Improved Synthetic Route to Dexamethasone Acetate from Tigogenin

Abstract

In the synthesis of dexamethasone acetate from tigogenin, the introduction of the 17α-hydroxy-16α-methyl and the 1,4-diene moieties was improved. For the introduction of the 17α-hydroxy-16α-methyl moiety, the key step, epoxidation, was accomplished in high yield with peracetic acid in a buffer solution of sodium acetate and acetic acid (overall yield from 17-ene substrate to 17α-hydroxy-16α-methyl intermediate: 95.3%). Then the introduction of the 1,4-diene in the A-ring was greatly improved by bromination−dehydrobromination, in which dehydrobromination proceeded smoothly in a solvent system that was a mixture of DMF and 6% of water (82.6% isolated yield of 1,4-diene based on 3-oxo compound).

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“…Introduction of ketone at C‐3 position was done by the oxidation of C‐3 OH by the treatment of calcium hypochlorite to produce 4.6. In the next step, dibromination was carried out at C‐2 and C‐4 positions by using Br 2 /AcOH in the mixture of dioxane‐AcOH as solvent to produce 4.7, which was then treated with DMF containing 6 % water for dehydrobromination reaction to introduce two double bonds in ring A (4.8) [133] . Next, hydrolysis of C‐21 acetyl group by NaOH and subsequent hydroxylation at C‐11 in presence of a fungi Peslalotia foedans produced 4.9.…”

“…[132] In the year 1997 Furukawa et al improved few steps of the existing synthetic routes to obtain Dexamethasone acetate with higher yield. [133] The synthesis starts from tigogenin, (4.1) (Scheme 8) which undergoes ring opening in the presence of acetic acid at 200°C, followed by oxidation with chromic acid and elimination by application of heat to form 4.2. [132] Then 4.2 was treated with CH 3 MgCl/CuCl for the introduction of methyl moiety at C-16 and further epoxidation was done using peracid followed by alkaline hydrolysis to produce 4.3.…”

“…In the next step, dibromination was carried out at C-2 and C-4 positions by using Br 2 /AcOH in the mixture of dioxane-AcOH as solvent to produce 4.7, which was then treated with DMF containing 6 % water for dehydrobromination reaction to introduce two double bonds in ring A (4.8). [133] Next, hydrolysis of C-21 acetyl group by NaOH and subsequent hydroxylation at C-11 in presence of a fungi Peslalotia foedans produced 4.9. Further, a double bond was incorporated in the C-ring (between C-9 and C-11) by the treatment with sodium acetate to produce 4.10.…”

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“…The longer route developed by Merck via the more expensive bovine bile acids was no longer an attractive approach. In the six decades since the first publication of the Schering route to dexamethasone, improvements to the route have been made using more modern chemistry and a different order of steps. In a review of industrial syntheses of corticosteroids in 2017, Herraiz described a 14-step manufacturing route to dexamethasone from 80 (Scheme ), available from 76 in four steps via Marker degradation (Scheme ).…”

Practical Application of Oxidation Using a Novel Na2WO4−H2O2 System under Neutral Conditions for Scale-Up Manufacturing of 12α-Hydroxy-3-oxooleanano-28,13-lactone: Key Intermediate of Endothelin A Receptor Antagonist S-0139

“…The oxidation of alcohol to ketone is one of the most important reactions in organic chemistry. Various oxidation methods have been reported, including Jones oxidation, Swern oxidation, Dess−Martin oxidation, Oppeneure oxidation, TEMPO oxidation, , Ca(OCl) 2 with acetic acid, and TPAP oxidation . However, oxidation is not often used in large-scale manufacturing because of inherent safety concerns and waste of byproducts .…”