阅读说明：本技术 一种10-甲氧基多西他赛的制备方法 (Preparation method of 10-methoxy docetaxel ) 是由 黄春 陆叶梦 王莉佳 王旭阳 石宏宇 于 2021-09-07 设计创作，主要内容包括：本发明公开了一种10-甲氧基多西他赛的制备方法,其技术方案包括以下步骤：S1、将Cab-3用二氯甲烷溶清,加入双二甲氨基萘,搅拌下加入三甲基氧鎓四氟硼酸；加水淬灭反应,萃取分液得混合物；S2、将S1所得混合物用二氯甲烷和吡啶溶清,加入氯甲酸三氯乙酯,搅拌反应,加水淬灭反应,经柱层析纯化得甲氧基多西他赛前体；S3、将甲氧基多西他赛前体用乙酸乙酯和乙酸溶清,加入锌粉,搅拌反应,加入碳酸氢钠溶液,浓缩有机相得甲氧基多西他赛前体,S4、10-甲氧基多西他赛前体用甲醇溶解,加入稀盐酸,搅拌反应,经柱层析纯化得10-甲氧基多西他赛；本发明的优点在于有效实现10-甲氧基多西他赛与极性相近的其他产物的分离,收率较高,操作简易。(The invention discloses a preparation method of 10-methoxy docetaxel, which comprises the following steps: s1, dissolving Cab-3 with dichloromethane, adding bis-dimethylamino-naphthalene, and adding trimethyloxonium tetrafluoroborate while stirring; adding water to quench the reaction, and extracting and separating liquid to obtain a mixture; s2, dissolving the mixture obtained in the step S1 with dichloromethane and pyridine, adding trichloroethyl chloroformate, stirring for reaction, adding water for quenching reaction, and purifying by column chromatography to obtain a methoxy docetaxel precursor; s3, dissolving the methoxy docetaxel precursor in ethyl acetate and acetic acid, adding zinc powder, stirring for reaction, adding a sodium bicarbonate solution, concentrating an organic phase to obtain a methoxy docetaxel precursor, dissolving the S4 and 10-methoxy docetaxel precursor in methanol, adding diluted hydrochloric acid, stirring for reaction, and purifying by column chromatography to obtain 10-methoxy docetaxel; the method has the advantages of effectively realizing the separation of the 10-methoxy docetaxel and other products with similar polarity, along with higher yield and simple and easy operation.)

1. A preparation method of 10-methoxy docetaxel is characterized by comprising the following steps:

s1, dissolving Cab-3 in dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, and adding trimethyl oxonium tetrafluoroborate while stirring; after the reaction is completed, adding water to quench the reaction, extracting and separating liquid, concentrating an organic phase until no solvent is evaporated, and performing column chromatography purification to obtain a mixture of Cab-3 and 10-methoxyl impurities;

s2, dissolving the mixture obtained in the step S1 with dichloromethane and pyridine, adding chloroformic acid-2, 2, 2-trichloroethyl ester, stirring for reaction, adding water for quenching reaction after the reaction is completed, adding hydrochloric acid for extraction, concentrating an organic phase, and purifying by column chromatography to obtain a 7-Troc-10-methoxydocetaxel precursor;

s3, dissolving and cleaning the 7-Troc-10-methoxy docetaxel precursor with ethyl acetate and acetic acid, adding zinc powder, stirring for reaction, after the reaction is completed, carrying out suction filtration on reaction liquid, adding a sodium bicarbonate solution into filtrate, neutralizing until no bubbles are generated, separating liquid, collecting an organic phase, washing with water, and concentrating the organic phase to obtain a 10-methoxy docetaxel precursor;

s4, dissolving the 10-methoxy docetaxel precursor in methanol, adding 1mol/L diluted hydrochloric acid, stirring for reaction, adding purified water after the reaction is completed, separating out a large amount of solid, performing suction filtration, and purifying a filter cake by column chromatography to obtain 10-methoxy docetaxel;

the reaction route of the preparation process is as follows:

2. the method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S1, the ratio of the amount of 1, 8-bisdimethylaminonaphthalene to the raw material Cab-3 is 0.69 to 0.92 (W/W).

3. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S1, the ratio of the amount of trimethyloxonium tetrafluoroborate to the amount of Cab-3 as the raw material is 0.32 to 0.48 (W/W).

4. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S1, the ratio of the amount of dichloromethane to the amount of the raw material Cab-3 is 18-22 (V/W), the reaction temperature is 20-25 ℃, and the reaction time is 1-2 h.

5. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S2, the ratio of chloroformic acid-2, 2, 2-trichloroethyl ester to the mixture is 0.68 to 0.80 (W/W).

6. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S2, the ratio of the dichloromethane amount to the mixture is 9-10 (V/W), the ratio of the pyridine amount to the mixture is 2.8-3.2 (V/W), the reaction temperature is 15-20 ℃, and the reaction time is 1-2 h.

7. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S3, the ratio of zinc powder to the precursor of 7-Troc-10-methoxy docetaxel is 1.16-1.50 (W/W).

8. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in the step S3, the ratio of the ethyl acetate to the 7-Troc-10-methoxy docetaxel precursor is 9.5-10 (V/W), the ratio of the acetic acid to the 7-Troc-10-methoxy docetaxel precursor is 2.5-2.8 (V/W), the reaction temperature is 0-10 ℃, and the reaction time is 2-3 h.

9. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S4, the ratio of 1mol/L diluted hydrochloric acid to 10-methoxy docetaxel precursor is 2.12-2.50 (W/W).

10. The method for preparing 10-methoxy docetaxel according to claim 1, wherein: in step S4, the reaction temperature is 0-10 ℃ and the reaction time is 2-3 h.

Technical Field

The invention relates to the technical field of preparation of anti-cancer drugs, in particular to a preparation method of 10-methoxy docetaxel.

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.

Cabazitaxel has many impurities, wherein 10-methoxy docetaxel is an impurity involved in almost all synthetic routes, and the impurities are generated as cabazitaxel precursor impurities due to the fact that partial materials cannot simultaneously complete methylation at 7-position and 10-position in the synthetic process, and finally 10-methoxy docetaxel is obtained through deprotection. The impurity has special properties, and the polarity of the impurity is close to that of docetaxel which is an impurity obtained by methylation derivation at the 7/10 position, so that the separation is difficult to realize. The preparation of 10-methoxy docetaxel is very important for quality control and quality research of bulk drugs.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a preparation method of 10-methoxy docetaxel, which has the advantages that the separation of 10-methoxy docetaxel and other products with similar polarity can be effectively realized by controlling reaction conditions and selective protection, the yield is high, and the operation is simple and easy.

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

a preparation method of 10-methoxy docetaxel comprises the following steps:

s1, dissolving cabazitaxel Cab-3 in dichloromethane, adding 1, 8-bis-dimethylamino-naphthalene, and adding trimethyloxonium tetrafluoroborate while stirring. After the reaction is completed, adding water to quench the reaction, extracting and separating liquid, concentrating an organic phase until no solvent is evaporated, and performing column chromatography purification to obtain a mixture of Cab-3 and 10-methoxyl impurities;

s2, dissolving the mixture obtained in the step S1 with dichloromethane and pyridine, adding chloroformic acid-2, 2, 2-trichloroethyl ester, stirring for reaction, adding water for quenching reaction after the reaction is completed, adding hydrochloric acid for extraction, concentrating an organic phase, and purifying by column chromatography to obtain a 7-Troc-10-methoxydocetaxel precursor;

s3, dissolving and cleaning the 7-Troc-10-methoxy docetaxel precursor with ethyl acetate and acetic acid, adding zinc powder, stirring for reaction, after the reaction is completed, carrying out suction filtration on reaction liquid, adding a sodium bicarbonate solution into filtrate, neutralizing until no bubbles are generated, separating liquid, collecting an organic phase, washing with water, and concentrating the organic phase to obtain a 10-methoxy docetaxel precursor;

s4, dissolving the 10-methoxy docetaxel precursor in methanol, adding 1mol/L diluted hydrochloric acid, stirring for reaction, adding purified water after the reaction is completed, separating out a large amount of solid, performing suction filtration, and purifying a filter cake by column chromatography to obtain 10-methoxy docetaxel;

the reaction route of the preparation process is as follows:

further, in step S1, the ratio of the amount of 1, 8-bisdimethylaminonaphthalene to the raw material Cab-3 is 0.69 to 0.92 (W/W).

Further, in step S1, the ratio of the amount of trimethyloxonium tetrafluoroborate to the starting material Cab-3 is 0.32 to 0.48 (W/W).

Further, in step S1, the ratio of the amount of dichloromethane to the raw material Cab-3 is 18-22 (V/W), the reaction temperature is 20-25 ℃, and the reaction time is 1-2 h.

Further, in step S2, the ratio of chloroformic acid-2, 2, 2-trichloroethyl ester to the mixture is 0.68 to 0.80 (W/W).

Further, in step S2, the ratio of the amount of dichloromethane to the mixture is 9-10 (V/W), the ratio of the amount of pyridine to the mixture is 2.8-3.2 (V/W), the reaction temperature is 15-20 ℃, and the reaction time is 1-2 h.

Further, in step S3, the ratio of zinc powder to the 7-Troc-10-methoxydocetaxel precursor is 1.16-1.50 (W/W).

Further, in step S3, the ratio of the amount of ethyl acetate to the 7-Troc-10-methoxydocetaxel precursor is 9.5 to 10(V/W), the ratio of the amount of acetic acid to the 7-Troc-10-methoxydocetaxel precursor is 2.5 to 2.8(V/W), the reaction temperature is 0 to 10 ℃, and the reaction time is 2 to 3 hours.

Further, in step S4, the ratio of 1mol/L diluted hydrochloric acid to 10-methoxy docetaxel precursor is 2.12-2.50 (W/W).

Further, in step S4, the reaction temperature is 0-10 ℃ and the reaction time is 2-3 h.

In conclusion, the invention has the following beneficial effects:

1. by strictly controlling methylation reaction conditions, 10-methoxy impurities (10-MeO Impurity) are generated as much as possible, column chromatography is carried out in the step 1, so that the target substance, the 10-methoxy impurities and Cab-4 are effectively separated, the target substance and the 10-methoxy impurities cannot be separated from the two substances after subsequent selective protection without separation, and then the 10-methoxy impurities and Cab-3 with consistent polarity are derived into products with larger polarity difference through selective protection, so that the separation is carried out through column chromatography purification, and finally the target substance is obtained by removing the protection, so that the yield is improved.

2. Four steps are adopted to separate related products, so that the steps are greatly simplified, and the time of related reaction is within several hours, thereby being beneficial to improving the production efficiency of the medicine.

3. The reaction condition is in the range of 0-25 ℃, the reaction condition is easy to achieve, and the method is suitable for large-scale industrial production.

Drawings

FIG. 1 is an HPLC chromatogram of 10-methoxy docetaxel obtained in example 1 of the present invention.

FIG. 2 is a MS spectrum of 10-methoxy docetaxel obtained in example 1 of the present invention.

FIG. 3 is a 1H NMR spectrum of 10-methoxydocetaxel obtained in example 1 of the present invention.

FIG. 4 is a 13C NMR spectrum of 10-methoxydocetaxel 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 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:

step S1: 10g of Cabazitaxel Cab-3 was dissolved in 200ml of dichloromethane, 6.9g of 1, 8-bisdimethylaminonaphthalene was added thereto, 3.2g of trimethyloxonium tetrafluoroborate was added thereto with stirring, and the mixture was reacted at 25 ℃ for 1 hour. After the reaction is completed, water is added to quench the reaction, extraction and liquid separation are carried out, an organic phase is concentrated until no solvent is evaporated, and column chromatography purification is carried out to obtain 8.2g of a mixture of Cab-3 and 10-methoxyl impurities.

S2: 8.2g of the above mixture was dissolved in 80ml of dichloromethane and 25ml of pyridine, and 5.6g of 2,2, 2-trichloroethyl chloroformate was added thereto, followed by stirring at 15 ℃ for 2 hours. After the reaction is completed, water is added to quench the reaction, hydrochloric acid is added to extract, an organic phase is concentrated, and 3.6g of 10-methoxy docetaxel precursor is obtained after column chromatography purification.

S3: 3.6g of 7-Troc-10-methoxy docetaxel precursor is dissolved and cleaned by 36ml of ethyl acetate and 10ml of acetic acid, 4.2g of zinc powder is added, and the mixture is stirred and reacted for 3 hours at 0 ℃ in ice bath. And after the reaction is completed, carrying out suction filtration on the reaction solution, adding a sodium bicarbonate solution into the filtrate, neutralizing until no bubbles are generated, separating the solution, collecting an organic phase, washing with water, and concentrating the organic phase to obtain 3.0g of a 10-methoxy docetaxel precursor.

S4: 3.0g of 10-methoxy docetaxel precursor is dissolved in 100ml of methanol, 6.4g of 1mol/L diluted hydrochloric acid is added, and the mixture is stirred and reacted for 3 hours at the temperature of 0 ℃. After the reaction is completed, 200ml of purified water is added, a large amount of solid is separated out, the filtration is carried out, and 2.5g of 10-methoxy docetaxel is obtained after the filter cake is purified by column chromatography, the purity is 99.234%, the total yield is 28.2%, and the liquid phase diagram is shown in figure 1.

As shown in fig. 2, the MS spectrum of 10-methoxy docetaxel in this example, wherein the mass/charge ratio M/z is 844.3[ M + Na ] +, the molecular weight is inferred to be 821, consistent with the target compound.

As shown in FIG. 3, which is a 1H NMR spectrum of 10-methoxydocetaxel of this example, 1H NMR (500MHz, CDCl3) delta: 8.10(2H, d, J ═ 7.5Hz, ArH),7.60(1H, t, J ═ 7.3Hz, ArH),7.49(2H, t, J ═ 7.8Hz, ArH),7.41(4H, m, ArH),7.32(1H, m, ArH),6.24(1H, t, J ═ 8.5Hz, H13),5.68(1H, d, J ═ 7.0Hz, H2),5.41(1H, d, J ═ 8.5Hz, H31),5.26(1H, m, H30),4.94(2H, H5 overlaid with H10),4.62(1H, s, H36),4.29(1H, d, J ═ 8.5, H5), H5 overlaid with H10),4.62(1H, s, H36, 4.29(1H, d, J ═ 8.5H, H8.8H, H7H, H7H, H8H, H7H, H8H, H7H, H7H, H7H, H7H, 7H, H7H, H7H, 7H, 7H, 7H, 18H, H7H, 1.81(1H, m, H6),1.69(3H, s, H19),1.35(9H, s, H39),1.22(3H, s,3H16/3H17),1.20(3H, s,3H16/3H 17).

As shown in fig. 4, the 13C NMR spectrum of 10-methoxy docetaxel of this example, wherein 13C NMR (125MHz, CDCl3) δ: 206.696,170.256,167.073,155.367,139.175,135.193,133.645,130.179,129.273,128.835,128.677,128.056,126.812,102.506,84.256,82.709,81.355,80.239,78.856,76.638,74.906,73.684,72.498,71.96,58.69,57.9,56.892,56.236,46.804,43.223,37.107,35.431,28.201,26.47,22.61,20.891,14.477,9.725.

The related maps are shown in the attached drawings.

Example 2:

step S1: 10g of Cab-3 was dissolved in 200ml of methylene chloride, 9.2g of 1, 8-bisdimethylaminonaphthalene was added, 4.8g of trimethyloxonium tetrafluoroborate was added with stirring, and the mixture was reacted at 20 ℃ for 2 hours. After the reaction is completed, water is added to quench the reaction, extraction and liquid separation are carried out, an organic phase is concentrated until no solvent is evaporated, and column chromatography purification is carried out to obtain 8.5g of a mixture of cab-3 and 10-methoxyl impurities.

S2: 8.5g of the above mixture was dissolved in 80ml of dichloromethane and 25ml of pyridine, and 6.8g of 2,2, 2-trichloroethyl chloroformate was added, followed by stirring at 20 ℃ for 1 hour. After the reaction is completed, water is added to quench the reaction, hydrochloric acid is added to extract, an organic phase is concentrated, and 3.8g of 10-methoxy docetaxel precursor is obtained after column chromatography purification.

S3: 3.8g of 7-Troc-10-methoxy docetaxel precursor was dissolved in 38ml of ethyl acetate and 10ml of acetic acid, and 5.7g of zinc powder was added thereto, followed by stirring at 10 ℃ for 2 hours. And after the reaction is completed, carrying out suction filtration on the reaction solution, adding a sodium bicarbonate solution into the filtrate, neutralizing until no bubbles are generated, separating the solution, collecting an organic phase, washing with water, and concentrating the organic phase to obtain 3.2g of a 10-methoxy docetaxel precursor.

S4: 3.2g of 10-methoxy docetaxel precursor is dissolved in 100ml of methanol, 8g of 1mol/L diluted hydrochloric acid is added, and the mixture is stirred and reacted for 2 hours at 10 ℃. After the reaction is completed, 200ml of purified water is added, a large amount of solid is separated out, the filtration is carried out, and 2.7g of 10-methoxy docetaxel is obtained after the filter cake is purified by column chromatography, the purity is 98.7 percent, and the total yield is 30.4 percent.

Comparative example 1: (replacement by the most common combination of methyl iodide and sodium hydride as methylating agent)

Step S1: 10g of Cab-3 was dissolved in 200ml of dichloromethane, 2ml of methyl iodide was added, the mixture was transferred into an ice bath, and 1.3g of sodium hydride (60%) was added with stirring and reacted for 2 hours. Adding water to quench the reaction, separating the extract, concentrating the organic phase until no solvent is evaporated, and purifying by column chromatography to obtain 2.8g of a mixture of Cab-3 and 10-methoxyl impurities. Because the combined methylation capacity of methyl iodide and sodium hydride is too strong, the methylation at multiple positions is easier to realize due to the difficulty of controlling the stage of the monomethylation product, and the required 10-methoxyl impurity is less.

S2: 2.8g of the above mixture was dissolved in 28ml of methylene chloride and 9ml of pyridine, and 2.2g of 2,2, 2-trichloroethyl chloroformate was added, followed by stirring at 20 ℃ for 1 hour. After the reaction is completed, water is added to quench the reaction, hydrochloric acid is added to extract, an organic phase is concentrated, and 0.2g of 10-methoxy docetaxel precursor is obtained after column chromatography purification.

S3: 0.2g of 10-methoxy docetaxel precursor is dissolved in 10ml of methanol, 0.5ml of 1mol/L diluted hydrochloric acid is added, and the mixture is stirred and reacted for 2 hours at 10 ℃. After the reaction is completed, 20ml of purified water is added, solid is separated out, the filtration is carried out, and 0.0528g of 10-methoxy docetaxel is obtained after the filter cake is purified by column chromatography, the purity is 95.4%, and the total yield is 0.6%.

The experimental results are as follows: comparing the purity and the total yield of the final 10-methoxy docetaxel, the purity and the yield of the 10-methoxy docetaxel prepared by the traditional method are far lower than those of the invention.

Comparative example 2: (1, 8-Dimethylaminonaphthalene was replaced with the same type of 2, 3-diaminonaphthalene)

The procedure was as in example 1, replacing the equivalent amount of 1, 8-bisdimethylaminonaphthalene used in S1 with 2, 3-diaminonaphthalene.

1g of Cab-3 was dissolved in 20ml of methylene chloride, 0.5g of 2, 3-diaminonaphthalene was added, and 0.3g of trimethyloxonium tetrafluoroborate was added with stirring and reacted at 25 ℃ for 1 hour. No target product was formed by TLC monitoring. 5.1g of 2, 3-diaminonaphthalene and 0.3g of trimethyloxonium tetrafluoroborate are added, the reaction is continued for 2 hours, and no obvious new product is generated after TLC monitoring. Abandoning the route.

The experimental results are as follows: since 2, 3-diaminonaphthalene and 1, 8-bisdimethylaminonaphthalene, although both bases and structures are similar, do not exhibit the methylation effect in combination with trimethyloxonium tetrafluoroborate.

Comparative example 3: (replacement of 1, 8-Dimethylaminonaphthalene with other types of bases)

The preparation procedure was the same as in example 1 except that 1, 8-bisdimethylaminonaphthalene used in S1 was replaced with sodium carbonate, N-diisopropylethylamine, 2, 6-di-tert-butyl-4-methylpyridine, triethylamine and potassium tert-butoxide, respectively, and the reaction was carried out. (all of the above bases can find literature reports, combined with trimethyloxonium tetrafluoroborate to achieve methylation of hydroxyl groups)

The experimental results are as follows: methylation cannot be achieved by changing to another base.

Comparative example 4: (Trimethyloxonium tetrafluoroborate was replaced by the same type of methyl p-trifluoromethanesulfonate)

The preparation steps are the same as example 1, the trimethyloxonium tetrafluoroborate used in S1 is replaced by methyl trifluoromethanesulfonate, and the optimal reaction result cannot be achieved with 1, 8-bis-dimethylamino-naphthalene, and 10-methoxy docetaxel is finally purified, the purity is 95.6%, and the total yield is 9.8%.

The experimental results are as follows: the methylation capacities of trimethyloxonium tetrafluoroborate and trifluoromethyl boric acid are different, the activity of methyl trifluoromethanesulfonate is too strong, target products are fewer, and the purity and the yield of the final 10-methoxy docetaxel are influenced.

Comparative example 5: (No derivatization, i.e., No treatment according to the invention with S2 and S3)

Step S1: 10g of Cab-3 was dissolved in 200ml of methylene chloride, 9.2g of 1, 8-bisdimethylaminonaphthalene was added, 4.8g of trimethyloxonium tetrafluoroborate was added with stirring, and the mixture was reacted at 20 ℃ for 2 hours. After the reaction is completed, water is added to quench the reaction, extraction and liquid separation are carried out, an organic phase is concentrated until no solvent is evaporated, and column chromatography purification is carried out to obtain 8.8g of a mixture of cab-3 and 10-methoxyl impurities.

S2: 8.8g of the above mixture was dissolved in 250ml of methanol, 8g of 1mol/L diluted hydrochloric acid was added, and the reaction was stirred at 10 ℃ for 2 hours. After the reaction is completed, 200ml of purified water is added, a large amount of solid is separated out, the filtration is carried out, and the filter cake is purified by column chromatography, so that the effective separation cannot be carried out.

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.