CN111793047A - 一种艾日布林中间体的制备方法 - Google Patents
一种艾日布林中间体的制备方法 Download PDFInfo
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- CN111793047A CN111793047A CN201910509222.9A CN201910509222A CN111793047A CN 111793047 A CN111793047 A CN 111793047A CN 201910509222 A CN201910509222 A CN 201910509222A CN 111793047 A CN111793047 A CN 111793047A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 229960003649 eribulin Drugs 0.000 title claims abstract description 15
- 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
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims description 85
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 125000006239 protecting group Chemical group 0.000 claims description 21
- 239000003446 ligand Substances 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 101100170604 Mus musculus Dmap1 gene Proteins 0.000 claims description 15
- 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 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- MPMSMUBQXQALQI-UHFFFAOYSA-N cobalt phthalocyanine Chemical compound [Co+2].C12=CC=CC=C2C(N=C2[N-]C(C3=CC=CC=C32)=N2)=NC1=NC([C]1C=CC=CC1=1)=NC=1N=C1[C]3C=CC=CC3=C2[N-]1 MPMSMUBQXQALQI-UHFFFAOYSA-N 0.000 claims description 7
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 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 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 239000012634 fragment Substances 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 34
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- 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 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 241000243142 Porifera Species 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- -1 macrolactone compound Chemical class 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 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 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229910021555 Chromium Chloride Inorganic materials 0.000 description 3
- 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 3
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000011651 chromium Substances 0.000 description 3
- QSWDMMVNRMROPK-UHFFFAOYSA-K chromium(3+) trichloride Chemical compound [Cl-].[Cl-].[Cl-].[Cr+3] QSWDMMVNRMROPK-UHFFFAOYSA-K 0.000 description 3
- 239000011572 manganese Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- QMBQEXOLIRBNPN-UHFFFAOYSA-L zirconocene dichloride Chemical compound [Cl-].[Cl-].[Zr+4].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 QMBQEXOLIRBNPN-UHFFFAOYSA-L 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229910021554 Chromium(II) chloride Inorganic materials 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- OBOHMJWDFPBPKD-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 OBOHMJWDFPBPKD-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 229910021559 Chromium(II) bromide Inorganic materials 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 241000353756 Halichondria okadai Species 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- XZQOHYZUWTWZBL-UHFFFAOYSA-L chromium(ii) bromide Chemical compound [Cr+2].[Br-].[Br-] XZQOHYZUWTWZBL-UHFFFAOYSA-L 0.000 description 1
- XBWRJSSJWDOUSJ-UHFFFAOYSA-L chromium(ii) chloride Chemical compound Cl[Cr]Cl XBWRJSSJWDOUSJ-UHFFFAOYSA-L 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 229960000439 eribulin mesylate Drugs 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000002194 synthesizing 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
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Classifications
-
- 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
- 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
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种艾日布林中间体的制备方法,具体涉及艾日布林B片段C14~C26片段的制备方法,本发明采用全新的路线和中间体制备关键中间体ERB,与现有技术相比,反应路线大大简化,反应收率和目标产物的新手性中心的选择性均显著提高;特别适合工业化应用。
Description
技术领域
本发明属于医药技术领域,具体涉及一种艾日布林中间体的制备方法。
背景技术
软海绵素B(Halichondrin B)是1986年日本科学家Hirata和Uemura从海绵Halichondria okadai中分离出了的一种只包含C、H、O原子的聚醚大环内脂类化合物,具有极强的体外抗肿瘤活性。软海绵素B的分子结构非常复杂,包含32个手性中心,有超过40亿个异构体,合成难度非常大。艾日布林是halichondrin B的衍生物,是一种微管蛋白抑制剂,WO9965894首次公开了艾日布林的结构及合成方法。2010年11月15日,FDA批准甲磺酸艾日布林(Halaven)注射液用于治疗至少接受过两种化疗方案的转移性乳腺癌患者。
艾日布林分子结构中含有19个手性中心,合成非常困难,化合物ERB是合成艾日布林的关键中间体。
Phillips等公开了如下一种ERB的制备方法,该方法反应过程中需要用到手性钌试剂和重氮甲烷,存在成本过高和安全风险问题,由化合物19经过五步反应制备ERB,总收率仅37.6%,其中,由化合物20制备化合物21的收率仅有52%(d.r.=6:1)(参见Angew.Chem.Ind.Ed.,2009,48,2346-2350.);
WO9317690A1中公开了一种ERB的制备方法,该方法反应过程中需要用到酮磷酸酯碘代化物和NaH,反应需要严格在无水条件下进行,反应条件苛刻,所用到的NaH易爆炸,大规模生产时,存在很大的安全隐患。并且最后一步还原反应过程中需要用到的CuH[P(C6H6)3]6没有常规供应商,成本高。
综上,在上述公开的报道的化合物ERB的合成方法不仅反应条件苛刻,合成成本高,操作繁琐,而且存在安全隐患,不适合产业化生产,并且由于收率低,导致艾日布林的整体生产成本高。
发明内容
针对现有技术存在的上述制备艾日布林以及其中间ERB存在的缺点,本发明提供了一种全新的ERB制备方法,本发明提供的方法,反应条件温和,后处理容易,收率高,异构体纯度高,适合工业化应用。
首先,本发明提供了一种化合物ERB的制备方法,包括,将化合物ERB-1与ERP反应,得到化合物ERB:
优选,反应过程中使用如下配体A或配体B:
更优选,上述反应在氩气条件下进行,首先将配体、CrCl2和质子海绵(protonsponge)在THF中搅拌一小时,然后依次加入酞菁钴、Mn粉、三乙胺盐酸盐和无水氯化锂,接着加入ERB-1与ERP的THF溶液,最后滴加三甲基氯硅烷,在20-30℃下搅拌,反应结束后,任选的通过纯化步骤如经柱层析后,得到产物ERB。
本发明提供的上述方法新手性中心的选择性非常高,例如可以达到d.r.=8:1优选d.r.=20:1以及以上,更优d.r.=30:1及以上,最优选d.r.=60:1及以上,并且同时满足反应收率显著提高。
本发明还提供了一种化合物ERB-1的制备方法,所述化合物ERB-1是由化合物ERB-2通过氧化反应制备得到:
优选,所述氧化反应所用氧化剂为Dess-Martin试剂或Swern试剂。
进一步的,所述化合物ERB-2是由化合物ERB-3选择性脱去羟基保护基R1制备得到:
其中R1为羟基保护基,优选R1为MMTr(对甲氧基苯基二苯基甲基);
优选,所述反应使用TsOH/MeOH/DCM脱去MMTr保护基;进一步的优选,脱去MMTr保护基是在TsOH存在条件下进行,反应溶剂为MeOH/DCM。
所述化合物ERB-3是由化合物ERB-4通过羟基保护制备得到:
其中R1为羟基保护基,优选R1为MMTr;进一步的优选所述反应条件为特戊酰氯/DMAP/二氯甲烷。
所述化合物ERB-4是由化合物ERB-5选择性脱去TBDPS制备得到:
其中R1为羟基保护基,优选R1为MMTr(对甲氧基苯基二苯基甲基),所述反应条件为TBAF/THF。
所述化合物ERB-5是由化合物ERB-6用羟基保护基R1保护,制备得到:
其中R1为羟基保护基,优选R1为MMTr;所述反应选择在吡啶中进行。
另一方面,本发明还提供一种化合物ERB-2的制备方法,包括以下步骤:
(1)由化合物ERB-6用羟基保护基R1保护,转化成化合物ERB-5;
(2)由化合物ERB-5选择性脱去TBDPS,转化成化合物ERB-4;
(3)由化合物ERB-4选择性脱去羟基保护基Pv,转化成化合物ERB-3;
(4)由化合物ERB-3选择性脱去羟基保护基R1,转化成化合物ERB-2:
其中,步骤(1)反应在吡啶中进行;
步骤(2)反应条件为TBAF/THF;
步骤(3)反应是在特戊酰氯/DMAP条件下进行;
步骤(4)反应是在在TsOH存在条件下进行,反应溶剂为MeOH/DCM;
R1为羟基保护基,优选R1为MMTr第三方面,本发明还提供了一种化合物ERB-1的制备方法,包括以下步骤:
(1)由化合物ERB-6用羟基保护基R1保护,转化成化合物ERB-5;
(2)由化合物ERB-5选择性脱去TBDPS,转化成化合物ERB-4;
(3)由化合物ERB-4选择性脱去羟基保护基Pv,转化成化合物ERB-3;
(4)由化合物ERB-3选择性脱去羟基保护基R1,转化成化合物ERB-2;
(5)由化合物ERB-2通过氧化反应,转化成化合物ERB-1;
其中,步骤(1)反应在吡啶中进行;
步骤(2)反应条件为TBAF/THF;
步骤(3)反应是在特戊酰氯/DMAP条件下进行;
步骤(4)反应是在在TsOH存在条件下进行,反应溶剂为MeOH/DCM;
步骤(5)反应是以二氯甲烷为溶剂,Dess Martin试剂或或Swern试剂作为氧化剂;
其中,R1为羟基保护基,优选R1为MMTr。
本发明还提供了具有如下结构的化合物:
其中,R1为羟基保护基,优选R1为MMTr。
另一方面,本发明还提供了一种艾日布林的制备方法,包括采用前述方法制备化合物ERB或ERB-1或ERB-2的步骤,和经式化合物ERB或化合物ERB-1或化合物ERB-2制备艾日布林的步骤。
本发明的所述的羟基保护基是本领域已知的适当的用于羟基保护的基团,参见文献(“Protective Groups in Organic Synthesis”,5Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例,优选地,所述的羟基保护基可以是(C1-10烷基或芳基)3硅烷基,例如:三乙基硅基,三异丙基硅基,叔丁基二甲基硅基,叔丁基二苯基硅基等;可以是C1-10烷基或取代烷基,例如:甲基,叔丁基,烯丙基,苄基,甲氧基甲基,乙氧基乙基,2-四氢吡喃基(THP)等;可以是(C1-10烷基或芳香基)酰基,例如:甲酰基,乙酰基,苯甲酰基等;可以是(C1-6烷基或C6-10芳基)磺酰基;也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。
本文使用了特定的缩写和简写。下面列出了这些缩写和简写的定义:
MMTr:对甲氧基苯基二苯基甲基;
Pv:特戊酰基;
TBDPS:叔丁基二苯基硅基;
TsOH:对甲基苯磺酸;
DCM:二氯甲烷;
DMAP:4-二甲氨基吡啶;
TBAF:四丁基氟化铵;
THF:四氢呋喃。
本发明提供了一种全新的制备化合物ERB-1和ERB的方法,发明人策略性的先对ERB的侧链醇羟基用Pv保护,然后再将ERB-1与碘化烯反应,选择性产生非对映异构体纯的手性化合物ERB,这与现有技术通常教导最后一步进行Pv保护侧链羟基是不同的;并且在该步反应过程中,发明人意外的发现反应过程中采用A、Cr2+,质子海绵(proton sponge)和酞菁钴、Mn粉作为不对称催化剂,相比于Ni/Cr介导的不对称合成,手性中心的选择性更高,并且反应收率和纯度显著提高;此外,发明人在合成化合物ERB-1时,采用全新的中间体化合物ERB-2和ERB-3等,并且通过先将ERB-5结构中侧链羟基保护基TBDPS替换成Pv得到化合物ERB-3并将该保护基Pv引入目标产物ERB,与现有技术相比,各个中间体制备方法简单,也易于固化,并大大缩短反应步骤,并且反应收率和中间体的新手性中心选择性均显著提高,从而大大降低反应周期和生产成本,特别适合工业化应用。
具体实施方式:
以下将结合具体实例详细地解释本发明,使得本专业技术人员更全面地理解本发明,具体实例仅用于说明本发明的技术方案,并不以任何方式限定本发明。
实施例1:化合物ERB-5a的制备
ERB-6(5克,11.4毫摩尔)溶解在50毫升干燥的吡啶中,搅拌条件下加入4-甲氧基三苯基氯甲烷(4.58克,14.8毫摩尔)。加后反应液在室温下,搅拌反应17小时。TLC检测反应完全后加入20毫升乙醇淬灭反应,旋蒸除去溶剂后,粗产品分散在40毫升饱和碳酸氢钠水溶液和100毫升二氯甲烷中,静置分液,有机相干燥浓缩后柱层析得到7.62克产品ERB-5a,收率94%。
实施例2:化合物ERB-4a的制备
ERB-5a(6克,8.44毫摩尔)溶于50毫升无水四氢呋喃中,在室温且氮气氛围下,在搅拌条件下加入四丁基氟化铵(1M in THF,11毫升,11毫摩尔),反应继续进行16小时。TLC检测反应结束后加入50毫升饱和氯化铵水溶液,接着用甲叔醚萃取;有机相合并干燥后浓缩,经柱层析纯化后得到3.82g的ERB-4a,收率96%。
实施例3:化合物ERB-3a的制备
ERB-4a(3克,6.35毫摩尔)和DMAP(44.4毫摩尔)溶解在40毫升的二氯甲烷中,冰水冷却反应体系到0~5℃,接着向体系中滴加特戊酰氯(4.98克,41.27毫摩尔)。滴加完毕后恢复到室温,搅拌;TLC检测反应完成后加入,加入二氯甲烷和碳酸氢钠水溶液,分液后有机相再用用食盐水洗涤,浓缩后,通过柱层析得到3.25克的ERB-3a,收率92%。
实施例3:化合物ERB-2的制备
ERB-3a(2.5克,4.49毫摩尔)溶解在20毫升的二氯甲烷中,冷至0℃,搅拌下向其中滴加20毫升4%对甲苯磺酸的甲醇溶液,TLC检测反应结束,加入碳酸氢钠水溶液至pH=7~8,旋干溶剂后柱层析得到1.2克的ERB-2,收率95%,HPLC:≥98%。
实施例4:化合物ERB-1的制备
ERB-2(0.95克,3.35毫摩尔)溶解在15毫升的二氯甲烷中,冷至0℃,搅拌下向其中分批加入Dess-Martin试剂(2.84克,6.70毫摩尔),TLC检测反应结束,加入10毫升饱和硫代硫酸钠水溶液,分液后有机相旋干溶剂,通过柱层析得到0.91克的ERB-1,收率96%。
实施例5:化合物ERB的制备
配体A(0.99克,0.99毫摩尔)和酞菁钴(9毫克,0.015毫摩尔)称量后装入反应瓶,反应瓶移入手套箱中,向其中加入质子海绵(212毫克,0.99毫摩尔),无水氯化铬(111毫克,0.90毫摩尔)和无水乙二醇二甲醚(5毫升)。反应混合物在手套箱中搅拌1小时,23℃。接着加入无水氯化锂(255毫克,6.02毫摩尔),锰粉(330毫克,6.02毫摩尔)和二氯二茂锆(1.76g,6.02毫摩尔)。最后加入ERB-1(0.85克,3.01毫摩尔)和ERP(1.45克,4.52毫摩尔)在5毫升无水乙二醇二甲醚中的溶液。反应物在手套箱中搅拌30小时,20℃~25℃。TLC显示反应结束后向其中加入1克硅藻土,搅拌,过滤,并用乙酸乙酯洗涤固体。收集的有机液浓缩后柱层析得到1.28克的ERB,收率92%,HPLC:≥98%,d.r.≥60:1。
其中,配体A结构如下:
实施例6:化合物ERB的制备
配体B(0.43克,0.83毫摩尔)和酞菁钴(7.6毫克,0.013毫摩尔)称量后装入反应瓶,反应瓶移入手套箱中,向其中加入质子海绵(178毫克,0.83毫摩尔),无水氯化铬(93毫克,0.76毫摩尔)和无水乙二醇二甲醚(5毫升)。反应混合物在手套箱中搅拌1小时,23℃。接着加入无水氯化锂(214毫克,5.06毫摩尔),锰粉(277毫克,5.06毫摩尔)和二氯二茂锆(1.48g,5.06毫摩尔)。最后加入ERB-1(0.71克,2.53毫摩尔)和ERP(1.22克,3.80毫摩尔)在5毫升无水乙二醇二甲醚中的溶液。反应物在手套箱中搅拌30小时,20℃~25℃。TLC显示反应结束后向其中加入1克硅藻土,搅拌,过滤,并用乙酸乙酯洗涤固体。收集的有机液浓缩后柱层析得到1.02克的ERB,收率91.8%,HPLC:≥97%,d.r.≥60:1。
对比实施例1:化合物ERB的制备:
配体C(0.27克,0.91毫摩尔)和酞菁钴(8.4毫克,0.013毫摩尔)称量后装入反应瓶,反应瓶移入手套箱中,向其中加入质子海绵(196毫克,0.91毫摩尔),无水氯化铬(102毫克,0.84毫摩尔)和无水乙二醇二甲醚(5毫升)。反应混合物在手套箱中搅拌1小时,23℃。接着加入无水氯化锂(235毫克,5.57毫摩尔),锰粉(305毫克,5.57毫摩尔)和二氯二茂锆(1.63g,5.57毫摩尔)。最后加入ERB-1(0.78克,2.78毫摩尔)和ERP(1.34克,4.18毫摩尔)在5毫升无水乙二醇二甲醚中的溶液。反应物在手套箱中搅拌30小时,20℃~25℃。TLC显示反应结束后向其中加入1克硅藻土,搅拌,过滤,并用乙酸乙酯洗涤固体。收集的有机液浓缩后柱层析得到0.97克的ERB,收率63.4%,HPLC约92%。
参考上述实施例5~6的类似方法,以下述配体D和配体E替代配体A或B制备ERB,试验结果发现采用配体A和B制备化合物ERB效果最好,其次是配体C,但由于配体C制备方法复杂,在工业化生产应用过程中获取成本高于配体A和B;而采用配体D和E时,目标产物的收率和HPLC纯度均低于实施例5和6,其中采用配体D和E制备的目标产物ERB的HPLC约为80%左右。
Claims (10)
7.根据权利要求1所述方法,其特征在于,所述化合物ERB-1是根据权利要求2~6任一项所述方法制备得到。
8.一种化合物ERB-2的制备方法,其特征在于,包括:
(1)由化合物ERB-6用羟基保护基R1保护,转化成化合物ERB-5;
(2)由化合物ERB-5选择性脱去TBDPS,转化成化合物ERB-4;
(3)由化合物ERB-4选择性脱去羟基保护基Pv,转化成化合物ERB-3;
(4)由化合物ERB-3选择性脱去羟基保护基R1,转化成化合物ERB-2;
其中,步骤(1)反应在吡啶中进行;
步骤(2)反应条件为TBAF/THF;
步骤(3)反应是在特戊酰氯/DMAP条件下进行;
步骤(4)反应是在在TsOH存在条件下进行,反应溶剂为MeOH,DCM或其混合液;
R1为羟基保护基,优选R1为MMTr。
9.一种艾日布林的制备方法,其特征在于,包括权利要求1所述的方法制备化合物ERB的步骤,或权利要求7所述的方法制备化合物ERB的步骤,或权利要求8所述的制备化合物ERB-2的步骤,或权利要求2~6任一项所述的方法制备化合物ERB-2的步骤;和经式化合物ERB或化合物ERB-1或化合物ERB-2制备艾日布林的步骤。
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