CN106146536B - A kind of preparation method of everolimus - Google Patents
A kind of preparation method of everolimus Download PDFInfo
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- CN106146536B CN106146536B CN201510205424.6A CN201510205424A CN106146536B CN 106146536 B CN106146536 B CN 106146536B CN 201510205424 A CN201510205424 A CN 201510205424A CN 106146536 B CN106146536 B CN 106146536B
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- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 title claims abstract description 41
- 229960005167 everolimus Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims abstract description 21
- 229960002930 sirolimus Drugs 0.000 claims abstract description 20
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims abstract description 19
- 230000004224 protection Effects 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 238000005903 acid hydrolysis reaction Methods 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007791 liquid phase Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 239000000523 sample Substances 0.000 description 8
- 230000008859 change Effects 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- -1 2- ethoxy Chemical group 0.000 description 1
- 108010036941 Cyclosporins Proteins 0.000 description 1
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 1
- PCSWWKIGJZLKHG-UHFFFAOYSA-N O(S(=O)(=O)C(F)(F)F)CC.[O] Chemical compound O(S(=O)(=O)C(F)(F)F)CC.[O] PCSWWKIGJZLKHG-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000026911 Tuberous sclerosis complex Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940042992 afinitor Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NWSBNVVOFKKFNV-UHFFFAOYSA-N chloroform;oxolane Chemical compound ClC(Cl)Cl.C1CCOC1 NWSBNVVOFKKFNV-UHFFFAOYSA-N 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000016065 neuroendocrine neoplasm Diseases 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 208000009999 tuberous sclerosis Diseases 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 230000009441 vascular protection Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a kind of preparation methods of everolimus；For this method the following steps are included: rapamycin is reacted with trim,ethylchlorosilane by after the double protections of 31,40 hydroxyls, acidic hydrolysis obtains the intermediate 1 of 31 hydroxyl protections；Intermediate 1 and ethylene oxide carry out condensation reaction, obtain intermediate 2,2 acidic hydrolysis of intermediate obtains everolimus crude product, and crude product is isolated and purified with preparation liquid phase, obtains everolimus.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of preparation method of everolimus.
Background technique
Everolimus (everolimus；Trade name: Afinitor) chemical name [40-O- (2- ethoxy)-rapamycin],
It is macrolides rapamycin derivative drug of new generation, structural formula is as follows:
Everolimus is the tool researched and developed by Novartis Co., Ltd, Switzerland centainly water-soluble rapamycin derivative, can take orally to
Medicine is clinically mainly used to prevent the rejection after kidney transplant and heart transplant operation.Its mechanism of action mainly includes being immunized
Inhibiting effect, antitumor action, antivirus action, vascular protection effect, often combining with other immunosuppressor such as cyclosporines makes
To reduce toxicity.Additionally for treating advanced renal cell cancer.Also it is carrying out to neuroendocrine tumor, lymthoma, other cancers
The research of disease and tuberous sclerosis can be used as single formulation or share with existing cancer treatment method.
WO9409010 reports the method for preparing everolimus as Material synthesis using rapamycin earliest；Document
J.labelled Compd Radiopharm.2000,43,113-120 also report the everolimus similar with the patent document
Synthesis preparation method.The above-mentioned method for preparing everolimus as Material synthesis using rapamycin includes two-step reaction: first two
It is reaction with rapamycin and 2- (tert-butyl diphenyl silicon substrate) oxygen ethyl triflate under wopropyl ethyl amine alkaline condition
Object, reaction prepares intermediate 1 in certain organic solvent；Intermediate 1 sloughs protecting group getting the product everolimus, above-mentioned
Preparation process low yield, at high cost, the yield for preparing intermediate is only 6%；The product yield of second step reaction is also only 21%.
CN102127092A discloses a kind of preparation method of everolimus, which has continued to use above-mentioned with thunder substantially
Pa mycin is the process route that Material synthesis prepares everolimus, only implements recycling to unreacted rapamycin raw material.
Since rapamycin reaction site is more, property is unstable, above-mentioned to prepare by Material synthesis of rapamycin according to dimension
In the preparation method that do not take charge of, reaction needs to control to be carried out under the conditions of relatively mild, and typical temperature is controlled at 50-60 DEG C, temperature
Spend low, reaction cannot be carried out sufficiently；Temperature is excessively high, and rapamycin and its intermediate are easy degradation or to generate other unknown miscellaneous
Matter, reaction temperature is too low or the excessively high total recovery that will lead to product is lower.Existing literature report scheme reaction temperature is effectively controlled
At 50-60 DEG C, can still have more than 50% rapamycin cannot effectively be able to participate in reaction system.
Summary of the invention
For deficiency existing for everolimus synthetic method in the prior art, the present invention provides a kind of everolimus preparation side
Method.Under alkaline condition by rapamycin, and after trim,ethylchlorosilane reaction double hydroxyl protection, in acid condition with epoxy
Ethane carries out condensation reaction, then hydrolyzed under acidic conditions obtains everolimus, and this method is easy to operate, rapamycin is easy to react,
Reaction yield is high, in order to achieve the above-mentioned object of the invention.
The present invention provides following technical scheme, the program includes tetra- steps of A, B, C, D:
Step A: rapamycin under alkaline condition, is reacted with trim,ethylchlorosilane by after 31,40 hydroxyl protections, acid
Hydrolysis, obtains the intermediate 1 of 31 hydroxyl protections；
Step B: in acid condition, intermediate 1 and ethylene oxide carry out condensation reaction, obtain intermediate 2,
Step C: intermediate 2 dissolves acidic hydrolysis in a solvent, obtains everolimus crude product,
D step: the crude product is isolated and purified with preparation liquid phase, obtains everolimus.
Specific reaction route is as follows:
Step A:
Step B
Step C:
D step:
Step A of the present invention: rapamycin under alkaline condition, is reacted with trim,ethylchlorosilane by 31,40 hydroxyl protections
Afterwards, acidic hydrolysis, obtain the intermediate 1 of 31 hydroxyl protections: the alkaline condition of this step is provided by organic base, organic base
It include: triethylamine, pyridine, diisopropyl ethyl ammonia, 2,6- lutidines, imidazoles etc.；As long as reaction dissolvent can dissolve reaction
Object, and do not have influential solvent to be ok reaction, such as ethyl acetate, methylene chloride, chloroform tetrahydrofuran.Reaction temperature with
The variation of reagent or solvent and change, usually -40 DEG C~30 DEG C, the reaction time is also the variation with reagent or solvent
And change, usually 1-8 hours；TLC detection, no rapamycin spot, then double protection reactions are completed；Then acidic hydrolysis obtains
To the intermediate 1 of 31 hydroxyl protections；Acid is mainly various inorganic acids, and sulfuric acid, hydrochloric acid, hydrobromic acid etc., reaction temperature is with reagent
Or solvent variation and change, usually -20 DEG C~30 DEG C, the reaction time is also the variation with reagent or solvent and becomes
Change, usually 3-28 hours；TLC detection, unparalleled protection rapamycin spot, then hydrolysis is completed；After the reaction was completed, with normal
The post processing mode processing of rule can be obtained by intermediate 1.
Step B of the present invention: intermediate 1 in a solvent, in acid condition, carries out condensation reaction with ethylene oxide, obtains
Intermediate 2；Solvent is the one or several kinds such as anhydrous ether, tetrahydrofuran, chloroform, methylene chloride, ethyl acetate, toluene；Make
Acid for catalyst is mainly micro or a small amount of various inorganic acids, such as sulfuric acid, hydrochloric acid, hydrobromic acid etc.；Reaction temperature is with examination
Agent or the variation of solvent and change, usually -20 DEG C~40 DEG C, the reaction time be also the variation with reagent or solvent and
Variation, usually 2-12 hours；TLC detection, no 1 spot of intermediate, then condensation reaction is completed；After the reaction was completed, with routine
Post processing mode processing can be obtained by intermediate 2.
Step C of the present invention: intermediate 2 dissolves acidic hydrolysis in a solvent, obtains everolimus crude product: as long as reaction dissolvent
Reactant can be dissolved, and do not have influential solvent to be ok reaction, as ethyl acetate, methylene chloride, chloroform, tetrahydrofuran,
Methanol etc.；Acid mainly various inorganic acids, sulfuric acid, hydrochloric acid, hydrobromic acid etc., reaction temperature become with the variation of reagent or solvent
Change, usually -10 DEG C~20 DEG C, the reaction time is also the variation with reagent or solvent and changes, usually 3-10 hours；
TLC detection, no 2 spot of intermediate, then hydrolysis is completed；After the reaction was completed, it is handled with conventional post processing mode, then mistake
Silicagel column processing can be obtained by everolimus crude product.
D step of the present invention: crude product is isolated and purified with preparation liquid phase, obtains everolimus；Crude product acetonitrile and purified water
Mixed liquor dissolution, with 500ml/min flow velocity sample introduction, collects the part of the main peak containing everolimus after the filtration of 0.45 micron membrane filter
It is handled, obtains everolimus.
Specific embodiment
Beneficial effects of the present invention are now further described by following embodiment, it is thus understood that these embodiments are only used for
The purpose of illustration, does not limit the scope of the invention, at the same those of ordinary skill in the art done according to the present invention it is apparent
Change and modification be also contained within the scope of the invention.
Embodiment 1: the preparation of everolimus intermediate 1:
By 9g flower bud pa mycin, 4.5g2,6- lutidines, 100ml tetrahydrofuran is added in the there-necked flask of 250ml, ice
Brine bath cools down, stirring and dissolving, starts (the CH that 7ml is added dropwise after 0.5h3)3SiCl, insulation reaction, after reaction 3 hours, TLC detection
Reaction process, no rapamycin spot, then double protection reactions are completed, and 5mlHCl is then added dropwise, after reaction 5 hours, TLC detection,
Unparalleled protection rapamycin spot, then hydrolysis is completed.Reaction solution 200ml ethyl acetate is extracted, ethyl acetate layer is used
Water 50ml, NaHCO3Saturated solution 50ml washing, then washed with 50ml salt, aqueous layer with ethyl acetate extracts 2 times, merges organic
Layer, anhydrous Na2SO4It is dry；It removes ethyl acetate under reduced pressure, obtains single protection 9.6g.
Embodiment 2: the preparation of everolimus intermediate 2
At 0~10 DEG C, 500ml toluene is added in 1L three neck round bottom flask, 4.4g ethylene oxide, cooling is then added
Afterwards, 9.6g rapamycin intermediate 1 is added in reaction solution, while a small amount of hydrochloric acid is added, the reaction was continued 6 hours, TLC monitoring
To fully reacting, with water 250ml, NaHCO3Saturated solution 250ml washing, then washed with 250ml salt, water layer extracts 2 with toluene
It is secondary, merge organic layer, anhydrous Na2SO4It is dry；It removes toluene under reduced pressure, obtains 2 sterling 6.8g of everolimus intermediate.
Embodiment 3: the preparation of everolimus crude product
6.8g coupled product is dissolved in a 1L single port bottle with 500ml methanol, ice-water bath cooling is added dropwise after half an hour
10ml HCl after being added dropwise to complete, reacts 4 hours, TLC tracing detection, after completion of the reaction, then evaporated under reduced pressure uses 500ml second
Acetoacetic ester dissolves residue, is washed with saturated brine, and ethyl acetate extracts water layer 3 times, merges organic layer, and anhydrous sodium sulfate is dry
Dry, evaporated under reduced pressure obtains yellow oil, and column separation obtains crude product 5.6g.
Embodiment 4: the preparation of everolimus
By everolimus crude product 5.6g, is dissolved with 200ml acetonitrile and 120ml purified water, sample solution is configured to, through 0.45
After micron membrane filter filtration, to sample introduction；Start sampling pump and gradient elution journey is then turned on 500ml/min flow velocity sample introduction 1.4min
Sequence starts to elute, until adjusting switching valve when target peak occurs, collects target peak, sampling is detected by HPLC, target peak other parts
It is collected to rejected product container including isomers peak, is then switched to waste collection bucket；It repeats the above process, until this batch
Sample is finished completely；Collection liquid is distilled with Rotary Evaporators low-temperature reduced-pressure, obtains everolimus pulverulent solids 3.8g.
Everolimus sample structure confirmation:
The element percentage composition of everolimus sample
The IR of everolimus sample composes each absorption peak ownership
Everolimus sample is in DMSO-d61H-NMR data
Claims (6)
1. a kind of preparation method of everolimus, this method comprises the following steps:
Step A: rapamycin under alkaline condition, reacts after carrying out the double protections of hydroxyl, containing acid item with trim,ethylchlorosilane
Part hydrolysis, obtains the intermediate 1 of hydroxyl protection
,
Step B: in acid condition, intermediate 1 and ethylene oxide carry out condensation reaction, obtain intermediate 2
,
Step C: intermediate 2 dissolves acidic hydrolysis in a solvent, obtains everolimus crude product
,
Step D: preparation liquid phase isolates and purifies after the dissolution of everolimus crude product solvent, obtains everolimus product
,
Wherein, the alkali under alkaline condition described in step A is selected from triethylamine, pyridine, diisopropyl ethyl ammonia, 2,6- dimethyl
One of pyridine and imidazoles are a variety of；Acid under the acid condition is one of sulfuric acid, hydrochloric acid or hydrobromic acid；Step
Solvent used in condensation reaction is one of anhydrous ether, tetrahydrofuran, chloroform, methylene chloride, ethyl acetate and toluene in B
Or it is several；Acid under the acid condition is one of sulfuric acid, hydrochloric acid or hydrobromic acid.
2. the method as described in claim 1, it is characterised in that the bis- protection reaction dissolvents of step A be ethyl acetate, methylene chloride,
One of chloroform and tetrahydrofuran are a variety of.
3. the method as described in claim 1, it is characterised in that the bis- protection reaction temperatures of step A are -40 DEG C -30 DEG C, when reaction
Between be 1-8 hours.
4. the method as described in claim 1, it is characterised in that step B reaction temperature is -20 DEG C -40 DEG C, reaction time 2-
12 hours.
5. the method as described in claim 1, it is characterised in that step C reaction dissolvent be ethyl acetate, methylene chloride, chloroform,
One of tetrahydrofuran and methanol are a variety of；The acid of step C hydrolysis is one of sulfuric acid, hydrochloric acid or hydrobromic acid.
6. the method as described in claim 1, it is characterised in that step C reaction temperature is -10 DEG C -20 DEG C, reaction time 3-
10 hours；Step D crude product acetonitrile and the dissolution of the mixed liquor of purified water.
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| CN109776570A (en) * | 2017-11-14 | 2019-05-21 | 上海医药工业研究院 | A kind of everolimus intermediate, preparation method and its application |
| CN109369680A (en) * | 2018-12-24 | 2019-02-22 | 江苏卓和药业有限公司 | A kind of purification process of everolimus |
| CN113929702A (en) * | 2020-06-29 | 2022-01-14 | 鲁南制药集团股份有限公司 | Preparation method of everolimus |
| CN116813642B (en) * | 2023-06-29 | 2024-04-19 | 浙江康润制药有限公司 | Everolimus purification method |
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| TWI256395B (en) * | 1999-09-29 | 2006-06-11 | Wyeth Corp | Regioselective synthesis of rapamycin derivatives |
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| CN102464668B (en) * | 2010-11-17 | 2015-04-29 | 浙江海正药业股份有限公司 | Preparative chromatography purification method for purifying rapamycin or derivative thereof |
| CN102268015B (en) * | 2011-08-30 | 2013-08-28 | 成都摩尔生物医药有限公司 | Synthesis method of everolimus |
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