CN107540689B - The synthetic method of anti-tumor drug - Google Patents

The synthetic method of anti-tumor drug Download PDF

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CN107540689B
CN107540689B CN201610464322.0A CN201610464322A CN107540689B CN 107540689 B CN107540689 B CN 107540689B CN 201610464322 A CN201610464322 A CN 201610464322A CN 107540689 B CN107540689 B CN 107540689B
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compound
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tumor drug
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CN107540689A (en
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乔创
张问
汉京春
李闯创
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Southwest University of Science and Technology
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Southwest University of Science and Technology
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Abstract

The present invention relates to a kind of synthetic methods of anti-tumor drug.The synthetic method of the anti-tumor drug use structural formula forCompound A construct the skeleton structure of molecule as initial reactant, and with combining efficient intramolecular [4+2] cycloaddition reaction and crucial ammonium ceric nitrate oxidation [3+2] rapid reaction, obtaining structural formula is

Description

The synthetic method of anti-tumor drug
Technical field
The present invention relates to the synthesis field of drug more particularly to a kind of synthetic methods of anti-tumor drug.
Background technique
Structural formula is(-)-Hypocrolide A acquired from Cangshan of Yunnan by After being separated in the meat seat bacterium separated in the saw armored scale category insect of load ear infection with the total amount of 3.7mg, research hair Existing its has good cytotoxicity to human tumor cell line HeLa, A549, and MCF-7, and IC50 value is respectively 11.8, 22.0 and 20.4 μM (cis-platinum is respectively 4.7,7.8 and 4.9 μM to the IC50 value of these three cell strains).
However, the yield for isolating (-)-Hypocrolide A from meat seat bacterium is lower, it is limited to a certain extent Using, and meat seat bacterium itself is expensive, so that (-)-Hypocrolide A's is expensive, its restricted application.
Summary of the invention
Based on this, it is necessary to a kind of synthetic method of anti-tumor drug is provided, with obtaining by chemically synthesized method (-)-Hypocrolide A of high yield, in favor of reducing its production cost.
A kind of synthetic method of anti-tumor drug, includes the following steps:
At room temperature, it is by structural formulaCompound A and trifluoroacetic acid It is dissolved in dioxane, 4,4- Dimethyl-cyclohex -2- alkene -1- ketone is then added and hydrogen peroxide reacts at 30~50 DEG C, obtains It is to structural formulaCompound B, wherein the molar ratio of the trifluoroacetic acid and the compound A is 1.5~ The molar ratio of 2.0:1, the compound A and 4, the 4- Dimethyl-cyclohex -2- alkene -1- ketone is 0.05~0.15:1, described double The molar ratio of oxygen water and the compound A are 12~18:1, and Me is methyl；
Anhydrous and under the conditions of -78 DEG C, by lithium diisopropylamine, hexamethylphosphoramide and the compound B in the It is reacted 1~3 hour in one organic solvent, obtains the first reaction solution, it is then that first reaction solution is anti-at -60~-40 DEG C It answers 2~4 hours, iodomethane is then added, and the reaction was continued at -60~-40 DEG C, and obtaining structural formula is's Compound C, wherein the molar ratio of the lithium diisopropylamine and the compound B are 1.0~1.5:1, the hempa The molar ratio of acyl triamine and the compound B are 3.0~4.5:1, and the molar ratio of the iodomethane and the compound B are 1.0 ~1.5:1；
Under conditions of -20 DEG C~-10 DEG C, by 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene, formaldehyde and described Compound C reacts 10~40 minutes in tetrahydrofuran, then reacts at room temperature again, obtains structural formula and isCompound D, wherein 1,8- diazabicylo [5.4.0], the 11 carbon -7- alkene and the compound The molar ratio of C is 1.7~2.3:1, and the molar ratio of the formaldehyde and the compound C are 3.4~4.6:1；
At room temperature, by the compound D and tert-butyl chloro-silicane, imidazoles, 4-dimethylaminopyridine in It is reacted in second organic solvent, obtaining structural formula isCompound E, wherein the tert-butyl diformazan The molar ratio of base chlorosilane and the compound D are 1.0~1.5:1, and the molar ratio of the imidazoles and the compound D are 1.0 ~1.5, it is fert-butyidimethylsilyl that the molar ratio of the 4-dimethylaminopyridine and the compound D, which are 0.05~0.20, OTBS, Siloxy；
At room temperature, the compound E, semicarbazide hydrochloride and sodium acetate are reacted in the mixed liquor of water and alcohol, Obtain crude product, wherein the molar ratio of the semicarbazide hydrochloride and the compound E are 5.0~10.0:1, the sodium acetate with The molar ratio of the compound E is 2.0~3.0:1；
Anhydrous and under conditions of -10~0 DEG C, lead tetraacetate and the crude product are reacted in methylene chloride, obtained Structural formula isCompound G, wherein the molar ratio of the lead tetraacetate and the compound E are 1.0 ~1.5:1；
Under the conditions of at -78 DEG C and anhydrous, n-BuLi is had with (Z)-butyl -2- alkene -1- diethyl phosphate in third It mixes in solvent, and is reacted 0.5~1 hour under conditions of 0 DEG C, being subsequently added into the compound G, the reaction was continued, obtains Two reaction solutions, wherein the molar ratio of the n-BuLi and the compound G are 2.0~3.0:1, (Z)-butyl -2- The molar ratio of alkene -1- diethyl phosphate and the compound G are 2.0~3.0:1；
Under conditions of -78 DEG C, second reaction solution is mixed with lithium diisopropylamine, then react 0.5 at 0 DEG C ~1 hour, di-tert-butyl dicarbonate is then added, and the reaction was continued, and obtaining structural formula is's Compound H, wherein the molar ratio of the lithium diisopropylamine and the compound G are 1.2~1.5:1, two carbonic acid two The molar ratio of the tert-butyl ester and the compound G are 2.0~3.0:1；
At room temperature, by (1,5- cyclo-octadiene) chlorine rhodium (I) dimer and the compound H in 2,2,2- trifluoro second It is reacted in alcohol, obtaining structural formula isCompound I, wherein (1, the 5- ring pungent two Alkene) molar ratio of chlorine rhodium (I) dimer and the compound H is 0.01~0.02:1；
Under conditions of protective gas, p-methyl benzenesulfonic acid and the compound I are flowed back instead in the 4th organic solvent It answers, obtaining structural formula isCompound K, wherein the p-methyl benzenesulfonic acid is with the compound I's Molar ratio is 2.0~3.0:1；
In anhydrous conditions, by potassium carbonate, to methoxy-benzyl chlorine and 2,6- resacetophenone is in the 5th organic solvent In reacted at 60~80 DEG C, obtaining structural formula isCompound M, wherein the potassium carbonate with it is described The molar ratio of 2,6- resacetophenones is 2.0~3.0:1, described to methoxy-benzyl chlorine and 2, the 6- resacetophenone Molar ratio be 1.5~2.0, wherein OPMB be to methoxy-benzyl oxygroup；
In anhydrous conditions, by sodium hydride and the compound M back flow reaction 10~40 minutes in the 6th organic solvent, It is subsequently added into dimethyl carbonate and continues back flow reaction, obtain third reaction solution, isolate water phase from the third reaction solution, adjust The pH value of the water phase is saved to 1~2, obtaining structural formula isCompound N, wherein the hydrogenation The molar ratio of sodium and the compound M are 7.0~10.0:1, and the molar ratio of the dimethyl carbonate and the compound M are 3.0 ~5.0:1；
Under conditions of protective gas, by ammonium ceric nitrate, copper acetate, the compound K and the compound N in acetic acid Middle reaction, obtaining structural formula isCompound O, wherein the ammonium ceric nitrate with it is described The molar ratio of compound K is 2.0~3.0:1, and the molar ratio of the copper acetate and the compound K is 2.0~3.0:1, described The molar ratio of compound N and the compound K is 2.0~3.0:1；
In anhydrous conditions, tetrahydrochysene lithium aluminium and compound O are reacted in the 7th organic solvent at -10~0 DEG C, is obtained Structural formula isCompound Q, wherein the tetrahydrochysene lithium aluminium is rubbed with the compound O's You are than being 2.0~3.0:1；
At -78 DEG C and under conditions of protective gas, oxalyl chloride and dimethyl sulfoxide are reacted 0.5 in methylene chloride~ Then 1.5 hour hour was added the compound Q and reacts 0.5~1.5 hour, and be subsequently added into triethylamine, after reacting at 0 DEG C Obtaining structural formula isCompound R, wherein the oxalyl chloride and the compound Q Molar ratio is 2.5~5.0:1, and the molar ratio of the dimethyl sulfoxide and the compound Q is 3.5~6.0:1, the triethylamine with The molar ratio of the compound Q is 6.0~10.0:1；
Under the conditions of 0 DEG C, trifluoroacetic acid is mixed in methylene chloride with the compound R, is then reacted at room temperature 10~20 hours, adding methanol, the reaction was continued, obtains the 4th reaction solution, is separated, and obtains structural formula and isAnti-tumor drug, wherein the molar ratio of the trifluoroacetic acid and the compound R is 8.0~12.0:1.
First organic solvent is tetrahydrofuran or ether in one of the embodiments,；Second organic solvent For methylene chloride or tetrahydrofuran；The third organic solvent is tetrahydrofuran or ether；4th organic solvent be toluene, Dimethylbenzene or trimethylbenzene；5th organic solvent is N,N-dimethylformamide or tetrahydrofuran；6th organic solvent For tetrahydrofuran or ether；7th organic solvent is ether or tetrahydrofuran.
In one of the embodiments, in the mixed liquor of the water and alcohol, the volume ratio of the alcohol and water is 1:1~2:1, The alcohol is ethyl alcohol or methanol.
In one of the embodiments, by the compound E, the semicarbazide hydrochloride and the sodium acetate in the water and The step of being reacted in the mixed liquor of alcohol specifically: mix the semicarbazide hydrochloride and the sodium acetate in the water, then The pure and mild compound E is added to be stirred to react.
The step of isolating the water phase from the third reaction solution in one of the embodiments, are as follows: described Water and ether is added in three reaction solutions so that the water phase and organic phase separate, and take out water phase.
The step of separating the anti-tumor drug from the 4th reaction solution in one of the embodiments, are as follows: by institute The 4th reaction solution vacuum concentration is stated, then through silica gel column chromatography, obtains the anti-tumor drug.
Further include in one of the embodiments, from the 4th reaction solution isolated structural formula beCompound S the step of and react the compound S to obtain the anti-tumor drug The step of, wherein the compound S is reacted into the step of obtaining the anti-tumor drug specifically: under the conditions of 0 DEG C, by three Fluoroacetic acid mixes in methylene chloride with the compound S, then reacts 0.5~1 hour at room temperature, is subsequently added into methanol continuation Reaction, then is separated, and obtains the anti-tumor drug, and the molar ratio of the trifluoroacetic acid and the compound S is 8.0~ 12.0:1。
The trifluoroacetic acid is reacted in the methylene chloride with the compound R in one of the embodiments, It further include by the trifluoroacetic acid and the compound R in the dichloro before the step of methanol is added after step The step of reaction solution concentration reacted in methane.
The iodomethane is added at -50 DEG C in first reaction solution after the reaction in one of the embodiments, After the step of the reaction was continued, using the aqueous solution quenching reaction of saturated ammonium chloride.
The lead tetraacetate and the crude product reacted in the methylene chloride in one of the embodiments, After step, adopts and reaction is quenched with water.
The synthetic method of above-mentioned anti-tumor drug can be achieved with chemically synthesized method by above-mentioned chemical step and be prepared into To the identical natural products of natural products (-)-Hypocrolide A structure, meanwhile, yield also with higher, avoid from In meat seat bacterium caused by extraction (-)-Hypocrolide A the problem of expensive and low yield, above-mentioned anti-tumor drug is not The cost for only advantageously reducing (-)-Hypocrolide A also adds its source, is conducive to it and is more widely applied.
Specific embodiment
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term " and or " used herein includes one or more phases Any and all combinations of the listed item of pass.
The synthetic method of the anti-tumor drug of one embodiment includes the following steps that (what wherein, the Me of this paper was represented is first Base):
Step S110: at room temperature, it is by structural formulaCompound A It is dissolved in dioxane with trifluoroacetic acid, 4,4- Dimethyl-cyclohex -2- alkene -1- ketone and hydrogen peroxide is then added 30~50 It is reacted at DEG C, obtaining structural formula isCompound B.
Wherein, compound A can be commercially available by market, and No. CAS is 287979-82-2.
Wherein, the molar ratio of trifluoroacetic acid and compound A are 1.5~2.0:1.
Wherein, the molar ratio of compound A and 4,4- Dimethyl-cyclohex -2- alkene -1- ketone is 0.05~0.15:1.
Wherein, the hydrogen peroxide of addition is the aqueous solution for the hydrogen peroxide that mass percentage is 25~35%.Hydrogen peroxide and change The molar ratio for closing object A is 12~18:1.
It wherein, after step silo, further include the purification step of compound B: by the anti-at 30~50 DEG C of step S110 Should after obtained reaction solution extracted using ether, then it is the organic phase extracted is dry with anhydrous sodium sulfate, filtering off sulphur removal Filtered organic phase is concentrated in vacuo by sour sodium, finally uses silica gel column chromatography, the compound B purified.
Step S120: anhydrous and under the conditions of -78 DEG C, by lithium diisopropylamine, hexamethylphosphoramide and compound B It is reacted 1~3 hour in the first organic solvent, obtains the first reaction solution, it is then that the first reaction solution is anti-at -60~-40 DEG C It answers 2~4 hours, iodomethane is then added, and the reaction was continued at -60~-40 DEG C, and obtaining structural formula is's Compound C.
Wherein, the first organic solvent is tetrahydrofuran or ether.
Wherein, the molar ratio of lithium diisopropylamine and compound B are 1.0~1.5:1.
Wherein, hexamethylphosphoramide and the molar ratio of compound B are 3.0~4.5:1.
Wherein, the molar ratio of iodomethane and compound B are 1.0~1.5:1.
Wherein, the reaction was continued at -60~-40 DEG C for addition iodomethane in the first reaction solution in step S120 after the reaction The step of after use the aqueous solution quenching reaction of saturated ammonium chloride.
Wherein, further include purification step to compound C: reaction is extracted with ethyl acetate in the reaction solution after quenching reaction Liquid, and the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through removal of sodium sulfate by filtration, vacuum concentration organic phase It is purified with silica gel column chromatography, the compound C purified.
Step S130: under conditions of -20 DEG C~-10 DEG C, by 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene, first Aldehyde and compound C react 10~40 minutes in tetrahydrofuran, then react at room temperature again, obtain structural formula and areCompound D.
Wherein, the molar ratio of 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene and compound C are 1.7~2.3:1.
Wherein, the molar ratio of formaldehyde and compound C are 3.4~4.6:1.
Wherein, in step s 130, the aqueous solution quenching reaction of saturated ammonium chloride can be used after room temperature reaction.
Wherein, further include purification step to compound D: reaction is extracted with ethyl acetate in the reaction solution after quenching reaction Liquid, and the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through removal of sodium sulfate by filtration, vacuum concentration organic phase It is purified with silica gel column chromatography, the compound D purified.
Step S140: at room temperature, by compound D and tert-butyl chloro-silicane, imidazoles, 4- dimethylamino pyrrole Pyridine is reacted in the second organic solvent, is obtained structural formula and isCompound E.
Wherein, OTBS is tertiary butyl dimethyl Si base.
Wherein, the molar ratio of tert-butyl chloro-silicane and compound D are 1.0~1.5:1；Imidazoles is with compound D's Molar ratio is 1.0~1.5:1；4-dimethylaminopyridine and the molar ratio of compound D are 0.05~0.20:1；Second organic solvent For methylene chloride or tetrahydrofuran.
Wherein, in step S140, by compound D and tert-butyl chloro-silicane, imidazoles, 4-dimethylaminopyridine in The aqueous solution quenching reaction of saturated ammonium chloride can be used after reacting in second organic solvent.
Wherein, further include purification step to compound E: reaction is extracted with ethyl acetate in the reaction solution after quenching reaction Liquid, and the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through filtering sodium sulphate, vacuum concentration organic phase and silicon Compound E that is gel column chromatography eluting, being purified.
Step S150: at room temperature, by compound E, semicarbazide hydrochloride and sodium acetate in the mixed liquor of water and alcohol Reaction is obtained containing crude product.
Wherein, the molar ratio of semicarbazide hydrochloride and compound E are 5.0~10.0:1；The molar ratio of sodium acetate and compound E For 2.0~3.0:1.
Wherein, in the mixed liquor of water and alcohol, the volume ratio of alcohol and water is 1:1~2:1.Alcohol is ethyl alcohol or methanol.
Wherein, the step of compound E, semicarbazide hydrochloride and sodium acetate react in the mixed liquor of water and alcohol specifically: will Semicarbazide hydrochloride and sodium acetate mix in water, and pure and mild compound E is then added and is stirred to react.
Wherein, it is containing structural formula in the crude product that step S150 is obtainedCompound F.
Step S160: anhydrous and under conditions of -10~0 DEG C, lead tetraacetate and crude product being reacted in methylene chloride, Obtaining structural formula isCompound G.
Wherein, the molar ratio of lead tetraacetate and compound E are 1.0~1.5:1.
Wherein, in step S160, water quenching can be used after lead tetraacetate and crude product are reacted in methylene chloride and go out instead It answers.
Wherein, the step of compound E, semicarbazide hydrochloride and sodium acetate being reacted in the mixed liquor of water and alcohol specifically: Semicarbazide hydrochloride and sodium acetate are mixed in water, pure and mild compound E is then added and is stirred to react.
Wherein, further include purification step to compound G: reaction is extracted with dichloromethane in the reaction solution after quenching reaction Liquid, and the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through removal of sodium sulfate by filtration, vacuum concentration organic phase It is purified with silica gel column chromatography, the compound E purified.
Step S170: under the conditions of at -78 DEG C and anhydrous, by n-BuLi and (Z)-butyl -2- alkene -1- diethyl phosphate It mixes in third organic solvent, and is reacted 0.5~1 hour under conditions of 0 DEG C, being subsequently added into compound G, the reaction was continued, obtains To the second reaction solution.
Wherein, the molar ratio of n-BuLi and compound G are 2.0~3.0:1；(Z)-butyl -2- alkene -1- diethyl phosphate Molar ratio with compound G is 2.0~3.0:1.
Wherein, third organic solvent is tetrahydrofuran or ether.
Step S180: under conditions of -78 DEG C, the second reaction solution being mixed with lithium diisopropylamine, then at 0 DEG C instead It answers 0.5~1 hour, di-tert-butyl dicarbonate is then added, and the reaction was continued, and obtaining structural formula isCompound H.
Wherein, the molar ratio of lithium diisopropylamine and compound G are 1.2~1.5:1；Di-tert-butyl dicarbonate with it is described The molar ratio of compound G is 2.0~3.0:1.
Wherein, the aqueous solution quenching reaction of saturated ammonium chloride can be used in step S180 after iodomethane reaction is added.
Wherein, further include purification step to compound H: reaction is extracted with ethyl acetate in the reaction solution after quenching reaction Liquid, and the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through removal of sodium sulfate by filtration, vacuum concentration organic phase It is purified with silica gel column chromatography, the compound H purified.
Step S190: at room temperature, by (1,5- cyclo-octadiene) chlorine rhodium (I) dimer and compound H 2,2,2- It is reacted in trifluoroethanol, obtaining structural formula isCompound I.
Wherein, the molar ratio of (1,5- cyclo-octadiene) chlorine rhodium (I) dimer and compound H are 0.01~0.02:1.
Wherein, further include purification step to compound I: by (1,5- cyclo-octadiene) chlorine rhodium (I) dimer and compound H Reaction solution vacuum concentration and silica gel column chromatography purifying after being reacted in 2,2,2- trifluoroethanols, the compound I purified.
Step S210: under conditions of protective gas, p-methyl benzenesulfonic acid and compound I are returned in the 4th organic solvent Stream reaction, obtaining structural formula isCompound K.
Wherein, the molar ratio of p-methyl benzenesulfonic acid and compound I are 2.0~3.0:1.
Wherein, the 4th organic solvent is toluene, dimethylbenzene or trimethylbenzene.
Wherein, protective gas is nitrogen or argon gas.
Wherein, the water-soluble of saturated sodium carbonate can be used after reacting under the reflux temperature of the 4th organic solvent in step S210 Liquid quenching reaction.
Wherein, further include purification step to compound I: the reaction solution after quenching reaction extracted with ethyl diacetate, And the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through removal of sodium sulfate by filtration, organic phase vacuum concentration and Silica gel column chromatography purifying, the compound I purified.
Step S220: in anhydrous conditions, by potassium carbonate, to methoxy-benzyl chlorine and 2,6- resacetophenone is the 5th It is reacted at 60~80 DEG C in organic solvent, obtaining structural formula isCompound M.
Wherein, potassium carbonate and 2, the molar ratio of 6- resacetophenone are 2.0~3.0:1；To methoxy-benzyl chlorine and 2, The molar ratio of 6- resacetophenone is 1.5~2.0, wherein.OPMB is to methoxy-benzyl oxygroup.
Wherein, the 5th organic solvent is n,N-Dimethylformamide or tetrahydrofuran.
Wherein, in step S220 by potassium carbonate, to methoxy-benzyl chlorine and 2,6- resacetophenone is organic the 5th Water quenching reaction can be used after reacting at 60~80 DEG C in solvent.
Wherein, further include purification step to compound I: the ether of the reaction solution after quenching reaction extracted into reaction solution, And the organic phase through extracting is dry using anhydrous sodium sulfate, then successively through removal of sodium sulfate by filtration, organic phase vacuum concentration and Silica gel column chromatography purifying, the compound I purified.
Step S230: in anhydrous conditions, by sodium hydride and compound M in the 6th organic solvent back flow reaction 10~40 Minute, it is subsequently added into dimethyl carbonate and continues back flow reaction, obtain third reaction solution, isolate water phase from third reaction solution, The pH value of water phase is adjusted to 1~2, obtaining structural formula isCompound N.
Wherein, the molar ratio of sodium hydride and compound M are 7.0~10.0:1, the molar ratio of dimethyl carbonate and compound M For 3.0~5.0:1.
Wherein, the 6th organic solvent is tetrahydrofuran or ether.
Wherein, the step of isolating water phase from third reaction solution are as follows: in third reaction solution water and ether is added so that Water phase and organic phase separation, and take out water phase.
Wherein, in step S230, the pH value of water phase is adjusted to 1~2 using hydrochloric acid.The concentration of hydrochloric acid is 2~6mol/L.
Wherein, further include purification step to compound N: the water phase for adjusting pH value extracts reaction solution with ether, and through extracting The organic phase of taking-up dries, filters removal sodium sulphate using anhydrous sodium sulfate, then organic phase is concentrated in vacuo, and adds dichloromethane Then water recrystallization, the compound N purified is added in alkane dissolution.
Step S240: under conditions of protective gas, by ammonium ceric nitrate, copper acetate, compound K and compound N in second It is reacted in acid, obtaining structural formula isCompound O.
Wherein, the molar ratio of ammonium ceric nitrate and compound K is 2.0~3.0:1；The molar ratio of copper acetate and compound K is 2.0~3.0:1；The molar ratio of compound N and compound K is 2.0~3.0:1.
Wherein, protective gas is argon gas or nitrogen.
It wherein, further include the purification step of compound O: in ammonium ceric nitrate, copper acetate, compound K and compound N in acetic acid The reaction solution obtained after middle reaction is added potassium carbonate and carries out neutralization reaction, then adopts the reaction after neutralization reaction is extracted with dichloromethane Liquid, and the organic phase through extracting is dry using anhydrous sodium sulfate, then is successively filtered and be concentrated in vacuo, and silica gel column layer is finally used Analysis, the compound O purified.
Step S250: in anhydrous conditions, by tetrahydrochysene lithium aluminium and compound O at -10~0 DEG C in the 7th organic solvent Reaction, obtaining structural formula isCompound Q.
Wherein, tetrahydrochysene lithium aluminium and the molar ratio of compound O are 2.0~3.0:1.7th organic solvent is ether or tetrahydro furan It mutters.
Wherein, in S250, tetrahydrochysene lithium aluminium and compound O use hydrogen-oxygen at 0 DEG C in the 7th organic solvent after reaction Change sodium quenching reaction.And the reaction solution after quenching reaction is filtered with diatomite, is successively really concentrated and silica gel column chromatography, is obtained pure The compound Q of change.
Step S260: under conditions of -78 DEG C and protective gas, oxalyl chloride and dimethyl sulfoxide is anti-in methylene chloride It answers 0.5~1.5 hour, compound Q is then added and reacts 0.5~1.5 hour, is subsequently added into triethylamine, after being reacted at 0 DEG C It is to structural formulaCompound R.
Wherein, the molar ratio of oxalyl chloride and compound Q is 2.5~5.0:1；The molar ratio of dimethyl sulfoxide and compound Q is 3.5~6.0:1；The molar ratio of triethylamine and compound Q is 6.0~10.0:1.
Wherein, protective gas is nitrogen or argon gas.
Wherein, further include the purification step of compound R: hydrochloric acid is added in the reaction solution being added after triethylamine reaction, then The reaction solution being extracted with dichloromethane after hydrochloric acid is added is adopted, and the organic phase through extracting is dry using anhydrous sodium sulfate, then passes through Removal of sodium sulfate by filtration, organic phase vacuum concentration, finally uses silica gel column chromatography, the compound R purified.
Step S270: under the conditions of 0 DEG C, trifluoroacetic acid is mixed in methylene chloride with compound R, then at room temperature Reaction 10~20 hours, adding methanol, the reaction was continued, obtains the 4th reaction solution, is separated, and obtains structural formula and isAnti-tumor drug.
Wherein, the molar ratio of trifluoroacetic acid and compound R is 8.0~12.0:1.
Wherein, anti-tumor drug step is separated from the 4th reaction solution are as follows: be concentrated in vacuo the 4th reaction solution, then through silica gel Column chromatography, obtains pure anti-tumor drug.
Wherein, after the step of trifluoroacetic acid being reacted in methylene chloride with compound R, the step of methanol is added it Before, further include the steps that for trifluoroacetic acid being concentrated with the reaction solution that compound R reacts in methylene chloride.Will by trifluoroacetic acid with The reaction solution concentration that compound R reacts in methylene chloride is until reaction solution is 2~3 milliliters.
Wherein, further include in the 4th reaction solution isolated structural formula beCompound The step of S and compound S is reacted into the step of obtaining anti-tumor drug, wherein react compound S to obtain anti-tumor drug The step of specifically: under the conditions of 0 DEG C trifluoroacetic acid is mixed in methylene chloride with compound S, then reacts 0.5 at room temperature ~1 hour, being subsequently added into methanol, the reaction was continued, then is separated, and anti-tumor drug is obtained, to improve the production of anti-tumor drug Rate.The molar ratio of trifluoroacetic acid and compound S are 8.0~12.0:1.
Wherein, isolated compound S can be obtained by silica gel column chromatography in the 4th reaction solution.
Wherein, the synthetic method of above-mentioned anti-tumor drug is not limited to prepare using said sequence, in other embodiments, step Rapid S220 can be prepared before step S110, or simultaneously with step S110.
The synthetic method of above-mentioned anti-tumor drug can be achieved with chemically synthesized method by above-mentioned chemical step and be prepared into To the identical natural products of natural products (-)-Hypocrolide A structure, meanwhile, yield also with higher, avoid from Problem expensive and lower yield caused by extraction (-)-Hypocrolide A, above-mentioned anti-tumor drug in meat seat bacterium The cost for not only contributing to reduce (-)-Hypocrolide A, also increases its source, is conducive to it and is more widely applied.
And above-mentioned synthetic method combines efficient intramolecular [4+2] cycloaddition reaction and crucial ammonium ceric nitrate to aoxidize [3+ 2] skeleton structure of molecule is constructed to rapid reaction, to obtain (-)-identical with Structures of Natural Products Hypocrolide A is conducive to people and carries out bioactivity research to (-)-Hypocrolide A, and passes through above-mentioned synthesis side Method is easy to modify its structure, to help to carry out pharmaceutical activity research to it.
The following are specific embodiment parts: where 0.25mm Haiyang Chemical Plant, Qingdao is used to produce when reaction detection Thin-layer chromatography silica gel plate (60F-254).The 200-300 mesh silica gel that column chromatography is generated using Qingdao Haiyang chemical industry, uses stone Oily ether boiling range is 60~90 DEG C.All infrared datas are measured by following instrument: Shimadzu IR Prestige21；It is all Nuclear magnetic resonance is measured by following instrument: Br ü ker Advance 500,400,300；All high-resolution data are by following Instrument measures: Bruker Apex IV FTMS；All optically-active data are measured by following instrument: Rudolph autopol I automatic polarimeter；Internal standard is done using non-deuterated solvent remaining in TMS or deuterated solvent.
Embodiment 1
The synthesis process of the anti-tumor drug of the present embodiment is as follows:
(1) compound A (16.1mmol) is dissolved in dioxane, obtains the dioxane solution of compound A；In room Under conditions of temperature, trifluoroacetic acid (32.2mmol) is added drop-wise in the dioxane solution of compound A, 4,4- diformazan is then added The stirring of base-hexamethylene -2- alkene -1- ketone (161mmol) after twenty minutes, then plus mass percentage be 30% hydrogen peroxide The aqueous solution of (242mmol) reacts 48 hours at 40 DEG C, and obtained reaction solution is extracted with ether, successively by the organic phase of extraction , filtering dry using anhydrous sodium sulfate and vacuum concentration, most the organic phase afterwards after being concentrated in vacuo is purified with silica gel column chromatography, is obtained To 20.4g compound B, yield 90%.Wherein, the detection data of compound B is as follows:
(c=1.0 chloroform)；IR(film)λmax 2960,2883,1671,1554,1110,1059, 1018,860；1H NMR (400MHz, CDCl3) δ 3.21 (d, J=4.0Hz, 1H), 3.16 (dd, J=4.0,1.1Hz, 1H), 2.35–2.42(m,1H),2.17–2.22(m,1H),1.86–1.92(m,1H),1.33–1.35(m,1H),1.20(s,3H), 1.05(s,3H)；13C NMR(100MHz,CDCl3)δ206.0,64.1,55.9,33.1,30.7,29.7,27.4,22.8； HRMS (ESI) C8H13O2+ [M+H]+molecular weight calculated value: 141.0910；Molecular weight measured value: 141.0911.
The synthesis path of compound B is as follows:
(2) compound B (7.1mmol) is dissolved in tetrahydrofuran, obtains the tetrahydrofuran solution of compound B；In nothing Under the conditions of water and -78 DEG C, by lithium diisopropylamine (8.6mmol) and hexamethylphosphoramide (25.6mmol) be added dropwise respectively in It in the tetrahydrofuran solution of compound B, reacts 2 hours, obtains the first reaction solution, then the reaction was continued under temperature is increased to -50 It 2.0 hours, is subsequently added into iodomethane (10.65mmol), continuation is reacted 3.0 hours at -50 DEG C, obtained reaction solution saturation Aqueous ammonium chloride solution is quenched, and ethyl acetate extracts reaction system, and anhydrous sodium sulfate dries, filters, and is concentrated in vacuo.Then silica gel is used Column chromatographic purifying obtains 0.72g compound C, yield 65%.Wherein, the detection data of compound C is as follows:
(c=1.0 chloroform)；IR(film)λmax 2959,2926,2872,1703,1464,1364, 1220,1048,1026,881,839,773；1H NMR(500MHz,CDCl3) δ 3.21 (d, J=3.8Hz, 1H), 3.15 (d, J= 3.6Hz, 1H), 2.24-2.09 (m, 1H), 1.63 (t, J=13.0Hz, 1H), 1.36 (dd, J=13.6,6.4Hz, 1H), 1.19 (s, 3H), 1.10 (d, J=7.0Hz, 3H), 1.08 (s, 3H)；13C NMR(125MHz,CDCl3)δ207.4,63.5,55.4, 38.1,37.5,31.1,27.8,22.7,16.2；HRMS(ESI)C9H15O2 +[M+H]+Molecular weight calculated value: 155.1067；Molecule Measure measured value: 155.1068.
The synthesis path of compound C is as follows:
(3) under conditions of -20 DEG C, by 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene (311.6mmol), formaldehyde Aqueous solution (mass percentage of formaldehyde is 37%) (mole of formaldehyde is 529.72mmol) and compound C (155.8mmol) is added in tetrahydrofuran solution, and reaction is warming up to room temperature after ten minutes, and the reaction was continued 3.0 hours, then uses Saturated aqueous ammonium chloride is quenched, and ethyl acetate extracts reaction system, and anhydrous sodium sulfate dries, filters, and is concentrated in vacuo, then uses Silica gel column chromatography purifying, obtains 23.2g compound D, yield 81%.Wherein, the detection data of compound D is as follows:
(c=1.0 chloroform)；IR(film)λmax 2975,2960,2893,1716,1261,1220, 773,668；1H NMR(400MHz,CDCl3) δ 3.53 (dd, J=10.6,4.1Hz, 1H), 3.44 (dd, J=10.5,7.5Hz, 1H), 3.35 (d, J=4.3Hz, 1H), 3.29 (dd, J=4.3,1.5Hz, 1H), 2.05-1.98 (m, 1H), 1.97 (d, J= 14.1Hz, 1H), 1.21 (s, 3H), 1.18 (d, J=14.1Hz, 1H), 1.15 (s, 3H), 1.08 (s, 3H)；13C NMR (10MHz,CDCl3)δ211.0,70.2,65.8,56.4,46.6,41.1,31.9,28.4,24.9,23.4；HRMS(ESI) C10H17O3 +[M+H]+Molecular weight calculated value: 185.1172；Molecular weight measured value: 185.1171.
The synthesis path of compound D is as follows:
(4) at room temperature, by compound D (81.4mmol), tert-butyl chloro-silicane (97.7mmol), imidazoles (81.4mmol) and 4-dimethylaminopyridine (4.1mmol) are dissolved in methylene chloride, are stirred overnight, and saturated ammonium chloride is then used Aqueous solution is quenched, then is successively extracted with dichloromethane, anhydrous sodium sulfate drying, filters and be concentrated in vacuo, and finally uses silica gel column layer Analysis purifying, obtains 23.0g compound E, yield 95%.Wherein, the detection data of compound E is as follows:
(c=1.0 chloroform)；IR(film)λmax 2958,2931,2858,1733,1699,1464, 1456,1260,1108,935,836；1H NMR(400MHz,CDCl3) δ 3.47 (dd, J=23.9,9.2Hz, 2H), 3.28 (d, J =4.3Hz, 1H), 3.19-3.21 (m, 1H), 2.04 (d, J=14.0Hz, 1H), 1.16 (s, 3H), 1.10 (dd, J=14.0, 1.6Hz,1H),1.06(s,3H),1.02(s,3H),0.86(s,9H),-0.01(s,6H)；13C NMR(100MHz,CDCl3)δ 210.5,70.2,65.6,56.5,47.2,41.5,32.0,28.5,25.7,24.7,23.3,18.2,-5.6,-5.6；HRMS (ESI)C16H30O3NaSi+[M+Na]+Molecular weight calculated value: 321.1856；Molecular weight measured value: 321.1856.
The synthesis path of compound E is as follows:
(5) at room temperature, semicarbazide hydrochloride (352mmol) and sodium acetate (140.8mmol) are dissolved in 200mL water In, 400mL ethyl alcohol and compound E (70.4mmol) is then added, is stirred overnight.Then dry hang is extracted with dichloromethane to do, Obtain the crude product containing compound F of 10.0g.Crude product is dissolved in anhydrous methylene chloride, obtain the dichloro of crude product Dichloromethane lead tetraacetate (70.4mmol) is added in the dichloromethane solution of crude product anhydrous and under conditions of 0 DEG C, Reaction 1 hour.Then it is quenched with water, and successively makes to be extracted with dichloromethane dry reaction system, anhydrous sodium sulfate, filtering and true Sky concentration, is finally purified with silica gel column chromatography, obtains 10.0g compound G, yield 50%.Wherein, the detection data of compound G It is as follows:
(c=1.0 chloroform)；IR(film)λmax 2956,2929,2857.59,1728,1472, 1363,1251,1098,1006,837,776,669,636；1H NMR(400MHz,CDCl3) δ 9.56 (s, 1H), 3.49 (d, J= 9.5Hz, 1H), 3.38 (d, J=9.5Hz, 1H), 2.11 (s, 1H), 1.95 (d, J=14.6Hz, 1H), 1.70 (d, J= 14.6Hz, 1H), 1.18 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H), 0.89 (d, J=2.9Hz, 9H), 0.05 (s, 6H)13C NMR(100MHz,CDCl3)δ206.4,88.6,71.8,70.4,46.2,44.0,35.9,29.7,25.9,25.8,23.5, 23.1,18.3；HRMS(ESI)calcd for C16H30O2NaSi+[M+Na]+Molecular weight calculated value: 305.1907；Molecular weight is real Measured value: 305.1908.
The synthesis path of compound G is as follows:
(6) (Z)-fourth will in the anhydrous tetrahydro furan of (Z)-butyl -2- alkene -1- diethyl phosphate (9.6mmol), be obtained The tetrahydrofuran solution of base -2- alkene -1- diethyl phosphate, under the conditions of then anhydrous with -78 DEG C, by n-BuLi (9.6mmol) is added in the tetrahydrofuran solution of (Z)-butyl -2- alkene -1- diethyl phosphate, and stirring was warming up to 0 after 0.5 hour DEG C continue stirring 0.5 hour, compound G (3.2mmol) then is added, after reaction 0.5 hour, obtain the second reaction solution, by the Two reaction solutions are cooled to -78 DEG C, are added lithium diisopropylamine (4.8mmol), and stirring is warming up to 0 DEG C after 0.5 hour and continues to stir It mixes 0.5 hour, di-tert-butyl dicarbonate (6.4mmol) then is added, react 0.5 hour, it is then water-soluble using saturated ammonium chloride Liquid is quenched, and successively through methylene chloride extraction reaction system, anhydrous sodium sulfate drying, filtering and vacuum concentration, finally uses silicagel column Chromatographic purifying obtains 1.1g compound H, yield 85%.Wherein, the detection data of compound H is as follows:
(c=1.0 chloroform)；IR(film)λmax 2957,2926,2855,2361,2332,1811, 1757,1709,1458,1373,1260,1119,1078,1020,800；1H NMR(500MHz,CDCl3) δ 6.26 (ddd, J= 15.5,10.8,0.9Hz, 1H), 6.06-5.93 (m, 1H), 5.79 (d, J=15.5Hz, 1H), 5.34-5.40 (m, 1H), 3.46 (dd, J=25.4,9.4Hz, 2H), 1.77-1.69 (m, 4H), 1.54 (d, J=14.3Hz, 1H), 1.47 (s, 9H), 1.20 (s, 3H), 1.17 (d, J=3.2Hz, 6H), 0.90 (s, 9H), 0.04 (s, 6H)；13C NMR(125MHz,CDCl3)δ153.1, 144.3,130.0,124.0,120.9,91.6,82.5,76.8,70.2,48.7,36.9,36.9,29.3,29.1,28.0, 25.9,25.0,18.3,13.4,-5.4,-5.5；HRMS(ESI)C25H44O3NaSi+[M+Na]+Molecular weight calculated value: 443.2952；Molecular weight measured value: 443.2953.
The synthesis path of compound H is as follows:
(7) compound H dissolution (7.1mmol) is dissolved in 2,2,2- trifluoroethanols, obtains the 2 of compound H, 2,2- tri- Fluoroethanol solution；At room temperature, (1,5- cyclo-octadiene) chlorine rhodium (I) dimer (0.07mmol) is added compound H's It in 2,2,2- trifluoroethanol solution, reacts 2.0 hours, reaction solution is concentrated in vacuo, then use silica gel column chromatography separating purification, point 2.28g compound I, yield 76% and 0.50g compound J, yield 15% are not obtained.Wherein, the detection data of compound I and J It is as follows:
Compound I:(c=1.0 chloroform)；IR(film)λmax 2957,2928,2859,2361, 1717,1462,1391,1368,1252,11589,1094,1069,837,804,775；1H NMR(500MHz,CDCl3)δ 5.70-5.74 (m, 1H), 5.54-5.56 (m, 1H), 3.93 (d, J=8.7Hz, 1H), 3.44 (d, J=8.7Hz, 1H), 3.26- 3.10 (m, 1H), 2.75-2.58 (m, 1H), 2.10 (d, J=12.8Hz, 1H), 1.50 (s, 9H), 1.23 (d, J=12.7Hz, 1H), 1.13 (s, 3H), 1.08 (s, 3H), 1.00 (d, J=7.0Hz, 3H), 0.90-0.85 (m, 9H), 0.71 (s, 3H), 0.03 (s,6H)；13C NMR(125MHz,CDCl3)δ169.6,149.8,130.79,129.2,122.8,80.4,71.3,52.9, 51.9,46.0,38.8,34.9,28.1,27.5,25.9,24.2,23.1,21.0,18.1,-5.3,-5.4；HRMS(ESI) C25H44O3NaSi+[M+Na]+Molecular weight measured value: 443.2952；Molecular weight calculated value: 443.2953.
Compound J:(c=1.0 chloroform)；IR(film)λmax 2957,2928,2857,2359, 1713,1634,1464,1368,1252,1165,1088,1057,837,776；1H NMR(500MHz,CDCl3)δ5.70–5.74 (m, 1H), 5.61-5.54 (m, 1H), 3.72 (d, J=9.1Hz, 1H), 3.38 (d, J=9.1Hz, 1H), 3.21-3.10 (m, 1H), 2.77-2.79 (m, 2.5Hz, 1H), 2.04 (d, J=13.5Hz, 1H), 1.51 (s, 9H), 1.32 (s, 3H), 1.23 (d, J =13.5Hz, 1H), 1.08 (s, 3H), 1.02 (d, J=7.0Hz, 3H), 0.88 (s, 9H), 0.67 (s, 3H), 0.01 (s, 6H) .13C NMR(125MHz,CDCl3)δ169.9,148.6,130.9,128.8,122.5,80.6,67.5,51.0,50.9,46.2, 39.0,34.9,28.1,28.0,27.0,25.9,23.7,20.6,18.2,-5.3,-5.4；HRMS(ESI)c C25H44O3NaSi+ [M+Na]+Molecular weight measured value: 443.2952；Molecular weight calculated value: 443.2953.
The synthesis path of compound I is as follows:
(8) compound I (4.3mmol) is dissolved in toluene, obtains the toluene solution of compound I；Then in nitrogen atmosphere Under enclosing, p-methyl benzenesulfonic acid (12.9mmol) is added in the toluene solution for closing object I, 120 DEG C is heated to and is stirred at reflux overnight, obtain Reaction solution be quenched with saturated sodium bicarbonate aqueous solution, then successively through ethyl diacetate extraction, anhydrous sodium sulfate is dry, filtering And vacuum concentration, finally purified with silica gel column chromatography, obtains 0.9g compound K, yield 90%.Wherein, the testing number of compound K According to as follows:
(c=1.0 chloroform)；IR(film)λmax 2924,2862,1712,1458,1381,1203, 1003；1HNMR(300MHz,CDCl3) δ 5.73 (dd, J=6.4,2.6Hz, 1H), 4.22 (d, J=10.3Hz, 1H), 3.99 (d, J=10.3Hz, 1H), 2.90-2.71 (m, 1H), 2.61 (ddd, J=17.5,9.8,2.6Hz, 1H), 2.25 (dd, J=17.6, 6.4Hz, 1H), 1.73 (d, J=13.1Hz, 1H), 1.52 (d, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.18 (s, 3H), 0.88 (d, J=7.0Hz, 3H)；13C NMR(100MHz,CDCl3)δ165.2,158.8,145.8,121.4,119.8,78.6, 51.0,41.7,38.9,31.7,31.0,31.0,23.1,23.0,17.9；HRMS(ESI)C15H21O2[M+H]+Molecular weight calculates Value: 233.1536；Molecular weight measured value: 233.1539.
The synthesis path of compound K is as follows:
(9) 2,6- resacetophenone (131.6mmol) is dissolved in n,N-Dimethylformamide, obtains 2,6- dihydroxy The N,N-dimethylformamide solution of benzoylformaldoxime；Then in anhydrous conditions, 2,6- bis- is added in potassium carbonate (263.2mol) In the n,N-Dimethylformamide solution of hydroxy acetophenone, 60 DEG C are warming up to, is stirred to react 1.0 hours, is then added to methoxy Base benzyl chloride (263.2mmol), at 60 DEG C, the reaction was continued 3.0 hours, then is quenched with aqueous solution, and obtained reaction solution successively uses second Ether extraction, anhydrous sodium sulfate are dried, filtered and are concentrated in vacuo, and are finally purified with silica gel column chromatography, are obtained 20.0g compound M, are produced Rate 56%.Wherein, the detection data of compound M is as follows:
IR(film)λmax2994,1767,1612,1458,1373,1242,1057,495；1H NMR(400MHz, CDCl3) δ 13.27 (s, 1H), 7.32-7.36 (m, 3H), 6.93 (d, J=8.5Hz, 2H), 6.53 (dd, J=41.3,8.3Hz, 2H),5.05(s,2H),3.83(s,3H),2.58(s,3H)；13C NMR(100MHz,CDCl3)δ205.2,164.7,160.7, 159.7,136.1,129.7,127.7,114.1,111.5,110.8,102.1,70.8,55.3,34.1；HRMS(ESI) C16H16NaO4[M+Na]+Molecular weight calculated value: 295.0941；Molecular weight measured value: 295.0942.
The synthesis path of compound M is as follows:
(10) compound M (73.5mmol) is dissolved in tetrahydrofuran, obtains the tetrahydrofuran solution of compound M；It connects In anhydrous conditions, by sodium hydride (600mmol) be added compound M tetrahydrofuran solution in, be heated to 60 DEG C and stir back Then stream 10 minutes is added dimethyl carbonate (220.5mmol) and flows back 3 hours at 60 DEG C, obtains third reaction solution, will Third reaction solution is added in 250mL water and 50mL ether, isolates water phase, and the salt acid for adjusting pH of 6mol/L is added extremely in water phase 2, water phase is finally extracted with dichloromethane, then be successively dried over anhydrous sodium sulfate, filter and be concentrated in vacuo, finally uses methylene chloride It is recrystallized with water, obtains 18.0g compound N, yield 82%.Wherein, the detection data of compound N is as follows:
IR(film)λmax2932,2361,1767,1721,1651,1612,1466,1242,1065,818,748；1H NMR(400MHz,CDCl3)δ9.65(s,1H),7.55–7.30(m,3H),7.08–6.83(m,4H),5.62(s,1H),5.18 (s,2H),3.83(s,3H)；13C NMR(100MHz,CDCl3)δ166.0,160.4,155.4,155.0,132.5,130.0, 125.8,114.5,111.3,106.8,105.1,99.9,92.8,72.5,55.3；HRMS(ESI)C17H14NaO5[M+Na]+Point Son amount calculated value: 321.0733；Molecular weight measured value: 321.0735.
The synthesis path of compound N is as follows:
(11) compound K (2.12mmol) and compound N (4.22mmol) are dissolved in acetic acid, obtain compound K and The acetic acid solution of compound N；Then under nitrogen atmosphere, ammonium ceric nitrate (6.36mmol) and copper acetate (6.36mmol) are added In the acetic acid solution of compound K and compound N, it is stirred overnight at room temperature, obtained reaction solution is used to be neutralized with 40g potassium carbonate, then according to It is secondary to be obtained through methylene chloride extraction, anhydrous sodium sulfate drying, filtering and vacuum concentration finally with silica gel column chromatography separating purification 520mg compound O, yield 47% obtain 200mg compound P, yield 18%.Wherein, the testing number of compound O and compound P According to as follows:
Compound O:(c=1.0i chloroform)；IR(film)λmax 2924,2338,1767,1612, 1466,1373,1242,1049,918,756；1H NMR(400MHz,CDCl3) δ 7.47 (t, J=8.4Hz, 1H), 7.35 (d, J =8.5Hz, 2H), 6.99 (d, J=8.4Hz, 1H), 6.91 (d, J=8.6Hz, 2H), 6.83 (d, J=8.4Hz, 1H), 5.02 (dd, J=24.2,10.3Hz, 2H), 4.01 (s, 2H), 3.84 (d, J=5.6Hz, 3H), 3.35 (dd, J=10.1,5.0Hz, 1H), 2.80-2.82 (m, 1H), 2.06-2.12 (m, 1H), 1.82-1.72 (m, 1H), 1.60 (s, 1H), 1.35 (d, J= 13.6Hz, 1H), 1.06 (d, J=7.1Hz, 3H), 1.03 (s, 3H), 0.97 (s, 3H), 0.84 (s, 3H)；13C NMR (100MHz,CDCl3)δ165.6,163.3,159.9,156.6,155.9,155.1,132.8,130.6,129.8,127.7, 114.1,109.7,106.4,106.2,103.4,99.5,97.6,77.6,71.3,55.4,47.6,45.4,37.1,33.7, 32.4,26.1,25.4,22.8,22.5,18.1；HRMS(ESI)C32H33O7[M+H]+Molecular weight calculated value: 529.2221；Molecule Measure measured value: 529.2224.
Compound P:(c=1.0 chloroform)；IR(film)λmax 3672,2924,1759,1573, 1458,1381,1242,1049,956,856,756；1H NMR(400MHz,CDCl3) δ 12.81 (s, 1H), 7.45 (t, J= 8.3Hz, 1H), 6.85 (ddd, J=13.9,8.3,0.9Hz, 2H), 4.15 (dd, J=24.5,10.6Hz, 2H), 3.58 (dd, J =9.8,5.0Hz, 1H), 2.90 (dd, J=11.7,4.7Hz, 1H), 2.18-2.10 (m, 1H), 1.97 (d, J=13.8Hz, 1H), 1.95-1.85 (m, 1H), 1.61 (d, J=13.8Hz, 1H), 1.46 (s, 3H), 1.15 (s, 3H), 1.13 (d, J= 7.1Hz,3H),1.05(s,3H)；13CNMR(100MHz,CDCl3)δ179.9,168.3,162.9,161.1,153.7, 153.66,133.7,131.4,112.9,109.7,106.9,99.6,98.7,77.6,47.9,45.4,37.3,34.2,32.1, 26.3,25.6,24.0,22.0,18.1；HRMS(ESI)C24H24NaO6[M+Na]+Molecular weight calculated value: 409.1646；Molecular weight Measured value: 431.1462.
The synthesis path of compound O and compound P are as follows:
(12) compound O (0.19mmol) is dissolved in ether, obtains the diethyl ether solution of compound O；Then anhydrous Under the conditions of, tetrahydrochysene lithium aluminium (0.38mmol) is added in the diethyl ether solution of compound O, is reacted 2 hours at 0 DEG C, then use 3mol/ The sodium hydroxide of L is quenched, and is then successively filtered and is concentrated in vacuo with diatomite, finally purified with silica gel column chromatography, obtain 85mg Compound Q, yield 87%.Wherein, the detection data of compound Q is as follows:
(c=0.50 chloroform)；IR(film)λmax 2927,2338,1767,1697,1612,1466, 1373,1250,1096,1034,895,756；1H NMR(500MHz,CDCl3) δ 7.41 (t, J=8.4Hz, 1H), 7.37-7.30 (m, 2H), 6.95 (dd, J=8.4,0.6Hz, 1H), 6.93-6.87 (m, 2H), 6.77 (d, J=8.2Hz, 1H), 5.01 (dd, J =34.1,10.7Hz, 2H), 4.25 (d, J=11.3Hz, 1H), 4.01 (d, J=11.3Hz, 1H), 3.83 (s, 3H), 3.64 (d, J=11.6Hz, 1H), 3.56 (dd, J=5.4,2.3Hz, 1H), 3.48 (d, J=11.6Hz, 1H), 2.84 (s, 1H), 2.54-2.57 (m, 1H), 2.28-2.33 (m, 1H), 2.22 (s, 1H), 1.63 (q, J=13.0Hz, 2H), 1.32-1.38 (m, 1H), 1.17 (d, J=7.0Hz, 3H), 0.99 (s, 6H), 0.84 (s, 3H)；13C NMR(125MHz,CDCl3)δ166.7, 160.4,159.8,156.4,155.9,143.1,141.4,132.3,130.1,128.0,114.0,109.6,106.4, 106.0,104.0,103.1,71.6,70.9,59.5,55.4,52.2,45.5,41.9,36.3,33.7,29.7,25.8, 24.1,21.3,18.4；HRMS(ESI)C32H36NaO7[M+Na]+Molecular weight calculated value: 555.2353；Molecule measuring magnitude: 555.2354.
The synthesis path of compound Q is as follows:
(13) under the conditions of -78 DEG C, in nitrogen atmosphere, by oxalyl chloride (0.95mmol) and dimethyl sulfoxide (1.44mmol) It is added in methylene chloride, after reaction 0.5 hour, is added compound Q (0.38mmol), three second are added after the reaction was continued 0.5 hour Amine (2.51mmol), stirring are warming up to 0 DEG C and react 0.5 hour after 0.5 hour, the hydrochloric acid for being subsequently added into 10mL 3.0mol/L is quenched It goes out reaction, obtains reaction solution and be extracted with dichloromethane, then be successively dried over anhydrous sodium sulfate, filter and be concentrated in vacuo, finally use Silica gel column chromatography purifying, obtains 180mg compound R, yield 90%.Wherein, the detection data of compound R is as follows:
(c=0.50in CHCl3)；IR(film)λmax 2361,1767,1612,1512,1366, 1258,1026,756；1H NMR(400MHz,CDCl3) δ 9.58 (s, 1H), 9.53 (s, 1H), 7.47 (t, J=8.4Hz, 1H), 7.34 (d, J=8.6Hz, 2H), 6.99 (d, J=8.3Hz, 1H), 6.91 (d, J=8.6Hz, 2H), 6.82 (d, J=8.3Hz, 1H), 5.00 (dd, J=27.7,10.3Hz, 2H), 3.83 (s, 3H), 3.56 (t, J=5.4Hz, 1H), 1.79 (s, 1H), 1.66 (d, J=7.6Hz, 1H), 1.59 (s, 3H), 1.17 (d, J=7.0Hz, 3H), 1.02 (s, 3H), 0.99 (s, 3H), 0.87 (s, 3H)；13C NMR(100MHz,CDCl3)δ200.2,191.6,165.8,160.0,159.9,156.5,155.9,153.3, 143.1,132.8,130.5,127.7,114.1,109.7,106.4,104.4,103.5,103.2,71.1,55.4,53.7, 49.0,43.6,34.7,33.2,26.3,23.5,23.1,20.7,19.1；HRMS(ESI)C32H33O7[M+H]+Molecular weight calculates Value: 529.2221；Molecular weight measured value: 529.2219.
The synthesis path of compound R is as follows:
(14) compound R (0.57mmol) is dissolved in 150ml methylene chloride, the methylene chloride for obtaining compound R is molten Liquid；Under the conditions of 0 DEG C, trifluoroacetic acid (5.70mmol) is added in the dichloromethane solution of compound R, is reacted after being warmed to room temperature Overnight, then reaction solution concentration is added 50mL methanol solution, is stirred at room temperature 12 hours, obtains the 4th reaction solution, by the 4th reaction Liquid vacuum concentration.Then it is isolated and purified with silica gel column chromatography F, obtains 80mg anti-tumor drug (-)-HypocrolideA, yield 31%, also obtain 77mg compound S, yield 30%.Wherein, the detection data of (-)-Hypocrolide A and compound S is such as Under:
(-)-Hypocrolide A:(c=0.50 chloroform)；Rf=0.45 (hexane/ethyl Acetate=3/1)；IR(film)λmax 3487,3449,2924,1721,1628,1466,1350,1265,1018,794, 748；1H NMR(400MHz,CDCl3) δ 7.42 (t, J=8.3Hz, 1H), 7.21 (s, 1H), 6.92 (d, J=8.4Hz, 1H), 6.77 (d, J=8.3Hz, 1H), 5.07 (s, 1H), 4.50 (s, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.45 (dd, J= 9.4,5.0Hz, 1H), 2.37 (dd, J=11.9,7.2Hz, 1H), 2.06-1.96 (m, 1H), 1.88 (ddd, J=13.4,9.4, 4.3Hz, 1H), 1.81 (d, J=14.1Hz, 1H), 1.73 (d, J=14.2Hz, 1H), 1.28 (s, 3H), 1.16 (d, J= 7.1Hz,3H),1.04(s,3H),0.96(s,3H)；13C NMR(100MHz,CDCl3)δ164.6,159.9,155.5,153.4, 138.9,137.9,133.5,110.9,108.9,106.0,105.6,101.8,101.2,100.3,56.9,55.9,47.6, 45.3,41.7,35.4,33.4,28.4,27.1,22.9,21.3,17.9；HRMS(ESI)C26H30NaO7[M+Na]+Molecular weights Calculation value: 477.1884；Molecular weight measured value: 477.1882.
Compound S:(c=0.50 chloroform)；IR(film)λmax 3500,2993,2361,1767, 1628,1466,1373,1242,1049,756；1H NMR(400MHz,CDCl3) δ 7.41 (t, J=8.3Hz, 1H), 7.21 (s, 1H), 6.91 (d, J=8.3Hz, 1H), 6.75 (d, J=8.3Hz, 1H), 5.20 (s, 1H), 4.63 (s, 1H), 3.48 (dd, J= 8.3,5.2Hz,1H),3.45(s,3H),3.43(s,3H),2.46–2.50(m,1H),2.08–1.99(m,2H),1.97–1.88 (m, 1H), 1.63 (d, J=13.4Hz, 1H), 1.43 (s, 3H), 1.08 (d, J=7.1Hz, 3H), 1.06 (s, 3H), 0.98 (s, 3H)；13C NMR(100MHz,CDCl3)δ164.5,159.9,155.3,153.3,137.3,135.7,133.3,110.7, 108.7,106.4,106.1,105.2,101.3,94.0,55.7,54.3,47.5,44.1,41.1,34.0,33.6,29.3, 26.2,25.2,23.2,17.1；HRMS(ESI)C26H30NaO7[M+Na]+Molecular weight calculated value: 477.1884；Molecular weight actual measurement Value: 477.1882.
The synthesis path of (-)-Hypocrolide A and compound S are as follows:
(16) compound S (0.17mmol) is dissolved in methylene chloride, obtains the dichloromethane solution of compound S；It connects Under the conditions of 0 DEG C, trifluoroacetic acid (1.70mmol) is added in the dichloromethane solution of compound S, it is 1 small to be warmed to room temperature reaction When, concentration of reaction solution, and the methanol of 2.0mL is added, it is stirred at room temperature 12 hours, then be concentrated in vacuo, it is then pure with silica gel column chromatography Change, obtains 32mg anti-tumor drug (-)-Hypocrolide A, yield 42% also obtains 32mg compound S, yield 42%.Its In, the detection data of (-)-Hypocrolide A obtained suddenly step by step and compound S is as follows:
(-)-Hypocrolide A:(c=0.50 chloroform)；Rf=0.45 (hexane/ethyl Acetate=3/1)；IR(film)λmax 3487,3449,2924,1721,1628,1466,1350,1265,1018,794, 748；1H NMR(400MHz,CDCl3) δ 7.42 (t, J=8.3Hz, 1H), 7.21 (s, 1H), 6.92 (d, J=8.4Hz, 1H), 6.77 (d, J=8.3Hz, 1H), 5.07 (s, 1H), 4.50 (s, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.45 (dd, J= 9.4,5.0Hz, 1H), 2.37 (dd, J=11.9,7.2Hz, 1H), 2.06-1.96 (m, 1H), 1.88 (ddd, J=13.4,9.4, 4.3Hz, 1H), 1.81 (d, J=14.1Hz, 1H), 1.73 (d, J=14.2Hz, 1H), 1.28 (s, 3H), 1.16 (d, J= 7.1Hz,3H),1.04(s,3H),0.96(s,3H)；13C NMR(100MHz,CDCl3)δ164.6,159.9,155.5,153.4, 138.9,137.9,133.5,110.9,108.9,106.0,105.6,101.8,101.2,100.3,56.9,55.9,47.6, 45.3,41.7,35.4,33.4,28.4,27.1,22.9,21.3,17.9；HRMS(ESI)C26H30NaO7[M+Na]+Molecular weights Calculation value: 477.1884；Molecular weight measured value: 477.1882.
Compound S:(c=0.50 chloroform)；IR(film)λmax 3500,2993,2361,1767, 1628,1466,1373,1242,1049,756；1H NMR(400MHz,CDCl3) δ 7.41 (t, J=8.3Hz, 1H), 7.21 (s, 1H), 6.91 (d, J=8.3Hz, 1H), 6.75 (d, J=8.3Hz, 1H), 5.20 (s, 1H), 4.63 (s, 1H), 3.48 (dd, J= 8.3,5.2Hz,1H),3.45(s,3H),3.43(s,3H),2.46–2.50(m,1H),2.08–1.99(m,2H),1.97–1.88 (m, 1H), 1.63 (d, J=13.4Hz, 1H), 1.43 (s, 3H), 1.08 (d, J=7.1Hz, 3H), 1.06 (s, 3H), 0.98 (s, 3H)；13C NMR(100MHz,CDCl3)δ164.5,159.9,155.3,153.3,137.3,135.7,133.3,110.7, 108.7,106.4,106.1,105.2,101.3,94.0,55.7,54.3,47.5,44.1,41.1,34.0,33.6,29.3, 26.2,25.2,23.2,17.1；HRMS(ESI)C26H30NaO7[M+Na]+Molecular weight calculated value: 477.1884；Molecular weight actual measurement Value: 477.1882.
The synthesis path of (-)-Hypocrolide A and compound S are as follows:
Embodiment 2
Following (the synthetic route and testing number of each substance of the present embodiment of the synthesis process of the anti-tumor drug of the present embodiment According to substantially the same manner as Example 1, therefore, details are not described herein again):
(1) compound A (16.1mmol) is dissolved in dioxane, obtains the dioxane solution of compound A；In room Under conditions of temperature, trifluoroacetic acid (24.15mmol) is added drop-wise in the dioxane solution of compound A, 4,4- bis- is then added Methyl-cyclohexyl -2- alkene -1- ketone (322mmol) stir after twenty minutes, then plus mass percentage be 35% hydrogen peroxide The aqueous solution of (193.2mmol), 30 DEG C react 48 hours, obtained reaction solution is extracted with ether, by the organic phase of extraction according to Secondary, filtering dry using anhydrous sodium sulfate and vacuum concentration, most the organic phase afterwards after being concentrated in vacuo is purified with silica gel column chromatography, Obtain 38g compound B, yield 84%.
(2) compound B (7.1mmol) is dissolved in ether, obtains the diethyl ether solution of compound B；Anhydrous and -78 DEG C Under the conditions of, lithium diisopropylamine (7.1mmol) and hexamethylphosphoramide (21.3mmol) are added dropwise respectively in compound B's It in tetrahydrofuran solution, reacts 1 hour, obtains the first reaction solution, then the reaction was continued 4 hours under temperature is increased to -60, then It is added iodomethane (7.1mmol), continuation is reacted 3 hours at -60 DEG C, and obtained reaction solution is quenched with saturated aqueous ammonium chloride It goes out, ethyl acetate extracts reaction system, and anhydrous sodium sulfate dries, filters, and is concentrated in vacuo.Then purified with silica gel column chromatography, obtained To 0.67g compound C, yield 61%.
(3) under conditions of -10 DEG C, by 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene (264.86mmol), first The aqueous solution (mass percentage of formaldehyde is 37%) (mole of formaldehyde is 529.72mmol) and compound C of aldehyde (155.8mmol) is added in tetrahydrofuran solution, and reaction is warming up to room temperature after forty minutes, and the reaction was continued 3.0 hours, then uses Saturated aqueous ammonium chloride is quenched, and ethyl acetate extracts reaction system, and anhydrous sodium sulfate dries, filters, and is concentrated in vacuo, then uses Silica gel column chromatography purifying, obtains 22g compound D, yield 77%.
(4) at room temperature, by compound D (81.4mmol), tert-butyl chloro-silicane (81.4mmol), imidazoles (81.4mmol) and 4-dimethylaminopyridine (16.28mmol) are dissolved in tetrahydrofuran, are stirred overnight, then using saturation chlorination Aqueous ammonium is quenched, then is successively extracted with dichloromethane, anhydrous sodium sulfate drying, filters and be concentrated in vacuo, and finally uses silicagel column Chromatographic purifying obtains 24g compound E, yield 99%.
(5) at room temperature, semicarbazide hydrochloride (704mmol) and sodium acetate (211.2mmol) are dissolved in 200mL water In, 200mL methanol and compound E (70.4mmol) is then added, is stirred overnight.Then dry hang is extracted with dichloromethane to do, Obtain the crude product containing compound F.Crude product is dissolved in anhydrous methylene chloride, the methylene chloride for obtaining crude product is molten Liquid lead tetraacetate (105.6mmol) is added in the dichloromethane solution of crude product, reaction 1 anhydrous and under conditions of 0 DEG C Hour.Then it is quenched with water, and it is dense successively to make to be extracted with dichloromethane dry reaction system, anhydrous sodium sulfate, filtering and vacuum Contracting, is finally purified with silica gel column chromatography, obtains 11g compound G, yield 55%.
(6) (Z)-butyl -2- will in the anhydrous ether of (Z)-butyl -2- alkene -1- diethyl phosphate (6.4mmol), be obtained Under the conditions of then anhydrous with -78 DEG C (Z)-is added in n-BuLi (6.4mmol) by the diethyl ether solution of alkene -1- diethyl phosphate In the tetrahydrofuran solution of butyl -2- alkene -1- diethyl phosphate, stirring is warming up to 0 DEG C and continues stirring 1 hour after 0.5 hour, so Compound G (3.2mmol) is added afterwards, after reaction 0.5 hour, obtains the second reaction solution, the second reaction solution is cooled to -78 DEG C, It is added lithium diisopropylamine (3.84mmol), stirring is warming up to 0 DEG C and continues stirring 1 hour after 0.5 hour, two carbon are then added Sour di tert butyl carbonate (9.6mmol) is reacted 0.5 hour, is then quenched using saturated aqueous ammonium chloride, is successively extracted through methylene chloride Dry reaction system, anhydrous sodium sulfate, filtering and vacuum concentration are taken, is finally purified with silica gel column chromatography, obtains 1.0g compound H, yield 77%.
(7) compound H (7.1mmol) is dissolved in 2,2,2- trifluoroethanols, obtains the 2 of compound H, 2,2- trifluoro second Alcoholic solution；At room temperature, (1,5- cyclo-octadiene) chlorine rhodium (I) dimer (0.142mmol) is added the 2,2 of compound H, It in 2- trifluoroethanol solution, reacts 2.0 hours, reaction solution is concentrated in vacuo, then use silica gel column chromatography separating purification, respectively To 2.0g compound I and 0.43g compound J, yield 66% and 13%.
(8) compound I (4.3mmol) is dissolved in dimethylbenzene, obtains the xylene solution of compound I；Then in argon Under atmosphere is enclosed, p-methyl benzenesulfonic acid (8.6mmol) is added in the toluene solution for closing object I, 120 DEG C is heated to and is stirred at reflux overnight, Obtained reaction solution is quenched with saturated sodium bicarbonate aqueous solution, then successively through ethyl diacetate extraction, anhydrous sodium sulfate it is dry, Filtering and vacuum concentration, are finally purified with silica gel column chromatography, obtain 0.92g compound K, yield 92%.
(9) 2,6- resacetophenone (131.6mmol) is dissolved in tetrahydrofuran, obtains 2,6- resacetophenone Tetrahydrofuran solution；Then in anhydrous conditions, potassium carbonate (394.8mol) is added to the tetrahydro of 2,6- resacetophenone In tetrahydrofuran solution, 80 DEG C are warming up to, is stirred to react 1.0 hours, is then added to methoxy-benzyl chlorine (197.4mmol), 60 DEG C the reaction was continued 3.0 hours, then is quenched with aqueous solution, and obtained reaction solution is successively dry with ether extraction, anhydrous sodium sulfate, mistake Filter and vacuum concentration, are finally purified with silica gel column chromatography, obtain 20.0g compound M, yield 56%.
(10) compound M (73.5mmol) is dissolved in ether, obtains the diethyl ether solution of compound M；Then anhydrous Under the conditions of, sodium hydride (514.5mmol) is added in the diethyl ether solution of compound M, 60 DEG C is heated to and is stirred at reflux 10 minutes, so Dimethyl carbonate (367.5mmol) is added afterwards to flow back 3 hours at 60 DEG C, third reaction solution is obtained, by 250mL water and 50mL second Ether be added third reaction solution, isolate water phase, and in water phase be added 2mol/L salt acid for adjusting pH to 1, finally use dichloromethane Alkane aqueous phase extracted, then be successively dried over anhydrous sodium sulfate, filter and be concentrated in vacuo, it is finally recrystallized, is obtained with methylene chloride and water To 17.0g compound N, yield 77%.
(11) compound K (2.12mmol) and compound M (4.24mmol) are dissolved in acetic acid, obtain compound K and The acetic acid solution of compound M；Then under nitrogen atmosphere, ammonium ceric nitrate (4.24mmol) and copper acetate (4.24mmol) are added In the acetic acid solution of compound K and compound M, it is stirred overnight at room temperature, obtained reaction solution is used to be neutralized with 40g potassium carbonate, then according to It is secondary to be obtained through methylene chloride extraction, anhydrous sodium sulfate drying, filtering and vacuum concentration finally with silica gel column chromatography separating purification 520mg compound O, yield 47% obtain 200mg compound P, yield 18%.
(12) compound O (0.19mmol) is dissolved in tetrahydrofuran, obtains the tetrahydrofuran solution of compound O；It connects In anhydrous conditions, tetrahydrochysene lithium aluminium (0.57mmol) is added in the tetrahydrofuran solution of compound O, reacts 2 small at 0 DEG C When, then with the sodium hydroxide quenching reaction of 3mol/L, then successively filtered and be concentrated in vacuo with diatomite, finally use silica gel column layer Analysis purifying, obtains 90mg compound Q, yield 92%.
(13) under the conditions of -78 DEG C, in nitrogen atmosphere, by oxalyl chloride (1.9mmol) and dimethyl sulfoxide (1.33mmol) It is added in methylene chloride, after reaction 1.5 hours, is added compound Q (0.38mmol), three second are added after the reaction was continued 1.5 hours Amine (2.28mmol), stirring are warming up to 0 DEG C and react 0.5 hour after 0.5 hour, the hydrochloric acid for being subsequently added into 10mL 3.0mol/L is quenched It goes out reaction, obtains reaction solution and be extracted with dichloromethane, then be successively dried over anhydrous sodium sulfate, filter and be concentrated in vacuo, finally use Silica gel column chromatography purifying, obtains 170mg compound R, yield 85%.
(14) compound R (0.57mmol) is dissolved in 150ml methylene chloride, the methylene chloride for obtaining compound R is molten Liquid；Under the conditions of 0 DEG C, trifluoroacetic acid (4.56mmol) is added in the dichloromethane solution of compound R, is reacted after being warmed to room temperature Overnight, then reaction solution concentration is added 50mL methanol solution, is stirred at room temperature 10 hours, obtains the 4th reaction solution, by the 4th reaction Liquid vacuum concentration.Then it is isolated and purified with silica gel column chromatography F, obtains 75mg anti-tumor drug (-)-Hypocrolide A, yield 26%, also obtain 77mg compound S, yield 27%.
(15) compound S (0.17mmol) is dissolved in methylene chloride, obtains the dichloromethane solution of compound S；It connects Under the conditions of 0 DEG C, by trifluoroacetic acid (1.36mmol) be added compound S dichloromethane solution in, be warmed to room temperature reaction 0.5 Hour, concentration of reaction solution, and excessive methanol is added, it is stirred at room temperature 12 hours, then be concentrated in vacuo, it is then pure with silica gel column chromatography Change, obtains 30mg anti-tumor drug (-)-Hypocrolide A, yield 39% also obtains 34mg compound S, yield 40%.
Embodiment 3
Following (the synthetic route and testing number of each substance of the present embodiment of the synthesis process of the anti-tumor drug of the present embodiment According to substantially the same manner as Example 1, therefore, details are not described herein again):
(1) compound A (16.1mmol) is dissolved in dioxane, obtains the dioxane solution of compound A；In room Under conditions of temperature, trifluoroacetic acid (24.15mmol) is added drop-wise in the dioxane solution of compound A, 4,4- bis- is then added Methyl-cyclohexyl -2- alkene -1- ketone (107.3mmol) stir after twenty minutes, then plus mass percentage be 35% hydrogen peroxide The aqueous solution of (289.8mmol), 50 DEG C react 48 hours, obtained reaction solution is extracted with ether, by the organic phase of extraction according to Secondary, filtering dry using anhydrous sodium sulfate and vacuum concentration, most the organic phase afterwards after being concentrated in vacuo is purified with silica gel column chromatography, Obtain 13g compound B, yield 88%.
(2) compound B (7.1mmol) is dissolved in tetrahydrofuran, obtains the tetrahydrofuran solution of compound B；In nothing Under the conditions of water and -78 DEG C, lithium diisopropylamine (10.65mmol) and hexamethylphosphoramide (31.95mmol) are dripped respectively It is added in the tetrahydrofuran solution of compound B, reacts 3 hours, obtain the first reaction solution, then temperature is increased to -40 lower continuation Reaction 2 hours, is subsequently added into iodomethane (8.52mmol), and continuation is reacted 3.0 hours at -40 DEG C, and obtained reaction solution is used full It is quenched with aqueous ammonium chloride solution, ethyl acetate extracts reaction system, and anhydrous sodium sulfate dries, filters, and is concentrated in vacuo.Then silicon is used It is gel column chromatography eluting, obtain 0.8g compound C, yield 72%.
(3) under conditions of -15 DEG C, by 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene (377.936mmol), first The aqueous solution (mass percentage of formaldehyde is 37%) (mole of formaldehyde is 716.68mmol) and compound C of aldehyde (155.8mmol) is added in tetrahydrofuran solution, and reaction is warming up to room temperature after forty minutes, and the reaction was continued 3.0 hours, then uses Saturated aqueous ammonium chloride is quenched, and ethyl acetate extracts reaction system, and anhydrous sodium sulfate dries, filters, and is concentrated in vacuo, then uses Silica gel column chromatography purifying, obtains 24g compound D, yield 84%.
(4) at room temperature, by compound D (81.4mmol), tert-butyl chloro-silicane (122.1mmol), miaow Azoles (122.1mmol) and 4-dimethylaminopyridine (8.14mmol) are dissolved in methylene chloride, are stirred overnight, then using saturation chlorine Change aqueous ammonium to be quenched, then be successively extracted with dichloromethane, anhydrous sodium sulfate drying, filter and be concentrated in vacuo, finally uses silica gel Column chromatographic purifying obtains 21g compound E, yield 87%.
(5) at room temperature, semicarbazide hydrochloride (704mmol) and sodium acetate (211.2mmol) are dissolved in 200mL water In, 200mL methanol and compound E (70.4mmol) is then added, is stirred overnight.Then dry hang is extracted with dichloromethane to do, Obtain the crude product containing compound F.Crude product is dissolved in anhydrous methylene chloride, the methylene chloride for obtaining crude product is molten Liquid lead tetraacetate (105.6mmol) is added in the dichloromethane solution of crude product, reaction 1 anhydrous and under conditions of 0 DEG C Hour.Then it is quenched with water, and it is dense successively to make to be extracted with dichloromethane dry reaction system, anhydrous sodium sulfate, filtering and vacuum Contracting, is finally purified with silica gel column chromatography, obtains 9.5g compound G, yield 48%.
(6) (Z)-fourth will in the anhydrous tetrahydro furan of (Z)-butyl -2- alkene -1- diethyl phosphate (6.4mmol), be obtained The tetrahydrofuran solution of base -2- alkene -1- diethyl phosphate, under the conditions of then anhydrous with -78 DEG C, by n-BuLi (6.4mmol) is added in the tetrahydrofuran solution of (Z)-butyl -2- alkene -1- diethyl phosphate, and stirring was warming up to 0 after 0.5 hour DEG C continue stirring 1 hour, compound G (3.2mmol) then is added, after reaction 0.5 hour, the second reaction solution is obtained, by second Reaction solution is cooled to -78 DEG C, is added lithium diisopropylamine (3.84mmol), and stirring is warming up to 0 DEG C after 0.5 hour and continues to stir 1 hour, di-tert-butyl dicarbonate (9.6mmol) then is added, reacts 0.5 hour, is then quenched using saturated aqueous ammonium chloride It goes out, successively through methylene chloride extraction reaction system, anhydrous sodium sulfate drying, filtering and vacuum concentration, finally uses silica gel column chromatography Purifying, obtains 0.95g compound H, yield 73%.
(7) compound H (7.1mmol) is dissolved in 2,2,2- trifluoroethanols, obtains the 2 of compound H, 2,2- trifluoro second Alcoholic solution；At room temperature, (1,5- cyclo-octadiene) chlorine rhodium (I) dimer (0.142mmol) is added the 2,2 of compound H, It in 2- trifluoroethanol solution, reacts 2.0 hours, reaction solution is concentrated in vacuo, then use silica gel column chromatography separating purification, respectively To 2.4g compound I and 0.53g compound J, yield is respectively 80% and 16%.
(8) compound I (4.3mmol) is dissolved in toluene, obtains the toluene solution of compound I；Then in nitrogen atmosphere Under enclosing, p-methyl benzenesulfonic acid (8.6mmol) is added in the toluene solution for closing object I, 120 DEG C is heated to and is stirred at reflux overnight, obtain Reaction solution be quenched with saturated sodium bicarbonate aqueous solution, then successively through ethyl diacetate extraction, anhydrous sodium sulfate is dry, filtering And vacuum concentration, finally purified with silica gel column chromatography, obtains 0.8g compound K, yield 80%.
(9) 2,6- resacetophenone (131.6mmol) is dissolved in n,N-Dimethylformamide, obtains 2,6- dihydroxy The N,N-dimethylformamide solution of benzoylformaldoxime；Then in anhydrous conditions, 2,6- bis- is added in potassium carbonate (394.8mol) In the n,N-Dimethylformamide solution of hydroxy acetophenone, 80 DEG C are warming up to, is stirred to react 1.0 hours, is then added to methoxy Base benzyl chloride (197.4mmol), at 60 DEG C, the reaction was continued 3.0 hours, then is quenched with aqueous solution, and obtained reaction solution successively uses second Ether extraction, anhydrous sodium sulfate are dried, filtered and are concentrated in vacuo, and are finally purified with silica gel column chromatography, are obtained 18g compound M, yield 50%.
(10) compound M (73.5mmol) is dissolved in tetrahydrofuran, obtains the tetrahydrofuran solution of compound M；It connects In anhydrous conditions, by sodium hydride (735mmol) be added compound M tetrahydrofuran solution in, be heated to 60 DEG C and stir back Then stream 30 minutes is added dimethyl carbonate (294mmol) and flows back 3 hours at 60 DEG C, third reaction solution obtained, by 250mL Third reaction solution is added in water and 50mL ether, isolates water phase, and the salt acid for adjusting pH of 4mol/L is added in water phase to 1, most After water phase is extracted with dichloromethane, then be successively dried over anhydrous sodium sulfate, filter and be concentrated in vacuo, finally use methylene chloride and water Recrystallization, obtains 18.5g compound K, yield 84%.
(11) compound K (2.12mmol) and compound M (4.24mmol) are dissolved in acetic acid, obtain compound K and The acetic acid solution of compound M；Then under nitrogen atmosphere, ammonium ceric nitrate (9.36mmol) and copper acetate (4.24mmol) are added In the acetic acid solution of compound K and compound M, it is stirred overnight at room temperature, obtained reaction solution is used to be neutralized with 40g potassium carbonate, then according to It is secondary to be obtained through methylene chloride extraction, anhydrous sodium sulfate drying, filtering and vacuum concentration finally with silica gel column chromatography separating purification 500mg compound O and 190mg compound P, yield is respectively 45% and 17%.
(12) compound O (0.19mmol) is dissolved in ether, obtains the diethyl ether solution of compound O；Then anhydrous Under the conditions of, tetrahydrochysene lithium aluminium (0.57mmol) is added in the diethyl ether solution of compound O, is reacted 2 hours at 0 DEG C, then use 3mol/ The sodium hydroxide of L is quenched, and is then successively filtered and is concentrated in vacuo with diatomite, finally purified with silica gel column chromatography, obtain 80mg Compound Q, yield 82%.
(13) under the conditions of -78 DEG C, in nitrogen atmosphere, by oxalyl chloride (1.9mmol) and dimethyl sulfoxide (2.28mmol) It is added in methylene chloride, after reaction 1 hour, is added compound Q (0.38mmol), triethylamine is added after the reaction was continued 1 hour (3.8mmol), stirring are warming up to 0 DEG C and react 0.5 hour after 0.5 hour, the hydrochloric acid for being subsequently added into 10mL 3.0mol/L is anti- It answers, obtains reaction solution and be extracted with dichloromethane, then be successively dried over anhydrous sodium sulfate, filter and be concentrated in vacuo, finally use silica gel Column chromatographic purifying obtains 170mg compound R, yield 85%.
(14) compound R (0.57mmol) is dissolved in 150ml methylene chloride, the methylene chloride for obtaining compound R is molten Liquid；Under the conditions of 0 DEG C, trifluoroacetic acid (6.84mmol) is added in the dichloromethane solution of compound R, is reacted after being warmed to room temperature Overnight, then reaction solution concentration is added 50mL methanol solution, is stirred at room temperature 20 hours, obtains the 4th reaction solution, by the 4th reaction Liquid vacuum concentration.Then it is isolated and purified with silica gel column chromatography F, obtains 80mg anti-tumor drug (-)-Hypocrolide A, yield 31%, also obtain 77mg compound S, yield 30%.
(15) compound S (0.17mmol) is dissolved in methylene chloride, obtains the dichloromethane solution of compound S；It connects Under the conditions of 0 DEG C, trifluoroacetic acid (2.04mmol) is added in the dichloromethane solution of compound S, it is 1 small to be warmed to room temperature reaction When, concentration of reaction solution, and excessive methanol is added, it is stirred at room temperature 12 hours, then be concentrated in vacuo, it is then pure with silica gel column chromatography Change, obtains 30mg anti-tumor drug (-)-Hypocrolide A, yield 39% also obtains 30mg compound S, yield 39%.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims (9)

1. a kind of synthetic method of anti-tumor drug, which comprises the steps of:
At room temperature, it is by structural formulaCompound A and trifluoroacetic acid dissolve In dioxane, 4,4- Dimethyl-cyclohex -2- alkene -1- ketone is then added and hydrogen peroxide reacts at 30~50 DEG C, is tied Structure formula isCompound B, wherein the molar ratio of the trifluoroacetic acid and the compound A are 1.5~2.0:1, The molar ratio of the compound A and 4, the 4- Dimethyl-cyclohex -2- alkene -1- ketone is 0.05~0.15:1, the hydrogen peroxide with The molar ratio of the compound A is 12~18:1, and Me is methyl；
Anhydrous and under the conditions of -78 DEG C, lithium diisopropylamine, hexamethylphosphoramide and the compound B are had in first It is reacted 1~3 hour in solvent, obtains the first reaction solution, first reaction solution then reacts to 2 at -60~-40 DEG C~ 4 hours, iodomethane is then added, and the reaction was continued at -60~-40 DEG C, and obtaining structural formula isCompound C, wherein the molar ratio of the lithium diisopropylamine and the compound B are 1.0~1.5:1, the hexamethylphosphoramide Molar ratio with the compound B is 3.0~4.5:1, and the molar ratio of the iodomethane and the compound B is 1.0~1.5: 1；
Under conditions of -20 DEG C~-10 DEG C, by 1,8- diazabicylo [5.4.0], 11 carbon -7- alkene, formaldehyde and the chemical combination Object C reacts 10~40 minutes in tetrahydrofuran, then reacts at room temperature again, obtains structural formula and is's Compound D, wherein the molar ratio of 1,8- diazabicylo [5.4.0], the 11 carbon -7- alkene and the compound C is 1.7~ The molar ratio of 2.3:1, the formaldehyde and the compound C are 3.4~4.6:1；
At room temperature, by the compound D and tert-butyl chloro-silicane, imidazoles, 4-dimethylaminopyridine in second It is reacted in organic solvent, obtaining structural formula isCompound E, wherein the tert-butyldimethylsilyl chloride The molar ratio of silane and the compound D are 1.0~1.5:1, the molar ratio of the imidazoles and the compound D is 1.0~ The molar ratio of 1.5:1, the 4-dimethylaminopyridine and the compound D are 0.05~0.20:1, and OTBS is tert-butyl diformazan Base siloxy；
At room temperature, the compound E, semicarbazide hydrochloride and sodium acetate are reacted in the mixed liquor of water and alcohol, is obtained Crude product, wherein the molar ratio of the semicarbazide hydrochloride and the compound E are 5.0~10.0:1, the sodium acetate with it is described The molar ratio of compound E is 2.0~3.0:1；
Anhydrous and under conditions of -10~0 DEG C, lead tetraacetate and the crude product are reacted in methylene chloride, obtain structure Formula isCompound G, wherein the molar ratio of the lead tetraacetate and the compound E is 1.0~ 1.5:1；
It is under the conditions of at -78 DEG C and anhydrous, n-BuLi and (Z)-butyl -2- alkene -1- diethyl phosphate is organic molten in third It mixes in agent, and is reacted 0.5~1 hour under conditions of 0 DEG C, being subsequently added into the compound G, the reaction was continued, and it is anti-to obtain second Answer liquid, wherein the molar ratio of the n-BuLi and the compound G are 2.0~3.0:1, (Z)-butyl -2- alkene -1- The molar ratio of diethyl phosphate and the compound G are 2.0~3.0:1；
Under conditions of -78 DEG C, second reaction solution is mixed with lithium diisopropylamine, then reacts 0.5~1 at 0 DEG C Hour, di-tert-butyl dicarbonate is then added, and the reaction was continued, and obtaining structural formula isChange Close object H, wherein the molar ratio of the lithium diisopropylamine and the compound G are 1.2~1.5:1, two dimethyl dicarbonate The molar ratio of butyl ester and the compound G are 2.0~3.0:1；
At room temperature, by (1,5- cyclo-octadiene) chlorine rhodium (I) dimer and the compound H in 2,2,2- trifluoroethanols Reaction, obtaining structural formula isCompound I, wherein (1, the 5- cyclo-octadiene) chlorine The molar ratio of rhodium (I) dimer and the compound H are 0.01~0.02:1；
Under conditions of protective gas, p-methyl benzenesulfonic acid and compound I back flow reaction in the 4th organic solvent obtain It is to structural formulaCompound K, wherein mole of the p-methyl benzenesulfonic acid and the compound I Than for 2.0~3.0:1；
In anhydrous conditions, by potassium carbonate, to methoxy-benzyl chlorine and 2,6- resacetophenone in the 5th organic solvent in It is reacted at 60~80 DEG C, obtaining structural formula isCompound M, wherein the potassium carbonate and described 2,6- The molar ratio of resacetophenone is 2.0~3.0:1, the rubbing to methoxy-benzyl chlorine and 2, the 6- resacetophenone You are than being 1.5~2.0, wherein OPMB is to methoxy-benzyl oxygroup；
In anhydrous conditions, by sodium hydride and the compound M back flow reaction 10~40 minutes in the 6th organic solvent, then Dimethyl carbonate is added and continues back flow reaction, obtains third reaction solution, water and ether is added in the third reaction solution so that The water phase and organic phase separation, then isolate water phase from the third reaction solution, adjust the pH value of the water phase to 1~2, Obtaining structural formula isCompound N, wherein the molar ratio of the sodium hydride and the compound M For 7.0~10.0:1, the molar ratio of the dimethyl carbonate and the compound M are 3.0~5.0:1；
It is under conditions of protective gas, ammonium ceric nitrate, copper acetate, the compound K and the compound N is anti-in acetic acid It answers, obtaining structural formula isCompound O, wherein the ammonium ceric nitrate and the chemical combination The molar ratio of object K is 2.0~3.0:1, and the molar ratio of the copper acetate and the compound K is 2.0~3.0:1, the chemical combination The molar ratio of object N and the compound K is 2.0~3.0:1；
In anhydrous conditions, tetrahydrochysene lithium aluminium and compound O are reacted in the 7th organic solvent at -10~0 DEG C, obtains structure Formula isCompound Q, wherein the molar ratio of the tetrahydrochysene lithium aluminium and the compound O For 2.0~3.0:1；
Under conditions of -78 DEG C and protective gas, it is small that oxalyl chloride and dimethyl sulfoxide are reacted 0.5~1.5 in methylene chloride When, the compound Q is then added and reacts 0.5~1.5 hour, is subsequently added into triethylamine, obtains structural formula after reacting at 0 DEG C ForCompound R, wherein the molar ratio of the oxalyl chloride and the compound Q is 2.5 The molar ratio of~5.0:1, the dimethyl sulfoxide and the compound Q is 3.5~6.0:1, the triethylamine and the compound Q Molar ratio be 6.0~10.0:1；
Under the conditions of 0 DEG C, trifluoroacetic acid is mixed in methylene chloride with the compound R, then at room temperature reaction 10~ 20 hours, adding methanol, the reaction was continued, obtains the 4th reaction solution, is separated, and obtains structural formula and isAnti-tumor drug, wherein the molar ratio of the trifluoroacetic acid and the compound R is 8.0~12.0:1.
2. the synthetic method of anti-tumor drug according to claim 1, which is characterized in that first organic solvent is four Hydrogen furans or ether；Second organic solvent is methylene chloride or tetrahydrofuran；The third organic solvent is tetrahydrofuran Or ether；4th organic solvent is toluene, dimethylbenzene or trimethylbenzene；5th organic solvent is N, N- dimethyl formyl Amine or tetrahydrofuran；6th organic solvent is tetrahydrofuran or ether；7th organic solvent is ether or tetrahydro furan It mutters.
3. the synthetic method of anti-tumor drug according to claim 1, which is characterized in that the mixed liquor of the water and alcohol In, the volume ratio of the alcohol and water is 1:1~2:1, and the alcohol is ethyl alcohol or methanol.
4. the preparation method of anti-tumor drug according to claim 1, which is characterized in that by the compound E, the salt The step of sour semicarbazides and the sodium acetate react in the mixed liquor of the water and alcohol specifically: by the semicarbazide hydrochloride and The sodium acetate mixes in the water, and the pure and mild compound E is then added and is stirred to react.
5. the synthetic method of anti-tumor drug according to claim 1, which is characterized in that divide from the 4th reaction solution The step of from the anti-tumor drug are as follows: the 4th reaction solution is concentrated in vacuo, then through silica gel column chromatography, is obtained described anti-swollen Tumor medicine.
6. the synthetic method of anti-tumor drug according to claim 1, which is characterized in that further include from the 4th reaction Isolated structural formula is in liquidCompound S the step of and by the compound S react The step of obtaining the anti-tumor drug, wherein it is specific that the compound S is reacted into the step of obtaining the anti-tumor drug Are as follows: under the conditions of 0 DEG C, trifluoroacetic acid is mixed in methylene chloride with the compound S, then reaction 0.5~1 is small at room temperature When, being subsequently added into methanol, the reaction was continued, then is separated, and the anti-tumor drug, the trifluoroacetic acid and the compound S are obtained Molar ratio be 8.0~12.0:1.
7. the preparation method of anti-tumor drug according to claim 1, which is characterized in that by the trifluoroacetic acid with it is described It further include by described three before the step of methanol is added after the step of compound R reacts in the methylene chloride The step of fluoroacetic acid is concentrated with the reaction solution that the compound R reacts in the methylene chloride.
8. the preparation method of anti-tumor drug according to claim 1, which is characterized in that described first after the reaction is anti- After answering the step of being added the iodomethane in liquid the reaction was continued at -60~-40 DEG C, quenched using the aqueous solution of saturated ammonium chloride It goes out reaction.
9. the preparation method of anti-tumor drug according to claim 1, which is characterized in that by the lead tetraacetate and institute After stating the step of crude product reacts in the methylene chloride, adopts and reaction is quenched with water.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103289976A (en) * 2002-08-16 2013-09-11 金克克国际有限公司 Novel variant of hypocrea jecorina CBH1 cellulases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103289976A (en) * 2002-08-16 2013-09-11 金克克国际有限公司 Novel variant of hypocrea jecorina CBH1 cellulases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
A Botryane Metabolite with a New Hexacyclic Skeleton from an Entomogenous Fungus Hypocrea sp.;Yafei Yuan;《ORGANIC LETTERS》;20131231;第15卷(第23期);6050-6053

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