119478-56-7

Basic information

• Product Name: (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
• Synonyms: Meropenem;MEROPENEMTRIHYDRATE(3-[[5-[(DIMETHYLAMINO)CARBONYL]-3-PYRROLIDINYL]THIO]-6-(1-HYDROXYETHYL)-4-METHYL-7-OXO-1-AZABICYCLO[3,2,0]HEPT-2-ENE-2-CARBOXYLICACIDTRIHYDRATE);MEROPENEM WITH SODIUM CARBONATE;3-(5-Dimethylcarbamoyl-pyrrolidin-3-ylsulfanyl)-6-(1-hydroxy-ethyl)-4-methyl-7-oxo-1-aza-bicy;Meropenem (300 mg);(1R,5S,6S)-2-[(3S,5S)-5-(dimethylaminocarbonyl)pyrrolidin-3-ylthio]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid trihydrate;(4R,5S,6S)-3-{[(3S,5S)-5-(diMethylcarbaMoyl)pyrrolidin-3-yl]sulfanyl}-6-[(1R)-1-hydroxyethyl]-4-Methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;(4R,5S,6S)-3-[[(3S,5S)-5-[(DiMeth-ylaMino)carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-Methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate
• CAS NO: 119478-56-7
• Molecular Formula: C17H25N3O5S
• Molecular Weight: 383.46
• EINECS: 1312995-182-4
• Mol File: 119478-56-7.mol

Chemical Properties

• Boiling Point: 627℃
• Flash Point: >110°(230°F)
• Appearance: white to off-white/
• Density: 1.42 g/cm³
• Vapor Pressure: 2.27E-18mmHg at 25°C
• Refractive Index: 1.639
• Storage Temp.: ?20°C
• Solubility: Soluble in aqueous solution at approximately 5mg/ml
• Merck: 14,5900
• CAS DataBase Reference: (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid(119478-56-7)
• EPA Substance Registry System: (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid(119478-56-7)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• RTECS: CL5446509
• Hazardous Substances Data: 119478-56-7(Hazardous Substances Data)

Usage

Uses

Used in Antibacterial Applications:
(4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is used as a broad-spectrum antibiotic for treating various bacterial infections. It is effective against both Gram-negative and Gram-positive bacteria, as well as anaerobic microorganisms such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter species, Serratia marcescens, Streptococcus pyogenes, Streptococcus agalactiae, and Citrobacter sp.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is used as an active pharmaceutical ingredient in the development of antibiotics. It is formulated into various dosage forms, such as injections and oral medications, for the treatment of serious bacterial infections, including complicated skin infections, intra-abdominal infections, urinary tract infections, severe pneumonia, broncho-pulmonary infections, and bacterial meningitis.
Used in Research and Development:
(4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is also used in research and development for the discovery of new antibiotics and the study of antibiotic resistance. It is employed in various assays, such as bacterial killing assays, antibiotic susceptibility testing, and screening for antibiotic resistance in clinical isolates.
Used in Hospital Settings:
In hospital settings, (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is used as a therapeutic agent for the treatment of serious bacterial infections in immunocompromised patients. It is administered intravenously or orally, depending on the severity and type of infection.
Used in Diagnostic Laboratories:
(4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)pyrrolidin-3-yl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid is used in diagnostic laboratories for the identification and characterization of bacterial isolates. It is employed in various microbiological tests, such as antibiotic susceptibility testing and minimum inhibitory concentration (MIC) determination, to guide the selection of appropriate antibiotics for treatment.

Antimicrobial activity

The unique side chain at C-2 is associated with increased activity against Gram-negative bacteria, including H. influenzae. It is slightly less active than imipenem against Gram-positive organisms. It is active against anaerobes and more active against some strains that are less susceptible to imipenem. Its excellent activity against Gram-negative organisms is due to high affinity for multiple penicillin-binding proteins. Activity is little affected by inoculum size or the presence of serum. It is bactericidal at concentrations close to the MIC.Stability to β-lactamases is similar to that of other carbapenems: it is highly resistant to most serine β-lactamases, including extended-spectrum enzymes, but can be hydrolyzed by metallo-β-lactamases and by serine carbapenemases.

Biological Activity

meropenem trihydrate (sm-7338) is an active ingredient carbapenem antibiotic [1].meropenem trihydrate has shown the potent effect against gram-negative organisms with the mic90 values of 0.03μm, 0.06μm, 0.06μm, 0.12μm,0.25μm, 0.12μm, 0.06μm, 0.12μm and 0.25μm for escherichia coli (30), klebsiella pneumonia(29), klebsiella oxytoca (20), enterobacter aerogenes (14), enterobacter cloacae (29), citrobacter freundii (20), citrobacter diversus (12), proteus mirabilis (15) and morganella morganii (15), respectively. in addition, meropenem trihydrate has also been revealed to restrain gram-positive and anaerobic organisms with the mic90 values of 0.008μm, 4μm and 0.015μm for streptococcus pyogenes (20), viridans group streptococci (27), streptococcus pneumonia (15), respectively. furthermore, meropenem trihydrate has shown the different effect of ph on mic, for example, the mean mic values of 0.06μm and 0.03μm in ph5.5 and ph7.5, respectively [1].

Biochem/physiol Actions

Meropenem trihydrate is an ultra-broad spectrum beta-lactam antibiotic active against both Gram-positive and Gram-negative bacteria.

Pharmacokinetics

Cmax 500 mg intravenous (30-min infusion): 23 mg/L end infusion 1 g intravenous (30-min infusion): 49 mg/L end infusion Plasma half-life: 1 h Volume of distribution: c. 0.3 L/kg Plasma protein binding: 2% Absorption and distribution Meropenem is not absorbed after oral administration. It penetrates well into most body fluids and tissues, including CSF, achieving concentrations matching or exceeding those required to inhibit most susceptible bacteria. In pediatric patients (1 month to 15 years) with inflamed meninges it achieves CSF levels of 0.9–6.5 mg/L after a single intravenous infusion (40 mg/kg) over 30 min. After a single intravenous dose, the highest mean concentrations of meropenem were found in tissues and fluids at 1 h (0.5–1.5 h) after the start of infusion. Metabolism and excretion The mean recovery of unchanged meropenem is approximately 70%. The remainder consists of the microbiologically inactive open-ring form. Renal excretion is greater than 70% of unchanged drug over 12 h. Co-administration with probenecid prolongs the half-life 38%, but peak concentrations are not greatly affected. In patients with renal impairment the dose should be adjusted. Parent drug and metabolite are removed by hemodialysis.

Clinical Use

Meropenem is a second-generation carbapenem that, todate, has undergone the most extensive clinical evaluation.It has recently been approved as Merrem for the treatmentof infections caused by multiply-resistant bacteria and forempirical therapy for serious infections, such as bacterialmeningitis, septicemia, pneumonia, and peritonitis.Meropenem exhibits greater potency against Gram-negativeand anaerobic bacteria than does imipenem, but it is slightlyless active against most Gram-positive species. It is not effectiveagainst MRSA. Meropenem is not hydrolyzed byDHP-I and is resistant to most β-lactamases, including a fewcarbapenemases that hydrolyze carbapenem.

Indications

Intra-abdominal infectionsBacterial meningitis (pediatric patients >3 months)Complicated skin and skin structure infections

Side effects

Seizures and other CNS adverse experiences have been reported in 0.7% of all adult patients, most commonly those with pre-existing CNS disorders. Pseudomembranous colitis has been reported. Other reactions include diarrhea (4.8%), nausea and vomiting (3.6%), inflammation at the site of injection (2.4%) and headache (2.3%). Moniliasis occurs in 1.9–3.1% of pediatric patients. Patients with a history of hypersensitivity reactions to other β-lactam agents should be treated cautiously.

Drug interactions

Potentially hazardous interactions with other drugs Antiepileptics: concentration of valproate reduced - avoid. Probenecid: avoid concomitant use

Metabolism

Meropenem is more stable to renal dehydropeptidase I than imipenem but undergoes some renal metabolism, and is mainly excreted in the urine by tubular secretion and glomerular filtration. About 70% of a dose is recovered unchanged in the urine over a 12-hour period. Meropenem is reported to have one metabolite (ICI 213689), which is inactive and is excreted in the urine.

references

[1] neu hc1, novelli a, chin nx.in vitro activity and beta-lactamase stability of a new carbapenem, sm-7338.antimicrob agents chemother. 1989 jul; 33(7):1009-18.

InChI:InChI=1/C17H25N3O5S/c1-7-12-11(8(2)21)16(23)20(12)13(17(24)25)14(7)26-9-5-10(18-6-9)15(22)19(3)4/h7-12,18,21H,5-6H2,1-4H3,(H,24,25)/t7-,8+,9-,10-,11-,12-/m0/s1

Upstream product

• 96036-03-2 meropenem 
• 93711-81-0 (4-nitrophenyl)methyl (4R,5R,6S)-3-[(diphenoxyphosphinyl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate 
• 96034-64-9 (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-thiolpyrrolidine 

Relevant articles and documents

A raw meluopeinan, method for preparing the same and pharmaceutical composition containing the same

The invention discloses a meropenem raw medicine which is characterized in that the content of meropenem in the raw medicine is 98.0-101.0% by weight based on anhydride; the content of the impurity A and impurity B in the related substances of the raw medicine is not greater than 0.25% respectively; the content of any unknown single impurity is not greater than 0.05%; the total content of other impurities except the A and B is not greater than 0.2%; the acetone residue is not greater than 500ppm. The invention also discloses a meropenem pharmaceutical composition for injection, and the pharmaceutical composition takes the meropenem raw medicine provided by the invention as an active ingredient and has excellent stability. The meropenem raw medicine provided by the invention has the advantages of high purity, clear impurity condition, low solvent residue, good solubility and good long-term storage stability, and can guarantee the effectiveness and safety of the medicine. In the invention, the process is simple and compact, the cost is remarkably low, and the control is simple. The invention is suitable for industrial large-scale aseptic production of the meropenem raw medicine and pharmaceutical preparation.

IMPROVED PROCESS FOR PRODUCING CARBAPENEM COMPOUND

The present invention has its object to provide an easy process for producing (4R,5S,6S)-3-[[(3S,5S)-5-(dimethylaminocarbonyl)-3-pyrrolid inyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicy clo[3.2.0]hept-2-ene-2-carboxylic acid, excellent in antimicrobial activity. The present invention relates to a process for continuously producing (4R,5S,6S)-3-[[(3S,5S)-5-(dimethylaminocarbonyl)-3-pyrrolid inyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicy clo[3.2.0]hept-2-ene-2-carboxylic acid without isolating/purifying the reaction intermediate.

A PROCESS FOR THE PREPARATION OF MEROPENEM

The present invention provides a one-pot process for the preparation of meropenem. The present invention further provides a process for the preparation of meropenem trihydrate.