Pipracil Chemical Properties
- Melting point:183-185?C (dec.)
- Density 1.51±0.1 g/cm3(Predicted)
- RTECS XH8952200
- storage temp. Hygroscopic, -20°C Freezer, Under Inert Atmosphere
- solubility Freely soluble in methanol. Only sparingly soluble in aqueous solution at 0.119 mg/mL
- CAS DataBase Reference61477-96-1(CAS DataBase Reference)
Pipracil Usage And Synthesis
- Chemical PropertiesCrystalline Solid
- OriginatorPentcillin, Toyama ,Japan ,1980
- UsesBroad spectrum semi-synthetic antibiotic related to Penicillin. Antibacterial.
- DefinitionChEBI: A penicillin in which the substituent at position 6 of the penam ring is a 2-[(4-ethyl-2,3-dioxopiperazin-1-yl)carboxamido]-2-phenylacetamido group.
- Manufacturing ProcessTo a suspension of 0.9 g of 6-[D(-)-α-aminophenylacetamido]penicillanic acid in 30 ml of anhydrous ethyl acetate were added at 5°C to 10°C 0.55 g of triethylamine and 0.6 g of trimethylsilyl chloride. The resulting mixture was reacted at 15°C to 20°C for 3 hours to form trimethylsilylated 6-[D(-)-αaminophenylacetamido]penicillanic acid.
To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride (from the reaction of N-ethylethylenediamine and diethyl oxalate to give 2,3-dioxo-4-ethyl-piperazine which is then reacted with phosgene) and the resulting mixture was reacted at 15°C to 20°C for 2 hours. After the reaction, a deposited triethylamine hydrochloride was separated by filtration, and the filtrate was incorporated with 0.4 g of n-butanol to deposit crystals. The deposited crystals were collected by filtration to obtain l.25 g of white crystals of 6-[D(-)α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido]penicillanic acid. Into a solution of these crystals in 30 ml of tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 2-ethylhexanoic acid in 10 ml of tetrahydrofuran, upon which white crystals were deposited. The deposited crystals were collected by filtration, sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6-[D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido] penicillanic acid, melting point 183°C to 185°C (decomposition), yield 90%.
- brand namePipracil (Wyeth).
- Therapeutic FunctionAntibiotic
- Antimicrobial activityIt displays good activity against non-β-lactamaseproducing strains of N. gonorrhoeae, ampicillin-susceptible H. influenzae and many Enterobacteriaceae. It is the most active of the antipseudomonal penicillins against Ps. aeruginosa and retains its activity in the absence of a β-lactamase inhibitor. Synergy with aminoglycosides has been demonstrated against many strains of Enterobacteriaceae and Ps. aeruginosa.
- Acquired resistanceThere is complete cross-resistance with other ureidopenicillins, but ticarcillin-resistant strains of Ps. aeruginosa may be susceptible. Piperacillin-resistant strains of B. fragilis and other Bacteroides spp. are common. Because piperacillin is hydrolyzed by most β-lactamases, many β-lactamaseproducing isolates are resistant unless it is protected by β-lactamase inhibitors.
- PharmacokineticsOral absorption: Negligible
Cmax 2 g (2–3 min intravenous injection): 305 mg/L after 5 min
Plasma half-life: 0.9 h
Volume of distribution: 16–24 L/1.73 m2
Plasma protein binding: 16%
In patients with meningitis, mean CSF penetration of 30% has been found. The urine is the principal route of excretion, 50–70% of the dose appearing over 12 h, most in the first 4 h. Most is excreted via the tubules, 75–90% in active form. The half-life is prolonged in renal failure but much less than is the case with carboxypenicillins. There is substantial biliary excretion, levels in the common duct bile after a 1 g intravenous dose commonly reaching 500 mg/L or more. During hemodialysis the plasma half-life remains elevated and only 10–15% of the dose is removed.
- Clinical UsePiperacillin (Pipracil) is the most generally useful of the extended-spectrum acylureidopenicillins. It is more active thanmezlocillin against susceptible strains of Gram-negativeaerobic bacilli, such as Serratia marcescens, Proteus,Enterobacter, Citrobacter spp., and P. aeruginosa.Mezlocillin, however, appears to be more active againstProvidencia spp. and K. pneumoniae. Piperacillin is alsoactive against anaerobic bacteria, especially B. fragilis andS. faecalis (enterococcus). β-Lactamase–producing strainsof these organisms are, however, resistant to piperacillin,which is hydrolyzed by S. aureus β-lactamase. The β-lactamase susceptibility of piperacillin is not absolute becauseβ-lactamase–producing, ampicillin-resistant strainsof N. gonorrhoeae and H. influenzae are susceptible topiperacillin.
Piperacillin is destroyed rapidly by stomach acid; therefore,it is active only by intramuscular or intravenousadministration. The injectable form is provided as the white,crystalline, water-soluble sodium salt. Its pharmacokineticproperties are very similar to those of the other acylureidopenicillins.
- Clinical UseIntra-abdominal infection
Urinary tract infections
Gynecological and gonococcal infections
Lower respiratory infections
Skin and skin structure infections
Bone and joint infections
- Side effectsPiperacillin is generally well tolerated, with mild to moderate pain on injection, thrombophlebitis and diarrhea in some patients. It otherwise exhibits side effects common to the group, including hypersensitivity, leukopenia and abnormalities of platelet aggregation without coagulation defect, except on prolonged treatment.
- Chemical SynthesisPiperacillin, (2S,5R,6R)-3,3-dimethyl-7-oxo-6-[(2R)-2-[(4-ethyl-2,3-dioxo-
1-piperazinyl)formamido]-2-phenylacetamido]-4-thia-1-azabicyclo[3.2.0]-heptan-2-carboxylic acid (184.108.40.206), is also synthesized by acylating ampicillin (220.127.116.11), but with
1-chlorocarbonyl-4-ethylpiperazin-2,3-dione (18.104.22.168). The necessary 1-chlorocarbonyl-4-
ethylpiperazin-2,3-dione (22.214.171.124) is synthesized by reacting N-ethylethylenediamine with
diethyloxalate, forming 4-ethylpiperazin-2,3-dione (126.96.36.199), and then acylating this with
phosgene after initial silylation of the product at the nitrogen atom with trimethylchlorosilane.
Pipracil Preparation Products And Raw materials
- Raw materials6-Aminopenicillanic acid
- PIPERAZINE-2,3-DIONE 1-Ethyl-2,3-dioxopiperazine SALOR-INT L169811-1EA PIPERAZINE CITRATE HYDRATE Fomidacillin Ampicillin PHENYL VALERATE CARBONYL SULFIDE Penicillin G PYRAZOPHOS PIPERACILLIN NA,PIPERACILLIN SODIUM ISOXADIFEN-ETHYL Ethyl acetate Ethanol Phenylacetic acid N-Aminoethylpiperazine 1,4-Dioxane Piperazine ferulate
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