CN104876827A - Synthetic method for methyl synephrine - Google Patents
Synthetic method for methyl synephrine Download PDFInfo
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- CN104876827A CN104876827A CN201510140174.2A CN201510140174A CN104876827A CN 104876827 A CN104876827 A CN 104876827A CN 201510140174 A CN201510140174 A CN 201510140174A CN 104876827 A CN104876827 A CN 104876827A
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- methyl
- synephrine
- hydroxyphenyl
- synthetic method
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/584—Recycling of catalysts
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Abstract
The invention provides a synthetic method for methyl synephrine, wherein easily available phenol, adopted as the raw material, is esterified to obtain phenol propionate. Through the friedel-crafts rearrangement reaction of the phenol propionate under the effect of a catalyst, para-hydroxypropiophenone is prepared. The para-hydroxypropiophenone is bromized to prepare 2-bromo-1-(4-hydroxyphenyl) acetone. The 2-bromo-1-(4-hydroxyphenyl) acetone reacts with methylamine to prepare 2-methyl amino-1-(4-hydroxyphenyl) acetone. The 2-methyl amino-1-(4-hydroxyphenyl) acetone is reduced to prepare 1-(4-hydroxyphenyl)-2-(methylamino). The synthetic method is simple to operate, mild in reaction condition, convenient in post-treatment, and high in yield. Therefore, the method is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of methyl synephrine.
Background technology
Methyl synephrine (Methylsynephrine) has another name called: methyl Xin Fulin, 4-hydroxyephedrine, oxilofrine, Ao Luofulin.Molecular weight: 181.23, CAS No.365-26-42, English name: Oxilofrine, Oxyephedrini Hydrochloridum, P-Hydroxyephedrine, SuprifenHydroxy ephedrine, Oxyephrine, (R*, S*)-4-hydroxy-alpha-[1-(methylamino) ethyl] benzyl alcohol (R*, S*)-4-hydroxy-alpha-[1-(methylamino) ethyl] benzyl alcohol; Oxyephedrine; Rac-4-[(1R*, 2S*)-1-Hydroxy-2-(methylamino) propyl] phenol; L-(p-Hydroxyphenyl)-2-(methylamino)-1-propanol; 1-Hydroxypholedrine; 4-(1-Hydroxy-2-methylaminopropyl) phenol; 4-Hydroxy-α-[1-(methylamino) ethyl] benzenemethanol, EINECS No.206-672-3, white or off-white color crystalline powder, in water soluble, be insoluble to the organic solvent such as sherwood oil, chloroform.M.p.209-210 DEG C, structural formula is as follows:
Foreign study finds, methyl synephrine is a kind of sympathomimetic medicine, has certain effect to alpha-receptor, can vasoconstriction, raising blood pressure, expansion trachea-bronchial epithelial cell and Antishock function.Also there is following effect: improve metabolism, increase heat exhaustion, improve basal metabolic rate(BMR), oxidation of fat etc., its effect is better than synephrine hydrochloride.By following acceptor generation effect: α 1: cause arterial contraction and cause blood pressure rising; α 2: blood pressure can be affected and rise, suppress the secretion of Regular Insulin; β 1: cause palpitating speed, cardiac contractile force is strengthened; β 2: cause tracheaectasy, the vasodilation of heart and skeletal muscle; β 3: increase basal metabolic rate(BMR).Methyl synephrine has another name called Ao Luofulin, to hydroxyephedrine, is amphetamines class stimulant, is 21 century novel stimulant, is widely used in the healthcare industry such as food, beverage.Methyl synephrine can be used for chronic hypotension, postural hypotension, blood pressure drops etc. during surgical operation.The compound preparation that this product and nucleosides form, can play dual regulation to hypertension and ypotension.
Methyl synephrine does not widely use in Britain, at the medicine that the U.S. neither get the Green Light.Methyl synephrine itself has above-described medical usage, but sportsmen's Misuse can promote competition field achievement.The excitability of methyl synephrine not exclusively makes people's spirit excited, more be to stimulate physical function, it can promote that suprarenin generates, improve endurance, focus and susceptibility, improve the oxygen level in heart rate and blood, methyl synephrine makes vasoconstriction, and blood pressure rises, expansion tracheae, improves the motor capacity of people.Methyl synephrine can accelerate body fat burning, has the effect of depress appetite, can not cause the side effects such as arrhythmia, also has the effect of soft stool simultaneously, is used as diet pill.Methyl synephrine is the nutritious supplementary of body-building personage, and some businesses and institutions can use methyl synephrine with the form of synephrine, make so-called nutrition of athlete's supplement, is used for accelerated motion person's body fat burning and losing weight.The modal use-pattern of methyl synephrine is added in nutritious supplementary, and other nutritious supplementarys mix, and takes with the form of soft capsule.Current domestic production producer is less, only have several company in production, and annual international demand amount is comparatively large, and produce market does not obtain effective exploitation, so the coming years, market outlook were very good, demand and the value of chemosynthesis methyl synephrine will double.
At present, there are no about methyl pungent not with the report of synthesis technique, the present invention with phenol simple and easy to get for raw material, bydropapacumaric acid ester is obtained through esterification, Fu-grammes per square metre row is there is and is obtained by reacting ethyl-para-hydroxyphenyl ketone in bydropapacumaric acid ester under catalyzer, ethyl-para-hydroxyphenyl ketone obtains the bromo-1-of 2-(4-hydroxyphenyl) acetone through bromination, the bromo-1-of 2-(4-hydroxyphenyl) acetone and methylamine react obtained 2-methyl amido-1-(4-hydroxyphenyl) acetone, and 2-methylamino-1-(4-hydroxyphenyl) acetone obtains 1-(4-hydroxy phenyl)-2-(methylamino) through reduction.
Summary of the invention
For overcoming the deficiency in background technology, the present invention aims to provide a kind of synthetic method of methyl synephrine.Technical solution of the present invention is:
A synthetic method for methyl synephrine, comprises the steps:
(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.
Embodiment
Synthetic route of the present invention is as follows:
1. being prepared in of bydropapacumaric acid ester is equipped with mechanical stirring, thermometer, phenol 100g is added with in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, morpholine 240mL, benzene 130mL, propionyl chloride 230g is slowly added under cryosel bath, add in 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 organic phase, water layer is containing the propionic acid produced that responds, alkylbenzyldimethylasaltsum saltsum and propionyl chloride, with isopyknic benzene extraction 2-4 time, combined benzene liquid, reclaim under reduced pressure benzene solvent, obtain water white bydropapacumaric acid ester.
2. being prepared in of ethyl-para-hydroxyphenyl ketone is equipped with mechanical stirring, thermometer, bydropapacumaric acid ester 50g is added with in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, aluminum trichloride (anhydrous) 70g is slowly added under cryosel bath, abundant stirring, control temperature 0-5 DEG C, add in 30-60min, obtain White Flocculus, 50-80 DEG C of reaction 1-3h is risen in 2h, obtain sorrel thing, cryosel bath borehole cooling, add frozen water, abundant stirring, with benzene liquid equal-volume extraction 3-5 time, 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 ethyl-para-hydroxyphenyl ketone.
3. the bromo-1-of 2-(4-hydroxyphenyl) being prepared in of acetone is equipped with mechanical stirring, thermometer, ethyl-para-hydroxyphenyl ketone 20g and 400mL methyl alcohol is added with in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, abundant stirring and dissolving, add cupric bromide 120g, heating reflux reaction 2-4h, cooling, filter, filter cake methanol wash, merge with filtrate, reclaim under reduced pressure methyl alcohol, be condensed into paste, add suitable quantity of water, there is off-white color solid, suction filtration, filtrate concentrates, cooling, separate out solid, merge twice solid, by recrystallizing methanol, obtain the bromo-1-of 2-(4-hydroxyphenyl) acetone.
4. 2-methyl amido-1-(4-hydroxyphenyl) being prepared in of acetone is equipped with mechanical stirring, thermometer, the bromo-1-of 2-(4-hydroxyphenyl) acetone 30g is added with in 1000mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube, add 450mL propyl carbinol,-5-0 DEG C is cooled under cryosel bath, slowly drip 15% aqueous methylamine solution 80mL, be added dropwise to complete rear solution and become yellowish red color,-5-0 DEG C of reaction 2-4h, solution becomes reddish-brown, thin-layer chromatography detects, react rear concentrating under reduced pressure, recycling design, obtain brown solid powder, with dissolve with methanol, add a small amount of water crystallization, obtain light yellow crystal 2-methyl amido-1-(4-hydroxyphenyl) acetone.
5. being prepared in of methyl synephrine is equipped with mechanical stirring, thermometer, 2-methyl amido-1-(4-hydroxyphenyl) acetone 20g is added with in 500mL tetra-mouthfuls of round-bottomed flasks of drying tube and reflux condensing tube,-5-0 DEG C is cooled under the bath of 300mL ethanol cryosel, slowly add POTASSIUM BOROHYDRIDE 12g, abundant stirring, produce gas, 1-3h is reacted at-5-0 DEG C, reaction system color is close to colourless, and produce without gas, 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 washing with alcohol, obtain the finished product methyl synephrine.
Claims (6)
1. a synthetic method for methyl synephrine, 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.
2. the synthetic method of a kind of methyl synephrine as claimed in claim 1, is characterized in that, esterifying agent used in step (1) is propionyl chloride or propionic anhydride, slowly add esterifying agent 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 methyl synephrine as claimed in claim 1, is characterized in that, in step (2), product in (1) 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 50-80 DEG C of reaction 1-3h, cryosel bath borehole cooling, adds frozen water, abundant stirring, with organic solvent equal-volume extraction 3-5 time, concentrating under reduced pressure, adds a small amount of water in enriched material, wet distillation, collect water liquid, concentrating under reduced pressure, crystallisation by cooling.
4. the synthetic method of a kind of methyl synephrine as claimed in claim 1, is characterized in that, in step (3) by middle to (2) product with methyl alcohol or dissolve with ethanol, fully stir, add cupric bromide, heating reflux reaction 2-4h, cooling, filter, filter cake methanol wash, merges with filtrate, decompression and solvent recovery, is condensed into paste, adds suitable quantity of water, suction filtration, filtrate concentrates, cooling, separate out solid, merge twice solid, use recrystallizing methanol.
5. the synthetic method of a kind of methyl synephrine as claimed in claim 1, it is characterized in that, in step (4), product in (3) is dissolved with propyl carbinol or Virahol, under cryosel bath, be cooled to-5-0 DEG C, slowly drip 15% aqueous methylamine solution,-5-0 DEG C of reaction 2-4h, thin-layer chromatography detects, and has reacted rear concentrating under reduced pressure, recycling design, obtain brown solid powder, with methyl alcohol or dissolve with ethanol, add a small amount of water crystallization.
6. the synthetic method of a kind of methyl synephrine as claimed in claim 1, it is characterized in that, in step (5) by middle to (4) product with methyl alcohol or dissolve with ethanol, be cooled to-5-0 DEG C under cryosel bath, slowly add POTASSIUM BOROHYDRIDE or sodium borohydride, fully stir, produce gas, at-5-0 DEG C, react 1-3h, reaction system color is close to colourless, and produces without gas, 3-5% gac reflux decolour 30min is added in reaction solution, heat filtering, concentrating under reduced pressure, reclaims ethanol, cooling, crystallization, suction filtration, with a small amount of methyl alcohol or washing with alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510140174.2A CN104876827A (en) | 2015-03-23 | 2015-03-23 | Synthetic method for methyl synephrine |
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| CN201510140174.2A CN104876827A (en) | 2015-03-23 | 2015-03-23 | Synthetic method for methyl synephrine |
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| CN104876827A true CN104876827A (en) | 2015-09-02 |
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| CN201510140174.2A Pending CN104876827A (en) | 2015-03-23 | 2015-03-23 | Synthetic method for methyl synephrine |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB297756A (en) * | 1927-04-22 | 1928-09-24 | Helmut Legerlotz | Monoxy-phenyl-alkyl-ketone derivatives |
| US1878021A (en) * | 1928-06-27 | 1932-09-20 | Winthrop Chem Co Inc | Alpha-para-hydroxyphenyl-beta-methylaminopropanol and process of preparing it |
-
2015
- 2015-03-23 CN CN201510140174.2A patent/CN104876827A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB297756A (en) * | 1927-04-22 | 1928-09-24 | Helmut Legerlotz | Monoxy-phenyl-alkyl-ketone derivatives |
| US1878021A (en) * | 1928-06-27 | 1932-09-20 | Winthrop Chem Co Inc | Alpha-para-hydroxyphenyl-beta-methylaminopropanol and process of preparing it |
Non-Patent Citations (2)
| Title |
|---|
| 张明光: "辛弗林及其类似物的合成研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
| 王立平等: "利托君的合成", 《中国医药工业杂志》 * |
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Application publication date: 20150902 |