1192491-61-4

Basic information

• Product Name: NXL 104
• Synonyms: AvibactaM SodiuM Salt;NXL 104;Sulfuric Acid Mono[(1R,2S,5R)-2-(aMinocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] Ester SodiuM Salt;Avibactam (sodium);AvibactaM SodiuM NXL 104;sodium (1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl sulfate;(2S,5R)-7-Oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide monosodium salt;(2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt
• CAS NO: 1192491-61-4
• Molecular Formula: C₇H₁₀N₃O₆S*Na
• Molecular Weight: 287.22557
• Product Categories: Amines;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;Amines, Chiral Reagents, Pharmaceuticals, Intermediates & Fine Chemicals, Sulfur & Selenium Compounds;API
• Mol File: 1192491-61-4.mol
• Article Data: 27

Chemical Properties

• Appearance: /
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated, Sonicated), Water (Slightly, Sonica
• CAS DataBase Reference: NXL 104(CAS DataBase Reference)
• NIST Chemistry Reference: NXL 104(1192491-61-4)
• EPA Substance Registry System: NXL 104(1192491-61-4)

Safety Data

• Hazardous Substances Data: 1192491-61-4(Hazardous Substances Data)

Usage

Description

NXL 104, also known as Avibactam, is a novel β-lactamase inhibitor with a non-lactam structural scaffold. It is an organic sodium salt that is the monosodium salt of avibactam. Avibactam is effective against various β-lactamases, including TEM-1, P99, and KPC-2, and restores the antimicrobial activity of several antibiotics against antibiotic-resistant bacteria. It is used in combination with ceftazidime pentahydrate for the treatment of complicated urinary tract infections, including pyelonephritis.

Uses

Used in Pharmaceutical Industry:
NXL 104 is used as a β-lactamase inhibitor for restoring the antimicrobial activity of antibiotics such as ceftazidime, ceftriaxone, imipenem, and piperacillin against antibiotic-resistant Enterobacteriaceae in vitro. This results in a significant reduction of the minimum inhibitory concentration (MIC90) across various clinical isolates of E. coli and K. pneumoniae.
Used in Treatment of Complicated Urinary Tract Infections:
NXL 104 is used in combination with ceftazidime pentahydrate for the treatment of complicated urinary tract infections, including pyelonephritis. This combination therapy helps in overcoming antibiotic resistance and provides effective treatment options for patients suffering from such infections.
Used in Inhibiting Lactamase from Mycobacterium tuberculosis:
NXL 104 is also used for inhibiting lactamase from Mycobacterium tuberculosis, an organism responsible for causing tuberculosis. By irreversibly inhibiting this enzyme, NXL 104 can potentially enhance the effectiveness of β-lactam antibiotics against this pathogen, contributing to the development of new treatment strategies for tuberculosis.

Synthetic route

({[(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) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
Stage #1: ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-oct-6-yl]oxy}sulfonyl)tetrabutylammonium salt With tetrafluoroboric acid; 2,2,2-trifluoroethanol Stage #2: With sodium hydrogencarbonate at 0℃; for 1h;	100%
With sodium 2-ethylhexanoic acid In ethanol; water at 20℃; for 3h;	99.6%
With sodium 2-ethylhexanoic acid In ethanol; water at 20℃; for 3h;	96.2%

2C7H10N3O6S(1-)*C30H66N2(2+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	89%

C7H10N3O6S(1-)*C16H34N(1+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	88%

C7H10N3O6S(1-)*C14H30N(1+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	86%

2C7H10N3O6S(1-)*C38H66N2(2+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	86%

2C7H10N3O6S(1-)*C29H64N2(2+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	86%

(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
Stage #1: (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide With pyridine; sulfur trioxide pyridine complex at 20℃; for 20h; Stage #2: With sodium dihydrogenphosphate In water	80%
Multi-step reaction with 2 steps 1.1: α-picoline; thiocyanate trioxide / tetrahydrofuran / 24 h / 20 °C / Inert atmosphere 2.1: 2,2,2-trifluoroethanol; tetrafluoroboric acid 2.2: 1 h / 0 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine; sulfur trioxide trimethylamine complex / ethanol; water 2: sodium 2-ethylhexanoic acid / ethanol View Scheme
Multi-step reaction with 2 steps 1: triethylamine; sulfur trioxide trimethylamine complex / ethanol; water 2: sodium 2-ethylhexanoic acid / ethanol View Scheme
Multi-step reaction with 3 steps 1.1: sodium hexamethyldisilazane; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / tetrahydrofuran / 0.17 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; hydrogen / acetonitrile / 1.33 h / 20 °C / Inert atmosphere 3.1: sodium hydrogencarbonate / dimethylsulfoxide-d6; water-d2 View Scheme

(1R,2S,5R)-7-oxo-6-sulfonyloxy-1,6-diazabicyclo[3,2,1]octane-2-carboxamide tributylbenzylammonium → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol; water at 15 - 40℃; for 4h;	80%
With sodium 2-ethylhexanoic acid In ethanol	4.6 g
With sodium isooctanoate In ethanol; water at 35 - 40℃; for 4h;

2C7H10N3O6S(1-)*C28H62N2(2+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	80%

(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%

2C7H10N3O6S(1-)*C23H52N2(2+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	74%

2C7H10N3O6S(1-)*C32H54N2(2+) → (2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
With sodium 2-ethylhexanoic acid In ethanol	74%

(1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (1192651-49-2) → (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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 2: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 3 steps 1.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide 1.2: 20 °C 1.3: pH > 6 2.1: dichloromethane; water 3.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 3 steps 1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr 2: water 3: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

(2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid amide (1416134-49-0) → (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 3 steps 1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 2: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 3: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 2.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide 2.2: 20 °C 2.3: pH > 6 3.1: dichloromethane; water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 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 3: water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

(2S,5R)-5-benzyloxyaminopiperidin-2-carboxylic acid benzyl ester oxalic acid salt (1171080-45-7) → (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 4 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1: ammonia / methanol 2: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 3: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 5 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 4.1: water 5.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalic acid salt (1416134-48-9) → (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 4 steps 1: 3-Methylpyridine / dichloromethane / 0 °C 2: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 3: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1: ammonia / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 3: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 5 steps 1.1: 3-Methylpyridine / dichloromethane / 0 °C 2.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 3.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide 3.2: 20 °C 3.3: pH > 6 4.1: dichloromethane; water 5.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate (113400-36-5) → (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 10 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 9.1: water 10.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 10 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 8.2: 20 °C 8.3: pH > 6 9.1: dichloromethane; water 10.1: sodium 2-ethylhexanoic acid / ethanol; water 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: ammonia / methanol 6.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 7.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 8.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

(S)-ethyl N-tert-butoxycarbonylpyroglutamate (144978-35-8, 144978-12-1) → (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 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: ammonia / methanol / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 7.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 8.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 9 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 8.1: water 9.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 9 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 7.2: 20 °C 7.3: pH > 6 8.1: dichloromethane; water 9.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

benzyl (2S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ6-sulfanylidene)-5-oxohexanoate → (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 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: ammonia / methanol 5.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 6.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 7.1: sodium 2-ethylhexanoic acid / ethanol; water 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: 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 7.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 8 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 8.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

(2S)-5-(benzyloxyimino)-piperidine-2-carboxylic acid benzyl ester (1133931-74-4) → (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 5 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 5.1: sodium 2-ethylhexanoic acid / ethanol; water 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: 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 5.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 6 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 5.1: water 6.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

(2S)-5-benzyloxyaminopiperidin-2-carboxylic acid benzyl ester oxalic acid salt → (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 5 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 5.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 5 steps 1: methanol / 25 °C / Reflux 2: ammonia / methanol 3: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 4: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 5: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 6 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 5.1: water 6.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

benzyl (2S)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate (1133931-73-3) → (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 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: ammonia / methanol 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 5.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 6.1: sodium 2-ethylhexanoic acid / ethanol; water 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: 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 6.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 7 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 7.1: sodium 2-ethylhexanoic acid / ethanol; water 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)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: ammonium carbamate / Novozyme 435 / acetonitrile / 40 °C / Enzymatic reaction 2: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 3: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1.1: ammonium carbamate / Novozyme 435 / acetonitrile / 40 °C / Enzymatic reaction 2.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide 2.2: 20 °C 2.3: pH > 6 3.1: dichloromethane; water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1: ammonium carbamate / Novozyme 435 / acetonitrile / 40 °C / Enzymatic reaction 2: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide / 2250.23 Torr 3: water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate / water; tetrahydrofuran / 0.25 h / 0 °C 2.1: triethylamine; isobutyl chloroformate / dichloromethane / 0.33 h / 0 °C 2.2: 1 h / 20 °C 3.1: hydrogen; palladium 10% on activated carbon / water; methanol / 0.75 h 4.1: pyridine; sulfur trioxide pyridine complex / 20 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: lithium hydroxide monohydrate / water; tetrahydrofuran / 0.25 h / 0 °C 2.1: 4-methyl-morpholine; isobutyl chloroformate / dichloromethane / 0.17 h / 0 °C 2.2: 0.5 h 3.1: ammonium hydroxide / dichloromethane / 1 h / 0 - 20 °C 4.1: hydrogen; palladium 10% on activated carbon / water; methanol / 0.75 h 5.1: pyridine; sulfur trioxide pyridine complex / 20 h / 20 °C 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)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: water; lithium hydroxide monohydrate / acetone / -12 °C 1.2: 0 °C 1.3: -20 - 0 °C 2.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 3.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 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 3.1: water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 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 2.2: 20 °C 2.3: pH > 6 3.1: dichloromethane; water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

methyl (2S,5R)-5-benzyloxyaminopiperidine-2-carboxylate oxalate (1416134-74-1) → (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 4 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1: ammonia / methanol / 20 °C 2: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 3: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 5 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 4.1: water 5.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

ethyl (S)-2-((tert-butoxycarbonyl)amino)-6-(dimethyl(oxo)-λ6-sulfanylidene)-5-oxohexanoate (1416134-58-1) → (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 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: ammonia / methanol / 20 °C 5.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 6.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 7.1: sodium 2-ethylhexanoic acid / ethanol; water 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: 3-Methylpyridine / dichloromethane / 0 °C 5.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 6.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 7.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 8 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 7.1: water 8.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

C20H29ClN2O5 (1416134-59-2) → (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 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: ammonia / methanol / 20 °C 4.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 5.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 6.1: sodium 2-ethylhexanoic acid / ethanol; water 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: 3-Methylpyridine / dichloromethane / 0 °C 4.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 5.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 6.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 7 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 6.1: water 7.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme

5-benzyloxyiminopiperidine-2S-carboxylic acid ethyl ester (1416134-60-5) → (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 5 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: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 5.1: sodium 2-ethylhexanoic acid / ethanol; water 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: ammonia / methanol / 20 °C 3.1: N-ethyl-N,N-diisopropylamine; (fluorenylmethoxy)carbonyl chloride / chlorobenzene / 30 °C 4.1: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 5.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 6 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 5.1: water 6.1: sodium 2-ethylhexanoic acid / ethanol; water 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)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 2: triethylamine; hydrogen; sulfur trioxide trimethylamine complex / palladium-on-charcoal / isopropyl alcohol; water 3: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1.1: ammonium carbamate / Novozyme 435 / dichloromethane; acetonitrile / 40 °C / Enzymatic reaction 2.1: hydrogen / 5% Pd-C / dichloromethane; N,N-dimethyl-formamide 2.2: 20 °C 2.3: pH > 6 3.1: dichloromethane; water 4.1: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 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 3: water 4: sodium 2-ethylhexanoic acid / ethanol; water View Scheme
Multi-step reaction with 4 steps 1.1: lithium hydroxide / 1 h / 10 - 20 °C 2.1: hydrogenchloride / dichloromethane; water 3.1: ammonia; sodium sulfate; triethylamine / -25 - 5 °C 4.1: 10 wt% Pd(OH)2 on carbon; ammonium formate / 5 h / 30 - 40 °C / Inert atmosphere 4.2: 4 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 1 h / -5 - 5 °C 2.1: triethylamine; isobutyl chloroformate; ammonium hydroxide / dichloromethane / 1 h / -10 - 20 °C 3.1: triethylamine; triethylamine sulfur trioxide; palladium 10% on activated carbon; hydrogen / isopropyl alcohol; water / 20 °C / Sealed tube 3.2: 1 h / 20 °C / Sealed tube 4.1: sodium isooctanoate / water; ethanol / 4 h / 35 - 40 °C View Scheme

(2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4) + tetra(n-butyl)ammonium hydroxide (2052-49-5) → ({[(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
In water at 20 - 25℃;	91.1%

(2S,5R)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 7-oxo-6-(sulfoxy)monosodium salt (1192491-61-4) + 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
In water at 20 - 25℃;	89%

Upstream product

• 1192651-49-2 (1R,2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 
• 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 
• 113400-36-5 benzyl (2S)-N-tert-butoxycarbonyl-5-oxoprolinate 
• 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 
• 1192651-80-1 ({[(2S,5R)-2-carbamoyl-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3,2,1]-oct-6-yl]oxy}sulfonyl)tetrabutylammonium 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 

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 

Relevant articles and documents

Orally Absorbed Derivatives of the β-Lactamase Inhibitor Avibactam. Design of Novel Prodrugs of Sulfate Containing Drugs

Only one FDA-approved β-lactamase inhibitor has ever been orally available: clavulanic acid, approved in 1984. Avibactam, approved by FDA in 2015, is the first of a new class of BLIs called diazabicyclooctanes, or "DBOs". This class has much broader coverage than clavulanic acid but can only be administered by intravenous injection. Herein, we describe the synthesis and testing of the first approved BLI to be rendered orally bioavailable since clavulanic acid (1984).

RETRACTED ARTICLE: A New Synthetic Route to Avibactam: Lipase Catalytic Resolution and the Simultaneous Debenzylation/Sulfation

An efficient synthesis of avibactam starting from commercially available ethyl-5-hydroxypicolinate was completed in 10 steps and 23.9% overall yield. The synthesis features a novel lipase-catalyzed resolution, in the preparation of (2S,5S)-5-hydroxypiperidine-2-carboxylate acid, which is a valuable precusor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate. An optimized one-pot debenzylation/sulfation reaction, followed by cation exchange, gave the avibactam sodium salt on a 400.0 g scale.

Preparation method of avibactam sodium

The invention discloses a synthesis method of avibactam sodium. (2S,5R)-benzyloxyamino piperidine-2-ethyl formate oxalate (I) is used as an initial raw material; and the method comprises the followingsteps: reacting the raw material with a protecting group, carrying out carbonylation cyclization, carrying out hydrolysis of ester, ammoniating, sulfonating with a sulfur trioxide complex, salifyingwith an ammonium ion source, and salifying with a sodium salt to obtain avibactam sodium, and has the advantages of simple operation, easily controlled conditions, easy industrial production and wideapplication prospect.

Preparation method of avibactam intermediate compound

The invention relates to medical compounds and organic chemical synthesis, in particular to an avibactam intermediate compound and a preparation method thereof. The preparation method of the avibactamintermediate compound comprises the following steps: (1) carrying out a hydrogenation sulfonation reaction on (2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-formamide; (2) after the reactionin the previous step is completed, carrying out washing once, and adding quaternary ammonium bromide for a reaction; and (3) after the reaction is finished, performing extracting, and then carrying out rotary evaporation and crystallizing. Compared with the prior art, the method of the invention has the advantages that operation is simple, raw materials are easy to obtain, cost is low, the purityof an obtained sulfonic acid quaternary ammonium salt is high, and the purity of avibactam sodium generated by sodium salt exchange of the sulfonic acid quaternary ammonium salt is 99.5T, so the method is suitable for large-scale production.