Synthetic method of paclitaxel

Abstract

The invention discloses a new process of paclitaxel, which comprises the following steps: by taking 10-DAB as a raw material, firstly selectively protecting 10-site hydroxyl, then protecting 7-site hydroxyl, then carrying out esterification reaction with five-membered ring acid, carrying out ring opening under acidity, and then removing the 7-site hydroxyl protecting group to obtain paclitaxel 1. The process successfully realizes a method for directly preparing paclitaxel without column chromatography purification. The method comprises the following steps: starting from a raw material 10-DAB, adding acetyl, adding a Troc protecting group, carrying out condensation reaction, carrying out ring opening, and removing the Troc protecting group to obtain the paclitaxel. The process meets the requirements of a large-scale production process, the pollution is reduced, the yield is improved, and the cost is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of raw material drug synthesis and intermediate synthesis, and in particular to a method for synthesizing paclitaxel. Background Art

[0002] Paclitaxel is a natural product with anti-tumor activity, isolated from the bark of Pacific yew by American chemists and professors. Paclitaxel is an anti-microtubule drug with a very novel mechanism of action, which can promote the polymerization of microtubules while inhibiting their depolymerization, and then block cell mitosis to exert anti-cancer effects. It is widely used in the treatment of malignant tumors such as breast cancer, ovarian cancer, head and neck cancer, and lung cancer, and is currently one of the most promising anti-tumor drugs.

[0003] At present, the semi-synthetic method of paclitaxel usually uses 10-deacetylbaccatin (10-DAB) and 10-deacetylpaclitaxel as raw materials, but mainly uses 10-deacetylbaccatin (10-DAB) as a raw material, first protects the hydroxyl group, then condenses with a five-membered cyclic acid, and then opens the ring to remove the protecting group to obtain the product paclitaxel.

[0004] However, since the activity of the four hydroxyl groups in the 10-DAB structure is in the following order: the activity of the hydroxyl group at position 7 > the activity of the hydroxyl group at position 10 > the activity of the hydroxyl group at position 13 > the activity of the hydroxyl group at position 1, in the chemical synthesis of paclitaxel, the hydroxyl group at position 7 in the 10-DAB structure is generally protected first.

[0005] like Figure 1 As shown, the synthetic route 1 of paclitaxel: This route is a semi-synthetic process using 10-deacetylpaclitaxel as raw material. Since the raw material is difficult to obtain, it is rarely used now.

[0006] like Figure 2 As shown, the synthetic route 2 of paclitaxel: this route uses the hydroxyl-protected side chain and the protected 10-DABⅢ for condensation, and then deprotection to obtain paclitaxel. The main problem of this method is that the condensation reaction speed is very slow, and the protected side chain must be in excess of 6-7 times, which is wasteful and has a low yield. It is no longer used.

[0007] like Figure 3 As shown in Figure 3, the synthesis route of paclitaxel: In 1993, D. Bourzat reported that cyclization protection of the side chain can greatly improve the condensation efficiency and reduce the amount of the side chain. This method is very convenient in the synthesis of docetaxel, so it is widely used in the synthesis of docetaxel. However, difficulties were encountered in the synthesis of paclitaxel. The corresponding paclitaxel side chain is more difficult to synthesize than the docetaxel side chain, the reaction yield is low, and the steps are long. Summary of the invention

[0008] The purpose of the present invention is to provide a method for synthesizing paclitaxel in view of the above-mentioned problems.

[0009] The present invention provides a method for synthesizing paclitaxel, comprising the following steps: dissolving an intermediate 2 in acetone, adding zinc powder and acetic acid to remove the protecting group, and obtaining pure paclitaxel 1 through simple purification, wherein the structural formula of the intermediate 2 is as follows:

[0010]

[0011] In some embodiments, the intermediate 2 is prepared by the following steps: dissolving the intermediate 3 in glacial acetic acid and acetone, replacing with nitrogen, adding a mixed solution of hydrochloric acid and acetone to remove the protecting group, dissolving the solid obtained by post-treatment, washing with a saturated sodium bicarbonate solution and water, drying, filtering, and concentrating to obtain the intermediate 2, wherein the structural formula of the intermediate 3 is as follows:

[0012]

[0013] In some embodiments, the intermediate 3 is prepared by the following steps: dissolving the intermediate 4 and the paclitaxel side chain in a solvent, adding a condensing agent, and after the reaction is completed, washing with a dilute hydrochloric acid solution, a sodium bicarbonate solution, water, etc., and concentrating and drying to obtain the intermediate 3, wherein the structural formula of the intermediate 4 is as follows:

[0014]

[0015] In some embodiments, the intermediate 4 is prepared by the following steps: dissolving the intermediate 5, DMAP, and imidazole in a non-protonic polar solvent THF / pyridine, and then adding a protecting group reagent. After the reaction is completed, the reaction solution is poured into water, and the mixed system of water and organic solvent removes impurities in the reaction system to obtain a relatively high purity intermediate 4, wherein the structural formula of the intermediate 5 is as follows:

[0016]

[0017] In some embodiments, under an inert gas atmosphere, 10-DAB is dissolved in THF or 2-MeTHF, and then acetic anhydride is added to prepare intermediate 5.

[0018] Compared with the prior art, the beneficial effect of the present invention is that it provides a new process for preparing paclitaxel. The process successfully realizes a method for directly preparing paclitaxel without column chromatography purification. Starting from the raw material 10-DAB, paclitaxel is obtained through five steps of reaction, namely, acetyl group addition, Troc protective group addition, condensation reaction, ring opening, and removal of Troc protective group. The process meets the requirements of large-scale production process, reduces pollution, improves yield, and reduces cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1The synthetic route 1 of paclitaxel in the background technology of the present invention;

[0020] Figure 2 This is the synthesis route 2 of paclitaxel in the background technology of the present invention;

[0021] Figure 3 The synthetic route 3 of paclitaxel in the background technology of the present invention;

[0022] Figure 4 The synthetic route of paclitaxel in one embodiment of the present invention is as follows;

[0023] Figure 5 The HPLC spectrum of paclitaxel in one embodiment of the present invention. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the appended claims of the application equally.

[0025] Embodiment 1, as Figure 1 As shown:

[0026] 1) Dissolve 50.0g (0.092mol) 10-DAB in 1000mL THF, add 4.0g (about 0.010mol) cerium trichloride, and stir evenly. Cool to 5-10℃, add 100mL acetic anhydride (0.098mol), and keep at 20-25℃ for 3h. After the reaction is completed, filter, and concentrate the filtrate to dryness under reduced pressure. Add 1L CH2Cl2 to dissolve, slowly add 500mL saturated sodium bicarbonate solution to the system, and stand to separate the water layer. Wash the organic phase with 500mL water and 500mL saturated brine respectively. Dry with anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure until a large amount of solid precipitates. Add 300ml n-heptane, filter, and dry to obtain 51.2g intermediate 5, with a yield of 94.9%.

[0027] 2) Dissolve 50g (0.085mol) of intermediate 5, 1.2g of DMAP, and 20g (0.294mol) of imidazole in 150mL of THF and stir evenly. Cool to -5℃~0℃, add 30.5ml of trichloroethyl chloroformate dropwise, and heat to 30℃ to react for 4h. After the reaction is complete, pour the reaction solution into 2L of water, a large amount of solid precipitates, filter, dissolve the filter cake with 500mL of CH2Cl2, wash with 500mL of saturated sodium bicarbonate solution, wash once with 500mL of 20% brine, dry with anhydrous Na2SO4, concentrate, add petroleum ether, a large amount of solid precipitates, filter, and dry to obtain 58.5g of intermediate 4, with a weight yield of 117%.

[0028] 3) Dissolve 50g (0.066mol) of intermediate 4 and 31.45g (0.093mol) of paclitaxel side chain acid in 500mL of toluene, add 18g (0.094mol) of EDC.HCl, and react at 25-30°C for 4 hours. After the reaction is complete, filter, wash the organic layer once with 300ml 0.1N HCl, 300ml 5% NaHCO3, and 300ml saturated brine, dry over anhydrous Na2SO4, concentrate until a large amount of solid precipitates, filter, and dry to obtain 69g of intermediate 3, with a weight yield of 138%.

[0029] 4) 60.0g of intermediate 3 was dissolved in 600ml of glacial acetic acid and 600ml of acetone, replaced with nitrogen, and stirred for 30 minutes. The temperature was controlled at 20-25°C, and a hydrochloric acid-acetone solution of 1ml of concentrated hydrochloric acid and 200ml of acetone was added dropwise. After the addition was completed, stirring was continued for 1 hour. After the reaction was completed, the reaction solution was added dropwise to 4500ml of water and stirred for 30 minutes. Filter, dissolve the filter cake with 1200ml of dichloromethane, wash the solution with 900ml of saturated sodium bicarbonate solution and 900ml of water respectively, dry with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate 2.

[0030] 5) Dissolve the intermediate 2 in 600 ml of acetone, replace with nitrogen, and stir for 30 minutes. Add zinc powder, control the temperature at 20-25°C, add 30 ml of acetic acid, and keep the temperature at 20-25°C for 1 hour after the addition. Filter, concentrate the filtrate, add 1200 ml of ethyl acetate, wash twice with 375 ml of saturated sodium bicarbonate solution and 375 ml of water, and then use 375 ml of saturated sodium chloride solution once. Dry with anhydrous sodium sulfate, filter, and concentrate to 3.5 times the volume of the remaining open-loop material. Add the concentrate dropwise to 600 ml of n-hexane to precipitate a white solid. After the addition is complete, cool the system to 5-10°C, control the temperature and stir for 30 minutes. Filter, dry the filter cake at 40-45°C in vacuum until constant weight, and obtain 43.2 g of paclitaxel 1, whose HPLC spectrum is shown as follows Figure 5 As shown, the weight yield is 70%.

[0031] Embodiment 2:

[0032] 1) Dissolve 50.0g (0.092mol) 10-DAB in 1000mL 2-THF, add 4.0g (about 0.010mol) cerium trichloride, and stir evenly. Cool to 5-10℃, add 100mL acetic anhydride (0.098mol), and keep at 20-25℃ for 3h. After the reaction is completed, filter, and concentrate the filtrate to dryness under reduced pressure. Add 1L CH2Cl2 to dissolve, slowly add 500mL saturated sodium bicarbonate solution to the system, and stand to separate the water layer. Wash the organic phase with 500mL water and 500mL saturated brine respectively. Dry with anhydrous Na2SO4, filter, and concentrate the filtrate under reduced pressure until a large amount of solid precipitates. Add 300ml n-heptane, filter, and dry to obtain 51.2g intermediate 5, with a yield of 94.9%.

[0033] 2) Dissolve 50g (0.085mol) of intermediate 5 and 1.2g of DMAP in 150mL of pyridine and stir evenly. Cool to -5℃~0℃, add 30.5ml of trichloroethyl chloroformate dropwise, and heat to 30℃ for 4h. After the reaction is complete, pour the reaction solution into 2L of water, a large amount of solid precipitates, filter, dissolve the filter cake with 500mL of CH2Cl2, wash with 500mL of saturated sodium bicarbonate solution, wash once with 500mL of 20% brine, dry with anhydrous Na2SO4, concentrate, add petroleum ether, a large amount of solid precipitates, filter, and dry to obtain 56g of intermediate 4, with a weight yield of 112%.

[0034] 3) Dissolve 50g (0.066mol) of intermediate 4 and 31.45g (0.093mol) of paclitaxel side chain acid in 500mL of toluene, add 18g (0.094mol) of EDC.HCl, and react at 25-30°C for 4 hours. After the reaction is complete, filter, wash the organic layer once with 300ml 0.1N HCl, 300ml 5% NaHCO3, and 300ml saturated brine, dry over anhydrous Na2SO4, concentrate until a large amount of solid precipitates, filter, and dry to obtain 68.5g of intermediate 3, with a weight yield of 137%.

[0035] 4) 60.0g of intermediate 3 was dissolved in 600ml of glacial acetic acid and 600ml of acetone, replaced with nitrogen, and stirred for 30 minutes. The temperature was controlled at 20-25°C, and a hydrochloric acid-acetone solution of 1ml of concentrated hydrochloric acid and 200ml of acetone was added dropwise. After the addition was completed, stirring was continued for 1 hour. After the reaction was completed, the reaction solution was added dropwise to 4500ml of water and stirred for 30 minutes. Filter, dissolve the filter cake with 1200ml of dichloromethane, wash the solution with 900ml of saturated sodium bicarbonate solution and 900ml of water respectively, dry with anhydrous sodium sulfate, filter, and concentrate to obtain intermediate 2.

[0036] 5) Dissolve the intermediate 2 in 600 ml of acetone, replace with nitrogen, and stir for 30 minutes. Add zinc powder, control the temperature at 20-25°C, add 30 ml of acetic acid, and keep the temperature at 20-25°C for 1 hour after adding. Filter, concentrate the filtrate, add 1200 ml of ethyl acetate, wash twice with 375 ml of saturated sodium bicarbonate solution and 375 ml of water, and then use 375 ml of saturated sodium chloride solution once. Dry with anhydrous sodium sulfate, filter, and concentrate to 3.5 times the volume of the remaining open-loop material. Add the concentrate dropwise to 600 ml of n-hexane to precipitate a white solid. After the addition is completed, cool the system to 5-10°C, control the temperature and stir for 30 minutes. Filter, the filter cake is 40-45°C, and the material is vacuum-dried to constant weight to obtain 44.4 g of paclitaxel 1, with a weight yield of 74%.

[0037] The embodiment of the present invention provides a new process for paclitaxel, which successfully realizes the process of directly obtaining paclitaxel without column purification, saving working hours, reducing pollution, improving yield and reducing cost.

[0038] Finally, it should be noted that: technicians in this industry should understand that the present invention is not limited to the above-mentioned implementation cases. The above-mentioned embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which shall fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing paclitaxel, characterized in that: The method comprises the following steps: dissolving the intermediate 2 in acetone, adding zinc powder and acetic acid to remove the protecting group, and obtaining pure paclitaxel 1 through simple purification, wherein the structural formula of the intermediate 2 is as follows:

2. The synthesis method according to claim 1, characterized in that The intermediate 2 is prepared by the following steps: dissolving the intermediate 3 in glacial acetic acid and acetone, replacing with nitrogen, adding a mixed solution of hydrochloric acid and acetone to remove the protecting group, dissolving the solid obtained by post-treatment, washing with a saturated sodium bicarbonate solution and water, drying, filtering, and concentrating to obtain the intermediate 2, wherein the structural formula of the intermediate 3 is as follows:

3. The synthesis method according to claim 2, characterized in that The intermediate 3 is prepared by the following steps: dissolving the intermediate 4 and the paclitaxel side chain in a solvent, adding a condensing agent, washing with a dilute hydrochloric acid solution, a sodium bicarbonate solution, water, etc. after the reaction is completed, and concentrating and drying to obtain the intermediate 3, wherein the structural formula of the intermediate 4 is as follows:

4. The synthesis method according to claim 2, characterized in that The intermediate 4 is prepared by the following steps: the intermediate 5, DMAP, and imidazole are dissolved in a non-protonic polar solvent THF / pyridine, and then a protecting group reagent is added. After the reaction is completed, the reaction solution is poured into water, and the mixed system of water and organic solvent removes impurities in the reaction system to obtain a relatively high purity intermediate 4, wherein the structural formula of the intermediate 5 is as follows:

5. The synthesis method according to claim 2, characterized in that Under an inert gas atmosphere, 10-DAB was dissolved in THF or 2-MeTHF, and acetic anhydride was added to prepare Intermediate 5.

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