CN102757410A - Simple and efficient method for preparing taxol analog Larotaxel - Google Patents

Abstract

The invention discloses a simple and efficient semi-synthetic method for preparing taxol analog Larotaxel (XRP9881). A Beta-lactam method is widely applied to synthesis of a C-13 side chain of taxol. The invention optimizes and improves the Beta-lactam method so as to apply the Beta-lactam method to large-scale preparation of synthetic Larotaxel. The taxol analog Larotaxel product is prepared by performing open-ring butting between optically pure Beta-lactam, which has silyl ether protection at a C-3 site and Boc-(t-butoxy-carbonyl) protection at an N-4 site, and a parent ring of the Larotaxel, and then stripping a silyl ether protecting group. The simple and efficient method for preparing the taxol analog Larotaxel has the advantages as follows: a preparation process is relatively high in efficiency; the preparation route is relatively short; the yield is relatively high, the cost is relatively low; and the non-corresponding selectivity of a key intermediate is relatively high. Therefore, the simple and efficient method for preparing the taxol analog Larotaxel is applicable for large scale preparation of the Larotaxel (XRP9881).

Description

The technology of a kind of simple and effective ground preparation paclitaxel analogs Larotaxel

Technical field

The present invention relates to the compound method of a kind of paclitaxel analogs Larotaxel (XRP9881) in the synthetic field of medicine, specifically a kind of beta-lactam method for preparing the C-13 position side chain of taxol is applied to mass preparation Larotaxel (XRP9881).Through being that the optical purity beta-lactam of Boc-(tertbutyloxycarbonyl) protection carries out open loop with the parent nucleus of Larotaxel and docks for silicon ether protection and N-4 position, slough silicon ether then and protect base to obtain product Larotaxel (XRP9881) the C-3 position.

Background technology

Taxol (Paclitaxel) and its semi-synthetic analogue Docetaxel (docetaxel) are the human up to now the most effectively cancer therapy drugs of finding; It is yew (yewtree at first from the Pacific Ocean; Taxus.brevifolia) the diterpene-kind compound that extracts in the bark with unique anti-tumor activity; It has characteristics such as novel structure, anticancer mechanism is unique, anticancer effect is remarkable, anticancer spectrum is wide; Continue the end of the year 1992 after U.S. listing; Successively go through to go on the market in more than 40 countries, and be widely used in mammary cancer, lung cancer, cancer of the stomach, esophagus cancer, ovarian cancer etc. as a line cancer therapy drug, its anticancer effect is apparently higher than conventional anticarcinogens such as Zorubicin, Fluracil, cis-platinums.Yet; Although they have significant anticancer therapeutic, the same with other chemotherapeutics, taxol also can cause a series of spinoffs; Such as to neural destruction, myalgia, cardiac toxic, vomiting, alopecia etc., and it is active relatively poor for multidrug resistance (MDR).Thereby development has a lower spinoff, the pharmacokinetic property of improvement and still to keep the cancer therapy drug of anticancer therapeutic for multidrug resistance cell be domestic and international pharmaceutical science man's research focus always.

Larotaxel (XRP9881) is a kind of novel novel more bearing taxanes of skeleton structure.Recent activity research shows; Its external antitumour activity is apparently higher than taxol and Docetaxel; Its activity research in vivo also is to make the people very excited, and in the second stage of clinical study process, people are to the significant anticancer therapeutic of Larotaxel; Lower spinoff is very satisfied, and is especially better for crossing ovarian cancer, the mammary cancer curative effect of expressing MDRG.The structure of taxol, Docetaxel and Larotaxel (XRP9881) is as follows:

At present, the existing report of the semisynthesis of Larotaxel (XRP9881), majority is through obtaining its parent nucleus and the side chain condensation of C-13 position:

Preparing method about Larotaxel (XRP9881) parent nucleus is described below:

To remove acetyl crust Ka Ting (10-DAB) is initiator; Earlier optionally carry out the fluoroform sulfonylation at the hydroxyl place, C-7 position of parent nucleus; Optionally carry out the acetylize protection then at the hydroxyl place, C-10 position of parent nucleus, the C-7 position and the methyl cyclisation of C-19 position that then in ionic by force organic solvent, prepare parent nucleus are the new parent nucleus of ternary isocyclic.(US0083497，US0021783，US7074821，US6911549，WO9509163，WO9533737)。

It is as follows to go acetyl crust Ka Ting (10-DAB) to prepare the synthetic route of parent nucleus of Larotaxel (XRP9881) for starting raw material:

The shortcoming of this method is earlier the C-7 position hydroxyl of parent nucleus to be carried out the fluoroform sulfonylation when again C-10 position hydroxyl being carried out the acetylize operation; Because trifyl is leavings group very easily; The midbody of gained is very unsettled, and the basic working order of this protection makes that the yield of midbody parent nucleus is very low.Moreover, because the solvability of midbody is relatively poor, on the purifying mode, all adopt single column chromatography purification, also will cause preparation efficiency low, be inappropriate for the parent nucleus of large-scale preparation Larotaxel (XRP9881).

Preparing method about the C-13 side chain of Larotaxel (XRP9881) mainly contains following two kinds:

With optically pure α-Ben Yian and phenyl aldehyde is starting raw material preparation schiffbase earlier; Obtain the beta-lactam midbody through [2+2] cycloaddition reaction taking place with α-alpha-Acetoxyacetyl chloride; Can obtain optically pure (3R through recrystallization then; 4S)-and the beta-lactam diastereomer, obtain amino and hydroxyl by the five-ring side chain of ketone fork protection through the reaction of some steps such as saponification reaction, alcoholysis ring-opening reaction, hydrogenolysis deprotection reaction successively again.(US0083497，US0021783，US7074821，US6911549，WO9509163，WO9533737)。

The side chain synthetic route for preparing Larotaxel (XRP9881) with optically pure α-Ben Yian starting raw material is as follows:

With the bromo acetyl bromide is starting raw material; First and suitable chirality prothetic group condensation obtains midbody 2 and obtains 3 with phenyl aldehyde generation nucleophilic substitution with high cis-selectivity then; Successively through removing hydrogen bromide, alcoholysis, epoxy addition, nitrine reduction, tertbutyloxycarbonyl protection amino obtains midbody 8, obtains five-ring side chain 10 through protection of ketone fork and saponification reaction successively again.(US0083497，US0021783，US7074821，WO9509163，WO9533737)。

The side chain synthetic route for preparing Larotaxel (XRP9881) with bromoacetyl bromide and suitable chirality prothetic group starting raw material is as follows:

Although these two kinds relatively more novel uniquenesses of method that prepare the side chain of Larotaxel (XRP9881); But this method has, and synthetic route is long, purification process is more single (being mostly column chromatography purification), the too high defectives such as (the chirality prothetic group cost an arm and a leg) of cost, has limited industrial large-scale preparation and application.

Summary of the invention

The object of the present invention is to provide the semisynthesis of a kind of simple and effective ground preparation Larotaxel (XRP9881), to address the deficiencies of the prior art.Seeing that the beta-lactam method has been applied to the C-13 position side chain of a large amount of taxol biosynthesis in industry, the present invention carries out process optimization with it and improves, to be applied to the synthetic Larotaxel of large-scale preparation.Through being that the beta-lactam of Boc-(tertbutyloxycarbonyl) protection carries out open loop with the parent nucleus of Larotaxel and docks for silicon ether protection and N-4 position, slough silicon ether then and protect base to obtain product Larotaxel (XRP9881) the C-3 position.The present invention has preparation process efficient (the part midbody need not purifying, and purge process is simple), weak point, yield are suitable for preparing on a large scale Larotaxel (XRP9881) than advantages such as height to the preparation route.

Technical scheme of the present invention is following:

1. the preparation of parent nucleus

This route is to be set out by 10-DAB, and preparation Ba Kating carries out the fluoroform sulfonylation to its C-7 position hydroxyl more earlier, and the concrete operations step is following:

What utilization had been reported prepares the method for clinging to Ka Ting by going acetyl to cling to Ka Ting (10-DAB); The hydroxyl in the C-10 position of parent nucleus that promptly can highly selective with acetic anhydride under the lanthanon catalysis of catalytic amount carries out acetylize; And be mostly column chromatography on the purifying for crust card booth bullion; In order to simplify technological operation, we carry out recrystallization purifying to it, and used recrystallization solvent is the short chain alkanes of ETHYLE ACETATE/C5 to C10 or the mixed solvents such as short chain alkanes of THF/C5 to C10; Recrystallization temperature is that the pure article of the Ba Kating of gained (A-1) carry out next step fluoroform sulfonylation between 0 ℃-60 ℃:

Wherein used solvent is single or mixed solvents such as ethers (for example ether, THF, dioxane etc.), halogenated aliphatic hydro carbons (for example methylene dichloride, chloroform etc.), aromatics (for example benzene, toluene etc.), acetonitrile, ETHYLE ACETATE, and optimum solvent is a THF.

The temperature of reaction of operation is between-40 ℃ to 25 ℃, and used organic bases is tertiary amine such as triethylamine, diisopropyl ethyl amine and pyridine etc., and best organic bases is a pyridine.

In view of the chemical instability of product A-2 and relatively poor solvability; Bullion adopts the precipitator method to carry out purifying; Used precipitation solvent is ethyl acetate/dichloromethane/sherwood oil, THF/methylene dichloride/mixed solvents such as sherwood oil; Best precipitation solvent is ethyl acetate/dichloromethane/sherwood oil (1: 2: 10), and precipitation temperature is-30 ℃ to 40 ℃, and the pure article A-2 of gained carries out cyclization:

Wherein used strong ionic solvent is the organic solvent of the proportional mixing of an amount of inorganic salt of dissolving, and the organic solvent of indication is THF/acetonitrile, THF/dioxane etc., and optimum solvent is THF/acetonitrile (1: 10).The inorganic salt of indication are alkali metal sulfates, base metal nitrate, alkali metal phosphate, basic metal halogen salt etc., and the temperature of reaction of indication is between 70 ℃ to 80 ℃.The gained bullion is through the pure article A-3 of rapid column chromatography.

2. parent nucleus carries out docking of high non-corresponding selection property with the racemic modification side chain and prepares Larotaxel (XRP9881)

The parent nucleus A-3 of preparation is docked reaction with side chain X-6:

Wherein the mother of indication to encircle an alkali metal salt of intermediate A-3 be lithium salts, sodium salt, used alkali is hexamethyl two silica-based amido lithiums (LiHMDS), sodium hexamethyldisilazide (NaHMDS), sodium hydride (NaH) etc., best organic bases is LiHMDS.The rare gas element of indication is argon gas, nitrogen etc.

Used solvent is THF, dioxane, N, dinethylformamide etc., and optimum solvent is a THF.The temperature of reaction of indication is between-60 ℃ to 25 ℃.

The described equivalents of wherein crucial lactan intermediate X-6 is 1.2 to 1.5 equivalents (encircling intermediate A-3 with respect to mother), and best equivalent is 1.5 equivalents, and the gained bullion does not need purification process directly to carry out the operation of desiliconization ether protection base:

Wherein the fluorion deprotecting regent of indication is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine etc., and it is TBAF that the best removes reagent, and the temperature of reaction of indication is between 30 ℃ to 60 ℃, and optimal reaction temperature is 40 ℃.The bullion of gained is through the pure article Larotaxel (XRP9881) of rapid column chromatography purifying.

Compare with background technology, semisynthesis of the present invention has preparation process efficient (the part midbody need not purification process, and purge process is simple), the preparation route is short, yield is higher, etc. advantage, be suitable for preparing on a large scale Larotaxel (XRP9881).

Embodiment

The present invention will combine following embodiment or Test Example to do further elaboration in detail, but should be appreciated that following embodiment only is used for setting forth and explaining the present invention, and not limit the scope of the invention.

Be to be understood that; For mentioning among the present invention but the method that does not have to specify, step, device, instrument, material etc.; Those of ordinary skill can adopt correlation method well known in the art, step, device, instrument, material etc., and perhaps the conventional knowledge and technology according to this area obtains.

1. the preparation of compd A-1

With 10-DAB (54.5g 100.0mmol) is dissolved in the exsiccant THF (2L), ice bath add down acetic anhydride (100.0mL, 1.0mol); Adding Cerous chloride heptahydrate under the argon shield, ice bath (1.86g, 5.0mmol), stirring at room reaction 3h; After the thin-layer chromatography detection reaction finishes, reaction solution is concentrated evaporate to dryness, gains are diluted with ETHYLE ACETATE (1.5L); Use zero(ppm) water (600mL * 3), saturated sodium-chloride water solution (500mL * 3) washing successively, anhydrous sodium sulfate drying concentrates and obtains white solid; Crude product obtains white solid product (A-1,56.0g, yield: 96.0%) through recrystallization; ¹H-NMR (600MHz, CDCl ₃): δ 8.10 (d, 2H, J=7.2Hz, Ph-H), 7.61 (t, 1H, J=7.8Hz, Ph-H), 7.48 (t, 2H; J=7.2Hz, Ph-H), 6.32 (s, 1H, H-10), 5.62 (d, 1H, J=7.2Hz, H-2), 4.99 (d; 1H, J=8.4Hz, H-5), 4.89 (t, 1H, J=7.8Hz, H-13), 4.47 (dd, 1H, J=10.8; 6.6Hz, H-7), 4.31 (d, 1H, J=8.4Hz, H-20a), 4.16 (d, 1H, J=8.4Hz, H-20b); 3.88 (d, 1H, J=7.2Hz, H-3), 2.62-2.54 (m, 1H, H-6a), 2.28 (s, 3H, C H ₃CO in C-4), 2.32-2.26 (m, 2H, H-6b and H-14a), 2.24 (s, 3H, C H ₃CO in C-10), 2.05 (s, 3H), 1.89-1.84 (m, 1H, H-14b), 1.67 (s, 3H), 1.11 (s, 6H, C H ₃In C-16 and C-17).

ESI-MS(m/z)：587.2[M+H] ⁺(Calcd?587.2)、609.2[M+Na] ⁺.

2. the preparation of compd A-2

(51.5g 88.0mmol) is dissolved in the exsiccant methylene dichloride (1000mL), and argon shield adds exsiccant pyridine (200.0mL with A-1; 2.2mol), reaction solution is cooled to-35 ℃, slowly drip triple raise ether (35.5mL; 220.0mmol), be controlled in the 1h and dropwise continuation stirring 4h; Slowly return to room temperature and stirred overnight, after the thin-layer chromatography detection reaction finishes, reaction solution is diluted with methylene dichloride (2.5L); Use the sodium pyrosulfate aqueous solution (750mL * 4), saturated sodium bicarbonate aqueous solution (500mL * 3), saturated sodium-chloride water solution (500mL * 3) washing of 1M successively, anhydrous sodium sulfate drying concentrates.The orange red solid crude product that obtains with ethyl acetate/dichloromethane=dissolving in 3: 5, is added sherwood oil and separates out to a large amount of solids, and-15 ℃ of following hold over night with the solid suction filtration, obtain white solid product (A-2,55.5g, yield: 87.4%); ¹H NMR (600MHz, CDCl ₃): δ 8.09 (d, 2H, J=6.6Hz, Ph-H), 7.62 (t, 1H, J=7.2Hz, Ph-H), 7.49 (t, 2H; J=7.8Hz, Ph-H), 6.62 (s, 1H, H-10), 5.61 (d, 1H, J=7.2Hz, H-2), 5.52 (dd; 1H, J=10.2,7.8Hz, H-7), 4.94 (d, 1H, J=8.4Hz, H-5), 4.85 (t, 1H; J=7.8Hz, H-13), 4.34 (d, 1H, J=9.0Hz, H-20a), 4.15 (d, 1H, J=9.0Hz, H-20b); 4.00 (d, 1H, J=7.2Hz, H-3), 2.89-2.84 (m, 1H, H-6a), 2.30 (s, 3H, C H ₃CO in C-4), 2.30 (s, 3H, H-19), 2.20 (s, 3H, C H ₃CO in C-10), 2.30-2.20 (m, 3H, H-6b andH-14), 1.86 (s, 3H, C H ₃In C-18), 1.20 (s, 3H, C H ₃In C-16), 1.05 (s, 3H, C H ₃In C-17).

¹³C?NMR(150MHz，CDCl ₃)：δ200.7(C-9)，171.0(CH ₃ CO?in?C-4)，168.8(CH ₃ CO?in?C-10)，?166.9(Ph CO?in?C-10)，144.9(C-12)，133.9(Ph)，131.8(C-11)，130.1(Ph)，129.0(Ph)，128.7(Ph)，86.1(C-7)，83.1(C-5)，79.6(C-4)，78.6(C-1)，76.3(C-20)，76.0(C-10)，74.0(C-2)，67.7(C-13)，57.5(C-8)，47.3(C-3)，42.6(C-15)，38.2(C-6)，34.1(C-14)，26.5(C-17)，22.5( CH ₃CO?in?C-10)，20.8( CH ₃CO?in?C-4)，20.0(C-16)，14.8(C-18)，10.7(C-19).

ESI-MS(m/z)：741.2[M+Na] ⁺(Calcd?741.2)、569.2[M-OTf+H] ⁺.

3. the preparation of compd A-3

With A-2 (50.0g, 70.0mmol), sodium-chlor (80.0g),

Molecular sieve (30.0g) is dissolved in exsiccant acetonitrile/THF=(1000mL/100mL), under the argon shield, stirs 1h prior under the room temperature; Rise to 75 ℃ of restir 2h, after the thin-layer chromatography detection reaction finishes, with the reaction solution suction filtration; With a large amount of ETHYLE ACETATE drip washing filter cakes, the evaporate to dryness of will filtrating dissolves with ETHYLE ACETATE (2L); Use saturated sodium bicarbonate aqueous solution (500mL * 3), saturated sodium-chloride water solution (500mL * 3) washing successively, anhydrous sodium sulfate drying concentrates; Through column chromatography (DCM/EtOAc=10: 1) obtain white solid product (A-3,36.9g, yield: 91.0%); ¹H NMR (600MHz, CDCl ₃): δ 8.13 (d, 2H, J=7.8Hz, Ph-H), 7.61 (t, 1H, J=7.2Hz, Ph-H), 7.48 (t, 2H, J=7.8Hz; Ph-H), 6.34 (s, 1H, H-10), 5.62 (d, 1H, J=7.8Hz, H-2), 4.83 (t, 1H, J=7.8Hz; H-13), 4.75 (d, 1H, J=3.6Hz, H-5), 4.30 (d, 1H, J=8.4Hz, H-20a), 4.18 (d, 1H; J=7.8Hz, H-3), 4.04 (d, 1H, J=9.0Hz, H-20b), 2.47 (m, 1H, H-6a), 2.37 (dd, 1H; J=15.6,6.6Hz, H-14a), 2.30 (dd, 1H, J=15.6,6.6Hz, H-14b), 2.26 (s, 3H, C H ₃CO in C-4), 2.23 (dd, 1H, J=10.2,5.4Hz, H-19a), 2.21 (s, 3H, C H ₃CO in C-10), 2.09 (brs, 1H, J=15.6Hz, H-6b), 2.02 (s, 3H, C H ₃In C-18), 1.64 (t, 1H, J=6.6Hz, H-19b), 1.34 (m, 1H, H-7), 1.22 (s, 3H, C H ₃In C-16), 1.09 (s, 3H, C H ₃In C-17).

¹³C?NMR(150MHz，CDCl ₃)：δ202.1(C-9)、170.1(CH ₃ CO?in?C-4)、169.7(CH ₃ CO?in?C-10)，167.3(Ph CO?in?C-2)，144.2(C-12)，133.6(Ph)，132.8(C-11)，130.1(Ph)，129.8(Ph)，129.4(Ph)，128.6(Ph)，128.4(Ph)，85.0(C-5)，80.0(C-2)，79.5(C-1)，79.4(C-4)，76.3(C-10)，74.4(C-20)，67.7?(C-13)，42.3(C-15)，39.0(C-3)，38.9(C-8)，35.3(C-14)，31.7(C-7)，26.5(C-17)，26.0(C-6)，22.1( CH ₃CO?in?C-4)，20.9( CH ₃CO?in?C-10)，20.5(C-16)，15.4(C-19)，15.3(C-18).

ESI-MS(m/z)：569.3[M+H] ⁺(Calcd?569.2)、591.2[M+Na] ⁺.

4. the preparation of compd A-4

With A-3 (8.87g, 16.0mmol) (9.08g 24.0mmol) is dissolved among the exsiccant THF (180mL) argon shield with x-6; Be cooled to-43 ℃, and the THF solution of the LiHMDS of adding 1M (24.0mL, 24.0mmol);-43 ℃ are continued reaction 2h down, after the TLC detection reaction finishes, add saturated NH ₄The Cl aqueous solution (100mL) termination reaction, reaction solution separates organic phase with EtOAc (200mL) dilution; Water extracts with EtOAc (100mL * 3); Merge organic phase, use zero(ppm) water (150mL * 3), the saturated NaCl aqueous solution (100mL * 3) washing successively, anhydrous sodium sulfate drying; Concentrate and to obtain the about 13.6g of white solid crude product A-4, not purifiedly directly carry out next step reaction.

5. the preparation of compounds X RP-9881

With crude product A-4 (13.6g 16.0mmol) is dissolved among the THF (200mL), ice bath add down TBAF (6.28g, 24mmol); 40 ℃ are stirred 2h down, after the TLC detection reaction finishes, reaction solution are concentrated evaporate to dryness, and gains are dissolved with EtOAc (400 mL); Use zero(ppm) water (150mL * 3), the saturated NaCl aqueous solution (150mL * 3) washing successively, anhydrous sodium sulfate drying concentrates; Obtain white solid product (XRP-9881,11.31g, two step total recoverys: 85.0%) through the appropriate solvent deposition.[α] _D ^20.2＝-33.4(0.564；Methanol)； ¹H?NMR(600MHz，CDCl ₃)：δ8.15(d，2H，J＝7.2Hz，Ph-H)，7.60(t，1H，J＝7.2Hz，Ph-H)，7.50(t，2H，J＝7.8Hz，Ph-H)，7.41-7.30(m，5H，Ph-H)，6.32(s，1H，H-10)，6.27(brt，1H，H-13)，5.66(d，1H，J＝7.8Hz，H-2)，5.37(d，1H，J＝9.0Hz，CON H)，5.28(brd，1H，J＝7.8Hz，H-3′)，4.73(d，1H，J＝3.6Hz，H-5)，4.61(s，1H，H-2′)，4.30(d，1H，J＝9.0Hz，H-20a)，4.08(d，1H，J＝7.2Hz，H-3)，4.03(d，1H，J＝9.0Hz，H-20b)，2.45(dt，1H，J＝15.6，4.8Hz，H-6a)，2.38(s，3H，C H ₃CO?in?C-4)，2.25-2.22(m，3H，H-19a?and?H-14)，2.21(s，3H，C H ₃CO?inC-10)，2.10(d，1H，J＝15.6Hz，H-6b)，1.84(s，3H，C H ₃in?C-18)，1.67(t?like，1H，H-19b)，1.36(m，1H，H-7)，1.28(s，12H， Me ₃C?and?C H ₃ )，1.25(s，3H，C H ₃ ).

¹³C?NMR(150MHz，CDCl ₃)：δ201.8(C-9)，172.9(O CO?in?C-1′)，169.7(CH ₃ CO?in?C-4)，169.6(CH ₃ CO?in?C-10)，167.5(Ph CO?in?C-2)，155.1(NH CO?in?C-3′)，140.5(C-12)，138.2(Ph)，133.6(Ph)，130.3(Ph)，129.2(Ph)，128.9(C-11)，128.7(Ph)，128.0(Ph)，126.6(Ph)，84.8(C-5)，80.1[(CH ₃) ₃ CO]，80.0(C-2)，79.6(C-1)，79.4(C-4)，75.7(C-10)，75.4(C-20)，73.7(C-2′)，72.1(C-13)，55.9(C-3′)，42.9(C-15)，38.5(C-3)，35.8(C-14)，35.1(C-8)，32.0(C-7)，28.1[OC( CH ₃) ₃]，26.0(C-6and?C-17)，22.2( CH ₃CO?in?C-4)，21.5( CH ₃CO?in?C-10)，20.9(C-16)，15.6(C-19)，14.6(C-18).

ESI-MS(m/z)：832.4[M+H] ⁺(Calcd?832.4)、854.4[M+Na] ⁺、870.4[M+K] ⁺。

Claims (6)

1. the compound method of simple and effective ground preparation paclitaxel analogs Larotaxel (XRP9881), its structural formula is:

It is characterized in that realizing through following steps:

The synthesis route of Larotaxel (XRP9881):

(1) synthesis step of key intermediate A-3 is following:

1. removing acetyl baccatin III (10-DAB) with 10-is initial reactant; Katalysis and acetic anhydride reaction through with lanthanon obtain baccatin III (A-1) with high yield and high regioselectivity, bullion are precipitated obtain highly purified baccatin III (A-1) under proper temperature;

2. with resulting baccatin III (A-1) under suitable organic bases effect with trifluoromethanesulfanhydride anhydride (Tf ₂O) reaction obtains the intermediate A-2 that C-7 position hydroxyl is trifyl (Tf-) protection with high yield and high regioselectivity, and bullion obtains high-purity intermediate A-2 through the deposition of suitable mixed solvent;

3. the intermediate A that obtains-2 reacting by heating in strong ionic organic solvent is encircled intermediate A-3 with the mother that high yield obtains Larotaxel (XRP9881);

(2) synthesis step of Larotaxel (XRP9881) is following:

1. under protection of inert gas; Through organic bases or mineral alkali the female ring of Larotaxel intermediate A-3 is formed an alkali metal salt; Be that the optical purity beta-lactam of Boc-(tertbutyloxycarbonyl) protection docks with the C-3 position for silicon ether protection and N-4 position again; Obtain intermediate A-4 with higher yields, the not purified deprotection that directly carries out C-2 ' hydroxyl;

The substituted silicon ether protection of alkyl or aryls such as wherein R is tertiary butyl dimethyl-silica-based (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS), trimethyl silicon based (TMS), diphenyl methyl is silica-based, 3,5-dimethylphenyl is silica-based base;

2. protect basic reagent through fluorion or hydrogen fluoride/pyridine for removing silicon ether, protect base to remove in the silicon ether of C-2 ' hydroxyl, thick product is obtained the pure article of Larotaxel (XRP9881) through the appropriate solvent deposition with higher yields.

2. the semisynthesis of paclitaxel analogs Larotaxel according to claim 1 (XRP9881); It is characterized in that the catalyzer described in the step a is lanthanon (for example cerous compounds etc.); The short chain alkanes that described crude product precipitation solvent is ETHYLE ACETATE/C5 to C10, the short chain alkanes of THF/C5 to C10 etc., the precipitation temperature of crude product is between 25 ℃ to 60 ℃.

3. the semisynthesis of paclitaxel analogs Larotaxel according to claim 1 (XRP9881); Between it is characterized in that the temperature of reaction described in the step b is-40 ℃ to 25 ℃; Said solvent is single or mixed solvents such as ethers (for example ether, THF, dioxane etc.), halogenated aliphatic hydro carbons (for example methylene dichloride, chloroform etc.), aromatics (for example benzene, toluene etc.), acetonitrile, ETHYLE ACETATE; Optimum solvent is a THF; Described organic bases is tertiary amines such as triethylamine, diisopropyl ethyl amine and pyridine etc., and best organic bases is a pyridine, and described crude product precipitation solvent is ethyl acetate/dichloromethane/sherwood oil, THF/methylene dichloride/mixed solvents such as sherwood oil; Best precipitation solvent is ethyl acetate/dichloromethane/sherwood oil (1: 2: 10), and precipitation temperature is-30 ℃ to 40 ℃.

4. the semisynthesis of paclitaxel analogs Larotaxel according to claim 1 (XRP9881); The organic solvent that it is characterized in that the proportional mixing of an amount of inorganic salt of strong ionic dissolution with solvents described in the step c; Described organic solvent is THF/7 nitriles, THF/dioxane etc., and optimum solvent is THF/acetonitrile (1: 10); The inorganic salt of indication are alkali metal sulfates, base metal nitrate, alkali metal phosphate, basic metal halogen salt etc., and described temperature of reaction is between 70 ℃ to 80 ℃.

5. the semisynthesis of paclitaxel analogs Larotaxel according to claim 1 (XRP9881); It is characterized in that an alkali metal salt that the mother described in the steps d encircles intermediate A-3 is lithium salts, sodium salt; Used alkali is hexamethyl two silica-based amido lithiums (LiHMDS), sodium hexamethyldisilazide (NaHMDS), sodium hydride (NaH) etc., and best organic bases is hexamethyl two silica-based amido lithiums (LiHMDS); Described rare gas element is argon gas, nitrogen etc.; Described solvent is THF, dioxane, N, dinethylformamide etc., and optimum solvent is a THF; Described temperature of reaction is between-60 ℃ to 25 ℃; Crucial lactan intermediate X-6 equivalents is 1.2 to 1.5 equivalents (encircling intermediate A-3 with respect to mother), and best equivalent is 1.5 equivalents; The substituted silicon ether protection of alkyl or aryls such as the silicon ether protective group R of described beta-lactam C-3 position is tertiary butyl dimethyl-silica-based (TBS), triethyl silica-based (TES), triisopropylsilyl (TIPS), trimethyl silicon based (TMS), diphenyl methyl is silica-based, 3,5-dimethylphenyl is silica-based base; Solvent for use is ethers (for example THF, dioxane etc.), acetonitrile, N; The dinethylformamide equal solvent; Optimum solvent is a THF, and temperature of reaction is between 0 ℃ to 30 ℃, and said organic bases is imidazoles, pyridine etc.; Catalyzer is a 4-dimethylamino pyridine (DMAP) etc., the short chain alkanes kind solvent that described drip washing solvent is C5 to C10.

6. the semisynthesis of paclitaxel analogs Larotaxel according to claim 1 (XRP9881); It is characterized in that the fluorion deprotecting regent described in the step e is tetrabutyl ammonium fluoride (TBAF), hydrogen fluoride/pyridine etc.; It is TBAF that the best removes reagent; Described temperature of reaction is between 25 ℃ to 40 ℃, and optimal reaction temperature is 40 ℃.