CN115010665A - Method for synthesizing terbutaline sulfate impurity B - Google Patents
Method for synthesizing terbutaline sulfate impurity B Download PDFInfo
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Abstract
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for synthesizing terbutaline sulfate impurity B. The terbutaline sulfate impurity B is prepared by taking p-2-bromo-3 ',5' -dihydroxy acetophenone as a raw material and carrying out 5 steps of esterification reaction, substitution reaction, cyclization reaction, hydrolysis reaction and reduction reaction. The synthesis method has the advantages of simple reaction process, easily obtained raw materials and total yield of more than 50 percent, and contributes to the strict control of the content of terbutaline sulfate impurity B by adopting an external standard method; the method has mild reaction conditions and high product purity, is suitable for medicine quality research, and provides guarantee for improving the quality of terbutaline sulfate bulk drugs.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for synthesizing terbutaline sulfate impurity B.
Background
Terbutaline sulfate (TBT), also known as Mexican, terbutaline sulfate, is a selective beta 2 The adrenoceptor stimulant has the effects of relieving asthma, eliminating phlegm and relaxing bronchus, can be clinically used for bronchospasm caused by bronchial asthma, chronic bronchitis, emphysema and other lung diseases, and can also be used for preventing premature delivery and fetal asphyxia. The structural formula is as follows:
the european pharmacopoeia standard for terbutaline sulfate reports 4 impurities, of which impurity B has the following structure:
in order to ensure the safety of clinical medication, the quality control of the impurity B in the terbutaline sulfate is required. Because only trace amount of impurity B is generated in the preparation process of terbutaline sulfate, the terbutaline sulfate is not easy to separate and purify as an impurity reference substance, and no literature reports a synthetic route of the impurity at the present stage, a method for researching the terbutaline sulfate impurity B is very necessary.
Disclosure of Invention
Aiming at the problem of quality control of the impurity B in terbutaline sulfate at the present stage, the invention provides a synthesis method of the terbutaline sulfate impurity B, which is prepared by taking 2-bromo-3 ',5' -dihydroxy acetophenone as a raw material and carrying out esterification reaction, substitution reaction, cyclization reaction, hydrolysis reaction and reduction reaction for 5 steps; the raw materials are easy to obtain, the reaction conditions are mild, the total yield is high, the product purity is high, and the quality of the terbutaline sulfate bulk drug is guaranteed.
The technical scheme of the invention is as follows:
a synthetic method of terbutaline sulfate impurity B comprises the following steps:
(1) 2-bromo-3 ',5' -dihydroxyacetophenone and acetic anhydride are subjected to esterification reaction under the action of alkali to obtain a compound 1;
(2) dissolving the compound 1 in a solvent 1, and carrying out substitution reaction with tert-butylamine to obtain a compound 2;
(3) dissolving the compound 2 in a solvent 2, and performing cyclization reaction to obtain a compound 3;
(4) dissolving the compound 3 in a solvent 3, adding an alkaline solution, and performing hydrolysis reaction to obtain a compound 4;
(5) the compound 4 is put in a solvent 4, and an impurity B is prepared through reduction reaction;
wherein the structural formulas of the compounds 1-4 and the impurity B are shown as follows:
further, the step (1) also comprises a solvent 4, after dissolving the 2-bromo-3 ',5' -dihydroxy acetophenone, adding acetic anhydride, and carrying out esterification reaction under the action of alkali; the solvent 4 is one or a mixture of several of dichloromethane, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF and DMSO in any proportion.
Preferably, the base in step (1) is one of potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine, and preferably triethylamine.
Preferably, the solvent 1 is a mixture of one or more of methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF and DMSO at any ratio, preferably methanol or ethanol.
Preferably, the molar ratio of the tert-butylamine to the compound 1 is 1-4: 1.
preferably, the solvent 2 is a mixed solution of one or more of water, methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF and DMSO at any ratio, preferably a mixed solution of methanol or ethanol and water.
Preferably, in step (3), the reagent used in the cyclization reaction is aqueous formaldehyde solution or paraformaldehyde, preferably paraformaldehyde.
Preferably, in the step (4), the solvent 3 is a mixed solution of one of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and water, preferably methanol; the alkaline solution is one of sodium hydroxide, potassium hydroxide or lithium hydroxide solution, and preferably sodium hydroxide solution.
Preferably, in the step (5), the solvent 4 is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane or 1, 2-dichloroethane, preferably methanol.
Preferably, in the step (5), the reducing agent is sodium borohydride or lithium aluminum hydride.
The synthesis process flow comprises the following steps:
compared with the prior art, the invention has the following beneficial effects:
1. the synthesis method of terbutaline sulfate impurity B provided by the invention has 5 steps of reaction, easily available raw materials and more than 50% of total yield, and contributes to the strict control of terbutaline sulfate impurity B content by adopting an external standard method.
2. The synthetic method disclosed by the invention is simple to operate, mild in reaction conditions, high in product purity, suitable for medicine quality research, and capable of providing guarantee for improving the quality of terbutaline sulfate bulk drugs.
Drawings
FIG. 1 is a nuclear magnetic spectrum of terbutaline sulfate impurity B prepared in example 3 of the present invention;
FIG. 2 is a mass spectrum of terbutaline sulfate impurity B prepared in example 3 of the present invention;
FIG. 3 is a liquid phase purity profile of terbutaline sulfate impurity B prepared in example 3 of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited thereto.
All the starting materials used in the examples are commercially available, except where otherwise indicated.
Example 1
1. Synthesis of Compound 1
2-bromo-3 ',5' -dihydroxyacetophenone (0.46 g, 2.0 mmol)) was dissolved in 4ml of dichloromethane, 1ml of acetic anhydride and diisopropylethylamine (1.3 g, 10.0 mmol) were added, the reaction was stirred at room temperature, and TLC monitored for the end of the reaction (petroleum ether: ethyl acetate = 2: 1, V/V). Evaporated to dryness under reduced pressure, 20ml water was added and extracted with 20ml x3 ethyl acetate and the organic layers were combined. Washing with saturated sodium bicarbonate solution, washing with pure water, drying with anhydrous sodium sulfate, evaporating to remove solvent, concentrating under reduced pressure, and purifying by column chromatography to obtain white solid 0.52g, i.e. compound 1, with yield of 83%.
2. Synthesis of Compound 2
Dissolving the compound 1 (0.52 g, 1.65 mmol) in 10ml of methanol, adding tert-butylamine (0.48 g, 6.6 mmol), heating to 60-70 ℃, stirring for 6 hours, detecting by TLC (petroleum ether: ethyl acetate = 2: 1, V/V) after the reaction is finished, distilling under reduced pressure, and separating and purifying the obtained residue by column chromatography to obtain a white solid 0.48g, namely the compound 2, with the yield of 95%.
3. Synthesis of Compound 3
Compound 2 (0.48 g, 1.56 mmol) was dissolved in a mixed solvent of 5ml of water and 5ml of ethanol, and 1ml of an aqueous formaldehyde solution was added, and the reaction was stirred at room temperature for 72 hours. TLC monitored the end of the reaction (petroleum ether: ethyl acetate = 2: 1, V/V). And (3) distilling the ethanol under reduced pressure, cooling to 0-5 ℃, stirring, crystallizing for 1h, filtering, and drying to constant weight to obtain 0.42g of white solid, namely the compound 3, with the yield of 84%.
4. Synthesis of Compound 4
Dissolving a compound 3 (0.42 g, 1.32 mmol) in 10mL ethanol, adding sodium hydroxide (0.4 g, 10.0 mmol) and purified water (2 mL) with stirring, heating to 50 +/-2 ℃, stirring for 2 hours, detecting the completion of the reaction by TLC (petroleum ether: ethyl acetate = 1: 1, V/V), adjusting the pH of the reaction system to 5-6 with 2M hydrochloric acid solution, cooling to 0-5 ℃, stirring for crystallization for 1 hour, filtering, and drying to constant weight to obtain 0.27g of a white solid, namely a compound 4 with yield of 87%.
5. Synthesis of impurity B
Dissolving a compound 4 (0.27 g and 1.15 mmol) in 5mL of tetrahydrofuran, stirring and cooling to 0-5 ℃, adding lithium aluminum hydride (0.17 g and 4.6 mmol), stirring for 4 hours, detecting the completion of the reaction by TLC (petroleum ether: ethyl acetate = 1: 1, V/V), slowly dropwise adding saturated ammonium chloride purified water (15 mL) into the reaction solution, adding ethyl acetate (15 mL), stirring for 5 minutes, standing for layering, retaining an ethyl acetate phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then carrying out column chromatography separation to obtain a white-like solid of 0.24g, namely an impurity B, wherein the yield is 88%, and the total yield of five steps is 50.5%.
Example 2
1. Synthesis of Compound 1
2-bromo-3 ',5' -dihydroxyacetophenone (0.46 g, 2.0 mmol)) was dissolved in 4ml of acetonitrile, 1ml of acetic anhydride and sodium carbonate (1.06 g, 10.0 mmol) were added, the reaction was stirred at room temperature, and TLC monitored for the end of the reaction (petroleum ether: ethyl acetate = 2: 1, V/V). Evaporated to dryness under reduced pressure, 20ml water was added and extracted with 20ml x3 ethyl acetate and the organic layers were combined. Washing with saturated sodium bicarbonate solution, washing with pure water, drying with anhydrous sodium sulfate, evaporating to remove solvent, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain white solid 0.52g, i.e. compound 1, with yield 83%.
2. Synthesis of Compound 2
Dissolving the compound 1 (0.52 g, 1.65 mmol) in 10ml tetrahydrofuran, adding tert-butylamine (0.48 g, 1.65 mmol), heating to 60-70 ℃, stirring for 6 hours, detecting by TLC that the reaction is finished (petroleum ether: ethyl acetate = 2: 1, V/V), distilling under reduced pressure, and separating and purifying the obtained residue by column chromatography to obtain 0.47g of white solid, namely the compound 2, with the yield of 91%.
3. Synthesis of Compound 3
Compound 2 (0.47 g, 1.50 mmol) was dissolved in a mixed solvent of 5ml of water and 5ml of ethanol, and 1ml of an aqueous formaldehyde solution was added, and the reaction was stirred at room temperature for 72 hours. TLC monitored the end of the reaction (petroleum ether: ethyl acetate = 2: 1, V/V). And (3) distilling the ethanol under reduced pressure, cooling to 0-5 ℃, stirring, crystallizing for 1h, filtering, and drying to constant weight to obtain 0.42g of white solid, namely the compound 3, with the yield of 88%.
4. Synthesis of Compound 4
Dissolving a compound 3 (0.42 g, 1.32 mmol) in 10mL of ethanol, adding lithium hydroxide (0.24 g, 10.0 mmol) and purified water (2 mL) with stirring, heating to 50 +/-2 ℃, stirring for 2 hours, detecting the completion of the reaction by TLC (petroleum ether: ethyl acetate = 1: 1, V/V), adjusting the pH of the reaction system to 5-6 with 2M hydrochloric acid solution, cooling to 0-5 ℃, stirring for crystallization for 1 hour, filtering, and drying to constant weight to obtain 0.26g of a white solid, namely a compound 4 with the yield of 87%.
5. Synthesis of impurity B
Dissolving a compound 4 (0.26 g, 1.11 mmol) in 5mL of dioxane, cooling to 0-5 ℃ under stirring, adding lithium aluminum hydride (0.17 g, 4.6 mmol), stirring for 4 hours, detecting the completion of the reaction by TLC (petroleum ether: ethyl acetate = 1: 1, V/V), slowly dropwise adding saturated ammonium chloride purified water (15 mL) into the reaction solution, adding ethyl acetate (15 mL), stirring for 5 minutes, standing for layering, retaining an ethyl acetate phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then carrying out column chromatography separation to obtain 0.25g of a white-like solid, namely an impurity B, wherein the yield is 95%, and the total yield of the five steps is 52.7%.
Example 3
1. Synthesis of Compound 1
2-bromo-3 ',5' -dihydroxyacetophenone (4.62 g, 0.02 mol)) was dissolved in 40ml of acetic anhydride, catalyzed by the addition of triethylamine (3.03 g, 0.03 mol), the reaction was stirred at room temperature, and the end of the reaction was monitored by TLC (petroleum ether: ethyl acetate = 2: 1, V/V). Evaporated to dryness under reduced pressure, 200ml water was added and extracted with 50ml x3 ethyl acetate and the organic layers were combined. Washing with saturated sodium bicarbonate solution, washing with pure water, drying with anhydrous sodium sulfate, evaporating to remove solvent, concentrating under reduced pressure, and separating and purifying by column chromatography to obtain white solid 5.50g, i.e. compound 1, with yield of 87%.
2. Synthesis of Compound 2
Dissolving the compound 1 (5.50 g, 0.0175 mol) in 50ml of ethanol, adding tert-butylamine (5.12 g, 0.070 mol), heating to 60-70 ℃, stirring for 6 hours, detecting by TLC (petroleum ether: ethyl acetate = 2: 1, V/V) after the reaction is finished, carrying out reduced pressure distillation, and carrying out column chromatography separation and purification on the obtained residue to obtain 5.12g of a white solid, namely the compound 2, wherein the yield is 95%.
3. Synthesis of Compound 3
Compound 2 (5.12 g, 0.0167 mol) was dissolved in a mixed solvent of 20ml of water and 20ml of methanol, and paraformaldehyde (4.51 g, 0.0501 mol) was added, and the reaction was stirred at room temperature for 72 hours. TLC monitored the end of the reaction (petroleum ether: ethyl acetate = 2: 1, V/V). And (3) evaporating methanol under reduced pressure, cooling to 0-5 ℃, stirring, crystallizing for 1h, filtering, and drying to constant weight to obtain 4.72g of white solid, namely the compound 3, with the yield of 88%.
4. Synthesis of Compound 4
Dissolving a compound 3 (4.72 g, 0.0148 mol) in 40mL of ethanol, adding sodium hydroxide (2.96 g, 0.074 mmol) and purified water (10 mL) with stirring, heating to 50 +/-2 ℃, stirring for 2 hours, detecting the completion of the reaction by TLC (petroleum ether: ethyl acetate = 1: 1, V/V), adjusting the pH of the reaction system to 5-6 by using 2M hydrochloric acid solution, cooling to 0-5 ℃, stirring for crystallization for 1 hour, filtering, drying to constant weight to obtain 3.05g of a white solid, namely a compound 4, with the yield of 88%.
5. Synthesis of impurity B
Dissolving a compound 4 (3.05 g and 0.0130 mol) in 40mL of methanol, stirring and cooling to 0-5 ℃, adding sodium borohydride (0.98 g and 0.026 mmol) in batches, stirring for 4 hours, detecting the completion of the reaction by TLC (petroleum ether: ethyl acetate = 1: 1, V/V), pouring the reaction solution into purified water (100 mL), adding ethyl acetate (100 mL), stirring for 5 minutes, standing and layering, retaining an ethyl acetate phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and then carrying out column chromatography separation to obtain 2.77g of a white-like solid, namely an impurity B, wherein the yield is 90%, and the total yield of five steps is 58.4%.
The obtained terbutaline sulfate impurity B is subjected to high resolution mass spectrometry, nuclear magnetic structure data and liquid phase purity analysis, and the result is HR-MS (R-MS: (R) (R))m/z）: 238.1530 [M+H] +1 ; H 1 -NMR（DMSO-d 6 , 400MHz） δ: 1.42（s, 6H, 3CH 3 ）,3.42（m, 2H, CH 2 ）, 4.18（m, 2H, CH 2 ) 4.92 (t, 1H, CH), 6.38 (s, 1H, Ph), 6.42 (s, 1H, Ph). The analysis result shows that the structure is correct, and the purity is 99.52%.
Claims (10)
1. A synthetic method of terbutaline sulfate impurity B is characterized in that: the method comprises the following steps:
(1) 2-bromo-3 ',5' -dihydroxyacetophenone and acetic anhydride are subjected to esterification reaction under the action of alkali to obtain a compound 1;
(2) dissolving the compound 1 in a solvent 1, and carrying out substitution reaction with tert-butylamine to obtain a compound 2;
(3) dissolving the compound 2 in a solvent 2, and performing cyclization reaction to obtain a compound 3;
(4) dissolving the compound 3 in a solvent 3, adding an alkaline solution, and performing hydrolysis reaction to obtain a compound 4;
(5) the compound 4 is put in a solvent 4, and an impurity B is prepared through reduction reaction;
wherein the structural formulas of the compounds 1-4 and the impurity B are shown as follows:
2. the method of synthesizing terbutaline sulfate impurity B according to claim 1, wherein: the step (1) also comprises a solvent 4, after dissolving the 2-bromo-3 ',5' -dihydroxy acetophenone, adding acetic anhydride, and carrying out esterification reaction under the action of alkali; the solvent 4 is one or a mixture of several of dichloromethane, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF and DMSO in any proportion.
3. The method for synthesizing terbutaline sulfate impurity B according to claim 1, wherein: the alkali in the step (1) is one of potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine, and triethylamine is preferred.
4. The method of synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (2), the solvent 1 is a mixture of one or more of methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion, preferably methanol or ethanol.
5. The method of synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (2), the molar ratio of the tert-butylamine to the compound 1 is 1-4: 1.
6. the method of synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (3), the solvent 2 is a mixed solution of one or more of water, methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion, preferably a mixed solution of methanol or ethanol and water.
7. The method for synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (3), the reagent used in the cyclization reaction is aqueous formaldehyde solution or paraformaldehyde, preferably paraformaldehyde.
8. The method of synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (4), the solvent 3 is a mixed solution of one of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and water, preferably methanol; the alkaline solution is one of sodium hydroxide, potassium hydroxide or lithium hydroxide solution, and preferably sodium hydroxide solution.
9. The method for synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (5), the solvent 4 is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane or 1, 2-dichloroethane, preferably methanol.
10. The method for synthesizing terbutaline sulfate impurity B according to claim 1, wherein: in the step (5), the reducing agent is sodium borohydride or lithium aluminum hydride.
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