Preparation method of important intermediate of paclitaxel

Abstract

According to the technical scheme, the preparation method comprises the following steps: (1) taking 10-DAB as a raw material, and carrying out 10-site acetylation to obtain an intermediate I; (2) dissolving the intermediate I in dichloromethane, adding pyridine for dissolving, dropwise adding chloroformic acid-2, 2, 2-trichloroethyl ester, and reacting to obtain an intermediate II; (3) dissolving the intermediate II in methylbenzene, adding (4S, 5R)-2, 4-diphenyl-4, 5-dihydrooxazole-5-carboxylic acid and 4-dimethylaminopyridine, adding a condensing agent, and reacting to obtain an intermediate III; and (4) dissolving the intermediate III in tetrahydrofuran or acetone, adding acid, stirring to react, adding alkali after the reaction is finished, and continuously reacting to obtain the 7-trichloroethoxycarbonyl paclitaxel. The synthesis method is simple, reaction conditions are easy to control, each step does not need column chromatography, the product with the purity of more than 99% can be obtained by recrystallizing the crude product, the operation links are reduced, the production cost is saved, and the method is very suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemicals, and in particular to a method for preparing an important intermediate of paclitaxel. Background Art

[0002] Paclitaxel, a natural anticancer drug, is currently the best anticancer drug in the world with a broad spectrum, few side effects and a completely new mechanism of action. It has been widely used in clinical practice for breast cancer and ovarian cancer, and also has certain effects on lung cancer, colorectal cancer, melanoma, head and neck cancer, lymphoma and brain cancer. As a diterpene alkaloid compound with anticancer activity, paclitaxel has been greatly favored by botanists, chemists, pharmacologists and molecular biologists for its novel and complex chemical structure, extensive and significant biological activity, completely new and unique mechanism of action and scarce natural resources, making it a world-renowned anticancer star and research focus in the second half of the 20th century.

[0003] Due to the long growth cycle of yew, it is impossible to meet the growing market demand simply by extracting natural paclitaxel from yew. People must find other ways to solve the problem of a large supply of paclitaxel. Chemical synthesis is a way that people first think of to solve the problem of paclitaxel drug source. Current chemical synthesis methods are divided into total synthesis and semi-synthesis. Total synthesis is expensive, although it has important theoretical significance, it is not suitable for large-scale industrial production. Practice has proved that semi-synthetic paclitaxel is the most valuable method.

[0004] At present, there are two main methods for the semi-synthesis of paclitaxel: one is based on 10-deacetylbaccatin III (10-DAB) as a raw material, and the other is based on 10-deacetylpaclitaxel (10-DAT) as a raw material. 10-Deacetylbaccatin III is present in a high concentration in Taxus chinensis, and is more suitable as a starting material for the chemical semi-synthesis of paclitaxel than 10-deacetylpaclitaxel in terms of price and availability.

[0005] There are many semi-synthetic methods of paclitaxel, mainly using 10-DAB as the starting material, protecting the 7-hydroxyl group, acetylation of the 10-hydroxyl group, and then condensing with the side chain and deprotecting to obtain paclitaxel. The route in the literature [Denis JN, Greene AE, Guenard D, et al. Highly efficient, practical approach to natural taxol [J]. Journal of the American Chemical Society, 1988, 110 (17): 5917-5919.] is the method used. The disadvantage of this route is that triethyl chlorosilane is used to protect the 7-hydroxyl group, triethyl chlorosilane needs to be greatly excessive, the reaction time is long, and low temperature is required to control the selectivity of triethyl chlorosilane, resulting in a very low yield and easy to produce by-products, which is not conducive to industrial production. Summary of the invention

[0006] In view of the above-mentioned shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing an important intermediate of paclitaxel, which has the advantages of short total process reaction time, loose reaction conditions, less by-products, high reaction yield, and is suitable for large-scale industrial production of 7-trichloroethoxycarbonyl paclitaxel.

[0007] The above technical objectives of the present invention are achieved through the following technical solutions:

[0008] A method for preparing an important intermediate of paclitaxel comprises the following steps:

[0009] Step S1 (acetylation of 10-DAB): 10-DAB is dissolved in tetrahydrofuran, cerium trichloride is added, acetic anhydride is added dropwise, and the mixture is stirred for reaction. After the stirring reaction is completed, water and dichloromethane are added to the stirred reaction product for extraction, and then the organic phase is collected, saturated sodium bicarbonate is added to the organic phase for neutralization until the organic phase is neutral, and the organic phase is concentrated and filtered to obtain intermediate I;

[0010] Step S2 (protection chain on intermediate I): intermediate I is dissolved in dichloromethane, and then pyridine is added to the mixed solution until the mixed solution is clear, and 2,2,2-trichloroethyl chloroformate is added dropwise to the mixed solution, and the mixture is stirred for reaction. After the stirring reaction is completed, water and dichloromethane are extracted, and the organic phase is collected, and the organic phase is acid-washed, alkali-washed, and salt-washed, anhydrous sodium sulfate is added to the organic phase, and the organic phase is dried and filtered, and the filtrate is concentrated and filtered to obtain intermediate II;

[0011] Step S3 (adding a side chain to intermediate II): intermediate II is dissolved in toluene, (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid, 4-dimethylaminopyridine and a condensing agent are added to intermediate II, and then stirred for reaction. After the reaction is completed, water and ethyl acetate are added to the mixture to quench the reaction. After the quenching reaction is completed, the reaction product is filtered to obtain a filtrate, the filtrate is washed with dilute hydrochloric acid and then extracted with brine, the extract obtains an organic phase, and then the organic phase is concentrated, methanol is added to the organic phase concentrate for pulping, and then filtered to obtain intermediate III;

[0012] Step S4 (ring-opening rearrangement of intermediate III): intermediate III is dissolved in tetrahydrofuran or acetone, acid is added to the solution, and then the solution is stirred for reaction. After the reaction is completed, acid is added to the solution and the stirring reaction is continued. After the reaction is completed, a concentrated reaction solution is obtained, water and dichloromethane are added to the concentrated reaction solution to extract an extract, and then the extract is dried over anhydrous sodium sulfate. Finally, the extract is filtered and concentrated to obtain a crude product of 7-trichloroethoxycarbonyl paclitaxel. The crude product of 7-trichloroethoxycarbonyl paclitaxel is recrystallized to obtain 7-trichloroethoxycarbonyl paclitaxel with a purity of >99%.

[0013] Furthermore, in step S1, the molar ratio of acetic anhydride to 10-DAB is 1 to 20:1; the molar ratio of cerium trichloride to 10-DAB is 0.2 to 1:1; the weight ratio of tetrahydrofuran to 10-DAB is 10 to 20:1; the stirring reaction temperature ranges from -5 to 50°C, and the stirring reaction time is controlled at 1 to 5 hours.

[0014] Furthermore, in step S2, the molar ratio of 2,2,2-trichloroethyl chloroformate to intermediate I is 1 to 5:1; the weight ratio of dichloromethane to intermediate I is 3 to 10:1; and the weight ratio of pyridine to intermediate I is 4.9 to 5.2:1.

[0015] Furthermore, in step S2, the temperature range of the stirring reaction is -10 to 10°C, and the time range of the stirring reaction is 0.5 to 2 hours.

[0016] Furthermore, in step S3, the molar ratio of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid to intermediate II is 2 to 5:1; the molar ratio of 4-dimethylaminopyridine to intermediate II is 0.5 to 2:1; and the weight ratio of toluene to intermediate II is 10 to 20:1.

[0017] Furthermore, in step S3, the condensing agent is selected from one or more combinations of N'N-dicyclohexylcarbodiimide, N'N-diisopropylcarbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and the molar ratio of the condensing agent to the intermediate II is 3 to 5:1.

[0018] Furthermore, in step S3, the temperature range of the stirring reaction is 0 to 20° C., and the reaction time range of the stirring reaction is 1 to 3 hours.

[0019] Furthermore, in step S4, the acid is one or more combinations of hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, formic acid, trifluoroboric acid and acetic acid; the molar ratio of the acid to the intermediate III is 1.5 to 3:1; the acid reaction temperature range is 10 to 30° C.; and the acid reaction time range is 2 to 5 hours.

[0020] Furthermore, in step S4, the base is one or more combinations of sodium bicarbonate, sodium carbonate, potassium bicarbonate, triethylamine, sodium hydroxide and potassium hydroxide; the base reaction temperature range is 20 to 70° C.; and the base reaction time range is 3 to 8 hours.

[0021] Furthermore, in step S4, the recrystallization solvent used for the crude 7-trichloroethoxycarbonyl paclitaxel is one or more of water, methanol, ethanol, dichloromethane, acetone, n-heptane, n-hexane and petroleum ether, and the volume mass ratio of the recrystallization solvent to the crude 7-trichloroethoxycarbonyl paclitaxel is 5 to 10:1.

[0022] In summary, the present invention has the following beneficial effects:

[0023] 1. A method is adopted in which the 10-hydroxyl group is first acetylated, a protective chain is added to the intermediate I, a side chain is added to the intermediate II, and the intermediate III is ring-opened and rearranged to protect the 7-hydroxyl group. This avoids the situation in which the 10-hydroxyl group is also protected when the 7-hydroxyl group is protected. The preparation method has a strong purpose, few by-products, and the yield of the target product is increased as much as possible.

[0024] 2. The reaction conditions of each step are low, and can be carried out evenly under normal pressure and room temperature. The reaction conditions are easy to control, and each step does not require column chromatography. The crude product can be recrystallized to obtain a product with a purity of >99%, which reduces the operation links, saves production costs, and is suitable for industrial production.

[0025] 3. In step S1, cerium trichloride is selected as a catalyst. Cerium trichloride itself is highly efficient and specific. The hydroxyl group at position 10 undergoes acetylation while the hydroxyl group at position 7 does not react, and the yield of the reaction product is high.

[0026] 4. In step S3, intermediate II reacts with (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid under the action of a condensing agent to produce dicyclohexyl urea which is insoluble in organic solvents and water and can be removed by suction filtration without affecting subsequent reactions, thereby further improving the yield of intermediate III. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a schematic diagram of the steps of the preparation method of the important intermediate of paclitaxel.

[0028] Figure 2 This is the MS spectrum of 7-trichloroethoxycarbonylpaclitaxel in Example 1 (positive ion mode).

[0029] Figure 3 is the 7-trichloroethoxycarbonyl paclitaxel in Example 1 1 H NMR spectrum.

[0030] Figure 4 It is 7-trichloroethoxycarbonylpaclitaxel 13 C NMR spectrum. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution proposed in the present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods. According to the following description, the advantages and features of the present invention will be clearer. In order to make the purpose, features and advantages of the present invention more obvious and easy to understand, please refer to the accompanying drawings. It should be noted that the drawings in this specification are only used to match the contents disclosed in the specification for people familiar with this technology to understand and read, and are not used to limit the limiting conditions for the implementation of the present invention, so they have no technical substantive significance. Any modification of the steps, changes in the proportional relationship or adjustment of the size should still fall within the scope of the technical content disclosed in the present invention without affecting the effects that the present invention can produce and the purposes that can be achieved.

[0032] Embodiment 1:

[0033] Step S1: 10-DAB acetylation: 10-DAB (50 g, 91.9 mmol) was dissolved in 600 ml of tetrahydrofuran (density of tetrahydrofuran is 0.888 g / cm 3 , the weight ratio of tetrahydrofuran to 10-DAB is 10.66:1, cerium trichloride (5g, 20.3mmol) is added, the molar ratio of cerium trichloride to 10-DAB is 0.221:1, the reaction solution is heated to 15-25°C, acetic anhydride (14.07g, 1.38mol) is added dropwise, the molar ratio of acetic anhydride to 10-DAB is 15.01:1, and the reaction is kept warm for 2h. After the reaction is completed, the filter cake is filtered, 400g of dichloromethane and 300g of purified water are added to the filter cake to dissolve, extract, and collect the organic phase. The organic phase is neutralized with saturated sodium bicarbonate solution until no obvious bubbles emerge, stirred and allowed to stand for stratification, the organic phase is washed with 600g of purified water and 600g of saturated brine successively and then allowed to stand for stratification, the organic phase is concentrated until a large amount of white solid precipitates, and 52.8g of intermediate I is obtained after filtration and drying, with a yield of 97.96%.

[0034] S2: Dissolve intermediate I (52.8 g, 90.07 mmol) in 350 ml of dichloromethane. The density of dichloromethane is 1.368 g / cm 3 The weight ratio of dichloromethane to intermediate I is 9.06:1. 270 ml of pyridine is added to dissolve. The density of pyridine is 0.983 g / cm 3 , the weight ratio of pyridine to intermediate I is 5.02:1, the temperature is lowered to -10~0℃, chloroformic acid-2,2,2-trichloroethyl ester (85.81g, 405mmol) is added dropwise, the molar ratio of chloroformic acid-2,2,2-trichloroethyl ester to intermediate I is 4.49:1, and the temperature is kept warm for 1h. After the reaction is completed, 50ml of water and dichloromethane are added to quench the reaction, and the pH is adjusted to 2 with 1% dilute hydrochloric acid. The organic phase is washed with 200ml of saturated brine and then dried with anhydrous sodium sulfate. The organic phase is concentrated after suction filtration, and the concentrate is slurried with n-heptane and suction filtered and dried to obtain 62.70g of intermediate II, with a yield of 92.11%.

[0035] S3: Dissolve intermediate II (62.70 g, 82.5 mmol) in 850 ml toluene. The density of toluene is 0.872 g / cm 3 , the weight ratio of toluene to intermediate II is 11.8:1, (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid (55.47 g, 206 mmol) and 4-dimethylaminopyridine (5.04 g, 41.25 mmol) are added, the molar ratio of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid to intermediate II is 2.5:1, the molar ratio of 4-dimethylaminopyridine to intermediate II is 0.5:1, the temperature is lowered to 5-15°C, N'N-dicyclohexylcarboximide (50.88 g, 247 mmol) is added dropwise, the molar ratio of N'N-dicyclohexylcarboximide to intermediate II is 2.99:1, and the reaction is kept warm for 1.5 hours after the addition is completed. After the reaction, the reaction liquid was filtered, and the filtrate was adjusted to pH 4 with 0.2 mol / L dilute hydrochloric acid. The organic phase was washed with 200 ml of saturated sodium bicarbonate and 200 ml of saturated brine in sequence, and dried with anhydrous sodium sulfate. After filtration, the organic phase was concentrated to an oily substance, and methanol was added for pulping, and then filtered and dried to obtain 77.17 g of intermediate III, with a yield of 92.70%.

[0036] S4: Dissolve the intermediate III (77.17 g, 76.47 mmol) in 480 ml of tetrahydrofuran, add p-toluenesulfonic acid (19.68 g, 115.75 mmol), the molar ratio of p-toluenesulfonic acid to intermediate III is 1.51:1, keep the temperature at 20-25°C for 3 h after addition, add triethylamine (23.15 g, 229.41 mmol), the molar ratio of triethylamine to intermediate III is 3:1, heat to 70°C after addition, and reflux for 4 h. After the reaction, concentrate the reaction solution, add 200 ml of purified water and 200 ml of dichloromethane for extraction, collect the organic phase, wash the organic phase with 350 ml of purified water and 350 ml of saturated brine in turn, add anhydrous sodium sulfate for drying, filter and concentrate the organic phase to obtain 78.54 g of crude 7-trichloroethoxycarbonylpaclitaxel. 7-Trichloroethoxycarbonylpaclitaxel crude product was added with 500 ml of methanol. The density of methanol is 0.791 g / cm 3 The volume mass ratio of methanol to crude 7-trichloroethoxycarbonyl paclitaxel was 5.04:1, heated to reflux and dissolved, cooled naturally for crystallization, cooled to room temperature and then cooled to 0°C, filtered and dried after crystallization for 2 hours to obtain 68.49g of 7-trichloroethoxycarbonyl paclitaxel, with a yield of 87.20% and a purity of 99.2%. The product was confirmed to have a correct structure by MS, 1H NMR, and 13C NMR.

[0037] The prepared 7-trichloroethoxycarbonyl paclitaxel has a structural formula as shown in formula (1):

[0038]

[0039] The preparation method is as follows Figure 1 The process shown is carried out.

[0040] like Figure 2 As shown in the MS spectrum of 7-trichloroethoxycarbonylpaclitaxel in this example, its mass-to-charge ratio m / z=1050.2[M+Na] + , it can be inferred that the molecular weight is 1027.2, which is consistent with the target compound.

[0041] As attached Figure 3The 1HNMR spectrum of 7-trichloroethoxycarbonylpaclitaxel in this example, wherein, 1HNMR (500 MHz, CDCl3): δ (ppm) = 8.10 (2H, d, J = 7.5 Hz, H23), 7.73 (2H, d, J = 7.5 Hz, H40), 7.60 (1H, t, J = 7.4 Hz, H25), 7.48 (2H, overlapped with H42, H34, H24), 7.48 (2H, overlapped with H42, H24, H34), 7.48 (1H, overlapped with H42, H24, H42), 7.36 (2H, overlapped with H41, H36, H35), 7.36 (2H, overlapped with H35, H36, H41), 7.36 (1H, overlapped with H35,H41,H36),7.13(1H,d,J=8.9Hz,H37),6.33(1H,s,H10),6.17(1H,t,J=8.6Hz,H13),5.78(1H,dd,J=2.1Hz,8.9Hz,H32),5.67(1H ,d,J=6.9Hz,H2),5.53(1H,dd,J=7.4Hz,10.6Hz,H7),5.02(1H,d,J=12Hz,H44),4.93(1H,d,J=9.1Hz,H5),4.78(1H,s,H31),4.64(1H, d,J=12Hz,H44),4.30(1H,d,J=8.5Hz,H20),4.18(1H,d,J=8.5Hz,H20),3.92(1H,d,J=6.9Hz,H3),3.80(1H,d,J=3.9Hz,31-OH),2.61( 1H,m,H6),2.37(3H,s,H27),2.32(2H,d,J=8.9Hz,H14),2.15(3H,s,H29),2.03(1H,m,H6),1.97(1H,brs,1-OH),1.83(3H,overlapped with H19,H18),1.83(3H,overlapped with H18,H19),1.19(3H,s,H16 / H17),1.15(3H,s,H16 / H17).

[0042] As attached Figure 4The 13C NMR spectrum of 7-trichloroethoxycarbonylpaclitaxel in this embodiment, wherein, 13C NMR (500MHz, CDCl3): δ (ppm) = 201.331, 172.483, 170.407, 169.061, 167.090, 166.750, 153.145, 140.617, 137.959, 133.717, 133.628, 132.971, 131.874, 130.111, 129.028, 128.919, 128.682, 128.633, 128.253, 127.00 9,94.479,83.688,80.825,78.500,77.257,77.224,77.002,76.747,76.416,76.341,75.264,74.251,73.161,72.090,56.110,54.978,46.858,43.169,35.549,33.185,26.482,22.457,20.935,20.677,14.487,10.670.

[0043] In summary, the target product prepared by this method is 7-trichloroethoxycarbonyl paclitaxel.

[0044] Embodiment 2:

[0045] S1: Take 10-DAB (50 g, 91.9 mmol) and dissolve it in 750 ml of tetrahydrofuran. The density of tetrahydrofuran is 0.888 g / cm 3 , the weight ratio of tetrahydrofuran to 10-DAB is 13.32:1, cerium trichloride (11.32g, 45.95mmol) is added, the molar ratio of cerium trichloride to 10-DAB is 0.5:1, the reaction solution is heated to -5~10℃, acetic anhydride (4.69g, 459.5mmol) is added dropwise, the molar ratio of acetic anhydride to 10-DAB is 5:1, and the reaction is kept warm for 5h. After the reaction is completed, the filter is filtered, 400g of dichloromethane and 300g of purified water are added to the filter cake to dissolve, extract, and collect the organic phase. The organic phase is neutralized with saturated sodium bicarbonate solution until no obvious bubbles emerge, stirred and allowed to stand for stratification, the organic phase is washed with 600g purified water and 600g saturated brine successively and then allowed to stand for stratification, the organic phase is concentrated until a large amount of white solid precipitates, and 47.62g of intermediate I is obtained after filtration and drying, with a yield of 88.43%.

[0046] S2: Dissolve intermediate I (47.62 g, 81.24 mmol) in 200 ml of dichloromethane. The density of dichloromethane is 1.368 g / cm 3The weight ratio of dichloromethane to intermediate I is 5.75:1. 250 ml of pyridine is added to dissolve. The density of pyridine is 0.983 g / cm 3 , the weight ratio of pyridine to intermediate I is 5.16:1, the temperature is lowered to -5~5℃, 2,2,2-trichloroethyl chloroformate (51.64g, 243.7mmol) is added dropwise, the molar ratio of 2,2,2-trichloroethyl chloroformate to intermediate I is 2.99:1, and the temperature is kept warm for 0.5h. After the reaction is completed, 50ml of water and dichloromethane are added to quench the reaction, and the pH is adjusted to 2 with 1% dilute hydrochloric acid. The organic phase is washed with 200ml of saturated brine and then dried with anhydrous sodium sulfate. The organic phase is concentrated after suction filtration, and the concentrate is slurried with n-heptane and suction filtered and dried to obtain 54.90g of intermediate II, with a yield of 88.92%.

[0047] S3: Dissolve intermediate II (54.90 g, 72.23 mmol) in 600 ml toluene. The density of toluene is 0.872 g / cm 3 , the weight ratio of toluene to intermediate II is 9.53:1, (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid (58.28 g, 144.46 mol) and 4-dimethylaminopyridine (8.82 g, 72.23 mmol) are added, the molar ratio of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid to intermediate II is 2:1, the molar ratio of 4-dimethylaminopyridine to intermediate II is 1:1, the temperature is lowered to 0-5°C, N'N-diisopropylcarbodiimide (27.35 g, 216.69 mmol) is added dropwise, the molar ratio of N'N-diisopropylcarbodiimide to intermediate II is 2.99:1, and the reaction is kept warm for 3 hours after the addition is completed. After the reaction, the reaction liquid was filtered, and the filtrate was adjusted to pH 4 with 0.2 mol / L dilute hydrochloric acid. The organic phase was washed with 200 ml of saturated sodium bicarbonate and 200 ml of saturated brine in sequence, and dried with anhydrous sodium sulfate. After filtration, the organic phase was concentrated to an oily substance, and methanol was added for pulping, and then filtered and dried to obtain 60.67 g of intermediate III, with a yield of 83.24%.

[0048] S4: Dissolve the intermediate III (60.67g, 60.12mmol) in 500ml acetone, add formic acid (5.53g, 120.24mmol), the molar ratio of formic acid to intermediate III is 2:1, keep the temperature at 10-20℃ for 5h, add sodium bicarbonate (15.15g, 180.36mmol), the molar ratio of sodium bicarbonate to intermediate III is 3:1, keep the temperature at 20-30℃ for 8h. After the reaction, concentrate the reaction solution and add 200ml purified water and 200ml dichloromethane for extraction, collect the organic phase, wash the organic phase with 350ml purified water and 350ml saturated brine in turn, add anhydrous sodium sulfate for drying, filter and concentrate the organic phase to obtain 61.74g of crude 7-trichloroethoxycarbonylpaclitaxel. Add 512ml methanol to the crude 7-trichloroethoxycarbonylpaclitaxel, the density of methanol is 0.791g / cm 3 The volume mass ratio of methanol to crude 7-trichloroethoxycarbonyl paclitaxel was 6.56:1. The mixture was heated to reflux and dissolved, and the temperature was naturally reduced to crystallize. After the temperature dropped to room temperature, the temperature was further reduced to 0°C. After crystallization for 2 hours, 55.20 g of 7-trichloroethoxycarbonyl paclitaxel was obtained by suction filtration and drying. The yield was 89.40% and the purity was 98.3%.

[0049] Embodiment 3:

[0050] S1: 10-DAB (50 g, 91.9 mmol) was dissolved in 1000 ml of tetrahydrofuran, the density of which is 0.888 g / cm 3 , the weight ratio of tetrahydrofuran to 10-DAB is 17.76:1, cerium trichloride (22.65g, 91.9mmol) is added, the molar ratio of cerium trichloride to 10-DAB is 1:1, the reaction solution is heated to 30-50°C, acetic anhydride (18.78g, 1.84mol) is added dropwise, the molar ratio of acetic anhydride to 10-DAB is 20:1, and the reaction is kept warm for 1h. After the reaction is completed, the filter is filtered, 400g of dichloromethane and 300g of purified water are added to the filter cake to dissolve, extract, and collect the organic phase. The organic phase is neutralized with saturated sodium bicarbonate solution until no obvious bubbles emerge, stirred and allowed to stand for stratification, the organic phase is washed with 600g of purified water and 600g of saturated brine successively and then allowed to stand for stratification, the organic phase is concentrated until a large amount of white solid precipitates, and 45.78g of intermediate I is obtained after suction filtration and drying, with a yield of 85.01%.

[0051] S2: Dissolve intermediate I (45.78 g, 78.10 mmol) in 250 ml of dichloromethane. The density of dichloromethane is 1.368 g / cm 3 The weight ratio of dichloromethane to intermediate I is 7.47:1. 232 ml of pyridine is added to dissolve. The density of pyridine is 0.983 g / cm 3, the weight ratio of pyridine to intermediate I is 4.98:1, the temperature is lowered to 5-10°C, chloroformic acid-2,2,2-trichloroethyl ester (82.73g, 390.5mmol) is added dropwise, the molar ratio of chloroformic acid-2,2,2-trichloroethyl ester to intermediate I is 5:1, and the temperature is kept for 1h. After the reaction is completed, 50ml of water and dichloromethane are added to quench the reaction, and the pH is adjusted to 2 with 1% dilute hydrochloric acid. The organic phase is washed with 200ml of saturated brine and then dried with anhydrous sodium sulfate. The organic phase is concentrated after suction filtration, and the concentrate is slurried with n-heptane and suction filtered and dried to obtain 53.81g of intermediate II, with a yield of 90.65%.

[0052] S3: Dissolve intermediate II (53.81 g, 70.79 mmol) in 1.2 L toluene. The density of toluene is 0.872 g / cm 3 , the weight ratio of toluene to intermediate II is 19.45:1, (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid (114.23 g, 283.16 mol) and 4-dimethylaminopyridine (12.97 g, 106.2 mmol) are added, the molar ratio of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid to intermediate II is 4:1, the molar ratio of 4-dimethylaminopyridine to intermediate II is 1.5:1, the temperature is lowered to 15-20°C, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (40.71 g, 212.37 mmol) is added dropwise, the molar ratio of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to intermediate II is 3:1, and the reaction is kept warm for 1h after the addition is completed. After the reaction, the reaction liquid was filtered, and the filtrate was adjusted to pH 4 with 0.2 mol / L dilute hydrochloric acid. The organic phase was washed with 200 ml of saturated sodium bicarbonate and 200 ml of saturated brine in sequence, and dried with anhydrous sodium sulfate. After filtration, the organic phase was concentrated to an oily substance, and methanol was added for pulping, and then filtered and dried to obtain 62.47 g of intermediate III, with a yield of 87.44%.

[0053] S4: Dissolve the intermediate III (62.47 g, 61.90 mmol) in 500 ml of tetrahydrofuran, add hydrochloric acid (4.51 g, 123.8 mmol), the molar ratio of hydrochloric acid to intermediate III is 2:1, keep the temperature at 25-30°C for 2 h, add potassium bicarbonate (18.59 g, 185.7 mmol), the molar ratio of potassium bicarbonate to intermediate III is 3:1, keep the temperature at 35-55°C for 6 h. After the reaction, concentrate the reaction solution, add 200 ml of purified water and 200 ml of dichloromethane for extraction, collect the organic phase, wash the organic phase with 350 ml of purified water and 350 ml of saturated brine in turn, add anhydrous sodium sulfate for drying, filter and concentrate the organic phase to obtain 63.58 g of crude 7-trichloroethoxycarbonylpaclitaxel. 625 ml of methanol was added to the crude 7-trichloroethoxycarbonyl paclitaxel, the volume mass ratio of the crude 7-trichloroethoxycarbonyl paclitaxel to methanol was 7.77:1, and the mixture was heated to reflux to dissolve clearly, and the temperature was naturally reduced to crystallize. After the temperature dropped to room temperature, the temperature was further reduced to 0°C. After crystallization for 2 hours, 47.28 g of 7-trichloroethoxycarbonyl paclitaxel was obtained by suction filtration and drying. The yield was 74.36% and the purity was 99.0%.

[0054] Analysis of test results:

[0055] The final product yield of Example 1 was 87.20% and the purity was 99.2%.

[0056] The final product yield of Example 2 was 89.40% and the purity was 98.3%.

[0057] The final product yield of Example 3 was 74.36% and the purity was 99.0%.

[0058] The solution described in Example 1 is the best solution:

[0059] The molar ratio of acetic anhydride to 10-DAB is preferably 10 to 15:1;

[0060] The molar ratio of cerium trichloride to 10-DAB is preferably 0.2:1;

[0061] The weight ratio of tetrahydrofuran to 10-DAB is preferably 10:1;

[0062] The molar ratio of 2,2,2-trichloroethyl chloroformate to intermediate I is preferably 4 to 5:1;

[0063] The weight ratio of methyl chloride to intermediate I is preferably 5:1;

[0064] The weight ratio of pyridine to intermediate I is preferably 4.9 to 5.2:1;

[0065] The preferred reaction temperature in step S2 is -10 to 0°C, and the reaction time is 0.5 to 1 h;

[0066] The molar ratio of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid to intermediate II is 2.5:1;

[0067] The molar ratio of 4-dimethylaminopyridine to intermediate II is preferably 0.5:1;

[0068] The weight ratio of toluene to intermediate II is preferably 10:1;

[0069] The preferred reaction temperature in step S3 is 5 to 15° C., and the reaction time is 1.5 to 2 h.

[0070] The molar ratio of the acid to the intermediate III is preferably 1.5:1, the acid reaction temperature range is preferably 20 to 25°C, and the reaction time is preferably 2 to 3 hours;

[0071] The molar ratio of the base to the intermediate III is preferably 3:1, the base reaction temperature range is preferably 60 to 70°C, and the reaction time is preferably 4 to 5 hours.

[0072] The optimal solvent for recrystallization is methanol, and the volume mass ratio of methanol to crude 7-trichloroethoxycarbonylpaclitaxel is preferably 6:1.

[0073] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0074] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing an important intermediate of paclitaxel, characterized in that: The following steps are involved: Step S1 (acetylation of 10-DAB): 10-DAB is dissolved in tetrahydrofuran, cerium trichloride is added, acetic anhydride is added dropwise, and the mixture is stirred for reaction. After the stirring reaction is completed, water and dichloromethane are added to the stirred reaction product for extraction, and then the organic phase is collected, saturated sodium bicarbonate is added to the organic phase for neutralization until the organic phase is neutral, and the organic phase is concentrated and filtered to obtain intermediate I; Step S2 (protection chain on intermediate I): intermediate I is dissolved in dichloromethane, and then pyridine is added to the mixed solution until the mixed solution is clear, and 2,2,2-trichloroethyl chloroformate is added dropwise to the mixed solution, and the mixture is stirred for reaction. After the stirring reaction is completed, water and dichloromethane are extracted, and the organic phase is collected, and the organic phase is acid-washed, alkali-washed, and salt-washed, anhydrous sodium sulfate is added to the organic phase, and the organic phase is dried and filtered, and the filtrate is concentrated and filtered to obtain intermediate II; Step S3 (adding a side chain to intermediate II): intermediate II is dissolved in toluene, (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid, 4-dimethylaminopyridine and a condensing agent are added to intermediate II, and then stirred for reaction. After the reaction is completed, water and ethyl acetate are added to the mixture to quench the reaction. After the quenching reaction is completed, the reaction product is filtered to obtain a filtrate, the filtrate is washed with dilute hydrochloric acid and then extracted with brine, the extract obtains an organic phase, and then the organic phase is concentrated, methanol is added to the organic phase concentrate for pulping, and then filtered to obtain intermediate III; Step S4 (ring-opening rearrangement of intermediate III): intermediate III is dissolved in tetrahydrofuran or acetone, acid is added to the solution, and then the solution is stirred for reaction. After the reaction is completed, acid is added to the solution and the stirring reaction is continued. After the reaction is completed, a concentrated reaction solution is obtained, water and dichloromethane are added to the concentrated reaction solution to extract an extract, and then the extract is dried over anhydrous sodium sulfate. Finally, the extract is filtered and concentrated to obtain a crude product of 7-trichloroethoxycarbonyl paclitaxel. The crude product of 7-trichloroethoxycarbonyl paclitaxel is recrystallized to obtain 7-trichloroethoxycarbonyl paclitaxel with a purity of >99%.

2. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S1, the molar ratio of acetic anhydride to 10-DAB is 1 to 20:1; the molar ratio of cerium trichloride to 10-DAB is 0.2 to 1:1; the weight ratio of tetrahydrofuran to 10-DAB is 10 to 20:1; the stirring reaction temperature range is -5 to 50°C, and the stirring reaction time is controlled at 1 to 5 hours.

3. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S2, the molar ratio of 2,2,2-trichloroethyl chloroformate to intermediate I is 1 to 5:1; the weight ratio of dichloromethane to intermediate I is 3 to 10:1; and the weight ratio of pyridine to intermediate I is 4.9 to 5.2:

1.

4. The method for preparing an important intermediate of paclitaxel according to claim 3, characterized in that: In step S2, the temperature range of the stirring reaction is -10 to 10°C, and the time range of the stirring reaction is 0.5 to 2 hours.

5. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S3, the molar ratio of (4S,5R)-2,4-diphenyl-4,5-dihydrooxazole-5-carboxylic acid to intermediate II is 2 to 5:1; the molar ratio of 4-dimethylaminopyridine to intermediate II is 0.5 to 2:1; and the weight ratio of toluene to intermediate II is 10 to 20:

1.

6. The method for preparing an important intermediate of paclitaxel according to claim 5, characterized in that: In step S3, the condensing agent is selected from one or more combinations of N'N-dicyclohexylcarbodiimide, N'N-diisopropylcarbodiimide, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, and the molar ratio of the condensing agent to the intermediate II is 3-5:

1.

7. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S3, the temperature range of the stirring reaction is 0 to 20°C, and the reaction time range of the stirring reaction is 1 to 3 hours.

8. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S4, the acid is one or more combinations of hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, formic acid, trifluoroboric acid and acetic acid; the molar ratio of the acid to the intermediate III is 1.5 to 3:1; the acid reaction temperature range is 10 to 30° C.; and the acid reaction time range is 2 to 5 hours.

9. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S4, the base is one or more combinations of sodium bicarbonate, sodium carbonate, potassium bicarbonate, triethylamine, sodium hydroxide and potassium hydroxide; the molar ratio of the base to the intermediate III is 1 to 5:1; the base reaction temperature range is 20 to 70° C.; the base reaction time range is 3 to 8 hours.

10. The method for preparing an important intermediate of paclitaxel according to claim 1, characterized in that: In step S4, the recrystallization solvent used for the crude 7-trichloroethoxycarbonyl paclitaxel is one or more of water, methanol, ethanol, dichloromethane, acetone, n-heptane, n-hexane and petroleum ether, and the volume mass ratio of the recrystallization solvent to the crude 7-trichloroethoxycarbonyl paclitaxel is 5 to 10:1.

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