CN1415602A - Method for synthesizing leonurine - Google Patents
Method for synthesizing leonurine Download PDFInfo
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- CN1415602A CN1415602A CN 02138364 CN02138364A CN1415602A CN 1415602 A CN1415602 A CN 1415602A CN 02138364 CN02138364 CN 02138364 CN 02138364 A CN02138364 A CN 02138364A CN 1415602 A CN1415602 A CN 1415602A
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- syringic acid
- delta
- ethoxycarbonyl
- ester
- guanidinobutyl
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Abstract
A process for synthesizing the leonurine from syringic acid as initial raw material includes such steps as carbonylation reaction, acylchlorination reaction, esterification reaction, ammonification reaction to obtain leonuriamine, and reacting with methylisothiourea. Its advantages are simple operation, easy control, high output rate, and high purity (99.8%).
Description
One, technical field
The present invention relates to a kind of artificially preparation method of natural alkaloid, exactly is the synthetic method of syringic acid.delta.-guanidinobutyl ester.
Two, background technology
Motherwort Herb is the dry aerial parts of labiate Motherwort Herb Leonurns heterophyllus Sweet, is the herbal species that Chinese Pharmacopoeia records, and is gynaecology's Chinese medicine commonly used clinically, and effects such as the stasis of blood have menstruation regulating, invigorate blood circulation and dispel.Its part that plays a role is an alkaloid, and alkaloid mainly contains syringic acid.delta.-guanidinobutyl ester and stachydrine, and document shows that syringic acid.delta.-guanidinobutyl ester (C14H21O5N3) has excitation to the uterus, is the main component that Motherwort Herb plays a role, and its effect is identical with motherwort formulation.Nineteen thirty, syringic acid.delta.-guanidinobutyl ester was separated from Motherwort Herb first, studies show that syringic acid.delta.-guanidinobutyl ester is the guanidine radicals alcohol ester of syringic acid, and syringic acid.delta.-guanidinobutyl ester is dissolving hardly in water, and mainly the form with hydrochloride exists in plant.
Studies show that syringic acid.delta.-guanidinobutyl ester content in plant is very low, below 0.1%, the extraction separation difficulty is big, the cost height, and formulations such as the Herba Leonuri paste of mainly making with the crude extract of Motherwort Herb, YIMUCAO CHONGJI are used clinically, and patient's taking dose is big, is difficult to accept.
Adopt the synthetic mode to prepare syringic acid.delta.-guanidinobutyl ester, and be made into the acceptable formulation of patient, help syringic acid.delta.-guanidinobutyl ester further investigation and development.
" Acta Pharmaceutica Sinica " (19 (6): 419～424,1984) a kind of method of synthesizing syringic acid.delta.-guanidinobutyl ester with methyl-isothiourea in DMF with Motherwort Herb amine is disclosed, but the unexposed Motherwort Herb amine that how to obtain.
" Tetrahedron " (25:5155,1969) disclose three kinds of synthetic methods of syringic acid.delta.-guanidinobutyl ester: (1) is that raw material obtains 4-phthalimide-based-1-butanols with 4-chloro-1-butanols, again with 4-ethoxycarbonyl-oxygen base-3,5-dimethoxy-benzoic acid is made Motherwort Herb amine, connects guanidine radicals at last and generates syringic acid.delta.-guanidinobutyl ester; (2) with 4-ethoxycarbonyl-oxygen base-3,5-dimethoxy-Benzoyl chloride be starting raw material through fatization, connect guanidine radicals again and generate syringic acid.delta.-guanidinobutyl ester; (3) be the synthetic syringic acid.delta.-guanidinobutyl ester of starting raw material with 4 amino-butanols.Above various preparation method's starting raw materials are not easy to obtain, and reaction conditions requires high.
Three, summary of the invention
The present invention is starting raw material with the syringic acid, prepares intermediate Motherwort Herb amine successively behind carbonylation, chloride, esterification and aminating reaction, and last Motherwort Herb amine is with the synthetic syringic acid.delta.-guanidinobutyl ester of methyl-isothiourea.
Specific embodiment is as follows:
Syringic acid is carbonylation at first; with its unusual active hydroxyl protection get up (syringic acid of calling carbonylation in the following text is A); after with the A chloride; boil off behind the acyl chlorinating agent promptly with tetrahydrofuran (THF) prepared in reaction carbonylation product 4-ethoxycarbonyl-oxygen base-syringic acid (4-chlorine) butyl ester (to call B in the following text); B obtains intermediate Motherwort Herb amine (syringic acid (4-amino) butyl ester with phthalic imidine salt and hydrazine hydrate reaction more successively; to call C in the following text), last C obtains product syringic acid.delta.-guanidinobutyl ester (to call D in the following text) with the methyl-isothiourea reaction.
Present 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 liquid-phase chromatographic analysis is 99.81%, the product yield height, four step chemical reactions, yield reaches 20%.
The syringic acid.delta.-guanidinobutyl ester of present method gained is in full accord with natural syringic acid.delta.-guanidinobutyl ester through result's conclusive evidence.1. syringic acid.delta.-guanidinobutyl ester solubility experiment
Get syringic acid.delta.-guanidinobutyl ester 5g, add water 50ml, stir into suspension solution, Dropwise 5 % hydrochloric acid soln is an amount of, dissolving, and it is an amount of slowly to add 5% sodium hydroxide solution, to white occurring, the sodium hydroxide solution that continues Dropwise 5 % is separated out white precipitate fully, filters, wash with water, 80 ℃ of drying under reduced pressure 3 hours, the white solid thing, this white solid thing is carried out infrared absorption spectrometry, the gained data are compared with syringic acid.delta.-guanidinobutyl ester, and both are in full accord as a result.
Above experimental result shows the easy and sour salify of syringic acid.delta.-guanidinobutyl ester, and its salt is easily dissolving in water.2. drug effect and toxicological experiment
Effect to the uterus: this product all is excitation to tame rabbit uterus, to unpregnancy, early pregnancy, the uterus in late pregnancy or postpartum is all effective, because syringic acid.delta.-guanidinobutyl ester is difficult for dissolving in water, so be that syringic acid.delta.-guanidinobutyl ester is dissolved with an amount of acid at the trial, example hydrochloric acid, test again, the test of pesticide effectiveness of syringic acid.delta.-guanidinobutyl ester adopts the syringic acid.delta.-guanidinobutyl ester hydrochloride to carry out so, the result shows its effect to the uterus, in the dosage range of 0.1～0.2mcg/ml, be the dose-dependently relation by syringic acid.delta.-guanidinobutyl ester calculating, dosage reaches maximum effect when surpassing 0.2mcg/ml, is lasting excitation.
Acute toxicity effect: irritate the LD that stomach gives mouse leonurine salt (calculating according to syringic acid.delta.-guanidinobutyl ester)
50Be 2452.8 ± 135.2mg/kg; Vein gives the LD of mouse leonurine salt (calculating according to syringic acid.delta.-guanidinobutyl ester)
50Be 601.2 ± 45.1mg/kg.
Four, embodiment 1. prepares A (4-ethoxycarbonyl-oxygen base-syringic acid) by syringic acid through carbonylation reaction
In the reactor of 1000ml, 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 reduces to below 10 ℃, drip Vinyl chloroformate 36.17g (0.33mol), control reaction soln temperature is at 0～10 ℃, stirring reaction 6 hours after reaction finishes, is regulated about pH value to 6.0 with hydrochloric acid soln, white crystals is separated out in placement, overanxious, get white solid, use acetone recrystallization, the product drying under reduced pressure is obtained the white crystalline title product of 64g, yield 72%, 180～184 ℃ of fusing points
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).
Chemical equation:
2. prepare B (4-ethoxycarbonyl-oxygen base-syringic acid (4-chlorine) butyl ester) through chloride and esterification successively by A
In the exsiccant reaction flask, add 4-ethoxycarbonyl-oxygen base-syringic acid 135.1g (0.5mol) and 109.4ml (1.5mol) sulfur oxychloride, 60～70 ℃ of backflows are after 1 hour, 60 ℃ of sulfur oxychlorides that underpressure distillation is excessive, add tetrahydrofuran (THF) 60ml, Zinc Chloride Anhydrous 10.8g fully stirs, and is heated to 80～90 ℃, make the zinc chloride dissolving, reacted 30～60 minutes, and in solution, added 100ml benzene, 5% sodium chloride solution, fully stir, Separation of Benzene solution adds anhydrous sodium sulfate dehydration, filters, solvent benzol is removed in underpressure distillation, and getting oily mater is title product.
Chemical equation:
3. prepare intermediate Motherwort Herb amine C (syringic acid (4-amino) butyl ester) by B through amination
Get 4-ethoxycarbonyl-oxygen base-syringic acid (4-chlorine) butyl ester 79g (0.22mol) in flask, add DMF 400ml, potassium phthalimide 45.5g (0.25mol), 90～110 ℃ of stirring reactions 2 hours, add hydrazine hydrate, sodium-acetate 20g, 95% ethanol 800ml refluxed 3 hours, concentrate, crystallization is separated out in cooling, filters, and crystal washes with water, and it is dissolved in 5% the sodium hydroxide solution, the hcl acidifying that adds 2mol/L filters, and filtrate is transferred between pH to 8～10 with 10% sodium bicarbonate aqueous solution, separate out crystallization, get solids 45.5g, yield 53.7%, fusing point: 209～211 ℃.
Chemical equation:
4. the product syringic acid.delta.-guanidinobutyl ester is synthetic
Syringic acid (4-amino) fourth fat 27g (0.1mol) is dissolved in the DMF solution of heat, adds the hydrochloride methyl isothiourea aqueous solution of 200ml 20% again, refluxed 4 hours, cooling, placed 3 hours for 4 ℃, separate out crystallization, filter, get the hydrochloride that solids is syringic acid.delta.-guanidinobutyl ester,, be dissolved in 10% sodium hydroxide solution the syringic acid.delta.-guanidinobutyl ester hydrochloride, room temperature is placed, and separates out crystallization, filters, get syringic acid.delta.-guanidinobutyl ester, ethyl alcohol recrystallization, drying, get crystal 14.3g, yield is 43.7%, and fusing point is 167～169 ℃.
Chemical equation:
Three, syringic acid.delta.-guanidinobutyl ester purity testing
The high performance liquid phase test experience
Chromatographic condition:
Chromatographic instrument: Shimadzu LC-10AT
Detector: Shimadzu SPD-10AVP
Chromatographic column: VP-ODS 150L * 4.6
Measure wavelength: 254nm
Moving phase: 0.025mol/L phosphoric acid solution (pH:3.5): acetonitrile=85: 15,
Flow velocity: 1.0ml/min
Sample size: 20 μ g/ml
It is an amount of that precision takes by weighing this product, adds the moving phase dissolving and make the solution that contains syringic acid.delta.-guanidinobutyl ester 0.2mg among every 1ml, as need testing solution; Precision is measured 1ml, puts in the 100ml measuring bottle, adds moving phase and is diluted to scale, shakes up, and solution is got contrast solution 20ul in contrast, injects liquid chromatograph, regulates detection sensitivity, and the peak height that makes principal constituent is the 10-20% of full range; Get need testing solution 20ul, inject liquid chromatograph, the record color atlas is compared with contrast solution to 2 times of principal constituent peak retention time, and the area summation of each impurity peaks must not be greater than the main peak area (1.0%) of contrast solution.Measuring this product purity is 99.81%.
Claims (1)
1, a kind of synthetic method of syringic acid.delta.-guanidinobutyl ester comprises the raw material syringic acid successively through carbonylation, chloride, and esterification and aminating reaction obtain Motherwort Herb amine, obtain syringic acid.delta.-guanidinobutyl ester with methyl-isothiourea is synthetic again, are characterised in that:
(1) described carbonylation reaction is that syringic acid and Vinyl chloroformate reacted 3～8 hours under 0～10 ℃ of condition in sodium hydroxide solution, and last pH value to 3～7 separate obtaining 4-ethoxycarbonyl syringic acid;
(2) described chloride and esterification are that 4-ethoxycarbonyl-syringic acid refluxed in excessive sulfur oxychloride 0.5～1.5 hour, slough excessive sulfur oxychloride 50～80 ℃ of underpressure distillation then, add tetrahydrofuran (THF) and Zinc Chloride Anhydrous again, after stirring, under 70～90 ℃ of conditions, reacted 0.5～1 hour, cooling separates obtaining 4-ethoxycarbonyl-syringic acid (4 chlorine) butyl ester;
(3) described aminating reaction is that 4-ethoxycarbonyl-syringic acid (4 chlorine) butyl ester and potassium phthalimide are dissolved in the DMF solution, under 90～110 ℃ of conditions, reacted 1～3 hour, added hydrazine hydrate, sodium-acetate and alcohol reflux then 3 hours, refrigerated separation obtains intermediate Motherwort Herb amine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021383642A CN1179943C (en) | 2002-09-26 | 2002-09-26 | Method for synthesizing leonurine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021383642A CN1179943C (en) | 2002-09-26 | 2002-09-26 | Method for synthesizing leonurine |
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| CN1415602A true CN1415602A (en) | 2003-05-07 |
| CN1179943C CN1179943C (en) | 2004-12-15 |
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Cited By (5)
| 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 |
| CN103086926A (en) * | 2011-10-27 | 2013-05-08 | 复旦大学 | Preparation method for leonurine and derivatives thereof |
| CN105481724A (en) * | 2015-12-11 | 2016-04-13 | 安徽省科学技术研究院 | Method for synthesizing leonurine |
| CN108840808A (en) * | 2018-06-13 | 2018-11-20 | 北京合力众盈医药科技有限责任公司 | A kind of leonurine derivative, preparation method and its usage |
-
2002
- 2002-09-26 CN CNB021383642A patent/CN1179943C/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086926A (en) * | 2011-10-27 | 2013-05-08 | 复旦大学 | Preparation method for leonurine and derivatives thereof |
| 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 |
| CN108840808A (en) * | 2018-06-13 | 2018-11-20 | 北京合力众盈医药科技有限责任公司 | A kind of leonurine derivative, preparation method and its usage |
| CN108840808B (en) * | 2018-06-13 | 2020-12-11 | 北京合力众盈医药科技有限责任公司 | Leonurine derivative, preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN1179943C (en) | 2004-12-15 |
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Application publication date: 20030507 Assignee: JINGDE XINXING BIOLOGY TECHNOLOGY Co.,Ltd. Assignor: Li Xiaoxiang Contract record no.: 2018340000011 Denomination of invention: Method for synthesizing leonurine Granted publication date: 20041215 License type: Exclusive License Record date: 20180628 |
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Granted publication date: 20041215 |