CN107759481A - Phenolethanolamine A preparation method - Google Patents
Phenolethanolamine A preparation method Download PDFInfo
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- CN107759481A CN107759481A CN201610674894.1A CN201610674894A CN107759481A CN 107759481 A CN107759481 A CN 107759481A CN 201610674894 A CN201610674894 A CN 201610674894A CN 107759481 A CN107759481 A CN 107759481A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
Abstract
The invention discloses a kind of phenolethanolamine A preparation method.The preparation method comprises the following steps：(1) to nitrobenzyl bromine and ethyl acetoacetate nucleo philic substitution reaction, compound shown in formula 1 is obtained；(2) in acid condition, compound shown in formula 1 obtains compound shown in formula 2 through acid hydrolytic reaction；(3) compound shown in formula 2 obtains compound shown in formula 3 with formamide through Leuckart reaction；(4) compound shown in formula 3 carries out nucleophilic substitution with bromo acetanisole；Potassium borohydride or sodium borohydride are added into the system of the nucleophilic substitution, through reduction reaction, produces the phenolethanolamine A.The reaction scheme of preparation method of the present invention is short, and combined coefficient is high, reduces the step of isolating and purifying, can largely produce.
Description
Technical field
The present invention relates to a kind of phenolethanolamine A preparation method, belong to organic synthesis field.
Background technology
Phenolethanolamine A is Phenylethanolamine A Chinese name.Phenolethanolamine A scientific name is { 1- (4-
Methoxyphenyl) -2- ((4- (4-nitrophenyl) butan-2-yl) amino) ethanol }, its molecular structural formula is such as
Under：
Phenolethanolamine A, also known as " Ke Lunba amine ", as clenbuterol hydrochloride.In recent years, criminal is by illegally adding benzyl carbinol
Amine A, to improve the lean meat percentage of pork, reduce fat content.The event being poisoned by a lot of edible porks containing phenolethanolamine A
Afterwards, it is set forth in detail in the bulletin of the Ministry of Agriculture the 1519th " forbid with the material that is used in drinking water for animals ".Work master station of Sichuan Province
It still further developed《Middle phenolethanolamine A measure high performance liquid chromatography-tandem mass method》With《The middle phenolethanolamine A efficient liquid of measure
Phase chromatography》Etc. detection method standard, issued and implemented by No. 1486 bulletins of the Ministry of Agriculture and Sichuan Province's provincial standard respectively.With
Different detection methods afterwards, e.g., enzyme linked immunosorbent assay analysis method (ELISA), superelevation Liquid Chromatography-Tandem Mass Spectrometry and collaurum are fast
Fast detection method is developed in succession.Because phenolethanolamine A standard items are needed from foreign procurement, and it is expensive, in order to full
Sufficient Domestic Scientific Research unit can carry out related detecting method foundation, standard formulation, toxicity and metabolic process measure demand, it is necessary to
A kind of a kind of phenolethanolamine A rapidly and efficiently of offer synthetic method is provided.
The content of the invention
It is an object of the invention to provide a kind of phenolethanolamine A preparation method, the inventive method must rapidly and efficiently can be made
Standby phenolethanolamine A.
Phenolethanolamine A provided by the present invention preparation method, comprises the following steps：
(1) to nitrobenzyl bromine and ethyl acetoacetate nucleo philic substitution reaction, compound shown in formula 1 is obtained；
(2) in acid condition, compound shown in formula 1 obtains compound shown in formula 2 through acid hydrolytic reaction；
(3) compound shown in formula 2 obtains compound shown in formula 3 with formamide through Leuckart reaction；
(4) compound shown in formula 3 carries out nucleophilic substitution with bromo acetanisole；It is anti-to the nucleophilic displacement of fluorine
Potassium borohydride or sodium borohydride are added in the system answered, through reduction reaction, produces the phenolethanolamine A.
In described preparation method, in step (1), the mol ratio to nitrobenzyl bromine and the ethyl acetoacetate is
1：1.0~1.5, concretely 1：1.2；
The nucleophilic substitution is carried out under the conditions of existing for caustic alcohol；
The caustic alcohol is with being 1.0~1.5 to the mol ratio of nitrobenzyl bromine：1, concretely 1.2：1；
The nucleophilic substitution is carried out in the case where heating 40~60 DEG C, concretely 50 DEG C；
The time of the nucleophilic substitution is 5~8 hours, concretely 5 hours.
In described preparation method, in step (2), the acid hydrolytic reaction is carried out in acetic acid solution；
The temperature of the acid hydrolytic reaction is 110~120 DEG C, and the time is 20~24 hours, specifically can be anti-at 110 DEG C
Answer 24 hours.
In described preparation method, in step (3), the temperature of the Leuckart reaction is 120~140 DEG C, the time is 6~
8 hours.
In described preparation method, in step (4), compound shown in formula 3 is rubbed with the bromo acetanisole
You are than being 1：1.5~2；
The mol ratio of the potassium borohydride or the sodium borohydride and compound shown in formula 3 is 1~5：1.
In described preparation method, in step (4), the process of the nucleophilic substitution is as follows：
Compound shown in formula 3 and the system of the bromo acetanisole are stirred under conditions of 20 DEG C~25 DEG C
2~3 hours；Then add to 40~45 DEG C and kept for 6~8 hours.
In described preparation method, in step (4), the temperature of the reduction reaction is 20 DEG C~25 DEG C, the time is 10~
12 hours, concretely 12 hours.
Phenolethanolamine A provided by the invention preparation method has the following advantages that：
The reaction scheme of preparation method of the present invention is short, and combined coefficient is high, reduces the step of isolating and purifying, can largely give birth to
Production.
Brief description of the drawings
Fig. 1 is phenolethanolamine A's1H NMR spectras.
Fig. 2 is phenolethanolamine A's13C NMR spectras.
Embodiment
Experimental method used in following embodiments is conventional method unless otherwise specified.
Material used, reagent etc., unless otherwise specified, are commercially obtained in following embodiments.
Bromo acetanisole used in the following embodiments of the present invention is prepared by the following method：
Reaction equation is as follows：
Course of reaction is as follows：
By 25.8g compound acetanisole, 500ml methanol is put into drying bottle plus stirring, and thermometer, stirring is extremely
Quan Rong, frozen water are cooled to 10 DEG C, add 10ml 40%HBr, stir 1h.28.5g Br are added dropwise at 10-15 DEG C2, after 3h, TLC prisons
It is complete to control raw material reaction, if there is raw material residual, adds Br in right amount2Reaction is to without raw material point.Solution cools 0 DEG C after completion of the reaction,
Filtering, dry, obtain 31g white solids, be identified as bromo acetanisole.
Embodiment 1, prepare phenolethanolamine A
The reaction equation of preparation method of the present invention is shown below：
(1) synthesis of compound shown in formula 1
By ethyl acetoacetate and P-nitrobenzyl bromide according to equivalent proportion (1.2：1) it is added to caustic alcohol (1.2 equivalent)
Ethanol solution, it is stirred vigorously, is heated to 50 DEG C, after flowing back 5 hours, stops reaction.After standing cooling, gone out with Rotary Evaporators
Ethanol, a certain amount of ethyl acetate and water are then added, with the isolated organic phase of normal pressure separatory funnel, organic phase uses saturation again
Brine It 3 times, organic phase is collected with conical flask, is added anhydrous magnesium sulfate and is dried, after being concentrated using Rotary Evaporators, obtains
The concentrate main component arrived is compound shown in formula 1.
(2) synthesis of compound shown in formula 2
Obtained concentrate will be reacted above to be added in 5M acetic acid solution, oil bath heating is to after 110 DEG C, keeping temperature
24 hours, during which there is bubble to emerge.After completion of the reaction, reaction is stopped, reaction is cooled to room temperature, adds the Na2CO of saturation3It is molten
Liquid, remove unnecessary acetic acid, regulation pH value to alkalescence (pH>10).It is eventually adding ethyl acetate and extracts three in normal pressure separatory funnel
It is secondary, organic phase is collected in conical flask, is added anhydrous magnesium sulfate and is dried, after being concentrated using Rotary Evaporators, obtains crude samples,
By column chromatography (petroleum ether：Ethyl acetate=10：1, volume ratio) purifying obtains compound shown in formula 2, above two-step reaction
Total output is 50%.
(3) synthesis of compound shown in formula 3
Compound shown in obtained formula 2 and formamide are added in round-bottomed flask, are put into oil bath heating to 130 DEG C, it is molten
Liquid is slowly changed into brown, after heating 5h, adds sodium carbonate and adjusts pH value to alkalescence (pH>10), then add ethyl acetate and satisfy
The saline solution of sum, brown product is extracted repeatedly with ethyl acetate.Obtained brown product is added to the round bottom equipped with concentrated hydrochloric acid
In flask, after being heated to 110 DEG C of backflows 1 hour, aqueous phase wash with ethyl acetate, reservation aqueous phase, by the pH value of aqueous phase adjust to
Alkalescence (pH>10), then add ethyl acetate and washing 3 times carried out to aqueous phase with separatory funnel, add anhydrous magnesium sulfate and dry,
After being concentrated using Rotary Evaporators, crude samples are obtained.It is final to place ventilation, dry to obtain compound shown in formula 3, yield is
70%.
(4) " one kettle way " synthesis phenolethanolamine A
Compound shown in formula 3 is dissolved completely in equipped with methanol, addition bromo acetanisole and 0.1ml distill
Water, 40 DEG C are gradually heated to after 3 hours are stirred at room temperature first, in oil bath, after keeping temperature heats 12 hours, is cooled to room
Temperature.Brown solution is obtained, completes nucleophilic attack reaction.The KBH of 5 equivalents is slowly added in brown solution4, continue to stir at room temperature
After 12 hours, using ethyl acetate solution sample, after being evaporated, by column chromatography (dichloromethane：Acetone：Triethylamine=10：1：
1%) sterling phenolethanolamine A is obtained, yield is more than 60%.
Phenolethanolamine A's manufactured in the present embodiment1H NMR spectras as shown in figure 1,13C NMR spectras are as shown in Fig. 2 by 2
Individual spectrogram, which can be seen that, to be seen, the structure of prepared compound is correct.
Claims (7)
1. phenolethanolamine A preparation method, comprises the following steps：
(1) to nitrobenzyl bromine and ethyl acetoacetate nucleo philic substitution reaction, compound shown in formula 1 is obtained；
(2) in acid condition, compound shown in formula 1 obtains compound shown in formula 2 through acid hydrolytic reaction；
(3) compound shown in formula 2 obtains compound shown in formula 3 with formamide through Leuckart reaction；
(4) compound shown in formula 3 carries out nucleophilic substitution with bromo acetanisole；To the nucleophilic substitution
Potassium borohydride or sodium borohydride are added in system, through reduction reaction, produces the phenolethanolamine A.
2. preparation method according to claim 1, it is characterised in that：It is described to nitrobenzyl bromine and the second in step (1)
The mol ratio of ethyl acetoacetic acid ethyl ester is 1：1.0~1.5；
The nucleophilic substitution is carried out under the conditions of existing for caustic alcohol；
The caustic alcohol is 1.0~1.5 with the mol ratio to nitrobenzyl bromine：1；
The nucleophilic substitution is carried out in the case where heating 40~60 DEG C；
The time of the nucleophilic substitution is 5~8 hours.
3. preparation method according to claim 1 or 2, it is characterised in that：In step (2), the acid hydrolytic reaction exists
Carried out in acetic acid solution；
The temperature of the acid hydrolytic reaction is 110~120 DEG C, and the time is 20~24 hours.
4. according to the preparation method any one of claim 1-3, it is characterised in that：In step (3), Liu Ka Te is anti-
The temperature answered is 120~140 DEG C, and the time is 6~8 hours.
5. according to the preparation method any one of claim 1-4, it is characterised in that：In step (4), chemical combination shown in formula 3
The mol ratio of thing and the bromo acetanisole is 1：1.5~2；
The mol ratio of the potassium borohydride or the sodium borohydride and compound shown in formula 3 is 1~5：1.
6. according to the preparation method any one of claim 1-5, it is characterised in that：In step (4), the nucleophilic displacement of fluorine
The process of reaction is as follows：
The system of compound shown in formula 3 and the bromo acetanisole is stirred 2~3 under conditions of 20 DEG C~25 DEG C
Hour；Then add to 40~45 DEG C and kept for 6~8 hours.
7. according to the preparation method any one of claim 1-6, it is characterised in that：In step (4), the reduction reaction
Temperature be 20 DEG C~25 DEG C, the time be 10~12 hours.
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| CN201610674894.1A CN107759481A (en) | 2016-08-16 | 2016-08-16 | Phenolethanolamine A preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658797A (en) * | 2018-06-19 | 2018-10-16 | 安徽德信佳生物医药有限公司 | A kind of synthesis of Mirabegron intermediate (R) -2- (4- nitrophenethyls amino) -1- phenylethanol hydrochlorides |
| CN111777518A (en) * | 2019-04-03 | 2020-10-16 | 上海安谱实验科技股份有限公司 | Synthetic preparation method of phenylethanolamine A labeled by stable isotope |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4391826A (en) * | 1978-07-03 | 1983-07-05 | Eli Lilly And Company | Phenethanolamines, compositions containing the same, and method for effecting weight control |
| CN1237574A (en) * | 1998-05-29 | 1999-12-08 | 中国科学院成都有机化学研究所 | Method for synthesizing phynylethanolamine compound |
| CN101898969A (en) * | 2010-07-15 | 2010-12-01 | 启东市沪东化工有限公司 | Synthesis method of 1,3-dimethylamylamine hydrochloride |
| CN102557851A (en) * | 2011-12-13 | 2012-07-11 | 安徽省新星药物开发有限责任公司 | New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride |
-
2016
- 2016-08-16 CN CN201610674894.1A patent/CN107759481A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4391826A (en) * | 1978-07-03 | 1983-07-05 | Eli Lilly And Company | Phenethanolamines, compositions containing the same, and method for effecting weight control |
| CN1237574A (en) * | 1998-05-29 | 1999-12-08 | 中国科学院成都有机化学研究所 | Method for synthesizing phynylethanolamine compound |
| CN101898969A (en) * | 2010-07-15 | 2010-12-01 | 启东市沪东化工有限公司 | Synthesis method of 1,3-dimethylamylamine hydrochloride |
| CN102557851A (en) * | 2011-12-13 | 2012-07-11 | 安徽省新星药物开发有限责任公司 | New method for synthesizing tapentadol hydrochloride and analogue of tapentadol hydrochloride |
Non-Patent Citations (3)
| Title |
|---|
| MINGYAN DAI,等: "Development of a colloidal gold-based lateral-flow immunoassay for the rapid detection of phenylethanolamine A in swine urine", 《ANAL. METHODS》 * |
| 王立平: "利托君的合成", 《中国医药工业杂志》 * |
| 黄惠琴 等: "N芳烷基取代苯乙醇胺类化合物的合成及药理活性", 《中国药物化学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658797A (en) * | 2018-06-19 | 2018-10-16 | 安徽德信佳生物医药有限公司 | A kind of synthesis of Mirabegron intermediate (R) -2- (4- nitrophenethyls amino) -1- phenylethanol hydrochlorides |
| CN111777518A (en) * | 2019-04-03 | 2020-10-16 | 上海安谱实验科技股份有限公司 | Synthetic preparation method of phenylethanolamine A labeled by stable isotope |
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Application publication date: 20180306 |