Atorvastatin route of synthesis

Discover the efficient and reliable method for synthesizing Atorvastatin, the powerhouse medication known for its cholesterol-lowering properties.

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Table of Contents

The Synthesis of Atorvastatin

Atorvastatin, also known as Lipitor, is a medication primarily used for the treatment of high cholesterol. It belongs to a class of drugs called statins, which work by inhibiting an enzyme called HMG-CoA reductase, an important step in cholesterol synthesis in the body.

The synthesis of Atorvastatin involves several key steps. It starts with the reaction of a chiral reagent, (R)-p-Toluenesulfinamide, with butyllithium to form a lithiated imine intermediate. This intermediate is then reacted with (R)-Malic Acid, resulting in the formation of an imine carboxylic acid. This is followed by the reduction of the imine group using sodium borohydride, resulting in the formation of the lactone ring.

Next, the lactone ring is opened by the reaction with hydroxylamine hydrochloride, resulting in the formation of a hydroxamic acid. This hydroxamic acid is then activated by reaction with dicyclohexylcarbodiimide (DCC) and treated with various reagents to undergo a series of transformations that lead to the final Atorvastatin product.

Overall, the synthesis of Atorvastatin is a complex and multi-step process requiring specialized reagents and conditions. However, due to its importance in treating high cholesterol and reducing the risk of cardiovascular events, it has become one of the most widely prescribed medications worldwide.

Chemical Properties of Atorvastatin

Atorvastatin is a white to off-white crystalline powder that is soluble in dichloromethane, slightly soluble in methanol and ethanol, and practically insoluble in water.

Its chemical formula is C33H35FN2O5 and its molecular weight is 558.65 g/mol.

The compound contains an HMG-CoA reductase inhibitor functionality, which is responsible for its cholesterol-lowering effects.

Atorvastatin is available as calcium salt, as it enhances its stability and solubility.

The compound has a pKa value of 4.46, indicating that at physiological pH it exists primarily in the ionized form.

In summary, Atorvastatin is a chemically stable, slightly soluble compound that inhibits HMG-CoA reductase and is commonly used for the treatment of hypercholesterolemia and prevention of cardiovascular diseases.

Chemical Properties of Atorvastatin

Atorvastatin is a lipophilic compound with a molecular weight of 558.64 g/mol. It is a white to off-white crystalline powder that is practically insoluble in aqueous solutions and freely soluble in ethanol, methanol, and acetonitrile.

The chemical structure of Atorvastatin consists of a pyrrole ring fused to a hexahydrofuro[2,3-b]furan ring and further linked to a tert-butyl group. It also contains a p-fluorophenyl substituent and a p-hydroxylphenyl substituent. These structural elements contribute to the pharmacological activity of Atorvastatin as a potent inhibitor of HMG-CoA reductase, the key enzyme involved in cholesterol synthesis.

Atorvastatin undergoes extensive metabolism in the liver, primarily by cytochrome P450 3A4, resulting in the formation of active metabolites. These metabolites exhibit similar pharmacological activity and contribute to the overall effectiveness of Atorvastatin in reducing cholesterol levels.

Important Safety Information

It is important to note that Atorvastatin is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. It may also interact with other medications, and patients should inform their healthcare provider about all the medicines they are taking.

Synthesis Route of Atorvastatin

Atorvastatin, a widely used medication for lowering cholesterol levels, is synthesized through a multi-step process. The synthesis begins with commercially available starting materials, such as N-benzyloxycarbonyl-L-valine, which is converted into an acid chloride. This acid chloride is then reacted with R-3-hydroxybutyrate to form the lactone intermediate.

The lactone intermediate is then treated with lithium hydroxide to open the lactone ring, leading to the formation of the corresponding hydroxy acid. The hydroxy acid is subsequently converted into an acid chloride and then reacted with N,N-diisopropylethylamine to generate the mixed anhydride.

The mixed anhydride is then reacted with (R)-3,5-dihydroxyhept-6-enoic acid, which undergoes a series of chemical transformations, including reduction and protection steps, to yield an important intermediate known as the alcohol intermediate.

The alcohol intermediate is then subjected to a series of reactions, including oxidation and hydrolysis, to form a key intermediate known as the acid intermediate. This acid intermediate is then treated with isobutanol to form the corresponding isobutyl ester.

The isobutyl ester is subjected to a series of hydrolysis and decarboxylation steps to obtain the final product, atorvastatin. The final product is purified and formulated into various pharmaceutical dosage forms, such as tablets or capsules, for administration to patients.

Industrial Production of Atorvastatin

Atorvastatin, a highly effective drug for lowering cholesterol levels, is produced on an industrial scale using a multi-step synthetic process. The production of Atorvastatin involves several key steps, including:

Selection of raw materials: High-quality starting materials are chosen to ensure the production of pure Atorvastatin.
Synthesis of intermediates: Various intermediates are synthesized using specific chemical reactions and purification techniques. These intermediates serve as building blocks for the final compound.
Assembling the final compound: The synthesized intermediates are carefully combined, following a precise sequence of reactions, to produce Atorvastatin.
Purification: The obtained Atorvastatin is purified using different methods, such as crystallization or chromatography, to remove impurities and ensure high product quality.
Formulation: After purification, Atorvastatin is formulated into different dosage forms, such as tablets or capsules, for convenient patient use.
Packaging and labeling: The final Atorvastatin products are carefully packaged and labeled, ready for distribution to pharmacies and medical facilities.
Quality control: Throughout the industrial production process, strict quality control measures are implemented to ensure the final product meets the required standards and specifications.
Regulatory compliance: Atorvastatin production is carried out in accordance with regulatory guidelines and requirements to ensure safety and efficacy.
Scale-up: The industrial production of Atorvastatin involves scaling up the synthesis process to meet the high demand for this widely-used medication.
Efficiency optimization: Manufacturers continually optimize and improve the production process to enhance efficiency and reduce costs.
Continuous monitoring: Industrial production of Atorvastatin involves continuous monitoring of various parameters, such as reaction conditions, solvent usage, and product yield, to ensure consistent and reliable production.

The industrial production of Atorvastatin involves a complex and intricate process that requires expertise in organic synthesis, quality control, and regulatory compliance. By ensuring high standards of production, manufacturers can provide patients with safe and effective Atorvastatin medications to help them manage their cholesterol levels effectively.