阅读说明：本技术 一种7-甲氧基多西他赛的制备方法 (Preparation method of 7-methoxy docetaxel ) 是由 黄春 陆叶梦 王莉佳 王旭阳 于 2021-09-29 设计创作，主要内容包括：本发明涉及一种7-甲氧基多西他赛的制备方法,在制备方法的步骤S2中,将步骤S1所得IMB-2用吡啶和乙腈溶清,加入70％氟化氢吡啶,搅拌反应；反应完全后,加水和二氯甲烷萃取,浓缩有机相,加正己烷旋蒸,得IMB-3；在步骤S3中将IMB-3用二氯甲烷溶清,加入1,8-双二甲氨基萘和分子筛,再加入三甲基氧鎓四氟硼酸,搅拌反应；反应完全后,反应液抽滤,滤液浓缩后过柱,得IMB-4；之后再经过步骤S4和步骤S5最终得到7-甲氧基多西他赛；本发明巧妙使用了氟化氢吡啶脱去7位保护基Tes,同时保证了侧链部分不会开环。(The invention relates to a preparation method of 7-methoxy docetaxel, in step S2 of the preparation method, dissolving IMB-2 obtained in step S1 with pyridine and acetonitrile, adding 70% hydrogen fluoride pyridine, stirring and reacting; after the reaction is completed, adding water and dichloromethane for extraction, concentrating an organic phase, adding n-hexane for rotary evaporation to obtain IMB-3; dissolving IMB-3 in dichloromethane in step S3, adding 1, 8-bis-dimethylamino-naphthalene and a molecular sieve, adding trimethyl oxonium tetrafluoroborate, and stirring for reaction; after the reaction is completed, carrying out suction filtration on the reaction solution, concentrating the filtrate, and then passing through a column to obtain IMB-4; then, the 7-methoxy docetaxel is finally obtained through the steps of S4 and S5; the invention skillfully uses the hydrogen fluoride pyridine to remove the protecting group Tes at the 7 th position, and simultaneously ensures that the side chain part can not be opened.)

1. A preparation method of 7-methoxy docetaxel is characterized by comprising the following steps:

s1, dissolving IMB-1 in toluene, adding a doxycycline side chain acid and 4-dimethylaminopyridine, and dropwise adding N, N' -dicyclohexylcarbodiimide under 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 recrystallizing to obtain IMB-2;

s2, dissolving the IMB-2 obtained in the step S1 in pyridine and acetonitrile, adding 70% of hydrogen fluoride pyridine, and stirring for reaction; after the reaction is completed, adding water and dichloromethane for extraction, concentrating an organic phase, adding n-hexane for rotary evaporation to obtain IMB-3;

s3, dissolving the IMB-3 obtained in the step S2 in dichloromethane, adding 1, 8-bis (dimethylamino) naphthalene and a molecular sieve, adding trimethyl oxonium tetrafluoroborate, and stirring for reaction; after the reaction is completed, carrying out suction filtration on the reaction solution, concentrating the filtrate, and then passing through a column to obtain IMB-4;

s4, dissolving the IMB-4 obtained in the step S3 in methanol, adding p-toluenesulfonic acid, and stirring for reaction; after the reaction is completed, adding purified water, separating out solids, and performing suction filtration to obtain IMB-5;

s5, dissolving the IMB-5 obtained in the step S4 in tetrahydrofuran, adding sodium bicarbonate and 30% hydrogen peroxide, and stirring for reaction; after the reaction is finished, adding dichloromethane for extraction, concentrating and passing through a column to obtain 7-methoxy docetaxel;

the reaction route of the preparation process is as follows:

2. the method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S1, the ratio of the amount of the docetaxel side chain acid to the amount of the IMB-1 raw material is 0.85 to 0.95 (W/W).

3. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S1, the ratio of the amount of 4-dimethylaminopyridine to the IMB-1 starting material is 0.08-0.10 (W/W).

4. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: (ii) a In step S1, the ratio of the amount of N, N' -dicyclohexylcarbodiimide used to the amount of IMB-1 as the raw material is 0.50 to 0.56 (W/W).

5. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S2, the ratio of the amount of 70% pyridine hydrogen fluoride to IMB-2 is 4-5 (V/W).

6. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S2, the ratio of the amount of acetonitrile to IMB-2 is 10-15 (V/W); the ratio of the pyridine dosage to the IMB-2 is 10-15 (V/W); the reaction temperature is 0-5 ℃, and the reaction time is 12-18 h.

7. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S3, the ratio of the amount of 1, 8-bis-dimethylamino naphthalene to IMB-3 is 2.2-2.4 (W/W); the ratio of the amount of the molecular sieve to the amount of the IMB-3 is 1-1.1 (W/W).

8. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S3, the ratio of the amount of trimethyloxonium tetrafluoroborate to IMB-3 is 1.5 to 1.6 (W/W).

9. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S4, the ratio of the amount of p-toluenesulfonic acid to IMB-4 is 0.35 to 0.37 (W/W).

10. The method for preparing 7-methoxy docetaxel according to claim 1, characterized in that: in step S5, the ratio of the amount of sodium bicarbonate to IMB-5 is 1-1.2 (W/W); the ratio of the consumption of 30% hydrogen peroxide to IMB-5 is 3-4 (V/W).

Technical Field

The invention relates to the technical field of preparation of anti-cancer drugs, in particular to a preparation method of 7-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, one of the impurities is contained, and almost all synthetic routes involve 7-methoxy docetaxel, because partial materials in the synthetic process cannot simultaneously complete methylation at positions 7 and 10, cabazitaxel precursor impurities are generated, and finally 7-methoxy docetaxel is obtained by deprotection. The impurity has special properties, the structure of the impurity is similar to that of cabazitaxel, the retention time of the impurity in liquid chromatography is very close to that of cabazitaxel, and the separation of 7-methoxy docetaxel and cabazitaxel cannot be realized by TLC (thin layer chromatography), so that the impurity cannot be separated by column chromatography (normal phase/reverse phase), and the high-purity 7-methoxy docetaxel cannot be obtained by the traditional separation means. Because the activity of the 7-position hydroxyl in the parent nucleus is stronger than that of the 10-position hydroxyl, the common hydroxyl protecting group can not realize selective protection of the 10-position hydroxyl, and the 7-position methylation is difficult to obtain a target object after the selective protection is designed. The preparation of 7-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 discloses a preparation method of 7-methoxy docetaxel.

The technical scheme adopted by the invention is as follows:

a preparation method of 7-methoxy docetaxel comprises the following steps:

s1, dissolving IMB-1 in toluene, adding a doxycycline side chain acid and 4-dimethylaminopyridine, and dropwise adding N, N' -dicyclohexylcarbodiimide under 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 recrystallizing to obtain IMB-2; IMB-1 is an intermediate in the common taxol synthesis process, and the structural formula is shown in the reaction route of the preparation process.

S2, dissolving the IMB-2 obtained in the step S1 in pyridine and acetonitrile, adding 70% of hydrogen fluoride pyridine (in percentage by mass), and stirring for reaction; after the reaction is completed, adding water and dichloromethane for extraction, concentrating an organic phase, adding n-hexane for rotary evaporation, and removing pyridine to obtain IMB-3;

s3, dissolving the IMB-3 obtained in the step S2 in dichloromethane, adding 1, 8-bis (dimethylamino) naphthalene and a molecular sieve, adding trimethyl oxonium tetrafluoroborate, and stirring for reaction; after the reaction is completed, carrying out suction filtration on the reaction solution, concentrating the filtrate, and then passing through a column to obtain IMB-4;

s4, dissolving the IMB-4 obtained in the step S3 in methanol, adding p-toluenesulfonic acid, and stirring for reaction; after the reaction is completed, adding purified water, separating out solids, and performing suction filtration to obtain IMB-5;

s5, dissolving the IMB-5 obtained in the step S4 in tetrahydrofuran, adding sodium bicarbonate and 30% hydrogen peroxide (mass percentage), and stirring for reaction; after the reaction is finished, adding dichloromethane for extraction, concentrating and passing through a column to obtain 7-methoxy docetaxel;

the reaction route of the preparation process is as follows:

further, in step S1, the ratio of the amount of the docetaxel side chain acid to the raw material IMB-1 is 0.85 to 0.95 (W/W). Herein, W/W refers to a mass ratio.

Further, in step S1, the ratio of the amount of 4-dimethylaminopyridine to the IMB-1 starting material is 0.08-0.10 (W/W).

Further, in step S1, the ratio of the amount of N, N' -dicyclohexylcarbodiimide used to the amount of IMB-1 as the raw material is 0.50 to 0.56 (W/W).

Further, in step S1, the ratio of the amount of toluene to the IMB-1 raw material is 10 to 15 (V/W). In this context, V/W refers to the volume/mass ratio.

Further, in step S1, the reaction temperature is 15-25 ℃ and the reaction time is 2-4 h.

Further, in step S2, the ratio of the amount of 70% pyridine hydrogen fluoride (in mass%) to the amount of IMB-2 is 4 to 5 (V/W).

Further, in step S2, the ratio of the amount of acetonitrile to IMB-2 is 10-15 (V/W); the ratio of the pyridine dosage to the IMB-2 is 10-15 (V/W).

Further, in step S2, the reaction temperature is 0-5 ℃ and the reaction time is 12-18 h.

Further, in step S3, the ratio of the amount of dichloromethane to IMB-3 is 20 to 22 (V/W).

Further, in step S3, the ratio of the amount of 1, 8-bis-dimethylamino naphthalene to IMB-3 is 2.2 to 2.4 (W/W); the ratio of the amount of the molecular sieve to the amount of the IMB-3 is 1-1.1 (W/W).

Further, in step S3, the ratio of the amount of trimethyloxonium tetrafluoroborate to the amount of IMB-3 is 1.5 to 1.6 (W/W).

Further, in step S3, the reaction temperature is 15-20 ℃ and the reaction time is 8-10 h.

Further, in step S4, the ratio of methanol to IMB-4 is 20 to 30 (V/W).

Further, in step S4, the ratio of the amount of p-toluenesulfonic acid to IMB-4 is 0.35 to 0.37 (W/W).

Further, in step S4, the reaction temperature is 15-25 ℃ and the reaction time is 2-3 h.

Further, in step S5, the ratio of tetrahydrofuran to IMB-5 is 10-12 (V/W).

Further, in step S5, the ratio of the amount of sodium bicarbonate to the amount of IMB-5 is 1 to 1.2 (W/W).

Further, in step S5, the ratio of the amount of 30% hydrogen peroxide (mass%) to the amount of IMB-5 is 3 to 4 (V/W).

Further, in step S5, the reaction temperature is 15-25 ℃ and the reaction time is 12-18 h.

The invention has the following beneficial effects:

IMB-1 is an intermediate in the common synthesis process of paclitaxel, and the raw material is selected to ensure the accessibility.

2. In step S2, the protecting group Tes is deprotected without the use of the usual acidic conditions, such as [ Kingston D G, Chaudhary A G, Gunatillaka A, et al.Synthesis of taxol from baccatin via an oxazoline intermediate.Tetrahedron Lett,1994,35(26):4483-4484.]Hydrolysis with 0.1N hydrochloric acid to remove the protecting group Tes, [ Mukaiyama T, Shiina I, Iwadare H, et al, asymmetry Total Synthesis of[J].Chemistry-A European Journal,1999,5(1):121-161.]Deprotection of the protecting group Tes by trifluoroacetic acid at 0 ℃ is reported. The invention skillfully uses the hydrogen fluoride pyridine to remove the protecting group Tes at the 7 th position, and simultaneously ensures that the side chain part can not be opened. However, under acidic conditions, the following reaction occurs upon side chain opening, and the target product cannot be obtained. In the post-treatment part of step S2, pyridine is removed by rotary evaporation with n-hexane (forming an azeotrope with pyridine), and the conventional post-treatment method for removing pyridine by hydrochloric acid washing during extraction (the following reaction also occurs) is not selected, so that the side chain of the product is not subjected to ring opening.

3. All the steps are reaction of a single site, no competitive reaction exists, the target object of each step is clear, and the yield is high.

Drawings

FIG. 1 is an HPLC chromatogram of 7-methoxy docetaxel obtained in example 1 of the present invention.

FIG. 2 is a MS spectrum of 7-methoxy docetaxel obtained in example 1 of the present invention.

FIG. 3 is a 1H NMR spectrum of 7-methoxydocetaxel obtained in example 1 of the present invention.

FIG. 4 is a 13C NMR spectrum of 7-methoxydocetaxel obtained in example 1 of the present invention.

Detailed Description

The following describes embodiments of the present invention with reference to the drawings.

Example 1:

step S1: 20g of IMB-1 is dissolved in 200ml of toluene, 17g of doxy-side chain acid and 1.6g of 4-dimethylaminopyridine are added, 10.6g of 10.6g N, N' -dicyclohexylcarbodiimide are added dropwise with stirring, and the mixture is stirred and reacted for 2 hours at room temperature of about 20 ℃. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated until no solvent was distilled off, recrystallized from ethyl acetate and n-heptane, and dried to obtain 29.7g of IMB-2.

Step S2: 29.7g of IMB-2 obtained in step S1 was dissolved in 300ml of pyridine and 300ml of acetonitrile, cooled in ice bath at 0 ℃, added with 120ml of 70% hydrogen fluoride pyridine, and stirred for reaction for 12 hours. After the reaction was completed, water and methylene chloride were added to extract, the aqueous phase was back-extracted with methylene chloride 3 times, the organic phase was concentrated, and n-hexane was added thereto to conduct rotary evaporation, whereby 24.5g of IMB-3 was obtained.

Step S3: 24.5g of IMB-3 was dissolved in 500ml of methylene chloride, 54g of 1, 8-bisdimethylaminonaphthalene and 24.5g of molecular sieve were added, and the mixture was stirred for 30 minutes, then 37g of trimethyloxonium tetrafluoroborate was added, and the mixture was stirred at 15 ℃ and reacted for 10 hours. After the reaction was completed, the reaction solution was filtered under suction, and the filtrate was concentrated and passed through a column to obtain 21.8g of IMB-4.

Step S4: 21.8g of IMB-4 was dissolved in 650ml of methanol, and 7.7g of p-toluenesulfonic acid was added thereto, followed by stirring at room temperature for 2 hours. After the reaction is completed, 2L of purified water is added, a large amount of solid is separated out, and 17.3g of IMB-5 is obtained by suction filtration and drying.

Step S5: 17.3g of IMB-5 was dissolved in 175ml of tetrahydrofuran, and 17.3g of sodium bicarbonate and 55ml of 30% hydrogen peroxide were added thereto, followed by stirring at room temperature for 17 hours. After the reaction is finished, dichloromethane is added for extraction, and 13.8g of 7-methoxy docetaxel is obtained by concentrating an organic phase, passing through a column and drying, wherein the purity is 99.179%, the total yield is 58.8%, and a liquid phase diagram is shown in an attached figure 1.

As shown in fig. 2, the MS spectrum of 7-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 7-methoxydocetaxel of this example, 1H NMR (500MHz, CDCl3) delta: 8.09(2H, d, J ═ 7.4Hz, ArH),7.60(1H, t, J ═ 7.2Hz, ArH),7.48(2H, t, J ═ 7.6Hz, ArH),7.38(4H, m, ArH),7.32(1H, m, ArH),6.19(1H, m, H13),5.63(1H, d, J ═ 6.8Hz, H2),5.44(1H, d, J ═ 9.1Hz, H31),5.26(1H, m, H30),5.13(1H, s, H10),4.96(1H, d, J ═ 9.0Hz, H5),4.62(1H, s, H36),4.30(1H, d, J ═ 3, H, 3.7H, 3H, 18H, H463H, H3, 7.7H, 3H, 7H, H13 Hz, J ═ 3H, H3H, 3H, H3H, 7.7H, 7.7.7H, 7.7H, 3H, 7H, 8H, 7H, 3H, 7, m,2H14),1.87(3H, s, H18),1.78(4H, m, H6 overlapped with H19),1.36(9H, s, H39),1.23(3H, s,3H16/3H17),1.13(3H, s,3H16/3H 17).

As shown in FIG. 4, the 13C NMR spectrum of 7-methoxydocetaxel of this example was analyzed by 13C NMR (125MHz, CDCl3) delta: 209.902,172.551,170.435,166.956,155.306,138.47,137.931,136.236,133.66,130.147,129.226,128.811,128.671,128.052,126.835,83.992,81.533,80.684,80.214,78.701,77.254,77,76.746,76.549,74.57,74.203,73.731,72.506,57.242,56.989,56.24,47.133,43.2,35.656,32.176,28.216,26.706,22.59,20.311,14.335,10.484.

Example 2:

step S1: 10g of IMB-1 is dissolved in 150ml of toluene, 9g of doxy-side chain acid and 1g of 4-dimethylaminopyridine are added, 5.6g N, N' -dicyclohexylcarbodiimide is added dropwise with stirring, and the mixture is stirred and reacted for 4 hours at room temperature of about 20 ℃. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated until no solvent was evaporated, and recrystallized from ethyl acetate and n-heptane, and dried to obtain 15g of IMB-2.

Step S2: and (3) dissolving 15g of IMB-2 obtained in the step S1 in 180ml of pyridine and 200ml of acetonitrile, cooling in an ice bath at 0 ℃, adding 70ml of 70% hydrogen fluoride pyridine, and stirring for reacting for 18 hours. After the reaction is completed, water and dichloromethane are added for extraction, the water phase is back-extracted for 3 times by using dichloromethane, the organic phase is concentrated, and n-hexane is added for rotary evaporation to obtain 12.5g of IMB-3.

Step S3: dissolving 12.5g of IMB-3 in 250ml of dichloromethane, adding 30g of 1, 8-bis-dimethylamino-naphthalene and 12.5g of molecular sieve, stirring for 30min, adding 20g of trimethyloxonium tetrafluoroborate, and stirring at 20 ℃ for reacting for 8.5 h. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated and then passes through a column, so that 11.4g of IMB-4 is obtained.

Step S4: 11.4g of IMB-4 was dissolved in 230ml of methanol, and 4.2g of p-toluenesulfonic acid was added thereto, followed by stirring at room temperature for 3 hours. After the reaction is completed, 1L of purified water is added, a large amount of solid is separated out, and 9.0g of IMB-5 is obtained by suction filtration and drying.

Step S5: 9.0g of IMB-5 was dissolved in 100ml of tetrahydrofuran, and 10g of sodium bicarbonate and 35ml of 30% hydrogen peroxide were added, followed by stirring at room temperature for 12 hours. After the reaction is finished, dichloromethane is added for extraction, and 7.1g of 7-methoxy docetaxel is obtained by concentrating an organic phase, passing through a column and drying, wherein the purity is 99.305%, and the total yield is 60.5%.

Comparative example 1: (removal of the protecting group Tes with hydrochloric acid)

Step S1: 5g of IMB-1 was dissolved in 50ml of toluene, 4.5g of doxy-side chain acid and 0.5g of 4-dimethylaminopyridine were added thereto, and 2.8g of 2.8g N, N' -dicyclohexylcarbodiimide was added dropwise with stirring, and the mixture was reacted at about 20 ℃ for 4 hours with stirring. After the reaction was completed, water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated until no solvent was evaporated, and then recrystallized from ethyl acetate and n-heptane, and dried to obtain 7.2g of IMB-2.

Step S2: 7.2g of IMB-2 obtained in step S1 was dissolved in 200ml of methanol, and 13ml of 1mol/L hydrochloric acid was added dropwise thereto, followed by stirring at room temperature for reaction for 8 hours. After completion of the reaction, water and methylene chloride were added to conduct extraction, and the organic phase was concentrated to obtain 5.3g of IMB-3'.

Step S3: dissolving 5g of IMB-3 in 100ml of dichloromethane, adding 11g of 1, 8-bis-dimethylamino-naphthalene and 5g of molecular sieve, stirring for 30min, adding 8g of trimethyl oxonium tetrafluoroborate, and stirring for reaction at 20 ℃ for 8 h. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated and then passes through a column, thus obtaining 5.5g of IMB-4'.

Step S4: 5.5g of IMB-4' was dissolved in 150ml of methanol, 2g of p-toluenesulfonic acid was added, the reaction was stirred at room temperature for 3 hours, and TLC monitoring showed no formation of a new product. After the reaction solution was treated, the following structure of IMB-4' was confirmed by MS. This route has been shown to result in the side chain opening during S2, resulting in failure to obtain the target.

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 foregoing description is illustrative of the present invention and is not to be construed as limiting thereof, the scope of the invention being defined by the appended claims, which may be modified in any manner without departing from the basic structure thereof.