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CN101386607A - Taxane derivatives, preparation method and applications thereof - Google Patents

Taxane derivatives, preparation method and applications thereof Download PDF

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Publication number
CN101386607A
CN101386607A CNA2008102020907A CN200810202090A CN101386607A CN 101386607 A CN101386607 A CN 101386607A CN A2008102020907 A CNA2008102020907 A CN A2008102020907A CN 200810202090 A CN200810202090 A CN 200810202090A CN 101386607 A CN101386607 A CN 101386607A
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acid
taxol
acetyl
docetaxel
taxane
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徐从立
黄山
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SHANGHAI SHUANGKE MEDICAL TECHNOLOGY Co Ltd
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SHANGHAI SHUANGKE MEDICAL TECHNOLOGY Co Ltd
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Abstract

The invention relates to new taxane derivatives, which are prepared from taxane compounds (taxol, docetaxel or 9-dihydro-taxol), organic acids with completely acetylated alcohol hydroxy, and 4-dimethylamino-pyridine and dicyclohexyl carbodiimide used as catalysts together through esterification reaction. The effects of pharmacological tests show that the derivatives have stronger cytotoxic biological activities to various human cancer cell lines and have broad-spectrum anti-tumor effects, and the tumor inhibiting effect of the derivative in mice is superior to that of the taxol and the docetaxel obviously. Toxicity tests also show that the toxicity of the derivatives is obviously reduced compared with the taxol and the docetaxel, which improves the safety in clinical application. Therefore, the taxane derivatives are effective anti-tumor agents, which can be applied to the preparation of anti-tumor drugs.

Description

Taxane derivative, its preparation method and application
Technical field
The present invention relates to side chain and contain the organic acid Taxane derivative, its preparation method and the application in the preparation antitumor drug.
Background technology
1971 (Wani Mc, et al, J.A.C.S.93,2325,1971.) such as Wani extract the taxol that obtains belonging to described bearing taxanes first from yewtree (Taxusbrevifolia) bark, its chemical structural formula is as follows:
Figure A200810202090D00041
Known taxol shows extremely strong antitumour activity to many tumor models such as B-16 melanoma, L-1210 and P-388 leukemia, MX-1 mammary cancer and heteroplastic CX-1 colorectal carcinoma, its mechanism of action can be impelled tubulin polymerization for it and become microtubule, and microtubule no longer disintegrates in the presence of it, cancer cells is limited in the framework and dead [Dentsch-HM et al, J.M.C.32 (4), 788,1989; Manfredi JJ, et al, Phannacolther25,83,1984].In December, 1992, the taxol of drugs approved by FDA BMS company is as the second line treatment medicine of transitivity ovarian cancer; Ratify this medicine again as the advanced breast cancer curative in December, 1993, and this medicine is more than 20 state approval listings at present.
But because the cytotoxicity of taxol makes to have more danger in clinical application.Structure to taxol and other reactive violet China fir alkane is carried out structural modification, seeks hypotoxicity, and highly active taxane prodrugs has become the emphasis of people's research.Docetaxel is by a kind of D51-7059 of structure of modification synthetic, has less toxicity and bioavailability preferably, at present more than 40 country's listings.Therefore the Taxane derivative of studying high-efficiency low-toxicity is significant.
Summary of the invention
The invention provides the new Taxane derivative of a class.
The invention provides the preparation method of the new Taxane derivative of this class.
The invention provides the application of the new Taxane derivative of this class in the preparation antitumor drug.
The chemical structure of general formula of Taxane derivative of the present invention is as follows:
In the formula: when R1 is C=O, R 2For Ph or-OC (CH 3) 3
R 1During for CHOH, R 2Be Ph;
R ' is an alcoholic extract hydroxyl group by complete acetylizad organic acid: forulic acid, rosmarinic acid, chlorogenic acid, shikimic acid, Betulinic acid, Oleanolic Acid, ursolic acid or glycyrrhetinic acid etc.
The preparation method of Taxane derivative of the present invention comprises following steps:
1) organic acid acetylize
Organic acid acetylization reaction method referring to document (Bi Yi etc., China Medicine University's journal, 2007,38 (2), 108-111).Get organic acid (forulic acid, rosmarinic acid, chlorogenic acid, shikimic acid, Betulinic acid, Oleanolic Acid, ursolic acid or glycyrrhetinic acid etc.) and be dissolved in the pyridine, carry out acetylization reaction with aceticanhydride and make alcoholic extract hydroxyl group by complete acetylize organic acid.1 mol organic acid uses 40-60 to rise pyridine, and the mole ratio of organic acid and aceticanhydride is 1-4:1, and temperature of reaction 10-90 ℃, reaction times 12-48 hour.Reaction finishes the back and adds ethyl acetate extraction, and 1 mol organic acid uses 40-60 to rise ethyl acetate, uses 1%-10% hydrochloric acid, water and saturated common salt water washing organic phase 2 times more respectively; anhydrous sodium sulfate drying; filter, be evaporated to driedly, obtain alcoholic extract hydroxyl group by complete acetylizad organic acid.
The acetylizad reaction equation of organic acid is as follows:
Figure A200810202090D00061
RCOOH is organic acids such as forulic acid, rosmarinic acid, chlorogenic acid, shikimic acid, Betulinic acid, Oleanolic Acid, ursolic acid or glycyrrhetinic acid in the formula, and R ' COOH is an alcoholic extract hydroxyl group by complete acetylizad organic acid: forulic acid, rosmarinic acid, chlorogenic acid, shikimic acid, Betulinic acid, Oleanolic Acid, ursolic acid or glycyrrhetinic acid etc.
2) Taxane derivative is synthetic
Taxane derivative synthetic reaction equation is as follows:
At rare gas element (nitrogen; argon gas; helium or neon) protection is down; taxane compounds (taxol; Docetaxel or 9-dihydro taxol) be dissolved in the methylene dichloride; add catalyzer 4-Dimethylamino pyridine (DMAP) and dicyclohexylcarbodiimide (DCC), add alcoholic extract hydroxyl group again, carry out esterification together and make Taxane derivative by complete acetylizad organic acid.1 mol taxane compounds uses 40-90 to rise methylene dichloride.Taxane compounds, DMAP, DCC and alcoholic extract hydroxyl group are 1:0.5-2:0:5-2:0.8-2 by complete acetylizad organic acid mole ratio, temperature of reaction 10-50 ℃, reaction times 1-5 hour.Reaction finishes the ethyl acetate of back adding as extraction agent, 1 mol taxane compounds uses 40-90 to rise ethyl acetate, reaction solution successively with the salt acid elution of 1%-10% once, saturated common salt water washing 2 times, 1 mol taxane compounds use 40-90 to rise hydrochloric acid and 40-90 rises saturated aqueous common salt, separate organic phase with anhydrous sodium sulfate drying, decompression receive to do solid, solid carries out purifying through silica gel column chromatography, gets Taxane derivative, and yield is 82-92%.
The pharmacological testing of Taxane derivative of the present invention
1) end user's tumor cell line carries out cell toxicity test
With Taxane derivative 2 of the present invention '-acetyl forulic acid taxol (T1), 2 '-acetyl forulic acid Docetaxel (T2), 2 '-acetyl forulic acid-9-dihydro taxol (T3), 2 '-acetyl ursolic acid taxol (T4), 2 '-acetyl ursolic acid Docetaxel (T5), 2 '-acetyl ursolic acid-9-dihydro taxol (T6), taxol and Docetaxel carry out the cell toxicity test of various human tumor cell line, adopt mtt assay to carry out cell growth inhibition test (referring to embodiment 25).The results are shown in Table 1, experimental result shows that Taxane derivative of the present invention has good inhibition tumor promotion.
2) use nude mouse people liver cancer model and press down the knurl experiment
With Taxane derivative 2 of the present invention '-acetyl forulic acid taxol (T1), 2 '-acetyl forulic acid Docetaxel (T2), 2 '-acetyl forulic acid-9-dihydro taxol (T3), 2 '-acetyl ursolic acid taxol (T4), 2 '-acetyl ursolic acid Docetaxel (T5), 2 '-acetyl ursolic acid-9-dihydro taxol (T6), taxol and Docetaxel are used nude mouse people liver cancer model and are pressed down knurl experiment (referring to embodiment 27).The results are shown in Table 3, experimental result shows, the nude mouse of T1, T2, T3, T4, T5, T6 experimental group tumor weight after 4 weeks of treatment is starkly lower than control group taxol and Docetaxel (P＜0.05), and experiment shows that Taxane derivative of the present invention obviously is better than taxol and Docetaxel to tumor inhibition effect.
Taxane derivative of the present invention is to the cytotoxicity experiment of human normal cell line
Taxane derivative of the present invention and taxol and Docetaxel have been carried out the cytotoxicity experiment (referring to embodiment 26) of human normal cell line.The results are shown in Table 2, experimental result show Taxane derivative of the present invention to the toxicity of human normal cell line than taxol, Docetaxel obviously reduces.
Effect by above pharmacological testing proves, Taxane derivative of the present invention is to the HCT-8 colorectal carcinoma, Bel-7402 liver cancer, the A2780 ovarian cancer, A549 adenocarcinoma of lung, BGC-823 cancer of the stomach, MCF-7 mammary cancer, the Hela cervical cancer, human cancer cell strains such as KeTr3 kidney have stronger cell toxicant biological activity, the antitumor action of You Guang Spectrum; Function of tumor inhibition obviously is better than taxol and Docetaxel in the Taxane derivative mouse body of the present invention; Toxicity test shows that the toxicity of Taxane derivative of the present invention is than taxol, and the toxicity of Docetaxel obviously reduces, and this makes the security of this analog derivative in clinical application increase.Therefore Taxane derivative of the present invention is a kind of effective antitumour agent, can be applicable to preparing anti-tumor medicine.Taxane derivative of the present invention can be used as the activeconstituents of antitumor drug, also can contain Taxane derivative and the pharmaceutically acceptable carrier and/or the vehicle of significant quantity in this antitumor drug, makes the formulation that is fit to use.Route of administration can be enteron aisle or non-enteron aisle.
Form of administration can be liquid, solid or semisolid dosage form.Liquid dosage form can be solution, emulsion, suspensoid, injection, eye drops, nasal drop, lotion, liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, effervescent tablet, orally disintegrating tablet, chewable tablet), capsule, granule, powder, pill, suppository, film, patch, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
Taxane derivative of the present invention can be made ordinary preparation, also can make sustained release preparation, controlled release preparation, targeting preparation and various particulate drug-delivery preparation.
For tablet is made in the administration unit, can be extensive use of various pharmaceutical carrier well known in the art.About pharmaceutical carrier, for example thinner and absorption agent are as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, Icing Sugar, sodium-chlor, glucose, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, Icing Sugar, honey, maltose, liquid glucose, mucialga of arabic gummy, gelatine size, Vltra tears, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent is as dry starch, alginates, agar powder, laminaran, yellow soda ash and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, tween-80, gas-producing disintegrant, crosslinked carboxymethyl fecula sodium, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; The disintegration inhibitor is as sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer is as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant is as magnesium laurylsulfate, palmitinic acid, fumaric acid, talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.; Sweeting agent is as protein sugar, Sodium Cyclamate, cyclohexane sulfamic acid, alcohol sugar, soluble saccharin (calcium), glycyrrhizin etc.; Correctives is as mentha camphor, various essence, Chinese cassia tree and various fruity material etc.Tablet further can also be made coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in the administration unit, can be extensive use of various pharmaceutical carrier well known in the art.About pharmaceutical carrier, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, syrup, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Refrigerant is as Liquid Paraffin, Simethicone and plant wet goods.For suppository is made in the administration unit, can be extensive use of various pharmaceutical carrier well known in the art.About this class pharmaceutical carrier ester etc. of theobroma oil, higher alcohols for example.For capsule is made in the administration unit, the Taxane derivative of effective constituent is mixed with above-mentioned various pharmaceutical carriers, and the mixture that will obtain the thus hard capsule or the soft capsule that place gelatin, gum arabic, methylcellulose gum, sodium alginate, polyvinylpyrrolidone and other macromolecular material to make.Also the Taxane derivative of effective constituent can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, for example solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners and emulsifying agent commonly used, as water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of ammediol, Yelkin TTS, Tweens, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.; For example liposome can use method preparations such as this area membrane process commonly used, reverse phase evaporation, solvent injection method, compound emulsion method.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine in order to prepare etc.; In addition, can also add conventional solubility promoter, PH conditioning agent etc.In addition, also can in pharmaceutical preparation, add tinting material, sanitas or other material.
The dosage of Taxane derivative of the present invention depends on all multifactor, for example will prevent or treat the character and the severity of disease, patient's sex, age, body weight and individual reaction, route of administration and administration number of times etc.Usually to the about 75 kilograms of patients of body weight, the per daily dose of the Taxane derivative of giving is the 1-10mg/kg body weight.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.Concrete case can be by the doctor according to state of an illness adjustment.
Innovation part of the present invention is:
1. obtain the new Taxane derivative of the present invention by chemosynthesis, and its preparation method is easy, yield is higher, is suitable for suitability for industrialized production.
2. show by the cell toxicant biological activity test, such new Taxane derivative is to the HCT-8 colorectal carcinoma, Bel-7402 liver cancer, the A2780 ovarian cancer, A549 adenocarcinoma of lung, BGC-823 cancer of the stomach, MCF-7 mammary cancer, the Hela cervical cancer, human cancer cell strains such as KeTr3 kidney have stronger cell toxicant biological activity, the antitumor action of You Guang Spectrum.
3. suppress experiment by mouse interior tumor and show that function of tumor inhibition obviously is better than taxol and Docetaxel in such new Taxane derivative body.Press down the knurl experiment and show that such Taxane derivative has certain targeting, make it in the enrichment of tumor tissues organ, strengthen its therapeutic action, this compounds produces Taxan by metabolism in vivo simultaneously, has slow release effect, this also makes this compounds transformation period in vivo prolong, and also is one of this compounds curative effect enhanced factor.
4. show by toxicity test that the toxicity of the Taxane derivative that such is new is than taxol, the toxicity of Docetaxel obviously reduces, and this makes the security of this compounds in clinical application increase, and dosage can strengthen, and the validity of treatment is strengthened.
5. the antitumor drug of the new Taxane derivative of the present invention preparation can be made different dosage form, and administration by different way increases the selectivity of clinical application.
Embodiment
The following examples only are used for further specifying the present invention, but this and do not mean that any limitation of the invention.
The preparation of embodiment 12 '-acetyl forulic acid taxol
Figure A200810202090D00101
1) acetylize of forulic acid
Getting the 5mmol forulic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl forulic acid.
2) 2 '-acetyl forulic acid taxol synthetic
Under the nitrogen protection; 0.41mmol taxol is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl forulic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively once with the salt acid elution of 30ml5%, saturated common salt water washing 2 times, organic phase is with anhydrous sodium sulfate drying; decompression is received and is done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl forulic acid taxol, yield is 90%.Spectral data is shown as 2 '-acetyl forulic acid taxol.
mp：197～201℃。Electrospray ionization mass spectrum (m/z:1094.9[M+Na of ESI-MS)].
IR (KBr) cm -1: 1700 (C=O), 1670,1610,1520 (aromatic rings), 860,810. 1H—NMR(C 5D 5N)δ：4.01(3H，s，OCH 3)，6.28，6.45(1H，d，J＝15.3Hz，ArCH)，7.35(1H，s，C 2-H)，7.00(1H，d，J＝7.2Hz，C 6-H)，7.20(1H，d，J＝7.2Hz，C 5-H)；1.14(s，3H)，1.24(s，3H)，1.69(s.3H)，1.79(s，3H)，1.83(s.1H)，1.83～1.93(m.1H)，2.23(s，3H)，2.28～2.39(m，2H)，2.38(s，3H)，2.48(d.J：4Hz，1H)，2.48～2.57(m，1H)，3.55(d.J＝5Hz，1H)，4.37～4.44(m，1H)，4.80(dd，J＝2.5，5Hz.1H)，4.94(bd，J＝8.0Hz.1H)，5.67(d，J＝7Hz.1H)，5.78(dd，J＝2.5，8.8Hz.1H)，6.23(t，J：9Hz.1H)，6.27(s.1H)，7.01(d，J＝8.9Hz，1H)，7.33～7.54(m，1H)，7.59～7.64(m.1H)，7.22～7.75(m.2H)，8.12～8.15(m，2H)。
The preparation of embodiment 22 '-acetyl forulic acid Docetaxel
Figure A200810202090D00111
1) acetylize of forulic acid
Getting the 5mmol forulic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl forulic acid.
2) 2 '-acetyl forulic acid Docetaxel synthetic
Under the nitrogen protection; 0.41mmol Docetaxel is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl forulic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively once with the salt acid elution of 30ml 5%, saturated common salt water washing 2 times, organic phase is with anhydrous sodium sulfate drying; decompression is received and is done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl forulic acid Docetaxel, yield is 92%.Spectral data is shown as 2 '-acetyl forulic acid Docetaxel.
mp：223～226℃。ESI—MS?m/z：1048.8[M+Na]。
IR (KBr) cm -1: 17120 (C=O), 1660,1620,1510 (aromatic rings), 850,820.
1H—NMR(C 5D 5N)δ：4.01(3H，s，OCH 3)，6.28，6.45(1H，d，J＝15.3Hz，ArCH)，7.35(1H，s，C 2-H)，7.00(1H，d，J＝7.2Hz，C 6-H)，7.20(1H，d，J＝7.2Hz，C 5-H)；8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m.1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.88(s，3H)，1.75(s，3H)，1.35(s，9H)，1.11(s，3H)； 13C—NMR(C 5D 5N)δ：211.1，172.6，170.3，167.0，155.5，138.6，138.5，136.0，133.0，130.2，129.2，128.8，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.7，57.6，56.6，46.6，43.2，36.7，35.8，28.2，26.5，22.5，20.6，14.2，10.1。
The preparation of embodiment 32 '-acetyl forulic acid-9-dihydro taxol
Figure A200810202090D00121
1) acetylize of forulic acid
Getting the 5mmol forulic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl forulic acid.
2) 2 '-acetyl forulic acid-9-dihydro taxol synthetic
Under the nitrogen protection; 0.41mmol 9-dihydro taxol is dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl forulic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively once with the salt acid elution of 30ml5%, saturated common salt water washing 2 times, organic phase is with anhydrous sodium sulfate drying; decompression is received and is done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '--acetyl forulic acid-9-dihydro taxol, yield is 91%.Spectral data is shown as 2 '-acetyl forulic acid-9-dihydro taxol.
mp：199～202℃。ESI—MS?m/z：1096.9[M+Na]。
IR (KBr) cm -1: 1710 (C=O), 1675,1620,1520 (aromatic rings), 865,810.
1H-NMR(600MHz，CDCl 3)δppm：4.01(3H，s，OCH 3)，6.28，6.45(1H，d，J＝15.3Hz，ArCH)，7.35(1H，s，C 2-H)，7.00(1H，d，J＝7.2Hz，C 6-H)，7.20(1H，d，J＝7.2Hz，C 5-H)；8.15(2H，dd，J＝8.4，0.6Hz，2-o-Ph)，7.75(2H，dd，J＝8.4，1.2Hz，N-o-Ph)，7.62(1H，tt，J＝7.2，1.1Hz，2-p-Ph)，7.52(2H，m，2-m-Ph)7.49(3H，m，N-m，p-Ph)7.44～7.40(4H，m，3’-o，p-Ph)7.37(1H，d，J＝7.8Hz，3’-p-Ph)6.98(1H，d，J＝9Hz，NH)6.28(1H，s，10-H)6.25(1H，t，J＝8.3Hz，13-H)5.80(1H，dd，J＝9，2.4Hz，3’-H)5.69(1H，d，J＝6.6Hz，2-H)4.95(1H，dd，J＝7.9，2.4Hz，5-H)4.80(1H，d，J＝2.4Hz，2’-H)4.40(1H，dd，J＝10.9，6.6Hz，7-H)4.31(1H，d，J＝8.4Hz，20-Ha)4.21(1H，d，J＝9Hz，20-H β)3.81(1H，d，J＝7.2Hz，3-H)2.54(1H，m，6-Ha)2.39(3H，s，4-COCH 3)2.36(2H，d，J＝9Hz，14-H2)2.25(3H，s，10-COCH 3)1.88(1H，m，6-H β)1.80(3H，d，J＝1.2Hz，18-CH 3)1.71(3H，s，19-CH3)1.25(3H，s，17-CH 3)1.15(3H，s，16-CH 3)。
The preparation of embodiment 42 '-acetyl ursolic acid taxol
1) acetylize of ursolic acid
Getting the 5mmol ursolic acid is dissolved in the pyridine 250m pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, acetyl ursolic acid.
2) 2 '-acetyl ursolic acid taxol synthetic
Under the nitrogen protection; 0.41mmol taxol is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add the 0.41mmol acetyl ursolic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively once with the salt acid elution of 30m5%, saturated common salt water washing 2 times, organic phase is with anhydrous sodium sulfate drying; decompression is received and is done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the acetyl ursolic acid taxol, yield is 85%.Spectral data is shown as 2 '-the acetyl ursolic acid taxol.
mp：257～259℃。ESI—MS?m/z：1356.9[M+Na]。
IR(KBr)cm -1：3419，2927，2871.1697.1457，1378.1029。
1H—NMR(C 5D 5N)δ：5.16(1H，t)，4.29(1H，t，3-H)，1.06(3H，s)，0.74(3H，s)，0.92(6H，s)，0.69(3H，s)，0.89(6H，s)；1.14(s，3H)，1.24(s，3H)，1.69(s.3H)，1.79(s，3H)，1.83(s.1H)，1.83～1.93(m.1H)，2.23(s，3H)，2.28～2.39(m，2H)，2.38(s，3H)，2.48(d.J：4Hz，1H)，2.48～2.57(m，1H)，3.55(d.J＝5Hz，1H)，4.37～4.44(m，1H)，4.80(dd，J＝2.5，5Hz.1H)，4.94(bd，J＝8.0Hz.1H)，5.67(d，J＝7Hz.1H)，5.75(dd，J＝2.5，8.8Hz.1H)，6.20(t，J：9Hz.1H)，6.26(s.1H)，7.01(d，J＝8.9Hz，1H)，7.32～7.54(m，1H)，7.59～7.64(m.1H)，7.22～7.74(m.2H)，8.12～8.14(m，2H)。
The preparation of embodiment 52 '-acetyl ursolic acid polyenoid Japanese yew
1) acetylize of ursolic acid
Getting the 5mmol ursolic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, acetyl ursolic acid.
2) 2 '-acetyl ursolic acid Docetaxel synthetic
Under the nitrogen protection; 0.41mmol Docetaxel is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add the 0.41mmol acetyl ursolic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively once with the salt acid elution of 30ml5%, saturated common salt water washing 2 times, organic phase is with anhydrous sodium sulfate drying; decompression is received and is done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the acetyl ursolic acid Docetaxel, yield is 88%.Spectral data is shown as 2 '-the acetyl ursolic acid Docetaxel.
mp：277～279℃。ESI—MS?m/z：1310.7[M+Na]。
IR(KBr)cm -1：3419，2927，2875.1695.1450，1370.1030。
1H—NMR(C 5D 5N)δ：5.16(1H，t)，4.29(1H，t，3-H)，1.06(3H，s)，0.74(3H，s)，0.92(6H，s)，0.69(3H，s)，0.89(6H，s)；8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m.1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.81(s，3H)，1.72(s，3H)，1.33(s，9H)，1.12(s，3H)；
13C—NMR(C 5D 5N)δ：211.1，172.5，170.5，167.0，155.0，138.4，138.5，136.4，133.0，130.2，129.2，128.8，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.7，57.6，56.6，46.6，43.5，36.7，35.5，28.5，26.4，22.4，20.5，14.3，10.2。
The preparation of embodiment 62 '-acetyl ursolic acid-9-dihydro taxol
1) acetylize of ursolic acid
Getting the 5mmol ursolic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, acetyl ursolic acid.
2) 2 '-acetyl ursolic acid-9-dihydro taxol synthetic
Under the nitrogen protection; 0.41mmol9-the dihydro taxol is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add the 0.41mmol acetyl ursolic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively once with the salt acid elution of 30ml5%, saturated common salt water washing 2 times, organic phase is with anhydrous sodium sulfate drying; decompression is received and is done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl ursolic acid-9-dihydro taxol, yield is 91.5%.Spectral data is shown as 2 '-acetyl ursolic acid-9-dihydro taxol.
mp：250～253℃。ESI—MS?m/z：1358.8[M+Na]。
IR(KBr)cm -1：3419，2927，2870.1690.1450，1370.1020。
1H-NMR(600MHz，CDCl 3)δppm：5.16(1H，t)，4.29(1H，t，3-H)，1.06(3H，s)，0.74(3H，s)，0.92(6H，s)，0.69(3H，s)，0.89(6H，s)；8.15(2H，dd，J＝8.4，0.6Hz，2-o-Ph)，7.75(2H，dd，J＝8.4，1.2Hz，N-o-Ph)，7.62(1H，tt，J＝7.2，1.1Hz，2-p-Ph)，7.52(2H，m，2-m-Ph)7.49(3H，m，N-m，p-Ph)7.42～7.40(4H，m，3’-o，p-Ph)7.32(1H，d，J＝7.8Hz，3’-p-Ph)6.92(1H，d，J＝9Hz，NH)6.28(1H，s，10-H)6.25(1H，t，J＝8.3Hz，13-H)5.80(1H，dd，J＝9，2.4Hz，3’-H)5.69(1H，d，J＝6.6Hz，2-H)4.92(1H，dd，J＝7.9，2.4Hz，5-H)4.80(1H，d，J＝2.4Hz，2’-H)4.40(1H，dd，J＝10.9，6.6Hz，7-H)4.31(1H，d，J＝8.4Hz，20-Ha)4.21(1H，d，J＝9Hz，20-H β)3.81(1H，d，J＝7.2Hz，3-H)2.52(1H，m，6-Ha)2.39(3H，s，4-COCH 3)2.36(2H，d，J＝9Hz，14-H 2)2.25(3H，s，10-COCH 3)1.86(1H，m，6-H β)1.84(3H，d，J＝1.2Hz，18-CH 3)1.75(3H，s，19-CH 3)1.22(3H，s，17-CH 3)1.12(3H，s，16-CH 3)。
The preparation of embodiment 72 '-acetyl rosmarinic acid taxol
Figure A200810202090D00161
1) acetylize of rosmarinic acid
Getting the 5mmol rosmarinic acid is dissolved in the pyridine 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl rosmarinic acid.
2) 2 '-acetyl rosmarinic acid taxol synthetic
Under the argon shield; 0.41mmol taxol is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl rosmarinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl rosmarinic acid taxol.Yield is 88%.Spectral data is shown as 2 '-acetyl rosmarinic acid taxol.
mp：216～218℃，ESI—MS?m/z：1386.7[M+Na]。
IR(KBr)cm-1：3500～3310，1750(sh)，1720，1630，1615。
1H—NMR(C5D5N)δ：7.49(1H，d，J＝16.0Hz)，7.14(1H，d，J＝2.0Hz)，6.96(1H，dd，J＝8.0Hz，2.0Hz)，6.82(1H，d，J＝2.0Hz)，6.82(1H，d，J＝8.0Hz)，6.68(1H，d，J＝8.0Hz)，6.62(1H，dd，J＝8.0Hz，2.0Hz)，6.26(1H，d，J＝16.0Hz)，5.09(1H，dd，J＝9.2Hz，3.2Hz)，3075(1H，dd，J＝14.4Hz，3.2Hz)，2.93(1H，dd，J＝14.4Hz，9.2Hz)；1.14(s，3H)，1.24(s，3H)，1.65(s.3H)，1.79(s，3H)，1.83(s.1H)，1.83～1.93(m.1H)，2.23(s，3H)，2.28～2.35(m，2H)，2.38(s，3H)，2.45(d.J：4Hz，1H)，2.48～2.57(m，1H)，3.55(d.J＝5Hz，1H)，4.37～4.45(m，1H)，4.80(dd，J＝2.5，5Hz.1H)，4.94(bd，J＝8.0Hz.1H)，5.67(d，J＝7Hz.1H)，5.78(dd，J＝2.5，8.8Hz.1H)，6.22(t，J：9Hz.1H)，6.25(s.1H)，7.05(d，J＝8.9Hz，1H)，7.32～7.54(m，1H)，7.51～7.60(m.1H)，7.20～7.72(m.2H)，8.10～8.11(m，2H)。
The preparation of embodiment 82 '-acetyl rosmarinic acid Docetaxel
Figure A200810202090D00181
1) acetylize of rosmarinic acid
Getting the 5mmol rosmarinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl rosmarinic acid.
2) 2 '-acetyl rosmarinic acid Docetaxel synthetic
Under the argon shield; 0.41mmol Docetaxel is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl rosmarinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the rosmarinic acid Docetaxel.Yield is 90%.Spectral data is shown as 2 '-acetyl rosmarinic acid Docetaxel.
mp：208～210℃，ESI—MS?m/z：1340.7[M+Na]。
IR(KBr)cm -1：3500～3310，1760(sh)，1710，1620，1610。
1H—NMR(C 5D 5N)δ：7.49(1H，d，J＝16.0Hz)，7.14(1H，d，J＝2.0Hz)，6.96(1H，dd，J＝8.0Hz，2.0Hz)，6.82(1H，d，J＝2.0Hz)，6.82(1H，d，J＝8.0Hz)，6.68(1H，d，J＝8.0Hz)，6.62(1H，dd，J＝8.0Hz，2.0Hz)，6.26(1H，d，J＝16.0Hz)，5.09(1H，dd，J＝9.2Hz，3.2Hz)，3075(1H，dd，J＝14.4Hz，3.2Hz)，2.93(1H，dd，J＝14.4Hz，9.2Hz)；8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m.1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.88(s，3H)，1.75(s，3H)，1.35(s，9H)，1.11(s，3H)； 13C—NMR(C 5D 5N)δ：211.2，172.2，170.5，167.1，155.5，138.2，138.1，136.2，133.0，130.2，129.2，128.8，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.7，57.6，56.6，46.4，43.6，36.5，35.5，28.4，26.5，22.2，20.1，14.0，10.2。
The preparation of embodiment 92 '-acetyl rosmarinic acid-9-dihydro taxol
1) acetylize of rosmarinic acid
Getting the 5mmol rosmarinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl rosmarinic acid.
2) 2 '-acetyl rosmarinic acid-9-dihydro taxol synthetic
Under the argon shield; 0.41mmol 9-dihydro taxol is dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl rosmarinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl rosmarinic acid-9-dihydro taxol.Yield is 91%.Spectral data is shown as 2 '-acetyl rosmarinic acid-9-dihydro taxol.mp：211～213℃，ESI—MS?m/z：1388.8[M+Na]。
IR(KBr)cm -1：3500～3310，1750(sh)，1710，1620，1610。
1H-NMR(600MHz，CDCl 3)δppm：7.49(1H，d，J＝16.0Hz)，7.14(1H，d，J＝2.0Hz)，6.96(1H，dd，J＝8.0Hz，2.0Hz)，6.82(1H，d，J＝2.0Hz)，6.82(1H，d，J＝8.0Hz)，6.68(1H，d，J＝8.0Hz)，6.62(1H，dd，J＝8.0Hz，2.0Hz)，6.26(1H，d，J＝16.0Hz)，5.09(1H，dd，J＝9.2Hz，3.2Hz)，3075(1H，dd，J＝14.4Hz，3.2Hz)，2.93(1H，dd，J＝14.4Hz，9.2Hz)；8.15(2H，dd，J＝8.4，0.6Hz，2-o-Ph)，7.75(2H，dd，J＝8.4，1.2Hz，N-o-Ph)，7.62(1H，tt，J＝7.2，1.1Hz，2-p-Ph)，7.52(2H，m，2-m-Ph)7.49(3H，m，N-m，p-Ph)7.44～7.40(4H，m，3’-o，p-Ph)7.37(1H，d，J＝7.8Hz，3’-p-Ph)6.98(1H，d，J＝9Hz，NH)6.28(1H，s，10-H)6.25(1H，t，J＝8.3Hz，13-H)5.80(1H，dd，J＝9，2.4Hz，3’-H)5.69(1H，d，J＝6.6Hz，2-H)4.95(1H，dd，J＝7.9，2.4Hz，5-H)4.80(1H，d，J＝2.4Hz，2’-H)4.40(1H，dd，J＝10.9，6.6Hz，7-H)4.36(1H，d，J＝8.4Hz，20-Ha)4.22(1H，d，J＝9Hz，20-H β)3.85(1H，d，J＝7.2Hz，3-H)2.52(1H，m，6-Ha)2.38(3H，s，4-COCH 3)2.36(2H，d，J＝9Hz，14-H 2)2.28(3H，s，10-COCH 3)1.88(1H，m，6-H β)1.82(3H，d，J＝1.2Hz，18-CH 3)1.73(3H，s，19-CH 3)1.29(3H，s，17-CH 3)1.18(3H，s，16-CH 3)。
The preparation of embodiment 10 2 '-acetyl chlorogenic acid taxol
Figure A200810202090D00201
1) acetylize of chlorogenic acid
Getting the 5mmol chlorogenic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl chlorogenic acid.
2) 2 '-acetyl chlorogenic acid taxol synthetic
Under the argon shield; 0.41mmol taxol be dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl chlorogenic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl chlorogenic acid taxol.Yield is 85%.Spectral data is shown as 2 '-acetyl chlorogenic acid taxol.
mp：222-225℃，ESI—MS?m/z：1158.7[M+Na]。
IR(KBr)cm -1：3480，3385，3220，1680，1645，1450，1300，1280。 1H—NMR(C 5D 5N)δ：7.56(1H，m，2-H)，5.25(1H，brs，3-H)，4.51(1H，ddd，J＝4.3，4.2，7.2Hz，4-H)，4.91(1H，ddd，J＝5.5，5.3，12.2Hz，5-H)，3.60(1H，dd，J＝17.8，2.0Hz，6-H)，3.11(1H，dd，J＝17.8，5.5Hz，6-H)；1.14(s，3H)，1.24(s，3H)，1.69(s.3H)，1.79(s，3H)，1.83(s.1H)，1.83～1.93(m.1H)，2.23(s，3H)，2.28～2.39(m，2H)，2.38(s，3H)，2.48(d.J：4Hz，1H)，2.48～2.57(m，1H)，3.55(d.J＝5Hz，1H)，4.37～4.44(m，1H)，4.80(dd，J＝2.5，5Hz.1H)，4.94(bd，J＝8.0Hz.1H)，5.69(d，J＝7Hz.1H)，5.72(dd，J＝2.5，8.8Hz.1H)，6.23(t，J：9Hz.1H)，6.27(s.1H)，7.01(d，J＝8.9Hz，1H)，7.30～7.54(m，
Figure A200810202090D0021092939QIETU
H)，7.59～7.68(m.1H)，7.25～7.75(m.2H)，8.10～8.15(m，2H)。
The preparation of embodiment 11 2 '-acetyl chlorogenic acid Docetaxel
Figure A200810202090D00211
1) acetylize of chlorogenic acid
Getting the 5mmol chlorogenic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl chlorogenic acid.
2) 2 '-acetyl chlorogenic acid Docetaxel synthetic
Under the argon shield; 0.41mmol Docetaxel is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl chlorogenic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the chlorogenic acid Docetaxel.Yield is 89%.Spectral data is shown as 2 '-acetyl chlorogenic acid Docetaxel.
mp：212-214℃，ESI—MS?m/z：1112.8[M+Na]。
IR(KBr)cm -1：3480，3385，3220，1650，1625，1420，1310。
1H—NMR(C 5D 5N)δ：7.56(1H，m，2-H)，5.25(1H，brs，3-H)，4.51(1H，ddd，J＝4.3，4.2，7.2Hz，4-H)，4.91(1H，ddd，J＝5.5，5.3，12.2Hz，5-H)，3.60(1H，dd，J＝17.8，2.0Hz，6-H)，3.11(1H，dd，J＝17.8，5.5Hz，6-H)；8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m.1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.88(s，3H)，1.75(s，3H)，1.35(s，9H)，1.11(s，3H)； 13C—NMR(C 5D 5N)δ：211.9，172.8，170.5，167.4，155.8，138.6，138.5，136.0，133.0，130.2，129.2，128.8，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.7，57.6，56.6，46.6，43.2，36.7，35.6，28.5，26.8，22.0，20.8，14.5，10.3。
The preparation of embodiment 12 2 '-acetyl chlorogenic acid-9-dihydro taxol
Figure A200810202090D00221
1) acetylize of chlorogenic acid
Getting the 5mmol chlorogenic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl chlorogenic acid.
2) 2 '-acetyl chlorogenic acid-9-dihydro taxol synthetic
Under the argon shield; 0.41mmol 9-dihydro taxol be dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl chlorogenic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl chlorogenic acid-9-dihydro taxol.Yield is 86%.Spectral data is shown as 2 '-acetyl chlorogenic acid-9-dihydro taxol.
mp：218-201℃，ESI—MS?m/z：1160.9[M+Na]。
IR(KBr)cm -1：3480，3385，3210，1670，1645。
1H-NMR(600MHz，CDCl 3)δppm：7.56(1H，m，2-H)，5.25(1H，brs，3-H)，4.51(1H，ddd，J＝4.3，4.2，7.2Hz，4-H)，4.91(1H，ddd，J＝5.5，5.3，12.2Hz，5-H)，3.60(1H，dd，J＝17.8，2.0Hz，6-H)，3.11(1H，dd，J＝17.8，5.5Hz，6-H)；8.15(2H，dd，J＝8.4，0.6Hz，2-o-Ph)，7.75(2H，dd，J＝8.4，1.2Hz，N-o-Ph)，7.62(1H，tt，J＝7.2，1.1Hz，2-p-Ph)，7.52(2H，m，2-m-Ph)7.49(3H，m，N-m，p-Ph)7.44～7.40(4H，m，3’-o，p-Ph)7.37(1H，d，J＝7.8Hz，3’-p-Ph)6.98(1H，d，J＝9Hz，NH)6.28(1H，s，10-H)6.25(1H，t，J＝8.3Hz，13-H)5.80(1H，dd，J＝9，2.4Hz，3’-H)5.69(1H，d，J＝6.6Hz，2-H)4.95(1H，dd，J＝7.9，2.4Hz，5-H)4.82(1H，d，J＝2.4Hz，2’-H)4.40(1H，dd，J＝10.9，6.6Hz，7-H)4.32(1H，d，J＝8.4Hz，20-Ha)4.21(1H，d，J＝9Hz，20-H β)3.82(1H，d，J＝7.2Hz，3-H)2.58(1H，m，6-Ha)2.39(3H，s，4-COCH 3)2.36(2H，d，J＝9Hz，14-H 2)2.28(3H，s，10-COCH 3)1.88(1H，m，6-H β)1.84(3H，d，J＝1.2Hz，18-CH 3)1.73(3H，s，19-CH 3)1.24(3H，s，17-CH 3)1.18(3H，s，16-CH 3)。
The preparation of embodiment 13 2 '-acetyl shikimic acid taxol
Figure A200810202090D00231
1) acetylize of shikimic acid
Getting the 5mmol shikimic acid is dissolved in the 250m pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl shikimic acid.
2) 2 '-acetyl shikimic acid taxol synthetic
The helium protection down; 0.41mmol taxol be dissolved in the 25ml methylene dichloride; the 4-Dimethylamino pyridine that adds 0.41mmol; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl shikimic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl shikimic acid taxol.Yield is 90%.Spectral data is shown as 2 '-acetyl shikimic acid taxol.
mp：233-236℃，ESI—MS?m/z：1422.8[M+Na]。
IR(KBr)cm -1：3400，2900，1710，1620。
1H—NMR(C 5D 5N)δ：1.76(2H，m，H-2)，5.06(1H，dt，J＝8.5，4.0Hz，H-3)，3.55(1H，m，H-4)，3.92(1H，m，H-5)，1.97(2H，m，H-6)，7.02(1H，d，J＝2.0Hz，H-2)，6.75(1H，d，J＝7.0Hz，H-5)，6.96(1H，dd，J＝7.0，2.0Hz，H-6′)，7.40(1H，d，J＝16.5Hz，H-7′)，6.13(1H，d，J＝16.5Hz，H-8′)；1.14(s，3H)，1.24(s，3H)，1.69(s.3H)，1.79(s，3H)，1.83(s.1H)，1.83～1.93(m.1H)，2.23(s，3H)，2.28～2.39(m，2H)，2.38(s，3H)，2.48(d.J：4Hz，1H)，2.48～2.57(m，1H)，3.55(d.J＝5Hz，1H)，4.37～4.44(m，1H)，4.80(dd，J＝2.5，5Hz.1H)，4.94(bd，J＝8.0Hz.1H)，5.67(d，J＝7Hz.1H)，5.78(dd，J＝2.5，8.8Hz.1H)，6.23(t，J：9Hz.1H)，6.27(s.1H)，7.01(d，J＝8.9Hz，1H)，7.35～7.54(m，1H)，7.59～7.68(m.1H)，7.22～7.85(m.2H)，8.10～8.13(m，2H)。
The preparation of embodiment 14 2 '-acetyl shikimic acid Docetaxel
Figure A200810202090D00241
1) acetylize of shikimic acid
Getting the 5mmol shikimic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl shikimic acid.
2) 2 '-acetyl shikimic acid Docetaxel synthetic
Under the argon shield; 0.41mmol Docetaxel be dissolved in the 25ml methylene dichloride; the 4-Dimethylamino pyridine that adds 0.41mmol; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl shikimic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the shikimic acid Docetaxel.Yield is 85%.Spectral data is shown as 2 '-acetyl shikimic acid Docetaxel.
mp：235-237℃，ESI—MS?m/z：1376.7[M+Na]。
IR(KBr)cm -1：3400，2900，1720。
1H—NMR(C 5D 5N)δ：1.76(2H，m，H-2)，5.06(1H，dt，J＝8.5，4.0Hz，H-3)，3.55(1H，m，H-4)，3.92(1H，m，H-5)，1.97(2H，m，H-6)，7.02(1H，d，J＝2.0Hz，H-2)，6.75(1H，d，J＝7.0Hz，H-5)，6.96(1H，dd，J＝7.0，2.0Hz，H-6′)，7.40(1H，d，J＝16.5Hz，H-7′)，6.13(1H，d，J＝16.5Hz，H-8′)；8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m.1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.88(s，3H)，1.75(s，3H)，1.35(s，9H)，1.11(s，3H)； 13C—NMR(C 5D 5N)δ：211.5，172.7，170.5，167.4，155.6，138.6，138.5，136.0，133.0，130.2，129.2，128.8，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.7，57.6，56.6，46.6，43.2，36.7，35.8，28.5，26.6，22.5，20.3，14.6，10.2。
The preparation of embodiment 15 2 '-acetyl shikimic acid-9-dihydro taxol
Figure A200810202090D00261
1) acetylize of shikimic acid
Getting the 5mmol shikimic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl shikimic acid.
2) 2 '-acetyl shikimic acid-9-dihydro taxol synthetic
The helium protection down; 0.41mmol 9-dihydro taxol be dissolved in the 25ml methylene dichloride; the 4-Dimethylamino pyridine that adds 0.41mmol; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl shikimic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with 305% salt acid elution once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl shikimic acid-9-dihydro taxol.Yield is 90%.Spectral data is shown as 2 '-acetyl shikimic acid-9-dihydro taxol.
mp：232-234℃，ESI—MS?m/z：1424.9[M+Na]。
IR(KBr)cm-1：3400，3000，1720，1615。
1H-NMR(600MHz，CDCl 3)δppm：1.76(2H，m，H-2)，5.06(1H，dt，J＝8.5，4.0Hz，H-3)，3.55(1H，m，H-4)，3.92(1H，m，H-5)，1.97(2H，m，H-6)，7.02(1H，d，J＝2.0Hz，H-2)，6.75(1H，d，J＝7.0Hz，H-5)，6.96(1H，dd，J＝7.0，2.0Hz，H-6′)，7.40(1H，d，J＝16.5Hz，H-7′)，6.13(1H，d，J＝16.5Hz，H-8′)；8.15(2H，dd，J＝8.4，0.6Hz，2-o-Ph)，7.75(2H，dd，J＝8.4，1.2Hz，N-o-Ph)，7.62(1H，tt，J＝7.2，1.1Hz，2-p-Ph)，7.52(2H，m，2-m-Ph)7.49(3H，m，N-m，p-Ph)7.44～7.40(4H，m，3’-o，p-Ph)7.37(1H，d，J＝7.8Hz，3’-p-Ph)6.98(1H，d，J＝9Hz，NH)6.28(1H，s，10-H)6.25(1H，t，J＝8.3Hz，13-H)5.80(1H，dd，J＝9，2.4Hz，3’-H)5.69(1H，d，J＝6.6Hz，2-H)4.95(1H，dd，J＝7.9，2.4Hz，5-H)4.80(1H，d，J＝2.4Hz，2’-H)4.40(1H，dd，J＝10.9，6.6Hz，7-H)4.31(1H，d，J＝8.4Hz，20-Ha)4.21(1H，d，J＝9Hz，20-H β)3.81(1H，d，J＝7.2Hz，3-H)2.54(1H，m，6-Ha)2.39(3H，s，4-COCH 3)2.36(2H，d，J＝9Hz，14-H 2)2.25(3H，s，10-COCH 3)1.88(1H，m，6-H β)1.80(3H，d，J＝1.2Hz，18-CH 3)1.71(3H，s，19-CH 3)1.25(3H，s，17-CH 3)1.15(3H，s，16-CH 3)。
The preparation of embodiment 16 2 '-acetyl Betulinic acid taxol
Figure A200810202090D00271
1) acetylize of Betulinic acid
Getting the 5mmol Betulinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl Betulinic acid.
2) 2 '-acetyl Betulinic acid taxol synthetic
Under the argon shield; 0.41mmol taxol be dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl Betulinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl Betulinic acid taxol.Yield is 84%.Spectral data is shown as 2 '-acetyl Betulinic acid taxol.
mp：233-236℃，ESI—MS?m/z：1356.9[M+Na]。
IR(KBr)cm -1：3462，3072，2943，2869，1688，1452，1376，1190，1043。 1H-NMR (C 5D 5N) δ: 4.67,4.64 (each 1H, m, 29-CH 2), 3.15 (1H, m, 3-H), 1.63,0.91,0.86,0.85,0.75,0.63 (each 3H, s, Me * 6); 1.14 (s, 3H), 1.24 (s, 3H), 1.69 (s.3H), 1.79 (s, 3H), 1.83 (s.1H), 1.83～1.93 (m.1H), 2.23 (s, 3H), 2.28～2.39 (m, 2H), 2.38 (s, 3H), 2.48 (d.J:4Hz, 1H), 2.48～2.57 (m, 1H), 3.55 (d.J=5Hz, 1H), 4.37～4.44 (m, 1H), 4.86 (dd, J=2.5,5Hz.1H), 4.96 (bd, J=8.0Hz.1H), 5.65 (d, J=7Hz.1H), 5.78 (dd, J=2.5,8.8Hz.1H), 6.23 (t, J:9Hz.1H), 6.37 (s.1H), 7.05 (d, J=8.9Hz, 1H), 7.35～7.56 (m, 1H), 7.59～7.68 (m.1H), 7.28～7.75 (m.2H), 8.02～8.10 (m, 2H).
The preparation of embodiment 17 2 '-acetyl Betulinic acid Docetaxel
Figure A200810202090D00281
1) acetylize of Betulinic acid
Getting the 5mmol Betulinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl Betulinic acid.
2) 2 '-acetyl Betulinic acid Docetaxel synthetic
The helium protection down; 0.41mmol Docetaxel be dissolved in the 25ml methylene dichloride; the 4-Dimethylamino pyridine that adds 0.41mmol; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl Betulinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the Betulinic acid Docetaxel.Yield is 82%.Spectral data is shown as 2 '-acetyl Betulinic acid Docetaxel.
mp：220-223℃，ESI—MS?m/z：1310.7[M+Na]。
IR(KBr)cm -1：3462，3070，2940，2870，1700，1450，1360。
1H-NMR (C 5D 5N) δ: 4.67,4.64 (each 1H, m, 29-CH 2), 3.15 (1H, m, 3-H), 1.63,0.91,0.86,0.85,0.75,0.63 (each 3H, s, Me * 6); 8.12 (m, 1H), 7.60 (m, 2H), 7.50 (m, 2H), 7.38 (m, 5H), 6.22 (t, J=9.0Hz, 1H), 5.68 (d, J=7.0Hz, 1H), 5.46 (d, J=9.0Hz, 1H), 5.26 (d, J=9.0Hz, 1H), 5.22 (s, 1H), 4.94 (d, J=9.0Hz, 1H), 4.62 (m.1H), 4.32 (d, J=9.0Hz, 1H), 4.26 (m, 1H), 4.19 (d, J=9.0Hz, 1H), 3.91 (d, J=7.0Hz, 1H), 2.58 (m, 1H), 2.37 (s, 3H), 2.28 (m, 2H), 1.88 (s, 3H), 1.75 (s, 3H), 1.35 (s, 9H), 1.11 (s, 3H); 13C-NMR (C 5D 5N) δ: 211.3,172.3,170.5,167.5,155.7,138.6,138.5,136.0,133.0,130.2,129.2,128.8,127.9,127.4,126.9,84.4,81.1,80.2,78.9,77.3,75.1,74.5,73.9,72.3,71.7,57.6,56.6,46.6,43.2,36.5,35.7,28.8,26.8,22.2,20.3,14.5,10.4.
The preparation of embodiment 18 2 '-acetyl Betulinic acid-9-dihydro taxol
Figure A200810202090D00291
1) acetylize of Betulinic acid
Getting the 5mmol Betulinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl Betulinic acid.
2) 2 '-acetyl Betulinic acid-9-dihydro taxol synthetic
Under the nitrogen protection; 0.41mmol 9-dihydro taxol be dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl Betulinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl Betulinic acid-9-dihydro taxol.Yield is 86%.Spectral data is shown as 2 '-acetyl Betulinic acid-9-dihydro taxol.
mp：230-233℃，ESI—MS?m/z：1358.8[M+Na]。
IR(KBr)cm -1：3462，3072，2950，1460，1370，1200，1040。
1H-NMR (600MHz, CDCl 3) δ ppm:4.67,4.64 (each 1H, m, 29-CH 2), 3.15 (1H, m, 3-H), 1.63,0.91,0.86,0.85,0.75,0.63 (each 3H, s, Me * 6); 8.15 (2H, dd, J=8.4,0.6Hz, 2-o-Ph), 7.75 (2H, dd, J=8.4,1.2Hz, N-o-Ph), 7.62 (1H, tt, J=7.2,1.1Hz, 2-p-Ph), 7.52 (2H, m, 2-m-Ph) 7.49 (3H, m, N-m, p-Ph) 7.44～7.40 (4H, m, 3 '-o, p-Ph) 7.37 (1H, d, J=7.8Hz, 3 '-p-Ph) 6.98 (1H, d, J=9Hz, NH) 6.28 (1H, s, 10-H) 6.25 (1H, t, J=8.3Hz, 13-H) 5.80 (1H, dd, J=9,2.4Hz, 3 '-H) 5.69 (1H, d, J=6.6Hz, 2-H) 4.95 (1H, dd, J=7.9,2.4Hz, 5-H) 4.83 (1H, d, J=2.4Hz, 2 '-H) 4.40 (1H, dd, J=10.9,6.6Hz, 7-H) 4.31 (1H, d, J=8.4Hz, 20-Ha) 4.21 (1H, d, J=9Hz, 20-H β) 3.81 (1H, d, J=7.2Hz, 3-H) 2.58 (1H, m, 6-Ha) 2.39 (3H, s, 4-COCH 3) 2.36 (2H, d, J=9Hz, 14-H 2) 2.29 (3H, s, 10-COCH 3) 1.88 (1H, m, 6-H β) 1.83 (3H, d, J=1.2Hz, 18-CH 3) 1.76 (3H, s, 19-CH 3) 1.29 (3H, s, 17-CH 3) 1.18 (3H, s, 16-CH 3).
The preparation of embodiment 19 2 '-acetyloleanolic acid taxol
1) acetylize of Oleanolic Acid
Getting the 5mmol Oleanolic Acid is dissolved in the 250m pyridine 1, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, acetyloleanolic acid.
2) 2 '-acetyloleanolic acid taxol synthetic
Under the argon shield; 0.41mmol taxol be dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add the 0.41mmol acetyloleanolic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the acetyloleanolic acid taxol.Yield is 90%.Spectral data is shown as 2 '-the acetyloleanolic acid taxol.
mp：232-234℃，ESI—MS?m/z：1356.9[M+Na]。
IR(KBr)cm -1：3400，2900，1715。
1H-NMR (C 5D 5N) δ: 5.28 (1H, t, J=3.3Hz, 12-H), 3.22 (1H, dd, J=11.0Hz, 4.4Hz, 3-H), 2.82 (1H, dd, J=13.7,4.3Hz, 18-H), 1.13,0.99,0.93,0.92,0.90,0.77,0.75 (each 3H, s, CH 3* 7); 1.14 (s, 3H), 1.24 (s, 3H), 1.69 (s.3H), 1.79 (s, 3H), 1.83 (s.1H), 1.83～1.93 (m.1H), 2.23 (s, 3H), 2.28～2.39 (m, 2H), 2.38 (s, 3H), 2.48 (d.J:4Hz, 1H), 2.48～2.57 (m, 1H), 3.55 (d.J=5Hz, 1H), 4.37～4.44 (m, 1H), 4.80 (dd, J=2.5,5Hz.1H), 4.94 (bd, J=8.0Hz.1H), 5.67 (d, J=7Hz.1H), 5.78 (dd, J=2.5,8.8Hz.1H), 6.23 (t, J:9Hz.1H), 6.27 (s.1H), 7.05 (d, J=8.9Hz, 1H), 7.33～7.44 (m, 1H), 7.59～7.68 (m.1H), 7.28～7.75 (m.2H), 8.05～8.16 (m, 2H).
The preparation of embodiment 20 2 '-acetyloleanolic acid Docetaxel
Figure A200810202090D00311
1) acetylize of Oleanolic Acid
Getting the 5mmol Oleanolic Acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, acetyloleanolic acid.
2) 2 '-acetyloleanolic acid Docetaxel synthetic
The neon protection down; 0.41mmol Docetaxel be dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add the 0.41mmol acetyloleanolic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the Oleanolic Acid Docetaxel.Yield is 85%.Spectral data is shown as 2 '-the acetyloleanolic acid Docetaxel.
mp：232-234℃，ESI—MS?m/z：1310.7[M+Na]。
IR(KBr)cm -1：3400，2910，1755。
1H-NMR (C 5D 5N) δ: 5.28 (1H, t, J=3.3Hz, 12-H), 3.22 (1H, dd, J=11.0Hz, 4.4Hz, 3-H), 2.82 (1H, dd, J=13.7,4.3Hz, 18-H), 1.13,0.99,0.93,0.92,0.90,0.77,0.75 (each 3H, s, CH 3* 7); 8.12 (m, 1H), 7.60 (m, 2H), 7.50 (m, 2H), 7.38 (m, 5H), 6.22 (t, J=9.0Hz, 1H), 5.68 (d, J=7.0Hz, 1H), 5.46 (d, J=9.0Hz, 1H), 5.26 (d, J=9.0Hz, 1H), 5.22 (s, 1H), 4.94 (d, J=9.0Hz, 1H), 4.62 (m.1H), 4.32 (d, J=9.0Hz, 1H), 4.26 (m, 1H), 4.19 (d, J=9.0Hz, 1H), 3.91 (d, J=7.0Hz, 1H), 2.58 (m, 1H), 2.37 (s, 3H), 2.28 (m, 2H), 1.88 (s, 3H), 1.75 (s, 3H), 1.35 (s, 9H), 1.11 (s, 3H); 13C-NMR (C 5D 5N) δ: 211.1,172.6,170.3,167.0,155.5,138.6,138.5,136.0,133.0,130.2,129.2,128.8,127.9,127.4,126.9,84.4,81.1,80.2,78.9,77.3,75.1,74.5,73.9,72.3,71.7,57.6,56.6,46.6,43.5,36.9,35.9,28.5,26.8,22.7,20.8,14.7,10.4.
The preparation of embodiment 21 2 '-acetyloleanolic acid-9-dihydro taxol
Figure A200810202090D00321
1) acetylize of Oleanolic Acid
Getting the 5mmol Oleanolic Acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, acetyloleanolic acid.
2) 2 '-acetyloleanolic acid-9-dihydro taxol synthetic
The neon protection down; 0.41mmol 9-dihydro taxol is dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add the 0.41mmol acetyloleanolic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30m5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyloleanolic acid-9-dihydro taxol.Yield is 89%.Spectral data is shown as 2 '-acetyloleanolic acid-9-dihydro taxol.
mp：232-234℃，ESI—MS?m/z：1358.8[M+Na]。
IR(KBr)cm -1：3400，2910，1750。
1H-NMR (600MHz, CDCl 3) δ ppm:5.28 (1H, t, J=3.3Hz, 12-H), 3.22 (1H, dd, J=11.0Hz, 4.4Hz, 3-H), 2.82 (1H, dd, J=13.7,4.3Hz, 18-H), 1.13,0.99,0.93,0.92,0.90,0.77,0.75 (each 3H, s, CH 3* 7); 8.15 (2H, dd, J=8.4,0.6Hz, 2-o-Ph), 7.75 (2H, dd, J=8.4,1.2Hz, N-o-Ph), 7.62 (1H, tt, J=7.2,1.1Hz, 2-p-Ph), 7.52 (2H, m, 2-m-Ph) 7.49 (3H, m, N-m, p-Ph) 7.44～7.40 (4H, m, 3 '-o, p-Ph) 7.37 (1H, d, J=7.8Hz, 3 '-p-Ph) 6.98 (1H, d, J=9Hz, NH) 6.28 (1H, s, 10-H) 6.25 (1H, t, J=8.3Hz, 13-H) 5.85 (1H, dd, J=9,2.4Hz, 3 '-H) 5.69 (1H, d, J=6.6Hz, 2-H) 4.95 (1H, dd, J=7.9,2.4Hz, 5-H) 4.80 (1H, d, J=2.4Hz, 2 '-H) 4.45 (1H, dd, J=10.9,6.6Hz, 7-H) 4.31 (1H, d, J=8.4Hz, 20-Ha) 4.21 (1H, d, J=9Hz, 20-H β) 3.85 (1H, d, J=7.2Hz, 3-H) 2.55 (1H, m, 6-Ha) 2.39 (3H, s, 4-COCH 3) 2.36 (2H, d, J=9Hz, 14-H 2) 2.25 (3H, s, 10-COCH 3) 1.89 (1H, m, 6-H β) 1.85 (3H, d, J=1.2Hz, 18-CH 3) 1.75 (3H, s, 19-CH 3) 1.28 (3H, s, 17-CH 3) 1.18 (3H, s, 16-CH 3).
The preparation of embodiment 22 2 '-acetyl glycyrrhetinic acid taxol
Figure A200810202090D00341
1) acetylize of glycyrrhetinic acid
Getting the 5mmol glycyrrhetinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl glycyrrhetinic acid.
2) 2 '-acetyl glycyrrhetinic acid taxol synthetic
Under the argon shield; 0.41mmol taxol is dissolved in the 25ml methylene dichloride; add the 0.41mmol4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl glycyrrhetinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl glycyrrhetinic acid taxol.Yield is 90%.Spectral data is shown as 2 '-acetyl glycyrrhetinic acid taxol.
rnp：281—283℃，ESI—MS?m/z：1370.8[M+Na]。
IR(KBr)cm -1：3424，1730，1644，1049。
1H—NMR(C 5D 5N)δ：3.50(1H，dd，J＝4Hz，16Hz，H-3)，3.22(1H，dd，J＝4Hz，12Hz，H-5)，2.99(2H，d，J＝4Hz，H-2)，2.29(1H，m，H-9)，0.8-1.3(21H，7×CH3)；1.14(s，3H)，1.24(s，3H)，1.69(s.3H)，1.79(s，3H)，1.83(s.1H)，1.83～1.93(m.1H)，2.23(s，3H)，2.28～2.39(m，2H)，2.38(s，3H)，2.48(d.J：4Hz，1H)，2.48～2.57(m，1H)，3.55(d.J＝5Hz，1H)，4.37～4.44(m，1H)，4.90(dd，J＝2.5，5Hz.1H)，4.94(bd，J＝8.0Hz.1H)，5.77(d，J＝7Hz.1H)，5.88(dd，J＝2.5，8.8Hz.1H)，6.33(t，J：9Hz.1H)，6.37(s.1H)，7.11(d，J＝8.9Hz，1H)，7.53～7.64(m，1H)，7.59～7.64(m.1H)，7.22～7.75(m.2H)，8.22～8.25(m，2H).
The preparation of embodiment 23 2 '-acetyl glycyrrhetinic acid Docetaxel
Figure A200810202090D00351
1) acetylize of glycyrrhetinic acid
Getting the 5mmol glycyrrhetinic acid is dissolved in the 250ml pyridine, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl glycyrrhetinic acid.
2) 2 '-acetyl glycyrrhetinic acid Docetaxel synthetic
Under the argon shield; 0.41mmol Docetaxel be dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl glycyrrhetinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-the glycyrrhetinic acid Docetaxel.Yield is 92%.Spectral data is shown as 2 '-acetyl glycyrrhetinic acid Docetaxel.
rnp：272—275℃，ESI—MS?m/z：1324.7[M+Na]。
IR(KBr)cm -1：3420，1740，1655，1050。
1H—NMR(C 5D 5N)δ：3.40(1H，dd，J＝4Hz，16Hz，H-3)，3.12(1H，dd，J＝4Hz，12Hz，H-5)，2.89(2H，d，J＝4Hz，H-2)，2.19(1H，m，H-9)，0.8-1.3(21H，7×CH3)；8.12(m，1H)，7.60(m，2H)，7.50(m，2H)，7.38(m，5H)，6.22(t，J＝9.0Hz，1H)，5.68(d，J＝7.0Hz，1H)，5.46(d，J＝9.0Hz，1H)，5.26(d，J＝9.0Hz，1H)，5.22(s，1H)，4.94(d，J＝9.0Hz，1H)，4.62(m.1H)，4.32(d，J＝9.0Hz，1H)，4.26(m，1H)，4.19(d，J＝9.0Hz，1H)，3.91(d，J＝7.0Hz，1H)，2.58(m，1H)，2.37(s，3H)，2.28(m，2H)，1.88(s，3H)，1.75(s，3H)，1.35(s，9H)，1.11(s，3H)； 13C—NMR(C 5D 5N)δ：211.1，172.6，170.3，167.0，155.5，138.6，138.5，136.0，133.0，130.2，129.2，128.8，127.9，127.4，126.9，84.4，81.1，80.2，78.9，77.3，75.1，74.5，73.9，72.3，71.9，57.6，56.8，46.8，43.4，36.9，35.9，28.4，26.7，22.8，20.7，14.5，10.3。
The preparation of embodiment 24 2 '-acetyl glycyrrhetinic acid-9-dihydro taxol
Figure A200810202090D00361
1) acetylize of glycyrrhetinic acid
Getting the 5mmol glycyrrhetinic acid is dissolved in the 250m pyridine 1, add aceticanhydride 50ml, induction stirring, room temperature reaction 24h adds ethyl acetate 250ml, uses 5% hydrochloric acid (150ml * 2), water and saturated aqueous common salt 150ml to wash again respectively 2 times, anhydrous sodium sulfate drying, filter, be evaporated to dried, the acetyl glycyrrhetinic acid.
2) 2 '-acetyl glycyrrhetinic acid-9-dihydro taxol synthetic
The neon protection down; 0.41mmol9-the dihydro taxol is dissolved in the 25ml methylene dichloride; add 0.41mmol 4-Dimethylamino pyridine; 0.82mmol after the dicyclohexylcarbodiimide; add 0.41mmol acetyl glycyrrhetinic acid again; induction stirring is 2 hours under the room temperature; after adding the 25ml ethyl acetate; reaction solution successively with the salt acid elution of 30ml 5% once; saturated common salt water washing 2 times, organic phase are with anhydrous sodium sulfate drying, and decompression is received and done; solids carries out purifying with 200-300 order silica gel column chromatography, obtain 2 '-acetyl glycyrrhetinic acid-9-dihydro taxol.Yield is 88%.Spectral data is shown as 2 '-acetyl glycyrrhetinic acid-9-dihydro taxol.rnp：269—271℃，ESI—MS?m/z：1370.8[M+Na]。
IR(KBr)cm -1：3430，1720，1640，1060。
1H-NMR(600MHz，CDCl 3)δppm：3.40(1H，dd，J＝4Hz，16Hz，H-3)，3.12(1H，dd，J＝4Hz，12Hz，H-5)，2.89(2H，d，J＝4Hz，H-2)，2.19(1H，m，H-9)，0.8-1.3(21H，7×CH3)；8.15(2H，dd，J＝8.4，0.6Hz，2-o-Ph)，7.75(2H，dd，J＝8.4，1.2Hz，N-o-Ph)，7.62(1H，tt，J＝7.2，1.1Hz，2-p-Ph)，7.52(2H，m，2-m-Ph)7.49(3H，m，N-m，p-Ph)7.44～7.40(4H，m，3’-o，p-Ph)7.37(1H，d，J＝7.8Hz，3’-p-Ph)6.98(1H，d，J＝9Hz，NH)6.28(1H，s，10-H)6.25(1H，t，J＝8.3Hz，13-H)5.80(1H，dd，J＝9，2.4Hz，3’-H)5.69(1H，d，J＝6.6Hz，2-H)4.95(1H，dd，J＝7.9，2.4Hz，5-H)4.80(1H，d，J＝2.4Hz，2’-H)4.40(1H，dd，J＝10.9，6.6Hz，7-H)4.31(1H，d，J＝8.4Hz，20-Ha)4.21(1H，d，J＝9Hz，20-H β)3.81(1H，d，J＝7.2Hz，3-H)2.54(1H，m，6-Ha)2.39(3H，s，4-COCH 3)2.39(2H，d，J＝9Hz，14-H 2)2.28(3H，s，10-COCH 3)1.89(1H，m，6-H β)1.83(3H，d，J＝1.2Hz，18-CH 3)1.73(3H，s，19-CH 3)1.27(3H，s，17-CH 3)1.17(3H，s，16-CH 3)。
Embodiment 25 growth of tumour cell suppress experiment
With Taxane derivative 2 of the present invention '-acetyl forulic acid taxol (T1), 2 '-acetyl forulic acid Docetaxel (T2), 2 '-acetyl forulic acid 9-dihydro taxol (T3), 2 '-acetyl ursolic acid taxol (T4), 2 '-acetyl ursolic acid Docetaxel (T5), 2 '-acetyl ursolic acid 9-dihydro taxol (T6), taxol and Docetaxel carry out the cytotoxicity test of various tumor cell strains, adopt mtt assay to carry out growth of tumour cell and suppress experiment.
The human cancer cell of various logarithmic phases is inoculated in 96 orifice plates, and every hole 800-1600 cell is cultivated dosing after 24 hours, and each sample establishes 0.5,2.0,4.0,10,20,40nM6 concentration, each concentration is established 3 parallel holes, in the Mc-Coy5A substratum, and 37 ℃, 2%CO 2Cultivated under the condition 4 days, and used the Bio-Red450 microplate reader, 450 and 570nm carry out dual wavelength and detect, calculate inhibitory rate of cell growth, and calculate IC 50(half-inhibition concentration, μ M).Experimental result sees Table 1.The result shows that derivative T1-T6 has good inhibition tumor promotion.
Table 1 derivative T1-T6, taxol, Docetaxel is to the IC of tumor cell line 50(μ M)
Sample HCT-8 colorectal carcinoma (μ M) Bel-7402 liver cancer (μ M) A2780 ovarian cancer (μ M) A549 adenocarcinoma of lung (μ M) BGC-823 cancer of the stomach (μ M) MCF-7 mammary cancer (μ M) Hela cervical cancer (μ M) KeTr3 kidney (μ M)
Taxol 0.019 0.021 0.00018 0.112 0.00018 0.00017 0.00017 0.00020
Docetaxel 0.00048 0.0094 0.00016 0.54 0.0002 0.00016 0.00017 0.00016
T1 0.028 0.035 0.00021 0.024 0.016 0.026 0.0032 0.0019
T2 0.019 0.011 0.00026 0.23 0.0068 0.0082 0.0045 0.0026
T3 0.0035 0.0016 0.00019 0.082 0.0012 0.022 0.0029 0.0017
T4 0.022 0.048 0.028 0.28 0.008 0.035 0.0082 0.0027
T5 0.013 0.021 0.014 0.47 0.024 0.087 0.0049 0.0035
T6 0.018 0.16 0.002 0.15 0.036 0.044 0.069 0.0042
The cytotoxicity experiment of embodiment 26 human normal cell lines
With Taxane derivative 2 of the present invention '-acetyl forulic acid taxol (T1), 2 '-acetyl forulic acid Docetaxel (T2), 2 '-acetyl forulic acid 9-dihydro taxol (T3), 2 '-acetyl ursolic acid taxol (T4), 2 '-acetyl ursolic acid Docetaxel (T5), 2 '-acetyl ursolic acid 9-dihydro taxol (T6), taxol and Docetaxel adopt mtt assay to carry out the cytotoxicity experiment of human normal cell line.
The HELF human embryonic lung cell of logarithmic phase is inoculated in 96 orifice plates, and every hole 800-1600 cell is cultivated dosing after 24 hours, each sample establishes 0.5,2.0, and 4.0,10,20,40 a nM6 concentration, each concentration is established 3 parallel holes, in the Mc-Coy5A substratum, and 37 ℃, cultivated under the 2%CO2 condition 4 days, and used Bio-Red 450 microplate reader, 450 and 570nm carry out dual wavelength and detect, calculate inhibitory rate of cell growth, and calculate IC 50(μ M).The result show Taxane derivative of the present invention to the toxicity of human normal cell line than taxol, the obvious reduction of Docetaxel.Experimental result sees Table 2.
Table 2 derivative T1-T6, taxol, Docetaxel is to HELF human embryonic lung cell's IC 50(μ M)
Sample HELF human embryonic lung cell (μ M)
Taxol 0.008
Docetaxel 0.038
T1 0.58
T2 0.32
T3 0.48
T4 0.88
T5 0.52
T6 0.63
Embodiment 27 uses nude mouse people liver cancer model and carries out the tumor suppression experiment
With Taxane derivative 2 of the present invention '-acetyl forulic acid taxol (T1), 2 '-acetyl forulic acid Docetaxel (T2), 2 '-acetyl forulic acid 9-dihydro taxol (T3), 2 '-acetyl ursolic acid taxol (T4), 2 '-acetyl ursolic acid Docetaxel (T5) and 2 '-acetyl ursolic acid 9-dihydro taxol (T6), with taxol and Docetaxel in contrast, use nude mouse people liver cancer model and press down knurl and test.
1. reagent
Paclitaxel injection (Hualian Pharmaceutical Co., Ltd., Shanghai produces, and specification is 5ml:30mg).
Docetaxel injection liquid (Hengrui Medicine Co., Ltd., Jiangsu Prov. produces, and specification is 1ml:20mg).
T1, T2, T3, T4, T5, T6 injection liquid (self-control ethanol-polyoxyethylenated castor oil (volume ratio is 1:1) injection liquid, specification 5ml:30mg)
2. the foundation of nude mouse people liver cancer model
SMMC one 7721 human liver cancer cells are at 37 ℃, 5%CO 2, contain in the substratum of RPMI 1 of 10% calf serum and cultivate, will be in cell 0.25% tryptic digestion of logarithmic phase, make 2.5 * 10 with aseptic PBS liquid is resuspended 7The single cell suspension of/ml, every nude mouse is in the subcutaneous vaccination 0.2ml of right side nape portion (5.0 * 10 6/ ml) cell suspension is observed each injection point every day and is had or not red and swollen ulceration.
3. press down the knurl experiment
90 nude mouses are divided into 9 groups at random, and 10 every group, taxol, Docetaxel control group, T1, T2, T3, T4, T5, T6 experimental group and negative control group are established in experiment.Each experimental group and control group are in taxol, Docetaxel, T1, T2, T3, T4, T5, the T6 injection liquid of inoculating cell suspension 2 all pneumoretroperitoneum injection 10mg/kg dosage, 3 days 1 time, 4 weeks of successive administration; Negative control group is the isopyknic physiological saline of abdominal injection then.Observe the gross tumor volume and the speed of growth in the experiment, experiment is carried out the back cervical vertebra dislocation of 4 weeks and is put to death nude mouse, it is heavy with knurl to weigh in, calculate tumour inhibiting rate, tumour inhibiting rate=(W the moon in the formula: the negative control group knurl is heavy for (the cloudy W of W is real)/W the moon * 100%, W is real: the experimental group knurl is heavy), statistical analysis technique adopts paired t-test.The results are shown in Table 3.Experimental result shows that body weight did not have evident difference before and after each organized the nude mouse experiment, thereby guaranteed the comparability of experimental data; The nude mouse of T1, T2, T3, T4, T5, T6 experimental group tumor weight after 4 weeks of treatment is starkly lower than control group (P＜0.05), and experiment shows that new Taxane derivative of the present invention obviously is better than taxol and Docetaxel to tumor inhibition effect.
Table 3 derivative T1, T2, T3, T4, T5, T6 are to lotus knurl nude mouse tumor inhibition effect
Figure A200810202090D00391

Claims (6)

1. a class Taxane derivative is characterized in that having the following chemical structure general formula:
Figure A200810202090C00021
In the formula: R 1During for C=O, R 2For Ph or-OC (CH 3) 3
R 1During for CHOH, R 2Be Ph;
R ' is an alcoholic extract hydroxyl group by complete acetylizad organic acid: forulic acid, rosmarinic acid, chlorogenic acid, shikimic acid, Betulinic acid, Oleanolic Acid, ursolic acid or glycyrrhetinic acid.
2. the preparation method of the described Taxane derivative of claim 1 is characterized in that may further comprise the steps:
(1) organic acid and aceticanhydride carry out acetylization reaction and make alcoholic extract hydroxyl group by complete acetylizad organic acid;
(2) Taxane derivative is synthetic
Under protection of inert gas, taxane compounds is dissolved in the methylene dichloride, adds catalyzer 4-Dimethylamino pyridine and dicyclohexylcarbodiimide, adds alcoholic extract hydroxyl group again by complete acetylizad organic acid, carries out esterification together and makes Taxane derivative; Taxane compounds, the 4-Dimethylamino pyridine, dicyclohexylcarbodiimide and alcoholic extract hydroxyl group are 1:0.5-2:0:5-2:0.8-2 by complete acetylizad organic acid mole ratio, 1 mol taxane compounds uses 40-90 to rise methylene dichloride, temperature of reaction 10-50 ℃, reaction times 1-5 hour; Reaction finishes the ethyl acetate of back adding as extraction agent, 1 mol taxane compounds uses 40-90 to rise ethyl acetate, reaction solution is successively with the hydrochloric acid of 1%-10%, the saturated common salt water washing, separate the organic phase drying, decompression receive to do solid, solid is through purification by silica gel column chromatography, Taxane derivative.
3. by the preparation method of the described Taxane derivative of claim 2, it is characterized in that organic acid described in the 1st step is forulic acid, rosmarinic acid, chlorogenic acid, shikimic acid, Betulinic acid, Oleanolic Acid, ursolic acid or glycyrrhetinic acid.
4. by the preparation method of the described Taxane derivative of claim 2, it is characterized in that taxane compounds described in the 2nd step is taxol, Docetaxel or 9-dihydro taxol.
5.. the preparation method by the described Taxane derivative of claim 2 is characterized in that rare gas element described in the 2nd step is nitrogen, argon gas, helium or neon.
6. the application of the described Taxane derivative of claim 1 is characterized in that the application of described Taxane derivative in the preparation antitumor drug.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102552123A (en) * 2011-12-31 2012-07-11 江苏奥赛康药业股份有限公司 Paclitaxel composition for injection and preparation method thereof
CN104814949A (en) * 2015-03-20 2015-08-05 四川九章生物科技有限公司 Chlorogenic acid acylate capable of improving bioavailability of chlorogenic acid and application thereof
CN111632032A (en) * 2020-06-08 2020-09-08 哈尔滨工业大学 A kind of natural small molecule co-assembled nano-drug delivery system and its preparation method and application

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102552123A (en) * 2011-12-31 2012-07-11 江苏奥赛康药业股份有限公司 Paclitaxel composition for injection and preparation method thereof
CN104814949A (en) * 2015-03-20 2015-08-05 四川九章生物科技有限公司 Chlorogenic acid acylate capable of improving bioavailability of chlorogenic acid and application thereof
CN111632032A (en) * 2020-06-08 2020-09-08 哈尔滨工业大学 A kind of natural small molecule co-assembled nano-drug delivery system and its preparation method and application

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