CN109096126B - Deuterium labeled D9Synthesis method of clenbuterol hydrochloride - Google Patents
Deuterium labeled D9Synthesis method of clenbuterol hydrochloride Download PDFInfo
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Abstract
The invention belongs to food safetyAnd the field of standard substance synthesis, and discloses a deuterium-labeled D9A method for synthesizing clenbuterol hydrochloride. The method uses 3, 5-dichloro-4-aminoacetophenone as raw material, and comprises the steps of bromination and D9Three-step reaction of-tert-butylamination and reduction to generate deuterium label D9Clenbuterol hydrochloride. The method has the advantages of simple operation, mild reaction conditions (most of the reaction is carried out at room temperature), reasonable reaction route, optional process, simple treatment method and easy purification of products. At the same time will D9Core material D in the process of synthesizing clenbuterol hydrochloride9The total conversion rate of the tert-butylamine is improved from 4.2% to 40%, the yield is also improved to 64%, and the method has good economic value and social value.
Description
Technical Field
The invention belongs to the field of food safety and standard substance synthesis, and particularly relates to deuterium-labeled D9A method for synthesizing clenbuterol hydrochloride.
Background
Clenbuterol hydrochloride (Clenbuterol hydrochloride) with the chemical name of alpha- [ (tert-butylamino) methyl ] -4-amino-3, 5-dichlorobenzyl alcohol hydrochloride and the medicine names of dichlorohydramine hydrochloride, ammonia asthma, amitutol, albuterol, clenbuterol and the like, and the clenbuterol hydrochloride is white or white-like crystalline powder with the melting point of 174-175.5 ℃, odorless and bitter taste, is soluble in water and ethanol, slightly soluble in acetone and insoluble in diethyl ether. It is a potent selective adrenergic beta 2 receptor agonist, can relax bronchial smooth muscle, and is used for the treatment of bronchial asthma, asthmatic bronchitis, bronchitis with emphysema, etc. There is a need for a convenient and efficient, highly sensitive technical method for detecting it.
At present, gas chromatography-mass spectrometry (GC-MS), High Performance Liquid Chromatography (HPLC), enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (HPLC-MS) are used for detecting clenbuterol in animal food at home and abroad. The GC-MS method organically combines the efficient and rapid chromatographic separation effect with the high-sensitivity qualitative analysis of mass spectrum, can perform qualitative and quantitative analysis on a certain specific residue under the condition that various residues exist simultaneously, and has higher detection limit, higher detection sensitivity and lower false positive rate. Therefore, the GC-MS is legal in China as a corroborative method for detecting clenbuterol, and the isotope internal standard is adopted, so that the deviation of the detection result caused by the loss of the sample treatment process can be avoided.
At present, deuterium-labeled Clenbuterol hydrochloride (Clenbuterol-D) is used in China9) All depend on import and the synthetic studies are reported little and can be found (Journal of laboratory Compounds and Radiopharmaceuticals,1996,38: 1007-1014; journal of laboratory Compounds and Radiopharmaceuticals,1990,28: 725-. They are prepared by reacting 4-amino-alpha-bromo-3, 5-dichloroacetophenone with D9After reaction with tert-butylamine, by NaBH4Reducing the ketocarbonyl group. Use thereof of D9More tert-butylamine, and D9Total conversion of tert-butylamine is only 4%, so that Chinese publication CN 104387284A replaces D with another organic base9Tert-butylamine, resulting in a significant improvement in D9The conversion rate of the tert-butylamine is high, but when other organic base is added, additional organic base is salified and separated out when the product is salified and separated out. And they are all 4-amino-alpha-bromo-3, 5-dichloroacetophenone and D under heating reflux conditions9-tert-butylamine is reacted, and 4-amino-alpha-D9-tert-butylamino-3, 5-dichloroacetophenone, this compound is poorly stable. Therefore, optimizing the reaction conditions, adopting mild reaction conditions, optimizing the process route and improving the reaction yield are the research directions of the invention.
Disclosure of Invention
To overcome the above-mentioned disadvantages and drawbacks of the prior art, it is a primary object of the present invention to provide a deuterium-labeled D9A method for synthesizing clenbuterol hydrochloride. The method uses 3, 5-dichloro-4-aminoacetophenone as raw material, and comprises the steps of bromination and D9Three-step reaction of-tert-butylamination and reduction to generate deuterium label D9Clenbuterol hydrochloride, which is mostly carried out at room temperature, mild reaction conditions, and yields and D9The conversion rate of the tert-butylamine is high.
The purpose of the invention is realized by the following scheme:
a kind ofDeuterium labeling of D9Clenbuterol hydrochloride, of the formula:
deuterium label D as described above9-a process for the synthesis of clenbuterol hydrochloride comprising the steps of:
(1) carrying out bromination reaction on 3, 5-dichloro-4-aminoacetophenone and a bromination reagent in the presence of a solvent, and purifying the obtained reaction solution to obtain 3, 5-dichloro-4-amino-alpha-bromoacetophenone; the reaction formula is as follows:
(2) in the presence of solvent, 3, 5-dichloro-4-amino-alpha-bromoacetophenone and D9Reacting the tert-butylamine at room temperature, filtering after the reaction is finished, and acidifying the obtained filtrate to obtain the stable isotope labeled 4-amino-alpha-D9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride; the reaction formula is as follows:
(3) reacting 4-amino-alpha-D9Dissolving tert-butylamino-3, 5-dichloroacetophenone hydrochloride in a solvent to obtain a solution A, adjusting the pH of the solution A to be neutral, adding a reducing agent to perform a reduction reaction, and purifying the obtained reaction solution after the reaction is finished to obtain a target product deuterium labeled D9Clenbuterol hydrochloride. The reaction formula is as follows:
the brominating reagent in the step (1) is liquid bromine or copper bromide;
when the brominating reagent in the step (1) is liquid bromine, the molar ratio of the 3, 5-dichloro-4-aminoacetophenone to the liquid bromine is 1:1-2, preferably 1: 1.1-1.5; the bromination reaction is carried out for 1 to 6 hours at a temperature of between 0 and 75 ℃, and preferably for 2 to 4 hours at a temperature of between 10 and 30 ℃;
when the brominating reagent in the step (1) is copper bromide, the molar ratio of the 3, 5-dichloro-4-aminoacetophenone to the copper bromide is 1:2-4, preferably 1: 2-2.5; the bromination reaction is carried out for 1 to 6 hours at a temperature of between 0 and 75 ℃, and preferably for 2 to 4 hours at a temperature of between 40 and 75 ℃;
the solvent in the step (1) is one or a mixture of tetrahydrofuran, dichloromethane, trichloromethane, ethanol or ethyl acetate.
The purification in the step (1) is to filter the obtained reaction solution, then wash the obtained filtrate with water and saturated salt water, then concentrate and recrystallize with chloroform, isopropyl ether or methyl tert-butyl ether, and filter and dry to obtain the purified product.
The solvent in the step (2) is at least one of tetrahydrofuran or acetonitrile;
3, 5-dichloro-4-amino-alpha-bromoacetophenone and D in step (2)9-tert-butylamine in a molar ratio of 1:1 to 3, preferably 1:1.2 to 2;
the room temperature in the step (2) is preferably 20-30 ℃; the reaction in the step (2) is carried out at room temperature for 4-10 h; preferably at room temperature for 6 h;
the reaction in the step (2) is carried out in a sealed container;
the filtration in the step (2) is to filter the reaction solution to remove D produced in the reaction process9-tert-butylamine hydrobromide.
The acidification treatment in the step (2) is to add a hydrogen chloride/organic solvent solution into the obtained filtrate to make the solution system acidic (pH 4), then filter and dry to obtain 4-amino-alpha-D9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride. Wherein the concentration of hydrogen chloride in the hydrogen chloride/organic solvent solution is 4mol/L, and the hydrogen chloride/organic solvent solution is preferably hydrogen chloride/diethyl ether solution, hydrogen chloride/ethanol solution, hydrogen chloride/ethyl acetate solution, hydrogen chloride/dioxane solution, hydrogen chloride/ethanol solutionLiquid or hydrogen chloride/methanol solution.
The solvent in the step (3) is one or a mixture of water, tetrahydrofuran, methanol and ethanol;
the reducing agent in the step (3) is any one of sodium borohydride, lithium borohydride, potassium borohydride, lithium aluminum hydride and borane.
4-amino-alpha-D described in step (3)9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride and reducing agent in a molar ratio of 1:1-4, preferably 1: 1-2;
adding the reducing agent in the step (3) preferably when the internal temperature of the solution A is controlled below 5 ℃, and naturally heating to room temperature after the addition is finished;
the reduction reaction in the step (3) is carried out at room temperature for 2-5 h; preferably at room temperature for 3 h;
the purification in the step (3) is to adjust the pH of the obtained reaction solution to 10, then decompress and remove the non-aqueous solvent, then add dichloromethane for extraction, stratify, wash the organic phase with saturated common salt solution once, dry the sodium sulfate, decompress and obtain white solid, dissolve the white solid with dichloromethane, drip hydrogen chloride/ethanol solution, separate out the solid, filter, dry and obtain the final product after purification.
The solvent in steps (1) to (3) functions as a reaction medium, and thus the amount of the solvent may not be limited.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. provides a method for synthesizing deuterium-labeled D by using 3, 5-dichloro-4-aminoacetophenone as a starting material9A complete process for the preparation of clenbuterol hydrochloride.
2. The method has the advantages of simple operation, mild reaction conditions (most of the reaction is carried out at room temperature), reasonable reaction route, optional process, simple treatment method and easy purification of products.
3. The method has good economic value and is easy for industrial production.
4. D of the invention9The conversion of tert-butylamine is markedly increased compared with the prior art, D9-tert-butylThe overall conversion of amine was 40%.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
The reagents used in the examples are commercially available without specific reference.
The room temperatures stated in the examples are all from 20 to 30 ℃. The stirring speed described in the examples is not intended to be limited, and is any stirring speed that is conventional in the art because the raw materials are sufficiently contacted with each other.
Example 1
In a 250ml three-necked flask, 4.8g of 3, 5-dichloro-4-aminoacetophenone, 10.8 g of copper bromide, 48ml of ethyl acetate and 48ml of chloroform were added, and after completion of the addition, the mixture was refluxed for 4 hours. Filtering, washing a filter cake by ethyl acetate, combining filtrates, washing twice by water, washing twice by saturated salt water, drying by sodium sulfate, recrystallizing by chloroform under reduced pressure, filtering, and drying to obtain solid 3, 5-dichloro-4-amino-alpha-bromoacetophenone 4.0g with the yield of about 62%.
The nuclear magnetic hydrogen spectrum data of the obtained solid are as follows:1H NMR(CDCl3) δ 7.85(s,2H),5.06 (s,2H),4.31(s,2H), illustrates that this example successfully synthesizes 3, 5-dichloro-4-amino- α -bromoacetophenone.
Example 2
Adding 2.8g of 3, 5-dichloro-4-amino-alpha-bromoacetophenone and D into a 50ml pressure-resistant bottle91.2g of tert-butylamine and 45ml of tetrahydrofuran, stirred at room temperature for 6 hours, filtered to remove D formed during the reaction9-tert-butylamine hydrobromide, washing the filter cake with 10ml tetrahydrofuran, combining the filtrates, concentrating about half of the tetrahydrofuran, adding 4mol/L hydrogen chloride/ethanol solution, adjusting the pH of the solution to 4, filtering, drying to obtain 4-amino-alpha-D93.0g of (E) -tert-butylamino-3, 5-dichloroacetophenone hydrochloride in a yield of 93%, D9-a conversion of 63% for tert-butylamine.
The nuclear magnetic hydrogen spectrum data of the obtained solid are as follows:1h NMR (MeOD) delta 8.00(s,2H),4.59(s,2H), indicating that example 2 succeeded in the synthesis of 4-amino-. alpha. -D9-tertButylamino-3, 5-dichloroacetophenone hydrochloride.
Example 3
Adding 1.0g of 3, 5-dichloro-4-amino-alpha-bromoacetophenone and D into a 25ml pressure-resistant bottle9-tert-butylamine 0.46g, 15ml acetonitrile, stirring at room temperature for 6 hours, filtering, washing the filter cake with 5ml acetonitrile, combining the filtrates, concentrating about half of the acetonitrile, adding 4mol/L hydrogen chloride/ethanol solution until the solution becomes acidic (pH 4), filtering, drying to obtain 4-amino-alpha-D9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride 1.1g, yield 96%, D9-tert-butylamine conversion 61%. Wherein the nuclear magnetic hydrogen spectrum data of the solid obtained by drying is as follows:1h NMR (MeOD) delta 8.00(s,2H),4.59(s,2H), indicating that example 3 also succeeded in synthesizing 4-amino-. alpha. -D9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride.
Example 4
4-amino-alpha-D prepared in example 29Dissolving 1.15 g of-tert-butylamino-3, 5-dichloroacetophenone hydrochloride in 17ml of water and 23ml of methanol, adjusting the pH value to about 7 by using a 2N sodium hydroxide aqueous solution under the cooling of an ice water bath, controlling the internal temperature to be below 5 ℃, adding 245mg of sodium borohydride, naturally heating and stirring for 3 hours after the addition is finished, adjusting the pH value to about 10 by using a 2N sodium hydroxide aqueous solution, removing the methanol under reduced pressure, adding 60ml of dichloromethane for extraction, separating layers, washing an organic phase once by using brine, drying the sodium sulfate, and reducing the pressure to obtain a white solid. Dissolving white solid with dichloromethane, dripping 4mol/L hydrogen chloride/ethanol solution, separating out solid, filtering, and drying to obtain solid deuterium labeled D9Clenbuterol hydrochloride 0.73g, yield about 64%, purity 98.98%, D9The total utilization of tert-butylamine is 40%. Wherein the nuclear magnetic hydrogen spectrum data of the solid obtained by filtering are as follows:1h NMR (MeOD) δ 7.28-7.19 (m,2H),4.55(dd, J ═ 8.8,4.2Hz,1H),2.67(qd, J ═ 11.4,6.5Hz,2H),1.14(s,1H), illustrates that this example successfully synthesized deuterium label D9Clenbuterol hydrochloride.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. Deuterium labeled D9-a method for the synthesis of clenbuterol hydrochloride, characterized in that it comprises the following steps:
(1) carrying out bromination reaction on 3, 5-dichloro-4-aminoacetophenone and a bromination reagent in the presence of a solvent, and purifying the obtained reaction solution to obtain 3, 5-dichloro-4-amino-alpha-bromoacetophenone;
(2) in the presence of solvent, 3, 5-dichloro-4-amino-alpha-bromoacetophenone and D9Reacting the tert-butylamine at room temperature, filtering after the reaction is finished, and acidifying the obtained filtrate to obtain the stable isotope labeled 4-amino-alpha-D9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride;
(3) reacting 4-amino-alpha-D9Dissolving tert-butylamino-3, 5-dichloroacetophenone hydrochloride in a solvent to obtain a solution A, adjusting the pH of the solution A to be neutral, adding a reducing agent to perform a reduction reaction, and purifying the obtained reaction solution after the reaction is finished to obtain a target product deuterium labeled D9-clenbuterol hydrochloride;
the solvent in the step (2) is at least one of tetrahydrofuran or acetonitrile.
2. Deuterium labeling D according to claim 19-a method for synthesizing clenbuterol hydrochloride, characterized in that:
the brominating reagent in the step (1) is liquid bromine or copper bromide;
the solvent in the step (1) is one or a mixture of tetrahydrofuran, dichloromethane, trichloromethane, ethanol or ethyl acetate.
3. Deuterium labeling D according to claim 29-a method for synthesizing clenbuterol hydrochloride, characterized in that:
when the bromination reagent in the step (1) is liquid bromine, the molar ratio of the 3, 5-dichloro-4-aminoacetophenone to the liquid bromine is 1: 1-2; the bromination reaction is carried out for 1 to 6 hours at a temperature of between 0 and 75 ℃;
when the brominating reagent in the step (1) is copper bromide, the molar ratio of the 3, 5-dichloro-4-aminoacetophenone to the copper bromide is 1: 2-4; the bromination reaction refers to the reaction at 0-75 ℃ for 1-6 h.
4. Deuterium labeling D according to claim 29-a method for synthesizing clenbuterol hydrochloride, characterized in that:
when the bromination reagent in the step (1) is liquid bromine, the molar ratio of the 3, 5-dichloro-4-aminoacetophenone to the liquid bromine is 1: 1.1-1.5; the bromination reaction is carried out for 2 to 4 hours at a temperature of between 10 and 30 ℃;
when the brominating reagent in the step (1) is copper bromide, the molar ratio of the 3, 5-dichloro-4-aminoacetophenone to the copper bromide is 1: 2-2.5; the bromination reaction refers to the reaction at 40-75 ℃ for 2-4 h.
5. Deuterium labeling D according to claim 19-a method for synthesizing clenbuterol hydrochloride, characterized in that:
3, 5-dichloro-4-amino-alpha-bromoacetophenone and D in step (2)9-tert-butylamine in a molar ratio of 1: 1-3;
the room temperature in the step (2) is 20-30 ℃; the reaction in the step (2) is carried out at room temperature for 4-10 h.
6. Deuterium labeling D according to claim 19-a method for synthesizing clenbuterol hydrochloride, characterized in that:
the reaction in the step (2) is carried out in a sealed container;
the acidification treatment in the step (2) is to add hydrogen chloride/organic solvent solution into the obtained filtrate to ensure that the pH value of the solution system is 4, then filter and dry to obtain the 4-amino-alpha-D9-tert-butylamino-3, 5-dichloroacetophenone hydrochloride; wherein the concentration of hydrogen chloride in the hydrogen chloride/organic solvent solution is 4 mol/L.
7. Deuterium labeling D according to claim 19-a method for synthesizing clenbuterol hydrochloride, characterized in that:
the solvent in the step (3) is one or a mixture of water, tetrahydrofuran, methanol and ethanol;
the reducing agent in the step (3) is any one of sodium borohydride, lithium borohydride, potassium borohydride, lithium aluminum hydride and borane;
4-amino-alpha-D described in step (3)9The mol ratio of the tert-butylamino-3, 5-dichloroacetophenone hydrochloride to the reducing agent is 1: 1-4.
8. Deuterium labeling D according to claim 19-a method for synthesizing clenbuterol hydrochloride, characterized in that:
the addition of the reducing agent in the step (3) refers to the addition when the internal temperature of the solution A is controlled below 5 ℃, and the temperature is naturally raised to the room temperature after the addition is finished;
the reduction reaction in the step (3) is carried out at room temperature for 2-5 h.
9. Deuterium labeling D according to claim 19-a method for synthesizing clenbuterol hydrochloride, characterized in that:
the purification in the step (3) is to adjust the pH of the obtained reaction solution to 10, then decompress and remove the non-aqueous solvent, then add dichloromethane for extraction, stratify, wash the organic phase with saturated common salt solution once, dry the sodium sulfate, decompress and obtain white solid, dissolve the white solid with dichloromethane, drip hydrogen chloride/ethanol solution, separate out the solid, filter, dry and obtain the final product after purification.
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