Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1996-11-18
1998-05-12
Prior, Kimberly J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C07J 7500
Patent
active
057507457
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The synthesis of corticosteroids having therapeutic utility, such as mometasone, betamethasone and beclomethasone, requires functionalization of the C-9 and C-11 positions of the steroid molecule. The functionality is generally introduced via .DELTA..sup.9,11 steroid intermediates.
Methods for preparing steroids having a 9,11 double bond are known in the art. For example, an 11-hydroxy steroid can be converted to the corresponding mesylate (by treating with mesyl chloride) which is transformed into a .DELTA..sup.9,11 steroid via an elimination reaction. However, the prior art methods are not regiospecific in the case of 11.alpha.-hydroxy steroids and typically lead to mixtures of .DELTA..sup.9,11 steroid containing 10-15% of the analogous .DELTA..sup.9,12 steroids. Separation of these regio-isomeric products is difficult, generally requiring laborious physical separation procedures, resulting in increased costs and lower yields. It would therefore be desirable to develop an efficient regioselective method for preparing .DELTA..sup.9,11 steroids, from either 11.alpha.- or 11.beta.-hydroxy steroids, for use as intermediates in the synthesis of corticosteroids.
The introduction of a 21-chloro group is also of commercial importance, e.g. for preparing intermediates and therapeutically important compounds such as mometasone. The conversion of 21-hydroxy steroids to the analogous 21-chloro steroid by chloride displacement of a 21-methanesulfonyl intermediate is known. However, this reaction is not regioselective in the case of 11-hydroxy steroids, as methanesulfonyl chloride reacts with both the 11- and 21-hydroxy groups. In addition, Wuts, et al., Syn. Comm., 23, (15) 2199-2211 (1993) describes a method for preparing 21-chloro steroids using the Vilsmeier reagent (prepared from DMF and POCl.sub.3 or phosgene).
DE 1,127,895 describes the preparation of 9(11)-unsaturated steroids from the corresponding 11.alpha.-sulfonate esters by reaction with a lithium halide in an anhydrous basic solvent.
J. Org. Chem., Vol. 31 (1), pages 26-31 (1966) describes the conversion of 16.beta.-methyl-11.alpha.,17,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-acetate 11-mesylate into the corresponding 1,4,9(11 )-triene by reaction with sodium acetate in acetic acid.
J.A.C.S. Vol. 80(16), page 4431 (1958) describes the conversion of 11.alpha.,17.alpha.,21-trihydroxy-16.alpha.-methyl-1,4-pregnadiene-3,20-di one 21-acetate 11 -tosylate into the corresponding 1,4,9(11)-triene by reaction with sodium acetate in acetic acid.
Reissue Pat. No. 28,369 describes (in Example 20) the 9,11 -dehydration of 11.beta.,17.alpha.,21-trihydroxy-16.beta.-methyl-4-pregnene-3,20-dione 21-acetate with methanesulfonyl chloride in pyridine and DMF to the corresponding 4,9(11 )-pregnadiene.
EPA 3,341 describes (in Example 50) the conversion of 9.alpha.-fluoro-11.beta.,21-dihydroxy-17.alpha.-methoxymethoxy-1,4-pregnad iene-3,20-dione 21-tosylate into 21-chloro-9.alpha.-fluoro-11.beta.-hydroxy-17.alpha.-methoxymethoxy-1,4-pr egnadiene-3,20-dione by reaction with lithium chloride in hexamethylphosphoramide.
U.S. Pat. No. 3,639,434 shows (in the scheme in the middle of column 5) the conversion of 11.alpha.,17.alpha.,21-trihydroxy-1,4-pregnadiene-3,20-dione 21-mesylate into 21-chloro-11.alpha.,17.alpha.,21-trihydroxy-1,4-pregnadiene-3,20-dione with lithium chloride in DMF.
In view of the importance of both 21-chloro groups and 9,11 -double bonds it would be desirable to develop a one-step process for efficiently introducing both functional groups in a single steroid molecule
SUMMARY OF THE INVENTION
The present invention provides a regioselective process for preparing .DELTA..sup.9,11 steroids of the formula I ##STR1## wherein: one of R.sup.2 or R.sup.3 is CH.sub.3 and the other is H; and X is H, halogeno or --OR, wherein R is H or --C(O)R.sup.1, and R.sup.1 is CF.sub.3, C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.6 alkoxy.
The process of the present invention is chemically efficient, and where a .DELTA..sup.9,11 group and a 21-chloro gr
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Colon Cesar
Fu Xiaoyong
Lee Junning
Tann Chou-Hong
Thiruvengadam Tiruvettipuram K.
Mann Arthur
Prior Kimberly J.
Schering Corporation
Thompson Paul A.
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