A method for preparing isoproterenol hydrochloride

Abstract

The invention provides a method for preparing isoproterenol hydrochloride, and belongs to the technical field of raw material drug synthesis. The method comprises the following steps: using water as a solvent and borohydride as a reducing agent to carry out a reduction reaction on isoproterenol hydrochloride, adjusting the pH value of a reaction solution to 2-3 with hydrochloric acid, extracting with one or more organic solvents, separating a water layer, adding ethanol to the water layer for desalting, concentrating with ethanol under reduced pressure after desalting, adding acetone to the concentrate for crystallization to obtain a crude isoproterenol hydrochloride product, and then recrystallizing to obtain a refined isoproterenol hydrochloride product. The refined isoproterenol hydrochloride product provided by the invention has high yield and high purity, can meet the requirements of the pharmacopoeia, and is suitable for the industrial production of isoproterenol hydrochloride as a pharmaceutical raw material drug product.

Description

Technical Field

[0001] The invention relates to the technical field of raw material drug synthesis, and in particular to a method for preparing high-purity isoproterenol hydrochloride. Background Art

[0002] The chemical name of isoproterenol hydrochloride is 4-[(2-(isopropylamino-1-hydroxy)ethyl]-1,2-benzenediol hydrochloride (Formula I). ​​Its clinical indications are cardiogenic or septic shock, complete atrioventricular block, and cardiac arrest. Isoproterenol hydrochloride aerosol is used to treat bronchial asthma. Isoproterenol hydrochloride is a non-selective β-adrenergic receptor agonist with effective peripheral vasodilation, bronchial dilation and cardiac stimulatory activity. However, it has low selectivity for β1- and β2-receptors. Isoproterenol hydrochloride mainly has a strong excitatory effect on β-receptors and has almost no effect on α-receptors. It can significantly excite the heart, dilate blood vessels, and relax bronchial smooth muscles. The relaxation effect is particularly obvious when the bronchial smooth muscles are in a spasmodic state. The results of clinical trials show that the success rate of isoproterenol hydrochloride in inducing patients with paroxysmal supraventricular tachycardia is higher than that of atropine.

[0003]

[0004] Isoproterenol hydrochloride has clinical applications including:

[0005] (1) Bronchial asthma: Suitable for controlling acute asthma attacks. It is usually administered by aerosol inhalation. It has a fast and strong effect, but a short duration.

[0006] (2) Cardiac arrest: It is used to treat cardiac arrest caused by drowning, electric shock, surgical accidents, drug poisoning, etc. If necessary, it can be used in combination with epinephrine and norepinephrine.

[0007] (3) Atrioventricular block.

[0008] (4) Anti-shock: It can be used for cardiogenic shock and septic shock. For patients with high central venous pressure and low cardiac output, this product should be used after replenishing blood volume.

[0009] Another academic paper reported that the oxygen-driven atomization treatment of isoproterenol hydrochloride is more efficient than terbutaline, and no obvious toxic side effects were found, which is worthy of clinical application and promotion. Recent studies have shown that isoproterenol has a therapeutic effect in depression, schizophrenia and post-traumatic stress disorder.

[0010] At present, the industrial production of isoproterenol hydrochloride mainly uses isoproterenol as a raw material, hydrogenates it under the catalysis of palladium, platinum or nickel, and then obtains the product through post-treatment (route 1), such as the method disclosed in US Pat. No. 2,308,232 and US20190367443A1. However, the catalyst is very easy to spontaneously combust and deactivate, and a certain hydrogen pressure needs to be maintained during the reaction process. In addition, hydrogen is very easy to explode, so the safety hazard is very large.

[0011]

[0012] Chinese patents CN 107382750 A and CN 112724027 A disclose a method for obtaining isoproterenol hydrochloride by reducing isoproterenolone as a raw material with sodium borohydride and acidifying the resultant product (route 2).

[0013]

[0014] In the method of CN 107382750A, the amount of sodium borohydride required is large (4 to 10 times the molar amount of isoproterenol), and it is extracted with ethyl acetate after concentration. In the post-treatment process, it is difficult to remove the inorganic salts in the reaction system, resulting in the product residue on ignition detection item not meeting the pharmaceutical quality requirements, and the product content entering the ethyl acetate during the extraction process is very small, making the product yield extremely low, and it is impossible to achieve industrial production. At the same time, too much sodium borohydride three waste treatment products are more harmful to the environment. Although the post-treatment process in the method of CN 112724027A can remove the inorganic salts in the reaction system, it is actually found that it is difficult to obtain isoproterenol hydrochloride when the method is actually repeated, and the yield is very low, which cannot meet the needs of industrialization. Summary of the invention

[0015] The inventors have found that the method of CN 112724027A evaporates the solvent (DMF / water, etc.) at a relatively high temperature before desalting. This process causes the boric acid generated by the reaction to react with isoproterenol hydrochloride to form a large amount of isoproterenol hydrochloride-boric acid complex. Even if ethanol is used with water (ethanol is added to reduce pressure and concentrate to remove the solvent), a large amount of boric acid esters (new impurities) will be generated. Therefore, the yield of isoproterenol hydrochloride actually obtained by this method is very low, and the impurities exceed the standard, which cannot meet the quality requirements; in addition, the method of refining isoproterenol hydrochloride in CN 112724027A uses ethanol heating and reflux, which can lead to the formation of new impurities, reduce the yield and affect the product quality, thereby failing to meet the needs of industrial preparation of qualified products.

[0016] The purpose of the present invention is to provide a method for preparing high-purity isoproterenol hydrochloride, which avoids the situation that the product forms a complex with boric acid after the hydroboration reaction, resulting in no precipitation of the product and low yield; and also avoids the generation of new impurities in the previous refining method. The method is simple to operate, mild in conditions and easy to industrialize, and the product purity can reach more than 99.5%, and the ignition residue is controlled below 0.1%.

[0017] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0018] The present invention provides a method for preparing isoproterenol hydrochloride, the method comprising the following steps:

[0019] (1) subjecting isoproterenol or its salt to a reduction reaction with borohydride in water, and then reacting with hydrochloric acid to form a salt to obtain a reaction solution;

[0020] (2) extracting the reaction solution to remove boric acid, wherein the extraction solvent used for the extraction is one or more selected from 2-butanone, 4-methyl-2-pentanone, n-butanol, and 2-methyltetrahydrofuran;

[0021] (3) the aqueous solution after extraction is concentrated under reduced pressure to remove water;

[0022] (4) adding anhydrous ethanol to the concentrate after water removal for desalination;

[0023] (5) the filtrate after desalting is concentrated under reduced pressure, and the residue is crystallized by adding acetone to obtain crude isoproterenol hydrochloride;

[0024] (6) Recrystallizing the crude isoproterenol hydrochloride to obtain refined isoproterenol hydrochloride.

[0025] The process route is:

[0026]

[0027] The following is a detailed description of each step:

[0028] Step (1):

[0029] In this step, isoproterenol or its salt is first subjected to reduction reaction with borohydride in water, and then reacted with hydrochloric acid to form a salt.

[0030] In step (1), the isoproterenol salt can be selected from its hydrochloride, sulfate, phosphate, hydrobromide and other inorganic acid salts, or acetate, formates, propionates, oxalates and other organic acid salts.

[0031] The borohydride in step (1) can be selected from sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, etc.

[0032] In step (1), the molar ratio of isoproterenol or its salt to borohydride may be 1:0.25-1:1.9, preferably 1:0.3-1:1.5, especially 1:0.6.

[0033] In step (1), the dosage ratio of isoproterenol or its salt to water can be 1 g: 5-20 ml.

[0034] The temperature of the reduction reaction in step (1) is 0-5°C.

[0035] In step (1), the pH of the reaction solution is adjusted to 2-3 with hydrochloric acid.

[0036] Step (2) removing boric acid:

[0037] After the hydroboration reaction is completed, boric acid exists in the reaction solution. The inventors found that the presence of boric acid can form a boric acid complex with isoproterenol hydrochloride, thereby causing the product to not precipitate and affecting the yield.

[0038]

[0039] In order to improve the purity and quality of isoproterenol hydrochloride and avoid the formation of boric acid complexes, boric acid is first removed during the preparation of isoproterenol hydrochloride. Therefore, the present invention uses a specific organic solvent as an extraction solvent to extract the reaction solution after the hydroboration reaction. The extraction solvent is selected from 2-butanone, 4-methyl-2-pentanone, n-butanol, 2-methyltetrahydrofuran or a mixture thereof, preferably one of the extraction solvents, and more preferably a mixture of two or more of the extraction solvents. As an example, the two extraction solvents are a mixture of 2-methyltetrahydrofuran and 2-butanone, and the volume ratio thereof is 1:99 to 99:1; or, the two extraction solvents are a mixture of 2-methyltetrahydrofuran and 4-methyl-2-pentanone, and the volume ratio thereof is 1:99 to 99:1; or, the two extraction solvents are a mixture of 2-methyltetrahydrofuran and n-butanol, and the volume ratio thereof is 1:99 to 99:1, especially 1:1.

[0040] In some embodiments, the volume of the extraction solvent added is 0.2-0.6 times the volume of the reaction solution.

[0041] There is no particular limitation on the number of extractions, and for example, the extraction may be performed 2 times, 3 times, 4 times, etc.

[0042] In some embodiments, after extraction with one or more of 2-butanone, 4-methyl-2-pentanone, n-butanol, and 2-methyltetrahydrofuran, the aqueous layer is extracted with ethyl acetate (to further remove the residual extraction solvent in the aqueous layer).

[0043] Firstly extract with one or more of 2-butanone, 4-methyl-2-pentanone, n-butanol, 2-methyltetrahydrofuran and then separate the liquids, the upper layer is an organic phase containing boric acid or boric acid ester, the lower layer is an aqueous solution containing isoproterenol hydrochloride after the boric acid is removed after extraction; the aqueous layer is continuously extracted with ethyl acetate twice.

[0044] Step (3) removing water:

[0045] In this step, the aqueous solution after extraction is concentrated under reduced pressure to remove water.

[0046] In some embodiments, the aqueous solution after extraction is added with anhydrous ethanol for reduced pressure concentration, and the temperature of reduced pressure concentration is ≤30°C, preferably 20-30°C.

[0047] Step (4) desalination:

[0048] In this step, the concentrate after water removal is added with anhydrous ethanol for desalination.

[0049] In some embodiments, the ratio of the added volume of anhydrous ethanol to the mass of isoproterenol is 10-30:1 (ml / g);

[0050] In some embodiments, the desalting temperature is 5-15°C, preferably 5-10°C.

[0051] After adding anhydrous ethanol, stir at the desalting temperature, the salt will precipitate, and filter to obtain the desalted filtrate.

[0052] Step (5) Concentration and crystallization:

[0053] In this step, the filtrate after desalination is further concentrated under reduced pressure and then acetone is added for crystallization.

[0054] In some embodiments, the temperature of reduced pressure concentration is ≤30°C, preferably 20-30°C;

[0055] In some embodiments, the ratio of the added volume of acetone to the mass of isoproterenol is 15-35:1 (ml / g);

[0056] In some embodiments, the crystallization temperature is 0-5°C.

[0057] In some embodiments, the crystallization time is 12-24 hours.

[0058] After crystallization, the product is filtered and the solid is dried (such as vacuum drying) to obtain crude isoproterenol hydrochloride.

[0059] The purity of the crude isoproterenol hydrochloride obtained through the above-mentioned boric acid removal, water removal, salt removal and crystallization process can reach more than 96%, and the ignition residue is less than 1%.

[0060] Step (6) Refining:

[0061] The inventors found that the existing refining method using alcohols for heating and reflux can lead to the formation of impurity ethers:

[0062]

[0063] In order to avoid this situation, the present invention adopts recrystallization to purify.

[0064] In this step, the crude isoproterenol hydrochloride is purified, and the specific operations include:

[0065] The crude isoproterenol hydrochloride is dissolved by heating with an isopropanol aqueous solution and then filtered, and the filtrate is cooled, stirred and crystallized to obtain a refined isoproterenol hydrochloride.

[0066] In some embodiments, the volume ratio of isopropanol to water in the isopropanol aqueous solution is 15:1 to 3:1, preferably 7:1;

[0067] In some embodiments, the volume-to-weight ratio of the isopropanol aqueous solution to the crude isoproterenol hydrochloride is 3-12 mL:1 g, preferably 8 mL / g.

[0068] In some embodiments, the heating dissolution temperature is 30 to 70°C;

[0069] In some embodiments, the crystallization temperature is -10 to -5°C, and the crystallization stirring time is 12 to 20 hours.

[0070] In some embodiments, the crude isoproterenol hydrochloride is dissolved by heating with an isopropanol aqueous solution, and then activated carbon is added to reflux, filtered after 20-40 minutes, and the filtrate is collected for the next step of crystallization.

[0071] After crystallization, the solid is filtered and then rinsed and dried (such as vacuum drying) to obtain refined isoproterenol hydrochloride.

[0072] The purity of the refined product after purification can reach more than 99.5%, and the ignition residue is controlled below 0.1%.

[0073] The remaining treatments not mentioned can be carried out according to conventional treatment methods in the art.

[0074] Beneficial Effects

[0075] 1. The refined isoproterenol hydrochloride provided by the present invention has high yield, purity and low impurities, and can meet the requirements of pharmacopoeia (such as European Pharmacopoeia). The preparation method is suitable for the industrial production of isoproterenol hydrochloride as a pharmaceutical raw material product.

[0076] 2. Avoid the incomplete hydrogenation reaction and the generation of impurities that are difficult to remove that are usually caused by using precious metal catalysts, and reduce the environmental risks of enterprises.

[0077] The present invention has been described in detail above, but the above embodiments are only illustrative in nature and are not intended to limit the present invention. In addition, this article is not limited by any theory described in the above prior art or invention content or the following examples. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] Figure 1 HPLC spectrum of blank solvent.

[0079] Figure 2 This is the HPLC spectrum of the isoproterenol hydrochloride reference substance (batch number 100166-202205) of the China Food and Drug Inspection Institutes.

[0080] Figure 3 This is the HPLC spectrum of isoproterenol hydrochloride in Example 1.

[0081] Figure 4 This is the HPLC spectrum of isoproterenol hydrochloride of Example 2.

[0082] Figure 5 This is the HPLC spectrum of isoproterenol hydrochloride of Example 3.

[0083] Figure 6 This is the HPLC spectrum of isoproterenol hydrochloride of Example 4. DETAILED DESCRIPTION

[0084] The present invention is further described below in conjunction with examples. It should be noted that the following examples are provided for illustrative purposes only and do not constitute a limitation on the scope of protection claimed for the present invention.

[0085] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, methods in the art.

[0086] Unless otherwise specified, for the compounds described in the examples, the analytical instruments and parameters used were as follows:

[0087] NMR:

[0088] Instrument: Quantum-I plus AS400 NMR instrument from Zhongke;

[0089] Solvent: DMSO;

[0090] Temperature: 25℃;

[0091] Internal Standard: None.

[0092] Mass Spectrometry:

[0093] Instrument model: Shimadzu LCMS-IT-TOF liquid-mass spectrometer;

[0094] Test conditions: Weigh 2.5 mg of sample, add 1.0 mL of water, vortex to dissolve, dilute 1000 times with methanol, and pass through the membrane for testing;

[0095] Solvent: water / methanol;

[0096] Ionization method: ESI (+);

[0097] The HPLC instrument used was SHIMADZU LC-2010A HT. The analysis details are as follows:

[0098] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (Waters XBridge C18, 4.6×250 mm Column, 5 μm); mobile phase A was methanol, mobile phase B was 0.03 mol / L sodium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid), column temperature was 30°C; gradient elution was performed according to the table below; flow rate was 1.0 ml / min; detection wavelength was 280 nm; injection volume was 10 μl.

[0099]

[0100] Test solution: Take an appropriate amount of the product, weigh accurately, add solvent to dissolve and make a solution containing about 1 mg per 1 ml.

[0101] raw material:

[0102] Isoproterenol hydrochloride (M2) is homemade and can be prepared by referring to the method of S1 in Example 1 of patent CN 112724027A;

[0103] Other reagents were commercially available of industrial grade or chemically pure.

[0104] Detection method:

[0105] Purity: Chromatographic determination, using HPLC normalization method.

[0106] Residue on ignition: The residue on ignition inspection method is based on the General Rules 0841 of Part III of the Chinese Pharmacopoeia 2020 Edition.

[0107] Example 1

[0108] (1) Preparation of crude isoproterenol hydrochloride

[0109] The feeding information table is as follows:

[0110]

[0111] Preparation process:

[0112] Add pure water and isoproterenol hydrochloride to a 25L reactor, cool the reaction solution to 0-5°C, add sodium borohydride to the reaction solution in batches while stirring, react at 0-5°C for 1-2h after addition, and HPLC monitoring shows that the reaction is complete. Adjust the pH of the reaction solution to 2-3 with hydrochloric acid, extract the reaction solution with a mixture of 2-methyltetrahydrofuran and 4-methyl-2-pentanone (1:1, v / v) as an extraction solvent, extract it three times, extract the water layer with ethyl acetate twice, separate the liquid to obtain an aqueous solution, add anhydrous ethanol three times, and concentrate under reduced pressure at a temperature below 30°C after each addition. Add anhydrous ethanol to the concentrate after dehydration, stir at 10°C for 30 minutes to precipitate salt, filter, and concentrate the filtrate after desalting under reduced pressure at a temperature below 30°C. After evaporating the solvent, add acetone to the residue, stir at 0-5°C for 12 hours to crystallize, filter, and vacuum dry the solid at 50°C for 6 hours to obtain crude isoproterenol hydrochloride. Yield: 80%, purity: 98.00%, residue on ignition: 1.00%.

[0113] (2) Refining of crude isoproterenol hydrochloride

[0114] The feeding information table is as follows:

[0115]

[0116] Preparation process:

[0117] Add crude isoproterenol hydrochloride and isopropanol aqueous solution to a 25-liter reactor, heat and stir the resulting mixture at 65-67°C for 1-2 hours, add activated carbon after the solid is dissolved, stir at reflux 50-60°C for 0.5 hours, cool the reaction solution to 20-30°C and filter, cool the filtrate to -10 to -5°C, stir for 12 hours, filter after crystallization, and rinse the filter cake with isopropanol. After washing, put the filter cake into a vacuum drying oven and dry it at 50 to 60°C and vacuum degree ≥0.08MPa for 6 to 8 hours to obtain an off-white crystalline powder, which is a refined product of isoproterenol hydrochloride. The yield is 82%, the purity is 99.95%, and the ignition residue is 0.05%. 1 H-NMR (400M, DMSO-d6), heavy water exchange hydrogen spectrum, 1H-1H COSY spectrum data

[0118]

[0119] 13 C-NMR, DEPT, HSQC and HMBC data

[0120]

[0121]

[0122] m / z = 212.10 and theoretical value (according to molecular formula C11 H 18 NO3 + Calculated) m / z = 212.26 [M-Cl - ] + m / z = 210.11 is consistent with the theoretical value (according to the molecular formula C 11 H 16 NO3 - Calculated) m / z = 210.25 [M-HCl-H + ] - m / z = 246.09 is consistent with the theoretical value (according to the molecular formula C 11 H 17 NO3Cl - Calculated) m / z = 246.71 [MH + ] - This indicates that the molecular composition of the test sample is consistent with that of the isoproterenol hydrochloride reference substance (China Food and Drug Inspection Institute, batch number 100166-202205).

[0123] Example 2

[0124] (1) Preparation of crude isoproterenol hydrochloride

[0125] The feeding information table is as follows:

[0126]

[0127]

[0128] Preparation process:

[0129] Add pure water and isoproterenol hydrochloride to a 25L reactor, cool the reaction solution to 0-5°C, add sodium borohydride to the reaction solution in batches while stirring, react at 0-5°C for 1-2h after addition, and HPLC monitoring shows that the reaction is complete. Adjust the pH of the reaction solution to 2-3 with hydrochloric acid, extract the reaction solution with a mixture of 2-methyltetrahydrofuran and n-butanol (1:1, v / v) as an extraction solvent, extract it three times, extract the water layer with ethyl acetate twice, separate the liquid to obtain an aqueous solution, add anhydrous ethanol three times, and concentrate under reduced pressure at a temperature below 30°C after each addition. Add anhydrous ethanol to the concentrate after dehydration, stir at 10°C for 30 minutes to precipitate salt, filter, and concentrate the filtrate after desalting under reduced pressure at a temperature below 30°C. After evaporating the solvent, add acetone to the residue, stir at 0-5°C for 12 hours to crystallize, filter, and vacuum dry the solid at 50°C for 6 hours to obtain crude isoproterenol hydrochloride. Yield: 74%, purity: 99.30%, residue on ignition: 0.10%.

[0130] (2) Refining of crude isoproterenol hydrochloride

[0131] The feeding information table is as follows:

[0132]

[0133] Preparation process:

[0134] Add crude isoproterenol hydrochloride and isopropanol aqueous solution to a 25-liter reactor, heat and stir the resulting mixture at 65-67°C for 1-2 hours, add activated carbon after the solid is dissolved, stir at reflux 50-60°C for 0.5 hours, cool the reaction solution to 20-30°C and filter, cool the filtrate to -10 to -5°C, stir for 12 hours, filter after crystallization, and rinse the filter cake with isopropanol. After washing, place the filter cake in a vacuum drying oven and dry it at 50 to 60°C, vacuum degree ≥ 0.08MPa for 6 to 8 hours to obtain an off-white crystalline powder, which is a refined product of isoproterenol hydrochloride. The yield is 80%, the chromatographic purity is 99.50%, and the ignition residue is 0.06%.

[0135] Example 3

[0136] (1) Preparation of crude isoproterenol hydrochloride

[0137] The feeding information table is as follows:

[0138]

[0139] Preparation process:

[0140] Add pure water and isoproterenol hydrochloride to a 25L reactor, cool the reaction solution to 0-5°C, add sodium borohydride to the reaction solution in batches while stirring, react at 0-5°C for 1-2h after addition, and HPLC monitoring shows that the reaction is complete. Adjust the pH of the reaction solution to 2-3 with hydrochloric acid, extract the reaction solution with 2-methyltetrahydrofuran as an extraction solvent for 3 times, extract the water layer with ethyl acetate for 2 times, separate the liquid to obtain an aqueous solution, add anhydrous ethanol three times, and concentrate under reduced pressure at a temperature below 30°C after each addition. Add anhydrous ethanol to the concentrate after dehydration, stir at 10°C for 30 minutes to precipitate salt, filter, and concentrate the filtrate after desalination under reduced pressure at a temperature below 30°C. After evaporating the solvent, add acetone to the residue, stir at 0-5°C for 12 hours to crystallize, filter, and vacuum dry the solid at 50°C for 6 hours to obtain crude isoproterenol hydrochloride. Yield 60%, chromatographic purity 98.50%, ignition residue 0.50%.

[0141] (2) Refining of crude isoproterenol hydrochloride

[0142] The feeding information table is as follows:

[0143]

[0144] Preparation process:

[0145] Add crude isoproterenol hydrochloride and isopropanol aqueous solution to a 25-liter reactor, heat and stir the resulting mixture at 65-67°C for 1-2 hours, add activated carbon after the solid is dissolved, stir at reflux 50-60°C for 0.5 hours, cool the reaction solution to 20-30°C and filter, cool the filtrate to -10 to -5°C, stir for 12 hours, filter after crystallization, and rinse the filter cake with isopropanol. After washing, put the filter cake into a vacuum drying oven and dry it at 50 to 60°C and vacuum degree ≥0.08MPa for 6 to 8 hours to obtain an off-white crystalline powder, which is a refined product of isoproterenol hydrochloride. The yield is 72%, the purity is 99.50%, and the ignition residue is 0.05%.

[0146] Example 4

[0147] (1) Preparation of crude isoproterenol hydrochloride

[0148] The feeding information table is as follows:

[0149]

[0150]

[0151] Preparation process:

[0152] Add pure water and isoproterenol hydrochloride to a 25L reactor, cool the reaction solution to 0-5°C, add sodium borohydride to the reaction solution in batches while stirring, react at 0-5°C for 1-2h after addition, and HPLC monitoring shows that the reaction is complete. Adjust the pH of the reaction solution to 2-3 with hydrochloric acid, extract the reaction solution with n-butanol as the extraction solvent for 3 times, extract the water layer with ethyl acetate for 2 times, separate the liquid to obtain an aqueous solution, add anhydrous ethanol three times, and concentrate under reduced pressure at a temperature below 30°C after each addition. Add anhydrous ethanol to the concentrate after dehydration, stir at 10°C for 30 minutes to precipitate salt, filter, and concentrate the filtrate after desalination under reduced pressure at a temperature below 30°C. After evaporating the solvent, add acetone to the residue, stir at 0-5°C for 12 hours to crystallize, filter, and vacuum dry the solid at 50°C for 6 hours to obtain crude isoproterenol hydrochloride with a yield of 65%, a chromatographic purity of 99.00%, and a residue on ignition of 0.50%.

[0153] (2) Refining of crude isoproterenol hydrochloride

[0154] The feeding information table is as follows:

[0155]

[0156]

[0157] Preparation process:

[0158] Add crude isoproterenol hydrochloride and isopropanol aqueous solution into a 25-liter reactor, heat and stir the resulting mixture at 65-67°C for 1-2 hours, add activated carbon after the solid is dissolved, stir at reflux 50-60°C for 0.5 hours, cool the reaction solution to 20-30°C and filter, cool the filtrate to -10 to -5°C, stir for 12 hours, filter after crystallization, and rinse the filter cake with isopropanol. After washing, put the filter cake into a vacuum drying oven, dry it at 50 to 60°C, vacuum degree ≥ 0.08MPa for 6 to 8 hours, and obtain an off-white crystalline powder, which is a refined product of isoproterenol hydrochloride, with a yield of 72%, a purity of 99.80%, and a residue on ignition of 0.03%.

[0159] Comparative Example 1

[0160] The difference from Example 4(1) is that the step of extraction with n-butanol is not included, and as a result, crude isoproterenol hydrochloride is not obtained.

[0161] Comparative Example 2

[0162] The reaction was carried out according to the preparation process of crude isoproterenol hydrochloride in Example 10 disclosed in CN 112724027, but no isoproterenol hydrochloride was obtained.

[0163] Investigation of the extraction solvent in the test example

[0164] (1) Study on the solubility of isoproterenol hydrochloride (API) and boric acid in different solvents

[0165] The research results are shown in the table below:

[0166]

[0167]

[0168] The solubility results show that n-butanol and 2-methyltetrahydrofuran have certain solubility in boric acid. Therefore, the solubility of the mixed solution of n-butanol and 2-methyltetrahydrofuran in boric acid is investigated. The results are shown in the following table:

[0169] Solubility of mixed solution of n-butanol and 2-methyltetrahydrofuran

[0170]

[0171] Conclusion: The solubility results show that the solubility of boric acid is the highest when the ratio of n-butanol:2-methyltetrahydrofuran (v / v) is 1:1. The mixed solvent of n-butanol:2-methyltetrahydrofuran (v / v) = 1:1 is preferred as the extraction solvent.

[0172] (2) Investigation of the volume ratio of n-butanol and 2-methyltetrahydrofuran mixed solvent as extraction solvent:

[0173] Different volume ratios of n-butanol and 2-methyltetrahydrofuran mixed solvents were investigated, with the stratification and solubility as parameters, so as to screen out the optimal parameters. The results of the investigation are shown in the following table:

[0174] Screening results of volume ratio of n-butanol to 2-methyltetrahydrofuran

[0175]

[0176]

[0177] Conclusion: The stratification effect of n-butanol and 2-methyltetrahydrofuran volume ratio of 1:1-1:2 is better than that of 2:1. Considering the solubility of boric acid, 1:1 is preferred.

Claims

1. A method for preparing isoproterenol hydrochloride, characterized in that: The following steps are involved: (1) subjecting isoproterenol or its salt to a reduction reaction with borohydride in water, and then reacting with hydrochloric acid to form a salt to obtain a reaction solution; (2) extracting the reaction solution to remove boric acid, wherein the extraction solvent used for the extraction is one or more selected from 2-butanone, 4-methyl-2-pentanone, n-butanol, and 2-methyltetrahydrofuran; (3) the aqueous solution after extraction is concentrated under reduced pressure to remove water; (4) adding anhydrous ethanol to the concentrate after water removal for desalination; (5) the filtrate after desalting is concentrated under reduced pressure, and the residue is crystallized by adding acetone to obtain crude isoproterenol hydrochloride; (6) Recrystallizing the crude isoproterenol hydrochloride to obtain refined isoproterenol hydrochloride.

2. The method according to claim 1, characterized in that In step (2), the extraction solvent is 2-butanone, or the extraction solvent is 4-methyl-2-pentanone, or the extraction solvent is n-butanol, or the extraction solvent is 2-methyltetrahydrofuran.

3. The method according to claim 1, characterized in that The extraction solvent in step (2) is a mixture of 2-methyltetrahydrofuran and 2-butanone in a volume ratio of 1:99 to 99:1; or The extraction solvent is a mixture of 2-methyltetrahydrofuran and 4-methyl-2-pentanone in a volume ratio of 1:99 to 99:1; or The extraction solvent is a mixture of 2-methyltetrahydrofuran and n-butanol, and the volume ratio thereof is 1:99 to 99:

1.

4. The method according to claim 1, characterized in that: In step (3), the aqueous solution after extraction is added with anhydrous ethanol and concentrated under reduced pressure, and the temperature of the reduced pressure concentration is ≤30°C.

5. The method according to claim 1, characterized in that In step (4), the ratio of the added volume of anhydrous ethanol to the mass of isoproterenol is 10-30 mL: 1 g.

6. The method according to claim 1, characterized in that The desalting temperature in step (4) is 5 to 10°C.

7. The method according to claim 1, characterized in that In step (5), the ratio of the added volume of acetone to the mass of isoproterenol is 15-35 mL: 1 g.

8. The method according to claim 1, characterized in that In step (5), the crystallization temperature is 0 to 5° C. and the crystallization time is 12 to 24 hours.

9. The method according to any one of claims 1 to 8, characterized in that: Step (6) comprises: heating and dissolving the crude isoproterenol hydrochloride in an isopropanol aqueous solution, filtering the solution, cooling the filtrate, stirring and crystallizing the solution, and obtaining a refined isoproterenol hydrochloride product.

10. The method according to claim 9, characterized in that The volume ratio of isopropanol to water in the isopropanol aqueous solution is 15:1 to 3:1; The volume weight ratio of the isopropanol aqueous solution to the crude isoproterenol hydrochloride is 3-12 mL:1 g; The crystallization temperature is -10 to -5°C, and the crystallization stirring time is 12 to 20 hours.

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