CN110922423B - Synthetic method of eribulin intermediate - Google Patents
Synthetic method of eribulin intermediate Download PDFInfo
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- CN110922423B CN110922423B CN201910984962.8A CN201910984962A CN110922423B CN 110922423 B CN110922423 B CN 110922423B CN 201910984962 A CN201910984962 A CN 201910984962A CN 110922423 B CN110922423 B CN 110922423B
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- 229960003649 eribulin Drugs 0.000 title claims abstract description 23
- 238000010189 synthetic method Methods 0.000 title claims abstract description 11
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound 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 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 title claims abstract 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 8
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- YUCBLVFHJWOYDN-PPIALRKJSA-N 4-[(r)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]-1-[(r)-[(2r,4r,5s)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@@H](OC=3C4=CC=CC=C4C(O[C@@H]([C@@H]4N5CC[C@@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-PPIALRKJSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 3
- 238000006735 epoxidation reaction Methods 0.000 claims description 3
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- FEMRXDWBWXQOGV-UHFFFAOYSA-N potassium amide Chemical compound [NH2-].[K+] FEMRXDWBWXQOGV-UHFFFAOYSA-N 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound 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 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 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 17
- 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 17
- 238000002360 preparation method Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 2
- 239000004721 Polyphenylene oxide Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 229960000439 eribulin mesylate Drugs 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000353756 Halichondria okadai Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000243142 Porifera Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940122530 Tubulin polymerization inhibitor Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006256 asymmetric dihydroxylation reaction Methods 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 230000001680 brushing effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- XXTZHYXQVWRADW-UHFFFAOYSA-N diazomethanone Chemical compound [N]N=C=O XXTZHYXQVWRADW-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- LQAVWYMTUMSFBE-UHFFFAOYSA-N pent-4-en-1-ol Chemical compound OCCCC=C LQAVWYMTUMSFBE-UHFFFAOYSA-N 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/28—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a synthetic method of an eribulin intermediate, which comprises the following steps: (1) carrying out a cyclization reaction on a compound shown in the formula X and a compound shown in the formula IX to obtain a compound shown in the formula VIII; (2) carrying out hydroxyl deprotection on the compound shown in the formula VIII to obtain a compound shown in a formula VII; (3) protecting hydroxyl of the compound shown in the formula VII by sulfonyl chloride to obtain a compound shown in a formula VI; (4) and (3) performing intramolecular cyclization reaction on the compound shown in the formula VI to obtain the compound shown in the formula V. The method has the advantages of convergent synthesis, short route, high yield, mild conditions, simple and convenient operation and the like, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthetic method of an eribulin intermediate.
Background
In 1985 Uemura et al isolated a macrocyclic polyether macrolide from Halichondria Okadai, a scarce sponge in Japan containing only C, H and O, named halichondrin B (formula I, halichondrin B). Biological experiments show that the halichondrin B has a strong inhibition effect on cancer cells in vivo and in vitro of mice, and deep activity research and evaluation are carried out on 60 cancer cell lines by the national tumor research institute (NCI) of the United states to find that the halichondrin B has a unique anti-cancer mechanism. Professor kashi et al, 1992 harvard university, characterized the structure of halichondrin B: the formula is C61H88O36, contains 32 chiral carbon atoms, 18 polyether segments and 12 macrolides. Then Kashi artificially synthesizes halichondrin B and simplification thereof by adopting a strategy of synthesis from simplification to reproduction and convergence, and splits halichondrin B into 4 fragments;
the successful development of Eribulin mesylate (formula II, Eribulin, tradename Halaven) is due to the full synthesis of halichondrin B. As a simplification of halichondrin B, eribulin is a tubulin polymerization inhibitor having the same mechanism of action as halichondrin B. The eribulin mesylate provides a new treatment means for improving the survival rate and the life quality of patients with locally advanced breast cancer or metastatic breast cancer. By the end of 2015, the cumulative sales of eribulin has exceeded 10 billion dollars;
compared with halichondrin B, eribulin has a somewhat simpler structure, but still has 19 chiral centers, and the theoretical isomer is up to 52.4 thousands (the theoretical isomer of halichondrin B is billions), which brings great difficulty to synthesis. The synthesis of eribulin adopts the same strategy as halichondrin B, the eribulin is synthesized by converging three segments, halichondrin B is synthesized by converging four segments, and the segments are respectively as follows:
four fragments of halichondrin B (formula I) (named formula II-A, B-13, I-C, I-D, respectively):
three fragments of eribulin (formula II) (named formula II-A, B-13, II-C, respectively):
it can be seen from the convergent synthesis of halichondrin B (formula I) and eribulin (formula II) in which the two fragments are completely identical, formula II-A and formula B-13, respectively, that the intermediates of halichondrin B (formula I) and eribulin (formula II) have attracted a high interest and interest from chemists, while the synthesis of B-13 is more challenging.
In 2009, a subject group of Philips professor of university of colorado reports a synthesis method using asymmetric hydrogenation and diazoketone rearrangement of Noyori as core steps (route one, aggregate. chem. int. ed, 2009,48,2346), wherein although the route is one of the current simple routes, the route uses expensive heavy metal catalyst, most importantly diazomethane with explosion risk needs to be used, and the purification has certain difficulty and is difficult to realize industrial production;
route one:
the Kishi leader subject group of Harvard university in USA also reports a method for constructing a B-13 fragment by NHK reaction, but the method uses chromium dichloride with strong toxicity, and the NHK reaction which strictly requires no water and oxygen is also not beneficial to industrial amplification, and in addition, the chiral selectivity of the preparation of another chiral fragment is poor, separation and purification are needed, and the cost is high;
and a second route:
CN104024237B, WO2014183211 and CN108341828A disclose a method for obtaining B-13 compound from 1,2,5, 6-diisopropylidene glucose, respectively. The method has the disadvantages of long and complicated route, difficult purification, high cost and difficult realization of large-scale industrial production;
and a third route:
disclosure of Invention
The invention aims to solve the problems of overlong synthetic route, poor selectivity, higher cost, difficult purification and difficult industrial production of the existing compounds, and provides a synthetic method of an eribulin intermediate, which has the advantages of convergent synthesis, short route, high yield, mild conditions, simple and convenient operation and the like, and is suitable for industrial scale-up production.
The technical scheme adopted by the invention for solving the technical problems is as follows:
a synthetic method of eribulin intermediate is disclosed, wherein the eribulin intermediate is a compound shown in formula V, and the synthetic method comprises the following steps:
wherein R is1,R2，R3，R4Are all hydroxy protecting groups;
(1) carrying out a cyclization reaction on a compound shown in the formula X and a compound shown in the formula IX to obtain a compound shown in the formula VIII;
(2) carrying out hydroxyl deprotection on the compound shown in the formula VIII to obtain a compound shown in a formula VII;
(3) protecting hydroxyl of the compound shown in the formula VII by sulfonyl chloride to obtain a compound shown in a formula VI;
(4) and (3) performing intramolecular cyclization reaction on the compound shown in the formula VI to obtain the compound shown in the formula V.
R1Being a silyl protecting group or a benzyl group, R2Is carbonyl or benzyl, R3Is a silyl protecting group, R4Is a sulfonyl group.
Preferably, R1Is TBDPS, R2Is pivaloyl, R3Is TBS, R4Is methanesulfonyl or p-toluenesulfonyl.
The alkene forming reaction in the step (1) is carried out under an alkaline condition, and the alkali providing the alkaline condition is hexamethyldisilazane.
And (3) deprotection reagent adopted in the deprotection of the hydroxyl in the step (2) is pyridine p-toluenesulfonate.
The protecting group protected by sulfonyl chloride in the step (3) is methane sulfonyl or p-toluene sulfonyl.
And (3) the base used in the sulfonyl chloride protection reaction is diisopropylethylamine or triethylamine.
Catalysts for the intramolecular cyclization reaction in the step (4) are AD-mix-alpha and methanesulfonamide.
A preferred method of synthesizing the compound of formula V is as follows:
specifically, the method comprises the following synthesis steps:
(1) reacting a compound of formula IXa with a compound of formula Xa in julian epoxidation reaction under the action of KHMDS to give a compound of formula VIIIa;
(2) carrying out hydroxyl deprotection on the compound shown in the formula VIIIa under the action of pyridine p-toluenesulfonate to obtain a compound shown in the formula VIIa;
(3) reacting the compound shown in the formula VIIa with methane sulfonyl chloride under the action of triethylamine to obtain a compound shown in a formula VIa;
(4) the compound shown in the formula VIa is subjected to intramolecular cyclization reaction under the catalytic action of an asymmetric dihydroxylation reagent AD-mix-alpha and methanesulfonamide to obtain the compound shown in the formula Va.
The synthesis method of the compound shown in the formula X comprises the following steps:
A. asymmetric epoxidation is carried out on the compound shown in the formula XIV to obtain a compound shown in the formula XIII; this procedure can be described in the references J.org. chem.2017,82, 11021-11034;
B. reacting a compound shown as the formula XIII with cyanide to obtain a compound shown as the formula XII;
C. protecting the compound shown in the formula XII through hydroxyl to obtain a compound shown in the formula XI;
D. and reducing the compound shown in the formula XI to obtain the compound shown in the formula X.
A preferred method of synthesizing the compound of formula X is as follows:
A. asymmetrically epoxidizing the compound shown in the formula XIVa to obtain a compound shown in the formula XIIIa; this procedure can be described in the references J.org. chem.2017,82, 11021-11034;
B. reacting a compound represented by XIIIa with sodium cyanide to obtain a compound represented by XIIa;
C. protecting the compound shown as the formula XIIa by TBS to obtain the compound shown as the formula XIIa;
D. DIBAL-H reduction of the compound of formula XIa affords the compound of formula Xa.
A synthetic method of eribulin intermediate B-13 comprises the following synthetic route:
(1)
(2)
the compound of formula V is synthesized using the synthesis method of claim 1.
The invention has the beneficial effects that: aiming at the defects in the existing eribulin intermediate synthesis method shown in formula V, the invention utilizes easily prepared (R) -6-tert-butyl diphenylsiloxane-3-hydroxyhexanal (formula X) and a Julia reagent (formula IX) to obtain an (R) -6-alkenyl-4-alcohol pelarganediol derivative (formula VIII) through an alkene forming reaction, and the molecular internal cyclization replaces the existing NHK reaction with harsh conditions or diazo rearrangement reaction with potential safety hazards under the catalysis of an asymmetric double hydroxylation reagent through simple functional group conversion, thereby providing a preparation method which has the advantages of low cost, simple and convenient operation and mild conditions and is more suitable for industrial amplification production for synthesizing the eribulin intermediate shown in formula B-13.
Detailed Description
The technical solution of the present invention will be further specifically described below by way of specific examples.
In the present invention, the raw materials and equipment used are commercially available or commonly used in the art, unless otherwise specified. The methods in the following examples are conventional in the art unless otherwise specified.
Example 1:
1. preparation of Compound XIVa
4-penten-1-ol (30.0g, 0.35mol) was dissolved in 150mL of DMF, imidazole (35.6g,0.52mol) was added, and TBDPSCl (100.5g, 0.365mol) was added dropwise to the reaction mixture, after cooling to 0 ℃. After stirring for 1 hour, quenched with water, extracted with 300mL of tert-butyl methyl ether, washed successively with 150mL of 5% HCl and 150mL of saturated brine. Concentration gave 110g of the product formula XIVa as a colorless oil in 97.3% yield.
1H NMR(400MHz,CDCl3)7.68-7.66(m，4H),7.43-7.35(m,6H)，5.84-5.75(m，1H),4.99(dd，1H),4.93(d，1H),3.67(t，2H),2.17-2.12(m，2H),1.67(q，2H),1.07(s，9H)。
2. Preparation of Compound XIIIa
Formula XIVa (25g, 77mmol) was dissolved in 400mL of anhydrous DCM, 50mL of 30% hydrogen peroxide (460mmol) and Ti-cis-salalen catalyst (23mmol) were added, and after 24 hours of vigorous stirring, 50mL of 30% hydrogen peroxide (460mmol) was added again, and after 24 hours, 50mL of 30% hydrogen peroxide (460mmol) was added again. After 48 hours of vigorous stirring, dichloromethane was added and extracted three times (600mL x 3), the dichloromethane layers were combined, washed sequentially with 600mL of 25% sodium thiosulfate and 10% sodium chloride water, concentrated and brushed onto a silica gel column to give 23.5g of product in 90% yield.
1H NMR(400MHz,CDCl3):7.67-7.64(m,4H),7.42-7.35(m，6H)，3.72-3.68(m,2H),2.93-2.89(m,1H),2.73(dd,1H),2.45(dd,J＝5.0,J＝2.7,1H),1.74-1.61(m,4H),1.05(s,9H)。
3. Preparation of Compound XIIa
Dissolving XIIIa (25.0g, 73.4mmol) in 250mL ethanol, adding 25mL water and 25mL acetic acid in turn, adding sodium cyanide (22.04g, 110mmol), heating to 50 ℃, reacting for 12 hours, HPLC/TLC showing complete reaction, adding 10% NaClO2(33.2g, 36.7mmol), stirring for 0.5-1 hour, concentrating to remove ethanol, adding 250, mL ethyl acetate and 200mL water, stirring for liquid separation, collecting EA layer, washing with saturated sodium bicarbonate and brine in turn, concentrating the EA layer, and brushing the column to obtain 23.5g of product with yield of 87%.
1H-NMR(CDCl3,400MHz)7.67-7.65(m,4H),7.42-7.35(m，6H)，3.92-3.89(m，1H)，3.72-3.68(m，2H)，2.53(dd,1H),2.45(dd,1H)，1.74-1.61(m,4H),1.05(s,9H)。
4. Preparation of Compound XIa
Dissolving formula XIIa (20.0g, 54.1mmol) in 100mL of DMF, adding imidazole (4.5g, 65.5mmol) and TBSCl (9.5g, 62.9mmol), stirring for 1-2 h, HPLC/TLC to show completion of the reaction, adding 200mL of water and 200mL of tert-butyl methyl ether MTBE, stirring for separation, collecting the MTBE layer, washing twice with 120mL of saline solution, and concentrating tert-butyl methyl ether product XIA24.6g with a yield of 94.7%.
1H-NMR(CDCl3,400MHz)7.67-7.65(m,4H),7.42-7.35(m，6H)，3.94-3.80(m，1H)，3.72-3.68(m，2H)，2.50-2.43(m,2H)，1.77-1.63(m,4H),1.05(s,9H)，0.87(s,9H),0.06-0.05(d,6H)。
5. Preparation of Compound Xa
Dissolving formula XIIa (18.5g, 38.4mmol) in 185mL of anhydrous DCM, cooling to-50-40 ℃, dropwise adding DIBAL-H (49.9mL, 49.9mmol) into a reaction flask, reacting for 1-2 hours, HPLC/TLC shows complete reaction, adding 20mL of MeOH, stirring for 0.5-1 hour, slowly raising the temperature to-20 ℃, dropwise adding 185mL of saturated potassium sodium tartrate, adding 185mLMTBE, stirring for 1-2 hours, standing for layering, collecting the upper organic layer, washing with 93mL of saline water, and concentrating to obtain 18.0g of a product with a yield of 96.7%.
1H-NMR(CDCl3,400MHz)9.80(s,1H),7.67-7.64(m,4H),7.44-7.35(m，6H)，4.22-4.19 (m，1H)，3.72-3.68(m，2H)，2.54-2.46(m,2H)，1.65-1.55(m,2H),1.05(s,9H), 0.87(s,9H),0.06-0.05(d,6H)。
6. Preparation of Compound Xa
Dissolving the formula XIIa (40g,83mmol) in 400mL of anhydrous THF, cooling to-20 deg.C, adding dropwise diisobutylaluminum hydride (100mL,100mmol) in n-hexane solution into a reaction flask, controlling the temperature to be lower than-10 deg.C, stirring for 1 hour, detecting by HPLC/TLC that the raw material reaction is complete, adding 10mL of methanol, adding dropwise 600mL of saturated aqueous solution of potassium sodium tartrate, adding 400mL of tert-butyl methyl ether, stirring for 1-2 hours at room temperature, separating out the aqueous layer, drying the organic layer with anhydrous sodium sulfate, filtering, and concentrating to obtain 38.2g of the formula Xa with a yield of 94.9%.
1H-NMR(CDCl-400MHz：9.80-9.79(t，1H),7.67-7.65(m,4H),7.44-7.41(m,2H),7.39-7.37(m,4H),4.22-4.19(m,1H),3.70-3.63(m,2H),2.54-2.46(m,2H), 1.67-1.55(m,4H),1.05(s,9H),0.87(s,9H),0.06-0.05(d,6H)。
7. Preparation of Compound VIIIa
Adding a compound of formula IXa Julia reagent (66.5g, 180mmol) into 400mL of tetrahydrofuran, cooling, controlling the temperature below-50 ℃, dropwise adding 180mL of tetrahydrofuran solution of 1.0M KHDMS into the reaction flask, and stirring for 15-20 minutes. A solution of 58.2g of an aldehyde (formula Xa, 120mmol) in tetrahydrofuran (300mL) was added dropwise to the flask, with the temperature controlled below-50 deg.C, and the starting material reaction was detected to be complete by HPLC/TLC. 400mL of saturated ammonium chloride and 1000mL of tetrahydrofuran were added, and the mixture was stirred for 30 minutes, and the aqueous layer was separated and discarded. The organic layer was washed with saturated sodium chloride water, concentrated and passed through a column to give 70g of the product (formula VIII) in 93.3% yield.
1H-NMR(CDCl-400MHz)：7.67-7.65(m,4H),7.43-7.40(m,2H),7.37-7.35(m,4H),5.43-5.40(m,2H),4.06-4.03(m,2H),3.66-3.64(m,3H),2.14-2.10(m,2H),
2.08-2.05(m,2H),1.70-1.66(m,2H),1.65-1.60(m,1H),1.58-1.51(m,3H), 1.19(s,9H),1.04(s,9H),0.87(s,9H),0.06-0.05(d,6H)。
8. Preparation of Compound VIIa
Formula VIIIa (40g, 64mmol) was dissolved in 400mL of ethanol and 2.0g of PPTS was added. After stirring at room temperature for 48-72 hours, HPLC/TLC checked complete reaction of starting material, 400mL H2O and 40mL saturated sodium bicarbonate were added, concentrated to almost no methanol slip-off, and extracted with MTBE (200mL x 3). MTBE is combined, washed with water, washed with salt and concentrated to obtain 34g of the product (formula VIIa) with the yield of 94.8%.
1H-NMR(CDCl3,400MHz)7.68-7.66(m,4H),7.44-7.41(m,2H),7.39-7.37(m,4H),5.54-5.43(m,2H),4.08-4.05(m,2H),3.70-3.68(m,2H),2.43-2.39(m,2H), 2.09-2.06(m,2H),1.75(s,1H),1.72-1.63(m,5H),1.52-1.48(m,1H), 1.19(s,9H),1.05(s,9H)。
9. Preparation of Compound VIa
Dissolving formula VIIa (26g, 31mmol) in DCM, adding Et3N (6.18g, 61mmol), cooling to-5 to 0 ℃, controlling the temperature below 0 ℃, adding methanesulfonyl chloride (6.42g, 56mmol), slowly returning to room temperature, stirring for 1 hour, detecting the completion of the raw material reaction by HPLC/TLC, washing with water, washing with salt, concentrating, and passing through the column to obtain 29.4g of product (formula VIa) with 99.4% yield.
1H-NMR(CDCl3,400MHz)7.68-7.66(m,4H),7.44-7.41(m,2H),7.39-7.37(m,4H),5.60-5.55(m，1H),5.44-5.39(m，1H),4.74-4.70(m，1H)，4.12-4.09(m,2H), 3.74-3.72(m,2H)，3.49(s,3H),2.14-2.10(m,2H),2.08-2.05(m,2H), 1.76-1.73(m,1H),1.72-1.63(m,5H),1.19(s,9H),1.05(s,9H)。
10. Preparation of Compound Va
Dissolving formula VIa (15.0g, 25.5mmol) in 550mL of a 1:1 tert-butanol/water mixed solution, adding in turn 37.0g of AD-mix-alpha and methanesulfonamide (4.85g, 51mmol), stirring for 16 hours, detecting the completion of the raw material reaction by HPLC/TLC, adding 1000mL of tert-butyl methyl ether and 1000mL of water, stirring, standing for separation, and washing the organic layer once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column to give the product 10.2g (formula Va) in 76% yield.
1H-NMR(CDCl3,400MHz)7.67-7.65(m,4H),7.44-7.41(m,2H),7.39-7.37(m,4H),4.33-4.28(m，1H)，4.08-4.06(t,2H),3.92-3.90(q,2H)，3.73-3.69(m，2H)，2.57-2.53(q,1H), 2.23-2.19(q,1H),1.78-1.67(m,6H),1.61-1.56(m,3H),1.19(s,9H),1.05(s,9H)。
Example 2:
1. preparation of Compound VIIIb
The compound of formula IXb, Julia reagent (28.8g, 77.4mmol) was added to 200mL tetrahydrofuran, the temperature was reduced to-50 deg.C or below, 1.0M KHDMS solution (77.4 mL tetrahydrofuran) was added dropwise to the reaction flask and stirred for 15-20 min. A solution of 25.0g of an aldehyde (formula Xa, 51.2mmol) in tetrahydrofuran (100mL) was added dropwise to the flask, with the temperature controlled below-50 deg.C, and the starting material was detected by HPLC/TLC to be completely reacted. 200mL of saturated ammonium chloride and 500mL of tetrahydrofuran were added, and the mixture was stirred for 30 minutes, and the aqueous layer was separated and discarded. The organic layer was washed with 150mL of saturated sodium chloride, concentrated and chromatographed to give 28g of product (formula VIIIb) with 86.0% yield.
1H-NMR(CDCl-400MHz)：7.69-7.66(m,4H),7.42-7.36(m,6H)，7.34～7.32(m,4H),7.30～7.26(m,1H),5.42-5.40(m，2H),4.49(s，2H)，3.66-3.63(t,2H)，3.47～3.45(t，2H),2.13-2.11(m,2H),2.10-2.06(m,2H),1.70-1.66(m,2H),1.64-1.60(m,1H),1.56-1.51(m,2H), 1.47-1.42(m,1H),1.04(s,9H),0.87(m,9H),0.06-0.05(d,6H)。
12. Preparation of Compound VIIb
Formula VIIIb (20g, 31.7mmol) is dissolved in 200mL ethanol and 1.0g PPTS is added. After stirring at room temperature for 48-72H, HPLC/TLC checked for complete reaction of starting material, 150mL H2O and 30mL saturated sodium bicarbonate were added, concentrated to almost no methanol slip-off, and extracted with MTBE (200mL x 3). MTBE is combined, washed with water, washed with salt and concentrated to obtain 15.8g (formula VIIb) of the product, and the yield is 96.5%.
1H-NMR(CDCl3,400MHz)7.69-7.66(m,4H),7.44-7.37(m,6H)，7.35～7.32(m,4H),7.30～7.26(m,1H),5.57-5.50(m，1H),5.46-5.40(m，1H),4.50(s，2H)，3.70-3.68(t,2H)，3.62～3.57(m，1H),3.49～3.46(t,2H),2.21-2.06(m,4H),1.74-1.67(m,3H), 1.66-1.57(m,2H),1.52～1.46(m,1H),1.09(s,9H)。
13. Preparation of Compound VIb
VIIb (22g, 42.6mmol) is dissolved in 220mL of DCM, Et3N (5.6g, 55.3mmol) is added, the temperature is reduced to-5 to 0 ℃, the temperature is controlled below 0 ℃, methanesulfonyl chloride (5.85g, 51.1mmol) is added, the temperature is slowly returned to room temperature, the mixture is stirred for 1 hour, HPLC/TLC detection is carried out to ensure that the raw materials are completely reacted, and the mixture is washed by water, salt and concentrated to obtain 24.2g of a product (formula VIb) through the column, wherein the yield is 95.6%.
1H-NMR(CDCl3,400MHz)7.67-7.63(m,4H),7.44-7.36(m,6H)，7.35～7.32(m,4H),7.29～7.27(m,1H)，5.59-5.52(m，1H),5.42-5.36(m,1H),4.72-4.68(m,1H)，4.49(s， 2H),3.71-3.65(t,2H)，3.47～3.45(t,2H),2.94(s,3H),2.42-2.39(t,2H),2.13-2.09(t,2H),1.87-1.55(m, 7H),1.06(s,9H)。
14. Preparation of Compound Vb
Dissolving formula VIb (7.6g, 12.8mmol) in 280mL of a 1:1 tert-butanol/water mixed solution, adding in turn 19.0g of AD-mix-alpha and methanesulfonamide (2.43g, 25mmol), stirring for 16 h, detecting the completion of the raw material reaction by HPLC/TLC, adding 500mL of tert-butyl methyl ether and 500mL of water, stirring, standing for separation, and washing the organic layer once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and passed through a column to obtain 5.4g (formula Vb) of a product with a yield of 79.3%.
1H-NMR(CDCl3,400MHz)7.67-7.65(m,4H),7.43-7.36(m,6H),7.35～7.32(m,4H),7.29～7.27(m,1H),4.52(s,2H),4.23(t,1H),4.21-4.16(m,1H),3.78-3.76(m,1H),3.71-3.66(m,2H), 3.57-3.49(m,2H),2.09-2.05(q,1H),1.79-1.58(m,10H),1.06(s,9H)。
Example 3 Synthesis method of eribulin intermediate B-13
The synthesis route is as follows:
(1)
(2)
the specific process of step (1) in this example refers to CN105330686A specifications [ 0015 ] to [ 0017 ].
The specific process of step (2) of this example is described in document j.am.chem.soc.2009,131, 15636-15641.
The compound shown in the formula V is synthesized by adopting the synthesis method of example 1 or example 2.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
Claims (4)
1. A synthetic method of eribulin intermediate is characterized in that the eribulin intermediate is a compound shown as formula V, and the synthetic method is as follows:
wherein R is1、R2、R3And R4Are all hydroxy protecting groups;
(1) carrying out a cyclization reaction on a compound shown in the formula X and a compound shown in the formula IX to obtain a compound shown in the formula VIII;
(2) carrying out hydroxyl deprotection on the compound shown in the formula VIII to obtain a compound shown in a formula VII;
(3) protecting hydroxyl of the compound shown in the formula VII by sulfonyl chloride to obtain a compound shown in a formula VI;
(4) performing intramolecular cyclization reaction on the compound shown in the formula VI to obtain a compound shown in a formula V;
R1being a silyl protecting group or a benzyl group, R2Is pivaloyl or benzyl, R3Is a silyl protecting group, R4Is a sulfonyl group; the alkene forming reaction in the step (1) is carried out under an alkaline condition, and the alkali providing the alkaline condition is hexamethyldisilazane-based amino potassium; deprotection reagent adopted by the deprotection of the hydroxyl in the step (2) is pyridine p-toluenesulfonate; the protecting group protected by sulfonyl chloride in the step (3) is methane sulfonyl or p-toluene sulfonyl; the base used in the sulfonyl chloride protection reaction in the step (3) is diisopropylethylamine or triethylamine; catalysts for the intramolecular cyclization reaction in the step (4) are AD-mix-alpha and methanesulfonamide.
2. The method of synthesis according to claim 1, characterized in that: r1Is TBDPS, R2Is pivaloyl, R3Is TBS, R4Is methanesulfonyl or p-toluenesulfonyl.
3. The method of claim 1, wherein the compound of formula X is synthesized as follows:
A. asymmetric epoxidation is carried out on the compound shown in the formula XIV to obtain a compound shown in the formula XIII;
B. reacting a compound shown as the formula XIII with cyanide to obtain a compound shown as the formula XII;
C. protecting the compound shown in the formula XII through hydroxyl to obtain a compound shown in the formula XI;
D. and reducing the compound shown in the formula XI to obtain the compound shown in the formula X.
4. A synthetic method of eribulin intermediate B-13 is characterized in that the synthetic route is as follows:
(1)
R1is TBDPS, R2Is pivaloyl or benzyl;
(2)
a compound of formula V synthesized by the method of claim 1.
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