Continuous production device and method for 4-AA, an intermediate of penem drugs

Abstract

The present invention provides a continuous production device and method for the intermediate 4-AA of penem drugs, which relates to the technical field of the synthesis of heterocyclic compounds. The peracetic acid feeding system and the raw material mixture storage tank of the production device are connected to the inlet of the fixed-bed reactor, and the outlet of the fixed-bed reactor is connected to the washing and separation system; the peracetic acid microbubble reactor is embedded with a foam metal plate, and the inside of the fixed-bed reactor is filled with 4Å molecular sieve. The present invention can realize the safe large-scale production of anhydrous peracetic acid, reduce the dosage of precious metal catalysts, improve the yield of the intermediate 4-AA of penem drugs, realize the continuous production of 4-AA at the same time, simplify the operation process, and improve the production efficiency and safety during the production process.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of heterocyclic compounds, and particularly relates to a continuous production device and method for 4-AA, an intermediate of penem drugs. Background Art

[0002] "Bacterial infection" is currently one of the most common infectious diseases, and has become a major problem seriously endangering human life and health and restricting 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 at present, and are mainly used for the treatment of 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 the key intermediate 4-AA of penem drugs are mainly divided into the following two types:

[0004] One route uses the raw material (3R,4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-1-(4-methoxyphenyl)-2-azetidinone, and obtains the 4-AA product through ozonation deprotection. The reaction equation is as follows: .

[0005] However, this process is prone to explosion and has extremely high safety risks. The reason is that the reaction temperature is low, and the solubility of the raw materials in the solvent methanol is small. In the early stage of the reaction, they mainly exist in the reaction solution in solid form. Under the combined action of stirring impact and ozone gas flow, a small amount of solids will stay in the upper part of the reactor and continue to react under solvent-free conditions, resulting in a rapid increase in the temperature of the gas phase space, increasing the risk of explosion after the mixing of methanol and ozone. At the same time, the frictional heat generation of mechanical stirring further increases the risk of explosion of the system.

[0006] Another route uses the raw material (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, and reacts with peracetic acid under the action of a catalyst in an anhydrous system to obtain 4-AA. The reaction equation is as follows:

[0007] .

[0008] Although this route has a high reaction yield and produces less waste, peracetic acid, which plays an important role as an oxidant during the preparation process, is very prone to decomposition itself, presenting risks such as explosion and fire. Low temperature will inhibit the decomposition rate of peracetic acid, while synthesizing peracetic acid from acetaldehyde and oxygen requires a certain temperature for the reaction to occur. Therefore, the synthesis of peracetic acid and the self-decomposition reaction of peracetic acid become a pair of competing reactions. Only by accelerating the reaction rate, shortening the reaction time, and rapidly cooling the generated peracetic acid within an extremely short time can the self-decomposition of peracetic acid be effectively avoided, and an organic solvent solution of peracetic acid with a certain concentration be obtained. Due to the lack of industrial equipment that can meet the above conditions, the preparation of peracetic acid is mostly at the small-batch level in the laboratory at present, and it cannot be mass-produced to meet industrial demands, thus restricting the industrial application of this method. In addition, when using precious metal ruthenium trichloride as a catalyst in this method, the dosage is as high as 2% (mass multiple, based on the substrate), resulting in high manufacturing costs. Therefore, how to achieve the safe large-scale production of anhydrous peracetic acid and how to reduce the dosage of precious metal catalysts have become the key issues for the large-scale application of this route. Summary of the Invention

[0009] 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 the penem intermediate 4-AA that can achieve the safe large-scale production of anhydrous peracetic acid, reduce the dosage of precious metal catalysts, and improve the yield.

[0010] The technical solution adopted by the present invention to solve its technical problems is: the continuous production device for the penem intermediate 4-AA includes a raw material mixture 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 mixture storage tank are connected to the inlet of the fixed-bed reactor, and the outlet of the fixed-bed reactor is connected to the washing and separation system;

[0011] The peracetic acid feeding system includes 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. 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, and the upper outlet of the peracetic acid microbubble reactor is sequentially connected to the first condenser, the back pressure valve, and the inlet of the peracetic acid temporary storage tank; 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.

[0012] Preferably, in the above continuous production device, the peracetic acid microbubble reactor is embedded with 2 - 5 layers of foam metal plates, whose function is to disperse oxygen into small bubbles about 1 mm in size, increase the gas-liquid contact area, and enhance the mass transfer and heat transfer effects.

[0013] Preferably, in the above continuous production device, the fixed bed reactor is filled with 4Å molecular sieve to adsorb the water generated during the reaction.

[0014] Preferably, in the above 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 the catalyst ruthenium trichloride.

[0015] Preferably, in the above continuous production device, the washing and separation system includes a wiped film evaporator, a first washing kettle, a second washing kettle, a first centrifuge, a second centrifuge, and a single cone dryer. The upper feed port of the wiped film evaporator is connected to the discharge port of the fixed bed reactor, and the lower discharge port of the wiped film evaporator is respectively connected to the first washing kettle and the second washing kettle. The first washing kettle is connected to the first centrifuge, the second washing kettle is connected to the second centrifuge, and the first centrifuge and the second centrifuge are connected in parallel to the single cone dryer.

[0016] Preferably, in the above continuous production device, the top of the wiped film evaporator is connected to an ethyl acetate recovery device through a second condenser for solvent recovery.

[0017] Preferably, in the above 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, enhancing the gas-liquid heat and mass transfer effect, accelerating the reaction rate, and shortening the reaction time. Since microbubbles are easily aggregated to form large bubbles, in the present invention, the foam metal plate is set to 2 to 5 layers, which can disperse the aggregated large bubbles into microbubbles again, ensuring the heat and mass transfer efficiency in the system and improving the reaction stability. The peracetic acid solution flowing out of the peracetic acid microbubble reactor is immediately cooled to below -15°C through a first condenser, effectively avoiding the decomposition of peracetic acid.

[0018] Preferably, in the above continuous production device, the fixed bed reactor is filled with 4Å molecular sieve to adsorb the water generated during the reaction. During the reaction of the cyclic compound (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone in the raw material mixed liquid with peracetic acid, one molecule of water will be generated. The present invention has found that water can cause the inactivation of the catalyst ruthenium trichloride. By adsorbing the water generated during the reaction through 4Å molecular sieve during the reaction process, the inactivation of the catalyst can be effectively avoided, thereby reducing the catalyst dosage and lowering the manufacturing cost.

[0019] A continuous production method of the penem intermediate 4-AA using the above continuous production device includes the following steps:

[0020] 1) Continuously introduce the acetaldehyde mixed solution in the acetaldehyde mixed solution storage tank and the oxygen in the oxygen storage tank into the peracetic acid microbubble reactor for reaction to generate peracetic acid. After being cooled by the first condenser, the peracetic acid enters the peracetic acid temporary storage tank;

[0021] 2) Introduce the raw material mixed solution in the raw material mixed solution storage tank and the peracetic acid in the peracetic acid temporary storage tank into the fixed bed reactor for reaction. The reacted material is evaporated by a wiped film evaporator, and the obtained concentrated solution is dissolved, washed, centrifuged, and then dried in a single cone dryer to obtain the penem drug intermediate 4-AA.

[0022] Preferably, in step 1) of the above continuous production method, the acetaldehyde mixed solution is an ethyl acetate solution of acetaldehyde and iron acetylacetonate, wherein the concentration of acetaldehyde is 15 wt% - 25 wt%, preferably 17 wt%; the concentration of iron acetylacetonate is 0.01‰ - 0.06‰ of the acetaldehyde concentration; iron acetylacetonate is used as a catalyst;

[0023] The feeding rate of the acetaldehyde mixed solution is 2.0 kg / min - 2.5 kg / min, and the feeding rate of oxygen is 200 L / min - 250 L / min, preferably 230 L / min - 240 L / min; the oxygen / acetaldehyde molar ratio is 1.1 - 1.4:1.

[0024] Preferably, in step 1) of the above continuous production method, in the peracetic acid microbubble reactor, the residence time of the reaction is 4 min - 5 min, the pressure is 0.6 MPa - 1.0 MPa, and the temperature is 45°C - 50°C; the peracetic acid is cooled to ≤ - 15°C by the first condenser, and the temperature in the peracetic acid temporary storage tank is maintained at ≤ - 15°C.

[0025] Preferably, in step 1) of the above continuous production method, the concentration of the peracetic acid generated by the reaction is 18 wt% - 22 wt%.

[0026] Preferably, in step 2) of the above continuous production method, the raw material mixed solution 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 used as a catalyst; the storage temperature of the raw material mixed solution in the raw material mixed solution storage tank is - 5°C - 0°C.

[0027] Preferably, in step 2) of the above continuous production method, the feeding rate of the raw material mixture is 2.5 kg / min to 3.0 kg / min, the feeding rate of peracetic acid is 2.2 kg / min to 2.6 kg / min. In the fixed bed reactor, the residence time of the reaction 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.

[0028] Preferably, in step 2) of the above continuous production method, the temperature of the wiped film evaporator is controlled at 45°C to 65°C, the vacuum degree ≥ 0.08 MPa, and the drying temperature is 50°C to 60°C.

[0029] The concentrated solution obtained from the wiped 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 to 5°C for crystallization, and then enters the first centrifuge or the second centrifuge for centrifugation; the dissolution temperature and the washing temperature are both 40°C to 60°C.

[0030] Step 2) is specifically as follows: The raw material mixture in the raw material mixture storage tank and peracetic acid in the peracetic acid temporary storage tank are introduced into a fixed bed reactor for reaction. The reacted material is evaporated by a wiped film evaporator, and the solvent is evaporated. The solvent is condensed by a second condenser and then enters an ethyl acetate recovery device; the first batch of materials (concentrated solution) after evaporation enters the first washing kettle, and after dissolution, washing, and cooling for crystallization, it enters the first centrifuge for centrifugation. The second batch of materials (concentrated solution) after evaporation enters the second washing kettle, and after dissolution, washing, and cooling for crystallization, it enters the second centrifuge for centrifugation. The materials after centrifugation in the two batches are combined and enter a single-cone dryer for drying to obtain the penem drug intermediate 4-AA.

[0031] The reaction equation of the present invention is as follows:

[0032] Step 1):

[0033] ;

[0034] Step 2):

[0035] 。

[0036] In step 2), (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone (cyclic compound) and peracetic acid are used under the action of a catalyst to introduce an acetoxy group at the 4th position to obtain the penem drug intermediate 4-AA product.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] (1) The peracetic acid microbubble reactor of the present invention is embedded with a foamed metal plate. Under the action of the foamed metal plate, the liquid is dispersed into a liquid film 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, enhancing the gas-liquid heat and mass transfer effect, accelerating the reaction rate, and shortening the reaction time. Since microbubbles are prone to aggregation to form large bubbles, the foamed metal plate in the present invention is set to 2 to 5 layers, which can disperse the aggregated large bubbles into microbubbles again, ensuring the heat and mass transfer efficiency in the system and improving the reaction stability. The peracetic acid solution flowing out of the peracetic acid microbubble reactor is immediately cooled to below -15°C by the first condenser, effectively avoiding the decomposition of peracetic acid, thus breaking through the problem of easy explosion in batch-scale production and realizing the efficient and safe large-scale production of anhydrous peracetic acid.

[0039] (2) The fixed-bed reactor described in the present invention is a continuous reactor with the characteristics of high mass and heat transfer efficiency. During the preparation of 4-AA with peracetic acid participation, the reaction rate is faster than that of a conventional batch reactor, making the utilization efficiency of peracetic acid higher, the corresponding usage less, and the amount of materials actually participating in the reaction per unit time significantly reduced compared with the kettle production method, thus greatly reducing the production safety risk. In addition, the continuous reaction significantly shortens the contact time between the product and the oxidant peracetic acid, effectively avoiding the over-oxidation and decomposition of the product and improving the reaction yield.

[0040] The present invention also discovers the factors that cause the deactivation of the noble metal catalyst ruthenium trichloride. By filling 4Å molecular sieve inside the fixed-bed reactor to remove the moisture generated during the reaction process, the deactivation of the catalyst is effectively avoided and the catalyst dosage is reduced.

[0041] (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, greatly improving the production safety and realizing the large-scale production of peracetic acid. Then, the prepared peracetic acid and raw material mixture are passed through a fixed-bed reactor to generate the penem drug intermediate 4-AA, and then the solvent is recovered through wiped-film evaporation. Finally, the final product 4-AA is obtained through 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 the production efficiency and safety during the production process.

[0042] In summary, the continuous production device and production method of the present invention can realize the safe large-scale production of anhydrous peracetic acid, reduce the dosage of noble metal catalysts, and improve the yield of the penem drug intermediate 4-AA. It is completed in a fully enclosed system, greatly reducing the VOC emissions and being environmentally friendly. Description of the Drawings

[0043] Figure 1 It is a schematic structural diagram of the production device of the present invention;

[0044] Figure 2 It is a schematic structural diagram of the peracetic acid microbubble reactor of the present invention;

[0045] Figure 3 It is a top view of the foam metal plate of the present invention;

[0046] Figure 4 It is an HPLC chromatogram of the product of the penem drug intermediate 4-AA in Example 1 of the present invention;

[0047] Figure 5 It is an HPLC chromatogram of the product of the penem drug intermediate 4-AA in Example 6 of the present invention;

[0048] Figure 6 It is an HPLC chromatogram of the product of the penem drug intermediate 4-AA in Comparative Example 2 of the present invention;

[0049] 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 liquid storage tank; 8. Fixed bed reactor; 9. Thin 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. Specific embodiments

[0050] The present invention will be specifically described below by way of examples. Unless otherwise specified, the raw materials used are commercially available.

[0051] Example 1

[0052] As Figures 1 - 3 shown, the continuous production device of the penem drug intermediate 4-AA of the present invention includes 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 outlet of the fixed bed reactor 8 is connected to the washing and separation system for subsequent treatment of the reacted materials;

[0053] The peracetic acid feeding system includes 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 outlet at the upper part of the peracetic acid microbubble reactor 3 is sequentially connected to the first condenser 4, the back pressure valve 5, and the inlet of the peracetic acid temporary storage tank 6, which is used to temporarily store the peracetic acid generated by the reaction. The bottom of the peracetic acid temporary storage tank 6 is connected to the inlet of a fixed bed reactor 8 through a discharge pipeline via a third metering pump 19. Through the third metering pump 19, the peracetic acid can be continuously pumped into the fixed bed reactor 8 to achieve continuous production.

[0054] Four layers of foam metal plates 20 are embedded in the peracetic acid microbubble reactor 3, 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 tubes 21 arranged in the peracetic acid microbubble reactor 3 are connected to the foam metal plates 20 in a through manner.

[0055] The fixed bed reactor 8 is filled with 4Å molecular sieve inside, which is used to adsorb the water generated by the reaction.

[0056] The bottom of the raw material mixed solution storage tank 7 is connected to the inlet of the fixed bed reactor 8 through a second metering pump 18. Through the second metering pump 18, the raw material mixed solution can be continuously pumped into the fixed bed reactor 8 to achieve continuous production. The raw material mixed solution in the raw material mixed solution storage tank 7 is composed of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone, ethyl acetate, glacial acetic acid, potassium acetate, and a catalyst ruthenium trichloride.

[0057] The washing and separation system includes a wiped film evaporator 9, a first washing kettle 11, a second washing kettle 12, a first centrifuge 13, a second centrifuge 14, and a single cone dryer 15. The upper feed port of the wiped film evaporator 9 is connected to the discharge port of the fixed bed reactor 8. The lower discharge port of the wiped film evaporator 9 is respectively connected to the first washing kettle 11 and the second washing kettle 12. The first washing kettle 11 is connected to the first centrifuge 13, and the second washing kettle 12 is connected to the second centrifuge 14. Two sets of independent washing and centrifugation systems take turns to wash and separate the materials to achieve continuous production; the first centrifuge 13 and the second centrifuge 14 are connected in parallel to the single cone dryer 15.

[0058] The top of the wiped film evaporator 9 is connected to an ethyl acetate recovery device 16 through a second condenser 10, which is used to recover the solvent.

[0059] The production method using the continuous production device for the penem intermediate 4-AA includes the following steps:

[0060] 1) Add 340 kg of acetaldehyde, 1660 kg of ethyl acetate, and 20 g of iron acetylacetonate catalyst to the anhydrous and dry acetaldehyde mixed solution storage tank 2. After mixing evenly, an acetaldehyde mixed solution is obtained. Continuously introduce the acetaldehyde mixed solution in the acetaldehyde mixed solution storage tank 2 and the oxygen in the oxygen storage tank 1 into the peracetic acid microbubble reactor 3 for reaction to generate peracetic acid. The peracetic acid is cooled to ≤ -15 °C by the first condenser 4 and enters the peracetic acid temporary storage tank 6 for temporary storage through a pipeline.

[0061] Among them: the feeding rate of the acetaldehyde mixed solution is 2.3 kg / min, and the feeding rate of oxygen is 230 L / min, maintaining an oxygen / acetaldehyde molar ratio of 1.16:1.

[0062] 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. After detection, the concentration of the peracetic acid generated by the reaction is 19 wt.%.

[0063] 2) Preparation of the raw material mixed solution: Mix 150 kg (1 w) of (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone (cyclic compound), 675 kg (4.5 w) of ethyl acetate, 300 kg (2 w) of glacial acetic acid, 30 kg (0.2 w) of potassium acetate, and 75 g (0.5‰ w) of ruthenium trichloride evenly, and store them at 0 °C in the raw material mixed solution storage tank 7.

[0064] Continuously introduce the raw material mixed solution in the raw material mixed solution storage tank 7 and the peracetic acid in the peracetic acid temporary storage tank 6 into the fixed-bed reactor 8 for reaction. Control the feeding rates of the raw material mixed solution and peracetic acid respectively through the second metering pump 18 and the third metering pump 19. The feeding rate of the raw material mixed solution is 3.0 kg / min, and the feeding rate of 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; using ice brine as the cooling medium, maintain the temperature in the fixed-bed reactor 8 at -7 - -3 °C.

[0065] 3) The material generated by the reaction in the fixed-bed reactor 8 is transported by pipeline to the wiped-film evaporator 9, and is evaporated under reduced pressure at 45 - 50 °C and a vacuum degree of 0.09 MPa. The ethyl acetate solvent evaporated above the wiped-film evaporator 9 is condensed by the second condenser 10 and enters the ethyl acetate recovery device 16 for recycling, and the concentrated liquid below the wiped-film evaporator 9 enters the subsequent treatment process through a pipeline.

[0066] The evaporated material (concentrate) enters the first washing kettle 11, and the temperature of the first washing kettle 11 is controlled at 55 °C with hot water as the medium. After being dissolved in n-heptane and washed with pure water, it 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 173.5 kg of the penem intermediate 4-AA.

[0067] The obtained penem intermediate 4-AA is analyzed by HPLC chromatography. The molar yield of the penem intermediate 4-AA is 92.0% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity is 99.70%. The HPLC chromatogram is shown in Figure 4 .

[0068] Examples 2 - 5

[0069] The continuous production device for the penem intermediate 4-AA is the same as that in Example 1.

[0070] In the continuous production method of the penem intermediate 4-AA, the feeding rate of the acetaldehyde mixed solution, the feeding rate of oxygen, and the oxygen / acetaldehyde molar ratio in step 1) are changed, and the remaining steps and reaction conditions are the same as those in Example 1. The yields and purities of the obtained penem intermediate 4-AA are shown in Table 1.

[0071] Table 1 Yield and purity data of the penem intermediate 4-AA in Examples 2 - 5

[0072] .

[0073] Examples 6 - 11

[0074] The continuous production device for the penem intermediate 4-AA is the same as that in Example 1.

[0075] In the continuous production method of the penem intermediate 4-AA, the residence time, pressure, and temperature in the peracetic acid microbubble reactor 3 for the reaction of the materials 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 yields and purities of the obtained penem intermediate 4-AA are shown in Table 2. The HPLC chromatogram of the penem intermediate 4-AA in Example 6 is shown in Figure 5 .

[0076] Table 2 Yield and purity data of the penem intermediate 4-AA in Examples 6 - 11

[0077] .

[0078] Examples 12 - 15

[0079] The continuous production device of the intermediate 4-AA of penem drugs is the same as that in Example 1.

[0080] In the continuous production method of the intermediate 4-AA of penem drugs, the dosages of each substance in the raw material mixture 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 3. The yields and purities of the intermediate 4-AA of penem drugs obtained are shown in Table 3.

[0081] Table 3 Yield and purity data of the intermediate 4-AA of penem drugs in Examples 12 - 15

[0082] 。

[0083] Examples 16 - 21

[0084] The continuous production device of the intermediate 4-AA of penem drugs is the same as that in Example 1.

[0085] In the continuous production method of the intermediate 4-AA of penem drugs, in step 2), the residence time, pressure of the material reaction in the fixed-bed reactor 8, and the temperature inside the fixed-bed reactor 8 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 yields and purities of the intermediate 4-AA of penem drugs obtained are shown in Table 4.

[0086] Table 4 Yield and purity data of the intermediate 4-AA of penem drugs in Examples 16 - 21

[0087] 。

[0088] Examples 22 - 26

[0089] The continuous production device of the intermediate 4-AA of penem drugs is the same as that in Example 1.

[0090] In the continuous production method of the intermediate 4-AA of penem drugs, in step 2), the feeding rate of the raw material mixture and the feeding rate of peracetic acid 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 yields and purities of the intermediate 4-AA of penem drugs obtained are shown in Table 5.

[0091] Table 5 Yield and purity data of the intermediate 4-AA of penem drugs in Examples 22 - 26

[0092] 。

[0093] Comparative Example 1

[0094] The peracetic acid microbubble reactor 3 does not embed a foam metal plate 20, and the rest of the production equipment and production method are the same as in Example 1. The concentration of the generated peracetic acid is 12.0 wt%, and 154.8 kg of the penem intermediate 4-AA is obtained. The molar yield of the penem intermediate 4-AA is 80.2% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity is 97.36%.

[0095] By comparing Example 1 and Comparative Example 1, it can be seen that in Comparative Example 1, the peracetic acid microbubble reactor 3 does not embed a foam metal plate 20, the liquid and gas are not evenly mixed, the gas-liquid heat and mass transfer effect is poor, the formation rate of peracetic acid is low, and the concentration of peracetic acid also decreases, thereby reducing the molar yield of the penem intermediate 4-AA.

[0096] Comparative Example 2

[0097] The fixed-bed reactor 8 is not filled with 4Å molecular sieve, and the rest of the production equipment and production method are the same as in Example 1, and 146.0 kg of the penem intermediate 4-AA is obtained. The molar yield of the penem intermediate 4-AA is 76.1% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity is 97.99%. The HPLC chromatogram is shown in Figure 6 .

[0098] By comparing Example 1 and 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 inactivation of the catalyst ruthenium trichloride and the reduction of the catalytic efficiency, thereby reducing the molar yield of the penem intermediate 4-AA.

[0099] Comparative Example 3

[0100] The penem intermediate 4-AA is prepared by the batch method, and the specific steps are as follows:

[0101] Under nitrogen protection, 848 g of the 19 wt.% peracetic acid obtained in Example 1 and 1156 g of the raw material mixture (prepared in the same way as in Example 1) are added to the reaction vessel, and the system temperature is maintained at -5~-3°C for heat preservation reaction for 1 hour. Then saturated NaHSO 3 aqueous solution is added for quenching, and the reaction system is directly concentrated at 45°C. The reaction solution is filtered, the filter cake is washed, and then dried at 50°C for 7 hours to obtain 153.4 g of the penem intermediate 4-AA. The molar yield is 79.4% (calculated based on (1R)-(tert-butyldimethylsilyloxy)ethyl-(3S)-azetidinone), and the HPLC purity is 97.38%.

[0102] It can be seen by comparing Example 1 with Comparative Example 3 that in Comparative Example 3, the intermittent method was used to prepare the southern drug intermediate 4-AA, and its yield was significantly reduced.

[0103] As described above, it is only the preferred embodiment of the present invention, and it is not a limitation of the present invention in other forms. Any person skilled in the art may use the technical content disclosed above to make changes or modifications into equivalent embodiments with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the technical solution content of the present invention still fall within 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) via a gas pipeline; the acetaldehyde mixed solution storage tank (2) is connected to the bottom of the peracetic acid microbubble reactor (3) via 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; the bottom of the peracetic acid temporary storage tank (6) is connected to the inlet of the fixed bed reactor (8) via a discharge pipeline via a third metering pump (19); 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).

2. 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).

3. A continuous production method of penem drug intermediate 4-AA using the device according to claim 1 or 2, 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.

4. The continuous production method of the penem drug intermediate 4-AA according to claim 3, 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.

5. The continuous production method of penem drug intermediate 4-AA according to claim 3, 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).

6. The continuous production method of penem drug intermediate 4-AA according to claim 3, 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.

7. The continuous production method of penem drug intermediate 4-AA according to claim 3, 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.

8. The continuous production method of penem drug intermediate 4-AA according to claim 3, 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.

9. The continuous production method of penem drug intermediate 4-AA according to claim 3, 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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