68373-14-8

Basic information

• Product Name: Sulbactam
• Synonyms: (2S,5R)-3,3-DIMETHYL-4,4,7-TRIOXO-4LAMBDA6-THIA-1-AZA-BICYCLO[3.2.0]HEPTANE-2-CARBOXYLIC ACID;(2S-CIS)-3,3-DIMETHYL-7-OXO-4-THIA-1-AZABICYCLO[3,2,0]HEPTANE-2-CARBOXYLIC ACID 4,4-DIOXIDE;3,3-DIMETHYL-4,4,7-TRIOXO-4LAMBDA6-THIA-1-AZA-BICYCLO[3.2.0]HEPTANE-2-CARBOXYLIC ACID;SULBACTAM;SULBACTAM ACID;sulbactam acid (base);PENICILLANIC ACID SULFONE;(2S,5R)-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 4,4-dioxide
• CAS NO: 68373-14-8
• Molecular Formula: C₈H₁₁NO₅S
• Molecular Weight: 233.24
• EINECS: 269-878-2
• Product Categories: Peptide Synthesis/Antibiotics;MERITAL
• Mol File: 68373-14-8.mol
• Article Data: 28

Chemical Properties

• Melting Point: 154-157℃
• Boiling Point: 567.7 °C at 760 mmHg
• Flash Point: 297.1 °C
• Appearance: white to tan/lyophilized powder
• Density: 1.62 g/cm³
• Vapor Pressure: 2.26E-14mmHg at 25°C
• Refractive Index: 1.605
• Storage Temp.: −20°C
• Solubility: H2O: ≥18mg/mL
• PKA: 2.62±0.40(Predicted)
• Water Solubility: Soluble in water at 18mg/ml
• Stability: Hygroscopic
• Merck: 14,8889
• CAS DataBase Reference: Sulbactam(CAS DataBase Reference)
• NIST Chemistry Reference: Sulbactam(68373-14-8)
• EPA Substance Registry System: Sulbactam(68373-14-8)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• Safety Statements: 24/25
• WGK Germany: 3
• Hazardous Substances Data: 68373-14-8(Hazardous Substances Data)

Usage

Description

Sulbactam is prepared by partial chemical synthesis from penicillins. The oxidation of the sulfur atom to a sulfone greatly enhances the potency of sulbactam. The combination of sulbactam and ampicillin (Unasyn) is now clinically popular.

Originator

Sulbactam-Sodium,Antibiotic Co.,Bulgaria

Uses

Different sources of media describe the Uses of 68373-14-8 differently. You can refer to the following data:
1. antidepressant, dopamine uptake inhibitor
2. Sulbactam sodium is a semi-synthetic penem antibiotic formed by the oxidation of penicillanic acid to its sulfone and was invented by Barth at Pfizer in 1978. Sulbactam sodium is a weak antibiotic but its action as an irreversible inhibitor of β-lactamase is exploited to block the degradation of other penicillin derivatives. Sulbactam acts as a synergist with cephalosporins and penicillins against Gram positive bacteria and is used commercially in combination with ampicillin.
3. A β-lactamase inhibitor.

Manufacturing Process

Sulbactam sodium is semi-synthetic antibiotic of penicillinic group. Start material for it's synthesis is 6-aminopenicillanic acid. First 6-aminopenicillanic acid was isolated in 1957 year from benzylpenicilline as resalt of treating of it by penicillinaze. Benzylpenicilline is produced by microorganism of genus Streptomyces.Further, 6-aminopenicillanic acid reacted with bromine, hydrochloric acid and NaNO2. As a result the 6,6-dibromopenicillanic acid was obtained.6,6-Dibromopenicillanic acid was oxidized by KMnO4, to give 6,6-dibromo-1,1-The 6,6-dibromo-1,1-dioxopenicillanic acid in presence of Fe was converted to the 1,1-dioxopenicillanic acid (sulbactam acid). The sulbactam acid was treated by sodium 2-ethylhexanoate and crude sulbactam sodium was obtained.

Antimicrobial activity

Sulbactam has very weak antimicrobial activity against most bacteria. Its only notable activity is against N. gonorrhoeae, N. meningitidis and Acinetobacter baumannii.

Clinical Use

Sulbactam is penicillanic acid sulfone or 1,1-dioxopenicillanicacid. This synthetic penicillin derivative is a potent inhibitorof S. aureus β-lactamase as well as many β-lactamaseselaborated by Gram-negative bacilli. Sulbactam has weak intrinsicantibacterial activity but potentiates the activity ofampicillin and carbenicillin against β-lactamase–producingS. aureus and members of the Enterobacteriaceae family. Itdoes not, however, synergize with either carbenicillin or ticarcillinagainst P. aeruginosa strains resistant to these agents.Failure of sulbactam to penetrate the cell envelope is a possibleexplanation for the lack of synergy.Fixed-dose combinations of ampicillin sodium and sulbactamsodium, marketed under the trade name Unasyn assterile powders for injection, have been approved for use inthe United States. These combinations are recommended forthe treatment of skin, tissue, intra-abdominal, and gynecologicalinfections caused by β-lactamase–producing strainsof S. aureus, E. coli, Klebsiella spp., P. mirabilis, B. fragilis,and Enterobacter and Acinetobacter spp.

InChI:InChI=1/C8H11NO5S/c1-8(2)6(7(11)12)9-4(10)3-5(9)15(8,13)14/h5-6H,3H2,1-2H3,(H,11,12)/t5-,6+/m0/s1

Synthetic route

(2S,5R)-3,3-Dimethyl-4,4,7-trioxo-4λ6-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylic acid 2-chloro-allyl ester → sulbactum (68373-14-8)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); sodium 4-methylbenzenesulfinate In tetrahydrofuran; methanol for 1h; Ambient temperature;	99%

6,6-dibromopenicillanic acid-1,1-dioxide (76646-91-8) → sulbactum (68373-14-8)

Conditions	Yield
With sulfuric acid; zinc In water at 12℃; for 2h; Temperature; Large scale;	96%
With hydrogenchloride; magnesium In dichloromethane; water at -5 - 3℃; for 0.5h; Reagent/catalyst; Solvent; Temperature;	93.1%
With tri-n-butyl-tin hydride In ethyl acetate at 20℃; for 2h; Temperature; Time; Inert atmosphere;	90.9%

(2S,5R)-Benzyl 3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo<3.2.0>heptane-2-carboxylate 4,4-Dioxide (69388-78-9) → sulbactum (68373-14-8)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethyl acetate for 1h; Ambient temperature;	96%

6-aminopenicillanic acid (551-16-6, 1079-37-4, 3115-55-7, 21794-93-4, 145920-51-0) → sulbactum (68373-14-8)

Conditions	Yield
Stage #1: 6-aminopenicillanic acid With sulfuric acid; hypophosphorous acid; sodium nitrite In water; ethyl acetate at -10℃; for 1.5h; Stage #2: With sodium tungstate (VI) dihydrate; dihydrogen peroxide In water at -5℃; for 1h; Temperature;	94.9%

sodium sulbactam (69388-84-7) → sulbactum (68373-14-8)

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In dichloromethane; water at 20℃; for 0.166667h; pH=6.9 - 7;	94.8%
With hydrogenchloride In water; ethyl acetate	87.2%
Multi-step reaction with 2 steps 1: 86 percent / hexamethylphosphoric acid triamide / 18 h / 55 °C 2: 99 percent / sodium p-toluenesulfinate tetrahydrate, Pd(PPh3)4 / methanol; tetrahydrofuran / 1 h / Ambient temperature View Scheme

6,6-dibromopenicillanic acid-1,1-dioxide (76646-91-8) + nickel (7440-02-0) → sulbactum (68373-14-8)

Conditions	Yield
With copper In dichloromethane; water; acetic acid; acetonitrile	84%

manganese (7439-96-5) + 6-bromo-1,1-dioxopenicillanic acid (810692-15-0) → sulbactum (68373-14-8)

Conditions	Yield
With phosphoric acid; iron In acetic acid methyl ester; water	80%

sodium salt of penicillanic acid → sulbactum (68373-14-8)

Conditions	Yield
With potassium permanganate; sodium chloride; sodium hydrogensulfite In water	78%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl penicillanate 1,1-dioxide (85871-31-4) → sulbactum (68373-14-8)

Conditions	Yield
With sodium hydrogencarbonate In water; acetone at 5 - 10℃; for 4h; pH 9;	65%

penicillanic acid (87-53-6) → sulbactum (68373-14-8)

Conditions	Yield
With hydrogenchloride; sodium hydroxide; potassium permanganate; sodium hydrogensulfite In water; acetic acid; ethyl acetate	26%
With potassium permanganate; phosphoric acid; sodium hydroxide In water at 0 - 5℃; for 2h; pH=7.5; Temperature; pH-value;	49.5 g

6,6-dibromopenicillanic acid-1,1-dioxide (76646-91-8) → sulbactum (68373-14-8) + 6β-bromopenicillanic acid 1,1-dioxide (75527-87-6) + (2S,5R,6S)-6β-bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid,S,S-dioxide (75527-88-7)

Conditions	Yield
With hydrogen; palladium on activated charcoal under 2250.2 - 3750.3 Torr; Product distribution; Ambient temperature; pH 7.0 - 8.0;

6,6-dibromopenicillanic acid (24158-88-1) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: KMnO4; phosphoric acid / CH2Cl2; H2O / 0.83 h / -5 °C 2: Mg; aq.HCl / ethyl acetate; H2O / 10 h / 20 °C / pH 3.5 View Scheme
Multi-step reaction with 2 steps 1: 67 percent / KMnO4, NaOH, H3PO4 / CH2Cl2; H2O / -5 °C 2: 60.4 percent / NaOH, Zn / acetonitrile; H2O / 0 - 10 °C / 1) pH 5.2 2) pH 3.5-4 (by addition of 4M HCl), 30 min View Scheme
Multi-step reaction with 3 steps 1: Sodium orthovanadate; dihydrogen peroxide / dichloromethane; water / 2.5 h / 5 - 10 °C 2: potassium permanganate; ammonium acetate / dichloromethane; water / 2 h / 5 - 15 °C 3: magnesium; sulfuric acid / water; ethyl acetate / 1.75 h / 0 - 5 °C / pH 3.8 - 4 View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide; water; potassium permanganate; phosphoric acid / 0 - 5 °C 2: zinc / water / 1.5 h / 0 °C / pH Ca. 3.5 View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide / water; ethyl acetate / 0.5 h / 5 °C / pH 7 1.2: 0.5 h / -5 °C 1.3: pH 1.23 2.1: hydrogenchloride; magnesium / water; ethyl acetate / 0.67 h / 0 °C / pH 3.5 - 4 View Scheme

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 6-diazopenicillanate (115923-36-9) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / bromine / CH2Cl2 / 1 h / 0 - 5 °C 2: 72 percent / hydrogen, K2HPO4 / 5percent palladium on calcium carbonate / ethyl acetate; H2O / 2 h / 2068.6 Torr / Ambient temperature 3: 75 percent / 30percent hydrogen peroxide, sodium tungstate / acetone / 48 h / Ambient temperature 4: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme
Multi-step reaction with 4 steps 1: 85 percent / bromine / CH2Cl2 / 1 h / 0 - 5 °C 2: 83.7 percent / m-chloroperbenzoic acid / CH2Cl2 / Ambient temperature 3: 80 percent / hydrogen, K2HPO4 / palladium on charcoal / ethyl acetate; H2O / 1 h / 2585.7 Torr / Ambient temperature 4: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl penicillanate (85871-33-6) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 75 percent / 30percent hydrogen peroxide, sodium tungstate / acetone / 48 h / Ambient temperature 2: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme

6-aminopenicillanic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (80715-30-6) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 85 percent / sodium nitrile, 5percent aq. H2SO4 / H2O; CH2Cl2 / 1 h / 0 - 5 °C 2: 85 percent / bromine / CH2Cl2 / 1 h / 0 - 5 °C 3: 72 percent / hydrogen, K2HPO4 / 5percent palladium on calcium carbonate / ethyl acetate; H2O / 2 h / 2068.6 Torr / Ambient temperature 4: 75 percent / 30percent hydrogen peroxide, sodium tungstate / acetone / 48 h / Ambient temperature 5: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme
Multi-step reaction with 5 steps 1: 85 percent / sodium nitrile, 5percent aq. H2SO4 / H2O; CH2Cl2 / 1 h / 0 - 5 °C 2: 85 percent / bromine / CH2Cl2 / 1 h / 0 - 5 °C 3: 83.7 percent / m-chloroperbenzoic acid / CH2Cl2 / Ambient temperature 4: 80 percent / hydrogen, K2HPO4 / palladium on charcoal / ethyl acetate; H2O / 1 h / 2585.7 Torr / Ambient temperature 5: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 6,6-dibromopenicillanate (103453-04-9) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 72 percent / hydrogen, K2HPO4 / 5percent palladium on calcium carbonate / ethyl acetate; H2O / 2 h / 2068.6 Torr / Ambient temperature 2: 75 percent / 30percent hydrogen peroxide, sodium tungstate / acetone / 48 h / Ambient temperature 3: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme
Multi-step reaction with 3 steps 1: 83.7 percent / m-chloroperbenzoic acid / CH2Cl2 / Ambient temperature 2: 80 percent / hydrogen, K2HPO4 / palladium on charcoal / ethyl acetate; H2O / 1 h / 2585.7 Torr / Ambient temperature 3: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 6,6-dibromopenicillanate 1,1-dioxide (103453-09-4) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 80 percent / hydrogen, K2HPO4 / palladium on charcoal / ethyl acetate; H2O / 1 h / 2585.7 Torr / Ambient temperature 2: 65 percent / NaHCO3 / acetone; H2O / 4 h / 5 - 10 °C / pH 9 View Scheme

(3S,4R)-4-<(2-Methyl-3-buten-2-yl)thio>-3-(trimethylsilyl)-2-azetidinone (128971-79-9) → sulbactum (68373-14-8)

Conditions

Yield

Multi-step reaction with 8 steps 1: 83 percent / i-Pr2NEt, N,N-(dimethylamino)pyridine / CH2Cl2 / 3 h / Ambient temperature 2: 1) O3, 2) Me2S / 1) CH2Cl2, -78 deg C, 2) 0 deg C, 15 min 3: 1) t-BuOK / 1) THF, t-BuOH, 0 deg C, 15 min, 2) 0 deg C, 40 h 4: 72 percent / Et3N, acetyl chloride / 20 h / 0 °C 5: 1) tetrabutylammonium fluoride, 2) ozone / 1) THF, -78 deg C, 1 h, 2) CH2Cl2, -78 deg C, 2 min 6: 91 percent / DBU / CH2Cl2 / 8 h 7: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 8: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

(3S,4R)-1-(tert-Butyldimethylsilyl)-4-<(2-methyl-3-buten-2-yl)thio>-3-(trimethylsilyl)-2-azetidinone (128971-80-2) → sulbactum (68373-14-8)

Conditions

Yield

Multi-step reaction with 7 steps 1: 1) O3, 2) Me2S / 1) CH2Cl2, -78 deg C, 2) 0 deg C, 15 min 2: 1) t-BuOK / 1) THF, t-BuOH, 0 deg C, 15 min, 2) 0 deg C, 40 h 3: 72 percent / Et3N, acetyl chloride / 20 h / 0 °C 4: 1) tetrabutylammonium fluoride, 2) ozone / 1) THF, -78 deg C, 1 h, 2) CH2Cl2, -78 deg C, 2 min 5: 91 percent / DBU / CH2Cl2 / 8 h 6: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 7: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

(3S,4R)-1-(tert-Butyldimethylsilyl)-4-<(2-methyl-3-oxo-2-propyl)thio>-3-(trimethylsilyl)-2-azetidinone (124831-31-8) → sulbactum (68373-14-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: 1) t-BuOK / 1) THF, t-BuOH, 0 deg C, 15 min, 2) 0 deg C, 40 h 2: 72 percent / Et3N, acetyl chloride / 20 h / 0 °C 3: 1) tetrabutylammonium fluoride, 2) ozone / 1) THF, -78 deg C, 1 h, 2) CH2Cl2, -78 deg C, 2 min 4: 91 percent / DBU / CH2Cl2 / 8 h 5: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 6: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

(3S,4R)-4-<<4-(Benzyloxy)-3-hydroxy-2-methyl-4-nitro-2-butyl>thio>-1-(tert-butyldimethylsilyl)-3-(trimethylsilyl)-2-azetidinone (128971-81-3) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 72 percent / Et3N, acetyl chloride / 20 h / 0 °C 2: 1) tetrabutylammonium fluoride, 2) ozone / 1) THF, -78 deg C, 1 h, 2) CH2Cl2, -78 deg C, 2 min 3: 91 percent / DBU / CH2Cl2 / 8 h 4: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 5: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

(3S,4R)-4-<<4-(Benzyloxy)-2-methyl-4-nitro-3(Z)-buten-2-yl>thio>-1-(tert-butyldimethylsilyl)-3-(trimethylsilyl)-2-azetidinone (124831-32-9) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1) tetrabutylammonium fluoride, 2) ozone / 1) THF, -78 deg C, 1 h, 2) CH2Cl2, -78 deg C, 2 min 2: 91 percent / DBU / CH2Cl2 / 8 h 3: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 4: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

(2R,5R)-Benzyl 3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo<3.2.0>heptane-2-carboxylate (124831-33-0) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / DBU / CH2Cl2 / 8 h 2: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 3: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

(2S,5R)-Benzyl 3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo<3.2.0>heptane-2-carboxylate (62263-72-3) → sulbactum (68373-14-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / oxone, NaHCO3 / H2O; methanol / 18 h / Ambient temperature; pH 3 2: 96 percent / H2 / Pd/C / ethyl acetate / 1 h / Ambient temperature View Scheme

6-chloro-6-iodopenicillanic acid 1,1-dioxide (76517-16-3) + tri-n-butyl-tin hydride (688-73-3) → sulbactum (68373-14-8)

Conditions	Yield
With chloro-trimethyl-silane; sodium hydrogencarbonate; triethylamine; 2,2'-azobis(isobutyronitrile) In ethyl acetate; benzene

6-bromo-6-iodopenicillanic acid 1,1-dioxide (76517-25-4) + tri-n-butyl-tin hydride (688-73-3) → sulbactum (68373-14-8)

Conditions	Yield
With chloro-trimethyl-silane; sodium hydrogencarbonate; triethylamine; 2,2'-azobis(isobutyronitrile) In hexane; ethyl acetate; benzene

6,6-dibromopenicillanic acid-1,1-dioxide (76646-91-8) + 6-aminopenicillanic acid (551-16-6, 1079-37-4, 3115-55-7, 21794-93-4, 145920-51-0) → sulbactum (68373-14-8)

Conditions	Yield
palladium In ethyl acetate
palladium In ethyl acetate

magnesium dihydride (7439-95-4) + 2,6 dichloroacetophenone (2040-05-3) + 6,6-dibromopenicillanic acid-1,1-dioxide (76646-91-8) → sulbactum (68373-14-8)

Conditions	Yield
With hydrogenchloride In hexane; water; ethyl acetate; acetone

6-bromo-1,1-dioxopenicillanic acid (810692-15-0) → sulbactum (68373-14-8)

Conditions	Yield
In acetic acid methyl ester; water

sulbactum (68373-14-8) → sodium sulbactam (69388-84-7)

Conditions	Yield
With sodium isooctanoate In ethyl acetate	99.3%
With sodium 2-ethylhexanoic acid In water; isopropyl alcohol at 20 - 35℃; for 2.33333h;	95%
With sodium acetate; sodium hydrogencarbonate at 20 - 25℃; pH=5.5 - 6;
With sodium isooctanoate In methanol; water at 25℃; pH=4.5; Reagent/catalyst; Solvent; Temperature; pH-value;	542g

chlorobromomethane (74-97-5) + sulbactum (68373-14-8) → chloromethyl penicillanate 1,1-dioxide (76247-40-0)

Conditions	Yield
With pyridine at 20℃; for 3.5h; Darkness;	92.6%

1-bromomethyl-4-iodobenzene (16004-15-2) + sulbactum (68373-14-8) → 4-iodobenzyl (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept ane-2-carboxylate 4,4-dioxide

Conditions	Yield
With potassium carbonate; potassium iodide at 20℃; for 12h;	92%

1,4-Diiodobutane (628-21-7) + sulbactum (68373-14-8) → C12H18INO5S

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 12h; Inert atmosphere;	86%

chlorosulfuric acid chloromethyl ester (49715-04-0) + sulbactum (68373-14-8) → chloromethyl penicillanate 1,1-dioxide (76247-40-0)

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane 1.) 20-22 deg C, 2.) 30 min;	80%

4-Methyl-1-pentanol (626-89-1) + sulbactum (68373-14-8) → 4-methylpentyl (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide

Conditions	Yield
With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; for 16h;	78%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Inert atmosphere;	74%

methyl chlorosulfate (812-01-1) + sulbactum (68373-14-8) → 2S,5R-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo<2.2.0>-heptane-2 carboxylic acid methyl ester 4,4-dioxide (65039-72-7)

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane 1.) 20-22 deg C, 2.) 30 min;	75%

sulbactum (68373-14-8) + methyl iodide (74-88-4) → 2S,5R-3,3-Dimethyl-7-oxo-4-thia-1-azabicyclo<2.2.0>-heptane-2 carboxylic acid methyl ester 4,4-dioxide (65039-72-7)

Conditions	Yield
With sodium hydrogencarbonate In N,N-dimethyl-formamide at 20℃; for 16h;	75%

sulbactum (68373-14-8) + [(chlorosulfonyl)oxy]methyl sulfurochloridate (92975-18-3) → C17H22N2O10S2 (81156-60-7)

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane 1.) 20-22 deg C, 2.) 30 min;	73%

1-(1-bromoethyl)-4-bromomethyl-benzene + sulbactum (68373-14-8) → C17H20BrNO5S

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 3h;	70%

Benzophenone oxime (574-66-3) + sulbactum (68373-14-8) → (2S,5R)-2-((((diphenylmethylene)amino)oxy)carbonyl)-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptan-7-one 4,4-dioxide

Conditions	Yield
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Schlenk technique; Inert atmosphere;	67%

4,5-di(bromomethyl)-2-oxo-1,3-dioxole (62458-19-9) + sulbactum (68373-14-8) → (5-bromomethyl-2-oxo-1,3-dioxol-4-yl)methyl penicillanate 1,1-dioxide (115946-67-3)

Conditions	Yield
With potassium hydrogencarbonate; sodium iodide In ethyl acetate; N,N-dimethyl-formamide for 8h; Ambient temperature;	61.5%

sulbactum (68373-14-8) + 3-bromo-N-(triphenylmethyl)propanamine (88811-16-9) → C30H32N2O5S

Conditions	Yield
Stage #1: sulbactum With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-bromo-N-(triphenylmethyl)propanamine In N,N-dimethyl-formamide at 20℃; for 16h;	52%

sulbactum (68373-14-8) + α-chloroethyl chlorosulfate (90906-61-9) → 1-chloroethyl penicillanate 1,1-dioxide (76350-32-8)

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane 1.) 20-22 deg C, 2.) 30 min;	47%

potassium bicarbonate + 4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one (80715-22-6) + sulbactum (68373-14-8) → (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl penicillanate 1,1-dioxide (85871-31-4)

Conditions	Yield
With sodium chloride In N-methyl-acetamide; water; ethyl acetate	47%

sulbactum (68373-14-8) + 2-nitrophenylmethyl bromide (3958-60-9) → 2-nitrobenzyl 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylate 4,4-dioxide

Conditions	Yield
Stage #1: sulbactum With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-nitrophenylmethyl bromide In N,N-dimethyl-formamide at 20℃; for 16h;	46%

sulbactum (68373-14-8) + 3,4-dichlorobenzyl bromide (18880-04-1) → 3,4-dichlorobenzyl 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylate 4,4- dioxide

Conditions	Yield
Stage #1: sulbactum With triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3,4-dichlorobenzyl bromide In N,N-dimethyl-formamide at 20℃; for 16h;	45%

diphenylmethylpiperazine (841-77-0) + sulbactum (68373-14-8) → (2S)-3,3-dimethyl-2-(4'-benzhydrylpiperazine-1'-carbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane 4,4-dioxide

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃;	40%

4-ethylbenzyl alcohol (768-59-2) + sulbactum (68373-14-8) → 4-ethylbenzyl (2S,5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate 4,4-dioxide

Conditions	Yield
Stage #1: sulbactum With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: 4-ethylbenzyl alcohol In dichloromethane at 0 - 20℃; for 48h; Inert atmosphere;	27%

Upstream product

• 76517-16-3 6-chloro-6-iodopenicillanic acid 1,1-dioxide 
• 688-73-3 tri-n-butyl-tin hydride 
• 76517-25-4 6-bromo-6-iodopenicillanic acid 1,1-dioxide 
• 7439-95-4 magnesium dihydride 
• 2040-05-3 2,6 dichloroacetophenone 
• 76646-91-8 6,6-dibromopenicillanic acid-1,1-dioxide 
• 87-53-6 penicillanic acid 
• 205320-24-7 6,6-dibromopenicillanic acid 
• 76646-91-8 6,6-dibromopenicillanic acid S,S-dioxide 
• 551-16-6 6-aminopenicillanic acid 
• 551-16-6 6-Aminopenicillanic Acid 
• 69388-90-5 p-nitrobenzyl penicillanate 1,1-dioxide 
• 810692-15-0 6-bromo-1,1-dioxopenicillanic acid 
• 7440-02-0 nickel 

Downstream Products

• 76247-40-0 chloromethyl penicillanate 1,1-dioxide 
• 854139-74-5 (3,3-dimethyl-4,4,7-trioxo-4-thia-1-azabicyclo[3.2.0]hept-2-yl)phenylselenylacetaldehyde 
• 854139-75-6 2-[[1,3]dioxolan-2-yl(phenylselenyl)methyl]-3,3-dimethyl-4,4-dioxo-4-thia-1-azabicyclo[3.2.0]heptan-7-one 
• 85871-32-5 1,1-dioxopenicillanic acid (5-phenyl-2-oxo-1,3-dioxolen-4-yl)-methyl ester 
• 69388-79-0 (pivaloyloxy)methyl 6,6-dihydropenicillanate S,S-dioxide 
• 76247-39-7 iodomethyl penicillanate 1,1-dioxide 
• 69388-84-7 sodium sulbactam 
• 90749-09-0 4-(6-(2-amino-2-phenylacetamido)penicillanoyl)oxymethyl-5-(1,1-dioxopenicillanoyl)oxymethyl-1,3-dioxol-2-one hydrochloride 

Relevant articles and documents

Synthesis method and application of amoxicillin and sulbactam hybrid molecule

The invention discloses a synthesis method and application of an amoxicillin and sulbactam hybrid molecule, and belongs to the technical field of organic synthesis. According to the method, chlorobromomethane is used as a chloromethyl reagent of sulbactam acid, so that the yield of a key intermediate sulbactam chloromethyl ester is effectively increased, and sulbactam chloromethyl ester and (Z)-6-(2-(4-hydroxyphenyl)-2-((4-methoxy-4-oxobutyl-2-ene-2-yl) amino) acetamido)-3, 3'-dihydroxyl-7-oxo-4-sulfo-1-azabicyclo[3.2.0]heptane-2-carboxylic acid as a raw material to carry out condensation reaction, and a protecting group is removed by using strong acid, so as to prepare the amoxicillin and sulbactam hybrid molecule. The synthesis method has the advantages of mild reaction conditions, cheap and easily available raw materials, low preparation cost, good safety, simple and feasible process and high product yield.

Sulbactam acid synthesis method

The present invention provides a sulbactam acid synthesis method, which is characterized by comprising: 1, carrying out a Griess deamination reaction: adopting 6-APA as a raw material, carrying out adiazotization reaction on the 6-APA and sodium nitrite in a sulfuric acid and ethyl acetate solution, and reducing with a reducing agent to obtain a 6, 6-dihydropenicillanic acid solution without separation to enter the next step; and 2, oxidizing the solution obtained in the step 1 with hydrogen peroxide under the action of a catalyst to obtain the target product sulbactam acid. The sulbactam acid is prepared by adopting a one-pot method, the sulbactam acid is synthesized by Griess deamination reaction and hydrogen peroxide oxidation two-step reaction; intermediates do not need separation, the method is short in route, low in raw material cost, high in yield, simple in reaction operation, convenient in three-waste treatment and easy to be suitable for large-scale industrial production, bromine with large pollution is not used, and oxidizing agent potassium permanganate is replaced with hydrogen peroxide, so that the method is simple to operate, green and environment-friendly, and avoids using metal powder or catalytic hydrogenation.

Method for preparing sulbactam acid

The invention relates to the field of pharmaceutical synthesis and provides a method for preparing sulbactam acid. The method is used for solving the problem of the traditional synthesis methods thatthe yield is low. The method comprises the following steps: S1. diazotation and bromination reaction: adding bromine, a dilute sulfuric acid solution and sodium nitrite solids into 6-aminopenicillanicacid, so as to obtain a first intermediate, wherein the dilute sulfuric acid solution adopts depleted deuterium water as a solvent; S2. oxidation reaction: dropwise adding potassium permanganate anda dilute sulfuric acid solution into the first intermediate, so as to obtain a second intermediate; and S3. hydrogenation reaction: add strontium powder and a dilute sulfuric acid solution into the second intermediate, thereby obtaining a product, i.e., the sulbactam acid, wherein the dilute sulfuric acid solution adopts depleted deuterium water as a solvent. Through preparing the dilute sulfuricacid solution by adopting the depleted deuterium water as the solvent and adopting the strontium powder as a catalyst, the improvement on reaction activity of dilute sulfuric acid is facilitated, theconversion ratio of reaction is increased, and thus, the increase of reaction yield is facilitated, so that the yield of reaction can be higher than 90%.