being spin-dried for
Ether), column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, obtain 1,2,4- trimethoxy -6- geranyls-benzene
(compound 3), unreacted product is dissolved in addition 10.4mmol KI and 14.56mmol tetramethyls at 30ml ethyl acetate, 0 DEG C
Ethylenediamine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and is added anhydrous
Sodium sulphate is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 62%；
Step 3, the trimethoxy -6- geranyls of 0.65mmol 1,2,4--benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is to -30 DEG C, then 2.29mmol ammonium ceric nitrates are dissolved in 2ml water, ceric ammonium nitrate solution is made, and ceric ammonium nitrate solution is added
Enter in 1,2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, react 3min, ethyl acetate extraction, saturated aqueous common salt
Wash 3 times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：10), it is made
Compound 4, yield is 36%.
Embodiment 7
Step 1, argon gas protection under, the trimethoxy-benzenes (compound 1) of 23.8mmol 1,2,4- are dissolved in 80ml tetrahydrochysene furans
In muttering, 47.6mmol tetramethylethylenediamines (TMEDA) are added dropwise in stirring, 0 DEG C is cooled to, 28.5mmol n-BuLis are added dropwise, instead
Answer after 2 hours, 35.7mmol trim,ethylchlorosilanes (TMSCl) are added dropwise, react 40min, saturated ammonium chloride is quenched, ethyl acetate extraction
Take three times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：50), it is made
1,2,4- trimethoxy -3- trimethyls silicon substrate-benzene (compound 2), yield 92%；
Step 2, under the protection of argon gas, by the above-mentioned trimethoxy -3- trimethyls silicon substrates of 4.16mmol 1,2,4--benzene (change
Compound 2) it is dissolved in 20ml tetrahydrofurans, stirring is lower to be added 8.32mmol tetramethylethylenediamines and is cooled to -75~-80 DEG C, then
5.5mmol n-BuLis are added, -10 DEG C of reaction 2h are warming up to, 6.24mmol geranyl bromides are added, stirring reaction 1.5h satisfies
It is quenched with ammonium chloride, ethyl acetate is extracted three times, adds anhydrous sodium sulfate drying, (pure oil is used column chromatography after being spin-dried for
Ether), column chromatography for separation formula is being used, portion of product is being had and directly takes off TMS, obtain 1,2,4- trimethoxy -6- geranyls-benzene
(compound 3), unreacted product is dissolved in addition 10.4mmol KI and 14.56mmol tetramethyls at 30ml ethyl acetate, 0 DEG C
Ethylenediamine (TMSCl) reacts 4h, plus saturated sodium bicarbonate is quenched, and ethyl acetate extraction, saturation sodium hydrogensulfite is washed, and is added anhydrous
Sodium sulphate is dried, and is spin-dried for, and through column chromatography for separation, (volume ratio of ethyl acetate and petroleum ether is 1：40) two step yields are 62%；
Step 3, the trimethoxy -6- geranyls of 0.65mmol 1,2,4--benzene (compound 3) is dissolved in 8ml acetonitriles and dropped
Temperature is to -30 DEG C, then 2.29mmol ammonium ceric nitrates are dissolved in 2ml water, ceric ammonium nitrate solution is made, and ceric ammonium nitrate solution is added
Enter in 1,2,4- trimethoxy -6- geranyls-benzene (compound 3) solution, react 8min, ethyl acetate extraction, saturated aqueous common salt
Wash 3 times, add anhydrous sodium sulfate drying, and use column chromatography (volume ratio of ethyl acetate and petroleum ether be 1：10), it is made
Compound 4, yield is 38%.
Scabellone B preparation method, this method is specially：
Embodiment 8
0.073mmol compounds 4 are dissolved in 8ml dichloromethane, 0.365mmol 2,6- lutidines, room temperature is added
Lower stirring 6h, plus saturated ammonium chloride are quenched, ethyl acetate extraction, and anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (acetic acid
The volume ratio of ethyl ester and petroleum ether is 1：10) Scabellone B yields 40% are obtained.
Embodiment 9
0.073mmol compounds 4 are dissolved in 8ml methanol, 0.365mmol 2 is added, 6- lutidines is stirred at room temperature
6h is mixed, plus saturated ammonium chloride is quenched, ethyl acetate extraction, anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (ethyl acetate
Volume ratio with petroleum ether is 1：10) Scabellone B yields 35% are obtained.
Embodiment 10
0.073mmol compounds 4 are dissolved in 8ml dichloromethane, 0.365mmol 4- picolines is added, stirs at room temperature
6h is mixed, plus saturated ammonium chloride is quenched, ethyl acetate extraction, anhydrous sodium sulfate drying is spin-dried for, obtained through column chromatography for separation
(volume ratio of ethyl acetate and petroleum ether is 1 to ScabelloneB：10) yield 70%.
Embodiment 11
0.073mmol compounds 4 are dissolved in 8ml dichloromethane, 0.365mmol triethylamines is added, stirs at room temperature
30min, plus saturated ammonium chloride are quenched, ethyl acetate extraction, and anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (ethyl acetate
Volume ratio with petroleum ether is 1：10) Scabellone B yields 99% are obtained.
Embodiment 12
0.073mmol compounds 4 are dissolved in 8ml methanol, 0.365mmol triethylamines is added, 30min is stirred at room temperature,
Plus saturated ammonium chloride is quenched, ethyl acetate extraction, anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (ethyl acetate and oil
The volume ratio of ether is 1：10) Scabellone B yields 95% are obtained.
Embodiment 13
0.073mmol compounds 4 are dissolved in 8ml dichloromethane, adds at 0.365mmol triethylamines, 0 DEG C and stirs
30min, plus saturated ammonium chloride are quenched, ethyl acetate extraction, and anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (ethyl acetate
Volume ratio with petroleum ether is 1：10) Scabellone B yields 99% are obtained.
Embodiment 14
0.073mmol compounds 4 are dissolved in 8ml pyridines (pyridine is not only when solvent is used but also works as nitrogenous organic base use herein)
In, 60 DEG C are warming up to, 4h is reacted, plus saturated ammonium chloride is quenched, ethyl acetate extraction, anhydrous sodium sulfate drying is spin-dried for, through post layer
(volume ratio of ethyl acetate and petroleum ether is 1 for analysis separation：10) Scabellone B yields 69% are obtained.
Embodiment 15
0.073mmol compounds 4 are dissolved in 8ml dichloromethane, 0.292mmol triethylamines is added, stirs at room temperature
30min, plus saturated ammonium chloride are quenched, ethyl acetate extraction, and anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (ethyl acetate
Volume ratio with petroleum ether is 1：10) Scabellone B yields 85% are obtained.
Embodiment 16
0.073mmol compounds 4 are dissolved in 8ml dichloromethane, 0.438mmol triethylamines is added, stirs at room temperature
30min, plus saturated ammonium chloride are quenched, ethyl acetate extraction, and anhydrous sodium sulfate drying is spin-dried for, through column chromatography for separation (ethyl acetate
Volume ratio with petroleum ether is 1：10) Scabellone B yields 80% are obtained.
Spectrogram testing result and it is analyzed as follows：
Magnetic resonance detection is carried out to embodiment 1, the products therefrom of embodiment 11, detection data result is as follows：
Embodiment 1 the specific detection data of product be1HNMR(CDCl3, 400MHz)：δ=5.92 (2H, s), 4.99
(2H, t, J=4Hz), 4.84 (2H, t, J=4Hz), 3.82 (6H, s), 3.12 (2H, m), 2.90 (2H, m), 1.95 (4H, m),
1.87 (4H, m), 1.63 (6H, s), 1.55 (6H, s), 1.52 (6H, s) ppm；13CNMR (100MHz, CDCl3)：δ=185.49,
181.23,158.73,143.53,138.60,138.32,131.72,123.91,118.20,107.23,77.48,77.16,
76.84,56.51,39.71,26.95,26.50,25.72,17.74,16.37ppm.
The specific detection data of the products therefrom of embodiment 11 are：1HNMR(CDCl3, 400MHz)：δ=6.40 (1H, s, H-
7), 6.00 (1H, d, J=9.3Hz, H-5), 5.80 (1H, s, H-2), 5.50 (1H, brs, OH), 5.28 (1H, d, J=9.3Hz,
H-1 '), 5.06 (1H, m, H-2 "), 5.01 (1H, t, J=6.6Hz, H-6 "), 4.93 (1H, t, J=6.6Hz, H-5 '), 3.89
(3H, s, 8-OCH3), 3.80 (3H, s, 3-OCH3), 3.57 (1H, m, H-1 " a), 3.36 (1H, dd, J=17.5,9.1Hz, H-1 "
B), 1.97 (4H, m, H2-4 ', H2-5 "), 1.94 (2H, m, H2-3 '), 1.92 (3H, s, H3-9 '), 1.87 (2H, m, H2-4 "),
1.62 (3H, s, H3-9 "), 1.59 (3H, s, H3-8 '), 1.57 (3H, s, H3-10 "), 1.51 (3H, s, H3-7 '), 1.49 (3H,
S, H3-8 ")13CNMR (100MHz, CDCl3)：δ=182.7 (C-1), 178.9 (C-4), 157.9 (C-3), 151.5 (C-6a),
150.2 (C-8), 144.5 (C-2 '), 139.3 (C-9), 137.7 (C-10b), 137.2 (C-3 "), 131.9 (C-6 '), 131.8*
(C-7 "), 130.9 (C-4a), 126.9 (C-10), 124.4 (C-2 "), 123.9 (C-6 "), 123.7 (C-5 '), 116.9 (C-
1 '), 111.1 (C-10a), 107.4 (C-2), 98.5 (C-7), 67.8 (C-5), 56.3 (3-OCH3), 56.2 (8-OCH3), 40.0
(C-4 "), 39.9 (C-3 '), 26.7 (C-1 "), 26.4 (C-4 '), 26.3 (C-5 "), 25.8 (C-8 '), 25.7 (C-9 "), 17.7
(C-7 '), 17.6 (C-8 "), 17.4 (C-9 '), 16.7 (C-10 ").
1HNMR(CDCl3, 400MHz)：δ=6.40 (1H, s, H-7), 6.00 (1H, d, J=9.3Hz, H-5), 5.80 (1H,
S, H-2), 5.48 (1H, brs, OH), 5.28 (1H, d, J=9.3Hz, H-1 '), 5.06 (1H, m, H-2 "), 5.01 (1H, t, J=
6.6Hz, H-6 "), 4.93 (1H, t, J=6.6Hz, H-5 '), 3.89 (3H, s, 8-OCH3), 3.80 (3H, s, 3-OCH3), 3.57
(1H, m, H-1 " a), 3.36 (1H, dd, J=17.5,9.1Hz, H-1 " b), 1.98 (4H, m, H2-4 ', H2-5 "), 1.94 (2H,
M, H2-3 '), 1.93 (3H, s, H3-9 '), 1.87 (2H, m, H2-4 "), 1.62 (3H, s, H3-9 "), 1.59 (3H, s, H3-8 '),
1.56 (3H, s, H3-10 "), 1.50 (3H, s, H3-7 '), 1.49 (3H, s, H3-8 ")；13CNMR (100MHz, CDCl3)：δ=
182.6 (C-1), 178.7 (C-4), 157.8 (C-3), 151.4 (C-6a), 150.0 (C-8), 144.3 (C-2 '), 139.2 (C-
9), 137.6 (C-10b), 137.1 (C-3 "), 131.7* (C-6 '), 131.6* (C-7 "), 130.8 (C-4a), 126.8 (C-
10), 124.2 (C-2 "), 123.8 (C-6 "), 123.6 (C-5 '), 116.9 (C-1 '), 111.0 (C-10a), 107.3 (C-2),
98.4 (C-7), 67.6 (C-5), 56.1 (3-OCH3), 56.1 (8-OCH3), 39.8* (C-4 "), 39.7* (C-3 '), 26.5 (C-
1 "), 26.3* (C-4 '), 26.2* (C-5 "), 25.6* (C-8 '), 25.5* (C-9 "), 17.6* (C-7 '), 17.5* (C-8 "),
17.2 (C-9 '), 16.5 (C-10 ").
By detecting data it can be seen that this method prepares different chemical environments in compound 4, Scabellone B
In H atom go out that peak position is stable, free from admixture peak, purity is high, and separation property is good, and yield is high.
Due to embodiment 2 to the detection data of any products therefrom of embodiment 7 and the detection data of the products therefrom of embodiment 1
Identical, the detection data of embodiment 8 to any products therefrom of embodiment 14 are identical with the detection data of the products therefrom of embodiment 11,
Therefore, no longer to carrying out data analysis except embodiment 1, any products therefrom of embodiment 11.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the scope of the present invention.
Claims (8)
1. a kind of preparation method of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives, it is characterised in that this method by walking as follows
It is rapid to realize：
Step 1,1,2,4- trimethoxy-benzene is dissolved in tetrahydrofuran, stirring is lower to be added tetramethylethylenediamine and be cooled to -10
~0 DEG C, add after n-BuLi, 1~2h of reaction, add trim,ethylchlorosilane, react 20~40min, afterwards, quenched
Go out, extract, drying and column chromatography for separation, 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene is made；
Step 2, made from step 11,2,4- trimethoxy -3- trimethyls silicon substrate-benzene is dissolved in tetrahydrofuran, stirring it is lower plus
Enter tetramethylethylenediamine and be cooled to -75~-80 DEG C, add n-BuLi, be warming up to -10~0 DEG C of 1~2h of reaction, then add
Enter geranyl bromide, react 0.5~1.5h, afterwards, be quenched, extracted, dried and column chromatography for separation, 1,2,4- trimethoxies are made
Base -6- geranyls-benzene；
Step 3, made from step 21,2,4- trimethoxy -6- geranyls-benzene is dissolved in acetonitrile and 0~-40 DEG C are cooled to,
Ammonium ceric nitrate is dissolved in 2~4ml water again, ceric ammonium nitrate solution is made, and ceric ammonium nitrate solution is added into 1,2,4- front threes
In epoxide -6- geranyls-benzole soln, 3~8min is reacted, afterwards, is quenched, extracted, dried and column chromatography for separation, 2- is made
Methoxyl group -5- geranyl p-benzoquinone derivatives.
2. a kind of preparation method of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives according to claim 1, its feature exists
In, in the step 1, described 1, between 2,4- trimethoxy-benzenes, tetramethylethylenediamine, n-BuLi and trim,ethylchlorosilane
Mol ratio is 1：(1.5~2.5)：(1~1.5)：(1.5~2).
3. a kind of preparation method of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives according to claim 2, its feature exists
In, in the step 2, described 1,2,4- trimethoxy -3- trimethyls silicon substrates-benzene, tetramethylethylenediamine, n-BuLi and spiceleaf
The mol ratio of bromide is 1：(2~2.5)：(1~1.5)：(1.5~2).
4. a kind of preparation method of 2- methoxyl groups -5- geranyl p-benzoquinone derivatives according to claim 4, its feature exists
In in the step 3, described 1,2,4- trimethoxy -6- geranyls-benzene and ammonium ceric nitrate mole are 1：(4~5).
5. a kind of Scabellone B preparation method, it is characterised in that this method is specially：
1 to 4 any described 2- methoxyl group -5- geranyl p-benzoquinone derivatives are dissolved in organic solvent, addition is nitrogenous to be had
Machine alkali, 0.5~6h is stirred at 0~60 DEG C, and saturated ammonium chloride is quenched, and is extracted, is washed, drying, being used column chromatography after drying, being made
Obtain Scabellone B.
6. a kind of Scabellone B according to claim 8 preparation method, it is characterised in that the organic solvent is
One or more in dichloromethane, methanol, pyridine.
7. a kind of Scabellone B according to claim 9 preparation method, it is characterised in that described nitrogenous organic
Alkali is the one or more in 2,6- lutidines, 4- picolines, triethylamine.
8. a kind of Scabellone B according to claim 10 preparation method, it is characterised in that the 2- methoxyl groups-
5- geranyls p-benzoquinone derivative and the mol ratio of nitrogenous organic base are 1：(4~6).
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