阅读说明：本技术 一种卡巴他赛的制备方法 (Preparation method of cabazitaxel ) 是由 黄春 王旭阳 王莉佳 陆叶梦 于 2021-08-27 设计创作，主要内容包括：本发明公开了一种卡巴他赛的制备方法,具体步骤包括：10-去乙酰基巴卡亭III用二氯甲烷和吡啶溶解,滴加氯甲酸-222-三氯乙酯进行反应,处理得中间体Ⅰ；将甲苯、4-二甲氨基吡啶、中间体I和多西侧链酸混合后搅拌,滴加N,N’-二环己基碳二亚胺,搅拌反应得中间体Ⅱ；中间体Ⅱ用乙酸乙酯和乙酸溶解,加入锌粉,搅拌反应得中间体Ⅲ,中间体Ⅲ用二氯甲烷溶清,加入1,8-双二甲氨基萘、分子筛和三甲基氧鎓四氟硼酸,搅拌反应得中间体Ⅳ；中间体Ⅳ用甲醇溶清,滴加1mol/L的盐酸甲醇溶液,搅拌反应得卡巴他赛,本发明常温即可实现甲基化,产品纯度好,收率高,起始物料易得,能进行大量制备。(The invention discloses a preparation method of cabazitaxel, which comprises the following specific steps: dissolving 10-deacetylbaccatin III with dichloromethane and pyridine, dropwise adding chloroformic acid-222-trichloroethyl ester for reaction, and processing to obtain an intermediate I; mixing toluene, 4-dimethylaminopyridine, the intermediate I and doxy side chain acid, stirring, dropwise adding N, N' -dicyclohexylcarbodiimide, and stirring to react to obtain an intermediate II; dissolving the intermediate II with ethyl acetate and acetic acid, adding zinc powder, stirring and reacting to obtain an intermediate III, dissolving the intermediate III with dichloromethane, adding 1, 8-bis (dimethylamino) naphthalene, a molecular sieve and trimethyl oxonium tetrafluoroborate, and stirring and reacting to obtain an intermediate IV; and dissolving the intermediate IV in methanol, dropwise adding 1mol/L hydrochloric acid methanol solution, and stirring to react to obtain cabazitaxel.)

1. A preparation method of cabazitaxel is characterized by comprising the following steps:

s1: dissolving 10-deacetylbaccatin III, hereinafter referred to as 10-DAB, by using dichloromethane and pyridine, slowly dropwise adding chloroformic acid-222-trichloroethyl, adding water to quench the reaction after the reaction is completed, then extracting, concentrating an organic phase until a large amount of solids are separated out, and performing suction filtration and drying to obtain an intermediate I;

s2: mixing toluene, 4-dimethylaminopyridine, an intermediate I and a doxy side chain acid, stirring, dropwise adding N, N' -dicyclohexylcarbodiimide, stirring for reaction, adding water and ethyl acetate to stop the reaction after the reaction is completed, centrifuging, collecting filtrate, extracting the filtrate, and concentrating an organic phase to obtain an intermediate II;

s3: adding ethyl acetate and acetic acid into the intermediate II, stirring to dissolve the mixture, slowly adding zinc powder, stirring to react, filtering and neutralizing after the reaction is finished, and collecting an organic phase; concentrating the organic phase until no solvent is evaporated, crystallizing, and performing suction filtration and drying to obtain an intermediate III;

s4: dissolving the intermediate III with dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, a molecular sieve and trimethyloxonium tetrafluoroborate, and stirring for reaction; after the reaction is finished, carrying out suction filtration, concentrating the filtrate until no solvent is evaporated, adding methanol, stirring to dissolve out, adding water to precipitate a solid, and drying after suction filtration to obtain an intermediate IV;

s5: dissolving the intermediate IV in methanol, dropwise adding 1mol/L hydrochloric acid methanol solution, stirring for reaction, adding water after the reaction is finished to separate out a solid, and performing suction filtration, drying and crystallization to obtain cabazitaxel;

the reaction route of the preparation process is as follows:

2. the method for preparing cabazitaxel according to claim 1, wherein: in step S1, dilute hydrochloric acid and sodium bicarbonate solution are used for extraction.

3. The method for preparing cabazitaxel according to claim 1, wherein: in step S2, N, N '-dicyclohexylcarbodiimide is diluted with toluene, and the ratio of toluene to N, N' -dicyclohexylcarbodiimide is 1.4 to 1.5 (W/W).

4. The method for preparing cabazitaxel according to claim 1, wherein: in step S2, the filtrate is extracted with dilute hydrochloric acid and sodium chloride solution, respectively.

5. The method for preparing cabazitaxel according to claim 1, wherein: in step S3, the filtrate after filtration is neutralized with a sodium bicarbonate solution; crystallization was carried out with ethyl acetate and n-heptane.

6. The method for preparing cabazitaxel according to claim 1, wherein: in step S1, the ratio of the chloroformic acid-222-trichloroethyl ester to the raw material 10-DAB is 1.2-1.4 (W/W); the reaction temperature is 0-10 ℃, and the reaction time is 0.5-1 h.

7. The method for preparing cabazitaxel according to claim 1, wherein: in step S2, the structure of the docetaxel side chain acid is shown below,the ratio of the intermediate I to the intermediate I is 0.62-0.64 (W/W); the ratio of the 4-dimethylaminopyridine to the intermediate I is 0.07-0.12 (W/W); the ratio of the toluene to the intermediate I is 8-11 (W/W); the ratio of the N, N' -dicyclohexylcarbodiimide to the intermediate I is 0.40-0.65 (W/W); the reaction temperature is 10-20 ℃, and the reaction time is 0.5-1 h.

8. The method for preparing cabazitaxel according to claim 1, wherein: in step S3, the ratio of the zinc powder to the intermediate I is 2.1-3.4 (W/W); the ratio of ethyl acetate to the intermediate I is 13-14 (W/W); the ratio of acetic acid to the intermediate I is 3.8-4.2 (W/W).

9. The method for preparing cabazitaxel according to claim 1, wherein: in step S4, the ratio of the 1, 8-bis-dimethylaminonaphthalene to intermediate III is 2.0 to 2.4(W/W), and the ratio of trimethyloxonium tetrafluoroborate to intermediate III is 1.4 to 1.6 (W/W); the ratio of the molecular sieve to the intermediate III is 0.9-1.1 (W/W); the reaction temperature is 10-20 ℃, and the reaction time is 8-12 h.

10. The method for preparing cabazitaxel according to claim 1, wherein: in step S5, the ratio of 1mol/L hydrochloric acid methanol solution to the intermediate IV is 1.50-1.65 (W/W); the reaction temperature is 10-20 ℃, and the reaction time is 3-5 h.

Technical Field

The invention relates to the technical field of preparation of anti-tumor bulk drugs, in particular to a preparation method of cabazitaxel.

Background

Cabazitaxel (Cabazitaxel, XRP-6258, trade name Jevtana) is a drug developed by Sanofi-aventis, Senoffel, France, which was approved by the U.S. Food and Drug Administration (FDA) for marketing on 17/6.2010. The medicine is an injection, and is mainly used for treating advanced, hormone refractory, and prostate cancer aggravated during or after docetaxel treatment.

There are many, roughly three, types of processes for preparing cabazitaxel. The first category uses 10-deacetylbaccatin III as raw material, and obtains cabazitaxel by methylation step by step under various measures for protecting hydroxyl, and the method disclosed in the patent US5847170 is a typical route. The disadvantage of this route is that it is a long route and the overall yield is low, and the methylating agent used is conventional methyl iodide, which is very toxic.

The second route is to take 10-deacetylbaccatin III/2' protected docetaxel as a raw material, directly carry out methylation on 7 and 10 positions, and finally carry out condensation with a side chain and ring opening/deprotection to obtain cabazitaxel. The methylation of the route needs to use methyl trifluoromethanesulfonate as a methylation reagent, the reaction conditions are very harsh, the temperature is low (-70 to-30 ℃), the used solvent tetrahydrofuran needs to be re-steamed by benzophenone, and the industrial production is very difficult.

The third patent is a hydrogenation route used by original sunkenofilphine, the domestic patent of the same family is CN1179775, the whole route is long, the methylation of 7, 10-position is carried out in two steps, firstly, 2 dimethylsulfide bonds are added under the condition of DMSO/acetic anhydride/acetic acid, and then, the methylation is realized by hydrogenation of raney nickel. The raney nickel is particularly easy to spark in a dry state, and has very high danger in cooperation with the existence of hydrogen, so that the requirement on scale-up production is high.

However, the above routes have their disadvantages, some of them have long routes due to the methylation at positions 7 and 10 in 2 steps, some of them use traditional highly toxic methylating agents (methyl iodide/dimethyl sulfate, etc.), some of them need to carry out Raney nickel hydrogenation with high risk, some of them need to carry out methylation at lower temperature, and they are not suitable for scale-up production in general.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a preparation method of cabazitaxel, which can complete methylation of 7-position and 10-position in one step, uses a very safe methylation reagent, can realize methylation at normal temperature, has good product purity and high yield, and can be used for large-scale preparation.

The technical purpose of the invention is realized by the following technical scheme:

a preparation method of cabazitaxel comprises the following steps:

s1: dissolving 10-deacetylbaccatin III, hereinafter referred to as 10-DAB, by using dichloromethane and pyridine, slowly dropwise adding chloroformic acid-222-trichloroethyl, adding water to quench the reaction after the reaction is completed, then extracting, concentrating an organic phase until a large amount of solids are separated out, and performing suction filtration and drying to obtain an intermediate I;

s2: mixing toluene, 4-dimethylaminopyridine, an intermediate I and a doxy side chain acid, stirring, dropwise adding N, N' -dicyclohexylcarbodiimide, stirring for reaction, adding water and ethyl acetate to stop the reaction after the reaction is completed, centrifuging, collecting filtrate, extracting the filtrate, and concentrating an organic phase to obtain an intermediate II;

s3: adding ethyl acetate and acetic acid into the intermediate II, stirring to dissolve the mixture, slowly adding zinc powder, stirring to react, filtering and neutralizing after the reaction is finished, and collecting an organic phase; concentrating the organic phase until no solvent is evaporated, crystallizing, and performing suction filtration and drying to obtain an intermediate III;

s4: dissolving the intermediate III with dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, a molecular sieve and trimethyloxonium tetrafluoroborate, and stirring for reaction; after the reaction is finished, carrying out suction filtration, concentrating the filtrate until no solvent is evaporated, adding methanol, stirring to dissolve out, adding water to precipitate a solid, and drying after suction filtration to obtain an intermediate IV;

s5: dissolving the intermediate IV in methanol, dropwise adding 1mol/L hydrochloric acid methanol solution, stirring for reaction, adding water after the reaction is finished to separate out a solid, and performing suction filtration, drying and crystallization to obtain cabazitaxel;

the reaction route of the preparation process is as follows:

further, in step S1, dilute hydrochloric acid and sodium bicarbonate solution are used for extraction.

Further, in step S2, N, N '-dicyclohexylcarbodiimide is diluted with toluene, and the ratio of toluene to N, N' -dicyclohexylcarbodiimide is 1.4 to 1.5 (W/W).

Further, in step S2, the filtrate is extracted with dilute hydrochloric acid and sodium chloride solution, respectively.

Further, in step S3, the filtrate after filtration is neutralized with sodium bicarbonate solution; crystallization was carried out with ethyl acetate and n-heptane.

Further, in step S1, the ratio of the chloroformic acid-222-trichloroethyl ester to the raw material 10-DAB is 1.2-1.4 (W/W); the reaction temperature is 0-10 ℃, and the reaction time is 0.5-1 h.

Further, in step S2, the structure of the docetaxel side chain acid is as follows,the ratio of the intermediate I to the intermediate I is 0.62-0.64 (W/W); the ratio of the 4-dimethylaminopyridine to the intermediate I is 0.07-0.12 (W/W); the ratio of the toluene to the intermediate I is 8-11 (W/W); the ratio of the N, N' -dicyclohexylcarbodiimide to the intermediate I is 0.40-0.65 (W/W); the reaction temperature is 10-20 ℃, and the reaction time is 0.5-1 h.

Further, in the step S3, the ratio of the zinc powder to the intermediate I is 2.1-3.4 (W/W); the ratio of ethyl acetate to the intermediate I is 13-14 (W/W); the ratio of acetic acid to the intermediate I is 3.8-4.2 (W/W).

Further, in step S4, the ratio of the 1, 8-bis-dimethylaminonaphthalene to intermediate III is 2.0 to 2.4(W/W), and the ratio of trimethyloxonium tetrafluoroborate to intermediate III is 1.4 to 1.6 (W/W); the ratio of the molecular sieve to the intermediate III is 0.9-1.1 (W/W); the reaction temperature is 10-20 ℃, and the reaction time is 8-12 h.

Further, in step S5, the ratio of 1mol/L methanol hydrochloride solution to the intermediate IV is 1.50-1.65 (W/W); the reaction temperature is 10-20 ℃, and the reaction time is 3-5 h.

In conclusion, the invention has the following beneficial effects:

1. all conditions in the process of the invention do not relate to extreme conditions such as ultralow temperature, hydrogenation and the like related to other routes, the conditions are mild, and the industrial production is easier to realize. In addition, the traditional methylating agent methyl iodide has a very low boiling point, is difficult to volatilize in the reaction process, and can generate high carcinogenic risk after being easily inhaled by production personnel.

2. The methylation of the 7-position and the 10-position is realized through one-step reaction, the reaction steps are shortened, and compared with a process route for carrying out the methylation of the 7-position and the 10-position step by step such as CN104109142A, the method improves the reaction yield and further improves the economic benefit.

3. The starting material 10-deacetylbaccatin III is a natural extraction product, and compared with semisynthetic industrial products used in some routes (such as CN103242267B which uses 7, 10-dimethoxy-10-deacetylbaccatin III as a raw material), the yield and the price are more advantageous, and the process is suitable for mass preparation.

Drawings

FIG. 1 is an HPLC chromatogram of cabazitaxel obtained in example 1 of the present invention.

Fig. 2 is a cabazitaxel MS spectrum obtained in example 1 of the present invention.

FIG. 3 is a 1H NMR spectrum of cabazitaxel obtained in example 1 of the present invention.

FIG. 4 is a 13C NMR spectrum of cabazitaxel obtained in example 1 of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail with reference to the accompanying drawings and the detailed description. The advantages and features of the present invention will become more apparent from the following description. It is to be noted that the drawings are in a very simplified form and are all used in a non-precise scale for the purpose of facilitating and distinctly aiding in the description of the embodiments of the present invention. To make the objects, features and advantages of the present invention comprehensible, reference is made to the accompanying drawings. Any structural modification, ratio change or numerical adjustment within the scope of the present disclosure should not affect the function and the achievement of the objective of the present disclosure.

Example 1:

a preparation method of cabazitaxel comprises the following steps:

step S1: adding 79.50kg of dichloromethane, 29.46kg of pyridine and 6kg of 10-deacetylbaccatin III (10-DAB for short) into a reaction kettle, stirring to enable the dichloromethane, the pyridine and the deacetylbaccatin III to be dissolved clearly, and cooling to 0-5 ℃; dissolving 7.2kg of chloroformic acid-222-trichloroethyl ester by using 3.99kg of dichloromethane, dropwise adding the solution into a reaction kettle, stirring and reacting for 30 minutes at the temperature of 0-10 ℃ after the solution is added, and monitoring the reaction by TLC.

After the reaction is finished, adding purified water to quench the reaction, adding about 125.4kg of 3mol/L diluted hydrochloric acid to neutralize the reaction, stirring the mixture, standing the mixture to separate layers, collecting an organic phase, washing the organic phase by 16.5kg of 9% sodium bicarbonate solution, and transferring the organic phase into a rotary evaporator in batches to be distilled under reduced pressure until no solvent is evaporated out, thereby obtaining 9kg of an intermediate I.

Step S2: adding 78kg of toluene, 0.63kg of 4-dimethylaminopyridine, 9kg of the intermediate I and 5.61kg of doxycycline side chain acid into a reaction kettle, and stirring; dissolving 3.6kg of N, N' -dicyclohexylcarbodiimide by using 5.19kg of toluene, dropwise adding the solution into a reaction kettle, and controlling the temperature to be 10-20 ℃ after the solution is added, and stirring and reacting for 30 minutes.

After the reaction is finished, adding 30kg of purified water and 27kg of ethyl acetate to terminate the reaction, stirring for about 1.5 hours, centrifuging to collect filtrate, washing with about 30.6kg of 0.2mol/L diluted hydrochloric acid, standing for layering, extracting an aqueous phase with 5.4kg of ethyl acetate, standing for layering, combining organic phases, washing twice with 9% sodium chloride solution (16.5 kg of sodium chloride solution each time), drying the organic phase with 24kg of anhydrous sodium sulfate, filtering, and concentrating the filtrate until no obvious solution flows out to obtain an intermediate II.

Step S3: 120L of ethyl acetate and 36L of acetic acid are added into the intermediate II, and the mixture is stirred and dissolved. Adding 19kg of zinc powder slowly in batches, and continuously stirring and reacting for 1 hour at the temperature of 0-10 ℃.

After the reaction was completed, filtration was carried out, the organic phase was neutralized with about 110kg of 9% sodium bicarbonate solution, the organic phase was collected, the organic phase was concentrated until no solvent was distilled off, 90L of ethyl acetate was added, stirring was carried out for 0.5h, 300L of n-heptane was slowly added, and stirring was continued for 1 h. The solid was collected by centrifugation and dried to give 7.8kg of intermediate III.

Step S4: adding 7.8kg of the intermediate III and 156L of dichloromethane into a reaction kettle, stirring to dissolve, adding 18kg of 1, 8-bis-dimethylamino-naphthalene and 7.8kg of molecular sieve, adding 12.48kg of trimethyloxonium tetrafluoroborate into the reaction kettle in batches, and stirring to react for 10 hours at 10-20 ℃.

After the reaction, the reaction solution was centrifuged, and the filtrate was concentrated until no solvent was evaporated. 138L of methanol is added, the solution is stirred to be clear, 330L of purified water is prepared, the solution is slowly added until the solution becomes turbid, the stirring is carried out for 0.5h, and then the rest of the purified water is added and stirred for 1 h. And centrifuging to collect the solid, and drying to obtain 8.8kg of an intermediate IV.

Step S5: 8.8kg of intermediate IV and 264L of methanol were added to the reaction vessel and stirred to dissolve it. Controlling the temperature to be 15 +/-5 ℃, and beginning to add 14.52kg of 1mol/L hydrochloric acid methanol solution dropwise. And after the feeding is finished, continuously controlling the temperature to be 10-20 ℃ and reacting for 3 hours.

After the reaction is finished, 500L of purified water is slowly added, a large amount of solid is separated out, and the coarse cabazitaxel product is obtained after suction filtration and drying. Dissolving the cabazitaxel crude product with 20L of dichloromethane and 5L of methanol, adding 50L of n-heptane while stirring to separate out a large amount of solid, carrying out suction filtration and drying, adding 28L of acetone to dissolve out the solid, slowly adding purified water to separate out a large amount of solid, carrying out suction filtration and drying to obtain 2.83kg of cabazitaxel with the purity of 99.47 percent (shown in an HPLC (high performance liquid chromatography) spectrum as figure 1) and the total yield of 30.7 percent (calculated by 10-deacetylbaccatin III). This is a level significantly improved over the total yield of about 4% in the case of cabazitaxel production according to the method disclosed in the prior international publication No. WO 96/30355.

As shown in fig. 2, the MS spectrum of cabazitaxel in this example, wherein the mass/charge ratio M/z is 858.3[ M + Na ] +, the molecular weight can be deduced to be 835, consistent with the target compound.

As shown in FIG. 3, which is a 1H NMR spectrum of Cabazitaxel of the present example, 1H NMR (500MHz, CDCl3) delta: 8.11(2H, d, J ═ 7.5Hz, ArH),7.62(1H, t, J ═ 7.0Hz, ArH),7.51(2H, t, J ═ 7.5Hz, ArH),7.41(4H, m, ArH),7.34(1H, m, ArH),6.24(1H, t, J ═ 8.3Hz, H13),5.66(1H, d, J ═ 6.5Hz, H2),5.55(1H, d, J ═ 9Hz, H32),5.29(1H, m, H31),4.99(1H, d, J ═ 9.5Hz, H5.83 (1H, s, H10),4.65(1H, s, H24), 4.31(1H, d, J ═ 9.5Hz, H5.42 Hz, H634.83H, H3H, 7H 3H, H3H, 7H 3H 8, J ═ 3H, H3H 8H, H3H 8H 7H, H3H 8H 7H 8H 3H 7H, H8H 3H 8H, H3H 8H 3H 8H 3H 7H 3H 8H, H8H 7H 8H, H8H 7H 8H 3H 8H 7H 8H 7H 3H, H3H 8H 3H 7H 3H 8H 7H 8H 7H 8H, H8H 3H 8H 3H 8H 3H 8H 3H 7H 3H 8H 3H 8H 7H 8H 3H 7H 8H 3H 8H 3H 8H 7H 8H 3H 8H 3H 8H 3H 8H 7H 8H 3H 8H 7H 8H 3H 8H 3H 8H 7H 8, 2.30(2H, m,2H14),1.91(3H, s, H18),1.84(1H, m, H6),1.74(3H, s, H19),1.38(9H, s, H40),1.24(3H, s,3H16/3H17),1.22(3H, s,3H16/3H17).

As shown in fig. 4, the cabazitaxel 13C NMR spectrum of this example, wherein 13C NMR (125MHz, CDCl3) δ: 206.816,204.834,172.592,170.315,166.842,155.267,138.617,138.466,135.587,133.499,130.047,129.24,128.68,128.538,127.903,126.777,84.041,82.584,81.664,80.682,80.053,78.655,77.251,74.564,73.69,72.373,57.228,56.91,56.852,56.211,47.337,43.241,35.256,32.046,30.773,28.139,26.762,22.567,20.655,14.504.

Example 2:

step S1: adding 1325g of dichloromethane, 491g of pyridine and 100g of 10-deacetylbaccatin III (10-DAB for short) into a 500mL reaction bottle, stirring to dissolve the mixture clearly, and cooling to 0-5 ℃; dissolving 140g of chloroformic acid-222-trichloroethyl ester by 66.5g of dichloromethane, then dropwise adding the solution into a reaction kettle, and stirring and reacting for 1 hour at the temperature of 0-10 ℃.

After the reaction is finished, adding purified water to quench the reaction, adding diluted hydrochloric acid to neutralize the reaction, stirring the mixture, standing the mixture to separate layers, collecting an organic phase, washing the organic phase by using 9% sodium bicarbonate solution, and distilling the organic phase under reduced pressure until no solvent is distilled out to obtain 149.5g of an intermediate I.

Step S2: adding 1495mL of toluene, 10.5g of 4-dimethylaminopyridine, 149.5g of the intermediate I and 95.7g of doxy side chain acid into a reaction bottle, and stirring; dissolving 59.9g N, N' -dicyclohexylcarbodiimide in toluene, then dropwise adding into the reaction solution, and after the addition is finished, controlling the temperature to be 10-20 ℃ and stirring for reaction for 1 h.

After the reaction is finished, adding purified water and ethyl acetate to terminate the reaction, stirring for about 1.5 hours, carrying out suction filtration to collect filtrate, washing with 0.2mol/L diluted hydrochloric acid, standing, layering, washing with 9% sodium chloride solution twice, drying an organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate until no obvious solution flows out to obtain an intermediate II.

Step S3: 1993mL of ethyl acetate and 598mL of acetic acid are added to the intermediate II, and the mixture is stirred to dissolve. 318.9g of zinc powder is slowly added in batches, and the mixture is continuously stirred and reacted for 1 hour at the temperature of 0-10 ℃.

After the reaction, filtering, neutralizing the organic phase with saturated sodium bicarbonate solution, collecting the organic phase, concentrating the organic phase until no solvent is evaporated, adding 4L ethyl acetate, stirring for 0.5h, slowly adding 15L n-heptane, and continuing stirring for 1 h. The solid was collected by suction filtration and dried to give 118.9g of intermediate III.

Step S4: adding 118.9g of intermediate III and 2.4L of dichloromethane into a reaction bottle, stirring to dissolve, adding 285g of 1, 8-bis-dimethylamino-naphthalene and 118.9g of molecular sieve, slowly adding 167g of trimethyloxonium tetrafluoroborate into the reaction bottle, and stirring to react for 12 hours at the temperature of 10-20 ℃.

After the reaction, the reaction solution was filtered, and the filtrate was concentrated until no solvent was evaporated. Adding 2.3L of methanol, stirring to dissolve, preparing 5.5L of purified water, slowly adding until the solution turns turbid, stirring for 0.5h, adding all the rest purified water, and stirring for 1 h. And (5) carrying out suction filtration to collect a solid, and drying to obtain 142g of an intermediate IV.

Step S5: 142g of intermediate IV and 4.3L of methanol were added to the reaction flask and stirred to dissolve. Controlling the temperature to be 15 +/-5 ℃, and beginning to dropwise add 213g of 1mol/L hydrochloric acid methanol solution. And after the feeding is finished, continuously controlling the temperature to be 10-20 ℃ and reacting for 5 hours.

After the reaction is finished, slowly adding 8L of purified water, separating out a large amount of solid, performing suction filtration, and drying to obtain a cabazitaxel crude product. The crude cabazitaxel product is dissolved and cleaned by 330mL of dichloromethane and 85mL of methanol, 800mL of n-heptane is added under stirring, a large amount of solid is separated out, and 45.6g of cabazitaxel is obtained by suction filtration and drying, wherein the total yield is 29.7% (calculated by 10-deacetylbaccatin III).

Example 3:

step S1: adding 1325g of dichloromethane, 491g of pyridine and 100g of 10-deacetylbaccatin III (10-DAB for short) into a 500mL reaction bottle, stirring to dissolve the mixture clearly, and cooling to 0-5 ℃; 130g of chloroformic acid-222-trichloroethyl ester is dissolved by 66.5g of dichloromethane and then is dripped into a reaction kettle, and the mixture is stirred and reacted for 40 minutes at the temperature of 0-10 ℃.

After the reaction is finished, adding purified water to quench the reaction, adding diluted hydrochloric acid to neutralize the reaction, stirring the mixture, standing the mixture, layering the mixture, collecting an organic phase, washing the organic phase by using 9% sodium bicarbonate solution, and distilling the organic phase under reduced pressure until no solvent is distilled out to obtain 146.4g of an intermediate I.

Step S2: adding 1500mL of toluene, 10.5g of 4-dimethylaminopyridine, 146.4g of the intermediate I and 93g of doxy side chain acid into a reaction bottle, and stirring; dissolving 60g N, N' -dicyclohexylcarbodiimide in toluene, then dropwise adding the solution into the reaction solution, and after the solution is completely added, controlling the temperature to be 10-20 ℃ and stirring for reaction for 1 h.

After the reaction is finished, adding purified water and ethyl acetate to terminate the reaction, stirring for about 1.5 hours, carrying out suction filtration to collect filtrate, washing with 0.2mol/L diluted hydrochloric acid, standing, layering, washing with 9% sodium chloride solution twice, drying an organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate until no obvious solution flows out to obtain an intermediate II.

Step S3: 2L of ethyl acetate and 600mL of acetic acid were added to intermediate II, and the mixture was stirred to dissolve it. And (3) slowly adding 310g of zinc powder in batches, and continuously stirring and reacting for 1 hour at the temperature of 0-10 ℃.

After the reaction, filtering, neutralizing the organic phase with saturated sodium bicarbonate solution, collecting the organic phase, concentrating the organic phase until no solvent is evaporated, adding 4L ethyl acetate, stirring for 0.5h, slowly adding 15L n-heptane, and continuing stirring for 1 h. The solid was collected by suction filtration and dried to obtain 114.5g of intermediate III.

Step S4: adding 114.5g of the intermediate III and 2.4L of dichloromethane into a reaction bottle, stirring to dissolve, adding 229g of 1, 8-bis-dimethylamino-naphthalene and 114.5g of molecular sieve, slowly adding 172g of trimethyloxonium tetrafluoroborate into the reaction bottle, and stirring to react for 8 hours at the temperature of 10-20 ℃.

After the reaction, the reaction solution was filtered, and the filtrate was concentrated until no solvent was evaporated. Adding 2.3L of methanol, stirring to dissolve, preparing 5.5L of purified water, slowly adding until the solution turns turbid, stirring for 0.5h, adding all the rest purified water, and stirring for 1 h. And (4) carrying out suction filtration to collect solids, and drying to obtain 135g of an intermediate IV.

Step S5: 135g of intermediate IV and 4L of methanol are introduced into a reaction flask and stirred to dissolve. Controlling the temperature to be 15 +/-5 ℃, and starting to dropwise add 205g of 1mol/L hydrochloric acid methanol solution. And after the feeding is finished, continuously controlling the temperature to be 10-20 ℃ and reacting for 5 hours.

After the reaction is finished, slowly adding 8L of purified water, separating out a large amount of solid, performing suction filtration, and drying to obtain a cabazitaxel crude product. The crude cabazitaxel product is dissolved and cleaned by 330mL of dichloromethane and 85mL of methanol, 800mL of n-heptane is added under stirring, a large amount of solid is separated out, and 43.0g of cabazitaxel is obtained by suction filtration and drying, wherein the total yield is 28.0% (calculated by 10-deacetylbaccatin III).

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, and the description thereof is more specific and detailed, but not construed as limiting the 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. Therefore, the protection scope of the present patent shall be subject to the appended claims.