A process for the preparation of landiolol hydrochloride and intermediates thereof

Abstract

The application discloses a preparation method of landiolol hydrochloride and an intermediate thereof. The application discloses a preparation method of landiolol I, which comprises the following steps: carrying out a nucleophilic substitution reaction on compound 2 and SM4 in an organic solvent to obtain landiolol I, wherein the organic solvent is a mixed solvent formed by one or two of tetrahydrofuran, dioxane and isopropanol. The preparation method disclosed by the application is simple in operation, has few by-products, is high in reaction yield, is high in product purity, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically to a method for preparing landilol hydrochloride and its intermediates. Background Technology

[0002] Landiolol hydrochloride (CAS: 144481-98-1), trade name Onoact, chemical name: [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholino-4-carboxamido)ethylamino]propoxy]phenyl]propionate hydrochloride, with the following chemical structure:

[0003]

[0004] Landilol hydrochloride is an ultra-short-acting, highly selective β1 receptor blocker that primarily antagonizes β1 receptors present in the heart. It improves tachycardia-related arrhythmias by inhibiting the increase in heart rate induced by catecholamines. Developed by Ono Pharmaceutical Co., Ltd. of Japan, it was first marketed in Japan in September 2002. Clinically, it is mainly used for the emergency treatment of tachycardia-related arrhythmias (including atrial fibrillation, atrial flutter, and sinus tachycardia) during surgery, and for the emergency treatment of tachycardia-related arrhythmias (including atrial flutter, atrial fibrillation, and sinus tachycardia) under dynamic circulatory monitoring after surgery.

[0005] The literature (Chem. Pharm. Bull. 40(6) 1462-1469 (1992)) reports a method for preparing brandylolol hydrochloride, the route of which is as follows:

[0006]

[0007] In the above synthetic route, each step requires column chromatography purification, resulting in low yields, cumbersome operations, and unsuitability for industrial production. Furthermore, the product is unstable during column chromatography, making it difficult to obtain high-purity, qualified samples (purity ≥99%, maximum single impurity ≤0.10%). Moreover, the key reaction steps in the synthesis of landilol (compound I), compounds 2 and SM4, are carried out in isopropanol or isopropanol / water systems. However, using alcohol solvents, especially alkyl alcohols, readily leads to transesterification reactions during the reaction, generating numerous exchange impurities. The target conversion rate is only 45%–55%, and the purification process is difficult, resulting in a final yield of only 15%–25%.

[0008] Ester exchange impurities are shown in Formula III (R is selected from alkyl groups, such as methyl, isopropyl, etc.):

[0009]

[0010] CN104003973A discloses that the compound landilol readily undergoes transesterification with alcohol solvents under alkaline conditions, posing a risk to the safety and efficacy of the drug. CN101012217A discloses that landilol readily decomposes in methanol to produce byproducts (Formula IV), and while avoiding the use of methanol in the process, it still uses isopropanol / water as the reaction solvent for the ring-opening reaction, thus failing to prevent the formation of isopropyl transesterification impurities (Formula V). Because the isopropyl transesterification impurity is relatively large and its structure is similar to that of landilolol, controlling it below 0.10% in the active pharmaceutical ingredient requires multiple recrystallizations to obtain landilolol hydrochloride products that meet pharmaceutical quality requirements. This is not only cumbersome but also significantly reduces the yield, resulting in low yield and high cost.

[0011]

[0012] CN104003973A discloses a method for synthesizing landilol using an aqueous sodium hydroxide solution and N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide as reaction solvents, with a yield of only 45%–55%. However, formamide solvents are easily decomposed in aqueous sodium hydroxide solution. For example, using N,N-dimethylformamide will decompose to produce a series of byproducts such as dimethylamine and dimethylamine formate. Similarly, dimethyl sulfoxide has poor stability to alkalis, easily decomposes and self-disproportionates to form sulfides. In addition, dimethyl sulfoxide itself has oxidizing properties, which will affect the easily oxidized groups of landilol, such as hydroxyl and amino groups, generating oxidized impurities such as ketones and nitrogen oxides, thereby affecting product quality.

[0013] In addition, CN102232930A discloses that landilol is easily hydrolyzed and isomerized under acidic or alkaline conditions. In particular, ester hydrolysis is prone to occur under alkaline conditions, producing hydrolytic impurities as shown in Formula VI, which affects product quality and yield.

[0014]

[0015] The prior art CN108752308B discloses the use of dioxane as a solvent in the synthesis of landilol. Although this avoids transesterification impurities, the reaction under this solvent results in a large number of byproducts, the target conversion rate is still low, the purification process is difficult, and the final yield is low (20% to 25% in this step). It is difficult to obtain a high-purity qualified sample (purity ≥99%, maximum single impurity ≤0.10%).

[0016] Therefore, there is an urgent need to find a synthetic process for landilol hydrochloride that has a high target conversion rate, few by-products, high product purity, and is suitable for industrial production. Summary of the Invention

[0017] The technical problem to be solved by this invention is to overcome the shortcomings of existing methods for synthesizing brandylol hydrochloride, such as numerous reaction byproducts, difficult purification, low yield, low purity of the prepared product, and high production and raw material costs. This invention provides a method for preparing brandylol hydrochloride and its intermediates. The preparation process of this invention is simple to operate, produces fewer byproducts, has a high reaction yield, and yields a high-purity product, making it suitable for industrial production.

[0018] This invention provides a method for preparing landilol I, which includes the following steps: in an organic solvent, compound 2 and SM4 are subjected to a nucleophilic substitution reaction to obtain landilol I, wherein the organic solvent is a mixed solvent formed by one or two of tetrahydrofuran and dioxane and isopropanol;

[0019]

[0020] The preparation of brandylol I can be carried out using conventional methods for this type of nucleophilic substitution reaction in the art. In this invention, the following reaction conditions are particularly preferred:

[0021] In the preparation method of Landilol I, the organic solvent is preferably a mixed solvent of tetrahydrofuran and dioxane or a mixed solvent of tetrahydrofuran and isopropanol. When a mixed solvent of tetrahydrofuran and dioxane is used, the volume ratio of tetrahydrofuran to dioxane is preferably (1:5) to (20:1), more preferably (1:1) to (10:1), for example 5:1.

[0022] When a mixed solvent of tetrahydrofuran and isopropanol is used, the volume ratio of tetrahydrofuran to isopropanol is preferably (1:5) to (20:1), more preferably (1:1) to (10:1), for example 5:1.

[0023] In the preparation method of Landilol I, the volume-to-mass ratio of the organic solvent to the compound 2 is preferably 1 mL / g to 30 mL / g, more preferably 2 mL / g to 10 mL / g, for example 3 mL / g.

[0024] In the preparation method of landilol I, the molar ratio of SM4 to compound 2 is preferably 1 to 5, more preferably 1 to 3, for example 2.

[0025] In the preparation method of landilol 1, the temperature of the nucleophilic substitution reaction is preferably 0-100℃, more preferably 20℃-60℃, and even more preferably 40℃-50℃.

[0026] In the preparation method of landilol I, the progress of the nucleophilic substitution reaction can be detected by conventional detection methods in the art (e.g., HPLC, TLC or NMR). Generally, the disappearance of compound 2 is taken as the endpoint of the reaction. The time of the nucleophilic substitution reaction is preferably 10 hours to 30 hours, more preferably 15 hours to 24 hours, for example 20 hours.

[0027] The preferred method for preparing landilol I includes the following post-processing steps: after the reaction is complete, the solvent is removed, and no further purification is required; the solution is then directly used in the next step to prepare landilol hydrochloride.

[0028] The present invention also provides a method for preparing brandylol hydrochloride, which includes the following steps: in a solvent, the aforementioned prepared brandylol I is reacted with ammonium chloride to form a salt, thereby obtaining the brandylol hydrochloride II;

[0029]

[0030] The preparation of brandylol II hydrochloride can be carried out using conventional methods for this type of salt-forming reaction in the art. In this invention, the following reaction conditions are particularly preferred:

[0031] In the preparation method of brandylol II hydrochloride, the solvent is preferably a mixture of water and an ester solvent, and the ester solvent is preferably ethyl acetate.

[0032] In the preparation method of brandylol II hydrochloride, the volume-to-mass ratio of the solvent to compound I is preferably 1 mL / g to 30 mL / g, more preferably 3 mL / g to 10 mL / g, for example 6.8 mL / g.

[0033] In the preparation method of brandylolol II hydrochloride, the molar ratio of ammonium chloride to compound I is preferably 1 to 50, more preferably 10 to 30, for example 20.

[0034] In the preparation method of brandylol II hydrochloride, the temperature of the salt formation reaction is preferably 0-40℃, more preferably 5℃-35℃, and even more preferably 20℃-30℃.

[0035] In the preparation method of brandylol II hydrochloride, the progress of the salt formation reaction can be detected by conventional detection methods in the art (e.g., HPLC, TLC or NMR). Generally, the disappearance of compound I is taken as the endpoint of the reaction. The salt formation reaction time is preferably 1 minute to 5 hours, more preferably 10 minutes to 1 hour, for example 30 minutes or 1 hour.

[0036] The preferred method for preparing brandylol II hydrochloride includes the following post-processing steps: after the reaction is completed, the solvent is removed, and the mixture is recrystallized to obtain purified brandylol hydrochloride.

[0037] The recrystallization preferably employs the following steps: a solution of crude brandylol hydrochloride and an organic solvent is cooled to allow crystallization, yielding purified brandylol hydrochloride. The organic solvent used for recrystallization is selected from one or more of ether solvents, ester solvents, and ketone solvents, with ketone solvents being preferred. Acetone is the preferred ketone solvent.

[0038] The recrystallization temperature is preferably 40℃~60℃, more preferably 45℃~55℃. The crystallization temperature is preferably 0℃~20℃, more preferably 5℃~15℃.

[0039] The preferred method for preparing landiolol hydrochloride according to the present invention is as follows:

[0040]

[0041] The positive and progressive effects of this invention are as follows: the preparation method of this invention produces fewer byproducts, has a high conversion rate, is simple in post-processing, and produces a product with high purity (both chemical purity and chiral purity are greater than 99.50%, with a maximum single impurity of ≤0.10%), and a total molar yield of over 80%; it can produce landiolol hydrochloride with a chemical purity of over 99.80%, other single impurities less than 0.10%, and a chiral purity of 99.98%, reaching the level of active pharmaceutical ingredient (API), and is suitable for industrial production. Detailed Implementation

[0042] The present invention will be further illustrated by way of embodiments below, but the present invention is not limited to the scope of the embodiments described herein.

[0043] Detection conditions for relevant substances and isomers:

[0044] ① Related substances testing

[0045] Testing instruments used in the laboratory:

[0046] Column: Octadecylsilane-bonded silica gel as the packing material

[0047] Detection wavelength: 223nm

[0048] Flow rate: 1.0 ml / min

[0049] Mobile phase A: 0.02 mol / L sodium dihydrogen phosphate solution

[0050] Mobile phase B: Acetonitrile

[0051] Elution gradients are set according to the table below:

[0052] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 93 7 5 93 7 25 68 32 43 45 55 45 93 7 60 93 7

[0053] ②Isomer impurity detection

[0054] Testing instruments used in the laboratory:

[0055] Chromatographic column: Normal-phase coated chiral column of polysaccharide derivatives

[0056] Detection wavelength: 220nm

[0057] Flow rate: 1.0 ml / min

[0058] Mobile phase: n-hexane-isopropanol-diethylamine (80:20:0.1)

[0059] Running time: 60 minutes

[0060] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.

[0061] Example 1, Preparation of Compound 2 (4-[(2S)-3-cyclopropoxy]phenylpropionic acid [(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl ester)

[0062]

[0063] At room temperature, 500g of compound 1, 5L of acetone, and 620g of potassium carbonate were added to a reaction flask. 600g of compound SM3 was then added, and the mixture was purged with nitrogen. The temperature was raised to 60-65℃ and reacted for 16 hours. The conversion of the starting materials was monitored by HPLC until complete. The mixture was then cooled to room temperature, and 2.5L of ethyl acetate and 1.5L of saturated sodium bicarbonate aqueous solution were added. The mixture was stirred and filtered. The filtrate was allowed to stand and separated. The aqueous phase was extracted once with 1L of ethyl acetate. The organic phases were combined and then dried with anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure at 45℃ to obtain 590g of compound 2 as an oily substance with an HPLC purity of 97.06%. The product was used directly in the next reaction step.

[0064] Example 2: Preparation of compound SM4 (N-(2-aminoethyl)-4-morpholinocarboxamide)

[0065]

[0066] 1 kg of N-(2-aminoethyl)-4-morpholine carboxamide oxalate, 1 kg of anhydrous sodium sulfate, 380 g of sodium hydroxide, and 7 L of dichloromethane were added to the reaction flask. The mixture was heated to 35–45 °C and stirred for 16 h. After filtration, the filter cake was washed with 2 L of dichloromethane. The filtrate was concentrated under reduced pressure at 35 ± 5 °C to obtain 640 g of off-white solid SM4 with an HPLC purity of 99.3% and a yield of 97.3%.

[0067] Example 3: Preparation of Landilol II Hydrochloride ([(4S)-2,2-dimethyl-1,3-dioxolane-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholino-4-formylamino)ethylamino]propoxy]phenyl]propionate hydrochloride)

[0068]

[0069] At room temperature (20℃~30℃), 610 g (1.81 mol) of compound 2 was added to a reaction flask, along with 6 L of tetrahydrofuran and 1.2 L of dioxane, and stirred until dissolved. The free 640 g (3.69 mol) of SM4 was added in portions to the reaction solution, stirred until dissolved, and then the temperature was raised to 40-50℃ for 20 h. The reaction was controlled by HPLC, and the starting material compound 2 reacted completely. The reaction solution was concentrated under reduced pressure until almost no solvent was distilled off, yielding 876 g of concentrate. 3 L of ethyl acetate and 3 L of water were added to the concentrate, and the mixture was stirred for 30 min. After standing, the liquid was separated. The aqueous phase was extracted and washed once with 3 L of ethyl acetate. The combined organic phases were extracted twice with 3 L of saturated ammonium chloride aqueous solution, stirring for 30 min each time. After standing, the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure at 35±5℃ to obtain an off-white solid. Add 1.8 L of acetone to the solid, heat to 45–55 °C until the system is dissolved, remove heating, cool to room temperature (5–15 °C), filter, and dry the filter cake at 40 ± 5 °C to obtain 791 g (1.45 mol) of white solid powder with HPLC purity of 99.91%, yield of 80.1%, and chiral HPLC purity of 99.98%.

[0070] LCMS: m / z = 510.3 [M+H] + . 1 H-NMR (400MHz, deuterated DMSO): δ: 7.10 (2

[0071] H, d), 6.84 (2H, d), 5.09 (1H, t), 4.38 (1H, q), 4.25 (1H, dd), 4.18 (1H, dd), 4.05 (1H, m), 4.01 (1H, dd), 3.93 (1H, dd), 3.90 (1H, dd), 3.60 (1H ,dd), 3.60(4H,t), 3.33(2H,q), 3.30(4H,t), 2.85(2H,t), 2.80(1H,dd), 2.82(2H,t), 2.79(1H,dd), 2.65(2H,t), 1.43(3H,s), 1.35(3H,s).

[0072] Example 4: Comparison of reaction conditions using different solvents

[0073] To compare the effects of different reaction solvents on the preparation reaction of brandylol II hydrochloride, typical experimental procedures were used to compare the reaction conditions of the process for obtaining brandylol hydrochloride.

[0074]

[0075] Note: Purity was determined using HPLC related substances detection method.

[0076] The structures of formulas IV, V, and compound 2 are shown below:

[0077]

[0078] Experimental data show that when tetrahydrofuran is used as a solvent, the reaction produces fewer byproducts, but the reaction rate is extremely slow, and the starting materials cannot be completely converted. When dioxane is used as a solvent, the reaction rate is fast, but there are significantly more byproducts, resulting in low conversion and low yield.

[0079] Example 5: Following the method of Example 3, the reaction conditions of different batches of compounds of formula VII prepared using tetrahydrofuran:dioxane = 5:1 (volume ratio) as the reaction solvent are compared in Table 2.

[0080]

Claims

1. A process for the preparation of landiolol I, characterized by The method comprises the following steps: carrying out a nucleophilic substitution reaction on compound 2 and SM4 in an organic solvent to obtain landiolol I, wherein the organic solvent is a mixed solvent of tetrahydrofuran and dioxane or a mixed solvent of tetrahydrofuran and isopropanol; when the mixed solvent of tetrahydrofuran and dioxane is used, the volume ratio of tetrahydrofuran to dioxane is (1:5) to (20:1); when the mixed solvent of tetrahydrofuran and isopropanol is used, the volume ratio of tetrahydrofuran to isopropanol is (1:5) to (20:1); 。 2. The method for preparing landiolol I according to claim 1, wherein: when the mixed solvent of tetrahydrofuran and dioxane is used in the method for preparing landiolol I, the volume ratio of tetrahydrofuran to dioxane is (1:1) to (10:1); and / or when the mixed solvent of tetrahydrofuran and isopropanol is used in the method for preparing landiolol I, the volume ratio of tetrahydrofuran to isopropanol is (1:1) to (10:1).

3. The method for preparing landiolol I according to claim 1, wherein: in the method for preparing landiolol I, the volume-mass ratio of the organic solvent to compound 2 is 1 mL / g to 30 mL / g; and / or in the method for preparing landiolol I, the molar ratio of SM4 to compound 2 is 1 to 5; and / or in the method for preparing landiolol I, the temperature of the nucleophilic substitution reaction is 0 to 100 DEG C; and / or in the method for preparing landiolol I, the time of the nucleophilic substitution reaction is 10 to 30 hours; and / or in the method for preparing landiolol I, the method comprises the following post-treatment step: after the reaction is completed, the solvent is removed, and landiolol I is directly used in the preparation of landiolol hydrochloride without further purification.

4. The method for preparing landiolol I according to claim 3, wherein: in the method for preparing landiolol I, the volume-mass ratio of the organic solvent to compound 2 is 2 mL / g to 10 mL / g; and / or in the method for preparing landiolol I, the molar ratio of SM4 to compound 2 is 1 to 3; and / or in the method for preparing landiolol I, the temperature of the nucleophilic substitution reaction is 20 to 60 DEG C; and / or in the method for preparing landiolol I, the time of the nucleophilic substitution reaction is 15 to 24 hours.

5. The method for preparing landiolol hydrochloride II according to claim 1 to 4, wherein: the method comprises the following steps: after landiolol I is prepared by the method according to any one of claims 1 to 4, a salt formation reaction is carried out on landiolol I and ammonium chloride in a solvent to obtain landiolol hydrochloride II.

6. The method for preparing landiolol hydrochloride II according to claim 5, wherein: in the method for preparing landiolol hydrochloride II, the solvent is a mixed solvent of water and an ester solvent; and / or in the method for preparing landiolol hydrochloride II, the volume-mass ratio of the solvent to compound I is 1 mL / g to 30 mL / g. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 5. A process for the preparation of Landiolol Hydrochloride II, characterized by ​ 。 ​ ​ ​ ​ ​ In the preparation method of Landiolol Hydrochloride II, the molar ratio of the ammonium chloride to the compound I is 1-50; and / or, In the preparation method of Landiolol Hydrochloride II, the temperature of the salification reaction is 0-40℃; and / or, In the preparation method of Landiolol Hydrochloride II, the time of the salification reaction is 1 minute-5 hours; and / or, The preparation method of Landiolol Hydrochloride II comprises the following post-treatment step: after the reaction is completed, the solvent is removed, and recrystallization is performed to obtain purified Landiolol Hydrochloride.

7. The preparation method of Landiolol Hydrochloride II according to claim 5, wherein: In the preparation method of Landiolol Hydrochloride II, the ester solvent is ethyl acetate; and / or, In the preparation method of Landiolol Hydrochloride II, the volume / mass ratio of the solvent to the compound I is 3 mL / g-10 mL / g; and / or, In the preparation method of Landiolol Hydrochloride II, the molar ratio of the ammonium chloride to the compound I is 10-30; and / or, In the preparation method of Landiolol Hydrochloride II, the temperature of the salification reaction is 5℃-35℃; and / or, In the preparation method of Landiolol Hydrochloride II, the time of the salification reaction is 10 minutes-1 hour; and / or, The preparation method of Landiolol Hydrochloride II preferably comprises the following post-treatment step: after the reaction is completed, the solvent is removed, and recrystallization is performed to obtain purified Landiolol Hydrochloride.

8. The process for the preparation of Landiolol Hydrochloride II as claimed in claim 5 wherein: The recrystallization is performed by the following steps: a solution of the crude Landiolol Hydrochloride and an organic solvent is prepared, and the solution is cooled to induce crystallization to obtain purified Landiolol Hydrochloride.

9. The preparation method of Landiolol Hydrochloride II according to claim 8, wherein: The organic solvent used in the recrystallization is one or more of an ether solvent, an ester solvent and a ketone solvent; and / or, The temperature of the recrystallization is 40℃-60℃; and / or, The temperature of the crystallization is 0℃-20℃.

10. The preparation method of Landiolol Hydrochloride II according to claim 9, wherein: The ketone solvent is acetone; and / or, The temperature of the recrystallization is 45℃-55℃; and / or, The temperature of the crystallization is 5℃-15℃.

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