The Synthetic Routes of (9b,11b,16a)-9,11-Epoxy-21-hydroxy-16-methylpregna-1,4-diene-3,20-dione

The synthesis of (9b,11b,16a)-9,11-Epoxy-21-hydroxy-16-methylpregna-1,4-diene-3,20-dione is a complex and challenging process that requires the use of advanced synthetic methods and techniques.
This synthetic route involves several steps, and each step requires careful planning and execution to ensure that the final product is obtained in a pure and soluble form.
The following article provides a comprehensive overview of the synthetic routes used to synthesize (9b,11b,16a)-9,11-Epoxy-21-hydroxy-16-methylpregna-1,4-diene-3,20-dione, and highlights the key considerations and challenges associated with each step.

Step 1: Preparation of 2-methyl-2-butenoic acid

The first step in the synthesis of (9b,11b,16a)-9,11-Epoxy-21-hydroxy-16-methylpregna-1,4-diene-3,20-dione involves the preparation of 2-methyl-2-butenoic acid.
This can be achieved by hydrolyzing 2-methyl-2-butyric acid, which is readily available in the market, using a strong acid, such as hydrochloric acid or sulfuric acid.
The acid hydrolysis reaction proceeds as follows:

2-methyl-2-butyric acid + H2O → 2-methyl-2-butenoic acid + H3O+ + e-

The resulting 2-methyl-2-butenoic acid can be isolated by traditional methods, such as filtration and washing with water.

Step 2: Preparation of Methyl 4-((4S)-hydroxy-2,6-dimethyl-1,4-oxazepan-3-yl)-2-methyl-2-butenoate

The second step in the synthesis of (9b,11b,16a)-9,11-Epoxy-21-hydroxy-16-methylpregna-1,4-diene-3,20-dione involves the preparation of methyl 4-((4S)-hydroxy-2,6-dimethyl-1,4-oxazepan-3-yl)-2-methyl-2-butenoate.
This compound can be synthesized by a sequence of reactions, which involves the following steps:

(a) Preparation of 4-((4S)-hydroxy-2,6-dimethyl-1,4-oxazepan-3-yl)butyl alcohol

This can be prepared by reducing 4-bromomethyl-2,6-dimethyl-1,4-oxazepan-3-one, which is readily available in the market, using lithium aluminum hydride (LiAlH4) in the presence of a solvent, such as dimethylformamide (DMF).
The reduction reaction proceeds as follows:

4-bromomethyl-2,6-dimethyl-1,4-oxazepan-3-one + 2LiAlH4 + DMF → 4-((4S)-hydroxy-2,6-dimethyl-1,4-oxazepan-3-yl)butyl alcohol + LiBr + H2O

(b) Preparation of methyl 4-((4S)-hydroxy-2,6-dimethyl-1,4-oxazepan-3-yl)-2-methyl-2-butenoate

This can be prepared by a simple aldol condensation reaction between 4-((4S)-hydroxy-2,6-dimethyl-1,4-oxazepan-3-yl)butyl alcohol and methyl 2-methyl-2-butenoate in the presence of a strong base, such as sodium hydroxide