Ho

CH2 C=O OH

From the synthetic chemist's point of view, another interesting way of making hydrocortisone consists of using progesterone as the starting substance. In the first stage of the synthesis, progesterone undergoes microbiological oxidation analogous to that described above, which forms 11a-hydroxyprogesterone (27.1.9). The resulting hydroxyl group is oxidized by chromium (VI) oxide in acetic acid, giving 11-ketoprogesterone (27.1.10). This is reacted with diethyloxalate in the presence of sodium ethoxide, forming the corresponding a-ketoester in the form of the sodium enolate 27.1.11, which undergoes bromi-nation by two equivalents of bromine, giving the dibromoketone 27.1.12. The resulting dibromoketone undergoes Favorskii rearrangement and is further hydrolyzed, giving an unsaturated acid 27.1.13. Then the carbonyl group at position C3 is ketalized using ethyl-englycol in the presence of p-toluenesulfonic acid, during which a migration of the double bond between carbon atoms C5 and C6 takes place, forming a ketal 27.1.14. The resulting product is reduced by lithium aluminum hydride. During this, the carboxyl and keto-groups at C11 are reduced to alcohol groups, forming a diol 27.1.15. The ketal protecting group is subsequently removed in acidic conditions, during which the double bond again migrates back to the initial position between C4 and C5, and the primary hydroxyl group is acylated by acetic anhydride in pyridine forming the product 27.1.16. The double bond in this compound is oxidized using hydrogen peroxide in the presence of osmium tetroxide in N-methylmorpholine, forming hydrocortisone acetate (27.1.17). Hydrolysis of the acetyl group with potassium hydroxide gives hydrocortisone (27.1.8) [6,7].

CH3 C=O

CH3 C=O

CH3 C=O

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