1192500-31-4

Basic information

• Product Name: AvibactaM
• Synonyms: AvibactaM;Sulfuric acid mono[(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] ester;Avibactam free acid;(E)-7-fluoro-3-methylhept-4-en-2-one;Avibactam,(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbox amide;(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogensulfate;(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carbox amide;EOS-60408
• CAS NO: 1192500-31-4
• Molecular Formula: C₇H₁₁N₃O₆S
• Molecular Weight: 265.24374
• Mol File: 1192500-31-4.mol
• Article Data: 8

Chemical Properties

• Appearance: /
• Density: 1.85
• PKA: -4.59±0.18(Predicted)
• CAS DataBase Reference: AvibactaM(CAS DataBase Reference)
• NIST Chemistry Reference: AvibactaM(1192500-31-4)
• EPA Substance Registry System: AvibactaM(1192500-31-4)

Safety Data

• Hazardous Substances Data: 1192500-31-4(Hazardous Substances Data)

Usage

Description

AfibactaM, also known as (2S,5R)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, is a member of the azabicycloalkanes class. It is characterized by the replacement of the amino hydrogen at position 6 with a sulfooxy group. AvibactaM is used in combination with ceftazidime pentahydrate and is primarily known for its pharmaceutical applications.

Uses

Used in Pharmaceutical Industry:
AfibactaM is used as an additive for ceftazidime pentahydrate, a type of antibiotic, to enhance its effectiveness against bacterial infections. The combination of AvibactaM and ceftazidime pentahydrate is particularly effective in treating complicated urinary tract infections, including pyelonephritis. This application takes advantage of AvibactaM's ability to improve the antibiotic's efficacy and overcome bacterial resistance.

Enzyme inhibitor

This non-β-lactam inhibitor of β-lactamase (FW = 261.27 g/mol; CAS 1192500-31-4), also known as NLX104 and AVE1330A, shows a spectrum of action against Classes A and C β-lactamase as well as selected Class D β-lactamase, enzymes that often confer resistance to β-lactam antibiotics. By forming a high-affinity complex with its target enzymes, avibactam enhances the antibacterial activity of certain β-lactam drugs, such as ceftaroline. With over 1000 known β-lactamase, the action of avibactam is apt to depend on the invidual active-site interactions. Mode of Action: Acylation and deacylation rates have been measured for the clinically important enzymes CTX-M-15, KPC-2, E. cloacae AmpC, P. aeruginosa AmpC, OXA-10, and OXA-48. The efficiency of acylation (kon/Ki) varies across the enzyme spectrum, from 1.1 x 101 M–1 s –1 for OXA-10 to 1.0 x 105 M–1 s –1 for CTX-M-15. Inhibition of OXA-10 was shown to follow a reversible covalent mechanism (see below), and the acylated OXA-10 displayed the longest residence time for deacylation, with a half-life of greater than 5 days. The inhibited enzyme forms are stable to hydrolysis for all enzymes with the exception of KPC-2, which displays slow hydrolytic route that involved fragmentation of the acyl-avibactam complex. In the case of TEM-1 lactamase, avibactam slowly covalently acylates its target, and the acylated enzyme subsequently undergoes slow deacylation (koff = 0.045 min?1 ) regenerating avibactam intact. Use as a Combined Drug: Combination of avibactim with extended-spectrum cephalosporins or aztreonam shows promise in inhibiting Klebsiella pneumoniae (KP) isolates harboring carbapenemases, or KPCs. Given abundant experience with ceftazidime and the significant improvement avibactam provides against contemporary β-lactamase-producing Gram-negative pathogens, this combination will likely play a role in the treatment of complicated urinary tract infections (as monotherapy) and complicated intra-abdominal infections (in combination with metronidazole) caused (or suspected to be caused) by otherwise resistant pathogens, such as extended spectrum β-lactamase-, AmpC-, or Klebsiella pneumoniae carbapenemase producing Enterobacteriaceae and multidrug-resistant P. aeruginosa.

Synthetic route

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
With chlorosulfonic acid In N,N-dimethyl-formamide at 30℃; for 48h; Reagent/catalyst;	97%

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: potassium tert-butylate / dimethyl sulfoxide; tetrahydrofuran / 20 °C 1.2: -12 °C 2.1: ethyl acetate / Reflux 3.1: methanesulfonic acid / ethyl acetate / 42 °C 3.2: 52 °C 4.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 4.3: 40 - 45 °C 5.1: ammonia / methanol 6.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 7.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 8 steps 1.1: potassium tert-butylate / dimethyl sulfoxide; tetrahydrofuran / 20 °C 1.2: -12 °C 2.1: ethyl acetate / Reflux 3.1: methanesulfonic acid / ethyl acetate / 42 °C 3.2: 52 °C 4.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 4.3: 40 - 45 °C 5.1: 1 h / 0 °C 5.2: 35 °C 6.1: ammonia / methanol / 20 °C 7.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 8.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1192651-49-2) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Stage #1: (1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide With hydrogen; 5% Pd-C In dichloromethane; N,N-dimethyl-formamide under 2250.23 Torr; Stage #2: With sulfur trioxide-N,N-dimethylformamide complex; acetic acid In dichloromethane; N,N-dimethyl-formamide
With palladium 10% on activated carbon; hydrogen; sulfur trioxide trimethylamine complex; triethylamine In water; isopropyl alcohol for 5h; Large scale; Industrial scale;
With palladium 10% on activated carbon; water; hydrogen; sulfur trioxide trimethylamine complex; triethylamine In isopropyl alcohol

(S)-ethyl N-tert-butoxycarbonylpyroglutamate (144978-35-8, 144978-12-1) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: potassium tert-butylate / dimethyl sulfoxide; tetrahydrofuran / 20 °C 1.2: -12 °C 2.1: ethyl acetate / Reflux 3.1: methanesulfonic acid / ethyl acetate / 42 °C 3.2: 52 °C 4.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 4.3: 40 - 45 °C 5.1: ammonia / methanol / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 7.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

benzyl (2S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ6-sulfanylidene)-5-oxohexanoate → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: ethyl acetate / Reflux 2.1: methanesulfonic acid / ethyl acetate / 42 °C 2.2: 52 °C 3.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 3.3: 40 - 45 °C 4.1: potassium hydrogencarbonate / water; 2-methyltetrahydrofuran 4.2: 0 °C 5.1: water; lithium hydroxide monohydrate / acetone / -12 °C 5.2: 0 °C 5.3: -20 - 0 °C 6.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1.1: ethyl acetate / Reflux 2.1: methanesulfonic acid / ethyl acetate / 42 °C 2.2: 52 °C 3.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 3.3: 40 - 45 °C 4.1: ammonia / methanol 5.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 6.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 7 steps 1.1: ethyl acetate / Reflux 2.1: methanesulfonic acid / ethyl acetate / 42 °C 2.2: 52 °C 3.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 3.3: 40 - 45 °C 4.1: 1 h / 0 °C 4.2: 35 °C 5.1: 3-Methylpyridine / dichloromethane / 0 °C 6.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 7.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 7 steps 1.1: ethyl acetate / Reflux 2.1: methanesulfonic acid / ethyl acetate / 42 °C 2.2: 52 °C 3.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 3.3: 40 - 45 °C 4.1: 1 h / 0 °C 4.2: 35 °C 5.1: ammonia / methanol / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 7.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(2S)-5-(benzyloxyimino)-piperidine-2-carboxylic acid benzyl ester (1133931-74-4) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 1.3: 40 - 45 °C 2.1: potassium hydrogencarbonate / water; 2-methyltetrahydrofuran 2.2: 0 °C 3.1: water; lithium hydroxide monohydrate / acetone / -12 °C 3.2: 0 °C 3.3: -20 - 0 °C 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 1.3: 40 - 45 °C 2.1: ammonia / methanol 3.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 1.3: 40 - 45 °C 2.1: 1 h / 0 °C 2.2: 35 °C 3.1: 3-Methylpyridine / dichloromethane / 0 °C 4.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 1.3: 40 - 45 °C 2.1: 1 h / 0 °C 2.2: 35 °C 3.1: ammonia / methanol / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(2S)-5-benzyloxyaminopiperidin-2-carboxylic acid benzyl ester oxalic acid salt → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: methanol / 25 °C / Reflux 2.1: potassium hydrogencarbonate / water; 2-methyltetrahydrofuran 2.2: 0 °C 3.1: water; lithium hydroxide monohydrate / acetone / -12 °C 3.2: 0 °C 3.3: -20 - 0 °C 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1: methanol / 25 °C / Reflux 2: ammonia / methanol 3: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 4: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: methanol / 25 °C / Reflux 2.1: 1 h / 0 °C 2.2: 35 °C 3.1: 3-Methylpyridine / dichloromethane / 0 °C 4.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: methanol / 25 °C / Reflux 2.1: 1 h / 0 °C 2.2: 35 °C 3.1: ammonia / methanol / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

benzyl (2S)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate (1133931-73-3) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: methanesulfonic acid / ethyl acetate / 42 °C 1.2: 52 °C 2.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 2.3: 40 - 45 °C 3.1: potassium hydrogencarbonate / water; 2-methyltetrahydrofuran 3.2: 0 °C 4.1: water; lithium hydroxide monohydrate / acetone / -12 °C 4.2: 0 °C 4.3: -20 - 0 °C 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: methanesulfonic acid / ethyl acetate / 42 °C 1.2: 52 °C 2.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 2.3: 40 - 45 °C 3.1: ammonia / methanol 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1.1: methanesulfonic acid / ethyl acetate / 42 °C 1.2: 52 °C 2.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 2.3: 40 - 45 °C 3.1: 1 h / 0 °C 3.2: 35 °C 4.1: 3-Methylpyridine / dichloromethane / 0 °C 5.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 6.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1.1: methanesulfonic acid / ethyl acetate / 42 °C 1.2: 52 °C 2.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 2.3: 40 - 45 °C 3.1: 1 h / 0 °C 3.2: 35 °C 4.1: ammonia / methanol / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 6.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-carboxylic acid methyl ester (1383814-58-1) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium carbamate / Novozyme 435 / acetonitrile / 40 °C / Enzymatic reaction 2: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-carboxylic acid benzyl ester (1192650-82-0) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: water; lithium hydroxide monohydrate / acetone / -12 °C 1.2: 0 °C 1.3: -20 - 0 °C 2.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid amide (1416134-49-0) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 2: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 20 - 30 °C 1.2: 11 h / 15 °C 1.3: 2 h / 15 - 20 °C 2.1: sulfur trioxide trimethylamine complex; palladium 10% on activated carbon; water; hydrogen; triethylamine / isopropyl alcohol View Scheme

(2S,5R)-5-benzyloxyaminopiperidin-2-carboxylic acid benzyl ester oxalic acid salt (1171080-45-7) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium hydrogencarbonate / water; 2-methyltetrahydrofuran 1.2: 0 °C 2.1: water; lithium hydroxide monohydrate / acetone / -12 °C 2.2: 0 °C 2.3: -20 - 0 °C 3.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: ammonia / methanol 2: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 3: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1.1: 1 h / 0 °C 1.2: 35 °C 2.1: 3-Methylpyridine / dichloromethane / 0 °C 3.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1.1: 1 h / 0 °C 1.2: 35 °C 2.1: ammonia / methanol / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalic acid salt (1416134-48-9) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 3-Methylpyridine / dichloromethane / 0 °C 2: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 3: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: ammonia / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 3: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

methyl (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylate oxalate (1416134-74-1) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium hydrogencarbonate / water; 2-methyltetrahydrofuran 1.2: -5 - -3 °C 2.1: ammonium carbamate / Novozyme 435 / acetonitrile / 40 °C / Enzymatic reaction 3.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 3 steps 1: ammonia / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 3: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

ethyl (S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ6-sulfanylidene)-5-oxohexanoate (1416134-58-1) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: ethyl acetate / Reflux 2.1: methanesulfonic acid / ethyl acetate / 42 °C 2.2: 52 °C 3.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 3.3: 40 - 45 °C 4.1: 3-Methylpyridine / dichloromethane / 0 °C 5.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 6.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 6 steps 1.1: ethyl acetate / Reflux 2.1: methanesulfonic acid / ethyl acetate / 42 °C 2.2: 52 °C 3.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 3.3: 40 - 45 °C 4.1: ammonia / methanol / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 6.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

C20H29ClN2O5 (1416134-59-2) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: methanesulfonic acid / ethyl acetate / 42 °C 1.2: 52 °C 2.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 2.3: 40 - 45 °C 3.1: 3-Methylpyridine / dichloromethane / 0 °C 4.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 5 steps 1.1: methanesulfonic acid / ethyl acetate / 42 °C 1.2: 52 °C 2.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 2.3: 40 - 45 °C 3.1: ammonia / methanol / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 5.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester (1416134-60-5) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 1.3: 40 - 45 °C 2.1: 3-Methylpyridine / dichloromethane / 0 °C 3.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme
Multi-step reaction with 4 steps 1.1: sodium tetrahydroborate; sulfuric acid; propionic acid / ethyl acetate / -20 °C 1.3: 40 - 45 °C 2.1: ammonia / methanol / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 4.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-carboxylic acid ethyl ester (1416134-63-8) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 2: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr View Scheme

C15H17F3N2O3 → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trifluoromethylsulfonic anhydride; 2,6-dimethylpyridine / 0.5 h / -25 - -20 °C 1.2: 20 h / -5 - 0 °C 2.1: potassium carbonate / methanol / 1 h 2.2: 0.17 h 3.1: pyridine / 4 h / -15 - 20 °C 4.1: palladium 10% on activated carbon; ammonium formate / methanol / 2 h / Reflux 5.1: chlorosulfonic acid / N,N-dimethyl-formamide / 48 h / 30 °C View Scheme

C22H24F3N3O3 → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / methanol / 1 h 1.2: 0.17 h 2.1: pyridine / 4 h / -15 - 20 °C 3.1: palladium 10% on activated carbon; ammonium formate / methanol / 2 h / Reflux 4.1: chlorosulfonic acid / N,N-dimethyl-formamide / 48 h / 30 °C View Scheme

(2S,5R)-N-benzyl-5-(benzyloxyamino)piperidin-2-carboxamide → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / 4 h / -15 - 20 °C 2: palladium 10% on activated carbon; ammonium formate / methanol / 2 h / Reflux 3: chlorosulfonic acid / N,N-dimethyl-formamide / 48 h / 30 °C View Scheme

(S)-5-oxo-2-piperidinecarboxylic acid (146467-21-2) → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: 2,6-dimethylpyridine / dichloromethane / 2 h / Reflux 2.1: D-glucose; citric acid; disodium hydrogenphosphate / ethyl acetate; water / 25 h / 30 °C 3.1: triethylamine / tetrahydrofuran / 0.5 h 3.2: 1 h / -7 - -5 °C 4.1: trifluoromethylsulfonic anhydride; 2,6-dimethylpyridine / 0.5 h / -25 - -20 °C 4.2: 20 h / -5 - 0 °C 5.1: potassium carbonate / methanol / 1 h 5.2: 0.17 h 6.1: pyridine / 4 h / -15 - 20 °C 7.1: palladium 10% on activated carbon; ammonium formate / methanol / 2 h / Reflux 8.1: chlorosulfonic acid / N,N-dimethyl-formamide / 48 h / 30 °C View Scheme

C13H16N2O2 → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: D-glucose; citric acid; disodium hydrogenphosphate / ethyl acetate; water / 25 h / 30 °C 2.1: triethylamine / tetrahydrofuran / 0.5 h 2.2: 1 h / -7 - -5 °C 3.1: trifluoromethylsulfonic anhydride; 2,6-dimethylpyridine / 0.5 h / -25 - -20 °C 3.2: 20 h / -5 - 0 °C 4.1: potassium carbonate / methanol / 1 h 4.2: 0.17 h 5.1: pyridine / 4 h / -15 - 20 °C 6.1: palladium 10% on activated carbon; ammonium formate / methanol / 2 h / Reflux 7.1: chlorosulfonic acid / N,N-dimethyl-formamide / 48 h / 30 °C View Scheme

C13H18N2O2 → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran / 0.5 h 1.2: 1 h / -7 - -5 °C 2.1: trifluoromethylsulfonic anhydride; 2,6-dimethylpyridine / 0.5 h / -25 - -20 °C 2.2: 20 h / -5 - 0 °C 3.1: potassium carbonate / methanol / 1 h 3.2: 0.17 h 4.1: pyridine / 4 h / -15 - 20 °C 5.1: palladium 10% on activated carbon; ammonium formate / methanol / 2 h / Reflux 6.1: chlorosulfonic acid / N,N-dimethyl-formamide / 48 h / 30 °C View Scheme

(2S,5S)-1-(tert-butyl) 2-ethyl 5-hydroxylpiperidine-1,2-dicarboxylate → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 2,6-dimethylpyridine; trifluoromethylsulfonic anhydride / acetonitrile / -30 °C 1.2: 12.5 h / -30 - 20 °C 2.1: trifluoroacetic acid / dichloromethane / 15 h / 0 - 20 °C 3.1: ammonia; methanol / 8 h / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 20 - 30 °C 4.2: 11 h / 15 °C 4.3: 2 h / 15 - 20 °C 5.1: sulfur trioxide trimethylamine complex; palladium 10% on activated carbon; water; hydrogen; triethylamine / isopropyl alcohol View Scheme

(2S,5R)-5-(benzyloxyamino)piperidin-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester → (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: trifluoroacetic acid / dichloromethane / 15 h / 0 - 20 °C 2.1: ammonia; methanol / 8 h / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 20 - 30 °C 3.2: 11 h / 15 °C 3.3: 2 h / 15 - 20 °C 4.1: sulfur trioxide trimethylamine complex; palladium 10% on activated carbon; water; hydrogen; triethylamine / isopropyl alcohol View Scheme

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4) + sodium 2-ethylhexanoic acid → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
In 2-methyl-propan-1-ol for 0.833333h; Solvent; Time; Concentration; Reflux;	77%

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4) + tetra(n-butyl)ammonium hydrogensulfate (32503-27-8) → ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (1192651-80-1, 1416134-53-6)

Conditions	Yield
In water

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / water; isopropyl alcohol; dichloromethane / Large scale; Industrial scale 2: sodium 2-ethylhexanoic acid / water; ethanol / 6 h / 30 °C / Large scale; Industrial scale View Scheme

(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicylco[3.2.1]octan-6-yl hydrogensulfate (1192500-31-4) + tetrabutylammonium acetate (10534-59-5) → ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt (1192651-80-1, 1416134-53-6)

Conditions	Yield
With acetic acid In dichloromethane; water; isopropyl alcohol Large scale; Industrial scale;	133 kg
With acetic acid In water	814 g

Upstream product

• 113400-36-5 benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate 
• 1192651-49-2 (1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 
• 144978-35-8 (S)-ethyl N-tert-butoxycarbonylpyroglutamate 
• 1133931-74-4 (2S)-5-(benzyloxyimino)-piperidine-2-carboxylic acid benzyl ester 
• 1416134-44-5 (2S)-5-benzyloxyaminopiperidin-2-carboxylic acid benzyl ester oxalic acid salt 
• 1133931-73-3 benzyl (2S)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate 
• 1383814-58-1 (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-carboxylic acid methyl ester 
• 1192650-82-0 (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-carboxylic acid benzyl ester 
• 1416134-49-0 (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid amide 
• 1171080-45-7 (2S,5R)-5-benzyloxyaminopiperidin-2-carboxylic acid benzyl ester oxalic acid salt 
• 1416134-48-9 ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalic acid salt 
• 1416134-74-1 methyl (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylate oxalate 
• 1416134-58-1 ethyl (S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ⁶-sulfanylidene)-5-oxohexanoate 
• 1416134-59-2 C₂₀H₂₉ClN₂O₅ 

Downstream Products

• 1192651-80-1 ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt 
• 1192491-61-4 sulfuric acid [(1R,2S,5R)-2-aminocarbonyl-7-oxo-1,6-azabicyclo[3.2.1]oct-6-yl]ester sodium salt 
• 1192491-61-4 (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt 

Relevant articles and documents

Method for synthesize Avibactam key intermediate (S)-N-t-butyloxycarboryl pyroglutamic acid-2-benzyl ester and recrystallization process of Avibactam key intermediate

The invention discloses a one-step method for synthesize Avibactam key intermediate (S)-N-t-butyloxycarboryl pyroglutamic acid-2-benzyl ester and a recrystallization process of the Avibactam key intermediate. L-pyroglutamic acid is taken as a raw material to synthesize faint yellow (S)-N-tert-butyloxycarboryl pyroglutamic acid-2-benzyl ester by one step, and recrystallizing is carried out to obtain white (S)-N-t-butyloxycarboryl pyroglutamic acid-2-benzyl ester, wherein the purity is 99% or above, and the yield is 95% or above. The method is mild in reaction condition and simple in operation and is green and efficient, the product is stable, a next-step reaction is facilitated, and industrial production is facilitated.

AVIBACTAM FREE ACID

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The invention discloses a synthetic method for avibactam sodium salt. The method comprises the following steps: taking (2S, 5R)-5-[(benzyl oxyl) amino] piperidine-2-formamide as a starting material; constructing a urea ring by carbonyl diimidazole under the effect of dimethyldichlorosilance to obtain (2S, 5R)-6-(benzyl oxyl)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide; then carrying out hydrogenation to remove benzyl; carrying out sulfonation reaction on the compound and a sulfonated reagent; synthesizing into a quaternary ammonium salt intermediate by using quaternary ammonium salt; and finally carrying out ion exchange to obtain the avibactam sodium salt. The improved process is low in cost, simple and convenient to operate, good in product quality and suitable for industrial production. In a process of synthesizing the intermediate (2S, 5R)-6-(benzyl oxyl)-7-oxo-1,6-diazabicyclo [3.2.1] octane-2-formamide, dimethyldichlorosilance which is low in price is used, and therefore, the production cost is greatly reduced.