CN116813641A

CN116813641A - Preparation method of everolimus

Info

Publication number: CN116813641A
Application number: CN202310683310.7A
Authority: CN
Inventors: 唐建飞; 曹康德; 姜文超; 王文霞; 吴元武; 张伟伟; 梅云云
Original assignee: HANGZHOU HUADONG MEDICINE GROUP KANGRUN PHARMACEUTICAL CO Ltd
Current assignee: HANGZHOU HUADONG MEDICINE GROUP KANGRUN PHARMACEUTICAL CO Ltd
Priority date: 2023-06-09
Filing date: 2023-06-09
Publication date: 2023-09-29

Abstract

The invention provides a preparation method of everolimus, and relates to the technical field of pharmaceutical chemistry. According to the preparation method provided by the invention, the process parameters are optimized, the isomer C is separated by adopting high-pressure forward chromatography, so that the concentration difficulty is avoided, the yield of the product is effectively improved, the 2, 6-di-tert-butyl-p-cresol (BHT) is dissolved by acetone, the good dispersion is realized, the crystallization efficiency is improved, and the everolimus finished product with high yield and high purity is prepared, so that the method is suitable for large-scale popularization.

Description

Preparation method of everolimus

Technical Field

The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of everolimus.

Background

Everolimus (Everolimu with molecular formula of C ₅₃ H ₈₃ NO ₁₄ 958.2) is derived from the precursor compound rapamycin (extracted from actinomycetes) and thus everolimus is a semisynthetic biologic. Everolimus is an mTOR inhibitor (mammalian target of rapamycin), under the PI3K/AKT pathwayA serine threonine kinase. Everolimus is approved under the trade name Certican for use in preventing organ rejection in heart and kidney transplant patients. The structural formula of everolimus is shown as follows:

everolimus can be used in patients with advanced renal cancer failure treated with sunitinib or sorafenib, and according to the North study, everolimus can slow down the growth of renal cancer cells, reducing the mortality rate by 67%. Directly acting on tumor cells by inhibiting the growth and proliferation of the tumor cells; by inhibiting angiogenesis, the tumor vascularity is reduced, thereby exerting an indirect effect (by effectively inhibiting the production of VEGF by tumor cells and the proliferation of VEGF-induced endothelial cells).

Everolimus is also being studied for neuroendocrine tumors, lymphomas, other cancers, and tuberous sclerosis, either as a single formulation or in combination with existing cancer therapies.

The existing synthesis methods of everolimus include the following steps:

the method comprises the following steps: the method disclosed in US5665772 uses sirolimus as a starting material, and is characterized in that the sirolimus is obtained through two-step reaction, the sirolimus and 2- (tert-butyldimethylsilyloxy) ethyl triflate are reacted in toluene to obtain an intermediate, the catalyst is 2, 6-lutidine, and then a silicon ether bond of the intermediate A is reacted in methanol under an acidic condition to obtain a target product. However, the first-step reaction yield in the method is extremely low and is only 5%, most of raw material sirolimus is still unreacted, the purity of the obtained product is low, and the later purification and refining of the product are not facilitated, so that the method is not suitable for industrial production.

The second method is as follows: CN201010017955 by the process disclosed, in the first step, 2- [ tert-butyldimethylsilyl (abbreviated as TBDPS) ] ethyl triflate is replaced by 2- [ tert-butyldimethylsilyl (abbreviated as TBDMS) ] ethyl triflate, thereby correspondingly improving the substitution conditions to prepare an intermediate product; then the silicon ether bond of the intermediate B is broken in hydrogen fluoride/pyridine to obtain the target product. The final yield of the method is improved to a certain extent compared with the method of US5665772, and part of sirolimus can be recycled through column chromatography, but the once-through reaction yield is still lower, so that the actual production requirement can not be met.

And a third method: the method disclosed in CN201210168250 is characterized in that the first step of reaction uses inorganic alkali potassium carbonate as alkali and acetone as solvent to react to obtain an intermediate product, the reaction yield is greatly improved (the yield of the intermediate A is 30%), but part of sirolimus still does not react completely, the second step of reaction uses US5665772, the purity of the obtained crude everolimus product is lower, and the method is unfavorable for obtaining the everolimus product with high quality and high yield.

The method four: in the method disclosed in CN103848849, sirolimus and 2- (tert-butyldimethylsilyloxy) ethyl triflate are reacted in the presence of an appropriate solvent and an organic base to obtain an intermediate A; 2) The intermediate A reacts with inorganic acid in an organic solvent to obtain everolimus; wherein: the organic base used in step 1) is selected from triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo undec-7-ene or N-methylmorpholine, and the acid used in step 2) is hydrochloric acid, sulfuric acid or phosphoric acid. The reaction process parameters of the process are generally consistent compared with other reporting methods, and the final step adopts inorganic acid to desilicate ether bond, so that epimerization impurities are easy to generate, the purification and refining of the later products are not facilitated, and the application does not provide an effective purification mode and is not suitable for industrial production.

According to the technical method reported in the literature, although the process and conditions of everolimus synthesis are improved, the reaction yield and the product purity of everolimus are improved, the organic layer containing the everolimus Mo Sigui etherification intermediate is extremely unstable, the process optimization of the post-treatment process is not mentioned in the technical method, the purification of everolimus is not involved or the efficiency is low, and therefore, the process of everolimus synthesis still needs to be further optimized and improved.

Aiming at the problems, the invention provides a preparation method of everolimus, which is characterized in that the preparation method is optimized in technological parameters, the isomer C is separated by adopting a high-pressure chromatography forward chromatography method, the yield of a product is effectively improved, and the BHT is dissolved by acetone, so that good dispersion is realized, the crystallization efficiency is improved, and the everolimus finished product with high yield and high purity is prepared, so that the preparation method is suitable for large-scale popularization.

The molecular formula of the isomer C is C ₅₃ H ₈₃ NO ₁₄ The structure is as follows:

disclosure of Invention

Aiming at the problems, the invention provides a preparation method of everolimus, which is characterized by optimizing technological parameters, a post-treatment mode and a purification mode, and the everolimus finished product with high yield and high purity is prepared.

In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:

in one aspect, the invention provides a preparation method of everolimus, wherein the reaction route is as follows:

comprises the following steps:

1) Dissolving ethylene glycol in dichloromethane, adding triethylamine, cooling to-10-0 ℃, adding tert-butyl dimethyl chlorosilane, reacting, rectifying and purifying to obtain A1;

2) Taking A1 and 2, 6-lutidine as raw materials, taking methylene dichloride as a solvent, adding trifluoromethanesulfonic anhydride, and reacting to obtain A2;

3) Rapamycin and N, N-diisopropylethylamine are dissolved in toluene and heated to 45-55 ℃; then adding toluene solution of A2 and N, N-diisopropylethylamine, stirring for 1-2h, and then adding toluene solution of A2 and N, N-diisopropylethylamine once every 1-2h, and adding 5 times; adding the mixture and continuing stirring for 1.5-2.5h for the last time, and purifying to obtain B1 after the reaction is finished;

4) Dissolving B1 with alcohol solvent, adding acidic substance, and stirring to obtain C1 crude product;

5) Carrying out high-pressure chromatography on the C1 crude product, collecting according to a chromatogram of chromatographic equipment, and concentrating under reduced pressure to obtain a refined everolimus product;

6) And dissolving the everolimus refined product and the 2, 6-di-tert-butyl-p-cresol with acetone, concentrating under reduced pressure to dryness, and drying to obtain an everolimus finished product.

Preferably, the molar ratio of ethylene glycol, tert-butyldimethylchlorosilane and triethylamine in step 1) may be 1:1:1-1.2; further preferably, it may be 1:1:1.2.

preferably, the time for dropwise adding the tert-butyldimethyl chlorosilane in the step 1) can be 1-1.5h; further preferably, it may be 1h.

Preferably, the reaction temperature in the step 1) can be 20-30 ℃ and the reaction time can be 12-16h; further preferably, the reaction temperature in step 1) may be 25 ℃ and the reaction time may be 16 hours.

Preferably, the reaction of step 1) further comprises the following post-treatments: dropwise adding a saturated ammonium chloride solution, standing for layering, and washing the water phase with methyl tertiary butyl ether; combining the organic phases and carrying out suction filtration; washing filter residues with methyl tertiary butyl ether; and (3) washing the organic phase with water and saturated saline, separating the organic phase, stirring and drying the organic phase with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and rectifying to obtain A1.

Preferably, the addition of the trifluoromethanesulfonic anhydride in step 2) requires a temperature of-10 ℃ to 0 ℃; further preferably, it may be 0 ℃.

Preferably, the molar ratio of t-butyldimethylhydroxyethoxysilane, 2, 6-lutidine and trifluoromethanesulfonic anhydride described in step 2) may be 1:1.1-1.5:1-1.2; further preferably, it may be 1:1.25:1.1.

preferably, the reaction time in the step 2) can be 10-20min, and the reaction temperature can be-10-0 ℃; further preferably, the reaction time in step 2) may be 15min and the reaction temperature may be 0 ℃.

Preferably, the reaction of step 2) further comprises a post-treatment: washing the reaction solution with saturated sodium chloride, and concentrating under reduced pressure; diluting the concentrate with n-hexane, filtering with active carbon, and concentrating the filtrate under reduced pressure to obtain A2.

Preferably, the molar ratio of rapamycin to A2 in step 3) may be 1:10.

preferably, the reaction temperature in step 3) may be 45 ℃ to 55 ℃; further preferably, the reaction temperature in step 3) may be 50 ℃.

Preferably, the reaction of step 3) further comprises a post-treatment: after the reaction is finished, filtering, diluting filtrate with ethyl acetate, and washing an organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution; the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.

Preferably, the purification in step 3) is a column chromatography, specifically: eluting the concentrate by using a silica gel column chromatography, eluting by using 15% -20% of acetone/n-hexane as a chromatography mobile phase, and concentrating the eluent under reduced pressure until the eluent is dried to obtain B1; further preferably, the purification of step 3) is a column chromatography, specifically: the concentrate is chromatographed on a silica gel column, eluting with 15% and 20% acetone/hexane as the mobile phase of the chromatography, and concentrating the eluent under reduced pressure until it is dry to obtain B1.

Preferably, the chromatographic mobile phase is recycled, and the recycling rate is more than or equal to 60%.

Preferably, the reaction temperature in the step 4) can be between-10 ℃ and 0 ℃ and the reaction time can be between 1.5 and 3 hours; further preferably, the reaction temperature in step 4) may be 0 ℃ and the reaction time may be 2h.

Preferably, the alcohol solvent in the step 4) may be methanol; further preferably, the amount of methanol may be 4-8mL/g; more preferably 8mL/g.

Preferably, the acidic substance in the step 4) may be hydrochloric acid; further preferably, the concentration of the hydrochloric acid is 0.1-1mol/L, and the dosage is 0.2-0.4mL/g; more preferably, the concentration of the hydrochloric acid in the step 4) can be 1mol/L, and the dosage can be 0.2mL/g.

Preferably, the reaction of step 4) further comprises a post-treatment: the reaction solution is washed by saturated sodium bicarbonate solution and saturated sodium chloride solution and dried by spin to obtain a crude product of C1.

Preferably, the pressure of the high-pressure chromatography in the step 5) is controlled to be 0.1-0.3Mpa; further preferably, it may be 0.2Mpa.

Preferably, the chromatography mobile phase of the high pressure chromatography in step 5) can be 30% -40% acetone/n-hexane; further preferably, 30%, 40% acetone/n-hexane may be used.

Preferably, the specific operation of the drying in step 6) is as follows: and (3) placing the dried product in a decompression drying oven (at 50 ℃ and less than or equal to-0.090 MPa), and drying for 40-50 hours to obtain the everolimus finished product.

Preferably, the amount of acetone used in step 6) is 4-8 times that of the everolimus fine product and 2, 6-di-tert-butyl-p-cresol.

Preferably, the reduced pressure in step 6) may be at a temperature of 30-50 ℃.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a preparation method of everolimus, which is characterized in that the preparation method is characterized in that the process parameters are optimized, the isomer C is separated by adopting high-pressure forward chromatography, the concentration difficulty is avoided, the yield of the product is effectively improved, the BHT is dissolved by acetone, the good dispersion is realized, the crystallization efficiency is improved, and the everolimus finished product with high yield and high purity is prepared, so that the everolimus preparation method is suitable for large-scale popularization.

Detailed Description

In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. It is to be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited. Technical and scientific terms used in the examples have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Example 1

Step 1

Ethylene glycol (6.2 g) was placed in a four-necked flask under nitrogen protection, anhydrous dichloromethane (62.2 mL) was added, and stirring was started; triethylamine (12.12 g) was slowly added at room temperature and cooled to 0 ℃; a solution of t-butyldimethylchlorosilane (15.1 g) in methylene chloride (17 mL) was added dropwise via a dropping funnel; the dripping time is not less than 1h, and the dripping is finished. The reaction was allowed to warm to room temperature naturally and was allowed to react overnight.

Saturated ammonium chloride solution (22.6 mL) was added dropwise, and the mixture was allowed to stand for separation, and the aqueous phase was washed with methyl tert-butyl ether. The organic phases were combined and suction filtered. The filter residue was washed with methyl tert-butyl ether. The organic phases were combined, washed with water and saturated brine, the organic phases were separated, dried with anhydrous sodium sulfate under stirring, filtered, concentrated under reduced pressure, and purified by distillation to give A1, 10.6g, weight yield 70.1% (product weight/t-butyldimethylchlorosilane weight 100%).

Step 2

Tert-butyldimethylhydroxyethoxysilane (1.00 g,5.67 mmol) and 2, 6-lutidine (0.76 g,7.09 mmol) were added to a solution of 20.00mL of methylene chloride, and trifluoromethanesulfonic anhydride (1.76 g,6.23 mmol) was added under nitrogen protection at 0deg.C, followed by 15min of reaction, washing with saturated sodium chloride, and concentrating under reduced pressure; the concentrate was diluted with n-hexane, filtered through activated carbon and the filtrate was concentrated under reduced pressure to give A2,1.5g with a weight yield of 150% (A2 weight/A1 weight x 100%).

Step 3

Rapamycin 9.14g (10 mmol) and (40 mmol) N, N-diisopropylethylamine 30mL toluene were added and heated to 55deg.C. Then, a solution of 6.17g (20 mmol) of 2- (tert-butyldisilyl) oxyethanol triflate and 2.59g (20 mmol) of N, N-diisopropylethylamine in toluene (20 mL) was added, and after stirring for 1.5 hours, a solution of 6.17g (20 mmol) of 2- (tert-butyldisilyl) oxyethanol triflate and 2.59g (20 mmol) of N, N-diisopropylethylamine in toluene (20 mL) was added, once every 1.5 hours. The last addition was continued to stir for 2h to give a brown suspension which was filtered.

The filtrate was diluted with ethyl acetate and the organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.

The concentrate is chromatographed on a silica gel column, eluting with 15% and 20% acetone/n-hexane, and concentrating the eluent under reduced pressure to dryness to obtain 40-O- [2- (tert-butyldisilyl) oxy ] ethyl rapamycin. The chromatographic mobile phase is recycled, the mobile phase is recycled by more than 60%, and the production cost is reduced by 1.2 ten thousand/kg; b1 was obtained at 6.6g and the weight yield of B1 was 72.2% (weight product/weight rapamycin. Times.100%).

Step 4

4.5g (4.2 mmol) of 40-O- [2- (tert-butyldisilyl) oxo ] ethyl rapamycin was dissolved in methanol (20 mL) and cooled to 0 ℃. 1N HCL 2mL was added and stirred for 2h. The reaction solution was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dried by spin to give 4.3g of crude everolimus product with a weight yield of 96% and a purity of 88.5%.

Step 5

And (3) subjecting the crude everolimus product to silica gel chromatography, eluting with 30% and 40% acetone/n-hexane, controlling the pressure to be 0.2MPa, collecting according to a chromatogram of chromatographic equipment, and concentrating under reduced pressure to obtain the refined everolimus product. The chromatographic mobile phase is recycled, the mobile phase is recycled by more than 60%, and the production cost is reduced by 2.1 ten thousand/kg; 2.7g of everolimus refined product is obtained, the yield is 60% (weight of product/weight of everolimus is 100%) and the purity is 99.2%.

Step 6

Dissolving everolimus essence and BHT with 6 times of acetone, and concentrating under reduced pressure at 40deg.C to dry; and (3) drying the dried product in a decompression drying oven (at 50 ℃ and less than or equal to-0.090 MPa) for 48 hours to obtain the everolimus finished product.

According to the process, the production yield of the product can reach 40% (weight of everolimus/weight of sirolimus is 100%).

Example 2

Step 2

The difference from example 1 is that the molar ratio of t-butyldimethylhydroxyethoxysilane, 2, 6-dimethylpyridine and trifluoromethanesulfonic anhydride is varied from 1:1.5:1.1.

example 3

The difference from example 1 is that the molar ratio of t-butyldimethylhydroxyethoxysilane, 2, 6-dimethylpyridine and trifluoromethanesulfonic anhydride is varied from 1:1.35:1.1.

example 4

The difference from example 1 is that the molar ratio of t-butyldimethylhydroxyethoxysilane, 2, 6-dimethylpyridine and trifluoromethanesulfonic anhydride is varied from 1:1.15:1.1.

examples 1-4 the effect on the quality of A2 due to varying the molar ratio of t-butyldimethylhydroxyethoxysilane, 2, 6-lutidine and trifluoromethanesulfonic anhydride is shown below:

comparative example 1

Step 1

In a 500mL round bottom flask under nitrogen, anhydrous tetrahydrofuran (154 mL) and 60% sodium hydride (3.13 g) were added with stirring, and anhydrous ethylene glycol (4.9 g) was added to form a large amount of precipitate, followed by stirring for 45min. Tert-butyldimethylchlorosilane (11.8 g) was then added and vigorously stirred for 45min, with the temperature controlled at 20-25 ℃.

After the completion of the reaction, diethyl ether (950 mL) was added for dilution, followed by washing with a saturated sodium chloride solution (420 mL), dehydration with anhydrous sodium sulfate, and concentration under reduced pressure.

A silica gel column, and performing normal temperature chromatography; n-hexane/diethyl ether=75: 25, and concentrating the main section to obtain 5.9g of A1 with a weight yield of 50% (weight of product/weight of tert-butyldimethylsilyl chloride: 100%).

Compared to example 1, the process comparison results are as follows:

comparative example 2

Step 2

Tert-butyldimethylhydroxyethoxysilane (1.00 g,5.67 mmol) and 2, 6-lutidine (0.76 g,7.09 mmol) were added to a solution of 20.00mL of methylene chloride, and trifluoromethanesulfonic anhydride (1.76 g,6.23 mmol) was added under nitrogen protection at 0deg.C, followed by 15min of reaction, washing with saturated sodium chloride, and concentrating under reduced pressure; silica gel column, n-hexane elution, main section concentration to obtain A2,1g, weight yield 100% (A2 weight/A1 weight 100%)

Comparative example 3

Step 3

Rapamycin (10 mmol) and (40 mmol) 2, 6-lutidine were added to 30mL toluene and heated to 60 ℃. Then, a solution of (20 mmol) of 2- (t-butyldisilyl) oxyethanol triflate and (20 mmol) of 2, 6-lutidine in toluene (20 mL) was added, and after stirring for 1.5 hours, a solution of (10 mmol) of 2- (t-butyldisilyl) oxyethanol triflate and (10 mmol) of 2, 6-lutidine in toluene (10 mL) was added, once every 1.5 hours. Adding the last stirring for 2h, and filtering.

The concentrate is chromatographed on a silica gel column, eluting with 15% and 20% acetone/n-hexane, and concentrating the eluent under reduced pressure to dryness to obtain 40-O- [2- (tert-butyldisilyl) oxy ] ethyl rapamycin. B1 yield 21.9%.

Comparative example 4

Rapamycin (10 mmol) and (40 mmol) 2, 6-lutidine were added to 30mL toluene and heated to 60 ℃. Then, a solution of (20 mmol) of 2- (t-butyldisilyl) oxyethanol triflate and (20 mmol) of 2, 6-lutidine in toluene (20 mL) was added, and after stirring for 1.5 hours, a solution of (20 mmol) of 2- (t-butyldisilyl) oxyethanol triflate and (20 mmol) of 2, 6-lutidine in toluene (20 mL) was added, once every 1.5 hours. Adding the last stirring for 2h, and filtering.

The concentrate is chromatographed on a silica gel column, eluting with 15% and 20% acetone/n-hexane, and concentrating the eluent under reduced pressure to dryness to obtain 40-O- [2- (tert-butyldisilyl) oxy ] ethyl rapamycin. B1 yield 39.4%.

Comparative example 5

Step 5

And (3) subjecting the crude everolimus product to silica gel chromatography, eluting with 30% and 40% acetone/n-hexane, controlling the pressure to be 0.5MPa, collecting according to a chromatogram of chromatographic equipment, and concentrating under reduced pressure to obtain the refined everolimus product. The chromatographic mobile phase is recycled, the mobile phase is recycled by more than 60%, and the production cost is reduced by 2.1 ten thousand/kg; 2.16g of everolimus refined product is obtained, the yield is 48% (weight of product/weight of everolimus is 100%), and the purity is 92.3%.

Comparative example 6

Step 5

And (3) subjecting the crude everolimus product to silica gel chromatography, eluting with 30% and 40% acetone/n-hexane, controlling the pressure to be 0.05MPa, collecting according to a chromatogram of chromatographic equipment, and concentrating under reduced pressure to obtain the refined everolimus product. The chromatographic mobile phase is recycled, the mobile phase is recycled by more than 60%, and the production cost is reduced by 2.1 ten thousand/kg; the everolimus refined product is 1.89g, the yield is 42% (the weight of the product/the weight of the everolimus is 100%) and the purity is 91.8%.

Comparative example 7

Step 6

The everolimus fine product and the BHT are dissolved by 6 times of ethanol, and are crystallized in water, so that the product can not be obtained.

Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.

Claims

1. The preparation method of everolimus is characterized in that the reaction route is as follows:

comprises the following steps:

2. The method according to claim 1, wherein the molar ratio of ethylene glycol, t-butyldimethylchlorosilane and triethylamine in step 1) is 1:1:1-1.2.

3. The method according to claim 1, wherein the molar ratio of t-butyldimethylhydroxyethoxysilane, 2, 6-lutidine, and trifluoromethanesulfonic anhydride in step 2) is 1:1.1-1.5:1-1.2.

4. The method of claim 1, wherein the reaction of step 2) further comprises post-treatment: washing the reaction solution with saturated sodium chloride, and concentrating under reduced pressure; diluting the concentrate with n-hexane, filtering with active carbon, and concentrating the filtrate under reduced pressure to obtain A2.

5. The method according to claim 1, wherein the molar ratio of rapamycin to A2 in step 3) is 1:10.

6. the method according to claim 1, wherein the purification in step 3) is a column chromatography, specifically: the concentrate is chromatographed by a silica gel column, eluting is carried out by using 15 to 20 percent of acetone/normal hexane as a chromatographic mobile phase, and the eluent is decompressed and concentrated to dryness to obtain B1.

7. The method according to claim 1, wherein the reaction temperature in step 4) is-10 ℃ to 0 ℃ and the reaction time is 1.5 to 3 hours.

8. The process according to claim 1, wherein the amount of methanol used in step 4) is 4-8mL/g.

9. The method according to claim 1, wherein the concentration of the hydrochloric acid in the step 4) is 0.1-1mol/L and the amount is 0.2-0.4mL/g.

10. The method according to claim 1, wherein the pressure of the high-pressure chromatography in step 5) is controlled to be 0.1-0.3Mpa.

11. The preparation method according to claim 1, wherein the chromatographic mobile phase of the high-pressure chromatography in the step 5) is recycled, and the recycling rate is more than or equal to 60%.

12. The process according to claim 1, wherein the amount of acetone used in step 6) is 4-8 times that of everolimus and 2, 6-di-t-butyl-p-cresol.

13. The process according to claim 1, wherein the reduced pressure in step 6) is at a temperature of 30-50 ℃.