Treatment method for wastewater from the production of meropenem side chain

Abstract

The present invention discloses a method for treating wastewater produced by the production of meropenem side chains, comprising the following steps: S1: after reaction I is completed, bubbling the aqueous phase with dry nitrogen, condensing the tail gas through a condenser, then absorbing it through a falling film absorber, and then hydrolyzing it under the action of a catalyst to destroy phosgene; S2: vacuum distilling the organic phase obtained from reaction II, using the obtained toluene for the next batch of reactions, and sending the remaining viscous organic matter to an incinerator for incineration; S3: adding a decolorizing agent to the mother liquor in reaction II, decolorizing and filtering it, heating the filtrate for evaporation and concentration, crystallizing sodium chloride, flash distilling the evaporated mother liquor at 50°C to precipitate potassium chloride, and selling the obtained sodium chloride and potassium chloride as by-products. The remaining high-salt wastewater is discharged to a sewage treatment plant; S4: vacuum distilling the organic phase in reaction III, and retrieving the recovered dichloromethane for use in the next batch. The present invention can greatly reduce the amount of wastewater discharged during the synthesis of the meropenem side chain, alleviate the pressure on sewage treatment, and has good economic and environmental benefits.

Description

Technical Field

[0001] The present invention relates to the technical field of wastewater treatment, and in particular to a method for treating meropenem side chain production wastewater. Background Art

[0002] Meropenem is a white or slightly yellow powder. Its English name is Meropenem for Injection. Its chemical name is (4R,5S,6S)-3-[[(3S,5S)-5-(dimethylcarbamoyl)-3-pyrrolidino]sulfur]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its molecular formula is C17H25N3O5S·3H2O, and its molecular weight is 437.51. Its structural formula is:

[0003]

[0004] Meropenem is the first beta-methylcarbapenem antibiotic with good antibacterial activity and broad-spectrum antibacterial properties. It can also enhance the metabolic stability of renal dehydrogenase in the human body. It is mainly used to treat pneumonia, meningitis, sepsis and other diseases caused by various bacterial infections.

[0005] The current domestic synthesis of the meropenem side chain involves first synthesizing compound A1 using L-hydroxyproline as the raw material. The intermediate meropenem side chain thiol lactone (i.e., (2S,4S)-dimethylcarbamoyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine) is obtained through a one-pot process of carboxyl activation, hydroxyl acylation, and sulfidation. The intermediate thiol lactone is then reacted in a single step to obtain the target product, the meropenem side chain. The following chemical reactions occur during the reaction:

[0006]

[0007]

[0008] The main process of synthesizing the meropenem side chain by this method is as follows:

[0009] (I) Preparation of p-nitrobenzyl chloroformate

[0010] Toluene, triphosgene, and p-nitrobenzyl alcohol were added to the reaction kettle, and then dimethylaniline was added dropwise. After the reaction was completed, the organic phases were combined to obtain a toluene solution of p-nitrobenzyl chloroformate;

[0011] (II) Synthesis of intermediate 1

[0012] Water and amino acid were added to the reaction kettle, stirred and dissolved, and then liquid alkali and potassium carbonate were added to obtain a toluene solution of p-nitrobenzyl chloroformate. The solution was allowed to stand and separate into layers. The aqueous phase was collected and the pH was adjusted with dilute hydrochloric acid. The solution was crystallized, centrifuged, and dried to obtain intermediate 1.

[0013] (III) Synthesis of Intermediate 2

[0014] Reactor 1 is charged with a solvent, intermediate 1, triethylamine, and isopropyl chloroformate, followed by dropwise addition of triethylamine and methylsulfonyl chloride; water and sodium hydrosulfide are added to another reactor 2, and after dissolving, a potassium carbonate solution and a phase transfer catalyst are added. After the reaction is satisfactory, the materials from the two reactors are combined and allowed to stand for separation; the organic phase is collected and subjected to heating for cyclization. After the reaction is complete, the organic phase is washed; vacuum concentration, centrifugation, washing, and vacuum drying are performed to obtain intermediate 2;

[0015] (IV) Synthesis of Meropenem Side Chain

[0016] The intermediate 2, solvent, and catalyst were added to the reactor, and the dimethylamine solution was added dropwise. After the reaction was completed, water was added, the pH was adjusted, and the mixture was allowed to stand for stratification. The organic phase was concentrated under reduced pressure, centrifuged, washed, and vacuum dried to obtain the finished product.

[0017] A large amount of wastewater is generated in each process of synthesizing the meropenem side chain by this method, and it is necessary to develop a method for treating the meropenem side chain production wastewater. Summary of the Invention

[0018] The technical problem to be solved by the present invention is to overcome the shortcomings of the existing technology and provide a method for treating meropenem side chain production wastewater, which can greatly reduce the wastewater discharge during the synthesis of meropenem side chain, alleviate the pressure of sewage treatment, and have good economic and environmental benefits.

[0019] The technical solution of the present invention is:

[0020] A method for treating wastewater produced by the production of meropenem side chain comprises the following steps:

[0021] After the completion of S1 reaction I, dry nitrogen is bubbled into the aqueous phase. The generated tail gas is first condensed by a condenser, then absorbed by a falling film absorber, and then hydrolyzed under the action of a catalyst to destroy the phosgene.

[0022] S2 distills the organic phase obtained in reaction II under reduced pressure, and the obtained toluene is used for the next batch of reaction, and the remaining viscous organic matter is sent to the incinerator for incineration;

[0023] S3 adds a decolorizing agent to the mother liquor in reaction II for decolorization, and after decolorization, the filtrate is filtered and heated to evaporate and concentrate, thereby crystallizing sodium chloride. The evaporated mother liquor is flash-evaporated at 50°C to precipitate potassium chloride. The obtained sodium chloride and potassium chloride are sold as by-products, and the remaining high-salt wastewater is discharged to a sewage treatment plant;

[0024] S4: The organic phase in reaction III is subjected to reduced pressure distillation, and the recovered dichloromethane is retained for use in the next batch.

[0025] Preferably, in step S1, the catalyst is one or more of α-alumina, activated carbon, β-alumina and SN-7501.

[0026] Preferably, in step S2, the reduced pressure distillation temperature is 55-65°C and the pressure is -0.1 to -0.15 MPa.

[0027] Preferably, in step S3, the decolorizing agent is activated carbon or diatomaceous earth, and the amount used is 5-10% by weight of the mother liquor.

[0028] Preferably, in step S3, the filtrate is heated to 100-120°C and evaporated to a density of 1.2-1.4 g / cm 3 .

[0029] Preferably, in step S4, the reduced pressure distillation temperature is 35-40° C. and the pressure is -0.08 to -0.1 MPa.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1. The treatment method of the present invention can greatly reduce the amount of wastewater discharged during the synthesis of the meropenem side chain, reduce the COD and salt content of the discharged wastewater, and alleviate the pressure on sewage treatment; the by-products obtained can be sold externally, and the recovered toluene and dichloromethane can be used in the reaction and recycled, thereby reducing production input costs and having good economic and environmental benefits.

[0032] 2. During the treatment process of the present invention, phosgene is hydrolyzed and destroyed by the catalyst, thereby avoiding leakage and environmental pollution.

[0033] 3. In the production of meropenem side chains, a large amount of high-salt wastewater is generated. If it is discharged directly, it will increase the pressure on sewage treatment and cause economic losses. However, the treatment method of the present invention can not only treat the high-salt wastewater, but also obtain by-products that can be sold externally, which has better economic benefits.

[0034] 4. The treatment method of the present invention is easy to operate, the solvent can be recycled, and has good environmental protection benefits. DETAILED DESCRIPTION

[0035] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention.

[0036] Example 1

[0037] The method for treating meropenem side chain production wastewater in this embodiment comprises the following steps:

[0038] After reaction I was completed, S1 used dry nitrogen to bubble the aqueous phase for 1 h, and the tail gas produced contained about 10m 3 Phosgene, a small amount of organic matter and 8m 3 Hydrogen chloride, the tail gas first enters the condenser, where a small amount of organic matter is condensed, and then passes through the falling film absorber to remove hydrogen chloride, and finally phosgene is hydrolyzed under the catalytic action of SN-7501;

[0039] About 1300 kg of OP phase was obtained in reaction II of S2, which was distilled at 55°C and -0.12 MPa to obtain 1180 kg of toluene with a yield of 90.77%. The remaining viscous organic matter was sent to the incinerator for incineration;

[0040] The mother liquor in S3 reaction II weighs 1462 kg, which contains about 191 kg potassium chloride, 108 kg sodium chloride and a small amount of unknown impurities. 117 kg activated carbon is added to the mother liquor, decolorized for 1 hour, and then filtered. The filtrate is heated to 110 ° C and evaporated to a density of 1.27 g / cm 3 , sodium chloride is crystallized to obtain 46 kg of sodium chloride product; when the mother liquor is evaporated and cooled to 50°C, potassium chloride is flash-evaporated to obtain 120 kg of potassium chloride. The obtained sodium chloride and potassium chloride are sold as by-products, and the remaining high-salt wastewater is discharged to the sewage treatment plant;

[0041] 5500 kg of organic phase in S4 reaction III was distilled at 38°C and -0.09 MPa to obtain 4000 kg of dichloromethane, which was reserved for the next batch.

[0042] Example 2

[0043] The method for treating meropenem side chain production wastewater in this embodiment comprises the following steps:

[0044] After reaction I was completed, S1 used dry nitrogen to bubble the aqueous phase for 1 h, and the tail gas produced contained about 18m 3 Phosgene, a small amount of organic matter and 14.5m 3 Hydrogen chloride, the tail gas first enters the condenser, where a small amount of organic matter is condensed, and then passes through the falling film absorber to remove hydrogen chloride, and finally phosgene is hydrolyzed under the catalytic action of β-alumina;

[0045] About 2100 kg of OP phase was obtained in reaction II of S2, which was distilled at 59°C and -0.15 MPa to obtain 1911 kg of toluene with a yield of 91.01%. The remaining viscous organic matter was sent to the incinerator for incineration;

[0046] The mother liquor in S3 reaction II weighs 2485 kg, which contains about 322 kg potassium chloride, 182 kg sodium chloride and a small amount of unknown impurities. 149 kg activated carbon is added to the mother liquor, decolorized for 1 hour, and then filtered. The filtrate is heated to 116 ° C and evaporated to a density of 1.35 g / cm 3 , sodium chloride is crystallized to obtain 91kg of sodium chloride product; when the mother liquor is evaporated and cooled to 50°C, potassium chloride is flash-evaporated to obtain 216kg of potassium chloride. The obtained sodium chloride and potassium chloride are sold as by-products, and the remaining high-salt wastewater is discharged to the sewage treatment plant;

[0047] 6000 kg of organic phase in S4 reaction III was distilled at 38°C and -0.1 MPa to obtain 4430 kg of dichloromethane, which was reserved for the next batch.

[0048] Example 3

[0049] The method for treating meropenem side chain production wastewater in this embodiment comprises the following steps:

[0050] After reaction I was completed, S1 used dry nitrogen to bubble the aqueous phase for 1 h, and the tail gas produced contained about 20m 3 Phosgene, a small amount of organic matter and 16.3m 3 Hydrogen chloride, the tail gas first enters the condenser, where a small amount of organic matter is condensed, and then passes through the falling film absorber to remove hydrogen chloride, and finally phosgene is hydrolyzed under the catalytic action of β-alumina;

[0051] About 1850 kg of OP phase was obtained in reaction II of S2, which was distilled at 59°C and -0.13 MPa to obtain 1681 kg of toluene with a yield of 90.89%. The remaining viscous organic matter was sent to the incinerator for incineration;

[0052] The mother liquor in S3 reaction II weighs 2777 kg, which contains about 380 kg potassium chloride, 217 kg sodium chloride and a small amount of unknown impurities. 270 kg activated carbon is added to the mother liquor, decolorized for 1 hour, and then filtered. The filtrate is heated to 110 ° C and evaporated to a density of 1.39 g / cm 3 , sodium chloride is crystallized to obtain 104 kg of sodium chloride product; when the mother liquor is evaporated and cooled to 50 ° C, potassium chloride is flash-evaporated to obtain 250 kg of potassium chloride. The obtained sodium chloride and potassium chloride are sold as by-products, and the remaining high-salt wastewater is discharged to the sewage treatment plant;

[0053] 4000 kg of organic phase in S4 reaction III was distilled at 40°C and -0.1 MPa to obtain 3320 kg of dichloromethane, which was reserved for the next batch.

Claims

1. A method for treating wastewater produced by the production of meropenem side chain, wherein: The method for synthesizing the meropenem side chain comprises the following steps: Reaction I: Preparation of p-nitrobenzyl chloroformate Toluene, triphosgene, and p-nitrobenzyl alcohol were added to the reaction kettle, and then dimethylaniline was added dropwise. After the reaction was completed, the organic phases were combined to obtain a toluene solution of p-nitrobenzyl chloroformate; Reaction II: Synthesis of Intermediate 1 Water and amino acid were added to the reactor, stirred and dissolved, and then liquid alkali and potassium carbonate were added to obtain a toluene solution of p-nitrobenzyl chloroformate. The solution was allowed to stand for stratification, and the aqueous phase was taken. The pH was adjusted with dilute hydrochloric acid, crystallized, centrifuged, and dried to obtain intermediate 1. The chemical structure of p-nitrobenzyl chloroformate is: ; Reaction III: Synthesis of Intermediate 2 Reactor 1 is charged with a solvent, intermediate 1, triethylamine, and isopropyl chloroformate, followed by dropwise addition of triethylamine and methylsulfonyl chloride; water and sodium hydrosulfide are added to another reactor 2, and after dissolving, a potassium carbonate solution and a phase transfer catalyst are added. After the reaction is satisfactory, the materials from the two reactors are combined and allowed to stand for separation; the organic phase is collected and subjected to heating for cyclization. After the reaction is complete, the organic phase is washed; vacuum concentration, centrifugation, washing, and vacuum drying are performed to obtain intermediate 2; Reaction IV: Synthesis of the Meropenem Side Chain Add intermediate 2, solvent and catalyst to the reactor, add dimethylamine solution dropwise, add water after the reaction is completed, adjust the pH, and let it stand for stratification; concentrate the organic phase under reduced pressure, centrifuge, wash, and vacuum dry to obtain the finished product; It is characterized in that the method for treating meropenem side chain production wastewater comprises the following steps: After the completion of S1 reaction I, the aqueous phase is bubbled with dry nitrogen. The generated tail gas is first condensed by a condenser, then absorbed by a falling film absorber, and then hydrolyzed under the action of a catalyst to destroy the phosgene. S2 is to distill the organic phase obtained in reaction II under reduced pressure, and the obtained toluene is used for the next batch of reaction, and the remaining viscous organic matter is sent to the incinerator for incineration; S3 adds a decolorizing agent to the mother liquor in reaction II for decolorization, and after decolorization, the filtrate is filtered and heated to evaporate and concentrate, thereby crystallizing sodium chloride. The evaporated mother liquor is flash-evaporated at 50°C to precipitate potassium chloride. The obtained sodium chloride and potassium chloride are sold as by-products, and the remaining high-salt wastewater is discharged to a sewage treatment plant; S4: The organic phase in reaction III is subjected to reduced pressure distillation, and the recovered dichloromethane is retained for use in the next batch.

2. The method for treating meropenem side chain production wastewater according to claim 1, wherein: In step S1, the catalyst is one or more of α-alumina, activated carbon, β-alumina and SN-7501.

3. The method for treating meropenem side chain production wastewater according to claim 1, wherein: In step S2, the reduced pressure distillation temperature is 55-65° C. and the pressure is -0.1 to -0.15 MPa.

4. The method for treating meropenem side chain production wastewater according to claim 1, wherein: In step S3, the decolorizing agent is activated carbon or diatomaceous earth, and the amount used is 5-10% of the weight of the mother liquor.

5. The method for treating meropenem side chain production wastewater according to claim 1, wherein: In step S3, the filtrate is heated to 100-120°C and evaporated to a density of 1.2-1.4 g / cm 3 .

6. The method for treating meropenem side chain production wastewater according to claim 1, wherein: In step S4, the reduced pressure distillation temperature is 35-40° C. and the pressure is -0.08 to -0.1 MPa.

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