CN110684036B - Method for preparing eribulin mesylate - Google Patents
Method for preparing eribulin mesylate Download PDFInfo
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- CN110684036B CN110684036B CN201911152952.4A CN201911152952A CN110684036B CN 110684036 B CN110684036 B CN 110684036B CN 201911152952 A CN201911152952 A CN 201911152952A CN 110684036 B CN110684036 B CN 110684036B
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- QAMYWGZHLCQOOJ-PWIVHLLHSA-N eribulin mesylate Chemical compound CS(O)(=O)=O.C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 QAMYWGZHLCQOOJ-PWIVHLLHSA-N 0.000 title claims abstract description 17
- 229960000439 eribulin mesylate Drugs 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000005543 phthalimide group Chemical group 0.000 claims description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 25
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 abstract description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract description 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 abstract 2
- 239000007983 Tris buffer Substances 0.000 abstract 1
- 239000001294 propane Substances 0.000 abstract 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 14
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 4
- -1 p-toluenesulfonyl Chemical group 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 241000243142 Porifera Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 2
- 239000004721 Polyphenylene oxide Substances 0.000 description 2
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 150000001414 amino alcohols Chemical group 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910001882 dioxygen Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 241000726101 Axinella Species 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 1
- 241000353756 Halichondria okadai Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 241001674052 Phakellia Species 0.000 description 1
- 238000006859 Swern oxidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a preparation method of eribulin mesylate. The reaction involves reacting 2- [ (2S) -2-benzoyloxy ] -3- [ (2R,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21S,24S,27S,29R,31R,32aS) -12,13, 15-tris [ [ (1, 1-dimethylethyl) dimethylsilyl ] oxy ] -3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32 a-triacontahydro-3-methoxy-29-methyl-23, 30-bis (methylene) -5, 18-dioxy-7, 11:10,14:21,24:27, 31-tetracyclooxy-2H-cyclotriundec [ b ] furan-2-yl ] propane The group ] -1H-phthalimide (N-ERBL-05) is used as an intermediate, and the eribulin mesylate is prepared through three steps of reactions.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to preparation of a crude drug complex natural modified drug eribulin mesylate.
Background
Halichondrin B is a poly (poly) ether macrolide isolated from Halichondria okadai, a scarce Japanese sponge in the last 80 th century by Japanese scientist Uemura et al, and although halichondrin B only contains three elements of C \ H \ O, the structure of the compound is quite complex. Further research finds that the halichondrin B has very strong inhibiting effect on cancer cells in and out of a mouse body in a mouse experiment. Further research by chemists has also revealed that common sponges, such as the Phakellia, Lissodendory and Axinella families, also contain halichondrin B. The systematic activity evaluation of halichondrin B in 60 cancer cell lines by the national institute of tumor in the united states has demonstrated that halichondrin B acts in a similar mechanism to known anti-tubulin drugs in anti-cancer cell proliferation, but in a different biochemical mechanism. The halichondrin B has strong activity and unique action mechanism, so that the halichondrin B has attracted the attention of academia and the industry. However, since nature has a limit in the amount of sample extracted and separated from the sponge, development has been slow. To this end, the preparation of halichondrin B and its analogs by means of chemical synthesis has attracted extensive interest to chemists.
Halichondrin B has the following structure:
professor Kishi, Harvard university, systematically studied the total synthesis of halichondrin B and its analogs. A great deal of research has found that the lactone segment on the right of halichondrin B as shown above is a more anticancer active carrier than the polyether segment on the left, because the segment on the right contains various functional groups, and the structure of the polyether segment is monotonous. These studies have further prompted synthetic chemists to prepare a series of halichondrin B analogs for activity testing. Eribulin mesylate is a halichondrin B analogOne, eventually approved by the FDA in the united states for the treatment of metastatic breast cancer in 2010 through phase III clinical trials under the trade name HALAVENTM. The chemical structure of eribulin mesylate contains 19 chiral centers, and the chemical structural formula is as follows:
to date, a large number of patents and literature reports have been published on the preparation of eribulin mesylate. However, many documents refer to the final conversion of both hydroxyl groups of the compound to terminal amino alcohols (ERBL-07 → eribulin mesylate), and the reaction mechanism of such synthetic strategies involves the formation of an oxatricyclic intermediate (intermediate 1 and intermediate 2) followed by the opening of the amino ring. Since the ring opening of the amino group of the terminal oxatricyclic ring inevitably produces isomer impurities (isomer-1, isomer-2, isomer-3) which are similar to the product structure and are very difficult to remove in the finished product, it is crucial to develop a new synthetic strategy for successfully avoiding the production of the amino isomer impurities. The conventional synthetic route to convert the terminal dihydroxy group to an amino alcohol and some isomeric impurity structures are as follows:
disclosure of Invention
The invention aims to provide a novel method for preparing eribulin mesylate, aiming at avoiding the defect that a traditional synthetic route is easy to cause a large amount of isomer impurities.
The synthetic route of the invention is as follows:
the first step of the reaction involves the oxidation of two hydroxyl groups in the structure of N-ERBL-01 (one hydroxyl group is oxidized into a ketone carbonyl group, and the other hydroxyl group is oxidized into an aldehyde group) by using N-ERBL-01 as a starting material under the oxidation condition to obtain an N-ERBL-02 intermediate.
The oxidant used in the first step of the reaction is Dess-Martin oxidant, and the reaction solvent is dichloromethane.
The second step of the reaction involves the reaction of the N-ERBL-02 intermediate in SmI2Removing the protecting group of p-toluenesulfonyl (Ts) under the action of the N-ERBL-03 intermediate.
The third step of the reaction involves the reaction of the N-ERBL-03 intermediate in CrCl2/NiCl2In the presence of the N-ERBL-04 intermediate, the terminal alkenyl iodine reacts with aldehyde groups in molecules to prepare the N-ERBL-04 intermediate. The solvents used for this step include acetonitrile and THF.
The fourth reaction step involves the oxidation of hydroxyl to carbonyl of the N-ERBL-04 intermediate under the oxidation condition to prepare the (2- [ (2S) -2-benzoyloxy) N-ERBL-05 intermediate]-3-[(2R,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21S,24S,27S,29R,31R,32aS)-12,13,15-
[ [ (1, 1-Dimethylethyl) dimethylsilyl group]Oxygen gas]-3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32 a-triacontahydro-3-methoxy-29-methyl-23, 30-bis (methylene) -5, 18-dioxy-7, 11:10,14:21,24:27, 31-tetracyclooxy-2H-cyclohentriacontane [ b]Furan-2-yl]Propyl radical]-1H-phthalimide). The oxidation reaction used in this step is Dess-Martin oxidation or Swern oxidation.
The fifth reaction step involves reacting the N-ERBL-05 intermediate in the presence of TBAF to produce the N-ERBL-06 intermediate (1R,2S,3S,4S,5S,6R,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S) -25- [ (2S) -3-phthalimido-2-benzoyloxypropyl ] -2, 5-dihydroxy-26-methoxy-19-methyl-13, 20-dimethylene-24, 35,36,37,38, 39-hexaoxaheptacyclo [29.3.1.13,6.14,34.111,14.117,21.023,27] nonadecane-8, 29-dione).
The sixth reaction step involves reacting the N-ERBL-06 intermediate in the presence of PPTS (pyridine p-toluenesulfonate) to prepare the N-ERBL-07 intermediate (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS) -2- [ (2S) -3-phthalimide-2-benzoyloxypropyl ] -3-methoxy-26-methyl-20, 27-dimethylene hexadecahydro-11, 15:18,21:24, 28-triepoxy-7, 9-ethano-12, 15-methano-9H, 15H-furo [3,2-i ] furo [2',3', 5,6] pyran [4,3-b ] [1,4] dioxocyclopentadecanyl-5 (4H) -one).
And the seventh step of the reaction involves removing the phthalimide protecting group and the benzoyl protecting group of the N-ERBL-07 intermediate under the ammonia water condition, and then adding methanesulfonic acid to prepare eribulin mesylate.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.
EXAMPLE I preparation of N-ERBL-02 intermediate
Into a four-necked flask was added N-ERBL-01 intermediate (25.00g,15.37mmol) and CH2Cl2(500mL), after stirring the supernatant, Dess-Martin oxidant (10g,23.58mmol) was added in portions. After the addition was complete, the system was stirred at room temperature to TLC to monitor the completion of the reaction of the starting material. After the reaction was complete, the system was quenched by addition of saturated aqueous sodium bicarbonate (500 mL). The system was allowed to stand and the organic phase was separated. The organic phase was stripped of organic solvent under reduced pressure at low temperature and the residue was purified by column chromatography to give N-ERBL-02 intermediate (20.23g, 81.1%).
EXAMPLE two preparation of N-ERBL-03 intermediate
Sm (13.05g,86.79mmol) and THF (500mL) were added to a four-necked flask, diiodomethane (25.0g,93.3mmol) was added with stirring, and after the addition, the system was stirred at room temperature for 5 hours. In another four-necked flask, N-ERBL-02 intermediate (15.05g,9.34mmol), methanol (200mL) and THF (500mL) were added, the system was cooled to-85 ℃ with stirring, and then the previously prepared Smi was added dropwise2And (3) solution. After the dropwise addition, the system was stirred for 4 hours until TLC confirmed that the reaction of the starting materials was complete. Adding saturated K at low temperature2CO3Aqueous solution (200mL) was quenched. TBME (1L) was added after the system was warmed to room temperature, stirred for 2 hours, and allowed to stand to separate an organic phase. The organic phase was removed under reduced pressure and the residue was purified by column chromatography to give N-ERBL-03 intermediate (10.51g, 76.7%).
EXAMPLE III preparation of N-ERBL-04 intermediate
Acetonitrile (550mL) and CrCl are added into a four-mouth bottle2(26.0g,211.55mmol) and ligand (CAS:480444-15-3,63.2g,213.24 mmol). After the addition was complete triethylamine (21.5g,212.5mmol) was slowly added dropwise with stirring. After the addition is finished, stirring for 2 hours at the temperature of 30-35 ℃, and then adding NiCl2(2.75g,21.1mmol) and stirred. A solution of the N-ERBL-03 intermediate (22.5g,15.33mmol) in THF (500mL) was then added dropwise to the reaction at room temperature. After the dropwise addition, the system is stirred for 5 hours at room temperature until the controlled raw material reaction in TLC is finished. The reaction was quenched by addition of water (300mL), the system was filtered, the filtrate was extracted three times with N-heptane, the organic phases were combined, the organic phase was removed under reduced pressure to remove the organic solvent, and the residue was purified by column chromatography to give N-ERBL-04 intermediate (15.26g, 75.0%).
EXAMPLE four N-ERBL-05 intermediate (2- [ (2S) -2-benzoyloxy]-3-[(2R,3R,3aS,7R,10S,11S,12S,13R,14S,15S,16E,21S,24S,27S,29R,31R,32aS)-12,13,15-
[ [ (1, 1-Dimethylethyl) dimethylsilyl group]Oxygen gas]-3,3a,4,5,6,7,8,9,10,11,12,13,14,15,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,32 a-triacontahydro-3-methoxy-29-methyl-23, 30-bis (methylene) -5, 18-dioxy-7, 11:10,14:21,24:27, 31-tetracyclooxy-2H-cyclohentriacontane [ b]Furan-2-yl]Propyl radical]-1H-phthalimide) preparation
N-ERBL-04 intermediate (11.80g,8.89mmol) and dichloromethane (150mL) were added to a four-necked flask, stirred to dissolve, and Dess-Martin oxidant (10.75g,25.35mmol) was added in portions at room temperature. And stirring the system for 2 hours after the addition is finished until the reaction of the raw materials in the TLC is finished. The system was quenched by addition of saturated aqueous sodium bicarbonate (300 mL). The system was allowed to stand and the organic phase was separated. The organic phase was stripped of organic solvent at low temperature under reduced pressure and the residue was purified by column chromatography to give N-ERBL-05 intermediate (10.66g, 90.5%).
EXAMPLE V preparation of N-ERBL-06 intermediate (1R,2S,3S,4S,5S,6R,11S,14S,17S,19R,21R,23S,25R,26R,27S,31R,34S) -25- [ (2S) -3-phthalimido-2-benzoyloxypropyl ] -2, 5-dihydroxy-26-methoxy-19-methyl-13, 20-dimethylene-24, 35,36,37,38, 39-hexaoxaheptacyclo [29.3.1.13,6.14,34.111,14.117,21.023,27] nonadecane-8, 29-dione)
N-ERBL-05 intermediate (7.1g,5.36mmol) and THF (115mL) were added to a three-necked flask, and after stirring, imidazole (1.85g,27.18mmol) and TBAF (1M in THF,11mL) were added to the system. After the addition is finished, the system reacts at room temperature until the raw materials are completely reacted in TLC. Methanol (50mL) and 30g of resin were added, stirred for 2 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give N-ERBL-06 intermediate (4.57g, 85.5%).
Example six: N-ERBL-07 intermediate (2R, 3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS) -2- [ (2S) -3-phthalimide-2-benzoyloxypropyl ] -3-methoxy-26-methyl-20, 27-dimethylenehexadecahydro-11, 15:18,21:24, 28-triepoxy-7, 9-ethano-12, 15-methano-9H, 15H-furo [3,2-i ] furo [2',3': preparation of 5,6] pyran [4,3-b ] [1,4] dioxopentacosan-5 (4H) -one).
N-ERBL-06 intermediate (4.0g,4.01mmol) and methylene chloride (100mL) were added to a three-necked flask, and PPTS (5.6g,22.3mmol) was added to the reaction system at room temperature after dissolution with stirring. The system was stirred at room temperature for 2 hours and the TLC medium control material reaction was complete. The reaction solution was subjected to solvent removal under reduced pressure at a temperature of not higher than 15 ℃ and the residue was purified by column chromatography to give N-ERBL-07 intermediate (3.22g, 81.9%).
EXAMPLE seventhly preparation of eribulin mesylate
A three-necked flask was charged with N-ERBL-07 intermediate (2.5g,2.55mmol), isopropanol (150mL), and ammonia (250 mL). After the addition, the system was stirred at a temperature of not higher than 15 ℃ for 36 hours. TLC (thin layer chromatography) is adopted to control the raw material to completely react, the reaction solution is concentrated under reduced pressure at the temperature of not higher than 15 ℃, the residue is purified by column chromatography, the obtained free base is dissolved in acetonitrile (30mL), methanesulfonic acid (250mg) is added under stirring, the system is stirred for 10 minutes, and then the solvent is removed from the system under high vacuum at the temperature of not higher than 15 ℃ to obtain eribulin mesylate (2.06g, 95.9%).
Claims (4)
1. A process for preparing eribulin mesylate having the formula:
2. the process according to claim 1, characterized in that the compound of formula N-ERBL-05 is reacted in the presence of TBAF to give a compound of formula N-ERBL-06.
3. The process for the preparation of eribulin mesylate according to claim 1, wherein the compound of formula N-ERBL-06 is reacted in the presence of PPTS (pyridine p-toluenesulfonate) to give the compound of formula N-ERBL-07.
4. The method for preparing eribulin mesylate according to claim 1, wherein the compound of formula N-ERBL-07 is subjected to simultaneous removal of the phthalimide protecting group and the benzoyl protecting group under an aqueous ammonia condition, and then methanesulfonic acid is added to prepare eribulin mesylate.
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| CN109694379A (en) * | 2017-10-24 | 2019-04-30 | 江苏恒瑞医药股份有限公司 | It is used to prepare the intermediate and preparation method thereof of eribulin |
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| CN105683198A (en) * | 2013-11-04 | 2016-06-15 | 卫材R&D管理有限公司 | Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b |
| WO2016031796A1 (en) * | 2014-08-27 | 2016-03-03 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for producing antitumor agent using homogenizer |
| CN109694379A (en) * | 2017-10-24 | 2019-04-30 | 江苏恒瑞医药股份有限公司 | It is used to prepare the intermediate and preparation method thereof of eribulin |
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