A method for refining bisoprolol

Abstract

The invention relates to a method for refining bisoprolol free base. The method comprises the following steps: dissolving bisoprolol free base in an organic solvent, first adding a certain amount of acid to completely salt an impurity A, then adding a base to selectively free the bisoprolol, extracting with an organic solvent, separating, drying the obtained organic phase, and concentrating under reduced pressure to obtain a refined bisoprolol free base. The technical solution provided by the invention has a simple operation process and low cost, can control the amount of impurity A to a level below 0.06%, and has a high refining yield, and can be used for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemical preparation, and in particular to a method for refining bisoprolol. The method can remove impurity A in bisoprolol. Background Art

[0002] The chemical name of bisoprolol fumarate is (±) l-[4-[[2-(l-methylethoxy)ethoxy]methyl]-phenoxy]-3-[(1-methylethyl)amino]-2-propanol fumarate, and its structural formula is as follows:

[0003]

[0004] Bisoprolol fumarate is a β1-adrenergic receptor blocker first developed by Merck in Germany in 1978. Since 1986, it has been marketed in over 20 countries and regions, including Germany, Switzerland, France, the United States, and Japan, in 2.5mg and 5mg film-coated tablets under the trade name Conxin. Bisoprolol fumarate has become one of the preferred β-blockers for the treatment of hypertension, angina pectoris, and tachycardia. This API has been marketed domestically and internationally for many years and is included in major European and American pharmacopoeias, demonstrating its proven safety and effectiveness.

[0005] Bisoprolol fumarate is a new-generation selective β1-adrenergic receptor blocker with no intrinsic sympathomimetic activity or membrane-stabilizing effects, but it inhibits renin secretion. It is almost completely absorbed orally, with a bioavailability exceeding 90%. Its half-life is 10-12 hours, and a single dose maintains its efficacy for 24 hours. Long-term use is non-accumulative. It combines the rapid absorption of lipophilic β1-adrenergic receptor blockers with the long half-life and low first-pass effect of hydrophilic β1-adrenergic receptor blockers. With a 50% metabolism rate in both the liver and kidneys, clearance is balanced, allowing its use even in patients with hepatic and renal insufficiency. Another advantage is minimal differences in pharmacokinetic profiles across gender, age, and individual groups, making it easy to manage clinically. Bisoprolol fumarate is highly selective, with an affinity for β1 receptors 11-34 times greater than for β2 receptors. Compared to atenolol and metoprolol, it exhibits the strongest β1-receptor selective inhibitory activity.

[0006] The synthetic route of bisoprolol fumarate first disclosed in U.S. Patent No. 4171370 of Merck, Germany is as follows:

[0007]

[0008] Using p-hydroxybenzaldehyde (Compound I) as the starting material, reduction is performed to obtain p-hydroxybenzyl alcohol (Compound II), which is then etherified with isopropoxyethanol to obtain Compound III, which is then further etherified with epichlorohydrin to obtain Compound IV, which is then subjected to a ring-opening reaction with isopropylamine to obtain bisoprolol free base.

[0009] Currently, the mainstream production process of bisoprolol still basically follows this route, and has made certain improvements based on this route, mainly improving the etherification reaction conditions and the post-processing and purification steps of various intermediates. For example, Indian patent WO2007 / 069266:

[0010]

[0011] Amberlyst-15 ion exchange resin was used to catalyze the first etherification reaction. Sodium borohydride was added as a reducing agent in the post-treatment process of the second step to remove the byproduct of the oxidation of phenolic hydroxyl groups to aldehyde groups. In the third post-treatment process, impurities were removed through a basic alumina bed.

[0012] For example, Chinese patent CN02141064 adopts a telescoping process, without taking out compound II and compound III, and obtains compound V (bisoprolol free base) in one pot, and obtains the final product after salt formation:

[0013]

[0014] For example, Chinese patent CN202110027842.6 uses compound III as the starting material and reacts with 3-isopropylamino-1,2-propanediol to obtain compound V (bisoprolol free base) in one step:

[0015]

[0016] In addition, people have improved the synthesis method of the important intermediate (Compound III) in the synthesis route of bisoprolol, such as Chinese patent CN201510270914.4:

[0017]

[0018] Using p-hydroxybenzaldehyde as the raw material, it reacts with acetic anhydride to obtain a phenolic hydroxyl group acetylation protection product, which is then reduced to the aldehyde group and then etherified with isopropoxyethanol to remove the protecting group to obtain compound III;

[0019] and Chinese patent CN20210005250.5:

[0020]

[0021] Using p-methylphenol as a raw material, after protecting the phenolic hydroxyl group, bromination, etherification reaction with isopropoxyethanol, and then removal of the protecting group to obtain compound III.

[0022] Impurity A in bisoprolol fumarate (EP9.0) is both a process impurity and a degradation impurity in the aforementioned existing mainstream industrial synthesis methods, and the final product inevitably contains impurity A. The control limit for impurity A in EP9.0 is 0.3%. Because this impurity will continue to increase during storage, the content of this impurity in newly produced bisoprolol fumarate API must be controlled to a level far below 0.3%.

[0023]

[0024] The reported mainstream industrial synthesis of bisoprolol, based on an improved version of Merck's original synthesis route, produces bisoprolol free base with an impurity A concentration generally ranging from 0.5% to 1.0%. The subsequent fumarate formation and refining processes are less effective in removing impurity A. For example, US Patent No. 4,171,370 uses isopropyl alcohol for recrystallization of bisoprolol fumarate; CN02141064.X uses an anhydrous ethanol-ethyl acetate solvent system for fumarate formation, followed by recrystallization from ethyl acetate. These processes achieve a 10-20% removal rate for impurity A, making it highly unlikely that the standard of less than 0.3% will be achieved in a single refining step. Furthermore, the yield of the aforementioned refining method is 80-85% per refining step, and multiple refining steps inevitably result in significant yield losses. Impurity A is also a degradation impurity that slowly increases during storage. Therefore, the internal release standard of 0.2% or less is required to ensure that the impurity remains below 0.3% throughout the shelf life.

[0025] Impurity A and bisoprolol have similar chemical properties. Previous literature has not reported methods for removing impurity A from bisoprolol, and the prior art rarely addresses methods for removing impurity A. From a process perspective, impurity A is unavoidable and is the primary impurity. Therefore, there is a need in the art for an efficient, low-cost, and simple impurity removal method to ensure product quality. Summary of the Invention

[0026] To solve the above problems, the present invention aims to provide a method for refining bisoprolol, which has low cost and simple operation, and can remove impurity A in bisoprolol while ensuring a high refining yield.

[0027] To achieve the above objectives, the technical solutions adopted by the present invention are as follows:

[0028] The present invention provides a method for refining bisoprolol, which comprises: dissolving bisoprolol free base in an organic solvent, adding an acid to form a salt, and then adding a base to free the bisoprolol free base, wherein the molar ratio of the acid to the bisoprolol free base is (0.05-0.2):1, wherein the bisoprolol free base contains impurity A:

[0029] In some embodiments, the present invention provides a method for refining bisoprolol, comprising: a) dissolving bisoprolol free base in an organic solvent, adding acid and water, or adding a pre-prepared aqueous acid solution; b) adding sodium bicarbonate to the solution of step a, separating to obtain a first organic phase, adding an organic solvent to the remaining aqueous phase, separating to obtain a second organic phase, and combining the organic phases.

[0030] In some embodiments, the molar ratio of sodium bicarbonate to bisoprolol free base is (0.1-0.44):1.

[0031] In some embodiments, the present invention provides a method for refining bisoprolol, comprising: a) dissolving bisoprolol free base in an organic solvent, adding acid and water, or adding a pre-prepared acid aqueous solution, and separating to obtain a first organic phase; b) adding a base to the remaining aqueous phase of step a, adjusting the pH to a suitable pH, and then adding an organic solvent, separating to obtain a second organic phase, and combining the organic phases; the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like.

[0032] In some embodiments, the pH in the purification method is adjusted to be weakly acidic, for example, 4-6, preferably 5-6.

[0033] In some embodiments, the acid can be any strong acid among organic or inorganic acids, such as sulfuric acid, hydrohalic acid, phosphoric acid, formic acid, acetic acid, fumaric acid, etc., wherein the hydrohalic acid is selected from hydrochloric acid, hydrobromic acid, etc.; preferably, the acid is selected from fumaric acid or hydrochloric acid.

[0034] In some embodiments, the organic solvent used is selected from halogenated alkanes, chloroform, ethyl acetate or toluene; preferably, the organic solvent is a halogenated alkanes, such as dichloromethane, chloroform and the like.

[0035] In some embodiments, a method for refining bisoprolol is provided, comprising: adding dichloromethane and bisoprolol free base to a reaction flask, stirring, controlling the temperature to 25±5° C., adding acid and water, or adding a pre-prepared acid aqueous solution, stirring for 20-30 minutes, adding solid sodium bicarbonate to the solution, stirring for 20-30 minutes, allowing to stand, separating a lower dichloromethane organic phase, adding dichloromethane to an upper aqueous phase, extracting, combining the lower organic phase with the first organic phase, stirring with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a refined bisoprolol free base product.

[0036] In some embodiments, a method for refining bisoprolol is provided, comprising: adding dichloromethane and bisoprolol free base to a reaction flask, stirring, controlling the temperature to 25±5° C., adding acid and water, or adding a pre-prepared acid aqueous solution, stirring for 20-30 minutes, allowing to stand, separating a lower dichloromethane organic phase, adding sodium hydroxide dropwise to the upper aqueous phase to adjust the pH to 5-6, stirring for 20-30 minutes, adding dichloromethane, extracting the aqueous phase, combining the lower organic phase with the first organic phase, stirring with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a refined bisoprolol free base product.

[0037] The beneficial effects achieved by the present invention are:

[0038] Currently, there is no purification method on the market for removing impurity A from bisoprolol free base, and impurity A is an impurity inevitably generated during the production process. The present invention has discovered an effective purification method for removing impurity A through a large number of experimental studies, while ensuring an extremely high purification yield, thereby improving the quality of the product. The purification method also has the advantages of simple operation, low cost, high impurity removal efficiency, high yield, and environmental friendliness.

[0039] 1. The inventors found through a series of experiments that the effect of impurity removal A is positively correlated with the amount of acid used within a certain range: when 0.05 times the molar amount (compared to bisoprolol free base) of acid is added, the impurity removal effect is very good; if it is lower than this limit, the impurity removal effect is greatly reduced; when the molar ratio of acid to bisoprolol free base is between 0.05 and 0.2, the best impurity removal effect can be achieved.

[0040] 2. Furthermore, in order to improve the refining yield, we further recovered the salted bisoprolol by adding alkali and then extracted it into the organic phase, which greatly improved the refining yield to above 89%, and up to 96%. In addition, the present invention controls the amount of impurity A to below 0.06%, which is far below the limit of 0.3% in the European Pharmacopoeia, achieving unexpected technical effects.

[0041] 3, in addition, we unexpectedly find in screening experiment, when removing free bisoprolol with sodium bicarbonate, there is good selectivity, can only dissociate the salt of bisoprolol, and cannot dissociate the salt of impurity A, even if add the sodium bicarbonate in excess of acid, the effect of removing impurity A is still very good, and the refining yield also loses very little, and need not regulate pH after separatory when adding sodium bicarbonate, greatly simplify operating procedure, and for industrial production, adjust pH value, particularly pH 4-8 near neutrality, more accurately just more troublesome, may consuming time 12 hours even longer, and manpower and material cost is all extremely high.So the selection of sodium bicarbonate of the present invention not only greatly simplifies operating procedure, also greatly saves cost.Except the alkali beyond sodium bicarbonate, for example sodium hydroxide, all must add and regulate pH after separatory and could reach suitable impurity removal effect. DETAILED DESCRIPTION

[0042] To make the present invention easier to understand, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. Specific experimental methods not mentioned in the following examples are generally carried out according to conventional experimental methods.

[0043] The molar ratios described in the present invention are approximate values, and fluctuations within ±0.005 are all within the scope of protection of the present invention.

[0044] The bisoprolol free base used in the present invention is a commercially available or homemade crude product, and the content of impurity A is about 0.5-1.0%.

[0045] The purity of bisoprolol in this application is determined by the following method (EP9.0 method):

[0046] Instruments and equipment: electronic balance, high performance liquid chromatography

[0047] Test solution, reagents: acetonitrile, phosphoric acid

[0048] Chromatographic conditions

[0049] Chromatographic column: Octadecylsilane bonded silica gel is used as filler;

[0050] Mobile phase:

[0051] Mobile phase A: 10 g / L phosphoric acid solution;

[0052] Mobile phase B: 10 g / L phosphoric acid in acetonitrile;

[0053] Detection wavelength: 225nm;

[0054] Injection volume: 10 μl;

[0055] Column temperature: 20℃±2℃;

[0056] Flow rate: 1ml / min.

[0057] Gradient program:

[0058]

[0059] Solution preparation:

[0060] Dilution solvent: acetonitrile: water = 20:80, V / V;

[0061] Test solution: Take 25 mg of the product, accurately weigh it, place it in a 25 ml volumetric flask, dilute it to the scale with diluent solvent, shake well, and you will get a 1 mg / ml test solution.

[0062] Control solution (a): Pipette 1 ml of the test solution into a 100 ml volumetric flask, dilute to the mark with diluent, then pipette 2.0 ml of the solution and dilute to 10.0 ml with diluent.

[0063] Reference solution (b): Dissolve the contents of a bottle of bisoprolol peak identification reference substance (containing impurities A and E) in 1.0 ml of diluent to obtain the solution.

[0064] Reference solution (c): Dissolve the contents of a bottle of Bisoprolol System Suitability Reference (containing Impurity G) in 1.0 ml of diluent to obtain the solution.

[0065] Sensitivity solution: Take 5 ml of the control solution and place it in a 20 ml volumetric flask. Dilute to the mark with diluent and shake well to obtain the sensitivity solution. (0.5 μg / ml, equivalent to 0.05% of the test solution)

[0066] Example 1

[0067] To a 20-liter reactor, add 5.0 kg of dichloromethane and 1.0 kg (3.07 mol) of bisoprolol free base (impurity A content 0.5-1.0%), stir evenly, and control the temperature to 25±5°C. Add an aqueous solution of fumaric acid (0.07 kg fumaric acid (0.6 mol) and 3.0 kg water by stirring and dissolving). After the addition is completed, stir for 20-30 minutes. Add 0.114 kg of solid sodium bicarbonate (1.35 mol) to the solution and stir for 20-30 minutes. Stop stirring, let it stand, separate the lower dichloromethane organic phase, add 2.5 kg of dichloromethane to the upper aqueous phase, extract the aqueous phase once, combine the lower organic phase with the first organic phase, stir with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 0.94 kg of refined bisoprolol free base, with an impurity A content of 0.02% and a refined yield of 94%.

[0068] Example 2

[0069] To a 3-liter three-necked flask, add 1.0 kg of dichloromethane and 0.2 kg (0.614 mol) of bisoprolol free base (impurity A content 0.5-1.0%), stir evenly, and control the temperature to 25±5°C. Add an aqueous solution of fumaric acid (0.0035 kg of fumaric acid (0.03 mol) and 0.6 kg of water by stirring and dissolving). After the addition is completed, stir for 20-30 minutes. Add 0.005 kg of solid sodium bicarbonate (0.06 mol) to the solution and stir for 20-30 minutes. Stop stirring, let it stand, separate the lower dichloromethane organic phase, add 0.5 kg of dichloromethane to the upper aqueous phase, extract the aqueous phase once, combine the lower organic phase with the first organic phase, stir with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 0.192 kg of refined bisoprolol free base, with an impurity A content of 0.03% and a refined yield of 96%.

[0070] Example 3

[0071] To a 3-liter three-necked flask, 1.0 kg of dichloromethane and 0.2 kg (0.614 mol) of bisoprolol free base (impurity A content 0.5-1.0%) were added, stirred, and the temperature was controlled to 25±5°C. 5 ml of 6 mol / L hydrochloric acid (0.03 mol) and 0.6 kg of water were added. After the addition was completed, stirring was continued for 20-30 minutes. 0.005 kg of sodium bicarbonate (0.06 mol) solid was added to the solution and stirred for 20-30 minutes. Stirring was stopped, the mixture was allowed to stand, and the lower dichloromethane organic phase was separated. 0.5 kg of dichloromethane was added to the upper aqueous phase. After extraction of the aqueous phase once, the lower organic phase was combined with the organic phase from the first demixing, stirred with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.186 kg of refined bisoprolol free base with an impurity A content of 0.02% and a refining yield of 93%.

[0072] Example 4

[0073] To a 3-liter three-necked flask, 1.0 kg of dichloromethane and 0.2 kg (0.614 mol) of bisoprolol free base (impurity A content 0.5-1.0%) were added, stirred uniformly, and the temperature was controlled to 25±5° C. 5 ml of 6 mol / L hydrochloric acid (0.03 mol) and 0.6 kg of water were added. After the addition was completed, the mixture was stirred for 20-30 min, allowed to stand, and the lower dichloromethane organic phase was separated. A 1 mol / L sodium hydroxide solution was added dropwise to the upper aqueous phase solution. The pH value of the aqueous phase was adjusted to 5-6. After stirring for 20-30 min, 0.5 kg of dichloromethane was added. After the aqueous phase was extracted, the lower organic phase was combined with the organic phase from the first layer, stirred with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.178 kg of refined bisoprolol free base with an impurity A content of 0.06% and a refined yield of 89%.

[0074] The embodiments described above are merely descriptions of preferred implementations of the present invention and are not intended to limit the scope of the present invention. Without departing from the spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should fall within the scope of protection determined by the claims of the present invention.

Claims

1. A method for refining bisoprolol free base, wherein the bisoprolol free base contains impurity A represented by the following formula (I): It is characterized in that The method comprises: dissolving bisoprolol free base in an organic solvent, adding acid to form a salt, and then adding base to form a free base; wherein, a) dissolving bisoprolol free base in an organic solvent, adding acid and water, or adding a pre-prepared aqueous solution of acid; b) adding sodium bicarbonate to the solution of step a, separating to obtain a first organic phase, adding an organic solvent to the remaining aqueous phase, separating to obtain a second organic phase, and combining the organic phases; The acid is selected from hydrochloric acid or fumaric acid; The molar ratio of the acid to bisoprolol free base is (0.05-0.2):1; The organic solvent is dichloromethane.

2. The purification method according to claim 1, wherein The molar ratio of the sodium bicarbonate to the bisoprolol free base is (0.1-0.44):

1.

3. A method for refining bisoprolol free base, wherein the bisoprolol free base contains impurity A represented by the following formula (I): It is characterized in that The method comprises: dissolving bisoprolol free base in an organic solvent, adding acid to form a salt, and then adding base to form a free base; wherein, a) dissolving bisoprolol free base in an organic solvent, adding acid and water, or adding a pre-prepared aqueous solution of acid, and separating to obtain a first organic phase; b) adding a base to the remaining aqueous phase of step a, adjusting to a suitable pH, then adding an organic solvent, separating to obtain a second organic phase, and combining the organic phases; the base is selected from sodium hydroxide; The acid is selected from hydrochloric acid or fumaric acid; The molar ratio of the acid to bisoprolol free base is (0.05-0.2):1; The pH is 5-6; The organic solvent is dichloromethane.

4. The purification method according to claim 1, wherein The method comprises the following steps: adding dichloromethane and bisoprolol free base into a reaction flask, stirring, controlling the temperature to 25±5°C, adding acid and water, or adding a pre-prepared acid aqueous solution, stirring for 20-30 minutes, adding sodium bicarbonate solid to the solution, stirring for 20-30 minutes, standing, separating a lower dichloromethane organic phase, adding dichloromethane to an upper aqueous phase, extracting, combining the lower organic phase with the first organic phase, stirring with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a refined bisoprolol free base product.

5. The purification method according to claim 3, wherein The method comprises the following steps: adding dichloromethane and bisoprolol free base into a reaction flask, stirring, controlling the temperature to 25±5°C, adding acid and water, or adding a pre-prepared acid aqueous solution, stirring for 20-30 minutes, standing, separating a lower dichloromethane organic phase, dripping sodium hydroxide into an upper aqueous phase to adjust the pH to 5-6, stirring for 20-30 minutes, adding dichloromethane, extracting the aqueous phase, combining the lower organic phase with the first organic phase, stirring with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a refined bisoprolol free base product.

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