Recycling method of avibactam intermediate production waste liquid

Abstract

The invention relates to a recycling method of avibactam intermediate production waste liquid, and belongs to the technical field of pharmaceutical chemicals. According to the method, 5-benzyloxyamino piperidine-2S-ethyl formate oxalate in the avibactam intermediate production waste liquid is desalted to be in a free state, under the condition that ethyl acetate serves as a solvent, a diluted solution of m-chloroperoxybenzoic acid is dropwise added, homogeneous reaction is carried out in the organic solvent, the utilization rate of raw materials is effectively increased, and the yield is increased. Compared with the prior art, the method has the advantages that by-products are few, the recovery rate is higher than that in the prior art, in addition, activated carbon loaded sodium triacetoxyborohydride is further prepared, the effect of catalyzing the reductive amination reaction of sodium triacetoxyborohydride can be achieved, the utilization rate of sodium triacetoxyborohydride is increased, and the yield of sodium triacetoxyborohydride is increased. The sodium triacetoxyborohydride is prevented from being in contact with water.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a method for recycling waste liquid produced by an avibactam intermediate, in particular to a method for preparing (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate from the avibactam intermediate waste liquid. Background Art

[0002] Avibactam has broad-spectrum antibacterial activity. When used in combination with various cephalosporin and carbapenem antibiotics, it can inhibit type A (including ESBL and KPC) and type C β-lactamases. It has significant activity against Escherichia coli and Klebsiella pneumoniae containing extended-spectrum β-lactamases, Escherichia coli containing excessive amounts of AmpC enzymes, and Escherichia coli containing both AmpC and extended-spectrum β-lactamases.

[0003] A Chinese patent application (publication number: CN107540600A) discloses a method for recycling waste liquid from the production of avibactam intermediates, which includes using an oxidizing agent, hydrogen peroxide, to oxidize the waste liquid of avibactam intermediates, so that the enantiomers of 5S-benzyloxyaminopiperidine-2S-formate and 5R-benzyloxyaminopiperidine-2S-formate are oxidized and converted into 5-benzyloxyiminopiperidine-2S-formate. However, the reaction is a heterogeneous reaction with low reaction efficiency, and it needs to be repeatedly treated multiple times to achieve a higher yield effect.

[0004] A Chinese patent (publication number: CN108373442A) discloses a method for recycling waste liquid from the production of an avibactam intermediate, comprising reacting (2S, 5S)-5-((benzyloxy)amino)piperidine-2-carboxylate with an amino protecting group Boc2O in the presence of a weakly alkaline substance to generate an intermediate product; performing a catalytic hydrogenation reduction reaction in the presence of a palladium-containing catalyst; then performing an oxidation reaction under the action of an oxidant to obtain a corresponding ketone intermediate product; and performing a condensation reaction of a compound of formula I with benzyloxyamine hydrochloride in the presence of an acidifying agent, followed by a deprotection reaction to obtain a final product. This route has a long number of steps, high cost, and uses a palladium metal catalyst and a hydrogen reaction in the reaction.

[0005] In view of the shortcomings of the prior art and in order to solve the problem of complicated recovery, a method for recovering an intermediate isomer of avibactam is provided, comprising: preparing 5R-benzyloxyaminopiperidine-2S-formate and 5R-benzyloxyaminopiperidine-2S-formate oxalate from the production waste liquid of the avibactam intermediate 5R-benzyloxyaminopiperidine-2S-formate oxalate (a filtrate containing 5S-benzyloxyaminopiperidine-2S-formate sulfate and (5R)-benzyloxyaminopiperidine 2S-formate oxalate with different enantiomeric ratios) in the presence of a weakly alkaline substance, and using meta-chloroperbenzoic acid (mCPBA) for homogeneous reaction in an organic solvent, the reaction efficiency is greatly improved, the yield is high, the reaction conditions are mild, and the environmental pollution is less. Summary of the invention

[0006] The object of the present invention is to provide a method for recycling waste liquid produced by the production of avibactam intermediates, so as to solve the problems mentioned in the above background technology.

[0007] The purpose of the present invention can be achieved through the following technical solutions: A method for recycling waste liquid produced by the production of an avibactam intermediate comprises the following steps: The first step is to mix N-n-butylimidazole, 3-chloropropyltriethoxysilane and toluene in a four-necked flask, install a condenser, a thermometer and a mechanical stirrer, and then stir and react at a temperature of 90-100° C. for 12 hours. After the reaction is completed, the solvent is removed by rotary evaporation to obtain an intermediate; Step 2: Mix the intermediate, activated carbon and acetonitrile in a four-necked flask, install a condenser, a thermometer and a mechanical stirrer, then add glacial acetic acid to the four-necked flask, and stir to react for 24 hours at a temperature of 50-60°C, then add sodium borohydride to the four-necked flask, and continue to stir to react for 24 hours at a temperature of 80°C. After the reaction is completed, vacuum filter, wash the obtained solid with anhydrous ethanol and dry to obtain activated carbon-supported sodium triacetoxyborohydride; The third step is to dry the avibactam intermediate production waste liquid, mix the obtained dry product with dichloromethane in an ice-water bath in a four-necked flask, install a mechanical stirrer, then add a saturated sodium bicarbonate solution to the four-necked flask, stir evenly and let stand for stratification, and drop a dichloromethane solution of m-chloroperbenzoic acid into the four-necked flask, react for 12 hours in an ice-water bath after the dropwise addition is complete, and after the reaction is completed, add a sodium sulfite solution to the four-necked flask, stir and stratify, separate the organic phase with a separatory funnel, and rotary evaporate the organic phase to obtain 5-benzyloxyiminopiperidine-2S-ethyl carboxylate; Step 4: Mix 5-benzyloxyiminopiperidine-2S-formic acid ethyl ester and ethyl acetate in a four-necked flask, install a thermometer and mechanical stirring, control the system temperature to -18 to -16 ° C, then add concentrated sulfuric acid to the four-necked flask, and stir the reaction at a temperature of -18 to -16 ° C for 1 hour, then add activated carbon-supported sodium triacetoxyborohydride to the four-necked flask, and then stir the reaction at a temperature of -18 to -16 ° C for 3 hours. After the reaction is completed, deionized water is added to the four-necked flask to quench the reaction, and 30% by mass of ammonia is added. The pH value of the system was adjusted to 8-10 with water, and then the organic phase was separated with a separatory funnel. The organic phase was washed twice with a saturated sodium chloride solution, and the washing liquid was combined with the aqueous phase in a four-necked flask. Ethanol and ethyl acetate were added to the four-necked flask, and the pH value of the system was adjusted to 5 with oxalic acid dihydrate. The reaction was stirred at 60°C for 2h. After the reaction was completed, the system temperature was cooled to room temperature and filtered. The filter cake was washed with an ethyl acetate solution of anhydrous ethanol and dried to obtain (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate.

[0008] The reaction process is as follows:

[0009] Furthermore, the amount ratio of N-n-butylimidazole, 3-chloropropyltriethoxysilane and toluene used in the first step is 0.05-0.1 mol: 0.05 mol: 50-60 mL.

[0010] Furthermore, the dosage ratio of the intermediate, activated carbon, acetonitrile, glacial acetic acid and sodium borohydride used in the second step is 0.04 mol: 30 g: 60-80 mL: 0.15-0.18 mol: 0.04 mol.

[0011] Furthermore, the methylene chloride solution of m-chloroperbenzoic acid in the third step is prepared by mixing 8-10 g of m-chloroperbenzoic acid and 50 mL of methylene chloride.

[0012] Furthermore, the dropping time of the dichloromethane solution of chloroperbenzoic acid in the third step is 0.5 to 1 hour.

[0013] Furthermore, the usage ratio of the avibactam intermediate waste liquid dry product, dichloromethane, saturated sodium bicarbonate solution, and dichloromethane solution of meta-chloroperbenzoic acid used in the third step is 12 g: 30-40 mL: 60-70 mL: 50 mL.

[0014] Furthermore, the mass fraction of concentrated sulfuric acid used in the fourth step is 95-98%.

[0015] Furthermore, the amount ratio of 5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester, ethyl acetate, concentrated sulfuric acid, activated carbon-supported sodium triacetoxyborohydride, saturated sodium chloride solution, ethanol, and ethyl acetate used in the fourth step is 8.8-8.9 g: 40 mL: 3-4 mL: 45-53 g: 30-40 mL: 8-12 mL: 0.8-1.2 mL.

[0016] Furthermore, the ethyl acetate solution of anhydrous ethanol used in the fourth step is prepared by mixing 10 parts of anhydrous ethanol and 1 part of ethyl acetate, by volume.

[0017] Beneficial effects of the present invention: The invention uses N-n-butyl imidazole and 3-chloropropyltriethoxysilane as raw materials to prepare an ionic liquid through a quaternary ammonium salt reaction, and then grafts the ionic liquid onto activated carbon through the silicon-oxygen bond of the intermediate ionic liquid, and uses the activated carbon to carry sodium triacetoxyborohydride, thereby effectively avoiding the contact between the sodium triacetoxyborohydride and water. Meanwhile, the imidazole-based ionic liquid can also play a role in catalyzing the reduction amination reaction, thereby improving the reaction efficiency. After the sodium triacetoxyborohydride in the sodium triacetoxyborohydride carried on the activated carbon is consumed, the activated carbon grafted with the ionic liquid can be recovered and reused, and the activated carbon can be repeatedly carried with sodium triacetoxyborohydride.

[0018] The invention desalts 5-benzyloxyaminopiperidine-2S-ethyl carboxylate oxalate in the avibactam intermediate production waste liquid to become a free state, and drips a diluted solution of meta-chloroperbenzoic acid under the condition of ethyl acetate as a solvent to carry out a homogeneous reaction in an organic solvent, thereby effectively improving the utilization rate of the raw materials, having the advantage of less by-products, and having a higher recovery rate than the prior art. DETAILED DESCRIPTION

[0019] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0020] Example 1: In order to accurately calculate the recovery rate, 5-benzyloxyaminopiperidine-2S-carboxylic acid ethyl ester oxalate was used to replace the avibactam intermediate waste liquid dry product, and a gas or liquid chromatograph was used to monitor the reaction process and product purity. The optical purity was detected by a liquid chromatograph equipped with a chiral column (CHIRALPAK AD-H, 250 mm×4.6 mm 5um Waters2489).

[0021] A method for recycling waste liquid produced by the production of an avibactam intermediate comprises the following steps: The first step is to mix 0.05 mol N-n-butyl imidazole, 0.05 mol 3-chloropropyltriethoxysilane and 50 mL toluene in a four-necked flask, and install a condenser, a thermometer and a mechanical stirrer, and then stir and react at a temperature of 90°C for 12 hours. After the reaction is completed, the solvent is removed by rotary evaporation to obtain an intermediate; Step 2: 0.04 mol of the intermediate, 30 g of activated carbon, and 60 mL of acetonitrile were mixed in a four-necked flask, and a condenser, a thermometer, and a mechanical stirrer were installed. Then, 0.15 mol of glacial acetic acid was added to the four-necked flask, and the mixture was stirred at 50°C for 24 hours. Then, 0.04 mol of sodium borohydride was added to the four-necked flask, and the mixture was stirred at 80°C for 24 hours. After the reaction was completed, vacuum filtration was performed, and the obtained solid was washed with anhydrous ethanol and dried to obtain activated carbon-supported sodium triacetoxyborohydride. The third step is to mix 12g of 5-benzyloxyaminopiperidine-2S-ethyl formate oxalate and 30mL of dichloromethane in a four-necked flask under ice-water bath conditions, and install a mechanical stirrer. Then, 60mL of saturated sodium bicarbonate solution is added to the four-necked flask, and the mixture is allowed to stand for stratification after stirring evenly. 50mL of a solution prepared by 10g of m-chloroperbenzoic acid and 50mL of dichloromethane is added dropwise to the four-necked flask for 0.5h. After the addition is complete, the mixture is reacted in an ice-water bath for 12h. After the reaction is completed, 15mL of a 10% sodium sulfite solution by mass is added to the four-necked flask, and the mixture is stirred and layered. After the organic phase is separated by a separatory funnel, the organic phase is rotary evaporated to obtain 8.8g of 5-benzyloxyiminopiperidine-2S-ethyl formate. The yield of this step is 97.78%. Step 4: Mix 8.8 g of 5-benzyloxyiminopiperidine-2S-ethyl carboxylate and 40 mL of ethyl acetate in a four-necked flask, install a thermometer and mechanical stirring, control the system temperature to -18 to -16 ° C, then add 3 mL of 95% concentrated sulfuric acid to the four-necked flask, and stir to react for 1 hour at a temperature of -18 to -16 ° C, then add 45 g of activated carbon-supported sodium triacetoxyborohydride to the four-necked flask, and then stir to react for 3 hours at a temperature of -18 to -16 ° C. After the reaction is completed, 20 mL of deionized water is added to the four-necked flask to quench the reaction, and the pH of the system is adjusted to 8 with 30% ammonia water by mass, and then a separatory filter is used. The organic phase was separated by a bucket, and the organic phase was washed twice with 30 mL of saturated sodium chloride solution, and the washing liquid was combined with the aqueous phase in a four-necked flask, and then 8 mL of ethanol and 0.8 mL of ethyl acetate were added to the four-necked flask, and the pH of the system was adjusted to 5 with oxalic acid dihydrate. Then, the reaction was stirred at 60°C for 2 hours. After the reaction, the system temperature was cooled to room temperature and filtered. The filter cake was washed with an ethyl acetate solution of anhydrous ethanol (volume ratio of anhydrous ethanol: ethyl acetate = 10:1) and dried to obtain 8.7 g of (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate with a chiral HPLC purity of 99.5%. The yield of this step was 73.77%.

[0022] The total yield of (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate in this example is 72.14%.

[0023] Example 2: In order to accurately calculate the recovery rate, 5-benzyloxyaminopiperidine-2S-carboxylic acid ethyl ester oxalate was used to replace the avibactam intermediate waste liquid dry product, and a gas or liquid chromatograph was used to monitor the reaction process and product purity. The optical purity was detected by a liquid chromatograph equipped with a chiral column (CHIRALPAK AD-H, 250 mm×4.6 mm 5um Waters2489).

[0024] A method for recycling waste liquid produced by the production of an avibactam intermediate comprises the following steps: The first step is to mix 0.075 mol N-n-butyl imidazole, 0.05 mol 3-chloropropyltriethoxysilane and 55 mL toluene in a four-necked flask, and install a condenser, a thermometer and a mechanical stirrer, and then stir and react at a temperature of 95°C for 12 hours. After the reaction is completed, the solvent is removed by rotary evaporation to obtain an intermediate; Step 2: 0.04 mol of the intermediate, 30 g of activated carbon, and 70 mL of acetonitrile were mixed in a four-necked flask, and a condenser, a thermometer, and a mechanical stirrer were installed. Then, 0.165 mol of glacial acetic acid was added to the four-necked flask, and the mixture was stirred at 55°C for 24 hours. Then, 0.04 mol of sodium borohydride was added to the four-necked flask, and the mixture was stirred at 80°C for 24 hours. After the reaction was completed, vacuum filtration was performed, and the obtained solid was washed with anhydrous ethanol and dried to obtain activated carbon-supported sodium triacetoxyborohydride. The third step is to mix 12g of 5-benzyloxyaminopiperidine-2S-ethyl formate oxalate and 35mL of dichloromethane in a four-necked flask under ice-water bath conditions, and install a mechanical stirrer. Then, 65mL of saturated sodium bicarbonate solution is added to the four-necked flask, and the mixture is allowed to stand for stratification after stirring evenly. 50mL of a solution prepared by 9g of m-chloroperbenzoic acid and 50mL of dichloromethane is added dropwise to the four-necked flask for 0.75h. After the addition is complete, the mixture is reacted in an ice-water bath for 12h. After the reaction is completed, 20mL of a 10% sodium sulfite solution by mass is added to the four-necked flask, and the mixture is stirred and layered. After the organic phase is separated by a separatory funnel, the organic phase is rotary evaporated to obtain 8.9g of 5-benzyloxyiminopiperidine-2S-ethyl formate. The yield of this step is 98.89%. The fourth step is to mix 8.9g of 5-benzyloxyiminopiperidine-2S-ethyl carboxylate and 40mL of ethyl acetate in a four-necked flask, install a thermometer and mechanical stirring, control the system temperature to -18 to -16°C, then add 3.5mL of 96% concentrated sulfuric acid to the four-necked flask, and stir the reaction at a temperature of -18 to -16°C for 1 hour, then add 49g of activated carbon-supported sodium triacetoxyborohydride to the four-necked flask, and then stir the reaction at a temperature of -18 to -16°C for 3h. After the reaction is completed, 20mL of deionized water is added to the four-necked flask to quench the reaction, and the pH of the system is adjusted to 9 with 30% ammonia water by mass, and then separated by separation. The organic phase was separated by a funnel, and the organic phase was washed twice with 35 mL of saturated sodium chloride solution, and the washing liquid was combined with the aqueous phase in the four-necked flask. Then 10 mL of ethanol and 1 mL of ethyl acetate were added to the four-necked flask, and the pH of the system was adjusted to 5 with oxalic acid dihydrate. Then, the reaction was stirred at 60 ° C for 2 h. After the reaction was completed, the system temperature was cooled to room temperature and filtered. The filter cake was washed with an ethyl acetate solution of anhydrous ethanol (volume ratio of anhydrous ethanol: ethyl acetate = 10:1) and dried to obtain 9.1 g of (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate with a chiral HPLC purity of 99.7%. The yield of this step was 76.48%.

[0025] The total yield of (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate in this example is 75.63%.

[0026] Example 3: In order to accurately calculate the recovery rate, 5-benzyloxyaminopiperidine-2S-carboxylic acid ethyl ester oxalate was used to replace the avibactam intermediate waste liquid dry product, and a gas or liquid chromatograph was used to monitor the reaction process and product purity. The optical purity was detected by a liquid chromatograph equipped with a chiral column (CHIRALPAK AD-H, 250 mm×4.6 mm 5um Waters2489).

[0027] A method for recycling waste liquid produced by the production of an avibactam intermediate comprises the following steps: The first step is to mix 0.1 mol N-n-butyl imidazole, 0.05 mol 3-chloropropyltriethoxysilane and 60 mL toluene in a four-necked flask, install a condenser, a thermometer and a mechanical stirrer, and then stir the reaction at a temperature of 100° C. for 12 hours. After the reaction is completed, the solvent is removed by rotary evaporation to obtain an intermediate; Step 2: 0.04 mol of the intermediate, 30 g of activated carbon, and 80 mL of acetonitrile were mixed in a four-necked flask, and a condenser, a thermometer, and a mechanical stirrer were installed. Then, 0.18 mol of glacial acetic acid was added to the four-necked flask, and the mixture was stirred at 60°C for 24 hours. Then, 0.04 mol of sodium borohydride was added to the four-necked flask, and the mixture was stirred at 80°C for 24 hours. After the reaction was completed, vacuum filtration was performed, and the obtained solid was washed with anhydrous ethanol and dried to obtain activated carbon-supported sodium triacetoxyborohydride. The third step is to mix 12g of 5-benzyloxyaminopiperidine-2S-ethyl formate oxalate and 30mL of dichloromethane in a four-necked flask under ice-water bath conditions, and install a mechanical stirrer. Then, 70mL of saturated sodium bicarbonate solution is added to the four-necked flask, and the mixture is allowed to stand for stratification after stirring evenly. 50mL of a solution prepared by 10g of m-chloroperbenzoic acid and 50mL of dichloromethane is added dropwise to the four-necked flask for 1h. After the addition is complete, the mixture is reacted in an ice-water bath for 12h. After the reaction is completed, 25mL of a 10% sodium sulfite solution by mass is added to the four-necked flask, and the mixture is stirred and layered. After the organic phase is separated by a separatory funnel, the organic phase is rotary evaporated to obtain 8.9g of 5-benzyloxyiminopiperidine-2S-ethyl formate. The yield of this step is 98.89%. Step 4: Mix 8.9 g of 5-benzyloxyiminopiperidine-2S-ethyl carboxylate and 40 mL of ethyl acetate in a four-necked flask, install a thermometer and mechanical stirring, control the system temperature to -18 to -16 ° C, then add 4 mL of 95-98% concentrated sulfuric acid to the four-necked flask, and stir the reaction for 1 hour at a temperature of -18 to -16 ° C, then add 53 g of activated carbon-supported sodium triacetoxyborohydride to the four-necked flask, and then stir the reaction for 3 hours at a temperature of -18 to -16 ° C. After the reaction, add 20 mL of deionized water to the four-necked flask to quench the reaction, and adjust the pH of the system to 10 with 30% ammonia water by mass, and then use a separatory The organic phase was separated by a funnel, and the organic phase was washed twice with 40 mL of saturated sodium chloride solution, and the washing liquid was combined with the aqueous phase in the four-necked flask. Then, 12 mL of ethanol and 1.2 mL of ethyl acetate were added to the four-necked flask, and the pH of the system was adjusted to 5 with oxalic acid dihydrate. Then, the reaction was stirred at 60 ° C for 2 h. After the reaction, the system temperature was cooled to room temperature and filtered. The filter cake was washed with an ethyl acetate solution of anhydrous ethanol (volume ratio of anhydrous ethanol: ethyl acetate = 10:1) and dried to obtain 9.2 g of (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate with a chiral HPLC purity of 99.8%. The yield of this step was 77.40%.

[0028] The total yield of (2S,5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate in this example is 76.54%.

[0029] Comparative Example 1: This comparative example is a method for recycling waste liquid from the production of an avibactam intermediate according to Chinese patent CN107540600A.

[0030] Add 50g of ethyl acetate and 11g of 5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester to a four-necked flask equipped with a stirrer and a thermometer, keep the system temperature between -20℃ and -15℃, add 20.1g of 98% concentrated sulfuric acid dropwise, stir for 1 hour after the addition is complete. Add 19g of sodium triacetoxyborohydride at -20℃, and stir and react at -20℃ to -15℃ for 5 hours. Keep the temperature below 0℃, add 20g of water to quench the reaction; neutralize with ammonia water to a pH value of 7-8. Separate the layers and wash the organic layer twice with saturated brine, 10g each time. Concentrate the organic phase to recover the solvent, then add 32g of ethyl acetate, 16g of methanol, and 5.2g of oxalic acid dihydrate to the residue, heat to 45℃, stir for 2 hours, cool, and filter. Wash the filter cake with 10g of ethyl acetate / methanol (2:1) mixed solution, and then wash with 5g of ethyl acetate. The filter cake was dried in vacuo to obtain 9.7 g of a single isomer, 5R-benzyloxyaminopiperidine-2S-carboxylic acid ethyl ester oxalate, with a chiral HPLC purity of 99.7% and a yield of 66.16%.

[0031] It can be seen from Comparative Example 1 that, compared with patent CN107540600A, the preparation method of the present invention has a better recovery rate.

[0032] The above is a detailed introduction to the recycling method of the avibactam intermediate production waste liquid provided by the present invention. The principle and implementation method of the present invention are described in detail using specific examples herein. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enables any technician in the field to practice the present invention, including manufacturing and using any device or system, and implementing any combination method. It should be pointed out that for ordinary technicians in the technical field, the present invention can also be improved and modified without departing from the principle of the present invention. In particular, as long as there is no structural conflict, the various features in the embodiments disclosed in the present invention can be used in combination with each other in any way. The fact that these combinations are not exhaustively described in this specification is only for the purpose of omitting space and saving resources. Therefore, the present invention is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

Claims

1. A method for recycling waste liquid produced by the production of avibactam intermediates, characterized in that: The following steps are involved: The first step is to mix N-n-butylimidazole, 3-chloropropyltriethoxysilane and toluene in a container, stir evenly, and react at a temperature of 90-100° C. for 12 hours to obtain an intermediate; Step 2: Mix the intermediate, activated carbon and acetonitrile in a container, stir evenly, add glacial acetic acid to the container, and react at a temperature of 50-60° C. for 24 hours, then add sodium borohydride to the container, and continue to react at a temperature of 80° C. for 24 hours to obtain activated carbon-supported sodium triacetoxyborohydride; The third step is to dry the avibactam intermediate production waste liquid, mix the obtained dry product with dichloromethane in a container under ice-water bath conditions, stir evenly, add saturated sodium bicarbonate solution to the container, and after the reaction solution is layered, add a dichloromethane solution of m-chloroperbenzoic acid dropwise to the container, and after the dropwise addition is completed, react for 12 hours under ice-water bath conditions to obtain 5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester; Step 4: Mix 5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester and ethyl acetate in a container, stir evenly, control the system temperature to -18 to -16°C, then add concentrated sulfuric acid to the container, react at -18 to -16°C for 1 hour, then add activated carbon-supported sodium triacetoxyborohydride to the container, and then react at -18 to -16°C for 3 hours. After the reaction, add deionized water to the container to quench the reaction, and adjust the pH of the system to 8 to 10 with 30% ammonia water by mass, then separate the organic phase, wash the organic phase twice with saturated sodium chloride solution, merge the washing liquid into the aqueous phase in the container, add ethanol and ethyl acetate to the container, and adjust the pH of the system to 5 with oxalic acid dihydrate, and then react at 60°C for 2 hours. After the reaction, cool the system to room temperature and filter, wash the obtained filter cake with anhydrous ethanol ethyl acetate solution and dry to obtain (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate.

2. The method for recycling waste liquid produced by an avibactam intermediate according to claim 1, characterized in that: The amount ratio of N-n-butylimidazole, 3-chloropropyltriethoxysilane and toluene used in the first step is 0.05-0.1 mol: 0.05 mol: 50-60 mL.

3. The method for recycling waste liquid produced by the production of an avibactam intermediate according to claim 1, characterized in that: The amount ratio of the intermediate, activated carbon, acetonitrile, glacial acetic acid and sodium borohydride used in the second step is 0.04 mol: 30 g: 60-80 mL: 0.15-0.18 mol: 0.04 mol.

4. The method for recycling waste liquid produced by the production of an avibactam intermediate according to claim 1, characterized in that: The methylene chloride solution of m-chloroperbenzoic acid in the third step is prepared by mixing 8-10 g of m-chloroperbenzoic acid with 50 mL of methylene chloride.

5. The method for recycling waste liquid produced by avibactam intermediate according to claim 1, characterized in that: The dropping time of the dichloromethane solution of chloroperbenzoic acid in the third step is 0.5 to 1 hour.

6. The method for recycling waste liquid produced by avibactam intermediate according to claim 1, characterized in that: The usage ratio of the avibactam intermediate waste liquid dry product, dichloromethane, saturated sodium bicarbonate solution, and dichloromethane solution of meta-chloroperbenzoic acid used in the third step is 12 g: 30-40 mL: 60-70 mL: 50 mL.

7. The method for recycling waste liquid produced by avibactam intermediate according to claim 1, characterized in that: The mass fraction of concentrated sulfuric acid used in the fourth step is 95-98%.

8. The method for recycling waste liquid produced by avibactam intermediate according to claim 1, characterized in that: The amount ratio of 5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester, ethyl acetate, concentrated sulfuric acid, activated carbon-supported sodium triacetoxyborohydride, saturated sodium chloride solution, ethanol, and ethyl acetate used in the fourth step is 8.8-8.9 g: 40 mL: 3-4 mL: 45-53 g: 30-40 mL: 8-12 mL: 0.8-1.2 mL.

9. The method for recycling waste liquid produced by avibactam intermediate according to claim 1, characterized in that: The ethyl acetate solution of anhydrous ethanol used in the fourth step is prepared by mixing 10 parts of anhydrous ethanol and 1 part of ethyl acetate by volume.

10. The method for recycling waste liquid produced by avibactam intermediate according to claim 1, characterized in that: The method is used for preparing (2S,5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate from the waste liquid of avibactam intermediate production.

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