A method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide

Abstract

A method for preparing the ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-formamide includes the following steps: Step 1: Dissolve a resolving agent in solvent A; Step 2: Add N-(2,6-dimethylyl)piperidine-2-formamide to a mixture of solvent A and solvent B and stir until dissolved; Step 3: Mix the solutions obtained in Step 1 and Step 2 and react for 1 hour; Step 4: Cool the reacted solution to -5°C to 5°C and stir to crystallize for 2-4 hours; Step 5: Centrifuge or filter and collect the mother liquor; Step 6: Concentrate the mother liquor under reduced pressure to remove solvent A; Step 7: Adjust the pH of the obtained concentrate to 11-14 with an alkaline neutralizing agent; Step 8: Extract and separate the solution obtained in Step 7, collect the organic phase, concentrate under reduced pressure, and obtain the product. The ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide prepared by the method of this invention has a stable yield of over 45%, good chiral purity, simple post-processing, high yield, controllable process, strong operability, and is easy to industrialize.

Description

Technical Field

[0001] This invention belongs to the field of ropivacaine hydrochloride impurities, specifically a method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide. Background Technology

[0002] Ropivacaine hydrochloride is a novel long-acting amide-type local anesthetic, marketed in 1996 and developed by the Astra Pain Control Center in Sweden. Its chemical name is (-)-(2S)-N-(2,6-dimethylphenyl)-1-n-propylpiperidine-2-carboxamide hydrochloride, and its trade name is Nexium. Ropivacaine hydrochloride is a new generation of long-acting, safe local anesthetic; it is used for surgical anesthesia, childbirth procedures, local or regional anesthesia, and the treatment of acute or postoperative pain.

[0003] The key intermediate in the ropivacaine production process is (S)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide, whose corresponding isomer is (R)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide. The content of this impurity affects the chiral purity of the finished ropivacaine product and cannot be ignored during quality studies. Its molecular formula is C14H20N2O, and its structural formula is as follows:

[0004]

[0005] This impurity is not currently available on the market, and there are very few publicly available reports on its synthesis methods. However, research on this impurity in ropivacaine hydrochloride is crucial, as it can be used for the qualitative and quantitative analysis of impurities in ropivacaine hydrochloride production, thereby improving the quality standards of ropivacaine hydrochloride and providing important guidance for safe medication use. Therefore, it is necessary to study the synthesis method of this impurity. Summary of the Invention

[0006] This invention provides a method for preparing (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide, an impurity for ropivacaine hydrochloride, to overcome the deficiencies in the prior art.

[0007] This invention is achieved through the following technical solution:

[0008] A method for preparing the ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide includes the following steps:

[0009] Step 1: Add the resolving agent to solvent A, heat to 20-30℃ and stir for 30 minutes until dissolved;

[0010] Step 2: Add N-(2,6-dimethylyl)piperidine-2-carboxamide to the mixture of solvent A and solvent B, heat to 40-50℃ and stir for 30 minutes until dissolved;

[0011] Step 3: Add the solution containing the resolving agent obtained in Step 1 dropwise to the system containing N-(2,6-dimethylyl)piperidine-2-carboxamide obtained in Step 2, and react at 40-50℃ for 1 hour;

[0012] Step 4: Cool the reaction solution to -5℃ to 5℃ and stir to allow crystals to precipitate for 2-4 hours;

[0013] Step 5: Centrifuge or filter to collect the mother liquor;

[0014] Step Six: Concentrate the mother liquor under reduced pressure to distill off solvent A;

[0015] Step 7: Adjust the pH of the obtained concentrate to 11-14 by adding an alkaline neutralizing agent;

[0016] Step 8: Add 4-6 times the volume of solvent C to the solution obtained in Step 7 for extraction and separation. Collect the organic phase, concentrate under reduced pressure, and obtain the product.

[0017] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, solvent A is any one of methanol, acetone, or ethanol.

[0018] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, solvent B is purified water.

[0019] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, the solvent C is any one of toluene, methyl isobutyl ketone, or ethyl acetate.

[0020] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, the resolving agent in step one is dibenzoyl tartaric acid.

[0021] The method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, wherein the two resolving agents, di-p-methylbenzoyl tartaric acid, are either D-type or L-type, or a mixture of D and L.

[0022] In the method for preparing the ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide as described above, the molar ratio between the amount of resolving agent and (R,S)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide is 0.4-2.0:1.

[0023] In the method for preparing the ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide as described above, the molar ratio between the amount of resolving agent and (R,S)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide is 0.5-1.0:1.

[0024] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, the solution containing the resolving agent obtained in step one of step three is added dropwise to the system containing N-(2,6-dimethylyl)piperidine-2-carboxamide obtained in step two over a period of 1-1.5 hours.

[0025] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, the temperature of vacuum concentration in step six is ​​not higher than 60°C.

[0026] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, the alkaline neutralizing agent in step seven is either sodium hydroxide solution or potassium hydroxide solution.

[0027] In the method for preparing ropivacaine hydrochloride impurity (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide as described above, the volume ratio of solvent A to solvent B in the mixture of solvent A and solvent B in step two is 3-5:1.

[0028] The advantages of this invention are: the yield of (R)-N-(2,6-dimethylyl)piperidine-2-carboxamide, an impurity in ropivacaine hydrochloride, prepared by the method of this invention can be consistently above 45%, exhibiting good chiral purity. The post-processing is simple, the yield is high, the process is controllable, highly operable, and easy to industrialize. It can provide a qualified impurity reference standard for the quality control of ropivacaine hydrochloride, solving the problem of quality control of ropivacaine hydrochloride impurity reference standards. Attached Figure Description

[0029] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the 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 based on these drawings without creative effort.

[0030] Figure 1 This is a flowchart of the preparation process of the present invention;

[0031] Figure 2This is the purity detection spectrum of Example 1 of the present invention;

[0032] Figure 3 This is the purity detection spectrum of Embodiment 2 of the present invention. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, 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.

[0034] Example 1

[0035] 10g of D-type benzoyl tartaric acid was dissolved in 35g of acetone by stirring and heating. 20g of N-(2,6-dimethylyl)piperidine-2-carboxamide was added to a reaction flask, along with 35g of acetone and 10g of purified water. The mixture was stirred and heated to 50°C until dissolved. Benzoyl tartaric acid solution was added dropwise, and the reaction was maintained at 50°C for 1 hour. The mixture was then cooled to -5°C for 1 hour to precipitate the solution, and the filtrate was obtained. The filtrate was concentrated under reduced pressure at 50°C until no condensate remained. The pH was adjusted to 14 with 10% potassium hydroxide. 30g of toluene was added to the system, and the organic phase was separated. The solution was concentrated at 50°C to obtain 9g of a white solid (45% yield, 99.8% optical purity).

[0036] Example 2

[0037] 100g of L-type di-p-methyldibenzoyl tartaric acid was dissolved in 350g of acetone by stirring and heating until dissolved. 200g of N-(2,6-xylyl)piperidine-2-carboxamide was added to a reaction flask, followed by 350g of acetone and 100g of purified water. The mixture was stirred and heated to 55°C until dissolved. Dibenzoyl tartaric acid solution was added dropwise, and the reaction was maintained at 55°C for 1 hour. The mixture was then cooled to -5°C for 2 hours to precipitate the solution, and the filtrate was obtained. The filtrate was concentrated under reduced pressure at 50°C until no condensate remained. The pH was adjusted to 14 with 10% sodium hydroxide. 300g of toluene was added to the system, and the organic phase was separated. The solution was concentrated at 50°C to obtain 94g of a white solid (47% yield, 99.8% optical purity).

[0038] 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 of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, characterized by: It comprises the following steps: Step one: add the resolving agent into solvent A, and stir for 30 min to dissolve at 20-30℃; the resolving agent in step one is D-tartrate acid or L-tartrate acid; Step two: add N-(2,6-dimethylphenyl)piperidine-2-carboxamide into the mixture of solvent A and solvent B, and stir for 30 min to dissolve at 40-50℃; Step three: add the solution containing the resolving agent obtained in step one into the system containing N-(2,6-dimethylphenyl)piperidine-2-carboxamide obtained in step two, and react for 1 h at 40-50℃; Step four: cool the solution to -5-5℃, and stir for 2-4 h to crystallize; Step five: centrifuge or filter, and collect the mother liquor; Step six: concentrate the mother liquor under reduced pressure to evaporate solvent A; Step seven: add the concentrated solution into alkaline neutralizer to adjust pH to 11-14; Step eight: add 4-6 times volume of solvent C into the solution obtained in step seven to extract and separate, collect the organic phase, and concentrate under reduced pressure to obtain the product.

2. The method for preparing the impurity (R)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide of ropivacaine hydrochloride according to claim 1, characterized in that: the solvent A is any one of methanol, acetone or ethanol; the solvent B is purified water; the solvent C is any one of toluene, methyl isobutyl ketone or ethyl acetate.

3. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, according to claim 1, characterized by: the molar ratio of the resolving agent to (R,S)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide is 0.4-2.0:

1.

4. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, according to claim 3, characterized by: the molar ratio of the resolving agent to (R,S)-2-(2,6-dimethylphenyl)-2-piperidinecarboxamide is 0.5-1.0:

1.

5. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, according to claim 1, characterized by: the dropping time of the solution containing the resolving agent obtained in step one into the system containing N-(2,6-dimethylphenyl)piperidine-2-carboxamide obtained in step two is 1-1.5 h.

6. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, according to claim 1, characterized by: the temperature of the concentration under reduced pressure in step six is not higher than 60℃.

7. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, according to claim 1, characterized by: the alkaline neutralizer in step seven is any one of sodium hydroxide solution or potassium hydroxide solution.

8. A process for preparing an impurity of ropivacaine hydrochloride, (R)-N-(2,6- dimethylphenyl)piperidine-2-carboxamide, according to claim 1, characterized by: the volume ratio of solvent A to solvent B in the mixture of solvent A and solvent B in step two is 3-5:1.

Images