Process method for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid

Abstract

The invention discloses a process method for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid, which comprises the following steps of: quickly mixing an acid solution containing L-glutamic acid and a sodium nitrite solution through a micro-mixer, and then introducing into a micro-packed bed reactor filled with a strong acid cation exchange resin catalyst for reaction, and carrying out continuous gas-liquid phase separation on an effluent mixture, collecting a solution, and carrying out post-treatment to obtain an oily crude product of (S)-5-oxotetrahydro-2-furancarboxylic acid. The method can effectively solve the problems of low production efficiency, poor process controllability, large acid consumption, unstable product quality and the like in the existing (S)-5-oxotetrahydro-2-furancarboxylic acid production process, obviously improves the yield and purity of the target product, and has the advantages of high reaction efficiency, safe and controllable process and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical production, and particularly relates to a process for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid. Background Art

[0002] The chiral intermediate (S)-5-oxotetrahydro-2-furancarboxylic acid (CAS: 21461-84-7) is a class of γ-butyrolactone derivatives with a unique structure. It has important applications in the pharmaceutical field, especially in the synthesis of (S)-4-amino-2-hydroxybutyric acid, a key intermediate in the aminoglycoside antibiotic amikacin.

[0003]

[0004] The current mainstream route for preparing (S)-5-oxotetrahydro-2-furancarboxylic acid via the diazotization and lactonization of L-glutamic acid is simple, using readily available, and inexpensive raw materials (refer to the literature). However, the highly exothermic nature of the diazotization reaction and the extreme instability of fatty diazonium salts lead to widespread problems with existing autoclave processes, including low production efficiency, unstable product quality, poor process controllability, and high safety risks. Excessively high local temperatures during the reaction can easily lead to a decrease in the product's EE value; using too little acid can easily lead to raw material precipitation, affecting the reaction outcome; while using too much acid can result in the use of large amounts of base in post-processing.

[0005] Micro-reaction continuous processes offer significant advantages in heat and mass transfer efficiency and process safety. Therefore, the present invention has developed a continuous process for producing (S)-5-oxotetrahydro-2-furancarboxylic acid based on a micro-packed bed reactor. This process effectively improves reaction efficiency, reduces reagent usage, improves product quality, and enhances process safety and controllability, thus possessing high industrial application value. Summary of the Invention

[0006] To address the shortcomings in the prior art, the present invention provides a process for preparing (S)-5-oxotetrahydro-2-furancarboxylic acid using a micro-packed bed reactor. This process aims to address the problems of low reaction efficiency, high safety risks, and unstable product quality in existing production processes, thereby improving production efficiency and process stability. The specific technical solution is as follows:

[0007] A process for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid comprises the following steps:

[0008] (1) using water as a solvent to prepare a sodium nitrite solution as feed liquid A;

[0009] (2) L-glutamic acid, inorganic acid and water are mixed and stirred to dissolve to obtain liquid B;

[0010] (3) Feed liquid A and feed liquid B are delivered to a micro mixer via two pumps, and the resulting mixed liquid C is directly reacted in a micro packed bed reactor containing an acidic solid catalyst to obtain a reaction liquid D containing gas;

[0011] (4) The reaction solution D enters a continuous gas-liquid separator, and the resulting solution is post-treated to obtain solid (S)-5-oxotetrahydro-2-furancarboxylic acid.

[0012] In step (1), the mass fraction of sodium nitrite in feed liquid A is 20-40%.

[0013] In step (2), the mass fraction of L-glutamic acid in the feed solution B is 10-30%; and the inorganic acid is hydrochloric acid.

[0014] The molar ratio of L-glutamic acid, sodium nitrite and acid in feed solution A and feed solution B is 1:(1.05-1.3):(1.1-1.5).

[0015] In step (3), the characteristic size of the micro mixer is 0.1 to 1 mm, and the mixing temperature is -5 to 5°C.

[0016] In step (3), the solid acid catalyst is a cation exchange resin containing a sulfonic acid group (including but not limited to Amberlys 15, Purolite C160), with a particle size of 100 to 500 μm and a capacity of 3.0 to 6.0 meq / g dry weight.

[0017] In step (3), the inner diameter of the channel in the micro-packed bed reactor is 0.5-10 mm, the reaction temperature is 5-25° C., the system pressure is 0.1-1 MPa, and the liquid residence time is 2-10 min.

[0018] In step (3), the total speed of the feed liquid A and the feed liquid B at the mixing point of the micro mixer is 2 to 8 m / s.

[0019] In step (4), the post-treatment includes alkali solution neutralization, decompression water removal, organic solvent extraction and distillation purification. The alkali solution is further preferably sodium hydroxide solution, and the organic solvent is further preferably tetrahydrofuran.

[0020] Compared with the prior art, the present invention has the following advantages and outstanding technical effects:

[0021] (1) The use of a micro mixer achieves rapid mixing of the two streams of feed liquid, avoiding uneven material mixing caused by large amounts of gas produced by the reaction, which in turn leads to problems such as low sodium nitrite utilization and low raw material conversion rate.

[0022] (2) A micro-packed bed reactor was introduced, and the hydrophilic phase of the solid-filled catalyst was used to decouple the residence time of the gas phase and the aqueous phase in the reaction fluid in the microchannel, which effectively increased the residence time of the aqueous phase reaction liquid in the microreactor and reduced the disturbance of the reaction caused by the generation of a large amount of gas.

[0023] (3) Taking advantage of the high heat and mass transfer efficiency of the microreactor, the rapid transfer of heat from the highly exothermic diazotization reaction is achieved, the reaction temperature is controllable, and the ee value of the hand-shaped product is effectively guaranteed.

[0024] (4) The use of strong acidic cation exchange resin provides a stronger acidic environment during the diazotization reaction, which can reduce the amount of acid used in the feed B and thus reduce the amount of alkali used in the post-treatment.

[0025] (5) The safety risks of the micro-reaction continuous process are controllable. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a process flow chart for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid. Specific implementation methods

[0027] The present invention provides a process for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid, which is further described below with reference to examples.

[0028] Example 1

[0029] Feed A consisted of a 30% aqueous sodium nitrite solution. To this mixture, 20g of L-glutamic acid was added 16g of concentrated hydrochloric acid (37%), followed by 64g of water, and stirred until dissolved. This served as Feed B. Feeds A and B were introduced into a T-type microdisperser (0.25mm internal dimension, -5°C) using two separate syringe pumps. Feed A flowed at 3.8g / min and feed B at 10g / min, resulting in a molar ratio of L-glutamic acid to sodium nitrite to acid of approximately 1:1.2:1.2. The mixed solution C then flowed into a tubular micropacked bed reactor (4mm outer diameter, 3mm inner diameter) filled with a strongly acidic cation exchange resin (Amberlys 15, particle size ~300μm, capacity 4.7meq / g dry weight) for reaction at 15°C, a pressure of 0.5MPa, and a liquid residence time of approximately 5min. The reaction liquid exiting the micro-packed bed reactor was degassed in a continuous gas-liquid phase separator. The resulting aqueous phase was neutralized with sodium hydroxide solution to a pH of 7 at 5°C. Water was then removed under reduced pressure and extracted with tetrahydrofuran. The extract was dried over molecular sieves and the solvent removed to yield 18.9 g of crude oily (S)-5-oxotetrahydro-2-furancarboxylic acid. Liquid chromatography revealed a purity of 90.2%, an ee of 98.5%, and a calculated yield of 95.6%.

[0030] Example 2

[0031] Feed A consisted of a 30% aqueous sodium nitrite solution. To this mixture, 20g of L-glutamic acid was added 16g of concentrated hydrochloric acid (37%), followed by 64g of water, and stirred until dissolved. This served as Feed B. Feeds A and B were introduced into a T-type microdisperser (0.25mm internal dimension, -5°C) using two separate syringe pumps. Feed A flowed at 3.8g / min and feed B at 10g / min, resulting in a molar ratio of L-glutamic acid to sodium nitrite to acid of approximately 1:1.2:1.2. The mixed solution C then flowed into a tubular micropacked bed reactor (4mm outer diameter, 3mm inner diameter) filled with a strongly acidic cation exchange resin (Amberlys 15, particle size ~300μm, capacity 4.7meq / g dry weight) for reaction at 25°C, 0.5MPa, and a liquid residence time of approximately 5min. The reaction liquid exiting the micro-packed bed reactor was degassed in a continuous gas-liquid phase separator. The resulting aqueous phase was neutralized with sodium hydroxide solution to a pH of 7 at 5°C. Water was then removed under reduced pressure and extracted with tetrahydrofuran. The extract was dried over molecular sieves and the solvent removed to yield 18.5 g of crude oily (S)-5-oxotetrahydro-2-furancarboxylic acid. Liquid chromatography revealed a purity of 83.2%, an ee of 94.2%, and a calculated yield of 84.51%.

[0032] Example 3

[0033] Feed A consists of a 30% aqueous sodium nitrite solution. To this solution, 20g of L-glutamic acid was added 16g of concentrated hydrochloric acid (37%), followed by 64g of water, and stirred to dissolve. This served as Feed B. Feeds A and B were introduced into a T-type microdisperser (0.25mm internal dimension, -5°C) using two separate syringe pumps. Feed A flowed at 3.8g / min and Feed B flowed at 10g / min, resulting in a molar ratio of L-glutamic acid to sodium nitrite to acid of approximately 1:1.2:1.2. The mixed solution C then flowed into a tubular microreactor (4mm outer diameter, 3mm inner diameter) for reaction at a temperature of 15°C, a pressure of 0.5MPa, and a liquid residence time of approximately 5min. The reaction liquid exiting the reactor was degassed in a continuous gas-liquid phase separator. The resulting aqueous phase was neutralized with sodium hydroxide solution to a pH of 7 at 5°C. Water was then removed under reduced pressure and extracted with tetrahydrofuran. The extract was dried over molecular sieves and the solvent removed to yield 15.7 g of crude oily (S)-5-oxotetrahydro-2-furancarboxylic acid. Liquid chromatography revealed a purity of 75.6%, an ee of 97.5%, and a calculated yield of 66.3%.

[0034] The results of Example 3 show that when a conventional tubular microreactor is used without adding a strongly acidic cation exchange resin, both the purity and the yield of the product are greatly reduced.

[0035] Example 4

[0036] Feed A consisted of a 30% aqueous sodium nitrite solution. To this mixture, 20g of L-glutamic acid was added 8.2g of concentrated sulfuric acid (98%) and 71.8g of water, stirred until dissolved. This served as Feed B. Feeds A and B were introduced into a T-type microdisperser (0.25mm internal dimension, -5°C) using two separate syringe pumps. Feed A flowed at 3.8g / min and feed B at 10g / min, resulting in a molar ratio of L-glutamic acid to sodium nitrite to acid of approximately 1:1.2:1.2. The mixed solution C then flowed into a tubular micropacked bed reactor (4mm outer diameter, 3mm inner diameter) filled with a strongly acidic cation exchange resin (Amberlys 15, particle size ~300μm, capacity 4.7meq / g dry weight) for reaction at 15°C, a pressure of 0.5MPa, and a liquid residence time of approximately 5min. The reaction liquid exiting the micro-packed bed reactor was degassed in a continuous gas-liquid phase separator. The resulting aqueous phase was neutralized with sodium hydroxide solution to a pH of 7 at 5°C. Water was then removed under reduced pressure and extracted with tetrahydrofuran. The extract was dried over molecular sieves and the solvent removed to yield 11.7 g of crude (S)-5-oxotetrahydro-2-furancarboxylic acid as an oil. Liquid chromatography revealed a purity of 70.2%, an ee of 90.5%, and a calculated yield of 44.2%.

[0037] The results of Example 4 show that when the hydrochloric acid in feed solution B is replaced by sulfuric acid, the purity and yield of the product are greatly reduced.

[0038] Example 5

[0039] Feed A consisted of a 30% aqueous sodium nitrite solution. 20g of L-glutamic acid was added to 16g of concentrated hydrochloric acid (37%), followed by 64g of water, and stirred to dissolve. This served as Feed B. Feeds A and B were introduced into a T-type microdisperser (0.25mm internal dimension, -5°C) using two separate syringe pumps. Feed A flowed at 5.6g / min and feed B flowed at 10g / min, resulting in a molar ratio of L-glutamic acid to sodium nitrite to acid of approximately 1:1.8:1.2. The mixed solution C then flowed into a tubular micropacked bed reactor (4mm outer diameter, 3mm inner diameter) filled with a strongly acidic cation exchange resin (Amberlys 15, particle size ~300μm, capacity 4.7meq / g dry weight) for reaction at 15°C, 0.5MPa pressure, and a liquid residence time of approximately 5min. The reaction liquid exiting the micro-packed bed reactor was degassed in a continuous gas-liquid phase separator. The resulting aqueous phase was neutralized with sodium hydroxide solution to a pH of 7 at 5°C. Water was then removed under reduced pressure and extracted with tetrahydrofuran. The extract was dried over molecular sieves and the solvent removed to yield 18.5 g of crude (S)-5-oxotetrahydro-2-furancarboxylic acid as an oil. Liquid chromatography revealed a purity of 88.2%, an ee of 97.5%, and a calculated yield of 91.09%.

[0040] Example 6

[0041] Feed A consisted of a 30% aqueous sodium nitrite solution. 20g of L-glutamic acid was added to 16g of concentrated hydrochloric acid (37%), followed by 64g of water, and stirred to dissolve. This served as Feed B. Feeds A and B were introduced into a T-type microdisperser (0.25mm internal dimension, -5°C) using two separate syringe pumps. Feed A flowed at 3.8g / min and feed B at 10g / min, resulting in a molar ratio of L-glutamic acid to sodium nitrite to acid of approximately 1:1.2:1.2. The mixed solution C then flowed into a tubular micropacked bed reactor (4mm outer diameter, 3mm inner diameter) filled with a strongly acidic cation exchange resin (Purolite C160, particle size ~300μm, capacity 2.3eq / L wet weight) for reaction at 15°C, 0.5MPa pressure, and a liquid residence time of approximately 5min. The reaction liquid exiting the micro-packed bed reactor was degassed in a continuous gas-liquid phase separator. The resulting aqueous phase was neutralized with sodium hydroxide solution to a pH of 7 at 5°C. Water was then removed under reduced pressure and extracted with tetrahydrofuran. The extract was dried over molecular sieves and the solvent removed to yield 18.2 g of crude (S)-5-oxotetrahydro-2-furancarboxylic acid as an oil. Liquid chromatography revealed a purity of 89.4%, an ee of 98.1%, and a calculated yield of 91.3%.

[0042] Comparative Example 1

[0043] 20g L-glutamic acid, 16g concentrated hydrochloric acid (37%), and 64g water were added to a 250mL three-necked flask in sequence, stirred and dissolved, and placed on 5°C cold hydrazine for insulation. 38g 30% sodium nitrite solution was slowly added, and the reaction liquid temperature was controlled to be no more than 15°C. After completion of the dropwise addition, the reaction was stopped after the reaction liquid temperature was controlled to be 15°C and continued to stir for 30min. The resulting reaction solution was neutralized to pH=7 with sodium hydroxide solution at 5°C, and then decompressed and dehydrated with tetrahydrofuran (THF) for extraction. The resulting extract was dried over molecular sieves and solvent removed to obtain 13.9g of an oily crude product (S)-5-oxotetrahydro-2-furancarboxylic acid. Liquid chromatography measured a purity of 80.2%, an ee value of 95.5%, and a calculated yield of 61.6%.

Claims

1. A process for continuously preparing (S)-5-oxotetrahydro-2-furancarboxylic acid, characterized in that: The following steps are involved: (1) using water as a solvent to prepare a sodium nitrite solution as feed liquid A; (2) L-glutamic acid, inorganic acid and water are mixed and stirred to dissolve to obtain liquid B; (3) Feed liquid A and feed liquid B are simultaneously fed into a micromixer, and the resulting mixed liquid C is directly reacted in a micropacked bed reactor equipped with a solid acid catalyst to obtain a reaction liquid D containing gas; (4) The reaction solution D enters a continuous gas-liquid separator to remove gas, and the resulting solution is post-treated to obtain solid (S)-5-oxotetrahydro-2-furancarboxylic acid.

2. The process according to claim 1, wherein: In step (1), the mass fraction of sodium nitrite in the feed liquid A is 20-40%.

3. The process according to claim 1, wherein: In step (2), the mass fraction of L-glutamic acid in the feed solution B is 10-30%; and the inorganic acid is hydrochloric acid.

4. The process according to claim 1, wherein: In step (3), the molar ratio of L-glutamic acid, sodium nitrite and inorganic acid in the feed liquid A and the feed liquid B is 1:(1.05-1.3):(1.1-1.5).

5. The process according to claim 1, wherein: In step (3), the micro mixer is a T-type micro disperser with a characteristic size of 0.1 to 1 mm and a mixing temperature of -5°C to 5°C.

6. The process according to claim 1, wherein: In step (3), the solid acid catalyst is a cation exchange resin containing a sulfonic acid group, with a particle size of 100 to 500 μm and a capacity of 3.0 to 6.0 meq / g dry weight.

7. The process according to claim 1, wherein: In step (3), the inner diameter of the channel in the micro-packed bed reactor is 0.5-10 mm, the reaction temperature is 5-25° C., the system pressure is 0.1-1 MPa, and the liquid residence time is 2-10 min.

8. The process according to any one of claims 1 to 3, characterized in that: In step (3), the total speed of the feed liquid A and the feed liquid B at the mixing point of the micro mixer is 2 to 8 m / s.

9. The process according to claim 1, wherein: In step (4), the post-treatment includes alkali solution neutralization, decompression water removal, organic solvent extraction and distillation purification.

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