CN114106014B - Preparation method of everolimus - Google Patents
Preparation method of everolimus Download PDFInfo
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- CN114106014B CN114106014B CN202010879190.4A CN202010879190A CN114106014B CN 114106014 B CN114106014 B CN 114106014B CN 202010879190 A CN202010879190 A CN 202010879190A CN 114106014 B CN114106014 B CN 114106014B
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- everolimus
- ethyl acetate
- derivative iii
- rapamycin derivative
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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 35
- 229960005167 everolimus Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical class 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 28
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000004321 preservation Methods 0.000 claims description 11
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 abstract description 10
- 239000012535 impurity Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000012467 final product Substances 0.000 abstract description 3
- 230000015556 catabolic process Effects 0.000 abstract description 2
- 238000006731 degradation reaction Methods 0.000 abstract description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000706 filtrate Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 22
- 239000003208 petroleum Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- -1 2- (tert-butyldimethylsilyloxy) ethyl Chemical group 0.000 description 14
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 239000002904 solvent Substances 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000008213 purified water Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 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 description 8
- 229960002930 sirolimus Drugs 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 238000004821 distillation Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000000843 powder Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010023439 Kidney transplant rejection Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 3
- 239000012488 sample solution Substances 0.000 description 3
- 201000004059 subependymal giant cell astrocytoma Diseases 0.000 description 3
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 206010019315 Heart transplant rejection Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000011519 second-line treatment Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 description 1
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 1
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010061819 Disease recurrence Diseases 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229960002418 ivermectin Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- 208000037911 visceral disease Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention provides a preparation method of everolimus, which comprises the steps of reacting a derivative compound II of glycol with good stability with a rapamycin derivative III, and then deprotecting to obtain everolimus; the derivative compound II has higher stability and reactivity, can effectively reduce the degradation of reactants and the generation of impurities in the reaction for preparing everolimus, has simple and convenient operation, high-efficiency reaction, simple post-treatment, high yield and high purity of the final product, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of everolimus.
Background
Everolimus (Everolimus, structure is as follows), which is derived from 40-OH of rapamycin to 40-O- (2-hydroxyethyl), so Everolimus is also known as 40-O- (2-hydroxyethyl) -rapamycin. Is a new generation of mammalian target of rapamycin (mammalian target ofrapamycin, mTOR) inhibitor. Everolimus was developed by northwest corporation, 4 th 2004 on the market in germany for the prevention of heart and kidney transplant rejection, and 2005 on the market in other countries in europe; everolimus was approved and marketed in the united states for the prevention of adult kidney transplant rejection in 2010; the heart transplant rejection was marketed in japan for 3 months in 2007, and the kidney transplant rejection was approved in japan for prevention in 12 months 2011. In 2009, 3 months are marketed in the united states for the second line treatment of advanced renal cell carcinoma, while in the european union, 8 months are marketed for the second line treatment of advanced renal cell carcinoma, and in japan, 4 months 2010 are marketed for the treatment of renal cell carcinoma. 10 months 2010 was marketed in the united states for the treatment of SEGA with TSC; the year 2011, 9, has received approval in the european union for the treatment of SEGA with TSC; the use of TSC-bearing SEGA was approved in the united states for treatment in month 8 2012. FDA approval for treatment of PNET was obtained 5 months 2011; approval for treatment of PNET was obtained in europe, 9 th 2011; approval for treatment of PNET was obtained in japan 12 months 2011. ER+/HER 2-breast cancer in women who have failed pre-treatment with letrozole or anastrozole in combination with exemestane in the United states, 7 months 2012; the same year 7 months later an approval was obtained in the eutectoid for the treatment of advanced hormone receptor positive, HER2/neu negative advanced breast cancer in menopausal women without signs of visceral disease function in combination with exemestane for the treatment of disease recurrence or progression after treatment with non-steroidal aromatase inhibitors.
At present, although a plurality of documents report schemes for preparing everolimus from rapamycin or serial derivatives thereof, the problems of low reaction yield, difficult treatment of impurities and low product purity still exist. For example, the technical scheme in patent US5665772 is that rapamycin and 2- (tert-butyldimethylsilyloxy) ethyl triflate react in toluene to obtain an intermediate, and then a silicon ether bond of the intermediate is removed in 1N HCl/methanol to obtain a target product. However, the method has the advantages that the reaction yield of the first step is only 5-15% lower due to the problem of lower stability of the 2- (tert-butyldimethylsilyloxy) ethyl triflate; the second step of reaction is easy to produce degradation products and isomerization, and the obtained products have low yield and low purity and are not suitable for industrial production.
Patent ZL201410111440.4, by an improvement of the prior art, still provides an intermediate by reacting rapamycin with 2- (tert-butyldimethylsilyloxy) ethyl triflate in a suitable solvent; the intermediate is reacted in organic solvent with hydrochloric acid, sulfuric acid, phosphoric acid or other inorganic acid to obtain everolimus as basic path, and the reaction condition is optimized with organic base with great steric hindrance and non-nucleophilic property, so as to further raise the yield and product purity. However, the problems of limited rapamycin conversion rate, more impurities in the final product and higher purification difficulty are not solved effectively due to the competition of 28, 40-hydroxyl groups in the alkylation reaction, more byproducts.
Patent WO2012103959A1 reports another improved everolimus synthesis process using 2- (tert-hexyldimethylsiloxy) ethyl triflate reacted with rapamycin in the presence of N, N-diisopropylethylamine to give an intermediate; the intermediate is protected by desilication group of hydrochloric acid to obtain everolimus, and the comprehensive yield of the crude product in two steps is more than 30%; although 2- (tert-hexyldimethylsiloxy) ethyl triflate was somewhat more stable than 2- (tert-butyldimethylsiloxy) ethyl triflate. However, the sulfonate is also unsuitable for long-term storage, relatively poor in fluidity and unsuitable for separate dripping, so that the rapamycin conversion rate is still not ideal, more byproducts are generated in the reaction, and the purification yield is still low.
Further, as in patent CN102786534a and patent CN109776570a, various side chain compounds of p-trifluoromethanesulfonic acid acetic acid reacted with trimethylsilyl, triethylsilyl, tripropylsilyl, tributylsilyl, t-butyldimethylsilyl (TBS), t-hexyldimethylsilyl (THDMS), t-butyldiphenylsilyl (TBDPS), tetrahydro-2H-pyran-2-yl (THP), tetrahydrofuran-2-yl or 1-ethoxyethyl to obtain hydroxyethyl reaction were reported, and rapamycin or its derivatives were reacted to synthesize everolimus; however, the defects of unstable side chain compound, easy decomposition and difficult storage are not overcome, the problems of low yield, more generated impurities and difficult purification during the coupling reaction with rapamycin derivatives are caused, and the yield is only 35% finally, which is not suitable for industrial production.
Disclosure of Invention
Aiming at the problems of low yield, more impurities and difficult removal in the technical route for preparing everolimus disclosed in the prior art, the invention aims to provide a high-efficiency everolimus preparation method. According to the invention, everolimus can be obtained through the reaction of the derivative compound II of ethylene glycol with stable properties and the rapamycin derivative III, the reaction yield of the technical route is high, less impurities are generated in the reaction process, and the final product with higher purity can be obtained through simple purification, so that the method is suitable for industrial production.
The invention provides a preparation method of everolimus, which specifically comprises the following steps:
wherein, step A: adding the rapamycin derivative III, the compound II and the organic base into an organic solvent, stirring and heating, and carrying out heat preservation and stirring reaction; adding triethylamine, heating to 35-40 ℃, continuing to perform heat preservation and stirring reaction, and performing aftertreatment after the reaction is finished to obtain an intermediate 1;
and (B) step (B): the intermediate 1 is dissolved in acetone, under the action of dilute hydrochloric acid, the 28-hydroxyl TMS protecting group is removed, and the everolimus is obtained after post-treatment and purification.
Preferably, the organic base in the step A is one or more of imidazole, pyridine, 2, 6-lutidine, N-diisopropylethylamine, 4-dimethylaminopyridine and the like; 2, 6-lutidine is preferred.
Preferably, the molar ratio of the rapamycin derivative III to the organic base in the step A is 1:2.2-2.6; more preferably 1:2.4.
Preferably, the organic solvent in step a is toluene, xylene; toluene is more preferred.
Preferably, the mass-volume ratio of the rapamycin derivative III to the organic solvent in the step A is 1:10-14; more preferably 1:12 g/ml.
Preferably, the molar ratio of the rapamycin derivative III to the compound II in the step A is 1:2.2-2.4; more preferably 1:2.3.
Preferably, the temperature of stirring and heating in the step A is 25-30 ℃.
Preferably, in the step A, the molar ratio of the rapamycin derivative III to the triethylamine is 1:1.6-1.8; more preferably 1:1.7.
Preferably, the post-treatment process described in step a comprises: filtering, adding purified water into the filtrate, extracting the separated liquid, extracting the water layer with toluene, combining the organic layers, washing with saturated saline water, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness in vacuum, separating and purifying by a silica gel column (eluting with petroleum ether/ethyl acetate=2/1 and petroleum ether/ethyl acetate=1/1 respectively), and concentrating the product eluent to dryness in vacuum to obtain an intermediate 1.
Preferably, the concentration of the dilute hydrochloric acid in step B is 1mol/l.
Preferably, the molar feed ratio of the intermediate 1 to the dilute hydrochloric acid in the step B is 1:0.6-0.8; more preferably 1:0.7.
Preferably, the mass-volume ratio of the intermediate 1 to the acetone in the step B is 1:8-12; more preferably 1:10 g/ml.
Preferably, the reaction temperature in step B is from 0 to 5 ℃.
Preferably, the post-treatment purification process in step B comprises:
after the reaction, the reaction solution was concentrated under reduced pressure, ethyl acetate and purified water were added to the concentrated solution, the solution was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined. Washing with saturated sodium bicarbonate and saturated saline, adding anhydrous sodium sulfate into the organic phase, drying, filtering, and evaporating the filtrate under reduced pressure; separating by column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1 respectively), and evaporating the product eluent under reduced pressure to obtain pale yellow bubble solid, namely everolimus.
Compared with the prior art, the invention has the technical effects that:
the invention provides a preparation method of everolimus, which is characterized in that everolimus can be obtained by using a derivative compound II of glycol with better stability to react with rapamycin derivative III; the compound II has higher stability and reactivity, can effectively reduce the degradation of reactants and the generation of impurities in the reaction for preparing everolimus, has simple and convenient operation, high-efficiency reaction, simple post-treatment and high yield and purity of final products, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
EXAMPLE 1 preparation of Compound II
Adding 31g of ethylene glycol and 180ml of tetrahydrofuran into a round-bottom flask, stirring and cooling to-5 ℃, adding 20g of sodium hydride in batches, slowly heating to room temperature after the addition is completed, continuing the reaction, cooling to 5-10 ℃ after the reaction is completed (TLC monitoring), dropwise adding 400ml of tetrahydrofuran solution of fluorenylmethoxycarbonyl chloride (142 g) under stirring, heating to room temperature after the dropwise addition is completed, and continuing the reaction until the reaction is complete (TLC monitoring); filtering, collecting filtrate, evaporating under reduced pressure to remove solvent, adding 400ml ethyl acetate and 250ml purified water into the residue, extracting, separating liquid, washing with 200ml saturated saline water, adding a proper amount of anhydrous sodium sulfate for drying, evaporating under reduced pressure to remove solvent, rectifying under reduced pressure, and collecting 110.2g of fraction with vacuum degree not lower than-0.095 MPa and fraction temperature of 95-102 ℃, namely Fmoc monosubstituted glycol.
110.2g of Fmoc monosubstituted glycol and 500ml of dichloromethane are added into a round-bottom flask, 50g of 2, 6-lutidine is added, the temperature is reduced to-20 ℃ to-25 ℃, 108g of trifluoromethanesulfonic anhydride is slowly added dropwise, the reaction is continued until the reaction is complete (monitored by TLC) after the dropwise addition, 300ml of purified water is used for washing 3 times, the organic phase is dried, filtered, and the solvent is distilled off under reduced pressure; 146.26g of Compound II are obtained, HPLC:98.36%.
Structural confirmation: ESI-MS (m/z): 417.2[ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ：8.01～7.99(d,J＝8.0Hz,2H),7.65～7.63(d,J＝8.0Hz,2H),7.37～7.30(m,4H),5.03～4.99(d,J＝16.0Hz,2H),4.78～4.74(m,1H),4.41～4.37(m,2H),3.81～3.76(m,2H)； 13 C NMR(100MHz,DMSO-d6)δ：157.6,145.7,145.5,142.9,142.7,128.8,128.6,127.5,127.3,126.7,126.5,121.3,121.1,115.7,79.3,68.2,65.8,49.9.
Example 2
49.32g of rapamycin derivative III, 47.89g of intermediate compound II, 600ml of toluene and 12.84g of 2, 6-lutidine are added into a three-necked flask, stirred and heated to 25-30 ℃, stirred and reacted under heat preservation, and TLC detects that the reaction is completed; adding 8.59g of triethylamine, heating to 35-40 ℃, continuing to keep the temperature and stirring for reaction, and detecting the completion of the reaction by TLC; filtering, adding 400ml of purified water into the filtrate, extracting the separated liquid, extracting the water layer with 100ml of toluene, combining the organic layers, washing with 300ml of saturated saline water, drying with anhydrous sodium sulfate for 4 hours, filtering, concentrating the filtrate to dryness in vacuo, separating and purifying the filtrate by a silica gel column (eluting with petroleum ether/ethyl acetate=2/1 and petroleum ether/ethyl acetate=1/1 respectively), concentrating the product eluent to dryness in vacuo at 30-35 ℃ to obtain 46.52g of intermediate 1 as white powder, ESI-MS (m/z): 1029.62[ M+H ]] + 。
46.52g of intermediate 1 and 450ml of acetone are added into a three-mouth bottle, the mixture is stirred and cooled to 0-5 ℃, 31.5ml of 1.0M hydrochloric acid solution is dripped, the mixture is stirred and reacted for 3-4 hours, TLC detection is carried out, after the reaction is finished, the mixture is concentrated at 35 ℃ under reduced pressure, the mixture is evaporated to concentrate, 300ml of ethyl acetate and 300ml of pure water are added into the concentrate after the distillation is finished, the mixture is separated, an organic phase is collected, the aqueous phase is extracted by 100ml of ethyl acetate,the organic phases are combined. The organic phase was dried over anhydrous sodium sulfate for 4 hours by washing with 200ml of saturated sodium bicarbonate and 200ml of saturated brine, and filtered, and the filtrate was evaporated under reduced pressure at 35℃to give a yellow powdery solid. Separating with column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1, eluting with ethyl acetate), and evaporating the product eluent at 35deg.C under reduced pressure to obtain 37.76g of pale yellow bubble solid (i.e. everolimus); HPLC:99.67%, ESI-MS (m/z): 958.21[ M+H ]] + 。
Example 3
49.32g of rapamycin derivative III, 45.81g of intermediate compound II, 500ml of toluene and 11.77g of 2, 6-lutidine are added into a three-necked flask, stirred and heated to 25-30 ℃, stirred and reacted under heat preservation, and TLC detects that the reaction is completed; adding 8.08g of triethylamine, heating to 35-40 ℃, continuing to keep the temperature and stirring for reaction, and detecting the completion of the reaction by TLC; filtering, adding 400ml of purified water into the filtrate, extracting the separated liquid, extracting the water layer with 100ml of toluene, combining the organic layers, washing with 300ml of saturated saline water, drying with anhydrous sodium sulfate for 4 hours, filtering, concentrating the filtrate to dryness in vacuo, separating and purifying the filtrate by a silica gel column (eluting with petroleum ether/ethyl acetate=2/1 and petroleum ether/ethyl acetate=1/1 respectively), concentrating the product eluent to dryness in vacuo at 30-35 ℃ to obtain an intermediate 1 white powder 45.49g, ESI-MS (m/z): 1029.62[ M+H ]] + 。
45.49g of intermediate 360ml of acetone is added into a three-port bottle, stirred and cooled to 0-5 ℃, 26.4ml of 1.0M hydrochloric acid solution is added dropwise, stirred and reacted for 3-4 hours, TLC detection is carried out, after the reaction is finished, the mixture is concentrated at 35 ℃ under reduced pressure, the mixture is evaporated to concentrate, 300ml of ethyl acetate and 300ml of pure water are added into the concentrate after the distillation is finished, the mixture is separated, an organic phase is collected, the aqueous phase is extracted by 100ml of ethyl acetate, and the organic phase is combined. The organic phase was dried over anhydrous sodium sulfate for 4 hours by washing with 200ml of saturated sodium bicarbonate and 200ml of saturated brine, and filtered, and the filtrate was evaporated under reduced pressure at 35℃to give a yellow powdery solid. Separating with column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1, eluting with ethyl acetate), and evaporating the product eluent at 35deg.C under reduced pressure to obtain 36.50g pale yellow bubble solid (i.e. ivermectin); HPLC:99.65%. ESI-MS (m/z): 958.22[ M+H ]] + 。
Example 4
49.32g of rapamycin derivative III, 49.97g of intermediate compound II, 690ml of toluene and 13.91g of 2, 6-lutidine are added into a three-necked flask, stirred and heated to 25-30 ℃, stirred and reacted under heat preservation, and TLC detects that the reaction is completed; adding 9.10g of triethylamine, heating to 35-40 ℃, continuing to keep the temperature and stirring for reaction, and detecting the completion of the reaction by TLC; filtering, adding 400ml of purified water into the filtrate, extracting the separated liquid, extracting the water layer with 100ml of toluene, combining the organic layers, washing with 300ml of saturated saline water, drying with anhydrous sodium sulfate for 4 hours, filtering, concentrating the filtrate to dryness in vacuo, separating and purifying the filtrate by a silica gel column (eluting with petroleum ether/ethyl acetate=2/1 and petroleum ether/ethyl acetate=1/1 respectively), concentrating the product eluent to dryness in vacuo at 30-35 ℃ to obtain an intermediate 1 white powder 45.13g, ESI-MS (m/z): 1029.62[ M+H ]] + 。
45.13g of intermediate 1 and 540ml of acetone are added into a three-port bottle, stirred and cooled to 0-5 ℃, 34.9ml of 1.0M hydrochloric acid solution is added dropwise, stirred and reacted for 3-4 hours, TLC detection is carried out, after the reaction is finished, the mixture is concentrated at 35 ℃ under reduced pressure, the mixture is evaporated to a concentrated solution, 300ml of ethyl acetate and 300ml of pure water are added into the concentrated solution after the distillation is finished, the organic phase is collected, the aqueous phase is extracted by 100ml of ethyl acetate, and the organic phase is combined. The organic phase was dried over anhydrous sodium sulfate for 4 hours by washing with 200ml of saturated sodium bicarbonate and 200ml of saturated brine, and filtered, and the filtrate was evaporated under reduced pressure at 35℃to give a yellow powdery solid. Separating with column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1, eluting with ethyl acetate), and evaporating the product eluent at 35deg.C under reduced pressure to obtain 36.46g pale yellow foamy solid (everolimus), HPLC:99.67%.
ESI-MS(m/z):958.21[M+H] + 。
Example 5
49.32g of rapamycin derivative III, 47.89g of intermediate compound II, 600ml of dimethylbenzene and 15.49g of N, N-diisopropylethylamine are added into a three-necked flask, stirred and heated to 25-30 ℃, stirred and reacted under heat preservation, and TLC detects that the reaction is completed; adding 8.59g of triethylamine, heating to 35-40 ℃, continuing to keep the temperature and stirring for reaction, and detecting the completion of the reaction by TLC; filtering, adding 400ml of purified water into the filtrate, and extractingThe liquid, aqueous layer were extracted with 100ml toluene, organic layers were combined, washed with 300ml saturated saline, dried over anhydrous sodium sulfate for 4 hours, filtered, the filtrate concentrated to dryness in vacuo, purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate=2/1, petroleum ether/ethyl acetate=1/1, respectively), and the product eluate concentrated to dryness in vacuo at 30-35℃to give intermediate 1 as a white powder 43.07g, ESI-MS (m/z): 1029.62[ M+H ]] + 。
43.07g of intermediate 1, 450ml of acetone are added into a three-port bottle, the mixture is stirred and cooled to 0-5 ℃, 31.5ml of 1.0M hydrochloric acid solution is added dropwise, the mixture is stirred and reacted for 3-4 hours, TLC detection is carried out, after the reaction is finished, the mixture is concentrated at 35 ℃ under reduced pressure, the mixture is evaporated to concentrate, 300ml of ethyl acetate and 300ml of pure water are added into the concentrate after the distillation is finished, the organic phase is collected after the separation, the aqueous phase is extracted by 100ml of ethyl acetate, and the organic phase is combined. The organic phase was dried over anhydrous sodium sulfate for 4 hours by washing with 200ml of saturated sodium bicarbonate and 200ml of saturated brine, and filtered, and the filtrate was evaporated under reduced pressure at 35℃to give a yellow powdery solid. Separating by column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1 respectively), and evaporating the product eluent at 35deg.C under reduced pressure to obtain 34.44g of light yellow bubble solid (everolimus); HPLC:99.61%.
ESI-MS(m/z):958.22[M+H] + 。
Example 6
49.32g of rapamycin derivative III, 41.64g of intermediate compound II, 600ml of toluene and 9.63g of 2, 6-lutidine are added into a three-necked flask, stirred and heated to 25-30 ℃, stirred and reacted under heat preservation, and TLC detects that the reaction is completed; 7.07g of triethylamine is added, the temperature is raised to 35-40 ℃, the reaction is continued to be carried out by heat preservation and stirring, and TLC (thin layer chromatography) detects that the reaction is completed; filtering, adding 400ml of purified water into the filtrate, extracting the separated liquid, extracting the water layer with 100ml of toluene, combining the organic layers, washing with 300ml of saturated saline, drying with anhydrous sodium sulfate for 4 hours, filtering, concentrating the filtrate to dryness in vacuo, separating and purifying the filtrate by a silica gel column (eluting with petroleum ether/ethyl acetate=2/1 and petroleum ether/ethyl acetate=1/1 respectively), and concentrating the product eluent to dryness in vacuo at 30-35 ℃ to obtain intermediate 1, 40.29g, ESI-MS (m/z): 1029.62[ M+H ] + ].
40.29g of intermediate 1, 400ml of acetone are added into a three-port bottle, the mixture is stirred and cooled to 0-5 ℃, 19.5ml of 1.0M hydrochloric acid solution is added dropwise, the mixture is stirred and reacted for 3-4 hours, TLC detection is carried out, after the reaction is finished, the mixture is concentrated at 35 ℃ under reduced pressure, the mixture is evaporated to a concentrated solution, 300ml of ethyl acetate and 300ml of pure water are added into the concentrated solution after the distillation is finished, the organic phase is collected, the aqueous phase is extracted by 100ml of ethyl acetate, and the organic phase is combined. The organic phase was dried over anhydrous sodium sulfate for 4 hours by washing with 200ml of saturated sodium bicarbonate and 200ml of saturated brine, and filtered, and the filtrate was evaporated under reduced pressure at 35℃to give a yellow powdery solid. Separating by column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1 respectively), and evaporating the product eluent at 35deg.C under reduced pressure to obtain 30.44g of light yellow bubble solid (everolimus); HPLC:98.56%.
ESI-MS(m/z):958.22[M+H] + 。
Example 7
49.32g of rapamycin derivative III, 54.14g of intermediate compound II, 600ml of toluene and 16.05g of 2, 6-lutidine are added into a three-necked flask, stirred and heated to 25-30 ℃, stirred and reacted under heat preservation, and TLC detects that the reaction is completed; adding 9.6g of triethylamine, heating to 35-40 ℃, continuing to keep the temperature and stirring for reaction, and detecting the completion of the reaction by TLC; filtering, adding 400ml of purified water into the filtrate, extracting the separated liquid, extracting the water layer with 100ml of toluene, combining the organic layers, washing with 300ml of saturated saline water, drying with anhydrous sodium sulfate for 4 hours, filtering, concentrating the filtrate to dryness in vacuo, separating and purifying the filtrate by a silica gel column (eluting with petroleum ether/ethyl acetate=2/1 and petroleum ether/ethyl acetate=1/1 respectively), concentrating the product eluent to dryness in vacuo at 30-35 ℃ to obtain intermediate 1 as white powder 41.32g, ESI-MS (m/z): 1029.62[ M+H ]] + 。
41.32g of intermediate 1, 410ml of acetone are added into a three-port bottle, the temperature is reduced to 0-5 ℃ by stirring, 40ml of 1.0M hydrochloric acid solution is added dropwise, the stirring reaction is carried out for 3-4 hours, TLC detection is carried out, after the reaction is finished, the solution is concentrated at 35 ℃ under reduced pressure, the solution is evaporated to concentrate, 300ml of ethyl acetate and 300ml of pure water are added into the concentrate after the distillation is finished, the solution is separated, an organic phase is collected, the aqueous phase is extracted by 100ml of ethyl acetate, and the organic phase is combined. The organic phase was dried over anhydrous sodium sulfate for 4 hours by washing with 200ml of saturated sodium bicarbonate and 200ml of saturated brine, and filtered, and the filtrate was evaporated under reduced pressure at 35℃to give a yellow powdery solid. Separating by column (eluting with petroleum ether and ethyl acetate in a solvent of 1:1 respectively), and evaporating the product eluent at 35deg.C under reduced pressure to obtain 31.56g of light yellow bubble solid (everolimus); HPLC:98.60%.
ESI-MS(m/z):958.21[M+H] + 。
The everolimus HPLC detection method is as follows:
taking a proper amount of the product, precisely weighing, adding acetonitrile for dissolving and quantitatively diluting to obtain a solution containing 2.0mg of the product per 1ml, and taking the solution as a sample solution; 2.5ml of the sample solution is precisely measured, placed in a 100ml measuring flask, diluted to a scale by adding acetonitrile, and shaken uniformly to serve as a control solution. According to high performance liquid chromatography (appendix V D of second edition 2005 edition of Chinese pharmacopoeia), octadecylsilane chemically bonded silica is used as filler; mobile phase A is 0.002mol/L potassium dihydrogen phosphate solution, mobile phase B is acetonitrile; a flow rate of 1.0ml per minute, a linear gradient elution; column temperature 55 ℃; the detection wavelength was 210nm. The theoretical plate number is not less than 5000 according to the Ev Mo Sifeng. Precisely measuring 20 μl of control solution, injecting into a liquid chromatograph, and adjusting detection sensitivity to ensure that the peak height of the main component peak is about 20% -25% of full range; precisely measuring 20 μl of each of the sample solution and the control solution, respectively, and injecting into a liquid chromatograph to record the chromatogram; the purity of everolimus was calculated according to the area normalization method.
Claims (9)
1. The preparation method of everolimus is characterized by comprising the following specific steps:
；
step A: adding the rapamycin derivative III, the compound II and the organic base into an organic solvent, stirring and heating, and carrying out heat preservation and stirring reaction; then adding triethylamine, heating to 35-40 ℃, continuing to perform heat preservation and stirring reaction, and performing aftertreatment after the reaction is finished to obtain an intermediate 1;
and (B) step (B): dissolving the intermediate 1 in acetone, removing a 28-hydroxyl TMS protecting group under the action of dilute hydrochloric acid, and performing post-treatment and purification to obtain everolimus;
the organic base in the step A is one or more of imidazole, pyridine, 2, 6-lutidine, N, N-diisopropylethylamine and 4-dimethylaminopyridine.
2. The method of claim 1, wherein the molar ratio of rapamycin derivative III to organic base in step A is 1:2.2-2.6.
3. The process of claim 1, wherein the organic solvent in step a is toluene or xylene.
4. The preparation method according to claim 1, wherein the mass-to-volume ratio of the rapamycin derivative III to the organic solvent in the step A is 1:10-14 g/ml.
5. The method of claim 1, wherein the molar ratio of rapamycin derivative III to compound II in step A is from 1:2.2 to 2.4.
6. The process according to claim 1, wherein in step A the molar ratio of rapamycin derivative III to triethylamine is from 1:1.6 to 1.8.
7. The process according to claim 1, wherein the molar ratio of the intermediate 1 to the diluted hydrochloric acid in step B is 1:0.6-0.8.
8. The preparation method according to claim 1, wherein the mass-to-volume ratio of the intermediate 1 to the acetone in the step B is 1:8-12 g/ml.
9. The process according to claim 1, wherein the reaction temperature in step B is 0 to 5 ℃.
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| CN1402731A (en) * | 1999-09-29 | 2003-03-12 | 惠氏公司 | Regioselective synthesis of rapamycin derivs. |
| KR101529963B1 (en) * | 2013-12-27 | 2015-06-19 | 주식회사 종근당바이오 | Method for preparing everolimus and its intermediates |
| CN109206441A (en) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | A kind of purification process of everolimus |
| 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 |
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| CN1402731A (en) * | 1999-09-29 | 2003-03-12 | 惠氏公司 | Regioselective synthesis of rapamycin derivs. |
| KR101529963B1 (en) * | 2013-12-27 | 2015-06-19 | 주식회사 종근당바이오 | Method for preparing everolimus and its intermediates |
| CN109206441A (en) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | A kind of purification process of everolimus |
| 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 |
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