Synthetic method of meropenem side chain

Abstract

This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing meropenem side chains. Using meropenem side chain intermediates and dimethylamine aqueous solution as raw materials, ethanol as solvent, and tributylphosphine as catalyst, the reaction is carried out. After the reaction, the solution is adjusted to acid, filtered, and crude meropenem side chain is obtained. The crude meropenem side chain is then added to water, alkali is adjusted, solvent extraction is performed, acid is adjusted again, crystallization occurs, filtration is performed, and drying is carried out to obtain purified meropenem side chains. This invention has low preparation cost, is easy to operate, and is suitable for industrialization. It can completely remove impurities such as meropenem side chain disulfides, obtaining high-purity purified meropenem side chains with a purity of over 99.9%, which is beneficial for improving the purity of subsequent synthesized meropenem.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing meropenem side chains. Background Technology

[0002] Meropenem side chains are an important intermediate in the synthesis of meropenem, and their structural formula is as follows:

[0003]

[0004] There are many synthetic routes for the meropenem side chain, as shown in the following examples:

[0005] In the presence of triethylamine, isopropyl chloroformate activates the carboxyl group of PNZ-protected L-hydroxyproline, which then reacts with dimethylamine to obtain an intermediate. The hydroxyl group is then activated with methanesulfonyl chloride, followed by reaction with potassium thioacetate and hydrolysis to obtain the meropenem side chain.

[0006] Heterocycles, 1995, 41(1): 147-159. Matsumura et al. first synthesized PNZ-protected thiolactone and used it as a key intermediate in the synthesis of meropenem side chain. This process synthesizes the key intermediate 3d, and the thiolactone is easily ammonolyzed to obtain the meropenem side chain.

[0007] Because the thiol group is unstable and easily oxidized to form a disulfide bond, the synthesis of meropenem side-chain disulfides is unavoidable. The structural formula of these disulfides is as follows: This impurity is a major impurity in the meropenem side chain; it is crucial for the subsequent synthesis of meropenem. At that time, this impurity cannot interact with the meropenem main ring. The reaction, after multiple batches of testing, revealed that this impurity was present to varying degrees in the final product meropenem, which was detrimental to the purification of meropenem.

[0008] Chinese patent CN 115490625A discloses a method for synthesizing and purifying meropenem side chains, including a reaction stage and a purification stage. The reaction stage includes the following steps: (1) under nitrogen protection, thiolactone, reaction solvent and catalyst are added to the reaction vessel and stirred to dissolve; (2) at a liquid temperature of 15-30℃, dimethylamine solution or dimethylamine hydrochloride solution is added dropwise to the reaction vessel to carry out the reaction; (3) after the reaction is completed, extraction water is added once, and then the pH value is adjusted to 6.0-8.0 with acid to extract crude organic phase; (4) the crude organic phase is extracted a second time with extraction water to obtain organic phase; (5) the organic phase is concentrated and distilled under reduced pressure to obtain concentrated liquid and reaction solvent; (6) the concentrated liquid is crystallized, centrifuged, washed and vacuum dried to obtain crude meropenem side chain. The refining stage includes the following steps: (a) dissolving the crude meropenem side chain in a dissolving agent, then adding activated carbon and stirring, filtering to obtain a filtrate; (b) adding a crystallizing agent to the filtrate at room temperature to induce crystallization, followed by crystal growth, centrifugation, and vacuum drying to obtain the refined meropenem side chain. This patent involves multiple extractions and distillation steps in its reaction stages, making the operation complex, energy-intensive, and unsuitable for industrial production. Furthermore, its refining stage cannot completely remove disulfide impurities.

[0009] A novel synthetic method for meropenem side chains was disclosed in November 2013 by the School of Pharmacy, Xuzhou Medical College, and Guangzhou Chemical Industry Research Institute. This method uses crude meropenem side chains synthesized in a one-pot process as raw material, followed by reverse extraction to obtain the meropenem side chains. However, this method involves adding methanol during alkali adjustment, which prevents complete extraction of meropenem side chain disulfide impurities using dichloromethane. Furthermore, after acid adjustment, extraction with ethyl acetate further extracts these disulfide impurities, thus failing to completely remove them. This method does not provide a detailed study of meropenem side chain disulfide impurities, and the crude meropenem side chain contains numerous impurities, resulting in low purity. Although purification improves the purity somewhat, it still only reaches 98.8%. These impurities negatively impact the purity of subsequent meropenem synthesis, hindering meropenem purification. Moreover, the post-processing involves saturated sodium chloride washing, drying, and distillation, making the operation complex and unsuitable for industrial production.

[0010] Currently, there is no effective method to remove the impurity meropenem side chain disulfide. Summary of the Invention

[0011] The purpose of this invention is to provide a method for synthesizing meropenem side chains. This method has low preparation cost, is easy to operate, and is suitable for industrialization. It can completely remove impurity meropenem side chain disulfides to obtain high-purity meropenem side chain products with a purity of over 99.9%, which is beneficial to improving the purity of meropenem synthesized in subsequent processes.

[0012] The method for synthesizing the meropenem side chain according to the present invention includes the following steps:

[0013] (1) Meropenem side chain intermediate and dimethylamine aqueous solution were used as raw materials, ethanol was used as solvent and tributylphosphine was used as catalyst. After the reaction was completed, the acid was adjusted and filtered to obtain crude meropenem side chain.

[0014] (2) The crude meropenem side chain was added to water, the alkali was adjusted, the solvent was extracted, the acid was adjusted, crystallization was carried out, the mixture was filtered and dried to obtain the fine meropenem side chain.

[0015] The structural formula of the meropenem side chain intermediate described in step (1) is as follows:

[0016]

[0017] The concentration of the dimethylamine aqueous solution in step (1) is 30-40%, preferably 40%.

[0018] The concentration of ethanol mentioned in step (1) is 95-99%, preferably 95%.

[0019] The mass ratio of meropenem intermediate to dimethylamine aqueous solution in step (1) is 45-98:20-70, the mass ratio of meropenem intermediate to ethanol is 1:1-5, and the mass ratio of meropenem intermediate to tributylphosphide is 1:0.006-0.035.

[0020] The reaction temperature in step (1) is -30 to -10°C, and the reaction time is 1 to 3 hours.

[0021] The acid adjustment mentioned in step (1) involves adding an acid to adjust the pH to 4-6. The acid is one or more of hydrochloric acid, acetic acid, or phosphoric acid, preferably acetic acid.

[0022] The mass ratio of crude meropenem side chain to water in step (2) is 1:2-20.

[0023] The alkali adjustment mentioned in step (2) involves adding alkali to adjust the pH to 9-12. The alkali is one or more of sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate, preferably sodium hydroxide. The molar ratio of crude meropenem side chain to alkali is 1:1-3.

[0024] The alkali adjustment temperature mentioned in step (2) is 0-25℃.

[0025] The solvent mentioned in step (2) is one or more of dichloromethane, chloroform, ethyl acetate or diethyl ether, preferably ethyl acetate, and the mass ratio of crude meropenem side chain to solvent is 1:1-5.

[0026] The acid adjustment mentioned in step (2) involves adding an acid to adjust the pH to 4-6. The acid is one or more of hydrochloric acid, phosphoric acid, or acetic acid, preferably acetic acid. The molar ratio of crude meropenem side chain to the acid is 1:1-3.

[0027] The acid-adjusting temperature mentioned in step (2) is 0-25℃.

[0028] The crystallization temperature in step (2) is 0-25℃ and the crystallization time is 1-2 hours.

[0029] The method for synthesizing the meropenem side chain according to the present invention includes the following specific steps:

[0030] (1) Under nitrogen protection, meropenem side chain intermediate and tributylphosphine were added to ethanol, and dimethylamine aqueous solution was added dropwise to carry out the reaction at a temperature of -30 to -10℃.

[0031] (2) After the reaction is complete, adjust the pH to 4-6 with acid; after adjusting the acid, filter and wash with 95% ethanol to obtain crude meropenem side chain.

[0032] (3) Under nitrogen protection, add crude meropenem side chain to water, add alkaline solution dropwise, and after the addition is complete, pH = 9-12. Stir for 1-2 hours to dissolve the solid completely.

[0033] (4) Extract twice with solvent, separate the liquid and collect the aqueous phase;

[0034] (5) Add acid solution to the aqueous phase to adjust the pH to 4-6, stir to precipitate crystals, filter, and dry to obtain high-purity meropenem side chain product.

[0035] The reaction equation of this invention is as follows:

[0036]

[0037] During the synthesis of meropenem side chains, meropenem side chain disulfide impurities are always present to varying degrees. These impurities persist in the final product, meropenem, thus affecting its purity and hindering purification. Existing techniques, including recrystallization with one or more solvents such as ethyl acetate, ethanol, petroleum ether, and acetonitrile, adsorption with activated carbon, silica gel, and diatomaceous earth, and solvent slurrying, have all failed to completely remove the meropenem side chain disulfide impurities.

[0038] This invention synthesizes meropenem side chains under low-temperature conditions, which can control the content of meropenem side chain disulfides to a minimum. Then, purification is carried out, which can not only completely remove meropenem side chain disulfides, but also increase the purity of meropenem side chains to more than 99.9%, thereby improving the purity of subsequent meropenem synthesis.

[0039] This invention involves adding crude meropenem side chain to water and adjusting the alkali, which allows the meropenem side chain to form a salt, but the disulfide impurities will not form a salt. The disulfide impurities are then removed by extraction with an organic solvent, and the meropenem side chain product is precipitated by adjusting the acid. The disulfide impurities can be completely removed by the above method.

[0040] The beneficial effects of this invention are as follows:

[0041] (1) The preparation cost is low, the operation is convenient, and it is suitable for industrialization;

[0042] (2) The obtained product has high purity, and the purity of the meropenem side chain can reach more than 99.9%;

[0043] (3) It can completely remove the meropenem side chain disulfide, which not only improves the purity of the meropenem side chain, but also helps to improve the purity of the meropenem synthesized in the subsequent process. Attached Figure Description

[0044] Figure 1 This is the infrared spectrum of the product obtained in Example 1.

[0045] Figure 2 This is the HPLC chromatogram of the product obtained in Example 1.

[0046] Figure 3 This is the HPLC chromatogram of the product obtained in Example 2.

[0047] Figure 4 This is the HPLC chromatogram of the product obtained in Example 3.

[0048] Figure 5 This is the HPLC chromatogram of the product obtained in Comparative Example 1.

[0049] Figure 6 This is the HPLC chromatogram of the product obtained in Comparative Example 2.

[0050] Figure 7 This is the HPLC chromatogram of the product obtained in Comparative Example 3.

[0051] Figure 8 This is the HPLC chromatogram of the product obtained in Comparative Example 4.

[0052] Figure 9 This is the HPLC chromatogram of the product obtained in Comparative Example 5. Detailed Implementation

[0053] The present invention will be further described below with reference to embodiments.

[0054] Example 1

[0055] Under nitrogen protection, 46 g of meropenem side chain intermediate, 138 g of 95% ethanol and 0.3 g of tributylphosphine were added to a four-necked flask. The temperature was lowered to -15℃, and 20.3 g of 40% dimethylamine aqueous solution was added dropwise. After the addition was completed, the temperature was controlled at -15 to -10℃ and kept at this temperature for 1 hour. The pH was adjusted to 4 with hydrochloric acid, filtered, and washed with 95% ethanol to obtain 50 g of crude meropenem side chain.

[0056] Under nitrogen protection, 50 g of crude meropenem side chain was added to a four-necked flask, followed by 150 g of purified water. The mixture was cooled to 2°C, and 18.9 g of 30% sodium hydroxide solution was added dropwise while maintaining the temperature at 0-5°C. After the addition was complete, the pH was 11, and the mixture was stirred for 1 hour until the solid was completely dissolved. 200 g of ethyl acetate was added, and the mixture was extracted twice. The liquid was separated, and the aqueous phase was collected. 8.5 g of acetic acid was added dropwise to the aqueous phase, and the temperature was maintained at 10-20°C with a pH of 5. The mixture was stirred at 10-20°C for 1 hour to induce crystallization. The crystals were filtered and dried under vacuum at 40°C to obtain 48.4 g of purified meropenem side chain, with a yield of 96.8% and a purity of 99.93%. The infrared spectrum of the product is shown below. Figure 1 The HPLC chromatogram of the product is shown below. Figure 2 .Depend on Figure 2 It can be seen that the product contains no meropenem side chain disulfide impurities.

[0057] Example 2

[0058] Under nitrogen protection, 95g of meropenem side chain intermediate, 475g of 95% ethanol and 3g of tributylphosphine were added to a four-necked flask. The temperature was lowered to -30℃, and 69.3g of 40% dimethylamine aqueous solution was added dropwise. After the addition was completed, the temperature was controlled at -30 to -25℃ and kept at this temperature for 3 hours. The pH was adjusted to 5 with acetic acid, filtered, and washed with 95% ethanol to obtain 100g of crude meropenem side chain.

[0059] Under nitrogen protection, 100g of crude meropenem side chain was added to a four-necked flask, followed by 500g of purified water. The mixture was cooled to 10℃, and 317g of 10% potassium hydroxide solution was added dropwise while maintaining the temperature at 10-15℃. After the addition was complete, the pH was 12, and the mixture was stirred for 2 hours until the solid was completely dissolved. 100g of dichloromethane was added, and the mixture was extracted twice. The liquid phase was separated, and the aqueous phase was collected. 83.2g of phosphoric acid was added dropwise to the aqueous phase while maintaining the temperature at 15-25℃ and the pH at 6. The mixture was stirred at 15-25℃ for 1.5 hours to induce crystallization. The crystals were filtered and dried under vacuum at 40℃ to obtain 96.4g of purified meropenem side chain, with a yield of 96.4% and a purity of 99.93%. The HPLC chromatogram of the product is shown below. Figure 3 .Depend on Figure 3 It can be seen that the product contains no meropenem side chain disulfide impurities.

[0060] Example 3

[0061] Under nitrogen protection, 48 g of meropenem side chain intermediate, 96 g of 95% ethanol and 0.3 g of tributylphosphine were added to a four-necked flask. The temperature was lowered to -20°C, and 26.3 g of 40% dimethylamine aqueous solution was added dropwise. After the addition was completed, the temperature was controlled at -20 to -10°C and kept at this temperature for 2 hours. The pH was adjusted to 6 with phosphoric acid, filtered, and washed with 95% ethanol to obtain 50 g of crude meropenem side chain.

[0062] Under nitrogen protection, 50 g of crude meropenem side chain was added to a four-necked flask, followed by 500 g of purified water and 600 g of 5% sodium carbonate solution. The temperature was controlled at 20-25℃. After the addition was complete, the pH was 9, and the mixture was stirred for 1.5 hours until the solid was completely dissolved. 250 g of diethyl ether was added, and the mixture was extracted twice. The liquid phase was separated, and the aqueous phase was collected. 36.9 g of 35% hydrochloric acid was added dropwise to the aqueous phase. The temperature was controlled at 0-10℃, and the pH was 4. The mixture was stirred at 0-10℃ for 2 hours to induce crystallization. After filtration, the product was dried under vacuum at 40℃ to obtain 48.3 g of purified meropenem side chain, with a yield of 96.6% and a purity of 99.92%. The HPLC chromatogram of the product is shown below. Figure 4 .Depend on Figure 4 It can be seen that the product contains no meropenem side chain disulfide impurities.

[0063] Comparative Example 1

[0064] Under nitrogen protection, 48 g of meropenem side chain intermediate, 96 g of 95% ethanol and 0.3 g of tributylphosphine were added to a four-necked flask. The temperature was lowered to 10°C, and 26.3 g of 40% dimethylamine aqueous solution was added dropwise. After the addition was completed, the temperature was controlled at 10-20°C and kept at that temperature for 2 hours. The pH was adjusted to 6 with phosphoric acid, filtered, and washed with 95% ethanol to obtain 50 g of crude meropenem side chain.

[0065] Under nitrogen protection, 50 g of crude meropenem side chain was added to a four-necked flask, followed by 500 g of purified water and 600 g of 5% sodium carbonate solution. The temperature was controlled at 20-25℃. After the addition was complete, the pH was 9, and the mixture was stirred for 1.5 hours until the solid was completely dissolved. 250 g of diethyl ether was added, and the mixture was extracted twice. The aqueous phase was collected, and 36.9 g of 35% hydrochloric acid was added dropwise. The temperature was controlled at 0-10℃, and the pH was 4. The mixture was stirred at 0-10℃ for 2 hours to induce crystallization. After filtration, the product was dried under vacuum at 40℃ to obtain 48.1 g of purified meropenem side chain, with a yield of 96.2% and a purity of 99.32%. The HPLC chromatogram of the product is shown below. Figure 5 .Depend on Figure 5 It is known that the product still contains meropenem side chain disulfide impurities, with a content of 0.41%.

[0066] Comparative Example 2

[0067] The preparation steps for the crude meropenem side chain are the same as in Example 1.

[0068] Under nitrogen protection, 20 g of crude meropenem side chain and 320 g of ethyl acetate were added to a four-necked flask. The mixture was heated until dissolved, then cooled to room temperature. Petroleum ether was added dropwise to the filtrate. After turbidity, crystals were grown for 1 hour. Petroleum ether was then added dropwise, for a total of 300 g. After the addition was complete, crystals were grown for 1 hour, centrifuged, and dried under vacuum at 30 °C to obtain 18.3 g of purified meropenem side chain, with a yield of 91.5% and a purity of 98.68%. The HPLC chromatogram of the product is shown below. Figure 6 .Depend on Figure 6 It is known that the product still contains meropenem side chain disulfide impurities, with a content of 0.85%.

[0069] Comparative Example 3

[0070] The preparation steps for the crude meropenem side chain are the same as in Example 1.

[0071] Under nitrogen protection, 20 g of crude meropenem side chain and 320 g of dichloromethane were added to a four-necked flask and stirred until dissolved. Then, 1 g of activated carbon and 2 g of silica gel were added, and the mixture was stirred for 1 hour. The mixture was filtered, and the filtrate was concentrated to obtain 18.4 g of purified meropenem side chain, with a yield of 92.0% and a purity of 98.80%. The HPLC chromatogram of the product is shown below. Figure 7 .Depend on Figure 7 It is known that the product still contains meropenem side chain disulfide impurities, with a content of 0.85%.

[0072] Comparative Example 4

[0073] The meropenem side chain was synthesized according to the process described in Heterocycles, 1995, 41(1):147-159, Matsumura. The yield of the synthesized meropenem side chain was 58.3%, and the purity was 98.73%. The HPLC chromatogram of the product is shown in [reference needed]. Figure 8 .Depend on Figure 8 It is known that the product still contains meropenem side chain disulfide impurities, with a content of 0.83%.

[0074] Comparative Example 5

[0075] The preparation steps for the crude meropenem side chain are the same as in Example 1.

[0076] Under nitrogen protection, 50 g of crude meropenem side chain was added to a four-necked flask, along with a small amount of methanol. The mixture was cooled to 2°C, and 18.9 g of 30% sodium hydroxide solution was added dropwise while maintaining the temperature between 0-5°C. After the addition was complete, the mixture was stirred for 0.5 hours. A small amount of water was added, followed by 200 g of dichloromethane. The mixture was extracted twice, and the liquid phases were separated. The aqueous phase was collected, and hydrochloric acid was added dropwise to adjust the pH to acidic. Then, 300 g of ethyl acetate was added, and the mixture was extracted twice. The organic phases were combined, washed once with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and distilled to obtain 45.4 g of purified meropenem side chain, with a yield of 90.8% and a purity of 98.57%. The HPLC chromatogram of the product is shown below. Figure 9 .Depend on Figure 9 It is known that the product still contains meropenem side chain disulfide impurities, with a content of 0.99%.

Claims

1. A process for the synthesis of the side chain of meropenem, characterized by The method comprises the following steps: (1) reacting a meropenem side chain intermediate and an aqueous dimethylamine solution as raw materials, ethanol as a solvent, and tributyl phosphine as a catalyst, adjusting the pH after the reaction, filtering, and obtaining a crude meropenem side chain; (2) adding the crude meropenem side chain into water, adjusting the pH, extracting the solvent, adjusting the pH, crystallizing, filtering, drying, and obtaining a fine meropenem side chain; The reaction temperature in step (1) is -30--10℃. The structure of the meropenem side chain intermediate in step (1) is as follows: 。 2. The process for the synthesis of the side chain of meropenem according to claim 1, characterized by In step (1), the concentration of the aqueous dimethylamine solution is 30-40%, the concentration of ethanol is 95-99%, the mass ratio of the meropenem intermediate to the aqueous dimethylamine solution is 45-98:20-70, the mass ratio of the meropenem intermediate to ethanol is 1:1-5, and the mass ratio of the meropenem intermediate to tributyl phosphine is 1:0.006-0.

035.

3. The method of claim 1, wherein The reaction time in step (1) is 1-3h.

4. The method of claim 1, wherein In step (1), the pH is adjusted to 4-6 by adding an acid, and the acid is one or more of hydrochloric acid, acetic acid, or phosphoric acid.

5. The method of claim 1, wherein In step (2), the mass ratio of the crude meropenem side chain to water is 1:2-20.

6. The method of claim 1, wherein In step (2), the pH is adjusted to 9-12 by adding a base, and the base is one or more of sodium hydroxide, sodium carbonate, potassium hydroxide, or potassium carbonate, the molar ratio of the crude meropenem side chain to the base is 1:1-3, and the temperature for adjusting the pH is 0-25℃.

7. The method of claim 1, wherein In step (2), the solvent is one or more of dichloromethane, chloroform, ethyl acetate, or diethyl ether, and the mass ratio of the crude meropenem side chain to the solvent is 1:1-5.

8. The method of claim 1, wherein In step (2), the pH is adjusted to 4-6 by adding an acid, and the acid is one or more of hydrochloric acid, phosphoric acid, or acetic acid, the molar ratio of the crude meropenem side chain to the acid is 1:1-3, and the temperature for adjusting the pH is 0-25℃.

9. The method of claim 1, wherein In step (2), the crystallization temperature is 0-25℃, and the crystallization time is 1-2 hours.

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