CN104592254B - The synthetic method of everolimus - Google Patents
The synthetic method of everolimus Download PDFInfo
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- CN104592254B CN104592254B CN201510088957.0A CN201510088957A CN104592254B CN 104592254 B CN104592254 B CN 104592254B CN 201510088957 A CN201510088957 A CN 201510088957A CN 104592254 B CN104592254 B CN 104592254B
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Abstract
The present invention provides the synthetic method of a kind of everolimus.The step of described synthetic method is as follows: the first step: the preparation of everolimus silicon etherification product (intermediate A)；Second step: hydrolysis, intermediate A is obtained by reacting everolimus in organic solvent with mineral acid or Fluohydric acid. organic base；Finally obtain target product everolimus.The present invention does alkali by DIPEA in the first step is reacted, and toluene makees solvent, adopts brand-new charging process and post processing mode, makes the response time significantly shorten；The purity and the yield that make everolimus silicon etherificate intermediate are greatly improved simultaneously.Present invention process passes through optimization and the selection of reaction condition, especially charging process and post-processing approach are carried out great process modification, solving the general character crucial problem during this product synthesized to become, two step total recoverys and all more existing bibliographical information of end-product purity are improved largely.
Description
Technical field
The present invention relates to the synthetic method of a kind of everolimus.
Background technology
Everolimus (Everolimus) is sirolimus derivant, a kind of suckling sirolimus target protein (mTOR) inhibitor developed by Novartis Co., Ltd of Switzerland, also known as 40-O-(2-ethoxy)-sirolimus, it is mainly used in the rejection (Figure1) after prevention renal transplantation and heart transplant operation clinically.Along with deepening continuously to everolimus pharmacologically active and study on mechanism, it starts to demonstrate its positive effect at therapeutic field of tumor.In recent years, everolimus uses extensive all the more at all types of therapeutic field of tumors, is used for treating renal cell carcinoma from everolimus in 2003 and lists in Sweden first, within 2006, captures European market comprehensively.Treatment gastrointestinal pancreas neurosecretion tumor within 2007, it is approved in Europe.In March, 2009 U.S. FDA approval everolimus (trade name: Afinitor), in November, 2010 U.S. FDA approval novel remedies for cancer everolimus was for treating the patient with the subependymal giant cell astrocytoma relevant to nodositas sclerencephaly for renal cell carcinoma patients.At present, the new indication of everolimus treatment tumor increases gradually, and existing being respectively used to again clinically treats neuroendocrine tumor, lymphoma, hepatocarcinoma and gastric cancer, nonsmall-cell lung cancer and breast carcinoma etc., and these treatments are in the clinical research of III phase.Based on antitumor drug market strong growth and everolimus oral administration and the feature being suitable for multiple indication, it will occupy critical positions on tumour medicine market, be selected in one of ten big new drugs of U.S.'s industry most market prospect.
The synthetic method of existing everolimus has following several:
Method disclosed in method one: US5665772, with sirolimus for initiation material, everolimus is obtained through two-step reaction, first sirolimus and trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester are reacted to obtain in toluene intermediate, then the silicon ehter bond of intermediate A methanol in acid condition will react to obtain target product (referring to route 1).But first step reaction yield pole is only 5% in the method, still have the reaction not of most raw material sirolimus and products therefrom purity relatively low, be unfavorable for the purification in product later stage and refining, be not suitable for industrialized production in this approach.
Method disclosed in method two: CN201010017955, trifluoromethanesulfonic acid 2-[t-Butyldimethylsilyl (is abbreviated as TBDMS)] ethyl ester is substituted with trifluoromethanesulfonic acid 2-[tert-butyl diphenyl silica-based (being abbreviated as TBDPS)] ethyl ester, thus having correspondingly improved substitution reaction condition to prepare midbody product in the first step is reacted；The silicon ehter bond of intermediate B be have employed fracture in fluohydric acid gas/pyridine again and obtain target product.The method ultimate yield method compared with US5665772 improves, and part sirolimus can be recycled by column chromatography, but one-time reaction yield is still relatively low, therefore still can not meet the needs of actual production.
Method disclosed in method three: CN201210168250, the characteristic of the method is in that first step reaction inorganic base potassium carbonate makes alkali, acetone as solvent reacts to obtain midbody product, reaction yield improves a lot (intermediate A yield is 30%), but still have part sirolimus not react completely, US5665772 has been continued to use in second step reaction, and the purity of gained everolimus crude product is relatively low, is unfavorable for obtaining the everolimus product of high-quality and high yield.
Method disclosed in method four: CN103848849, is first obtained by reacting intermediate A with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester by sirolimus under appropriate solvent exists with organic base；2) intermediate A and mineral acid are obtained by reacting everolimus in organic solvent；In wherein: step 1), organic base used is selected from the big steric hindrance such as triethylamine, DIPEA, 1,8-diazabicylo 11 carbon-7-alkene or N-methylmorpholine or non-nucleophilic alkali, step 2) in acid used be hydrochloric acid, sulphuric acid or phosphoric acid.This technique each reaction process parameter is unanimous on the whole compared with other report method, and final step adopts mineral acid desiliconization ehter bond, it is easy to produce epimerization impurity, is unfavorable for the purifying products in later stage and refining, is not suitable for being applied to industrialized production.
Method disclosed in method five: CN201110253059, first with sirolimus for raw material, first by this raw material and trifluoromethanesulfonic acid anhydride reactant, obtains intermediate；Again by the intermediate glycol reaction with single protection, obtain intermediate everolimus silicon etherificate intermediate after obtain product everolimus through deprotection.Though the method has bigger innovation compared with the synthesis route of other process, but owing to first sirolimus hydroxyl being become sulphonic acid ester, in second step etherification reaction, configuration inversion can be produced, generate the epimer of everolimus silicon etherification product, then the same epimer producing everolimus product in three-step reaction, is unfavorable for the refining of product and purification, is not suitable for industrialized great production.
The to sum up process of document above report, although the technique of bigger Optimal improvements everolimus synthesis and condition, improves the product purity of reaction yield and everolimus, but is all only optimization just for parameter each in course of reaction.Owing to the organic layer containing everolimus silicon etherificate intermediate is extremely unstable, the process optimization of all not mentioned last handling process in process above, and this last handling process exactly final quality on everolimus product affects most important, therefore, the technique of everolimus synthesis still needs to further optimize and improve.
Summary of the invention
It is an object of the invention to solve existing everolimus synthetically prepared in the relatively low not enough problem of existing product yield, particularly charging process and aftertreatment technology are optimized, obtain the key process parameter affecting this product quality, by the synthetic process reliable and stable for the offer of everolimus industrialized production.
In order to realize foregoing invention purpose, the invention provides techniques below scheme:
The synthetic method of a kind of everolimus, it comprises the steps:
(1) in suitable solvent, in the presence of an organic base, make sirolimus shown in following formula:
(also can be depicted as in this article
React with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, obtain being called the following formula product of intermediate A:
Intermediate A；
(2) make intermediate A react in organic solvent with mineral acid or organic base hydrofluoride, obtain everolimus shown in following formula:
The method according to the invention, wherein in step (1), described solvent dichloroethanes, benzene, toluene, it is preferred to toluene.
The method according to the invention, wherein in step (1), described organic base is selected from triethylamine, DIPEA, it is preferred that organic base is DIPEA (being generally also known as diisopropylethylamine or DIPEA).
The method according to the invention, wherein in step (1), the mol ratio of described sirolimus and trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester is 1:2～1:6；It is preferably 1:4.
The method according to the invention, wherein in step (1), the mol ratio of described trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester and organic base is 1:1～1:3；It is preferably 1:2.
The method according to the invention, wherein in step (1), the temperature that described sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester is 40～60 DEG C；It is preferably 55 DEG C.
The method according to the invention, wherein in step (1), described trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester feeds in raw material to adopt and is dividedly in some parts or the method for disposable addition etc., it is preferred to the method for disposable addition.
The method according to the invention, wherein in step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to-20～10 DEG C (such as-10～10 DEG C, such as 5 DEG C), sucking filtration, filtrate is down to-20～0 DEG C (such as-10～0 DEG C, such as-5 DEG C), filtrate is loaded directly on silicagel column and carries out column chromatography, (the two volume ratio is 1～6:1 to use petrol ether/ethyl acetate mixed solvent, such as 2～5:1, such as 3～4:1, such as 1:1, such as 2:1, such as 3:1, such as 4:1, such as 5:1, such as 6:1) eluting, obtain intermediate A.
nullThe method according to the invention，Wherein in step (1)，After sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester，Make reactant fast cooling to-20～10 DEG C (such as-10～10 DEG C，Such as 5 DEG C)，Sucking filtration，Filtrate is successively through acidic aqueous solution (such as hydrochloric acid solution，Such as 1M aqueous hydrochloric acid solution)、Alkaline aqueous solution (such as saturated sodium bicarbonate solution)、After saturated aqueous common salt extraction is washed，Take organic layer，Temperature is made to be down to-20～0 DEG C (such as-10～0 DEG C，Such as-5 DEG C)，It is loaded directly on silicagel column again and carries out column chromatography，(the two volume ratio is 1～6:1 to use petrol ether/ethyl acetate mixed solvent，Such as 2～5:1，Such as 3～4:1，Such as 1:1，Such as 2:1，Such as 3:1，Such as 4:1，Such as 5:1，Such as 6:1) eluting，Obtain intermediate A.
The method according to the invention, wherein in step (2), described organic solvent is selected from dichloroethanes, benzene, toluene, oxolane.
The method according to the invention, wherein in step (2), described mineral acid or organic base hydrofluoride are Fluohydric acid. pyridines.This Fluohydric acid. pyridine can make intermediate A be hydrolyzed.
The method according to the invention, wherein in step (2), intermediate A is reacted at ambient temperature (such as 25 DEG C) in organic solvent react with mineral acid or organic base hydrofluoride.
The method according to the invention, wherein in step (2), after intermediate A is reacted in organic solvent with mineral acid or organic base hydrofluoride, reactant liquor is neutralized to pH=8 by dropping saturated sodium bicarbonate solution, adds extraction into ethyl acetate layering；Merge organic facies, more successively with saturated sodium bicarbonate solution, saturated brine washing；Use anhydrous sodium sulfate dries；Concentrating under reduced pressure obtains grease, prepares target product everolimus through silicagel column column chromatography (such as using ethyl acetate eluting).
Further the present invention will be described below.
In order to realize foregoing invention purpose, the invention provides techniques below scheme:
The synthetic method of a kind of everolimus, comprises the following steps:
(1) with sirolimus or sirolimus for raw material, reacting with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, the aftertreatment technology after optimized obtains intermediate A, sees reaction equation 1:
(2) intermediate A obtains everolimus crude product through acid desiliconization ether protection, sees reaction equation 2:
In the synthetic method of above-mentioned everolimus, in step (1), primary raw material used is sirolimus, and organic base used is selected from triethylamine, DIPEA (DIPEA), it is preferred to DIPEA.
Further, in the synthetic method of above-mentioned everolimus, appropriate solvent used is selected from dichloroethanes, benzene, toluene, preferably toluene.
Further, in the synthetic method of above-mentioned everolimus, in the first step, sirolimus used is 1:2～1:6 with the mol ratio of trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester；It is preferably 1:4.The mol ratio of trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester used and organic base is 1:1～1:3；It is preferably 1:2.
Further, in the synthetic method of above-mentioned everolimus, in the first step, reaction temperature used is 40～65 DEG C；It is preferably 55 DEG C.
Further, in the synthetic method of above-mentioned everolimus, in the first step, reinforced being respectively adopted of trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester used is dividedly in some parts and the method such as disposable addition, it is preferred to disposable Adding Way.
Further, in the synthetic method of above-mentioned everolimus, in the first step, post-processing approach used have employed common sucking filtration, pickling, alkali cleaning and saturated common salt water washing, dry and concentrate to obtain the processing method of intermediate A；Have employed fast cooling after unconventional stopped reaction, sucking filtration is down to-20～10 DEG C again, and mother solution is directly through the method for column chromatography, and direct column chromatography is method for optimizing.
Further, in the synthetic method of above-mentioned everolimus, in the first step, make sirolimus be dissolved in solvent, add organic base, make reactant be warmed up to 40～65 DEG C, adding trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, stirring makes abundant reaction；Make reactant fast cooling to-20～10 DEG C (such as-10～10 DEG C, such as 5 DEG C), sucking filtration, filtrate is down to-20～0 DEG C (such as-10～0 DEG C, such as-5 DEG C), being loaded directly on silicagel column by filtrate and carry out column chromatography, (the two volume ratio is 1～6:1, for instance 2～5:1 to use petrol ether/ethyl acetate mixed solvent, such as 3～4:1, such as 1:1, for instance 2:1, for instance 3:1, such as 4:1, such as 5:1, for instance 6:1) eluting, obtain intermediate A and following formula: compound:
Or, further, in the synthetic method of above-mentioned everolimus, in the first step, make sirolimus be dissolved in solvent, add organic base, making reactant be warmed up to 40～65 DEG C, add trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, stirring makes abundant reaction；Make reactant fast cooling to-20～10 DEG C (such as-10～10 DEG C, such as 5 DEG C), sucking filtration, filtrate is successively through acidic aqueous solution (such as hydrochloric acid solution, such as 1M aqueous hydrochloric acid solution), alkaline aqueous solution (such as saturated sodium bicarbonate solution), after saturated aqueous common salt extraction is washed, take organic layer, temperature is made to be down to-20～0 DEG C (such as-10～0 DEG C, such as-5 DEG C), it is loaded directly on silicagel column again and carries out column chromatography, (the two volume ratio is 1～6:1 to use petrol ether/ethyl acetate mixed solvent, such as 2～5:1, such as 3～4:1, such as 1:1, such as 2:1, such as 3:1, such as 4:1, such as 5:1, such as 6:1) eluting, obtain intermediate A.
The method according to the invention, although making the everolimus otherwise prepared have similar purity with use the inventive method products therefrom, but, have been found that, only having when using eluting solvent of the present invention, the everolimus obtained by its obtained intermediate A presents beat all stability.The above results of the present invention is still unaccountable at present.
In the synthetic method of above-mentioned everolimus, in second step reaction, acid used is mineral acid or organic base hydrofluoride, and wherein acid is preferably organic base hydrofluoride.
Detailed description of the invention
Embodiment 1
(1) preparation of everolimus silicon etherification product intermediate A:
In the there-necked flask of 100mL; under dry toluene, nitrogen protection; weigh 1g sirolimus; join in 10mL toluene organic solvent, stirring and dissolving, then add diisopropylethylamine (DIPEA) 1.1g; it is warmed up to 55 DEG C; disposable addition trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester 1.53g, after reaction 3h, sirolimus raw material reaction is complete.It is cooled to 5 DEG C, sucking filtration, filtrate is through 1NHCl acid, saturated sodium bicarbonate, saturated aqueous common salt extraction is washed, and organic layer is down to low temperature (-5 DEG C) directly through silicagel column column chromatography, uses petrol ether/ethyl acetate mixed solvent (the two volume ratio is 6:1) eluting, obtaining intermediate A 0.77g, yield is 63%.
(2) preparation of everolimus
In the many mouthfuls of flasks of 50mL, at room temperature 20 DEG C, 1g everolimus intermediate A 10mL oxolane is dissolved.Being cooled to 0 DEG C, drip Fluohydric acid. pyridine solution, be naturally warmed up to 25 DEG C of insulation reaction, stopped reaction after reacting completely, dropping saturated sodium bicarbonate is neutralized to pH=8, adds ethyl acetate 100mL × 2 extracting and demixing.Merging organic facies to wash 1 time with saturated sodium bicarbonate 100mL, saturated brine 100mL washs 1 time again.Use anhydrous sodium sulfate dries.Concentrating under reduced pressure obtains grease, prepares target product everolimus 0.73g through silicagel column column chromatography (using ethyl acetate eluting), and yield is 86%, purity (HPLC) > 98%.The present embodiment everolimus total recovery: 54.2%.
Embodiment 2
(1) preparation of everolimus silicon etherification product intermediate A:
In the there-necked flask of 250mL; under dry toluene, nitrogen protection; weigh 6g sirolimus; join in 50mL toluene organic solvent, stirring and dissolving, then add diisopropylethylamine (DIPEA) 6.6g; it is warmed up to 55 DEG C; disposable addition trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester 9.2g, after reaction 3.5h, sirolimus raw material reaction is complete.Being cooled to 5 DEG C, sucking filtration, filtrate cools to-5 DEG C, directly through silicagel column column chromatography, uses petrol ether/ethyl acetate mixed solvent (the two volume ratio is 1:1) eluting, obtains intermediate A 4.8g, and yield is 65.6%.
(2) preparation of everolimus
In the many mouthfuls of flasks of 100mL, at room temperature 20 DEG C, 4.8g everolimus intermediate A 30mL oxolane is dissolved.Being cooled to 0 DEG C, drip Fluohydric acid. pyridine solution, be naturally warmed up to 25 DEG C of insulation reaction, stopped reaction after reacting completely, dropping saturated sodium bicarbonate is neutralized to pH=8, adds ethyl acetate 100mL × 2 extracting and demixing.Merging organic facies and wash once with saturated sodium bicarbonate 100mL again, saturated brine 100mL washs 1 time.Use anhydrous sodium sulfate dries.Concentrating under reduced pressure obtains grease, prepares target product everolimus 3.6g through silica gel column chromatography (using ethyl acetate eluting), and yield is 85%, purity (HPLC) > 98%.The present embodiment everolimus total recovery: 56%.
Embodiment 3
The method of reference example 1, the volume ratio except that petrol ether/ethyl acetate mixed solvent is 2:1,3:1,4:1 or 5:1, obtains four batches of everolimuses.In four tests, intermediate A yield is all in 64～72% scopes, and everolimus total recovery is all in 53～59% scopes, and everolimus purity (HPLC) is equal > 98%.
Embodiment 4
(1) preparation of everolimus silicon etherification product intermediate A:
In the there-necked flask of 100mL; under dry toluene, nitrogen protection; weigh 1g sirolimus; join in 10mL toluene organic solvent, stirring and dissolving, then add diisopropylethylamine (DIPEA) 1.1g; it is warmed up to 55 DEG C; disposable addition trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester 1.53g, after reaction 3h, sirolimus raw material reaction is complete.It is cooled to 5 DEG C, sucking filtration, filtrate is successively after acidic aqueous solution (1M aqueous hydrochloric acid solution), alkaline aqueous solution (such as saturated sodium bicarbonate solution), saturated aqueous common salt extraction are washed, take organic layer, make temperature be down to-5 DEG C, then be loaded directly on silicagel column and carry out column chromatography, use petrol ether/ethyl acetate mixed solvent (the two volume ratio is 6:1) eluting, obtaining intermediate A, yield is 64%.
(2) preparation of everolimus
In the many mouthfuls of flasks of 50mL, at room temperature 20 DEG C, 1g everolimus intermediate A 10mL oxolane is dissolved.Being cooled to 0 DEG C, drip Fluohydric acid. pyridine solution, be naturally warmed up to 25 DEG C of insulation reaction, stopped reaction after reacting completely, dropping saturated sodium bicarbonate is neutralized to pH=8, adds ethyl acetate 100mL × 2 extracting and demixing.Merging organic facies to wash 1 time with saturated sodium bicarbonate 100mL, saturated brine 100mL washs 1 time again.Use anhydrous sodium sulfate dries.Concentrating under reduced pressure obtains grease, prepares target product everolimus through silicagel column column chromatography (using ethyl acetate eluting), and yield is 83%, purity (HPLC) > 98%.The present embodiment everolimus total recovery: 53.1%.
Embodiment 5
The method of reference example 1, the difference is that using petroleum ether, ethyl acetate, methanol, ethanol or cyclohexane give to be in step (1) respectively, eluent replacement petrol ether/ethyl acetate mixed solvent carries out silicagel column column chromatography eluting, obtains five batches of everolimuses.In testing at five, intermediate A yield all in 32～44% scopes, everolimus total recovery all in 35～40% scopes, everolimus purity (HPLC) all < 70%.
Embodiment 6
The method of reference example 1, different is only in step (1), ethyl ester is after completion of the reaction with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) for sirolimus, make reactant liquor successively through sucking filtration, 0.1M chlorohydric acid pickling, 0.1M sodium hydroxide alkali cleaning and saturated common salt water washing, divide the organic facies anhydrous sodium sulfate taken to dry, concentrate, dry except solvent.Intermediate A yield is 33%, everolimus total recovery 38%, everolimus purity (HPLC) < 70%.
Embodiment 7
Make the everolimus crude product that various embodiments above prepares, the method adopting CN103360411A description [0060] section, carry out recrystallization process, obtain everolimus highly finished product.Owing to the purity of various embodiments above gained everolimus product can be different, it is possible to carry out repeatedly the recrystallization of method like this as required, the everolimus content of gained highly finished product is made all to reach the degree (between 99.1～99.6%) more than 99.0%.Then by by the different embodiment everolimus crude products highly finished product through refining gained, seal, be placed in 45 DEG C of calorstats placement March, for every batch of highly finished product, everolimus relative amount time when measuring its March relative to its 0 month.Result shows, the whole everolimus crude product of embodiment 1,2,3,4 gained is after refining, and these highly finished product everolimus relative amount after high-temperature treatment, all in 98.2%～99.7% scope, shows excellent stability；The whole everolimus crude product of embodiment 5,6 gained is after refining, although their purity and embodiment 1,2,3,4 product (or its highly finished product) purity are quite (all between 99.1～99.6%), but these highly finished product after high-temperature treatment everolimus relative amount all in 91.4%～93.7% scope, it is shown that significantly stability is undesirable.
Although the foregoing describing the specific embodiment of the present invention; but those familiar with the art is to be understood that; we are merely exemplary described specific embodiment; rather than for the restriction to the scope of the present invention; those of ordinary skill in the art, in the equivalent modification made according to the spirit of the present invention and change, should be encompassed in the scope of the claimed protection of the present invention.
Claims (19)
1. a synthetic method for everolimus, it comprises the steps:
(1) in suitable solvent, in the presence of an organic base, make sirolimus shown in following formula:
React with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, obtain being called the following formula product of intermediate A:
Intermediate A；
(2) make intermediate A react in organic solvent with mineral acid or organic base hydrofluoride, obtain everolimus shown in following formula:
Wherein
In step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to-20～10 DEG C, sucking filtration, filtrate is down to-20～0 DEG C, add filtrate to be loaded directly on silicagel column and carry out column chromatography, the petrol ether/ethyl acetate mixed solvent eluting using volume ratio to be 1～6:1, obtain intermediate A；Or,
In step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to-20～10 DEG C, sucking filtration, filtrate after acidic aqueous solution, alkaline aqueous solution, saturated aqueous common salt extraction are washed, takes organic layer successively, temperature is made to be down to-20～0 DEG C, it is loaded directly on silicagel column again and carries out column chromatography, the petrol ether/ethyl acetate mixed solvent eluting using volume ratio to be 1～6:1, obtain intermediate A.
2. method according to claim 1, wherein in step (1), described solvent is selected from dichloroethanes, benzene, toluene.
3. method according to claim 1, wherein in step (1), described organic base is selected from triethylamine, DIPEA.
4. method according to claim 1, wherein in step (1), the mol ratio of described sirolimus and trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester is 1:2～1:6.
5. method according to claim 1, wherein in step (1), the mol ratio of described sirolimus and trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester is 1:4.
6. method according to claim 1, wherein in step (1), the mol ratio of described trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester and organic base is 1:1～1:3.
7. method according to claim 1, wherein in step (1), the mol ratio of described trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester and organic base is 1:2.
8. method according to claim 1, wherein in step (1), the temperature that described sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester is 40～60 DEG C.
9. method according to claim 1, wherein in step (1), the temperature that described sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester is 55 DEG C.
10. method according to claim 1, wherein in step (1), described trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester feeds in raw material to adopt and is dividedly in some parts or the method for disposable addition.
11. method according to claim 1, wherein in step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to-10～10 DEG C, sucking filtration, filtrate is down to-10～0 DEG C, adds filtrate and is loaded directly on silicagel column and carries out column chromatography, the petrol ether/ethyl acetate mixed solvent eluting using volume ratio to be 2～5:1, obtains intermediate A.
12. method according to claim 1, wherein in step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to 5 DEG C, sucking filtration, filtrate is down to-5 DEG C, adds filtrate and is loaded directly on silicagel column and carries out column chromatography, the petrol ether/ethyl acetate mixed solvent eluting using volume ratio to be 3～4:1, obtains intermediate A.
13. method according to claim 1, wherein in step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to-10～10 DEG C, sucking filtration, filtrate is successively after 1M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution, saturated aqueous common salt extraction are washed, take organic layer, temperature is made to be down to-10～0 DEG C, it is loaded directly on silicagel column again and carries out column chromatography, the petrol ether/ethyl acetate mixed solvent eluting using volume ratio to be 2～5:1, obtains intermediate A.
14. method according to claim 1, wherein in step (1), after sirolimus reacts with trifluoromethanesulfonic acid 2-(tertiary butyl dimethyl Si base) ethyl ester, make reactant fast cooling to 5 DEG C, sucking filtration, filtrate is successively after 1M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution, saturated aqueous common salt extraction are washed, take organic layer, temperature is made to be down to-5 DEG C, it is loaded directly on silicagel column again and carries out column chromatography, the petrol ether/ethyl acetate mixed solvent eluting using volume ratio to be 3～4:1, obtains intermediate A.
15. method according to claim 1, wherein in step (2), described organic solvent is selected from dichloroethanes, benzene, toluene, oxolane.
16. method according to claim 1, wherein in step (2), described organic base hydrofluoride is Fluohydric acid. pyridine.
17. method according to claim 1, wherein in step (2), intermediate A is reacted in organic solvent react at ambient temperature with mineral acid or organic base hydrofluoride.
18. method according to claim 1, wherein in step (2), after intermediate A is reacted in organic solvent with mineral acid or organic base hydrofluoride, reactant liquor is neutralized to pH=8 by dropping saturated sodium bicarbonate solution, adds extraction into ethyl acetate layering；Merge organic facies, more successively with saturated sodium bicarbonate solution, saturated brine washing；Use anhydrous sodium sulfate dries；Concentrating under reduced pressure obtains grease, prepares target product everolimus through silicagel column column chromatography.
19. method according to claim 18, wherein use ethyl acetate eluting through silicagel column column chromatography.
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