Sulbactam

Ingredient	UNII	CAS	InChI Key
Sulbactam benzathine	49MU89FVBV	83031-43-0	YSEPFTSCLHUBNH-HFKSPEPWSA-N
Sulbactam sodium	DKQ4T82YE6	69388-84-7	NKZMPZCWBSWAOX-IBTYICNHSA-M

68373-14-8 (free acid)

WeightAverage: 233.242
Monoisotopic: 233.035793157

Chemical FormulaC₈H₁₁NO₅S

(2S,5R)-3,3-dimethyl-4,4,7-trioxo-4λ⁶-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

Betamaze, Penicillanic Acid Sulfone, Sulbactamum, CP 45899, CP-45899, CP45899

FDA 2023, Xacduro, 5/23/2023, To treat hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex
Press Release
Drug Trials Snapshots

Sulbactam is a β-lactamase inhibitor. This drug is given in combination with β-lactam antibiotics to inhibit β-lactamase, an enzyme produced by bacteria that destroys the antibiotics.^[1]

It was patented in 1977 and approved for medical use in 1986.^[2]

Sulbactam is a beta (β)-lactamase inhibitor and a derivative of the basic penicillin nucleus. When given in combination with β-lactam antibiotics, sulbactam produces a synergistic effect as it blocks the enzyme responsible for drug resistance by hydrolyzing β-lactams.

PATENT

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9309245	No	2016-04-12	2033-04-02
US9623014	No	2017-04-18	2033-04-02
US9968593	No	2018-05-15	2035-11-17
US10376499	No	2019-08-13	2035-11-17

doi:10.1016/S0040-4039(00)89275-8

SYN

European Journal of Medicinal Chemistry

Volume 265, 5 February 2024, 116124

https://doi.org/10.1016/j.ejmech.2024.116124

On May 23, 2023, the FDA granted approval to Xacduro for the treatment of Baumannii-sensitive strains causing hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia in
patients aged 18 years or older [4]. Xacduro consists of Sulbactam and Durlobactam. Sulbactam, a medication with a similar structure to Penicillin, has the ability to eliminate Acinetobacter baumannii. On the other hand, Durlobactam shields Sulbactam from being broken down by enzymes that may be produced by Acinetobacter baumannii [5].
The production process of Sulbactam started with 6-aminopenicilanic acid (6-APA) (SULB-001) as the starting material (Scheme 1) [6]. It underwent bromination reaction with sodium nitrite and bromine
in the presence of sulfuric acid. Then, SULB-002 was oxidized by potassium permanganate to obtain sulfone SULB-003. Finally, the sulfonewas catalytically hydrogenated and dehalogenated in the presence of Raney nickel to get Sulbactam

[5] A. El-Ghali, A.J. Kunz Coyne, K. Caniff, C. Bleick, M.J. Rybak, Sulbactamdurlobactam: a novel β-lactam-β-lactamase inhibitor combination targeting
carbapenem-resistant Acinetobacter baumannii infections, Pharmacotherapy 43
(2023) 502–513.
[6] Z.M. Song, W. Liu, J. Yang, Y. Sun, Improvement on the synthetic process of
sulbactam, Chin. J

PATENT

https://patents.google.com/patent/CN101967155A/en

Embodiment 1

In the four-hole boiling flask of 2000ML, add 600ML methylene dichloride and 180ML2.5N sulfuric acid, stirring is cooled to below 0 ℃, add 28ML bromine and 25g Sodium Nitrite, 0 ± 0.2 ℃, gradation adds 40g 6-APA, and controlled temperature is lower than 5 ℃, stirring reaction 1h, be cooled to then below 0 ℃, 20% aqueous solution of sodium bisulfite of dropping below 0 ℃ leaves standstill phase-splitting to the color fade of bromine, water 100ML dichloromethane extraction 3 times, merge organic phase, with 100ML saturated sodium-chloride water solution washing 2 times, obtain 6, the 6-dibromo penicillanic acid;

To go up 6, the 6-dibromo penicillanic acid changes in the 2000ML beaker mutually. and add 250ML distilled water and stir, be cooled to below 5 ℃, drip 4NNaHCO ₃The aqueous solution leaves standstill phase-splitting to pH=7, organic phase extracts 3 times with the 80ML deionized water, merge water, water changes in the 2000ML four-hole boiling flask, stirring is cooled to 0 ℃, and beginning dropping oxidizing agent (44g KMn04+10.8ML H3P04+700MLH20 stirring and dissolving) dripped in 30 minutes, controlled temperature is lower than 10 ℃ in the dropping process, keep 0～5 ℃ then, stirring reaction 1h adds the 500ML ethyl acetate, drip 6N sulfuric acid to pH=1.25, be cooled to 0 ℃, slowly add the color fade of 27.5% hydrogen peroxide (about 45g) to KMn04, during continue to keep pH=1.25 with 6N sulfuric acid, controlled temperature is lower than 10 ℃, reaction 10mi n filters, and adds sodium-chlor in the filtrate to no longer dissolving, leave standstill the branch phase of anhydrating, water 250ML ethyl acetate extraction 4 times merge organic phase, and wash 2 times with the 100ML saturated sodium-chloride water solution, organic phase contains 6, the acid of 6-dibromo sulbactam;

To go up 6,6-dibromo sulbactam acid organic phase changes in the 2000ML four-hole boiling flask, adds 350ML water, is cooled to below 5 ℃, uses 4N NaHCO ₃The aqueous solution is transferred pH to 5.0, and add 25ML methyl alcohol, add the 26g zinc powder in batches, and drip 6N sulfuric acid maintenance pH:4.5～5.5, after adding zinc powder, keep stirring reaction 4h below 5 ℃, keep pH=4.5～5.5 with 6N sulfuric acid simultaneously, filter, with 25ML ethyl acetate and 25ML water washing, merging filtrate is transferred pH to 2.0 with 6N sulfuric acid, add sodium-chlor to water insoluble till, leave standstill the branch phase of anhydrating, water merges organic phase with 150ML ethyl acetate extraction 4 times, washs to redness with the 50ML-100ML5% potassium permanganate solution earlier at organic layer and does not take off, again with 150ML saturated sodium-chloride water solution washing 2 times, layering, organic layer add the 2g activated carbon decolorizing, the 15g anhydrous magnesium sulfate drying, suction filtration, be evaporated to feed liquid and be creamy white, cool to 0 ℃ after centrifuging, after the oven dry product Sulbactam (sulbactam acid) 32g, the product yield is 74%, the product colour pure white was placed 30 days the color no change under the room temperature.

Embodiment 2

In the reactor of 2000L, add 600L methylene dichloride and 180L2.5N sulfuric acid, stirring is cooled to below 0 ℃, add 28L bromine and 25Kg Sodium Nitrite, 0 ± 0.2 ℃, gradation adds 40Kg 6-APA, and controlled temperature is lower than 5 ℃, stirring reaction 1h, be cooled to then below 0 ℃, 20% aqueous solution of sodium bisulfite of dropping below 0 ℃ leaves standstill phase-splitting to the color fade of bromine, water 100L dichloromethane extraction 3 times, merge organic phase, with 100L saturated sodium-chloride water solution washing 2 times, obtain 6, the 6-dibromo penicillanic acid;

Will on obtain 6, the 6-dibromo penicillanic acid changes in the 2000L reactor mutually. add the 250L tap water and stir, be cooled to below 5 ℃, drip 4NNaHCO ₃The aqueous solution leaves standstill phase-splitting to pH=7, organic phase extracts 3 times with the 80L deionized water, merge water, water changes in the 2000L reactor, stirring is cooled to 0 ℃, and beginning dropping oxidizing agent (44Kg KMn04+10.8L H3P04+700LH20 stirring and dissolving) dripped in 30 minutes, controlled temperature is lower than 10 ℃ in the dropping process, keep 0～5 ℃ then, stirring reaction 1h adds the 500L ethyl acetate, drip 6N sulfuric acid to pH=1.25, be cooled to 0 ℃, slowly add 28% hydrogen peroxide (about 44Kg) color fade to KMn04, during continue to keep pH=1.25 with 6N sulfuric acid, controlled temperature is lower than 10 ℃, reaction 10mi n filters, and adds sodium-chlor in the filtrate to no longer dissolving, leave standstill the branch phase of anhydrating, water 250L ethyl acetate extraction 4 times merge organic phase, and wash 2 times with the 100L saturated sodium-chloride water solution, organic phase contains 6, the acid of 6-dibromo sulbactam;

To go up organic phase and contain 6, the acid of 6-dibromo sulbactam changes in the 2000L reactor, adds 350L water, is cooled to below 5 ℃, uses 4N NaHCO ₃The aqueous solution is transferred pH to 5.0, and add 25L methyl alcohol, add the 26Kg zinc powder in batches, and drip 6N sulfuric acid maintenance pH:4.5～5.5, after adding zinc powder, keep stirring reaction 4h below 5 ℃, keep pH=4.5～5.5 with 6N sulfuric acid simultaneously, filter, with 25L ethyl acetate and 25L water washing, merging filtrate is transferred pH to 2.0 with 6N sulfuric acid, add sodium-chlor to water insoluble till, leave standstill the branch phase of anhydrating, water merges organic phase with 150L ethyl acetate extraction 4 times, washs to redness with the 30-50L10% potassium permanganate solution earlier at organic layer and does not take off, again with 150L saturated sodium-chloride water solution washing 2 times, layering, organic layer add the 2Kg activated carbon decolorizing, the 15Kg anhydrous magnesium sulfate drying, suction filtration, be evaporated to feed liquid and be creamy white, cool to 0 ℃ after centrifuging, after the oven dry product Sulbactam (sulbactam acid) 31.5Kg, the product yield is 72.8%, the product colour pure white was placed 30 days the color no change under the room temperature.

Embodiment 3

In the four-hole boiling flask of 1000ML, add 300ML methylene dichloride and 90ML2.5N Hydrogen bromide, stirring is cooled to below 0 ℃, add 14ML bromine and 12.5g Sodium Nitrite, 0 ± 0.2 ℃, gradation adds 20g 6-APA, and controlled temperature is lower than 5 ℃, stirring reaction 1h, be cooled to then below 0 ℃, 20% aqueous solution of sodium bisulfite of dropping below 0 ℃ leaves standstill phase-splitting to the color fade of bromine, water 50ML dichloromethane extraction 3 times, merge organic phase, with 50ML saturated sodium-chloride water solution washing 2 times, obtain 6, the 6-dibromo penicillanic acid;

To go up 6, the 6-dibromo penicillanic acid changes in the 1000ML beaker mutually. and add 125ML distilled water and stir, be cooled to below 5 ℃, drip 4NNaHCO ₃The aqueous solution leaves standstill phase-splitting to pH=7, organic phase extracts 3 times with the 40ML deionized water, merge water, water changes in the 1000ML four-hole boiling flask, stirring is cooled to 0 ℃, and beginning dropping oxidizing agent (22g KMn04+5.4ML H3P04+300MLH20 stirring and dissolving) dripped in 30 minutes, controlled temperature is lower than 10 ℃ in the dropping process, keep 0～5 ℃ then, stirring reaction 1h adds the 250ML ethyl acetate, drip 6N sulfuric acid to pH=1.25, be cooled to 0 ℃, slowly add 25% hydrogen peroxide (about 29g) color fade to KMn04, during continue to keep pH=1.25 with 6N sulfuric acid, controlled temperature is lower than 10 ℃, reaction 10mi n filters, and adds sodium-chlor in the filtrate to no longer dissolving, leave standstill the branch phase of anhydrating, water 125ML ethyl acetate extraction 4 times merge organic phase, and wash 2 times with the 50ML saturated sodium-chloride water solution, organic phase contains 6, the acid of 6-dibromo sulbactam.

To go up organic phase and contain 6, the acid of 6-dibromo sulbactam changes in the 1000ML four-hole boiling flask, adds 175ML water, is cooled to below 5 ℃, uses 4N NaHCO ₃The aqueous solution is transferred pH to 5.0, and add 12.5ML methyl alcohol, add the 13g zinc powder in batches, and drip 6N sulfuric acid maintenance pH:4.5～5.5, after adding zinc powder, keep stirring reaction 4h below 5 ℃, keep pH=4.5～5.5 with 6N sulfuric acid simultaneously, filter, with 12.5ML ethyl acetate and 12.5ML water washing, merging filtrate is transferred pH to 2.0 with 6N sulfuric acid, add sodium-chlor to water insoluble till, leave standstill the branch phase of anhydrating, water merges organic phase with 75ML ethyl acetate extraction 4 times, washs to redness with the 15ML-35ML7% potassium permanganate solution earlier at organic layer and does not take off, again with 75ML saturated sodium-chloride water solution washing 2 times, layering, organic layer add the 1g activated carbon decolorizing, the 7.5g anhydrous magnesium sulfate drying, suction filtration, be evaporated to feed liquid and be creamy white, cool to 0 ℃ after centrifuging, after the oven dry product Sulbactam (sulbactam acid) 15.9g, the product yield is 73.5%, the product colour pure white was placed 30 days the color no change under the room temperature.

PATENT

https://patents.google.com/patent/US4420426A/en

Medical uses

The combination ampicillin/sulbactam (Unasyn) is available in the United States.^[3]

The combination cefoperazone/sulbactam (Sulperazon) is available in many countries but not in the United States.^[4]

The co-packaged combination sulbactam/durlobactam was approved for medical use in the United States in May 2023.^[5]

Mechanism

Sulbactam is primarily used as a suicide inhibitor of β-lactamase, shielding more potent beta-lactams such as ampicillin.^[6] Sulbactam itself contains a beta-lactam ring, and has weak antibacterial activity by inhibiting penicillin binding proteins (PBP) 1 and 3, but not 2.^[7]

References

1. ^ Totir MA, Helfand MS, Carey MP, Sheri A, Buynak JD, Bonomo RA, Carey PR (August 2007). “Sulbactam forms only minimal amounts of irreversible acrylate-enzyme with SHV-1 beta-lactamase”. Biochemistry. 46 (31): 8980–8987. doi:10.1021/bi7006146. PMC 2596720. PMID 17630699.
2. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 492. ISBN 9783527607495.
3. ^ “Unasyn- ampicillin sodium and sulbactam sodium injection, powder, for solution”. DailyMed. U.S. National Library of Medicine. 29 March 2023. Retrieved 25 May 2023.
4. ^ “Sulperazon”. drugs.com.
5. ^ “FDA Approves New Treatment for Pneumonia Caused by Certain Difficult-to-Treat Bacteria”. U.S. Food and Drug Administration (Press release). 24 May 2023. Retrieved 24 May 2023.
6. ^ Crass RL, Pai MP (February 2019). “Pharmacokinetics and Pharmacodynamics of β-Lactamase Inhibitors”. Pharmacotherapy. 39 (2): 182–195. doi:10.1002/phar.2210. PMID 30589457. S2CID 58567725.
7. ^ Penwell WF, Shapiro AB, Giacobbe RA, Gu RF, Gao N, Thresher J, et al. (March 2015). “Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii”. Antimicrobial Agents and Chemotherapy. 59 (3): 1680–1689. doi:10.1128/AAC.04808-14. PMC 4325763. PMID 25561334.

Further reading

Singh GS (January 2004). “Beta-lactams in the new millennium. Part-II: cephems, oxacephems, penams and sulbactam”. Mini Reviews in Medicinal Chemistry. 4 (1): 93–109. doi:10.2174/1389557043487547. PMID 14754446.

Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a693021
Routes of administration	Intravenous, intramuscular
ATC code	J01CG01 (WHO)
Legal status
Legal status	UK: POM (Prescription only)
Pharmacokinetic data
Protein binding	29%
Elimination half-life	0.65–1.20 hrs
Excretion	Mainly kidneys (41–66% within 8 hrs)
Identifiers
showIUPAC name
CAS Number	68373-14-8
PubChem CID	130313
ChemSpider	115306
UNII	S4TF6I2330
KEGG	D08533
ChEBI	CHEBI:9321
ChEMBL	ChEMBL403
CompTox Dashboard (EPA)	DTXSID1023605
ECHA InfoCard	100.063.506
Chemical and physical data
Formula	C8H11NO5S
Molar mass	233.24 g·mol−1
3D model (JSmol)	Interactive image
Melting point	148 to 151 °C (298 to 304 °F)
showSMILES
showInChI

//////////Sulbactam, Xacduro, FDA 2023, APPROVALS 2023, Betamaze, Penicillanic Acid Sulfone, Sulbactamum, CP 45899, CP-45899, CP45899