Oxiracetam
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Product Description
Oxiracetam is an organooxygen and organonitrogen nootropic compound structurally related to alpha-amino acids. As a small-molecule racetam derivative, it has reached Phase II clinical development and is under investigation for one cognitive indication. Extensive trials—including a large, multicenter, double-blind Phase IV study in post-stroke patients—have explored its potential to attenuate vascular cognitive impairment, either alone or combined with physical exercise, yet robust evidence of clinically meaningful benefit remains elusive.
Synthesis and Production
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Key Starting Materials: The process begins with protecting the hydroxyl group of 4-hydroxy-2-pyrrolidone using either a tert-butyldimethylsilyl (TBDMS) or tert-butyldiphenylsilyl group.
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Reaction Steps:
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Alkylation: The protected pyrrolidone reacts with a low molecular weight halogenated acetic ester (e.g., 2-bromoacetic acid ethyl, isopropyl, or benzyl ester) in a non-protic solvent (like THF) under basic conditions (using HMDSLi) to form an ester intermediate.
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Ammonolysis (Amide Formation): The ester intermediate is reacted with concentrated ammonia water, yielding the corresponding amide compound. A key advantage noted is that this intermediate often crystallizes directly from the reaction mixture with high purity (>99%), allowing impurities to be removed by simple filtration.
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Deprotection: The silyl protecting group is removed using an acidic methanol solution (e.g., HCl/MeOH). The inventors found that during this step, any residual carboxylic acid impurities esterify with the methanol solvent and remain in solution, while the target Oxiracetam precipitates as a solid with high purity (>99%).
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Advantages over Prior Art: This method avoids the need for complex and destructive purification processes like repeated ion-exchange resin chromatography and extensive water concentration, which in other methods led to product hydrolysis and low purity. It offers high overall yield (e.g., ~85% for alkylation, ~92% for ammonolysis, ~96% for deprotection) and is suitable for large-scale GMP production.
Uses and Applications
Oxiracetam is a nootropic agent with established and investigated therapeutic applications, primarily in cognitive disorders.
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Primary Therapeutic Uses:
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Cognitive Enhancement: Used to improve memory, learning capacity, focus, and logical reasoning.
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Post-Stroke Cognitive Impairment (PSCI): A significant indication, particularly in some regions like South Korea, where it has been widely prescribed and reimbursed.
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Dementia and Cognitive Decline: Used for treating vascular dementia, multi-infarct dementia, and age-related cognitive impairment, including Alzheimer's disease.
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Traumatic Brain Injury (TBI): Investigated for improving memory and cognitive function in patients with mild-to-moderate TBI.
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Pharmacological Classification:
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ATC Code: N06BX07 (Other psychostimulants and nootropics).
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MeSH Classification: Classified under Nootropic Agents and Psychotropic Drugs.
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Chemical and Physical Properties
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Chemical Identifiers:
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IUPAC Name: 2-(4-hydroxy-2-oxopyrrolidin-1-yl)acetamide
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Molecular Formula: C₆H₁₀N₂O₃
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CAS Registry Number: 62613-82-5
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Other IDs: UNII (P7U817352G), ChEBI (CHEBI:134788), DrugBank (DB13601), InChIKey (IHLAQQPQKRMGSS-UHFFFAOYSA-N)
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Computed Physicochemical Properties:
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Molecular Weight: 158.16 g/mol
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XLogP3: -2.2 (Indicates high hydrophilicity)
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Hydrogen Bond Donor Count: 2
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Hydrogen Bond Acceptor Count: 3
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Rotatable Bond Count: 2
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Topological Polar Surface Area (TPSA): 83.6 Ų
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Monoisotopic Mass: 158.06914219 Da
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Structural Characteristics:
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Oxiracetam is a derivative of 2-pyrrolidone and is a cyclic derivative of GABA.
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It contains one undefined stereocenter, meaning it is typically used as a racemic mixture.
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Safety and Handling
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Hazard Identification (GHS Classification):
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Pictogram: GHS07 (Exclamation mark)
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Signal Word: Warning
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Hazard Statements:
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H315: Causes skin irritation.
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H319: Causes serious eye irritation.
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Precautionary Statements: Codes include P264, P280, P305+P351+P338, P337+P317, etc., advising measures like washing skin thoroughly after handling, wearing protective gloves/eye protection, and rinsing eyes cautiously if exposed.
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Toxicity Information:
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The provided data does not indicate high acute toxicity. It is generally considered to have low toxicity, with reported side effects in clinical use being mild (e.g., headache, insomnia, nausea).
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Handling Precautions:
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Standard personal protective equipment (PPE) is recommended, including gloves and eye protection, to avoid skin and eye contact.
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Adequate ventilation should be ensured during handling.
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