Method and system for preparing 4-AA medical intermediate through continuous flow ozone oxidation

Abstract

The invention discloses a method and a system for preparing a 4-AA medical intermediate through continuous flow ozone oxidation. The method comprises the following steps: continuously introducing a raw material solution containing (3R)-3-((R)-1-((tert-butyldimethylsilyl) oxy) ethyl)-1-(4-methoxyphenyl)-4-oxo azetidine-2-yl acetate and a gas containing ozone into a microreactor for reaction; after the reaction liquid is subjected to reduction quenching, the (3R, 4R) 4-acetoxyl-3-[R-(tert-butyldimethylsiloxy) ethyl]-2-azetidinone is obtained. On one hand, the reaction time is shortened from the hour level to the minute level, and the production efficiency is remarkably improved; and on the other hand, the reaction temperature is increased to 10-30 DEG C from deep cooling, so that the refrigeration energy consumption and the equipment requirement are greatly reduced. According to the invention, local peroxidation is fundamentally avoided, byproducts are obviously reduced, the product purity is improved, the method is suitable for continuous operation, the reaction process is controllable, and the method is safe and reliable.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a method and system for preparing 4-AA pharmaceutical intermediates by continuous flow ozone oxidation. BACKGROUND

[0002] 4-AA, whose chemical name is 4-acetoxyazetidinone, is a key intermediate of carbapenem (penem) antibiotics, is an essential raw material for the synthesis of penem drugs, can also be used for the production of antibiotics, and can be developed into antibacterial agents, anti-hyperlipidemia drugs, etc., so the industry has a large demand for it.

[0003] The key advanced intermediate for synthesizing 4-AA is HAM70, whose chemical name is (3R, 4R) 4-acetoxy-3-[R-(tert-butyldimethylsiloxy) ethyl]-2-azetidinone, and the structural formula is .

[0004] At present, the precursor HAM60 of HAM70 is mainly subjected to ozone oxidation by batch reactor in industry to prepare HAM70. The chemical name of HAM60 is (3R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-methoxyphenyl)-4-oxoazetidin-2-yl acetate, and the structural formula is .

[0005] For example, the world patent WO9807690 discloses a typical batch method: HAM60 is dissolved in methanol, reacted for 3 hours in a deep cold environment at-20℃, ozone is slowly introduced, and after the reaction is completed, post-processing steps such as quenching, concentration, cooling crystallization are carried out to prepare HAM70, and the final yield is about 85%.

[0006] However, the present inventors found at least the following technical problems in the process of implementing the technical scheme of the embodiments of the present application: The reaction conditions are harsh, the equipment and energy consumption are large, the ozone is not uniformly distributed in the batch system, there are many by-products, the production time is long, the efficiency is low, and there is a safety hazard of ozone leakage. SUMMARY

[0007] The present application provides a method and system for preparing 4-AA pharmaceutical intermediates by continuous flow ozone oxidation, which can solve the above-mentioned deficiencies in the prior art.

[0008] To solve the above technical problems, the present application provides a method for preparing 4-AA pharmaceutical intermediates by continuous flow ozone oxidation, wherein the 4-AA pharmaceutical intermediates are (3R, 4R) 4-acetoxy-3-[R-(tert-butyldimethylsiloxy) ethyl]-2-azetidinone. The method involves continuously introducing a raw material solution containing (3R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-methoxyphenyl)-4-oxoazacyclobutane-2-ylacetate and ozone-containing gas into a microreactor, and reacting under the following conditions: Reaction temperature: 10-30℃; System back pressure: 0.3-0.7 MPa; The mixture after the reaction was reduced and quenched to obtain (3R,4R)4-acetoxy-3-[R-(tert-butyldimethoxy)ethyl]-2-azacyclobutanone.

[0009] In a preferred embodiment of the present invention, the feed flow rate of the (3R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-methoxyphenyl)-4-oxoazonicyclobutane-2-yl acetate is 0.5-6 mL / min.

[0010] In a preferred embodiment of the present invention, the flow rate of the ozone-containing gas is 0.5-0.6 L / min.

[0011] In a preferred embodiment of the present invention, the reaction temperature is 15°C.

[0012] In a preferred embodiment of the present invention, the system back pressure is 0.5 MPa.

[0013] In a preferred embodiment of the present invention, the concentration of ozone is 35-215 mg / L.

[0014] In a preferred embodiment of the present invention, the concentration of ozone is 200-215 mg / L.

[0015] In a preferred embodiment of the present invention, the ozone is produced from oxygen or air via an ozone generator.

[0016] To address the aforementioned technical problems, the present invention also provides a continuous flow reaction system for implementing the above method, comprising: Raw material preparation vessel and fluid delivery unit; Ozone generator and gas delivery control unit; A microreactor unit that includes a mixing function; Back pressure valve and gas-liquid separation ozone quencher; The raw material preparation vessel and the fluid conveying unit, as well as the ozone generator and the gas conveying control unit, are connected to the microreactor unit via pipelines. The outlet of the microreactor unit is connected in sequence to the back pressure valve and the gas-liquid separation ozone quencher via pipelines, forming a complete continuous reaction system.

[0017] In a preferred embodiment of the present invention, the gas delivery control unit includes a gas flow meter and an ozone booster; the fluid delivery unit includes a high-pressure constant flow feed pump.

[0018] The beneficial effects of this invention are as follows: The method and system for preparing 4-AA pharmaceutical intermediates by continuous flow ozone oxidation, through the use of microreactors and the design of specific reaction temperatures and system back pressures, on the one hand, shortens the reaction time from hours to minutes, significantly improving production efficiency; on the other hand, it raises the reaction temperature from cryogenic to 10-30℃, greatly reducing refrigeration energy consumption and equipment requirements. This invention, through the ultimate mass transfer and precise control of continuous flow technology, fundamentally avoids local over-oxidation, significantly reduces by-products, improves product purity, is suitable for continuous operation, and ensures a controllable, safe, and reliable reaction process. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the structure of a system for preparing 4-AA pharmaceutical intermediates by continuous flow ozone oxidation according to the present invention; The components in the attached diagram are labeled as follows: 1. Ozone generator, 2. Gas flow meter, 3. Ozone booster, 4. Raw material preparation vessel, 5. High-pressure constant flow feed pump, 6. Microreactor, 7. Back pressure valve, 8. Gas-liquid separation ozone quencher, 9. Micro mixer. Detailed Implementation

[0020] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.

[0021] This invention discloses a method for preparing 4-AA pharmaceutical intermediates by continuous flow ozone oxidation, wherein the 4-AA pharmaceutical intermediate is (3R,4R)4-acetoxy-3-[R-(tert-butyldimethoxy)ethyl]-2-azacyclobutanone.

[0022] This invention discloses a high-purity (3R,4R)4-acetoxy-3-[R-(tert-butyldimethoxy)ethyl]-2-azacyclobutanone (HAM70) prepared efficiently and safely via ozone oxidation in a continuous flow microreactor system. This compound is an important precursor for the synthesis of 4-AA (4-acetoxyazacyclobutanone), a key intermediate in the synthesis of carbapenem antibiotics.

[0023] The specific synthesis steps are as follows: A feed solution containing (3R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-methoxyphenyl)-4-oxoazacyclobutane-2-ylacetate is continuously introduced into a microreactor at a feed flow rate of 0.5-6 mL / min and an ozone-containing gas flow rate of 0.5-0.6 L / min, and the reaction is carried out under the following conditions: Reaction temperature: 10-30℃, preferably 15℃; System back pressure: 0.3-0.7 MPa, preferably 0.5 MPa; The mixture after the reaction was reduced and quenched to obtain (3R,4R)4-acetoxy-3-[R-(tert-butyldimethoxy)ethyl]-2-azacyclobutanone.

[0024] Ozone is produced from oxygen or air by an ozone generator, and the concentration of ozone is 35-215 mg / L, preferably 200-215 mg / L.

[0025] By applying a system back pressure of 0.3-0.7 MPa, the solubility of ozone in the solvent can be significantly improved, thereby compensating for the decrease in ozone solubility at reaction temperatures of 15-30℃, and achieving high-temperature, high-efficiency, and peroxidation-free reactions in a continuous flow microreactor system.

[0026] The above reaction is carried out in the following continuous flow reaction system. Specifically, as follows: Figure 1 As shown, the system includes: The raw material preparation vessel 4 and the fluid conveying unit include a high-pressure constant flow feed pump 5; Ozone generator 1 and gas delivery control unit, wherein the gas delivery control unit includes gas flow meter 2 and ozone booster 3; A microchannel reactor unit with mixing capabilities, specifically a micromixer 9 and a microreactor 6; Back pressure valve 7 and gas-liquid separation ozone quencher 8; The material storage tank 4 and the ozone generator 1 are respectively connected to the micro mixer 9 through pipelines. The high-pressure constant flow feed pump 5 is installed on the pipeline between the material storage tank 4 and the micro mixer 9. The gas flow meter 2 and the ozone booster 3 are sequentially installed on the pipeline between the ozone generator 1 and the micro mixer 9. The outlet of the micro mixer 9 is sequentially connected to the microreactor 6, the back pressure valve 7 and the gas-liquid separation ozone quencher 8 through pipelines, forming a complete continuous reaction system.

[0027] The technical solution of the present invention will be described in detail below through specific embodiments.

[0028] Example 1 Weigh 40g of HAM60 and dissolve it in 354g of methanol to obtain a methanol solution of HAM60.

[0029] The resulting methanol solution of HAM60 was pumped into a continuous flow reaction system at a flow rate of 2 mL / min, while ozone-containing oxygen (215 mg / L) was introduced at a rate of 0.6 L / min. The temperature of the continuous flow reaction system was adjusted to 15 °C and the back pressure to 0.5 MPa. Under these conditions, HAM70 was produced. The reaction process is as follows: .

[0030] The material flow time into and out of the microchannel reactor was 7 minutes. The reaction liquid flowing out of the microchannel reactor was quenched with sodium thiosulfate pentahydrate and thiourea, and then extracted and crystallized to obtain HAM70 with a yield of 88.2% and a purity of 99.4%, without the formation of peroxidation products.

[0031] Example 2 All other conditions were exactly the same as in Example 1, except that the ozone source was replaced with air (ozone concentration approximately 100 mg / L). The final yield was 87.4%, the purity was 99.2%, and no peroxidation products were generated, demonstrating that this method has good adaptability and stability to different gas sources.

[0032] Examples 3-8 All other conditions were exactly the same as in Example 1, except that the concentration of ozone was changed. The results are shown in Table 1 below.

[0033] Table 1 As shown in Table 1, ozone concentration is a key parameter for achieving high conversion rates. When the ozone concentration is below 100 mg / L, the reaction of the raw materials is incomplete; when the concentration reaches above 200 mg / L, the residual amount of raw materials is extremely low, and the reaction tends to be complete.

[0034] Examples 9-14 Compared with Example 1, the back pressure and reaction temperature remained unchanged, the ozone concentration was 200 mg / L, and the ratio of HAM60 to ozone was changed to investigate the conversion rate of HAM60. The results are shown in Table 2 below.

[0035] Table 2 The data in Table 2 show that maintaining a high absolute ozone flow rate (e.g., 120 mg / min) and a suitable material ratio is crucial for ensuring a high conversion rate. When the feed flow rate increases while the ozone flow rate remains constant, the conversion rate decreases significantly.

[0036] Comparative Example 1 In a conventional jacketed glass reactor, 40g of HAM60 was dissolved in 354g of methanol, the reactor temperature was lowered to -20°C, and ozone gas of the same concentration was slowly introduced and reacted for 3 hours. The same quenching, extraction, concentration, and cooling crystallization process was then followed. The final yield was 83%. HPLC analysis showed that the product contained more types of impurities than in Example 1, and the content of the main impurities was 1.5 times that of the product in Example 1.

[0037] Comparative Example 2 All other conditions were exactly the same as in Comparative Example 1, except that the reaction temperature was changed from -20℃ to 15℃. After the reaction started, a significant darkening of the mixture's color was quickly observed (indicating over-oxidation), and the reaction system was violently exothermic and difficult to control.

[0038] After the reaction was completed, HPLC analysis showed that the yield of the main product HAM70 was less than 30%, the product purity was less than 70%, and several highly polar impurity peaks that were not detected in Example 1 were observed.

[0039] The system and method described in this invention can achieve excellent results because: First, extreme mass transfer efficiency: Micromixers and microchannel reactors can generate micron-sized bubbles and extremely large specific surface areas, enabling the gas and liquid phases to mix fully within milliseconds. This solves the problem of uneven ozone distribution in batch reactions and avoids localized over-oxidation at its source.

[0040] Second, precise parameter control: Maintaining a high system pressure (0.3-0.7 MPa) through a back pressure regulating valve significantly improves the solubility of ozone in the solution, thereby ensuring the reaction rate. Simultaneously, precise control of residence time ensures that all material molecules experience almost the same reaction time, preventing some molecules from underreacting while others overreact.

[0041] It is the combination of the above two principles that enables this invention to break through and raise the reaction temperature from the -20℃ required by existing technologies to a mild range of 10-30℃, while simultaneously achieving effective suppression of byproducts.

[0042] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or procedural transformations made based on the content of the present invention's specification and drawings, or direct or indirect applications in other related technical fields, are similarly included within the patent protection scope of the present invention.

Claims

1. A method for the continuous flow ozonation preparation of 4-AA pharmaceutical intermediates, characterized in that, The 4-AA pharmaceutical intermediate is (3R, 4R) 4-acetoxy-3-[R- (tert-butyldimethylsiloxy) ethyl]-2-azetidinone; The method steps are: continuously feeding a raw material solution containing (3R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-methoxyphenyl)-4-oxoazetidin-2-yl acetate and a gas containing ozone into a microreactor, and performing the reaction under the following conditions: Reaction temperature: 10-30℃; System back pressure: 0.3-0.7 MPa; After the mixture after the reaction is quenched by reduction, the (3R, 4R) 4-acetoxy-3-[R-(tert-butyldimethylsiloxy) ethyl]-2-azetidinone is obtained.

2. The method of claim 1, wherein, The feed flow rate of the (3R)-3-((R)-1-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-methoxyphenyl)-4-oxoazetidin-2-yl acetate is 0.5-6 mL / min.

3. The method of claim 1, wherein, The flow rate of the gas containing ozone is 0.5-0.6 L / min.

4. The method of claim 1, wherein, The reaction temperature is 15℃.

5. The method of claim 1, wherein, The system back pressure is 0.5 MPa.

6. The method of claim 1, wherein, The concentration of the ozone is 35-215 mg / L.

7. The method of claim 6, wherein, The concentration of the ozone is 200-215 mg / L.

8. The method of any one of claims 1, 6, or 7, wherein, The ozone is prepared by an ozone generator from oxygen or air.

9. A continuous flow reaction system for carrying out the method according to any one of claims 1 to 7, characterized in that Comprise: A raw material preparation kettle and a fluid delivery unit; An ozone generator and a gas delivery control unit; A microreactor unit comprising a mixing function; A back pressure valve and a gas-liquid separation ozone quencher; The raw material preparation kettle and the fluid delivery unit and the ozone generator and the gas delivery control unit are respectively connected to the microreactor unit through pipelines, and the outlet of the microreactor unit is sequentially connected to the back pressure valve and the gas-liquid separation ozone quencher through pipelines, to form a complete continuous reaction system.

10. The system of claim 9, wherein, The gas delivery control unit comprises a gas flow meter and an ozone booster; the fluid delivery unit comprises a high-pressure constant-flow feed pump.

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