CN103694297A - Synthesis method for increasing ginsenoside M1 and decanoylchloride monoesterification selectivity - Google Patents
Synthesis method for increasing ginsenoside M1 and decanoylchloride monoesterification selectivity Download PDFInfo
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- CN103694297A CN103694297A CN201310577993.4A CN201310577993A CN103694297A CN 103694297 A CN103694297 A CN 103694297A CN 201310577993 A CN201310577993 A CN 201310577993A CN 103694297 A CN103694297 A CN 103694297A
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Abstract
The present invention provides a synthesis method for increasing ginsenoside M1 and decanoylchloride monoesterification selectivity. According to the synthesis method, the hydroxyl at the site 6 of the ginsenoside M1 glycoside group is protected by using tert-butyldimethylsilyl chloride through an etherification manner, the obtained material and equivalent decanoylchloride are subjected to a monoesterification reaction in an ice water bath under nitrogen protection by adopting dichloromethane as a solvent and adopting triethylamine as an acid binding agent under a DMAP (4-dimethylaminopyridine) catalysis condition, and finally tetrabutylammonium fluoride is adopted to remove the silicon-protected group to obtain the product of the monoesterification reaction of the tert-butyldimethyl siloxane of the ginsenoside M1 and the decanoylchloride.
Description
Technical field
The present invention relates to the chlorosilane protective reaction of ginsenoside M1, belong to Chemistry for Chinese Traditional Medicine field.
Background technology
That ginseng has is anti-ageing, anti-inflammatory, antianaphylaxis, hypoglycemic, repairing nerve damage and the effect such as protect the liver.Research in recent years shows, ginsenoside has antineoplastic action, and major part is all with Rg
3, Rh
1, Rh
2deng being main study subject.They show remarkable effect at aspects such as promoting apoptosis of tumor cells and tumour cell differentiation, and the ginsenoside of different structure there are differences aspect anti-tumor activity, and wherein diol type ginsenoside anti-tumor activity is obviously better than triol type ginsenoside.Along with going deep into of saponin(e pharmacokinetic, what find real performance antitumor action is that secondary metabolite Compound K in saponin(e animal body claims again ginsenoside M1, and ginsenoside Compound K belongs to protopanoxadiol type saponin(e.Research shows that the esterified derivative of ginsenoside Compound K has better anti-tumor activity.EM1 (mixture of the stearate of M1, cetylate and oleic acid ester) compares with M1 has stronger anti-tumor activity.But EM1 source is limited, is difficult to separation and purification.And the serial M1 derivative poorly water-soluble that utilizes chemical synthesising technology to obtain.Adopt the modes such as ester bond, ehter bond to introduce water-soluble good group to the modification base of M1, it is had concurrently fat-soluble and water-soluble, on the structural formula of ginsenoside M1, have six hydroxyls, thereby selective esterification and raising mono-esterification productive rate have very important researching value.
Chlorosilane protects-goes protection process to be widely used in the protective reaction of hydroxyl; with chlorosilane by No. 6 position hydroxyl protections the most active on the glycosyl of Compound K; again with acyl chlorides generation esterification; the impact on esterification position according to kinetics and group steric hindrance size; thereby optimized the selectivity of single-esterification; be easy to separating-purifying, improve esterification productive rate.
Summary of the invention
Ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE are single etherification product of the synthetic ginsenoside M1 of raw material; by the decanoyl chloride of its product and equivalent at ice-water bath; nitrogen protection; methylene dichloride is solvent; triethylamine is acid-binding agent; under the condition of DMAP catalysis, there is single-esterification, finally with tetrabutyl ammonium fluoride, slough t-Butyldimethylsilyl.
Positively effect of the present invention is with chlorosilane on No. 6 position hydroxyl protections the most active on the glycosyl of Compound K; again with acyl chlorides generation esterification; the impact on esterification position according to kinetics and group steric hindrance size; thereby optimized the selectivity of single-esterification; be easy to separating-purifying, improve esterification productive rate.
Experiment: ginsenoside M1 and decanoyl chloride mono-esterification are optionally synthetic
Instrument and reagent:
Instrument: Agilent 1260 LC high performance liquid chromatographs; Buddhist nun Koryo 550 type Fourier transform infrared spectrometer; RE52CS-1 Rotary Evaporators, Shanghai Yarong Biochemical Instrument Plant; SHZ-D (III) rotation ability of swimming vacuum pump, Gongyi City Ying Yu Yu Hua instrument plant; ETS-D4 heats magnetic stirring apparatus, German IKA company; BT 323S electronic balance, Beijing Sai Duolisi instrument system company limited; FH-203 ultraviolet analysis instrument for three purposed (UV), Industrial Co., Ltd. of upper Nereid section; KQ-50B ultrasonic cleaner, Kunshan Ultrasonic Instruments Co., Ltd.; Column chromatography silica gel (200-300 order), Mouping District, Yantai Kombi promise chemical reagent factory; Tlc silica gel (GF254), Mouping District, Yantai Kombi promise chemical reagent factory;
Reagent: TERT-BUTYL DIMETHYL CHLORO SILANE, A Faaisha Chemical Co., Ltd.; Decanoyl chloride, A Faaisha Chemical Co., Ltd.; Triethylamine, Tianjin Ke Miou chemical reagent company limited; Methylene dichloride, Chemical Reagent Co., Ltd., Sinopharm Group; Anhydrous sodium sulphate, Tianjin Ke Miou chemical reagent company limited; Sherwood oil, Tianjin Ke Miou chemical reagent company limited; Ethyl acetate, Tianjin Ke Miou chemical reagent company limited
1. the monoether of ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE is combined to
At the 25mL that magnetic stirrer is housed, stop in good gram of bottle; add 100 mg ginsenoside M1; the TERT-BUTYL DIMETHYL CHLORO SILANE of 5 times of equivalents; nitrogen protection, adds appropriate triethylamine to dissolve under ice-water bath, after reaction 10 min; rise to room temperature; tlc monitoring reaction process, 24h after completion of the reaction, adds saturated ammonium chloride solution stopped reaction.Through CH
2cl
2(3 * 10 mL) extraction, Brine washes organic phase, anhydrous Na
2sO
4dry, concentrated solvent.
Column chromatography purification process: silica gel amount, 6g; Moving phase, ethanol/methylene;
After gradient elution, obtaining Rf value is 9/34 (8%MeOH/CH
2cl
2) product 109 mg products be Off-white solid, for the monoether of ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE is combined to the tertiary butyl dimethyl-silicon ether of product ginsenoside M1.
2. the tertiary butyl dimethyl-silicon ether of ginsenoside M1 and the single-esterification of decanoyl chloride
At the 25mL that magnetic stirrer is housed, stop in good gram of bottle; the tertiary butyl dimethyl-silicon ether that adds 90 mg ginsenoside M1; the DMAP of 5% equivalent; nitrogen protection, adds appropriate methylene dichloride to dissolve and triethylamine under ice-water bath, after reaction 10 min; the decanoyl chloride that adds equivalent; tlc monitoring reaction process, 24h after completion of the reaction, adds saturated ammonium chloride solution stopped reaction.Through CH
2cl
2(3 * 10 mL) extraction, Brine washes organic phase, anhydrous Na
2sO
4dry, concentrated solvent.
Column chromatography purification process: silica gel amount, 6 g;
Moving phase, ethyl acetate/petroleum ether;
After gradient elution, obtaining Rf value is product 80 mg of 16/38 (30%EA/PE)
Product is white solid, and productive rate is about 80%
The tertiary butyl dimethyl-silicon ether of ginsenoside M1 and the single-esterification product of decanoyl chloride, Structural Identification: through infrared spectrometer, high performance liquid chromatograph, nuclear magnetic spectrogram identifies that Fig. 1 is products therefrom structural formula of compound.
3. deprotection reaction
The product of experimental example 2 is joined in the round-bottomed flask of 50 ML, with anhydrous tetrahydro furan, dissolve, add the tetrabutyl ammonium fluoride of 1.5 equivalents, after reaction 2h, stop.
The monoesters product structure formula that obtains ginsenoside M1 after post separation is shown in Fig. 2
Accompanying drawing explanation
The single-esterification product structure formula of the tertiary butyl dimethyl-silicon ether of Fig. 1 ginsenoside M1 and decanoyl chloride
The monoesters product structure formula of Fig. 2 ginsenoside M1
Embodiment
the monoether of embodiment 1 ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE is combined to
At the 25mL that magnetic stirrer is housed, stop in good gram of bottle; add 100 mg ginsenoside M1; the TERT-BUTYL DIMETHYL CHLORO SILANE of 5 times of equivalents; nitrogen protection, adds appropriate triethylamine to dissolve under ice-water bath, after reaction 10 min; rise to room temperature; tlc monitoring reaction process, 24h after completion of the reaction, adds saturated ammonium chloride solution stopped reaction.Through CH
2cl
2(3 * 10 mL) extraction, Brine washes organic phase, anhydrous Na
2sO
4dry, concentrated solvent.
Column chromatography purification process: silica gel amount, 6g; Moving phase, ethanol/methylene; After gradient elution, obtaining Rf value is 9/34 (8%MeOH/CH
2cl
2) product 109 mg products be that Off-white solid is the tertiary butyl dimethyl-silicon ether that the monoether of ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE is combined to product ginsenoside M1.
At the 25mL that magnetic stirrer is housed, stop in good gram of bottle; the tertiary butyl dimethyl-silicon ether that adds 90 mg ginsenoside M1; the DMAP of 5% equivalent; nitrogen protection, adds appropriate methylene dichloride to dissolve and triethylamine under ice-water bath, after reaction 10 min; the decanoyl chloride that adds equivalent; tlc monitoring reaction process, 24h after completion of the reaction, adds saturated ammonium chloride solution stopped reaction.Through CH
2cl
2(3 * 10 mL) extraction, Brine washes organic phase, anhydrous Na
2sO
4dry, concentrated solvent.After column chromatography purification, obtain the tertiary butyl dimethyl-silicon ether of ginsenoside M1 and the single-esterification product of decanoyl chloride.
Claims (4)
1. improve an optionally synthetic method of ginsenoside M1 and decanoyl chloride mono-esterification, reaction process is protection-ester-go to protect
Concrete grammar: first; at the 25mL that magnetic stirrer is housed, stop in good gram of bottle, add 100 mg ginsenoside M1, the TERT-BUTYL DIMETHYL CHLORO SILANE of 5 times of equivalents; nitrogen protection; under ice-water bath, add appropriate triethylamine to dissolve, after reaction 10 min, rise to room temperature; tlc monitoring reaction process; 24h after completion of the reaction, adds saturated ammonium chloride solution stopped reaction, through CH
2cl
2(3 * 10 mL) extraction, Brine washes organic phase, anhydrous Na
2sO
4dry, concentrated solvent; Column chromatography purification process: silica gel amount, 6g; Moving phase, ethanol/methylene; After gradient elution, obtaining Rf value is 9/34 (8%MeOH/CH
2cl
2) product 109 mg products be that Off-white solid is the tertiary butyl dimethyl-silicon ether that the monoether of ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE is combined to product ginsenoside M1; Secondly, at the 25mL that magnetic stirrer is housed, stop in good gram of bottle, the tertiary butyl dimethyl-silicon ether that adds 90 mg ginsenoside M1, the DMAP of 5% equivalent, nitrogen protection, under ice-water bath, add appropriate methylene dichloride to dissolve and triethylamine, react after 10 min, add the decanoyl chloride of equivalent, tlc monitoring reaction process, 24h after completion of the reaction, adds saturated ammonium chloride solution stopped reaction; Finally, through CH
2cl
2(3 * 10 mL) extraction, Brine washes organic phase, anhydrous Na
2sO
4dry, concentrated solvent, obtains the tertiary butyl dimethyl-silicon ether of ginsenoside M1 and the single-esterification product of decanoyl chloride after column chromatography purification.
2. according to claim 1; ginsenoside M1 and TERT-BUTYL DIMETHYL CHLORO SILANE are single etherification product of the synthetic ginsenoside M1 of raw material; by the decanoyl chloride of its product and equivalent at ice-water bath; nitrogen protection; methylene dichloride is solvent, and triethylamine is acid-binding agent, under the condition of DMAP catalysis, single-esterification occurs; finally with tetrabutyl ammonium fluoride, slough t-Butyldimethylsilyl, complete building-up reactions.
3. according to claim 1, in the tertiary butyl dimethyl-silicon ether of second step reaction ginsenoside M1 and the single-esterification product of decanoyl chloride, the productive rate of No. 3 position monoesters of selectivity generation reaches 80%.
4. according to claim 1, the monoesters product structure formula of ginsenoside M1 is shown in Fig. 2.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019201280A1 (en) * | 2018-04-17 | 2019-10-24 | Lee Sheau Long | Use of ginsenoside m1 for manufacturing medicament for treating oral cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880305A (en) * | 2010-06-23 | 2010-11-10 | 大连大学 | Preparation method of ginsenoside metabolin M1 fatty acid ester compound |
| CN102898495A (en) * | 2012-11-12 | 2013-01-30 | 浙江神洲药业有限公司 | Method for preparing abiraterone acetate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880305A (en) * | 2010-06-23 | 2010-11-10 | 大连大学 | Preparation method of ginsenoside metabolin M1 fatty acid ester compound |
| CN102898495A (en) * | 2012-11-12 | 2013-01-30 | 浙江神洲药业有限公司 | Method for preparing abiraterone acetate |
Non-Patent Citations (1)
| Title |
|---|
| 毛多斌 等: "葡萄糖及葡萄糖苷的生物催化选择性酯化研究进展", 《日用化学工业》, vol. 34, no. 6, 20 December 2004 (2004-12-20) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019201280A1 (en) * | 2018-04-17 | 2019-10-24 | Lee Sheau Long | Use of ginsenoside m1 for manufacturing medicament for treating oral cancer |
| CN111615393A (en) * | 2018-04-17 | 2020-09-01 | 理筱龙 | Use of ginsenoside M1 for the manufacture of a medicament for the treatment of oral cancer |
| CN111615393B (en) * | 2018-04-17 | 2023-10-10 | 理筱龙 | Application of ginsenoside M1 in preparing medicine for treating oral cancer |
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Application publication date: 20140402 |