CN111560044A - 一种11-o-罗汉果醇肟醚衍生物及其制备方法 - Google Patents
一种11-o-罗汉果醇肟醚衍生物及其制备方法 Download PDFInfo
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- CN111560044A CN111560044A CN202010482693.8A CN202010482693A CN111560044A CN 111560044 A CN111560044 A CN 111560044A CN 202010482693 A CN202010482693 A CN 202010482693A CN 111560044 A CN111560044 A CN 111560044A
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- China
- Prior art keywords
- mogrol
- oxime
- oxime ether
- ether derivative
- alcohol
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- -1 alcohol oxime ether derivative Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 12
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 235000013305 food Nutrition 0.000 claims abstract description 5
- 230000036541 health Effects 0.000 claims abstract description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 29
- 239000000741 silica gel Substances 0.000 claims description 29
- 229910002027 silica gel Inorganic materials 0.000 claims description 29
- 239000003208 petroleum Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical group Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000006266 etherification reaction Methods 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 238000006146 oximation reaction Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 150000002443 hydroxylamines Chemical class 0.000 claims description 4
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical class ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 4
- 239000013588 oral product Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 3
- 235000013365 dairy product Nutrition 0.000 claims description 3
- HYYHQASRTSDPOD-UHFFFAOYSA-N hydroxylamine;phosphoric acid Chemical compound ON.OP(O)(O)=O HYYHQASRTSDPOD-UHFFFAOYSA-N 0.000 claims description 3
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 3
- 229940023486 oral product Drugs 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 150000001350 alkyl halides Chemical class 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000005275 alkylenearyl group Chemical group 0.000 claims description 2
- 125000005218 alkyleneheteroaryl group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 claims description 2
- QOJQQKQMWDEPRB-UHFFFAOYSA-N dimethyl(15-phenylpentadecyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CCCCCCCCCCCCCCCC1=CC=CC=C1 QOJQQKQMWDEPRB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 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
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 238000012360 testing method Methods 0.000 abstract description 14
- 239000003814 drug Substances 0.000 abstract description 7
- 235000013361 beverage Nutrition 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 231100000956 nontoxicity Toxicity 0.000 abstract 2
- 125000000468 ketone group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 24
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 23
- 235000019441 ethanol Nutrition 0.000 description 19
- 230000000694 effects Effects 0.000 description 11
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 description 7
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 6
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
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- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 6
- JLYBBRAAICDTIS-AYEHCKLZSA-N mogrol Chemical compound C([C@H]1[C@]2(C)CC[C@@H]([C@]2(C[C@@H](O)[C@]11C)C)[C@@H](CC[C@@H](O)C(C)(C)O)C)C=C2[C@H]1CC[C@H](O)C2(C)C JLYBBRAAICDTIS-AYEHCKLZSA-N 0.000 description 6
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- 238000004809 thin layer chromatography Methods 0.000 description 6
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- GHBNZZJYBXQAHG-KUVSNLSMSA-N (2r,3r,4s,5s,6r)-2-[[(2r,3s,4s,5r,6r)-6-[[(3s,8s,9r,10r,11r,13r,14s,17r)-17-[(2r,5r)-5-[(2s,3r,4s,5s,6r)-4,5-dihydroxy-3-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@H](CC[C@@H](C)[C@@H]1[C@]2(C[C@@H](O)[C@@]3(C)[C@H]4C(C([C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]6[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O6)O)O5)O)CC4)(C)C)=CC[C@H]3[C@]2(C)CC1)C)C(C)(C)O)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GHBNZZJYBXQAHG-KUVSNLSMSA-N 0.000 description 2
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Abstract
本发明提供了一种11‑O‑罗汉果醇肟醚衍生物及其制备方法。所述11‑O‑罗汉果醇肟醚衍生物的结构式如下式(I)所示。是在11‑O‑罗汉果醇的酮基肟化后再进行醚化,得到产物11‑O‑罗汉果醇肟醚衍生物。本发明提供的11‑O‑罗汉果醇肟醚衍生物制备方法简单,纯度和产率高。所得11‑O‑罗汉果醇肟醚衍生物相比于11‑O‑罗汉果醇,具有明显增强的抗氧化活性,而且水溶性增强,经过测试,没有毒性,而且具有明显增强的体内半衰期,可以作为食品,饮品,保健品,药品等口服产品中的抗氧化功能添加剂。
Description
技术领域
本发明涉及天然产物衍生物领域,具体涉及一种11-O-罗汉果醇肟醚衍生物及其制备方法。
背景技术
罗汉果是我国独有的药食同源植物,富含各种营养元素和黄酮,多糖,多酚等生物活性物质。罗汉果苷,特别是罗汉果甜苷V是目前最受欢迎的代替蔗糖的甜味剂,以高甜度,低热量的特点在欧美市场备受欢迎。有文献对罗汉果苷的生物活性特别是抗氧化作用进行了研究,发现罗汉果苷V具有一定的抗氧化能力,对羟基和超氧阴离子自由基均有一定的清除作用。一般认为罗汉果苷具有抗氧化活性是因为苷元上氢原子有一定活性,可以和羟基自由基结合,皂苷母核上的碳原子可以形成碳自由基,进一步氧化形成过氧自由基。四环三萜类皂苷的苷元以及羟基是具有抗氧化活性的关键集团。但罗汉果皂苷类化合物的抗氧化机制还没有深入研究,有待进一步探究。
罗汉果醇(Mogrol)是罗汉果甜苷ⅠA1、ⅠE1、ⅡE、Ⅲ、Ⅳ、ⅣE、Ⅴ和赛门苷I等的苷元;11-O-罗汉果醇(11-O-Mogrol)则是11-O-罗汉果苷V的苷元。
现代科学研究发现,罗汉果醇对于老年性痴呆(阿尔茨海默症,AD)以及缺血性脑痴呆引起的空间认知障碍和学习记忆功能下降具有明显的改善作用。罗汉果醇能够增加老年性痴呆大鼠大脑皮层抑制性氨基酸、甘氨酸、γ-氨基丁酸的含量,降低兴奋性谷氨酸的毒性,并能减少AD大鼠大脑海马组织中β-AP的产生,对于脑缺血引起的学习记忆功能下降也具有明显改善作用。罗汉果醇也能明显改善NaNO2所致的小鼠记忆障碍。由此可见,罗汉果醇具有明显的抗老年痴呆的作用,可以作为临床药物开发使用。
近年来,具有肟醚结构的化合物因其独特的结构特征,以及在生物化学上特有的生理活性,已经引起了科学工作者的研究兴趣。具有肟醚结构的化合物有的与生物内分泌系统相关,有的具有抗菌消炎、抗氧化、杀虫除草等作用,而且还有低毒和环境友好的特点,可以广泛的应用到生物医药、生物农药、保健食品和药品中,因此具有很好的发展前景。因此,本专利公开一种11-O-罗汉果醇肟醚衍生物及其制备方法。
目前,尚没有11-O-罗汉果醇肟醚衍生物的相关报道。本发明探究并确定了11-O-罗汉果醇肟醚衍生物的合成方法以及抗氧化的生物活性。
发明内容
本发明解决其技术问题所采用的技术方案如下:
一种11-O-罗汉果醇肟醚衍生物,结构式如下式(I)所示:
其中,R为H、烷基、烷氧基、烯基、炔基、亚烷基-芳基、亚烷基-杂芳基。
所述烷基、烷氧基、烯基、炔基具有1-20个碳原子,优选具有1-6个碳原子;所述亚烷基具有1-3个碳原子;所述芳基,杂芳基具有4-20个碳原子,优选具有5-12个碳原子,所述杂芳基还有1-3个杂原子,所述杂原子选自O,S,N,P。
优选地,所述烷基选自C1-6的烷基,比如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基;所述烯基选自乙烯基、丙烯基、丁烯基;所述炔基选自乙炔基,丙炔基,丁炔基;所述芳基选自苯基,萘基;所述杂芳基选自呋喃基,哌啶呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、1,3,4-噁二唑基、噻唑基、苯并咪唑,苯并噻吩,苯并呋喃。
更为优选地,本发明提供以下具体化合物:
发明人发现,相比于11-O-罗汉果醇,11-O-罗汉果醇肟醚衍生物有着更强的抗氧化活性和更好的水溶性,更有利于人体吸收利用,特别是口服,生物利用率显著提高。
本发明还提供了所述11-O-罗汉果醇肟醚衍生物的制备方法,包括以下步骤:
(1)肟化:将11-O-罗汉果醇溶解于醇,加入羟胺盐以及缚酸剂,回流反应,反应结束后减压浓缩,浓缩液冷却,搅拌结晶,过滤,干燥,得11-肟-罗汉果醇;
(2)醚化:将11-肟-罗汉果醇溶解于DMF,加入卤化试剂以及催化剂,低温反应,反应结束后将反应液倒入冰水中,石油醚萃取,收集石油醚层,用水将石油醚层洗至中性,将石油醚层通过硅胶层析柱,用洗脱剂洗脱,收集洗脱液,浓缩,挥干溶剂,得11-肟醚-罗汉果醇。
所述11-O-罗汉果醇肟醚衍生物的合成线路如下:
优选地,步骤(1)中,所述的11-O-罗汉果醇来源于天然成分11-O-罗汉果苷V水解后得到得苷元,或者由罗汉果醇半合成,或者全合成。
优选地,步骤(1)中,所述的醇为无水甲醇或无水乙醇,醇的用量为11-O-罗汉果醇重量的4~20倍(ml/g)。
优选地,步骤(1)中,所述的羟胺盐为盐酸羟胺、硫酸羟胺、磷酸羟胺,其中羟胺基团与11-O-罗汉果醇的摩尔比为(1.0~1.5):1。
优选地,步骤(1)中,所述的缚酸剂为有机碱,具体是指吡啶、哌啶、咪唑、甲基咪唑、二甲胺、二乙胺、三甲胺、三乙胺、乙二胺、丙二胺、环己胺、二环己胺中的一种或几种,所述缚酸剂与11-O-罗汉果醇的摩尔比为(0.5~5):1。优选地,步骤(1)中,所述的反应温度为65~85℃,反应的时间为2~10小时。
优选地,步骤(1)中,所述的浓缩液中固形物含量为20%~30%,所述冷却的温度为5~10℃,所述搅拌的速度为10~20r/min,所述析晶的时间为12~24小时。
优选地,步骤(2)中,所述DMF的用量为11-肟-罗汉果醇重量的5~10倍(ml/g)。
优选地,步骤(2)中,所述的卤化试剂为饱和卤代烷、不饱和卤代烷或卤代芳香烃,所述卤化试剂与11-肟-罗汉果醇的摩尔比为(1.0~1.05):1。
优选地,步骤(2)中,所述的催化剂为氢化钠、甲醇钾、甲醇钠、乙醇钾、乙醇钠、叔丁醇钾、叔丁醇钠、氢氧化钠、碳酸钠、碳酸钾、碳酸铵、苄基十四烷二甲基氯化铵、四丁基碘化铵,所述催化剂的用量为11-肟-罗汉果醇物质的量(mol)的0.1%~2%。
优选地,步骤(2)中,所述的反应温度为-10~10℃,反应的时间为2~10小时。
优选地,步骤(2)中,所述石油醚的的用量为11-肟-罗汉果醇重量的20~80倍(ml/g)。石油醚萃取的目的是将醚化反应的产物从水相转移至石油醚相,便于后续硅胶柱层析分离。
优选地,步骤(2)中,所述的硅胶为柱层析硅胶,硅胶的规格为60~300目,硅胶的用量为11-肟-罗汉果醇重量的10~40倍,所述硅胶柱的高径比为(2~8):1。使用硅胶层析柱的目的吸附并分离高含量的11-肟醚-罗汉果醇。
优选地,步骤(2)中,所述石油醚层通过硅胶层析柱的流速为0.5~1BV/小时。
优选地,步骤(2)中,所述的洗脱剂为石油醚与乙酸乙酯、二氯甲烷或三氯甲烷(三者中任意一种溶液)的混合溶液,石油醚与乙酸乙酯、二氯甲烷或三氯甲烷的体积比为(7~10):1,所述洗脱剂的用量为2~5BV。
优选地,步骤(2)中,所述洗脱的流速为0.5~2BV/小时。
本发明方法中,1BV=1个硅胶层析柱体积。
本发明还提供了一种口服品,包括上述11-O-罗汉果醇肟醚衍生物作为抗氧化活性成分,所述口服品为食品,保健品,饮品,乳制品或药品。
具体实施方式
下面结合实施例对本发明作进一步说明。
本发明实施例所使用的11-O-罗汉果醇购于湖南华诚生物资源股份有限公司,是用罗汉果天然成分——11-O-罗汉果甜苷V——经盐酸水解得到的苷元,经高效液相(HPLC)面积归一法测得纯度为97.5%,另测得该11-O-罗汉果醇样品得干燥失重、灰分均小于0.5%;本发明实施例所使用的辅料或化学试剂,如无特殊说明,均通过常规商业途径获得。
实施例1
(1)肟化、后处理:取11-O-罗汉果醇23.8g,溶解于120ml无水乙醇,加入盐酸羟胺4.17g(含羟胺0.06mol)以及吡啶7.9g,82℃回流反应4小时,硅胶TLC检验反应结束后,减压浓缩至浓缩液固形物含量20%,将浓缩液冷却至温度5℃,以10r/min的速度搅拌,析晶20小时,抽滤,干燥,得11-肟-罗汉果醇22.1g。
(2)醚化、后处理:取步骤(1)所得11-肟-罗汉果醇20.2g溶解于110ml DMF,加入溴乙烷4.58g以及甲醇钠0.022g,0℃反应6小时,硅胶TLC检验反应结束后,将反应液倒入1000ml冰水中,用500ml石油醚萃取,收集石油醚层,用水将石油醚层洗至中性,将石油醚层以0.7BV/小时的流速通过硅胶层析柱(柱层析硅胶的规格为100~200目,硅胶的用量为300g,硅胶层析柱的高径比为6:1),用5BV洗脱剂(石油醚:乙酸乙酯=9:1,V/V)洗脱,洗脱的流速为1BV/小时,收集洗脱液,浓缩,挥干溶剂,得11-肟乙醚-罗汉果醇18.7g,纯度99.4%,产率72%,其结构如式(I-1)所示。
1H NMR(CDCl3):1.05(d,3H),1.13-1.21(m,15H),1.24-1.26(m,11H),1.29(q,2H),1,43-1.47(m,5H),1.65(t,1H),1.92(d,2H)1.97(t,1H),3.23(t,1H),3.28(t,1H),3.58(q,2H),5.37(s,1H)。Anal.Calcd.for C32H55NO4:C.74.22,H.10.72,N.2.71,O.12.35。m/z:517.41,Found:517.73。
实施例2
(1)肟化、后处理:取11-O-罗汉果醇23.8g,溶解于150ml无水甲醇,加入硫酸羟胺4.5g(含羟胺0.055mol)以及三乙胺20.2g,70℃回流反应5小时,硅胶TLC检验反应结束后,减压浓缩至浓缩液固形物含量25%,将浓缩液冷却至温度10℃,以10r/min的速度搅拌,析晶18小时,抽滤,干燥,得11-肟-罗汉果醇21.6g。
(2)醚化、后处理:取步骤(1)所得11-肟-罗汉果醇20.2g(0.04mol)溶解于110mlDMF,加入氯丙烯3.14g以及叔丁醇钠0.08g,5℃反应5小时,硅胶TLC检验反应结束后,将反应液倒入1000ml冰水中,用800ml石油醚萃取,收集石油醚层,用水将石油醚层洗至中性,将石油醚层以1BV/小时的流速通过硅胶层析柱(柱层析硅胶的规格为80~100目,硅胶的用量为400g,硅胶层析柱的高径比为5:1),用3BV洗脱剂(石油醚:二氯甲烷=7:1,V/V)洗脱,洗脱的流速为1.5BV/小时,收集洗脱液,浓缩,挥干溶剂,得11-肟丙烯醚-罗汉果醇17.4g,纯度99.1%,产率65.7%,其结构如式(I-2)所示。
1H NMR(CDCl3):1.05(d,3H),1.13-1.21(m,12H),1.24-1.26(m,11H),1.29(q,2H),1,43-1.47(m,5H),1.65(t,1H),1.92(d,2H)1.97(t,1H),3.23(t,1H),3.28(t,1H),4.22(d,2H),5.23(d,2H),,5,37(s,1H),5.92(s,1H)。Anal.Calcd.for C33H55NO4:C.74.81,H.10.45,N.2.64,O.12.09。m/z:529.38,Found:529.56。
实施例3
(1)肟化、后处理:取11-O-罗汉果醇23.8g,溶解于150ml无水乙醇,加入磷酸羟胺3.94g(含羟胺0.06mol)以及二乙胺11g,85℃回流反应6小时,硅胶TLC检验反应结束后,减压浓缩至浓缩液固形物含量22%,将浓缩液冷却至温度7℃,以15r/min的速度搅拌,析晶16小时,抽滤,干燥,得11-肟-罗汉果醇20.6g。
(2)醚化、后处理:取步骤(1)所得11-肟-罗汉果醇20.2g溶解于120ml DMF,加入溴化苄6.84g以及四丁基碘化铵0.3g,-3℃反应8小时,硅胶TLC检验反应结束后,将反应液倒入1000ml冰水中,用1000ml石油醚萃取,收集石油醚层,用水将石油醚层洗至中性,将石油醚层以0.5BV/小时的流速通过硅胶层析柱(柱层析硅胶的规格为200~300目,硅胶的用量为230g,硅胶层析柱的高径比为8:1),用4BV洗脱剂(石油醚:三氯甲烷=9.5:1,V/V)洗脱,洗脱的流速为0.7BV/小时,收集洗脱液,浓缩,挥干溶剂,得11-肟苄基醚-罗汉果醇15.7g,纯度98.7%,产率54.2%,其结构如式(I-3)所示。
1H NMR(CDCl3):1.05(d,3H),1.12-1.19(m,12H),1.24-1.26(m,11H),1.29(q,2H),1,43-1.47(m,5H),1.65(t,1H),1.92(d,2H)1.97(t,1H),3.23(t,1H),3.28(t,1H),4.82(s,2H),5.38(s,1H),7.22-7.24(m,5H)。Anal.Calcd.for C37H57NO4:C.76.62,H.9.92,N.2.42,O.11.04。m/z:579.64,Found:579.82。
效果例1毒性实验
(1)口服给药
用昆明种小鼠,体重20g±2g,雌雄各半,共20只。将实施例1-3制备得到的11-O-罗汉果醇肟醚衍生物制成5%的水混悬液,一日3次灌胃给予禁食小鼠、每次0.5mL,连续观察7天,未见死亡,未见毒副反应。
(2)注射给药
用昆明种小鼠,体重20g±2g,雌雄各半。将实施例1-3制备得到的11-O-罗汉果醇肟醚衍生物配制成3%的注射液。注射给药,每次0.4mL。连续观察7天,未见死亡,未见毒副反应。
(3)长期毒性试验
用SD大鼠,体重200±20g,雌雄各半,共180只。分别灌胃给药。将实施例1-3制备得到的11-O-罗汉果醇肟醚衍生物配制成10%的水混悬液,剂量按照每两周按照2mg/kg/d,、5mg/kg/d、10mg/kg/d、20mg/kg/d、30mg/kg/d,40mg/kg/d六个浓度递增,每天连续给药,每个浓度持续2周,共持续12周。对外周血象和肝,肾功能及血糖等生化指标均无明显差异;对重要脏器未引起明显的病理改善,表明40mg/kg/d时没有明显的毒副反应。
效果例2抗氧化性的测试
1.自由基DPPH的清除试验.采用DPPH法定量测定11-O-罗汉果醇肟醚衍生物抗氧化能力。原理是根据DPPH自由基有单电子,在520nm处有一强吸收,其醇溶液呈紫色。抗氧化剂能使单电子配对,从而使A520nm值降低,溶液褪色。由于这种变化其接受电子数量成定量关系,因而可用比色法(如分光光度计)进行测量。步骤如下:
(1)DPPH试剂的配制:精密称取DPPH(1,1-diphenyl-2-picrylhydrazyl)粉末(分子量=394)0.00990g,置于250mL容量瓶,用适量95%乙醇溶解定容至250mL,得浓度为0.10mmol/L的DPPH试剂。
(2)供试品的制备:取实施例所得11-O-罗汉果醇肟醚衍生物样品,加入95%乙醇溶液定容,分别配制成100μg/mL试液。同样发放配制11-O-罗汉果醇对照组和维生素C组,浓度均为100μg/mL。
(3)测定方法:
a.在10ml试管中依次加入4.0ml DPPH溶液和1.0ml95%乙醇,混合摇匀,避光反应30min,稳定后,以95%乙醇为参比,在520nm处测吸光值,得空白管吸光值,记为A0。
b.在10ml试管中依次加入4.0ml DPPH溶液和1.0ml待测试样溶液,混合摇匀,避光反应30min,稳定后,以95%乙醇为参比,在520nm处测吸光值,得样品管吸光值,记为A1。
c.在10ml试管中依次加入4.0ml95%乙醇溶液和1.0ml待测试样溶液,混合摇匀,避光反应30min,稳定后,以95%乙醇为参比,在520nm处测吸光值,得本底管吸光值,记为A2。
d.计算公式:样品对DPPH自由基的清除率SA(%):
2.超氧阴离子自由基(O2-)的清除试验:邻苯三酚自氧化法。
采用邻苯三酚自氧化法,取4mL 0.1mol/L pH8.2Tris-HCl缓冲溶液和蒸馏水2mL,混匀后在25℃水浴中保温20min,然后加入样品溶液(100μg/mL)2mL,取出后立即加入在25℃预热过的5mmol/L邻苯三酚0.5mL(以10mmol/L HCL配制,空白管用10mmol/L HCL代替邻苯三酚的HCL溶液),摇匀后倒入比色皿,325nm下每隔30s测定吸光度,连续测定4min,计算线性范围内每分钟吸光度的增加。在加入一定体积样品溶液时,减少蒸馏水的体积。
抑制率(%)=(△A0-△A)/△A0×100式中:△A0为邻苯三酚的自氧化速率;△A为加入样品溶液后邻苯三酚的自氧化速率。
3.水中溶解度采用HPLC外标法测试,所用水为去离子水,测试温度20℃。
4.药代动力学。
试验用犬:40只,每组十只,雌雄各半,10±1kg,购自湖南省动物实验中心。
将样品配制为50mg/mL无菌水溶液,通过口饲管法给予禁食状态的狗,每组十只狗,雌雄各半,按照10mg/kg剂量给药。给药后,按照在0min,15min,30min,45min,1h,1.5h,2h,4h,6h,8h,10h每个时间段在相同部位采血,分离出血浆供测试用。本发明11-O-罗汉果醇肟醚衍生物在狗血浆中的浓度用HPLC/MS方法测试。T1/2表示药物半衰期。
所得数据结果如下表1所示:
表1
表1数据表明,本发明提供的11-O-罗汉果醇肟醚衍生物相比于母体化合物11-O-罗汉果醇具有明显增强的抗氧化活性和溶解度,是一种有待开发和研究的新型来自于天然产物的抗氧化剂,其具有接近于常用抗氧化剂Vc的活性,而且在生物体内半衰期明显延长,适合作为用于口服产品,比如食品,饮品,保健品,乳制品等中的抗氧化添加剂。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
2.如权利要求1所述的11-O-罗汉果醇肟醚衍生物,其特征在于,所述烷基、烷氧基、烯基、炔基具有1-20个碳原子,优选具有1-6个碳原子;所述亚烷基具有1-3个碳原子;所述芳基,杂芳基具有4-20个碳原子,优选具有5-12个碳原子,所述杂芳基还有1-3个杂原子,所述杂原子选自O,S,N,P。
3.如权利要求1所述的11-O-罗汉果醇肟醚衍生物,其特征在于,所述烷基选自C1-6的烷基,比如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基;所述烯基选自乙烯基、丙烯基、丁烯基;所述炔基选自乙炔基,丙炔基,丁炔基;所述芳基选自苯基,萘基;所述杂芳基选自呋喃基,哌啶呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、三唑基、噁唑基、1,3,4-噁二唑基、噻唑基、苯并咪唑,苯并噻吩,苯并呋喃。
6.权利要求1-4任一项所述11-O-罗汉果醇肟醚衍生物的制备方法,其特征在于,包括以下步骤:
(1)肟化:将11-O-罗汉果醇溶解于醇,加入羟胺盐以及缚酸剂,回流反应,反应结束后减压浓缩,浓缩液冷却,搅拌结晶,过滤,干燥,得11-肟-罗汉果醇;
(2)醚化:将11-肟-罗汉果醇溶解于DMF,加入卤化试剂以及催化剂,低温反应,反应结束后将反应液倒入冰水中,石油醚萃取,收集石油醚层,用水将石油醚层洗至中性,将石油醚层通过硅胶层析柱,用洗脱剂洗脱,收集洗脱液,浓缩,挥干溶剂,得11-肟醚-罗汉果醇。
7.如权利要求6所述的制备方法,其特征在于,步骤(1)中,所述的醇为无水甲醇或无水乙醇,醇的用量为11-O-罗汉果醇重量的4~20倍(ml/g);和/或所述的羟胺盐为盐酸羟胺、硫酸羟胺、磷酸羟胺,其中羟胺基团与11-O-罗汉果醇的摩尔比为(1.0~1.5):1;和/或所述缚酸剂与11-O-罗汉果醇的摩尔比为(0.5~5):1。
8.如权利要求6所述的制备方法,其特征在于,步骤(1)中,所述的浓缩液中固形物含量为20%~30%,所述冷却的温度为5~10℃,所述搅拌的速度为10~20r/min,所述析晶的时间为12~24小时。
9.如权利要求6所述的制备方法,其特征在于,步骤(2)中,所述DMF的用量为11-肟-罗汉果醇重量的5~10倍(ml/g);和/或所述的卤化试剂为饱和卤代烷、不饱和卤代烷或卤代芳香烃,所述卤化试剂与11-肟-罗汉果醇的摩尔比为(1.0~1.05):1;和/或所述的催化剂为氢化钠、甲醇钾、甲醇钠、乙醇钾、乙醇钠、叔丁醇钾、叔丁醇钠、氢氧化钠、碳酸钠、碳酸钾、碳酸铵、苄基十四烷二甲基氯化铵、四丁基碘化铵,所述催化剂的用量为11-肟-罗汉果醇物质的量(mol)的0.1%~2%。
10.一种口服品,包括权利要求1-4任一项所述11-O-罗汉果醇肟醚衍生物作为作为抗氧化活性成分,所述口服品为食品,保健品,饮品,乳制品或药品。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105832748A (zh) * | 2016-05-06 | 2016-08-10 | 深圳以诺生物制药有限公司 | 一种从罗汉果总皂苷中制备罗汉果醇新型衍生物的方法 |
CN106800580A (zh) * | 2017-01-12 | 2017-06-06 | 中国药科大学 | 甾醇类衍生物及其制备方法和应用 |
CN108473528A (zh) * | 2015-10-29 | 2018-08-31 | 赛诺米克斯公司 | 高强度甜味剂 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108473528A (zh) * | 2015-10-29 | 2018-08-31 | 赛诺米克斯公司 | 高强度甜味剂 |
CN105832748A (zh) * | 2016-05-06 | 2016-08-10 | 深圳以诺生物制药有限公司 | 一种从罗汉果总皂苷中制备罗汉果醇新型衍生物的方法 |
CN106800580A (zh) * | 2017-01-12 | 2017-06-06 | 中国药科大学 | 甾醇类衍生物及其制备方法和应用 |
Non-Patent Citations (2)
Title |
---|
XIE B J: "The antioxidant activities of natural sweeteners, mogrosides, from fruits of Siraitia grosvenori.", 《INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION》 * |
邹健: "罗汉果皂甙类化合物的抗氧化活性研究", 《核农学报》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111560046B (zh) * | 2020-06-01 | 2021-02-05 | 湖南华诚生物资源股份有限公司 | 一种作为护肤品抗氧剂的11-o-罗汉果醇肟酯衍生物以及一种护肤品 |
WO2021244051A1 (zh) * | 2020-06-01 | 2021-12-09 | 湖南华诚生物资源股份有限公司 | 一种11-o-罗汉果醇肟醚衍生物及其制备方法 |
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