CN102633792A - Method for preparing epothilone D and B - Google Patents
Method for preparing epothilone D and B Download PDFInfo
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- CN102633792A CN102633792A CN2011100381758A CN201110038175A CN102633792A CN 102633792 A CN102633792 A CN 102633792A CN 2011100381758 A CN2011100381758 A CN 2011100381758A CN 201110038175 A CN201110038175 A CN 201110038175A CN 102633792 A CN102633792 A CN 102633792A
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Abstract
The invention relates to a preparation method of epothilone D and B, which comprises the following steps: reacting carboxylic acid (6) and hydroxyl compound (7) to obtain an ester (8), reacting with a key intermediate (9) in an Aldol mode to obtain a compound (10), carrying out hydroxy protection with proper protective group to obtain a compound (11), carrying out RCM reaction to close the cycle to obtain a compound (12), removing the hydroxy protective group to obtain the compound epothilone D, and epoxidating to obtain the epothilone B.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, specifically, relate to the complete synthesis preparation method of ebormycine D and B, method reaction yield provided by the invention is high, and is simple to operate, is easy to industriallization.
Background technology
The discovery of ebomycin A and B is in the nineties in 20th century; Hofle and colleague thereof find a kind of glutinous bacteria cellulose heap capsule bacterium Sorangium cellulosum (Myxococcales) bacterial strain Soce90 at first from the earth on Zambesi riverbank, South Africa, from its culture separation and Extraction a kind of anti-mycotic activity compound and it has been carried out property research.Before and after nineteen ninety-five; People such as Bollag find that ebormycine is a kind ofly to have the short tubulin polymerization characteristic of similar purple triol, in the multidrug-resistant carcinoma clone of p-P-glycoprotein expression type, show very strong anti-tumor activity, and the anti-cell of novel structure poisons compound.And find strong 10 to more than 1000 times of the specific activity taxols of natural ebormycine; To taxol and other cancer therapy drug have chemical sproof cancer cells also have very high activity, water-soluble better than taxol, be convenient to prepare and use, structure are simple relatively, easily through complete synthesis obtain so ebormycine as the PTS that has potentiality; This result receives the structure biology relevant with target point protein, complete synthesis, the biosynthesizing of chemistry, medicament immediately and pays close attention to widely with fields such as drug delivery system, preclinical test and clinical trials, and a large amount of bibliographical informations and patented claim are arranged every year.
Up to the present, the clinical I-III phase that the whole world has at least seven ebormycine medicines to be used for tens of kinds of cancers tests, and is used to treat diseases such as nonsmall-cell lung cancer, mammary cancer, ovarian cancer and prostate cancer.In addition, also has a large amount of good potential drugs in preclinical test.These 7 medicines comprise: two natural compounds epothilone B (EPO906) and epothilone D (KOS-862); The semi-synthetic verivate of three epothilone B (BMS247550, BMS310705 and ABJ879) and two complete synthesis analogues (KOS-1584, ZK-EPO) have at least a complete synthesis compound (KOS-1803) to be about to get into clinical first phase in addition.In October, 2007, BMS247550 (has another name called Ixempra, ixabepilone) releases listing through drugs approved by FDA by Bristol-Myer Scripps company.In these seven medicines, the selectivity of in clinical experiment, cancer cells being killed and wounded except that natural product Epothilone B and D was relatively poor, other compound curative effect was comparatively remarkable, particularly surmounts taxol far away to multidrug resistant tumor treatment effect.As and if complete synthesis compound K OS-1584 and ZK-EPO are more potential with regard to curative effect.With KOS-1584 is example, and very serious in clinical one interim patient's state of an illness, cancer types is many again; Under many disadvantageous conditions such as initial dosage is too small, still observe certain efficiently, estimate that its efficient meeting increases substantially in clinical second phase experiment; KOS-1584 is used for the clinical second phase test of nonsmall-cell lung cancer at present, and well-known, lung cancer is the first cancer killer of China; And nonsmall-cell lung cancer accounts for 85% of lung cancer, and patient's survival rate is very low.As for being about to get into complete synthesis compound K OS-1803 and relevant series compound, in experiment, all experiment nude mices MX-1 human tumor has on one's body fully been eliminated, and cancer after discontinuing medication for a long time in all not have to recur.
The ebormycine compound of several kinds of clinical trials
Epothilones B lactam derivates Ixabepilone is used for the treatment of mammary cancer, and these article are injection.This is the ebormycine verivate of first listing so far.This semisynthetic ebormycine lactam derivatives has shown good antitumor action in the II clinical trial phase; Especially to accepting the doubly mammary cancer patient of his shore treatment of Zorubicin, taxol, card late period simultaneously; The independent medication of Ixabepilone, objective reactivity can reach 18%.The Ixabepilone drug combination is evident in efficacy for three the moon (estrogen receptor negative, progesterone receptor feminine gender and HER-2 receptor negative) patient.This " three cloudy types " mammary cancer is a kind of hypotype of uniqueness, selects owing to lack corresponding efficacious therapy, and this type mammary cancer case is refractory especially.Ixabepilone and card be his shore drug combination doubly, and " three the moon " the mammary cancer patient in late period of Zorubicin and paclitaxel treatment was accepted in treatment in the past, and the partial reaction rate reaches 23%.Always have 126 cases, accepted Ixabepilone per three all 40mg/m
2, quiet notes administration, the treatment in maximum 18 cycles, the objective reactivity of the independent radiation evaluation council (IRRC) and researchist's statistics is respectively 11.5% and 18.3%.In all treatment groups, the middle bit time that reaction occurs was 6.1 weeks, and the middle bit time that reaction continues is 5.3 months.The get nowhere median of survival time and total survival time of the state of an illness was respectively 3.1 months and 8.6 months; Survival rate was 68.2% in 6 months.Clinical application of taxol causes tumour cell to produce the multidrug resistance (MDR) of P-P-glycoprotein expression type, makes paclitaxel treatment invalid.Ixabepilone keeps very big cytotoxicity to this kind cell, and all with the invalid cancer of paclitaxel treatment, Ixabepilone shows significant curative effect.
These excellent experimental results greatly excite the research enthusiasm of people to ebormycine.Although several complete synthesis ebormycine curative effect of medication such as KOS-1584, KOS-1803 and ZK-EPO are fine; But the synthetic route of these potential drugs all surpasses the reaction of 30 steps, and the route of wherein clinical the second stage of medicine ZK-EPO (Schering-AG research and development) reaches the reaction of 39 steps.Therefore, they are very restricted on producing, and the bulk drug of synthetic clinical trial all is a problem in a large number.Simultaneously ebormycine also exists a lot of modifiable sites, and wherein some site fits structure activity relationship through computer mould and infers to have good biological activity.
The output that the method for microbial fermentation is produced ebormycine is all lower, and can only produce some ebormycine compound.Therefore, the complete synthesis ebormycine of the present invention chemistry is for the production of ebormycine provides an alternative method.
Summary of the invention
The invention provides a kind of compound method for preparing ebormycine D and B, method reaction yield provided by the invention is high, and is simple to operate, is easy to industriallization.
In order to realize above-mentioned purpose of the present invention, the present invention provides following technical scheme:
1, a kind of method for preparing ebormycine D and B is characterized in that: carboxylic acid (6) becomes ester (8) with oxy-compound (7), then with key intermediate 9; Through Aldol reacting generating compound 10, proper protection radical protection hydroxyl gets compound 11, through RCM react compound 12; Remove hydroxy-protective group; Get compound ebormycine D, get epothilone B through epoxidation again, concrete steps are as shown in Figure 1.
2, wherein P can be for trimethyl silicon based, and triethyl is silica-based, triisopropylsilyl, and the dimethyl-sec.-propyl is silica-based, and the diethylammonium sec.-propyl is silica-based, and tertiary butyl dimethyl-is silica-based, and tert-butyl diphenyl is silica-based, tri-benzyl-silyl, triphenyl is silica-based, and diphenyl methyl is silica-based.
3, wherein Lewis acid can be TiCl
4, BCl
3, InCl
3, AlCl
3, RAlCl
2, R
2AlCl, wherein R is an alkyl; Lewis alkali is tertiary amine, pyridine, substituted pyridines.
4, wherein catalyzer is the diolefin catalysts for metahesis reactions, can be Grubbs first-generation catalyzer, Grubbs s-generation catalyzer, Hoveyda-Grubbs catalyzer, Zhan Shi catalyzer.
5, wherein P1 and P2 can be trimethyl silicon based at the same time or separately, and triethyl is silica-based, triisopropylsilyl, and the dimethyl-sec.-propyl is silica-based, and the diethylammonium sec.-propyl is silica-based, and tertiary butyl dimethyl-is silica-based; Tert-butyl diphenyl is silica-based, tri-benzyl-silyl, and triphenyl is silica-based, and diphenyl methyl is silica-based, methoxymethyl, benzyloxymethyl; The tert.-butoxy methyl, the siloxy methyl, THP trtrahydropyranyl, tetrahydrofuran base, benzyl is to methoxy-benzyl; Trityl group, ethanoyl, chloracetyl, dichloro-acetyl, tribromo-acetyl base; The methoxyl group ethanoyl, valeryl, benzoyl-, it is silica-based wherein to be preferably triethyl, and tertiary butyl dimethyl-is silica-based.
6, midbody compound 7,9 and 23 preparation method:
The preparation method of ebormycine D of the present invention and B, synthesis step is few, and yield is high, and is simple to operate, is convenient to produce in enormous quantities.
Embodiment
In order to understand the present invention, further specify the present invention with embodiment below, but be not meant to restriction protection scope of the present invention.
Ebormycine D and B's is synthetic
(D)-acetyl camphor in sulphonamide (2) synthetic
Under the nitrogen protection, (102.8mmol) is added in the round-bottomed flask with the 4.1g sodium hydride, adds petroleum ether and stirring 30min then, leaves standstill; Remove supernatant, add the 500mL THF in the round-bottomed flask then and be cooled to 0 ℃, dropwise add the 150mL tetrahydrofuran solution of sulphonamide (93.5mmol) in the 20g camphor, drip off the back and stir 1h; Dropwise add 8.3mL Acetyl Chloride 98Min. (112.2mmol) then, add the back temperature and rise to room temperature, stirred overnight; Add 62mL sodium bicarbonate aqueous solution (1.19M) after reacting completely, stir 20min, most of THF is screwed out; Use ethyl acetate extraction, anhydrous sodium sulfate drying filters; Revolve dried solvent, obtain the 22.8g white solid with ethyl alcohol recrystallization, productive rate: 94.9%.
1H?NMR(300MHz，CDCl
3)δ3.86(m，1H，-CHN)，3.46(AB，2H，-CHHSO
2)，2.37(s，3H，CH
3CO)，2.13-2.03(m，2H)，1.91-1.87(m，3H)，1.41-1.35(m，2H)，1.12(s，3H，-CH
3)，0.94(s，3H，-CH
3).
Synthesizing of compound 3
Under the room temperature; 200mL isobutyric aldehyde (2.19mol) and 200mL toluene are joined in the round-bottomed flask of 1L, dropwise add 173.6mL morphine quinoline (1.99mol) then, reflux 2h; Remove the water of generation with water trap; The bullion that obtains obtains colourless liquid 219.94g, productive rate: 78.1% through underpressure distillation (95-100 ℃) purifying.
Under the nitrogen protection, 136.4mL propionyl chloride (1.56mol) and 400mL toluene are joined in the round-bottomed flask of 2L, temperature drops to 0 ℃; The colourless liquid that obtains above adding then also keeps temperature to be no more than 10 ℃, adds the back temperature and is raised to 80 ℃ and stir 14h, and then reduce the temperature to room temperature; Have this moment a large amount of solids to generate, filter, ether is washed five times; The yellow solid that obtains adds water to dissolving fully, ethyl acetate extraction, anhydrous sodium sulfate drying; Suction filtration, underpressure distillation (30-35 ℃) obtains yellow liquid 84.6g, productive rate: 40.4%.
1H?NMR(400MHz，CDCl
3)δ9.59(s，1H，-CHO)，2.46(m，2H，CH
3CH
2-)，1.31(s，6H，-CCH
3)，1.01(t，3H，J＝7.2Hz，-CH
2CH
3).
Synthesizing of compound 4
Under the nitrogen protection, sulphonamide (92.5mmol) in 25g (D)-acetyl camphor and 250mL methylene dichloride are joined in the round-bottomed flask, temperature is reduced to 0 ℃, slowly adds 110mL TiCl then
4(110mmol), stir 30min, add 19.2mL diisopropylethylamine (115.8mmol) then, cool the temperature to-78 ℃ behind the stirring 30min; Add 17.5mL 2 then, 2-dimethyl--3-carbonyl valeral (129.2mmol), the back that reacts completely adds the saturated aqueous ammonium chloride stopped reaction; Ethyl acetate extraction, anhydrous magnesium sulfate drying, suction filtration; Revolve dried solvent, cross column purification and obtain white solid, productive rate: 64%.
1H?NMR(400MHz，CDCl
3)δ4.30(m，1H)，3.87(m，1H)，3.45(m，2H)，3.25(m，1H)，2.80(m，2H)，2.55(m，2H)，2.08(m，2H)，1.89(m，3H)，1.37(m，2H)，1.17(s，3H)，1.15(s，3H)，1.12(s，3H)，1.02(t，J＝7.2Hz，3H)，0.97(s，3H)；
13C?NMR(100MHz，CDCl
3)δ216.1，171.5，73.0，65.4，53.1，51.2，48.7，48.0，44.9，38.6，38.0，33.1，31.4，26.6，21.8，21.06，20.1，19.4，8.1.
Synthesizing of compound 5
Under the nitrogen protection, 13.04g compound 4 (33.8mmol) and 95mL methylene dichloride are added in the round-bottomed flask, temperature is reduced to-78 ℃; Slowly add 5.90mL 2 then, 6-lutidine (50.7mmol) and the silica-based triflate of 9.32mL tertiary butyl dimethyl-(40.6mmol), low temperature stirs 2.5h; Slowly rise to room temperature then, the back that reacts completely adds 32mL water and ends ethyl acetate extraction; Saturated lemon pickling twice, anhydrous magnesium sulfate drying, suction filtration; Revolve dried solvent, ethyl alcohol recrystallization gets the 15.6g white solid, productive rate: 92.2%.
1H?NMR(400MHz，CDCl
3)δ4.65(m，1H)，3.83(m，1H)，3.45(m，2H)，2.93(m，1H)，2.65(m，1H)，2.50(m，2H)，2.10(m，2H)，1.86(m，3H)，1.36(m，2H)，1.14(s，3H)，1.13(s，3H)，1.05(s，3H)，0.95(m，6H)，0.83(s，9H)，0.06(s，3H)，0.04(s，3H).
Synthesizing of compound 6
With 1g compound 5 (2.0mmol), 85.5mL THF and 21.5mL water add in the round-bottomed flask of 750mL, and temperature is reduced to 0 ℃; Add 1.26g Lithium Hydroxide MonoHydrate (30.0mmol) and 26.5mL ydrogen peroxide 50 (324mmol) then, temperature slowly rises to room temperature, the reaction stirred overnight; After reacting completely, reduce the temperature to 0 ℃, add water (250mL) the solution stopped reaction of 9.0g sodium sulfite anhy 96 (85.5mmol); Ethyl acetate extraction, organic addition anhydrous sodium sulfate drying, suction filtration; Revolve dried solvent, cross column purification and obtain the colourless viscous liquid of 400mg, productive rate: 66.2%.
1H?NMR(400MHz，CDCl
3)δ4.47(m，1H)，2.51(m，3H)，2.31(dd，J＝16.4，6.8Hz，1H)，1.13(s，3H)，1.07(s，3H)，0.99(t，J＝7.2Hz，3H)，0.83(s，9H)，0.04(s，3H)，0.02(s，3H)；
13C?NMR(100MHz，CDCl
3)δ215.4，178.3，73.7，52.8，39.5，32.0，26.1，21.2，20.8，18.3，7.9，-4.2，-4.7.
Synthesizing of compound 7
Under the nitrogen protection, 5.0g compound 16 (29.94mmol) and 106.8mL ether are joined in the round-bottomed flask, temperature is reduced to-100 ℃; Slowly add 112.4mL (+)-IPC2Ballyl (44.9mmol) then, stir 1h, add 10.6mL methyl alcohol then; Temperature is risen to room temperature, add 17.9mL thanomin and stirred overnight subsequently, add 53.2mL saturated aqueous ammonium chloride stopped reaction; Ethyl acetate extraction, anhydrous magnesium sulfate drying, suction filtration; Revolve dried solvent, cross column purification and obtain the 9.9g colourless liquid, productive rate: 89.2%.
1H?NMR(400MHz，CDCl
3)δ6.91(s，1H)，6.54(s，1H)，5.84-5.77(m，1H)，?5.13(d，J＝18.8Hz，1H)，5.09(d，J＝11.2Hz，1H)，4.20(m，1H)，2.68(s，3H)，2.65(bs，1H)，2.38(m，2H)，2.01(s，3H)；
13C?NMR(100MHz，CDCl
3)δ164.8，152.9，141.7，134.8，119.2，117.9，115.6，76.6，40.1，19.3，14.5.
Synthesizing of compound 8
Under the nitrogen protection, with 378mg compound 6 (1.25mmol), 914mg compound 7 (4.37mmol) and 7.0mL methylene dichloride join in the round-bottomed flask of 25mL; Add 306mg N then, N-lutidine (2.5mmol) and 959mg 1-ethyl-3-(3-dimethylamine propyl) carbodiimide (5.0mmol) at room temperature stir 2h; Reacting completely, the back adds ether and water dilutes, and water is used extracted with diethyl ether, and the organic phase of merging is used anhydrous magnesium sulfate drying; Suction filtration; Revolve dried solvent, cross column purification and obtain the 470mg colourless liquid, productive rate: 76.3%.[α]
20 D＝-28.2(c＝10mg/mL，CHCl
3)；IR(KBr/cm
-1)：2954，2930，2856，1737，1705，1643，1505，1471，1374，1293，1248，1177，1088，1047，825，769；?
1H?NMR(400MHz，CDCl
3)δ6.94(s，1H)，6.48(s，1H)，5.71(m，1H)，5.28(t，J＝6.8Hz，1H)，5.11(d，J＝16.8，1.6Hz，1H)，5.04(d，J＝10.4，1.2Hz，1H)，4.46(dd，J＝6.4，4.0Hz，1H)，2.55-2.45(m，5H)，2.31(dd，J＝16.8，6.4Hz，1H)，2.06(s，3H)，1.09(s，3H)，1.05(s，3H)，0.97(t，J＝7.2Hz，3H)，0.84(s，9H)，O.06(s，3H)，0.02(s，3H)；
13C?NMR(100MHz，CDCl
3)δ215.2，171.3，164.8，152.6，136.9，133.5，121.4，118.1，116.6，79.0，73.7，52.8，39.7，37.7，31.9，26.1，21.1，20.9，19.4，18.3，14.8，17.9，-4.0，-4.8；HRMS(ESI)(M+H)calculated?for?C
26H
43NO
4SSi：494.2755，found，494.2759.
Synthesizing of compound 9
Method one:
Under the nitrogen protection, Lithium Aluminium Hydride is joined in the anhydrous tetrahydro furan, under 0 ℃; The tetrahydrofuran solution of compound 23 is added drop-wise in the above-mentioned reaction solution, behind reinforced the finishing, stirring reaction 2h; The back that reacts completely adds the THF dilution, in reaction solution impouring 5% Hydrogen chloride, with dichloromethane extraction three times; Merge organic phase, concentrate bullion.
Above-mentioned bullion is dissolved in the methylene dichloride, adds PCC (1.3equiv), stirring at room reaction 4h filters, and the low temperature of will filtrate carefully concentrates, and it is subsequent use to get 9 ,-20 ℃ of preservations of compound.
Method two:
Under the nitrogen protection, 2.63g compound 22 (7.4mmol) and 8.8mL methylene dichloride are joined in the round-bottomed flask, temperature of reaction system is reduced to-78 ℃, slowly adds 9.7mL diisobutyl aluminium hydride (9.7mmol) then; Low temperature stirs 1.5h, and the back that reacts completely adds 2.84g sodium pyrosulfate and 22mL water, and temperature rises to room temperature rapidly; Add the dilution of 6.5mL normal hexane, syringe needle takes out water, with twice of n-hexane extraction; Merge organic phase, concentrate to such an extent that 9 ,-20 ℃ of preservations of compound are subsequent use carefully.
Synthesizing of compound 10
Under the nitrogen protection, 3.24g compound 8 (6.47mmol) and 12.5mL methylene dichloride are added in the round-bottomed flask, reaction system is cooled to-78 ℃, slowly adds 7.1mL titanium tetrachloride solution (dichloromethane solution of 1.0M) then; Add 1.2mL diisopropylethylamine (7.1mmol) subsequently, obtain dark red solution, behind the stirring 1h, slowly add 22mL compound 9; Temperature is slowly risen to room temperature (about 3h), and the back adding 39mL pH value that reacts completely is 7 phosphoric acid buffer stopped reaction, adds ether and water then; Extracted with diethyl ether, anhydrous magnesium sulfate drying, suction filtration; Revolve dried solvent, bullion is crossed column purification and is obtained the colourless viscous liquid of 3.1g, productive rate: 74.0%.[α]
20 D＝-51.4(c＝10mg/mL，CHCl
3)；IR(KBr/cm
-1)：2929，2856，1735，1684，1506，1471，1376，1292，1252，1178，1079，976，283，832，776；
1H?NMR(400MHz，CDCl
3)δ6.94(s，1H)，6.48(s，1H)，5.70(m，1H)，5.28(t，J＝6.8Hz，1H)，5.07(d，J＝17.2Hz，1H)，5.04(d，J＝10.0Hz，1H)，4.66(s，1H)，4.64(s，1H)，4.40(m，1H)，3.44(s，1H)，3.26(m，2H)，2.69(s，3H)，2.48-2.43(band，3H)，2.31(dd，J＝17.2，6.0Hz，1H)，2.05(s，3H)，1.96(m，2H)，1.69(s，3H)，1.69-1.31(band，4H)，1.18(s，3H)，1.09(s，3H)，1.02(d，J＝6.8Hz，3H)，0.87(s，9H)，0.82(d，J＝6.8Hz，3H)，0.10(s，3H)，0.05(s，3H)；?
13C?NMR(100MHz，CDCl
3)δ171.1，164.8，152.6，146.4，136.8，133.5，121.3，118.0，116.6，109.8，79.0，74.8，73.7，54.1，41.5，40.4，38.4，37.7，35.7，32.8，26.2，25.0，22.6，22.2，20.2，19.4，18.3，15.5，14.8，9.9，-4.1，-4.6；HRMS(ESI)(M+H)calculated?for?C
35H
59NO
5SSi：634.3956，found，634.3954.
Synthesizing of compound 11
Under the nitrogen protection, the round-bottomed flask that will fill compound 10 (0.2mmol) and 1.5mL methylene dichloride is cooled to-45 ℃, slowly adds 0.07mL 2 then, 6-lutidine (0.6mmol); Add the silica-based triflate of 0.09mL tertiary butyl dimethyl-(0.4mmol) subsequently, be reflected at-45 ℃ and stir 6h down, slowly rise to room temperature then, add 2.0mL water stopped reaction; Methylene dichloride is screwed out, ethyl acetate extraction, the organic phase of merging is washed twice with saturated aqueous citric acid solution earlier; Then with saturated common salt washing twice, anhydrous magnesium sulfate drying, suction filtration; Revolve dried solvent, cross column purification and get the colourless viscous liquid of 0.14g, productive rate: 91.0%.
1H?NMR(400MHz，CDCl
3)δ6.94(s，1H)，6.49(s，1H)，5.70(m，1H)，5.29(t，J＝6.8Hz，1H)，5.05(m，2H)，4.68(s，1H)，4.65(s，1H)，4.34(dd，J＝6.0，3.6Hz，1H)，3.72(d，J＝4.8Hz，1H)，3.15(m，1H)，2.69(s，3H)，2.54-2.44(band，3H)，2.28(dd，J＝16.8，6.0Hz，1H)，2.06(s，3H)，1.97(m，2H)，1.69(s，3H)，1.50(m，1H)，1.33-1.29(band，3H)，1.25-1.21(band，4H)，1.04-1.03(band，6H)，0.91-0.88(band，21H)，0.10(s，3H)，0.06(s，3H)，0.04(s，6H)；
13C?NMR(100MHz，CDCl
3)δ217.9，171.4，164.7，152.7，146.2，137.0，133.6，121.3，118.0，116.6，110.0，78.9，77.8，74.2，53.5，45.4，40.5，38.9，38.5，37.7，31.1，26.4，26.2，25.9，23.4，22.6，20.5，19.4，18.7，18.4，17.9，15.6，14.8，-3.4，-3.6，-4.1，-4.5.
Synthesizing of compound 12:
Under the nitrogen protection, with 1, the 2-ethylene dichloride joins in the there-necked flask; Use the oil pump degasification, then temperature is raised to 80 ℃, take out 5mL dissolution with solvents compound 11 (0.13mmol) and Grubbs ll (0.026mmol) respectively; Simultaneously two kinds of solution slowly are added drop-wise in the there-necked flask then, reaction mixture heated and stirred 5h revolves dried solvent then; Bullion is crossed column purification and is obtained colourless liquid 40mg, productive rate: 43.0%.
Epothilone D's is synthetic:
Under the nitrogen protection, (0.024mmol) joins in the round-bottomed flask with compound 12, and temperature is reduced to-20 ℃, slowly adds the trifluoroacetic acid/dichloromethane (V/V=1: 4 of new system then; 1mL), rise to 0 ℃ behind the stirring 30min, the back that reacts completely adds the ETHYLE ACETATE dilution, adds the saturated sodium bicarbonate solution stopped reaction then; Use ethyl acetate extraction, dried over mgso, suction filtration; Revolve dried solvent, thick product obtains 5mg ebormycine D, productive rate: 83% through the preparation plate.
1H?NMR(400MHz，CDCl
3)δ6.96(s，1H)，6.59(s，1H)，5.21(dd，J＝10.0，1.5Hz，1H)，5.13(dd，J＝10.0，5.0Hz，1H)，4.28(dd，J＝11.0Hz，1H)，3.73(3.15(m，1H)，3.02(br?s，1H)，2.68(s，3H)，2.63(m，1H)，2.45(dd，J＝14.6，11.0Hz，1H)，2.35-2.29(m，1H)，2.38(m，1H)，2.22(m，1H)，2.06(s，3H)，1.89-1.83(m，1H)，1.78-1.68(m，2H)，1.65(s，3H)，1.33(s，3H)，1.31-1.24(m，4H)，1.18(d，J＝7.0Hz，3H)，1.06(s，3H)，1.01(d，J＝7.0Hz，3H).
Epothilone B's is synthetic:
Ebormycine D is dissolved in the anhydrous methylene chloride, adds m-CPBA (1.4equiv) down at-18 ℃, reaction mixture stirring reaction 5h under this temperature with the methylene dichloride dilution, adds the saturated sodium bicarbonate solution termination reaction then.Layering with dichloromethane extraction three times, merges organic phase, anhydrous sodium sulfate drying, and concentrating under reduced pressure, thick product obtains the 4.2mg epothilone B through the preparation plate, and nuclear magnetic spectrum is consistent with standard control.
Synthesizing of compound 16
Under the nitrogen protection; 433mg compound 15 (1.36mmol), 150mg compound 14 (1.18mmol) and 2.5mL toluene are joined in the round-bottomed flask, and temperature rises to 70 ℃, revolves dried solvent after reacting completely; Bullion is crossed column purification and is obtained the 163mg white solid, productive rate: 83.2%.
1H?NMR(400MHz，CDCl
3)δ9.56(s，1H)，9.46(s，1H)，7.26(s，1H)，2.76(s，3H)，2.20(s，3H).
Synthesizing of compound 18
Under the nitrogen protection, sulphonamide (232.9mmol) in 50.0g (L)-camphor and 980mL acetonitrile are joined in the round-bottomed flask, slowly add 32.8mL 3-chlorpromazine chloride (349.3mmol); Reflux 13h, temperature is reduced to room temperature then, adds 64.5g salt of wormwood (466.0mmol) continued backflow 4h; Revolve dried solvent, add 320mL water, with an amount of ethyl acetate extraction three times; Merge organic phase, anhydrous magnesium sulfate drying filters; Revolve dried solvent, the crude product that obtains gets the 54.1g white solid with re-crystallizing in ethyl acetate, productive rate 76.7%.
1H?NMR(300MHz，CDCl
3)δ6.86(m，1H)，6.50(dd，J＝16.8，1.8Hz，1H)，5.85(dd，J＝10.5，1.8Hz，1H)，3.94(m，1H)，3.48(m，2H)，2.11-2.15(m，2H)，1.88-1.93(m，3H)，1.37-1.43(m，2H)，1.17(s，3H)，0.98(s，3H).
Synthesizing of compound 20
Under 0 ℃, 50.0mL 3-methyl-3-butenol (493.5mmol) is dropwise joined in the 103.5g Tosyl chloride (542.7mmol), add 21mg N then, N-lutidine and 78.0mL pyridine; Reaction solution is heated to 80 ℃ of backflow 4h, is cooled to room temperature then and continues to stir 30min, and temperature of reaction is dropped to 0 ℃, adds 250mL water; Use boiling point to be 30-60 ℃ petroleum ether extraction, give a baby a bath on the third day after its birth time twice of 80mL washing then with the hydrochloric acid of 100mL5N; The 60mL saturated sodium bicarbonate washes twice, anhydrous magnesium sulfate drying, suction filtration; Careful concentrating part solvent, air distillation then (101-104 ℃) gets 21.2g colourless liquid, productive rate: 43.3%.
1H?NMR(400MHz，CDCl
3)δ4.86(s，1H，-CC
H 2)，4.78(s，1H，-CC
H 2)，3.62(t，J＝9.6Hz，2H，ClC
H 2-)，2.48(t，J＝9.4Hz，2H，CC
H 2-)，1.75(s，1H，C
H 3-).
Synthesizing of compound 21
With the 1.3g magnesium chips, iodine and 15mL THF join in the there-necked flask of 50mL, add 0.04mL 1 then; 2-ethylene dibromide, temperature rise to 35 ℃, and 0.02mL 3-methyl-3-butene-1-chlorine is added in the above-mentioned mixed solution; By the time after the color of iodine is decorporated, dropwise add remaining 4.6mL 3-methyl-3-butene-1-chlorine again, after adding temperature is risen to 60 ℃ of reaction 3h; Leave standstill, obtain transparent grey supernatant, subsequent use.
Synthesizing of compound 22
Under the nitrogen protection, 10g compound 18 (37.5mmol) and 500mL THF join in the round-bottomed flask, and temperature is reduced to-78 ℃, slowly add 150mL compound 21 (101.6mmol); After stirring 3h, slowly add 23.0mL methyl iodide (371.0mmol) and 37.0mL hexamethylphosphoramide (210mmol), slowly rise to room temperature; The back adding saturated aqueous ammonium chloride that reacts completely is ended, and ethyl acetate extraction, the organic phase water of merging are given a baby a bath on the third day after its birth inferior; Saturated aqueous common salt is given a baby a bath on the third day after its birth inferior, anhydrous magnesium sulfate drying, suction filtration; Revolve dried solvent, cross post and get the 8.15g white solid, productive rate: 67.7%.
1H?NMR(400MHz，CDCl
3)δ4.66(m，?2H，-CC
H 2)，3.89(t，J＝8.4Hz，1H，C
HN)，3.46(m，2H，-C
HHSO
2)，3.06(m，1H，CH
3C
H-)，1.97-2.05(m，4H)，1.74-1.91(m，4H)，1.68(s，3H，C
H 3C-)，1.34-1.45(m，5H)，1.19(m，3H，C
H 3CH-)，1.15(s，3H，-C
H 3)，0.96(s，3H，-C
H 3).
Synthesizing of compound 23
With 5.0g compound 22 (14mmol), 598mL THF and 150mL water add in the round-bottomed flask of 2L, and temperature is reduced to 0 ℃; Add 8.8g Lithium Hydroxide MonoHydrate (210mmol) and 185mL ydrogen peroxide 50 (2.26mol) then, temperature slowly rises to room temperature, the reaction stirred overnight; After reacting completely, reduce the temperature to 0 ℃, add the aqueous solution stopped reaction of 63g sodium sulfite anhy 96 (598mmol); Ethyl acetate extraction, organic addition anhydrous sodium sulfate drying, suction filtration; Revolve dried solvent, cross column purification and obtain colourless viscous liquid, productive rate: 70.0%.
1H?NMR(400MHz，CDCl
3)δ12.08(br，1H)，4.70(s，1H)，4.66(s，1H)，2.46(m，1H)，2.03(m，2H)，1.69(s，3H)，1.69-1.63(m，1H)，1.51-1.39(m，3H)，1.18(d，J＝8Hz，3H).
Compound of the present invention, purposes and method are described through concrete embodiment.Those skilled in the art can use for reference links such as content appropriate change raw material of the present invention, processing condition and realize corresponding other purpose; Its relevant change does not all break away from content of the present invention; All similar replacements and change will become apparent to those skilled in the art that all to be regarded as and are included within the scope of the present invention.
Claims (6)
1. method for preparing ebormycine D and B, it is characterized in that: carboxylic acid (6) becomes ester (8) with oxy-compound (7), then with key intermediate 9; Through Aldol reacting generating compound 10, proper protection radical protection hydroxyl gets compound 11, through RCM react compound 12; Remove hydroxy-protective group; Get compound ebormycine D, get epothilone B through epoxidation again, comprise that specifically step is as shown in Figure 1.
2. preparation method according to claim 1, wherein P can be for trimethyl silicon based, and triethyl is silica-based; Triisopropylsilyl, the dimethyl-sec.-propyl is silica-based, and the diethylammonium sec.-propyl is silica-based; Tertiary butyl dimethyl-is silica-based, and tert-butyl diphenyl is silica-based, tri-benzyl-silyl; Triphenyl is silica-based, and diphenyl methyl is silica-based.
3. preparation method according to claim 1, wherein Lewis acid can be TiCl
4, BCl
3, InCl
3, AlCl
3, RAlCl
2, R
2AlCl, wherein R is an alkyl; Lewis alkali is tertiary amine, pyridine, substituted pyridines.
4. preparation method according to claim 1, wherein catalyzer is the diene catalysts for metahesis reactions, can be Grubbs first-generation catalyzer, Grubbs s-generation catalyzer, Hoveyda-Grubbs catalyzer, Zhan Shi catalyzer.
5. preparation method according to claim 1, wherein P1 and P2 can be trimethyl silicon based at the same time or separately, triethyl is silica-based, triisopropylsilyl, the dimethyl-sec.-propyl is silica-based; The diethylammonium sec.-propyl is silica-based, and tertiary butyl dimethyl-is silica-based, and tert-butyl diphenyl is silica-based, tri-benzyl-silyl, and triphenyl is silica-based; Diphenyl methyl is silica-based, methoxymethyl, benzyloxymethyl, tert.-butoxy methyl, siloxy methyl; THP trtrahydropyranyl, tetrahydrofuran base, benzyl, to methoxy-benzyl, trityl group; Ethanoyl, chloracetyl, dichloro-acetyl, tribromo-acetyl base, methoxyl group ethanoyl; Valeryl, benzoyl-, it is silica-based wherein to be preferably triethyl, and tertiary butyl dimethyl-is silica-based.
6. following midbody compound 9 and 23 preparation method, concrete synthetic route is as shown in Figure 3.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864834A (en) * | 2012-12-10 | 2014-06-18 | 天津尚德药缘科技有限公司 | Preparation method of epothilone B and D key intermediate |
| CN104593444A (en) * | 2013-10-31 | 2015-05-06 | 重庆乾泰生物医药有限公司 | Fermentation method for preparation of Epothilone B |
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|---|---|---|---|---|
| WO1998008849A1 (en) * | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Method for producing epothilones, and intermediate products obtained during the production process |
| CN102134246A (en) * | 2011-01-06 | 2011-07-27 | 王文怡 | Epothilone derivatives as well as preparation and medicament application thereof |
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2011
- 2011-02-15 CN CN2011100381758A patent/CN102633792A/en active Pending
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|---|---|---|---|---|
| WO1998008849A1 (en) * | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Method for producing epothilones, and intermediate products obtained during the production process |
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| STEVEN D. DONG，等: "Rapid access to epothilone analogs via semisynthetic degradation and reconstruction of epothilone D", 《TETRAHEDRON LETTERS》, vol. 45, no. 9, 31 December 2004 (2004-12-31), pages 1945 - 1947, XP004488581, DOI: doi:10.1016/j.tetlet.2003.12.123 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864834A (en) * | 2012-12-10 | 2014-06-18 | 天津尚德药缘科技有限公司 | Preparation method of epothilone B and D key intermediate |
| CN104593444A (en) * | 2013-10-31 | 2015-05-06 | 重庆乾泰生物医药有限公司 | Fermentation method for preparation of Epothilone B |
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