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CN-122010942-A - Chemical synthesis method of avibactam sodium

CN122010942ACN 122010942 ACN122010942 ACN 122010942ACN-122010942-A

Abstract

The invention discloses a chemical synthesis method of avibactam sodium, which takes (2S) -5- [ (benzyloxy) imino ] piperidine-2-carboxylic acid ethyl ester as a starting material, carries out selective reduction under the action of a chiral inducer and a reducing agent, constructs 5-site chiral carbon, splits oxalic acid to obtain high-purity oxalate, and then carries out five steps of reactions of intramolecular urea, catalytic hydrolytic amidation, debenzenesulfonate salification and sodium ion exchange to obtain avibactam sodium. According to the invention, the chiral inducer is adopted to induce selective reduction and is combined with the optimization of the catalytic ammonolysis process of the acylase, so that the content of isomer impurities in the product is obviously reduced, and the purity and the overall yield of the product are improved. The method has the advantages that the condition of the catalytic ammonolysis reaction of the acylase is mild, the energy consumption is reduced, and meanwhile, the process safety risk is greatly reduced.

Inventors

  • LI ZHUOHUA
  • FAN SONG
  • YANG YANTAO
  • WANG SHICHUAN
  • MA BINBIN
  • Hou sha
  • LIU YINQIANG
  • MENG LINGHUA
  • ZHAI CHANGJUN

Assignees

  • 山东安信制药有限公司

Dates

Publication Date
20260512
Application Date
20260204

Claims (10)

  1. 1. The chemical synthesis method of the avibactam sodium is characterized by comprising the following steps of: S1, in an aprotic solvent, the compound I and a reducing agent undergo selective reduction reaction under the action of a chiral inducer and strong acid, and then oxalic acid salt formation resolution is carried out to obtain a compound II; s2, in an organic solvent, under the action of organic alkali, reacting the compound II with triphosgene to obtain a compound III; S3, carrying out hydrolysis and amidation reaction on the compound III in a mixed solvent through the catalysis of an acylase and ammonia water to obtain a compound IV; S4, in an organic solvent, reacting the compound IV with hydrogen to remove benzyl under the catalysis of palladium-carbon, simultaneously carrying out sulfonic acid esterification with a sulfur trioxide complex, and then reacting with ammonium salt to form salt to obtain the compound V; S5, carrying out ion exchange reaction on the compound V and sodium salt in an organic solvent to obtain the avibactam sodium.
  2. 2. A chemical synthesis method of avibactam sodium as claimed in claim 1, wherein in step S1, The aprotic solvent is one of dichloromethane, 1, 2-dichloroethane, ethyl acetate and tetrahydrofuran; the strong acid is one of hydrochloric acid, sulfuric acid and trifluoroacetic acid; The reducing agent is one of sodium borohydride, sodium triacetoxyborohydride and sodium tripropionoxyborohydride; the chiral inducer is one of L-camphorsulfonic acid, L-threonine, L-glutamic acid and L-tartaric acid.
  3. 3. The chemical synthesis method of avibactam sodium according to claim 1, wherein in the step S1, the reduction reaction time is 8-12 h, and the reaction temperature is-20-0 ℃.
  4. 4. The chemical synthesis method of avibactam sodium according to claim 1, wherein in the step S2, the organic solvent is one of ethyl acetate, isopropyl acetate and toluene, and the organic base is one of triethylamine, pyridine and piperazine.
  5. 5. The chemical synthesis method of avibactam sodium according to claim 1, wherein in the step S2, the reaction time is 0.5-5 h, and the reaction temperature is 20-50 ℃.
  6. 6. The chemical synthesis method of avibactam sodium according to claim 1, wherein the mixed solvent used in the step S3 is one of isooctanol/water mixed solution and acetone/water mixed solution, and the used acylase is one of immobilized penicillin G acylase and immobilized cephalosporin C acylase.
  7. 7. The chemical synthesis method of avibactam sodium according to claim 1, wherein the pH required by hydrolysis reaction in the step S3 is controlled to be 6.0-6.8, the pH required by amidation reaction is controlled to be 6.8-7.5, the amidation reaction time is 5-10 h, and the reaction temperature is 10-15 ℃.
  8. 8. The chemical synthesis method of avibactam sodium according to claim 1, wherein the organic solvent used for debenzylation in the step S4 is one of methanol and ethanol, the hydrogen pressure is 0.4-0.6 mpa, the sulfur trioxide complex used is one of sulfur trioxide trimethylamine and sulfur trioxide pyridine, the debenzylation control reaction temperature is 15-35 ℃, the organic solvent used for salification reaction is ethanol, the salification reaction time is 2-3 h, and the reaction temperature is 15-30 ℃.
  9. 9. The chemical synthesis method of avibactam sodium according to claim 1, wherein the organic solvent used in the step S5 is ethanol, the sodium salt is sodium isooctanoate, the reaction time is 4-5 h, and the reaction temperature is-5 ℃.
  10. 10. A process for the chemical synthesis of avibactam sodium as claimed in any one of claims 1 to 9, S1, adding a compound I and ethyl acetate into a reaction container, dropwise adding concentrated sulfuric acid at a temperature of minus 10 to minus 5 ℃, adding a chiral inducer after the dropwise adding, controlling the temperature to minus 10 to minus 5 ℃, adding sodium tripropionoyloxy borohydride, carrying out heat preservation reaction after the adding, adding water after the reaction is finished for quenching reaction, regulating the pH of the system to 7.5-8.5 by using concentrated ammonia water, standing for layering, separating an organic phase, washing the organic phase with salt, stirring and heating to 40-50 ℃, adding oxalic acid, carrying out heat preservation reaction, cooling after the reaction is finished, and separating out solid matters to obtain a compound II; S2, adding the compound II, ethyl acetate and triethylamine into a reaction container, dropwise adding an ethyl acetate solution of triphosgene at room temperature, heating to 20-50 ℃ after the dropwise addition, carrying out heat preservation reaction, adding a sodium carbonate aqueous solution after the reaction is finished, extracting and separating liquid, merging organic phases, and evaporating under reduced pressure to obtain a yellow oily compound III, and directly carrying out the next reaction; S3, adding the compound III into isooctanol/water mixed solution, controlling the temperature to be 10-15 ℃, adjusting the pH to be 6.0-6.8, adding immobilized penicillin G acylase for heat preservation reaction, then slowly dropwise adding ammonia water, controlling the pH to be 7.0-7.3, carrying out heat preservation reaction after the ammonia water is dropwise added, adjusting the pH to be 1-2 after the reaction is finished, filtering, leaching the acylase with purified water, recovering the acylase, taking a water layer, subsequently adjusting the pH to be 7.5-8.0 with ammonia water, controlling the temperature to be 10-15 ℃, crystallizing, carrying out suction filtration, and carrying out vacuum drying to obtain the compound IV; s4, dissolving the compound IV in methanol, adding palladium carbon, sulfur trioxide trimethylamine and triethylamine, then introducing hydrogen into the system for pressurizing reaction, maintaining the pressure at 0.4-0.6 MPa, maintaining the temperature at 25-30 ℃ for reaction, then adding tetrabutylammonium acetate, cooling to 5-10 ℃ for crystallization after heat preservation reaction, filtering, taking a filter cake, and vacuum drying to obtain the compound V; (5) Sodium salt formation And (3) dissolving the compound V in ethanol, then dropwise adding an ethanol solution of sodium iso-octoate at a temperature of 20-30 ℃ for ion exchange reaction, wherein the reaction temperature is-5 ℃, and carrying out suction filtration, washing and drying after the reaction is finished to finally obtain the avibactam sodium.

Description

Chemical synthesis method of avibactam sodium Technical Field The invention belongs to the technical field of chemical synthesis medicines, and particularly relates to a chemical synthesis method of avibactam sodium. Background Avermentan sodium (Avibactan soduim) is a new generation of long acting beta-lactamase inhibitors which have no obvious antimicrobial activity per se, but are capable of inhibiting beta-lactamase of both form A (including ESBL and KPC) and form C. When the avibactam sodium is used in combination with various cephalosporin and carbapenem antibiotics, the avibactam sodium has broad-spectrum antibacterial activity, and particularly has remarkable activity on drug-resistant bacteria such as escherichia coli and klebsiella pneumoniae containing ultra-broad-spectrum lactamase, escherichia coli containing excessive AmpC enzyme, escherichia coli containing AmpC and ultra-broad-spectrum beta-lactamase, and the like. The avibactam sodium and various medicines can form a compound preparation, such as avibactam sodium+ceftazidime, avibactam sodium+ceftaroline, avibactam sodium+aztreonam, ceftazidime-avibactam sodium-metronidazole and the like. Abamectin sodium (Avibactan soduim) belongs to diazabicyclooctane class compounds. The chemical name is [ (2S, 5R) -2-carbamoyl-7-oxo-1, 6-diazabicyclo [3.2.1] octane-6-yl ] sodium sulfate, the molecular formula is C 14H17N3O3, the molecular weight is 287.23, the CAS number is 1192491-61-4, and the structural formula is as follows: the synthesis method of the avibactam sodium reported at home and abroad at present mainly comprises the following steps: The original patent CN1289500C discloses a preparation method of avibactam sodium, and the synthetic route is as follows: The synthesis route starts from an L-pyroglutamic acid derivative, allyl is removed through triphosgene cyclization and saponification reaction to obtain a carboxylic acid intermediate, the carboxylic acid intermediate is reacted with ammonia water after isobutyl chloroformate is activated to generate a primary amide intermediate, benzyl is removed through hydrogenolysis reaction, and the primary amide intermediate is acidified and salified under the action of a sulfur trioxide-pyridine complex to obtain the tetrabutyl ammonium salt of the avibactam, and sodium ion exchange resin is used to obtain the avibactam sodium, wherein the total yield is about 30%. In the route, the raw material L-pyroglutamic acid derivative contains 2 chiral centers and has the advantages of high synthesis difficulty and high price, the saponification reaction yield in the leaving reaction of allyl is low, ring-opening impurities are easy to generate, and industrial production is difficult to realize. Another synthesis method of avibactam sodium is disclosed in patent WO2012172368A1, the synthesis route is as follows: The method takes N-Boc-L-pyroglutamic acid ethyl ester (or benzyl ester) as a starting raw material, and obtains avibactam sodium through 13 steps of reactions including ring opening, nucleophilic substitution, boc removal, cyclization, reduction, ammonolysis, intramolecular carbamido, debenzylation, sulfonic acid esterification, salification and cation exchange. But the route still faces the outstanding problems of high price of starting materials, harsh process conditions, complex operation, low selectivity of key reduction reaction, influence on yield, and high toxicity by-product accompanying the reaction, and is safe and environment-friendly. These factors all prevent its mass production. The third method is that patent WO2012086241A1 discloses another synthesis method of avibactam sodium, and the synthesis route is as follows: The synthesis method takes (S) -1- (carbobenzoxy) -5-oxo pyrrolidine-2-carboxylic acid as an initial raw material, and obtains avibactam sodium through 15 steps of reactions of tertiary butyl esterification, sulfur ylide reaction, cyclization, reduction, cbz removal, acylation protection, nucleophilic substitution, deprotection, intramolecular urea, acidolysis deprotection, esterification, ammonolysis, debenzylation, sulfonic acid esterification and cation exchange. The synthetic route has the problems of long route, complicated operation, low yield and the like. The starting materials are expensive, the reaction time is long, and silica gel column chromatography separation is needed in each intermediate step, so that the overall production cost is high, the efficiency is low, and the requirement of industrial production is difficult to meet. Disclosure of Invention In order to overcome the defects in the prior art, the invention provides a chemical synthesis method of avibactam sodium. According to the method, (2S) -5- [ (benzyloxy) imino ] piperidine-2-carboxylic acid ethyl ester (compound I) is used as a starting material, selective reduction is carried out under the action of a chiral inducer and a reducing agent, 5-site chiral carbon is constructed, oxalic acid is s