CN1086389C - Isoesperamicin and its synthesizing process and usage - Google Patents
Isoesperamicin and its synthesizing process and usage Download PDFInfo
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Abstract
The present invention relates to dissimilar esperamicin with the following molecule formula, a synthesizing method thereof and an application of the dissimilar esperamicin in anticancer medicine. In the molecule formula, X is S or O, Y is 0 or carbon 11-12 double bonds without elements, R7 or R8 is H, alkyl with one to six carbon atoms or acyl with one to six carbon atoms.
Description
The present invention relates to a kind of isomer of esperamicin of macrolide, specifically a kind of isoesperamicin and synthetic method.
1992, taxol was ratified in whole world to have comprised at present that for since the treatment advanced ovarian cancer China applies by united States food and drug administration (FDA).Confirmed since the clinical application in several years, because taxol has different with all anticarcinogen mechanism of action, thereby when not gathering effect with other all anticarcinogens, still have result preferably with taxol, but also there are many shortcomings and limited and applied, mainly be that side effect is more serious, as neutrophil cell is reduced, cause peripheral neuropathy and anaphylaxis, cancer cells easily produces resistance to taxol, poorly water-soluble must also can cause arrhythmia and increase the weight of anaphylaxis and compose material with composing material, and raw material is hard-earned, medical expense is very expensive, shortcomings such as therapeutic efficiency is not high, and therapeutic domain is wideless, thereby can not become a kind of routine prescription anticarcinogen.
Since unique antitumous effect mechanism of finding taxol, the World Science man just comes a large amount of SCREENED COMPOUND with the model of taxol mechanism of action, choose from about 140,000 synthetic and natural sample sifters, nineteen ninety-five finds that first esperamicin has identical taxol antitumous effect machine, but chemical structure is entirely different.External anti-parent's activity of tumor cells and taxol are similar, but to the toxic action of multidrug resistance tumor cells than the individual order of magnitude of taxol Senior Three.(1)Bollag，D.M.，et?al.，Cancer?Research，1995，55，2325。Most in general anticarcinogen energy kill cancer cell, but can not all kill, and remaining cancer cells is more obstinate, easily forms the cancerogenic transfer and relapse of new focus and causes a disease the people in the fatal position.Thereby development is extremely paid attention to the strong esperamicin of multidrug resistance tumor cells lethality.Animal anti-tumor in vivo test has recently confirmed its superiority.(2)Su，D-S.，Danishefrry，S.J.，et?al.，Angew.Chem.Int.Ed.Engl.，1997，36，2093。Recent research shows that again esperamicin does not have the cytotoxic activity of taxol, and this is one of the reason of taxol clinical side effects just, thereby people estimate that making anticarcinogen with esperamicin can not have the such side effect of taxol.(3)Muehlradt，P.E.，et?al.，Cancer?Research，1997，57，3344。
Esperamicin has seven chiral centres and one three novel texture compound that replaces 16 membered macrolides of two keys, may have 256 isomer, thereby on synthetic great difficulty be arranged.
Since the stereochemistry of esperamicin in 1996 is announced, caused the whole nation, world scholar's very big attention immediately.Esperamicin complete synthesis, structure activity study and biological study have formed new research focus.Existingly in the world at present severally be combined into esperamicin for a short time, but synthetic route is long, or stereoselectivity is not high, or agents useful for same costliness and do not have practicality too, thereby to seek better synthetic route also be one of current vital task.(4)Nicolaou，K.C.，et?a1.，Angew.Chem.Int.Ed.Engl.，1997，36，2097.(8)Nicolaou，K.C.，et?a1.，Angew.Chem.Int.Ed.Engl.，1998，37，2015。Because the relevant company in the world all has an optimistic view of the esperamicin application prospect, all apply for a patent trying to be the first, Nicolaou reaches 213 pages for U.S. Squibb applies for a patent.(5)CA129：81625.PCT?Int.Appl?WO?9825929?AI?18?Jun?1998，213pp。The a patent of Danishefrry application also reaches 175 pages.(6)CA?130：124934.PCT?Int.Appl.WO?9901124?AI?14?Jan?1999，175PP。The a patent of Germany Schering company application also reaches 185 pages.(7)CA?130：196529?PCT?Int.Appl?WO?9907692?A2?18Feb.1999，185PP。Thereby to formulate some new analogues also be the research direction that the famous scholar in countries in the world starts economic mind.
So far the biological activity that studies show that epothilone B (structural formula 1) and D (structural formula 2) is best, and discovery carbon 12-13 epoxy, two keys are cis, trans or all biological activity is not had great influence for α epoxy and β epoxy, be that chemical improvement can be carried out in this zone, the patent of invention of relevant esperamicin is existing many pieces so far.Main structural changes is shown in the chemical formula 3.X is S, O.Y=O, or not contain element be the two keys of 12-13.R
1Be various alkyl, oxygen-containing substituents.AA is O, NH, two keys, C
3-5Carbon bond.R
2Be various substituted alkyls, acyl group.R
3Be methyl, ethyl.R
4, R
5Be methyl or ethylene, R
6Be various substituted alkyls, acyl group, Z are O, NH etc.
The object of the invention provides a kind of compound of similar esperamicin structure, and we are called isoesperamicin.
Another object of the present invention provides the method for synthetic above-mentioned isoesperamicin.
1 epothilone B, 2 epothilone ds
4 isoesperamicins
Isoesperamicin of the present invention such as structural formula 4 description, wherein X is S or O, Y is that O or element-free are the two keys of carbon 11-12, R
7, R
8Be H, C
1-6Alkyl or C
1-6Acyl groups etc., isoesperamicin promptly of the present invention can be
Isoesperamicin of the present invention can be synthetic by following reaction formula:
X=S or O in the above-mentioned reaction, R
7Or R
8=H, C
1-6Alkyl or C
1-6Acyl group, R
9=triethyl silicon, tertiary butyl dimethyl-silicon are to methoxy-benzyl; R
10=tertiary butyl dimethyl-silicon, phenylbenzene tertiary butyl silicon or methoxymethyl, R
11=butyl or phenyl, R
12=triethyl silicon or tertiary butyl dimethyl-silicon, Bn are benzyl, and Ph is a phenyl.
It is of the present invention that the isoesperamicin synthetic method can details are as follows:
Compound 7 oxidizing reactions are in organic solvent, and as the hydrochloric ether of 2-5 carbon, in the carboxylicesters of 1-5 carbon (alcohol is the ester of the 1-6 carbon) solvent, oxygenant is a tin anhydride, peroxy tert-butyl alcohol, hydrogen peroxide, peroxybenzoic acid, peracetic acid, metachloroperbenzoic acid, monoperphthalic acid etc., or its mixture.The mol ratio of compound 7 and oxygenant is 1: 0.6-4, and temperature of reaction is-10 ℃ to 80 ℃, the reaction times is 10 minutes to 8 hours.Obtain compound 8 through oxidizing reaction.Described hydrochloric ether can be a methylene dichloride, ethylene dichloride, tert-butyl chloride, chloro-pentane etc.
Compound 8 in organic solvent, as ether, tetrahydrofuran (THF), glycol dimethyl ether, dioxane, 1-5 carbon hydrochloric ether, benzene, toluene is in the dimethylbenzene equal solvent, with triphenyl phosphine, front three phosphine oxide, triethoxy phosphine, tributylphosphine is made catalyzer, replacement reagent is PhNCS, and temperature of reaction is-10 ℃ to 50 ℃, and the reaction times is half an hour to three day.After above-mentioned substitution reaction, generate compound 9.During reaction, the mol ratio of compound 8, PhNCS and catalyzer is 1: 0.8-3: 0.8-3.
Compound 9 is at ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, toluene, dimethylbenzene and C
1-5In the organic solvents such as carbon hydrochloric ether, especially with hexamethylphosphoramide, the hexamethyl phosphoramidite, methyl-sulphoxide is good as cosolvent, butyllithium, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base potassium, hexamethyl two silica-based sodium, lithium ethide or lithium methide are made alkali, with compound 10, temperature of reaction-100 ℃ is to 50 ℃, and the reaction times is half an hour to two day.After above-mentioned ring-opening reaction, obtain compound 11.The mol ratio of described compound 9, compound 10 and alkali is 1: 0.3-5: 1-3.The volume ratio of wherein recommending organic solvent and cosolvent is 1: 005-0.5.
Protective material is a TERT-BUTYL DIMETHYL CHLORO SILANE, phenylbenzene tertiary butyl chloride silane, methoxychlor methane; Methylal(dimethoxymethane) is at 1-5 carbon hydrochloric ether, ether; dioxane, tetrahydrofuran (THF), benzene; methyl, glycol dimethyl ether is in the organic solvents such as diethylene glycol dimethyl ether; with triethylamine; pyridine, 2, the 6-lutidine; diisopropyl ethyl amine; diisopropylamines etc. are basifier, boron trifluoride diethyl etherate, tosic acid; Vanadium Pentoxide in FLAKES; when perchloric acid is acid catalyst, compound 11 and protection reagent; to 50 ℃, the reaction times is to obtain compound 12 after half an hour to 48 hour in temperature of reaction-10 ℃ for alkali or acid catalyst.Described compound 11, the mol ratio of protective material, basifier, acid catalyst is 1: 0.8-5: 0.01-2.
Compound 12 can obtain compound 13 through the reaction of desulfurization ether, uses the monovalence metallic reducing, as uses Li, Na, reduction such as K are at one or more liquefied ammonia, methyl alcohol, ethanol, butanols, methylamine, ethamine and ether, tetrahydrofuran (THF), when dioxane solvent neutralization reaction temperature is-100 ℃ to 50 ℃, 10 minutes to 8 hours reaction times.The mol ratio of compound 12, monovalence metal is 1: 0.8-4.
Catalytic desulfurization ethers such as the also available nickel of compound 12, palladium reactions, as benzene, toluene, tetrafluoro furans, ether, in the solvent of 1-5 carbon hydrochloric ether, temperature of reaction-10 is reacted acquisition compound 13 after 10 minutes to 20 hours ℃ to 50 ℃.The weight ratio of compound 12 and nickel or palladium is 1: 0.1-5%.
Compound 13 can obtain compound 14 through oxidizing reaction, and oxygenant is a sulfur trioxide pyridine complex, the agent of chromium degree, oxalyl chloride, high price iodide.In organic solvent, as 1-5 carbon hydrochloric ether, ether, tetrahydrofuran (THF), dioxane, dimethyl sulfoxide (DMSO), dimethylin methane amide etc.Under-10 ℃ to 80 ℃ temperature.Reaction half an hour to 18 hour.The mol ratio of compound 13 and oxygenant is 1: 0.5-5.
Compound 14 is at ether, tetrahydrochysene furan furan, dioxane, benzene, toluene, dimethylbenzene, in the organic solvents such as 1-5 carbon hydrochloric ether, alkali is lithium methide, butyllithium, potassium tert.-butoxide etc. when temperature of reaction is-10 ℃ to 80 ℃, can obtain compound 16 in 0.5 hour to 3 days with the alkali reaction of compound 15 and alkali.Wherein X is S in the compound 15, O.R
11Be butyl or phenyl.The mol ratio of compound 14, compound 15 and alkali is 1: 0.8-5: 0.8-5.
In one or more solvent, as acetic acid, tetrahydrofuran (THF), water, methyl alcohol, ethanol, butanols, propyl alcohol equal solvent or mixed solvent.Compound 16 reacts under acid catalysis and can obtain compound 17 in 0.5 hour to 48 hours.Described sour acid catalyst is a tosic acid, sulfuric acid, and oxalic acid, perchloric acid, hydrochloric acid, acetic acid etc., the mol ratio of compound 16 and acid catalyst is 1: 0.4-300.
Compound 17 is at acetic acid, benzene, and toluene, dimethylbenzene, 1-5 carbon hydrochloric ether, ether, tetrahydrofuran (THF), in the organic solvents such as dioxane, temperature of reaction is-30 ℃-50 ℃, can obtain compound 18 in 5 minutes to 48 hours with oxidant reaction.Wherein said oxygenant can be a Periodic acid, potassium periodate, and sodium periodate, lead tetra-acetate etc., the mol ratio of compound 17 and oxygenant are 1: 0.4-3.
Compound 18 is at toluene, dimethylbenzene, and ether, in the organic solvents such as tetrahydrofuran (THF), temperature of reaction-100 with compound 19 reactions 1 minute to 5 hours, can obtain compound 20 during ℃ to 50 ℃ in the presence of alkali.Wherein in the compound 19, R
9Be tertiary butyl dimethyl-silicon, triethyl silicon is to methoxy-benzyl.Described alkali is diisopropylamine lithium, hexamethyldisilazane lithium, hmds base potassium or hmds base sodium etc.The mol ratio of compound 18, compound 19 and alkali is 1: 1-8: 1.5-16.
Compound 20 is at 1-5 carbon hydrochloric ether; ether; tetrahydrofuran (THF); dioxane; glycol dimethyl ether; diethylene glycol dimethyl ether, dimethyl formamide is in the organic solvents such as dimethyl sulfoxide (DMSO); in the presence of alkaline catalysts with the protection reagent react; temperature of reaction is-78 ℃ to 50 ℃, and the reaction times is 10 minutes to 3 days, and protection reagent is chlorotriethyl silane; triethiodide silane; three fluosulfonic acid triethyl estersil, TERT-BUTYL DIMETHYL CHLORO SILANE, the tertiary butyl two methiodide silane or three fluosulfonic acid tertiary butyl dimethyl estersil etc.With triethylamine, Diisopropylamine, diisopropyl ethyl amine, pyridine, to dimethylamino pyridine, 2,6-lutidine etc. is an alkaline catalysts, described compound 20, the mol ratio of protection reagent and alkaline catalysts is 1: 0.8-5: 0.8-5.
Above-mentioned reaction product is at methyl alcohol, and ethanol in water or its admixture solvent, when temperature of reaction is-10 ℃ to 50 ℃, obtained compound 21 in 10 minutes to 2 days with macromolecule alkali for hydrolysis.Described alkali is salt of wormwood, yellow soda ash, lithium hydroxide, oxychlorination sodium, potassium hydroxide, hydrated barta etc.The mol ratio of previous reaction product and alkali is 1: 0.8-10.
At 1-5 carbon hydrochloric ether, toluene in the organic solvents such as dimethylbenzene, when temperature of reaction is-100 ℃ to 50 ℃, reacted 5 minutes to 8 hours, and compound 21 obtains compound 23 with compound 22 reaction deprotection agents.The mol ratio of described compound 21 and compound 22 is 1: 0.8-3.
Be reflected at ether, tetrahydrofuran (THF), dioxane, during-30 ℃ to 120 ℃ of organic solvents such as 1-5 carbon hydrochloric ether neutralizations, compound 23 obtained compound 24 in 10 minutes to 2 days with the cyclization reagent reaction.Wherein cyclization reagent is dicyclohexylcarbodiimide (being called for short DCC), to dimethylamino pyridine; 2,4, the 6-trichloro-benzoyl chloride, triethylamine, to dimethylamino pyridine etc., compound 23 and cyclization reagent mol ratio are 1: 0.8-8.
At 1-5 carbon hydrochloric ether, ether, tetrahydrofuran (THF), acetone, methyl alcohol, during-40 ℃ to 120 ℃ of organic solvents such as ethanol neutralizations, compound 24 with go to protect reagent react to obtain compound 25 in 10 minutes to 5 hours.Described to remove to protect reagent be tetrabutyl fluoride amine, trifluoracetic acid, oxalic acid, tosic acid, sulfuric acid, perchloric acid, pyridine hydrofluoride etc.Compound 24 is 1 with going to protect the reagent mol ratio: 0.001-10.
Compound 25 or 28 is at 1-5 carbon hydrochloric ether, tetrahydrofuran (THF), and ether, methyl alcohol, during-10 ℃ to 50 ℃ of organic solvents such as ethanol neutralizations, compound 25 or 28 and removed to protect reagent react 10 minutes to 8 hours can obtain compound 26 or 29 respectively.Wherein removing to protect reagent is dichlorodicyanobenzoquinone, trifluoracetic acid, tosic acid etc.Compound 25 or 28 is 1 with going to protect the mol ratio of reagent: 0.8-1000.
Compound 25 is at 1-5 carbon hydrochloric ether, tetrahydrofuran (THF), and ether, acetone, during-78 ℃ to 50 ℃ of organic solvents such as butanone neutralizations, compound 25 can obtain compound 27 in 5 minutes to 10 hours with oxidant reaction.Described oxygenant is a hydrogen peroxide, peracetic acid, m-chlorobenzoic acid, peroxy propanone, peroxide trifluoroacetone etc.Compound 25 is 1 with the mol ratio of oxygenant: 0.8-10.
In organic solvent, as ether, tetrahydrofuran (THF), dioxane, C
1-5Alkyl chloride, benzene,toluene,xylene, dimethyl formamide, dimethyl sulfoxide (DMSO) equal solvent, compound 26 or 29 and alkylating agent and alkali in the time of-10 °-50 ℃, react and can obtain compound 27 or 30 (R in 10 minutes to 3 days
7, R
8=C
1-6Alkyl), compound 26 or 29, the mol ratio of alkylating agent and alkali is 1: 1-10: 1-10.Described alkylating agent is C
1-6Haloalkane, as C
1-6Alkyl chloride, C
1-6Bromoalkane or C
1-6Idoalkane.Described alkali is lithium hydride, sodium hydride, potassium hydride KH, tertiary butyl potassium alcoholate, isobutyl potassium alcoholate, C
1-6Lithium alkylide or silver suboxide.
At ether, tetrahydrofuran (THF), C
1-5Alkyl chloride, triethylamine, pyridine or its mixed solvent in, compound 26 or 29 and acylating agent and alkali reaction reacts-30 to 50 ℃ in the presence of catalyzer, 10 minutes to 3 days reaction times can obtain compound 27 or 30 (R
7, R
8=C
1-6Acyl group).Wherein the mol ratio of compound 26 or 29, acylating agent, alkali and catalyzer is 1: 0.8-3: 1-100.Described acylating agent is C
1-6Carboxylic acid anhydride, C
1-6Carboxylic acid halides, formic acid and C
1-6The carboxylic acid anhydride mixed solution, described alkali is lithium hydride, sodium hydride, potassium hydride KH, potassium tert.-butoxide, isobutyl potassium alcoholate, C
1-6Lithium alkylide, diisopropylamine lithium, pregnancy two silicon amido lithium pregnancy two silicon amido potassium or 4-dimethylamino pyridine etc.
Above-mentioned two reactions also can intersect carry out and control respectively compound 26 and 29 and the mol ratio of acylating agent and alkylating agent be 1: 0.8-1.5, acylation reaction after alkylation or the first alkylation after the promptly first acidylate in the compound 27 or 30 that is obtained, can be R
7=C
1-6Alkyl, R
8=C
1-6Acyl group or be R on the contrary
7=C
1-6Alkyl, R
8=C
1-6Acylated compound.
From existing reported in literature as can be known, near the two keys esperamicin carbon 12 or the variation of epoxy construction as long as keep the macrolide basic framework, all have antitumour activity.Isoesperamicin of the present invention has kept the macrolide basic structure of this compounds, thus all should have antitumour activity, and simple synthetic method, be expected to suitability for industrialized production.
The present invention will be helped to understand by following embodiment, but content of the present invention can not be limited.
Embodiment 1
Add peroxy tert-butyl alcohol 35mL and tin anhydride 1 gram in the 30-100ml methylene dichloride, drip compound 714.4 grams then, stirring at room was handled with 10%KOH solution 20mL after 5 hours, and organic solution is washed to neutrality, anhydrous Na
2SO
4Drying, concentrating under reduced pressure, resistates are with 300 gram silica gel column chromatography sherwood oils: ethyl acetate=wash in 9: 1 product 88.5g and raw material 6 restrain.Reclaim raw material and repeat above operation secondary again, product 86.8 restrains overall yield～95% again.
Embodiment 2
Above-claimed cpd 8 3.2 grams are dissolved in the 20mL tetrahydrofuran (THF), add PhSCN 2.5 grams, drip tributyl phosphorus 3 grams then, stirred overnight at room temperature concentrates, with 100 gram silica gel column chromatographies, use sherwood oil: ethyl acetate=wash to such an extent that compound 94 restrains productive rate～90% at 95: 5.
Embodiment 3
Compound 92 grams are dissolved in tetrahydrofuran (THF) 20mL, add hexamethylphosphoramide 1mL again, be chilled to-78 ℃, drip butyllithium hexane solution 1.6M 3.9mL, after adding, drip the tetrahydrofuran solution 10mL of compound 10 1.2 grams, after 2 hours, rise to room temperature naturally in this temperature reaction, add 5mL methyl alcohol and saturated ammonium chloride 5mL solution after 10 hours, 3 * 50mL ethyl acetate extraction, and organic phase washing 2 times (2 * 20mL), anhydrous Na
2SO
4Drying concentrates, and with 80 gram silica gel column chromatographies, uses sherwood oil: ethyl acetate=wash to such an extent that compound 11 2.77 restrains productive rate 90% at 8: 2.
Embodiment 4
Compound 111.2 gram is dissolved among the methylene dichloride 50mL, is chilled to-5 ℃, drip diisopropyl ethyl amine 2mL, and then drip methoxychlor methane 1.5mL, be warming up to room temperature naturally, stirring is spent the night, and dilutes with ethyl acetate 50mL, washes with water successively, 5%NaHCO
3The aqueous solution is washed, anhydrous Na
2SO
4Drying concentrates.With 60 gram silica gel column chromatographies, use sherwood oil: ethyl acetate=flushing in 85: 15 gets product 1213 grams, productive rate 96%.
Embodiment 5
In 20mL liquefied ammonia, be chilled to-78 ℃, add metallic lithium or sodium 0.3 gram, be added dropwise to compound 12 1.32 grams in the solution of tetrahydrofuran (THF) 10mL then, this temperature was reacted 1 hour down, add saturated ammonium chloride 10mL solution, heat up naturally and spend the night, allow ammonia volatilize, add water 20mL dilution, (3 * 20mL), anhydrous sodium sulfate drying concentrates with ethyl acetate extraction.50 gram silica gel column chromatographies, sherwood oil: ethyl acetate=8.2 are washed to such an extent that compound 13 0.766 restrains productive rate 93%.
Embodiment 6
Compound 13 6.776 grams are dissolved in the 50mL methylene dichloride, add Dess-Martin oxygenant 2.9 grams, stirring at room 3 hours, add saturated sodium sulfite 20mL, stir half an hour after, tell organic layer, water ethyl acetate extraction (3 * 30mL), merge organic phase, (2 * 20mL) anhydrous sodium sulfate dryings concentrate in washing.20 gram silica gel column chromatographies are used sherwood oil: ethyl acetate=wash to such an extent that compound 140.74 restrains productive rate 96% at 9: 1.
Embodiment 7
Compound 152.8 grams are dissolved in the 20mL tetrahydrofuran (THF), and room temperature adds potassium tert.-butoxide 0.9 gram, reacts after 20 minutes, adds the 5-20mL tetrahydrofuran solution of compound 14 0.96 grams, and stirring at room is 2 hours then.With 20mL saturated ammonium chloride stopped reaction.Tell organic phase, and the water ethyl acetate extraction (3 * 50mL), merge organic phase, (2 * 30mL), anhydrous sodium sulfate drying concentrates in washing then.50 gram silica gel column chromatographies, use sherwood oil: ethyl acetate=flushing in 9: 1 gets compound 160.8 grams, productive rate 91%.
Embodiment 8
Compound 16 0.75 gram is dissolved in 80% acetic acid (20mL) solution, stirring at room 2 hours, and 50 ℃ were stirred 5 hours, the dilution of 60mL ethyl acetate, water proposes to get (3 * 20mL) with ethyl acetate again.Merge organic phase, anhydrous sodium sulfate drying concentrates, and with 30 gram silica gel column layer inspections, uses sherwood oil: ethyl acetate=wash to such an extent that compound 170.63 restrains productive rate 92% at 8: 2.
Embodiment 9
To be adsorbed with 66 milligrams of NaIO
4450 milligrams of silica gel be suspended in the 4mL methylene dichloride, add the solution of 84 milligrams of compounds 17 in methylene dichloride (3mL) then, stirring at room is after 10 minutes, the solids removed by filtration thing concentrates to such an extent that 18 72 milligrams of compounds are standby.
Drip butyllithium (1.39M to the solution of 0.22mL Diisopropylamine in tetrahydrofuran (THF) (1mL), 0.95mL) diethyl ether solution, stirring at room 40 minutes, be chilled to-78 ℃ then, 19 200 milligrams of drips of solution at tetrahydrofuran (THF) (1.5mL) of compound are added, and this temperature kept 70 minutes, dripped tetrahydrofuran (THF) (1.5mL) solution of the above-mentioned compound that makes 18 then, after this temperature stirs 25 minutes, add saturated ammonium chloride (5mL) solution.Ethyl acetate extraction (4 * 20mL), anhydrous sodium sulfate drying, decompression is removed behind the solution and is restrained silica gel column chromatographies with 15, uses sherwood oil: ethyl acetate=wash to such an extent that 20 106 milligrams of compounds are standby at 6: 4.
Embodiment 10
100 milligrams of compounds (20) are dissolved in the 5mL methylene dichloride, add 2 at 0 ℃, 6-lutidine 0.3mL and tertiary butyl dimethyl-silicon trifluoromethane sulfonic acid ester 0.4mL, stirring at room 2 hours, add 10%HCl (2mL), (4 * 20mL), organic layer washes with water so to use ethyl acetate extraction, behind the anhydrous sodium sulfate drying, removal of solvent under reduced pressure gets oily matter.Above-mentioned oily matter is dissolved in 5mL methyl alcohol, adds 140 milligrams of salt of wormwood then, reaction mixture violent stirring 30 minutes.Be acidified to PH4～5 with 10%HCl then,, wash that 2 times (2 * 10mL), removal of solvent under reduced pressure gets 21 crude product, and is standby with the dilution of 50mL ethyl acetate.
Above-mentioned 21 crude product is dissolved among the methylene dichloride 20mL, drip the compound 22 (dichloromethane solution of 0.2M in-78 ℃, 1mL), react and add triethylamine (0.1mL) after 30 minutes, removal of solvent under reduced pressure, 15 gram silica gel column chromatographies, use sherwood oil: ethyl acetate=wash at 1: 1 6S, the 7R isomer (43 milligrams) of 23 48 milligrams of compounds and compound 16.
Embodiment 11
Compound is dissolved in the tetrahydrofuran (THF) (1-5mL) for (23) 75 milligrams, at 0 ℃, add triethylamine (0.1mL) and 2,4 successively, 6-trichloro-benzoyl chloride (0.1mL), reaction mixture stirred 1 hour, toluene (20mL) solution that adds 130 milligrams of dimethylamine pyridines then, reaction mixture stirring at room 2 hours, removal of solvent under reduced pressure, resistates uses column chromatography, and gets the Δ of 24 31 milligrams of compounds and chemical combination 24
12,13Isomer (15 milligrams).
Embodiment 12
30 milligrams of compounds 24 be dissolved in trifluoracetic acid and methylene dichloride (2: 8, in mixed solution 0.5mL), stirred 1.5 hours at 0 ℃, removal of solvent under reduced pressure, resistates gets 25 18 milligrams of chemical combination with column chromatography purification.
Embodiment 13
35 milligrams of compounds 25 are dissolved in the mixed solution of methylene dichloride (1mL) and water (0.06mL), add 18 milligrams of dichlorodicyanobenzoquinones, stirring at room 30 minutes, removal of solvent under reduced pressure, resistates gets isoesperamicin D compound 26 (R, X=S) 28 milligrams through column chromatography purification.
Embodiment 14
32 milligrams of compounds 25 are dissolved in the 2mL methylene dichloride, add 3 milligrams of sodium bicarbonates successively, 14 milligrams of metachloroperbenzoic acids, and stirring at room 3 hours, removal of solvent under reduced pressure, resistates gets 28 25 milligrams of compounds through column chromatography purification.
Embodiment 15
32 milligrams of compounds 28 are dissolved in the mixture liquid of 1mL methylene dichloride and 0.06mL water, add 18 milligrams of dichlorodicyanobenzoquinone stirring at room 30 minutes, removal of solvent under reduced pressure, and resistates gets 24 milligrams of isoesperamicin B29 (X=S) through column chromatography purification.
Embodiment 16
Be dissolved in tetrahydrofuran (THF) 2mL, add the mixed 48 milligrams of 1mmol of thing of sodium hydride 50% sodium hydride-mineral oil and under nitrogen gas stream, add the 2mL tetrahydrofuran (THF), add 25 milligrams of compounds 26 (X=S) then, 0.05mmol, methyl iodide 0.062mL, 1mmoL.Stirring at room 8 hours, removal of solvent under reduced pressure, silica gel column chromatography gets 27a (X=S, R
7=R
8=CH
3) 22 milligrams (85%).
Embodiment 17
24 milligrams of 0.05mmol of compound 26 (X=O) are dissolved in the 0.5mL pyridine, add diacetyl oxide 0.092mL at-10 ℃, (1mmoL), stirred overnight at room temperature with the dilution of 20mL ethyl acetate, is washed then, copper/saturated copper sulphate is washed (3 * 5ml) washings (5ml), the anhydrous sodium sulfate drying removal of solvent under reduced pressure, resistates gets 27b (X=O, R through column chromatography purification
7=R
8=Ac).26 milligrams (91%).
Embodiment 18
48 milligrams of 50% sodium hydrides-mineral oil mixture, 1mmoL adds anhydrous dimethyl formamide 1ml and 25 milligrams of 0.05mmoL of compound 29 (X=O) and butyl iodide 0.114mL under nitrogen gas stream, (1mmoL), stirring at room 18 hours, removal of solvent under reduced pressure, silica gel column chromatography gets 30a (X=S, R
7=R
8=Bu) 22 milligrams (71%).
Embodiment 19
25 milligrams of 0.05mmoL of compound 29 (X=S) are dissolved in the 0.5mL pyridine, add catalytic amount 4-Dimethylamino pyridines～1 milligram at-10 ℃, (0.008mmoL), butyryl oxide 0.13mL (0.8mmoL), stirred overnight at room temperature, with the dilution of 20mL ethyl acetate, washing, copper/saturated copper sulphate washes (3 * 5mL), washing, anhydrous sodium sulfate drying, removal of solvent under reduced pressure get 30b (X=S, R
7=R
8=CH
3CH
2C (O)-) 24 milligrams (76%).
Above-claimed cpd analytical results: 8 ultimate analysis measured value: C, 68.24; H, 10.74; Cl
3H
24O
3Calculated value C, 68.38; H, 10.60.NMR, δ (CDCl
3): 5.35 (m, 1H), 4.02～3.92 (m, 3H), 3.87 (dd, 1H, J=13.5,6.6Hz), 3.58 (t, 1H, J=7.5Hz), 2.20～1.95 (m, 2H), 1.88 (S, 1H), 1.64 (S, 3H), 1.75～1.50 (m, lH), 1.38 (S, 3H), 1.32 (S, 3H), 1.26～1.06 (m, 2H), 0.95 (d, 3H, J=6.6Hz) .MS (m/e): 228 (M
+, 8), 211 (21), 153 (69), 135 (100), 123 (20), 109 (23), 95 (61) .[α]
D 20=-22.9 ° of (C, 1.37, CHCl
3) 9 ultimate analysis measured value: C, 71.20; H, 9.05; C
19H
28O
2S calculated value C, 71.20; H, 8.85.NMR, δ (CDCl
3): 7.40～7.17 (m, 5H), 5.17 (brt, 1H, J=7.1Hz), 3.95 (dd, 1H, J=6.1,7.6Hz), 3.83 (dd, lH, J=13.6,6.8Hz), 3.48 (S, 2H), 3.53 (t, 1H, j=7.6Hz), 2.31～1.86 (m, 2H), 1.73 (S, 3H), 1.39 (S, 3H), 1.34 (S, 3H), 1.57～1.37 (m, 1H), 1.32～1.20 (m, 1H) 1.12～0.97 (m, 1H), 6.91 (d, J=6.6Hz, 3H).MS (m/e): 319 (M
+-1,2.5), 263 (5), 245 (10), 211 (18), 177 (9), 153 (27), 135 (100), 123 (23), 109 (44), [α]
D 20=-19.1 ° of (C, 1.64, CHCl
3) 11 ultimate analysis measured value: C, 72.35; H, 8.58; C
30H
42O
4S calculated value C, 72.2S; H, 8.49.NMR, δ (CDCl
3): 7.50～7.10 (m, 10H), 5.07 (brt, 1H, J=6.8Hz), 4.62 (d, 1H, J=11.8Hz), 4.48 (d, 1H, J=11.8 (Hz), 4.02～3.85 (m, 2H), 3.81 (dd, 1H, J=6.8,13.3Hz), 3.60 (brs, 1H), 3.53～3.40 (m, 2H), 2.24 (d, 1H, J=3.8Hz), 2.10～1.91 (m, 1H), 1.90～1.70 (m, 3H), 1.62 (S, 3H), 1.39 (S, 3H), 1.34 (S, 3H), 1.52～1.25 (m, 2H), 1.25～1.06 (m, 1H), 1.06～0.79 (m, 1H) .MS (m/e): 497 (M
+-1,0.34), 440 (0.95), 331 (2.6), 261 (2.5), 223 (6), 181 (5.92), 135 (6), 109 (11), 91 (100), 81 (13.92) .[α]
D 20=-33 ° of (C, 0.21, CHCl
3) 12 ultimate analysis measured value: C, 66.12; H, 10.64; C
19H
36O
5Calculated value C, 66.24; H, 10.53.NMR, δ (CDCl
3): 5.20 (brt, 1H, J=7.0Hz), 4.74 (d, 1H, J=6.8 H
2), 4.64 (d, 1H, J=6.8Hz), 4.03～3.88 (m, 1H), 3.92～3.82 (m, 1H), 3.82～3.69 (m, 1H), 3.64～3.56 (m, 1H), 3.52～3.43 (m, 1H), 3.44 (S, 3H), 3.10 (d, 1H, J=7.6Hz), 2.20～1.86 (m, 4H), 1.72～1.64 (m, 1H), 1.64～1.44 (m, 2H), 1.40～1.25 (m, 1H), 1.20～1.06 (m, 1H), 1.68 (S, 3H), 1.48 (S, 3H), 1.43 (S, 3H), 1.22 (d, 3H, J=6.6Hz), 1.06 (d, 3H, J=6.6Hz) .MS (m/e): 344 (M
+, 1.65), 312 (3.51), 255 (7.52), 237 (7.37), 225 (4.01), 219 (4.22), 191 (4.30), 161 (9.01), 201 (3.88), 133 (6.18), 121 (13.21), 95 (24.19), 81 (30.8), 45 (100) .14 ultimate analysis measured values: C, 66.69; H, 10.18; C
19H
34O
5Calculated value C, 66.64; H, 10.01.NMR, δ (CDCl
3): 5.14 (brt, 1 H, J=7.0Hz), 4.62～4.50 (m, 2H), 4.08～3.81 (3H), 3.60 (t, 1H, J=7.6Hz), 3.39 (S, 3H), 2.52～2.33 (m, 1H), 2.18 (S, 3H), 2.17-1.87 (m, 3H), 1.82～1.66 (m, 2H), 1.60 (S, 3H), 1.40 (S, 3H), 1.35 (S, 3H), 1.66～1.48 (m, 1H), 1.48～1.22 (m, 1H), 1.22～1.10 (m, 1H), 0.98 (d, 3H, J=6.6Hz) .MS (m/e): 342 (M
+, 1.47), 327 (1.12), 297 (0.69), 248 (2.96), 199 (1.23), 173 (2.87), 161 (7.48), 131 (2.33), 149 (5.86), 118 (9.66), 109 (10.83), 93 (13.55), 31 (21.85), 45 (100), [α]
D 20=-25.4 ° of (C, 2.75, CHCl
3) 16 ultimate analysis measured value: C, 65.83; H, 9.13; C
24H
39O
4NS calculated value C, 65.87; H, 8.98.NMR, δ (CDCl
3): 6.94 (S, 1H), 6.45 (S, 1H), 5.10 (t, 1H, J=7.2Hz), 4.64 (d, 1H, J=6.6Hz), 4.49 (d, 1H, J=6.6Hz), 4.10～3.93 (m, 2H), 3.92～3.77 (m, 1H), 3.62～3.50 (m, 1H), 3.38 (S, 3H), 2.69 (S, 3H), 2.45～2.21 (m, 1H), 2.20～1.85 (m, 3H), 1.85～1.49 (m, 2H), 1.45～1.23 (m, 2H), 1.23～1.02 (m, 1H), 1.95 (S, 3H), 1.56 (S, 3H), 1.37 (S, 3H), 1.33 (S, 3H), 0.95 (9,1H, J=6.6Hz) .MS (m/e): 438 (M
++ 1,0.1), 422 (1.0), 392 (0.93), 376 (7.93), 318 (6.29), 300 (2.06), 212 (39.0), 180 (4.53), 164 (11.24), 152 (11.43), 45 (100) .[α]
D 20=-60.8 ℃ of (C, 1.24, CHCl
3).17 ultimate analysis measured value: C, 63.35; H, 9.28; N, 3.56; C
21H
35O
4NS calculated value C, 63.44; H, 8.87; N, 3.52.NMR, δ (CDCl
3): 6.98 (S, 1H), 6.49 (S, 1H), 5.24～5.03 (m, 1H), 4.66 (d, 1H, J=6.6Hz), 4.51 (d, 1H, J=6.6Hz), 4.11～3.99 (m, 1H), 3.76～3.47 (m, 3H), 3.40 (S, 3H), 2.90～2.66 (brs, 2H), 2.71 (S, 3H), 2.51～2.26 (m, 1H), 2.22～1.91 (m, 4H), 1.91～1.74 (m, 1H), 1.74～1.57 (m, 1H), 1.57～1.38 (m, 1H), 1.38～1.08 (m, 1H), 1.61 (S, 3H), 0.93 (d, 3H, J=6.7H2) .MS (m/e): 398 (M
++ 1,4.13), 380 (1.9), 352 (1.46), 336 (23.6), 304 (2.13), 219 (9), 184 (1.53), 164 (5.7), 45 (100) .[α]
D 20=-51.9 ° of (C, 0.68, CHCl
3) 18,20,21,23,24,25,26 27,2823 ultimate analysis measured value: C, 66.04; H, 8.99; N, 1.86, calculated value .C, 66.18; H, 8.81; N, 1.88.NMR, δ (CDCl
3): 7.28～7.15 (m, 2H), 7.03～6.96 (m, 1H), 6.89～6.78 (m, 2H), 6.58 (S, 1H), 5.23～5.04 (m, 1H), 4.64 (d, 1H, J=10.5Hz), 4.49 (d, 1H, J=10.5H
2), 4.38～4.24 (m, 1H), 4.14～4.00 (m, 1H), 3.81 (S, 3H), 3.86～3.78 (m, 1H), 3.11～2.94 (m, 1H), 2.72 (S, 3H), 2.61～2.3 (m, 2H), 2.10 (S, 3H), 2.40～2.25 (m, 2H), 2.18～1.94 (m, 2H), 1.64 (S, 3H), 1.48～1.20 (m, 5H), 1.17 (S, 3H), 1.11 (S, 3H), 1.08 (d, 3H, J=6.5H
2), 0.98～0.82 (m, 11H), 0.04 (S, 3H), 0.03 (S, 3H) .MS (m/e): 727 (M
+-H
2O+1,0.1), 121 (100) .[α]
D 20=-6.4 (C0.6, CHCl
3) .24 ultimate analysis measured value: C; 67.86; H, 8.74; N, 1.93.C
41H
63O
6NSSi calculated value C, 67.82; H, 8.75; N, 1.93.NMR, δ (CDCl
3): 7.18 (d, 2H, J=8.2H2), 6.98 (S, 1H), 6.86 (d, 2H, J=8.2Hz), 6.58 (S, 1H), 5.44～5.32 (m, 1H), 5.13 (t, 1H, J=9.8Hz), 4.62 (d, 1H, J=10.2 H
2), 4.42 (d, 1H, J=10.2H
2), 4.23 (d, 1H, J=6.5Hz), 3.84 (d, 1H, J=6.8H
2), 3.78 (S, 3H), 3.08 (m, 1H), 2.71 (S, 3H), 2.61～2.43 (m, 1H), 2.42～2.26 (m, 2H), 2.24～1.96 (m, 2H), 2.09 (S, 3H), 1.62 (S, and 3H) 1.60～1.10 (m, 5H), 1.17 (S, 3H), 1.13 (S, 3H), 1.04 (S, 3H), 0.92 (d, 3H, J=6.4Hz), 0.91 (S, 9H), 0.05 (S, 3H), 0.04 (S, 3H) .MS (m/e): 727 (M
++ 1,6.5), 693 (20.5), 121 (100) .[α]
D 20=-32 (C 0.3, CHCl
3) .25 ultimate analysis measured value: C, 68.68; H, 8.01; N, 2.29.C
35H
49O
6NS calculated value C, 68.71; H, 8.07; N, 2.29.NMR, δ (CDCl
3): 7.16 (d, 2H, J=8.2Hz), 6.96 (S, 1H), 6.84 (d, 2H, J=8.2Hz), 6.52 (S, 1H), 5.42～5.30 (m, 1H), 5.10 (t, 1H, J=9.8H
2), 4.60 (d, 2H, J=10.2Hz), 4.40 (d, 1H, J=10.2Hz), 4.30 (d, 1H, J=6.5Hz), 3.88 (d, 1H, J=6.8Hz), 3.75 (S, 3H), 3.10 (m, 1H), 2.70 (S, and 3H) 2.68～2.48 (m, 1H), 2.48～2.28 (m, 2H), 2.24～1.94 (m, 2H), 2.14 (S, 3H), 1.60 (S, 3H), 1.67～1.13 (m, 5H), 1.17 (S, 3H), 1.10 (S, 3H), 1.02 (S, 3H), 0.93 (d, 3H, J=6.4Hz).MS (m/e): 595 (M
+-H
2O+1,0.2), 121 (100) .[α]
D 20=-70 (C 1.7, CHCl
3) .26 ultimate analysis measured value: C, 65.90; H, 8.38; N, 2.88.C
27H
41O
5NS calculated value C, 66.00; H
28.41; N, 2.85.NMR, δ (CDCl
3); 6.98 (S, 1H), 6.53 (S, 1H), 5.40～5.28 (m, 1H), 5.23 (t, 1H, J=8.7Hz), 4.20 (d, 1H, J=6.6H
2), 3.86 (d, 1H, J=6.8Hz), 3.12 (m, 1H), 3.01 (brs, 2H), 2.71 (S, 3H), 2.70～2.61 (m, 1H), 2.48～2.38 (m, 2H), 2.28～1.98 (m, 2H), 2.10 (S, 3H), 1.89～1.69 (m, 2H), 1.63 (S, 3H), 1.32 (S, 3H), 1.31～1.21 (m, 4H), 1.11 (d, 3H, J=6.5H
2), 1.01 (S, 3H), 0.99 (d, 3H, J=6.4Hz) .MS (m/e): 474 (M
+-H
2O, 0.2), 456 (1.2) .[α]
D 20=-86 (C0.3, CHCl
3) .27a ultimate analysis measured value: C, 69.86; H, 8.68; N, 2.73.C
29H
45O
5NS calculated value C, 67.02; H, 8.73; N, 2.70. δ (CDCl
3): 6.97 (S, 1H), 6.51 (S, 1H), 5.38～5.24 (m, 1H), 5.21 (t, 1H, J=8.7Hz), 4.21 (d, 1H, J=6.5Hz), 3.84 (d, 1H, J=6.7Hz), 3.54 (S, 3H), 3.52 (S, 3H), 3.10 (m, 1H), 2.70 (S, 3H), 2.75～2.64 (m, 1H), 2.49～2.33 (m, 2H), 2.26～1.94 (m, 2H), 2.10 (9, and 3H) 1.86～1.64 (m, 2H), 1.60 (S, 3H), 1.30 (S, 3H), 1.30～1.18 (m, 4H), 110 (d, 3H, J=6.5Hz), 1.00 (S, 3H), 0.97 (d, J=6.4H
2) .MS (m/e): 520 (M
+, 0.2), 490 (1.2), 460 (6.5) .[α]
D 20=-79 (C0.4, CDCl
3) .27b ultimate analysis measured value: C, 64.50; H, 7.80; N, 2.46.C
31H
45O
7NS calculated value C, 64.67; H, 7.88; N, 2.43.NMR, δ (CDCl
3): 6.86 (S, 1H), 6.46 (S, 1H), 5.30～5.20 (m, 1H), 5.20 (t, 1H, J=8.5Hz), 5.10 (d, 1H, J=6.5H
2), 4.50 (d, 1H, J=6.8Hz), 3.22 (m, 1H), 2.86 (S, 3H), 2.70～2.58 (m, 1H), 2.36～2.24 (m, 2H), 2.16 (S, 3H) 2.08～1.88 (m, 2), 2.04 (S, 3H), 2.00 (S, 3H), 1.86～1.68m, 2H), 1.68 (S, 3H), 1.33 (S, 3H), 1.30～1.19 (m, 4H), 1.10 (d, 3H, J=6.4Hz), 1.00 (S, 3H), 0.94 (d, 3H, J=6.3Hz) .MS (m/e): 516 (M
+-HOAr, 0.1), 456 (3.2) .[α]
D 20=-84 (C0.3, CHCl
3) .27b ultimate analysis measured value: C, 64.50; H, 7.80; N, 2.46.C
31H
45O
7NS calculated value C, 64.67; H, 7.88; N, 2.43.NMR, δ (CDCl
3): 6.86 (S, 1H), 6.46 (S, 1H), 5.30～5.20 (m, 1H), 5.20 (t, 1H, J=8.5Hz), 5.10 (d, 1H, J=6.5H2), 4.50 (d, 1H, J=6.8Hz), 3.22 (m, 1H), 2.86 (S, 3H), 2.70～2.58 (m, 1H), 2.36～2.24 (m, 2H), 2.16 (S, 3H) 2.08～1.88 (m, 2), 2.04 (S, 3H), 2.00 (S, 3H), 1.86～1.68 (m, 2H), 1.68 (S, 3H), 1.33 (S, 3H), 1.30～1.19 (m, 4H), 1.10 (d, 3H, J=6.4Hz), 1.00 (S, 3H), 0.94 (d, 3H, J=6.3Hz) .MS (m/e): 516 (M
+-HOAr, 0.1), 456 (3.2) .[α]
D 20=-84 (C0.3, CHCl
3) .28 ultimate analysis measured value: C, 67.18; H, 7.79; N, 2.20.C
35H
48O
7NS calculated value C, 67.06; H, 7.72; N, 2.23.NMR δ (CDCl
3): 4.95 (S, 1H), 6.49 (S, 1H), 5.38 (t, 1H, J=6.5Hz), 4.00 (brs, 2H), 3.65 (d, 1H, J=6.2Hz), 3.20～3.02 (m, 1H), 2.93 (t, 1H, J=5.0Hz), 2.70 (S, 3H), 2.61 (brs, 1H), 2.58～2.30 (m, 2H), 2.20～2.10 (m, 1H), 2.04 (S, 3H), 1.98～1.84 (m, 1H), 1.79～1.64 (m, 3H), 1.62～1.46 (m, 2H), 2.40～1.30 (m, 2H), 1.34 (S, 3H), 1.29 (S, 3H), 1.10 (d, 3H, J=5.0Hz), 1.02 (S, 3H), 0.95 (d, 3H, J=6.2Hz) .MS (m/e): 490 (M
+-H
2O+1,0.3), 472 (1.2) .[α]
D 20=-30 (C, 0.3, CDCl
3).30a ultimate analysis measured value: C, b 4.88; H, 8.00; N, 2.19.C
35H
52O
8NS calculated value C, 64.99; H, 8.10; N, 2.17.NMR, δ (CDCl
3): 6.98 (S, 1H), 6.51 (S, 1H), 5.32 (t, 1H, J=6.5H
2), 4.55 (d, 1 H, J=6.0Hz), 3.80～3.62 (m, 1H), 2.92 (t, 1H, J=5.0 H
2), 2.69 (S, 3H), 2.68～2.52 (m, 1H), 2.58～2.34 (m, 2H), 2.26～2.04 (m, 5H), 2.00 (S, 3H), 1.98～1.82 (m, 1H), 1.78～1.60 (m, 3H), 1.60～1.46 (m, 2H), 1.43～1.26 (m, 6H), 1.25 (S, 3H), 1.28 (S, 3H), 1.18～1.02 (m, 6H), 0.98～0.88 (m, 9H) .MS (m/e): 560 (M
+-C
4H
8O
2, 0.2), 472 (1.2) .[α]
D 20=-40 (C0.3, CHCl
3) .30b ultimate analysis measured value: C, 67.84; H, 9.07; N, 2.29.C
35H
56O
6NS calculated value C, 64.99; H, 8.10; N, 2.17.NMR, δ (CDCl
3): 6.94 (S, 1H), 6.43 (S, 1H), 5.37 (t, 1H, J=6.4Hz), 3.65 (d, 1H, J=6.2 H
2), 3.63～3.48 (m, 2H), 3.38～3.20 (m, 2H), 3.18～3.1 (m, 1H), 2.90 (t, 1H, J=5.2H
2), 2.69 (S, 3H), 2.40～2.30 (m, 7H), 2.24～2.08 (m, 5H), 2.00 (S, 3H), 1.98～1.80 (m, 1H), 1.79～1.64 (m, 3H), 1.60～1.40 (m, 2H), 1.40～1.28 (m, 2H), 1.32 (S, 3H), 1.29 (S, 3H), 1.20～1.02 (m, 5), 1.01 (S, 3H), 0.98～0.82 (m, 6H) .MS (m/e): 546 (M
+-C4H9,0.2), 473 (1.2) .[α]
D 20=-46 (C0.2, CHCl
3).
Claims (7)
1, a kind of isoesperamicin with following structural formula:
Wherein X=S or O, the two keys of carbon 11-12 when Y=O or element-free, R
7Or R
8Be H, C
1-6Alkyl or C
1-6Acyl group.
2, a kind of isoesperamicin as claimed in claim 1 is characterized in that having following structural formula:
R wherein
7Or R
8Be H, C
1-6Alkyl or C
1-6Acyl group.
3, a kind of isoesperamicin as claimed in claim 1 is characterized in that having following structural formula:
R wherein
7Or R
8Be H, C
1-6Alkyl or C
1-6Acyl group.
4, a kind of isoesperamicin as claimed in claim 1 is characterized in that having following structural formula:
R wherein
7Or R
8Be H, C
1-6Alkyl or C
1-6Acyl group.
5, a kind of isoesperamicin as claimed in claim 1 is characterized in that having following structural formula:
R wherein
7Or R
8Be H, C
1-6Alkyl or C
1-6Acyl group.
6, a kind of esperamicin synthetic method as claimed in claim 1 is characterized in that by following step synthetic:
(1) structural formula is
Compound and oxygenant mol ratio be 1: 0.6-4, in the organic solvent
Reaction obtained product in 10 minutes to 8 hours during with-10 ℃ to 80 ℃
Described oxygenant is tin anhydride, peroxy tert-butyl alcohol, hydrogen peroxide, peroxybenzoic acid, peracetic acid, metachloroperbenzoic acid, monoperphthalic acid or its mixture;
(2) in organic solvent,
Catalyzer, replacement reagent mol ratio are 1: 0.8-3: during 0.8-3 ,-10 ℃ to 50 ℃ reaction day acquisitions half an hour to three
Wherein catalyzer is triphenylphosphine, front three phosphine oxide, triethoxy phosphine, tributylphosphine, and described replacement reagent is phenylthioisocyanate fat;
(3) in organic solvent,
With the mol ratio of alkali be 1: 0.3-5: 1-3, temperature of reaction-100 is to 50 ℃, day obtains reaction half an hour to two
Described alkali is diisopropylamine lithium, hmds lithium, hmds potassium, hexamethyl two silicon sodium, lithium ethide or butyllithium, lithium methide;
(4) in organic solvent,
Protective material, alkali or acid catalyst mol ratio are 1: 0.8-5: during 0.01-1, hour obtain half an hour to 48-10 to 50 ℃ of reactions
Described protective material is TERT-BUTYL DIMETHYL CHLORO SILANE, phenylbenzene tertiary butyl chloride silane, methoxychlor methane or Methylal(dimethoxymethane), basifier is triethylamine, pyridine, 2,6-lutidine, diisopropyl ethyl amine or diisopropylamine, acid catalyst is a boron trifluoride diethyl etherate, tosic acid, Vanadium Pentoxide in FLAKES or perchloric acid;
(5) in one or more solvent,
Monovalence metal molar ratio is 1: when 0.8-4 and-100 to 50 ℃, react and obtained in 10 minutes to 8 hours
Described monovalence metal is Li, Na or K;
(6) in organic solvent,
With palladium or nickel catalyzator weight ratio be 1: when 0.001-0.05 and-10 to 50 ℃, react and obtained in 10 minutes to 20 hours
(7) in organic solvent,
With the oxygenant mol ratio be 1: when 0.5-5 and-10 to 80 ℃, reaction half an hour to 18 hour is obtained
Described oxygenant is sulfur trioxide pyridine complex, chromium reagent, oxalyl chloride, t-butyl hypochlorate or high iodine compound;
(8) in organic solvent,
With the alkali mol ratio be 1: when 0.8-5: 0.8-5 and-10 to 80 ℃, react and obtained in 0.5 hour to 3 days
(9) in one or more solvent,
With the souring agent mol ratio be 1: when 0.01-1000 and-30 to 100 ℃, react and obtained in 0.5 hour to 48 hours
Described acid catalyst is a tosic acid, sulfuric acid, oxalic acid, acetate, formic acid, perchloric acid, hydrochloric acid;
(10) in organic solvent,
With the oxygenant mol ratio be 1: when 0.4-3 and-30 to 50 ℃, react acquisition in 5 minutes to 48 hours
Described oxygenant is a Periodic acid, potassium periodate, sodium periodate or lead tetra-acetate;
(11) in organic solvent,
With
The mol ratio of alkali is 1: when 1-8: 1.5-16 and-100 to 50 ℃, react and obtained in 1 minute to 5 hours
Described alkali is diisopropylamine lithium, hexamethyldisilazane lithium, hmds base potassium or hmds base sodium;
(12) in organic solvent,
Protection reagent and alkali or acid catalyst mol ratio 1: 0.8-5: 0.8-5, reaction is 10 minutes to 3 days in the time of-78 to 50 ℃, and this product and alkali mol ratio are 1 then: during 0.8-10, reaction obtained in 10 minutes to 2 days in the time of-10 to 50 ℃
Described protection reagent is chlorotriethyl silane, triethiodide silane, three fluosulfonic acid triethyl estersil, TERT-BUTYL DIMETHYL CHLORO SILANE, uncle's fourth two methiodide silane or three fluosulfonic acid tertiary butyl dimethyl estersil, alkaline catalysts is triethylamine, Diisopropylamine, diisopropyl ethyl amine, pyridine, to dimethylamino pyridine or 2,6-lutidine, described alkali are salt of wormwood or sodium, lithium hydroxide, sodium hydroxide, potassium hydroxide, hydrated barta;
(13) in organic solvent,
With
When mol ratio 1: 08-3 and-100 to 50 ℃, react and obtained in 5 minutes to 8 hours
(14) in organic solvent,
With the cyclization reagent mol ratio be 1: when 0.8-8 and-30 to 120 ℃, react and obtained in 10 minutes to 2 days
Described cyclization reagent is a dicyclohexylcarbodiimide, the dimethylin pyrrole formed sediment, and 2,4,6-trichloro-benzoyl chloride, triethylamine or to dimethylamino pyridine;
(15) in organic solvent,
With going to protect the reagent mol ratio is 1: when 0.001-10 and-10 to 50 ℃, react and obtained in 10 minutes to 5 hours
It is described that to remove to protect reagent be tetrabutyl fluoride amine, trifluoracetic acid, oxalic acid, tosic acid, sulfuric acid, perchloric acid or pyridine hydrofluoride;
(16) in organic solvent,
With the oxygenant mol ratio be 1: when 0.8-10 and-78 to 50 ℃, react and obtained in 5 minutes to 10 hours
Wherein oxygenant is hydrogen peroxide, peracetic acid, m-chlorobenzoic acid, peroxy propanone or peroxide trifluoroacetone;
(17) in organic solvent
Or
With going to protect the reagent mol ratio is 1: when 0.8-1000 and-10 to 50 ℃, react acquisition respectively in 10 minutes to 8 hours
With
Described to remove to protect reagent be dichloro dicyan para benzoquinone, trifluoracetic acid or tosic acid;
(18) in organic solvent,
Or
With alkylating agent and alkali mol ratio be 1: 1-10: during 1-10, can obtain in 10 minutes to three days-10 °-50 ℃ reactions
Or
Described alkane is C for agent
1-6Oxidation alkane, described alkali is lithium hydride, sodium hydride, potassium hydride KH, tertiary butyl potassium alcoholate, C
1-6Lithium alkylide or silver suboxide;
(19) in organic solvent,
Or
With acylating agent and alkali mol ratio be 1: 08-3: during 1-100, temperature of reaction is-30 to 50 ℃, reacts and can obtain in 10 minutes to 3 days
Or
Described acylating agent is C
1-6Carboxylic acid anhydride, C
1-6The carboxylic acid anhydride mixed solution of carboxylic acid halides, formic acid and C1-6, described alkali is lithium alkylide, diisopropylamine lithium, pregnancy two silicon amido lithiums, pregnancy two silicon amido potassium, 4-dimethylamino pyridine or the triethylamine of lithium hydride, sodium hydride, potassium hydride KH, potassium tert.-butoxide, isobutyl potassium alcoholate, C1-6;
X=S or O in the above-mentioned molecular formula, R
7Or R
8=H, C
1-6Alkyl or C
1-6Acyl group, R
9=triethyl silicon tertiary butyl dimethyl-silicon, R
10=tertiary butyl dimethyl-silicon, phenylbenzene tertiary butyl silicon or methoxymethyl silicon, R
11=butyl or phenyl, R
12=triethyl silicon or tertiary butyl dimethyl-silicon, Bn are benzyl, and Ph is a phenyl.
7, a kind of synthetic method as claimed in claim 6 is characterized in that the organic solvent in described (3) method is ether, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, di-alcohol dme, toluene, dimethylbenzene or C
1-5The mixed solvent of the cosolvent of the chlorohydrocarbon organic solvent of carbon and hexamethylphosphoramide, hexamethyl phosphoramidite or methyl-sulphoxide, wherein the volume ratio of organic solvent and cosolvent is 1: 0.05-5.
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| CN1086389C true CN1086389C (en) | 2002-06-19 |
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| CN100359014C (en) * | 2003-01-28 | 2008-01-02 | 北京华昊中天生物技术有限公司 | Novel epothilones compound and its preparation method and application |
| CN100387706C (en) * | 2003-08-15 | 2008-05-14 | 北京华昊中天生物技术有限公司 | Epothilone -a microtubule stabilizer for treating tumor and blood vessel restenosis |
| CN109576999A (en) * | 2018-12-25 | 2019-04-05 | 象山新光针织印染有限公司 | A kind of preparation method of deodorization breathable garment fabric |
| CN116102586B (en) * | 2023-01-18 | 2024-05-28 | 四川大学 | Method for synthesizing diaryl silicon-based methane |
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Non-Patent Citations (5)
| Title |
|---|
| ANGER CHEM.INT.ED.ENGL.(1997,36.NO.19,2097) 1997.1.1 Nicolaou,K.C * |
| ANGER CHEM.INT.ED.ENGL.(1997,36.NO.19,2097) 1997.1.1 Nicolaou,K.C;CA129:81625Q 1998.1.1 Nicolaou,K.C;CA130:124934E 1999.1.1 Danishefsky,SamuelJ.;CA130:196529Z 1999.1.1 Klar,Ulrich * |
| CA129:81625Q 1998.1.1 Nicolaou,K.C * |
| CA130:124934E 1999.1.1 Danishefsky,SamuelJ. * |
| CA130:196529Z 1999.1.1 Klar,Ulrich * |
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