CN116239630A - 一种脱水淫羊藿素中间体化合物 - Google Patents
一种脱水淫羊藿素中间体化合物 Download PDFInfo
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- TUUXBSASAQJECY-UHFFFAOYSA-N Anhydroicaritin Natural products C1=CC(OC)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C(CC=C(C)C)=C2O1 TUUXBSASAQJECY-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 150000001875 compounds Chemical class 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 23
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003960 organic solvent Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 7
- 150000007517 lewis acids Chemical class 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
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- VHBFFQKBGNRLFZ-UHFFFAOYSA-N flavone Chemical group O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 4
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- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 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 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000002274 desiccant Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000008213 purified water Substances 0.000 description 12
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- 239000000203 mixture Substances 0.000 description 11
- CTGVBHDTGZUEJZ-UHFFFAOYSA-N Noricaritin Natural products CC(C)(O)CCC1=C(O)C=C(O)C(C(C=2O)=O)=C1OC=2C1=CC=C(O)C=C1 CTGVBHDTGZUEJZ-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 238000005821 Claisen rearrangement reaction Methods 0.000 description 3
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- 238000001819 mass spectrum Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 229910052693 Europium Inorganic materials 0.000 description 2
- YGCCASGFIOIXIN-UHFFFAOYSA-N Lupiwighteone Chemical compound CC(C)=CCC1=C(O)C=C(O)C(C2=O)=C1OC=C2C1=CC=C(O)C=C1 YGCCASGFIOIXIN-UHFFFAOYSA-N 0.000 description 2
- 229910052769 Ytterbium Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
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- 229910052761 rare earth metal Inorganic materials 0.000 description 2
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- NAWDYIZEMPQZHO-UHFFFAOYSA-N ytterbium Chemical compound [Yb] NAWDYIZEMPQZHO-UHFFFAOYSA-N 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000893536 Epimedium Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- TZJALUIVHRYQQB-XFDQAQKOSA-N Icariin Natural products O(C)c1ccc(C2=C(O[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O3)C(=O)c3c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O4)c(C/C=C(\C)/C)c3O2)cc1 TZJALUIVHRYQQB-XFDQAQKOSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000008930 Low Back Pain Diseases 0.000 description 1
- ZKEHDQGXEYXKFI-UHFFFAOYSA-N Lupiwighteone hydrate Natural products CC(C)(O)CCC1=C(O)C=C(O)C(C2=O)=C1OC=C2C1=CC=C(O)C=C1 ZKEHDQGXEYXKFI-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
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- HVQAJTFOCKOKIN-UHFFFAOYSA-N flavonol Natural products O1C2=CC=CC=C2C(=O)C(O)=C1C1=CC=CC=C1 HVQAJTFOCKOKIN-UHFFFAOYSA-N 0.000 description 1
- 235000011957 flavonols Nutrition 0.000 description 1
- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 description 1
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
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- 230000004054 inflammatory process Effects 0.000 description 1
- 229910001496 lithium tetrafluoroborate Inorganic materials 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
-
- 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
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- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于医药化工领域,具体涉及一种脱水淫羊藿素中间体化合物。本发明以羟基被TBDMS单保护的黄酮骨架为起始原料,在催化剂的作用下与1‑溴‑3‑甲基丁‑2‑烯反应得脱水淫羊藿素新中间体化合物。本发明提供的新中间体合成方法简单,通过邻位重排引入异戊烯基,最后可一步去除保护基,得到脱水淫羊藿素。该合成路线短,收率高,反应条件温和,工艺稳定,适合大量的工业化生产。
Description
技术领域
本发明属于医药化工领域,具体涉及一种脱水淫羊藿素中间体化合物。
背景技术
脱水淫羊藿素(Icariin),化学名为3,5,7-三羟基-2-(4-甲氧基苯)-8-(3-甲基丁-2-烯)查尔-4-酮,分子式:C21H20O6;分子量:368.13;CAS登记号:118525-40-9,结构式如下:
脱水淫羊藿素属于黄酮醇类化合物,普遍存在于植物中,数量众多,结构复杂多样,具有许多重要的生物活性和药理作用。淫羊藿素类化合物广泛用于治疗心血管疾病健忘症、关节炎、乏力、阳痿、不孕症、腰痛等其他慢性病。其中脱水淫羊藿素是该类化合物的基本骨架结构和重要的活性成分,如具有抗氧化、抗炎、抗骨质疏松、抗癌、刺激血管生成等生物活性。目前主要是通过从植物中提取获取淫羊藿素,但自然界含量较低,且分离纯化较为复杂。所以用化学方法合成淫羊藿素类化合物就具有重要的意义。
现有技术关于全合成淫羊藿素的相关报道较少,在中国专利申请号CN101723999A的中国专利中公开了一种淫羊藿素的合成方法,该路线以苯甲醇和溴乙腈为起始原料制备得到淫羊藿素,该专利介绍的合成步骤如下:
在上述方法中,需要11步反应才能得到脱水淫羊藿素,需要用到氢化钠、Raneynickel、四氟硼锂等危险试剂,反应条件苛刻,总收率低,不利于工业化生产。
更多的研究者采用Claisen重排的方法来在黄酮结构中引入异戊烯基团,如Jean-BaPtiste oaskiewicz等(J.Med.chem.,2005,48,2790-2804)采用该方法合成的去甲脱水淫羊霍素Claisen重排得到8位异戊烯基的目标产物的收率约为50%左右:
为提高该方法的收率,近年来随着有机金属催化剂的发展,很多研究者采用新型催化剂来达到高选择性重排的目的。Nawaf AI-Maharik等(Ttrahedron,2003,59,4177-4151)在合成Lupiwighteone时采用β-双酮类稀土配合物催化剂Eu(fod)3催化如下的Claisen重排反应,据报道得到对位产物的比例高达83%。但是稀土金属价格昂贵,用它来提高收率在成本上不能接受,而且由于毒性、不稳定性等问题,稀土有机化合物催化剂远未达到工业化应用的程度:
申请号为CN201910220551.1的中国专利中报道了先将异戊烯基通过邻位重排连接到8位碳,随后再进行黄酮骨架的形成系列反应,得到脱水淫羊藿素,该专利介绍的合成步骤如下:
该路线虽然反应条件较为温和,但合成路线较长,保护基团的引入和除去较为困难,不利于纯化和工业化生产。
在所有的合成方法中,异戊烯基骨架的构建最为困难和关键,需要用到铕、铋、镱等昂贵金属或高温的合成条件,成本高,收率低。所以用简单、廉价的方法合成异戊烯基骨架结构具有重要的意义。
发明内容
为了克服现有的异戊烯基引入困难、保护基去除困难,工艺复杂、催化剂昂贵、副产物多、收率低等缺点。本发明以提供了一种新的脱水淫羊藿素中间体化合物及制备方法,该方法在温和的条件下,在黄酮骨架上引入异戊烯基。利用该中间体合成脱水淫羊藿素收率高,反应条件温和,适合大量的工业化生产。
本发明具体通过如下技术方案实现:
本发明第一方面提供了一种新的脱水淫羊藿素中间体化合物,其结构如式Ⅲ所示:
本发明第二方面提供了一种化合物Ⅲ的制备方法,包括如下步骤:
将化合物Ⅰ、化合物Ⅱ、碱及有机溶剂A加入到反应瓶中,搅拌溶解,控温搅拌反应,检测反应完全后得到化合物Ⅲ,合成路线如下:
优选地,所述的碱选自碳酸钾、碳酸铯、氢氧化钾、叔丁醇钾中的一种或其组合,其中特别优选碳酸钾。
优选地,所述的化合物Ⅰ、化合物Ⅱ和碱的投料摩尔比为1:1.0~1.8:1.0~2.0,其中特别优选1:1.2:1.1。
优选地,所述的有机溶剂A选自四氢呋喃、丙酮、乙腈、甲苯、二甲苯中的一种或其组合。
优选地,所述的反应温度为30~80℃,其中特别优选50℃~55℃。
在一优选方案中,反应结束后需进行后处理操作,具体的为:反应液加入萃取剂,收集有机相,有机相用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得化合物Ⅲ;所述萃取剂为乙酸乙酯、二氯甲烷、三氯甲烷中的一种或其组合。
本发明第三方面提供一种化合物Ⅲ用于制备脱水淫羊藿素的用途。
化合物Ⅲ用于制备脱水淫羊藿素的方法,包括如下方案:中间体化合物Ⅲ在催化剂作用下邻位重排得到中间体化合物Ⅳ;中间体化合物Ⅳ脱去保护基得到脱水淫羊藿素,其合成路线如下:
优选地,在以下部分进一步详细的描述以上步骤:
化合物Ⅳ的制备
化合物Ⅳ的制备方法如下步骤:将化合物Ⅲ、路易斯酸及有机溶剂B加入到三口瓶中,室温搅拌至反应结束,反应经后处理得化合物Ⅳ;
优选地,所述路易斯酸选自三氯化硼、三氯化铝、氯化锌中的一种,其中特别优选三氯化硼。
优选地,所述的化合物Ⅲ、路易斯酸的投料摩尔比为1:1.0~2.0,其中特别优选1:1.1。
优选地,所述的有机溶剂B选自二氯甲烷、1.2-二氯乙烷、四氢呋喃、甲苯中的一种或其组合。
在一优选方案中,反应结束后需进行后处理操作,具体的为:将反应液过滤,滤液减压浓缩得中间体Ⅳ,然后用用有机溶剂精制;所述有机溶剂为乙酸乙酯、二氯甲烷、乙醇、甲醇中的一种或其组合。
脱水淫羊藿素V的制备
将化合物Ⅳ,酸和有机溶剂C加入到三口瓶中,室温反应至反应结束得到脱水淫羊藿素V。
优选地,所述的酸选自三氟乙酸、盐酸和硫酸中的一种,其中特别优选三氟乙酸。
优选地,所述化合物Ⅳ、酸的投料摩尔比为1:0.3~0.8,其中特别优选1:0.5。
优选地,所述的有机溶剂C选自二氯甲烷、乙醇、四氢呋喃中的一种或其组合。
在一优选方案中,反应结束后需进行后处理操作,具体的为:反应液冷却至室温,加入纯化水及萃取剂,收集有机相,有机相用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩后所得固体加入甲醇中重结晶得脱水淫羊藿素V;所述萃取剂为乙酸乙酯、二氯甲烷、三氯甲烷中的一种或其组合。
与现有技术相比,本发明取得的技术效果是:
1、本发明提供了一种新的脱水淫羊藿素中间体化合物,该新化合物通过邻位重排引入异戊烯基,解决了传统对位重排选择性差的问题。
2、本发明以路易斯酸为催化剂实现邻位异戊烯基重排,避免现有工艺需要用到铕、铋、镱等昂贵金属或高温的合成条件,成本高,收率低的问题。
3、以本发明提供的新中间体制备脱水淫羊藿素工艺简单,收率高。
具体实施方式
下面通过实施例来进一步说明本发明。应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
对本发明得到的化合物结构确证:
化合物Ⅲ的高分辨质谱:ESI-HRMS:m/z=558.2212[M+H]+,1H-NMR(400MHz,CDCl3):δ10.29(s,1H),7.32-7.51(m,7H),6.62-6.83(m,4H),4.80(d,J=7.5Hz,1H),3.81(s,3H),0.9(m,9H),0.20(m,6H);13C-NMR(400MHz,CDCl3)δ178.2,163.5,158.2,138.4,136.1,128.0,120.1,114.2,109.6,101.1,93.1,71.2,64.9,55.8,30.2,25.4.
化合物Ⅳ的高分辨质谱:ESI-HRMS:m/z=573.2213[M+H]+,1H-NMR(400MHz,CDCl3)
:δ9.68(s,1H),7.21-7.50(m,10H),5.72(t,J=6.8Hz,1H),4.80(s,3H),3.33-3.29(m,2H),1.82-1.73(m,6H),0.9(m,9H),0.20(m,6H);13C-NMR(400MHz,CDCl3)δ178.9,163.2,159.1,154.7,137.8,131.8,127.6,122.8,114.2,109.2,102.1,73.2,57.2,22.6,18.1.
脱水淫羊藿素V高分辨质谱:ESI-HRMS:m/z=369.1263[M+H]+,1H-NMR(400MHz,CDCl3):δ12.38(s,1H),10.76(s,1H),9.49(s,1H,),8.13(d,J=9.0Hz,2H),7.13(d,J=9.1Hz),6.30(s,1H),5.18(t,J=6.8Hz),3.85(s,3H,),3.44(d,J=6.7Hz),1.75(s,3H),1.63(s,3H);13C NMR(100MHz,DMSOd6):δ176.7,161.7,160.9,158.8,153.9,146.6,136.4,131.5,129.6,124.1,122.9,114.6,106.1,103.5,98.3,55.9,25.9,21.7,18.3.
化合物Ⅲ的制备
实施例1
向三口瓶中加入化合物Ⅰ(100.86g,0.20mol),化合物Ⅱ(35.72g,0.24mol),碳酸钾(30.36g,0.22mol)和463mL乙腈,搅拌溶解,50℃~55℃反应2小时,反应液缓慢降温至室温,加入600mL纯化水和600mL乙酸乙酯,收集有机相,加入无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得白色固体粉末状化合物Ⅲ,收率96.4%,HPLC纯度99.82%。
实施例2
向三口瓶中加入化合物Ⅰ(100.86g g,0.20mol),化合物Ⅱ(29.77g,0.20mol),氢氧化钾(12.34g,0.22mol)和463mL丙酮,搅拌溶解,50℃~55℃反应2小时,反应液缓慢降温至室温,加入600mL纯化水和600mL乙酸乙酯,收集有机相,加入无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得白色固体粉末状化合物Ⅲ,收率90.4%,HPLC纯度99.60%。
实施例3
向三口瓶中加入化合物Ⅰ(100.86g,0.20mol),化合物Ⅱ(53.59g,0.36mol),碳酸铯(71.68g,0.22mol)和480mL乙腈,搅拌溶解,50℃~55℃反应2小时,反应液缓慢降温至室温,加入600mL纯化水和600mL乙酸乙酯,收集有机相,加入无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得白色固体粉末状化合物Ⅲ,收率93.4%,HPLC纯度99.55%。
实施例4
向三口瓶中加入化合物Ⅰ(100.86g,0.20mol),化合物Ⅱ(35.72g,0.24mol),碳酸钾(27.6g,0.20mol)和463mL四氢呋喃,搅拌溶解,30℃~35℃反应2小时,反应液缓慢降温至室温,加入600mL纯化水和600mL乙酸乙酯,收集有机相,加入无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得白色固体粉末状化合物Ⅲ,收率90.4%,HPLC纯度99.62%。
实施例5
向三口瓶中加入化合物Ⅰ(100.86g,0.20mol),化合物Ⅱ(35.72g,0.24mol),碳酸钾(55.2g,0.40mol)和463mL甲苯,搅拌溶解,75℃~80℃反应2小时,反应液缓慢降温至室温,加入600mL纯化水和600mL乙酸乙酯,收集有机相,加入无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得白色固体粉末状化合物Ⅲ,收率93.4%,HPLC纯度99.57%。
实施例6
向三口瓶中加入化合物Ⅰ(100.86g,0.20mol),化合物Ⅱ(59.54g,0.4mol),碳酸钾(60.72g,0.44mol)和500mL二甲苯,搅拌溶解,80℃~85℃反应2小时,反应液缓慢降温至室温,加入600mL纯化水和600mL乙酸乙酯,收集有机相,加入无水硫酸钠干燥,过滤除去干燥剂,减压浓缩得白色固体粉末状化合物Ⅲ,收率84.4%,HPLC纯度98.72%。
化合物IV的制备
实施例7
向三口瓶中加入化合物Ⅲ(114.45g,0.20mol),三氯化硼(28.12g,0.24mol),500mL二氯甲烷,室温搅拌至反应结束,过滤,减压浓缩得化合物IV粗品,乙醇(200mL)精制,得到黄色化合物IV,收率98.2%,HPLC纯度99.84%。
实施例8
向三口瓶中加入化合物Ⅲ(114.45g,0.20mol),三氯化铝(53.34g,0.40mol),500mL1,2-二氯甲烷,室温搅拌至反应结束,过滤,减压浓缩得化合物IV粗品,二氯甲烷(200mL)精制,得到黄色化合物IV,收率94.3%,HPLC纯度99.54%。
实施例9
向三口瓶中加入化合物Ⅲ(114.45g,0.20mol),氯化锌(27.26g,0.20mol),500mL四氢呋喃,室温搅拌至反应结束,过滤,减压浓缩得化合物IV粗品,乙酸乙酯(200mL)精制,得到黄色化合物IV,收率95.3%,HPLC纯度99.41%。
实施例10
向三口瓶中加入化合物Ⅲ(114.45g,0.20mol),三氯化硼(51.55g,0.44mol),500mL甲苯,室温搅拌至反应结束,过滤,减压浓缩得化合物IV粗品,甲醇(200mL)精制,得到黄色化合物IV,收率88.4%,HPLC纯度98.81%。
脱水淫羊藿素V制备
实施例11
向三口瓶中加入化合物IV(106.20g,0.20mol),三氟乙酸(11.40g,0.1mol),500mL二氯甲烷,室温搅拌至反应结束,向其中加入500ml纯化水和500mL乙酸乙酯,剧烈震荡后静置,收集有机相,用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩至干,甲醇(200mL)重结晶、抽滤、烘干,得黄色固体脱水淫羊藿素V,收率98.3%,HPLC纯度99.92%。
实施例12
向三口瓶中加入化合物IV(106.20g,0.20mol),三氟乙酸(18.24g,0.16mol),500mL乙醇,室温搅拌至反应结束,向其中加入500ml纯化水和500mL乙酸乙酯,剧烈震荡后静置,收集有机相,用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩至干,甲醇(200mL)重结晶、抽滤、烘干,得黄色固体脱水淫羊藿素V,收率94.5%,HPLC纯度99.62%。
实施例13
向三口瓶中加入化合物IV(106.20g,0.20mol),三氟乙酸(6.84g,0.06mol),500mL四氢呋喃,室温搅拌至反应结束,向其中加入500ml纯化水和500mL乙酸乙酯,剧烈震荡后静置,收集有机相,用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩至干,甲醇(200mL)重结晶、抽滤、烘干,得黄色固体脱水淫羊藿素V,收率93.8%,HPLC纯度99.66%。
实施例14
向三口瓶中加入化合物IV(106.20g,0.20mol),盐酸(0.73g,0.02mol),500mL二氯甲烷,室温搅拌至反应结束,向其中加入500ml纯化水和500mL乙酸乙酯,剧烈震荡后静置,收集有机相,用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩至干,甲醇(200mL)重结晶、抽滤、烘干,得黄色固体脱水淫羊藿素V,收率88.5%,HPLC纯度98.82%。
实施例15
向三口瓶中加入化合物IV(106.20g,0.20mol),硫酸(19.62g,0.2mol),500mL二氯甲烷,室温搅拌至反应结束,向其中加入500ml纯化水和500mL乙酸乙酯,剧烈震荡后静置,收集有机相,用无水硫酸钠干燥,过滤除去干燥剂,减压浓缩至干,甲醇(200mL)重结晶、抽滤、烘干,得黄色固体脱水淫羊藿素V,收率87.4%,HPLC纯度98.52%。
Claims (10)
3.根据权利要求2所述的制备方法,其特征在于,所述的碱选自碳酸钾、碳酸铯、氢氧化钾、叔丁醇钾中的一种或其组合。
4.根据权利要求2所述的制备方法,其特征在于,所述的有机溶剂A选自四氢呋喃、丙酮、乙腈、甲苯、二甲苯中的一种或其组合;所述的反应温度为30~80℃。
5.根据权利要求2所述的制备方法,其特征在于,所述的化合物II、化合物III和碱的投料摩尔比为1:1.0~1.8:1.0~2.0。
6.权利要求1所述的脱水淫羊藿素中间体化合物Ⅲ用于制备脱水淫羊藿素的用途。
8.根据权利要求7所述的用途,其特征在于,步骤(1)中所述的路易斯酸选自三氯化硼、三氯化铝、氯化锌中的一种;所述的化合物Ⅲ、路易斯酸的投料摩尔比为1:1.0~2.0。
9.根据权利要求7所述的用途,其特征在于,步骤(1)中所述的有机溶剂B选自二氯甲烷、1.2-二氯乙烷、四氢呋喃、甲苯中的一种或其组合。
10.根据权利要求7所述的用途,其特征在于,步骤(2)中所述的酸选自三氟乙酸、盐酸和硫酸中的一种;所述化合物Ⅳ、酸的投料摩尔比为1:0.3~0.8;所述的有机溶剂C选自二氯甲烷、乙醇、四氢呋喃中的一种或其组合。
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