Efficient Synthesis of 21-Acetoxypregna-1,4,9(11),16-Tetraene-3,20-Dione, a Key Intermediate in the Synthesis of Highly Active Fluorinated Corticosteroids from 9α-Hydroxyandrostenedione

Transformation of phytosterols into pregnatetraenedione by a combined microbial and chemical process

“…Therefore, the overall yield from phytosterols to pregnatetraenedione via 9-OHPDC-M was up to 35.4%, which was significantly higher than the diosgenin-pregnatetraenedione route (about 10%) and the 9-OHAD-pregnatetraenedione route (about 22.2%). 7,12 As for the production time of the new route, it was estimated to be about 10 days without taking into account the preparation and product purification processes: 6 days for the conversion of phytosterols to 9-OHPDC-M, 3–5 hours for the ester hydrolysis of 9-OHPDC-M to 9-OHPDC, 10–12 hours for the decarboxylation rearrangement of 9-OHPDC to 9-OHP-16-ene, 6–8 hours for the dehydration of 9-OHP-16-ene to P-9(11),16-diene, and 48 hours for the dehydrogenation of P-9(11),16-diene to pregnatetraenedione. This is close to the production time of the traditional phytosterol-based 9α-OHAD route, but significantly lower than that of the diosgenin-based route (Table 2).…”

“…First, it required only 5 steps from phytosterols to pregnatetraenedione, whereas the other two routes were composed of at least 8 steps. Second, all the reactions in the 9-OHPDC-M-pregnatetraenedione route proceeded under milder conditions, such as normal reaction temperature (25–30 °C) and pressure, whereas some reactions in the other two routes involved harsh conditions, such as the dehydration reaction of 16,17-epoxy-11alpha-hydroxypregn-1,4-diene-3,21-dione at −50 °C 48 and the opening reaction of the spiroketal ring system of diosgenin at 220 °C under 5 bar pressure 2 in the diosgenin-pregnatetraenedione route and the esterification of 17α-hydroxyl at 80–85 °C 7 in the 9-OHAD-pregnatetraenedione route. Third, the whole process of the 9-OHPDC-M-pregnatetraenedione route proceeded in aqueous phases and only methanol and acetone were needed.…”

“…Pregna-1,4,9 (11), 16(17)-tetraene-3,20-dione (abbreviated as pregnatetraene-dione) or its derivative 21-acetoxyl-pregnatetraenedione is generally used as the pivotal precursor for the synthesis of numerous commercial corticosteroids because there are four double bonds facilitating the required modification of the steroidal nucleus at C1, C2, C9, C11, C16 and C17 positions. 1,7,12,13 Until now, there are two kinds of semi-synthetic routes for the commercial production of pregnatetraenedione in industry. One is a diosgenin-based route (Fig.…”

“…In general, the second route has distinct advantages over the first one in production cost and environmental friendliness. In recent years, the microbial transformation of phytosterols to 9α-OHAD has been widely used in industry, 7,12 which greatly promoted the development of the phytosterol-based route in the production of pregnatetraenedione. Nevertheless, the conversion from 9α-OHAD to pregnatetraenedione is still a cumbersome process with a low yield.…”

“…However, this method showed no satisfying stereoselectivity because a useless epimer of 17β-cyano-intermediate was inevitably generated in the first step, and its effective yield is generally not more than 70%. 7,12 Moreover, some toxic reagents, such as acetone cyanohydrin, trimethyl orthoformate, and chlorosulfonic acid, need to be used in this process. Therefore, to produce pregnatetraenedione by the phytosterols-based route via 9α-OHAD still needs to be further improved.…”