A method for synthesizing important impurities of bisoprolol

Abstract

The invention discloses a method for synthesizing a bisoprolol European Pharmacopoeia EP impurity E, comprising the following steps: (1) using free bisoprolol API as a starting material, protecting the amino group with p-methoxybenzyl chloride, and obtaining an intermediate 1; (2) brominating the hydroxyl group of the intermediate 1 with triphenylphosphine and carbon tetrabromide, and obtaining an intermediate 2; (3) eliminating the bromine from the intermediate 2 with a base to generate a double bond, and obtaining an intermediate 3; and (4) removing the p-methoxybenzyl protection from the intermediate 3 with an oxidant, and obtaining a target product, bisoprolol EP impurity E. ... and comprising the following steps: (1) using free bisoprolol API as a starting material, protecting the amino group with p-methoxybenzyl chloride, and obtaining an intermediate 1; (2) brominating the hydroxyl group of the intermediate 1 with triphenylphosphine and carbon tetrabromide, and obtaining an intermediate 2; (3) removing the bromine from the intermediate 2 with a base to generate a double bond, and obtaining an intermediate 3; and (4) removing the p-methoxybenzyl

Description

Technical Field

[0001] The invention belongs to the technical field of drug impurity preparation, and particularly relates to a method for synthesizing bisoprolol European Pharmacopoeia EP impurity E. Background Art

[0002] Bisoprolol fumarate is a beta-receptor blocker with high affinity for the beta1-receptors of bronchial and vascular smooth muscle, thereby dilating blood vessels and lowering blood pressure. It is suitable for hypertension, coronary heart disease, and moderate to severe chronic stable heart failure. It blocks the neuroendocrine system, and more importantly, targets the mechanism of myocardial remodeling, prevents and delays the development of myocardial remodeling, improves myocardial compliance, and significantly improves left ventricular diastolic function, so that the enlarged left ventricular cavity gradually returns to normal. Long-term use of bisoprolol fumarate to treat hypertension can improve cardiac systolic and diastolic function, reverse ventricular remodeling, and has antioxidant and anti-apoptotic effects, thereby fully protecting heart function. It has obvious advantages and broad application prospects among drugs with the same target. For human use, due to safety requirements, domestic and international regulatory agencies have set very low limits for unconfirmed or undetermined toxic impurities in APIs, usually less than 0.1% (weight). These important impurities need to be studied in depth to ensure that APIs that meet pharmaceutical standards and can be used to prepare safe and effective pharmaceutical preparations are prepared. Bisoprolol EP Impurity E, English name Bisoprolol EP Impurity E, molecular formula: C18H29NO3, molecular weight: 307.43, it is an important impurity in the synthesis of bisoprolol fumarate, a drug for the treatment of angina pectoris, arrhythmia and hypertension, and is included in the European Pharmacopoeia. At present, there is no publicly reported method for synthesizing Bisoprolol EP Impurity E, so finding a method for preparing Bisoprolol EP Impurity E that is simple to operate, low in cost, and easy to separate and purify is of great significance for safe drug use, improving consistency evaluation, and improving product quality. Summary of the invention

[0003] In order to solve the above problems, the present invention discloses a method for synthesizing bisoprolol EP impurity E.

[0004] To achieve the above object, the technical solution of the present invention is as follows:

[0005] A method for synthesizing an important impurity of bisoprolol comprises the following steps:

[0006] (1) Dissolving bisoprolol in a solvent, adding a base and p-methoxybenzyl chloride, and reacting to obtain intermediate 1;

[0007] (2) Dissolving intermediate 1 in a solvent, adding triphenylphosphine and carbon tetrabromide, and reacting to obtain intermediate 2;

[0008] (3) Dissolving intermediate 2 in a solvent, adding a base, and reacting to obtain intermediate 3;

[0009] (4) The intermediate 3 is dissolved in a solvent, an oxidant is added, and the reaction is performed to obtain the bisoprolol impurity EP impurity E.

[0010] The synthetic process route is as follows:

[0011]

[0012] Furthermore, in step (1), the molar ratio of bisoprolol to p-methoxybenzyl chloride is 1:1-2, preferably, the molar ratio of bisoprolol to p-methoxybenzyl chloride is 1:1.2; the volume ratio of the solvent to bisoprolol is 1-10:1; the molar ratio of the base to bisoprolol is 1-5:1, preferably, the molar ratio of the base to bisoprolol is 1.5:1.

[0013] Furthermore, in step (1), the reaction temperature is 20 to 30° C. and the reaction time is 6 to 12 hours.

[0014] Furthermore, in step (1), the solvent is one or more of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetone, and water, preferably, the solvent is acetonitrile; the base is one or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene, preferably, the base is potassium carbonate.

[0015] Furthermore, in step (2), the molar ratio of the intermediate 1 to triphenylphosphine to carbon tetrabromide is 1:1-2:1-2; and the volume ratio of the solvent to the intermediate 1 is 1-10:1.

[0016] Furthermore, in step (2), the solvent is one or more of dichloromethane, dichloroethane, acetonitrile, acetone, ethyl acetate, and tetrahydrofuran, preferably, the solvent is dichloromethane; the reaction temperature is 20 to 30° C.; and the reaction time is 6 to 12 hours.

[0017] Furthermore, in step (3), the molar ratio of the intermediate 2 to the base is 1:1-5; the volume ratio of the solvent to the intermediate 2 is 1-10:1; the reaction temperature is 25-60°C, preferably, the reaction temperature is 25-30°C; and the reaction time is 12-24 hours.

[0018] Further, in step (3), the solvent is one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, and acetone, and preferably, the solvent is carbon tetrachloride; the base is one or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene, and preferably, the base is 1,8-diazabicyclo[5.4.0]-7-undecene.

[0019] Furthermore, in step (4), the molar ratio of the intermediate 3 to the oxidant is 1:1 to 5; the volume ratio of the solvent to the intermediate 3 is 1 to 10:1; the reaction temperature is 30 to 60° C.; and the reaction time is 12 to 24 hours.

[0020] Furthermore, in step (4), the solvent is one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, and toluene, and preferably, the solvent is dichloromethane; the oxidant is one or more of 2,3-dichloro-5,6-dicyanobenzoquinone and cerium ammonium nitrate, and preferably, the oxidant is 2,3-dichloro-5,6-dicyanobenzoquinone.

[0021] The beneficial effects of the present invention are:

[0022] The invention adopts a strategy of first protecting the amino group and then converting the hydroxyl group into bromine, and then eliminating the double bond formed under the action of a base to obtain the target product, and the route is short, the raw materials are readily available, the cost is low, and the purification is easy. The prepared bisoprolol EP impurity E discloses a new synthesis method of bisoprolol EP impurity E, fills the synthesis technology gap of the impurity, and the synthesis of the impurity is of great significance for improving consistency evaluation and improving product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the NMR spectrum of the product of Example 7 of the present invention;

[0024] Figure 2 is the mass spectrum of the product of Example 7 of the present invention;

[0025] Figure 3 This is the synthetic process route of the present invention. DETAILED DESCRIPTION

[0026] The present invention will be further explained below in conjunction with the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0027] Example 1

[0028] 10.0g (0.031mol) of free bisoprolol raw material was added to a 250ml three-necked flask, and then 60ml of acetonitrile was added, followed by 6.4g (0.046mol) of potassium carbonate and 5.8g (0.037mol) of p-methoxybenzyl chloride, and the mixture was reacted at 30°C for 6 hours. After TLC detection, the reaction was completed, the solvent was removed by concentration, 60ml of water was added for stirring, 60ml*2 of ethyl acetate was added for extraction, the organic phases were combined, 30ml of water was added for washing, and then 30ml of saturated sodium chloride was added for washing, the organic phase was separated by layers, 10g of anhydrous sodium sulfate was added for drying, and then the salt was removed by suction filtration, and the solvent was removed by concentration to obtain 12.3g of intermediate 1, with a yield of 89.8% and a HPLC purity of 95%.

[0029] Example 2

[0030] 10.0g (0.031mol) of free bisoprolol raw material was added to a 250ml three-necked flask, 100ml of acetone was added, and then 9.8g (0.093mol) of sodium carbonate and 9.7g (0.062mol) of p-methoxybenzyl chloride were added, and the reaction was carried out at 20°C for 12 hours. After TLC detection, the solvent was concentrated to remove the solvent, 60ml of water was added and stirred, 60ml*2 ethyl acetate was added to extract, the organic phases were combined, 30ml of water was added to wash the organic phase; then 30ml of saturated sodium chloride was added to wash the organic phase, the organic phase was separated by layers, 10g of anhydrous sodium sulfate was added to dry, and then the salt was removed by suction filtration, and the solvent was concentrated to remove the solvent to obtain 11.1g of intermediate 1, with a yield of 80.4% and a HPLC purity of 93%.

[0031] Example 3

[0032] Add 12.3g (0.028mol) of intermediate 1 and 74ml of acetonitrile to a 250ml three-necked flask. Cool down to 0-5°C under nitrogen protection, add 10.1g (0.038mol) of triphenylphosphine, then add 11.1g (0.033mol) of carbon tetrabromide using a constant pressure dropping funnel, and heat to 25°C for 12 hours after addition. TLC detection shows that the reaction is complete, and 100ml of water is added to the reaction solution to quench the reaction. Then add 100ml*2 dichloromethane to extract, combine the organic phases, add 50ml of saturated sodium chloride for washing, separate the organic phases by layers, add 20g of anhydrous sodium sulfate to dry the organic phase. After filtering to remove salt, the organic phase is concentrated to dryness, and column chromatography (30% petroleum ether ethyl acetate) is used to obtain 6.2g of intermediate 2, with a yield of 42.7% and an HPLC purity of 97%.

[0033] Example 4

[0034] Add 12.3g (0.028mol) of intermediate 1 and 123ml of tetrahydrofuran to a 250ml three-necked flask. Cool down to 0-5°C under nitrogen protection, add 14.7g (0.056mol) of triphenylphosphine, then add 18.5g (0.056mol) of carbon tetrabromide using a constant pressure dropping funnel, and heat to 30°C for 6 hours after addition. TLC detection shows that the reaction is complete, and 100ml of water is added to the reaction solution to quench the reaction. Then add 100ml*2 dichloromethane to extract, combine the organic phases, add 50ml of saturated sodium chloride for washing, separate the organic phases by layers, add 20g of anhydrous sodium sulfate to dry the organic phase. After suction filtration to remove salt, the organic phase is concentrated to dryness, and 5.4g of intermediate 2 is obtained by column chromatography (30% petroleum ether ethyl acetate), with a yield of 38.0% and a HPLC purity of 95%.

[0035] Example 5

[0036] Add 6.2g (0.012mol) of intermediate 2 to a 100ml three-necked flask, add 62ml of carbon tetrachloride, stir to dissolve, then drop 1.9g (0.012mol) of 1,8-diazabicyclo[5.4.0]-7-undecene, keep at 40-45℃ for 12 hours. TLC detection shows that the reaction is complete, add 30ml of water to quench the reaction, add 60ml*2 of dichloromethane to extract the reaction solution, separate the organic phases, combine them, add 30ml of saturated sodium chloride to wash the organic phase, separate the organic phases, add 10g of anhydrous sodium sulfate to dry, filter to remove salt, and concentrate the organic phase to dryness to obtain 3.6g of intermediate 3, with a yield of 69% and a HPLC purity of 90%.

[0037] Example 6

[0038] Add 6.2g (0.012mol) of intermediate 2 to a 100ml three-necked flask, add 62ml of acetonitrile, stir to dissolve, then drop 8.3g (0.060mol) of potassium carbonate, keep at 40-45℃ for 24 hours. TLC detection shows that the reaction is complete, add 30ml of water to quench the reaction, add 60ml*2 of dichloromethane to extract the reaction liquid, separate the organic phases by layers, combine them, add 30ml of saturated sodium chloride to wash the organic phase, separate the organic phase, add 10g of anhydrous sodium sulfate to dry, filter to remove salt, and concentrate the organic phase to dryness to obtain 2.9g of intermediate 3, with a yield of 56.9% and a HPLC purity of 86%.

[0039] Example 7

[0040] Add 3.6g (0.008mol) of intermediate 3 to a 100ml three-necked flask, add 25ml of dichloromethane and stir to dissolve, add 2.3g (0.010mol) of 2,3-dichloro-5,6-dicyanobenzoquinone oxidant, and react at 30-35°C for 12 hours. TLC detection shows that the reaction is complete, and 15ml of saturated sodium bicarbonate is added to quench the reaction. Some dark red solids are insoluble in the system, and the solids are removed by suction. The filtrate is separated into layers and the aqueous phase is extracted with 25ml of dichloromethane, the organic phase is combined and washed with 15ml of water, the organic phase is separated into layers and washed with 15ml of saturated sodium chloride, the organic phase is separated and dried with 5g of anhydrous sodium sulfate, the salt is removed by suction, and the organic phase is concentrated to dryness. Column chromatography (5% methanol and dichloromethane) is used to obtain 1.4g of the target product with a yield of 53.8% and a HPLC purity of 98%.

[0041] Example 8

[0042] 3.6g (0.008mol) of intermediate 3 was added to a 100ml three-necked flask, 36ml of carbon tetrachloride was added and stirred to dissolve, 8.5g (0.016mol) of cerium ammonium nitrate oxidant was added, and the reaction was carried out at 30-35°C for 24 hours. TLC detected that the reaction was complete, 15ml of saturated sodium bicarbonate was added to quench the reaction, 72ml of dichloromethane was added to separate the layers, the filtrate was separated into the aqueous phase, 25ml of dichloromethane was added to extract, the organic phase was combined and washed with 15ml of water, the organic phase was separated into the organic phase, 15ml of saturated sodium chloride was added to wash, 5g of anhydrous sodium sulfate was added to dry the organic phase, the salt was removed by suction filtration, and the organic phase was concentrated to dryness. 1.2g of the target product was obtained by column chromatography (5% methanol and dichloromethane), with a yield of 48.8% and a HPLC purity of 96%.

[0043] It should be noted that the above content only illustrates the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications all fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing important impurities of bisoprolol, characterized in that: The following steps are involved: (1) Dissolving bisoprolol in a solvent, adding a base and p-methoxybenzyl chloride, and reacting to obtain intermediate 1; (2) Dissolving intermediate 1 in a solvent, adding triphenylphosphine and carbon tetrabromide, and reacting to obtain intermediate 2; (3) Dissolving intermediate 2 in a solvent, adding a base, and reacting to obtain intermediate 3; (4) dissolving the intermediate 3 in a solvent, adding an oxidant, and reacting to obtain the bisoprolol impurity EP impurity E; 2. A method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that, In step (1), the molar ratio of bisoprolol to p-methoxybenzyl chloride is 1:1-2; the volume ratio of the solvent to bisoprolol is 1-10:1; and the molar ratio of the base to bisoprolol is 1-5:

1.

3. A method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that, In step (1), the reaction temperature is 20 to 30° C. and the reaction time is 6 to 12 hours.

4. A method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that, In step (1), the solvent is one or more of DMF, tetrahydrofuran, acetonitrile, acetone, and water; and the base is one or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

5. A method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that, In step (2), the molar ratio of the intermediate 1 to triphenylphosphine and carbon tetrabromide is 1:1-2:1-2, and the volume ratio of the solvent to the intermediate 1 is 1-10:

1.

6. A method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that: In step (2), the solvent is one or more of dichloromethane, dichloroethane, acetonitrile, acetone, ethyl acetate, and tetrahydrofuran; the reaction temperature is 20 to 30° C.; and the reaction time is 6 to 12 hours.

7. The method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that: In step (3), the molar ratio of the intermediate 2 to the base is 1:1-5; the volume ratio of the solvent to the intermediate 2 is 1-10:1; the reaction temperature is 25-60°C; and the reaction time is 12-24 hours.

8. A method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that: In step (3), the solvent is one or more of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, toluene, and acetone; and the base is one or more of potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]-7-undecene.

9. The method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that: In step (4), the molar ratio of the intermediate 3 to the oxidant is 1:1 to 5; the volume ratio of the solvent to the intermediate 3 is 1 to 10:1; the reaction temperature is 30 to 60° C.; and the reaction time is 12 to 24 hours.

10. The method for synthesizing a bisoprolol important impurity according to claim 1, characterized in that: In step (4), the solvent is one or more of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, acetonitrile, and toluene; and the oxidant is one or more of 2,3-dichloro-5,6-dicyanobenzoquinone and cerium ammonium nitrate.

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