Continuous production device and method of penem drug intermediate 4-AA

Abstract

The invention provides a continuous production device and method for a penem drug intermediate 4-AA, and relates to the technical field of heterocyclic compound synthesis. A peracetic acid feeding system and a raw material mixed liquid storage tank of the production device are connected with an inlet of a fixed bed reactor, and a discharge port of the fixed bed reactor is connected with a washing and separating system; a foam metal plate is embedded in the peracetic acid microbubble reactor, and the fixed bed reactor is filled with 4 molecular sieves. According to the invention, safe and large-scale production of anhydrous peracetic acid can be realized, the dosage of a noble metal catalyst can be reduced, the yield of the penem drug intermediate 4-AA can be improved, continuous production of 4-AA can be realized, the operation process is simplified, and the production efficiency and the safety in the production process are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of heterocyclic compound synthesis, and in particular to a continuous production device and method for a penem drug intermediate 4-AA. Background Art

[0002] "Bacterial infection" is currently the most common infectious disease. Every year, about 700,000 people die from bacterial infection worldwide. It has become a major problem that seriously endangers human life and health and restricts social and economic development. Penem drugs are a new type of β-lactam antibacterial drug with the broadest antibacterial spectrum and the strongest antibacterial activity. They are mainly used to treat severe infections and have good antibacterial effects on anaerobic bacteria, Gram-positive bacteria, and Gram-negative bacteria.

[0003] At present, the mainstream industrial synthesis routes of 4-AA, a key intermediate of penem drugs, are mainly divided into the following two types: One route uses the raw material (3R, 4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-1-(4-methoxyphenyl)-2-azetidinone, and ozonolytically deprotects to obtain the 4-AA product. The reaction equation is as follows: .

[0004] However, this process is prone to explosion and has a very high safety risk. The reason is that the reaction temperature is low and the solubility of the raw materials in the solvent methanol is low. In the early stage of the reaction, they are mainly present in the reaction liquid in solid form. Under the combined action of stirring impact and ozone flow, a small amount of solids will remain in the upper part of the reactor and continue to react under solvent-free conditions, causing the temperature of the gas phase space to rise rapidly, increasing the risk of explosion after the mixture of methanol and ozone. At the same time, the friction heat release of mechanical stirring further increases the risk of explosion in the system.

[0005] Another route uses (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone as a raw material, which reacts with peracetic acid in an anhydrous system under the action of a catalyst to obtain 4-AA. The reaction equation is as follows: .

[0006] Although this route has a high reaction yield and produces less waste, peracetic acid, which plays an important role as an oxidant in the preparation process, is easily decomposed by itself, and there are dangers such as explosion and fire. Low temperature will inhibit the decomposition rate of peracetic acid, and the synthesis of peracetic acid using acetaldehyde and oxygen as raw materials requires a certain temperature to react. Therefore, the synthesis of peracetic acid and the self-decomposition reaction of peracetic acid become a pair of competitive reactions. Only by accelerating the reaction rate, shortening the reaction time, and rapidly cooling the peracetic acid generated by the reaction in a very short time can the self-decomposition of peracetic acid be effectively avoided to obtain a certain concentration of peracetic acid organic solvent solution. Because there is no industrial equipment that can meet the above conditions, the preparation of peracetic acid is currently mostly laboratory small batch level, and cannot be mass-produced to meet industrial needs, thereby limiting the industrial application of this method. In addition, when the method uses the precious metal ruthenium trichloride as a catalyst, the dosage is as high as 2% (mass multiple, based on the substrate), resulting in high manufacturing costs. Therefore, how to achieve safe large-scale production of anhydrous peracetic acid and how to reduce the dosage of precious metal catalysts have become key issues for the large-scale application of this route. Summary of the invention

[0007] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a continuous production device and method for a penicillin drug intermediate 4-AA, which can realize safe large-scale production of anhydrous peracetic acid, reduce the amount of precious metal catalyst used, and improve the yield.

[0008] The technical solution adopted by the present invention to solve the technical problem is: the continuous production device of the penem-type drug intermediate 4-AA comprises a raw material mixed liquid storage tank, a fixed bed reactor, a peracetic acid feeding system and a washing and separation system, the peracetic acid feeding system and the raw material mixed liquid storage tank are connected to the inlet of the fixed bed reactor, and the discharge port of the fixed bed reactor is connected to the washing and separation system; The peracetic acid feeding system comprises an oxygen storage tank, an acetaldehyde mixed solution storage tank, a peracetic acid microbubble reactor, a first condenser, a back pressure valve and a peracetic acid temporary storage tank, wherein the oxygen storage tank is connected to the bottom of the peracetic acid microbubble reactor through a gas pipeline, the acetaldehyde mixed solution storage tank is connected to the bottom of the peracetic acid microbubble reactor through a first metering pump, the discharge port above the peracetic acid microbubble reactor is connected to the first condenser, the back pressure valve and the inlet of the peracetic acid temporary storage tank in sequence; and the bottom of the peracetic acid temporary storage tank is connected to the inlet of the fixed bed reactor through a discharge pipeline via a third metering pump.

[0009] Preferably, in the above-mentioned continuous production device, the peracetic acid microbubble reactor is embedded with 2 to 5 layers of foam metal plates, which function to disperse oxygen into small bubbles of about 1 mm, increase the gas-liquid contact area, and enhance the mass transfer and heat transfer effects.

[0010] Preferably, in the above-mentioned continuous production device, the fixed bed reactor is filled with 4Å molecular sieve to adsorb water produced by the reaction.

[0011] Preferably, in the above-mentioned continuous production device, the bottom of the raw material mixed liquid storage tank is connected to the inlet of the fixed bed reactor through a second metering pump. The raw material mixed liquid in the raw material mixed liquid storage tank is composed of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate, and catalyst ruthenium trichloride.

[0012] Preferably, in the above-mentioned continuous production device, the washing and separation system includes a scraped film evaporator, a first washing tank, a second washing tank, a first centrifuge, a second centrifuge, and a single cone dryer. The upper feed port of the scraped film evaporator is connected to the discharge port of the fixed bed reactor, and the lower discharge port of the scraped film evaporator is respectively connected to the first washing tank and the second washing tank, the first washing tank is connected to the first centrifuge, the second washing tank is connected to the second centrifuge, and the first centrifuge and the second centrifuge are connected in parallel to the single cone dryer.

[0013] Preferably, in the above-mentioned continuous production device, the top of the scraped film evaporator is connected to an ethyl acetate recovery device through a second condenser to achieve solvent recovery.

[0014] Preferably, in the above-mentioned continuous production device, the peracetic acid microbubble reactor is embedded with a foam metal plate. The advantage of this structure is that the liquid becomes a liquid film after being dispersed inside the reactor, and the gas is dispersed into microbubbles with a diameter of about 1 mm. The liquid and gas are fully mixed inside the reactor, which enhances the gas-liquid heat and mass transfer effect, accelerates the reaction speed, and shortens the reaction time; because microbubbles are easy to gather to form large bubbles, the present invention sets the foam metal plate to 2 to 5 layers, which can disperse the large bubbles formed by the aggregation into microbubbles again, ensuring the heat and mass transfer efficiency in the system and improving the stability of the reaction. The peracetic acid solution flowing out of the peracetic acid microbubble reactor is immediately cooled to below -15°C through the first condenser, effectively avoiding the decomposition of peracetic acid.

[0015] Preferably, in the above-mentioned continuous production device, the fixed bed reactor is filled with 4Å molecular sieves to adsorb water generated by the reaction. During the reaction of the cyclocompound (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone in the raw material mixture with peracetic acid, a molecule of water is produced. The present invention has found that water can cause the catalyst ruthenium trichloride to be deactivated. During the reaction, the water generated by the reaction is adsorbed by the 4Å molecular sieve, which can effectively avoid the deactivation of the catalyst, thereby reducing the amount of catalyst used and reducing the manufacturing cost.

[0016] A continuous production method of the penem drug intermediate 4-AA using the above-mentioned continuous production device comprises the following steps: 1) The acetaldehyde mixed solution in the acetaldehyde mixed solution storage tank and the oxygen in the oxygen storage tank are continuously introduced into the peracetic acid microbubble reactor for reaction to generate peracetic acid, and the peracetic acid is cooled by the first condenser and then enters the peracetic acid temporary storage tank; 2) The raw material mixed liquid in the raw material mixed liquid storage tank and the peracetic acid in the peracetic acid temporary storage tank are introduced into a fixed bed reactor for reaction, and the materials after the reaction are evaporated by a scraped film evaporator, and the obtained concentrated liquid is dissolved, washed, centrifuged, and dried in a single cone dryer to obtain a penem drug intermediate 4-AA.

[0017] Preferably, in step 1) of the above continuous production method, the acetaldehyde mixed solution is an ethyl acetate solution of acetaldehyde and ferric acetylacetonate, wherein the concentration of acetaldehyde is 15wt%~25wt%, preferably 17wt%; the concentration of ferric acetylacetonate is 0.01‰~0.06‰ of the concentration of acetaldehyde; ferric acetylacetonate is a catalyst; The feed rate of the acetaldehyde mixed solution is 2.0 kg / min to 2.5 kg / min, the feed rate of oxygen is 200 L / min to 250 L / min, preferably 230 L / min to 240 L / min; the molar ratio of oxygen to acetaldehyde is 1.1 to 1.4:1.

[0018] Preferably, in step 1) of the above-mentioned continuous production method, the residence time of the reaction in the peracetic acid microbubble reactor is 4 min to 5 min, the pressure is 0.6 MPa to 1.0 MPa, and the temperature is 45°C to 50°C; the peracetic acid is cooled to ≤-15°C through the first condenser, and the temperature in the peracetic acid temporary storage tank is maintained at ≤-15°C.

[0019] Preferably, in step 1) of the above-mentioned continuous production method, the concentration of peracetic acid generated by the reaction is 18wt%~22wt%.

[0020] Preferably, in step 2) of the above-mentioned continuous production method, the raw material mixture is composed of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate, and ruthenium trichloride, wherein the mass ratio of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate, and ruthenium trichloride is 1:4.5~6.0:2.0~3.0:0.2~0.3:0.0005~0.001; ruthenium trichloride is a catalyst; and the storage temperature of the raw material mixture in the raw material mixture storage tank is -5°C~0°C.

[0021] Preferably, in step 2) of the above-mentioned continuous production method, the feed rate of the raw material mixture is 2.5kg / min~3.0kg / min, the feed rate of peracetic acid is 2.2kg / min~2.6kg / min, and the residence time of the reaction in the fixed bed reactor is 5min~8min, the pressure is 0.5MPa~1.0MPa, and the temperature is -10℃~0℃.

[0022] Preferably, in step 2) of the above-mentioned continuous production method, the temperature of the wiped film evaporator is controlled at 45°C-65°C, the vacuum degree is ≥0.08MPa, and the drying temperature is 50°C-60°C.

[0023] The concentrated liquid obtained by the scraped film evaporator enters the first washing kettle or the second washing kettle, is dissolved with n-heptane, washed with pure water, then cooled to 0°C~5°C for crystallization, and then enters the first centrifuge or the second centrifuge for centrifugation; the dissolution temperature and washing temperature are both 40°C~60°C.

[0024] Step 2) is specifically as follows: the raw material mixed liquid in the raw material mixed liquid storage tank and the peracetic acid in the peracetic acid temporary storage tank are introduced into a fixed bed reactor to react, the reacted material is evaporated by a scraped film evaporator to evaporate the solvent, the solvent is condensed by a second condenser and then enters an ethyl acetate recovery device; the first batch of materials (concentrated liquid) after evaporation enters a first washing kettle, and after being dissolved, washed, cooled and crystallized, enters a first centrifuge for centrifugation, the second batch of materials (concentrated liquid) after evaporation enters a second washing kettle, and after being dissolved, washed, cooled and crystallized, enters a second centrifuge for centrifugation, the two batches of centrifuged materials are combined and dried in a single cone dryer to obtain a penem drug intermediate 4-AA.

[0025] Reaction equation of the present invention is as follows: Step 1): ; Step 2): .

[0026] In step 2), (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone (cyclic complex) is reacted with peracetic acid in the presence of a catalyst to introduce an acetoxy group at the 4-position to obtain the penicillin drug intermediate 4-AA product.

[0027] Compared with the prior art, the present invention has the following beneficial effects: (1) The peracetic acid microbubble reactor of the present invention is embedded with a foam metal plate. Under the action of the foam metal plate, the liquid inside the reactor is dispersed into a liquid film, and the gas is dispersed into microbubbles with a diameter of about 1 mm. The liquid and gas are fully mixed inside the reactor, which enhances the gas-liquid heat and mass transfer effect, accelerates the reaction speed, and shortens the reaction time. Since microbubbles are easy to aggregate to form large bubbles, the present invention sets the foam metal plate to 2 to 5 layers, which can disperse the large bubbles formed by aggregation into microbubbles again, ensuring the heat and mass transfer efficiency in the system and improving the stability of the reaction. The peracetic acid solution flowing out of the peracetic acid microbubble reactor is immediately cooled to below -15°C through the first condenser, effectively avoiding the decomposition of peracetic acid, thereby breaking through the problem of easy explosion in intermittent large-scale production, and realizing efficient, safe and large-scale production of anhydrous peracetic acid.

[0028] (2) The fixed bed reactor described in the present invention is a continuous reactor with high mass and heat transfer efficiency. In the process of preparing 4-AA with peracetic acid, the reaction rate is faster than that of a conventional intermittent reactor, making the utilization efficiency of peracetic acid higher and the corresponding usage less. The amount of material actually involved in the reaction per unit time is greatly reduced compared with the kettle production method, thereby greatly reducing the production safety risk. In addition, the continuous reaction greatly shortens the contact time between the product and the oxidant peracetic acid, effectively avoiding excessive oxidation and decomposition of the product and improving the reaction yield.

[0029] The present invention also discovered the factors that lead to the deactivation of the noble metal catalyst ruthenium trichloride. By filling a 4Å molecular sieve inside a fixed bed reactor to remove moisture generated during the reaction, the deactivation of the catalyst was effectively avoided and the amount of catalyst used was reduced.

[0030] (3) The continuous production method of the penem drug intermediate 4-AA described in the present invention first continuously prepares peracetic acid through a microbubble reactor, which greatly improves the safety of production and realizes the large-scale production of peracetic acid. Then, the prepared peracetic acid and the raw material mixture are passed through a fixed bed reactor to generate the penem drug intermediate 4-AA, and then the solvent is recovered by scraping evaporation. Finally, the final product 4-AA is obtained by washing, centrifugation and drying. This method realizes the continuous production of 4-AA through continuous equipment configuration and operation, simplifies the operation process, and improves production efficiency and safety during the production process.

[0031] In summary, the continuous production device and production method of the present invention can realize the safe large-scale production of anhydrous peracetic acid, and can reduce the amount of precious metal catalysts, thereby increasing the yield of penem drug intermediate 4-AA. It is completed in a fully closed system, greatly reducing VOC emissions, and is environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a structural schematic diagram of the production device of the present invention; Figure 2 It is a schematic structural diagram of the peracetic acid microbubble reactor of the present invention; Figure 3 A top view of the foam metal plate of the present invention; Figure 4 This is the HPLC spectrum of the penem drug intermediate 4-AA product in Example 1 of the present invention; Figure 5 This is the HPLC spectrum of the penem drug intermediate 4-AA product in Example 6 of the present invention; Figure 6 This is the HPLC spectrum of the penem drug intermediate 4-AA product in Comparative Example 2 of the present invention; In the figure: 1. oxygen storage tank; 2. acetaldehyde mixed solution storage tank; 3. peracetic acid microbubble reactor; 4. first condenser; 5. back pressure valve; 6. peracetic acid temporary storage tank; 7. raw material mixed solution storage tank; 8. fixed bed reactor; 9. scraped film evaporator; 10. second condenser; 11. first washing kettle; 12. second washing kettle; 13. first centrifuge; 14. second centrifuge; 15. single cone dryer; 16. ethyl acetate recovery device; 17. first metering pump; 18. second metering pump; 19. third metering pump; 20. foam metal plate; 21. heat exchange tube. DETAILED DESCRIPTION

[0033] The present invention is described in detail below by way of examples. Unless otherwise specified, all raw materials used are commercially available.

[0034] Example 1 like Figures 1 to 3 As shown, the continuous production device of the penem-type drug intermediate 4-AA of the present invention comprises a raw material mixed liquid storage tank 7, a fixed bed reactor 8, a peracetic acid feeding system and a washing and separation system, the peracetic acid feeding system and the raw material mixed liquid storage tank 7 are both connected to the inlet of the fixed bed reactor 8, and the discharge port of the fixed bed reactor 8 is connected to the washing and separation system for subsequent treatment of the materials after the reaction; The peracetic acid feeding system comprises an oxygen storage tank 1, an acetaldehyde mixed solution storage tank 2, a peracetic acid microbubble reactor 3, a first condenser 4, a back pressure valve 5 and a peracetic acid temporary storage tank 6, wherein the oxygen storage tank 1 is connected to the bottom of the peracetic acid microbubble reactor 3 through a gas pipeline, the acetaldehyde mixed solution storage tank 2 is connected to the bottom of the peracetic acid microbubble reactor 3 through a first metering pump 17, the discharge port above the peracetic acid microbubble reactor 3 is connected to the first condenser 4, the back pressure valve 5 and the entrance of the peracetic acid temporary storage tank 6 in sequence, and is used for temporarily storing the peracetic acid generated by the reaction; the bottom of the peracetic acid temporary storage tank 6 is connected to the entrance of the fixed bed reactor 8 through a discharge pipeline via a third metering pump 19, and the peracetic acid can be continuously pumped into the fixed bed reactor 8 through the third metering pump 19 to realize continuous production.

[0035] The peracetic acid microbubble reactor 3 is embedded with 4 layers of foam metal plates 20, which are used to disperse oxygen into small bubbles of about 1 mm, increase the gas-liquid contact area, and enhance the mass transfer and heat transfer effects. The heat exchange pipe 21 arranged in the peracetic acid microbubble reactor 3 is connected to the foam metal plates 20.

[0036] The fixed bed reactor 8 is filled with 4Å molecular sieve to adsorb water produced by the reaction.

[0037] The bottom of the raw material mixed liquid storage tank 7 is connected to the inlet of the fixed bed reactor 8 through the second metering pump 18, and the raw material mixed liquid can be continuously pumped into the fixed bed reactor 8 through the second metering pump 18 to achieve continuous production. The raw material mixed liquid in the raw material mixed liquid storage tank 7 is composed of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate, and catalyst ruthenium trichloride.

[0038] The washing and separation system includes a scraped film evaporator 9, a first washing tank 11, a second washing tank 12, a first centrifuge 13, a second centrifuge 14, and a single cone dryer 15. The upper feed port of the scraped film evaporator 9 is connected to the discharge port of the fixed bed reactor 8, and the lower discharge port of the scraped film evaporator 9 is connected to the first washing tank 11 and the second washing tank 12 respectively. The first washing tank 11 is connected to the first centrifuge 13, and the second washing tank 12 is connected to the second centrifuge 14. Two independent washing centrifuge systems take turns to wash and separate materials to realize continuous production; the first centrifuge 13 and the second centrifuge 14 are connected in parallel to the single cone dryer 15.

[0039] The top of the wiped film evaporator 9 is connected to an ethyl acetate recovery device 16 through a second condenser 10 for recovering the solvent.

[0040] The production method using a continuous production device for the penem drug intermediate 4-AA comprises the following steps: 1) Add 340 kg of acetaldehyde, 1660 kg of ethyl acetate and 20 g of ferric acetylacetonate as a catalyst to an anhydrous and dried acetaldehyde mixed solution storage tank 2, and mix them evenly to obtain an acetaldehyde mixed solution. The acetaldehyde mixed solution in the acetaldehyde mixed solution storage tank 2 and the oxygen in the oxygen storage tank 1 are continuously introduced into the peracetic acid microbubble reactor 3 to react and generate peracetic acid, which is cooled to ≤-15°C by the first condenser 4 and enters the peracetic acid temporary storage tank 6 through a pipeline for temporary storage.

[0041] Wherein: the feed rate of the acetaldehyde mixed solution is 2.3 kg / min, the feed rate of oxygen is 230 L / min, and the molar ratio of oxygen to acetaldehyde is maintained at 1.16:1.

[0042] In the peracetic acid microbubble reactor 3, the residence time of the material reaction is 4.5 min, the pressure is 0.7-0.8 MPa, and the temperature is 46-48° C.; the temperature in the peracetic acid temporary storage tank 6 is maintained at ≤-15° C., and the concentration of peracetic acid generated by the reaction is detected to be 19 wt.%.

[0043] 2) Preparation of the raw material mixture: Mix 150 kg (1w) of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone (cyclocomplex), 675 kg (4.5w) of ethyl acetate, 300 kg (2w) of glacial acetic acid, 30 kg (0.2w) of potassium acetate and 75 g (0.5‰w) of ruthenium trichloride, and store them at 0°C in the raw material mixture storage tank 7.

[0044] The raw material mixed liquid in the raw material mixed liquid storage tank 7 and the peracetic acid in the peracetic acid temporary storage tank 6 are continuously introduced into the fixed bed reactor 8 for reaction. The feed rates of the raw material mixed liquid and the peracetic acid are respectively controlled by the second metering pump 18 and the third metering pump 19. The feed rate of the raw material mixed liquid is 3.0 kg / min, and the feed rate of the peracetic acid is 2.5 kg / min. In the fixed bed reactor 8, the residence time of the material reaction is 7.2 min, and the pressure is 0.9~1.0 MPa; ice brine is used as a cooling medium to maintain the temperature in the fixed bed reactor 8 at -7~-3°C.

[0045] 3) The material generated by the reaction in the fixed bed reactor 8 is transported to the scraped film evaporator 9 through a pipeline, and evaporated under reduced pressure at 45-50° C. and a vacuum degree of 0.09 MPa. The ethyl acetate solvent evaporated above the scraped film evaporator 9 is condensed by the second condenser 10 and enters the ethyl acetate recovery device 16 for recycling. The concentrated liquid below the scraped film evaporator 9 enters the subsequent treatment process through a pipeline.

[0046] The evaporated material (concentrated liquid) enters the first washing tank 11, and the temperature of the first washing tank 11 is controlled to be 55° C. using hot water as a medium. After being dissolved in n-heptane and washed with pure water, the temperature is cooled to 0-5° C. for crystallization, and then enters the first centrifuge 13 for centrifugation. The centrifuged material enters the single cone dryer 15 and is dried at 55° C. to obtain 3.5 kg of penicillin drug intermediate 4-AA17.

[0047] The obtained penem drug intermediate 4-AA was subjected to HPLC chromatography analysis. The molar yield of the penem drug intermediate 4-AA was 92.0% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity was 99.70%. The HPLC spectrum is shown in Figure 4 .

[0048] Embodiment 2~5 The continuous production device of penem-based drug intermediate 4-AA is the same as that in Example 1.

[0049] In the continuous production method of penem drug intermediate 4-AA, the feed rate of acetaldehyde mixed solution, the feed rate of oxygen, and the oxygen / acetaldehyde molar ratio in step 1) were changed, and the remaining steps and reaction conditions were the same as those in Example 1. The yield and purity of the obtained penem drug intermediate 4-AA are shown in Table 1.

[0050] Table 1 Yield and purity data of penem drug intermediate 4-AA in Examples 2 to 5 .

[0051] Embodiments 6 to 11 The continuous production device of penem-based drug intermediate 4-AA is the same as that in Example 1.

[0052] In the continuous production method of penem-type drug intermediate 4-AA, the residence time, pressure and temperature of the material reaction in the peracetic acid microbubble reactor 3 in step 1) are changed, and the remaining steps and reaction conditions are the same as those in Example 1. The specific data are shown in Table 2. The yield and purity of the obtained penem-type drug intermediate 4-AA are shown in Table 2. The HPLC spectrum of the penem-type drug intermediate 4-AA in Example 6 is shown in Figure 5 .

[0053] Table 2 Yield and purity data of penem drug intermediate 4-AA in Examples 6 to 11 .

[0054] Embodiment 12-15 The continuous production device of penem-based drug intermediate 4-AA is the same as that in Example 1.

[0055] In the continuous production method of penem-type drug intermediate 4-AA, the amount of each substance in the raw material mixture in step 2) is changed, and the remaining steps and reaction conditions are the same as in Example 1, and the specific data are shown in Table 3. The yield and purity of the obtained penem-type drug intermediate 4-AA are shown in Table 3.

[0056] Table 3 Yield and purity data of penem drug intermediate 4-AA in Examples 12 to 15 .

[0057] Embodiments 16 to 21 The continuous production device of penem-based drug intermediate 4-AA is the same as that in Example 1.

[0058] In the continuous production method of penem-type drug intermediate 4-AA, the residence time, pressure and temperature of the fixed bed reactor 8 in the fixed bed reactor 8 in step 2) are changed, and the remaining steps and reaction conditions are the same as those in Example 1. The specific data are shown in Table 4. The yield and purity of the obtained penem-type drug intermediate 4-AA are shown in Table 4.

[0059] Table 4 Yield and purity data of penem drug intermediate 4-AA in Examples 16 to 21 .

[0060] Embodiments 22 to 26 The continuous production device of penem-based drug intermediate 4-AA is the same as that in Example 1.

[0061] In the continuous production method of penem-type drug intermediate 4-AA, the feed rate of the raw material mixture and the feed rate of peracetic acid in step 2) are changed, and the remaining steps and reaction conditions are the same as those in Example 1. The specific data are shown in Table 5. The yield and purity of the obtained penem-type drug intermediate 4-AA are shown in Table 5.

[0062] Table 5 Yield and purity data of penem drug intermediate 4-AA in Examples 22 to 26 .

[0063] Comparative Example 1 The foam metal plate 20 is not embedded in the peracetic acid microbubble reactor 3, and the remaining production devices and production methods are the same as those in Example 1. The concentration of peracetic acid generated by the reaction is 12.0wt%, and 154.8kg of penem drug intermediate 4-AA is obtained. The molar yield of penem drug intermediate 4-AA is 80.2% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity is 97.36%.

[0064] By comparing Example 1 with Comparative Example 1, it can be seen that the foam metal plate 20 is not embedded in the peracetic acid microbubble reactor 3 of Comparative Example 1, the liquid and gas are not mixed evenly, the gas-liquid heat and mass transfer effect is poor, the generation rate of peracetic acid is low, and the concentration of peracetic acid is also reduced, thereby reducing the molar yield of the penem drug intermediate 4-AA.

[0065] Comparative Example 2 The fixed bed reactor 8 was not filled with 4Å molecular sieves, and the remaining production equipment and production methods were the same as in Example 1, to obtain 146.0 kg of penem drug intermediate 4-AA. The molar yield of penem drug intermediate 4-AA was 76.1% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity was 97.99%. The HPLC spectrum is shown in Figure 6 .

[0066] By comparing Example 1 with Comparative Example 2, it can be seen that in Comparative Example 2, the fixed bed reactor 8 is not filled with 4Å molecular sieve, and the water generated by the reaction cannot be removed in time, resulting in the deactivation of the catalyst ruthenium trichloride, reducing the catalytic efficiency, and thus resulting in a decrease in the molar yield of the penem drug intermediate 4-AA.

[0067] Comparative Example 3 The intermittent method is used to prepare the southern drug intermediate 4-AA, and the specific steps are as follows: Under nitrogen protection, 848 g of 19 wt.% peracetic acid obtained in Example 1 and 1156 g of a raw material mixture (same configuration as in Example 1) were added to a reaction vessel, the system temperature was maintained at -5 to -3 ° C for 1 hour, saturated NaHSO3 aqueous solution was added for quenching, and the reaction system was directly concentrated at 45 ° C. The reaction solution was filtered, the filter cake was washed, and dried at 50 ° C for 7 hours to obtain 153.4 g of a penicillin drug intermediate 4-AA, with a molar yield of 79.4% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity was 97.38%.

[0068] By comparing Example 1 with Comparative Example 3, it can be seen that the yield of the southern drug intermediate 4-AA prepared by the intermittent method in Comparative Example 3 is significantly reduced.

[0069] The above is only a preferred embodiment of the present invention, and does not limit the present invention in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still belongs to the protection scope of the technical solution of the present invention.

Claims

1. A continuous production device for penem-based drug intermediate 4-AA, characterized in that: It comprises a raw material mixed liquid storage tank (7), a fixed bed reactor (8), a peracetic acid feeding system and a washing and separation system, wherein the peracetic acid feeding system and the raw material mixed liquid storage tank (7) are connected to an inlet of the fixed bed reactor (8), and the discharge port of the fixed bed reactor (8) is connected to the washing and separation system; The peracetic acid feeding system comprises an oxygen storage tank (1), an acetaldehyde mixed solution storage tank (2), a peracetic acid microbubble reactor (3), a first condenser (4), a back pressure valve (5) and a peracetic acid temporary storage tank (6); the oxygen storage tank (1) is connected to the bottom of the peracetic acid microbubble reactor (3) through a gas pipeline; the acetaldehyde mixed solution storage tank (2) is connected to the bottom of the peracetic acid microbubble reactor (3) through a first metering pump (17); the discharge port above the peracetic acid microbubble reactor (3) is connected to the first condenser (4), the back pressure valve (5) and the inlet of the peracetic acid temporary storage tank (6) in sequence; and the bottom of the peracetic acid temporary storage tank (6) is connected to the inlet of the fixed bed reactor (8) through a discharge pipeline via a third metering pump (19).

2. The continuous production device of penem drug intermediate 4-AA according to claim 1, characterized in that: The peracetic acid microbubble reactor (3) is embedded with 2 to 5 layers of foam metal plates (20), and the fixed bed reactor (8) is filled with 4Å molecular sieve; the bottom of the raw material mixed liquid storage tank (7) is connected to the inlet of the fixed bed reactor (8) via a second metering pump (18).

3. The continuous production device of penem drug intermediate 4-AA according to claim 1, characterized in that: The washing and separation system comprises a scraped film evaporator (9), a first washing tank (11), a second washing tank (12), a first centrifuge (13), a second centrifuge (14) and a single cone dryer (15); the upper feed port of the scraped film evaporator (9) is connected to the discharge port of the fixed bed reactor (8); the lower discharge port of the scraped film evaporator (9) is connected to the first washing tank (11) and the second washing tank (12), respectively; the first washing tank (11) is connected to the first centrifuge (13); the second washing tank (12) is connected to the second centrifuge (14); the first centrifuge (13) and the second centrifuge (14) are connected in parallel to the single cone dryer (15); and the top of the scraped film evaporator (9) is connected to an ethyl acetate recovery device (16) via a second condenser (10).

4. A continuous production method of penem drug intermediate 4-AA using the device according to any one of claims 1 to 3, characterized in that The following steps are involved: 1) The acetaldehyde mixed solution in the acetaldehyde mixed solution storage tank (2) and the oxygen in the oxygen storage tank (1) are continuously introduced into the peracetic acid microbubble reactor (3) for reaction to generate peracetic acid, and the peracetic acid is cooled by the first condenser (4) and then enters the peracetic acid temporary storage tank (6); 2) The raw material mixed liquid in the raw material mixed liquid storage tank (7) and the peracetic acid in the peracetic acid temporary storage tank (6) are introduced into a fixed bed reactor (8) for reaction. The materials after the reaction are evaporated by a scraped film evaporator (9). The obtained concentrated liquid is dissolved, washed, centrifuged, and then dried in a single cone dryer (15) to obtain a penicillin drug intermediate 4-AA.

5. The continuous production method of penem drug intermediate 4-AA according to claim 4, characterized in that: The acetaldehyde mixed solution described in step 1) is an ethyl acetate solution of acetaldehyde and ferric acetylacetonate, wherein the concentration of acetaldehyde is 15wt%~25wt%, and the concentration of ferric acetylacetonate is 0.01‰~0.06‰ of the concentration of acetaldehyde; The feed rate of the acetaldehyde mixed solution is 2.0kg / min~2.5kg / min, the feed rate of oxygen is 200 L / min~250L / min, and the molar ratio of oxygen / acetaldehyde is 1.1~1.4:

1.

6. The continuous production method of penem drug intermediate 4-AA according to claim 4, characterized in that: In the peracetic acid microbubble reactor (3) described in step 1), the reaction residence time is 4 min to 5 min, the pressure is 0.6 MPa to 1.0 MPa, and the temperature is 45° C. to 50° C.; the peracetic acid is cooled to ≤-15° C. via the first condenser (4).

7. The continuous production method of penem drug intermediate 4-AA according to claim 4, characterized in that: The raw material mixture described in step 2) is composed of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate and ruthenium trichloride, wherein the mass ratio of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate and ruthenium trichloride is 1:4.5~6.0:2.0~3.0:0.2~0.3:0.0005~0.

001.

8. The continuous production method of penem drug intermediate 4-AA according to claim 4, characterized in that: The feed rate of the raw material mixture in step 2) is 2.5 kg / min to 3.0 kg / min, and the feed rate of peracetic acid is 2.2 kg / min to 2.6 kg / min; the residence time of the reaction in the fixed bed reactor (8) is 5 min to 8 min, the pressure is 0.5 MPa to 1.0 MPa, and the temperature is -10°C to 0°C.

9. The continuous production method of penem drug intermediate 4-AA according to claim 4, characterized in that: The temperature of the wiped film evaporator (9) in step 2) is controlled at 45°C to 65°C and the vacuum degree is ≥ 0.08 MPa.

10. The continuous production method of penem drug intermediate 4-AA according to claim 4, characterized in that: The concentrated liquid obtained by the scraped film evaporator (9) enters the first washing kettle (11) or the second washing kettle (12), is dissolved with n-heptane, washed with pure water, then cooled to 0°C to 5°C for crystallization, and then enters the first centrifuge (13) or the second centrifuge (14) for centrifugation; the dissolution temperature and the washing temperature are both 40°C to 60°C.

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