Synthesis of 16β-Methylpregn-4,9(11)-Diene-17α-Ol-3,20-Dione From 9α-Hydroxyandrostenedione

Since the microbial degradation of the side chain of sterol mixture has been developed, this process provides an inexpensive source of 17-ketosteroids such as androst-4-ene3,17-dione (AD), androsta-1,4-diene-3,17-dione (ADD) and 9 -hydroxyandrost-4-ene-3,17-dione (9 -OH-AD) [1, 2]. The latter compound [3] and its 9 -analog [4, 5] are considered at present to be the most attractive intermediates for the synthesis of commercially important corticoids [6 – 9] such as prednisolone, betamethasone, dexamethasone, triamcinolone, etc. Previously, we reported a very efficient procedure for extraction and purification of phytosterols mixture from by-product of soybean oil production [10] and its conversion to AD [11] and 9 OH AD in very good yields [12 – 15]. 16 -Methyl-pregn-4,9(11)-diene-17 -ol-3,20-dione is an important intermediate for the synthesis of betamethasone [16]. As is known, an efficient process for the preparation of 16 -methylsteroids from 9 -AD consists in combination of the cyanohydrin synthesis of 20-ketopregnanes and the methylation method of introduction of the 17 -hydroxy16 -methyl fragment. This approach was used for the modification of 4 -3-ketosteroids after preliminary protection of 3and 20-keto groups by ketalization [17]. We present here an improved method for converting 9 -hydroxyandrost-4-ene-3,17-dione into 16 -methylpregn-4,9(11)-diene-17 -ol-3,20-dione, featuring the formation of stable 6-cycle ketal blocking 3and 20-keto groups, which was not described in [17]. Initially, because of stable 6-cycle ketal blocking, synthesis of 16 ,17 -epoxy-3,20-diketal (8) is intended to use for the methylation reaction to obtain corresponding 16 -methyl-17 -hydroxydiketal (9) by using methyl magnesium bromide, which is preferably in this study. The reaction of compound 8 with other methylation agents such as MeLi, MeMgCl, etc. will be studied and reported in the near future. As a result, reaction of 16 ,17 -epoxy-3,20-diketal (8) with the methylation agent MeMgBr gives 16 -methyl17 -hydroxy-3,20-diketal derivative (9). Then, unblocking ketone functions in the 3and 20-positions leads to 16 -methyl-17 -hydroxypregnane (10) in good yield over two steps using known method [17]. The structure of 16 -methyl-17 -hydroxypregnane (10) has been studied by IR, 1 H NMR, and DEPT 13 C NMR spectroscopy. The stereochemistry of 16and 17-centers of compound 10 is determined by the synthesis method [17] and, for the first time, additionally confirmed by interpretation of the results of NOESY measurements (Fig. 1). In particular, Pharmaceutical Chemistry Journal, Vol. 49, No. 7, October, 2015 (Russian Original Vol. 49, No. 7, July, 2015)