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

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

Uses

Used in Pharmaceutical Industry:
Sulbactam is used as a β-lactamase inhibitor to block the degradation of other penicillin derivatives, such as ampicillin and cephalosporins. This action helps to enhance the effectiveness of these antibiotics against Gram-positive bacteria.
Used in Antidepressant Applications:
Sulbactam is used as an antidepressant and dopamine uptake inhibitor, potentially offering therapeutic benefits for individuals with depression and related disorders.

Originator

Sulbactam-Sodium,Antibiotic Co.,Bulgaria

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

• 24158-88-1 6,6-dibromopenicillanic acid 
• 69388-84-7 sodium sulbactam 
• 128971-79-9 (3S,4R)-4-<(2-Methyl-3-buten-2-yl)thio>-3-(trimethylsilyl)-2-azetidinone 
• 7439-96-5 manganese 
• 810692-15-0 6-bromo-1,1-dioxopenicillanic acid 
• 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 
• 76646-91-8 6,6-dibromopenicillanic acid-1,1-dioxide 
• 551-16-6 6-aminopenicillanic acid 
• 7439-95-4 magnesium dihydride 
• 2040-05-3 2,6 dichloroacetophenone 
• 87-53-6 penicillanic acid 
• 551-16-6 6-Aminopenicillanic Acid 

Downstream Products

• 76247-40-0 chloromethyl penicillanate 1,1-dioxide 
• 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 
• 69388-84-7 sodium sulbactam 
• 76247-39-7 iodomethyl penicillanate 1,1-dioxide 
• 90749-09-0 4-(6-(2-amino-2-phenylacetamido)penicillanoyl)oxymethyl-5-(1,1-dioxopenicillanoyl)oxymethyl-1,3-dioxol-2-one hydrochloride 
• 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 
• 854139-74-5 (3,3-dimethyl-4,4,7-trioxo-4-thia-1-azabicyclo[3.2.0]hept-2-yl)phenylselenylacetaldehyde 

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.

Synthesis method of sulbactam

The invention relates to a synthesis method of sulbactam, and belongs to the field of beta-lactamase inhibitor synthesis. In the method, 6-aminopenicillanic acid (6-APA) as a raw material is dissolvedin an organic solvent, and is adopted together with bromine as substrates under a strong acid condition, 6,6-dibromo penicillanic acid is formed through diazotization bromination in a manner of dropwise adding a sodium nitrite solution, and then one-step oxidation and reduction are performed to obtain sulbactam. According to the method, a hydrogen peroxide one-step oxidation mode is adopted, andthe use of potassium permanganate is avoided from the source, so that the generation of waste salt is reduced, and meanwhile, the use of a large amount of ethyl acetate is avoided. The method not onlyreduces the emission of three wastes from the source and greatly reduces the emission of organic matters and waste salt in the original process, but also greatly reduces the side reaction and the rawmaterial cost.

Method for preparing sulbactam acid

The invention discloses a preparation method of sulbactam acid, hypophosphorous acid is used as a diazotization reaction reagent and a reduction reagent at the same time, a diazotization and reductionreaction one-pot method is realized, and an obtained intermediate is oxidized by potassium permanganate to obtain the sulbactam acid. The product is the sulbactam acid, the generation amount of wastesalt is greatly reduced compared with that of a traditional process, the production cost and the reaction danger coefficient are obviously reduced, and good economic benefits and social values are achieved.

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.

Extends the batanbatan acid synthesis method (by machine translation)

The present invention relates to the field of drug synthesis, directed to the problem of low yield synthesis mode, provides a method of synthesizing extends the batanbatan acid, comprises the following steps: S1, diazotization and bromination reaction: in the 6 - amino penicillanic acid bromine is added in, the dilute sulfuric acid solution and sodium nitrite solid, dilute sulfuric acid concentration of the solution is 20% - 25%, to obtain the 1st intermediate; S2, oxidation reaction: to the 1st intermediate dropping potassium permanganate and dilute sulfuric acid solution, the concentration of the dilute sulfuric acid solution is 20% - 25%; S3, hydrogenation reaction: to the 2nd intermediate [...] and in dilute sulfuric acid solution, to obtain the extends the batanbatan acid. By using the 20% - 25% of the dilute sulfuric acid solution react, help to improve the diazo and bromination reaction and oxidation reaction of the active, so that the reactant more completely, thus help to improve the diazo and bromination reaction and oxidation of the yield of the reaction, and then make the overall yield of the reaction. (by machine translation)

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%.

New indications of troxofine ceftriaxone sodium pharmaceutical preparation for treatment of infection of patients with immunodeficiency

The invention belongs to the technical field of drug preparation, and discloses new indications of a troxofine ceftriaxone sodium pharmaceutical preparation for treatment of infection of patients withimmunodeficiency. By improving a raw material synthesis process, ceftriaxone sodium with the high effective constituent content and the low impurity content is provided so as to solve the problems ofpoor stability and reducing of the antibacterial effect of a ceftriaxone sodium preparation due to impurities. The ceftriaxone sodium provided by the specific production process is very low in impurity content and significant in efficacy, the quality of a preparation product is improved advantageously, safety and effectiveness of the preparation product are ensured, and the preparation product has uses in the aspects of preparing drugs for treating infection of the patients with immunodeficiency.

Preparation method of sulbactam acid

The invention discloses a preparation method of sulbactam acid, and belongs to the field of preparation of pharmaceutical intermediates. The preparation method comprises the steps of: adopting sodiumsulbacetanate as a raw material, adding a dissolution-assistant agent to a concentrated liquid, introducing carbon dioxide at the same time, and performing crystallization so as to obtain sulbatam. Through the method, sodium sulbacetanate which does not meet the quality standard can be recycled and utilized fully, and the prepared sulbactam acid has the advantages of high content, less impurities,low color grade, good fluidity and good stability; and the preparation method is simple, energy-saving and environmentally friendly, and is suitable for large-scale industrial production.

New synthesis method for sulbactam acid

The invention discloses a new synthesis method for sulbactam acid. The new synthesis method comprises the following steps: performing reaction between 6-amino-penicillanic acid and sodium nitrite and bromine in water-insoluble organic solvent under an acidic condition to obtain a reaction product: bis-bromo-penicillanic acid, and then, performing oxidation reaction and hydrogenation to obtain sulbactam. According to the new synthesis method disclosed by the invention, by adopting the water-insoluble solvent, emission of organic matter in water is reduced; by adopting a mode of step-by-step-oxidation, not only is the usage level of potassium permanganate reduced but also the phenomenon that a large amount of ethyl acetate is used originally is avoided; filtering separation is performed on manganese dioxide by the solvent, and thus, not only is emission of the three wastes reduced but also the solvent can also be utilized as a by-product; emission of organic matter and waste salt in an original process is greatly reduced, and side reaction and raw material cost are also greatly reduced.

A [...] synthetic method

The invention discloses a synthetic method of salbactam acid. The synthetic method comprises the following steps: carrying out diazotized bromination reaction on 6-aminopenicillanic acid to form bromopenicillanic acid; and then, carrying out oxidation reaction and reduction reaction to obtain salbactam acid, wherein in the diazotized bromination reaction, 6-aminopenicillanic acid is continuously added in form of an acidic solution, the acidic solution of 6-aminopenicillanic acid is 5-8% sulfuric acid aqueous solution, 13-15% hydrobromic acid aqueous solution or 5-8% hydrochloric acid aqueous solution. 6-aminopenicillanic acid is dropwise added in form of the acidic solution, so that dust pollution is avoided and the work environment of field personnel is improved. Meanwhile, 6-aminopenicillanic acid exists in form of stable salt, decomposition reaction is avoided, and the reaction quality is improved. The three-step yield of the method is over 70%, the HPCL purity is over 99.7%, the individual impurity content is less than 0.1% and the total impurity content is less than 0.5%.