CN102260198A - Leonurine preparation method - Google Patents
Leonurine preparation method Download PDFInfo
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- CN102260198A CN102260198A CN2010101870210A CN201010187021A CN102260198A CN 102260198 A CN102260198 A CN 102260198A CN 2010101870210 A CN2010101870210 A CN 2010101870210A CN 201010187021 A CN201010187021 A CN 201010187021A CN 102260198 A CN102260198 A CN 102260198A
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- leonurine
- syringic acid
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- 0 COc1cc(C(O)=O)cc(OC)c1* Chemical compound COc1cc(C(O)=O)cc(OC)c1* 0.000 description 6
- OVCCGNWMGBKDIZ-UHFFFAOYSA-N COc1cc(C(O)=O)cc(OC)c1OCc1ccccc1 Chemical compound COc1cc(C(O)=O)cc(OC)c1OCc1ccccc1 OVCCGNWMGBKDIZ-UHFFFAOYSA-N 0.000 description 1
- OJXMMVMHYPFHBS-UHFFFAOYSA-N COc1cc(C(OCCCCN)=O)cc(OC)c1O Chemical compound COc1cc(C(OCCCCN)=O)cc(OC)c1O OJXMMVMHYPFHBS-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to a pharmaceutical field of traditional Chinese medicines, and relates to a leonurine preparation method. The leonurine preparation method provided by the invention comprises the following steps of: selecting cheap aminobutyric acid as a raw material, conveniently synthesizing protected aminobutanol by amino protection and reduction reaction,taking a benzyl group as a protecting group of syringic acid phenolic hydroxyl group, reflowing in an ethanol-sodium hydroxide aqueous solution and crystallizing, synthesizing benzyl group protected syringic acid, performing a condensation reaction of the benzyl group protected syringic acid and the aminobutanol by adopting CDI or DCC, reducing protected leonurus amine by hydrogen under a condition of catalysis by palladium hydroxide of 10% and finally synthesizing the leonurine. The method provided by the invention avoids the preparation of leonurine by Gabriel amine preparation method in the prior art, overcomes the separation difficulty and minimizes the use of reagents that pollute the environment. The method provided by the invention has advantages of less separation process, simple operation and mild reaction, is easy to control, and can be used to synthesize leonurine in large amounts; in addition, the raw materials are easily available, the purity of the product reaches 99.8%, and the structure of the product is consistent with that of natural leonurine.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, relate to a kind of method for preparing syringic acid.delta.-guanidinobutyl ester.
Background technology
Syringic acid.delta.-guanidinobutyl ester is the alkaloid that contains in the Labiatae mother wort plant, and prior art has the bibliographical information of its extraction, separation, pharmacology and structural formula (I) thereof.Document also disclose syringic acid.delta.-guanidinobutyl ester have activate blood circulation and disperse blood clots, the effect of inducing diuresis to remove edema, be TCM Gynecology good medicine, it can suppress hematoblastic gathering, the formation of anti-hemostasis suppository; The expansion peripheral blood vessel reduces vascular resistance, has certain hypertension, reduces coronary resistance, and coronary blood flow increasing, pharmacological actions such as protection heart.
It is reported, the content of syringic acid.delta.-guanidinobutyl ester in the bulk drug Motherwort Herb is very low, at present, domestic have research group to its synthetic research, and the method for direct economy has the most: people's such as the Zhu Renfa of China, Wang Xiaoshan synthesis technique (having applied for national inventing patent).It is starting raw material that syringic acid is adopted in this research; Vinyl chloroformate is to its active carbonyl-protection, acidylate successively; reach prepared in reaction carbonylation product 4-ethoxycarbonyls such as alcoholysis-oxygen base-syringic acid (4-chlorine) butyl ester of tetrahydrofuran (THF) open loop under the Louis acid catalysis condition, acyl chlorides; committed step adopts this drop cloth riel to become the amine legal system to be equipped with intermediate Motherwort Herb amine (syringic acid (4-amino) butyl ester), at last again through preparing syringic acid.delta.-guanidinobutyl ester in a small amount with the methyl-isothiourea reaction.
The present invention is in preparation experiment before; once be prepared with reference to above-mentioned document and patented technology route; at first adopt Vinyl chloroformate that the phenolic hydroxyl group of syringic acid is protected; this reaction needed is done to react 6 hours under the alkali condition with sodium hydroxide at 0 ℃; obtain pure product through acidifying and acetone recrystallization again, yield is 72% (Scheme1.1).
Then, the syringic acid of protection generates acyl chlorides under the sulfur oxychloride effect, and under the zinc chloride existence condition, direct and tetrahydrofuran (THF) carries out the open loop alcoholysis reaction then, generates carbonylation syringic acid neoprene alcohol ester.But, this experiment final product is because a large amount of zinc salt existence, aftertreatment has difficulties, the method of reference literature, with extraction again after 5% the sodium hydroxide cancellation reaction, still, still there is following problems in the experimentation: if amount of sodium hydroxide is little, then generate the zinc hydroxide precipitation, separate very difficulty; If a large amount of sodium hydroxide adds, then there is the esterlysis reaction of product.
Therefore, in the Experiment Preparation process before the present invention, adopt following steps: after at first reaction mixture being diluted with ethyl acetate, earlier through saturated common salt water washing three times, with washings such as sodium bicarbonates, obtained carbonylation syringic acid neoprene alcohol ester (Scheme1.2) preferably again.
Then, through drop cloth riel method halohydrocarbon is converted into amino.This reaction at first with the 100 ℃ of reactions 12 hours in DMF of carbonylation syringic acid neoprene alcohol ester and potassium phthalimide, after extracting and separating, prepares Motherwort Herb amine with the hydrazine hydrate reduction again.This reactions steps usual method all is to separate Motherwort Herb amine through the working method of alkalization-acidifying-alkalization.
But, in this experimentation,, make very difficulty of aftertreatment because a large amount of by products exists and the solubility problem of Motherwort Herb amine, bring difficulty (Scheme1.3) to purifying.
Scheme1.3
At last, Motherwort Herb amine and S-methyl-isourea reacted 4 hours in 140 ℃ DMF, generated syringic acid.delta.-guanidinobutyl ester vitriol (Scheme1.4).
In sum, after the prior art relating operation improved, though can prepare the syringic acid.delta.-guanidinobutyl ester that uses for experiment in a small amount, in the preparation process, still have some aforesaid many disadvantages, then difficulty is bigger for synthesizing syringic acid.delta.-guanidinobutyl esters in a large number.
Summary of the invention
But the defective that the objective of the invention is prior art provides a kind of method for preparing syringic acid.delta.-guanidinobutyl ester, especially in a large number the method for synthetic syringic acid.delta.-guanidinobutyl ester.The inventive method can reduce uses environmental pollution reagent, processing condition facility.
In the inventive method, the operation of prior art, condition etc. are optimized, have set up the approach of the new synthetic syringic acid.delta.-guanidinobutyl ester of a cheapness, environmental protection.Particularly, the method for preparing syringic acid.delta.-guanidinobutyl ester of the present invention is characterized in that, in the building-up process, avoids becoming the amine legal system to be equipped with Motherwort Herb amine by the drop cloth riel, has solved the defective of separation difficulty.
Synthesis strategy of the present invention is shown in Scheme1.5.
The new synthesis strategy of Scheme1.5 syringic acid.delta.-guanidinobutyl ester
It is raw material that the present invention chooses cheap aminobutyric acid, through amino protection and reduction reaction, has synthesized the amino butanol (Scheme1.6) of protection very easily.
Among the present invention, choose benzyl and be the protecting group to the syringic acid phenolic hydroxyl group, this is reflected at the 6 hours post crystallizations that reflux in ethanol-aqueous sodium hydroxide solution, with the fixation acid of protecting greater than 90% yield synthesize benzyl.Then, adopt CDI or DCC to make the syringic acid and the amino butanol condensation of benzyl protection, obtain 73% yield.The Motherwort Herb amine of protection through hydrogen reducing, obtains Motherwort Herb amine (Scheme1.7) with quantitative yield under 10% palladium hydroxide catalytic condition.Adopt the method for prior art at last, synthetic syringic acid.delta.-guanidinobutyl ester.
The inventive method sepn process is few, and is easy and simple to handle, reaction temperature and, be easy to control, raw material is easy to get, the product purity height, measuring purity through efficient liquid phase chromatographic analysis is 99.8%.Present method gained syringic acid.delta.-guanidinobutyl ester is in full accord with natural syringic acid.delta.-guanidinobutyl ester through structural identification.
For the ease of understanding, below will describe in detail the present invention by specific embodiment.It needs to be noted, specific examples only is in order to illustrate, obviously those of ordinary skill in the art can illustrate according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Embodiment
Embodiment 1
Following instrument and reagent and solvent are adopted in this experiment:
Nuclear magnetic resonance analyser is a JEOL JNM.ECP nuclear magnetic resonance spectrometer; Mass spectrograph be Q.TofUltima Global (ion source: ESI, APCI, MAI, DI).All reagent and solvent are import or homemade analytical pure, and solvent is not further handled.
1, synthetic 4-ethoxycarbonyl-oxygen base-syringic acid
In the 1000ml reactor, the sodium hydroxide solution that adds the 1mol/L of 800ml, whipped state adds syringic acid 66g (0.33mol) down, after the dissolving, treat that solution temperature drops to below 10 ℃, drip Vinyl chloroformate 36.17g (0.33mol), control reaction soln temperature is at 0-10 ℃, stirring reaction 6 hours, TCL follows the tracks of level of response, after reaction finishes, transfer pH value about 6.0 with hydrochloric acid, white crystals is separated out in placement, filters, and gets the white solid acetone recrystallization, obtain the white crystalline title product of 64g through the product drying under reduced pressure, yield 72%, fusing point 180-184 ℃
1HNMR: δ H:1.33 CH
3(CH
3CH
2-), δ H:3.39 (CH
3O-), δ H:4.29-CH
2-(CH
3CH
2-), δ H:7.38 (Ar-H).
2, synthesizing carbonyl cloves acyl chlorides
(200g 0.83mol), adds fully to stir in the 400ml ethylene dichloride and makes its dissolving, and heated and stirred is to refluxing, and (154.7g 1.3mol), dropwised in one hour slowly to splash into the thionyl chloride that ethylene dichloride dilutes with constant voltage titration funnel to get the carbonylation syringic acid.Keep backflow 2h, TLC follows the tracks of.Reclaim solvent, the ether recrystallization obtains white crystal 193g, mp:78 ~ 79 ℃, and yield is 90%.If want to improve productive rate, also recrystallization not is directly used in next step reaction.
3, synthesizing carbonyl syringic acid neoprene alcohol ester
(150g 0.58mol), adds 360gTHF and solid ZnCl to get carbonylation cloves acyl chlorides
2(20g, 0.147mol), heated and stirred, temperature maintenance were reacted one and a half hours at 60 ℃, and TLC follows the tracks of.Earlier with sodium chloride aqueous solution 3 * 80mL washing, aqueous phase discarded; Use sodium bicarbonate aqueous solution 3 * 80ml washing again, aqueous phase discarded; Use methylene dichloride and water sepn again, aqueous phase discarded, the organic phase anhydrous sodium sulfate drying, suction filtration reclaims solvent, obtains the oily product, uses the sherwood oil recrystallization, and is freezing, obtains white crystals 143.4g, mp:145～14 ℃, yield 74.8%.
4, synthetic phthalimide-based-1-butanols carbonylation cloves acid esters
(165.3g 0.5mol) is dissolved among the 300ml DMF, and (111g 0.6mol) is dissolved in (DMF: H in the mixing solutions of DMF and water to get potassium phthalimide again to get carbonylation syringic acid neoprene alcohol ester
2O=4: 1), they are mixed, stirring heating remains on 100 ℃, and reaction 12h, TLC follow the tracks of reaction and carry out degree.With methylene dichloride and this reaction mixture of water sepn, aqueous phase discarded.Dichloromethane layer is with sodium bicarbonate 3 * 100ml washing, and anhydrous sodium sulfate drying spends the night, and suction filtration reclaims solvent, obtains crude product, uses recrystallizing methanol, obtains white crystal 119.4g, mp:125 ~ 127 ℃, and yield is 65.1%.
5, synthetic Motherwort Herb amine
Get 4-phthalimide-based-1-butanols ethanoyl cloves acid esters (111.2g, 0.25mol) and sodium-acetate 12g be dissolved in the 300ml ethanol, add a hydrazine hydrate of 50% (50g, 0.5mol), reaction mixture reflux 4h, TLC follows the tracks of the degree that reacts completely.Cooling, suction filtration with the suitable quantity of water washing, obtains white crystal again.White crystal is dissolved in 8% the potassium hydroxide solution, transfers to slightly acidic with dilute hydrochloric acid afterwards, transfer to neutrality with sodium bicarbonate aqueous solution again, concentrating under reduced pressure must produce incarnadine crystallization 48.6g, mp:214 ~ 215 ℃, yield 69.6%.
Or,
(4-(Benzyloxycarbonyl) the butyl 4-(benzyloxy)-3 of the Motherwort Herb amine of protection; 5-dimethoxybenzoate) (12.3 gram) and 10%Pd/C (1.25 gram) the careful anhydrous methanol 120ml that adds under nitrogen; reaction system is replaced into hydrogen then; the room temperature normal pressure feeds under the hydrogen condition and stirred 20 hours; filter through the silica gel funnel; concentrate, obtain pink Motherwort Herb amine 6.18 grams (92%).
6, synthetic syringic acid.delta.-guanidinobutyl ester
(55.80g 0.2mol) is dissolved among the DMF of 150mL, and (231g 0.25mol), is heated with stirring to 140 ℃ to the S-methyl-isourea of adding 15%, reaction 5h, TLC tracking to get Motherwort Herb amine.Reclaim solvent, add sodium chloride aqueous solution and saltout, with the sodium bicarbonate alkalization, have a large amount of crystal to separate out immediately again, put into refrigerator cold-storage, suction filtration obtains the purplish grey crystallization.Use recrystallizing methanol, obtain white crystals 40.7g, mp:214 ~ 215 ℃, purity 99.5% (HPLC normalization method), yield 65.4%.
1H-NMR(DMSO-d6)δ7.22(2H，s，H-2’，6’)，3.82(6H，s，-CH3)，9.41(1H，s，OH，4.26(2H，t，H-3，3.15(2H，H-6)，1.73(2H，H-4)，1.58(2H，H-5)ppm。
13C-NMR(DMSO-d6)δ165.4(C-7’)，156.6(C-1)，147.2(C-3’，5‘)，141.0(C-4’)，119.3(C-1)，106.2(C-2’，6’)，63.8(C-6)，56.4(C-8’，9’)，25.8(C-5)，25.4(C-4)，40.1(C-3)ppm。
7,4-benzyloxy 3,5 dibenzoic acids is synthetic
50 gram syringic acids are in the 2M sodium hydroxide of the ethanol of 100ml and 400ml after the reflux, slowly drip the sodium hydroxide solution of 400ml 5M, dropwising the back continues to reflux 4 hours, reactant cooling back concentrates, filters, the yellow thick solid that obtains is separated out white needle-like crystals 67 grams (yield 93%) through ethyl alcohol recrystallization.
8, Bao Hu Motherwort Herb amine is synthetic
4 benzyloxies 3,5-dimethoxybenzoic acid (18 gram), DMAP (8.4 gram) and DCC (14.15 gram) are dissolved in the methylene dichloride, and be cooled to 0 ℃ of stirring, disposable adding 4-benzyl 4-hydroxybutylcarbamate (16.75 gram), stir after 2 hours, rise to stirred overnight at room temperature naturally.Reactant through shrend go out and methylene dichloride dilution after, separatory, water be with dichloromethane extraction three times, merges organic phase with dilute hydrochloric acid, saturated common salt water washing, filter with the silica gel funnel dry back, concentrates, and obtains crude product 24 grams (yield 79.5%).
9, benzyloxy 4-maloyl group amine
Under the ice-water bath condition, 49g Carbobenzoxy Chloride (0.29mol) slowly joins in the 100ml 2M sodium hydroxide solution of dissolving 25 gram aminobutyric acids, be incubated and rise to room temperature continuation stirring 4 hours after 1 hour naturally, after the reactant usefulness extracted with diethyl ether 1 time, use ethyl acetate extraction 3 times after the aqueous phase as acidified, dry concentrating obtains white solid carboxylic acid crude product 53 grams.Thick midbody product is dissolved in (53g) is dissolved in the tetrahydrofuran (THF) (400ml), be cooled to 0 ℃, add NMM (24ml) to dissolving, after stirring 10min, drip Vinyl chloroformate (22ml), behind the stirring 10min, quick suction filtration, and filtrate is cooled to 0 ℃, add NaBH in batches
4(8.49g) the slow methyl alcohol (400ml) that drips in back is emitted a large amount of gases, finishes, and continues to stir after 1 hour to concentrate, and residuum extracts (150ml * 3) through EtOAc, saturated NaCl washing (150ml * 3), anhydrous Na
2SO
4Dry back concentrates and obtains white solid product (40.1g, 81%).
Claims (3)
1. a method for preparing syringic acid.delta.-guanidinobutyl ester is characterized in that, adopts the synthetic route shown in the Scheme1.5, in the building-up process, avoid becoming the amine legal system to be equipped with Motherwort Herb amine by the drop cloth riel,
2. by the described method of claim 1, it is characterized in that in this method, selecting aminobutyric acid for use is raw material, through amino protection and reduction reaction, the amino butanol shown in the Scheme1.6 of synthetic protection,
3. by the described method of claim 1, it is characterized in that, comprise in this method: selecting benzyl for use is protecting group to the syringic acid phenolic hydroxyl group, and this is reflected at the 6 hours post crystallizations that reflux in ethanol-aqueous sodium hydroxide solution, with the fixation acid greater than 90% yield synthesize benzyl protection; Then, adopt CDI or DCC to make the syringic acid and the amino butanol condensation of benzyl protection, obtain 73% yield; The Motherwort Herb amine of protection through hydrogen reducing, obtains the Motherwort Herb amine shown in the Scheme1.7 with quantitative yield under 10% palladium hydroxide catalytic condition, synthetic at last syringic acid.delta.-guanidinobutyl ester,
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659638A (en) * | 2012-04-11 | 2012-09-12 | 董小平 | Synthetic method of leonurine |
| CN102659639A (en) * | 2012-04-11 | 2012-09-12 | 董小平 | Preparation technology of leonurine |
| CN105481724A (en) * | 2015-12-11 | 2016-04-13 | 安徽省科学技术研究院 | Method for synthesizing leonurine |
| CN106866464A (en) * | 2017-03-20 | 2017-06-20 | 绵阳市润土农业科技开发有限公司 | A kind of synthetic method of leonurine |
| CN113603570A (en) * | 2021-09-28 | 2021-11-05 | 潍坊科技学院 | Leonurine borneol derivative, preparation method and application thereof |
| US11446270B2 (en) * | 2017-10-23 | 2022-09-20 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co., Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
-
2010
- 2010-05-28 CN CN2010101870210A patent/CN102260198A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 刘新华: "益母草碱的合成及其对心血管保护作用的研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659638A (en) * | 2012-04-11 | 2012-09-12 | 董小平 | Synthetic method of leonurine |
| CN102659639A (en) * | 2012-04-11 | 2012-09-12 | 董小平 | Preparation technology of leonurine |
| CN102659638B (en) * | 2012-04-11 | 2014-03-12 | 杭州和正医药有限公司 | Synthetic method of leonurine |
| CN105481724A (en) * | 2015-12-11 | 2016-04-13 | 安徽省科学技术研究院 | Method for synthesizing leonurine |
| CN106866464A (en) * | 2017-03-20 | 2017-06-20 | 绵阳市润土农业科技开发有限公司 | A kind of synthetic method of leonurine |
| CN106866464B (en) * | 2017-03-20 | 2018-08-10 | 绵阳市润土农业科技开发有限公司 | A kind of synthetic method of leonurine |
| US11446270B2 (en) * | 2017-10-23 | 2022-09-20 | Zhuhai Hengqin New District Zhongzhu Zhengtai Medical Management Co., Ltd. | Leonurine crystal and use thereof in preparation of insulin sensitizer, hypoglycemic drug and lipid-lowering drug |
| CN113603570A (en) * | 2021-09-28 | 2021-11-05 | 潍坊科技学院 | Leonurine borneol derivative, preparation method and application thereof |
| CN113603570B (en) * | 2021-09-28 | 2022-02-11 | 潍坊科技学院 | Leonurine borneol derivative, preparation method and application thereof |
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Application publication date: 20111130 |