Levetiracetam CAS 102767-28-2
Introduction：Basic information about Levetiracetam CAS 102767-28-2, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Levetiracetam Basic informationDescription Generic formulation Indications Dose titration Plasma levels monitoring Cautions Adverse effects Interactions Special populations Behavioural and cognitive effects in patients with epilepsy Psychiatric use
| Product Name: | Levetiracetam |
| Synonyms: | (S)-2-(2-Oxo-1-pyrrolidinyl)butanamide;levetiracetam raw materi;(2S)-2-(2-Oxopyrrolidin-1-yl)butanamide;(2S)-(2-Oxopyrrolidin-1-yl)butyramide;1-Pyrrolidineacetamide, .alpha.-ethyl-2-oxo-, (.alpha.S)-;Levetiracetam (200 mg);(2R)-2-(2-oxopyrrolidin-1-yl)butanaMide;(αS)-α-Ethyl-2-oxo- |
| CAS: | 102767-28-2 |
| MF: | C8H14N2O2 |
| MW: | 170.20896 |
| EINECS: | 600-348-9 |
| Product Categories: | Other APIs;Pharmaceutical raw material;API;Amines;Chiral Reagents;Heterocycles;Nootropic;Smart drug;Miscellaneous Compounds;Intermediates & Fine Chemicals;Pharmaceuticals;Anticonvulsant;pharmaceutical intermdiate;102767-28-2 |
| Mol File: | 102767-28-2.mol |
Levetiracetam Chemical Properties
| Melting point | 118-119°C |
| alpha | -89.7 º |
| Fp | 9℃ |
| storage temp. | 2-8°C |
| solubility | H2O: >5mg/mL |
| form | powder |
| color | white |
| Optical Rotation | [α]/D -90±5°, c = 1 in acetone |
| BCS Class | 3 |
| Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month. |
| Major Application | clinical testing |
| InChI | InChI=1/C8H14N2O2/c1-2-6(8(9)12)10-5-3-4-7(10)11/h6H,2-5H2,1H3,(H2,9,12)/t6-/s3 |
| InChIKey | HPHUVLMMVZITSG-UHFFFAOYSA-N |
| SMILES | C(N)(=O)[C@@H](N1CCCC1=O)CC |&1:3,r| |
| CAS DataBase Reference | 102767-28-2(CAS DataBase Reference) |
Safety Information
| Hazard Codes | Xn,T,F |
| Risk Statements | 22-36-39/23/24/25-23/24/25-11 |
| Safety Statements | 26-45-36/37-16-7 |
| RIDADR | UN1230 - class 3 - PG 2 - Methanol, solution |
| WGK Germany | 3 |
| RTECS | UX9656166 |
| HS Code | 29337900 |
| Storage Class | 3 - Flammable liquids |
| Hazard Classifications | Acute Tox. 3 Dermal Acute Tox. 3 Inhalation Acute Tox. 3 Oral Flam. Liq. 2 STOT SE 1 |
| Hazardous Substances Data | 102767-28-2(Hazardous Substances Data) |
| Toxicity | LD50 in male mice, male rats (mg/kg): 1081, 1038 i.v. (Gobert, 1990) |
| Description | Levetiracetam is a third-generation antiepileptic drug known under the proprietary brand name of Keppra® (UCB Pharma, Slough) in the UK and USA. |
| Generic formulation | MHRA/ CHM advice to minimize risk when switching patients with epilepsy between different manufacturers’ products (including generic products):
|
| Indications | Epilepsy: monotherapy (not approved in USA) and adjunctive therapy of focal seizures with or without secondary generalization. Recommendations summarized from NICE (2012)
|
| Dose titration | Epilepsy— monotherapy 250 mg od for 7– 14 days, 250 mg bd for 14 days, then increased by 250 mg bd every 14 days (max. maintenance dose 1500 mg bd). Epilepsy— adjunctive therapy 250 mg bd for 14 days, then increased by 500 mg bd every 14–28 days (max. maintenance dose 1500 mg bd). If levetiracetam has to be discontinued, it is recommended to withdraw it gradually (e.g. in patients weighing more than 50 kg: 500 mg decreases bd every 14– 28 days). |
| Plasma levels monitoring | Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam and, therefore, there is no need for plasma level monitoring of levetiracetam. |
| Cautions | Nil. |
| Adverse effects | Levetiracetam can be associated with adverse effects at the level of the nervoussystem and other systems. |
| Interactions | With AEDs Nil With other drugs
With alcohol/ food There are no known specific interactions between alcohol and levetiracetam, and there are no specific foods that must be excluded from diet when taking levetiracetam. |
| Special populations | Hepatic impairment Halve dose in severe impairment with significant reduction in creatinine clearance Renal impairment Reduce maintenance dose according to degree of reduction in creatinine clearance Pregnancy
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| Behavioural and cognitive effects in patients with epilepsy | Behavioural adverse event are often reported by patients with epilepsy taking levetiracetam. The most relevant ones are irritability and emotional lability. Marked behavioural changes with psychotic symptoms and episodes of severe aggression have occasionally been reported. On the contrary, levetiracetam is one of the safest AEDs in terms of interference with cognitive processes, despite occasional reports of decreased cognition. |
| Psychiatric use | Despite its widespread use in epilepsy, Levetiracetam does not have approved indications in psychiatry. Initial reports suggesting a possible role for Levetiracetam in the treatment of bipolar depression and anxiety disorders have not been confirmed by the findings of controlled trials. Evidence for the possible usefulness of levetiracetam for the treatment of patients with Tourette syndrome is equally inconsistent. |
| Description | Levetiracetam was first introduced in the US as an adjunctive therapy in the treatmentof partial-onset seizures in adults with epilepsy. This second-generation analog ofpiracetam can be prepared by condensation of (S)-2-aminobutyramide with 4-chlorobutyrylchloride. Although its mechanism of action is not well established, it was shown that [3H]-levetiracetamreversibly binds to a specific site predominantly present in the membranes ofthe brain. Unlike conventional anticonvulsants such as phenytoin, carbamazepine, valproicacid, phenobarbital, diazepam and clonazepam, compounds structurally-related tolevetiracetam, such as piracetam and aniracetam, also have affinity for this site.Levetiracetam reveals a broad and unique profile in animal seizure models, includingpromising antiepileptogenic properties. Besides being rapidly and almost completelyabsorbed in man (oral bioavailability>95%), it possesses a favorable pharmacokineticprofile since it is not hepatically metabolized but only partly hydrolized into the inactivecarboxylic acid by enzymes in a number of tissues including blood cells, it is minimallybound to plasma proteins (<10%) and does not inhibit or induce hepatic enzymes.Therefore levetiracetam has a low potential for drug interaction, providing a usefulalternative as adjunctive therapy to treat seizures refractory to conventionalanticonvulsants. |
| Chemical Properties | White Crystalline Solid |
| Originator | UCB (Belgium) |
| History | Levetiracetam was originally discovered by UCB and is now marketed as Keppra® in over 90 countries worldwide. It was discovered in 1992 through screening in audiogenic seizure susceptible mice. It is available as regular and extended release oral formulations and as intravenous formulations. The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011. The patent for the extended release tablet will expire in 2028. In 2015, Aprecia's orally disintegrating tablet form of the drug manufactured using pharmaceutical 3D printing techniques was approved by the FDA, under the trade name Spritam. |
| Uses | The (S)-enantiomer of the ethyl analog of Piracetam. Used as an anticonvulsant. |
| Uses | The (S)-enantiomer of Etiracetam (E932970) and the ethyl analog of Piracetam (P500800). Used as an anticonvulsant. |
| Uses | A compound which inhibits burst firing without affecting normal neuronal excitability |
| Uses | Used as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. |
| Definition | ChEBI: A pyrrolidinone and carboxamide that is N-methylpyrrolidin-2-one in which one of the methyl hydrogens is replaced by an aminocarbonyl group, while another is replaced by an ethyl group (the S enantiomer). An anticonvulsat, it is used for the treatment of epilepsy in both human and veterinary medicine. |
| Manufacturing Process | (a) Preparation of the (R)-α-methyl-benzylamine salt of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid 8.7 kg (50.8 moles) of racemic ()-α-ethyl-2-oxo-1-pyrrolidineacetic acid aresuspended in 21.5 liters of anhydrous benzene in a 50 liter reactor. To thissuspension is added gradually a solution containing 3.08 kg (25.45 moles) of(R)-(+)-α-methyl-benzylamine and 2.575 kg (25.49 moles) of triethylamine in2.4 liters of anhydrous benzene. This mixture is then heated to refluxtemperature until complete dissolution. It is then cooled and allowed tocrystallize for a few hours. 5.73 kg of the (R)-α-methyl-benzylamine salt of(S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid are thus obtained. Melting point:148°-151°C. Yield: 77.1%. This salt may be purified by heating under reflux in 48.3 liters of benzene for4 hours. The mixture is cooled and filtered to obtain 5.040 kg of the desiredsalt. Melting point: 152°-153.5°C. Yield: 67.85%. (b) Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid 5.04 kg of the salt obtained in (a) above are dissolved in 9 liters of water. 710g of a 30% sodium hydroxide solution are added slowly so that the pH of thesolution reaches 12.6 and the temperature does not exceed 25°C. Thesolution is stirred for a further 20 minutes and the α-methylbenzylamineliberated is extracted with a total volume of 18 liters of benzene. The aqueousphase is then acidified to a pH of 1.1 by adding 3.2 liters of 6 N hydrochloricacid. The precipitate formed is filtered off, washed with water and dried. Thefiltrate is extracted repeatedly with a total volume of 50 liters ofdichloromethane. The organic phase is dried over sodium sulfate and filteredand evaporated to dryness under reduced pressure. The residue obtained afterthe evaporation and the precipitate isolated previously, are dissolved togetherin 14 liters of hot dichloromethane. The dichloromethane is distilled andreplaced at the distillation rate, by 14 liters of toluene from which the productcrystallizes. The mixture is cooled to ambient temperature and the crystalsare filtered off to obtain 2.78 kg of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid.Melting point: 125.9°C. [α]D20 = -26.4° (c = 1, acetone). Yield: 94.5%. (c) Preparation of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide 34.2 g (0.2 mole) of (S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid are suspendedin 225 ml of dichloromethane cooled to -30°C. 24.3 g (0.24 mole) oftriethylamine are added dropwise over 15 minutes. The reaction mixture isthen cooled to -40°C and 24.3 g (0.224 mole) of ethyl chloroformate areadded over 12 minutes. Thereafter, a stream of ammonia is passed throughthe mixture for 4 ? hours. The reaction mixture is then allowed to return toambient temperature and the ammonium salts formed are removed byfiltration and washed with dichloromethane. The solvent is distilled off underreduced pressure. The solid residue thus obtained is dispersed in 55 mltoluene and the dispersion is stirred for 30 minutes and then filtered. Theproduct is recrystallized from 280 ml of ethyl acetate in the presence of 9 g of0.4 nm molecular sieve in powder form 24.6 g of (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide are obtained. Melting point: 115°-118°C. [α]D25 = -89.7°(c = 1, acetone). Yield: 72.3%. |
| Brand name | Keppra (UCB). |
| Therapeutic Function | Antiepileptic, Nootropic |
| Biological Functions | Levetiracetam (Keppra) has recently been approved forthe treatment of partial-onset seizures. It appears to besafe and effective; its exact therapeutic profile has yet tobe determined. It does not appear to share any of themechanisms of action of agents that have been discussedto this point. It does have a highly specific brainbinding site, but the significance of this observation toits mechanism of action has not been elucidated. |
| General Description | LEV is an analog of the nootropic agent, piracetam. Onlythe S-isomer has any anticonvulsant activity. Unlike piracetam, LEV does not have any affinity for the AMPA receptor thereby has no nootropic activity forthe treatment of Alzheimer disease. LEV also has no affinityfor GABA receptors, BZD receptors, the various excitatoryamino acid related receptors, or the voltage-gated ionchannels.For this reason, its mechanism of anticonvulsantaction remains unclear, but it appears to exert itsantiepileptic action by modulating kainite/AMPA-inducedexcitatory synaptic currents, thus decreasing membraneconductance.Furthermore, the anticonvulsant activity ofthis drug appears to be mediated by the parent moleculerather than by its inactive metabolite,(S)-α-ethyl-2-oxo-1-pyrrolidineacetic acid (i.e., via the hydrolysis of amidegroup).Like gabapentin, LEV has few drug interactionswith other AEDs thereby can be used in combination to treatrefractory epilepsy. |
| Biological Activity | Antiepileptic that displays distinctive properties from conventional antiepileptic drugs. Displays potent seizure protection in animal models of chronic epilepsy but lacks activity in acute seizure models. Binds synaptic vesicle protein 2A (SV2A) and inhibits Na + -dependent Cl - /HCO 3 - exchange. |
| Biochem/physiol Actions | Levetiracetam is a pyrrolidine with antiepileptic activity. Stereoselective binding of levetiracetam was confined to synaptic plasma membranes in the central nervous system with no binding occurring in peripheral tissue. Levetiracetam inhibits burst firing without affecting normal neuronal excitability, which suggests that it may selectively prevent hyper-synchronization of epileptiform burst firing and propagation of seizure activity. |
| Mechanism of action | The mechanism of action for S-(–)-levetiracetam is unknown. It does not appear to interact with any of the recognizedexcitatory or inhibitory neural mechanism. A CNS-specific binding site for S-(–)-levetiracetam has been identified as thesynaptic vesicle protein (SV2A). Knockout animals without SV2A proteins accumulated presynaptic Ca2+ during consecutiveaction potentials that destabilized synaptic circuits and induced epilepsy. Thus, it appears that SV2A plays a major role in theantiepileptic properties of S-(–)-levetiracetam, which acts by modulating the function of SV2A and the regulation ofCa2+ mediated synaptic transmission. These data support previous indications that S-(–)-levetiracetam possesses a mechanismof action distinct from that of other antiepileptic drugs. Three SV2 isoforms (SV2A, SV2B, and SV2C) have been identified, eachof which has a unique distribution in brain, suggesting synapse-specific functions as well as antagonism of neuronalsynchronization. |
| Pharmacokinetics | S-(–)-levetiracetam displays rapid and complete absorption, although food slows the rate but not the extent of absorption. It exhibits linear pharmacokinetics and is minimally protein bound. Approximately 60% of an oral dose is excreted into theurine unchanged and 24 to 30% as its carboxylic acid metabolite, with an elimination half-life in adults of approximately 7hours. Although S-(–)-levetiracetam is not metabolized by hepatic CYP450, UGT, or epoxide hydrolase, it is esterasehydrolyzed to its carboxylic acid metabolite (loss of amido group), which is not affected by the hepatic metabolizing enzymes. |
| Clinical Use | S-(–)-levetiracetam is a pyrrolidone derivative unrelated to the structures of other AEDs. It is indicated as an adjunct in thetreatment of partial onset seizures in adults, and it has shown some benefit in clinical trials for generalized tonic-clonicseizures (GTC) and myoclonic seizures in adults and children. |
| Side effects | The risk of clinically relevant drug interactions is minimal with S-(–)-levetiracetam, because it does not alter thepharmacokinetics of coadministered drugs by inhibition or induction of hepatic enzymes. Toxic effects include mild tomoderate somnolence, asthenia, ataxia, and dizziness; these effects seldom require discontinuance. An increase in theincidence of behavioral abnormalities in children and in adults having a previous history of neuropsychiatric problems has beennoted. Its use in the elderly or in patients with renal impairment will require an individualization of dose, and an additionaldose is needed after renal dialysis. Levetiracetam was associated with developmental toxicity in the offspring of pregnantanimals. |
| Veterinary Drugs and Treatments | Levetiracetam may be useful as a third antiseizure medication indogs that are not well controlled with phenobarbital and bromidesor when either bromides or phenobarbital are not tolerated. Someevidence suggests that in dogs suffering from phenobarbital livertoxicity, the addition of levetiracetam will allow reduction of theirphenobarbital dosage without increasing seizure frequency. Levetiracetam may also be useful as add-on therapy in cats. |
| storage | Store at RT |
| References | [1] CHANIN WRIGHT. Clinical pharmacology and pharmacokinetics of levetiracetam.[J]. Frontiers in Neurology, 2013, 4: 192. DOI:10.3389/fneur.2013.00192 [2] TIM DE SMEDT. Levetiracetam: The Profile of a Novel Anticonvulsant Drug—Part I: Preclinical Data[J]. CNS drug reviews, 2007, 13 1: 43-56. DOI:10.1111/j.1527-3458.2007.00004.x [3] HENRIK KLITGAARD Peter V. Levetiracetam: the first SV2A ligand for the treatment of epilepsy.[J]. Expert Opinion on Drug Discovery, 2007, 2 11: 1537-1545. DOI:10.1517/17460441.2.11.1537 [4] BERKLEY A LYNCH. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2004, 101 26: 9861-9866. DOI:10.1073/pnas.0308208101 [5] NISHA NAGARKATTI Robert J D Laxmikant S Deshpande. Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture[J]. Neuroscience Letters, 2008, 436 3: Pages 289-293. DOI:10.1016/j.neulet.2008.02.076 [6] UDO BONNET . Levetiracetam mediates subtle pH-shifts in adult human neocortical pyramidal cells via an inhibition of the bicarbonate-driven neuronal pH-regulation – Implications for excitability and plasticity modulation[J]. Brain Research, 2019, 1710: Pages 146-156. DOI:10.1016/j.brainres.2018.12.039 |
Levetiracetam Preparation Products And Raw materials
| Raw materials | Dichloromethane-->Tetrabutylammonium bromide-->4-Chlorobutyryl chloride-->Piracetam-->H-MET-NH2-->Ethyl chloroformate-->Triethylamine |
