CN1297552C - 木犀草素的合成方法 - Google Patents
木犀草素的合成方法 Download PDFInfo
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- IQPNAANSBPBGFQ-UHFFFAOYSA-N luteolin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(O)C(O)=C1 IQPNAANSBPBGFQ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 title claims abstract description 23
- LRDGATPGVJTWLJ-UHFFFAOYSA-N luteolin Natural products OC1=CC(O)=CC(C=2OC3=CC(O)=CC(O)=C3C(=O)C=2)=C1 LRDGATPGVJTWLJ-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 235000009498 luteolin Nutrition 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims description 13
- 230000002194 synthesizing effect Effects 0.000 title description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 12
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 10
- JPYHHZQJCSQRJY-UHFFFAOYSA-N Phloroglucinol Natural products CCC=CCC=CCC=CCC=CCCCCC(=O)C1=C(O)C=C(O)C=C1O JPYHHZQJCSQRJY-UHFFFAOYSA-N 0.000 claims description 6
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 6
- 229960001553 phloroglucinol Drugs 0.000 claims description 6
- 238000010520 demethylation reaction Methods 0.000 claims description 4
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- 238000006297 dehydration reaction Methods 0.000 claims description 3
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- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical group C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 3
- BHSYONGONOKNAI-UHFFFAOYSA-N ethyl 3-(3,4-dimethoxyphenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(OC)C(OC)=C1 BHSYONGONOKNAI-UHFFFAOYSA-N 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 2
- AOLOMULCAJQEIG-UHFFFAOYSA-N Luteolin 3',4'-dimethyl ether Natural products C1=C(OC)C(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 AOLOMULCAJQEIG-UHFFFAOYSA-N 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 7
- -1 dimethoxy ethyl Chemical group 0.000 abstract description 3
- RTIXKCRFFJGDFG-UHFFFAOYSA-N chrysin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 abstract 2
- MPYXTIHPALVENR-UHFFFAOYSA-N benzene-1,3,5-triol;dihydrate Chemical compound O.O.OC1=CC(O)=CC(O)=C1 MPYXTIHPALVENR-UHFFFAOYSA-N 0.000 abstract 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
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- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 229930015036 aurone Natural products 0.000 description 2
- 150000001530 aurones Chemical class 0.000 description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
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- 235000005513 chalcones Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- PEFNSGRTCBGNAN-QNDFHXLGSA-N luteolin 7-O-beta-D-glucoside Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C=C(C=3C=C(O)C(O)=CC=3)OC2=C1 PEFNSGRTCBGNAN-QNDFHXLGSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 229920000447 polyanionic polymer Polymers 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
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Classifications
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种新的合成木犀草素的方法，该方法以间苯三酚为起始原料，无需保护基，直接与3，4-二甲氧基苯甲酰乙酸乙酯缩合、环合得3′，4′-二甲氧基-5，7-二羟基黄酮，然后经三氯化铝/吡啶催化脱甲基得木犀草素，总收率34.2%。
Description
发明领域
本发明涉及有机药物化学和功能食品化学领域，具体而言，本发明涉及止咳、祛痰药物和功能食品木犀草素新的全合成制造工艺。
背景技术
木犀草素的化学名为：3’，4’，5，7-四羟基黄酮；英文名：Luteolin。分子式：C15H10O6；分子量：286.24；CAS：[491-70-3]。
木犀草素又名青兰甙元，是自新疆治疗气管炎有效中草药金叶青兰以及安徽产的白毛夏枯草中分离出来的共同有效成份。其天然品已应用于临床治疗止咳、祛痰、消炎有较好的疗效。但由于天然品提取率较低，纯化有难度，临床应用有一定困难。国内外关于半合成木犀草素的报道也比较多。半合成大部分是以橙皮甙为起始原料，经去氢、水解、去甲基三步反应得到木犀草素(邢有权等，中国医药工业杂志，25(11)484-487)，或以橙皮甙为起始原料经水解、去甲基和去氢，同样得到产品(孙志忠等，中国现代应用药学杂志，16(1)30-31，1999)，工艺过程比较复杂，成本较高。
有关全合成木犀草素的报道主要是查尔酮(Chalkone)路线，国外较早有报道(W.A.Hutchins，J.Chem.Soc，91-94，1939)。国内有报道：以间苯三酚为起始原料按常规Hoesch法则得2，4，6-三羟基苯乙酮，用甲基保护4，6位上二羟基与异香草醛缩合合成相应的查尔酮，耗时6天，收率偏低，再经环合氧化，氢碘酸脱甲基，木犀草素总收率仅3-5％，且存在副产品橙酮(也称噢弄)，影响产品质量(卢玉华等，药学学报，15(8)，1980)；而后有报道通过氯甲基甲醚保护相应的醛、酮的酚羟基先合成查尔酮，进而制备多羟基黄酮，收率提高至22％(戈夏等，中国医药工业杂志，34(4)2003)。但使用致癌化合物氯甲醚作保护剂是不合适的。
另外，全合成木犀草素尚有1，3取代丙烷二酮的方法(D.Nagarathnam et al，J.Org.Chem，56(16)，4884-4887，1991)，中间体要硅烷保护羟基，使用LIHMDS聚阴离子锂，反应条件是充氮气和-78℃，难以实现规模生产。
在木犀草素全合成的过程中，我们研究了大量的文献和实验过程、单元反应，参考罗伯特·特乌勒的3’，4’-二苄氧基-5，7-二羟基黄酮的合成方法，(Robert Teoule，etal，Bull.Soc.Chim.France，546，1961)发明了木犀草素新的全合成制造方法，并通过中试优化了工艺。
发明目的
本发明的目的是提供一种直接用间苯三酚为原料与3，4-二甲氧基苯甲酰乙酸乙酯，在真空中温下脱醇脱水，即先缩合后环合，得到3’，4’-二甲氧基-5，7-二羟基黄酮；然后在催化剂AlCl3/吡啶存在下，脱去3’，4’位上的二个甲基即得到木犀草素。
发明内容
本发明内容之一是提供了一种以中间体3’，4’-二甲氧基-5，7-二羟基黄酮脱甲基的方法制造木犀草素：
本发明以3’，4’-二甲氧基-5，7-二羟基黄酮为原料，用三氯化铝/吡啶为催化剂，以吡啶为溶剂，在温度如160℃-180℃常压下进行3-5小时的反应，然后进行水解、水洗、除去铝盐母液，得到粗品，用DMF/H2O及95％乙醇重结晶。
本发明内容之二是提供了一种直接以间苯三酚与3，4-二甲氧基甲酰乙酸乙酯在真空下中等温度(如140℃-160℃)进行缩合、环合制备中间体3’，4’-二甲氧基-5，7-二羟基黄酮：
本发明无需保护间苯三酚的两个羟基，直接与容易制备的3，4-二甲氧基苯甲酰乙酸乙酯在高沸点溶剂如二苯醚或者硝基苯存在下，在真空下中等温度(如140℃-160℃)下脱醇脱水，共反应6-7小时得到中间体3’，4’-二甲氧基-5，7-二羟基黄酮，其中真空度优选是1330Pa-6600Pa。
3，4-二甲氧基苯甲酰乙酸乙酯按(吴安心等，《化学试剂》，1998，20(6)，376-377)制备。
本发明的优点是：工艺过程简短、反应条件温和，操作方便，使工业化生产可行，基本无橙酮副产物，产品品质有保证，木犀草素总收率34.2％，收率高，优于其他工艺路线之方法。
下面通过实施例对本发明作进一步说明。应该理解的是，本发明实施例所述制备方法仅仅是用于说明本发明，而不是对本发明的限制，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。除非另有说明，本发明中的百分数是重量百分数。
实施例
实施例一、木犀草素的制备
将30Kg 3’，4’-二甲氧基-5，7-二羟基黄酮及120Kg纯无水吡啶加入搪瓷反应釜内，搅拌，使溶解，加热将温度慢慢升高至100℃左右，分批加入三氯化铝，大量放热，控制温度不超过180℃，约1小时加完三氯化铝。加完后在160℃-180℃之间反应3-5小时，由高效液相跟踪去甲基是否完全，并确定反应时间。
将1000Kg水抽入水解釜，预先冷却至10℃，趁热将上述反应物放入水解釜内搅拌，排除气体，冷却，离心机内分离得粗品。用50Kg冷水洗涤，用DMF/H2O和95％乙醇二次重结晶，得木犀草素22.1Kg，收率81％，含量HPLC≥98.5％，产品与天然木犀草素对照，质谱、红外光谱均一致。
实施例二、3’，4’-二甲氧基-5，7-二羟基黄酮的制备
将20Kg间苯三酚及60Kg 3，4-二甲氧基苯甲酰乙酸乙酯加入搪瓷反应釜内，搅拌、溶解、加热，升温至140℃-160℃，在真空(1330Pa)减压下回流2小时，稍冷投入80Kg二苯醚，再在真空(6600Pa)减压下140℃-160℃回流反应4-5小时，冷却，冷至30℃时，抽滤，用40Kg95％乙醇浸泡30分钟，打浆，离心机甩滤，得3’，4’-二甲氧基-5，7-二羟基黄酮黄色粗品21Kg。母液冷却，静置后过滤又得少量粗品，收率42.2％，HPLC≥92％。该粗品可用于脱甲基反应，不必进一步纯化。
Claims (4)
1.一种制备木犀草素的方法，该方法是在三氯化铝/吡啶存在下，反应温度是160℃-180℃，将3’，4’-二甲氧基-5，7-二羟基黄酮脱甲基制备木犀草素：
其中中间体3’，4’-二甲氧基-5，7-二羟基黄酮由间苯三酚与
3，4-二甲氧基苯甲酰乙酸乙酯在高沸点溶剂存在下，真空下脱醇脱水制备得到：
2.根据权利要求1的方法，其中溶剂是二苯醚或硝基苯。
3.根据权利要求1的方法，其中真空度是1330Pa-6600Pa。
4.根据权利要求1的方法，其中反应温度是140℃-160℃。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013111148A1 (en) * | 2011-12-13 | 2013-08-01 | Laurus Labs Private Limited | Process for preparation of luteolin |
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| BRPI0814876A2 (pt) | 2007-07-31 | 2014-09-30 | Limerick Biopharma Inc | Análogos de pirona fosforilados e métodos |
| CN102010393A (zh) * | 2010-11-09 | 2011-04-13 | 杭州福斯特药业有限公司 | 一种5,7-二羟基黄酮的合成方法 |
| CN103833714B (zh) * | 2014-02-23 | 2016-07-13 | 闻永举 | 木犀草素、木犀草苷、木犀草素芸香糖苷半合成的方法 |
| CN109020940A (zh) * | 2018-10-24 | 2018-12-18 | 陕西嘉禾生物科技股份有限公司 | 一种野黄芩素的合成方法 |
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| CN1325393A (zh) * | 1998-10-30 | 2001-12-05 | 默克专利股份有限公司 | 木犀草素和木犀草素衍生物的制备方法 |
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| WO2013111148A1 (en) * | 2011-12-13 | 2013-08-01 | Laurus Labs Private Limited | Process for preparation of luteolin |
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