A method for synthesizing terbutaline sulfate impurity B
The five-step synthesis of terbutaline sulfate impurity B solves the problem of difficult separation and purification of impurity B in existing technologies, achieving high yield and high purity synthesis, and improving drug quality control capabilities.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG INST FOR FOOD & DRUG CONTROL
- Filing Date
- 2022-08-05
- Publication Date
- 2026-07-21
AI Technical Summary
The lack of an effective synthetic route at present makes it difficult to separate and purify impurity B in terbutaline sulfate, which affects the quality control of the drug.
Terbutaline sulfate impurity B was synthesized from 2-bromo-3',5'-dihydroxyacetophenone via a five-step process involving esterification, substitution, cyclization, hydrolysis, and reduction. The reaction conditions were mild, the overall yield was high, and the product purity was high.
This invention provides a simple, high-yield, and high-purity synthesis method that is suitable for pharmaceutical quality research and improves the quality control capability of terbutaline sulfate raw material.
Smart Images
Figure CN115010665B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a method for synthesizing terbutaline sulfate impurity B. Background Technology
[0002] Terbutaline sulfate (TBT), also known as terbutaline sulfate, is a selective β2-adrenergic receptor agonist. It has both bronchodilatory and expectorant effects, as well as bronchodilator effects. Clinically, it can be used for bronchospasm caused by bronchial asthma, chronic bronchitis, emphysema, and other lung diseases. It can also be used to prevent premature birth and fetal asphyxia. Its structural formula is as follows: The European Pharmacopoeia standard for terbutaline sulfate reports four impurities, among which impurity B has the following structure: To ensure the safety of clinical medication, it is necessary to control the quality of impurity B in terbutaline sulfate. Since only trace amounts of impurity B are generated during the preparation of terbutaline sulfate, it is difficult to separate and purify it for use as an impurity reference standard. Furthermore, there is currently no literature reporting a synthetic route for this impurity. Therefore, it is essential to develop a method for detecting impurity B in terbutaline sulfate. Summary of the Invention
[0003] To address the current problems in quality control of impurity B in terbutaline sulfate, this invention provides a method for synthesizing impurity B in terbutaline sulfate. Using 2-bromo-3',5'-dihydroxyacetophenone as a raw material, the method involves five steps: esterification, substitution, cyclization, hydrolysis, and reduction. The raw materials are readily available, the reaction conditions are mild, the overall yield is high, and the product purity is high, thus ensuring the quality of terbutaline sulfate raw material.
[0004] The technical solution of the present invention is as follows: A method for synthesizing terbutaline sulfate impurity B includes the following steps: (1) Compound 1 was prepared by esterification of 2-bromo-3',5'-dihydroxyacetophenone with acetic anhydride under alkaline conditions; (2) Compound 1 was dissolved in solvent 1 and reacted with tert-butylamine via a substitution reaction to obtain compound 2; (3) Compound 2 was dissolved in solvent 2 and compound 3 was obtained by cyclization reaction; (4) Compound 3 is dissolved in solvent 3, an alkaline solution is added, and compound 4 is obtained by hydrolysis reaction; (5) Compound 4 was reduced in solvent 4 to obtain impurity B; The structural formulas of compounds 1-4 and impurity B are shown below: .
[0005] Furthermore, step (1) also includes solvent 4, which is used to dissolve 2-bromo-3',5'-dihydroxyacetophenone, add acetic anhydride, and carry out esterification reaction under alkaline conditions; the solvent 4 is one or more of dichloromethane, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF, and DMSO in any proportion.
[0006] Preferably, the alkali mentioned in step (1) is one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine, with triethylamine being preferred.
[0007] Preferably, solvent 1 is one or a mixture of several of methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion, with methanol or ethanol being preferred.
[0008] Preferably, the molar ratio of tert-butylamine to compound 1 is 1 to 4:1.
[0009] Preferably, the solvent 2 is one or more of water, methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion, preferably a mixture of methanol or ethanol and water.
[0010] Preferably, in step (3), the reagent used in the cyclization reaction is an aqueous formaldehyde solution or paraformaldehyde, preferably paraformaldehyde.
[0011] Preferably, in 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, preferably sodium hydroxide solution.
[0012] Preferably, in step (5), the solvent 4 is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane or 1,2-dichloroethane in any proportion, with methanol being preferred.
[0013] Preferably, in step (5), the reducing agent is sodium borohydride or lithium aluminum hydride.
[0014] The synthesis process is as follows: Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The method for synthesizing terbutaline sulfate impurity B according to the present invention consists of 5 steps, the raw materials are readily available, and the overall yield is greater than 50%. It contributes to the use of external standard method to strictly control the content of terbutaline sulfate impurity B.
[0015] 2. The synthesis method of this invention is simple to operate, the reaction conditions are mild, and the product has high purity. It is suitable for drug quality research and provides a guarantee for improving the quality of terbutaline sulfate raw material. Attached Figure Description
[0016] Figure 1 This is the NMR spectrum of terbutaline sulfate impurity B prepared in Example 3 of this invention; Figure 2 This is the mass spectrometry of terbutaline sulfate impurity B prepared in Example 3 of this invention; Figure 3 This is the liquid phase purity spectrum of terbutaline sulfate impurity B prepared in Example 3 of the present invention. Detailed Implementation
[0017] The present invention will be further described below with reference to embodiments, but the invention is not limited thereto.
[0018] Unless otherwise specified, all raw materials used in the examples were commercially available.
[0019] Example 1 1. Synthesis of Compound 1 2-Bromo-3',5'-dihydroxyacetophenone (0.46 g, 2.0 mmol) was dissolved in 4 mL of dichloromethane, and 1 mL of acetic anhydride and diisopropylethylamine (1.3 g, 10.0 mmol) were added. The mixture was stirred at room temperature, and the reaction was monitored by TLC until completion (petroleum ether:ethyl acetate = 2:1, v / v). The mixture was evaporated to dryness under reduced pressure, 20 mL of water was added, and the extract was obtained by extraction with 20 mL x 3 ethyl acetate. The organic layers were combined. The extract was washed with saturated sodium bicarbonate solution, then with pure water, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The extract was concentrated under reduced pressure and purified by column chromatography to give 0.52 g of a white solid, compound 1, in 83% yield.
[0020] 2. Synthesis of Compound 2 Compound 1 (0.52 g, 1.65 mmol) was dissolved in 10 mL of methanol, and tert-butylamine (0.48 g, 6.6 mmol) was added. The mixture was heated to 60–70 °C and stirred for 6 hours. The reaction was completed by TLC (petroleum ether: ethyl acetate = 2:1, V / V). The mixture was then distilled under reduced pressure, and the residue was purified by column chromatography to give 0.48 g of a white solid, which was compound 2, with a yield of 95%.
[0021] 3. Synthesis of Compound 3 Compound 2 (0.48 g, 1.56 mmol) was dissolved in a mixture of 5 mL water and 5 mL ethanol, and 1 mL of formaldehyde aqueous solution was added. The mixture was stirred at room temperature for 72 h. The reaction was monitored by TLC until completion (petroleum ether: ethyl acetate = 2:1, v / v). The ethanol was distilled off under reduced pressure, and the mixture was cooled to 0–5 °C and stirred to crystallize for 1 h. The crystals were filtered and dried to constant weight to give 0.42 g of a white solid, which was compound 3, with a yield of 84%.
[0022] 4. Synthesis of Compound 4 Compound 3 (0.42 g, 1.32 mmol) was dissolved in 10 mL of ethanol, and sodium hydroxide (0.4 g, 10.0 mmol) and purified water (2 mL) were added with stirring. The mixture was heated to 50 ± 2 °C and stirred for 2 hours. The reaction was completed by TLC (petroleum ether: ethyl acetate = 1:1, V / V). The pH of the reaction system was adjusted to 5-6 with 2 M hydrochloric acid solution, and the mixture was cooled to 0-5 °C and stirred to crystallize for 1 hour. The crystals were filtered and dried to constant weight to obtain 0.27 g of white solid, which is compound 4, with a yield of 87%.
[0023] 5. Synthesis of Impurity B Compound 4 (0.27 g, 1.15 mmol) was dissolved in 5 mL of tetrahydrofuran, stirred and cooled to 0–5 °C, and lithium aluminum hydride (0.17 g, 4.6 mmol) was added. The mixture was stirred for 4 hours, and the reaction was detected by TLC (petroleum ether: ethyl acetate = 1:1, V / V). Slowly dropwise, saturated ammonium chloride purified water (15 mL) was added to the reaction solution, followed by ethyl acetate (15 mL). The mixture was stirred for 5 minutes, allowed to stand for separation, and the ethyl acetate phase was retained. The phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 0.24 g of an off-white solid, i.e., impurity B, with a yield of 88% and an overall yield of 50.5% for the five steps.
[0024] Example 2 1. Synthesis of Compound 1 2-Bromo-3',5'-dihydroxyacetophenone (0.46 g, 2.0 mmol) was dissolved in 4 mL of acetonitrile, and 1 mL of acetic anhydride and sodium carbonate (1.06 g, 10.0 mmol) were added. The mixture was stirred at room temperature, and the reaction was monitored by TLC until completion (petroleum ether:ethyl acetate = 2:1, v / v). The mixture was evaporated to dryness under reduced pressure, 20 mL of water was added, and the extract was obtained by extraction with 20 mL x 3 ethyl acetate solutions. The organic layers were combined. The extract was washed with saturated sodium bicarbonate solution, then with pure water, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The extract was concentrated under reduced pressure and purified by column chromatography to give 0.52 g of a white solid, compound 1, in 83% yield.
[0025] 2. Synthesis of Compound 2 Compound 1 (0.52 g, 1.65 mmol) was dissolved in 10 mL of tetrahydrofuran, and tert-butylamine (0.48 g, 1.65 mmol) was added. The mixture was heated to 60–70 °C and stirred for 6 hours. The reaction was completed by TLC (petroleum ether: ethyl acetate = 2:1, V / V). The mixture was then distilled under reduced pressure, and the residue was purified by column chromatography to give 0.47 g of a white solid, which was compound 2, with a yield of 91%.
[0026] 3. Synthesis of Compound 3 Compound 2 (0.47 g, 1.50 mmol) was dissolved in a mixture of 5 mL water and 5 mL ethanol, and 1 mL of formaldehyde aqueous solution was added. The mixture was stirred at room temperature for 72 h. The reaction was monitored by TLC until completion (petroleum ether: ethyl acetate = 2:1, v / v). The ethanol was distilled off under reduced pressure, and the mixture was cooled to 0–5 °C and stirred to crystallize for 1 h. The crystals were filtered and dried to constant weight to give 0.42 g of a white solid, which was compound 3, with a yield of 88%.
[0027] 4. Synthesis of Compound 4 Compound 3 (0.42 g, 1.32 mmol) was dissolved in 10 mL of ethanol, and lithium hydroxide (0.24 g, 10.0 mmol) and purified water (2 mL) were added with stirring. The mixture was heated to 50 ± 2 °C and stirred for 2 hours. The reaction was completed by TLC (petroleum ether: ethyl acetate = 1:1, V / V). The pH of the reaction system was adjusted to 5-6 with 2 M hydrochloric acid solution, and the mixture was cooled to 0-5 °C and stirred to crystallize for 1 hour. The crystals were filtered and dried to constant weight to obtain 0.26 g of white solid, which is compound 4, with a yield of 87%.
[0028] 5. Synthesis of Impurity B Compound 4 (0.26 g, 1.11 mmol) was dissolved in 5 mL of dioxane, stirred, and cooled to 0–5 °C. Lithium aluminum hydride (0.17 g, 4.6 mmol) was added, and the mixture was stirred for 4 hours. The reaction was detected by TLC (petroleum ether: ethyl acetate = 1:1, V / V). Saturated ammonium chloride purified water (15 mL) was slowly added dropwise to the reaction solution, followed by ethyl acetate (15 mL). The mixture was stirred for 5 minutes, allowed to stand for separation, and the ethyl acetate phase was retained. The phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 0.25 g of an off-white solid, i.e., impurity B, with a yield of 95% and an overall yield of 52.7% for the five steps.
[0029] Example 3 1. Synthesis of Compound 1 2-Bromo-3',5'-dihydroxyacetophenone (4.62 g, 0.02 mol) was dissolved in 40 mL of acetic anhydride, and triethylamine (3.03 g, 0.03 mol) was added as a catalyst. The reaction was stirred at room temperature, and the reaction was monitored by TLC until completion (petroleum ether:ethyl acetate = 2:1, v / v). The mixture was evaporated to dryness under reduced pressure, 200 mL of water was added, and the mixture was extracted with 50 mL x 3 ethyl acetate. The organic layers were combined. The mixture was washed with saturated sodium bicarbonate solution, washed with pure water, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. The solution was concentrated under reduced pressure and purified by column chromatography to give 5.50 g of white solid, namely compound 1, with a yield of 87%.
[0030] 2. Synthesis of Compound 2 Compound 1 (5.50 g, 0.0175 mol) was dissolved in 50 ml of ethanol, and tert-butylamine (5.12 g, 0.070 mol) was added. The mixture was heated to 60-70 °C and stirred for 6 hours. The reaction was completed by TLC (petroleum ether: ethyl acetate = 2:1, V / V). The mixture was then distilled under reduced pressure, and the residue was purified by column chromatography to give 5.12 g of white solid, which was compound 2, with a yield of 95%.
[0031] 3. Synthesis of Compound 3 Compound 2 (5.12 g, 0.0167 mol) was dissolved in a mixture of 20 mL water and 20 mL methanol, and paraformaldehyde (4.51 g, 0.0501 mol) was added. The mixture was stirred at room temperature for 72 h. The reaction was monitored by TLC until completion (petroleum ether: ethyl acetate = 2:1, v / v). Methanol was distilled off under reduced pressure, and the mixture was cooled to 0–5 °C and stirred to crystallize for 1 h. The crystals were filtered and dried to constant weight to give 4.72 g of a white solid, which was compound 3, with a yield of 88%.
[0032] 4. Synthesis of Compound 4 Compound 3 (4.72 g, 0.0148 mol) was dissolved in 40 mL of ethanol, and sodium hydroxide (2.96 g, 0.074 mmol) and purified water (10 mL) were added with stirring. The mixture was heated to 50 ± 2 °C and stirred for 2 hours. The reaction was completed by TLC (petroleum ether: ethyl acetate = 1:1, V / V). The pH of the reaction system was adjusted to 5-6 with 2 M hydrochloric acid solution, and the mixture was cooled to 0-5 °C and stirred to crystallize for 1 hour. The crystals were filtered and dried to constant weight to obtain 3.05 g of white solid, which is compound 4, with a yield of 88%.
[0033] 5. Synthesis of Impurity B Compound 4 (3.05 g, 0.0130 mol) was dissolved in 40 mL of methanol, stirred and cooled to 0–5 °C, and sodium borohydride (0.98 g, 0.026 mmol) was added in portions. The mixture was stirred for 4 hours, and the reaction was detected by TLC (petroleum ether: ethyl acetate = 1:1, V / V). The reaction solution was poured into purified water (100 mL), ethyl acetate (100 mL) was added, and the mixture was stirred for 5 minutes. The mixture was allowed to stand and separate into layers. The ethyl acetate phase was retained, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 2.77 g of off-white solid, i.e., impurity B, with a yield of 90% and an overall yield of 58.4% for the five steps.
[0034] The obtained terbutaline sulfate impurity B was subjected to high-resolution mass spectrometry, nuclear magnetic resonance structural data, and liquid chromatography purity analysis. The results were obtained by HR-MS ( m / z ): 238.1530 [M+H] +1 H 1 -NMR (DMSO- d 6 (400MHz) δ: 1.42 (s, 6H, 3CH3), 3.42 (m, 2H, CH2), 4.18 (m, 2H, CH2), 4.92 (t, 1H, CH), 6.38 (s, 1H, Ph), 6.42 (s, 1H, Ph). Analysis results show the structure is correct, with a purity of 99.52%.
Claims
1. A method for synthesizing terbutaline sulfate impurity B, characterized in that: Includes the following steps: (1) Compound 1 was prepared by esterification of 2-bromo-3',5'-dihydroxyacetophenone with acetic anhydride under alkaline conditions; (2) Compound 1 was dissolved in solvent 1 and reacted with tert-butylamine via a substitution reaction to obtain compound 2; (3) Compound 2 was dissolved in solvent 2 and compound 3 was obtained by cyclization reaction; (4) Compound 3 is dissolved in solvent 3, an alkaline solution is added, and compound 4 is obtained by hydrolysis reaction; (5) Compound 4 was reduced in solvent 4 to obtain impurity B; The structural formulas of compounds 1-4 and impurity B are shown below: ； Step (1) also includes a solvent, which is used to dissolve 2-bromo-3',5'-dihydroxyacetophenone, add acetic anhydride, and carry out esterification reaction under alkaline conditions; the solvent is one or a mixture of several of dichloromethane, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF, and DMSO in any proportion. In step (2), solvent 1 is one or more of methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion. In step (2), the molar ratio of tert-butylamine to compound 1 is 1 to 4:1; In step (3), the solvent 2 is one or more of water, methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion. In step (4), solvent 3 is a mixed solution of one of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and water; the alkaline solution is one of sodium hydroxide, potassium hydroxide or lithium hydroxide solution. In step (5), the solvent 4 is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane or 1,2-dichloroethane in any proportion.
2. The method for synthesizing terbutaline sulfate impurity B according to claim 1, characterized in that: In step (1), the alkali is one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine.
3. The method for synthesizing terbutaline sulfate impurity B according to claim 1, characterized in that: In step (2), solvent 1 is methanol or ethanol.
4. The method for synthesizing terbutaline sulfate impurity B according to claim 1, characterized in that: In step (3), solvent 2 is a mixture of methanol or ethanol and water; the reagent used in the cyclization reaction is paraformaldehyde.
5. The method for synthesizing terbutaline sulfate impurity B according to claim 1, characterized in that: In step (4), the solvent 3 is methanol; the alkaline solution is sodium hydroxide solution.
6. The method for synthesizing terbutaline sulfate impurity B according to claim 1, characterized in that: In step (5), the solvent 4 is methanol.
7. The method for synthesizing terbutaline sulfate impurity B according to claim 1, characterized in that: In step (5), the reducing agent is sodium borohydride or lithium aluminum hydride.