CN104876828A - Method for synthesizing synephrine, its hydrochloride and tartrate - Google Patents
Method for synthesizing synephrine, its hydrochloride and tartrate Download PDFInfo
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- CN104876828A CN104876828A CN201510140201.6A CN201510140201A CN104876828A CN 104876828 A CN104876828 A CN 104876828A CN 201510140201 A CN201510140201 A CN 201510140201A CN 104876828 A CN104876828 A CN 104876828A
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- synephrine
- tartrate
- hydrochloride
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Abstract
The invention provides a method for synthesizing synephrine, its hydrochloride thereof and tartrate. The method comprises the steps of (1) preparing phenol acetate; (2) preparing parahydroxyacetophenone; (3) preparing 2-Br-1-(4-hydroxyphenyl) butanone; (4) preparing 2-methyl amino-1-(4-hydroxyphenyl)-ethanone; (5) preparing 1-(4-hydroxy phenyl)-2-(methylamino); (6) preparing 1-(4-hydroxy phenyl)-2-(methylamino)-ethanol hydrochloride; (7) preparing 1-(4-hydroxy phenyl)-2-(methylamino) ethanol tartrate. According to the invention, the synephrine is prepared from phenol by the esterification, Friedel-Crafts rearrangement, bromination, amination and reduction treatment. After that, the synephrine reacts with hydrochloric acid and tartaric acid to obtain hydrochloride and tartrate. The above method is simple and readily available in raw materials, easy to operate, mild in reaction condition, convenient in post-treatment and high in yield, thus being suitable for industrial production.
Description
Technical field
The present invention relates to the synthetic method of a kind of synephrine and hydrochloride thereof, tartrate.
Background technology
Synephrine Synephrine, molecular formula: C
9h
13nO
2molecular weight: 167.20, chemical name: 1-(4-hydroxy phenyl)-2-(methylamino), 1-(4-Hydroxyphenyl)-2-(methylamino)-ethanol, another name: Synephrine, Synthenate, Synephrine, sympathol, synephrine.Plant origin, in the dry young fruit of rutaceae bitter orange (Citrusaurantium L.), originates in Sichuan, Jiangxi, zhejiang and other places.Synephrine hydrochloride molecular formula: C
9h
13nO
2hCl, molecular weight: 203.67, chemical name: 1-(4-hydroxy phenyl)-2-(methylamino)-ethylate hydrochlorate, 1-(4-Hydroxyphenyl)-2-(methylamino)-ethanol hydrochloride, CAS:5985-28-4, EINECS:227-804-6, m.p.151-152 DEG C, soluble in water.Tartrate synephrine molecular formula: 2 (C
9h
13nO
2) C
4h
6o
6molecular weight: 484.50, chemical name: 1-(4-hydroxy phenyl)-2-(methylamino) ethanol tartrate, 1-(4-Hydroxyphenyl)-2-(methylamino) methylammonium, m.p.188-189 DEG C, soluble in water, be insoluble in ethanol, be dissolved in chloroform, ether hardly.Synephrine and hydrochloride thereof, tartrate structural formula are as follows:
Synephrine has recorded in Northern Europe three state's pharmacopeia and Ph.G.For suprarenin alpha-receptor stimulant, there is certain excitation to heart receptor.Synephrine has vasoconstriction, produces the effect of raising blood pressure.Synephrine has recorded in Northern Europe three state's pharmacopeia and Ph.G.For suprarenin alpha-receptor stimulant.Synephrine has vasoconstriction, produces the effect of raising blood pressure.Synephrine has the effect of stronger expansion trachea and bronchus.Anesthetized cat intravenous injection completely to the bronchoconstriction caused by antihistaminic, also can have same purpose to guinea-pig isolated trachea.Synephrine is clinical when being used for the treatment of bronchial asthma and operation and anesthesia ypotension, collapse and shock, postural hypotension etc.Synephrine is 21 century natural stimulant, and without any side effects and positive reaction, is widely used in the healthcare industry such as medicine, food, beverage, and along with the forbidding of chemical synthetic drug, demand and the value of synephrine will double.
Foreign study finds that synephrine is except having boosting, Antishock function, also has following effect: improve metabolism, increase heat exhaustion, improve energy level, oxidation of fat, fat-reducing.Therefore, synephrine is commonly used as the effective constituent in slimming medicine.Reversibility Pseudocholinesterase (ACHE) inhibitor.The effect for the treatment of myasthenia gravis is posthumously admitted as mutually with prostigmin(e), and hold time and be obviously longer than prostigmin(e), toxicity is low, and untoward reaction is few, has selective inhibitory to vagusstoff vinegar undergraduate course, easily by blood, cerebrospinal fluid barrier.This product is applicable to benign memory deficits, can significantly improve AD cognitive function of patients, behavior and mood disorder.Also effect is improved to the dysmnesia that dementia patients and brain organic disease cause.
Have in a lot of plant of synephrine, what comparision contents was high is the dried immature fruit of citron orange, tradition is plant extract mainly, pulverize rear water and alcohol extraction, extracting solution concentrating under reduced pressure, add ethanol and reach more than 70% to alcohol content, leave standstill 12h, get supernatant liquor and reclaim ethanol, concentrated solution adds suitable quantity of water, filter with sand filtration post, filtrate adds cation exchange resin column, first rinse by suitable quantity of water, again with certain density ammoniacal liquor wash-out, collect elutriant, cryoconcentration is to appropriate, leave standstill crystallization, filter, recrystallization, obtain white crystals and synephrine, although but method increases than in the past cost or higher in this.Germany scientist has synthesized synephrine first in nineteen twenty-seven, bibliographical information have tindioxide hydrogenation parahydroxyacet-ophenone, in methylamine, hydrogenation.Phenol and methylamino ethylbenzene ethyl ketone synthesize, in hydrogenation.Phenyl aldehyde is obtained by reacting synephrine through five steps.
Synephrine hydrochloride is a kind of medicine, ypotension, collapse and shock, postural hypotension etc. when being used for the treatment of bronchial asthma and operation and anesthesia.There is vasoconstriction, produce the effect of raising blood pressure; Expansion trachea and bronchus; Antithrombus formation; Make the of short duration enhancing of vascular smooth muscular tension; Anti-allergic.For shock, heart failure, treatment bronchial asthma and operation and anesthesia time at the bottom of blood pressure, collapse and shock, body, position ypotension etc., also have improve metabolism, increase heat exhaustion, fat-reducing effect.
Synthesis document about synephrine and hydrochloride thereof has report, bibliographical information have tindioxide hydrogenation parahydroxyacet-ophenone, in methylamine, hydrogenation.Phenol and methylamino ethylbenzene ethyl ketone synthesize, then hydrogenation.Phenyl aldehyde is obtained by reacting synephrine through five steps; Phenol be raw material through over-churning, hydrolysis, ammonification obtains synephrine, and all these side reactions are many, and separation and purification is difficult, and preparation cost is high, also has more remote from suitability for industrialized production.The present invention take phenol as raw material, obtains synephrine through over-churning, Friedel-Crafts rearrangement, bromination, amination and reduction, then synephrine and hydrochloric acid and tartrate are reacted to hydrochloride and tartrate.Raw materials technology is simple and easy to get, reaction conditions easy handling, reaction conditions gentleness, convenient post-treatment, productive rate advantages of higher, is applicable to suitability for industrialized production.
Summary of the invention
For overcoming the deficiency in background technology, the present invention aims to provide the synthetic method of a kind of synephrine and hydrochloride thereof, tartrate.
Technical solution of the present invention is:
A synthetic method for synephrine and hydrochloride thereof, tartrate, comprises the steps:
(1) preparation of phenol acetic ester
(2) preparation of parahydroxyacet-ophenone
(3) preparation of the bromo-1-of 2-(4-hydroxyphenyl) ethyl ketone
(4) preparation of 2-methyl amido-1-(4-hydroxyphenyl) ethyl ketone
(5) preparation of 1-(4-hydroxy phenyl)-2-(methylamino)
(6) preparation of 1-(4-hydroxy phenyl)-2-(methylamino)-ethylate hydrochlorate
(7) preparation of 1-(4-hydroxy phenyl)-2-(methylamino) ethanol tartrate
Embodiment
Synthetic route of the present invention is as follows:
1. being prepared in of phenol acetic ester is equipped with mechanical stirring, thermometer, phenol 50g and dimethyl formamide 160ml is added with in 500mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, add benzene 76ml, Acetyl Chloride 98Min. 105g is slowly added under cryosel bath, add in 20-30min, rise to room temperature, continue reaction and generate White Flocculus, continue reaction 1-3h, detect with thin-layer chromatography, reaction solution concentrates, add and fully stir with the water of 5-10 DEG C, stratification, collect benzene liquid, with isopyknic benzene extraction water liquid 2-4 time, combined benzene liquid, reclaim under reduced pressure benzene solvent, obtain water white phenol acetic ester.
2. being prepared in of parahydroxyacet-ophenone is equipped with mechanical stirring, thermometer, phenol acetic ester 50g is added with in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, add the mixing of 150ml trichloromethane, abundant stirring, the lower control temperature 5-10 DEG C of cryosel bath, aluminum trichloride (anhydrous) 35g is slowly added under abundant stirring, add in 30min, obtain White Flocculus, 50-60 DEG C of reaction 1-3h is risen in 2h, obtain sorrel thing, cryosel bath borehole cooling, add the hydrochloric acid solution 50ml of 5-10%, abundant stirring, with isopyknic chloroform extraction 3-5 time, extraction liquid concentrating under reduced pressure, a small amount of water is added in enriched material, wet distillation, collect water liquid, concentrating under reduced pressure, crystallisation by cooling, obtain off-white color parahydroxyacet-ophenone.
3. the bromo-1-of 2-(4-hydroxyphenyl) being prepared in of ethyl ketone is equipped with mechanical stirring, thermometer, parahydroxyacet-ophenone 40g and 300ml benzene is added with in 500mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, abundant stirring and dissolving, slow dropping bromine water 56g, starting reaction solution fades slower, after redness is decorporated, be cooled to 0-5 DEG C, continue to drip bromine water, color disappears very soon, with the bromize hydrogen gas that alkali liquor absorption discharges, stirring reaction 30-60min, with isopyknic water extraction 3-5 time, discard water liquid, concentrated benzene liquid, cooling, precipitation, there is off-white color solid, suction filtration, by recrystallizing methanol, obtain the bromo-1-of 2-(4-hydroxyphenyl) ethyl ketone.
4. 2-methyl amido-1-(4-hydroxyphenyl) being prepared in of ethyl ketone is equipped with mechanical stirring, thermometer, the bromo-1-of 2-(4-hydroxyphenyl) ethyl ketone 50g is added with in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, add 450ml benzene liquid, add the sodium hydroxide solution of 30-60% again, 0-5 DEG C is cooled under cryosel bath, slowly drip 30% aqueous methylamine solution 80ml, be added dropwise to complete rear solution and become yellowish brown, 0-5 DEG C of stirring reaction 2-5h, solution becomes reddish-brown, thin-layer chromatography detects, after having reacted, stratification, lower layer of water liquid is again with benzene equal-volume extraction 2-3 time, combined benzene liquid, concentrated, concentrated solution with 1: 1 (v/v) hcl acidifying to pH2-4, collect acid liquid, be condensed into paste, add a small amount of ethanol, abundant stirring, separate out solid, suction filtration, dry, obtain brown solid powder 2-methyl amido-1-(4-hydroxyphenyl) acetone.
5. mechanical stirring is equipped with in the preparation of 1-(4-hydroxy phenyl)-2-(methylamino), thermometer, with adding 2-methyl amido-1-(4-hydroxyphenyl) ethyl ketone 50g in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube and 300ml tetrahydrofuran (THF) dissolves, 0-5 DEG C is cooled under cryosel bath, slowly add sodium borohydride 12g, stir lower maintenance temperature of reaction at 0-5 DEG C, response situation is followed the tracks of with thin-layer chromatography, abundant stirring, produce gas, reaction system color is close to colourless, and produce without gas, with a small amount of water quencher, 3-5% gac reflux decolour 30min is added in reaction solution, heat filtering, concentrating under reduced pressure, reclaim ethanol, cooling, crystallization, suction filtration, with a small amount of methanol wash, obtain the finished product synephrine.
6. 1-(4-hydroxy phenyl)-2-(methylamino)-being prepared in of ethylate hydrochlorate is equipped with mechanical stirring, constant pressure funnel, thermometer, synephrine 20g is added with in 500mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, with 300ml dissolve with methanol, drip concentrated hydrochloric acid, reflux 1-2h, till generating without precipitation, filter, filter cake deionized water heating for dissolving, add 3-5% gac 50-60 DEG C decolouring 30min, heat filtering, be evaporated to proportion 1.15-1.20, place, crystallization, obtain white crystals thing synephrine hydrochloride.
7. being prepared in of 1-(4-hydroxy phenyl)-2-(methylamino) ethanol tartrate is equipped with mechanical stirring, constant pressure funnel, thermometer, synephrine 30g is added with in 500mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, dissolve with 300ml isopropyl alcohol, drip L-TARTARIC ACID/aqueous isopropanol, reflux 1-2h, till generating without precipitation, slowly cool, filter, filter cake deionized water heating for dissolving, access 3-5% gac 50-60 DEG C of decolouring 30min, heat filtering, be evaporated to proportion 1.15-1.20, place, crystallization, obtain white crystals thing synephrine tartrate.
Claims (8)
1. a synthetic method for synephrine and hydrochloride thereof, tartrate, be raw material with phenol, the method includes the steps of:
(1) preparation of bydropapacumaric acid ester.
(2) preparation of ethyl-para-hydroxyphenyl ketone.
(3) preparation of the bromo-1-of 2-(4-hydroxyphenyl) acetone.
(4) preparation of 2-methyl amido-1-(4-hydroxyphenyl) acetone.
(5) preparation of methyl synephrine.
(6) preparation of 1-(4-hydroxy phenyl)-2-(methylamino)-ethylate hydrochlorate
(7) preparation of 1-(4-hydroxy phenyl)-2-(methylamino) ethanol tartrate.
2. the synthetic method of a kind of synephrine as claimed in claim 1 and hydrochloride thereof, tartrate, it is characterized in that, esterifying agent used in step (1) is Acetyl Chloride 98Min. or diacetyl oxide, slowly esterifying agent is added under cryosel bath, rise to room temperature, reaction 1-3h, detect with thin-layer chromatography, reaction solution concentrates, and adds and fully stirs with the water of 5-10 DEG C, stratification, collect organic phase, water layer equal-volume organic phase solvent extraction 2-4 time, merges the organic phase of layering and extraction liquid, decompression and solvent recovery.
3. the synthetic method of a kind of synephrine as claimed in claim 1 and hydrochloride thereof, tartrate, is characterized in that, in step (2), middle to (1) product is added Lewis catalyst A lCl
3, FeCl
3, H
2sO
4, H
3pO
4, BF
3with one of in HF, fully stir, control temperature 0-5 DEG C, in 2h, rise to 50-60 DEG C of reaction 1-3h, obtain sorrel thing, cryosel bath borehole cooling, add the hydrochloric acid solution 50ml of 5-10%, fully stir, with isopyknic chloroform extraction 3-5 time, extraction liquid concentrating under reduced pressure, add a small amount of water in enriched material, wet distillation, collect water liquid, concentrating under reduced pressure, crystallisation by cooling.
4. a kind of synephrine as claimed in claim 1 and hydrochloride thereof, the synthetic method of tartrate, it is characterized in that, in step (3), product in (2) is dissolved with benzene, abundant stirring, slow dropping bromine water, starting reaction solution fades slower, after redness is decorporated, be cooled to 0-5 DEG C, continue to drip bromine water, color disappears very soon, with the bromize hydrogen gas that alkali liquor absorption discharges, stirring reaction 30-60min, with isopyknic water extraction 3-5 time, discard water liquid, concentrated benzene liquid, cooling, precipitation, there is off-white color solid, suction filtration, filter cake benzene liquid washs, use recrystallizing methanol.
5. a kind of synephrine as claimed in claim 1 and hydrochloride thereof, the synthetic method of tartrate, it is characterized in that, in step (4), product in (3) is added benzene liquid to dissolve, add the sodium hydroxide solution of 30-60% again, 0-5 DEG C is cooled under cryosel bath, slowly drip 30% aqueous methylamine solution, be added dropwise to complete rear solution and become yellowish brown, 0-5 DEG C of stirring reaction 2-5h, solution becomes reddish-brown, thin-layer chromatography detects, after having reacted, stratification, lower layer of water liquid is again with benzene equal-volume extraction 2-3 time, combined benzene liquid, concentrated, concentrated solution with 1: 1 (v/v) hcl acidifying to pH2-4, collect acid liquid, be condensed into paste, add a small amount of ethanol, abundant stirring, separate out solid, suction filtration, dry.
6. a kind of synephrine as claimed in claim 1 and hydrochloride thereof, the synthetic method of tartrate, it is characterized in that, in step (5), product in (4) is dissolved with tetrahydrofuran (THF), 0-5 DEG C is cooled under cryosel bath, slowly add sodium borohydride or POTASSIUM BOROHYDRIDE, stir lower maintenance temperature of reaction at 0-5 DEG C, response situation is followed the tracks of with thin-layer chromatography, abundant stirring, produce gas, reaction system color is close to colourless, and produce without gas, with a small amount of water quencher, 3-5% gac reflux decolour 30min is added in reaction solution, heat filtering, concentrating under reduced pressure, reclaim ethanol, cooling, crystallization, suction filtration, with a small amount of methanol wash, drain.
7. the synthetic method of a kind of synephrine as claimed in claim 1 and hydrochloride thereof, tartrate, is characterized in that, in step (6) by middle to (5) product with methyl alcohol or dissolve with ethanol, drip concentrated hydrochloric acid, reflux 1-2h, till generating without precipitation, filters, filter cake deionized water heating for dissolving, add 3-5% gac 50-60 DEG C decolouring 30min, heat filtering, is evaporated to proportion 1.15-1.20, place, crystallization.
8. the synthetic method of a kind of synephrine as claimed in claim 1 and hydrochloride thereof, tartrate, is characterized in that, is dissolved by middle to (6) product in step (7) with Virahol, drip L-TARTARIC ACID/aqueous isopropanol, reflux 1-2h, till generating without precipitation, slowly cool, filter, filter cake deionized water heating for dissolving, access 3-5% gac 50-60 DEG C of decolouring 30min, heat filtering, be evaporated to proportion 1.15-1.20, place, crystallization.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776296A (en) * | 2019-03-21 | 2019-05-21 | 济南大学 | A kind of synthetic method of 5- (2- acetyl bromide)-Benzaldehyde,2-hydroxy |
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|---|---|---|---|---|
| GB640492A (en) * | 1948-01-28 | 1950-07-19 | Philips Nv | Improvements in or relating to methods of preparing aminoketones or their reduction products or salts thereof |
| WO2007026313A2 (en) * | 2005-08-30 | 2007-03-08 | The Procter & Gamble Company | 4-aminophenol derivatives and colorants comprising these compounds |
| WO2008077560A1 (en) * | 2006-12-22 | 2008-07-03 | Lonza Ag | Process for the preparation of optically active 2-amino-1-phenylethanols |
| CN102040529A (en) * | 2010-11-09 | 2011-05-04 | 杭州福斯特药业有限公司 | Method for synthesizing synephrine hydrochloride |
| CN102381989A (en) * | 2010-08-30 | 2012-03-21 | 苏州洪瑞医药科技有限公司 | Chemical synthetic method for synephrine hydrochloride |
-
2015
- 2015-03-23 CN CN201510140201.6A patent/CN104876828A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB640492A (en) * | 1948-01-28 | 1950-07-19 | Philips Nv | Improvements in or relating to methods of preparing aminoketones or their reduction products or salts thereof |
| WO2007026313A2 (en) * | 2005-08-30 | 2007-03-08 | The Procter & Gamble Company | 4-aminophenol derivatives and colorants comprising these compounds |
| WO2008077560A1 (en) * | 2006-12-22 | 2008-07-03 | Lonza Ag | Process for the preparation of optically active 2-amino-1-phenylethanols |
| CN102381989A (en) * | 2010-08-30 | 2012-03-21 | 苏州洪瑞医药科技有限公司 | Chemical synthetic method for synephrine hydrochloride |
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Non-Patent Citations (1)
| Title |
|---|
| 张明光: "辛弗林及其类似物的合成研究", 《工程科技I辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109776296A (en) * | 2019-03-21 | 2019-05-21 | 济南大学 | A kind of synthetic method of 5- (2- acetyl bromide)-Benzaldehyde,2-hydroxy |
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