CN115974710A - Bisoprolol fumarate impurity and preparation method thereof - Google Patents
Bisoprolol fumarate impurity and preparation method thereof Download PDFInfo
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- CN115974710A CN115974710A CN202211697897.9A CN202211697897A CN115974710A CN 115974710 A CN115974710 A CN 115974710A CN 202211697897 A CN202211697897 A CN 202211697897A CN 115974710 A CN115974710 A CN 115974710A
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Abstract
The invention discloses a bisoprolol fumarate impurity and a preparation method thereof. The method comprises the following steps: 1) Reacting the compound I with dimethyl butynedioate to obtain an intermediate II; 2) Reacting the intermediate II with sodium cyanoborohydride to obtain an intermediate III; 3) And carrying out hydrolysis reaction on the intermediate III and potassium trimethylsilanolate to obtain an impurity IV. The invention has reasonable design of synthetic route, simple post-treatment, mild reaction condition and strong operability. The bisoprolol fumarate impurity IV prepared by the method can be used as an impurity standard substance for bisoprolol fumarate finished product detection analysis, so that the accurate positioning and qualification of the bisoprolol fumarate finished product detection analysis on the impurity IV are improved, the control on the impurity is favorably strengthened, and the quality of a bisoprolol fumarate finished product is improved.
Description
Technical Field
The invention relates to bisoprolol fumarate, and in particular relates to bisoprolol fumarate impurities and a preparation method thereof.
Background
Bisoprolol Fumarate (Bisoprolol Fumarate) is a highly selective β 1 adrenoreceptor antagonist. The traditional Chinese medicine composition is clinically used for treating mild and moderate essential hypertension, coronary heart disease and angina, and also used for treating moderate and severe chronic stable heart failure. The chemical name is (+/-) 1- [4- [ [2- (1-methylethoxy) ethoxy ] methyl ] -phenoxy ] -3[ (1-methylethyl) amino ] -2-propanol fumarate, and the structural formula is shown as the following formula (I).
For safety reasons, national and international regulatory agencies typically limit the content of unidentified or toxicity-undetermined impurities in APIs (drug substances) to less than 0.1%. If the content of the related impurities in the API is more than 0.1%, the impurities need to be deeply researched to ensure that the raw materials of the pharmaceutical preparation which meets the pharmaceutical standard and is safe and effective are obtained.
Bisoprolol fumarate as a drug substance may contain impurities from various sources, some of which are generated during storage of the drug substance, some of which are generated by self-degradation, and some of which are generated by a preparation method, including but not limited to unreacted starting materials, synthesis byproducts, degraded products and the like, and the impurities bring potential safety hazards to human administration. The applicant analyzes bisoprolol fumarate by a liquid chromatography-mass spectrometry (LCMS) detection means in the earlier stage to find a brand new impurity IV (the content is more than 0.1%), and meanwhile, no literature reports a preparation method of the impurity. Therefore, the preparation method for preparing bisoprolol fumarate impurity IV, which is simple in synthetic route and easy to separate and purify, is found, and has important significance for perfecting consistency evaluation, improving product quality and ensuring safe medication of human beings.
Disclosure of Invention
The invention aims to: the invention provides a preparation method of bisoprolol fumarate impurities, which has the advantages of reasonable design of synthetic route, simple post-treatment, mild reaction conditions and strong operability.
The technical scheme is as follows: the invention adopts the following technical route:
bisoprolol fumarate impurity IV with structural formula shown in formula IV
The preparation method of bisoprolol fumarate impurity IV is characterized by comprising the following steps:
the method comprises the following operation steps:
s1 Synthesis of intermediate II
Dissolving the compound I in an organic solvent, adding dimethyl butynedioate, stirring at 80 ℃ for reaction, detecting by TLC (thin layer chromatography) until the compound I disappears, concentrating under reduced pressure, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain an intermediate II;
s2: synthesis of intermediate III
Dissolving the intermediate II in an organic solvent, adding sodium cyanoborohydride, then placing at 25 ℃ for reaction, detecting by TLC (thin layer chromatography) until the intermediate II disappears, adding water into the reaction solution, extracting by ethyl acetate, separating, and removing the organic phase solvent by decompression to obtain an intermediate III;
s3: synthesis of impurity IV
Dissolving the intermediate III in an organic solvent, adding TMSOK at 0 ℃, then stirring at 25 ℃ for reaction, detecting by TLC until the intermediate III disappears, cooling to 0 ℃, dropwise adding a dilute hydrochloric acid aqueous solvent (1 mol/L), adjusting the pH of the solution to be 2-3, performing suction filtration, and pulping a filter cake by petroleum ether/dichloromethane to be =20/1 to obtain a pure bisoprolol fumarate impurity IV.
Wherein the organic solvent used in the synthesis of the intermediate II in the step S1 is 1,4-dioxane; the molar ratio of the compound I to the dimethyl butynedioate is 1.8-2.2
Wherein, the organic solvent used in the synthesis of the intermediate III in the step S2 is acetonitrile; the molar ratio of the intermediate II to the cyano sodium borohydride is 1:2-3.
Wherein, the organic solvent used in the synthesis of the impurity IV in the step S3 is one or more of methanol, tetrahydrofuran and acetonitrile, preferably acetonitrile; the molar ratio of the intermediate III to TMSOK is 1:2-3.
Advantageous effects
The invention discovers a brand-new compound (bisoprolol fumarate impurity IV), the structure of which is not reported in documents, and in addition, the invention provides a preparation method of the bisoprolol fumarate impurity IV, the synthesis route is reasonable in design, the post-treatment is simple, the reaction condition is mild, and the operability is strong. The bisoprolol fumarate impurity IV prepared by the method can be used as an impurity standard substance for bisoprolol fumarate finished product detection analysis, so that the accuracy and the qualification of the bisoprolol fumarate finished product detection analysis on the impurity IV are improved, the control on the impurity is favorably strengthened, and the quality of a bisoprolol fumarate finished product is improved.
Drawings
FIG. 1 is a LCMS detection spectrum of bisoprolol fumarate impurity IV prepared in experimental example 3;
FIG. 2 shows bisoprolol fumarate impurity IV prepared in test example 3 1 H NMR check spectrum.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, LCMS or NMR), typically at the end of the reaction when starting material is lost.
The mixed solvent in the embodiment of the invention is calculated by volume ratio.
Example 1:
the preparation method specifically comprises the following steps:
compound I (5.00g, 15.36mmol) and 1,4-dioxane (30 ml) were added to a 100ml single neck flask, stirred at room temperature until clear, added dimethyl butynedioate (4.37g, 30.73mmol) and reacted at 80 ℃ for 3h. After completion of the reaction monitored by TLC, silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) gave intermediate II (6.98 g, yield: 97.17%) as an oil. ESI-MS (m/z): 468.2
Example 2:
the preparation method specifically comprises the following steps:
a50 mL single-neck flask was charged with intermediate II (6.98g, 14.93mmol), sodium cyanoborohydride (2.35g, 37.32mmol) and acetonitrile (40 mL), reacted at room temperature for 5h under the protection of N2, and after the reaction was monitored by TLC, water (5 mL) was added to the reaction solution, extracted with ethyl acetate, separated, and the organic phase solvent was removed under reduced pressure to give intermediate III (6.1 g, yield: 93.39%). ESI-MS (m/z): 438.2
Example 3:
example 3 of the present invention provides a method for preparing impurity IV:
the preparation method specifically comprises the following steps:
adding the intermediate III (2g, 4.57mmol) into a 50mL single-neck flask, dissolving the intermediate III with acetonitrile (5 mL), adding TMSOK (1.47g, 11.43mmol) at 0 ℃, then stirring the reaction at 25 ℃, detecting by TLC until the intermediate III disappears, cooling to 0 ℃, dropwise adding a dilute hydrochloric acid aqueous solvent (1 mol/L), adjusting the pH of the solution to be 2-3, performing suction filtration, and pulping a filter cake by petroleum ether/dichloromethane =20/1 to obtain white solid impurity IV (1.8 g, yield: 89.19%). ESI-MS (m/z): 442.3. 1 H NMR(400MHz,DMSO)δ7.55(s,0H),7.17(s,1H),6.86(d,J＝5.7Hz,2H),4.36(s,1H),3.80(s,2H),3.56(d,J＝27.2Hz,1H),3.46(s,2H),2.92(s,0H),2.65(s,1H),2.24(s,0H),2.01(s,1H),1.54(s,0H),1.24(s,0H),1.06(d,J＝4.7Hz,3H),0.96(d,J＝16.6Hz,2H).
Example 4:
example 4 of the present invention provides a method for preparing impurity IV:
adding the intermediate III (2g, 4.57mmol) into a 50mL single-neck flask, dissolving with tetrahydrofuran (5 mL), adding TMSOK (1.17g, 9.14mmol) at 0 ℃, then stirring at 25 ℃, detecting by TLC until the intermediate III disappears, cooling to 0 ℃, dropwise adding a dilute hydrochloric acid aqueous solvent (1 mol/L), adjusting the pH of the solution to be =2-3, performing suction filtration, and pulping a filter cake by petroleum ether/dichloromethane =20/1 to obtain white solid impurity IV (1.7 g, yield: 84.23%). ESI-MS (m/z): 442.3
Example 5:
example 4 of the present invention provides a method for preparing impurity IV:
adding the intermediate III (2g, 4.57mmol) into a 50mL single-neck flask, dissolving with methanol (5 mL), adding TMSOK (1.76g, 13.71mmol) at 0 ℃, then stirring the reaction at 25 ℃, detecting by TLC until the intermediate III disappears, cooling to 0 ℃, dropwise adding a dilute hydrochloric acid aqueous solvent (1 mol/L), adjusting the pH of the solution to be 2-3, filtering, and pulping the filter cake by petroleum ether/dichloromethane =20/1 to obtain white solid impurity IV (1.5 g, yield: 74.32%). ESI-MS (m/z): 442.3
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (5)
1. Bisoprolol fumarate impurity IV with structural formula shown in formula IV
2. The preparation method of bisoprolol fumarate impurity IV according to claim 1, which is realized by the following steps:
the method comprises the following operation steps:
s1 Synthesis of intermediate II
Dissolving a compound I in an organic solvent, adding dimethyl butynedioate, stirring at 80 ℃ for reaction, detecting by TLC (thin layer chromatography) until the compound I disappears, concentrating under reduced pressure, performing silica gel column chromatography, and purifying to obtain an intermediate II, wherein the volume ratio of petroleum ether to ethyl acetate is = 4/1;
s2: synthesis of intermediate III
Dissolving the intermediate II in an organic solvent, adding sodium cyanoborohydride, then placing at 25 ℃ for reaction, detecting by TLC until the intermediate II disappears, adding water into the reaction solution, extracting by ethyl acetate, separating, and removing the organic phase solvent by decompression to obtain an intermediate III;
s3: synthesis of impurity IV
Dissolving the intermediate III in an organic solvent, adding TMSOK at 0 ℃, then stirring at 25 ℃ for reaction, detecting by TLC until the intermediate III disappears, cooling to 0 ℃, dropwise adding a dilute hydrochloric acid aqueous solvent (1 mol/L), adjusting the pH of the solution to be 2-3, performing suction filtration, and pulping a filter cake by using petroleum ether/dichloromethane volume ratio to be =20/1 to obtain a pure bisoprolol fumarate impurity IV.
3. Bisoprolol fumarate impurity IV according to claim 2, characterized in that the organic solvent used in the synthesis of compound I in step S1 is 1,4-dioxane; the molar ratio of the compound I to the dimethyl butynedioate is 1.8-2.2.
4. Bisoprolol fumarate impurity IV according to claim 2, characterized in that the organic solvent used in the synthesis of intermediate III in step S2 is acetonitrile; the molar ratio of the intermediate II to the cyano sodium borohydride is 1:2-3.
5. The bisoprolol fumarate impurity IV according to claim 2, wherein the organic solvent used in the synthesis of the impurity IV in step S3 is one or more of methanol, tetrahydrofuran and acetonitrile; the molar ratio of the intermediate III to TMSOK is 1:2-3.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107973761A (en) * | 2017-06-26 | 2018-05-01 | 江苏悦兴医药技术有限公司 | The synthetic method of bisoprolol fumarate's process contaminants |
| CN112441932A (en) * | 2020-12-29 | 2021-03-05 | 深圳市祥根生物科技有限公司 | Preparation method of bisoprolol fumarate impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107973761A (en) * | 2017-06-26 | 2018-05-01 | 江苏悦兴医药技术有限公司 | The synthetic method of bisoprolol fumarate's process contaminants |
| CN112441932A (en) * | 2020-12-29 | 2021-03-05 | 深圳市祥根生物科技有限公司 | Preparation method of bisoprolol fumarate impurity |
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