A method for preparing and controlling byproduct impurity compounds in the baclofen production process.

Abstract

This invention relates to the field of pharmaceutical quality control, and discloses a method for preparing and controlling a byproduct impurity compound in the production process of baclofen. The method for preparing the byproduct impurity compound includes reacting baclofen methyl ester hydrochloride in an organic solvent under the action of an alkali and N,N'-carbonyldiimidazole, concentrating the resulting intermediate product, washing with water and filtering to obtain a filter cake; then reacting the obtained filter cake in an organic solvent under the action of an alkali, adjusting the pH to 2-3, to obtain impurity compound I. This method yields the impurity compound with high purity (≥96%), which can be used to accurately quantify the content of this impurity in the production process of baclofen raw material, further aiding in the control of this impurity in actual production. Furthermore, this invention, through process optimization, can control the byproduct impurity to undetectable levels under current quality standards during the production of baclofen, thereby improving the quality of the final product, baclofen.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical quality control, specifically to a method for preparing and controlling a byproduct impurity compound produced during the production of baclofen. Background Technology

[0002] Baclofen, chemically known as (±)-4-amino-3-(4-chlorophenyl)-butyric acid, is an important centrally acting muscle relaxant. Clinically, baclofen is widely used to treat skeletal muscle spasms caused by multiple sclerosis, syringomyelia, spinal cord tumors, transverse myelitis, spinal cord injury, and motor neuron disease. It can also relieve spasm symptoms caused by cerebrovascular diseases, cerebral palsy, meningitis, and craniocerebral trauma. It also has certain efficacy in treating spasms caused by infectious, degenerative, traumatic, tumor, or unexplained spinal cord diseases. It can effectively improve patients' muscle stiffness and limited mobility, thereby improving their quality of life and rehabilitation outcomes. Its mechanism of action is mainly through stimulating γ-aminobutyric acid (GABA) receptors in the spinal cord, inhibiting the release of excitatory amino acids such as glutamate and aspartate, thereby inhibiting the transmission of monosynaptic and polysynaptic reflexes in the spinal cord, exerting a significant skeletal muscle spasm-relieving effect. At the same time, recent studies have further expanded its application scenarios, showing good application prospects in the comprehensive treatment of spasticity-related diseases, and its clinical value is outstanding.

[0003] Currently, there are many patented methods for the synthesis of baclofen, but the technical route that can achieve industrial production uses p-chlorophenylglutamate as a key intermediate and the core step of Hoffmann degradation reaction to finally synthesize the target product baclofen.

[0004]

[0005] In the industrial production process, baclofen is prepared using liquid bromine and sodium hydroxide in the final Hoffmann degradation reaction. According to the Hoffmann degradation mechanism, the amide first produces an isocyanate with one less carbon atom, then reacts with water molecules to give carbamic acid, and finally decarboxylates under heating to give an amino compound with one less carbon atom. However, when preparing baclofen under these conditions, the generated baclofen molecules react with the incompletely converted isocyanate intermediates to produce urea byproducts. Urea byproducts are common in baclofen, and their content directly affects the quality of the final product. If the urea impurity content is too high, the related substances in the final baclofen product will fail to meet quality standards, and multiple purifications will not meet the requirements, posing a significant quality risk to production.

[0006]

[0007] Therefore, this invention provides a method for preparing urea byproducts to improve their purity, making them usable as standards and further aiding in the control of this impurity in actual production processes. Simultaneously, this invention also provides a method for preparing baclofen to improve the main reaction conversion efficiency of the isocyanate intermediate during the reaction process, reduce the content of urea byproducts, and directly improve the quality of the final product, baclofen. Summary of the Invention

[0008] Purpose of the invention: The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing a method for preparing and controlling by-product impurity compounds in the baclofen production process.

[0009] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[0010] In a first aspect, the present invention discloses a method for preparing impurity compound I.

[0011]

[0012] The preparation method includes the following steps:

[0013] (1) Baclofen methyl ester hydrochloride was reacted in an organic solvent with an alkali and N,N'-carbonyldiimidazole (CDI). The intermediate product was concentrated, washed with water and filtered to obtain a filter cake.

[0014] (2) The filter cake obtained in an organic solvent is reacted under the action of alkali, and the pH is adjusted to 2-3 to obtain impurity compound I.

[0015] In step (1), the molar ratio of baclofen methyl hydrochloride, base and N,N'-carbonyldiimidazole is 1:1.0~1.2:0.4~0.6, and in some embodiments it is 1:1.1:0.5; the mass-volume ratio of baclofen methyl hydrochloride and organic solvent is 1g:8-12mL, and in some embodiments it is 1g:10mL.

[0016] In step (1), the base is any one or a combination of two of triethylamine and N,N-diisopropylethylamine, and in some embodiments it is triethylamine; the organic solvent is any one or a combination of several of dichloromethane, chloroform and tetrahydrofuran, and in some embodiments it is dichloromethane.

[0017] In step (1), baclofen methyl ester hydrochloride, an organic solvent, and a base are mixed, and then N,N'-carbonyldiimidazole is added to react. In some embodiments, the mixing is performed by stirring at room temperature for 5-15 minutes, such as 8 minutes, 10 minutes, or 12 minutes. In some embodiments, baclofen methyl ester hydrochloride, an organic solvent, and a base are mixed and stirred for 5-15 minutes, and then CDI is added to react. After the reaction is completed, the resulting reaction solution containing the intermediate is concentrated to remove the solvent, and the concentrate is washed with water and filtered. The resulting filter cake is the intermediate. In some embodiments, the reaction is performed at 20-30°C for 0.5-2 hours, such as 1 hour at 20-30°C. In some embodiments, the filter cake does not need to be dried and can be used directly in the next reaction.

[0018] In step (1), the filter cake is urea intermediate II.

[0019] In step (2), in some embodiments, water is added after the reaction is completed, the pH is adjusted to 2-3, the mixture is filtered, the filter cake is washed with water, and dried to obtain impurity compound I; in some embodiments, the wet filter cake from step (1) is mixed with an organic solvent, dissolved, and then alkali is added for reaction; after the reaction is completed, the reaction solution is cooled to room temperature, water is added, the pH is adjusted to 2-3 with hydrochloric acid, the mixture is filtered, washed with water, and dried to obtain impurity compound I.

[0020] In step (2), the molar ratio of baclofen methyl hydrochloride to the base is 1:2-5, and in some embodiments it is 1:3-4; the base is sodium hydroxide; the organic solvent is methanol; the mass-volume ratio of baclofen methyl hydrochloride to the organic solvent is 1g:2-8mL, and in some embodiments it is 1g:5mL.

[0021] In step (2), the reaction temperature is 40-50℃; the reaction is carried out under stirring for 0.5-1.5h.

[0022] In some embodiments, the method for preparing urea by-product impurity compound I in the baclofen production process includes the following steps:

[0023] 1) Baclofen methyl ester hydrochloride was added to an organic solvent at room temperature, and then an alkali was added. After stirring for 10 min, CDI was added. The temperature was controlled at 20~30℃ and the reaction was carried out for 0.5~1 h to generate a urea intermediate. After the reaction was completed, the solvent was removed by concentration. The concentrate was washed with water and filtered. The filter cake was directly used for subsequent hydrolysis reaction.

[0024] 2) Add the filter cake obtained in step 1) to methanol, stir to dissolve, then add sodium hydroxide, and react at 40~50℃ for 1 h. After adding water, adjust the pH to 2-3 with hydrochloric acid to generate the target product. Filter and dry the filter cake to obtain urea byproduct impurity compound I.

[0025] Secondly, this invention discloses a method for controlling by-product impurity compounds in the baclofen production process, namely a method for preparing baclofen, which replaces liquid bromine in the traditional process with sodium hypochlorite solution.

[0026] The preparation method involves adding sodium hypochlorite solution to a mixed solution of p-chlorophenylglutarate monoamide, alkali, and solvent at a temperature not exceeding 10°C, reacting, adjusting the pH to 4-6 after the reaction, filtering, and drying the filter cake to obtain baclofen; the content of impurity compound I in the baclofen is less than 0.1%.

[0027] .

[0028] Wherein, the solvent is water; the alkali is sodium hydroxide; the sodium hydroxide is added in the form of a sodium hydroxide solution, and the concentration of the sodium hydroxide is 20%-30%; the available chlorine in the sodium hypochlorite solution is 8%-12%, and in some embodiments it is 10%.

[0029] The amount of sodium hypochlorite solution used is 2.8-3.6 times the mass of p-chlorophenylglutarate monoamide; the amount of sodium hydroxide solution used is 1.8-2.6 times the mass of p-chlorophenylglutarate monoamide.

[0030] The reaction temperature is 75-80℃; the reaction time is 0.5-1.5h, such as 1h; after the reaction is completed, the temperature is lowered, hydrochloric acid is added to adjust the pH to 4-6, the mixture is stirred and filtered, the resulting filter cake is slurried with water, filtered, and the resulting filter cake is dried to obtain baclofen.

[0031] The concentration of sodium hydroxide in this invention is a mass percentage.

[0032] The available chlorine content mentioned in this invention refers to the total amount of chlorine element in the sodium hypochlorite solution that has oxidizing, bactericidal, and bleaching effects, converted to the mass fraction of elemental chlorine gas (Cl2). Taking 10% available chlorine as an example, it means that 100g of sodium hypochlorite stock solution contains 10g of chlorine gas, providing disinfection and oxidation capabilities. Measurement method: The available chlorine content of the sodium hypochlorite solution is measured using the iodometric titration method (GB / T19106-2013), as per national standard arbitration.

[0033] This invention reveals that during the preparation of baclofen using the Hoffmann degradation reaction, the generated baclofen molecules readily react with incompletely converted isocyanate intermediates in the system, forming a urea byproduct. This byproduct is a common impurity in baclofen synthesis, and its content directly affects the quality and purity of the final product. Replacing the key reagent liquid bromine in this process step with commercially available sodium hypochlorite solution completely avoids the formation of the urea byproduct, significantly improving the purity and quality stability of the baclofen product, and providing a safer, more efficient, and higher-quality process route for industrial production.

[0034] The present invention provides a method for preparing and controlling urea byproduct impurities in the baclofen production process. By preparing urea byproduct impurities in high yield, these impurities can be used as a reference standard to monitor the impurity content in baclofen. Furthermore, through process optimization, the generation of urea byproduct impurities can be avoided in the synthesis of baclofen, thereby effectively controlling the quality of baclofen and ensuring its safety and effectiveness in clinical use.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) Urea byproduct impurities are inevitably generated during the preparation of baclofen by the Hoffmann degradation reaction using traditional processes. This invention provides a method for preparing urea byproduct impurities, which not only has a high yield but also a purity of up to 96%. It can be used as a standard to accurately quantify the content of urea byproduct impurities in the production process of baclofen raw materials, and further help control the impurities in the actual production process.

[0037] (2) The content of urea byproduct impurities in baclofen synthesized by traditional process is usually around 0.2%. By replacing the reagent liquid bromine in the Hoffmann degradation reaction in the traditional process with sodium hypochlorite solution, the present invention can effectively control the generation of urea byproduct impurities in the production process of baclofen, so that the impurities are not detected under the current quality standards, significantly improve the purity of the final product of baclofen, and avoid the product quality being affected by excessive impurities. Attached Figure Description

[0038] Figure 1 MS spectrum of urea byproduct impurities prepared in Example 1.

[0039] Figure 2 The urea byproduct impurities prepared in Example 1 1 H-NMR spectrum.

[0040] Figure 3 The image shows a high-performance liquid chromatogram of urea byproduct impurities in baclofen prepared in Example 3.

[0041] Figure 4 High-performance liquid chromatography (HPLC) chromatogram of urea byproduct impurities in baclofen prepared in Comparative Example 1. Detailed Implementation

[0042] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0043] Specific experimental methods not mentioned in the following examples are generally performed according to conventional experimental methods. Unless otherwise specified, all raw materials and reagents used are commercially available products.

[0044] Example 1:

[0045] The method for preparing urea byproduct impurities in this embodiment is as follows:

[0046] (1) Preparation of urea intermediate II

[0047] At room temperature, 10.0 g (37.86 mmol) baclofen methyl ester hydrochloride, 100 mL dichloromethane, and 4.2 g (41.64 mmol) triethylamine were added to a reaction vessel. After the addition was complete, the mixture was stirred at room temperature for 10 min. Then, 3.1 g (18.93 mmol) CDI was added, and the reaction mixture was stirred at 20-30 °C for 1 h. The solvent was removed from the reaction solution under reduced pressure. The concentrate was washed with 200 mL of water, filtered, and the filter cake was the urea intermediate. It did not require drying and could be used directly in the next reaction step.

[0048] (2) Preparation of urea byproduct impurity I

[0049] The wet urea intermediate obtained in the previous step and 50 mL of methanol were added to the reaction vessel. After stirring to dissolve, 4.5 g (113.57 mmol) of sodium hydroxide was added, and the mixture was stirred at 40-50 °C for 1 h. After the reaction solution was cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 2-3 with hydrochloric acid while stirring. The mixture was filtered, the filter cake was washed with water, and dried to obtain 15.6 g (34.45 mmol) of urea byproduct impurities, with a yield of 91% and a purity of 97.4%.

[0050] like Figure 1 As shown, MS (ESI) found 453.4 [M+H]. + .

[0051] like Figure 2 As shown, 1 H NMR (400 MHz, DMSO-d6): δ = 7.35 – 7.32 (m, 4H), 7.22 –7.20 (m, 4H), 5.79 (s, 2H), 3.48 – 3.23 (m, 2H), 3.21 – 3.08 (m, 4H), 2.60 –2.53 (m, 2H), 2.50 – 2.44 (m, 2H).

[0052] Example 2:

[0053] The method for preparing urea byproduct impurities in this embodiment is as follows:

[0054] (1) Preparation of urea intermediate II

[0055] At room temperature, 10.0 g (37.86 mmol) baclofen methyl ester hydrochloride, 100 mL tetrahydrofuran, and 5.4 g (41.64 mmol) N,N-diisopropylethylamine were added to a reaction vessel. After addition, the mixture was stirred at room temperature for 10 min. Then, 3.1 g (18.93 mmol) CDI was added, and the mixture was stirred and reacted at 20-30 °C for 1 h. The solvent was removed from the reaction solution under reduced pressure. The concentrate was washed with 200 mL of water, filtered, and the filter cake was the urea intermediate. It did not require drying and could be used directly in the next reaction step.

[0056] (2) Preparation of urea byproduct impurity I

[0057] The wet urea intermediate obtained in the previous step and 50 mL of methanol were added to the reaction vessel. After stirring to dissolve, 6.1 g (151.43 mmol) of sodium hydroxide was added, and the mixture was stirred at 40-50 °C for 1 h. After the reaction solution was cooled to room temperature, 100 mL of water was added, and the pH was adjusted to 2-3 with hydrochloric acid while stirring. The mixture was filtered, the filter cake was washed with water, and dried to obtain 14.8 g (32.56 mmol) of urea byproduct impurities, with a yield of 86%.

[0058] Example 3:

[0059] The method for preparing baclofen in this embodiment is as follows:

[0060] At room temperature, 100.0 g (413.79 mmol) of p-chlorophenylglutarate monoamide, 800 mL of water, and 218.5 g (1.37 mol) of 25% sodium hydroxide solution were added to a reaction vessel. 322.7 g (455.16 mmol) of sodium hypochlorite solution (10% available chlorine) was added while maintaining the temperature below 10°C. After the addition was complete, the reaction mixture was kept at 75-80°C for 1 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with hydrochloric acid. After stirring for 30 min, the mixture was filtered. The filter cake was slurried with water at room temperature for 30 min, filtered again, and dried to obtain 75.1 g (351.49 mmol) of baclofen, with a yield of 85%.

[0061] The obtained baclofen was analyzed using HPLC area normalization method, such as... Figure 3 As shown, no urea byproduct impurity I was detected.

[0062] Comparative Example 1:

[0063] In this embodiment, the original process is used to prepare baclofen as follows:

[0064] At room temperature, 38.2 g (955.86 mmol) of sodium hydroxide and 160 mL of water were added to the reaction vessel and stirred to dissolve. 72.7 g (455.17 mmol) of liquid bromine was added dropwise while maintaining the temperature below 5°C. After the addition was complete, a sodium hypobromite solution was prepared for later use.

[0065] In a separate reaction vessel, 100.0 g (413.79 mmol) of p-chlorophenylglutarate monoamide, 800 mL of water, and 218.5 g (1.37 mol) of 25% sodium hydroxide solution were added. A self-made sodium hypobromite solution was added while maintaining the temperature below 10°C. After the addition was complete, the reaction mixture was kept at 75-80°C for 1 h. The reaction solution was cooled to room temperature, and the pH was adjusted to 5 with hydrochloric acid. After stirring for 30 min, the mixture was filtered. The filter cake was then slurried with water at room temperature for 30 min, filtered again, and dried to obtain 73.4 g (343.54 mmol) of baclofen, with a yield of 83%.

[0066] The obtained baclofen was analyzed using HPLC area normalization method, such as... Figure 4 As shown, the content of urea byproduct impurity I (retention time 50.186 min) is 0.2%.

[0067] Compared with the original process for preparing baclofen, the baclofen preparation process provided by this invention can not only improve the yield, but also significantly reduce the content of urea byproduct impurities.

[0068] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing impurity compound I, characterized in that, Includes the following steps: (1) Baclofen methyl ester hydrochloride was reacted in an organic solvent with an alkali and N,N'-carbonyldiimidazole. The intermediate product was concentrated, washed with water and filtered to obtain a filter cake. (2) The filter cake obtained in an organic solvent is reacted under the action of alkali, and the pH is adjusted to 2-3 to obtain impurity compound I; 。 2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of baclofen methyl hydrochloride, base and N,N'-carbonyldiimidazole is 1:1.0~1.2:0.4~0.6, optionally 1:1.1:0.5; the mass-volume ratio of baclofen methyl hydrochloride and organic solvent is 1g:8-12mL, optionally 1g:10mL.

3. The preparation method according to claim 1, characterized in that, In step (1), the base is any one or a combination of two of triethylamine and N,N-diisopropylethylamine; the organic solvent is any one or a combination of several of dichloromethane, chloroform and tetrahydrofuran.

4. The preparation method according to claim 1, characterized in that, In step (1), baclofen methyl ester hydrochloride, organic solvent and base are mixed and then N,N'-carbonyldiimidazole is added to carry out the reaction; optionally, the mixing is carried out by stirring at room temperature for 5-15 min; optionally, the reaction is carried out at 20-30℃ for 0.5-2 h.

5. The preparation method according to claim 1, characterized in that, In step (1), the filter cake is intermediate II; 。 6. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of baclofen methyl hydrochloride to the base is 1:2-5, optionally 1:3-4; the base is sodium hydroxide; the organic solvent is methanol; the mass-volume ratio of baclofen methyl hydrochloride to the organic solvent is 1g:2-8mL, optionally 1g:5mL; and the reaction temperature is 40-50℃.

7. A method for preparing baclofen, characterized in that, At a temperature not exceeding 10°C, sodium hypochlorite solution is added to a mixed solution of p-chlorophenylglutarate monoamide, alkali, and solvent. After the reaction is completed, the temperature is lowered to adjust the pH to 4-6, the mixture is filtered, and the filter cake is dried to obtain baclofen. The content of impurity compound I in the baclofen is less than 0.1%. 。 8. The preparation method according to claim 7, characterized in that, The solvent is water; the alkali is sodium hydroxide; the sodium hydroxide is added in the form of a sodium hydroxide solution with a concentration of 20%-30%; and the sodium hypochlorite solution has an available chlorine concentration of 8%-12%.

9. The preparation method according to claim 8, characterized in that, The amount of sodium hypochlorite solution used is 2.8-3.6 times the mass of p-chlorophenylglutarate monoamide; the amount of sodium hydroxide solution used is 1.8-2.6 times the mass of p-chlorophenylglutarate monoamide.

10. The preparation method according to claim 8, characterized in that, The reaction temperature is 75-80℃; after the reaction is completed, the temperature is lowered, hydrochloric acid is added to adjust the pH to 4-6, the mixture is stirred and filtered, the resulting filter cake is slurried with water, filtered, and the resulting filter cake is dried to obtain baclofen.

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