The Synthetic Routes of Atorvastatin 3-Deoxyhept-2E-Enoic Acid

Atorvastatin, also known as Ravulast, is a selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), which is the rate-controlling enzyme in cholesterol biosynthesis.
It is widely used to treat dyslipidemia and hypercholesterolemia, which are associated with an increased risk of cardiovascular disease.
Atorvastatin is synthesized from 3-deoxyhept-2E-enoic acid 2, which is a key intermediate in the synthesis of some steroids, statins and other drugs.

Synthetic Route 1: Via a Claisen condensation

One of the synthetic routes to atorvastatin 3-deoxyhept-2E-enoic acid 2 is via a Claisen condensation of 2-methyl-2-butenoic acid with hexamethylene diamine.
The reaction is performed under basic conditions and the resulting intermediate is then reduced with lithium aluminum hydride to obtain 2,6-dimethyl-4-oxo-4H-spiro[cyclohex-2,4]-1,3-oxazine.
The spirocompound is then treated with hydrogen peroxide and sodium hydroxide to cleave the protecting groups and obtain the corresponding 1,2-oxazepine.
The 1,2-oxazepine is then subjected to a P25-mediated regioselective condensation with 1,6-diiodohexane to obtain the final product, 3-deoxyhept-2E-enoic acid 2.

Synthetic Route 2: Via a Stereo-specific Desymmetrization

Another synthetic route to atorvastatin 3-deoxyhept-2E-enoic acid 2 is via a stereo-specific desymmetrization of the precursor, sym-4,5-dimethyl-2-(imino-methyl)-1,3-oxazepine.
The desymmetrization is achieved by treatment with Lawesson's reagent, which is a chiral phosphoric acid derivative.
The resulting intermediate is then reduced with lithium aluminum hydride to obtain the corresponding 1,2-oxazepine, which is then treated with hexamethylene diamine and triethylamine to obtain the final product, 3-deoxyhept-2E-enoic acid 2.

Synthetic Route 3: via a Condensation of 2-formyl-2-methyl-4-oxopent-4-ene and 1,3-oxazepine

Another synthetic route of atorvastatin 3-deoxyhept-2E-enoic acid 2 is via a condensation of 2-formyl-2-methyl-4-oxopent-4-ene with 1,3-oxazepine in the presence of a base catalyst, such as sodium hydroxide.
The reaction results in the formation of 2-methyl-2-butenoic acid which is then reduced with lithium aluminum hydride to obtain the corresponding 2,6-dimethyl-4-oxo-4H-spiro[cyclohex-2,4]-1,3-oxazine.
The spirocompound is then treated with hydrogen peroxide and sodium hydroxide to cleave the protecting groups and obtain the corresponding 1,2-oxazepine.
The 1,2-oxazepine is then subjected to a P25-mediated regioselective condensation with 1,6-diiodohexane to obtain the final product, 3-deoxyhept-2E-enoic acid 2.

Synthetic Route 4: via an Ullmann condensation

A similar synthetic route is also possible via an Ullmann condensation.
In this case, 2-methyl-2-butenoic acid is treated with an equimolar amount of phenyl chloride and anhydrous aluminum chloride in the presence of a solvent such as DMF.
The resulting