阅读说明：本技术 用于制备紫杉醇的中间体化合物及其合成方法以及紫杉醇的合成方法 (Intermediate compound for preparing paclitaxel, synthesis method thereof and synthesis method of paclitaxel ) 是由 李闯创 胡亚剑 顾辰辰 于 2021-08-06 设计创作，主要内容包括：本发明涉及用于制备紫杉醇的中间体化合物及其合成方法以及紫杉醇的合成方法。所述用于制备紫杉醇的中间体化合物选自以下化合物中的至少一种：其中,Ts表示对甲苯磺酰基,TES表示三乙基硅基,TMS表示三甲基硅基,Ms表示甲磺酰基。以这些中间体化合物为原料可以高收率的制备得到紫杉醇,并容易对其结构进行修饰,可从中筛选出一系列先导化合物来研究其生物活性,相信会在肿瘤药物研发领域上有所突破。本发明的紫杉醇及其中间体的合成方法具有手性可控、收率高、产品纯度高、简洁高效的优点,并且原料来源广泛、试剂廉价易得、反应简单、操作简便、绿色环保、适合工业化放大生产。(The present invention relates to an intermediate compound for preparing taxol, a synthetic method thereof and a synthetic method of taxol. The intermediate compound for preparing paclitaxel is selected from at least one of the following compounds: wherein Ts represents a p-toluenesulfonyl group, TES represents a triethylsilyl group, TMS represents a trimethylsilyl group, and Ms represents a methanesulfonyl group. The intermediate compounds can be used as raw materials for preparing the compounds with high yieldThe taxol is obtained, the structure of the taxol is easy to modify, a series of lead compounds can be screened out from the taxol to research the biological activity of the taxol, and the taxol has a breakthrough in the research and development field of tumor drugs. The synthesis method of the taxol and the intermediate thereof has the advantages of chiral controllability, high yield, high product purity, simplicity and high efficiency, and is wide in raw material source, cheap and easily available in reagent, simple in reaction, simple and convenient to operate, green and environment-friendly, and suitable for industrial amplification production.)

1. An intermediate compound for the preparation of paclitaxel, characterized in that it is selected from at least one of the following compounds:

wherein Ts represents a p-toluenesulfonyl group, TES represents a triethylsilyl group, TMS represents a trimethylsilyl group, and Ms represents a methanesulfonyl group.

2. A method for synthesizing an intermediate compound having a structure represented by formula 10, comprising the steps of:

(a) the compound shown in the formula 1 is subjected to benzyl protection reaction under the action of 2,2, 2-trichloroacetamide benzyl ester and trifluoromethanesulfonic acid to generate an intermediate compound shown in the formula 2;

(b) the intermediate compound shown in the formula 2 firstly undergoes Vilsmeier reaction under the action of phosphorus tribromide, and then undergoes reduction reaction under the action of alkali and a reduction reagent to generate an intermediate compound shown in a formula 3;

(c) the intermediate compound shown in the formula 3 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to reduction reaction under the action of a reducing reagent to generate an intermediate compound shown in a formula 4;

(d) carrying out an oxidation cutting reaction on the intermediate compound shown in the formula 4 under the action of an oxidizing reagent to generate an intermediate compound shown in a formula 5;

(e) reacting the intermediate compound shown in the formula 5 under the action of alkali and tert-butyldimethylsilyl chloride to generate an intermediate compound shown in a formula 6;

(f) the intermediate compound shown in the formula 6 is firstly subjected to oxidation reaction under the action of m-chloroperoxybenzoic acid, then subjected to upper protection reaction under the action of a protective agent and a catalyst, and then subjected to hydrolysis reaction under the action of alkali to generate an intermediate compound shown in a formula 7;

(g) the intermediate compound shown in the formula 7 firstly undergoes 1, 2-addition reaction under the action of alkali and the compound shown in the formula 8, and then undergoes acetonylidene protection reaction under the action of a protective agent and a catalyst to generate the compound shown in the formula 9;

(h) the intermediate compound shown in the formula 9 reacts with DMF after being lithiated to introduce aldehyde group, and then the aldehyde group reacts with N-bromosuccinimide in a pot to carry out desulfurization, so that the intermediate compound shown in the formula 10 is generated;

the reaction formula is as follows:

wherein TBS represents tert-butyldimethylsilyl group.

3. The method for synthesizing an intermediate compound having a structure represented by formula 10 according to claim 2, wherein the molar ratio of the compound represented by formula 1,2, 2, 2-trichloroacetamide benzyl ester and trifluoromethanesulfonic acid in step (a) is 1: (1.0-2.0): (0.04 to 0.2); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (b) is sodium bicarbonate, the reducing agent is sodium borohydride, and the molar ratio of the intermediate compound shown in the formula 2, the phosphorus tribromide and the reducing agent is 1: (2.0-4.0): (0.3-4.0); and/or the presence of a catalyst in the reaction mixture,

the base in the step (c) is triethylamine, the reducing reagent is lithium aluminum hydride, and the molar ratio of the intermediate compound shown in the formula 3, the methylsulfonyl chloride and the reducing reagent is 1: (1.2-2): (1.0-4.5); and/or the presence of a catalyst in the reaction mixture,

the oxidizing reagent in step (d) is potassium osmate dihydrate, 4-methylmorpholine-N-oxide and sodium periodate, and the molar ratio of the intermediate compound shown in formula 4, the potassium osmate dihydrate, the 4-methylmorpholine-N-oxide and the sodium periodate is 1: (0.02-0.1): (2.2-3.0): (2.0-4.0); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (e) is sodium hydride, and the molar ratio of the intermediate compound shown in the formula 5 to tert-butyldimethylsilyl chloride is 1: (1.2-2.4); and/or the presence of a catalyst in the reaction mixture,

the protective agent in the step (f) is 2-methoxypropene, the catalyst is pyridinium p-toluenesulfonate, the alkali is an aqueous solution of sodium hydroxide, and the molar ratio of the intermediate compound shown in the formula 6, m-chloroperoxybenzoic acid, the protective agent, the catalyst and the alkali is 1: (1.2-1.5): (5.0-20.0): (0.03-0.4): (4.0-16.0); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (g) is tert-butyl lithium, the protective agent is 2, 2-dimethoxypropane, the catalyst is p-toluenesulfonic acid monohydrate, and the molar ratio of the intermediate compound shown in the formula 7, the compound shown in the formula 8, the protective agent, the catalyst and the alkali is 1: (1.2-3.0): (5.0-20.0): (0.05-0.2): (2.4-6.0); and/or the presence of a catalyst in the reaction mixture,

the base in the step (h) is tert-butyllithium, and the molar ratio of the intermediate compound represented by the formula 9, the N-bromosuccinimide and the base is 1: (3.0-20.0): (2.5-10.0).

4. The method for synthesizing an intermediate compound having a structure represented by formula 10 according to claim 3, wherein the reaction temperature in the step (a) is-5 ℃ to 40 ℃ and the reaction time is 10h to 30 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 2 in the step (b) and phosphorus tribromide is 80-90 ℃, and the reaction time is 1-2 h; the reaction temperature of the reduction reaction is-5 ℃ to 0 ℃, and the reaction time is 10min to 60 min; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 3 in the step (c), alkali and methylsulfonyl chloride is-5-0 ℃, and the reaction time is 10-60 min; the reaction temperature of the reduction reaction is-50 to-30 ℃, and the reaction time is 30 to 60 min; and/or the presence of a catalyst in the reaction mixture,

the step (d) includes:

under the condition of 20-40 ℃, the intermediate compound shown in the formula 4 is firstly oxidized under the action of potassium osmate dihydrate and 4-methylmorpholine-N-oxide for 20-40 h, and then oxidized under the action of sodium periodate for 1-5 h to generate the intermediate compound shown in the formula 5; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 5 in the step (e) between alkali and tert-butyldimethylsilyl chloride is 20-40 ℃, and the reaction time is 5-15 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 6 in the step (f) and m-chloroperoxybenzoic acid is 20-40 ℃, the reaction time is 1-5 h, after 2-methoxypropene and pyridinium p-toluenesulfonate are added, the reaction temperature of the reaction mixture is-5-0 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

step (g) comprises:

under the condition of being lower than minus 60 ℃, adding tert-butyl lithium pentane solution into ether solution of a compound shown as a formula 8, stirring for 1h to 2h, adding tetrahydrofuran solution and methanol of an intermediate compound shown as a formula 7 into a reaction mixture, heating the reaction mixture to 20 ℃ to 25 ℃, concentrating to obtain crude residue, dissolving the crude residue into dichloromethane, and adding 2, 2-dimethoxypropane and p-toluenesulfonic acid monohydrate for reaction; and/or the presence of a catalyst in the reaction mixture,

the step (h) comprises:

adding tert-butyl lithium pentane solution into the intermediate compound ether solution shown in the formula 9 at the temperature lower than-60 ℃, stirring for 1-2 h, adding N, N-dimethylformamide into the reaction mixture, heating the reaction mixture to 20-25 ℃, reacting for 1-2 h, adding a mixed solvent of tetrahydrofuran and water into the reaction mixture, cooling to below 0 ℃, and adding N-bromosuccinimide for reaction; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (a) is selected from at least one of dichloromethane, toluene, tetrahydrofuran and n-ethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (b) is selected from at least one of N, N-dimethylformamide, chloroform and N-ethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (c) is selected from at least one of tetrahydrofuran, toluene and dichloromethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (d) is selected from at least one of tetrahydrofuran and toluene; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (e) is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (f) is selected from at least one of dichloromethane, toluene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (g) is selected from at least one of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (h) is selected from at least one of diethyl ether, methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran.

5. A method for synthesizing an intermediate compound having a structure represented by formula 20, comprising the steps of:

preparing an intermediate compound represented by formula 10 according to the synthesis method of an intermediate compound having a structure represented by formula 10 of any one of claims 2 to 4;

(i) reacting the intermediate compound shown in the formula 10 under the action of samarium powder and samarium diiodide to generate an intermediate compound shown in a formula 11;

(j) reacting the intermediate compound shown in the formula 11 under the action of alkali and triphosgene to generate an intermediate compound shown in a formula 12;

(k) reacting the intermediate compound shown in the formula 12 under the action of acid to generate an intermediate compound shown in a formula 13;

(l) Reacting the intermediate compound shown as the formula 13 under the action of acetic anhydride and a catalyst to generate an intermediate compound shown as a formula 14;

(m) the intermediate compound shown in the formula 14 is firstly subjected to oxidation reaction under the action of an oxidation reagent and a catalyst, and then subjected to epimerization reaction under the action of 1, 5-diazabicyclo [4.3.0] non-5-ene to generate the intermediate compound shown in the formula 15;

(n) the intermediate compound shown in the formula 15 firstly undergoes debenzylation reaction under the action of hydrogen and a catalyst, and then undergoes hydroxyl protection reaction under the action of alkali and triethyl silyl trifluoromethanesulfonate to generate an intermediate compound shown in a formula 16;

(o) carrying out an oxidation reaction on the intermediate compound shown in the formula 16 under the action of sodium acetate and pyridinium chlorochromate to generate an intermediate compound shown in a formula 17;

(p) the intermediate compound shown in the formula 17 is subjected to condensation reaction under the action of p-toluenesulfonyl hydrazide and boron trifluoride diethyl etherate, and then is subjected to reaction under the action of alkali and a reducing reagent to generate the intermediate compound shown in the formula 18;

(q) reacting the intermediate compound represented by formula 18 with N- (trimethylsilyl) imidazole to produce an intermediate compound represented by formula 19;

(r) the intermediate compound shown in the formula 19 is subjected to a reduction reaction under the action of catechol borane and then subjected to a reaction under the action of sodium acetate trihydrate to generate an intermediate compound shown in a formula 20;

the reaction formula is as follows:

wherein Ts represents a p-toluenesulfonyl group, TES represents a triethylsilyl group, and TMS represents a trimethylsilyl group.

6. The method according to claim 5, wherein the molar ratio of the intermediate compound represented by formula 10 to samarium powder to samarium diiodide in step (i) is 1: (2.0-5.0): (3.0-10.0); and/or the presence of a catalyst in the reaction mixture,

the base in step (j) is pyridine, and the molar ratio of the intermediate compound shown in formula 11, the base and the triphosgene is 1: (3.0-10.0): (2.1-5.0); and/or the presence of a catalyst in the reaction mixture,

the acid in step (k) is hydrochloric acid, and the molar ratio of the intermediate compound represented by formula 12 to hydrochloric acid is 1: (5.0-40.0); and/or the presence of a catalyst in the reaction mixture,

the catalyst in the step (l) is 4-dimethylaminopyridine, and the molar ratio of the intermediate compound shown as the formula 13 to acetic anhydride to the catalyst is 1: (1.0-1.5): (1.0-1.5); and/or the presence of a catalyst in the reaction mixture,

the oxidation reagent in step (m) is 4-methylmorpholine-N-oxide, the catalyst is tetrapropylamine perruthenate, and the molar ratio of the intermediate compound represented by formula 14, the oxidation reagent and the catalyst is 1: (1.5-5.0): (0.05-0.5); and/or the presence of a catalyst in the reaction mixture,

the catalyst in the step (n) is palladium/carbon, the base is triethylamine, the hydrogen pressure is 1-2 atmospheric pressures, and the molar ratio of the intermediate compound shown in the formula 15, the base and the triethyl trisilicate trifluoromethanesulfonate is 1: (2.0-20.0): (2.0-10.0); and/or the presence of a catalyst in the reaction mixture,

in the step (o), the molar ratio of the intermediate compound represented by the formula 16 to sodium acetate to pyridinium chlorochromate is 1: (10.0-40.0): (10.0-40.0); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (p) is sodium bicarbonate, the reducing reagent is sodium borohydride, and the molar ratio of the intermediate compound shown in the formula 17, the p-toluenesulfonyl hydrazide, the boron trifluoride diethyl etherate complex, the alkali and the reducing reagent is 1: (3.0-10.0): (3.0-20.0): (3.0-20.0): (5.0-50.0); and/or the presence of a catalyst in the reaction mixture,

in the step (q), the molar ratio of the intermediate compound represented by formula 18 to N- (trimethylsilyl) imidazole is 1: (2.0-20.0); and/or the presence of a catalyst in the reaction mixture,

in the step (r), the molar ratio of the intermediate compound represented by formula 19 to the catechol borane to sodium acetate trihydrate is 1: (5.0-50.0): (5.0-80.0).

7. The method for synthesizing an intermediate compound having a structure represented by formula 20 according to claim 6, wherein the reaction temperature of the intermediate compound represented by formula 10, samarium powder and samarium diiodide in step (i) is 45 to 80 ℃ and the reaction time is 2 to 5 hours; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature in the step (j) is-5 ℃ to 0 ℃, and the reaction time is 1h to 2 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature in the step (k) is 10-40 ℃, and the reaction time is 10-30 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the step (l) is-5 ℃ to 40 ℃, and the reaction time is h to 5 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 14 in the step (m), the oxidizing reagent and the catalyst is 0-40 ℃, and the reaction time is 1-5 h; the reaction temperature after adding 1, 5-diazabicyclo [4.3.0] non-5-ene is 90-110 ℃, and the reaction time is 12-20 h; and/or the presence of a catalyst in the reaction mixture,

the reaction time of the intermediate compound shown in the formula 15 in the step (n), the reducing reagent and the catalyst is 10-15 h; the reaction temperature after adding the alkali and the triethyl trifluoromethanesulfonate is 10-40 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

in the step (o), the reaction temperature of the intermediate compound shown in the formula 16 in sodium acetate and pyridinium chlorochromate is 80-90 ℃, and the reaction time is 8-10 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 17 in the step (p), p-toluenesulfonyl hydrazide and boron trifluoride diethyl etherate is 60-80 ℃, and the reaction time is 10-5 h; the reaction temperature after adding the alkali and the reducing reagent is-5 ℃ to 0 ℃, and the reaction time is 20min to 60 min; and/or the presence of a catalyst in the reaction mixture,

in the step (q), the reaction temperature of the intermediate compound shown in the formula 18, sodium acetate and N- (trimethylsilyl) imidazole is 10-40 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

in the step (q), the reaction temperature of the intermediate compound shown in the formula 18, sodium acetate and N- (trimethylsilyl) imidazole is 10-40 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 19 and the catechol borane in the step (r) is 10-40 ℃, and the reaction time is 2-6 h; the reaction temperature after adding the sodium acetate trihydrate is 10-40 ℃, and the reaction time is 20-60 min; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (i) comprises tetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (j) is selected from at least one of dichloromethane, toluene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (k) is selected from at least one of methanol, ethanol and isopropanol; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (l) is selected from at least one of dichloromethane, toluene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (m) is selected from at least one of dichloromethane, dichloroethane and toluene; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (n) is selected from at least one of dichloromethane, dichloroethane and toluene; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (o) is selected from at least one of benzene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (p) is selected from at least one of tetrahydrofuran, toluene and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (q) comprises at least one of dichloromethane, dichloroethane, and tetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (r) comprises at least one of 1, 2-dichloroethane and chloroform.

8. A method for synthesizing an intermediate compound having a structure represented by formula 23, comprising the steps of:

preparing an intermediate compound represented by formula 20 according to the synthesis method of an intermediate compound having a structure represented by formula 20 of any one of claims 5 to 7;

(s) the intermediate compound shown in the formula 20 is firstly oxidized under the action of 5,10,15, 20-tetraphenylporphyrin, oxygen and ultraviolet light, and then reacted under the action of trimethylphosphine to generate the intermediate compound shown in the formula 21;

(t) the intermediate compound shown in the formula 21 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to dihydroxylation reaction under the action of an oxidizing reagent to generate the intermediate compound shown in the formula 22;

(u) the intermediate compound shown in the formula 22 firstly carries out a ring closing reaction under the action of N, N-diisopropylethylamine, then carries out an acetylation reaction under the action of alkali, 4-dimethylaminopyridine and acetic anhydride, and then carries out a trimethylsilyl removal reaction under the action of tetrabutylammonium fluoride to generate the intermediate compound shown in the formula 23;

the reaction formula is as follows:

wherein Ts represents a p-toluenesulfonyl group, TES represents a triethylsilyl group, TMS represents a trimethylsilyl group, and Ms represents a methanesulfonyl group.

9. The method for synthesizing an intermediate compound having a structure represented by formula 23 according to claim 8, wherein in step(s), the oxygen pressure is 1 to 2 atmospheres, and the molar ratio of the intermediate compound represented by formula 20, 5,10,15, 20-tetraphenylporphyrin and trimethylphosphine is 1: (0.01-0.05): (2.0-10.0): and/or the presence of a catalyst in the reaction mixture,

in the step (t), the alkali is pyridine, the oxidizing agent is osmium tetroxide, the reducing agent is sodium bisulfite, and the molar ratio of the intermediate compound shown in the formula 21, the methylsulfonyl chloride, the oxidizing agent and the sodium bisulfite is 1: (1.2-20.0): (1.0-5.0): (10.0 to 500); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (u) is sodium bicarbonate, and the molar ratio of the intermediate compound shown as the formula 22, the alkali, the 4-dimethylaminopyridine, the acetic anhydride and the tetrabutylammonium fluoride is 1: (2.0-50.0): (2.0-20.0) and (2.0-20.0): (1.0-1.5); and/or the presence of a catalyst in the reaction mixture,

the reaction temperature in the step(s) is 10-40 ℃, and the reaction time is 70-90 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 21 in the step (t), alkali and methylsulfonyl chloride is 10-40 ℃, and the reaction time is 3-10 h; the reaction temperature after adding the oxidizing reagent is 10-40 ℃, and the reaction time is 0.5-1 h; the reaction temperature after the reduction reagent is added is 10-40 ℃, and the reaction time is 10-20 h; and/or the presence of a catalyst in the reaction mixture,

in the step (u), the reaction temperature of the intermediate compound shown in the formula 22 and N, N-diisopropylethylamine is 100-120 ℃, and the reaction time is 15-20 h; the reaction temperature after adding the alkali, the 4-dimethylaminopyridine and the acetic anhydride is 100-120 ℃, and the reaction time is 6-10 h; the reaction temperature after adding tetrabutylammonium fluoride is-50 ℃ to-30 ℃, and the reaction time is 6h to 10 h; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step(s) is selected from at least one of 1, 2-dichloroethane, chloroform and tetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (t) is selected from at least one of tetrahydrofuran, methyl t-butyl ether and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (u) is selected from at least one of toluene, methyl t-butyl ether, 2-methyltetrahydrofuran and tetrahydrofuran.

10. A method for synthesizing paclitaxel, which is characterized by comprising the following steps:

(a) reacting a compound shown in a formula 1 under the action of 2,2, 2-trichloroacetamide benzyl ester and trifluoromethanesulfonic acid to generate an intermediate compound shown in a formula 2;

(b) the intermediate compound shown in the formula 2 firstly undergoes Vilsmeier reaction under the action of phosphorus tribromide, and then undergoes reduction reaction under the action of alkali and a reduction reagent to generate an intermediate compound shown in a formula 3;

(c) the intermediate compound shown in the formula 3 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to reduction reaction under the action of a reducing reagent to generate an intermediate compound shown in a formula 4;

(d) carrying out an oxidation reaction on the intermediate compound shown in the formula 4 under the action of an oxidation reagent to generate an intermediate compound shown in a formula 5;

(e) carrying out a phosphoenolsilylation reaction on the intermediate compound shown in the formula 5 under the action of alkali and tert-butyldimethylsilyl chloride to generate an intermediate compound shown in a formula 6;

(f) the intermediate compound shown in the formula 6 is firstly subjected to oxidation reaction under the action of m-chloroperoxybenzoic acid, then subjected to upper protection reaction under the action of a protective agent and a catalyst, and then subjected to hydrolysis reaction under the action of alkali to generate an intermediate compound shown in a formula 7;

(g) the intermediate compound shown in the formula 7 firstly undergoes 1, 2-addition reaction under the action of alkali and a compound shown in the formula 8, and then undergoes reaction under the action of a protective agent and a catalyst to generate an intermediate compound shown in the formula 9;

(h) desulfurizing the intermediate compound shown in the formula 9 under the action of alkali and N-bromosuccinimide to generate an intermediate compound shown in a formula 10;

(i) the intermediate compound shown in the formula 10 reacts under the action of samarium powder and samarium diiodide to generate an intermediate compound shown in a formula 11;

(j) reacting the intermediate compound shown in the formula 11 under the action of alkali and triphosgene to generate an intermediate compound shown in a formula 12;

(k) reacting the intermediate compound shown in the formula 12 under the action of acid to generate an intermediate compound shown in a formula 13;

(l) Reacting the intermediate compound shown as the formula 13 under the action of acetic anhydride and a catalyst to generate an intermediate compound shown as a formula 14;

(m) the intermediate compound shown in the formula 14 is firstly oxidized under the action of an oxidizing reagent and a catalyst, and then reacted under the action of 1, 5-diazabicyclo [4.3.0] non-5-ene to generate an intermediate compound shown in a formula 15;

(n) the intermediate compound shown in the formula 15 is subjected to debenzylation reaction under the action of hydrogen and a catalyst, and then is subjected to reaction under the action of alkali and triethyl silyl trifluoromethanesulfonate to generate an intermediate compound shown in a formula 16;

(o) reacting the intermediate compound shown in the formula 16 under the action of sodium acetate and pyridinium chlorochromate to generate an intermediate compound shown in a formula 17;

(p) the intermediate compound shown in the formula 17 is subjected to condensation reaction under the action of p-toluenesulfonyl hydrazide and boron trifluoride diethyl etherate, and then is subjected to reaction under the action of alkali and a reducing reagent to generate the intermediate compound shown in the formula 18;

(q) reacting the intermediate compound represented by formula 18 with N- (trimethylsilyl) imidazole to produce an intermediate compound represented by formula 19;

(r) the intermediate compound shown in the formula 19 is subjected to a reduction reaction under the action of catechol borane and then subjected to a reaction under the action of sodium acetate trihydrate to generate an intermediate compound shown in a formula 20;

(s) the intermediate compound shown in the formula 20 is firstly oxidized under the action of 5,10,15, 20-tetraphenylporphyrin, oxygen and ultraviolet light, and then reacted under the action of trimethylphosphine to generate the intermediate compound shown in the formula 21;

(t) the intermediate compound shown in the formula 21 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to dihydroxylation reaction under the action of an oxidizing reagent to generate the intermediate compound shown in the formula 22;

(u) the intermediate compound shown in the formula 22 firstly carries out a ring closing reaction under the action of N, N-diisopropylethylamine, then carries out an acylation reaction under the action of alkali, 4-dimethylaminopyridine and acetic anhydride, and then carries out a trimethylsilyl removal reaction under the action of tetrabutylammonium fluoride to generate the intermediate compound shown in the formula 23;

(v) the intermediate compound shown in the formula 23 reacts with pyridine hydrofluoride under the action of alkali, the compound shown in the formula 24 and pyridine hydrofluoride to obtain taxol;

the reaction formula is as follows:

wherein TBS represents tert-butyldimethylsilyl group, Bz represents benzoyl group, and TES represents triethylsilyl group;

the molar ratio of the intermediate compound represented by formula 23, the base, the intermediate compound represented by formula 24, and the pyridine hydrofluoride salt in step (v) is 1: (2.5-3.5): (2.5-5.0): (10.0 to 500).

Technical Field

The invention relates to the technical field of drug synthesis, in particular to an intermediate compound for preparing paclitaxel, a synthesis method thereof and a synthesis method of paclitaxel.

Background

Paclitaxel (Taxol, see formula I) is a natural product of taxane diterpenes isolated from Taxus brevifolia. Wani et al, 1971, determined their structures by X-ray single crystal diffraction experiments on their derivatives. Paclitaxel has excellent antitumor activity. Horwitz et al discovered in subsequent biological studies that the antitumor activity of paclitaxel has a unique mechanism. Paclitaxel irreversibly promotes microtubule aggregation during mitosis of tumor cells. The U.S. Food and Drug Administration (FDA) approved paclitaxel for the treatment of drug-resistant ovarian cancer in 1992 and paclitaxel for the treatment of breast cancer in 1994. Subsequently, paclitaxel became the first "heavy pound bomb" grade drug of the company Bristol-Myers Squibb (BMS), which sold in 2006 to $ 37 billion, the first of all antineoplastic drugs on the international market.

In conclusion, it can be seen that Taxol has excellent antitumor activity and a unique action mechanism, and has produced great economic benefits in the market. Research on the total synthesis of paclitaxel has been actively conducted, and the total synthesis of paclitaxel has been reported internationally in the groups of Holton, Nicolaou, Danishefsky, Wender, Mukaiyama, Kuwajima, Baran, from 1994 to 2020. However, these reported synthetic routes have problems of long steps and low overall yield. There is a need to develop a simple and efficient total synthesis method, which can rapidly construct a paclitaxel analog compound library, so as to provide a material basis for the subsequent activity research.

Disclosure of Invention

Based on this, the present invention provides intermediate compounds for preparing paclitaxel and a synthetic method thereof, as well as a synthetic method of paclitaxel.

The technical scheme is as follows:

an intermediate compound for the preparation of paclitaxel selected from at least one of the following compounds:

wherein Ts represents a p-toluenesulfonyl group, TES represents a triethylsilyl group, and TMS represents a trimethylsilyl group.

The invention also provides a synthesis method of the intermediate compound with the structure shown in the formula 10, which comprises the following steps:

(a) the compound shown in the formula 1 is subjected to benzyl protection reaction under the action of 2,2, 2-trichloroacetamide benzyl ester and trifluoromethanesulfonic acid to generate an intermediate compound shown in the formula 2;

(b) the intermediate compound shown in the formula 2 firstly undergoes Vilsmeier reaction under the action of phosphorus tribromide, and then undergoes reduction reaction under the action of alkali and a reduction reagent to generate an intermediate compound shown in a formula 3;

(c) the intermediate compound shown in the formula 3 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to reduction reaction under the action of a reducing reagent to generate an intermediate compound shown in a formula 4;

(d) carrying out an oxidation cutting reaction on the intermediate compound shown in the formula 4 under the action of an oxidizing reagent to generate an intermediate compound shown in a formula 5;

(e) reacting the intermediate compound shown in the formula 5 under the action of alkali and tert-butyldimethylsilyl chloride to generate an intermediate compound shown in a formula 6;

(f) the intermediate compound shown in the formula 6 is firstly subjected to oxidation reaction under the action of m-chloroperoxybenzoic acid, then subjected to upper protection reaction under the action of a protective agent and a catalyst, and then subjected to hydrolysis reaction under the action of alkali to generate an intermediate compound shown in a formula 7;

(g) the intermediate compound shown in the formula 7 firstly undergoes 1, 2-addition reaction under the action of alkali and the compound shown in the formula 8, and then undergoes acetonylidene protection reaction under the action of a protective agent and a catalyst to generate the compound shown in the formula 9;

(h) the intermediate compound shown in the formula 9 reacts with DMF after being lithiated to introduce aldehyde group, and then the aldehyde group reacts with N-bromosuccinimide in a pot to carry out desulfurization, so that the intermediate compound shown in the formula 10 is generated;

the reaction formula is as follows:

wherein TBS represents tert-butyldimethylsilyl group.

In some of these embodiments, the molar ratio of the compound of formula 1,2, 2, 2-trichloroacetamide benzyl ester, and triflic acid in step (a) is 1: (1.0-2.0): (0.04 to 0.2); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (b) is sodium bicarbonate, the reducing agent is sodium borohydride, and the molar ratio of the intermediate compound shown in the formula 2, the phosphorus tribromide and the reducing agent is 1: (2.0-4.0): (0.3-4.0); and/or the presence of a catalyst in the reaction mixture,

the base in the step (c) is triethylamine, the reducing reagent is lithium aluminum hydride, and the molar ratio of the intermediate compound shown in the formula 3, the methylsulfonyl chloride and the reducing reagent is 1: (1.2-2): (1.0-4.5); and/or the presence of a catalyst in the reaction mixture,

the oxidizing reagent in step (d) is potassium osmate dihydrate, 4-methylmorpholine-N-oxide and sodium periodate, and the molar ratio of the intermediate compound shown in formula 4, the potassium osmate dihydrate, the 4-methylmorpholine-N-oxide and the sodium periodate is 1: (0.02-0.1): (2.2-3.0): (2.0-4.0); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (e) is sodium hydride, and the molar ratio of the intermediate compound shown in the formula 5 to tert-butyldimethylsilyl chloride is 1: (1.2-2.4); and/or the presence of a catalyst in the reaction mixture,

the protective agent in the step (f) is 2-methoxypropene, the catalyst is pyridinium p-toluenesulfonate, the alkali is an aqueous solution of sodium hydroxide, and the molar ratio of the intermediate compound shown in the formula 6, m-chloroperoxybenzoic acid, the protective agent, the catalyst and the alkali is 1: (1.2-1.5): (5.0-20.0): (0.03-0.4): (4.0-16.0); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (g) is tert-butyl lithium, the protective agent is 2, 2-dimethoxypropane, the catalyst is p-toluenesulfonic acid monohydrate, and the molar ratio of the intermediate compound shown in the formula 7, the compound shown in the formula 8, the protective agent, the catalyst and the alkali is 1: (1.2-3.0): (5.0-20.0): (0.05-0.2): (2.4-6.0); and/or the presence of a catalyst in the reaction mixture,

the base in the step (h) is tert-butyllithium, and the molar ratio of the intermediate compound represented by the formula 9, the N-bromosuccinimide and the base is 1: (3.0-20.0): (2.5-10.0).

In some embodiments, the reaction temperature in step (a) is-5 ℃ to 40 ℃, and the reaction time is 10h to 30 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 2 in the step (b) and phosphorus tribromide is 80-90 ℃, and the reaction time is 1-2 h; the reaction temperature of the reduction reaction is-5 ℃ to 0 ℃, and the reaction time is 10min to 60 min; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 3 in the step (c), alkali and methylsulfonyl chloride is-5-0 ℃, and the reaction time is 10-60 min; the reaction temperature of the reduction reaction is-50 to-30 ℃, and the reaction time is 30min to 60 min.

In some of these embodiments, step (d) comprises:

under the condition of 20-40 ℃, the intermediate compound shown in the formula 4 is firstly oxidized under the action of potassium osmate dihydrate and 4-methylmorpholine-N-oxide for 20-40 h, and then oxidized under the action of sodium periodate for 1-5 h to generate the intermediate compound shown in the formula 5; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 5 in the step (e) between alkali and tert-butyldimethylsilyl chloride is 20-40 ℃, and the reaction time is 5-15 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 6 in the step (f) and m-chloroperoxybenzoic acid is 20-40 ℃, the reaction time is 1-5 h, after 2-methoxypropene and pyridinium p-toluenesulfonate are added, the reaction temperature of the reaction mixture is-5-0 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

step (g) comprises:

under the condition of being lower than minus 60 ℃, adding tert-butyl lithium pentane solution into ether solution of a compound shown as a formula 8, stirring for 1h to 2h, adding tetrahydrofuran solution and methanol of an intermediate compound shown as a formula 7 into a reaction mixture, heating the reaction mixture to 20 ℃ to 25 ℃, concentrating to obtain crude residue, dissolving the crude residue into dichloromethane, and adding 2, 2-dimethoxypropane and p-toluenesulfonic acid monohydrate for reaction; and/or the presence of a catalyst in the reaction mixture,

the step (h) comprises:

adding tert-butyl lithium pentane solution into the intermediate compound ether solution shown in the formula 9 at the temperature lower than-60 ℃, stirring for 1 h-2 h, adding N, N-dimethylformamide into the reaction mixture, heating the reaction mixture to 20-25 ℃, reacting for 1 h-2 h, adding a mixed solvent of tetrahydrofuran and water into the reaction mixture, cooling to below 0 ℃, and adding N-bromosuccinimide for reaction.

In some of these embodiments, the reaction solvent of step (a) is selected from at least one of dichloromethane, toluene, tetrahydrofuran, and n-ethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (b) is selected from at least one of N, N-dimethylformamide, chloroform and N-ethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (c) is selected from at least one of tetrahydrofuran, toluene and dichloromethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (d) is selected from at least one of tetrahydrofuran and toluene; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (e) is selected from at least one of tetrahydrofuran, diethyl ether, methyl tert-butyl ether and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (f) is selected from at least one of dichloromethane, toluene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (g) is selected from at least one of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (h) is selected from at least one of diethyl ether, methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran.

It will be appreciated that the intermediate compound 10 described above may be prepared by carrying out the subsequent reaction directly using the reaction product obtained in any of steps (a) to (h) as a starting material. For example, intermediate compound 10 can be prepared by using a compound represented by formula 8 as a starting material and performing steps (g) to (h) as described above, or intermediate compound 10 can be prepared by using an intermediate compound represented by formula 3 as a starting material and performing steps (c) to (h) as described above.

The invention also provides a synthesis method of the intermediate compound with the structure shown in the formula 11, which comprises the following steps:

(i) reacting the intermediate compound shown in the formula 10 under the action of samarium powder and samarium diiodide to generate an intermediate compound shown in a formula 11;

the reaction formula is as follows:

wherein TBS represents tert-butyldimethylsilyl group.

In some of the embodiments, the molar ratio of the intermediate compound represented by formula 10, samarium powder and samarium diiodide in step (i) is 1: (2.0-5.0): (3.0-10.0).

In some embodiments, the reaction temperature of the intermediate compound represented by formula 10, samarium powder and samarium diiodide in step (i) is 45 to 80 ℃ and the reaction time is 2 to 5 hours.

In some of these embodiments, the reaction solvent of step (i) comprises tetrahydrofuran.

It will be appreciated that the reaction product obtained in any of steps (a) to (i) may be used as a starting material for the direct subsequent reaction to prepare the intermediate compound 11 described above. For example, intermediate compound 11 can be prepared by using a compound of formula 9 as a starting material and performing steps (h) to (i) as described above, or intermediate compound 11 can be prepared by using a compound of formula 3 as a starting material and performing steps (c) to (i) as described above.

The invention also provides a synthesis method of the intermediate compound with the structure shown in the formula 20, which comprises the following steps:

(i) reacting the intermediate compound shown in the formula 10 under the action of samarium powder and samarium diiodide to generate an intermediate compound shown in a formula 11;

(j) reacting the intermediate compound shown in the formula 11 under the action of alkali and triphosgene to generate an intermediate compound shown in a formula 12;

(k) reacting the intermediate compound shown in the formula 12 under the action of acid to generate an intermediate compound shown in a formula 13;

(l) Reacting the intermediate compound shown as the formula 13 under the action of acetic anhydride and a catalyst to generate an intermediate compound shown as a formula 14;

(m) the intermediate compound shown in the formula 14 is firstly subjected to oxidation reaction under the action of an oxidation reagent and a catalyst, and then subjected to epimerization reaction under the action of 1, 5-diazabicyclo [4.3.0] non-5-ene to generate the intermediate compound shown in the formula 15;

(n) the intermediate compound shown in the formula 15 firstly undergoes debenzylation reaction under the action of hydrogen and a catalyst, and then undergoes hydroxyl protection reaction under the action of alkali and triethyl silyl trifluoromethanesulfonate to generate an intermediate compound shown in a formula 16;

(o) carrying out an oxidation reaction on the intermediate compound shown in the formula 16 under the action of sodium acetate and pyridinium chlorochromate to generate an intermediate compound shown in a formula 17;

(p) the intermediate compound shown in the formula 17 is subjected to condensation reaction under the action of p-toluenesulfonyl hydrazide and boron trifluoride diethyl etherate, and then is subjected to reaction under the action of alkali and a reducing reagent to generate the intermediate compound shown in the formula 18;

(q) reacting the intermediate compound represented by formula 18 with N- (trimethylsilyl) imidazole to produce an intermediate compound represented by formula 19;

(r) the intermediate compound shown in the formula 19 is subjected to a reduction reaction under the action of catechol borane and then subjected to a reaction under the action of sodium acetate trihydrate to generate an intermediate compound shown in a formula 20;

the reaction formula is as follows:

wherein TES represents triethylsilyl, and TMS represents trimethylsilyl.

In some of these embodiments, the base in step (j) is pyridine, and the molar ratio of the intermediate compound of formula 11, the base, and the triphosgene is 1: (3.0-10.0): (2.1-5.0); and/or the presence of a catalyst in the reaction mixture,

the acid in step (k) is hydrochloric acid, and the molar ratio of the intermediate compound represented by formula 12 to hydrochloric acid is 1: (5.0-40.0); and/or the presence of a catalyst in the reaction mixture,

the catalyst in the step (l) is 4-dimethylaminopyridine, and the molar ratio of the intermediate compound shown as the formula 13 to acetic anhydride to the catalyst is 1: (1.0-1.5): (1.0-1.5); and/or the presence of a catalyst in the reaction mixture,

the oxidation reagent in step (m) is 4-methylmorpholine-N-oxide, the catalyst is tetrapropylamine perruthenate, and the molar ratio of the intermediate compound represented by formula 14, the oxidation reagent and the catalyst is 1: (1.5-5.0): (0.05-0.5); and/or the presence of a catalyst in the reaction mixture,

the catalyst in the step (n) is palladium/carbon, the base is triethylamine, the hydrogen pressure is 1-2 atmospheric pressures, and the molar ratio of the intermediate compound shown in the formula 15, the base and the triethyl trisilicate trifluoromethanesulfonate is 1: (2.0-20.0): (2.0-10.0); and/or the presence of a catalyst in the reaction mixture,

in the step (o), the molar ratio of the intermediate compound represented by the formula 16 to sodium acetate to pyridinium chlorochromate is 1: (10.0-40.0): (10.0-40.0); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (p) is sodium bicarbonate, the reducing reagent is sodium borohydride, and the molar ratio of the intermediate compound shown in the formula 17, the p-toluenesulfonyl hydrazide, the boron trifluoride diethyl etherate complex, the alkali and the reducing reagent is 1: (3.0-10.0): (3.0-20.0): (3.0-20.0): (5.0-50.0); and/or the presence of a catalyst in the reaction mixture,

in the step (q), the molar ratio of the intermediate compound represented by formula 18 to N- (trimethylsilyl) imidazole is 1: (2.0-20.0); and/or the presence of a catalyst in the reaction mixture,

in the step (r), the molar ratio of the intermediate compound represented by formula 19 to the catechol borane to sodium acetate trihydrate is 1: (5.0-50.0): (5.0-80.0).

In some embodiments, the reaction temperature in step (j) is-5 ℃ to 0 ℃, and the reaction time is 1h to 2 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature in the step (k) is 10-40 ℃, and the reaction time is 10-30 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the step (l) is-5 ℃ to 40 ℃, and the reaction time is h to 5 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 14 in the step (m), the oxidizing reagent and the catalyst is 0-40 ℃, and the reaction time is 1-5 h; the reaction temperature after adding 1, 5-diazabicyclo [4.3.0] non-5-ene is 90-110 ℃, and the reaction time is 12-20 h; and/or the presence of a catalyst in the reaction mixture,

the reaction time of the intermediate compound shown in the formula 15 in the step (n), the reducing reagent and the catalyst is 10-15 h; the reaction temperature after adding the alkali and the triethyl trifluoromethanesulfonate is 10-40 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

in the step (o), the reaction temperature of the intermediate compound shown in the formula 16 in sodium acetate and pyridinium chlorochromate is 80-90 ℃, and the reaction time is 8-10 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 17 in the step (p), p-toluenesulfonyl hydrazide and boron trifluoride diethyl etherate is 60-80 ℃, and the reaction time is 10-5 h; the reaction temperature after adding the alkali and the reducing reagent is-5 ℃ to 0 ℃, and the reaction time is 20min to 60 min; and/or the presence of a catalyst in the reaction mixture,

in the step (q), the reaction temperature of the intermediate compound shown in the formula 18, sodium acetate and N- (trimethylsilyl) imidazole is 10-40 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

in the step (q), the reaction temperature of the intermediate compound shown in the formula 18, sodium acetate and N- (trimethylsilyl) imidazole is 10-40 ℃, and the reaction time is 1-5 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 19 and the catechol borane in the step (r) is 10-40 ℃, and the reaction time is 2-6 h; the reaction temperature after adding the sodium acetate trihydrate is 10-40 ℃, and the reaction time is 20-60 min.

In some of these embodiments, the reaction solvent of step (k) is selected from at least one of methanol, ethanol, and isopropanol; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (l) is selected from at least one of dichloromethane, toluene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (m) is selected from at least one of dichloromethane, dichloroethane and toluene; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (n) is selected from at least one of dichloromethane, dichloroethane and toluene; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (o) is selected from at least one of benzene and dichloroethane; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (p) is selected from at least one of tetrahydrofuran, toluene and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (q) comprises at least one of dichloromethane, dichloroethane, and tetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (r) comprises at least one of 1, 2-dichloroethane and chloroform.

It will be appreciated that the above-described intermediate compound 20 (intermediate compound represented by formula 20) can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps (a) to (r) as a starting material. For example, intermediate compound 20 can be prepared by starting with a compound of formula 11 and performing steps (j) to (r) as described above, or intermediate compound 20 can be prepared by starting with a compound of formula 9 and performing steps (h) to (r) as described above, or intermediate compound 20 can be prepared by starting with a compound of formula 3 and performing steps (c) to (r) as described above.

The invention also provides a synthesis method of the intermediate compound with the structure shown in the formula 23, which comprises the following steps:

(s) the intermediate compound shown in the formula 20 is firstly oxidized under the action of 5,10,15, 20-tetraphenylporphyrin, oxygen and ultraviolet light, and then reacted under the action of trimethylphosphine to generate the intermediate compound shown in the formula 21;

(t) the intermediate compound shown in the formula 21 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to dihydroxylation reaction under the action of an oxidizing reagent to generate the intermediate compound shown in the formula 22;

(u) the intermediate compound shown in the formula 22 firstly carries out a ring closing reaction under the action of N, N-diisopropylethylamine, then carries out an acetylation reaction under the action of alkali, 4-dimethylaminopyridine and acetic anhydride, and then carries out a trimethylsilyl removal reaction under the action of tetrabutylammonium fluoride to generate the intermediate compound shown in the formula 23;

the reaction formula is as follows:

wherein TES represents triethylsilyl, TMS represents trimethylsilyl, and Ms represents methanesulfonyl.

In some embodiments, in step(s), the oxygen pressure is 1 to 2 atmospheres, and the molar ratio of the intermediate compound represented by formula 20, 5,10,15, 20-tetraphenylporphyrin and trimethylphosphine is 1: (0.01-0.05): (2.0-10.0): and/or the presence of a catalyst in the reaction mixture,

in the step (t), the alkali is pyridine, the oxidizing agent is osmium tetroxide, the reducing agent is sodium bisulfite, and the molar ratio of the intermediate compound shown in the formula 21, the methylsulfonyl chloride, the oxidizing agent and the sodium bisulfite is 1: (1.2-20.0): (1.0-5.0): (10.0 to 500); and/or the presence of a catalyst in the reaction mixture,

the alkali in the step (u) is sodium bicarbonate, and the molar ratio of the intermediate compound shown as the formula 22, the alkali, the 4-dimethylaminopyridine, the acetic anhydride and the tetrabutylammonium fluoride is 1: (2.0-50.0): (2.0-20.0) and (2.0-20.0): (1.0-1.5); and/or the presence of a catalyst in the reaction mixture,

the reaction temperature in the step(s) is 10-40 ℃, and the reaction time is 70-90 h; and/or the presence of a catalyst in the reaction mixture,

the reaction temperature of the intermediate compound shown in the formula 21 in the step (t), alkali and methylsulfonyl chloride is 10-40 ℃, and the reaction time is 3-10 h; the reaction temperature after adding the oxidizing reagent is 10-40 ℃, and the reaction time is 0.5-1 h; the reaction temperature after the reduction reagent is added is 10-40 ℃, and the reaction time is 10-20 h; and/or the presence of a catalyst in the reaction mixture,

in the step (u), the reaction temperature of the intermediate compound shown in the formula 22 and N, N-diisopropylethylamine is 100-120 ℃, and the reaction time is 15-20 h; the reaction temperature after adding the alkali, the 4-dimethylaminopyridine and the acetic anhydride is 100-120 ℃, and the reaction time is 6-10 h; the reaction temperature after adding the tetrabutylammonium fluoride is-50 ℃ to-30 ℃, and the reaction time is 6h to 10 h.

In some of these embodiments, the reaction solvent of step(s) is selected from at least one of 1, 2-dichloroethane, chloroform, and tetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (t) is selected from at least one of tetrahydrofuran, methyl t-butyl ether and 2-methyltetrahydrofuran; and/or the presence of a catalyst in the reaction mixture,

the reaction solvent of step (u) is selected from at least one of toluene, methyl t-butyl ether, 2-methyltetrahydrofuran and tetrahydrofuran.

It will be appreciated that the above-described intermediate compound 22 (intermediate compound represented by formula 22) can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps (a) to (t) as a starting material. For example, intermediate compound 22 can be prepared by starting with a compound of formula 11 and performing steps (j) to (t) as described above, or intermediate compound 22 can be prepared by starting with a compound of formula 9 and performing steps (h) to (t) as described above, or intermediate compound 22 can be prepared by starting with a compound of formula 3 and performing steps (c) to (t) as described above.

It will also be appreciated that the above-described intermediate compound 23 (intermediate compound represented by formula 23) can be produced by directly carrying out the subsequent reaction using the reaction product obtained in any one of steps (a) to (u) as a starting material. For example, intermediate compound 23 can be prepared by starting with a compound of formula 11 and performing steps (j) to (u) as described above, or intermediate compound 23 can be prepared by starting with a compound of formula 9 and performing steps (h) to (u) as described above, or intermediate compound 23 can be prepared by starting with a compound of formula 3 and performing steps (c) to (u) as described above.

The invention also provides a synthesis method of paclitaxel, which comprises the following steps:

(a) reacting a compound shown in a formula 1 under the action of 2,2, 2-trichloroacetamide benzyl ester and trifluoromethanesulfonic acid to generate an intermediate compound shown in a formula 2;

(b) the intermediate compound shown in the formula 2 firstly undergoes Vilsmeier reaction under the action of phosphorus tribromide, and then undergoes reduction reaction under the action of alkali and a reduction reagent to generate an intermediate compound shown in a formula 3;

(c) the intermediate compound shown in the formula 3 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to reduction reaction under the action of a reducing reagent to generate an intermediate compound shown in a formula 4;

(d) carrying out an oxidation reaction on the intermediate compound shown in the formula 4 under the action of an oxidation reagent to generate an intermediate compound shown in a formula 5;

(e) carrying out a phosphoenolsilylation reaction on the intermediate compound shown in the formula 5 under the action of alkali and tert-butyldimethylsilyl chloride to generate an intermediate compound shown in a formula 6;

(f) the intermediate compound shown in the formula 6 is firstly subjected to oxidation reaction under the action of m-chloroperoxybenzoic acid, then subjected to upper protection reaction under the action of a protective agent and a catalyst, and then subjected to hydrolysis reaction under the action of alkali to generate an intermediate compound shown in a formula 7;

(g) the intermediate compound shown in the formula 7 firstly undergoes 1, 2-addition reaction under the action of alkali and a compound shown in the formula 8, and then undergoes reaction under the action of a protective agent and a catalyst to generate an intermediate compound shown in the formula 9;

(h) desulfurizing the intermediate compound shown in the formula 9 under the action of alkali and N-bromosuccinimide to generate an intermediate compound shown in a formula 10;

(i) the intermediate compound shown in the formula 10 reacts under the action of samarium powder and samarium diiodide to generate an intermediate compound shown in a formula 11;

(j) reacting the intermediate compound shown in the formula 11 under the action of alkali and triphosgene to generate an intermediate compound shown in a formula 12;

(k) reacting the intermediate compound shown in the formula 12 under the action of acid to generate an intermediate compound shown in a formula 13;

(l) Reacting the intermediate compound shown as the formula 13 under the action of acetic anhydride and a catalyst to generate an intermediate compound shown as a formula 14;

(m) the intermediate compound shown in the formula 14 is firstly oxidized under the action of an oxidizing reagent and a catalyst, and then reacted under the action of 1, 5-diazabicyclo [4.3.0] non-5-ene to generate an intermediate compound shown in a formula 15;

(n) the intermediate compound shown in the formula 15 is subjected to debenzylation reaction under the action of hydrogen and a catalyst, and then is subjected to reaction under the action of alkali and triethyl silyl trifluoromethanesulfonate to generate an intermediate compound shown in a formula 16;

(o) reacting the intermediate compound shown in the formula 16 under the action of sodium acetate and pyridinium chlorochromate to generate an intermediate compound shown in a formula 17;

(p) the intermediate compound shown in the formula 17 is subjected to condensation reaction under the action of p-toluenesulfonyl hydrazide and boron trifluoride diethyl etherate, and then is subjected to reaction under the action of alkali and a reducing reagent to generate the intermediate compound shown in the formula 18;

(q) reacting the intermediate compound represented by formula 18 with N- (trimethylsilyl) imidazole to produce an intermediate compound represented by formula 19;

(r) the intermediate compound shown in the formula 19 is subjected to a reduction reaction under the action of catechol borane and then subjected to a reaction under the action of sodium acetate trihydrate to generate an intermediate compound shown in a formula 20;

(s) the intermediate compound shown in the formula 20 is firstly oxidized under the action of 5,10,15, 20-tetraphenylporphyrin, oxygen and ultraviolet light, and then reacted under the action of trimethylphosphine to generate the intermediate compound shown in the formula 21;

(t) the intermediate compound shown in the formula 21 is firstly subjected to mesylation reaction under the action of alkali and methylsulfonyl chloride, and then subjected to dihydroxylation reaction under the action of an oxidizing reagent to generate the intermediate compound shown in the formula 22;

(u) the intermediate compound shown in the formula 22 firstly carries out a ring closing reaction under the action of N, N-diisopropylethylamine, then carries out an acylation reaction under the action of alkali, 4-dimethylaminopyridine and acetic anhydride, and then carries out a trimethylsilyl removal reaction under the action of tetrabutylammonium fluoride to generate the intermediate compound shown in the formula 23;

(v) the intermediate compound shown in the formula 23 reacts with pyridine hydrofluoride under the action of alkali, the compound shown in the formula 24 and pyridine hydrofluoride to obtain taxol;

the reaction formula is as follows:

wherein Bz represents benzoyl, and TES represents triethylsilyl.

The detailed description of the steps (a) to (u) is omitted here for brevity.

In some embodiments, the intermediate compound of formula 23, the base, the compound of formula 24, and the pyridine hydrofluoride salt in step (v) are present in a molar ratio of 1: (2.5-3.5): (2.5-5.0): (10.0 to 500).

In some embodiments, the paclitaxel synthesis method comprises the following steps: adding phenyl lithium into tetrahydrofuran solution of the intermediate compound shown in the formula 23 at the temperature lower than-60 ℃, stirring for 10min to 60min, adding tetrahydrofuran solution of the compound shown in the formula 24, heating the reaction mixture to 20 ℃ to 25 ℃, stirring for 30min to 60min, adding pyridine hydrofluoride, and stirring for 1h to 3 h.

It will be appreciated that the corresponding intermediate compounds described above may be synthesized at the corresponding steps in the above method for synthesizing paclitaxel. For example, intermediate compound 3 (compound represented by formula 3) can be synthesized using step (b), intermediate compound 9 (compound represented by formula 9) can be synthesized using steps (c) to (g), intermediate compound 11 (compound represented by formula 11) can be synthesized using steps (c) to (i), and the like.

The invention has the following beneficial effects:

the invention prepares a series of new intermediate compounds, can prepare taxol with high yield by taking the intermediates as raw materials, is easy to modify the structure of the taxol, can screen a series of lead compounds from the taxol to research the biological activity of the taxol, and is believed to break through in the research and development field of tumor drugs.

The synthesis method of the taxol and the intermediate thereof has the advantages of chiral controllability, high yield, high product purity, simplicity and high efficiency, and is wide in raw material source, cheap and easily available in reagent, simple in reaction, simple and convenient to operate, green and environment-friendly, and suitable for industrial amplification production.

Drawings

FIG. 1 is a NMR spectrum of intermediate compound 10;

FIG. 2 is a NMR carbon spectrum of intermediate compound 10;

FIG. 3 is a NMR spectrum of intermediate compound 11;

FIG. 4 is a NMR carbon spectrum of intermediate compound 11;

FIG. 5 is a NMR spectrum of intermediate compound 12;

FIG. 6 is a NMR carbon spectrum of intermediate compound 12;

FIG. 7 is a NMR spectrum of intermediate compound 20;

FIG. 8 is a NMR carbon spectrum of intermediate compound 20;

figure 9 is a nuclear magnetic resonance hydrogen spectrum of intermediate compound 23;

figure 10 is a nuclear magnetic resonance carbon spectrum of intermediate compound 23;

FIG. 11 is a NMR spectrum of paclitaxel;

FIG. 12 is a NMR carbon spectrum of paclitaxel.

Detailed Description

The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Example 1: synthesis of intermediate Compound 2

Compound 1(20.0g,118.9mmol) and benzyl 2,2, 2-trichloroacetamide (44.2mL,237.8mmol) were dissolved in dichloromethane (240mL) and trifluoromethanesulfonic acid (525 μ L,5.945mmol) was added dropwise at 0 ℃. The resulting reaction solution was warmed to room temperature and reacted overnight. The reaction was quenched with saturated sodium bicarbonate solution (100mL) at 0 deg.C, followed by extraction with dichloromethane solution (150mL x 3). The combined organic phases were washed once with saturated brine (150mL), dried over anhydrous sodium sulfate, filtered and the resulting organic phase was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate, vol.70: 1 to 30:1) to give product 2(25.2g, 82% yield) as a colorless oil.

R_f＝0.55(hexane:EtOAc＝10:1)；

[α]25D＝+25(c＝0.5,CH₂Cl₂)；

IR(film):2963,2942,1700,1261,1097,1029,801cm^-1；

¹H NMR(500MHz,CDCl₃)δ7.36–7.25(m,5H),5.74–5.64(m,1H),5.07–5.05(m,1H),5.05–5.01(m,1H),4.61(d,J＝11.7Hz,1H),4.39(d,J＝11.7Hz,1H),3.58(dd,J＝6.9,2.8Hz,1H),2.43–2.36(m,4H),2.11–1.97(m,2H),1.96–1.87(m,1H),1.70–1.63(m,1H),1.16(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ213.5,138.7,133.9,128.4,127.6,127.5,118.1,82.2,71.1,54.6,40.5,38.0,24.1,20.4,18.6.

HRMS(ESI-TOF):calcd for C₁₇H₂₃O₂[M+H]⁺259.1693,found 259.1695.

Example 2: synthesis of intermediate Compound 3

Phosphorus tribromide (22.8mL,193.5mmol) was slowly added to N, N-dimethylformamide (300mL) at 0 ℃. The resulting system was slowly warmed to 25 ℃ and stirred vigorously for 30 minutes intermediate compound 2(20.0g,77.40mmol) was dissolved in N, N-dimethylformamide (10mL) and added slowly. The resulting reaction was heated to 80 ℃ and stirred for 100 minutes, then cooled to 25 ℃. The solvent was spun off and tetrahydrofuran (200mL) and water (30mL) were added sequentially. The resulting system was cooled to 0 ℃. Solid sodium bicarbonate (80g,952.4mmol), sodium borohydride (5.88g,154.8mmol) were added sequentially. After stirring was continued for 15 minutes, water (200mL) was added to the system and extracted with ethyl acetate (300 mL. times.3). The combined organic phases were washed once with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered and the resulting organic phase was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate, vol.10: 1 to 4:1) to give product 3 as a yellow oil (15.2g, 56% yield).

R_f＝0.45(hexane:EtOAc＝5:1)；

[α]25D＝-33(c＝0.5,CH₂Cl₂)；

IR(film):2936,2872,1636,1452,1072,915,734,697cm^-1；

¹H NMR(500MHz,CDCl₃)δ7.37–7.27(m,5H),5.67–5.57(m,1H),5.05–4.95(m,2H),4.65(d,J＝11.6Hz,1H),4.44(d,J＝11.6Hz,1H),4.23(q,J＝12.6Hz,2H),3.57(dd,J＝10.9,3.1Hz,1H),2.47–2.37(m,3H),2.23–2.15(m,1H),2.02–1.95(m,1H),1.75–1.66(m,1H),1.18(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ138.9,136.4,134.9,130.8,128.5,127.7,127.7,118.2,78.3,71.3,66.9,47.3,42.3,27.7,22.3,21.8；

HRMS(ESI-TOF):calcd for C₁₈H₂₇BrNO₂[M+NH₄]⁺368.1220,found 368.1220.

Example 3: synthesis of intermediate Compound 5

To a solution of intermediate compound 3(20.0g,56.93mmol) and triethylamine (19.68mL,142.32mmol) in tetrahydrofuran (300mL) at 0 deg.C was added methanesulfonyl chloride (5.3mL,68.32 mmol). After 15 minutes, the reaction mixture was cooled to-40 ℃ and stirred for 10 minutes. Lithium aluminum hydride (2.5M in THF, 91.12mL, 227.8mmol) was added. After 1 hour, the reaction was quenched by careful slow addition of saturated aqueous sodium potassium tartrate (700mL) and the system was gradually warmed to 25 ℃ and stirred overnight. The reaction mixture was extracted with ethyl acetate (800mL x 3). The combined organic phases were washed with brine (500mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude intermediate compound 4, which was used directly in the next step without further purification.

The crude intermediate compound 4 was dissolved in a mixed solvent of tetrahydrofuran/water 4:1(500 mL). To the resulting solution was added potassium osmate (531mg,1.708mmol) and 4-methylmorpholine-N-oxide (15.32g,130.96mmol) in that order. The resulting mixture was stirred for 36 hours, then sodium periodate (24.37g, 113.88mmol) was added. After 2h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate (250mL) and extracted with ethyl acetate (300 mL. times.3). The combined organic layers were washed with brine (300mL), dried over anhydrous sodium sulfate, filtered and concentrated. Filtering, and concentrating the obtained organic phase to obtain a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate, vol.200: 1 to 100:1) to give product 5(14.4g, 75% yield) as a yellow oil.

R_f＝0.65(hexane:EtOAc＝10:1)；

[α]25D＝-44(c＝0.5,CH₂Cl₂)；

IR(film):2923,2854,1718,1457,1103,1074,921,736,697cm^-1；

¹H NMR(500MHz,CDCl₃)δ9.65(t,J＝2.8Hz,1H),7.37–7.27(m,5H),4.60(d,J＝11.4Hz,1H),4.38(d,J＝11.4Hz,1H),3.53(dd,J＝11.7,3.3Hz,1H),2.75(dd,J＝15.5,2.7Hz,1H),2.58(dd,J＝15.4,2.9Hz,1H),2.27–2.13(m,2H),2.03–1.94(m,1H),1.82(s,3H),1.75–1.64(m,1H),1.28(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ202.4,138.3,133.7,128.5,127.9,127.8,126.6,80.1,71.2,52.3,46.8,31.5,24.3,22.7,20.9；

HRMS(ESI-TOF):calcd for C₁₇H₂₂BrO₂[M+H]⁺337.0798,found 337.0794.

Example 4: synthesis of intermediate Compound 6

Intermediate compound 5(20.0g,59.29mmol) and tert-butyldimethylsilyl chloride (13.43g,88.94mmol) were dissolved in tetrahydrofuran (300 mL). To the resulting solution was added sodium hydride (4.74g,118.6mmol, 60% dispersion in mineral oil) at 0 ℃. The resulting mixture was stirred at 25 ℃ for 12 hours, and then the reaction was quenched by addition of saturated aqueous ammonium chloride (200mL) at 0 ℃. The reaction mixture was extracted with acetic acid (200mL x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (100mL) and brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate, vol.% from pure petroleum ether to 100:1) to give product 6 as a yellow oil (26.2g, 98% yield).

R_f＝0.55(hexane:EtOAc＝10:1)；

[α]25D＝+48(c＝0.5,CH₂Cl₂)；

IR(film):2930,1660,1472,1257,1193,838,781,735,698cm^-1；

¹H NMR(500MHz,CD₂Cl₂)δ7.36–7.24(m,5H),6.23(d,J＝12.0Hz,1H),4.84(d,J＝12.1Hz,1H),4.59(d,J＝11.5Hz,1H),4.44(d,J＝11.5Hz,1H),3.41(dd,J＝6.9,2.2Hz,1H),2.32–2.23(m,1H),2.04(dt,J＝17.3,5.6Hz,1H),1.96–1.88(m,1H),1.82(s,3H),1.81–1.75(m,1H),1.27(s,3H),0.91(s,9H),0.13(s,6H)；

¹³C NMR(126MHz,CD₂Cl₂)δ143.2,139.4,133.5,128.6,128.1,127.8,126.8,118.7,82.4,72.1,47.5,30.2,25.8,24.3,23.0,21.9,18.5,-5.0,-5.1.

HRMS(ESI-TOF):calcd for C₂₃H₃₆BrO₂Si[M+H]⁺451.1662,found 451.1670.

Example 5: synthesis of intermediate Compound 7

To a solution of intermediate compound 6(10.0g,22.15mmol) in DCM (200mL) was added m-chloroperoxybenzoic acid (85% by mass, 5.41g,26.58mmol) at 25 ℃. Stirring was continued at the same temperature for 1 hour, and then the reaction mixture was cooled to 0 ℃. 2-methoxypropene (31mL, 332.2mmol) and pyridinium p-toluenesulfonate (1.668g, 6.664mmol) were added to the system. After 1 hour, 1.0M aqueous NaOH (110mL, 110mmol) was added. The reaction mixture was brought to 25 ℃ and concentrated under reduced pressure to a volume of about 30 mL. To the residue were added tetrahydrofuran (400mL) and 1.0M aqueous NaOH solution (10mL, 110 mmol). Stirring was continued overnight at 25 ℃. The reaction mixture was extracted with ethyl acetate (400 mL. times.3), and the combined organic phases were washed with brine (400mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by neutral alumina column chromatography (petroleum ether: ethyl acetate, vol.100: 1 to 30:1) to afford product 7 as a white solid (5.1g, 54% yield).

R_f＝0.50(hexane:EtOAc＝10:1)；

[α]25D＝-54(c＝0.5,CH₂Cl₂)；

IR(film):2945,1719,1457,1075,1028,931,734,698cm^-1；

¹H NMR(500MHz,CD₂Cl₂)δ9.37(d,J＝3.9Hz,1H),7.39–7.25(m,5H),4.68(d,J＝11.7Hz,1H),4.47(d,J＝11.7Hz,1H),4.20(d,J＝3.9Hz,1H),4.16(dd,J＝12.1,3.4Hz,1H),3.20(s,3H),2.29–2.14(m,2H),2.11–2.03(m,1H),1.83(s,3H),1.68–1.58(m,1H),1.38(s,3H),1.31(s,3H),1.14(s,3H)；

¹³C NMR(126MHz,CD₂Cl₂)δ203.4,138.7,135.1,128.7,127.8,127.6,126.7,102.0,81.4,76.5,70.5,52.6,49.7,31.8,25.4,24.9,24.6,22.5,17.2；

HRMS(ESI-TOF):calcd for C₂₁H₂₉BrNaO₄[M+Na]⁺447.1141,found 447.1149.

Example 6: synthesis of intermediate Compound 9

To a solution of compound 8(4.8g, 14.11mmol) in diethyl ether (75mL) was added tert-butyllithium (1.3M pentane solution, 21.71mL, 28.22mmol) at-78 ℃. The resulting mixture was stirred at-78 ℃ for 1 hour. To the reaction mixture was then added a solution of intermediate compound 7(5.0g, 11.75mmol) in tetrahydrofuran (25 mL). After 10min, methanol (4.78mL, 117.5mmol.) was added. The reaction mixture was slowly warmed to 25 ℃ and concentrated under reduced pressure to give a crude residue, which was then dissolved in dichloromethane (100mL) at 25 ℃. Then 2, 2-dimethoxypropane (14.38mL,117.5mmol) and p-toluenesulfonic acid monohydrate (448mg,2.35mmol) were added in succession. Stirring was continued for 1 hour, then the reaction mixture was quenched with saturated aqueous sodium bicarbonate (50mL) and extracted with dichloromethane (50 mL. times.3). The combined organic phases were washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate, vol.100: 1 to 40:1) to give product 9 as a white foam (5.4g, 76% yield).

R_f＝0.52(hexane:EtOAc＝10:1)；

[α]25D＝+12(c＝0.5,CH₂Cl₂)；

IR(film):2982,2942,1635,1237,1042,901,732,698cm^-1；

¹H NMR(500MHz,CDCl₃,observed signals)δ5.35(d,J＝9.3Hz,1H),4.99(d,J＝9.5Hz,1H),4.94(d,J＝9.3Hz,1H),4.67(d,J＝3.1Hz,1H),4.65(d,J＝3.0Hz,1H),4.63(d,J＝9.5Hz,1H),4.51(d,J＝11.7Hz,1H),4.44(d,J＝11.9Hz,1H),4.12(dd,J＝9.0,2.3Hz,1H),4.00(dd,J＝9.8,2.5Hz,1H)；

¹³C NMR(126MHz,CDCl₃,observed signals)δ139.0,138.9,135.7,133.7,133.1,128.4,127.9,127.6,127.5,127.5,106.5,105.5,81.7,81.0,80.3,79.2,75.4,70.4,70.3,45.0,39.8,39.7,39.3,39.2,37.2,36.9,34.1,33.2,30.6,30.4,28.1,27.8,27.5,27.4,27.0,25.4,25.0,22.8,22.8,21.7,21.2,18.7；

HRMS(ESI-TOF):calcd for C₃₁H₄₃BrNaO₃S₂[M+Na]⁺629.1729,found 629.1716.

Example 7: synthesis of intermediate Compound 10

To a solution of intermediate compound 9(5.0g, 8.228mmol) in diethyl ether (80mL) was added tert-butyllithium (1.3M in pentane, 25.3mL, 32.91mmol) at-78 ℃. After 1h, N-dimethylformamide (6.3mL, 82.28mmol) was added. After 10 minutes, the reaction mixture was gradually warmed to 25 ℃ and the reaction was continued for 2 hours at 25 ℃. A mixture of tetrahydrofuran/water (80mL/20mL) was added. The reaction was then cooled to 0 ℃ and N-bromosuccinimide (14.6g, 82.28mmol) was added in sequence. After 5 min, the reaction was quenched by addition of solid sodium bicarbonate (6.9g, 82.28mmol) and water (60mL) and the reaction mixture was extracted with ethyl acetate (100mL x 3). The combined organic phases were washed with brine (50mL), dried, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.20: 1 to 7:1) to afford product 10(2.4g, 61% yield) as a yellow gum.

R_f＝0.45(hexane:EtOAc＝5:1)；

[α]25D＝+96(c＝0.5,CH₂Cl₂)；

IR(film):2983,2897,1711,1682,1607,1239,1044,747,696cm^-1；

¹H NMR(500MHz,CDCl₃,major conformer)δ10.07(s,1H),7.36–7.27(m,5H),5.05(d,J＝9.5Hz,1H),4.68(d,J＝11.5Hz,1H),4.26(dd,J＝20.2,10.5Hz,2H),3.80(dd,J＝10.5,3.0Hz,1H),2.00(s,3H),1.97(s,3H),1.43(s,6H),1.37(s,3H),1.11(s,3H),1.06(s,3H)；

¹³C NMR(126MHz,CDCl₃,major conformer)δ214.6,194.1,138.6,137.2,137.0,131.8,128.6,127.7,127.4,106.0,80.2,76.9,75.3,69.8,48.9,43.7,35.8,33.8,32.8,27.7,26.7,25.9,23.7,21.6,20.8,20.3,19.0.

HRMS(ESI-TOF):calcd for C₃₀H₄₀NaO₅[M+Na]⁺503.2768,found 503.2775.

Example 8: synthesis of intermediate Compound 12

(1) Samarium powder (1.25g, 8.323mmol) was charged to a 100ml Schlenk flask. The vacuum was repeatedly evacuated/filled with argon three times under an argon atmosphere and under vacuum. Samarium diiodide (167mL, 16.65mmol, 0.1M in tetrahydrofuran) was added at 25 ℃. After the resulting mixture was heated to 65 ℃ and stirred for 10 minutes, a solution of intermediate compound 10(2.0g, 4.161mmol) in tetrahydrofuran (10mL) was added dropwise over 0.5 hour by means of a syringe pump. The reaction was continued at 65 ℃ for 2 hours. The reaction mixture was gradually cooled to 25 ℃, and the reaction system was quenched with a saturated aqueous sodium bicarbonate solution (80mL) and a saturated aqueous sodium sulfite solution (80mL) at 0 ℃, and extracted with ethyl acetate (160mL × 3). The combined organic phases were washed with brine (100mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give crude intermediate compound 11. The crude product was used directly in the next step without further purification.

R_f＝0.30(hexane:EtOAc＝3:1)；

[α]25D＝+140(c＝0.2,CH₂Cl₂)；

IR(film):2984,1456,1369,1233,1059,964,739cm^-1；

¹H NMR(500MHz,CD₂Cl₂)δ7.37–7.27(m,5H),4.56(d,J＝11.3Hz,1H),4.40(d,J＝11.3Hz,1H),4.23–4.18(m,2H),3.91(d,J＝9.2Hz,1H),3.65(t,J＝2.7Hz,1H),3.20(s,1H),3.09(s,1H),2.49–2.36(m,2H),2.23–2.10(m,2H),2.09(s,3H),1.94–1.81(m,3H),1.80(s,3H),1.78–1.72(m,1H),1.42(s,3H),1.36(s,3H),1.31(s,3H),1.26(s,3H),1.12(s,3H)；

¹³C NMR(126MHz,CD₂Cl₂)δ142.5,139.3,134.5,132.2,128.7,128.5,128.4,128.0,107.6,83.7,82.6,82.1,75.0,73.7,72.0,44.1,42.6,31.9,30.8,28.0,27.9,27.5,27.0,23.0,21.9,21.6,20.0,16.7；

HRMS(ESI-TOF):calcd for C₃₀H₄₂NaO₅[M+Na]⁺505.2924,found 505.2932.

(2) The crude intermediate compound 11 was dissolved in dichloromethane (80mL) and then cooled to 0 ℃. Pyridine (2.35mL, 29.13mmol) and triphosgene (3.708g, 12.48mmol) were added sequentially. After 0.5 hour, add saturated aqueous sodium bicarbonate (40mL), raise to 25 ℃, stir for 10 minutes, stand to separate layers, and extract the aqueous layer again with dichloromethane (40mL x 2). The combined organic layers were washed with brine (40mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.20: 1 to 10:1) to afford product 12 as a white solid (1.3g, 62% yield).

R_f＝0.60(hexane:EtOAc＝3:1)；

m.p.(hexane/DCM):180-183℃；

[α]25D＝+200(c＝0.5,CH₂Cl₂)；

IR(film):2936,1800,1455,1369,1235,751,703,616,511cm^-1；

¹H NMR(500MHz,CDCl₃)δ7.35–7.26(m,5H),5.02(s,1H),4.57(d,J＝11.9Hz,1H),4.44(d,J＝11.8Hz,1H),4.24(d,J＝9.3Hz,1H),3.86(d,J＝9.3Hz,1H),3.74(dd,J＝4.0,1.5Hz,1H),2.67–2.52(m,2H),2.32–2.22(m,1H),2.08–1.95(m,2H),2.01(s,3H),1.94–1.85(m,2H),1.92(s,3H),1.77–1.68(m,1H),1.46(s,3H),1.39(s,3H),1.37(s,3H),1.30(s,3H),1.25(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ154.0,145.4,140.7,139.3,128.3,127.5,127.4,127.3,122.4,107.7,95.3,83.3,80.3,79.2,74.0,71.4,44.5,41.8,31.4,30.4,27.9,27.0,26.2,25.2,23.1,22.0,21.7,20.0,17.0；

HRMS(ESI-TOF):calcd for C₃₁H₄₁O₆[M+H]⁺509.2898,found 509.2908.

Example 9: synthesis of intermediate Compound 14

To a solution of intermediate compound 12(500mg,0.983mmol) in methanol (98mL) at 25 deg.C was added 1.0M hydrochloric acid (19.7mL,19.7 mmol). The resulting mixture was stirred at this temperature for 12 hours and then carefully quenched with solid sodium bicarbonate (1.98g,23.6mmol) at 0 ℃. The volatiles were removed under reduced pressure and the residue was diluted with water (20mL) and extracted with ethyl acetate (20 mL. times.3). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude product 13. The crude product 13 was taken up in water with toluene (10mL × 2) and then used in the next step without further purification.

To a solution of crude product 13 and 4-dimethylaminopyridine (120mg, 0.983mmol) in dichloromethane (50mL) was added acetic anhydride (102uL, 1.081mmol) dropwise at 0 ℃. After 0.5 hour, the mixture was slowly warmed to 25 ℃ and stirred for 2 hours. Next, methanol (10mL) and triethylamine (2.5mL) were added. Stirring was continued for 12 hours at 25 ℃. The reaction was diluted with dichloromethane (50mL), washed with brine (30mL) and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.5: 1 to 2:1) to give 14(457mg, 91% yield in two steps) as a yellow solid.

R_f＝0.45(hexane:EtOAc＝2:1)；

m.p.(hexane/DCM):214-217℃；

[α]25D＝+192(c＝0.5,CH₂Cl₂)；

IR(film):2933,1735,1457,1096,1037,1018,735,694cm^-1；

¹H NMR(500MHz,CDCl₃)δ7.35–7.26(m,5H),5.07(s,1H),5.03(d,J＝9.8Hz,1H),4.57(d,J＝11.9Hz,1H),4.44(d,J＝11.9Hz,1H),4.14(dd,J＝9.8,3.4Hz,1H),3.97(dd,J＝4.0,1.4Hz,1H),2.56–2.41(m,2H),2.29–2.16(m,2H),2.08(s,3H),2.03(s,3H),2.02–1.97(m,1H),1.94–1.87(m,1H),1.85–1.77(m,2H),1.75(s,3H),1.53(s,3H),1.28(s,3H),1.20(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ170.2,154.2,142.6,139.2,138.6,130.4,128.4,127.5,127.5,123.4,94.8,80.8,78.4,75.9,75.7,71.4,47.5,41.5,30.5,30.5,25.4,24.4,22.8,22.4,21.2,20.5,19.8,18.5；

HRMS(ESI-TOF):calcd for C₃₀H₃₈ClO₇[M+Cl]^-545.2312,found 545.2302.

Example 10: synthesis of intermediate Compound 15

Intermediate compound 14(300mg,0.588mmol) was dissolved in dichloromethane (5mL) and added sequentiallyMolecular sieves (100mg), 4-methylmorpholine-N-oxide (206mg,1.763 mmol). The resulting reaction was cooled to 0 ℃ and then tetrapropylamine perruthenate (41.2mg,0.118mmol) was added. The reaction was warmed to 25 ℃ and stirred for 2 hours. The reaction mixture was then concentrated to dryness. Toluene (4mL) and 1, 5-diazabicyclo [4.3.0] were added sequentially]Non-5-ene (0.2 mL). The resulting mixture was refluxed at 110 ℃ for 12 hours and allowed to cool to 25 ℃ naturally. The reaction was quenched by addition of saturated aqueous ammonium chloride (10mL) and the system was extracted with ethyl acetate (10 mL. times.3). The combined organic phases were washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated, in particular the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.10: 1 to 5:1) to give 15(215mg, 73% yield) as a yellow solid.

R_f＝0.60(hexane:EtOAc＝3:1)；

m.p.(hexane/DCM):176-179℃；

[α]25D＝-20(c＝0.5,CH₂Cl₂)；

IR(film):2921,1796,1224,1099,1023,736,699cm^-1；

¹H NMR(500MHz,CDCl₃)δ7.32–7.26(m,5H),6.47(s,1H),4.64–4.55(m,2H),4.50(s,1H),3.99(dd,J＝12.0,4.3Hz,1H),2.55(dd,J＝19.9,11.2Hz,1H),2.47–2.41(m,1H),2.36–2.26(m,1H),2.20(s,3H),2.18–2.03(m,3H),2.00(s,3H),1.93–1.85(m,1H),1.80(s,3H),1.73–1.67(m,1H),1.32(s,3H),1.24(s,3H),1.17(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ205.1,169.6,153.6,142.7,138.1,132.8,128.6,128.5,128.0,127.9,127.8,94.4,81.8,76.4,76.4,70.5,59.4,40.5,32.3,29.9,27.3,24.3,22.4,22.1,22.0,21.2,20.1,18.9；

HRMS(ESI-TOF):calcd for C₃₀H₃₆NaO₇[M+Na]⁺531.2353,found 531.2364.

Example 11: synthesis of intermediate Compound 16

Intermediate compound 15(250mg,0.492mmol) was dissolved in dichloromethane (10 mL). Then, dry palladium/carbon (10%, 250mg) was added to the reaction solution, and the reaction solution was purged with air 3 times under a hydrogen atmosphere and stirred for 12 hours. The system was then cooled to-78 ℃. Triethylamine (1.38mL, 9.84mmol) and triethylsilyl trifluoromethanesulfonate (1.11mL, 4.92mmol) were added successively. After 2 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (20mL), warmed to 25 ℃, filtered through celite, and allowed to stand for stratification. The aqueous phase was further extracted with dichloromethane (10mL x 2). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.20: 1 to 5:1) to give the product 16 as a white solid (241mg, 92% yield).

R_f＝0.48(hexane:EtOAc＝5:1)；

m.p.(hexane/DCM):188-190℃；

[α]25D＝-23(c＝0.4,CH₂Cl₂)；

IR(film):2952,1718,1241,1038,971,872,741cm^-1；

¹H NMR(500MHz,CDCl₃)δ6.56(s,1H),4.52(s,1H),4.36(dd,J＝11.8,4.6Hz,1H),2.57(dd,J＝19.7,11.3Hz,1H),2.49–2.34(m,2H),2.17(s,3H),2.14–2.04(m,2H),2.01(s,3H),2.00(s,3H),1.97–1.77(m,3H),1.25(s,3H),1.25(s,3H),1.16(s,3H),0.89(t,J＝8.0Hz,9H),0.59–0.54(m,6H).

¹³C NMR(126MHz,CDCl₃)δ205.1,169.7,153.6,142.9,132.3,129.0,128.0,94.4,82.1,76.3,71.1,60.8,40.5,32.5,30.0,27.4,26.9,24.3,22.3,22.0,21.1,19.4,18.9,6.9,5.5；

HRMS(ESI-TOF):calcd for C₂₉H₄₄ClO₇Si[M+Cl]^-567.2550,found 567.2542.

Example 12: synthesis of intermediate Compound 17

Intermediate compound 16(60mg,0.113mmol), anhydrous sodium acetate (185mg,2.253mmol), diatomaceous earth (486mg), and pyridinium chlorochromate (486mg,2.253mmol) were suspended in benzene (12 mL). The mixture was heated to 80 ℃ and after stirring for 8h, the mixture was filtered over silica gel, washed with petroleum ether/ethyl acetate (1:1,10mL x 2) and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.40: 1 to 10:1) to give product 17(48mg, 75% yield) as a yellow gum.

R_f＝0.45(hexane:EtOAc＝10:1)；

[α]25D＝+60(c＝0.2,CH₂Cl₂)；

IR(film):2924,1700,1653,1559,1231,1044,853cm^-1；

¹H NMR(500MHz,CDCl₃)δ6.65(s,1H),4.87(s,1H),4.54(dd,J＝12.6,5.6Hz,1H),3.24(d,J＝19.6Hz,1H),3.03(d,J＝19.6Hz,1H),2.89(dd,J＝17.1,5.6Hz,1H),2.58(dd,J＝17.1,12.6Hz,1H),2.24(s,3H),2.06(s,3H),2.01(s,3H),1.45(s,3H),1.41(s,3H),1.35(s,3H),0.90(t,J＝7.9Hz,9H),0.60(q,J＝8.0Hz,6H)；

¹³C NMR(126MHz,CDCl₃)δ200.1,195.2,194.2,169.1,151.7,149.2,147.3,141.4,134.7,91.1,80.5,76.5,68.6,62.2,42.9,42.4,40.8,31.3,20.9,18.8,18.5,15.6,14.8,6.8,5.3；

HRMS(ESI-TOF):calcd for C₂₉H₃₉O₉Si[M-H]^-559.2369,found 559.2351.

Example 13: synthesis of intermediate Compound 18

To a solution of intermediate compound 17(40mg, 0.0713mmol) and p-toluenesulfonylhydrazide (66.4mg, 0.356mmol) in tetrahydrofuran (4mL) at 25 ℃ was added boron trifluoride etherate complex (80. mu.L, 0.713 mmol). The resulting mixture was heated to 65 ℃ for 12 hours and then cooled to 25 ℃. Then, tetrahydrofuran (4mL), solid sodium bicarbonate (90mg, 1.07mmol), and water (1mL) were added sequentially at 0 ℃. After that, sodium borohydride (27mg, 0.713mmol) was added slowly. After 30min, the reaction mixture was diluted with water (10mL) and extracted with ethyl acetate (10 mL. times.2). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.7: 1 to 2:1) to afford product 18 as a white foam (42mg, 81% yield).

R_f＝0.45(hexane:EtOAc＝2:1)；

[α]25D＝-120(c＝0.5,CH₂Cl₂)；

IR(film):2964,1793,1260,1092,1017,801,741cm^-1；

¹H NMR(500MHz,CD₂Cl₂)δ7.83(d,J＝8.4Hz,2H),7.41(s,1H),7.35(d,J＝8.0Hz,2H),6.43(s,1H),4.73(q,J＝6.1,5.3Hz,1H),4.66(s,1H),4.41(dd,J＝11.3,6.2Hz,1H),2.72(dd,J＝16.3,6.2Hz,1H),2.60(d,J＝6.7Hz,2H),2.43(s,3H),2.15(s,3H),2.06(s,3H),2.05(s,3H),1.25(s,3H),1.16(s,3H),1.12(s,3H),0.89(t,J＝7.9Hz,9H),0.60(q,J＝7.9Hz,6H).

¹³C NMR(126MHz,CD₂Cl₂)δ203.7,169.6,152.8,150.9,145.4,145.3,137.2,135.1,132.3,130.2,130.0,128.6,92.2,82.1,76.6,68.4,68.0,60.9,41.7,36.4,30.6,26.8,21.8,21.0,19.4,18.2,17.9,17.1,6.9,5.7；

HRMS(ESI-TOF):calcd for C₃₆H₅₁N₂O₁₀SSi[M+H]⁺731.3028,found 731.3039.

Example 14: synthesis of intermediate Compound 19

To a solution of intermediate compound 18(40mg,0.0547mmol) in dichloromethane (2mL) was added N- (trimethylsilyl) imidazole (40. mu.L, 0.274mmol) at 25 ℃ pieces. Stirring was continued for 2h at this temperature and the reaction mixture was quenched with saturated aqueous sodium bicarbonate (4mL) and extracted with dichloromethane (5mL x 3). The combined organic layers were washed with brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.20: 1 to 5:1) to give 19(37mg, 85% yield) as a colorless oil.

R_f＝0.55(hexane:EtOAc＝3:1)；

[α]25D＝-35(c＝0.2,CH₂Cl₂)；

IR(film):2958,1817,1724,1167,1016,824,733,678,589cm^-1；

¹H NMR(500MHz,CDCl₃)δ7.87(d,J＝8.4Hz,2H),7.55(s,1H),7.33(d,J＝8.0Hz,2H),6.44(s,1H),4.64(s,1H),4.58–4.54(m,1H),4.39(dd,J＝11.2,6.2Hz,1H),2.70(dd,J＝16.3,6.2Hz,1H),2.58–2.49(m,2H),2.44(s,3H),2.16(s,3H),2.08–2.03(m,1H),2.00(s,3H),1.91(s,3H),1.25(s,3H),1.17(s,3H),1.12(s,3H),0.87(t,J＝7.9Hz,9H),0.57(q,J＝7.9Hz,6H),0.11(s,9H)；

¹³C NMR(126MHz,CDCl₃)δ203.7,169.5,152.9,150.2,146.0,144.8,136.2,134.8,132.3,129.7,129.2,128.5,92.2,81.9,76.6,68.1,68.0,60.6,41.4,37.2,30.1,26.9,21.8,21.0,19.3,18.5,18.2,17.0,6.9,5.5,0.1；

HRMS(ESI-TOF):calcd for C₃₉H₅₉N₂O₁₀SSi₂[M+H]⁺803.3423,found 803.3439.

Example 15: synthesis of intermediate Compound 20

To a suspension of intermediate compound 19(50mg,0.0623mmol) and silica gel (250mg) in 1, 2-dichloroethane (1.5mL) at 0 deg.C was added catecholborane (66.1. mu.L, 0.623 mmol). The resulting mixture was stirred at 25 ℃ for 1.5 hours. Then, catechol borane (66.1. mu.L, 0.623mmol) was added thereto at 25 ℃. After 2h, the reaction mixture was cooled to 0 ℃ and sodium acetate trihydrate (254mg, 1.868mmol) was added carefully. Thereafter, the reaction mixture was gradually warmed to 25 ℃ and stirring was continued for 0.5 hour. Toluene (4mL) was added and the resulting mixture was heated to 110 ℃ and stirred for 12 hours. After cooling the system to 25 ℃, the reaction mixture was diluted with dichloromethane (20mL), washed with 10% aqueous potassium carbonate (8mL × 3) and brine (5mL) in that order, and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.40: 1 to 20:1) to give product 20 as a white solid (21mg, 54% yield).

R_f＝0.70(hexane:EtOAc＝5:1)；

m.p.(hexane/DCM):161-162℃；

[α]25D＝-80(c＝0.5,CH₂Cl₂)；

IR(film):2959,1813,1701,1233,1015,877,843,747cm^-1；

¹H NMR(500MHz,CDCl₃)δ6.40(s,1H),5.30(bs,1H),4.78–4.73(m,1H),4.39(d,J＝4.4Hz,1H),4.08(dd,J＝9.8,6.2Hz,1H),3.69(bs,1H),2.63(dd,J＝15.4,9.4Hz,1H),2.39–2.30(m,2H),2.17(s,3H),2.07(d,J＝1.4Hz,3H),2.05–2.02(m,1H),1.91(s,3H),1.25(s,3H),1.20(s,3H),1.17(s,3H),0.90(t,J＝8.0Hz,9H),0.56(q,J＝7.9Hz,6H),0.18(s,9H).

¹³C NMR(126MHz,CDCl₃)δ203.9,169.4,153.4,147.0,133.1,131.6,121.8,90.0,82.5,77.0,71.5,68.4,61.4,46.7,41.2,38.1,33.3,27.5,23.8,21.0,19.4,17.2,11.0,6.9,5.3,0.2.

HRMS(ESI-TOF):calcd for C₃₂H₅₂ClO₈Si₂[M+Cl]^-655.2895,found 655.2888.

Example 16: synthesis of intermediate Compound 21

To a solution of intermediate compound 20(50mg,0.0805mmol) in 1, 2-dichloroethane (DCE,4mL) was added 5,10,15, 20-tetraphenylporphyrin (0.99mg, 1.61. mu. mol) at 25 ℃. The reaction mixture was stirred under an oxygen atmosphere and irradiated using a Phillips fluorescent lamp as a light source. After 3 days, the light source was removed and then trimethylphosphine (1.0M) was added dissolved in tetrahydrofuran, 403. mu.L, 0.403 mmol). The reaction mixture was stirred for an additional 1 hour and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.40: 1 to 10:1) to give the product 21 as a colorless oil (42mg, 82% yield).

R_f＝0.55(hexane:EtOAc＝5:1)；

[α]25D＝-90(c＝0.5,CH₂Cl₂)；

IR(film):2957,1802,1700,1233,1017,881,851,749cm^-1；

¹H NMR(500MHz,CDCl₃)δ6.60(s,1H),5.59(s,1H),5.22(s,1H),4.77(dd,J＝9.2,3.1Hz,1H),4.56(dd,J＝11.1,4.8Hz,1H),4.30(d,J＝4.9Hz,1H),4.25(t,J＝3.1Hz,1H),4.01(d,J＝4.9Hz,1H),2.59(dd,J＝15.5,9.6Hz,1H),2.25(s,3H),2.17(s,3H),2.17–2.01(m,3H),1.20(s,3H),1.15(s,3H),1.11(s,3H),0.89(t,J＝7.9Hz,9H),0.59–0.54(m,6H),0.19(s,9H)；

¹³C NMR(126MHz,CDCl₃)δ203.7,169.4,153.3,146.9,143.0,131.1,117.0,90.3,82.3,76.6,75.5,69.5,68.8,63.1,42.5,40.7,38.4,38.4,27.4,21.1,19.3,17.5,10.1,6.9,5.4,0.1；

HRMS(ESI-TOF):calcd for C₃₂H₅₃O₉Si₂[M+H]⁺637.3223,found 637.3237.

Example 17: synthesis of intermediate Compound 22

To a solution of intermediate compound 21(72.0mg,0.113mmol) in pyridine (1mL) at 25 deg.C was added methanesulfonyl chloride (87.8. mu.L, 1.13 mmol). The resulting mixture was stirred at 25 ℃ for 5 hours. After this time, the mixture was cooled to 0 ℃ and osmium tetroxide (862. mu.L, 0.136mmol,40mg/mL in tetrahydrofuran) was added. The resulting mixture was slowly warmed to 25 ℃ and stirred for 0.5 hour. Thereafter, solid sodium bisulfite (360mg) and water (2mL) were added in this order. The resulting mixture was stirred at 25 ℃ for 12 hours. The system was cooled to 0 ℃, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10mL) and extracted with ethyl acetate (10mL × 3). The combined organic layers were washed with brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.7: 1 to 2:1) to give product 22(64.0mg, 75% yield) as a colorless oil.

R_f＝0.45(hexane:EtOAc＝2:1)；

[α]25D＝-32(c＝0.5,CH₂Cl₂)；

IR(film):2958,1751,1369,1233,1015,881,847,749cm^-1；

¹H NMR(500MHz,CDCl₃)δ6.57(s,1H),4.95–4.90(m,1H),4.84(t,J＝2.9Hz,1H),4.34(dd,J＝11.2,4.3Hz,1H),4.29(d,J＝4.8Hz,1H),4.11(dd,J＝10.9,2.6Hz,1H),3.61–3.53(m,3H),3.15(s,3H),3.11(dd,J＝15.3,6.1Hz,1H),2.74(s,1H),2.38(dd,J＝15.3,9.3Hz,1H),2.32(dt,J＝15.0,4.0Hz,1H),2.24(d,J＝1.5Hz,3H),2.17(s,3H),1.98–1.91(m,1H),1.26(s,3H),1.20(s,3H),1.17(s,3H),0.90(t,J＝7.9Hz,9H),0.60–0.51(m,6H),0.19(s,9H)；

¹³C NMR(126MHz,CDCl₃)δ202.1,169.2,153.5,148.8,129.9,91.2,82.5,81.5,76.0,73.9,68.5,68.4,62.9,61.4,44.8,41.5,38.7,36.6,34.8,26.1,21.0,20.3,16.2,12.5,6.8,5.1,0.2；

HRMS(ESI-TOF):calcd for C₃₃H₅₆NaO₁₃SSi₂[M+Na]⁺771.2872,found 771.2884.

Example 18: synthesis of intermediate Compound 23

To a solution of intermediate compound 22(30mg,0.0401mmol) in toluene (2mL) was added N, N-diisopropylethylamine (0.2mL) dropwise at 25 ℃. The resulting mixture was stirred at 110 ℃ for 18 hours. After that, the mixture was cooled to 25 ℃ and then sodium bicarbonate (33.6mg,0.401mmol), 4-dimethylaminopyridine (48.9mg,0.401mmol) and acetic anhydride (37.8. mu.L, 0.401mmol) were added in this order. The resulting mixture was refluxed at 110 ℃ for 8 hours. Thereafter, the system was cooled naturally to 25 ℃ and then to-40 ℃ and tetrabutylammonium fluoride (40.1. mu.L, 0.0401mmol, 1.0mL of tetrahydrofuran solution) was added. After 6h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (5mL) and extracted with dichloromethane (5mL × 3). The combined organic layers were washed with brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.5: 1 to 2:1) to give the product 23 as a white powder (8.0mg, 32% yield).

R_f＝0.25(hexane:EtOAc＝2:1)；

m.p.(hexane/DCM):202-204℃；

[α]25D＝-72(c＝0.5,CH₂Cl₂)；

IR(film):2959,1813,1718,1233,1011,832,734cm^-1；

¹H NMR(500MHz,CDCl₃)δ6.42(s,1H),4.97(d,J＝8.9Hz,1H),4.94–4.87(m,1H),4.62(d,J＝8.9Hz,1H),4.49–4.41(m,3H),3.47(d,J＝5.7Hz,1H),2.63–2.51(m,2H),2.28(d,J＝5.3Hz,1H),2.18(d,J＝1.4Hz,3H),2.16(s,3H),2.15(s,3H),1.93–1.84(m,1H),1.73(s,3H),1.19(s,3H),1.19(s,3H),0.91(t,J＝7.9Hz,9H),0.61–0.53(m,6H)；

¹³C NMR(126MHz,CDCl₃)δ202.4,171.3,169.3,153.2,147.2,131.0,90.4,84.3,81.4,79.7,76.5,76.4,71.7,67.2,60.4,44.3,41.1,38.0,35.8,25.8,22.8,21.0,20.0,15.9,10.2,6.9,5.3；

HRMS(ESI-TOF):calcd for C₃₁H₄₇O₁₁Si[M+H]⁺623.2882,found 623.2891.

Example 19: synthesis of Compound Taxol

To a solution of intermediate compound 23(40mg, 0.0642mm ol) in tetrahydrofuran (1.5mL) was added phenyl lithium (193. mu.L, 0.193mmol, 1.0M in diethyl ether) dropwise at-78 ℃. After the resulting mixture was stirred at this temperature for 0.5 hour, a solution of compound 24(73.6mg,0.193mmol) in tetrahydrofuran (1mL) was added. The reaction mixture was then gradually warmed to 25 ℃ and stirred for 1 hour. Pyridine hydrofluoride (0.2mL, 70% by weight of hydrogen fluoride) was added. The mixture was stirred at 25 ℃ for 2 hours, then cooled to 0 ℃ and quenched with saturated aqueous sodium bicarbonate (10 mL). The resulting mixture was extracted with ethyl acetate (10mL x 3). The combined organic layers were washed with brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography on silica gel (petroleum ether: ethyl acetate, vol.2: 1 to 1:3) to give the product Taxol (37.3mg, 68% yield) as a white powder.

R_f＝0.45(hexane:EtOAc＝1:3)；

m.p.(hexane/DCM):209-211℃；

[α]25D＝-50(c＝0.5,CHCl₃)；

IR(film):3492,1735,1246,1176,1073,982,709cm^-1；

¹H NMR(500MHz,CDCl₃)δ8.16–8.11(m,2H),7.77–7.71(m,2H),7.64–7.58(m,1H),7.54–7.46(m,5H),7.45–7.31(m,5H),7.00(d,J＝8.9Hz,1H),6.27(s,1H),6.23(td,J＝9.1,1.8Hz,1H),5.78(dd,J＝9.0,2.7Hz,1H),5.67(d,J＝7.0Hz,1H),4.94(dd,J＝9.6,2.3Hz,1H),4.79(dd,J＝5.3,2.7Hz,1H),4.44–4.36(m,1H),4.30(d,J＝8.4Hz,1H),4.19(d,J＝8.4Hz,1H),3.79(d,J＝7.0Hz,1H),3.62–3.57(m,1H),2.59–2.50(m,1H),2.48(d,J＝4.1Hz,1H),2.38(s,3H),2.37–2.26(m,2H),2.24(s,3H),1.92–1.84(m,1H),1.79(d,J＝1.5Hz,3H),1.68(s,3H),1.24(s,3H),1.14(s,3H)；

¹³C NMR(126MHz,CDCl₃)δ203.8,172.9,171.4,170.5,167.2,167.1,142.1,138.1,133.9,133.7,133.3,132.1,130.4,129.3,129.2,128.9,128.9,128.5,127.2,127.2,84.5,81.3,79.2,76.6,75.7,75.1,73.3,72.5,72.3,58.7,55.2,45.7,43.3,35.8,35.7,27.0,22.8,22.0,21.0,15.0,9.7；

HRMS(ESI-TOF):calcd for C₄₇H₅₂NO₁₄[M+H]⁺854.3382,found 854.3388.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the present invention as set forth in the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.