阅读说明：本技术 一种紫杉醇衍生物及其制备方法 (Paclitaxel derivative and preparation method thereof ) 是由 朱训 黄春 于 2021-09-14 设计创作，主要内容包括：本发明公开了一种紫杉醇衍生物及其制备方法,包属于紫杉烷类抗癌药物的制备领域,包括所述紫杉醇衍生物为2-去苯甲酰基-2-惕格酰基紫杉醇,制备方法包括：将紫杉醇和2-甲基咪唑用N,N-二甲基甲酰胺溶解,搅拌下滴加三乙基氯硅烷,得到产物I；产物I用四氢呋喃溶解,低温下搅拌滴加红铝溶液,反应完并纯化得到产物II；将惕格酸加入二氯亚砜中回流反应得到惕格酰氯,将产物II溶于二氯甲烷和三乙胺中,低温下搅拌滴加惕格酰氯,得到产物III；将产物III溶于乙腈中,加入盐酸溶液搅拌反应,产物经过柱层析纯化并除去溶剂得到2-去苯甲酰基-2-惕格酰基紫杉醇,本发明的优点在于各步骤收率高,产品纯度好,易分离,可以进行大量制备。(The invention discloses a paclitaxel derivative and a preparation method thereof, belonging to the field of preparation of taxane anticancer drugs, the paclitaxel derivative is 2-debenzoyl-2-tiglyl paclitaxel, and the preparation method comprises the following steps: dissolving paclitaxel and 2-methylimidazole by using N, N-dimethylformamide, and dropwise adding triethylchlorosilane while stirring to obtain a product I; dissolving the product I with tetrahydrofuran, stirring and dropwise adding a red aluminum solution at low temperature, and obtaining a product II after reaction and purification; adding tiglic acid into thionyl chloride for reflux reaction to obtain tiglic acyl chloride, dissolving the product II into dichloromethane and triethylamine, and dropwise adding the tiglic acyl chloride while stirring at low temperature to obtain a product III; dissolving the product III in acetonitrile, adding a hydrochloric acid solution, stirring for reaction, purifying the product by column chromatography, and removing the solvent to obtain the 2-debenzoyl-2-tiglyl paclitaxel.)

1. A paclitaxel derivative and a preparation method thereof are characterized by comprising the following steps:

s1, dissolving paclitaxel and 2-methylimidazole in N, N-dimethylformamide, dropwise adding triethylchlorosilane while stirring for reaction, after the reaction is finished, adding the reaction solution into ice water, stirring, separating out a product in the ice water, performing suction filtration, washing a filter cake with purified water, and drying to obtain a product I;

s2, dissolving the product I with tetrahydrofuran, cooling to-10-15 ℃, dropwise adding an aluminum red solution while stirring, dropwise adding a potassium sodium tartrate solution after the reaction is finished to quench the reaction, extracting with ethyl acetate, back-extracting the water phase with ethyl acetate once, concentrating the organic phase to obtain a crude product, performing flash column chromatography purification, collecting the product, concentrating and drying to obtain a product II;

s3, adding tiglic acid into thionyl chloride in stirring, heating to 40 ℃ for reflux, performing rotary evaporation to remove the residual thionyl chloride after the reaction is finished to obtain tiglic acyl chloride, adding dichloromethane for dilution to obtain dichloromethane solution of the tiglic acyl chloride, dissolving a product II into dichloromethane and triethylamine, cooling to 0 ℃ in an ice bath, dropwise adding the tiglic acyl chloride solution, stirring at low temperature for reaction, adding water to quench the reaction after the reaction is finished, adding sodium bicarbonate solution for liquid separation, washing an organic phase once by using sodium chloride solution, and concentrating the organic phase to obtain a product III;

s4, dissolving the product III in acetonitrile, adding a hydrochloric acid solution, stirring at room temperature for reaction, adding a sodium bicarbonate solution to neutralize the reaction solution after the reaction is finished, adding dichloromethane for extraction and liquid separation, performing back extraction on the water phase once by using dichloromethane, combining the organic phases, washing once by using saturated saline solution, concentrating the organic phases to obtain a crude product, performing rapid column chromatography purification on the crude product, collecting a product section, concentrating and drying to obtain a product 2-debenzoyl-2-tiglyl paclitaxel;

the reaction route of the preparation process is as follows:

2. the paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S1, the ratio of the amount of N, N-dimethylformamide to the amount of paclitaxel is 4-6V/W; the ratio of the using amount of the 2-methylimidazole to the raw materials is 7-12W/W; the ratio of the consumption of the triethylchlorosilane to the raw material of the taxol is 12-18V/W.

3. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S1, the reaction temperature is 0-5 ℃ and the reaction time is 1-2 h.

4. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S2, the ratio of tetrahydrofuran to the product I is 6-10V/W; the ratio of the red aluminum solution to the product I is 1.3-3V/W.

5. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S2, the reaction temperature is-15 to-10 ℃, the reaction time is 0.5 to 1 hour, and the reaction temperature of the quenching reaction is-10 to-5 ℃.

6. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S3, the ratio of thionyl chloride to tiglic acid is 1.2-1.7W/W; the ratio of the dichloromethane to the product II is 40-50V/W; the ratio of triethylamine to the product II is 4-7V/W; the ratio of tiglic acyl chloride to the product II is 0.133-0.157W/W.

7. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S3, the temperature of the stirring reaction is-5 to 0 ℃, and the reaction time of the stirring reaction is 10 to 30 min.

8. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in the step S4, the ratio of acetonitrile to the product III is 10-20V/W; the concentration of the hydrochloric acid solution is 6-8 Mol/L; the ratio of the hydrochloric acid solution to the product III is 6-10V/W.

9. The paclitaxel derivative and the preparation method thereof according to claim 1, wherein: in step S4, the reaction temperature of the stirring reaction is 15-25 ℃, and the reaction time of the stirring reaction is 0.5-2 h.

10. A paclitaxel derivative prepared by the method for preparing paclitaxel derivatives according to any one of claims 1 to 9, wherein: the taxol derivative is 2-debenzoyl-2-tigloxy taxol, and the structural formula is shown as follows:

Technical Field

The invention relates to the technical field of preparation of taxane antitumor drugs, in particular to a paclitaxel derivative and a preparation method thereof.

Background

In 1996, doctor Wall of Research Triangle Institute obtained paclitaxel, a chemical that showed significant toxic activity on KB cells, from 30lb bark extract. In 1971, paclitaxel was identified as a complex diterpenoid with specific propylene oxide and ester side chains by the combined use of X-ray diffraction and nuclear magnetic resonance. In the past four decades and over, 560 kinds of taxanes were isolated and identified from Taxus genus plant. Clinical experimental results of American NCI statistics show that the taxol has obvious curative effect on various cancers, the total effective rate reaches more than 75%, and the taxol is considered as the last line of defense of patients with advanced cancers. The taxane medicines mainly comprise paclitaxel and docetaxel, and the two compounds have more important positions in the anti-tumor market. Through the development of many years, the research on the impurities of paclitaxel and docetaxel is very complete, and the european pharmacopoeia contains a plurality of characteristic impurities of paclitaxel and docetaxel, wherein the paclitaxel impurity a and the docetaxel impurity a contained in the european pharmacopoeia have similar structures (the structures are shown as below),

in the prior art, most of paclitaxel and docetaxel are produced by a semi-synthesis process, and the main raw materials of the paclitaxel and the docetaxel are 10-deacetylbaccatin III (10-DAB), a natural product extracted from branches and leaves of taxus chinensis. Both impurities A are specific single impurities (10-deacetyl-2-debenzoyl-2-tigloxycacetin III, structure shown in the following figure) in the raw material 10-deacetylbaccatin III,finally introduced into paclitaxel/docetaxel, therefore, the specific single impurity has very important significance for the quality control of the synthesized paclitaxel. However, the traditional method has low total yield, excessive products and complicated separation and purification.

Disclosure of Invention

The invention aims to provide a preparation method of a taxol derivative, which has the advantages of simple and convenient steps, high yield of target products, high purity of the target products and capability of large-scale preparation.

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

a paclitaxel derivative and a preparation method thereof comprise the following steps:

s1, dissolving paclitaxel and 2-methylimidazole in N, N-dimethylformamide, dropwise adding triethylchlorosilane while stirring for reaction, after the reaction is finished, adding the reaction solution into ice water, stirring, separating out a product in the ice water, performing suction filtration, washing a filter cake with purified water, and drying to obtain a product I;

s2, dissolving the product I with tetrahydrofuran, cooling to-15 ℃, dropwise adding an aluminum red solution while stirring, reacting for 1 hour, dropwise adding a potassium sodium tartrate solution after the reaction is finished to quench the reaction, extracting with ethyl acetate, back-extracting the water phase with ethyl acetate once, concentrating the organic phase to obtain a crude product, purifying by fast column chromatography, collecting the product, concentrating and drying to obtain a product II;

s3, adding tiglic acid into thionyl chloride in stirring, heating to 40 ℃ for reflux, performing rotary evaporation to remove the residual thionyl chloride after the reaction is finished to obtain tiglic acyl chloride, adding dichloromethane for dilution to obtain dichloromethane solution of the tiglic acyl chloride, dissolving a product II into dichloromethane and triethylamine, cooling to 0 ℃ in an ice bath, dropwise adding the tiglic acyl chloride solution, stirring at low temperature for reaction, adding water to quench the reaction after the reaction is finished, adding sodium bicarbonate solution for liquid separation, washing an organic phase once by using sodium chloride solution, and concentrating the organic phase to obtain a product III;

s4, dissolving the product III in acetonitrile, adding a hydrochloric acid solution, stirring at room temperature for reaction, adding a sodium bicarbonate solution to neutralize the reaction solution after the reaction is finished, adding dichloromethane for extraction and liquid separation, performing back extraction on the water phase once by using dichloromethane, combining the organic phases, washing once by using saturated saline solution, concentrating the organic phases to obtain a crude product, performing rapid column chromatography purification on the crude product, collecting a product section, concentrating and drying to obtain a product 2-debenzoyl-2-tiglyl paclitaxel;

the reaction route of the preparation process is as follows:

further, in the step S1, the ratio of the dosage of the N, N-dimethylformamide to the raw material paclitaxel is 4-6V/W; the ratio of the using amount of the 2-methylimidazole to the raw materials is 7-12W/W; the ratio of the consumption of the triethylchlorosilane to the raw material of the taxol is 12-18V/W.

Further, in step S1, the reaction temperature is 0-5 ℃ and the reaction time is 1-2 h.

Further, in the step S2, the ratio of tetrahydrofuran to the product I is 6-10V/W; the ratio of the red aluminum solution to the product I is 1.3-3V/W. .

Further, in step S2, the reaction temperature is-15 to-10 ℃, the reaction time is 0.5 to 1 hour, and the reaction temperature of the quenching reaction is-10 to-5 ℃. .

Further, in step S3, the ratio of thionyl chloride to tiglic acid is 1.2-1.7W/W; the ratio of the dichloromethane to the product II is 40-50V/W; the ratio of triethylamine to the product II is 4-7V/W; the ratio of tiglic acyl chloride to the product II is 0.133-0.157W/W. .

Further, in step S3, the temperature of the stirring reaction is-5 to 0 ℃, and the reaction time of the stirring reaction is 10 to 30 min.

Further, in the step S4, the ratio of acetonitrile to the product III is 10-20V/W; the concentration of the hydrochloric acid solution is 6-8 Mol/L; the ratio of the hydrochloric acid solution to the product III is 6-10V/W. .

Further, in step S4, the reaction temperature of the stirring reaction is 15 to 25 ℃, and the reaction time of the stirring reaction is 0.5 to 2 hours. .

A paclitaxel derivative prepared by a preparation method of paclitaxel derivative is 2-debenzoyl-2-tiganoyl paclitaxel, and the structural formula is as follows:

by adopting the technical scheme.

In conclusion, the invention has the following beneficial effects:

1. the required 2-debenzoyl-2-tiglyl paclitaxel is prepared by four steps, tiglyl chloride is used as a reactant to be condensed with the 2-debenzoyl paclitaxel to replace carbodiimide condensing agents such as N, N-diisopropyl carbodiimide and the like used in the prior art, and the obtained product III has fewer impurities, is easy to post-treat and separate, and has mild and rapid reaction conditions and high yield in the whole process.

2. The reaction condition requirement is low, the reaction time is short, and the preparation reaction is mild, so that the reaction equipment has no strict requirement, and is favorable for large-scale industrial production and preparation.

Drawings

FIG. 1 is a schematic flow diagram of the steps of a process for the preparation of paclitaxel derivatives;

FIG. 2 is the MS positive ion mode spectrum of 2-debenzoyl-2-tiganoyl paclitaxel in example 1;

FIG. 3 is the MS anion pattern of 2-debenzoyl-2-tiganoyl paclitaxel of example 1;

FIG. 4 is the 2-debenzoyl-2-tiganoyl paclitaxel of example 1¹H 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. 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. It should be understood that the structures, ratios, sizes, and the like shown in the drawings and described in the specification are only used for matching with the disclosure of the specification, so as to be understood and read by those skilled in the art, and are not used to limit the implementation conditions of the present invention, so that the present invention has no technical significance, and any structural modification, ratio relationship change or size adjustment should still fall within the scope of the present invention without affecting the efficacy and the achievable purpose of the present invention.

Example 1:

a method for preparing paclitaxel derivative is shown in figure 1, and comprises the following steps:

step S1: weighing 10.0g of paclitaxel into a 250mL reactor, adding 9.7g of 2-methylimidazole, stirring and dissolving the mixture by using 48mL of N, N-dimethylformamide, cooling to 0 ℃, and dropwise adding 14.4mL of triethylchlorosilane. After the dropwise addition, the reaction mixture is stirred at room temperature for 2 hours. After the reaction is finished, dropwise adding the reaction liquid into ice water for quenching, separating out a product in the ice water, carrying out suction filtration, washing a filter cake with purified water, and drying to obtain a product I12.1g.

Step S2: dissolving 12.1g of product I in a 100mL reaction bottle by using 45mL of tetrahydrofuran, cooling to-15 ℃, dropwise adding 20mL of 70% red aluminum solution while stirring, reacting for 1h, then dropwise adding a potassium sodium tartrate solution to quench the reaction, extracting by using ethyl acetate, carrying out back extraction on a water phase by using ethyl acetate once, carrying out flash column chromatography purification on a crude product obtained by concentrating an organic phase, eluting by using dichloromethane/methanol (200: 1, V/V) as a mobile phase, collecting a product section, concentrating and drying to obtain 9.9g of product II.

Step S3: adding 5.4mL of thionyl chloride into a 25mL reaction bottle, adding 5.0g of tiglic acid, heating to 40 ℃ for refluxing for 1h, performing rotary evaporation to remove the residual thionyl chloride after the reaction is finished to obtain tiglic acid chloride, adding 10mL of dichloromethane to dilute the tiglic acid chloride to obtain a dichloromethane solution of the tiglic acid chloride, dissolving 9.9g of a product II into 150mL of dichloromethane and 20mL of triethylamine, adding the dichloromethane solution into the 250mL reaction bottle, cooling to 0 ℃ in an ice bath, dropwise adding 2.2mL of tiglic acid chloride solution, stirring at a low temperature for reaction for 20min, adding water to quench the reaction after the reaction is finished, adding a saturated sodium bicarbonate solution for separating, washing an organic phase once with a saturated sodium chloride solution, and concentrating the organic phase to obtain III10.5g of a product.

Step S4: dissolving 10.5g of the product III in 250mL of acetonitrile, adding the acetonitrile into a 500mL reaction bottle, adding 8mL of 6M/L hydrochloric acid solution, stirring at room temperature for reaction for 2 hours, adding a sodium bicarbonate solution to neutralize the reaction solution after the reaction is finished, adding dichloromethane to extract and separate the solution, back-extracting the water phase with dichloromethane once, combining the organic phases, washing the organic phases with saturated saline solution once, concentrating the organic phases to obtain a crude product, performing rapid column chromatography purification on the crude product, eluting with dichloromethane and methanol (100/1-50/1, V/V) as mobile phases, collecting product segments, concentrating and drying to obtain 6.9g of the product 2-debenzoyl-2-tiglyl taxol; purity 97.2% (HPLC), total molar yield 70.83%. The reaction route of the above preparation process is shown in FIG. 1.

The structure of the prepared 2-debenzoyl-2-tigloxy paclitaxel is shown as a formula (1):

as shown in FIGS. 2 and 3, the MS pattern of 2-debenzoyl-2-tiganoyl paclitaxel in this example was shown, wherein its mass/charge ratio M/z was 854.3[ M + Na ═]⁺，m/z＝830.3[M-H]^-The molecular weight was inferred to be 831.3, consistent with the target compound.

As shown in FIG. 4, the method of the present example for the preparation of 2-debenzoyl-2-tiganoyl paclitaxel¹A HNMR map wherein,¹HNMR(500MHz,CDCl₃)δ:1.09(3H,s,H₁₆/H₁₇),δ:1.22(3H,s, H₁₆/H₁₇),δ:1.64(3H,s,H₂₁),δ:1.76(3H,s,H₂₉),δ:1.85(1H,m, H₆/H₂₅),δ:1.89(3H,s,H₁₈),δ:2.19(3H,s,H₂₀),δ:2.27(3H,s,H₂₄), δ:2.53(1H,m,H₆),δ:3.70(1H,d,H₃),δ:4.17(1H,d,H₂₂),δ:4.37 (1H,m,H₇),δ:4.75(1H,m,H₃₁),δ:4.93(1H,d,H₅),δ:5.49(1H,d, H₂),δ:5.75(1H,d,H₃₂),δ:6.20(1H,m,H₁₃),δ:6.24(1H,s,H₁₀), δ:7.00(1H,m,H₂₇/H₃₉)。

as shown in FIG. 4, this example shows 2-debenzoyl-2-tiganoyl paclitaxel¹³A C NMR spectrum in which,¹³C NMR(500MHz,CDCl₃)δ:167.064,168.401,170.266,171.213, 172.718,127.044,128.027,128.343,128.743,129.015,131.983, 133.306,133.787,138.056,140.149,141.834,55.003,58.629,72.163, 72.485,73.154,74.386,75.576,76.506,76.746,76.999,77.254,79.040, 81.095,84.445,43.146,45.604,9.526,12.005,14.722,14.777,20.805, 21.741,22.485,26.854,35.534,35.632。

example 2:

step S1: weighing 12.0g of paclitaxel and 13.85g of 2-methylimidazole, dissolving in a 250mL reaction bottle by using 75mL of LN, N-dimethylformamide, cooling to 0 ℃, dropwise adding 20.5mL of triethylchlorosilane while stirring for reaction, adding the reaction liquid into ice water after the reaction is finished, stirring, separating out a product in the ice water, performing suction filtration, washing a filter cake by using purified water, and drying to obtain 14.8g of a product.

Step S2: dissolving 14.8g of product I in a 250mL reaction bottle by using 67mL of tetrahydrofuran, cooling to-15 ℃, dropwise adding 27mL of 70% red aluminum solution while stirring, reacting for 1h, dropwise adding a potassium sodium tartrate solution after the reaction is finished, quenching the reaction, extracting by using ethyl acetate, carrying out back extraction on a water phase by using ethyl acetate once, carrying out flash column chromatography purification on a crude product obtained by concentrating an organic phase, eluting by using dichloromethane/methanol (200: 1, V/V) as a mobile phase, collecting a product section, concentrating and drying to obtain 12.5g of product II.

Step S3: adding 7mL of thionyl chloride into a 25mL reaction bottle, adding 6.0g of tiglic acid, heating to 40 ℃, refluxing for 1h, removing the residual thionyl chloride by rotary evaporation after the reaction is finished to obtain tiglic acid chloride, adding 12mL of dichloromethane to dilute the tiglic acid chloride to obtain a dichloromethane solution of the tiglic acid chloride, dissolving 12.5g of a product II into 250mL of dichloromethane and 28mL of triethylamine, adding the dichloromethane solution into a 500mL reaction bottle, cooling to 0 ℃ in an ice bath, dropwise adding 3mL of tiglic acid chloride solution, stirring at a low temperature for reaction for 30min, adding water to quench the reaction after the reaction is finished, adding a saturated sodium bicarbonate solution to separate the solution, washing an organic phase once with a saturated sodium chloride solution, and concentrating the organic phase to obtain 13.1g of a product III.

Step S4: dissolving 13.1g of the product III in 250mL of acetonitrile, adding the acetonitrile into a 500mL reaction bottle, adding 10mL of 6M/L hydrochloric acid solution, stirring at room temperature for reaction for 2 hours, adding a sodium bicarbonate solution to neutralize the reaction solution after the reaction is finished, adding dichloromethane to extract and separate liquid, back-extracting the water phase with dichloromethane once, combining the organic phases, washing the organic phases with saturated saline solution once, concentrating the organic phases to obtain a crude product, performing rapid column chromatography purification on the crude product, collecting a product section, concentrating and drying to obtain 7.4g of the product 2-debenzoyl-2-tiglyl taxol; purity 96.4% (HPLC), total molar yield 63.38%.

Example 3:

step S1: weighing 7.0g of paclitaxel and 6.0g of 2-methylimidazole, dissolving the paclitaxel and the 2-methylimidazole in 25mL of N, N-dimethylformamide in a 100mL reaction bottle, cooling to 0 ℃, dropwise adding 8.5mL of triethylchlorosilane while stirring for reaction, adding the reaction solution into ice water after the reaction is finished, stirring, separating out a product in the ice water, performing suction filtration, washing a filter cake with purified water, and drying to obtain 8.8g of a product I.

Step S2: dissolving 8.8g of the product I in 26.4mL of tetrahydrofuran in a 100mL reaction bottle, cooling to-15 ℃, dropwise adding 12.6mL of 70% red aluminum solution while stirring, reacting for 1h, dropwise adding a potassium sodium tartrate solution after the reaction is finished, quenching the reaction, extracting with ethyl acetate, back-extracting the water phase with ethyl acetate once, concentrating the organic phase to obtain a crude product, purifying by fast column chromatography, eluting with dichloromethane/methanol (200: 1, V/V) as a mobile phase, collecting the product, concentrating and drying to obtain 7.8g of the product II.

Step S3: adding 5mL of thionyl chloride into a 25mL reaction bottle, adding 4.0g of tiglic acid, heating to 40 ℃, refluxing for 1h, removing the residual thionyl chloride by rotary evaporation after the reaction is finished to obtain tiglic acid chloride, adding 8mL of dichloromethane to dilute the tiglic acid chloride to obtain a dichloromethane solution of the tiglic acid chloride, dissolving 7.8g of a product II into 50mL of dichloromethane and 11mL of triethylamine, adding the dichloromethane solution into a 100mL reaction bottle, cooling to 0 ℃ in an ice bath, dropwise adding 1.8mL of tiglic acid chloride solution, stirring at a low temperature for reaction for 15min, adding water to quench the reaction after the reaction is finished, adding a saturated sodium bicarbonate solution to separate the solution, washing an organic phase once with a saturated sodium chloride solution, and concentrating the organic phase to obtain 8.3g of a product III.

Step S4: dissolving 8.3g of the product III in 80mL of acetonitrile, adding the acetonitrile into a 250mL reaction bottle, adding 5mL of 6M/L hydrochloric acid solution, stirring at room temperature for reaction for 1.5h, adding a sodium bicarbonate solution to neutralize the reaction solution after the reaction is finished, adding dichloromethane for extraction and liquid separation, back-extracting the water phase with dichloromethane once, combining the organic phases, washing the organic phases with saturated saline solution once, concentrating the organic phases to obtain a crude product, performing rapid column chromatography purification on the crude product, collecting a product section, concentrating and drying to obtain 5.36g of the product 2-debenzoyl-2-tiglyl taxol; purity 98.4% (HPLC), total molar yield 78.6%.

Comparative example 1:

tiglic acid chloride, triethylamine and dichloromethane were replaced with tiglic acid, dicyclohexylcarbodiimide, 4-dimethylaminopyridine and toluene in step S3 of example 1, and the following reaction was used:

adding 5.0g of the product II into a 250mL reaction bottle, adding 4.0g of tiglic acid, 15.6g of 4-dimethylaminopyridine, 32.3g of dicyclohexylcarbodiimide, 100mL of toluene and 3.0g of a molecular sieve, heating to 80 ℃, refluxing for 26h, filtering to remove the molecular sieve after the reaction is finished, adding ethyl acetate to dilute the reaction solution, washing for 3 times with water, spin-drying an ethyl acetate phase, and separating by using flash column chromatography to obtain 0.6g of the product III.

The experimental results are as follows: the final product was 84.3% pure (HPLC) with a total molar yield of 11.07%.

Comparative example 2:

the procedure of comparative example 1 was used to replace dicyclohexylcarbodiimide and toluene with diisopropylcarbodiimide and dichloromethane.

The experimental results are as follows: the final product was 86.5% pure (HPLC) with a total molar yield of 20.30%.

Comparative example 3:

the procedure of comparative example 1 was used to replace dicyclohexylcarbodiimide, toluene with 1-ethyl-3-dimethylaminopropylcarbodiimide hydrochloride and dichloromethane.

The experimental results are as follows: the final product was 92.1% pure (HPLC) with a total molar yield of 16.61%.

And (3) analyzing an experimental result: the average purity of the target product of the examples was 94.00% (HPLC), and the average total molar yield was 72.90%; the average purity of the target product of the comparative example was 87.63% (HPLC) and the average total molar yield was 15.93%. The tiglic acyl chloride is used as a condensing agent, and is matched with dicyclohexylcarbodiimide, dicyclohexylcarbodiimide and toluene, the formulated reaction route is direct, and few byproducts are generated in the preparation process, so that the total molar yield of the target product in the embodiment is far higher than that of the target product in the comparative example, and the purity of the obtained target product is improved due to few side reactions and less impurities.

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.