Pregabalin lactam methylene dimer and preparation method thereof
Pregabalinlactam methylene dimer is prepared through a simple and efficient method, which solves the problems of low yield and difficult separation in traditional methods, and achieves high yield and high purity preparation, which is suitable for use as a standard product.
Patent Information
- Application Number
- CN202411470204.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2018-11-06
- Publication Date
- 2025-03-07
AI Technical Summary
There is an unknown impurity in the pregabalin tablets, pregabalin lactam methylene dimer, which has a large content in long-term stability and accelerated stability samples, and its content will continue to increase with the extension of storage time, making it difficult to efficiently separate and prepare by traditional methods.
A simple and efficient method is used to prepare a pregabalin lactam methylene dimer, which includes adding pregabalin, acid and aldehyde to the reaction solvent, heating the reaction, and then removing the reaction solvent and separating the target product by column chromatography or liquid chromatography.
The yield of pregabalinlactam methylene dimer is improved, with a yield of up to 35-50%, and a purity of up to 99.0%, which is more than 100 times higher than the traditional method. The separation difficulty is greatly reduced, and the preparation process is simple and cost is low.
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Abstract
Description
[0001] This invention is a divisional application of the Chinese invention patent (the international application number filed with the International Bureau on November 6, 2018 is "PCT / CN2018 / 114113", entered the national stage on March 24, 2021, the application number is 2018800979827, and the name of the invention is "Pregabalin lactam methylene dimer and its preparation method"). Technical Field
[0002] The present application relates to the field of pharmaceutical manufacturing technology, and in particular to a pregabalin lactam methylene dimer and a preparation method thereof. Background Art
[0003] Pregabalin, chemical name: (S)-3-aminomethyl-5-methylhexanoic acid, molecular formula C8H 17 NO2, molecular weight is 159.23, its structural formula is as follows:
[0004]
[0005] Lyrica It was launched in the United States in 2004 and in China in 2010. As the first drug jointly certified by the United States and Europe for the treatment of two types of neuralgia, its main indications are diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and spinal cord injury neuralgia. Summary of the invention
[0006] During the long-term stability and accelerated stability studies of pregabalin tablets, the inventors found that there was an unknown impurity in pregabalin tablets. The content of this impurity in the long-term stability and accelerated stability samples of pregabalin tablets was relatively large, and its peak area ratio was generally around 0.10-0.70%, and its content continued to increase with the extension of storage time. When the prescription parameters are not properly controlled, this impurity can easily exceed the unknown single impurity limit index of 0.20%.
[0007] After high-resolution mass spectrometry and nuclear magnetic resonance characterization, the impurity was determined to be pregabalin lactam methylene dimer, and its structural formula is as follows:
[0008]
[0009] During the development of the analytical method for pregabalin tablets and the subsequent inspection of finished products, standard samples of the impurity are needed to locate and quantify the impurity in pregabalin tablets. Therefore, a large amount of pregabalin lactam methylene dimer standard samples are needed.
[0010] In order to prepare pregabalin lactam methylene dimer, a traditional impurity separation method can be used: separating the target impurity (pregabalin lactam methylene dimer) from the forced degradation sample or the long-term stability sample of pregabalin tablets. However, the target impurity is detected by HPLC (high performance liquid chromatography), and its content can only reach 0.7% at most. In addition, there are many similar impurities with similar contents in the sample. At the same time, the presence of auxiliary materials will also interfere with the separation. The separation cycle is long, and multiple separations are required to obtain a pure product. The total yield is generally only about 0.3%.
[0011] Based on this, the present application provides a pregabalin lactam methylene dimer and a preparation method thereof; the technical scheme is as follows:
[0012] The present application first provides a pregabalin lactam methylene dimer, the structural formula of which is as follows:
[0013]
[0014] The present application also provides a method for preparing pregabalin lactam methylene dimer in a simple and efficient manner, which comprises the following steps:
[0015] (a) adding pregabalin, acid and aldehyde to a reaction solvent to obtain a reaction system;
[0016] (b) heating the reaction system to 30 to 100° C. and reacting for 0.5 to 36 hours;
[0017] (c) After the reaction is completed, pregabalin lactam methylene dimer is obtained.
[0018] In some embodiments of the present application, the reaction solvent in step (a) is selected from water, a polar organic solvent, or a mixture of water and a polar organic solvent.
[0019] In some embodiments of the present application, the polar organic solvent is selected from one of methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone, or any combination thereof.
[0020] In some embodiments of the present application, the acid in step (a) is selected from an organic acid, an inorganic acid or a combination thereof.
[0021] In some embodiments of the present application, the organic acid is selected from one of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, or any combination thereof.
[0022] In some embodiments of the present application, the inorganic acid is selected from one of hydrochloric acid, sulfuric acid and phosphoric acid or any combination thereof. In the specific implementation process, dilute hydrochloric acid, dilute sulfuric acid and dilute phosphoric acid can be used.
[0023] In some embodiments of the present application, the aldehyde is selected from one of formaldehyde, paraformaldehyde, trimolecular formaldehyde and polyformaldehyde or any combination thereof.
[0024] In some embodiments of the present application, the aldehyde is selected from formaldehyde or trioxymethylene.
[0025] In some embodiments of the present application, the molar ratio of the acid in step (a) to the pregabalin molecule is 0.01:1 to 50:1.
[0026] In some embodiments of the present application, the molar ratio of the acid in step (a) to the pregabalin molecule is 0.1:1 to 2.5:1.
[0027] In some embodiments of the present application, the molar ratio of the acid in step (a) to the pregabalin molecule is 0.1:1 to 1.6:1.
[0028] In some embodiments of the present application, the molar ratio of the aldehyde to the pregabalin molecule in step (a) is 0.1:1 to 10:1.
[0029] In some embodiments of the present application, the molar ratio of the aldehyde to the pregabalin molecule in step (a) is 0.3:1 to 3:1.
[0030] In some embodiments of the present application, the molar ratio of the aldehyde to the pregabalin molecule in step (a) is 0.3:1 to 1.1:1.
[0031] In some embodiments of the present application, in step (b), the reaction system is heated to 55-75° C., and the reaction time is 12-24 hours.
[0032] In some embodiments of the present application, step (c) comprises: after the reaction is completed, removing the reaction solvent, and separating the pregabalin lactam methylene dimer from the obtained solid.
[0033] In some embodiments of the present application, the separation method is selected from column chromatography or preparative liquid chromatography.
[0034] In some embodiments of the present application, the reaction system at the end of the reaction is tested by HPLC for purity, and the content of pregabalin lactam methylene dimer is about 43-55%.
[0035] In some embodiments of the present application, the purity of the pregabalin lactam methylene dimer separated in step (c) can reach more than 99.0% through HPLC detection.
[0036] The methylene dimer of pregabalin lactam prepared in the present application is detected by nuclear magnetic resonance hydrogen spectrum and carbon spectrum, and its nuclear magnetic resonance hydrogen spectrum and carbon spectrum are shown inFigure 1 , Table 1 and Figure 2 , Table 2, compound atom number see Figure 3 .
[0037] Table 1 is the nuclear magnetic resonance hydrogen spectrum analysis of the pregabalin lactam methylene dimer prepared in the present application.
[0038] Table 1
[0039] Proton type Chemical shift (ppm) Peak shape Attribution H number Number of protons CH 0.77 d H-7 / 8 / 16 / 17 12 CH 1.18 t H-5 / 14 4 CH 1.44 m H-6 / 15 2 CH 1.93,2.38 d H-2 / 11 4 CH 2.28 m H-3 / 12 2 CH 2.85,3.38 dd H-4 / 13 4 CH 4.62 s H-9 2
[0040] Table 2 is the carbon NMR spectrum analysis of the pregabalin lactam methylene dimer prepared in the present application.
[0041] Table 2
[0042]
[0043]
[0044] The methylene dimer of pregabalin lactam prepared by the method was detected by high performance liquid chromatography-high resolution mass spectrometry (HPLC-HRMS), and its [M+H+] accurate molecular weight was 295.2380, [M+K+] accurate molecular weight was 333.1943, and the matching molecular formula was C 17 H 30 N2O2, see Figure 4 .
[0045] Through the above structural characterization, it can be determined that the method provided in the present application achieves the preparation of pregabalin lactam methylene dimer.
[0046] The pregabalin lactam methylene dimer provided in the present application has high purity and can be used as a standard product.
[0047] The method for preparing pregabalin lactam methylene dimer provided in the present application has the following advantages:
[0048] 1. The method provided in the present application is used to prepare pregabalin lactam methylene dimer, and the yield of pregabalin lactam methylene dimer can reach between 35-50%, which is greatly improved; compared with the traditional method, the yield can be increased by more than one hundred times.
[0049] 2. According to the preparation method provided in the present application, after the reaction is completed, the content of the target product pregabalin lactam methylene dimer in the reaction system can reach between 43% and 58%, and the remaining components are mainly unreacted pregabalin, as well as by-products pregabalin lactam and N-methyl pregabalin lactam, whose retention behaviors are quite different, so the separation difficulty is greatly reduced.
[0050] 3. The reaction solvent used in the method provided in the present application can be a polar organic solvent such as methanol, ethanol, acetonitrile, N,N-dimethylformamide, or a mixed solvent of a polar organic solvent and water. Uncommon or expensive organic solvents are not involved. Under acidic conditions, the chiral center of the product is stable and no isomerization occurs.
[0051] 4. During the entire preparation process, no special equipment or raw materials are required, the preparation cycle is short, easy to operate, and low cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0052] In order to more clearly illustrate the embodiments of the present application and the technical solutions of the prior art, the following briefly introduces the drawings required for use in the embodiments and the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0053] Figure 1 The nuclear magnetic resonance hydrogen spectrum of the pregabalin lactam methylene dimer prepared in this application is ( 1 H-NMR).
[0054] Figure 2 The C NMR spectrum of the methylene dimer of pregabalin lactam prepared in this application ( 13 C-NMR).
[0055] Figure 3 The structural formula atom number of the pregabalin lactam methylene dimer prepared in the present application.
[0056] Figure 4 HPLC-HRMS spectrum of the pregabalin lactam methylene dimer prepared in the present application. DETAILED DESCRIPTION
[0057] In order to make the purpose, technical scheme, and advantages of the present application more clearly understood, the present application is further described in detail with reference to the accompanying drawings and examples. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.
[0058] Example 1
[0059] 10.0 g (0.0628 mol) of pregabalin was added to 100 ml of methanol, and 4.0 ml of formic acid (0.0912 mol) was added. After stirring until dissolved, 6.0 ml of 30% (mass fraction) formaldehyde solution (0.0659 mol) was added, and the mixture was heated to 60° C. for reaction for 18 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 52%, the solvent was removed by vacuum distillation, and the obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was n-hexane:ethyl acetate=(12:1), V / V] to obtain 7.95 g of pregabalin lactam methylene dimer with HPLC purity of 99.2% and yield of 43%.
[0060] Example 2
[0061] 10.0 g of pregabalin (0.0628 mol) was added to 120 ml of ethanol, and 5.6 ml of glacial acetic acid (0.0979 mol) was added. After stirring until dissolved, 5.0 ml of 30% formaldehyde solution (0.0549 mol) was added, and the temperature was raised to 60° C. for reaction for 18 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 44%, the solvent was removed by reduced pressure distillation, and the obtained solid was separated by preparative liquid phase separation method [chromatographic column: YMC-Pack ODS-AQ, 250×20 mm, 5 μm, mobile phase A was water, mobile phase B was acetonitrile, and the mobile phase gradient was: 0 min (40% B), 20 min (40% B), 30 min (60% B), 30.1 min (40% B), and 35 min (40% B), running time: 35 min] to separate and obtain 7.02 g of pregabalin lactam methylene dimer with HPLC purity of 99.6% and a yield of 38%.
[0062] Example 3
[0063] 10.0 g of pregabalin (0.0628 mol) was added to 150 ml of a water-methanol mixture (water:methanol volume ratio of 1:1), 3.0 ml of trifluoroacetic acid (0.0404 mol) was added, and the mixture was stirred until dissolved. Then, 2.1 g of trioxymethylene solid (0.0233 mol) was added, and the mixture was heated to 60° C. for reaction for 24 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 56%, the pH of the reaction system was adjusted to about 8 with sodium carbonate solution, and the solvent was removed by freeze drying. The obtained solid was separated by column chromatography [HP-Silica normal phase silica gel, eluent was n-hexane:ethyl acetate = (15:1, V / V)] to obtain 8.32 g of pregabalin lactam methylene dimer with HPLC purity of 99.2% and a yield of 45%.
[0064] Example 4
[0065] 10.0 g of pregabalin (0.0628 mol) was added to 80 ml of dimethyl sulfoxide, 4.2 ml of formic acid (0.0958 mol) was added, and the mixture was stirred until dissolved. Then, 4.5 ml of 30% formaldehyde solution (0.0495 mol) was added, and the mixture was heated to 60° C. for 14 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 43%, the solvent was removed by lyophilization, and the obtained solid was separated by preparative liquid phase separation method [chromatographic column: YMC-Pack ODS-AQ, 250×20 mm, 5 μm, mobile phase A was water, mobile phase B was acetonitrile, and the mobile phase gradient was: 0 min (40% B), 20 min (40% B), 30 min (60% B), 30.1 min (40% B), and 35 min (40% B), running time: 35 min] to separate and obtain 6.47 g of pregabalin lactam methylene dimer with HPLC purity of 99.1% and a yield of 35%.
[0066] Example 5
[0067] 10.0 g of pregabalin (0.0628 mol) was added to 24 ml of a water-ethanol mixture (water: ethanol volume ratio of 1:1), 3.0 g of p-toluenesulfonic acid (0.0174 mol) was added, and the mixture was stirred until dissolved. Then, 3.2 g of trioxymethylene (0.0355 mol) was added, and the mixture was heated to 70° C. for 16 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 53%, the pH of the reaction system was adjusted to about 8 with sodium carbonate solution, and the solvent was removed by freeze-drying. The obtained solid was separated by column chromatography (model: HP-Silica normal phase silica gel, eluent: n-hexane: ethyl acetate = 12:1, V / V) to obtain 8.68 g of pregabalin lactam methylene dimer with HPLC purity of 99.0% and a yield of 47%.
[0068] Example 6
[0069] 10.0 g of pregabalin (0.0628 mol) was added to 120 ml of methanol, and 1.5 ml of methanesulfonic acid (0.0231 mol) was added. After stirring until dissolved, 6.2 ml of 30% formaldehyde solution (0.0681 mol) was added, and the temperature was raised to 75° C. for reaction for 20 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 58%, the pH of the reaction system was adjusted to about 8 with sodium carbonate solution, and the water was removed by freeze-drying. The obtained solid was separated by column chromatography (model: HP-Silica normal phase silica gel, eluent: n-hexane: ethyl acetate = 10:1, V / V) to obtain 9.24 g of pregabalin lactam methylene dimer with HPLC purity of 99.2% and a yield of 50%.
[0070] Example 7
[0071] 3.0 g of pregabalin (0.0188 mol) was added to 40 ml of N,N-dimethylformamide (DMF), and 0.4 ml of 6N dilute hydrochloric acid (0.0024 mol) was added. After stirring until dissolved, 1.2 ml of 30% formaldehyde solution (0.0132 mol) was added, and the mixture was heated to 65° C. for 14 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 46%, the pH of the reaction system was adjusted to about 8 with sodium carbonate solution, and the solvent was removed by freeze drying. The obtained solid was separated by preparative liquid phase separation method [chromatographic column: YMC-Pack ODS-AQ, 250×20 mm, 5 μm, mobile phase A was water, mobile phase B was acetonitrile, and the mobile phase gradient was: 0 min (40% B), 20 min (40% B), 30 min (60% B), 30.1 min (40% B), and 35 min (40% B), running time: 35 min] to separate and obtain 2.0 g of pregabalin lactam methylene dimer with HPLC purity of 99.4% and a yield of 36%.
[0072] Example 8
[0073] 3.0 g of pregabalin (0.0188 mol) was added to 50 ml of a water-N-methylpyrrolidone mixture (water: N-methylpyrrolidone volume ratio of 1:1), 0.4 ml of 6N dilute sulfuric acid (0.0024 mol) was added, and the mixture was stirred until dissolved. Then, 0.7 g of trioxymethylene (0.0078 mol) was added, and the mixture was heated to 55° C. for reaction for 24 hours. The reaction system was monitored by HPLC. When the content of pregabalin lactam methylene dimer was 47%, the pH of the reaction system was adjusted to about 8 with sodium carbonate solution, and the water was removed by freeze-drying. The obtained solid was separated by column chromatography (model: HP-Silica normal phase silica gel, eluent: n-hexane: ethyl acetate = 15:1, V / V) to obtain 2.11 g of pregabalin lactam methylene dimer with HPLC purity of 99.0% and a yield of 38%.
[0074] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.
Claims
1. Pregabalin lactam methylene dimer, the structural formula of which is as follows:
2. A method for preparing a pregabalin lactam methylene dimer, comprising the following steps: (a) adding pregabalin, acid and aldehyde to a reaction solvent to obtain a reaction system; (b) heating the reaction system to 30 to 100° C. and reacting for 0.5 to 36 hours; (c) after the reaction is completed, obtaining pregabalin lactam methylene dimer; Wherein, the structural formula of the pregabalin lactam methylene dimer is as follows:
3. The preparation method according to claim 2, wherein The reaction solvent in step (a) is selected from water, a polar organic solvent, or a mixture of water and a polar organic solvent; preferably, the polar organic solvent is selected from one or any combination of methanol, ethanol, propanol, isopropanol, acetonitrile, acetone, N,N-dimethylformamide, dimethyl sulfoxide and N-methylpyrrolidone.
4. The preparation method according to claim 2 or 3, wherein The acid in step (a) is selected from an organic acid, an inorganic acid or a combination thereof; preferably, the organic acid is selected from one or any combination of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid; the inorganic acid is selected from one or any combination of hydrochloric acid, sulfuric acid and phosphoric acid.
5. The preparation method according to any one of claims 2 to 4, characterized in that: The aldehyde is selected from one of formaldehyde, paraformaldehyde, trimoxane and polyformaldehyde or any combination thereof; preferably formaldehyde or trimoxane.
6. The preparation method according to any one of claims 2 to 5, wherein The molar ratio of the acid in step (a) to the pregabalin molecule is 0.01:1 to 50:1, preferably 0.1:1 to 2.5:
1.
7. The preparation method according to any one of claims 2 to 6, wherein The molar ratio of the aldehyde to the pregabalin molecule in step (a) is 0.1:1 to 10:1, preferably 0.3:1 to 3:
1.
8. The preparation method according to any one of claims 2 to 7, wherein In step (b), the reaction system is heated to 55-75° C., and the reaction time is 12-24 hours.
9. The preparation method according to any one of claims 2 to 8, wherein Step (c) comprises: after the reaction is completed, removing the reaction solvent, and separating and obtaining the pregabalin lactam methylene dimer from the obtained solid.
10. The preparation method according to claim 9, wherein: The separation method is selected from column chromatography or preparative liquid chromatography.