CN114380840B - 艾日布林的合成 - Google Patents
艾日布林的合成 Download PDFInfo
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- CN114380840B CN114380840B CN202210097729.XA CN202210097729A CN114380840B CN 114380840 B CN114380840 B CN 114380840B CN 202210097729 A CN202210097729 A CN 202210097729A CN 114380840 B CN114380840 B CN 114380840B
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- 229960003649 eribulin Drugs 0.000 title claims description 14
- 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 3
- 238000003786 synthesis reaction Methods 0.000 title abstract description 7
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 2
- 229960000439 eribulin mesylate Drugs 0.000 abstract description 20
- 239000012535 impurity Substances 0.000 abstract description 10
- 239000000539 dimer Substances 0.000 abstract description 8
- 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 abstract 2
- 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 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 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 11
- 239000000243 solution Substances 0.000 description 11
- 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 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 3
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000004721 Polyphenylene oxide Substances 0.000 description 2
- 241000243142 Porifera Species 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PDVFSPNIEOYOQL-UHFFFAOYSA-N (4-methylphenyl)sulfonyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OS(=O)(=O)C1=CC=C(C)C=C1 PDVFSPNIEOYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 239000004593 Epoxy Substances 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241001674052 Phakellia Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 238000010828 elution 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
- 229940118951 halaven Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 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
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
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- 230000000171 quenching effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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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
Abstract
本发明涉及甲磺酸艾日布林的合成。具体为提供一种制备甲磺酸艾日布林制备的方法，该方法可以规避专利中USRE46965E提及的二聚杂质(Dimer杂质)的产生。
Description
技术领域
本发明属于化学合成领域，具体涉及复杂天然改构药物甲磺酸艾日布林的合成。
背景技术
软海绵素B是上世纪80年代日本科学家Uemura等人从稀缺日本海绵Halichondriaokadai中分离出来的一种多(聚)醚类大环内酯，虽然软海绵素B只含有C\H\O三种元素，但是化合物结构十分复杂。进一步研究发现软海绵素B在老鼠实验中对老鼠体内外癌细胞具有非常强的抑制作用。化学家们进一步研究还发现，常见的海绵，诸如Phakellia、Lissodendory和Axinella中同样含有软海绵素B。美国国家肿瘤研究所使用软海绵素B在60个癌细胞系做了系统的活性评价，证明了软海绵素B在抗癌细胞增殖作用机理类似于已知的抗微管蛋白药物，但是生物化学机理不同。由于软海绵素B的极强活性和独特的作用机制,引起学术界、企业界的关注。然而由于自然界单纯依靠从海绵中提取分离的样品量有限,研发进展较慢。为此，依靠化学合成的方法制备软海绵素B及其类似物引起了化学家们的广泛兴趣。软海绵素B的结构如下：
哈佛大学Kishi教授系统地研究了软海绵素B及其类似物的全合成。大量研究发现，软海绵素B如上图所示的右边片段比左边的聚醚片段是更具抗癌活性的载体，因为右边片段含有多样的功能基团，而聚醚片段的结构单调。这些研究进一步促使合成化学家们制备了一系列的软海绵素B类似物供以活性测试。甲磺酸艾日布林就是软海绵素B类似物之一，最终通过III期临床实验，在2010年被美国FDA批准用于治疗转移性乳腺癌，商品名HALAVENTM。甲磺酸艾日布林化学结构中含有19个手性中心，其化学结构式如下：
迄今,已有大量专利和文献资料报道了甲磺酸艾日布林的制备,报道的合成路线通常涉及将(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-[(2S)-2,3-二羟基丙基]-3-甲氧基-26-甲基-20,27-二亚甲基十六氢-11,15:18,21:24,28-三环氧-7,9-桥亚乙基-12,15-桥亚甲基-9H,15H-呋喃[3,2-i]呋喃[2',3':5,6]吡喃[4,3-b][1,4]二氧环二十五烷-5(4H)-酮在碱作用下和MsCl或者TsCl或者Ts2O反应，随后所得到的反应产物和氨水反应得到艾日布林游离碱，最后艾日布林游离碱和甲磺酸成盐，制备得到甲磺酸艾日布林。反应路线如下：
上述合成甲磺酸艾日布林的路线收率较低，主要是反应过程中游离的氨基亲核进攻底物的OMs或者OTs基团时，非常容易产生结构如下的Dimer杂质,专利USRE46965E对含有该Dimer杂质的甲磺酸艾日布林进行了专利保护。Dimer杂质的结构如下：
发明内容
本发明的目的在于提供一种制备甲磺酸艾日布林的方法，旨在避免传统合成路线会产生专利USRE46965RE提及的Dimer杂质问题。
研究发现，环氧化合物(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-[(2S)-2,3-环氧丙基]-3-甲氧基-26-甲基-20,27-二亚甲基十六氢-11,15:18,21:24,28-三环氧-7,9-桥亚乙基-12,15-桥亚甲基-9H,15H-呋喃[3,2-i]呋喃[2',3':5,6]吡喃[4,3-b][1,4]二氧环二十五烷-5(4H)-酮(化合物式I)在碱和溶剂存在下和邻苯二甲酰亚胺或邻苯二甲酰亚胺盐(化合物式II)反应，制备得到(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-[(2S)-3-邻苯二甲酰亚胺-2-羟基丙基]-3-甲氧基-26-甲基-20,27-二亚甲基十六氢-11,15:18,21:24,28-三环氧-7,9-桥亚乙基-12,15-桥亚甲基-9H,15H-呋喃[3,2-i]呋喃[2',3':5,6]吡喃[4,3-b][1,4]二氧环二十五烷-5(4H)-酮(化合物式III)。化合物式III在碱的作用下去除邻苯二甲酰亚胺保护，制备得到艾日布林。最后，通过该方法制备得到的艾日布林在溶剂下加入等当量的甲磺酸成盐，成功完成甲磺酸艾日布林的制备，该合成路线制备得到的甲磺酸艾日布林不含有专利USRE46965E提及的Dimer杂质。本发明的合成路线如下：
反应第一步使用的碱选自三乙胺，二异丙基乙基胺，碳酸钾，碳酸钠，碳酸氢钾，碳酸氢钠，碳酸铯，DMAP，吡啶，磷酸氢二钠，吗啉，KHMDS，NaHMDS，LiOH，NaOH，KOH。
反应第一步使用的溶剂为THF，MeOH，EtOH，iPrOH，TBME，甲苯，乙腈，乙酸乙酯，DCM。
反应第二步使用的溶剂为乙腈，乙醇，乙酸乙酯，DCM，iPrOH，MeOH。
反应第二步使用的碱选自NH2NH2.H2O，R1NH2(R1为C1-C5的烷基)，R2R3NH(R2为C1-C5的烷基,R2为C1-C5的烷基)，吗啉，哌嗪，(R4为C1-C5的烷基)。
化合物式II中R为H,K,Na,Li,Cs。
本发明提供的制备甲磺酸艾日布林的方法，可以有效规避专利USRE46965E中提及的二聚杂质的产生，对于复杂结构甲磺酸艾日布林的合成以及产品质量的提升具有十分重要的意义。
具体实施方式
以下典型实施例用来说明本发明，在本领域内的技术人员对本发明所做的简单替换和改进等均属于本发明所保护的技术方案之内。
实施例一:化合物式III的制备(使用邻苯二甲酰亚胺)
将式II化合物(R＝H)(61.9mg，0.42mmol)、KOH(25.2mg，0.45mmol)，加入式I化合物(100.0mg，0.14mmol)的乙醇(10mL)溶液中，并于65℃搅拌8h。反应液自然降至室温，减压浓缩后，将残余物直接上样，经柱色谱纯化(50％乙酸乙酯-正庚烷至100％乙酸乙酯)，得到式III化合物(105mg，87％)。
1H NMR(600MHz,CDCl3)δ7.80-7.88(m,2H),7.68-7.75(m,2H),5.07(s,1H),4.93(s,1H),4.86(s,1H),4.78(s,1H),4.65-4.73(m,1H),4.56-4.64(m,1H),4.30-4.39(m,2H),4.23-4.32(m,1H),4.16-4.22(m,1H),4.08-4.16(m,2H),4.00-4.06(m,1H),3.96(t,J＝11.4Hz,1H),3.80-3.91(m,3H),3.69-3.78(m,1H),3.58-3.68(m,2H),3.45-3.53(m,1H),3.41(s,3H),3.26(s,1H),2.81-2.93(m,2H),2.71(dd,J＝15.6,10.2Hz,1H),2.38-2.54(m,3H),2.12-2.35(m,7H),2.02-2.13(m,1H),1.79-2.01(m,6H),1.64-1.74(m,3H),1.52-1.62(m,2H),1.20-1.50(m,4H),1.08(d,3H).QTOF-MS(m/z)calcd for C48H61NO13[M+H]+:860.4216；Found:860.4636.
实施例二:化合物式III的制备(使用三乙胺作碱)
将式II化合物(R＝H)(61.9mg，0.42mmol)，Et3N(45.5mg,0.45mmol)加入式I化合物(100.0mg，0.14mmol)的乙腈(10mL)溶液中，并于60℃搅拌12h。反应液自然降至室温，减压浓缩后，将残余物直接上样，经柱色谱纯化(50％乙酸乙酯-正庚烷至100％乙酸乙酯)，得到式III化合物(101mg，84％)。
实施例三:化合物式III的制备(使用邻苯二甲酰亚胺钾)
将式II化合物(R＝K)(77.9mg，0.42mmol)，加入式I化合物(100.0mg，0.14mmol)的乙醇(10mL)溶液中，并于65℃搅拌过夜。反应液自然降至室温，减压浓缩后，将残余物直接上样，经柱色谱纯化(50％乙酸乙酯-正庚烷至100％乙酸乙酯)，得到式III化合物(109mg，90％)。
实施例四:艾日布林的制备(使用水合肼)
将水合肼(80％溶液，14.0μL，0.23mmol)，加入实施例二制备得到的式III化合物(100mg，0.12mmol)的乙醇(5mL)溶液中，并于70℃搅拌12小时。反应液自然降至室温，减压浓缩后，将残余物直接上样，经柱色谱纯化(50％乙酸乙酯-正庚烷至30％乙酸乙酯-甲醇)，得到艾日布林(72mg，85％)。
实施例五:艾日布林的制备(使用乙胺)
将乙胺溶液(68-72wt％in H2O，15.0μL，～0.23mmol)，加入实施例三制备得到的式III化合物(100mg，0.12mmol)的iPrOH(5mL)溶液中，并于65℃搅拌6h。反应液自然降至室温，减压浓缩后，将残余物直接上样，经柱色谱纯化(50％乙酸乙酯-正庚烷至30％乙酸乙酯-甲醇)，得到艾日布林(75mg，89％)。
实施例六:制备甲磺酸艾日布林
将甲磺酸(7.9mg，0.082mmol)/氨水(25％溶液，506μL，0.33mmol)的混合溶液，加入实施例四和实施例五所制备得到的艾日布林(实施例四和实施例五制备的艾日布林各取30mg混合)(60mg，0.082mmol)的乙腈(2mL)溶液中，室温搅拌30分钟，减压浓缩去除有机溶剂，所得残余物为甲磺酸艾日布林(67mg，99％)，该产品经Q-tof质谱检测不含有dimer杂质(附图1)。
实施例七:制备甲磺酸艾日布林(对比实施例)
参照USRE46965E合成甲磺酸艾日布林：将三甲基吡啶(64.9mg,0.54mmol)和吡啶(0.5mg,0.0067mmol)加入溶于二氯甲烷(0.5mL)的ER-076349(100mg,0.13mmol)溶液中(氮气氛围加入，溶剂经无水处理)，体系降温至-20～-25℃，缓慢滴加对甲苯磺酸酐(44.6mg,0.14mmol)的二氯甲烷(0.1mL)溶液，控温≤-16℃，反应控温-20～-25℃搅拌80min后升温至0℃继续反应40min，加入纯化水(0.2mL)淬灭反应，反应液升温至15-20℃搅拌20min。反应体系加入异丙醇(10mL)和氨水溶液(10mL)，于20℃搅拌36h。反应液浓缩至干，加入二氯甲烷(3mL)溶清后用碳酸钠/碳酸氢钠缓冲水溶液(1mL，pH＝10)洗涤，二氯甲烷(2.5mL)萃取水相并合并有机相浓缩至干，经柱色谱纯化(乙腈/水缓冲液洗脱)，收集目标产物浓缩除去乙腈，剩余的产品水溶液加入二氯甲烷(4mL)和碳酸钠/碳酸氢钠缓冲水溶液(3mL，pH＝10)，混合液经充分搅拌并静置分层，水相用二氯甲烷(2.5mL)反萃后合并有机相浓缩至干，粗品溶于二氯甲烷/戊烷(3/1)混合液经精密过滤并浓缩至干，得到艾日布林ER-086526(73.2mg)，该游离碱和等当量甲磺酸成盐，得到甲磺酸艾日布林(81.9mg,61％),该产品经Q-tof质谱检测含有dimer杂质(附图2)。
Claims (3)
1.制备艾日布林的方法，具体为化合物式I在碱和溶剂存在下和化合物式II反应，制备得到化合物式III；化合物式III在碱和溶剂的作用下，制备得到艾日布林，反应式如下：
反应第一步使用的碱选自三乙胺，NaOH，KOH；
反应第二步使用的碱选自NH2NH2.H2O，乙胺。
2.如权利要求1所示的制备方法，反应第一步使用的溶剂为EtOH，乙腈。
3.如权利要求1所示的制备方法，反应第二步使用的溶剂为乙醇，iPrOH。
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