Organic Process Research & Development 2003, 7, 306−308
A One-Pot Efficient Process for 16-Dehydropregnenolone Acetate
Amrit Goswami,* Rumi Kotoky, Romesh C. Rastogi, and Anil C. Ghosh
Regional Research Laboratory, Jorhat-785006, Assam, India
Abstract:
Scheme 1
A one-pot eco-friendly and efficient transformation of steroidal
sapogenin diosgenin (1) and solasodine (2) to a commercially
very important drug intermediate 16-dehydropregnenolone
acetate (16-DPA, 9) was developed with an overall yield of 75%.
This process can easily be exploited for industrial production.
Introduction
16-Dehydropregnenolone acetate (16-DPA, 9) finds in-
creasing application as a versatile scaffold and building block
for different steroidal drugs for it is an ideal platform for
preparation of dexamethasone, â-methasone, 5R-reductase
synthesis of 16-DPA and related other compounds from
different sapogenins but with low-to-moderate yield. Micovic
1
1
et al. have made an improvement through which 16-DPA
could be prepared in 65-69% yield from diosgenin through
acetylation without application of any pressure. In all the
reports quoted above, the oxidizing agent used for the
purpose of cleaving the double bond in the substituted furan
ring of pseudodiosgenin or pseudosolasodine diacetate (7,
Scheme 2) is chromium trioxide which is highly toxic.
1
inhibitor, and related other steroidal pharmacophores. 16-
Dehydropregnenolone acetate (9) is best prepared either from
steroidal sapogenin diosgenin (1) or from solasodine (2)
obtained by extraction from naturally occurring Dioscorea
2
floribunda or Solanum khasianum tuber berries, respectively.
Marker and co-workers first reported this transformation
through acetolysis of diosgenin with acetic anhydride by
autoclaving, oxidation, and eventually, acid hydrolysis of the
oxidized product to afford 16-DPA without using any
catalyst. Different acid catalysts, such as hydrochloric acid,
Results and Discussion
Potassium permanganate,12 an oxidizing agent used in
organic chemistry for over a century and friendly to the
environment, is one of the most versatile and vigorous of
the commonly used oxidants and has been extensively used
in acid, alkaline and neutral media. In 1978 Irismetov13 et
al. demonstrated that treatment of solasodenone (3) or
diosgeninone (4) (a conjugated enone system) with potassium
permanganate in water-tert-butyl alcohol solvent system
attacks the 4,5 double bond to form a diol (5) which on
further treatment with sodium periodate cleaves the diol to
the corresponding keto acid (6) (Scheme 1). Now, in our
programme for development of new process know-how for
1
4
1
6-DPA we have developed for the first time a one-pot
process for 16-dehydropregnenolone acetate (16-DPA, 9)
with more than 70% yield replacing the highly toxic
chromium trioxide oxidizing agent by eco-friendly potassium
permanganate in the presence of tetraethylammonium iodide
under PTC conditions. Preparation of pseudodiosgenin
diacetate or pseudosolasodine diacetate (7) was carried out
by refluxing diosgenin or solasodine with acetic anhydride
octanoic acid, pyridine/acetyl chloride, ammonium chloride,
and so forth, were examined in the above reaction later on.
3
-10
Subsequently, several other workers have reported
the
*
To whom correspondence should be addressed. E-mail: amritgoswami@
yahoo.com.
(1) Cabeza, M.; Heuze, I.; Bratoeff, E.; Ramirez, E.; Martinez, R. Chem. Pharm.
Bull. 2001, 49(5), 525.
(2) Marker, R. E.; Rohrmann, E. J. Am. Chem. Soc. 1939, 6, 3592; J. Am.
Chem. Soc. 1949, 71, 3856.
(9) Gould, D. V.; Staendle, H.; Hersberg, E. B. J. Am. Chem. Soc. 1952, 74,
3685.
(10) Cameron, A. F. B.; Evans, R. M.; Hamlet, J. C.; Hunt, J. S.; Jones, P. G.;
Long, A. G. J. Chem. Soc. 1955, 2807 and references therein.
(11) Micovic, I. V.; Ivanovic, M. D.; Piatak, D. M. Synthesis 1990, 591.
(12) Fatiadi, A. J. Synthesis 1987, 85.
(
(
(
3) Muller, G. P.; Norton, L. L. J. Am. Chem. Soc. 1955, 77, 143.
4) Zderic, J. A. U.S. Patent 3,102,892, 1963; Chem. Abstr. 1964, 42, 7082d.
5) Velgova, H.; Kohout, L. Collect Czech. Chem Commun 1985, 50, 962;
Chem. Abstr. 1985, 103, 123776k.
(6) Chemerda, J. M.; Ruyle, W. V.; Mandell, L. U.S. Patent 3,136,758, 1964;
Chem. Abstr. 1964, 61, 7081a.
7) Dauben, W. G.; Fonken, G. J. J. Am. Chem. Soc. 1954, 78, 4618.
8) Wall, M. E.; Kenney, H. G.; Rothmor, E. S. J. Am. Chem. Soc. 1955, 77,
(13) Irismetov, M. P.; Goryaev, M. I.; Kurl’skaya, V. V. IsV. Akad. Nauk Kaz.
SSR, Ser. Khim. 1978, 28, 58; Chem. Abstr. 1978, 89, 163849k.
(14) Goswami, A.; Kotoky, R.; Rastogi, R. C.; Ghosh, A. C. U.S. Patent
6,160,139, 2000; Chem. Abstr. 2001, 134, 17621m.
(
(
5
665 and references therein.
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Vol. 7, No. 3, 2003 / Organic Process Research & Development
10.1021/op0200625 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/14/2003