JP6358877B2 - Method for producing liquiritigenin precursor - Google Patents
Method for producing liquiritigenin precursor Download PDFInfo
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- JP6358877B2 JP6358877B2 JP2014136494A JP2014136494A JP6358877B2 JP 6358877 B2 JP6358877 B2 JP 6358877B2 JP 2014136494 A JP2014136494 A JP 2014136494A JP 2014136494 A JP2014136494 A JP 2014136494A JP 6358877 B2 JP6358877 B2 JP 6358877B2
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- JBQATDIMBVLPRB-UHFFFAOYSA-N isoliquiritigenin Natural products OC1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 JBQATDIMBVLPRB-UHFFFAOYSA-N 0.000 title claims description 40
- FURUXTVZLHCCNA-UHFFFAOYSA-N Liquiritigenin Natural products C1=CC(O)=CC=C1C1OC2=CC(O)=CC=C2C(=O)C1 FURUXTVZLHCCNA-UHFFFAOYSA-N 0.000 title claims description 23
- FURUXTVZLHCCNA-AWEZNQCLSA-N liquiritigenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC=C2C(=O)C1 FURUXTVZLHCCNA-AWEZNQCLSA-N 0.000 title claims description 23
- GSZUGBAEBARHAW-UHFFFAOYSA-N sophoraflavone B Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C=2OC3=CC(O)=CC=C3C(=O)C=2)C=C1 GSZUGBAEBARHAW-UHFFFAOYSA-N 0.000 title claims description 23
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 239000002243 precursor Substances 0.000 title description 3
- 238000000034 method Methods 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 235000008718 isoliquiritigenin Nutrition 0.000 claims description 17
- DXDRHHKMWQZJHT-FPYGCLRLSA-N isoliquiritigenin Chemical compound C1=CC(O)=CC=C1\C=C\C(=O)C1=CC=C(O)C=C1O DXDRHHKMWQZJHT-FPYGCLRLSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- -1 methoxy, ethoxy Chemical group 0.000 claims 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 9
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 9
- 229940010454 licorice Drugs 0.000 description 9
- 241000202807 Glycyrrhiza Species 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 4
- AFDXODALSZRGIH-QPJJXVBHSA-N (E)-3-(4-methoxyphenyl)prop-2-enoic acid Chemical compound COC1=CC=C(\C=C\C(O)=O)C=C1 AFDXODALSZRGIH-QPJJXVBHSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 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
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 3
- AFDXODALSZRGIH-UHFFFAOYSA-N p-coumaric acid methyl ether Natural products COC1=CC=C(C=CC(O)=O)C=C1 AFDXODALSZRGIH-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 244000303040 Glycyrrhiza glabra Species 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000004576 sand Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DZLOUWYGNATKKZ-VMPITWQZSA-N (e)-3-(4-ethoxyphenyl)prop-2-enoic acid Chemical compound CCOC1=CC=C(\C=C\C(O)=O)C=C1 DZLOUWYGNATKKZ-VMPITWQZSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- HAEJSGLKJYIYTB-ZZXKWVIFSA-N 4-carboxycinnamic acid Chemical compound OC(=O)\C=C\C1=CC=C(C(O)=O)C=C1 HAEJSGLKJYIYTB-ZZXKWVIFSA-N 0.000 description 1
- DZLOUWYGNATKKZ-UHFFFAOYSA-N 4-ethoxycinnamic acid Natural products CCOC1=CC=C(C=CC(O)=O)C=C1 DZLOUWYGNATKKZ-UHFFFAOYSA-N 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229930183217 Genin Natural products 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
- 235000017443 Hedysarum boreale Nutrition 0.000 description 1
- 235000007858 Hedysarum occidentale Nutrition 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical group 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- USLKCMBGQFYUFI-UHFFFAOYSA-N dichloromethane;tribromoborane Chemical compound ClCCl.BrB(Br)Br USLKCMBGQFYUFI-UHFFFAOYSA-N 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001947 glycyrrhiza glabra rhizome/root Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002521 isoliquiritigenin Chemical class 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
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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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- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は甘草素リキリチゲニンの前駆物質としてイソリキリチゲニンの製造方法に関する。 The present invention relates to a process for producing isoliquiritigenin as a precursor of licorice liquiritigenin.
甘草素リキリチゲニンは広く薬効が認められる優れた漢方薬であって、一般に甘草から抽出される。しかし、その抽出方法は甘草根を熱抽出した後、加水分解後の糖類部（グルコースやアビオース）を除去し、得られるリキリチゲニンの逆相クロマトグラフによる精製を必要とする。そのため、甘草素の甘草からの抽出はコスト高で、貴重であり、1ｇ1万元以上で販売されている。その上甘草の栽培が困難なことから甘草が減少傾向にあって、入手困難に伴い、ますます高騰しつつある。 Licorice liquiritigenin is an excellent herbal medicine with widely recognized medicinal effects, and is generally extracted from licorice. However, the extraction method requires extraction of the liquoritigenin by reverse phase chromatography after removing saccharide parts (glucose and abiose) after hydrolysis after extracting licorice root with heat. Therefore, extraction of licorice from licorice is expensive and valuable, and it is sold at over 10,000 yuan per gram. In addition, licorice is declining because it is difficult to cultivate licorice.
そこで、甘草素リキリチゲニンを人工的に合成しようとする試みがある。第１の方法は図２に示すように、p−ヒドロキシベンズアルデヒドを出発原料とする方法で、４−カルボキシケイヒ酸を合成し、これを経由して１、３−ジヒドロキシベンゼンを付加してイソリキリチゲニンを得る方法である（非特許文献１）が、収率が低いという欠点がある。そこで、第２の方法として、図３に示すように、p−ヒドロキシベンズアルデヒドを出発原料とし、p位の水酸基をMOM試薬で保護する一方、１、３−ジヒドロキシベンゼンの水酸基をMOM試薬で保護し、両者を付加する方法が提案される（非特許文献２）。しかしながら、実際に検証してみると、ほぼ全段階（収率や生成物がオイル状など）でカラムクロマトによる精製工程が必要となる。しかも、我々の追試実験ではスケールアップした場合のカップリング工程の収率が42%まで低下し、その上最終工程のイソリキリチゲニンからリキリチゲニンへの閉環反応で，原料と目的物が平衡状態にあって，収率が上がらないという結果を得た。また、閉環段階での原料と目的物の分離が，困難で、最終クロマト精製条件でリキリチゲニンはテーリングし，大幅に回収率が低下した。しかもMOM保護試薬の発がん性，さらに保護，脱保護で２段階の余分な工程が必要であり、第２法は実験室レベルでは有効であるものの、量産には適しないとの知見を得た。 There is an attempt to artificially synthesize licorice liquiritigenin. As shown in FIG. 2, the first method is a method in which p-hydroxybenzaldehyde is used as a starting material, and 4-carboxycinnamic acid is synthesized, and 1,3-dihydroxybenzene is added via this to isomerize. Although it is a method for obtaining lithigenin (Non-patent Document 1), there is a disadvantage that the yield is low. Therefore, as a second method, as shown in FIG. 3, p-hydroxybenzaldehyde is used as a starting material and the hydroxyl group at the p-position is protected with a MOM reagent, while the hydroxyl group of 1,3-dihydroxybenzene is protected with a MOM reagent. A method of adding both is proposed (Non-Patent Document 2). However, when actually verified, purification steps by column chromatography are required in almost all stages (yield, product is oily, etc.). Moreover, in our follow-up experiment, the yield of the coupling process when scaled up decreased to 42%, and in addition, the ring-closing reaction from isoliquiritigenin to liquiritigenin in the final process brought the equilibrium between the raw material and the target product. As a result, the yield was not increased. In addition, it was difficult to separate the raw material and the target product at the ring closure stage, and liquiritigenin tailed under the final chromatographic purification conditions, resulting in a significant reduction in recovery. In addition, two extra steps are required for the carcinogenicity of the MOM protecting reagent, and further protection and deprotection, and the second method was effective at the laboratory level, but it was found that it was not suitable for mass production.
そこで、本発明者らはリキリチゲニンの量産方法ではクロマトグラフを使用せず、晶出させる方法を選択し、しかも発がん性のあるMOM保護試薬を使用せず、さらに人工的にイソリキリチゲニンをリキリチゲニンに変換するに平衡反応に伴って収率が向上しないことを考慮し、また、有機合成したリキリチゲニンは天然物と違って（＋）体と（−）体が共存し、新たに毒性試験を必要とするとの知見を考慮し,リキリチゲニンの量産方法として適切な方法を提供することを目的とする。 Therefore, the present inventors selected a method for crystallization without using a chromatograph in the method for mass production of liquiritigenin, and without using a carcinogenic MOM protecting reagent, and further artificially isolyquiritigenin into liquiritigenin. In consideration of the fact that the yield does not increase with the equilibrium reaction when converted to, the organically synthesized liquiritigenin coexists with the (+) and (-) isomers, and requires a new toxicity test. The purpose of this study is to provide an appropriate method for mass production of liquiritigenin.
本発明者らは、有機合成的にイソリキリチゲニンをリキリチゲニンに変換すると天然物と違って（＋）体と（−）体が共存するが、人体に投与すると、体内組織内で（−）体のリキリチゲニンに変換される可能性に着目し、リキリチゲニンを有機合成せず、その前駆体であるイソリキリチゲニンを合成し、これを人体に投与し、体内で目的のリキリチゲニンに変換しようとするもので、イソリキリチゲニンの製造はp−アルコキシ桂皮酸を出発原料とし、これにフィーデルクラフト反応を利用してp−アルコキシベンゼンをカップリングさせ、高収率でトリアルコキシイソリキリチゲニンが形成されて晶出し、これを脱保護してイソリキリチゲニンを量産するに適する方法を提供するものである。このイソリキリチゲニンは体内変換でリキリチゲニンに変換される可能性があり、体内でリキリチゲニン（−）体の薬理効果を得ることができる。 The inventors of the present invention organically synthetically convert isoliquiritigenin to liquiritigenin, and unlike the natural product, the (+) body and the (−) body coexist, but when administered to a human body, (−) Focusing on the possibility of being converted to liquiritigenin in the body, it does not synthesize liquiritigenin, synthesizes its precursor isoliquiritigenin, administers it to the human body, and attempts to convert it to the target liquiritigenin in the body In the production of isoliquiritigenin, p-alkoxycinnamic acid is used as a starting material, and p-alkoxybenzene is coupled to this using the Feidelcraft reaction to form trialkoxyisolithicigenin in a high yield. Thus, a method suitable for mass production of isoliquiritigenin by crystallization and deprotection is provided. This isoliquiritigenin may be converted to liquiritigenin by in vivo conversion, and the pharmacological effect of liquiritigenin (−) form can be obtained in the body.
本発明の反応式は図１で示すように、第１にカップリング反応（Ａ）からなり、式（i
）で示されるpーアルコキシ桂皮酸と式（ii）で示される１、３−ジアルコキシベンゼンとから式（iii）で示されるトリアルコキシイソリキリチゲニンを合成し、保護基を離脱してイソリキリチゲニンを合成する方法にある。式（i）、（ii）、（iii）はその一般式において、Rはメチル、エチルまたはブチルであるアルコキシ基であるのが望ましく、通常入手が容易なRがメチルであるメトキシ基が用いられる。反応は式（i）で示されるp−アルコキシ桂皮酸にハロゲン化剤を添加してハロゲン化し、そこに式（ii）で示されるp−アルコキシベンゼンを添加し、次いで、触媒（金属ハロゲン化物、例えば塩化アルミニウム等）存在下に所定の芳香環の水素に求電子置換し、式（iiiａ）で示されるトリアルコキシ桂皮酸が得られる。第２に反応式（B）では、この保護機を脱離すると、式（iv）で示される目的のイソリキリチゲニンが得られる。イソリキリチゲニンは閉環反応（Ｃ）により、式（iv）で示されるイソリキリチゲニンが式（v）で示されるリキリチゲニンに変換されるが、有機合成では（＋）体と（−)体が得られるため、要すればキラル分割により両者を分離する必要がある。そこで、甘草から得られるリキリチゲニンは（−）体であるため、イソリキリチゲニンのイソメラーゼ酵素を使って、リキリチゲニン（−）体を得るようにするか、またはイソリキリチゲニンを人体に投与すると酵素反応で体内組織内でキリチゲニンの（−）体を得ることもできる。p−アルコキシ桂皮酸としてはp−メトキシ桂皮酸が好ましいが、p−エトキシ桂皮酸、p−ブトキシ桂皮酸を使用しても良い。以下の実施例では、具体的には式（iａ）で示されるp−メトキシ桂皮酸と式（iiａ）で示される１、３−ジメトキシベンゼンとから式（iiiａ）で示されるトリメトキシイソリキリチゲニンを合成し、保護基を離脱してイソリキリチゲニンを合成する方法にある。
As shown in FIG. 1, the reaction formula of the present invention comprises a coupling reaction (A), and the formula (i
) -P-alkoxycinnamic acid represented by formula (ii) and 1,3-dialkoxybenzene represented by formula (ii) to synthesize trialkoxyisolithicigenin represented by formula (iii), and the protective group is removed to remove The method synthesizes lithigenin. In formulas (i), (ii) and (iii), R is preferably an alkoxy group in which R is methyl, ethyl or butyl, and a methoxy group in which R is methyl is usually available. . The reaction is halogenated by adding a halogenating agent to p-alkoxycinnamic acid represented by formula (i), to which p-alkoxybenzene represented by formula (ii) is added, and then a catalyst (metal halide, For example, trialkoxycinnamic acid represented by the formula (iiia) is obtained by electrophilic substitution with hydrogen of a predetermined aromatic ring in the presence of aluminum chloride or the like. Secondly, in the reaction formula (B), when the protective device is removed, the target isoliquiritigenin represented by the formula (iv) is obtained. Isoliquiritigenin is converted to liquiritigenin represented by formula (v) by ring-closure reaction (C), but in organic synthesis, (+) and (−) isomers are converted. Therefore, it is necessary to separate the two by chiral resolution if necessary. Therefore, liquiritigenin obtained from licorice is a (−) isomer. Therefore, by using the isomerase enzyme of isoliquiritigenin, the liquiritigenin (−) isomer is obtained, or the enzyme is administered when isoliquiritigenin is administered to the human body. A (−) body of Kirichigenin can also be obtained in the body tissue by the reaction. As p-alkoxycinnamic acid, p-methoxycinnamic acid is preferable, but p-ethoxycinnamic acid and p-butoxy cinnamic acid may be used. In the following Examples, specifically, p-methoxycinnamic acid represented by the formula (ia) and 1,3-dimethoxybenzene represented by the formula (iia) are used to obtain trimethoxyisolithici represented by the formula (iiia). There is a method for synthesizing isoliquiritigenin by synthesizing genin and removing the protecting group.
4-メトキシケイヒ酸 式(ia）10ｇをジメチルホルムアミド0.25 mLを含む無水塩化メチレン50 mLに溶解し，室温にてオキザリルクロリド9.6 mLを発泡に注意しながら10分かけて滴下した。そのまま，室温にて2時間撹拌の後，溶媒を減圧下で除去した。得られた残渣に，1，3-ジメトキシベンゼン7.4 mL（式iiａ）と無水エーテル200 mLを加え，氷浴中で，粉末にした触媒無水三塩化アルミニュウム22.4 gを15分かけてゆっくりと加えた。そのまま室温にて一晩放置した後，内容物を氷上(500 g)にあけ，６M 塩酸を10 mL加え，氷が溶解した後，酢酸エチル(300 mL)で4回抽出した。抽出液を無水硫酸ナトリウムで乾燥後，減圧下で濃縮し，残渣をエーテル-ヘキサン混液で結晶化することにより，14.2 gの目的物(式iiia)の結晶を得た。
収率85% 1H-NMR (CDCl3) δ 7.73 (1H, d, J=8.1 Hz), 7.64 (1H, d, J=15.1 Hz), 7.54 (2H, d, J=7.7 Hz), 7.38 (1H, d, J=15.1 Hz), 6.90 (2H, d, J=7.7 Hz), 6.55 (1H, brd, J=8.1 Hz), 6.49 (1H, brs), 3.89 (3H, s), 3.85 (3H, s), 3.83 (3H, s).
4-methoxycinnamic acid 10 g of formula (ia) was dissolved in 50 mL of anhydrous methylene chloride containing 0.25 mL of dimethylformamide, and 9.6 mL of oxalyl chloride was added dropwise at room temperature over 10 minutes while paying attention to foaming. After stirring for 2 hours at room temperature, the solvent was removed under reduced pressure. To the obtained residue, 7.4 mL of 1,3-dimethoxybenzene (formula iia) and 200 mL of anhydrous ether were added, and 22.4 g of powdered catalyst anhydrous aluminum trichloride was slowly added over 15 minutes in an ice bath. . The mixture was allowed to stand at room temperature overnight, then the contents were poured on ice (500 g), 10 mL of 6M hydrochloric acid was added, and the ice was dissolved, followed by extraction four times with ethyl acetate (300 mL). The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was crystallized from an ether-hexane mixture to obtain 14.2 g of the desired product (formula iiia).
Yield 85% 1 H-NMR (CDCl 3 ) δ 7.73 (1H, d, J = 8.1 Hz), 7.64 (1H, d, J = 15.1 Hz), 7.54 (2H, d, J = 7.7 Hz), 7.38 (1H, d, J = 15.1 Hz), 6.90 (2H, d, J = 7.7 Hz), 6.55 (1H, brd, J = 8.1 Hz), 6.49 (1H, brs), 3.89 (3H, s), 3.85 (3H, s), 3.83 (3H, s).
上記生成物(式iiia)3 gを塩化メチレン60 mLに溶解し0 ℃にて1 M BBr3塩化メチレン溶液を滴下した。室温まで昇温し，そのまま2日間撹拌した。セニエット塩34 gを含む氷冷水700 mLとメタノール350 mLを加え，室温で一晩撹拌した。得られた黄色溶液を酢酸エチルで2回抽出し，1 Mセニエット塩-飽和食塩水で洗浄後，無水硫酸ナトリウムで乾燥，濃縮した。残渣をエーテル-ヘキサンで結晶化し，目的物(式iv)1.95 gを得た。またその母液を濃縮後再度エーテル-ヘキサンで結晶化することにより0.59 gの目的物第２晶を得た。
合計収率98%1H-NMR (acetone-d6) δ 13.5 (1H, s), 8.10 (1H, d, J=8.3 Hz), 7.82 (1H, d, J=15.4 Hz), 7.74 (1H, d, J=15.4 Hz), 7.72 (2H, d, J=8.2 Hz), 6.90 (2H, d, J=8.2 Hz), 6.44 (1H, dd, J=8.3 and 1.7 Hz), 6.34 (1H, d, J=1.7 Hz).
（実施例２）
3 g of the above product (formula iiia) was dissolved in 60 mL of methylene chloride, and 1 M BBr 3 methylene chloride solution was added dropwise at 0 ° C. The mixture was warmed to room temperature and stirred for 2 days. Ice-cooled water (700 mL) containing 34 g of Sennet salt and methanol (350 mL) were added, and the mixture was stirred overnight at room temperature. The resulting yellow solution was extracted twice with ethyl acetate, washed with 1 M seniette-saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ether-hexane to obtain 1.95 g of the desired product (formula iv). The mother liquor was concentrated and recrystallized from ether-hexane to obtain 0.59 g of the second crystal of the desired product.
Total yield 98% 1 H-NMR (acetone-d 6 ) δ 13.5 (1H, s), 8.10 (1H, d, J = 8.3 Hz), 7.82 (1H, d, J = 15.4 Hz), 7.74 (1H , d, J = 15.4 Hz), 7.72 (2H, d, J = 8.2 Hz), 6.90 (2H, d, J = 8.2 Hz), 6.44 (1H, dd, J = 8.3 and 1.7 Hz), 6.34 (1H , d, J = 1.7 Hz).
(Example 2)
原料200 mg（式iv）に海砂3 gを加え，撹拌し，よく分散した後に，水20 mLを加えた。その懸濁液にピロリジン合計200 μLを三回に分け，1日1回加え，3日間撹拌した。海砂をろ過除去し，ろ液を１M HCｌに加え，残渣を少量のメタノールに溶かし，それらを併せて酢酸エチルで3回抽出した。抽出液を無水硫酸ナトリウムで乾燥後，濃縮し，エーテルで結晶化することによりリキリチゲニンの粗結晶96 mgを得た（式v）。
収率48%.
1H-NMR (DMSO-d6) δ 9.65 (1H, brs), 7.58 (1H, m), 7.27 (2H, m), 6.74 (2H, m), 6.45 (1H, m), 6.28 (1H, m), 5.39 (1H, brd, J=11.6 Hz), 3.65 (1H, brt, J=15.0 Hz), 2.58 (1H, brd, J=15.7 Hz).
To 200 mg (formula iv) of raw material, 3 g of sea sand was added, stirred and well dispersed, and then 20 mL of water was added. To the suspension, a total of 200 μL of pyrrolidine was divided into three times, added once a day, and stirred for 3 days. The sea sand was removed by filtration, the filtrate was added to 1M HCl, the residue was dissolved in a small amount of methanol, and they were combined and extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, concentrated, and crystallized with ether to obtain 96 mg of liquiritigenin crude crystals (formula v).
Yield 48%.
1H-NMR (DMSO-d 6 ) δ 9.65 (1H, brs), 7.58 (1H, m), 7.27 (2H, m), 6.74 (2H, m), 6.45 (1H, m), 6.28 (1H, m ), 5.39 (1H, brd, J = 11.6 Hz), 3.65 (1H, brt, J = 15.0 Hz), 2.58 (1H, brd, J = 15.7 Hz).
Claims (4)
但し、式（I）、式（II）、式（III）中Ｒはメトキシ、エトキシ又はブトキシである。
However, in formula (I), formula (II), and formula (III), R is methoxy, ethoxy, or butoxy.
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| CN201580036037.2A CN106536468B (en) | 2014-07-02 | 2015-07-01 | Preparation method of liquiritigenin precursor |
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