Resolution method of melogabalin

Abstract

The invention belongs to the technical field of separation and purification of melogabalin, and discloses a resolution method of melogabalin, which comprises the following steps: adding racemic melogabalin into dichloromethane, heating and dissolving to obtain a clear solution; cooling the obtained clear solution, adding a melogabalin seed crystal into the clear solution to form (1R, 5S, 6S), and stirring to crystallize; after crystal growing, filtering and drying to obtain a target product. According to the method, a target configuration product can be directly obtained without a resolution reagent, and the process steps are shortened. The chiral purity of the obtained target product is 98% or above.

Description

Technical Field

[0001] This invention belongs to the field of meropenem separation and purification technology, specifically relating to a method for separating meropenem. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] Merogabalin reduces calcium ion influx by binding with a high affinity to the α2-δ subunit of voltage-gated calcium channels on neurons, thereby inhibiting the excessive release of various excitatory neurotransmitters (such as glutamate and norepinephrine) in the central nervous system, ultimately achieving analgesic, anti-anxiety, and anticonvulsant effects. However, merogabalin contains three chiral centers, meaning it has multiple stereoisomers, of which only one specific isomer (1 R 5 S 6 S It has the best analgesic and anticonvulsant activity, so this specific isomer needs to be separated.

[0004] The traditional resolution method is salt formation resolution, which involves reacting a racemic acidic intermediate with a basic resolving agent to form two diastereomer salts. These salts have different solubilities in specific solvents and can be separated by distribution crystallization. The resulting salt with the desired configuration is then treated with acid to release the acidic intermediate, followed by further processing to obtain merogabaline, as shown below: .

[0005] The basic intermediate reacts with the acidic resolving reagent to form a salt, as described above. Therefore, traditional resolving methods are quite cumbersome. Steps such as salt formation, crystallization, leaching, extraction, and functional group transformation all lead to material losses, resulting in low yields of the target product. Furthermore, resolving reagents are generally expensive, so their consumption and recovery also increase resolving costs.

[0006] Merogabalin is typically obtained by reacting a basic intermediate with an acidic resolving agent to form a salt, or vice versa. The intermediate is then released, extracted, and finally hydrolyzed to obtain merogabalin, or the ester group is reduced to obtain merogabalin. This process is cumbersome and has high production costs.

[0007] . Summary of the Invention

[0008] To address the shortcomings of existing technologies, the purpose of this invention is to provide a method for resolving meropenem, which allows the target configuration product to be obtained directly without resolving reagents, thus shortening the process steps. The obtained target product has a chiral purity of over 98%.

[0009] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention provides a method for dissecting merogabarine, comprising the following steps: Racemic melogabalin was added to dichloromethane and heated to dissolve, yielding a clear solution. After cooling the resulting clear solution, melogabalin seed crystals were added to it, with the configuration being (1 R 5 S 6 S ), stirring to induce crystallization; After crystal growth, the product is filtered, dried, and the target product is obtained.

[0010] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows: This invention provides a method for the separation of melogabalin. The separation process is simple to operate, eliminates the salt formation and freeing steps in ordinary separation methods, reduces the number of process steps, is conducive to environmental protection and industrial production, and conforms to the concepts of green chemistry and green production. Attached Figure Description

[0011] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0012] Figure 1 The HPLC chromatogram of the merogabarine product obtained in Example 1 is shown below. Figure 2 The HPLC chromatogram of the merogabarine product obtained in Example 2 is shown below. Figure 3 The HPLC chromatogram of the merogabarine product obtained in Comparative Example 1; Figure 4 The HPLC chromatogram of the merogabarine product obtained in Comparative Example 2; Figure 5 The HPLC chromatogram of the merogabarine product obtained in Comparative Example 3; Figure 6 The HPLC chromatogram of the merogabarine product obtained in Comparative Example 4; Figure 7 The HPLC chromatogram of the merogabarine product obtained in Comparative Example 5; Figure 8 The image shows the HPLC chromatogram of the merogabarine product obtained in Comparative Example 6. Detailed Implementation

[0013] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0014] To address the technical problems mentioned in the background art, the present invention provides a method for dissociating merogabarine, comprising the following steps: Racemic melogabalin was added to dichloromethane and heated to dissolve, yielding a clear solution. After cooling the resulting clear solution, melogabalin seed crystals were added to it, with the configuration being (1 R 5 S 6 S ), stirring to induce crystallization; After crystal growth, the product is filtered, dried, and the target product is obtained.

[0015] The splitting route is as follows: .

[0016] Dichloromethane can fully dissolve racemic merogabaline under reflux at 38-42℃ to form a clear solution. After cooling to 0-10℃, combined with seed induction of the target configuration (1R, 5S, 6S), the target product can be precipitated with high selectivity, while the non-target configuration remains in the solution, thus efficiently separating chiral isomers.

[0017] Compared to other solvents (such as ethanol + water, acetonitrile + water), the resolution products in the dichloromethane system have higher chiral purity. In the examples, the chiral purity of the products using dichloromethane reached over 99%, while in the comparative examples, the chiral purity of the products obtained using a mixed solvent of ethanol and water was only 68.1%, and the purity of the products obtained using a mixed solvent of acetonitrile and water was only 51.1%, demonstrating that dichloromethane has better selectivity for crystallization of the target configuration.

[0018] Merogabalin contains three chiral centers, and only the (1R, 5S, 6S) configuration exhibits the best analgesic and anticonvulsant activity. By adding seed crystals of this configuration, merogabalin molecules of the same configuration in solution can be preferentially crystallized out, achieving precise enrichment of the active isomer and avoiding interference from the inactive configuration.

[0019] By cultivating crystals, the target configuration (1R, 5S, 6S) melogabalin molecules attached to the surface of the seed crystals grow slowly and completely, improving the crystallization yield. The crystal cultivation process can reduce impurity encapsulation, allowing non-target configuration isomers to remain in solution and preventing them from precipitating with the target product.

[0020] In some embodiments, the mass ratio of dichloromethane to racemic melogabalin is 3-5:1.

[0021] A mass ratio of 3:1 or higher ensures complete dissolution of racemic merogabarine under reflux at 38-42°C, forming a clear solution. If the ratio is lower than 3:1, insufficient solvent will result in some racemic compounds remaining undissolved, and residual solids may contaminate subsequent crystallization products, reducing the purity of the target configuration. Excessive solvent will lead to insufficient supersaturation, reducing crystallization efficiency. A mass ratio of 5:1 or lower avoids insufficient supersaturation after cooling, which would reduce the precipitation of the target configurations (1R, 5S, 6S) and decrease the yield.

[0022] In some embodiments, the temperature for heating and melting is 38-42°C.

[0023] Preferably, the heating and dissolving process is a reflux heating and dissolving process, which can effectively prevent the loss of dichloromethane.

[0024] In some embodiments, the resulting clarified solution is cooled to 0-10°C for crystallization.

[0025] When the temperature is lowered to 0-10℃, the solubility of the target configuration (1R, 5S, 6S) melogabalone in dichloromethane is significantly reduced. Combined with seed induction of this configuration, the target product can be preferentially precipitated in a directional manner, while the non-target configuration remains in the solution, thereby efficiently separating chiral isomers.

[0026] This temperature range avoids "burst nucleation" (resulting in small crystals that easily trap impurities) caused by excessively low temperatures (such as below 0°C), or excessively high temperatures (such as above 10°C) leading to high solubility of the target product and reduced precipitation (decreased yield). 0-10°C balances crystallization rate and crystal quality, reduces impurity trapping, and ensures high product purity.

[0027] In some embodiments, the amount of seed crystals added is 0.5-5% of the mass of racemic melogabalin.

[0028] Preferably, the amount of seed crystals added is 1-5% of the mass of racemic melogabalin, more preferably 2-5%.

[0029] In some embodiments, the temperature for crystal growth is 0-10°C.

[0030] Preferably, the crystal growth time is 6-8 hours.

[0031] The present invention will be further described below with reference to embodiments and comparative examples.

[0032] The preparation method of the R,S intermediates used in the examples and comparative examples is as follows: 1500 ml of isopropyl ether, 41.0 g of sodium hydroxide, and 181 g of dimethoxyphosphono-tert-butyl ester were added to a reaction flask. The mixture was stirred and cooled to 10°C. 100.0 g of the starting material (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one was slowly added, and the mixture was kept at 50°C for 4 h after addition. After quenching with ammonium chloride solution (80.0 g ammonium chloride, 750 ml water), the mixture was distilled under reduced pressure to obtain an oily substance. 67.0 g of nitromethane was added, and 134.0 g of DBU was added dropwise below 10°C. After the addition was complete, the temperature was raised to 70-80°C and the reaction was carried out for 16 h. The post-treatment organic phase was distilled under reduced pressure to obtain an oily substance. 1200 ml of tetrahydrofuran, 21.0 g of Raney nickel, and 231 g of hydrazine hydrate were added, and the mixture was then refluxed at 60-65°C for 3 h. After filtering out Raney nickel, vacuum distillation yielded 141.6 g of an oily substance with a yield of 72.7%, which was the R,S intermediate.

[0033] Example 1 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of dichloromethane. The mixture was stirred and heated to 40 °C under reflux for 0.5 h to dissolve. The solution was filtered, and the filtrate was cooled to 5 °C. 0.5 g of (1R,5S,6S) melogabalone was added, and the mixture was stirred for 30 minutes until a solid precipitated. Crystallization was then carried out at 5 °C for 6 hours. The crystals were filtered and dried at 40 °C to obtain the melogabalone product, with a yield of 78.0% and a chiral purity of 99.1%. Figure 1 As shown.

[0034] Detection method: Chromatographic column: amylose-tris(3,5-dimethylphenylcarbamate) silica gel as packing material (Chiralpak AD-H, 4.6mm×250mm, 5μm or equivalent column); Detector: UV detector (detection wavelength: 222nm); Mobile phase: n-hexane-isopropanol (50:50); Column temperature: 30℃; Flow rate: 0.75 ml / min; Injection volume: 10 μl; Running time: 35 minutes; Solvent: n-hexane-isopropanol-acetonitrile (40:40:20).

[0035] Specific experimental procedures: Take an appropriate amount of this product, accurately weigh it, dissolve and dilute it with solvent to prepare a solution containing approximately 0.5 mg per ml, shake well, and use it as the test solution; accurately measure an appropriate amount of the test solution, dilute it with solvent to prepare a solution containing approximately 0.5 μg per ml, shake well, and use it as the control solution; accurately weigh 25 mg of melogabalin besylate, place it in a 50 ml volumetric flask, accurately add 1 ml of system suitability stock solution (take 5 mg of melogabalin besylate, weigh it, place it in a 100 ml volumetric flask, add 80 ml of hexane-isopropanol-acetonitrile (40:40:20), add 1 ml of 1 mol / L tetrabutylammonium hydroxide methanol solution, let it stand at room temperature for 20 minutes, add 1 ml of trifluoroacetic acid, add hexane-isopropanol-acetonitrile (40:40:20) and dilute to the mark, shake well), dissolve and dilute to the mark with solvent, shake well, and use it as the system suitability solution. The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512), using a linear starch-tris(3,5-dimethylphenylcarbamate) silica gel column (Chiralpak AD-H, 4.6 mm × 250 mm, 5 μm or equivalent column); the mobile phase was n-hexane-isopropanol (50:50); the flow rate was 0.75 mL / min; the detection wavelength was 222 nm; and the column temperature was 30 °C. 10 μL of the system suitability solution was accurately injected into the liquid chromatograph, and the chromatogram was recorded. The resolution between impurity A and the main component peak should be greater than 2.0.

[0036] Example 2 20.0 g of the R,S intermediate (same as in Example 1) was added to a reaction flask, along with 80 ml of dichloromethane. The mixture was stirred and heated to 39°C under reflux for 0.5 h to dissolve. After filtration, the filtrate was cooled to 0°C, and 1.0 g of (1R,5S,6S) melogabalone was added. After crystallization, the mixture was stirred at 0°C for 6 h to allow for crystal growth. After filtration and drying at 40°C, the melogabalone product was obtained, with a yield of 85.0%. Chiral purity: 99.5%. Figure 2 As shown.

[0037] Example 3 20.0 g of the R,S intermediate (same as in Example 1) was added to a reaction flask, along with 75 ml of dichloromethane. The mixture was stirred and heated to 40 °C under reflux for 0.5 h to dissolve. The mixture was filtered, and the filtrate was cooled to 7 °C. 0.2 g of (1R,5S,6S) melogabalone was added, and after crystallization, the crystals were grown by stirring at 7 °C for 8 h. The crystals were then filtered and dried at 40 °C to obtain the melogabalone product, with a yield of 84.7%. Chiral purity: 99.3%.

[0038] Comparative Example 1 120 ml of acetonitrile and 20.0 g of R,S intermediate were added to a 500 ml reaction flask; 10.0 g of D-mandelic acid was added, and the mixture was stirred at 60 °C for 2 h. The mixture was then cooled to allow crystals to precipitate. After filtration and drying, 10.5 g of solid was obtained, with a yield of 35%.

[0039] Add 10.0g of the intermediate obtained in the previous step, 100ml of dichloromethane, and sodium hydroxide solution (1.1g / 25ml water) to a reaction flask, stir for 15min, let stand and separate the liquid; wash the organic phase twice with 25ml of purified water, concentrate and obtain the free intermediate.

[0040] After adding 50 ml of tetrahydrofuran, the temperature was lowered to below 10°C, and hydrochloric acid solution was slowly added dropwise while stirring for 4 hours. After the reaction was complete, the mixture was distilled under reduced pressure, and a dilute ammonia solution was added to precipitate a white solid. The solid was dried under blast furnace to obtain merogabarine product, with a yield of 50.0% and a chiral purity of 99.1%. Figure 3 As shown.

[0041] Comparative Example 2 The difference from Example 1 is that the solvent is a mixture of ethanol and water.

[0042] 20.0 g of the R,S intermediate (same as in Example 1) was added to a reaction flask, along with 40 ml of ethanol and 20 ml of water. The mixture was stirred and heated to 75°C for 0.5 h to dissolve. The mixture was filtered, and the filtrate was cooled to 5°C to crystallize. After crystallization, the mixture was stirred at 5°C for 6 h. The crystals were then filtered and dried at 40°C to obtain the merogabine product, with a yield of 82.0% and a chiral purity of 68.1%. Figure 4 As shown.

[0043] Comparative Example 3 The difference from Example 1 is that the solvent is a mixture of acetonitrile and water.

[0044] 20.0 g of the R,S intermediate was added to a reaction flask, along with 40 ml of acetonitrile and 30 ml of water. The mixture was stirred and heated to 75°C for 0.5 h to dissolve. The solution was filtered, and the filtrate was cooled to 5°C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the mixture was stirred at 5°C for 6 h. The solution was filtered again and dried at 40°C to obtain the melogabalone product, with a yield of 98.0% and a chiral purity of 51.1%. Figure 5 As shown.

[0045] Comparative Example 4 The difference from Example 1 is that the crystallization temperature is 25°C.

[0046] Add 20.0 g of the R,S intermediate to a reaction flask, add 60 ml of dichloromethane, stir and heat to 40 °C, then reflux to dissolve. Filter, cool the filtrate to 25 °C, and add 0.5 g (1 R 5 S 6 SMerogabalin was crystallized and stirred at 5°C for 6 hours. The mixture was then filtered and dried at 40°C to obtain the merogabalin product, with a yield of 48.0% and a chiral purity of 65.1%. Figure 6 As shown.

[0047] Comparative Example 5 The difference from Example 1 is that the addition of seed crystals is omitted.

[0048] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of dichloromethane. The mixture was stirred and heated to 40 °C under reflux to dissolve. The solution was filtered, and the filtrate was cooled to 5 °C to allow crystallization. The mixture was then stirred at 5 °C for 6 hours. After filtration and drying at 40 °C, merogabarine was obtained, with a yield of 83.0% and a chiral purity of 75.3%. Figure 7 As shown.

[0049] Comparative Example 6 The difference from Example 1 is that the crystal growth temperature is -8°C.

[0050] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 mL of dichloromethane. The mixture was stirred and heated to reflux until dissolved. The solution was filtered, and the filtrate was cooled to 5°C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the solution was stirred at -8°C for 6 hours. The solution was filtered again and dried at 40°C to obtain the melogabalone product, with a yield of 87.0% and a chiral purity of 59.4%. Figure 8 As shown.

[0051] Comparative Example 7 The difference from Example 1 is that the mass ratio of dichloromethane to racemic melogabalone (R,S intermediate) is greater than 5:1.

[0052] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 80 mL of dichloromethane. The mixture was stirred and heated to reflux until dissolved. After filtration, the filtrate was cooled to 5 °C, and 0.5 g of (1R,5S,6S) melogabalone was added. After crystallization, the mixture was stirred at 5 °C for 6 hours. After filtration and drying at 40 °C, the melogabalone product was obtained with a yield of 64% and a chiral purity of 99.5%.

[0053] Comparative Example 8 The difference from Example 1 is that the mass ratio of dichloromethane to racemic melogabalone (R,S intermediate) is less than 3:1.

[0054] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 40 ml of dichloromethane. The mixture was stirred and heated to reflux until completely dissolved. The insoluble matter was removed by filtration, and the filtrate was cooled to 5°C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the mixture was stirred at 5°C for 6 hours. The crystals were then filtered and dried at 40°C to obtain the melogabalone product, with a yield of 68% and a chiral purity of 98.1%.

[0055] Comparative Example 9 The difference from Example 1 is that the crystallization temperature is -2℃.

[0056] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 mL of dichloromethane. The mixture was stirred and heated to reflux until dissolved. The solution was filtered, and the filtrate was cooled to -2°C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the mixture was stirred at 5°C for 6 hours. The solution was filtered again and dried at 40°C to obtain the melogabalone product, with a yield of 79.1% and a chiral purity of 95.3%.

[0057] Comparative Example 10 The difference from Example 1 is that dichloromethane is replaced with anhydrous ethanol.

[0058] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of anhydrous ethanol. The mixture was stirred and heated to 50 °C for 0.5 h to dissolve. The solution was filtered, and the filtrate was cooled to 5 °C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the mixture was stirred at 5 °C for 6 h. The solution was filtered again and dried at 40 °C to obtain the melogabalone product, with a yield of 92% and a chiral purity of 68.8%.

[0059] Comparative Example 11 The difference from Example 1 is that dichloromethane is replaced with acetonitrile.

[0060] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of acetonitrile. The mixture was stirred and heated to 45 °C for 0.5 h to dissolve. After filtration, the filtrate was cooled to 5 °C, and 0.5 g of (1R,5S,6S) melogabalin was added. After stirring for 3 hours, no solid precipitated.

[0061] Comparative Example 12 The difference from Example 1 is that dichloromethane is replaced with trichloromethane.

[0062] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of chloroform. The mixture was stirred and heated to 40 °C for 0.5 h to dissolve. The solution was filtered, and the filtrate was cooled to 5 °C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the mixture was stirred at 5 °C for 6 h. The solution was filtered again and dried at 40 °C to obtain the melogabalone product, with a yield of 71% and a chiral purity of 98.8%.

[0063] Comparative Example 13 The difference from Example 1 is that dichloromethane is replaced with ethyl acetate.

[0064] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of ethyl acetate. The mixture was stirred and heated to 40 °C for 0.5 h to dissolve. The solution was filtered, and the filtrate was cooled to 5 °C. 0.5 g of (1R,5S,6S) melogabalone was added, and after crystallization, the mixture was stirred at 5 °C for 6 h. The solution was filtered again and dried at 40 °C to obtain the melogabalone product, with a yield of 46% and a chiral purity of 98.3%.

[0065] Comparative Example 14 The difference from Example 1 is that dichloromethane is replaced with tetrahydrofuran.

[0066] 20.0 g of the R,S intermediate was added to a reaction flask, followed by 60 ml of tetrahydrofuran. The mixture was stirred and heated to 45 °C for 0.5 h to dissolve. After filtration, the filtrate was cooled to 5 °C, and 0.5 g of (1R,5S,6S) melogabalone was added. After stirring for 3 hours, no solid precipitated.

[0067] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for dissociating merogabarine, characterized in that: Includes the following steps: Racemic melogabalin was added to dichloromethane and heated to dissolve, yielding a clear solution. After cooling the resulting clear solution, melogabalin seed crystals were added to it, with the configuration being (1 R 5 S 6 S ), stirring to induce crystallization; After crystal growth, the product is filtered, dried, and the target product is obtained.

2. The method for dissociating merogabarine according to claim 1, characterized in that: The mass ratio of dichloromethane to racemic melogabalin is 3-5:

1.

3. The method for dissociating merogabarine according to claim 1, characterized in that: The temperature for heating and melting is 38-42℃.

4. The method for dissociating merogabarine according to claim 3, characterized in that: The heating and dissolving process is a heating and reflux dissolving process.

5. The method for dissociating merogabarine according to claim 1, characterized in that: Cool the resulting clear solution to 0-10℃.

6. The method for dissociating merogabarine according to claim 1, characterized in that: The amount of seed crystals added is 0.5-5% of the mass of racemic melogabalin.

7. The method for dissociating merogabarine according to claim 6, characterized in that: The amount of seed crystals added is 1-5% of the mass of racemic melogabalin, preferably 2-5%.

8. The method for dissociating merogabarine according to claim 1, characterized in that: The amount of seed crystals added is 2-5% of the mass of racemic melogabalin.

9. The method for dissociating merogabarine according to claim 1, characterized in that: The temperature for crystal growth is 0-10℃.

10. The method for dissociating merogabarine according to claim 9, characterized in that: The crystal growth time is 6-8 hours.

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