CN115010665A - Method for synthesizing terbutaline sulfate impurity B - Google Patents

Abstract

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for synthesizing impurity B of terbutaline sulfate. Using p-2-bromo-3', 5'-dihydroxyacetophenone as a raw material, terbutaline sulfate impurity B is prepared through 5 steps of esterification reaction, substitution reaction, cyclization reaction, hydrolysis reaction and reduction reaction. The synthesis method of the invention has the advantages of simple reaction process, readily available raw materials, and a total yield of more than 50%, which contributes to strictly controlling the content of impurity B of terbutaline sulfate by using an external standard method; the reaction conditions are mild, and the product purity is High, suitable for drug quality research, to provide assurance for improving the quality of terbutaline sulfate APIs.

Description

A kind of synthetic method of terbutaline sulfate impurity B

technical field

The invention belongs to the technical field of medicinal chemistry, and in particular relates to a method for synthesizing impurity B of terbutaline sulfate.

Background technique

Terbutaline sulfate (terbutaline, TBT), also known as metahydroxysalbutamol, terbutaline, terbutaline sulfate, is a selective beta ₂ adrenergic receptor stimulant, both antiasthmatic, It has expectorant effect and bronchial relaxation effect. It can be used clinically 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 of terbutaline sulfate reports 4 impurities, wherein the impurity B structure is as follows:

In order to ensure the safety of clinical medication, the quality control of impurity B in terbutaline sulfate is required. Since only a trace amount of impurity B is produced in the preparation process of terbutaline sulfate, it is not easy to separate and purify as an impurity reference substance, and there is no literature report on the synthetic route of this impurity at this stage. Therefore, it is very useful to study a method of terbutaline sulfate impurity B. necessary.

SUMMARY OF THE INVENTION

Aiming at the problem that the impurity B in terbutaline sulfate is carried out quality control at the present stage, the invention provides a kind of synthetic method of terbutaline sulfate impurity B, to 2-bromo-3', 5'-dihydroxyl Acetophenone is used as a raw material, and is obtained through 5 steps of esterification reaction, substitution reaction, cyclization reaction, hydrolysis reaction and reduction reaction; the raw materials are easily available, the reaction conditions are mild, the total yield is high, and the product purity is high. Guarantee the quality of butaline APIs.

The technical scheme of the present invention is as follows:

A synthetic method of terbutaline sulfate impurity B, comprising the following steps:

(1) Compound 1 is prepared by esterification of 2-bromo-3', 5'-dihydroxyacetophenone and acetic anhydride under the action of alkali;

(2) Compound 1 is dissolved in solvent 1, and compound 2 is prepared by substitution reaction with tert-butylamine;

(3) Compound 2 is dissolved in solvent 2, and compound 3 is prepared by cyclization reaction;

(4) Compound 3 is dissolved in solvent 3, an alkaline solution is added, and compound 4 is prepared by hydrolysis reaction;

(5) Compound 4 is prepared in solvent 4 through reduction reaction to obtain impurity B;

Wherein, the structural formula of above-mentioned compound 1-4 and impurity B is as follows:

。

.

Further, step (1) also includes solvent 4, after dissolving 2-bromo-3', 5'-dihydroxyacetophenone, adding acetic anhydride, and carrying out an esterification reaction under the action of alkali; the solvent 4 It is a mixed solution of one or more of dichloromethane, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF and DMSO in any proportion.

Preferably, the base described in step (1) is one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine, preferably triethylamine.

Preferably, the solvent 1 is a mixed solution of one or more of methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF or DMSO in any proportion, preferably methanol or ethanol.

Preferably, the molar ratio of the tert-butylamine to 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 or DMSO in any proportion, preferably methanol or ethanol and water mixture.

Preferably, in step (3), the reagent used in the cyclization reaction is an aqueous formaldehyde solution or paraformaldehyde, preferably paraformaldehyde.

Preferably, in step (4), the solvent 3 is a mixed solution of methanol, ethanol, isopropanol, tetrahydrofuran or dioxane and water, preferably methanol; the alkaline solution is hydrogen One of sodium oxide, potassium hydroxide or lithium hydroxide solution, preferably sodium hydroxide solution.

Preferably, in step (5), the solvent 4 is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, dichloromethane or 1,2-dichloroethane. Mixed solution in any proportion, preferably methanol.

Preferably, in step (5), the reducing agent is sodium borohydride and lithium aluminum tetrahydrogen.

The synthetic process is as follows:

Compared with the prior art, the beneficial effects of the present invention are as follows:

1, the synthetic method of the terbutaline sulfate impurity B of the present invention, a total of 5 steps are reacted, the raw materials are easy to obtain, and the total yield is greater than 50%, and the external standard method is used to strictly control the terbutaline sulfate impurity B content. make a contribution.

2. The synthesis method of the present invention has simple operation, mild reaction conditions and high product purity, is suitable for drug quality research, and provides guarantee for improving the quality of terbutaline sulfate crude drug.

Description of drawings

Fig. 1 is the nuclear magnetic spectrum of the terbutaline sulfate impurity B prepared by the embodiment of the present invention 3;

Fig. 2 is the mass spectrum of the terbutaline sulfate impurity B prepared by the embodiment of the present invention 3;

Fig. 3 is the liquid phase purity spectrum of terbutaline sulfate impurity B prepared in Example 3 of the present invention.

Detailed ways

The present invention will be further described below in conjunction with the examples, but the present invention is not limited.

All raw materials used in the examples are commercially available unless otherwise specified.

Example 1

1. Synthesis of Compound 1

2-Bromo-3',5'-dihydroxyacetophenone (0.46g, 2.0mmol)) was dissolved in 4ml of dichloromethane, and 1ml of acetic anhydride and diisopropylethylamine (1.3g, 10.0mmol) were added. , the reaction was stirred at room temperature, and the reaction was monitored by TLC (petroleum ether:ethyl acetate=2:1, V/V). Evaporate to dryness under reduced pressure, add 20 ml of water, extract with 20 ml×3 ethyl acetate, and combine the organic layers. Washed with saturated sodium bicarbonate solution, washed with pure water, dried over anhydrous sodium sulfate, evaporated to dryness, concentrated under reduced pressure, separated and purified by column chromatography to obtain 0.52 g of white solid, namely compound 1, with a yield of 83%.

2. Synthesis of Compound 2

Compound 1 (0.52 g, 1.65 mmol) was dissolved in 10 ml of methanol, tert-butylamine (0.48 g, 6.6 mmol) was added, the temperature was raised to 60-70 ° C, and stirred for 6 hours. TLC detected the completion of the reaction (petroleum ether: ethyl acetate = 2:1, V/V), distilled under reduced pressure, and the obtained residue was separated and purified by column chromatography to obtain 0.48 g of white solid, which was compound 2, and the yield was 95%.

3. Synthesis of Compound 3

Compound 2 (0.48 g, 1.56 mmol) was dissolved in a mixed solvent of 5 ml of water and 5 ml of ethanol, and 1 ml of aqueous formaldehyde solution was added, and the reaction was stirred at room temperature for 72 h. The completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate=2:1, V/V). The ethanol was evaporated under reduced pressure, cooled to 0~5°C, stirred and crystallized for 1 h, filtered, and dried to constant weight to obtain 0.42 g of a white solid, namely compound 3, with a yield of 84%.

4. Synthesis of Compound 4

Compound 3 (0.42 g, 1.32 mmol) was dissolved in 10 mL of ethanol, sodium hydroxide (0.4 g, 10.0 mmol) and purified water (2 mL) were added with stirring, the temperature was raised to 50±2 °C, stirred for 2 hours, TLC detected the completion of the reaction (Petroleum ether:ethyl acetate=1:1, V/V), adjust the pH of the reaction system to 5-6 with 2M hydrochloric acid solution, cool down to 0~5 °C, stir for crystallization for 1 h, filter, and dry to constant weight to obtain a white solid 0.27g, namely compound 4, yield 87%.

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, added with lithium tetrahydroaluminum (0.17 g, 4.6 mmol), stirred for 4 hours, TLC detected the completion of the reaction (petroleum ether: acetic acid) ethyl ester=1:1, V/V), slowly add saturated ammonium chloride purified water (15 mL) dropwise to the reaction solution, add ethyl acetate (15 mL), stir for 5 minutes, stand for stratification, keep ethyl acetate The ester 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, namely impurity B, with a yield of 88% and a five-step total yield of 50.5%.

Example 2

1. Synthesis of Compound 1

2-Bromo-3', 5'-dihydroxyacetophenone (0.46g, 2.0mmol)) was dissolved in 4ml acetonitrile, 1ml acetic anhydride and sodium carbonate (1.06g, 10.0mmol) were added, and the reaction was stirred at room temperature. TLC The completion of the reaction was monitored (petroleum ether:ethyl acetate=2:1, V/V). Evaporate to dryness under reduced pressure, add 20 ml of water, extract with 20 ml×3 ethyl acetate, and combine the organic layers. Washed with saturated sodium bicarbonate solution, washed with pure water, dried over anhydrous sodium sulfate, evaporated to dryness, concentrated under reduced pressure, and purified by column chromatography to obtain 0.52 g of white solid, namely compound 1, with a yield of 83%.

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 temperature was raised to 60-70 ° C, and stirred for 6 hours. TLC detected the completion of the reaction (petroleum ether: ethyl acetate = 2:1, V/V), distilled under reduced pressure, and the obtained residue was separated and purified by column chromatography to obtain 0.47 g of white solid, which was compound 2, with a yield of 91%.

3. Synthesis of Compound 3

Compound 2 (0.47 g, 1.50 mmol) was dissolved in a mixed solvent of 5 ml of water and 5 ml of ethanol, 1 ml of aqueous formaldehyde solution was added, and the reaction was stirred at room temperature for 72 h. The completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate=2:1, V/V). The ethanol was evaporated under reduced pressure, cooled to 0~5°C, stirred and crystallized for 1 h, filtered, and dried to constant weight to obtain 0.42 g of a white solid, namely compound 3, with a yield of 88%.

4. Synthesis of Compound 4

Compound 3 (0.42 g, 1.32 mmol) was dissolved in 10 mL of ethanol, lithium hydroxide (0.24 g, 10.0 mmol) and purified water (2 mL) were added with stirring, the temperature was raised to 50±2 °C, stirred for 2 hours, TLC detected the completion of the reaction (Petroleum ether:ethyl acetate=1:1, V/V), adjust the pH of the reaction system to 5-6 with 2M hydrochloric acid solution, cool down to 0~5 °C, stir for crystallization for 1 h, filter, and dry to constant weight to obtain a white solid 0.26g, namely compound 4, yield 87%.

5. Synthesis of Impurity B

Compound 4 (0.26g, 1.11mmol) was dissolved in 5mL of dioxane, stirred and cooled to 0~5°C, added with lithium tetrahydroaluminum (0.17g, 4.6mmol), stirred for 4 hours, TLC detected the completion of the reaction (petroleum ether: ethyl acetate=1:1, V/V), slowly dropwise added saturated ammonium chloride purified water (15 mL) to the reaction solution, added ethyl acetate (15 mL), stirred for 5 minutes, allowed to stand for layers, The ethyl acetate phase was retained, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 0.25 g of an off-white solid, namely impurity B, with a yield of 95% and a five-step total yield of 52.7%.

Example 3

1. Synthesis of Compound 1

2-Bromo-3', 5'-dihydroxyacetophenone (4.62g, 0.02mol)) was dissolved in 40ml of acetic anhydride, triethylamine (3.03g, 0.03mol) was added for catalysis, the reaction was stirred at room temperature and monitored by TLC The reaction was completed (petroleum ether:ethyl acetate=2:1, V/V). Evaporate to dryness under reduced pressure, add 200 ml of water, extract with 50 ml×3 ethyl acetate, and combine the organic layers. Washed with saturated sodium bicarbonate solution, washed with pure water, dried over anhydrous sodium sulfate, evaporated to dryness, concentrated under reduced pressure, separated and purified by column chromatography to obtain 5.50 g of white solid, namely compound 1, with a yield of 87%.

2. Synthesis of Compound 2

Compound 1 (5.50 g, 0.0175 mol) was dissolved in 50 ml of ethanol, tert-butylamine (5.12 g, 0.070 mol) was added, the temperature was raised to 60-70 ° C, and stirred for 6 hours. TLC detected the completion of the reaction (petroleum ether: ethyl acetate = 2:1, V/V), distilled under reduced pressure, and the obtained residue was separated and purified by column chromatography to obtain 5.12 g of white solid, which was compound 2, and the yield was 95%.

3. Synthesis of Compound 3

Compound 2 (5.12 g, 0.0167 mol) was dissolved in a mixed solvent of 20 ml of water and 20 ml of methanol, and paraformaldehyde (4.51 g, 0.0501 mol) was added, and the reaction was stirred at room temperature for 72 h. The completion of the reaction was monitored by TLC (petroleum ether:ethyl acetate=2:1, V/V). The methanol was evaporated under reduced pressure, cooled to 0~5°C, stirred for crystallization for 1 h, filtered, and dried to constant weight to obtain 4.72 g of a white solid, namely compound 3, with a yield of 88%.

4. Synthesis of Compound 4

Compound 3 (4.72 g, 0.0148 mol) was dissolved in 40 mL of ethanol, sodium hydroxide (2.96 g, 0.074 mmol) and purified water (10 mL) were added with stirring, the temperature was raised to 50±2 °C, stirred for 2 hours, TLC detected the completion of the reaction (Petroleum ether:ethyl acetate=1:1, V/V), adjust the pH of the reaction system to 5-6 with 2M hydrochloric acid solution, cool down to 0~5 °C, stir for crystallization for 1 h, filter, and dry to constant weight to obtain a white solid 3.05g, namely compound 4, yield 88%.

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, sodium borohydride (0.98 g, 0.026 mmol) was added in batches, stirred for 4 hours, TLC detected the completion of the reaction (petroleum ether: ethyl acetate = 1:1, V/V), pour the reaction solution into purified water (100 mL), add ethyl acetate (100 mL), stir for 5 minutes, stand for stratification, keep the ethyl acetate phase, anhydrous It was dried over sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 2.77 g of off-white solid, namely impurity B, with a yield of 90% and a five-step total yield of 58.4%.

The obtained terbutaline sulfate impurity B was subjected to high-resolution mass spectrometry, nuclear magnetic structure data, and liquid phase purity analysis, and the results were HR-MS ( 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 analytical results showed that the structure was correct and the purity was 99.52%.

Claims (10)

1. a synthetic method of terbutaline sulfate impurity B, is characterized in that: may further comprise the steps: (1) Compound 1 is prepared by esterification of 2-bromo-3', 5'-dihydroxyacetophenone and acetic anhydride under the action of alkali; (2) Compound 1 is dissolved in solvent 1, and compound 2 is prepared by substitution reaction with tert-butylamine; (3) Compound 2 is dissolved in solvent 2, and compound 3 is prepared by cyclization reaction; (4) Compound 3 is dissolved in solvent 3, an alkaline solution is added, and compound 4 is prepared by hydrolysis reaction; (5) Compound 4 is prepared in solvent 4 through reduction reaction to obtain impurity B; Wherein, the structural formula of above-mentioned compound 1-4 and impurity B is as follows:

. 2. the synthetic method of terbutaline sulfate impurity B according to claim 1, is characterized in that: also comprises solvent 4 in step (1), 2-bromo-3', 5'-dihydroxyacetophenone After dissolving, add acetic anhydride, carry out esterification under the action of alkali; Described solvent 4 is one or more in methylene chloride, toluene, dioxane, acetonitrile, tetrahydrofuran, DMF, DMSO in any proportion of the mixture. 3. the synthetic method of terbutaline sulfate impurity B according to claim 1, is characterized in that: the alkali described in step (1) is potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethyl ether One of amine or diisopropylethylamine, preferably triethylamine. 4. the synthetic method of terbutaline sulfate impurity B according to claim 1, is characterized in that: in step (2), described solvent 1 is methanol, ethanol, toluene, dioxane, acetonitrile, tetrahydrofuran A mixed solution of one or more of , DMF or DMSO in any proportion, preferably methanol or ethanol. 5 . The method for synthesizing terbutaline sulfate impurity B according to claim 1 , wherein in step (2), the molar ratio of the terbutaline to compound 1 is 1 to 4:1. 6 . 6. The synthetic method of terbutaline sulfate impurity B according to claim 1, characterized in that: in step (3), the solvent 2 is water, methanol, ethanol, toluene, dioxane, acetonitrile A mixed solution of one or more of , 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 step (3), the reagent used in the cyclization reaction is an aqueous formaldehyde solution or paraformaldehyde, preferably a polymer formaldehyde. 8. The synthetic method of terbutaline sulfate impurity B according to claim 1, characterized in that: in step (4), the solvent 3 is methanol, ethanol, isopropanol, tetrahydrofuran or dioxane One of the mixed solution with water, preferably methanol; the alkaline solution is one of sodium hydroxide, potassium hydroxide or lithium hydroxide solution, preferably sodium hydroxide solution. 9. The synthetic method of terbutaline sulfate impurity B according to claim 1, characterized in that: in step (5), the solvent 4 is methanol, ethanol, isopropanol, tetrahydrofuran, dioxane A mixed solution of one or more of , dichloromethane or 1,2-dichloroethane in any proportion, preferably methanol. 10 . The method for synthesizing terbutaline sulfate impurity B according to claim 1 , wherein in step (5), the reducing agent is sodium borohydride and lithium aluminum tetrahydrogen. 11 .

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