Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-07-25
1996-03-26
Kestler, Kimberly J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
552612, 552616, 552533, 552562, 552566, 552559, 552593, C07J 2100
Patent
active
055021832
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The 9.alpha.-hydroxy steroids are known to be useful intermediates for preparing commercially valuable corticosteroids. These corticosteroids such as betamethasone find utility in the treatment of psoriasis, dermatological diseases and inflammation. U.S. Pat. No. 4,127,596 describes a process for dehydrating 9.alpha.-hydroxysteroid type compounds with a strong acid (pKa less than 1) to give .DELTA.9,11 steroids. A .DELTA.9,11 steroid is one which possesses a double bond between positions 9 and 11 in the steroid ring.
U.S. Pat. No. 4,102,907 and European Patent Application No. 87201933.6 teach dehydration of steroid intermediates. John Fried and John A. Edwards, Organic Reactions in Steroid Chemistry, Vol. II, Van Nostrand Reinhold Co., New York, N.Y. (1972), pp., 382-385; L. F. Fieser and M. Fieser, Steroids, Reinhold Publishing Corp., New York (1959), Chapter 18, Homo and Nor Steroids, pp. 577-599 and R. W. Draper and M. S. Puar Carbon-13 Nuclear Magnetic Resonance Spectra of D-homoannulated 17-hydroxypregnan-20-ones, Steroids 54/1, July, 1989, pp. 1-10, disclose undesirable D-ring homologation of 17-hydroxy-20-keto steroids by utilizing conventional acidic or alkaline reagents. J. Org. Chem., 44, pp. 1582-1584 (1979) notes that C-9.alpha. esters are not readily preparable. The .DELTA.9,11 steroids are useful intermediates for the preparation of pharmaceutically active corticosteroids as taught in L. F. Fieser and M. Fieser, Steroids, Chapter 19, Adrenocortical Hormones, pp. 600-726, supra, I. Nitta and H. Ueno, New Synthesis of Corticoids, Yuki Gosei Kagaku, Vol. 45, No. 5 (1987), pp. 445-461, and in J. Redpath and F. J. Zeelen, in Chem. Soc. Rev., Stereoselective Synthesis of Steroid Sidechains, Vol. 12 (1983), pp. 75-98. Thus, it would be desirable to provide a process for preparing .DELTA.9,11 steroids by dehydration of 9.alpha.-oxygenated steroids possessing the requisite 17,21-dihydroxy-20-ketone (corticoid) or 17-hydroxy-20-ketone (pregnane) side chain which avoids D-ring homo-rearrangement and which can also reduce the steps required for their preparation. The present invention utilizes a 9.alpha.-carbonate of the 9.alpha.-hydroxy steroid as an intermediate in the synthesis of commercially valuable steroids. 9.alpha.-carbonates are prepared from the commercially available 9.alpha.-hydroxyandrost-4-ene-3,17-dione or its derivatives by a sequence of either excess base, trialkylsilyl halide, alkyl, vinyl, or phenyl haloformate and alkanol; or a sequence of excess base, excess alkylhaloformate and alkoxide. The use of the 9.alpha.-carbonate allows for elimination in the presence of a 17-hydroxy group.
SUMMARY OF THE INVENTION
The present invention is concerned with a process for the preparation of steroid intermediates of the formula ##STR1## wherein Z is an acyl group; alkoxy group; represents an optional double bond;
which comprises: ##STR2## wherein R.sub.1 is as hereinbefore defined and ##STR3## represents i) an enol ether of the formula: ##STR4## wherein R.sub.3 is a lower alkyl or a trisubstituted silyl group wherein the silyl substituents are independently lower alkyl, phenyl or phenylalkyl; the dashed line represents a double bond present in one or the other position; and R.sub.2 is as hereinbefore defined; ##STR5## wherein R.sub.10 and R.sub.11 independently are lower alkyl groups, optionally connected together to form a five or six membered ring; the dashed lines represent an optional bond present in either the A or B ring; and R.sub.2 is as hereinbefore defined; or ##STR6## wherein R.sub.2, R.sub.10 and R.sub.11 are as hereinbefore defined with the proviso that the optional six membered ring may optionally contain an oxygen or nitrogen atom; ##STR7## wherein R.sub.4 is a lower alkyl, vinyl or phenyl carbonate group, and R.sub.1, R.sub.2, R.sub.3, R.sub.10 and R.sub.11 are as hereinbefore defined; 9.alpha.-hydroxy starting material of formula III with lithium acetylide or lithium trimethylsilyl acetylide, optionally in the presence of LiX wherein X is a chloro
Andrews David R.
Sudhakar Anantha R.
Kestler Kimberly J.
Mazer Edward H.
Schering Corporation
Thompson Paul A.
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