阅读说明：本技术 一种n-甲基紫杉醇c的制备方法 (Preparation method of N-methyl paclitaxel C ) 是由 黄春 陆叶梦 王莉佳 王旭阳 毛纪原 于 2021-09-07 设计创作，主要内容包括：本发明公开了一种N-甲基紫杉醇C的制备方法,其技术方案包括以下步骤：S1：TIMF-1以甲酸溶解,加入二氯甲烷和饱和碳酸氢钠,得TIMF-2；S2：将TIMF-2溶于甲酰胺中,加咪唑,加氯硅烷,搅拌反应,加乙酸乙酯萃取,得TIMF-3；S3：TIMF-3溶于二氯甲烷,加入正己酸和吡啶,加碳二亚胺,搅拌反应,得TIMF-4；S4：将TIMF-4溶于二氯甲烷中,加萘和氧鎓四氟硼酸,搅拌反应,得TIMF-5；S5：将TIMF-5用甲醇和乙酸溶清,加入锌粉,搅拌反应,得TIMF-6；S6：TIMF-6用酰胺溶清,加2-甲基咪唑,加氯硅烷,搅拌反应,得TIMF-7；S7：TIMF-7用四氢呋喃溶清,加入吡啶,滴加乙酸酐,得TIMF-8；S8：TIMF-8用乙腈溶清,加盐酸,加二氯甲烷和碳酸氢钠溶液萃取,得N-甲基紫杉醇C,本发明的优点在于,反应条件温和,目标产物纯度高。(The invention discloses a preparation method of N-methyl paclitaxel C, which comprises the following steps: s1: dissolving the TIMF-1 with formic acid, and adding dichloromethane and saturated sodium bicarbonate to obtain TIMF-2; s2: dissolving the TIMF-2 in formamide, adding imidazole and chlorosilane, stirring for reaction, and adding ethyl acetate for extraction to obtain TIMF-3; s3: dissolving the TIMF-3 in dichloromethane, adding n-hexanoic acid and pyridine, adding carbodiimide, and stirring for reaction to obtain TIMF-4; s4: dissolving the TIMF-4 in dichloromethane, adding naphthalene and oxonium tetrafluoroborate, and stirring for reaction to obtain TIMF-5; s5: dissolving the TIMF-5 in methanol and acetic acid, adding zinc powder, and stirring for reaction to obtain TIMF-6; s6: dissolving the TIMF-6 in amide, adding 2-methylimidazole and chlorosilane, and stirring for reaction to obtain TIMF-7; s7: dissolving the TIMF-7 in tetrahydrofuran, adding pyridine, and dropwise adding acetic anhydride to obtain TIMF-8; s8: the method has the advantages of mild reaction conditions and high purity of target products.)

1. A preparation method of N-methyl paclitaxel C is characterized by comprising the following steps:

s1: dissolving the methyl paclitaxel TIMF-1 with formic acid, stirring at room temperature for reaction, adding dichloromethane and saturated sodium bicarbonate solution after the reaction is finished, collecting and concentrating an organic phase to obtain TIMF-2;

s2: dissolving the TIMF-2 in N, N-dimethylformamide, adding 2-methylimidazole, dropwise adding triethylchlorosilane, stirring for reaction, adding water for quenching reaction after the reaction is finished, adding ethyl acetate for extraction, and concentrating an organic phase to obtain TIMF-3;

s3: dissolving the TIMF-3 in dichloromethane, adding N-hexanoic acid and 4-dimethylaminopyridine, dropwise adding N, N-diisopropylcarbodiimide, stirring for reaction, adding water for extraction after the reaction is finished, collecting an organic phase, concentrating, and performing column chromatography to obtain the TIMF-4;

s4: dissolving the TIMF-4 in dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene and trimethyl oxonium tetrafluoroborate, stirring for reaction, after the reaction is finished, performing suction filtration on a reaction solution, adding dilute hydrochloric acid into a filtrate for extraction, collecting an organic phase, and concentrating to obtain the TIMF-5;

s5: dissolving the TIMF-5 with methanol and acetic acid, adding zinc powder, stirring for reaction, after the reaction is finished, carrying out suction filtration on the reaction solution, neutralizing the filtrate with saturated sodium bicarbonate solution, concentrating the organic phase, and passing through a column to obtain the TIMF-6;

s6: dissolving TIMF-6 in N, N-dimethylformamide, adding 2-methylimidazole, dropwise adding triethylchlorosilane, stirring for reaction, adding water for quenching reaction after the reaction is finished, adding ethyl acetate for extraction, and concentrating an organic phase to obtain TIMF-7;

s7: dissolving TIMF-7 in tetrahydrofuran, adding 4-dimethylaminopyridine, dripping acetic anhydride, stirring at room temperature for reaction, adding water for quenching reaction after the reaction is finished, concentrating, and performing suction filtration to obtain TIMF-8;

s8: dissolving TIMF-8 in acetonitrile, adding 3mol/L hydrochloric acid, stirring at room temperature for reaction, adding dichloromethane and saturated sodium bicarbonate solution for extraction after the reaction is finished, concentrating an organic phase, passing through a column, and drying to obtain N-methyl paclitaxel C;

the reaction route of the preparation process is as follows:

2. the method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S1, the ratio of formic acid to paclitaxel is 10(W/V), the reaction temperature is 0-35 deg.C, and the reaction time is 3-4 h.

3. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S2, the weight ratio of 2-methylimidazole to TIMF-2 is 0.79-0.89, the weight ratio of triethylchlorosilane to TIMF-2 is 0.15-0.17, the reaction temperature is 0-10 ℃, and the reaction time is 0.5-2 h.

4. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S3, the weight ratio of N-hexanoic acid to TIMF-3 is 0.124-0.129, the weight ratio of dimethylaminopyridine to TIMF-3 is 0.008-0.032, the weight ratio of N, N-diisopropylcarbodiimide to TIMF-3 is 0.179-0.242, and the reaction time is 1.5-2 h.

5. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: . In step S4, the weight ratio of 1, 8-bis-dimethylaminonaphthalene to TIMF-4 is 0.5 to 0.8, the weight ratio of trimethyloxonium tetrafluoroborate to TIMF-4 is 0.3 to 0.35, the reaction temperature is 20 to 30 ℃, and the reaction time is 4 to 8 hours.

6. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S5, the weight ratio of zinc powder to TIMF-5 is 0.48-0.53, and the reaction time is 2-2.5 h.

7. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S6, the weight ratio of 2-methylimidazole to TIMF-6 is 0.13-0.21, the weight ratio of triethylchlorosilane to TIMF-6 is 0.23-0.29, the reaction temperature is 0 ℃ in an ice bath, and the reaction time is 30-45 min.

8. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S7, the weight ratio of dimethylaminopyridine to TIMF-7 is 0.12-0.18, the weight ratio of acetic anhydride to TIMF-7 is 0.12-0.18, and the reaction time is 1-3 h.

9. The method of claim 1, wherein the N-methyl paclitaxel C is prepared by the following steps: in step S8, the concentration of hydrochloric acid is 3-3.5 mol/L, the ratio of hydrochloric acid to TIMF-8 is 1.22-1.33 (W/V), and the ratio of dichloromethane to TIMF-8 is 7.31-7.94 (W/V).

Technical Field

The invention relates to the technical field of preparation of taxane natural products, in particular to a preparation method of N-methyl paclitaxel C.

Background

Paclitaxel, a natural anticancer drug, has been widely used clinically in the treatment of breast cancer, ovarian cancer, and some head and neck and lung cancers. Paclitaxel is taken as diterpene alkaloid compound with anticancer activity, has novel and complex chemical structure, wide and remarkable biological activity, completely new and unique action mechanism and scarce natural resources, is greatly favored by phytologists, chemists, pharmacologists and molecular biologists, and becomes an anticancer star which draws attention in the next half of the 20 th century and research focus.

As a mature raw material medicine variety, the impurity spectrum of the medicine is well researched. The European Pharmacopoeia (EP) contains a characteristic impurity N-methyl paclitaxel C (N-methyl paclitaxel C), the structure of which is shown in formula 1, and in order to better study the impurity, the preparation of the impurity becomes an object that each pharmaceutical manufacturer must complete. It has been found through search that there is substantially no literature reporting a synthetic method using accessible compounds as raw materials, and it is very difficult to separate the impurities from many natural extracts, so it is of great importance to develop a feasible preparation method.

Disclosure of Invention

In view of the above disadvantages of the prior art, the present invention provides a method for preparing N-methyl paclitaxel C, which has the advantages of accessibility of the starting materials, mild reaction conditions, high purity of the target product, and suitability for mass production.

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

a preparation method of N-methyl paclitaxel C comprises the following steps:

s1: dissolving the methyl paclitaxel TIMF-1 with formic acid, stirring at room temperature for reaction, adding dichloromethane and saturated sodium bicarbonate solution after the reaction is finished, collecting and concentrating an organic phase to obtain TIMF-2;

s2: dissolving the TIMF-2 in N, N-dimethylformamide, adding 2-methylimidazole, dropwise adding triethylchlorosilane, stirring for reaction, adding water for quenching reaction after the reaction is finished, adding ethyl acetate for extraction, and concentrating an organic phase to obtain TIMF-3;

s3: dissolving the TIMF-3 in dichloromethane, adding N-hexanoic acid and 4-dimethylaminopyridine, dropwise adding N, N-diisopropylcarbodiimide, stirring for reaction, adding water for extraction after the reaction is finished, collecting an organic phase, concentrating, and performing column chromatography to obtain the TIMF-4;

s4: dissolving the TIMF-4 in dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene and trimethyl oxonium tetrafluoroborate, stirring for reaction, after the reaction is finished, performing suction filtration on a reaction solution, adding dilute hydrochloric acid into a filtrate for extraction, collecting an organic phase, and concentrating to obtain the TIMF-5;

s5: dissolving the TIMF-5 with methanol and acetic acid, adding zinc powder, stirring for reaction, after the reaction is finished, carrying out suction filtration on the reaction solution, neutralizing the filtrate with saturated sodium bicarbonate solution, concentrating the organic phase, and passing through a column to obtain the TIMF-6;

s6: dissolving TIMF-6 in N, N-dimethylformamide, adding 2-methylimidazole, dropwise adding triethylchlorosilane, stirring for reaction, adding water for quenching reaction after the reaction is finished, adding ethyl acetate for extraction, and concentrating an organic phase to obtain TIMF-7;

s7: dissolving TIMF-7 in tetrahydrofuran, adding 4-dimethylaminopyridine, dripping acetic anhydride, stirring at room temperature for reaction, adding water for quenching reaction after the reaction is finished, concentrating, and performing suction filtration to obtain TIMF-8;

s8: dissolving TIMF-8 in acetonitrile, adding 3mol/L hydrochloric acid, stirring at room temperature for reaction, adding dichloromethane and saturated sodium bicarbonate solution for extraction after the reaction is finished, concentrating an organic phase, passing through a column, and drying to obtain N-methyl paclitaxel C;

the reaction route of the preparation process is as follows:

further, in step S1, the ratio of formic acid to paclitaxel is 10(W/V), the reaction temperature is 0-35 ℃, and the reaction time is 3-4 h.

Further, in step S2, the weight ratio of 2-methylimidazole to TIMF-2 is 0.79-0.89, the weight ratio of triethylchlorosilane to TIMF-2 is 0.15-0.17, the reaction temperature is 0-10 ℃, and the reaction time is 0.5-2 h.

Further, in step S3, the weight ratio of N-hexanoic acid to TIMF-3 is 0.124-0.129, the weight ratio of dimethylaminopyridine to TIMF-3 is 0.008-0.032, the weight ratio of N, N-diisopropylcarbodiimide to TIMF-3 is 0.179-0.242, and the reaction time is 1.5-2 h.

Further, in step S4, the weight ratio of 1, 8-bis-dimethylamino naphthalene to TIMF-4 is 0.5 to 0.8, the weight ratio of trimethyl oxonium tetrafluoroborate to TIMF-4 is 0.3 to 0.35, the reaction temperature is 20 to 30 ℃, and the reaction time is 4 to 8 hours.

Further, in step S5, the weight ratio of zinc powder to TIMF-5 is 0.48-0.53, and the reaction time is 2-2.5 h.

Further, in step S6, the weight ratio of 2-methylimidazole to TIMF-6 is 0.13-0.21, the weight ratio of triethylchlorosilane to TIMF-6 is 0.23-0.29, the reaction temperature is 0 ℃ in an ice bath, and the reaction time is 30-45 min.

Further, in step S7, the weight ratio of dimethylaminopyridine to TIMF-7 is 0.12-0.18, the weight ratio of acetic anhydride to TIMF-7 is 0.12-0.18, and the reaction time is 1-3 h.

Further, in step S8, the concentration of hydrochloric acid is 3 to 3.5mol/L, the ratio of hydrochloric acid to TIMF-8 is 1.22 to 1.33(W/V), and the ratio of dichloromethane to TIMF-8 is 7.31 to 7.94 (W/V).

In conclusion, the invention has the following beneficial effects:

1. the starting material TIMF-1 can be easily prepared by carrying out 3-step reaction on 10-DAB, and compared with some natural extract impurities with similar structures, the starting material is easier to obtain, the corresponding raw material cost is lower, and the method is favorable for large-batch industrial production.

2. According to the invention, through cross protection, main reactions of all steps are clear, no obvious side reaction exists basically, and product points are easy to judge; the stability of each intermediate is good, particularly the naked amino intermediate TIMF-2 is not easy to oxidize, and the TIMF-2 has better stability compared with the product produced in the traditional preparation process, and the overall yield and the judgment of the subsequent reaction product are obviously improved.

Drawings

FIG. 1 is an HPLC chromatogram of N-methyltaxol C prepared in example 1.

FIG. 2 is the MS spectrum (positive ion mode) of N-methyl paclitaxel C in example 1.

FIG. 3 is a drawing showing the preparation of N-methyltaxol C in example 1¹H NMR spectrum.

FIG. 4 is a drawing showing the preparation of N-methyltaxol C in example 1¹³C NMR spectrum.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the present invention is provided 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. To make the objects, features and advantages of the present invention comprehensible, reference is made to the accompanying drawings. It should be understood that the drawings and figures are only for the purpose of illustration and description, and are not intended to limit the scope of the invention, which is defined by the claims, but rather by the claims.

Example 1:

s1: 50g of paclitaxel TIMF-1 is dissolved by 500ml of formic acid, stirred and reacted for 4h at room temperature (about 23 ℃), 500ml of dichloromethane is added after the reaction is finished, saturated sodium bicarbonate solution is added for neutralization till no bubbling occurs, and extraction liquid separation is carried out to collect and concentrate an organic phase, thus obtaining 59.4g of viscous material TIMF-2.

S2: dissolving the TIMF-2 in 250ml of N, N-dimethylformamide, adding 5.3g (1.5eq) of 2-methylimidazole, dropwise adding 9.7g of triethylchlorosilane, stirring and reacting for 2 hours under ice bath (0 ℃), adding water to quench the reaction after the reaction is finished, adding 500ml of ethyl acetate to extract, washing an organic phase with purified water for 2 times, and concentrating the organic phase to obtain 60.3g of viscous TIMF-3.

S3: dissolving the TIMF-3 in 400ml dichloromethane, adding 7.5g N-hexanoic acid and 0.5g 4-dimethylaminopyridine, dropwise adding 10.8g N, N-diisopropylcarbodiimide, stirring at room temperature for reaction for 2h, adding water for extraction after the reaction is finished, collecting an organic phase, concentrating, and passing through a column to obtain 42.8g TIMF-4.

S4: dissolving 40g of TIMF-4 in 400ml of dichloromethane, adding 20g of 1, 8-bis-dimethylamino naphthalene and 12g of trimethyl oxonium tetrafluoroborate, stirring at 30 ℃ for reaction for 4 hours, after the reaction is finished, carrying out suction filtration on a reaction solution, adding 0.1mol/L diluted hydrochloric acid into a filtrate for extraction, collecting an organic phase, and concentrating to obtain 70.3g of gum TIMF-5.

S5: dissolving the TIMF-5 in 400ml of methanol and 120ml of acetic acid, adding 35g of zinc powder, stirring at room temperature for reaction for 2 hours, after the reaction is finished, carrying out suction filtration on a reaction solution, neutralizing a filtrate with a saturated sodium bicarbonate solution, concentrating an organic phase, and passing through a column to obtain 25.0g of TIMF-6.

S6: dissolving 25.0g of TIMF-6 in 125ml of N, N-dimethylformamide, adding 3.3g of 2-methylimidazole, stirring in an ice bath (0 ℃), dropwise adding 6g of triethylchlorosilane, continuing stirring in the ice bath for reaction for 30min, adding water to quench the reaction after the reaction is finished, adding ethyl acetate to extract, and concentrating an organic phase to obtain 37.3g of gum TIMF-7.

S7: dissolving the TIMF-7 in 200ml of tetrahydrofuran, adding 6.5g of 4-dimethylaminopyridine, dropwise adding 5.4g of acetic anhydride, and stirring at room temperature for reacting for 2 hours. After the reaction, 500ml of water is added to quench the reaction, and after concentration, 37.8g of TIMF-8 (wet product) is obtained by suction filtration.

S8: the above TIMF-8 was dissolved in 250ml of acetonitrile, and 50ml of 3mol/L hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. After the reaction is finished, adding 300ml of dichloromethane, then adding saturated sodium bicarbonate solution until no bubbles are generated, extracting and separating liquid, collecting concentrated organic phase, passing through a column, and drying to obtain 16.1g of N-methyl paclitaxel C, wherein the HPLC purity is 97.7%, the total yield is 43.3%, and the liquid phase spectrum is shown in figure 1.

As shown in FIG. 2, in this example, the MS spectrum of N-methyl paclitaxel C,wherein the mass-to-charge ratio M/z is 884.3[ M + Na [ ]]⁺So that its molecular formula is C₄₇H₅₉NO₁₄。

As shown in FIG. 3, the present example shows the preparation of N-methyl paclitaxel C¹A HNMR map wherein,¹H NMR(500MHz,CDCl₃)δ:7.33～8.11(10H,ArH),6.30(1H,s,H₁₀),6.17(1H,t,J＝8.6Hz,H₁₃),5.78(1H,d,J＝2.9Hz,H₃₂),5.68(1H,d,J＝7.0Hz,H₂),4.93(1H,d,J＝8.8Hz,H₅),4.89(1H,d,J＝3.3Hz,H₃₁),4.41(1H,dd,J＝10.7Hz,6.8Hz,H₇),4.28(1H,d,J＝8.4Hz,H₂₀),4.17(1H,d,J＝8.4Hz,H₂₀),3.80(1H,d,J＝6.9Hz,H₃),2.89(3H,s,H₃₈),2.55(1H,m,H₆),2.34(4H,m,2H₁₄overlapped with 2H₄₀),2.24(3H,s,H₂₇),2.22(3H,s,H₂₉),1.89(3H,s,H₁₈),1.86(3H,m,2×-OH overlapped with H₆),1.67(3H,s,H₁₉),1.60(2H,m,H₄₁),1.28(7H,m,2H₄₂/2H₄₃overlapped with 3H₄₄),1.15(3H,s,H₁₆/H₁₇),0.86(3H,s,H₁₆/H₁₇). The carbon atom numbering refers to the following structural formula:

as shown in FIG. 4, this example is N-Methylpaclitaxel C¹³A C NMR spectrum, wherein 13C NMR (125MHz, CDCl3) δ:203.853,175.054,173.588,171.223,170.213,166.948,142.752,136.655,133.616,132.843,130.212,129.298,128.881,128.636,128.131,128.098,84.446,80.9,79.124,76.457,75.681,75.119,72.839,72.129,61.509,58.593,45.627,43.237,35.728,35.574,35.337,34.025,31.493,26.759,24.704,22.385,22.194,21.924,20.812,14.796,13.853, 9.544.

Example 2:

s1: dissolving 5g of TIMF-1 in 50ml of formic acid, stirring at room temperature (about 25 ℃) for reaction for 3 hours, adding 50ml of dichloromethane after the reaction is finished, adding saturated sodium bicarbonate solution for neutralization till no bubbling occurs, extracting, separating, collecting and concentrating an organic phase to obtain 6.0g of viscous TIMF-2.

S2: dissolving the TIMF-2 in 25ml of N, N-dimethylformamide, adding 0.5g of 2-methylimidazole, dropwise adding 1g of triethylchlorosilane, stirring at the temperature of below 10 ℃ for reaction for 30min, adding water for quenching reaction after the reaction is finished, adding 50ml of ethyl acetate for extraction, washing an organic phase with purified water for 2 times, and concentrating the organic phase to obtain 6.0g of a viscous substance TIMF-3;

s3: dissolving the TIMF-3 in 40ml of dichloromethane, adding 0.75g of N-hexanoic acid and 0.1g of 4-dimethylaminopyridine, dropwise adding 1.1g N, N-diisopropylcarbodiimide, stirring at room temperature for reacting for 2 hours, adding water for extraction after the reaction is finished, collecting an organic phase, concentrating, and passing through a column to obtain 4.3g of TIMF-4.

S4: dissolving 4.3g of TIMF-4 in 40ml of dichloromethane, adding 3.4g of 1, 8-bis-dimethylamino naphthalene and 1.5g of trimethyloxonium tetrafluoroborate, stirring at 20 ℃ for reacting for 8 hours, after the reaction is finished, carrying out suction filtration on a reaction solution, adding 0.1mol/L dilute hydrochloric acid into a filtrate for extraction, collecting an organic phase, and concentrating to obtain 7.2g of gum TIMF-5.

S5: dissolving the TIMF-5 in 40ml of methanol and 12ml of acetic acid, adding 3.5g of zinc powder, stirring at room temperature for reacting for 2 hours, after the reaction is finished, carrying out suction filtration on a reaction solution, neutralizing a filtrate with a saturated sodium bicarbonate solution, concentrating an organic phase, and passing through a column to obtain 2.6g of TIMF-6.

S6: dissolving 2.6g of TIMF-6 in 15ml of N, N-dimethylformamide, adding 0.5g of 2-methylimidazole, stirring in an ice bath (0 ℃), dropwise adding 0.6g of triethylchlorosilane, continuing stirring in the ice bath for reaction for 30min, adding water after the reaction is finished, quenching the reaction, adding ethyl acetate for extraction, and concentrating 3.8g of an organic phase to obtain a gum TIMF-7.

S7: dissolving the TIMF-7 in 20ml of tetrahydrofuran, adding 0.6g of 4-dimethylaminopyridine, dropwise adding 0.5g of acetic anhydride, and stirring at room temperature for reaction for 2 hours. After the reaction, 80ml of water was added to quench the reaction, and after concentration, 3.8g of TIMF-8 (wet product) was obtained by suction filtration.

S8: the above TIMF-8 was dissolved in 25ml of acetonitrile, and 5ml of 3mol/L hydrochloric acid was added thereto, followed by stirring at room temperature for 2 hours. After the reaction is finished, dichloromethane is added, saturated sodium bicarbonate solution is added until no bubbles are generated, extraction and liquid separation are carried out, a concentrated organic phase is collected, and then the concentrated organic phase is subjected to column chromatography and drying to obtain the 1.8g N-methyl paclitaxel C with the HPLC purity of 98.8 percent and the total yield of 48.4 percent.

Example 3:

s1: dissolving 5g of TIMF-1 in 50ml of formic acid, stirring at room temperature (about 25 ℃) for reaction for 3 hours, adding 50ml of dichloromethane after the reaction is finished, adding saturated sodium bicarbonate solution for neutralization till no bubbling occurs, extracting, separating, collecting and concentrating an organic phase to obtain 6.3g of viscous TIMF-2.

S2: dissolving the TIMF-2 in 25ml of N, N-dimethylformamide, adding 0.5g of 2-methylimidazole, dropwise adding 1g of triethylchlorosilane, stirring at about 5 ℃ for reacting for 45min, adding water for quenching reaction after the reaction is finished, adding 50ml of ethyl acetate for extraction, washing an organic phase with purified water for 2 times, and concentrating the organic phase to obtain 6.2g of a viscous substance TIMF-3;

s3: dissolving the TIMF-3 in 40ml of dichloromethane, adding 0.8g of N-hexanoic acid and 0.2g of 4-dimethylaminopyridine, dropwise adding 1.5g N, N-diisopropylcarbodiimide, stirring at room temperature for reacting for 1.5h, adding water for extraction after the reaction is finished, collecting an organic phase, concentrating, and passing through a column to obtain 4.7g of TIMF-4.

S4: dissolving 4.7g of TIMF-4 in 90ml of dichloromethane, adding 3.5g of 1, 8-bis-dimethylamino naphthalene and 1.5g of trimethyloxonium tetrafluoroborate, stirring at about 26 ℃ for reaction for 6 hours, after the reaction is finished, carrying out suction filtration on a reaction solution, adding 0.1mol/L dilute hydrochloric acid into a filtrate for extraction, collecting an organic phase, and concentrating to obtain 7.5g of gum TIMF-5.

S5: dissolving the TIMF-5 in 50ml of methanol and 15ml of acetic acid, adding 4.0g of zinc powder, stirring at room temperature for reacting for 2.5h, after the reaction is finished, carrying out suction filtration on a reaction solution, neutralizing a filtrate with a saturated sodium bicarbonate solution, concentrating an organic phase, and passing through a column to obtain 2.8g of TIMF-6.

S6: dissolving 2.8g of TIMF-6 in 15ml of N, N-dimethylformamide, adding 0.6g of 2-methylimidazole, stirring in an ice bath (0 ℃), dropwise adding 0.8g of triethylchlorosilane, continuing stirring in the ice bath for reaction for 45min, adding water after the reaction is finished, quenching the reaction, adding ethyl acetate for extraction, and concentrating an organic phase to obtain 4.0g of gum TIMF-7.

S7: dissolving the TIMF-7 in 20ml of tetrahydrofuran, adding 0.8g of 4-dimethylaminopyridine, dropwise adding 0.8g of acetic anhydride, and stirring at room temperature for reacting for 2 hours. After the reaction, 80ml of water is added to quench the reaction, and the obtained product is concentrated and filtered to obtain the TIMF-8 (wet product).

S8: the above TIMF-8 was dissolved in 25ml of acetonitrile, and 5ml of 3mol/L hydrochloric acid was added thereto, followed by stirring at room temperature for reaction for 3 hours. After the reaction is finished, dichloromethane is added, saturated sodium bicarbonate solution is added until no bubbles are generated, extraction and liquid separation are carried out, a concentrated organic phase is collected, and then the concentrated organic phase is subjected to column chromatography and drying to obtain 2.0g N-methyl paclitaxel C, wherein the HPLC purity is 97.5 percent, and the total yield is 53.7 percent.

Comparative example 1:

attempts were made to prepare N-methyltaxol C from taxol TIMF-1'.

Weighing 5.0g of TIMF-1 'into a reaction bottle, adding 50ml of formic acid, stirring to dissolve the mixture, stirring at room temperature for reacting for 3 hours, adding 50ml of dichloromethane after the reaction is finished, adding a saturated sodium bicarbonate solution for neutralizing until no bubbling occurs, extracting, separating, collecting and concentrating an organic phase to obtain a viscous substance TIMF-2', wherein a TLC monitoring product is two points with similar polarities, and the ratio is close to 1: 1;

s2: dissolving the TIMF-2 'in 25ml of N, N-dimethylformamide, adding 0.5g of 2-methylimidazole, dropwise adding 1g of triethylchlorosilane, stirring at the temperature of below 10 ℃ for reaction for 30min, adding water for quenching reaction after the reaction is finished, adding 50ml of ethyl acetate for extraction, washing an organic phase with purified water for 2 times, concentrating the organic phase to obtain a viscous substance, wherein the product is complex and cannot be distinguished which is the main product TIMF-3', and abandoning the route;

and (4) conclusion: the amino group of the TIMF-2' is easily oxidized, resulting in the formation of degradation products, and then more corresponding products are produced in step 2, the overall yield of the route is significantly reduced, and it is not easy to identify which is an intermediate of the target structure, and the purification difficulty is also increased.

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.