Comprehensive treatment method and device for 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor

Abstract

The present invention belongs to the field of medicine, and in particular to a comprehensive treatment method and device for a 2α-methyl-2β-azidomethyl-penicillin-3α-carboxyldiphenylmethyl ester mother liquor. The following steps are included: 1) the mother liquor is transferred to a regulating kettle and the pH is adjusted with liquid alkali; 2) a sodium hypochlorite solution is added dropwise to the mother liquor until the sodium hydride reaction is complete; 3) the mother liquor is transferred to a high-efficiency evaporator with a pump, the vaporized gas phase is distilled into an ethyl acetate distillation tower, the remaining salt-containing DMF solution is cooled and crystallized in a cooling kettle, centrifuged and desalted by a centrifuge, the filtrate is heated in a reboiler and then enters a dehydration tower, the gas phase at the top of the cooling kettle enters a two-stage condenser A through a vacuum pump, and then enters an ethyl acetate distillation tower; 4) the vaporized gas phase at the top of the dehydration tower enters a wastewater tank after passing through a three-stage condenser; the dehydration tower bottom material is heated by a reboiler, enters a DMF distillation tower, and then passes through a two-stage condenser B, and enters a finished product tank after sampling and testing. The present invention solves the potential safety hazards in actual production and reduces production costs.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a comprehensive treatment method and device for 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor. Background Art

[0002] Tazobactam is the third β-lactamase inhibitor to be clinically used, following clavulanic acid and sulbactam. Tazobactam exhibits stronger inhibitory activity and stability against multiple enzyme types than sulbactam and clavulanic acid. Its combination with piperacillin and cefoperazone is clinically used to treat systemic and localized infections and sepsis, and has gained widespread market recognition due to its proven clinical efficacy.

[0003] According to literature reports, the current synthesis methods for tazobactam can be categorized by starting material: the penicillin G salt method, the sulbactam method, and the 6-APA method. The most widely used method uses 6-APA as the starting material, and proceeds through bromination, oxidation, esterification, reduction, thermal cracking, chloromethylation, azidation, double oxidation, cycloaddition, and deprotection to obtain tazobactam. 2α-Methyl-2β-azidomethylpenicillin-3α-carboxybenzyl ester is the product obtained by azidation and is an important intermediate in the tazobactam reaction. The synthesis of 2α-Methyl-2β-azidomethylpenicillin-3α-carboxybenzyl ester is a key step in tazobactam. This step uses sodium azide to provide the trinitrogen group, and N,N-dimethylformamide (DMF) is used as the solvent. Excess sodium azide is used in this step, and this excess sodium azide is present in the mother liquor containing DMF. Sodium azide itself is highly toxic, and the mother liquor of this reaction will also generate hydrazoic acid gas when it comes into contact with acid. This gas is highly toxic and explosive.

[0004] DMF is a polar (hydrophilic) aprotic solvent with a high boiling point. It is unstable in the presence of a strong base such as sodium hydroxide or a strong acid such as hydrochloric acid or sulfuric acid. It is hydrolyzed into formic acid and dimethylamine, and a large amount of salt remains in the mother liquor, which makes it very difficult to recover DMF. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a comprehensive treatment method for 2α-methyl-2β-azidomethylpenicillane-3α-carboxydiphenylmethyl ester mother liquor. The method is scientific, reasonable, simple and easy to implement, solves potential safety hazards in actual production, effectively reduces production costs, and recovers DMF with a high yield and stable quality. The present invention also provides a device used in the method, which has simple equipment and low operating costs.

[0006] The comprehensive treatment method of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor of the present invention comprises the following steps:

[0007] 1) Transfer the mother liquor of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester to a regulating kettle and adjust the pH with liquid caustic soda;

[0008] 2) adding sodium hypochlorite solution dropwise to the mother liquor until the sodium azide reaction is complete;

[0009] 3) The mother liquor after removing sodium azide is transferred to a high-efficiency evaporator by a pump. The vapor phase evaporated from the high-efficiency evaporator is fed into an ethyl acetate distillation tower. The remaining salt-containing DMF solution is fed into a cooling kettle for cooling and crystallization. The solution is centrifuged and desalted in a centrifuge. The filtrate is heated in a reboiler and fed into a dehydration tower. The vapor phase at the top of the cooling kettle is fed into a two-stage condenser A via a vacuum pump and then into an ethyl acetate distillation tower.

[0010] 4) The vapor phase evaporated from the top of the dehydration tower enters the wastewater tank after passing through the three-stage condenser and is treated by the wastewater pump; the material at the bottom of the dehydration tower is heated by the reboiler and enters the DMF distillation tower, and then passes through the two-stage condenser B. After sampling and testing, it is put into the finished product tank.

[0011] In step 1), the pH is adjusted to greater than 7.5 with liquid caustic soda, and the concentration of the liquid caustic soda used is 30%.

[0012] In step 2), the concentration of the sodium hypochlorite solution is 10-25%, and the dropping temperature is 10-25°C.

[0013] In step 2), the complete reaction of sodium azide is detected by using FeCl 3 solution, and the concentration of FeCl 3 solution is 10-20%.

[0014] In step 3), the operating conditions of the high-efficiency evaporator are: the temperature of the reduced pressure distillation is 40-75° C., and the vacuum degree is -0.09 to -0.096 MPa.

[0015] In step 4), the operating conditions of the DMF distillation tower are: the distillation vacuum degree of the reduced pressure distillation is -0.09 to -0.096 MPa; and the distillation temperature is 100-150°C.

[0016] A device for implementing a comprehensive treatment method for 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor comprises a regulating kettle, wherein a mother liquor input pipeline is connected to the regulating kettle, the outlet of the regulating kettle is connected to the inlet of a pump, the outlet of the pump is connected to the inlet of a high-efficiency evaporator, the gas phase outlet of the high-efficiency evaporator is connected to the inlet of an ethyl acetate distillation tower, the liquid phase outlet of the high-efficiency evaporator is connected to the inlet of a cooling kettle, the gas phase outlet of the cooling kettle is connected to the inlet of a two-stage condenser A, the outlet of the two-stage condenser A is connected to the inlet of the ethyl acetate distillation tower, the bottom discharge port of the cooling kettle is connected to the inlet of a centrifuge, the outlet of the centrifuge is connected to the inlet of a dehydration tower, the gas phase outlet of the dehydration tower is connected to the inlet of a three-stage condenser, the outlet of the three-stage condenser is connected to the inlet of a wastewater tank, the outlet of the wastewater tank is connected to a sewage treatment pipeline, the liquid phase outlet of the dehydration tower is connected to the inlet of a DMF distillation tower, the outlet of the DMF distillation tower is connected to the inlet of a two-stage condenser B, and the outlet of the two-stage condenser B is connected to the inlet of a finished product tank.

[0017] The top of the regulating kettle is connected to the sodium hypochlorite storage tank and the liquid alkali storage tank respectively.

[0018] The regulating kettle is equipped with refrigerant, pH meter and sampling valve.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] 1. The present invention recovers DMF and ethyl acetate from the mother liquor of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester, thereby realizing the recycling of DMF and ethyl acetate and reducing production costs.

[0021] 2. The comprehensive treatment method provided by the present invention avoids the generation of toxic and explosive gas hydrazoic acid, and the process is safe and environmentally friendly.

[0022] 3. The comprehensive treatment method provided by the present invention is scientific and reasonable, simple and easy to implement, has few operating steps, short process cycle, low energy consumption, can effectively reduce production costs, and can be applied to large-scale production.

[0023] 4. The products obtained by the present invention have a high yield of DMF and ethyl acetate, which can reach over 92.0%, stable quality, a DMF content of over 99.0%, a moisture content of less than 0.2%, and an ethyl acetate content of over 95.0%, a moisture content of less than 5%, and can be directly reused. The residual organic solvent in the distillation wastewater is less than 0.1%, making it easy to treat.

[0024] 5. The device described in the present invention has simple equipment and low operating cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a structural schematic diagram of the device of the present invention;

[0026] In the figure: 1. regulating kettle; 2. mother liquor input pipeline; 3. sodium hypochlorite storage tank; 4. liquid alkali storage tank; 5. pump; 6. high-efficiency evaporator; 7. ethyl acetate distillation tower; 8. cooling kettle; 9. two-stage condenser A; 10. centrifuge; 11. dehydration tower; 12. three-stage condenser; 13. wastewater tank; 14. DMF distillation tower; 15. two-stage condenser B; 16. finished product tank. DETAILED DESCRIPTION

[0027] The present invention is further described below with reference to the following examples, which however do not limit the implementation of the present invention.

[0028] Reference Figure 1 As shown, the comprehensive treatment device for the mother liquor of 2α-methyl-2β-azidomethyl penicillin-3α-carboxyl diphenyl ester includes a regulating kettle 1, the regulating kettle 1 is connected to a mother liquor input pipeline 2, the outlet of the regulating kettle 1 is connected to the inlet of a pump 5, the outlet of the pump 5 is connected to the inlet of a high-efficiency evaporator 6, the gas phase outlet of the high-efficiency evaporator 6 is connected to the inlet of an ethyl acetate distillation tower 7, the liquid phase outlet of the high-efficiency evaporator 6 is connected to the inlet of a cooling kettle 8, the gas phase outlet of the cooling kettle 8 is connected to the inlet of a two-stage condenser A9, and the outlet of the two-stage condenser A9 is connected to the inlet of an ethyl acetate distillation tower 7. The inlet of the acid ethyl ester distillation tower 7 and the bottom discharge port of the cooling kettle 8 are connected to the inlet of the centrifuge 10, the outlet of the centrifuge 10 is connected to the inlet of the dehydration tower 11, the gas phase outlet of the dehydration tower 11 is connected to the inlet of the three-stage condenser 12, the outlet of the three-stage condenser 12 is connected to the inlet of the wastewater tank 13, the outlet of the wastewater tank 13 is connected to the sewage treatment pipeline, the liquid phase outlet of the dehydration tower 11 is connected to the inlet of the DMF distillation tower 14, the outlet of the DMF distillation tower 14 is connected to the inlet of the two-stage condenser B15, and the outlet of the two-stage condenser B15 is connected to the inlet of the finished product tank 16.

[0029] The top of the regulating kettle 1 is connected to a sodium hypochlorite storage tank 3 and a liquid caustic soda storage tank 4 respectively.

[0030] The regulating kettle 1 is equipped with a refrigerant, a pH meter and a sampling valve.

[0031] The following is a specific implementation description of the treatment of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor using the above-mentioned device:

[0032] The 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor was obtained from the pilot process, and its composition is shown in Table 1.

[0033] Table 1 Mass fraction of substances in mother liquor

[0034]

[0035]

[0036] Example 1

[0037] The method for recovering DMF and ethyl acetate from 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor comprises the following steps:

[0038] (1) Add 5000L of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor to the regulating kettle 1, start stirring, and add 30% liquid alkali solution dropwise to the regulating kettle 1 through the metering tank to adjust the pH to 7.5.

[0039] (2) Then, 10% sodium hypochlorite solution is added dropwise to the mother liquor in the regulating kettle 1 through the metering tank. The temperature of this process is controlled at 10°C by the refrigerant water. When the mother liquor no longer produces an obvious blood red color after the 10% FeCl3 solution is added dropwise, the addition of sodium hypochlorite solution is stopped.

[0040] (3) The mother liquor in step (2) is transferred to a high-efficiency evaporator 6 by a pump 5, and the temperature of the reduced pressure distillation is controlled to be 40°C and the vacuum degree is -0.09 MPa. The gas phase evaporated from the high-efficiency evaporator 6 is fed into an ethyl acetate distillation tower 7, and the remaining salt-containing DMF solution is fed into a cooling kettle 8 for cooling and crystallization. The salt is removed by centrifugal filtration, and the filtrate is heated in a reboiler and fed into a dehydration tower 11. A two-stage condenser A9 is provided after the vacuum pump, and the condensate is accumulated and then fed into the ethyl acetate distillation tower 7. 370 L of ethyl acetate is collected, with a recovery rate of 92.5%, a content of 96.82%, and a moisture content of 3.0%.

[0041] (4) The vapor phase distilled from the top of dehydration tower 11 was condensed in a three-stage condenser 12 and then sent to wastewater tank 13 for decontamination by a wastewater pump. The bottom material of dehydration tower 11 was heated by a reboiler and sent to DMF rectification tower 14. The vacuum degree of the vacuum distillation was controlled at -0.09 MPa and the distillation temperature was 100°C. The product then passed through a two-stage condenser B15. After sampling and testing, it was sent to finished product tank 16. 1162L of DMF was collected with a recovery rate of 92.96%, a content of 99.56%, and a moisture content of 0.12%.

[0042] Example 2

[0043] The method for recovering DMF and ethyl acetate from 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor comprises the following steps:

[0044] (1) Add 5000 L of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor to the regulating kettle 1, start stirring, and add 30% liquid alkali solution dropwise to the regulating kettle 1 through the metering tank to adjust the pH to 8.0.

[0045] (2) Then, 15% sodium hypochlorite solution is added dropwise to the mother liquor in the regulating kettle 1 through the metering tank. The temperature of this process is controlled at 20°C by the refrigerant water. When the mother liquor no longer produces a clear blood red color after the 15% FeCl3 solution is added dropwise, the addition of sodium hypochlorite solution is stopped.

[0046] (3) The mother liquor in step (2) is transferred to a high-efficiency evaporator 6 by a pump 5, and the temperature of the reduced pressure distillation is controlled to be 50°C and the vacuum degree is -0.091 MPa. The gas phase evaporated from the high-efficiency evaporator 6 is fed into an ethyl acetate distillation tower 7, and the remaining salt-containing DMF solution is fed into a cooling kettle 8 for cooling and crystallization. The salt is removed by centrifugal filtration, and the filtrate is heated in a reboiler and fed into a dehydration tower 11. A two-stage condenser A9 is provided after the vacuum pump, and the condensate is accumulated and then fed into the ethyl acetate distillation tower 7. 368 L of ethyl acetate is collected, with a recovery rate of 92.0%, a content of 95.03%, and a moisture content of 4.3%.

[0047] (4) The vapor phase distilled from the top of dehydration tower 11 was condensed in a three-stage condenser 12 and then sent to wastewater tank 13 for decontamination by a wastewater pump. The bottom material of dehydration tower 11 was heated by a reboiler and sent to DMF rectification tower 14. The vacuum degree of the vacuum distillation was controlled at -0.09 MPa and the distillation temperature was 110°C. The product was then passed through a two-stage condenser B15. After sampling and testing, it was sent to finished product tank 16. 1187L of DMF was collected with a recovery rate of 94.96%, a content of 99.06%, and a moisture content of 0.18%.

[0048] Example 3

[0049] The method for recovering DMF and ethyl acetate from 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor comprises the following steps:

[0050] (1) Add 5000L of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor to the regulating kettle 1, start stirring, and add 30% liquid alkali solution dropwise to the regulating kettle 1 through the metering tank to adjust the pH to 7.5.

[0051] (2) Then, 20% sodium hypochlorite solution is added dropwise to the mother liquor in the regulating kettle 1 through the metering tank. The temperature of the mother liquor is controlled at 25°C by the refrigerant water. When the mother liquor no longer produces a clear blood red color after the 20% FeCl3 solution is added dropwise, the addition of sodium hypochlorite solution is stopped.

[0052] (3) The mother liquor in step (2) is transferred to a high-efficiency evaporator 6 by a pump 5, and the temperature of the reduced pressure distillation is controlled to be 75°C and the vacuum degree is -0.096 MPa. The gas phase evaporated from the high-efficiency evaporator 6 is fed into an ethyl acetate distillation tower 7, and the remaining salt-containing DMF solution is fed into a cooling kettle 8 for cooling and crystallization. The salt is removed by centrifugal filtration, and the filtrate is heated in a reboiler and fed into a dehydration tower 11. A two-stage condenser A9 is provided after the vacuum pump, and the condensate is accumulated and then fed into the ethyl acetate distillation tower 7. 385 L of ethyl acetate is collected, with a recovery rate of 96.25%, a content of 95.0%, and a moisture content of 4.5%.

[0053] (4) The vapor phase distilled from the top of dehydration tower 11 was condensed in a three-stage condenser 12 and then sent to wastewater tank 13 for decontamination by a wastewater pump. The bottom material of dehydration tower 11 was heated by a reboiler and sent to DMF rectification tower 14. The vacuum degree of the distillation was controlled at -0.096 MPa and the distillation temperature was 140°C. The product then passed through a two-stage condenser B15. After sampling and testing, it was sent to finished product tank 16. 1190L of DMF was collected, with a recovery rate of 95.2%, a content of 99.01%, and a moisture content of 0.18%.

Claims

1. A comprehensive treatment method for 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor, characterized by: The following steps are involved: 1) transferring the mother liquor of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester to a regulating kettle (1) and adjusting the pH with liquid alkali; wherein the mother liquor of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester is obtained from the pilot process; 2) Sodium hypochlorite solution is added dropwise to the mother liquor until the sodium azide reaction is complete; 3) The mother liquor after removing sodium azide is transferred to a high-efficiency evaporator (6) by a pump (5). The gas phase evaporated from the high-efficiency evaporator (6) enters an ethyl acetate distillation tower (7). The remaining salt-containing DMF solution enters a cooling kettle (8) for cooling and crystallization. The solution is centrifuged and desalted by a centrifuge (10). The filtrate is heated in a reboiler and then enters a dehydration tower (11). The gas phase at the top of the cooling kettle (8) enters a two-stage condenser A (9) through a vacuum pump and then enters an ethyl acetate distillation tower (7). 4) The vapor phase evaporated from the top of the dehydration tower (11) passes through the three-stage condenser (12) and enters the wastewater tank (13), and is treated by the wastewater pump; the bottom material of the dehydration tower (11) is heated by the reboiler and enters the DMF distillation tower (14), and then passes through the two-stage condenser B (15). After sampling and testing, it is sent to the finished product tank (16); In step 1), the pH is adjusted to greater than 7.5 with liquid caustic soda, and the concentration of the liquid caustic soda used is 30%; In step 2), the concentration of the sodium hypochlorite solution is 10-25%, and the dropwise addition temperature is 10-25°C; In step 2), the complete reaction of sodium azide is detected by FeCl3 solution, and the concentration of FeCl3 solution is 10-20%; In step 3), the operating conditions of the high-efficiency evaporator (6) are: the temperature of the reduced pressure distillation is 40-75°C, and the vacuum degree is -0.09 to -0.096 MPa; In step 4), the operating conditions of the DMF distillation tower (14) are: the distillation vacuum degree of the reduced pressure distillation is -0.09 to -0.096 MPa; the distillation temperature is 100-150°C; The device of the comprehensive treatment method of the mother liquor of 2α-methyl-2β-azidomethyl penicillin-3α-carboxyldiphenyl ester comprises a regulating kettle (1), the regulating kettle (1) is connected to a mother liquor input pipeline (2), the outlet of the regulating kettle (1) is connected to the inlet of a pump (5), the outlet of the pump (5) is connected to the inlet of a high-efficiency evaporator (6), the gas phase outlet of the high-efficiency evaporator (6) is connected to the inlet of an ethyl acetate distillation tower (7), the liquid phase outlet of the high-efficiency evaporator (6) is connected to the inlet of a cooling kettle (8), the gas phase outlet of the cooling kettle (8) is connected to the inlet of a two-stage condenser A (9), and the outlet of the two-stage condenser A (9) is connected to the ethyl acetate distillation tower (7). The inlet of the ester distillation tower (7) and the bottom discharge port of the cooling kettle (8) are connected to the inlet of the centrifuge (10), the outlet of the centrifuge (10) is connected to the inlet of the dehydration tower (11), the gas phase outlet of the dehydration tower (11) is connected to the inlet of the three-stage condenser (12), the outlet of the three-stage condenser (12) is connected to the inlet of the wastewater tank (13), the outlet of the wastewater tank (13) is connected to the sewage treatment pipeline, the liquid phase outlet of the dehydration tower (11) is connected to the inlet of the DMF distillation tower (14), the outlet of the DMF distillation tower (14) is connected to the inlet of the two-stage condenser B (15), and the outlet of the two-stage condenser B (15) is connected to the inlet of the finished product tank (16).

2. The comprehensive treatment method of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor according to claim 1, characterized in that: The top of the regulating kettle (1) is connected to a sodium hypochlorite storage tank (3) and a liquid caustic soda storage tank (4) respectively.

3. The comprehensive treatment method of 2α-methyl-2β-azidomethylpenicillin-3α-carboxydiphenylmethyl ester mother liquor according to claim 1, characterized in that: The regulating kettle (1) is equipped with a refrigerant, a pH meter and a sampling valve.

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