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CN103833821A - A kind of synthetic method of 3-succinic acid-30-stearyl glycyrrhetinate - Google Patents

A kind of synthetic method of 3-succinic acid-30-stearyl glycyrrhetinate Download PDF

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CN103833821A
CN103833821A CN201410114390.5A CN201410114390A CN103833821A CN 103833821 A CN103833821 A CN 103833821A CN 201410114390 A CN201410114390 A CN 201410114390A CN 103833821 A CN103833821 A CN 103833821A
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glycyrrhetinic acid
silica gel
stearyl alcohol
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王秀丽
徐昕
王鹏龙
廖艳
赵保胜
李耿
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Abstract

The invention discloses an improved synthesis method of 3-succinic acid-30-stearyl alcohol glycyrrhetinic acid ester. The method takes glycyrrhetinic acid, stearyl alcohol and succinic anhydride as initial raw materials, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride is taken as a condensing agent in the first-step condensation reaction, byproducts can be washed away by water conveniently, the purification process is simplified, and the yield can be obviously improved after a small amount of 4-dimethylaminopyridine is added; in the second step, tetrahydrofuran is used as a solvent, and the reaction is carried out in a reflux state, so that the reaction conditions are simplified, and the reaction yield is improved.

Description

A kind of 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester synthetic method
Technical field
The present invention relates to a kind of synthetic method of liver target part, relate in particular to a kind of 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester novel synthesis.
Background technology
3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester, CA registration number is 952185-09-0, molecular structural formula is as follows:
Figure BSA0000102322700000011
3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester is the part with liver targeting, on drug delivery system, can significantly improve the avidity with hepatic parenchymal cells, promote the probability that particle is absorbed by hepatic parenchymal cells, and then be conducive to medicine in intracellular release, improve drug bioavailability, drug targeting is brought into play to pharmacological action in hepatic parenchymal cells, realize " initiatively target " to hepatic parenchymal cells, be better than the conventional liposome of passive target, can avoid being engulfed by Hepatic nonparenchymal cell, thus the target rate of raising liposome.
About the chemical synthesis process of 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester, related data has been reported two kinds of different synthetic methods both at home and abroad, all to prepare key intermediate 30-stearyl alcohol glycyrrhetinic acid ester taking stearyl alcohol as raw material by condensation reaction, then by becoming ester to prepare the finished product with succinyl oxide.Synthetic route is mainly following two kinds:
Pharmazie, 2007,62 (9): 14-619 and CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2003,28 (4), it is condensing agent that 328-331 adopts dicyclohexylcarbodiimide, cuprous chloride catalysis, the condensation in DMF solvent of glycyrrhetinic acid and stearyl alcohol, obtains intermediate 30-stearyl alcohol glycyrrhetinic acid ester through column chromatography purification, mix in pyridine with succinyl oxide again, under microwave, react, obtain final compound through column chromatography purification, total recovery 42%.This route operation steps complexity, reaction process needs condensing agent to participate in, and reaction waste is many, and total recovery is general.
Pharmacy and clinical study, 2011,19 (3): it is condensing agent that 207-210 adopts dicyclohexylcarbodiimide equally, prepare intermediate 30-stearyl alcohol glycyrrhetinic acid ester with DMAP as catalyzer, mix in pyridine with succinyl oxide again, after reacting by heating, recrystallization obtains final product, total recovery 7-6%.This route total recovery is low, is not suitable for industrial production.
By the synthesis technique of 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester is carried out to deep research, a kind of simple and effective method for improving synthesis process is provided, overcome prior art yield not high, operational path complexity, complex operation, the many defects of reaction waste, total recovery exceedes 60%, is more beneficial to suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of method for improving synthesis process of 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester.
The invention provides a kind of synthetic method of 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester, react as follows:
Figure BSA0000102322700000021
A kind of method that the object of this invention is to provide synthetic 3-succsinic acid-30-stearyl alcohol glycyrrhetinic acid ester, comprises the following steps:
Step 1: glycyrrhetinic acid, stearyl alcohol are dissolved in DMF, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, DMAP, react under room temperature; Rotary evaporation (oil pump) is removed most of DMF, and remaining oily matter adds water, dichloromethane extraction; Organic phase saturated common salt water washing, anhydrous sodium sulfate drying; Add silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains glycyrrhetinic acid octadecane ester;
Step 2: glycyrrhetinic acid octadecane ester is dissolved in anhydrous tetrahydro furan, adds succinyl oxide, reflux under nitrogen protection; Reaction solution is cooled to room temperature, adds saturated sodium bicarbonate solution, vigorous stirring.Ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying; Add silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains succsinic acid glycyrrhetinic acid octadecane ester.
In preferred embodiments, wherein described in step 1, reacting material ratio glycyrrhetinic acid: stearyl alcohol: 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride=1: 1.3～1-5: 1-1～1-3 (mol ratio).
In preferred embodiments, wherein described in step 1, the anti-reaction times is generally 14 hours～and 20 hours, preferably 15～17 hours.
In preferred embodiments,, wherein described in step 2,30-stearyl alcohol glycyrrhetinic acid ester: succinyl oxide=1: 1-3～1-7 (mol ratio).
In preferred embodiments, wherein described in step 2, the reaction times is generally 6 hours～and 10 hours, preferably 7 hours～9 hours.
In preferred embodiments, wherein, described in step 2, be down to after completion of the reaction room temperature, add alkali lye to stir 10 hours～14 hours.
In preferred specific embodiments, method of the present invention comprises the following steps:
Step 1: glycyrrhetinic acid, stearyl alcohol are dissolved in to N, in dinethylformamide, add condensing agent 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, catalyzer DMAP, reacting material ratio glycyrrhetinic acid: stearyl alcohol: condensing agent: catalyzer=1: 1: 1-3: 0-1 (mol ratio); Under room temperature, react; Rotary evaporation (oil pump) is removed most of DMF, and remaining oily matter adds water, dichloromethane extraction; Organic phase saturated common salt water washing, anhydrous sodium sulfate drying; Add silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains glycyrrhetinic acid octadecane ester.
Step 2: glycyrrhetinic acid octadecane ester is dissolved in anhydrous tetrahydro furan, adds succinyl oxide, reacting material ratio glycyrrhetinic acid octadecane ester: succinyl oxide=1: 1 (mol ratio); Under nitrogen protection, reflux; Reaction solution is cooled to room temperature, adds saturated sodium bicarbonate solution, vigorous stirring; Ethyl acetate extraction, organic phase saturated common salt water washing, anhydrous sodium sulfate drying; Add silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains succsinic acid glycyrrhetinic acid octadecane ester.
The invention has the advantages that:
One, the reagent that the first step condensation adopted in reaction process is in the past DMF, and the by-product of dicyclohexylurea of generation can not be removed very easily, and productive rate is not high yet, only has very small amount of product to generate; The present invention is using 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride as condensing agent, by product can wash with water away very easily, simplify purge process, and after adding a small amount of DMAP, can obviously improve productive rate.
Two, second step uses pyridine as solvent in reaction process in the past, and under the condition of conventional heating or microwave, in the present invention, second step is made solvent with tetrahydrofuran (THF), under reflux state, reacts, and has simplified reaction conditions.
Three, make reaction be easy to carry out through synthetic method of the present invention, greatly improved reaction yield (total recovery exceedes 60%) simultaneously.
Brief description of the drawings
Below, describe by reference to the accompanying drawings embodiment of the present invention in detail, wherein:
Fig. 1 succsinic acid glycyrrhetinic acid octadecane ester nuclear magnetic spectrogram (H spectrum)
Fig. 2 succsinic acid glycyrrhetinic acid octadecane ester nuclear magnetic spectrogram (C spectrum)
Embodiment
Following examples are to further illustrate of the present invention, but never limit the scope of the present invention.Further elaborate the present invention below with reference to embodiment, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modify the present invention according to description of the invention, but these all will comprise within the scope of the invention.
embodiment 1
By glycyrrhetinic acid 470mg (1mmol), stearyl alcohol 270-5mg (1mmol) is dissolved in 40mLN, in dinethylformamide, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 249mg (1-3mmol), DMAP 13mg (0-1mmol), reacts under room temperature 16 hours.Rotary evaporation (oil pump) is removed most of DMF, and remaining oily matter adds 50mL water, dichloromethane extraction (50mL*3).30mL saturated common salt water washing for organic phase, anhydrous sodium sulfate drying.Add 3g silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains glycyrrhetinic acid octadecane ester 477mg (0-62mmol).Glycyrrhetinic acid octadecane ester 477mg (0-62mmol) is dissolved in 20mL anhydrous tetrahydro furan, adds succinyl oxide 62mg (0-62mmol), under nitrogen protection, reflux 8 hours.Reaction solution is cooled to room temperature, adds 20mL saturated sodium bicarbonate solution, vigorous stirring 12 hours.Ethyl acetate extraction (20mL*3), 30mL saturated common salt water washing for organic phase, anhydrous sodium sulfate drying.Add 3g silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains succsinic acid glycyrrhetinic acid octadecane ester 469mg (0-57mmol, overall yield 67%).
the checking of compound:mp:168-8-170.1 DEG C. 1H?NMR(400MHz，CDCl 3)δ5.61(s，1H，=CH-)，4.59-4.55(m，1H，O-CH-)，4.13-4.09(m，2H，O-CH 2-)，2.85-2.80?(m，1H)，2.72-2.66(m，4H，-CH 2CH 2-)，2.38(s，1H)，1.40(s，3H，-CH 3)，1.27(brs，35H)，1.18(s，3H，-CH 3)，1.16(s，3H，-CH 3)，1.14(s，3H，-CH 3)，0.90(s，6H，-CH 3×2)，0.82(s，3H，-CH 3)，2.15-0.82(m，21H)。
13C?NMR(100MHz，CDCl 3)δ200.01,177.51,176.51,171.82,169.34,128.49,81.24,64.84,64.19,55.78,48.31,45.40,44.00,40.65,38.85,38.11,38.76,36.95,32.79,31.93,31.83,31.69,29.70,29.64,29.57,29.53,29.36,29.19,28.72,28.56,28.00,26.41,25.98,23.41,23.36,22.69,19.70,16.70,16.38.16.32,14.18.
embodiment 2
By glycyrrhetinic acid 4.7g (10mmol), stearyl alcohol 2.7g (10mmol) is dissolved in 300mL N, in dinethylformamide, add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride 2.5g (13mmol), DMAP 122mg (1mmol), reacts under room temperature 16 hours.Rotary evaporation (oil pump) is removed most of DMF, and remaining oily matter adds 500mL water, dichloromethane extraction (500mL*3).300mL saturated common salt water washing for organic phase, anhydrous sodium sulfate drying.Add 15g silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains glycyrrhetinic acid octadecane ester 4.7g (6.5mmol).Glycyrrhetinic acid octadecane ester 4.7g (6.5mmol) is dissolved in 200mL anhydrous tetrahydro furan, adds succinyl oxide 700mg (7mmol), under nitrogen protection, reflux 8 hours.Reaction solution is cooled to room temperature, adds 30mL saturated sodium bicarbonate solution, vigorous stirring 12 hours.Ethyl acetate extraction (300mL*3), 300mL saturated common salt water washing for organic phase, anhydrous sodium sulfate drying.Add 10g silica gel, rotary evaporation is mixed sample, and silica gel column chromatography separates and obtains succsinic acid glycyrrhetinic acid octadecane ester 5.0g (6.1mmol, overall yield 61%).
the checking of compound:mp:168.8-170.1 DEG C. 1H?NMR(400MHz，CDCl 3)δ5.61(s，1H，=CH-)，4.59-4.55(m，1H，O-CH-)，4.13-4.09(m，2H，O-CH 2-)，2.85-2.80(m，1H)，2.72-2.66(m，4H，-CH 2CH 2-)，2.38(s，1H)，1.40(s，3H，-CH 3)，1.27(brs，35H)，1.18(s，3H，-CH 3)，1.16(s，3H，-CH 3)，1.14(s，3H，-CH 3)，0.90(s，6H，-CH 3×2)，0.82(s，3H，-CH 3)，2.15-0.82(m，21H)。
13C?NMR(100MHz，CDCl 3)δ200.01,177.51,176.51,171.82,169.34,128.49,81.24,64.84,64.19,55.78,48.31,45.40,44.00,40.65,38.85,38.11,38.76,36.95,32.79,31.93,31.83,31.69,29.70,29.64,29.57,29.53,29.36,29.19,?28.72,28.56,28.00,26.41,25.98,23.41,23.36,22.69,19.70,16.70,16.38.16.32,14.18。

Claims (6)

1.一种合成3-琥珀酸-30-硬脂醇甘草次酸酯的方法，其特征在于包括以下步骤：1. a method for synthesizing 3-succinic acid-30-stearyl glycyrrhetinate, is characterized in that comprising the following steps: 步骤一：将甘草次酸、硬脂醇溶解于N,N-二甲基甲酰胺中，加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、4-二甲氨基吡啶，室温下反应；旋转蒸发(油泵)除去大部分N,N-二甲基甲酰胺，残余油状物加入水，二氯甲烷萃取；有机相用饱和食盐水洗涤，无水硫酸钠干燥；加入硅胶，旋转蒸发拌样，硅胶柱色谱分离得到甘草次酸十八烷酯；Step 1: Dissolve glycyrrhetinic acid and stearyl alcohol in N,N-dimethylformamide, add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4- Dimethylaminopyridine, react at room temperature; rotary evaporation (oil pump) removes most of N,N-dimethylformamide, add water to the residual oil, extract with dichloromethane; wash the organic phase with saturated brine, anhydrous sodium sulfate Drying; adding silica gel, rotary evaporating and mixing samples, silica gel column chromatography separation to obtain octadecyl glycyrrhetinate; 步骤二：将甘草次酸十八烷酯溶解于无水四氢呋喃中，加入琥珀酸酐，氮气保护下回流；反应液冷却至室温，加入饱和碳酸氢钠溶液，剧烈搅拌。乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥；加入硅胶，旋转蒸发拌样，硅胶柱色谱分离得到琥珀酸甘草次酸十八烷酯。Step 2: dissolving octadecyl glycyrrhetinate in anhydrous tetrahydrofuran, adding succinic anhydride, and refluxing under nitrogen protection; cooling the reaction solution to room temperature, adding saturated sodium bicarbonate solution, and vigorously stirring. Extract with ethyl acetate, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate; add silica gel, mix the sample by rotary evaporation, and separate by silica gel column chromatography to obtain octadecyl glycyrrhetinate succinate. 2.如权利要求1所述的方法，其中步骤一中所述，反应物料比甘草次酸：硬脂醇：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐=1∶1.3～1.5∶1.1～1.3(摩尔比)。2. The method as claimed in claim 1, wherein said in step 1, the reaction mass ratio glycyrrhetinic acid: stearyl alcohol: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt Salt of salt=1:1.3～1.5:1.1～1.3 (molar ratio). 3.如权利要求1-2任一项所述的方法，其中步骤一中所述，反反应时间一般为14小时～20小时，优选15～17小时。3. The method according to any one of claims 1-2, wherein in step 1, the reaction time is generally 14 hours to 20 hours, preferably 15 to 17 hours. 4.如权利要求1-3任一项所述的方法，其中步骤二中所述，30-硬脂醇甘草次酸酯：琥珀酸酐=1∶1.3～1.7(摩尔比)。4. The method according to any one of claims 1-3, wherein said in step 2, 30-stearyl glycyrrhetinate:succinic anhydride=1:1.3-1.7 (molar ratio). 5.如权利要求1-4任一项所述的方法，其中步骤二中所述，反应时间一般为6小时～10小时，优选7小时～9小时。5. The method according to any one of claims 1-4, wherein in step 2, the reaction time is generally 6 hours to 10 hours, preferably 7 hours to 9 hours. 6.如权利要求1-5任一项所述的方法，其中步骤二中所述，反应完毕后降至室温，加入碱液搅拌10小时～14小时。6. The method according to any one of claims 1-5, wherein as described in step 2, after the reaction is completed, the reaction is cooled down to room temperature, and lye is added and stirred for 10 hours to 14 hours.
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CN105968163A (en) * 2016-05-24 2016-09-28 江苏耐雀生物工程技术有限公司 Preparation method and intermediate of stearyl glycyrrhetinate
CN110028544A (en) * 2019-05-05 2019-07-19 湖南中医药大学 11- deoxy-glycyrrhetinic acid tristearin alcohol ester, derivative, cantharidin liposome, preparation method and application
CN110776550A (en) * 2019-11-28 2020-02-11 广东工业大学 C3 and C20 double-esterified glycyrrhetinic acid derivative and preparation method and application thereof

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CN105968163A (en) * 2016-05-24 2016-09-28 江苏耐雀生物工程技术有限公司 Preparation method and intermediate of stearyl glycyrrhetinate
CN110028544A (en) * 2019-05-05 2019-07-19 湖南中医药大学 11- deoxy-glycyrrhetinic acid tristearin alcohol ester, derivative, cantharidin liposome, preparation method and application
CN110028544B (en) * 2019-05-05 2022-01-04 湖南中医药大学 11-deoxy glycyrrhetinic acid stearyl ester, derivative, cantharidin liposome, preparation method and application
CN110776550A (en) * 2019-11-28 2020-02-11 广东工业大学 C3 and C20 double-esterified glycyrrhetinic acid derivative and preparation method and application thereof

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