Introduction

Ketorolac, CAS 74103-06-3 is a nonsteroidal anti-inflammatory drug (NSAID) and an important compound in the clinical treatment of pain. Originally developed for its analgesic and anti-inflammatory properties, ketorolac’s chemical structure, a bicyclic pyrroloindole scaffold, has attracted considerable attention for its reactivity.

Its effectiveness in reducing pain and inflammation, particularly in the postoperative setting, underscores the clinical importance of this compound. As researchers continue to research its chemical basis, ketorolac serves as an exemplary model for the interaction between molecular structure and pharmacological activity. The study of ketorolac’s chemical reactions expands its utility in both drug development and research. The reactivity of its carboxyl group allows for classical transformations such as oxidation, decarboxylation, and salt formation, each of which can alter its pharmacokinetic and pharmacodynamic properties.

This article describes ketorolac, its properties, various chemical reactions and range of applications. The study of its application in clinical conditions and pharmaceutical formulations highlights the multifaceted role of this compound in modern medicine.

Physical and Chemical Properties of Ketorolac

Ketorolac, 5-benzoyl-2,3-dihydro-1h-pyrrolizine-1-carboxylic acid, CAS 74103-06-3 appears as a white or almost white crystalline powder. Its molecular formula is C₁₅H₁₃NO₃, with a molecular weight of 255.27 g/mol. The density of ketorolac is 1.33 ± 0.1 g/cm³. The melting point of ketorolac is in the range of 160–161°C. For example, while the free form is insoluble in water, slightly soluble in chloroform and methanol, conversion to salt forms such as tromethamine salt significantly improves its solubility in water.

Chemically, the structure of ketorolac is determined by the presence of a reactive carboxyl group and a chiral center, since it is sold as a racemic mixture. The stereochemistry of ketorolac is important, the S-enantiomer is largely responsible for its analgesic and anti-inflammatory effects. Chemically, the carboxylic acid group can undergo standard transformations such as oxidation, decarboxylation, and salt formation. The ability to form stable salts, in ketorolac tromethamine, is critical to solubility and stability for clinical use.

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Synthesis of Ketorolac

The synthesis of ketorolac, CAS 74103-06-3, involves a series of organic transformations. Key steps include formation of a pyrrole Grignard reagent with 2-bromo-4-chlorobutanamide, cyclization to pyrrolizinecarboxamide, and Friedel-Crafts acylation.

Pyrrole is converted to its Grignard reagent using methyl magnesium chloride in a solvent such as tetrahydrofuran or diethylene glycol dibutyl ether. This step is carried out under an inert atmosphere at temperatures between 0 and 50 °C to ensure high reactivity and selectivity.

The pyrrole Grignard reagent is reacted with 2-bromo-4-chlorobutanamide in THF, toluene, or butyldiglyme at 25-30°C. This reaction yields N-methyl-N-phenyl-4-chloro-2-(2-pyrrolyl)butanamide which uses as an intermediate.

The intermediate undergoes intramolecular cyclization in the presence of a strong base such as NaOH and a phase transfer catalyst (e.g., Aliquat 336). The reaction occurs at 85°C, leading to the formation of N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine 1-carboxamide.

The pyrrolizine carboxamide is then subjected to an aroylation reaction to introduce a benzoyl group. Reaction with (1-сhloroethyl)benzene in the presence of lithium carbonate at 100-105°C. This step produces N-methyl-N-phenyl-5-benzoyl-2,3-dihydro-1H pyrrolizine-1-carboxamides.

The ketorolac amide undergoes hydrolysis under alkaline conditions (NaOH in methanol) at 65°C. The reaction mixture is then acidified (pH 1-2) to precipitate ketorolac.

Chemical Reactions of Ketorolac

The reactivity of ketorolac, CAS 74103-06-3 is primarily controlled by its carboxylic acid functionality and aromatic pyrroloindole core. Main reactions of ketorolac include oxidation, decarboxylation, and salt formation, each of which has applications in drug modification and pharmaceutical development.

Oxidation Reactions

Ketorolac can undergo oxidation under specific conditions, leading to oxidative degradation products or modified derivatives. Oxidation using potassium permanganate (KMnO₄) can lead to the hydroxylation of the indole ring, altering the drug’s biological activity.

Decarboxylation Reactions

Decarboxylation of ketorolac results in the removal of the carboxyl functional group, producing a non-acidic derivative that may exhibit altered pharmacological properties. Heating ketorolac with a decarboxylation catalyst such as copper powder or strong base leads to the formation of a ketorolac derivative.

Salt Formation

Ketorolac is often converts into its salt form to improve aqueous solubility and stability. The most commonly used salt is ketorolac tromethamine, which is formed through neutralization with tromethamine (tris(hydroxymethyl)aminomethane). Ketorolac is dissolved in methanol and reacted with tromethamine to form ketorolac tromethamine. This salt form is widely used in injectable and ophthalmic formulations due to its enhanced solubility and bioavailability.

Applications of Ketorolac

Ketorolac, CAS 74103-06-3 is best known for its clinical use as a potent nonsteroidal anti-inflammatory drug, primarily used to treat moderate to severe pain. In the clinical setting, it is widely used to control postoperative pain by reducing inflammation and providing effective analgesia without the addiction associated with opioids. For example, ketorolac is often used in hospitals following surgery, where its parenteral forms (often as the tromethamine salt) allow for rapid onset of pain relief. Its mechanism of action, which involves inhibition of cyclooxygenase (COX) enzymes, reduces prostaglandin synthesis—a key factor in the inflammatory process—thus simultaneously addressing both pain and inflammation.

In addition to its established clinical use, ketorolac has applications in pharmaceutical formulation and prodrug development. Its chemical versatility, particularly the reactivity of its carboxylic acid functional group, allows the synthesis of various derivatives designed to optimize pharmacokinetic and pharmacodynamic properties. These chemical modifications and resulting derivatives pave the way for the development of next-generation NSAIDs and related compounds with improved clinical profiles.

Health Effects of Ketorolac

The health effects of ketorolac, CAS 74103-06-3, which is used for short-term relief of moderate to severe pain, especially after surgery. Despite its high effectiveness, this drug has a number of side effects and risks that are important to know about.

Common side effects include gastrointestinal problems such as nausea, abdominal pain, heartburn, and diarrhea. Headache, dizziness, and drowsiness may also occur. Some people experience skin reactions, including rash, itching, and increased sweating.

Serious side effects are less common. One of the most dangerous complications is the development of a stomach ulcer or intestinal bleeding, especially with prolonged use or high doses. In rare cases, perforation of the stomach or intestinal walls is possible, which causes severe pain and requires emergency medical care.

Cardiovascular risks include an increased risk of heart attack and stroke, especially with long-term use or in people with a predisposition to heart disease. Blood pressure may also increase and fluid retention may occur, leading to swelling of the legs and arms.

Kidney damage includes impaired kidney function, which may lead to acute renal failure, especially in older patients and people with dehydration. Ketorolac may also worsen existing kidney disease.

Allergic reactions can range from a mild rash to life-threatening anaphylactic shock. Asthma attacks may occur in people who are sensitive to aspirin or other NSAIDs.

Ketorolac should be used with caution. It should not be used for a long time. The drug is contraindicated in gastric ulcer, severe kidney and liver diseases, cardiovascular pathologies and in the third trimester of pregnancy. It is not prescribed to children under 17 years of age.

Interaction with other drugs can increase its side effects. Combined use with other NSAIDs (eg, ibuprofen or aspirin) increases the risk of bleeding. When used together with anticoagulants such as warfarin, the likelihood of bleeding also increases. Some drugs for lowering blood pressure (ACE inhibitors, diuretics) can increase the risk of renal failure. into the development of modified ketorolac formulations and dosing regimens.

Safety Precautions

When working with ketorolac, CAS 74103-06-3 and its derivatives in the laboratory, following safety precautions is essential to reduce health hazards and ensure a safe work environment. Researchers should wear appropriate personal protective equipment (PPE), including lab coats, safety goggles, and nitrile gloves at all times to prevent accidental exposure through skin contact or unintentional ingestion. Additionally, ketorolac should be handled in well-ventilated areas or, preferably, in a fume hood, especially when handling its powder form or when performing reactions that generate volatile by-products.

Ketorolac must be stored under specific conditions to maintain its potency and prevent possible changes in chemical composition:

Temperature: Optimum storage temperature is between 15°C and 25°C. The drug should not be exposed to freezing or excessive heat, as this may alter its properties.

Storage location: The medicine should be stored in a dry, dark place, protected from direct sunlight and moisture.

Conclusion

In conclusion, ketorolac, CAS 74103-06-3 has a strong analgesic and anti-inflammatory effect, making it an effective agent for short-term control of acute pain. However, its use may be accompanied by side effects such as gastrointestinal irritation and potential nephrotoxicity, which requires careful and strictly dosed use. The chemical reactivity of ketorolac provides the potential for modification of its pharmacokinetic and pharmacodynamic properties.

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