A process for the preparation of labetalol hydrochloride

Abstract

This invention provides a method for preparing labetalol hydrochloride, belonging to the field of pharmaceutical synthesis. The method uses 5-acetylsalicylic acid as a starting material, obtains 3-bromo-5-(2-bromoacetyl)-2-hydroxybenzamide through bromination, then undergoes a substitution reaction with 1-methyl-3-phenylpropylamine, followed by hydrogenation reduction, and finally salt formation to obtain labetalol hydrochloride. The method provides a high conversion rate and few byproducts by using the synthesized 3-bromo-5-(2-bromoacetyl)-2-hydroxybenzamide intermediate to replace 5-bromoacetylsalicylic acid. The obtained product can be directly used in the next reaction, followed by substitution and reduction to obtain the final product. This method is low-cost, high-yield, simple, and controllable, facilitating industrialized production and showing excellent application prospects.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing labetalol hydrochloride. Background Technology

[0002] Labetalol hydrochloride is an antihypertensive drug that acts as an α1- and β-adrenergic receptor blocker. It is suitable for various types of hypertension, such as hypertensive crisis, pheochromocytoma crisis, preeclampsia, hypertensive encephalopathy, hypertension caused by extensive burns, hypertension associated with coronary artery disease or acute myocardial infarction, and postoperative hypertension. It can also be used to control blood pressure during anesthesia. It simultaneously blocks α1-adrenergic receptors and non-selectively blocks β-adrenergic receptors. α-receptor blocking reduces peripheral vascular resistance, improves insulin responsiveness to glucose, and decreases insulin resistance; β-receptor blocking inhibits myocardial contractility, keeps heart rate unchanged or slightly slows it, reduces myocardial contractility, decreases myocardial oxygen consumption, and lowers blood pressure. Currently, labetalol hydrochloride is listed as a recommended treatment for hypertension in the "Chinese Expert Consensus on the Application of α / β-Receptor Blockers in the Treatment of Hypertension 2016" and as a first-line treatment for gestational hypertension in the "International Society of Hypertension 2020 International Hypertension Practice Guidelines," indicating a promising market prospect.

[0003]

[0004] Patent GB2149399A discloses a method for preparing labetalol hydrochloride. This route uses acetylsalicylate as a starting material, which is brominated to obtain 5-bromoacetylsalicylate, then substituted with 1-methyl-3-phenylpropylamine, followed by hydrogenation reduction using sodium borohydride, and finally salt formation to obtain labetalol hydrochloride. However, the intermediate 5-bromoacetylsalicylate obtained by this method has low purity (not exceeding 75%) due to the formation of multiple bromines and incomplete reaction of the starting material, requiring secondary purification, resulting in a low overall yield. The synthetic route is as follows:

[0005]

[0006] Patent CN113698316A discloses a method for preparing labetalol hydrochloride. This route uses 5-haloacetylsalicylic acid as a starting material to undergo a nucleophilic substitution reaction with benzylamine, followed by a nucleophilic substitution reaction with 3-halobutylbenzene, and then a palladium-catalyzed hydrogenation reaction to form a salt, yielding labetalol hydrochloride. However, this method introduces benzylamine, resulting in higher costs.

[0007]

[0008] Therefore, it is still necessary in this field to develop a low-cost, high-yield, and simple and controllable method for the synthesis of labetalol hydrochloride, which has very high application value. Summary of the Invention

[0009] The purpose of this invention is to provide a low-cost, high-yield, simple and controllable method for preparing labetalol hydrochloride.

[0010] A method for preparing labetalol hydrochloride includes the following steps:

[0011] (1) Compound II was subjected to bromination to obtain compound III;

[0012] (2) Compound III was subjected to a substitution reaction with compound IV to obtain compound V;

[0013] (3) The compound V was subjected to hydrogenation reduction to obtain compound VI;

[0014] (4) The compound IV was salted with HCl to obtain labetalol hydrochloride having the structure shown in Formula I;

[0015] The reaction formula is as follows:

[0016]

[0017] Preferably, in step (1), the brominating reagent used in the bromination reaction is selected from at least one of N-bromosuccinimide, bromine, or pyridinium tribromide; the solvent is an organic solvent.

[0018] Preferably, in step (1), the brominating reagent used in the bromination reaction is N-bromosuccinimide; the molar ratio of compound II to the brominating reagent is 1:(1-3); the reaction temperature is 20-80℃; and the reaction time is 1-12h.

[0019] Preferably, in step (1), the brominating reagent used in the bromination reaction is bromine; the molar ratio of compound II to the brominating reagent is 1:(1~3); the reaction temperature is -10~40℃, and the reaction time is 1~12h.

[0020] Preferably, in step (2), the substitution reaction is carried out under the action of a base, wherein the base is selected from at least one of compound IV, an organic base or an inorganic base.

[0021] Preferably, in step (2), the molar ratio of compound III to compound IV is 1:(1-5); the temperature of the substitution reaction is -10 to 50°C; and the reaction solvent is an organic solvent.

[0022] Preferably, in step (3), the catalyst for hydrogenation reduction is palladium on carbon.

[0023] Preferably, in step (3), the hydrogenation reduction process involves a hydrogen pressure of 0.1–10 MPa, a temperature of 10–60 °C, and a reaction time of 2–24 h.

[0024] Preferably, in step (4), the form of HCl is selected from hydrogen chloride gas, hydrogen chloride aqueous solution or hydrogen chloride organic solution.

[0025] Preferably, in step (4), the salt formation temperature is 0-50°C, the time is 1-5 hours, and the pH value is 1-4.

[0026] Experimental results show that the method for preparing labetalol hydrochloride provided by this invention, which uses 3-bromo-5-(2-bromoacetyl)-2-hydroxybenzamide intermediate to replace 5-bromoacetylsalicylic acid amide, has a high conversion rate and few by-products. The obtained product can be directly used in the next reaction. After substitution and reduction, the final product is obtained. The preparation method has high yield, low cost, simple and controllable process, and high purity, making it suitable for commercial-scale production.

[0027] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0028] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0029] Figure 1 The NMR spectrum of the compound of formula III prepared in Example 1;

[0030] Figure 2 The mass spectrum of compound III prepared in Example 1;

[0031] Figure 3 The NMR spectrum of the compound of formula I prepared in Example 1;

[0032] Figure 4 The mass spectrum of the compound of formula I prepared in Example 1;

[0033] Figure 5 The liquid phase spectrum of the compound of formula I prepared in Example 1. Detailed Implementation

[0034] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0035] Example 1: Synthesis of Compound I of the Present Invention

[0036] The synthesis method route in this embodiment is as follows:

[0037]

[0038] The specific steps include:

[0039] Step 1, Preparation of Compound III:

[0040] Compound II (10 g, 0.0558 mol), N-bromosuccinimide (20.86 g, 0.1172 mol), and methanol (100 mL) were added to a reaction flask and reacted at 40 °C for 4 h. The mixture was filtered, and the filter cake was dried at 60 °C to give 17.5 g of solid (compound III), yield 93%. ¹H NMR (400 M, CD₃OD): 4.630 (2H, s), 8.333 (1H, s), 8.492 (1H, s); MS: m / z 336.0 (M+H+).

[0041] The second step is the preparation of compound V:

[0042] Compound III (17 g, 0.0504 mol), compound IV (37.61 g, 0.2520 mol), and methanol (85 mL) were added to a reaction flask and reacted at room temperature for 4 h. Hydrochloric acid was added dropwise to adjust the pH to 2, and the mixture was concentrated under reduced pressure until a large amount of solid precipitated. 170 mL of water was added, and stirring continued to induce crystallization. The mixture was filtered, and the filter cake was dried at 60 °C to give 21.2 g of solid (compound V), with a yield of 95%.

[0043] Step 3, preparation of compound VI:

[0044] Compound V (20 g, 0.0453 mol), 10% Pd / C (1.00 g), and methanol (150 mL) were added to a hydrogenation reactor. After purging with nitrogen, hydrogen gas was introduced at a pressure of 0.2 MPa. The mixture was heated to 40 °C and reacted for 6 h. The mixture was then cooled to room temperature and filtered to obtain a filtrate. The filtrate was concentrated to constant weight, and 200 mL of 3% sodium hydroxide solution was added. The mixture was stirred to dissolve the filtrate, and the pH was adjusted to 8 with concentrated hydrochloric acid. A large amount of solid precipitated out. The filtrate was filtered, and the filter cake was dried at 60 °C to obtain 13.5 g of solid (compound VI), with a yield of 91%.

[0045] Step 4, Preparation of Formula I:

[0046] Compound VI (13 g, 0.0396 mol) and methanol (65 mL) were added to a reaction flask and stirred at room temperature. Concentrated hydrochloric acid was added dropwise to adjust the pH to 2. Isopropanol (130 mL) was added dropwise to induce crystallization. The mixture was cooled to 10 °C and kept at that temperature for 1 h. After filtration, the filter cake was dried at 60 °C to obtain 12.9 g of product (compound I), with a yield of 90%.

[0047] Characterization of compounds of formula III as follows: Figure 1 , 2 As shown, the characterization of compound I is as follows: Figure 3 , 4 As shown in Figure 5. Compound I, labetalol hydrochloride: H NMR (400M, DMSO): 1.319-1.352 (3H, t), 1.779-1.835 (1H, m), 2.151 (1H, m), 2.559-2.618 (1H, m), 2.693-2.752 (1H, m), 3.090 (2H, m), 3.214 (1H, m), 4.927 (1 H,m), 6.124(1H,m), 6.903-6.924(1H,d), 7.200-7.321(5H,m), 7.443-7.464(1H,d), 7 .913-7.956(2H,m), 8.537-8.677(2H,m), 9.292-9.364(1H,m), 12.941(1H,s); MS:m / z 329.2(M-HCl+H + ).

[0048] 1H NMR and mass spectrometry analysis showed that the labetalol hydrochloride obtained in this invention has the correct structure and high purity, indicating that the preparation of labetalol hydrochloride was successful.

[0049] Example 2: Synthesis of Compound I of the Present Invention

[0050] Step 1, Preparation of Compound III:

[0051] Compound II (10 g, 0.0558 mol) and N,N-dimethylformamide (100 mL) were added to a reaction flask. Bromine (18.73 g, 0.1172 mol) was added dropwise at room temperature. The reaction was allowed to proceed for 4 h, and then 200 mL of water was added to induce crystallization. The mixture was filtered, and the filter cake was dried at 60 °C to give 17.9 g of solid (compound III), with a yield of 95%.

[0052] Compound V was prepared according to step 2 of Example 1.

[0053] Compound VI was prepared according to step 3 of Example 1.

[0054] Compound I was prepared according to step four of Example 1.

[0055] Example 3: Synthesis of Compound I of the Present Invention

[0056] Compound III was prepared according to the first step of Example 1.

[0057] The second step is the preparation of compound V:

[0058] Compound III (17 g, 0.0504 mol), compound IV (15.04 g, 0.1008 mol), triethylamine (5.10 g, 0.0504 mol), and methanol (85 mL) were added to a reaction flask and reacted at room temperature for 4 h. Hydrochloric acid was added dropwise to adjust the pH to 2, and the mixture was concentrated under reduced pressure until a large amount of solid precipitated. 170 mL of water was added, and stirring continued to induce crystallization. The mixture was filtered, and the filter cake was dried at 60 °C to give 19.8 g of solid (compound V), with a yield of 89%.

[0059] Compound VI was prepared according to step 3 of Example 1.

[0060] Compound I was prepared according to step four of Example 1.

[0061] Example 4: Synthesis of Compound I of the Present Invention

[0062] Compound III was prepared according to the first step of Example 1.

[0063] The second step is the preparation of compound V:

[0064] Compound III (17 g, 0.0504 mol), compound IV (15.04 g, 0.1008 mol), sodium hydroxide (2.02 g, 0.0504 mol), and methanol (85 mL) were added to a reaction flask and reacted at room temperature for 4 h. Hydrochloric acid was added dropwise to adjust the pH to 2, and the mixture was concentrated under reduced pressure until a large amount of solid precipitated. 170 mL of water was added, and stirring continued to induce crystallization. The mixture was filtered, and the filter cake was dried at 60 °C to give 19.2 g of solid (compound V), with a yield of 86%.

[0065] Compound VI was prepared according to step 3 of Example 1.

[0066] Compound I was prepared according to step four of Example 1.

[0067] In summary, this invention provides a method for preparing labetalol hydrochloride. The method provides a high conversion rate and few byproducts by using a 3-bromo-5-(2-bromoacetyl)-2-hydroxybenzamide intermediate to replace 5-bromoacetylsalicylic acid amide. The resulting product can be directly used in the next reaction step, followed by substitution and reduction to obtain the final product. This method is low-cost, high-yield, simple and controllable, and produces high purity, making it suitable for commercial-scale production.

Claims

1. A process for the preparation of labetalol hydrochloride, characterized in that, The method comprises the following steps: (1) carrying out bromination reaction on compound II to obtain compound III; (2) carrying out substitution reaction on compound III and compound IV to obtain compound V; (3) carrying out hydrogenation reduction on compound V to obtain compound VI; (4) carrying out salt formation on compound IV and HCl to obtain labetalol hydrochloride with the structure shown in formula I; In step (3), the hydrogenation reduction is carried out under the conditions of hydrogen pressure of 0.1-10 MPa, temperature of 10-60 DEG C and reaction time of 2-24 h, and the catalyst for the hydrogenation reduction is palladium-carbon; The reaction formula is as follows:

2. The production method according to claim 1, wherein In step (1), the bromination reagent used in the bromination reaction is at least one selected from N-bromosuccinimide, bromine or pyridinium tribromide, and the solvent is an organic solvent.

3. The production method according to claim 2, wherein In step (1), the bromination reagent used in the bromination reaction is N-bromosuccinimide, the molar ratio of compound II to the bromination reagent is 1:(1-3), the reaction temperature is 20-80 DEG C, and the reaction time is 1-12 h.

4. The production method according to claim 2, wherein In step (1), the bromination reagent used in the bromination reaction is bromine, the molar ratio of compound II to the bromination reagent is 1:(1-3), the reaction temperature is-10-40 DEG C, and the reaction time is 1-12 h.

5. The production method according to claim 1, wherein In step (2), the substitution reaction is carried out under the action of a base, and the base is at least one selected from an organic base or an inorganic base.

6. The production method according to claim 5, wherein In step (2), the substitution reaction is carried out under the action of a base, and the base is at least one selected from an organic base or an inorganic base, and the organic base is selected from compound IV.

7. The production method according to claim 1, wherein In step (2), the molar ratio of compound III to compound IV is 1:(1-5), the temperature of the substitution reaction is-10-50 DEG C, and the reaction solvent is an organic solvent.

8. The production method according to claim 1, wherein In step (4), the form of HCl is selected from hydrogen chloride gas, hydrogen chloride aqueous solution or hydrogen chloride organic solution.

9. The production method according to claim 1, wherein In step (4), the temperature of the salt formation is 0-50 DEG C, the time is 1-5 h, and the pH value is 1-4.

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