Preparation of bupivacaine hydrochloride and injection thereof

Abstract

The application relates to the technical field of medicine and chemical industry, in particular to a preparation method of bupivacaine hydrochloride and an injection thereof, and steps are as follows: 1) at 50-55 DEG C, N-(2,6-dimethylphenyl)-2-piperidine carboxamide, 4-dimethylaminopyridine, octadecyl dimethyl hydroxyethyl ammonium nitrate and n-butyl bromide are sequentially added into pyridine, the temperature is increased to 70-75 DEG C after stirring and dissolving, and the reaction is continuously carried out for 2-3 h, then the temperature is decreased to room temperature for filtration and drying, and bupivacaine is obtained; 2) the bupivacaine obtained in step 1) is dissolved in isobutyl alcohol, hydrogen chloride gas is continuously introduced for salting, and the bupivacaine hydrochloride is obtained after filtration and drying; 3) the bupivacaine hydrochloride obtained in step 2) is crystallized in isopropyl alcohol to obtain high-purity bupivacaine hydrochloride; the high-purity bupivacaine hydrochloride is prepared by optimizing the synthesis conditions, the product quality is stable, the yield is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical technology, and in particular to a method for preparing bupivacaine hydrochloride and bupivacaine hydrochloride injection. Background Technology

[0002] Bupivacaine hydrochloride is an organic compound with the chemical formula C. 18 H 29 ClN2O is a local anesthetic, mainly used for local anesthesia during surgery and postoperative analgesia. Bupivacaine hydrochloride is an amide-type local anesthetic, generally used for nerve block anesthesia, local infiltration anesthesia, and epidural anesthesia. Its mechanism of action is similar to that of amide-type local anesthetics, that is, the drug first binds to plasma proteins, is metabolized by the liver, and then excreted in urine through the kidneys. Its characteristics are: (1) strong anesthetic power (about 4 times that of carbocaine); (2) long duration (generally up to 5 hours, and up to 10 hours or more); (3) less impact on the respiratory and circulatory systems; (4) less likely to spread and affect the fetus when used by pregnant women.

[0003] In existing technologies, piperidine amide is commonly used as a starting material to react with bromobutane, potassium carbonate is used as an acid-binding agent, and DMF is used as a reaction solvent to obtain bupivacaine. This reaction has a low yield, long reaction time (around 40 hours), and low purity, resulting in a cumbersome process and high production costs. This product is already a relatively mature product, and there are abundant literature reports on its synthesis, with many domestic reports detailing its synthetic route. This invention mainly involves the final alkylation and salt formation reactions. According to literature reports, the alkylation reaction is mostly carried out in DMF solvent, and after the reaction is complete, it is added to ice water to obtain bupivacaine base. The salt formation reaction involves dissolving the bupivacaine base in isopropanol, then passing hydrogen chloride gas through it, and filtering to obtain bupivacaine hydrochloride. Alternatively, after the reaction in DMF is complete, dilute hydrochloric acid is added directly, followed by cooling and crystallization to obtain bupivacaine hydrochloride. The disadvantages of existing preparation methods reported in the literature are the large amount of DMF used, difficulty in recovery, high production costs, and unfavorable conditions for industrial production. In the field of bupivacaine hydrochloride preparation technology, there is a need to develop a simpler, more mature, and cost-effective process route. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a mild and low-cost method for preparing bupivacaine hydrochloride. This method involves adding pyridine, N-(2,6-dimethylyl)-2-piperidinecarboxamide, 4-dimethylaminopyridine, octadecyldimethylhydroxyethylammonium nitrate, and n-butane bromide to prepare bupivacaine. The method uses N-(2,6-dimethylyl)-2-piperidinecarboxamide as the starting material and reacts it with n-butane bromide. Pyridine is used as the reaction solvent, 4-dimethylaminopyridine as the deacidifying agent, and octadecyldimethylhydroxyethylammonium nitrate as the phase transfer catalyst to improve reaction efficiency. By using a novel deacidifying agent and phase transfer catalyst, and optimizing the reaction conditions, the reaction is simple to operate, produces stable products with high yields, and is suitable for industrial production.

[0005] To achieve the above-mentioned objectives, the technical solution adopted by the present invention is as follows:

[0006] On one hand, the present invention provides a method for preparing bupivacaine hydrochloride, characterized in that:

[0007] 1) Slowly heat the pyridine in the flask to 50-55℃ and maintain the temperature within this range. Then, add N-(2,6-dimethylyl)-2-piperidinecarboxamide, 4-dimethylaminopyridine, octadecyl dimethylhydroxyethylammonium nitrate and n-butane bromide to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 70-75℃. Continue the reaction for 2-3 hours, then cool to room temperature, filter and dry to obtain bupivacaine.

[0008] 2) Dissolve the bupivacaine obtained in step 1) in isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain crude bupivacaine hydrochloride.

[0009] 3) The crude bupivacaine hydrochloride obtained in step 2) is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride.

[0010] In some embodiments, the molar ratio of N-(2,6-dimethylyl)-2-piperidinecarboxamide to 4-dimethylaminopyridine is 4 to 5:1.

[0011] In some embodiments, the molar ratio of N-(2,6-dimethylyl)-2-piperidinecarboxamide to 4-dimethylaminopyridine is 4:1.

[0012] In some embodiments, the molar ratio of the brominated n-butane to octadecyl dimethyl hydroxyethyl ammonium nitrate is 3 to 3.5:1.

[0013] In some embodiments, the molar ratio of the brominated n-butane to octadecyl dimethyl hydroxyethyl ammonium nitrate is 3:1.

[0014] In some implementations, the volume ratio of crude bupivacaine hydrochloride to isopropanol is 1:1-5.

[0015] In some embodiments, n-heptane may also be added to the isopropanol, wherein the volume ratio of isopropanol to n-heptane is 1:1.

[0016] On the other hand, the present invention provides a method for preparing bupivacaine hydrochloride injection, characterized in that:

[0017] 1) Slowly heat the pyridine in the flask to 50-55℃ and maintain the temperature within this range. Add N-(2,6-xylyl)-2-piperidinecarboxamide, 4-dimethylaminopyridine, octadecyl dimethylhydroxyethylammonium nitrate and n-butane bromide to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 70-75℃. Continue the reaction for 2-3 hours, then cool to room temperature, filter, and dry to obtain bupivacaine.

[0018] 2) Dissolve the bupivacaine obtained in step 1) in isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain crude bupivacaine hydrochloride.

[0019] 3) The crude bupivacaine hydrochloride obtained in step 2) is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0020] 4) Dissolve the high-purity bupivacaine obtained from crystallization in step 3) in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution at 120°C for 20 minutes, fill it into ampoules, and seal it to obtain bupivacaine hydrochloride injection solution.

[0021] In some implementations, the volume ratio of crude bupivacaine hydrochloride to isopropanol in step 3) is 1:1-5.

[0022] On the other hand, the present invention provides a bupivacaine hydrochloride injection solution, wherein the bupivacaine hydrochloride injection solution comprises bupivacaine hydrochloride prepared by the aforementioned bupivacaine hydrochloride preparation method. Detailed Implementation

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0024] All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of conflict, this specification (including definitions) shall prevail. Furthermore, the materials, methods, and examples described herein are illustrative only and not intended to be restrictive.

[0025] When the terms “about” and “approximately” are used with numerical variables, they generally mean that the value of the variable and all values ​​of the variable are within the measurement or experimental error (e.g., the 95% confidence interval of the mean) or within a wider range of specified values ​​(e.g., ±5% or ±10%).

[0026] The term "comprising," or its variations such as "containing," "having," or "including," means to include the stated steps or elements, but does not exclude any other steps or elements. "Constitutes of," means to exclude steps or elements not listed. "Substantially constitutes of," means to include steps or elements that do not substantially affect the fundamental and novel features of the protected invention. The term "comprising" and its variations also include the cases of "consisting of specific steps or elements" and "substantially constitutes specific steps or elements."

[0027] When referring to a numerical range, it should be understood that the specific values ​​of its upper and lower limits are disclosed, as well as all intermediate ranges included therein, such as the intermediate range between its upper or lower limit and any intermediate value, or the intermediate range between any two intermediate values. Furthermore, any intermediate ranges, subranges, and all individual numerical values ​​described in the numerical range can be excluded from the numerical range.

[0028] The term “and / or” should be understood as any one of the multiple elements connected by the term, or a combination of any number of elements.

[0029] In some embodiments, pyridine in a flask is slowly heated to 50°C, 51°C, 52°C, 53°C, 54°C, and 55°C, and maintained at this temperature. N-(2,6-dimethylmethyl)-2-piperidinecarboxamide, 4-dimethylaminopyridine, octadecyl dimethylhydroxyethylammonium nitrate, and n-butane bromide are added sequentially, and stirred until completely dissolved. Then, the temperature is rapidly increased to 70°C, 71°C, 72°C, 73°C, 74°C, and 75°C, and the reaction is continued for 2 hours and 3 hours, respectively. After cooling to room temperature, the mixture is filtered and dried to obtain bupivacaine.

[0030] In some embodiments, the molar ratio of N-(2,6-dimethylyl)-2-piperidinecarboxamide to 4-dimethylaminopyridine is 4:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, or 5.0:1.

[0031] In some embodiments, the molar ratio of the brominated n-butane to octadecyl dimethyl hydroxyethyl ammonium nitrate is 3:0.1, 3.1:0.1, 3.2:0.1, 3.3:0.1, 3.4:0.1, or 3.5:0.1.

[0032] In some embodiments, the volume ratio of crude bupivacaine hydrochloride to isopropanol is 1:1, 1:2, 1:3, 1:4, or 1:5.

[0033] In some embodiments, n-heptane may also be added to the isopropanol, wherein the volume ratio of isopropanol to n-heptane is 1:1.

[0034] The present invention is further described through the following embodiments, which should not be construed as limiting the present invention.

[0035] Unless otherwise specified, all reagents used in the following examples are commercially available products.

[0036] Example 1

[0037] 1. Add 80 ml of pyridine to a 200 ml flask, slowly heat to 50 °C, and maintain this temperature. Then, add 38 g of N-(2,6-xylene45)-2-piperidinecarboxamide, 5 g of 4-dimethylaminopyridine, 2.5 g of octadecyldimethylhydroxyethylammonium nitrate, and 20 ml of n-butane bromide to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 70 °C. Continue the reaction for 3 hours, then cool to room temperature, filter, and dry to obtain bupivacaine.

[0038] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through for 1 h until salt is formed, filter and dry to obtain 40 g of bupivacaine hydrochloride.

[0039] 3. The crude bupivacaine hydrochloride obtained in step 2 is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0040] 4. Dissolve the high-purity bupivacaine obtained from crystallization in step 3 in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

[0041] Example 2

[0042] 1. Add 80 ml of pyridine to a 200 ml flask, slowly heat to 55 °C, and maintain this temperature. Then, add 38 g of N-(2,6-dimethyl)-2-piperidinecarboxamide, 5 g of 4-dimethylaminopyridine, 2.5 g of octadecyl dimethyl hydroxyethyl ammonium nitrate, and 20 ml of n-bromobutane to the pyridine in sequence. Stir to dissolve, then rapidly raise the temperature to 75 °C and continue the reaction for 2 hours. After cooling to room temperature, filter and dry to obtain bupivacaine.

[0043] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through for 1 h to form a salt, filter and dry to obtain 44 g of bupivacaine hydrochloride.

[0044] 3. The crude bupivacaine hydrochloride obtained in step 2 is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0045] 4. Dissolve the high-purity bupivacaine 35 obtained from crystallization in step 3 in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution by steaming at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

[0046] Example 3

[0047] 1. Add 80 ml of pyridine to a 200 ml flask, slowly heat to 50 °C, and maintain this temperature. Then, add 45.6 g of N-(2,6-dimethyl)-2-piperidinecarboxamide, 5 g of 4-dimethylaminopyridine, 2.5 g of octadecyl dimethyl hydroxyethyl ammonium nitrate, and 20 ml of n-bromobutane to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 70 °C. Continue the reaction for 3 hours, then cool to room temperature, filter, and dry to obtain bupivacaine.

[0048] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain 49.5 g of bupivacaine hydrochloride.

[0049] 3. The crude bupivacaine hydrochloride obtained in step 2 is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0050] 4. Dissolve the high-purity bupivacaine 20 obtained from crystallization in step 3 in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution by steaming at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

[0051] Example 4

[0052] 1. Add 80 ml of pyridine to a 200 ml flask, slowly heat to 55 °C, and maintain this temperature. At 55 °C, add 45.6 g of N-(2,6-dimethyl)-2-piperidinecarboxamide, 5 g of +-dimethylaminopyridine, 2.5 g of octadecyl dimethylhydroxyethylammonium nitrate, and 20 ml of n-bromobutane to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 75 °C. Continue the reaction for 2 hours, then cool to room temperature, filter, and dry to obtain bupivacaine.

[0053] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain 50.2 g of bupivacaine hydrochloride;

[0054] 3. The crude bupivacaine hydrochloride obtained in step 2 is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0055] 4. Dissolve the high-purity bupivacaine obtained from crystallization in step 3 in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

[0056] Example 5

[0057] 1. Add 80 ml of pyridine to a 200 ml flask, slowly heat to 50 °C, and maintain this temperature. Then, add 38 g of N-(2,6-dimethyl)-2-piperidinecarboxamide, 5 g of 4-dimethylaminopyridine, 2.5 g of octadecyl dimethyl hydroxyethyl ammonium nitrate, and 23.4 ml of n-bromobutane to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 70 °C. Continue the reaction for 3 hours, then cool to room temperature, filter, and dry to obtain bupivacaine.

[0058] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain 51.6.0 g of bupivacaine hydrochloride;

[0059] 3. The crude bupivacaine hydrochloride obtained in step 2 is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0060] 4. Dissolve the high-purity bupivacaine obtained from crystallization in step 3 in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

[0061] Example 6

[0062] 1. Add 80 ml of pyridine to a 200 ml flask, slowly heat to 55 °C, and maintain this temperature. Then, add 38 g of N-(2,6-dimethyl)-2-piperidinecarboxamide, 5 g of 4-dimethylaminopyridine, 2.5 g of octadecyl dimethyl hydroxyethyl ammonium nitrate, and 23.4 ml of n-bromobutane to the pyridine in sequence, stir to dissolve, and then rapidly raise the temperature to 75 °C. Continue the reaction for 2 hours, then cool to room temperature, filter, and dry to obtain bupivacaine.

[0063] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter, and dry to obtain 54.6 g of bupivacaine hydrochloride;

[0064] 3. The crude bupivacaine hydrochloride obtained in step 2 is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride;

[0065] 4. Dissolve the high-purity bupivacaine obtained from crystallization in step 3 in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

[0066] Comparative Example 1:

[0067] 1. Add 80 ml of pyridine to a 200 ml flask. At room temperature, add 38 g of N-(2,6-dimethyl)-2-piperidinecarboxamide, 5 g of 4-dimethylaminopyridine, 2.5 g of octadecyl dimethyl hydroxyethyl ammonium nitrate and 20 ml of n-butane bromide in sequence. Stir to dissolve, then rapidly raise the temperature to 75 °C and continue the reaction for 2 h. After cooling to room temperature, filter and dry to obtain bupivacaine.

[0068] 2. Dissolve the bupivacaine obtained in step 1 in 100 ml of isobutanol, continuously pass hydrogen chloride gas through for 1 h to form a salt, filter and dry to obtain 12.15 g of bupivacaine hydrochloride.

[0069] The embodiments of the present invention are not limited to those described above. Without departing from the spirit and scope of the present invention, those skilled in the art can make various changes and improvements to the present invention in form and detail, and these are all considered to fall within the protection scope of the present invention.

Claims

1. A method for preparing bupivacaine hydrochloride, characterized in that: 1) Slowly heat the pyridine in the flask to 50-55°C and maintain the temperature within this range. Then, add N-(2,6-xylyl)-2-piperidinecarboxamide, 4-dimethylaminopyridine, octadecyl dimethylhydroxyethylammonium nitrate, and n-butane to the pyridine in sequence. The molar ratio of N-(2,6-xylyl)-2-piperidinecarboxamide to 4-dimethylaminopyridine is 4:1, and the molar ratio of n-butane to octadecyl dimethylhydroxyethylammonium nitrate is 3.5:0.

1. Stir to dissolve, then rapidly raise the temperature to 70-75°C and continue the reaction for 2-3 hours. After cooling to room temperature, filter and dry to obtain bupivacaine. 2) Dissolve the bupivacaine obtained in step 1) in isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain crude bupivacaine hydrochloride. 3) The crude bupivacaine hydrochloride obtained in step 2) is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride.

2. The preparation method according to claim 1, characterized in that: The volume ratio of crude bupivacaine hydrochloride to isopropanol in step 3) is 1:1-5.

3. A method for preparing bupivacaine hydrochloride injection, characterized in that: 1) Slowly heat the pyridine in the flask to 50-55℃ and maintain the temperature within this range. Add N-(2,6-dimethylyl)-2-piperidinecarboxamide, 4-dimethylaminopyridine, octadecyl dimethylhydroxyethylammonium nitrate, and n-butane bromide sequentially to the pyridine. The molar ratio of N-(2,6-dimethylyl)-2-piperidinecarboxamide to 4-dimethylaminopyridine is 4:1, and the molar ratio of n-butane bromide to octadecyl dimethylhydroxyethylammonium nitrate is 3.5:0.

1. Stir to dissolve, then rapidly raise the temperature to 70-75℃ and continue the reaction for 2-3 hours. After cooling to room temperature, filter and dry to obtain bupivacaine. 2) Dissolve the bupivacaine obtained in step 1) in isobutanol, continuously pass hydrogen chloride gas through to form a salt, filter and dry to obtain crude bupivacaine hydrochloride. 3) The crude bupivacaine hydrochloride obtained in step 2) is crystallized in isopropanol to obtain high-purity bupivacaine hydrochloride; 4) Dissolve the high-purity bupivacaine obtained from crystallization in step 3) in water for injection to obtain solution A. Adjust the pH to 5.0-5.5 using 0.1% hydrochloric acid solution or 0.1% sodium hydroxide solution. Sterilize the solution by steaming at 120°C for 20 minutes, fill it into ampoules, and seal the ampoules to obtain bupivacaine hydrochloride injection solution.

4. The preparation method according to claim 3, characterized in that: The volume ratio of crude bupivacaine hydrochloride to isopropanol in step 3) is 1:1-5.