CN115197176A - Preparation method of 7-trichloroethoxycarbonyl docetaxel - Google Patents
Preparation method of 7-trichloroethoxycarbonyl docetaxel Download PDFInfo
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Abstract
The invention discloses a preparation method of 7-trichloro ethoxycarbonyl docetaxel, which adopts the technical scheme that: s1: stirring and dissolving 10-DAB and 2-methylimidazole with DMF, dropwise adding triethylchlorosilane for reaction, and adding water for quenching to obtain an intermediate I; s2: dissolving the intermediate I with tetrahydrofuran, adding DMAP, and dropwise adding benzyl chloroformate for reacting to obtain an intermediate II; s3: dissolving the intermediate II with pyridine, adding hydrogen fluoride pyridine for reaction, adding dichloromethane, dropwise adding Trocci for reaction, and adding water for quenching to obtain an intermediate III; s4: dissolving the intermediate III with toluene, adding docetaxel side chain acid, DMAP and DCC for reaction, adding water for quenching, and adding hydrochloric acid for reaction to obtain an intermediate IV; s5: dissolving the intermediate IV with methanol, adding palladium carbon, sealing, replacing nitrogen for three times, replacing hydrogen, reacting at normal pressure, and purifying to obtain a target product; the method has the advantages that each target intermediate is directionally obtained in a selective protection mode, the overall yield is high, the separation difficulty is low, and the operation is simple and easy.
Description
Technical Field
The invention relates to the technical field of preparation of anti-cancer drugs, in particular to a preparation method of 7-trichloroethoxycarbonyl docetaxel.
Background
Docetaxel is a novel taxane antitumor drug widely researched and applied at present, and is widely applied to the treatment of ovarian cancer, breast cancer, non-small cell lung cancer and other various cancers clinically. Docetaxel has many impurity types, and has a key effect on the deep research of docetaxel.
The current docetaxel process generally involves the use of Troc protecting groups, such as those disclosed in [ Ojima I, zucco M, duclos O, et al, N-Acyl-3-hydroxy- β -lactams as key intermediates for taxot re and its analogues [ J ]. Bioorganic & Medicinal Chemistry Letters,1993,3 (11): 2479-2482 ], and [ St.Haicheng. Docetaxel synthesis process research [ D ]. Zhejiang university, 2013 ] although four-membered ring side chain acids and five-membered ring side chain acids are used, the route involves the use of Troccl (chloroformate-2, 2-trichloroethyl) to protect the 7-and 10-hydroxy groups, involving reactions of formula 2:
a byproduct 7-trichloroethoxycarbonyl docetaxel (7-Troc-docetaxel) appears in a relevant reaction, and the structure of the byproduct is shown as a formula 1:
the properties of 7-trichloroethoxycarbonyl docetaxel need to be researched, and the target product needs to be prepared industrially and massively. The current researchers using the experimental reaction route described in formula 2 to prepare 7-trichloroethoxycarbonyl docetaxel have the following problems:
1. the reaction relates to four-membered ring side chain acid and five-membered ring side chain acid, trocc is used for protecting 7-and 10-hydroxyl to prepare docetaxel, 7-trichloro-ethoxycarbonyl docetaxel is one of target product docetaxel by-products, the by-products with similar structures in the reaction route are more, the separation of 7-trichloro-ethoxycarbonyl docetaxel is very difficult, and the high-purity 7-trichloro-ethoxycarbonyl docetaxel is difficult to obtain.
2. The reaction conditions required by the side chain acid of the four-membered ring and the side chain acid of the five-membered ring are harsh, the price is high, and the method is not suitable for large-scale industrial preparation.
Researchers have also tried to control zinc powder equivalents to expect a single deprotected product, but in practice this approach failed to yield 7-trichloroethoxycarbonyl docetaxel.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of 7-trichloroethoxycarbonyl docetaxel, which has the advantages of reasonable design of a reaction route, single reaction product in each step, directional obtaining of each target intermediate, great improvement of the purity of the target product, low separation difficulty of the final target product and simple operation.
The technical purpose of the invention is realized by the following technical scheme:
a preparation method of 7-trichloro-ethoxycarbonyl docetaxel comprises the following steps:
s1: stirring and dissolving 10-DAB and 2-methylimidazole with DMF (dimethyl formamide), then dropwise adding triethylchlorosilane, stirring and reacting, adding water into reaction liquid for quenching, extracting the reaction liquid with dichloromethane, collecting and concentrating an organic phase, crystallizing the organic phase with ethyl acetate and n-heptane, and drying to obtain an intermediate I;
s2: dissolving the intermediate I with tetrahydrofuran, adding DMAP into the solution, dropwise adding benzyl chloroformate, stirring for reaction, adding water after the reaction is finished to quench the reaction, carrying out acid washing on the reaction solution, then carrying out water washing, collecting and concentrating an organic phase, and crystallizing to obtain an intermediate II;
s3: dissolving the intermediate II with pyridine, controlling the temperature, adding hydrogen fluoride pyridine, stirring for reaction, adding dichloromethane into the reaction, dropwise adding TrocCl, stirring for reaction, adding water for quenching reaction, washing the reaction solution with hydrochloric acid and water, concentrating an organic phase, and crystallizing to obtain an intermediate III;
s4: dissolving the intermediate III with toluene, adding docetaxel side chain acid, DMAP and DCC, stirring for reaction, adding water for quenching after reaction, adding ethyl acetate for dilution, carrying out acid washing and alkali washing, drying with anhydrous sodium sulfate, carrying out suction filtration, adding hydrochloric acid into filtrate, stirring for reaction, adding a sodium bicarbonate solution into a reaction solution, adding ethyl acetate for extraction, washing an organic phase with a sodium bisulfite solution, concentrating the organic phase, dripping a concentrate into n-heptane, separating out a solid, carrying out suction filtration, and drying to obtain an intermediate IV;
s5: dissolving the intermediate IV with methanol, adding palladium carbon, sealing, replacing nitrogen for three times, replacing hydrogen again, reacting at normal pressure, filtering after the reaction is finished, concentrating the filtrate, and purifying by column chromatography to obtain 7-trichloro-ethoxycarbonyl docetaxel;
the preparation route of 7-trichloro-ethoxycarbonyl docetaxel is as follows:
further, in the step S1, the ratio of the dosage of the triethylchlorosilane to the dosage of the 10-DAB is 0.5-0.7 (V/W), the reaction temperature of the stirring reaction is 0-5 ℃, and the reaction time is 30-60 min.
Further, in the step S2, the ratio of the dosage of the 4-dimethylaminopyridine to the dosage of the intermediate I is 0.5-0.6 (W/W), the reaction temperature of the stirring reaction is 40-50 ℃, and the reaction time is 1-2 h.
Furthermore, in step S3, the ratio of the amount of the hydrogen fluoride pyridine to the amount of the intermediate II is 3-3.5 (W/W), the reaction temperature of the hydrogen fluoride pyridine reaction stage is 15-25 ℃, and the reaction time is 8-15 h.
Furthermore, in step S3, the ratio of the amount of TrocCl to the amount of the intermediate II is 0.4-0.5 (W/W), the reaction temperature in the reaction stage of TrocCl is 0-10 ℃, and the reaction time is 20-40 min.
Further, in step S4, the ratio of the amount of the docetaxel side chain acid to the amount of the intermediate III is 0.9 to 1.0 (W/W), and the ratio of the amount of the DMAP to the amount of the intermediate III is 0.02 to 0.03 (W/W); the ratio of the DCC dosage to the intermediate III dosage is 0.5-0.6 (W/W).
Further, in step S4, the reaction temperature of the reaction stage of the doxycycline side chain acid is 15-25 ℃, and the reaction time is 2-3 h.
Further, in step S4, the ratio of the amount of the hydrochloric acid methanol solution to the intermediate III is 4-5 (V/W), and the concentration of the hydrochloric acid methanol solution is 1mol/L.
Further, in the step S4, the reaction temperature of the hydrochloric acid methanol solution reaction stage is 15-25 ℃, and the reaction time is 3-5 h.
Further, in step S5, the palladium carbon is 10% palladium carbon, the ratio of the amount of the 10% palladium carbon to the amount of the intermediate IV is 0.05-0.1 (W/W), the reaction temperature is 15-25 ℃, and the reaction time is 5-8 h.
In conclusion, the invention has the following beneficial effects:
1. the method comprises the following steps of 5 steps of synthesizing a target product, firstly constructing a docetaxel parent nucleus (namely an intermediate I) through 10-DAB, then forming Cbz benzyloxycarbonyl on carbonyl of the docetaxel parent nucleus through DMAP and benzyl chloroformate, using the Cbz benzyloxycarbonyl as a heat preservation base to be stable, then adding hydrogen fluoride and Troccl, selectively constructing Troc trichloroethoxycarbonyl on the docetaxel parent nucleus, then introducing docetaxel side chain acid to construct a docetaxel side chain on the docetaxel parent nucleus to form a docetaxel intermediate, finally introducing hydrogen and using palladium carbon as a catalyst, selectively replacing the Cbz benzyloxycarbonyl to complete construction of the carbonyl, obtaining a final current product, strictly controlling conditions of related reactions, ensuring that each step of reaction in the process is a main single product, and having strong purpose and no obvious by-product, and greatly improving the yield of the target product.
2. The temperature reaction condition of each step of reaction is easy to achieve, and a large amount of four-membered ring side chain acid and five-membered ring side chain acid are not needed, so that on one hand, the reaction is not carried out under extreme conditions in the preparation route, the reaction difficulty is low, on the other hand, the expensive four-membered ring side chain acid and five-membered ring side chain acid are not needed, the related cost is reduced, and the method is suitable for preparing the target product in an industrial large scale.
3. Necessary purification is only carried out in the final step, a large amount of purification operation is avoided in the intermediate process, the operation difficulty of workers is greatly reduced, and the preparation period is favorably shortened.
Drawings
FIG. 1 is a schematic diagram of the steps of a process for preparing 7-trichloroethoxycarbonyl docetaxel.
FIG. 2 is an HPLC chromatogram of 7-trichloroethoxycarbonyl docetaxel obtained in example 1 of the present invention.
FIG. 3 is an MS spectrum of 7-trichloroethoxycarbonyl docetaxel obtained in example 1 of the present invention.
FIG. 4 is a 1H NMR spectrum of 7-trichloroethoxycarbonyl docetaxel obtained in example 1 of the present invention.
FIG. 5 is a 13C NMR spectrum of 7-trichloroethoxycarbonyl docetaxel obtained in example 1 of the present invention.
FIG. 6 HPLC chromatogram of the sample obtained in comparative 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 embodiments of the present invention will be described in detail with reference to the accompanying drawings and the following detailed description. The advantages and features of the present invention will become more apparent from the following description.
Example 1:
a preparation method of 7-trichloroethoxycarbonyl docetaxel, as shown in fig. 1, comprising the following steps:
s1, 5g of 10-DAB (10-deacetylbaccatin III), 2.5g of 2-methylimidazole and 20ml of DMF (N, N-dimethylformamide) are added into a 100ml reaction bottle, and the mixture is stirred and dissolved. 3.5ml of triethylchlorosilane is added dropwise, and the mixture is stirred and reacts in an ice bath (0-5 ℃). After reacting for 30min, adding water into the reaction solution, extracting with dichloromethane, collecting and concentrating the organic phase, adding 15ml of ethyl acetate to dissolve, dropwise adding 50ml of n-heptane while stirring, and performing suction filtration and drying to obtain 6.8g of an intermediate I.
S2 and 6.8g of intermediate I are dissolved in 68ml of tetrahydrofuran, 4g of DMAP (4-dimethylaminopyridine) is added, the temperature is raised to 40 ℃, 2.7g of benzyl chloroformate (diluted by a small amount of tetrahydrofuran) is added dropwise, and the mixture is stirred and reacted for 1 hour at the temperature of 40-50 ℃. After the reaction is finished, water is added to quench the reaction, diluted hydrochloric acid and water are used for washing once respectively, the organic phase is collected and concentrated, 15ml of ethyl acetate is added to dissolve the organic phase, 50ml of n-heptane is added dropwise while stirring, and 6.3g of intermediate II is obtained after suction filtration and drying.
S3, 6.3g of the intermediate II is dissolved and cleared by 60ml of pyridine, 19g of hydrogen fluoride pyridine is added after temperature control, and the reaction is stirred at room temperature (about 20 ℃). After reacting for 15h, adding 60ml dichloromethane, moving into ice bath, dripping 3.15g Troccl (chloroformic acid-2, 2-trichloroethyl ester), stirring and reacting for 20min at 0-10 ℃. Water is added to quench the reaction, hydrochloric acid and water are used for washing, the organic phase is concentrated, 20ml of ethyl acetate is used for dissolving, 100ml of n-heptane is dripped into the organic phase, solid is separated out, and 5.2g of intermediate III is obtained after suction filtration and drying.
S4, 5.2g of intermediate III were dissolved in 50ml of toluene, 5.2g of doxy-side chain acid and 0.11g of DMAP (4-dimethylaminopyridine) were added, 2.6g of DCC (N, N' -dicyclohexylcarbodiimide) was added, and the mixture was stirred at room temperature (about 18 ℃ C.) for reaction for 3 hours. After the reaction is finished, adding water for quenching, adding ethyl acetate for diluting, carrying out acid washing and alkali washing, drying by using anhydrous sodium sulfate, carrying out suction filtration and collecting filtrate, adding 21ml 1mol/L hydrochloric acid into the filtrate, and stirring for reaction. Adding sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction, washing an organic phase with sodium bisulfite solution, concentrating the organic phase to a small amount, dropwise adding the concentrate into 100ml of n-heptane, separating out a solid, performing suction filtration, and drying to obtain 5.8g of an intermediate IV.
S5, adding 0.3g of 10% palladium carbon into 5.8g of the intermediate IV with 120ml of methanol, sealing, replacing nitrogen for three times, replacing hydrogen again, stirring at room temperature (25 ℃), and reacting for 8 hours at normal pressure. After the reaction, the mixture is filtered, the filtrate is concentrated, and 3.8g of 7-trichloroethoxycarbonyl docetaxel is obtained through column chromatography purification (the mobile phase is dichloromethane and methanol), the purity is 95.47 percent, and the total yield is 42 percent as shown in figure 2.
The preparation route of the 7-trichloroethoxycarbonyl docetaxel is shown as a formula 3:
as shown in FIG. 3, MS spectrum of 7-trichloroethoxycarbonyl docetaxel in the present example, wherein its mass-to-charge ratio m/z =1006.2, [ 2 ], [ M ] +Na ]] + The exact Mass of the original molecule can be deduced to be 981, consistent with the target compound.
As shown in FIG. 4, which is a 1H NMR spectrum of 7-trichloroethoxycarbonyl docetaxel of this example, 1 H NMR(500MHz,CDCl3)δ:7.30~8.11(10H,ArH),6.21(1H,t,J=8.2Hz,H 13 ),5.69(1H,d,J=6.9Hz,H 2 ),5.39(3H,H 3’ was overlapped with H 7 and H 10 ),5.27(1H,m,-NH),4.94(1H,d,J=8.4Hz,H 5 ),4.82(1H,d,J=11.9Hz,-CH 2 of Troc),4.69(1H,d,J=11.9Hz,-CH 2 of Troc),4.62(1H,s,H 2’ ),4.33(1H,d,J=8.6Hz,H 20 ),4.22(1H,d,J=8.6Hz,H 20 ),4.00(1H,d,J=6.8Hz,H 3 ),2.64(1H,m,H 6 ),2.39(3H,s,H 27 ),2.29(2H,m,H 14 ),2.06(1H,m,H 6 ),1.89(6H,s,3H 18 was overlapped with 3H 19 ),1.35(9H,s,t-Bu),1.23(3H,s,3H 16 /3H 17 ),1.10(3H,s,3H 16 /3H 17 )。
as shown in FIG. 5, the 13C NMR spectrum of violet 7-trichloroethoxycarbonyl docetaxel of this example was analyzed, wherein, 13 C NMR(125MHz,CDCl3)δ:210.153,172.697,170.389,166.933,155.319,153.313,138.975,138.433,135.775,133.756,130.169,129.077,128.85,128.743,128.074,126.747,94.273,83.457,80.602,80.222,78.788,77.255,77.001,76.904,76.747,76.55,74.601,73.619,72.404,56.346,46.191,42.986,35.786,33.219,28.197,26.282,22.476,20.485,14.161,10.887。
and (4) determining that the target product prepared by the reaction is 7-trichloroethoxycarbonyl docetaxel by combining the spectrum detection results.
Example 2:
s1, adding 10-DAB 1g, 2-methylimidazole 0.5g and DMF 10ml into a 100ml reaction bottle, and stirring to dissolve the mixture to be clear. 0.5ml of triethyl chlorosilane is added dropwise, and the mixture is stirred and reacts in an ice bath (0-5 ℃). After the reaction for 60min (monitoring the midway point plate), adding water into the reaction liquid, extracting with dichloromethane, collecting and concentrating an organic phase, adding 3ml of ethyl acetate to dissolve, dropwise adding 10ml of n-heptane while stirring, and performing suction filtration and drying to obtain an intermediate I1.5g.
S2 and 1.5g of intermediate I are dissolved in 15ml of tetrahydrofuran, 0.8g of DMAP (4-dimethylaminopyridine) is added, the temperature is raised to 45 ℃, 0.6g of benzyl chloroformate (diluted by a small amount of tetrahydrofuran) is added dropwise, and the mixture is stirred and reacted for 2 hours at the temperature of 40-50 ℃. After the reaction is finished, adding water to quench the reaction, washing with dilute hydrochloric acid and water once respectively, collecting and concentrating an organic phase, adding 3ml of ethyl acetate to dissolve the organic phase, dropwise adding 10ml of n-heptane while stirring, and performing suction filtration and drying to obtain 1.1g of an intermediate II;
s3, dissolving 1.1g of the intermediate II in 10ml of pyridine, controlling the temperature, adding 3.8g of hydrogen fluoride pyridine, and stirring at room temperature (about 20 ℃) for reaction. After reacting for 8h, 10ml of dichloromethane is added, the mixture is moved into an ice bath, 0.45g of TrocL (chloroformic acid-2, 2-trichloroethyl ester) is dripped, and the mixture is stirred and reacted for 40min at the temperature of 0-10 ℃. Adding water to quench the reaction, washing with hydrochloric acid and water, concentrating the organic phase, dissolving with 5ml ethyl acetate, adding dropwise into 30ml n-heptane to precipitate solid, filtering, and drying to obtain 0.8g of intermediate III;
s4, dissolving 0.8g of intermediate III in 10ml of toluene, adding 0.8g of doxy-side chain acid and 0.02g of DMAP (4-dimethylaminopyridine), adding 0.48g of DCC (N, N' -dicyclohexylcarbodiimide), and stirring at room temperature (about 20 ℃) for reaction for 2 hours. After the reaction is finished, adding water for quenching, adding ethyl acetate for diluting, carrying out acid washing and alkali washing, drying by using anhydrous sodium sulfate, carrying out suction filtration and collecting filtrate, adding 4ml of 1mol/L hydrochloric acid into the filtrate, and stirring for reaction. Adding sodium bicarbonate solution into the reaction solution, adding ethyl acetate for extraction, washing an organic phase with sodium bisulfite solution, concentrating the organic phase to a small amount, dropwise adding the concentrate into 30ml of n-heptane, separating out a solid, performing suction filtration, and drying to obtain 0.8g of an intermediate IV.
S5, adding 0.08g of 10% palladium carbon into 0.8g of the intermediate IV by using 20ml of methanol, sealing, replacing nitrogen for three times, replacing hydrogen again, stirring at room temperature (about 20 ℃), and reacting for 5 hours at normal pressure. After the reaction, the mixture is filtered, the filtrate is concentrated, and the 0.6g of 7-trichloroethoxycarbonyl docetaxel is obtained after column chromatography purification (the mobile phase is dichloromethane and methanol), the purity is 97.096 percent, and the total yield is 33.2 percent.
And (3) verification experiment:
designing a reaction route thought: the 7-trichloroethoxycarbonyl docetaxel is obtained by using zinc powder and controlling the equivalent weight of the zinc powder to create the condition of reducing the zinc powder on docetaxel N-1.
Designing a reaction:
using 100ml of methanol to dissolve 5g of docetaxel N-1, adding 15ml of acetic acid, moving the mixture into an ice bath, controlling the temperature to be 0-10 ℃, slowly adding 2.8g of zinc powder, carrying out suction filtration after reacting for 1 hour, adding sodium bicarbonate to filtrate, neutralizing the filtrate, extracting the neutralized filtrate with dichloromethane, concentrating and inspecting, and referring to figure 6, wherein 46 percent of raw material (docetaxel N-1) is not reacted completely, but the target product 7-trichloroethoxycarbonyl docetaxel is not detected basically.
And (4) conclusion: 7-trichloro-ethoxycarbonyl docetaxel itself is a potential impurity, and 7-trichloro-ethoxycarbonyl docetaxel cannot be obtained by directly mono-removing docetaxel N-1.
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.
Claims (10)
1. A preparation method of 7-trichloro-ethoxycarbonyl docetaxel is characterized by comprising the following steps:
s1: stirring and dissolving 10-DAB and 2-methylimidazole with DMF (dimethyl formamide), then dropwise adding triethylchlorosilane, stirring for reaction, adding water into reaction liquid for quenching, extracting the reaction liquid with dichloromethane, collecting and concentrating an organic phase, crystallizing the organic phase with ethyl acetate and n-heptane, and drying to obtain an intermediate I;
s2: dissolving the intermediate I with tetrahydrofuran, adding DMAP into the solution, dropwise adding benzyl chloroformate, stirring for reaction, adding water after the reaction is finished to quench the reaction, carrying out acid washing on the reaction solution, then carrying out water washing, collecting and concentrating an organic phase, and crystallizing to obtain an intermediate II;
s3: dissolving the intermediate II with pyridine, controlling the temperature, adding hydrogen fluoride pyridine, stirring for reaction, adding dichloromethane into the reaction, dropwise adding TrocCl, stirring for reaction, adding water for quenching reaction, washing the reaction solution with hydrochloric acid and water, concentrating an organic phase, and crystallizing to obtain an intermediate III;
s4: dissolving the intermediate III with toluene, adding docetaxel side chain acid, DMAP and DCC, stirring for reaction, adding water for quenching after reaction, adding ethyl acetate for dilution, carrying out acid washing and alkali washing, drying with anhydrous sodium sulfate, carrying out suction filtration, adding hydrochloric acid into filtrate, stirring for reaction, adding a sodium bicarbonate solution into a reaction solution, adding ethyl acetate for extraction, washing an organic phase with a sodium bisulfite solution, concentrating the organic phase, dripping a concentrate into n-heptane, separating out a solid, carrying out suction filtration, and drying to obtain an intermediate IV;
s5: dissolving the intermediate IV with methanol, adding palladium carbon, sealing, replacing nitrogen for three times, replacing hydrogen again, reacting at normal pressure, filtering after the reaction is finished, concentrating the filtrate, and purifying by column chromatography to obtain 7-trichloroethoxycarbonyl docetaxel;
the preparation route of 7-trichloro-ethoxycarbonyl docetaxel is as follows:
2. the method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 1, wherein: in the step S1, the proportion of the consumption of the triethylchlorosilane to the consumption of the 10-DAB is 0.5-0.7 (V/W), the reaction temperature of the stirring reaction is 0-5 ℃, and the reaction time is 30-60 min.
3. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 2, wherein: in step S2, the ratio of the dosage of the 4-dimethylaminopyridine to the dosage of the intermediate I is 0.5-0.6 (W/W), the reaction temperature of stirring reaction is 40-50 ℃, and the reaction time is 1-2 h.
4. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 3, wherein: in step S3, the ratio of the amount of the hydrogen fluoride pyridine to the amount of the intermediate II is 3-3.5 (W/W), the reaction temperature of the hydrogen fluoride pyridine reaction stage is 15-25 ℃, and the reaction time is 8-15 h.
5. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 4, wherein: in step S3, the ratio of the consumption of TrocCl to the consumption of the intermediate II is 0.4-0.5 (W/W), the reaction temperature in the reaction stage of TrocCl is 0-10 ℃, and the reaction time is 20-40 min.
6. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 5, wherein: in step S4, the ratio of the dosage of the doxychaic acid to the dosage of the intermediate III is 0.9-1.0 (W/W), and the ratio of the dosage of the DMAP to the dosage of the intermediate III is 0.02-0.03 (W/W); the ratio of the DCC dosage to the intermediate III dosage is 0.5-0.6 (W/W).
7. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 6, wherein: in step S4, the reaction temperature of the reaction stage of the side chain acid of the doxycycline is 15-25 ℃, and the reaction time is 2-3 h.
8. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 7, wherein: in step S4, the ratio of the dosage of the hydrochloric acid methanol solution to the intermediate III is 4-5 (V/W), and the concentration of the hydrochloric acid methanol solution is 1mol/L.
9. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 8, wherein: in the step S4, the reaction temperature of the hydrochloric acid methanol solution in the reaction stage is 15-25 ℃, and the reaction time is 3-5 h.
10. The method for preparing 7-trichloroethoxycarbonyl docetaxel according to claim 9, wherein: in step S5, the palladium carbon is 10% palladium carbon, the ratio of the amount of the 10% palladium carbon to the amount of the intermediate IV is 0.05-0.1 (W/W), the reaction temperature is 15-25 ℃, and the reaction time is 5-8 h.
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