Process for the preparation of ropivacaine base and its use

Abstract

The application provides a preparation method of ropivacaine base and application thereof, relates to the technical field of organic synthesis, and comprises the following steps: (a) subjecting L-lysine to an amidation reaction to obtain an amidation product; (b) subjecting the amidation product to an enzymatic cyclization reaction to obtain a cyclization product; and (c) subjecting the cyclization product to an N-alkylation reaction to obtain the ropivacaine base. The application solves the technical problems of the existing ropivacaine base synthesis route, such as the need for resolution, high cost, complicated steps, and many by-products, achieves the technical effects of no need for chiral resolution, simple process, green environmental protection, high product yield, high product purity, and low production cost, is suitable for industrial large-scale production, and has important industrial application value.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for preparing ropivacaine base and its application. Background Technology

[0002] Ropivacaine, chemically known as (-)-(S)-N-(2,6-dimethylphenyl)-1-propylpiperidine-2-carboxamide, is a pure levorotatory, long-acting amide-type local anesthetic with both anesthetic and analgesic effects. High doses of ropivacaine can be used for surgical anesthesia, while low doses can be used for postoperative or labor analgesia. Due to its low toxicity to the cardiovascular and central nervous systems and its long duration of action, it is widely used in clinical practice.

[0003] Currently, the synthetic routes for ropivacaine bases mainly use piperidine carboxylic acid compounds as key intermediates. Conventional preparation methods have many shortcomings and cannot meet the requirements of green, efficient, and low-cost industrial production: First, most routes use racemic piperidine carboxylic acid as raw material, which requires a chiral resolution step to obtain optically pure intermediates. The resolution process not only increases the number of process steps and production costs but also generates a large number of byproducts, reducing atom utilization and failing to meet the concept of green synthesis. Second, some routes use expensive chiral sources or chiral catalysts as raw materials, resulting in high preparation costs and making it difficult to achieve large-scale industrial production. Third, the existing synthetic routes introduce chiral resolving agents, which impose stricter requirements on the residual impurities in the drug, making subsequent separation and purification difficult and affecting product purity and yield.

[0004] In view of this, the present invention is hereby proposed. Summary of the Invention

[0005] One of the objectives of this invention is to provide a method for preparing ropivacaine base, which solves the technical problems of existing ropivacaine base synthesis routes, such as the need for splitting, high cost, cumbersome steps, and numerous byproducts.

[0006] The second objective of this invention is to provide an application of a method for preparing ropivacaine base.

[0007] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted: In a first aspect, a method for preparing ropivacaine base includes the following steps: (a) The L-lysine was subjected to an amidation reaction to obtain the amidated product; (b) The amidation product is subjected to an enzymatic cyclization reaction to obtain the cyclized product; (c) The cyclized product is subjected to an N-alkylation reaction to obtain the ropivacaine base.

[0008] Furthermore, in step (a), the amidation reaction includes the following steps: L-lysine, acyl chloride reagent, anhydrous solvent and catalyst are mixed to undergo acyl chloride reaction. Then 2,6-dimethylaniline and acid-binding agent are added and mixed to undergo condensation reaction to obtain amidated product.

[0009] Furthermore, the anhydrous solvent used in the acyl chloride reaction includes at least one of anhydrous dichloromethane, n-hexane, and n-heptane, preferably anhydrous dichloromethane; Preferably, the catalyst used in the acyl chloride reaction includes N,N-dimethylformamide; Preferably, the amount of N,N-dimethylformamide used is 0.5% to 2% of the mass of L-lysine; Preferably, the acyl chloride reagent includes at least one of thionyl chloride and oxalyl chloride; Preferably, the amount of the acyl chloride reagent used is 1.5 eq to 2.0 eq of L-lysine; Preferably, the molar ratio of L-lysine to 2,6-dimethylaniline is 1:1.0~1.3, more preferably 1:1.1~1.2; Preferably, the acid-binding agent includes at least one of triethylamine and pyridine.

[0010] Furthermore, in step (b), the enzymatic cyclization reaction includes the following steps: The amidation product, buffer solution, and enzyme cyclization reagent are mixed to undergo an enzymatic cyclization reaction, yielding the cyclized product.

[0011] Furthermore, the enzyme cyclization reagent includes at least one of lysine cyclization deaminase, ornithine cyclization deaminase, and modified oxidized amide synthase, preferably lysine cyclization deaminase. Preferably, the amount of the enzyme cyclizing reagent used is 0.5% to 3% of the mass of the amidation product, and more preferably 1% to 2%. Preferably, the buffer solution comprises a phosphate buffer solution; Preferably, the pH of the environment for the enzymatic cyclization reaction is 7.0 to 8.0.

[0012] Furthermore, in step (c), the N-alkylation reaction includes the following steps: The cyclized product, bromopropane, base reagent, and solvent are mixed to undergo an N-alkylation reaction, yielding the ropivacaine base.

[0013] Furthermore, the molar ratio of the cyclized product to bromopropane is 1:1.2~1.6, preferably 1:1.3~1.5; Preferably, the alkaline reagent includes at least one of potassium carbonate, sodium carbonate, and sodium hydroxide, with potassium carbonate being the most preferred. Preferably, the solvent includes at least one of ethanol, N,N-dimethylformamide and acetone, with ethanol being the most preferred.

[0014] Furthermore, the post-processing of the N-alkylation reaction includes the following steps: After filtering the reaction system to remove salt impurities, the solid was added dropwise to water at 0-5°C to precipitate, and then recrystallized to obtain the ropivacaine base. Preferably, the solvent for recrystallization includes at least one of ethanol and ethyl acetate; Preferably, the volume ratio of ethanol to ethyl acetate in the recrystallization solvent is 1:1 to 2.

[0015] Furthermore, the total yield of the ropivacaine base is ≥82%, the purity is ≥99.8%, and the optical purity ee value is ≥99.5%.

[0016] Secondly, the application of any of the above-described preparation methods in chemical production.

[0017] Compared with the prior art, the present invention has at least the following beneficial effects: The method for preparing ropivacaine base provided by this invention uses natural L-lysine as the starting material. First, an amidation and enzymatic cyclization reaction is carried out to obtain a high optical purity intermediate that does not require resolution. Then, an N-alkylation reaction is carried out to efficiently prepare ropivacaine base. The method of this invention does not require chiral resolution, which is not only simple and environmentally friendly, but also has high product yield, high product purity, and low production cost, making it suitable for large-scale industrial production. Attached Figure Description

[0018] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0019] Figure 1 This is a schematic diagram of the preparation route of ropivacaine base according to one embodiment of the present invention. Detailed Implementation

[0020] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] According to a first aspect of the present invention, a method for preparing ropivacaine base is provided, comprising the following steps: (a) The L-lysine was subjected to an amidation reaction to obtain the amidated product; (b) The amidation product was subjected to an enzymatic cyclization reaction to obtain the cyclized product; (c) The cyclized product was subjected to N-alkylation to obtain ropivacaine base.

[0022] The method of this invention uses natural L-lysine as the starting material, first undergoing amidation and enzymatic cyclization reactions to obtain a high optical purity intermediate that does not require resolution, and then undergoing N-alkylation reaction to efficiently prepare ropivacaine base. The method of this invention does not require chiral resolution, is not only simple and environmentally friendly, but also has high product yield and high product purity, while having low production cost, making it suitable for large-scale industrial production.

[0023] In a preferred embodiment, step (a) includes the following steps: L-lysine, acyl chloride reagent, anhydrous solvent and catalyst are mixed to undergo acyl chloride reaction. Then 2,6-dimethylaniline and acid-binding agent are added and mixed to undergo condensation reaction to obtain amidated product.

[0024] L-Lysine is an essential natural α-amino acid for the human body, widely available and inexpensive. It possesses a natural chiral configuration (L-configuration), making it a suitable starting material. Its inherent chiral structure allows for the avoidance of subsequent resolution steps, simplifying the process. The L-lysine molecule contains α-amino, ε-amino, and carboxyl groups. Its amidation reaction with 2,6-dimethylaniline is the core step in constructing the key amide bond in ropivacaine bases.

[0025] L-lysine is activated at the α-carboxyl group by an acyl chloride reagent to generate a highly reactive acyl chloride intermediate. Under the action of an acid-binding agent, this intermediate undergoes a nucleophilic substitution reaction with 2,6-dimethylaniline, selectively generating N-(2,6-dimethylphenyl)-L-lysine amide, i.e., the amidation product. By controlling the reaction conditions, the ε-aminoacylation side reaction can be avoided, thus improving the reaction selectivity.

[0026] In this invention, L-lysine is added to a reaction vessel along with anhydrous solvent, acyl chloride reagent, and catalyst. Under inert gas (nitrogen or argon) protection, the reaction is carried out at 40°C to 50°C for 2 to 4 hours to ensure full activation of the α-carboxyl group of L-lysine and complete the acyl chloride treatment of L-lysine. The reaction system is then cooled to 0°C, and 2,6-dimethylaniline and an acid-binding agent are slowly added. The heating rate is controlled, and the temperature is slowly raised to room temperature to avoid local overheating that could trigger ε-aminoacylation side reactions. The selective amidation of α-carboxyl group and 2,6-dimethylaniline is preferentially achieved. The reaction is carried out for 1 to 3 hours to complete the condensation reaction. After the reaction is completed, the reaction is cooled to room temperature, and insoluble impurities are removed by filtration. The solvent is removed by vacuum distillation to obtain the amidated product (N-(2,6-dimethylphenyl)-L-lysine amide).

[0027] Under specific amidation reaction conditions, L-lysine and 2,6-dimethylaniline can react efficiently to yield the amidated product.

[0028] In a preferred embodiment, the anhydrous solvent used in the acyl chloride reaction includes, but is not limited to, at least one of anhydrous dichloromethane, n-hexane, and n-heptane, and is more preferably anhydrous dichloromethane, which has good solubility, a moderate boiling point, and is easy to recycle and reuse, thereby reducing production costs.

[0029] In a preferred embodiment, the catalyst used in the acyl chloride reaction includes, but is not limited to, N,N-dimethylformamide. The amount of N,N-dimethylformamide can be 0.5% to 2% of the mass of L-lysine, for example, 0.5%, 1%, 1.5%, 2%, but is not limited thereto.

[0030] In a preferred embodiment, the acyl chloride reagent includes, but is not limited to, at least one of thionyl chloride and oxalyl chloride. The amount of acyl chloride reagent used can be 1.5 eq to 2.0 eq of L-lysine, for example, 1.5 eq, 1.6 eq, 1.7 eq, 1.8 eq, 1.9 eq, 2.0 eq, but is not limited thereto.

[0031] In a preferred embodiment, the molar ratio of L-lysine to 2,6-dimethylaniline can be 1:1.0 to 1.3, for example, 1:1.0, 1:1.1, 1:1.2, or 1:1.3, but is not limited thereto, and can be further preferably 1:1.1 to 1.2.

[0032] In a preferred embodiment, the acid-binding agent includes, but is not limited to, at least one of triethylamine and pyridine, which can neutralize the hydrogen chloride generated in the reaction, prevent 2,6-dimethylaniline from forming a salt, and ensure its full participation in the acylation reaction; the amount of acid-binding agent can be 2.0 eq, but is not limited thereto.

[0033] In a preferred embodiment, step (b) of the enzymatic cyclization reaction includes the following steps: The amidation product, buffer solution, and enzyme cyclization reagent are mixed to undergo an enzymatic cyclization reaction, yielding a cyclized product with an optical purity ee value ≥ 99.5%.

[0034] Since L-lysine itself has a natural L-configuration, the chiral structure is preserved during amidation and cyclization reactions. Therefore, high-optical-purity cyclized products can be obtained without resolution and can be directly used for subsequent reactions.

[0035] Under the catalysis of an enzyme-based cyclizing agent, the amidation product undergoes an intramolecular cyclization reaction between the ε-amino group and the α-carboxyl group to form a piperidine ring structure, while strictly preserving the native chiral configuration of L-lysine, directly yielding a cyclized product with high optical purity.

[0036] In this invention, the amidation product is added to a reaction vessel, along with a buffer solution and an enzyme cyclization reagent. After stirring until homogeneous, the mixture is reacted at 30°C to 50°C for 3 to 6 hours to carry out an intramolecular cyclization reaction, causing the ε-amino group to cyclize with the α-carboxyl group to form a piperidine ring. After the reaction is complete, the enzyme preparation is removed by filtration, and an alkaline reagent is added to the reaction solution to adjust the pH to 7 to 8. A white solid precipitates out, which is then filtered, washed, and vacuum dried to obtain the cyclization product.

[0037] Washing can be done with a mixture of ethanol and deionized water (volume ratio of 1:2~3), which can effectively remove residual cyclizing reagents and water-soluble impurities, and improve the purity of the cyclization product. At the same time, the vacuum drying temperature can be 50℃~60℃, the vacuum degree can be 0.07MPa~0.09MPa, and the vacuum drying time can be 2h~3h, which is more conducive to the thorough drying of the cyclization product.

[0038] In a preferred embodiment, the enzyme cyclizing agent includes, but is not limited to, at least one of lysine cyclization deaminase, ornithine cyclization deaminase, and modified oxidized amide synthase, and is further preferably lysine cyclization deaminase, which has high catalytic specificity and no risk of racemization.

[0039] In a preferred embodiment, the amount of enzyme cyclizing agent can be 0.5% to 3% of the mass of the amidation product, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, but is not limited thereto, and can be further preferably 1% to 2%.

[0040] In a preferred embodiment, the buffer solution includes, but is not limited to, phosphate buffer solution, to maintain the pH of the reaction environment at a stable level of 7.0 to 8.0, thereby ensuring the catalytic activity of the enzyme.

[0041] In a preferred embodiment, step (c) of the N-alkylation reaction includes the following steps: The cyclization product, bromopropane, base reagent, and solvent are mixed to undergo an N-alkylation reaction, yielding ropivacaine base.

[0042] The nitrogen atom of the piperidine ring in the cyclization product is activated by a base reagent and undergoes a nucleophilic substitution reaction with bromopropane to introduce a n-propyl group, generating the target product, ropivacaine base. After post-treatment and recrystallization, a high-purity product is obtained.

[0043] In this invention, the cyclization product and bromopropane are added to a reaction vessel, along with a solvent and a base reagent. After stirring until homogeneous, the mixture is reacted at 60°C to 90°C for 5 to 10 hours to carry out an N-alkylation reaction. The alkylation reaction proceeds fully to improve the reaction conversion rate and introduce n-propyl groups into the piperidine ring. After the reaction is completed, the mixture is cooled to room temperature, filtered to remove salt impurities, and the reaction solution is post-treated. The crude product is purified by recrystallization to obtain the ropivacaine base product.

[0044] In a preferred embodiment, the molar ratio of the cyclized product to bromopropane can be 1:1.2 to 1.6, for example, 1:1.2, 1:1.3, 1:1.4, 1:1.5, or 1:1.6, but is not limited thereto. It is more preferably 1:1.3 to 1.5, which helps to ensure a full reaction and reduce the formation of by-products.

[0045] In a preferred embodiment, the alkaline reagent includes, but is not limited to, at least one of potassium carbonate, sodium carbonate, and sodium hydroxide, and is more preferably potassium carbonate. It has moderate alkalinity, which can effectively neutralize the hydrobromic acid generated in the reaction and is not likely to cause the product to racemize. At the same time, it can avoid side reactions under strongly alkaline conditions.

[0046] The molar ratio of the base reagent to the cyclization product can be 1.3 to 1.8:1, and can be further preferred to be 1.4 to 1.6:1.

[0047] In a preferred embodiment, the solvent includes, but is not limited to, at least one of ethanol, N,N-dimethylformamide and acetone, and is more preferably ethanol, which has low toxicity, good solubility, can effectively dissolve each reaction raw material, is more conducive to improving the reaction rate, and is also convenient for subsequent recovery.

[0048] In a preferred embodiment, the post-treatment of the N-alkylation reaction includes the following steps: After filtering the reaction system to remove salt impurities, the solid was added dropwise to water at 0-5℃ to precipitate. Recrystallization yielded ropivacaine base.

[0049] After the N-alkylation reaction is completed, the mixture is cooled to room temperature and filtered to remove potassium carbonate and potassium bromide and other salt impurities. The clarified reaction solution is then slowly added dropwise to cold water at 0-5°C (the volume of cold water can be 3-5 times the volume of the reaction solution) while stirring rapidly. Ropivacaine base is fully precipitated as a white solid. After the addition is complete, stirring is continued for 0.5-1 h to ensure that the solid is fully precipitated. The solid is collected by filtration and the filter cake is washed 2-3 times with a small amount of ice water to remove residual water-soluble impurities. The crude ropivacaine base is obtained by vacuum drying and then purified by recrystallization.

[0050] In a preferred embodiment, the recrystallization solvent can be a mixture of ethanol and ethyl acetate (volume ratio 1:1~2), heated to 50℃~60℃ to completely dissolve the crude product, cooled to 0~5℃, kept at that temperature for 1h~2h, filtered, and vacuum dried to obtain high-purity ropivacaine base product.

[0051] The post-processing method of this invention can effectively remove residual solvents and water-soluble impurities, avoid product decomposition caused by vacuum distillation, and further improve the purity and yield of the product.

[0052] In a preferred embodiment, the total yield of ropivacaine base can be ≥82%, the purity can be ≥99.8%, and the optical purity ee value can be ≥99.5%.

[0053] In summary, compared with the prior art, the present invention has the following significant advantages: Using natural L-lysine as the starting material, which is widely available and inexpensive, avoids the use of expensive chiral raw materials or chiral catalysts, significantly reducing production costs and making it suitable for large-scale industrial production. By utilizing the natural L-configuration of L-lysine, an intermediate with an ee value ≥99.5% can be directly obtained after enzymatic cyclization, omitting the chiral resolution step, simplifying the process, improving atom utilization, reducing byproduct generation, and conforming to the concept of green synthesis. The enzyme catalysis is carried out under mild aqueous phase conditions, without the need for high temperature and high pressure, strong corrosive reagents, few by-products that are easy to handle, mild reaction conditions, reduced environmental treatment costs, and in line with the requirements of green chemical development. Each step of the reaction has high selectivity and few byproducts. By optimizing the reaction parameters and post-processing, the final product, ropivacaine base, has a total yield of over 82%, a purity of ≥99.8%, and an optical purity ee value of ≥99.5%, meeting the requirements for clinical drug use. The amidation and alkylation reactions use conventional chemical reagents and equipment, and are simple to operate; the enzymatic cyclization conditions are mild and easy to scale up, and the post-processing optimization process is simple and controllable, requiring no special equipment, making it suitable for large-scale industrial production.

[0054] According to a second aspect of the present invention, an application of the preparation method described in any of the above claims in chemical production is provided.

[0055] The present invention will be further illustrated below through examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or purchased directly from the market.

[0056] Example 1 A method for preparing ropivacaine base, see [link to relevant documentation]. Figure 1 This includes the following steps: (1) Amide reaction: Under nitrogen protection, L-lysine (14.6 g, 0.1 mol), anhydrous dichloromethane (150 mL), and N,N-dimethylformamide (0.1 mL, 0.68% of the mass of L-lysine) were added to a 500 mL three-necked flask. After stirring until homogeneous, thionyl chloride (17.85 g, 0.15 mol, 1.5 eq) was slowly added dropwise. After the addition was complete, the mixture was heated to 45 °C and refluxed for 3 h. After the reaction was completed, the reaction system was cooled to 0 °C, and then slowly added... 2,6-Dimethylaniline (13.3 g, 0.11 mol, 1.1 eq) and triethylamine (20.2 g, 0.2 mol, 2.0 eq) were added, and the temperature was slowly increased to room temperature at a rate of 5 °C / h, and the reaction was allowed to proceed for 2 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove insoluble impurities, and dichloromethane was removed by vacuum distillation (40 °C, 0.08 MPa) to obtain a pale yellow oily intermediate A with a yield of 23.8 g and a yield of 93.2%. (2) Enzymatic cyclization reaction: To a 500 mL three-necked flask, add intermediate A (23.8 g, 0.093 mol), 200 mL of phosphate buffer (pH 7.5), and lysine cyclization deaminase (0.36 g, 1.5% of the mass of intermediate A). After stirring thoroughly, heat to 40 °C and stir for 4.5 h. After the reaction, filter to remove the enzyme preparation. Adjust the pH of the reaction solution to 7.5 with 10% sodium carbonate solution, and a white solid precipitates. Filter the solid, wash the filter cake three times with an ethanol-water mixture (volume ratio 1:2), and vacuum dry (60 °C, 0.08 MPa) for 2 h to obtain white solid intermediate 1, yield 20.9 g, yield 90.5%, and HPLC analysis showed an optical purity ee value of 99.7%. (3) N-alkylation reaction: Add intermediate 1 (20.9 g, 0.084 mol), 120 mL of anhydrous ethanol, potassium carbonate (17.4 g, 0.126 mol, 1.5 eq), and bromopropane (12.4 g, 0.101 mol, 1.2 eq) to a 500 mL three-necked flask. After stirring until homogeneous, heat to 75 °C and react at this temperature for 7 h. After the reaction is complete, cool to room temperature, filter to remove potassium carbonate and potassium bromide salts and other impurities, and slowly add the clear reaction solution dropwise to 400 mL of 0 °C cold water (3.3 times the volume of the reaction solution) while stirring rapidly (stirring speed 300 r / min). Ropivacaine base was extracted as a white solid. After the addition was complete, stirring was continued for 1 hour. The solid was collected by filtration, and the filter cake was washed twice with a small amount of ice water. The cake was then dried under vacuum (55℃, 0.08MPa) for 2 hours to obtain crude ropivacaine base. The crude product was added to 50 mL of an ethanol-ethyl acetate mixture (volume ratio 1:1.5), heated to 55℃ to completely dissolve the crude product, cooled to 0℃, and kept at that temperature for 1.5 hours. The mixture was then filtered and dried under vacuum to obtain 21.5 g of ropivacaine base product, with a total yield of 83.1%. The purity was 99.9% as determined by GC and 99.6% as determined by HPLC.

[0057] Example 2 A method for preparing ropivacaine base includes the following steps: (1) Amide reaction: Under argon protection, L-lysine (29.2 g, 0.2 mol), anhydrous n-heptane (300 mL), and N,N-dimethylformamide (0.2 mL, 0.68% of L-lysine by mass) were added to a 1000 mL three-necked flask. After stirring until homogeneous, oxaloyl chloride (25.4 g, 0.2 mol, 2.0 eq) was slowly added dropwise. After the addition was complete, the mixture was heated to 50 °C and refluxed for 2.5 h. After the reaction was completed, the mixture was cooled to 0 °C, and 2... 6-Dimethylaniline (26.6 g, 0.22 mol, 1.1 eq) and pyridine (31.6 g, 0.4 mol, 2.0 eq) were reacted at a controlled heating rate of 4 °C / h, slowly heated to room temperature, and reacted for 3 h. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove insoluble impurities, and n-heptane was removed by vacuum distillation (60 °C, 0.08 MPa) to obtain a pale yellow oily intermediate A, with a yield of 47.5 g and a yield of 93.0%. (2) Enzymatic cyclization reaction: To a 1000 mL three-necked flask, add intermediate A (47.5 g, 0.186 mol), 400 mL of phosphate buffer (pH 7.8), and ornithine cyclization deaminase (0.71 g, 1.5% of the mass of intermediate A). After stirring thoroughly, heat to 45 °C and stir for 4 h. After the reaction is complete, filter to remove the enzyme preparation. Adjust the pH of the reaction solution to 7.8 with 10% sodium carbonate solution, and a white solid precipitates. Filter the solid, wash the filter cake three times with an ethanol-water mixture (volume ratio 1:3), and vacuum dry (temperature 60 °C, vacuum degree 0.08 MPa) for 2 h to obtain white solid intermediate 1, yield 42.3 g, yield 91.2%, and HPLC analysis showed an optical purity ee value of 99.8%. (3) N-alkylation reaction: Add intermediate 1 (42.3 g, 0.17 mol), 250 mL of acetone, sodium carbonate (21.6 g, 0.204 mol, 1.2 eq), and bromopropane (24.8 g, 0.204 mol, 1.2 eq) to a 1000 mL three-necked flask. After stirring thoroughly, heat to 80 °C and react at this temperature for 6 hours. After the reaction is complete, cool to room temperature, filter to remove sodium carbonate and sodium bromide salts and other impurities, and slowly add the clear reaction solution dropwise to 800 mL of 5 °C cold water (3.2 times the volume of the reaction solution) while stirring rapidly. Ropivacaine base was added dropwise at a rate of 300 r / min, and was released as a white solid. After the addition was complete, the mixture was stirred for 0.5 h, filtered to collect the solid, washed twice with a small amount of ice water, and dried under vacuum to obtain the crude product. The crude product was added to 100 mL of an ethanol-ethyl acetate mixture (volume ratio 1:2), heated to 60 °C to completely dissolve the crude product, cooled to 5 °C, kept at that temperature for 1 h, filtered, and dried under vacuum to obtain 43.2 g of ropivacaine base product, with a total yield of 84.2%. The purity was 99.8% as determined by GC and 99.7% as determined by HPLC.

[0058] Example 3 A method for preparing ropivacaine base includes the following steps: (1) Amide reaction: Under nitrogen protection, L-lysine (14.6 g, 0.1 mol), anhydrous dichloromethane (150 mL), and N,N-dimethylformamide (0.29 mL, 2.0% of L-lysine by mass) were added to a 500 mL three-necked flask. After stirring until homogeneous, thionyl chloride (23.8 g, 0.2 mol, 2.0 eq) was slowly added dropwise. After the addition was complete, the mixture was heated to 40 °C and refluxed for 4 h. After the reaction was completed, the mixture was cooled to 0 °C, and 2,6-dimethylaniline (15.6 g, 0.13 mol, 1.3 eq) and triethylamine (20.2 g, 0.2 mol, 2.0 eq) were slowly added. The temperature was controlled at a rate of 5 °C / h, and the mixture was slowly heated to room temperature and reacted for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and insoluble impurities were removed by filtration. Dichloromethane was removed by vacuum distillation to obtain a pale yellow oily intermediate A with a yield of 23.6 g and a yield of 92.4%. (2) Enzymatic cyclization reaction: Intermediate A (23.6 g, 0.092 mol), 200 mL of phosphate buffer (pH 7.0), and modified oxidized amide synthase (0.71 g, 3.0% of the mass of intermediate A) were added to a 500 mL three-necked flask. After stirring, the mixture was heated to 30 °C and stirred at this temperature for 6 h. After the reaction was completed, the enzyme preparation was removed by filtration. The pH of the reaction solution was adjusted to 7.0 with 10% sodium carbonate solution, and a white solid precipitated. The solid was filtered, and the filter cake was washed three times with an ethanol-water mixture (volume ratio 1:2). The solid was then vacuum dried for 2 h to obtain white solid intermediate 1, with a yield of 20.3 g and a yield of 89.8%. The optical purity ee value was 99.5% as determined by HPLC. (3) N-alkylation reaction: Add intermediate 1 (20.3 g, 0.082 mol), 120 mL of N,N-dimethylformamide, sodium hydroxide (5.25 g, 0.131 mol, 1.6 eq), and bromopropane (13.1 g, 0.107 mol, 1.3 eq) to a 500 mL three-necked flask. After stirring thoroughly, the mixture was heated to 60°C and reacted at this temperature for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered to remove salt impurities, and the clear reaction solution was slowly added dropwise to 360 mL of cold water at 3°C ​​(3 times the volume of the reaction solution) while stirring rapidly. Ropivacaine base was completely separated as a white solid. After the addition was complete, stirring was continued for 0.8 hours, the solid was collected by filtration, the filter cake was washed twice with a small amount of ice water, and the crude product was obtained by vacuum drying. The crude product was added to 50 mL of an ethanol-ethyl acetate mixture (volume ratio 1:1), heated to dissolve, cooled to 3°C, and kept at this temperature for 2 hours. After filtration and drying, 20.7 g of ropivacaine base product was obtained, with a total yield of 82.0%. The purity was 99.8% as determined by GC and 99.5% as determined by HPLC.

[0059] Example 4 The difference between this embodiment and Example 1 is that the amount of thionyl chloride used in the amidation reaction is 1.0 eq; Everything else is the same as in Example 1; The yield of intermediate A was 22.3 g, with a yield of 87.5%.

[0060] Example 5 The difference between this embodiment and Example 1 is that the amount of thionyl chloride used in the amidation reaction is 2.0 eq; Everything else is the same as in Example 1; The yield of intermediate A was 24.0 g, with a yield of 94.1%.

[0061] Example 6 The difference between this embodiment and Example 1 is that triethylamine was not added in the amidation reaction; Everything else is the same as in Example 1; The yield of intermediate A was 21.3 g, with a yield of 83.3%.

[0062] Example 7 The difference between this embodiment and Example 1 is that the amount of lysine cyclization deaminase used in the enzymatic cyclization reaction is 0.5% of the mass of intermediate A; Everything else is the same as in Example 1; The yield of intermediate 1 was 16.4 g, with a yield of 71.2%, and the optical purity ee value was 95.5% as determined by HPLC.

[0063] Example 8 The difference between this embodiment and Example 1 is that the amount of lysine cyclization deaminase used in the enzymatic cyclization reaction is 1% of the mass of intermediate A; Everything else is the same as in Example 1; The yield of intermediate 1 was 20.1 g, with a yield of 86.9%, and the optical purity ee value was 98.2% as determined by HPLC.

[0064] Example 9 The difference between this embodiment and Example 1 is that the amount of lysine cyclization deaminase used in the enzymatic cyclization reaction is 2% of the mass of intermediate A; Everything else is the same as in Example 1; The yield of intermediate 1 was 21.1 g, with a yield of 91.3%, and the optical purity ee value was 99.8% as determined by HPLC.

[0065] Comparative Example 1 Compared with Example 1, the difference in the preparation method of ropivacaine base in this comparative example (traditional resolution method) is that racemic piperidine-2-carboxylic acid is used as raw material, and (S)-piperidine-2-carboxylic acid is obtained by chiral resolving agent (tartaric acid), and then ropivacaine base is prepared by amidation reaction with 2,6-dimethylaniline and N-alkylation reaction with bromopropane. The remaining steps and reaction parameters are the same as in Example 1; The final product yield was 62.3%, the purity was 99.2% as determined by GC, and the optical purity ee value was 99.0% as determined by HPLC. The separation process generated a large number of byproducts, resulting in high environmental treatment costs and a cumbersome process flow.

[0066] Comparative Example 2 Compared with Example 1, the difference in the preparation method (chemical cyclization method) of the ropivacaine base in this comparative example is that thionyl chloride is used as the chemical cyclization reagent in the cyclization reaction; The remaining steps and reaction parameters are the same as in Example 1; Intermediate 1 yielded 85.1%, with an optical purity ee value of 99.2% as determined by HPLC. The final total yield of ropivacaine base was 78.5%, with a purity of 99.5% as determined by GC. The cyclization stage requires a reaction temperature of 110℃~120℃, posing a safety hazard. Slight racemization was observed, and a significant number of byproducts were produced.

[0067] In summary, the method of this invention uses natural L-lysine as a raw material and reacts it with 2,6-dimethylaniline under specific amidation reaction conditions to obtain an amidated product. The amidated product can be cyclized enzymatically without resolution to obtain a cyclized product with high optical purity. The cyclized product is then alkylated with bromopropane to obtain ropivacaine base. This method not only simplifies the process and reduces production costs, but also improves the yield and purity of the product, and has significant industrial application value and market prospects.

[0068] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing ropivacaine base, characterized in that, Includes the following steps: (a) The L-lysine was subjected to an amidation reaction to obtain the amidated product; (b) The amidation product is subjected to an enzymatic cyclization reaction to obtain the cyclized product; (c) The cyclized product is subjected to N-alkylation to obtain the ropivacaine base.

2. The preparation method according to claim 1, characterized in that, In step (a), the amidation reaction includes the following steps: L-lysine, acyl chloride reagent, anhydrous solvent and catalyst are mixed to undergo acyl chloride reaction. Then 2,6-dimethylaniline and acid-binding agent are added and mixed to undergo condensation reaction to obtain amidated product.

3. The preparation method according to claim 2, characterized in that, The anhydrous solvent used in the acyl chloride reaction includes at least one of anhydrous dichloromethane, n-hexane, and n-heptane, preferably anhydrous dichloromethane; Preferably, the catalyst used in the acyl chloride reaction includes N,N-dimethylformamide; Preferably, the amount of N,N-dimethylformamide used is 0.5% to 2% of the mass of L-lysine; Preferably, the acyl chloride reagent includes at least one of thionyl chloride and oxalyl chloride; Preferably, the amount of the acyl chloride reagent used is 1.5 eq to 2.0 eq of L-lysine; Preferably, the molar ratio of L-lysine to 2,6-dimethylaniline is 1:1.0~1.3, more preferably 1:1.1~1.2; Preferably, the acid-binding agent includes at least one of triethylamine and pyridine.

4. The preparation method according to claim 1, characterized in that, In step (b), the enzymatic cyclization reaction includes the following steps: The amidation product, buffer solution, and enzyme cyclization reagent are mixed to undergo an enzymatic cyclization reaction, yielding the cyclized product.

5. The preparation method according to claim 4, characterized in that, The enzyme cyclization reagent includes at least one of lysine cyclization deaminase, ornithine cyclization deaminase, and modified oxidized amide synthase, preferably lysine cyclization deaminase. Preferably, the amount of the enzyme cyclizing reagent used is 0.5% to 3% of the mass of the amidation product, and more preferably 1% to 2%. Preferably, the buffer solution comprises a phosphate buffer solution; Preferably, the pH of the environment for the enzymatic cyclization reaction is 7.0 to 8.

0.

6. The preparation method according to claim 1, characterized in that, In step (c), the N-alkylation reaction includes the following steps: The cyclized product, bromopropane, base reagent, and solvent are mixed to undergo an N-alkylation reaction, yielding the ropivacaine base.

7. The preparation method according to claim 6, characterized in that, The molar ratio of the cyclized product to bromopropane is 1:1.2~1.6, preferably 1:1.3~1.5; Preferably, the alkaline reagent includes at least one of potassium carbonate, sodium carbonate, and sodium hydroxide, with potassium carbonate being the most preferred. Preferably, the solvent includes at least one of ethanol, N,N-dimethylformamide and acetone, with ethanol being the most preferred.

8. The preparation method according to claim 7, characterized in that, The post-treatment of the N-alkylation reaction includes the following steps: After filtering the reaction system to remove salt impurities, the solid was added dropwise to water at 0-5°C to precipitate, and then recrystallized to obtain the ropivacaine base. Preferably, the solvent for recrystallization includes at least one of ethanol and ethyl acetate; Preferably, the volume ratio of ethanol to ethyl acetate in the recrystallization solvent is 1:1 to 2.

9. The preparation method according to any one of claims 1-8, characterized in that, The total yield of the ropivacaine base is ≥82%, the purity is ≥99.8%, and the optical purity ee value is ≥99.5%.

10. The application of the preparation method according to any one of claims 1-9 in chemical production.

Images