A method for recycling of avibactam intermediate production waste liquid

Abstract

The present application relates to a kind of recycling method of avibactam intermediate production waste liquid, belong to pharmaceutical chemical technology field;The present application will be in the 5-benzyloxyamine piperidin-2S-formic acid ethyl ester oxalate in avibactam intermediate production waste liquid by desalination into free state, under the condition of ethyl acetate as solvent, using the dilute solution of m-chloroperbenzoic acid drop, homogeneous reaction in organic solvent, effectively improve the utilization of raw material, with the advantage of less by-product, and have higher recovery rate than prior art, in addition, the present application also prepares a kind of activated carbon loaded sodium triacetoxyborohydride, can play the role of catalytic sodium triacetoxyborohydride reduction amination reaction, improve the utilization of sodium triacetoxyborohydride, and prevent sodium triacetoxyborohydride from contacting with water.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine and chemical industry, and particularly relates to a recycling method of an avibactam intermediate production waste liquid, in particular to a method for preparing (2S, 5R)-benzyloxyaminopiperidine-2-methylate ethyl oxalate from the avibactam intermediate waste liquid. BACKGROUND

[0002] The avibactam has broad-spectrum antibacterial activity, and when combined with various cephalosporins and carbapenem antibiotics, can inhibit type A (including ESBL and KPC) and type C beta-lactamase, and has significant activity on escherichia coli containing super broad-spectrum beta-lactamase and klebsiella pneumoniae, escherichia coli containing excessive AmpC enzyme, and escherichia coli containing AmpC and super broad-spectrum beta-lactamase at the same time.

[0003] Chinese patent application (publication number: CN107540600A) discloses a recycling method of an avibactam intermediate production waste liquid, which comprises oxidizing the avibactam intermediate waste liquid by using an oxidizing agent hydrogen peroxide, so that 5S-benzyloxyaminopiperidine-2S-methylate and 5R-benzyloxyaminopiperidine-2S-methylate enantiomeric isomers are oxidized and converted into 5-benzyloxyiminopiperidine-2S-methylate. However, the reaction is a heterogeneous reaction, the reaction efficiency is low, and multiple repeated treatments are required to achieve a high yield effect.

[0004] Chinese patent (publication number: CN108373442A) discloses a recycling method of an avibactam intermediate production waste liquid, which comprises the following steps: in the presence of a weak alkaline substance, (2S, 5S)-5-((benzyloxy) amino) piperidine-2-methylate is reacted with an amino protecting group Boc2O to generate an intermediate product; in the presence of a palladium catalyst, a catalytic hydrogenation reduction reaction is carried out; then under the action of an oxidizing agent, an oxidation reaction is carried out to obtain a corresponding ketone intermediate product; in the presence of an acid agent, a condensation reaction of the compound of formula I with a benzyloxyamine hydrochloride is carried out, and then a deprotection reaction is carried out to obtain a final product. The route has long steps, high cost, and uses a palladium metal catalyst and hydrogen gas in the reaction.

[0005] In view of the deficiencies of the prior art, in order to solve the existing recycling complex problems, the application provides a recycling method of avibactam intermediate isomer, which comprises the following steps: in the presence of weak alkaline substance, 5R-benzyloxyaminopiperidine-2S-carboxylate oxalate production waste liquid (containing 5S-benzyloxyaminopiperidine-2S-carboxylate sulfate, filtrate of (5R)-benzyloxyaminopiperidine 2S-carboxylate oxalate with different enantiomer proportions) is used to prepare 5R-benzyloxyaminopiperidine-2S-carboxylate and 5R-benzyloxyaminopiperidine-2S-carboxylate oxalate, and the reaction efficiency is greatly improved by using m-chloroperoxybenzoic acid (mCPBA) in a homogeneous reaction in an organic solvent, and the method has the advantages of high yield, mild reaction conditions, and less environmental pollution. SUMMARY

[0006] The application aims to provide a recycling method of avibactam intermediate production waste liquid, which is used to solve the problems mentioned in the background.

[0007] The application can achieve the above-mentioned purposes by the following technical scheme.

[0008] The application provides a recycling method of avibactam intermediate production waste liquid, which comprises the following steps:

[0009] In the first step, N-n-butylimidazole, 3-chloropropyl triethoxysilane and toluene are mixed in a four-necked flask, a condenser tube, a thermometer and a mechanical stirrer are installed, then the mixture is stirred at a temperature of 90-100 DEG C for 12 hours, after the reaction is completed, the solvent is removed by rotary evaporation to obtain an intermediate;

[0010] In the second step, the intermediate, activated carbon and acetonitrile are mixed in a four-necked flask, a condenser tube, a thermometer and a mechanical stirrer are installed, then glacial acetic acid is added to the four-necked flask, and the mixture is stirred at a temperature of 50-60 DEG C for 24 hours, then sodium borohydride is added to the four-necked flask, and the mixture is continuously stirred at a temperature of 80 DEG C for 24 hours, after the reaction is completed, the mixture is vacuum filtered, the obtained solid is washed with anhydrous ethanol and dried to obtain activated carbon loaded sodium triacetoxyborohydride;

[0011] In the third step, the avibactam intermediate production waste liquid is dried, and the obtained dry product is mixed with dichloromethane in a four-necked flask under the condition of ice water bath, a mechanical stirrer is installed, then saturated sodium bicarbonate solution is added to the four-necked flask, the mixture is stirred uniformly, then it is left to stand and separate into layers, and m-chloroperoxybenzoic acid dichloromethane solution is added dropwise to the four-necked flask, after the dropwise addition is completed, the mixture is reacted at the condition of ice water bath for 12 hours, after the reaction is completed, sodium sulfite solution is added to the four-necked flask, the mixture is stirred and separated into layers, the organic phase is separated by a separatory funnel, and then 5-benzyloxyiminopiperidine-2S-carboxylate is obtained by rotary evaporation of the organic phase;

[0012] Fourth step, 5-benzyloxyimino piperidine-2S-ethyl formate and ethyl acetate are mixed in a four-necked flask, a thermometer and a mechanical stirrer are installed, the temperature of the system is controlled at-18 to-16℃, then concentrated sulfuric acid is added to the four-necked flask, and stirred at a temperature of-18 to-16℃ for 1 hour, then activated carbon loaded sodium triacetoxyborohydride is added to the four-necked flask, then stirred at a temperature of-18 to-16℃ for 3 hours, after the reaction is completed, deionized water is added to the four-necked flask to quench the reaction, and the pH of the system is adjusted to 8-10 with 30% ammonia water, then the organic phase is separated with a separatory funnel, the organic phase is washed twice with saturated sodium chloride solution, then the washing liquid is combined into the aqueous phase in the four-necked flask, then ethanol, ethyl acetate and oxalic acid dihydrate are added to the four-necked flask to adjust the pH of the system to 5, then stirred at a temperature of 60℃ for 2 hours, after the reaction is completed, the temperature of the system is cooled to room temperature and filtered, the obtained filter cake is washed with anhydrous ethanol in ethyl acetate and dried to obtain (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate.

[0013] The reaction process is as follows:

[0014]

[0015] Further, the amount ratio of N-n-butyl imidazole, 3-chloropropyl triethoxysilane and toluene used in the first step is 0.05-0.1 mol: 0.05 mol: 50-60 mL.

[0016] Further, 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.

[0017] Further, the dichloromethane solution of meta-chloroperoxybenzoic acid in the third step is mixed by 8-10 g of meta-chloroperoxybenzoic acid and 50 mL of dichloromethane.

[0018] Further, the dropwise time of the dichloromethane solution of meta-chloroperoxybenzoic acid in the third step is 0.5-1 h.

[0019] Further, the amount ratio of the dried product of the avibactam intermediate waste liquid, dichloromethane, saturated sodium bicarbonate solution and dichloromethane solution of meta-chloroperoxybenzoic acid used in the third step is 12 g: 30-40 mL: 60-70 mL: 50 mL.

[0020] Further, the mass fraction of concentrated sulfuric acid used in the fourth step is 95-98%.

[0021] Further, the amount ratio of 5-benzyloxyimino piperidin-2S-carboxylic acid ethyl ester, ethyl acetate, concentrated sulfuric acid, activated carbon loaded sodium triacetoxyborohydride, saturated sodium chloride solution, ethanol, 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.

[0022] Further, the solution of anhydrous ethanol in ethyl acetate used in the fourth step is mixed by 10 parts of anhydrous ethanol and 1 part of ethyl acetate.

[0023] The beneficial effects of the present application are:

[0024] The present application uses N-n-butyl imidazole and 3-chloropropyl triethoxysilane as raw materials to prepare an ionic liquid through quaternary ammonium salt reaction, and then grafts the ionic liquid on activated carbon through the silicon-oxygen bond of the intermediate ionic liquid, and uses the activated carbon to carry sodium triacetoxyborohydride, which effectively avoids the contact of sodium triacetoxyborohydride with water, and the imidazole-based ionic liquid can also play a role in catalyzing the reduction amination reaction, which can improve the efficiency of the reaction. After the consumption of sodium triacetoxyborohydride in the activated carbon loaded sodium triacetoxyborohydride, the activated carbon can be recycled and reused to graft the ionic liquid, and the activated carbon can be reused to carry sodium triacetoxyborohydride.

[0025] The present application uses N-n-butyl imidazole and 3-chloropropyl triethoxysilane as raw materials to prepare an ionic liquid through quaternary ammonium salt reaction, and then grafts the ionic liquid on activated carbon through the silicon-oxygen bond of the intermediate ionic liquid, and uses the activated carbon to carry sodium triacetoxyborohydride, which effectively avoids the contact of sodium triacetoxyborohydride with water, and the imidazole-based ionic liquid can also play a role in catalyzing the reduction amination reaction, which can improve the efficiency of the reaction. After the consumption of sodium triacetoxyborohydride in the activated carbon loaded sodium triacetoxyborohydride, the activated carbon can be recycled and reused to graft the ionic liquid, and the activated carbon can be reused to carry sodium triacetoxyborohydride. DETAILED DESCRIPTION

[0026] The technical solutions in the embodiments of the present application will be clearly and completely described below in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0027] Example 1: In order to accurately calculate the recovery rate, 5-benzyloxyimino piperidin-2S-carboxylic acid ethyl ester oxalate is used to replace the dried product of the intermediate waste liquid of avibactam, and gas or liquid chromatographs are used to monitor the reaction process and product purity, and a liquid chromatograph equipped with a chiral column (CHIRALPAK AD-H, 250mmx4.6mm 5um Waters 2489) is used to detect optical purity.

[0028] A recycling method of an avibactam intermediate production waste liquid, comprising the following steps:

[0029] The first step, 0.05 mol of N-n-butyl imidazole, 0.05 mol of 3-chloropropyl triethoxysilane, 50 mL of toluene are mixed in a four-necked flask, and a condenser tube, a thermometer and a mechanical stirrer are installed, then the reaction is stirred at a temperature of 90 DEG C for 12 hours, after the reaction is completed, the solvent is removed by rotary evaporation to obtain an intermediate;

[0030] The second step, 0.04 mol of the intermediate, 30 g of activated carbon, and 60 mL of acetonitrile are mixed in a four-necked flask, and a condenser tube, a thermometer and a mechanical stirrer are installed, then 0.15 mol of glacial acetic acid is added to the four-necked flask, and the reaction is stirred at a temperature of 50 DEG C for 24 hours, then 0.04 mol of sodium borohydride is added to the four-necked flask, and the reaction is continued to stir at a temperature of 80 DEG C for 24 hours, after the reaction is completed, vacuum filtration is carried out, and the obtained solid is washed with anhydrous ethanol and dried to obtain activated carbon loaded sodium triacetoxy borohydride;

[0031] The third step, 12 g of 5-benzyloxyamino piperidine-2S-methyl acetate oxalate is mixed with 30 mL of dichloromethane in a four-necked flask under ice water bath condition, and a mechanical stirrer is installed, then 60 mL of saturated sodium bicarbonate solution is added to the four-necked flask, stirred uniformly, and then separated into layers, and 50 mL of a solution prepared by dissolving 10 g of m-chloroperbenzoic acid in 50 mL of dichloromethane is added dropwise to the four-necked flask, the dropwise time is 0.5 h, after the dropwise addition is completed, the reaction is carried out under ice water bath condition for 12 h, after the reaction is completed, 15 mL of 10% sodium sulfite solution is added to the four-necked flask, stirred and separated into layers, and the organic phase is separated by a separatory funnel, then the organic phase is rotary evaporated to obtain 8.8 g of 5-benzyloxyamino piperidine-2S-methyl acetate, and the yield of this step is 97.78%;

[0032] Fourth step, 8.8 g of 5-benzyloxyimino piperidin-2S-carboxylic acid ethyl ester and 40 mL of ethyl acetate were mixed in a four-necked flask, equipped with a thermometer and mechanical stirring, and the temperature of the system was controlled at -18 to -16°C, then 3 mL of 95% concentrated sulfuric acid was added to the four-necked flask, and the reaction was stirred at a temperature of -18 to -16°C for 1 hour, then 45 g of activated carbon supported sodium triacetoxyborohydride was added to the four-necked flask, and the reaction was stirred at a temperature of -18 to -16°C for 3 hours, then 20 mL of deionized water was added to the four-necked flask to quench the reaction, and the pH of the system was adjusted to 8 with 30% ammonia water, then the organic phase was separated with a separatory funnel, and the organic phase was washed twice with 30 mL of saturated sodium chloride solution, then the washing liquid was combined with the aqueous phase in the four-necked flask, 8 mL of ethanol, 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 a temperature of 60°C for 2 hours, after the reaction was completed, the temperature of the system was cooled to room temperature and filtered, the obtained filter cake was washed with anhydrous ethanol in ethyl acetate solution (volume ratio of anhydrous ethanol: ethyl acetate = 10:1) and dried to obtain 8.7 g of (2S, 5R)-benzyloxyamino piperidine-2-carboxylic acid ethyl ester oxalate, the chiral HPLC purity was 99.5%, and the yield of this step was 73.77%.

[0033] The total yield of (2S, 5R)-benzyloxyamino piperidine-2-carboxylic acid ethyl ester oxalate in this example was 72.14%.

[0034] Example 2: In order to accurately calculate the recovery rate, 5-benzyloxyamino piperidine-2S-carboxylic acid ethyl ester oxalate was used to replace the dried product of the intermediate waste liquid of avibactam, and gas or liquid chromatography was used to monitor the reaction process and product purity, and a liquid chromatograph equipped with a chiral column (CHIRALPAK AD-H, 250mm x 4.6mm 5um Waters 2489) was used to detect optical purity.

[0035] A method for recycling avibactam intermediate production waste liquid, comprising the following steps:

[0036] First step, 0.075 mol of N-n-butyl imidazole, 0.05 mol of 3-chloropropyl triethoxysilane, and 55 mL of toluene were mixed in a four-necked flask, equipped with a condenser, a thermometer, and mechanical stirring, then the reaction was stirred at a temperature of 95°C for 12 hours, after the reaction was completed, the solvent was removed by rotary evaporation to obtain an intermediate;

[0037] Second step, 0.04 mol of intermediate, 30 g of activated carbon, 70 mL of acetonitrile were mixed in a four-necked flask, and a condenser tube, 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 reaction was stirred at 55°C for 24 h. Then 0.04 mol of sodium borohydride was added to the four-necked flask, and the reaction was continuously stirred at 80°C for 24 h. After the reaction was completed, vacuum filtration was performed, and the obtained solid was washed with anhydrous ethanol and dried to obtain activated carbon loaded sodium triacetoxyborohydride;

[0038] Third step, 12 g of 5-benzyloxyamino piperidin-2S-carboxylic acid ethyl ester oxalate salt was mixed with 35 mL of dichloromethane in a four-necked flask under ice water bath condition, and a mechanical stirrer was installed. Then 65 mL of saturated sodium bicarbonate solution was added to the four-necked flask, and after stirring uniformly, it was allowed to stand and separate into layers. Then 50 mL of a solution prepared by dissolving 9 g of meta-chloro peroxybenzoic acid in 50 mL of dichloromethane was added dropwise to the four-necked flask, and the dropwise addition was performed for 0.75 h. After the dropwise addition was completed, the reaction was performed at ice water bath condition for 12 h. After the reaction was completed, 20 mL of 10% by mass sodium sulfite solution was added to the four-necked flask, and it was stirred and separated into layers. Then the organic phase was separated using a separatory funnel, and the organic phase was rotary evaporated to obtain 8.9 g of 5-benzyloxyamino piperidin-2S-carboxylic acid ethyl ester. The yield of this step was 98.89%.

[0039] Fourth step, 8.9 g of 5-benzyloxyamino piperidin-2S-carboxylic acid ethyl ester and 40 mL of ethyl acetate were mixed in a four-necked flask, and a thermometer and a mechanical stirrer were installed. Then the temperature of the system was controlled to be -18 to -16°C, and then 3.5 mL of 96% by mass concentrated sulfuric acid was added to the four-necked flask, and the reaction was stirred at -18 to -16°C for 1 h. Then 49 g of activated carbon loaded sodium triacetoxyborohydride was added to the four-necked flask, and the reaction was stirred at -18 to -16°C for 3 h. After the reaction was completed, 20 mL of deionized water was added to the four-necked flask to quench the reaction, and the pH of the system was adjusted to 9 using 30% by mass ammonia water. Then the organic phase was separated using a separatory funnel, and the organic phase was washed twice using 35 mL of saturated sodium chloride solution. Then the washing liquid was combined with the aqueous phase in the four-necked flask, and 10 mL of ethanol, 1 mL of ethyl acetate and oxalic acid dihydrate were added to the four-necked flask to adjust the pH of the system to 5. Then the reaction was stirred at 60°C for 2 h. After the reaction was completed, the temperature of the system was cooled to room temperature, and then filtration was performed. The obtained filter cake was washed with anhydrous ethanol in ethyl acetate solution (volume ratio of anhydrous ethanol: ethyl acetate = 10:1) and dried to obtain 9.1 g of (2S, 5R)-benzyloxyamino piperidin-2-carboxylic acid ethyl ester oxalate salt. The chiral HPLC purity was 99.7%, and the yield of this step was 76.48%.

[0040] The total yield of (2S, 5R)-benzyloxyamino piperidin-2-carboxylic acid ethyl ester oxalate salt in this example was 75.63%.

[0041] Example 3: To accurately calculate the recovery rate, 5-benzyloxyaminopiperidin-2S-ethyl carboxylate oxalate salt was used to replace the drying product of the intermediate waste liquid of avibactam, and gas or liquid chromatography was used to monitor the reaction process and product purity, and optical purity was detected by a liquid chromatograph equipped with a chiral column (CHIRALPAK AD-H, 250mm x 4.6mm 5um Waters 2489).

[0042] A recycling method of an avibactam intermediate production waste liquid, comprising the following steps:

[0043] Step 1, 0.1 mol of N-n-butyl imidazole, 0.05 mol of 3-chloropropyl triethoxysilane, and 60 mL of toluene were mixed in a four-necked flask, equipped with a condenser, a thermometer, and mechanical stirring, and then stirred at a temperature of 100°C for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation to obtain an intermediate;

[0044] 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, equipped with a condenser, a thermometer, and mechanical stirring, and then 0.18 mol of glacial acetic acid was added to the four-necked flask, and stirred at a temperature of 60°C for 24 hours. Then, 0.04 mol of sodium borohydride was added to the four-necked flask, and the stirring was continued at a temperature of 80°C for 24 hours. After the reaction was completed, vacuum filtration was performed, and the obtained solid was washed with anhydrous ethanol and then dried to obtain activated carbon loaded sodium triacetoxyborohydride;

[0045] Step 3, 12 g of 5-benzyloxyaminopiperidin-2S-ethyl carboxylate oxalate salt was mixed with 30 mL of dichloromethane in a four-necked flask under ice water bath conditions, and then equipped with mechanical stirring. Then, 70 mL of saturated sodium bicarbonate solution was added to the four-necked flask, stirred uniformly, and then allowed to stand and separate into layers. Then, 50 mL of a solution prepared by dissolving 10 g of m-chloroperbenzoic acid in 50 mL of dichloromethane was added dropwise to the four-necked flask, and the dropwise addition was performed for 1 hour. After the dropwise addition was completed, the reaction was performed at an ice water bath temperature for 12 hours. After the reaction was completed, 25 mL of 10% sodium sulfite solution was added to the four-necked flask, stirred and separated into layers, and then the organic phase was separated by a separatory funnel. Then, the organic phase was rotary evaporated to obtain 8.9 g of 5-benzyloxyiminopiperidin-2S-ethyl carboxylate, and the yield of this step was 98.89%.

[0046] Fourth step, 8.9 g of 5-benzyloxyimino piperidine-2S-carboxylic acid ethyl ester and 40 mL of ethyl acetate were mixed in a four-necked flask, equipped with a thermometer and mechanical stirring, the temperature of the system was controlled at-18~ -16 ℃, then 4 mL of 95-98% concentrated sulfuric acid was added to the four-necked flask, and stirred at a temperature of-18~ -16 ℃ for 1 hour, then 53 g of activated carbon supported sodium triacetoxyborohydride was added to the four-necked flask, then stirred at a temperature of-18~ -16 ℃ for 3 h, after the reaction was completed, 20 mL of deionized water was added to the four-necked flask to quench the reaction, and the pH of the system was adjusted to 10 with 30% ammonia water, then the organic phase was separated with a separatory funnel, the organic phase was washed twice with 40 mL of saturated sodium chloride solution, then the washing liquid was combined into the aqueous phase in the four-necked flask, 12 mL of ethanol, 1.2 mL of ethyl acetate and oxalic acid dihydrate were added to the four-necked flask, and the pH of the system was adjusted to 5, then the reaction was stirred at a temperature of 60 ℃ for 2 h, after the reaction was completed, the temperature of the system was cooled to room temperature and filtered, the obtained filter cake was washed with anhydrous ethanol ethyl acetate solution (volume ratio of anhydrous ethanol: ethyl acetate = 10: 1) and dried to obtain 9.2 g of (2S, 5R)-benzyloxyamino piperidine-2-carboxylic acid ethyl ester oxalate, the chiral HPLC purity was 99.8%, and the yield of this step was 77.40%.

[0047] The total yield of (2S, 5R)-benzyloxyamino piperidine-2-carboxylic acid ethyl ester oxalate in this example was 76.54%.

[0048] Comparative Example 1: This comparative example is a method for recycling waste liquid in the production of an intermediate of avibactin in Chinese patent CN107540600A.

[0049] A four-necked flask equipped with stirring, thermometer was added with 50 g of ethyl acetate, 11 g of 5-benzyloxyimino piperidine-2S-carboxylic acid ethyl ester was added, the temperature of the system was maintained at-20~ -15 ℃, 20.1 g of 98% concentrated sulfuric acid was added dropwise, after the dropwise addition was completed, the system was stirred for 1 hour. At-20 ℃, 19 g of sodium triacetoxyborohydride was added, and the reaction was stirred at-20~ -15 ℃ for 5 hours. The temperature was maintained below 0 ℃, 20 g of water was added to quench the reaction; the pH of the system was adjusted to 7-8 with ammonia water. The layers were separated, and the organic layer was washed twice with 10 g of saturated brine each time. The organic phase was concentrated to recover the solvent, then 32 g of ethyl acetate, 16 g of methanol and 5.2 g of oxalic acid dihydrate were added to the obtained residue, heated to 45 ℃, stirred for 2 hours, then cooled and filtered. The filter cake was washed with 10 g of ethyl acetate / methanol (2:1) mixture, then washed with 5 g of ethyl acetate. The filter cake was vacuum dried to obtain 9.7 g of single isomer 5R-benzyloxyamino piperidine-2S-carboxylic acid ethyl ester oxalate, the chiral HPLC purity was 99.7%, and the yield was 66.16%.

[0050] It can be seen from the comparative example 1 that, compared with the patent CN107540600A, the preparation method of the present application has a better recovery rate.

[0051] The above has carried on the detailed introduction to the recycling method of the intermediate production waste liquid of avibactam provided by the present application, the principle and implementation mode of the present application are described by applying specific examples in this paper, the above example is only used to help understanding the method of the present application and its core idea, including the best mode, and also enable any person skilled in the art to practice the present application, including manufacturing and using any device or system, and implementing any combined method. It should be pointed out that, for ordinary skilled in the art, some improvements and modifications can be made to the present application without departing from the principles of the present application. Especially, as long as there is no structural conflict, each feature in the disclosed embodiments of the present application can be combined with each other in any way, and the description of these combinations in this specification is not exhaustive, but only for the consideration of omitting the length and saving resources. Therefore, the present application 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 an avibactam intermediate production waste liquor to produce (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt, characterized by, The method comprises the following steps: The first step is to mix N-n-butyl imidazole, 3-chloropropyl triethoxysilane and toluene in a container, stir uniformly, and then react at 90-100℃ for 12 hours to obtain an intermediate; The second step is to mix the intermediate, activated carbon and acetonitrile in a container, stir uniformly, add glacial acetic acid into the container, react at 50-60℃ for 24 hours, then add sodium borohydride into the container, and continue to react at 80℃ for 24 hours to obtain activated carbon loaded sodium triacetoxy borohydride; 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, stir uniformly, add saturated sodium bicarbonate solution into the container, separate the reaction liquid, then add m-chloroperoxybenzoic acid dichloromethane solution dropwise into the container, react at ice water bath for 12 hours to obtain 5-benzyloxy imino piperidine-2S-methyl ester; The fourth step is to mix 5-benzyloxy imino piperidine-2S-methyl ester and ethyl acetate in a container, stir uniformly, control the temperature of the system to be -18 to -16℃, then add concentrated sulfuric acid into the container, react at -18 to -16℃ for 1 hour, add activated carbon loaded sodium triacetoxy borohydride into the container, then react at -18 to -16℃ for 3 hours, add deionized water into the container to quench the reaction after the reaction is completed, adjust the pH of the system to 8-10 with 30% ammonia water, then separate the organic phase, wash the organic phase with saturated sodium chloride solution twice, combine the washing liquid to the water phase in the container, then add ethanol, ethyl acetate and oxalic acid dihydrate into the container, adjust the pH of the system to 5, then react at 60℃ for 2 hours, cool the system to room temperature after the reaction is completed, filter, wash the obtained filter cake with anhydrous ethanol ethyl acetate solution, and dry to obtain (2S, 5R)-benzyloxy amine piperidine-2-methyl ester oxalate.

2. The method for recycling the (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt from the production waste liquid of avibactin intermediate according to claim 1, characterized in that, The amount ratio of N-n-butyl imidazole, 3-chloropropyl triethoxysilane and toluene used in the first step is 0.05-0.1 mol: 0.05 mol: 50-60 mL.

3. The method for recycling the (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt from the production waste liquid of avibactin 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 the (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt from the production waste liquid of avibactin intermediate according to claim 1, characterized in that, The m-chloroperoxybenzoic acid dichloromethane solution in the third step is mixed by 8-10 g of m-chloroperoxybenzoic acid and 50 mL of dichloromethane.

5. The method for recycling the (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt from the production waste liquid of avibactin intermediate according to claim 1, characterized in that, The dropwise time of the m-chloroperoxybenzoic acid dichloromethane solution in the third step is 0.5-1 hour.

6. The method for recycling the (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt from the production waste liquid of avibactin intermediate according to claim 1, characterized in that, The amount ratio of the avibactam intermediate waste liquid dry product, dichloromethane, saturated sodium bicarbonate solution and m-chloroperoxybenzoic acid dichloromethane solution used in the third step is 12 g: 30-40 mL: 60-70 mL: 50 mL.

7. The method for recycling the (2S, 5R)-benzyloxyaminopiperidine-2-carboxylic acid ethyl ester oxalate salt from the production waste liquid of avibactin intermediate according to claim 1, characterized in that, The mass fraction of the concentrated sulfuric acid used in the fourth step is 95-98%. 8.The method for recycling the (2S, 5R) -benzyloxyaminopiperidine-2-methyl acid ethyl ester oxalate prepared from the avibactin intermediate production waste liquid according to claim 1, characterized in that, The amount ratio of 5-benzyloxyimino piperidine-2S-carboxylic acid ethyl ester, ethyl acetate, concentrated sulfuric acid, activated carbon supported sodium triacetoxyborohydride, saturated sodium chloride solution, ethanol, 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 the (2S, 5R) -benzyloxyaminopiperidin-2-carboxylic acid ethyl ester oxalate produced from the avibactam intermediate production waste liquid according to claim 1, characterized in that, The solution of anhydrous ethanol in ethyl acetate used in the fourth step is mixed by 10 parts of anhydrous ethanol and 1 part of ethyl acetate, in terms of volume fraction.

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