7534
J . Org. Chem. 1994,59, 7534-7538
Synthesis of Triamcinolone Acetonide from 9-Hydroxy-3-methoxy-17-(2-methoxy-3oxazolin-4-yl)androsta-3,5, l&trienel
Scheme 1
Daan van Leusen and Albert M. van Leusen'
Department of Organic and Molecular Inorganic Chemistry, Groningen Center for Catalysis and Synthesis, Groningen University, Ngenborgh 4, 9747 AG Groningen, The Netherlands Received June 23, 1994 I n a series of papers2%we and others have shown t h a t
17-(isocyano-tosylmethylene)-steroids4 are useful pre-
HO
&& +
\
(j-sitosterol (1)
'0
\
OH
\
9-hydroxy-3-methoxyandrosta-3,bdien-l7-One (2a)
.&
cursors in the synthesis of 20-oxosteroids a t and 17-(hydroxyacetyl)stroidsin p a r t i ~ u l a r . ~17-(Hydroxy~J acetyl) side chains - typical of corticosteroids - are TosCH,N=C (3) CH20, baseMeOH, conveniently build up in three reaction steps (Scheme 11, starting with 17-oxosteroids such a s 9-hydroxy-3-meth'0 oxyandrosta-3,5-dien-17-one (2a).224Compound 2a is available from 9-hydroxyandrost-4-ene-3,17-dione,b which is a n intermediate of increasing importance, obtained by Me0 fermentation of plant sterols, like p-sitosterol (l),from %O soybeans.'j This paper describes a new synthesis of triamcinolone acetonide (6),which is a widely used anti-inflammatory drug.' The present discussion starts with (2'-R,S)-9hydroxy-3-methoxy- 17-(2-methoxy-3-oxazolin-4-yl)androsta-3,5,16-triene The two carbons - C20 and C21 - of the intended 17-(hydroxyacetyl) group (of 6) are 5a triamcinolone acetonide (6) already present in compound Sa. They have been introduced previously in two steps. First, a formal Knoevenagel-type condensation of tosylmethyl isocyanide side chains; and, (3) a s a handle for the introduction of (TosMIC, 3) with the 17-oxo group of 2a gives 4a, in the C16,C17 oxygen functions in compounds like 6. The which the TosMIC-methylene group provides C20.2c original synthesis of triamcinolone acetonide ( 6 ) by Next, the C21 carbon is introduced by reaction Of 4a with Bernstein et al. is based on cortisol-21-acetate, in which formaldehyde and MeOH to give 5a. The conversion of C20 and C21 are present from the beginning, and which 4a to 5a takes place with concomitant formation of the uses a C l l p - O H , rather t h a n the C9a-OH as in 2a-5a, C16,C17 double bond through allylic deprotonation of for the introduction of the fluoride function at C9.8 4a.2a,dThis double bond is nicely set up for the bisComplete hydrolysis (4N HzSO4, r t , 18 h, Scheme 2) hydroxylation t h a t eventually leads to triamcinolone of 2-methoxy-3-oxazolines 5 was previously shown to give 6. In fact, i t is the purpose of this paper to acetonide 17-(hydroxyacetyl)steroids 8, whereas partial hydrolysis demonstrate, through the synthesis of 6, the versatility (60% aqueous HCOOH, rt, 45 min) gave C2l-formates of the 16-dehydro-l7-(2-methoxy-3-oxazolin-4-yl) moiety 7.2d Bis-hydroxylation (KMn04) of the C16,C17 double of compounds 5 in three ways: (1)a s a precursor, a s well bond to form compounds of type 10 - 12, a s well a s the as a protective group, of 17-(hydroxyacetyl) side chains; introduction of the Sa-fluoro and llp-hydroxy substitu(2) a s a precursor of formyl protected 17-(hydroxyacetyl) ents in the ultimate product 6, requires protection of the C2l-hydroxy group. Normally the acetyl group is used (1)Chemistry of Sulfonylmethyl Isocyanides Part 41;For Part 40 see: ref. 2d. for these purpose^.^ A case in point, due to Bernstein et (2)(a) van Leusen, D.; van Echten, E.; van Leusen, A. M. Recl. Trav. U Z . , ~ is the conversion (KMn04 or Os04) of 3,20-dioxo(b) van Leusen, D.; van Leusen, A. M. Chim. Pays-Bas 1992,111,469. pregna-4,9(11),16-trien-21-y1 acetate to the corresponding Synthesis 1991,531.(c) van Leusen, D.; van Leusen, A. M. Red. Trav. Chim. Pays-Bas 1991,110,393.(d) van Leusen, D.; Batist, J. N. M.; 16a,l7a-dihydroxy derivative. Potentially, the 2-methLei, J.;van Echten, E.; Brouwer, A. C.; van Leusen, A. M. J. Org. Chem. oxy-3-oxazolinyl group of compounds 5 could serve the 1994,59,5650. same goal, i.e. the application as a protected 17-(hy(3)Kochanny, M. J.; VanBrocklin, H. F.; Kym, P. R.; CarlSOn, K E.; O'Neil, J. P.; Bonasera, T. A.;Welch, M. J.; Katzenellenbogen, J. droxyacetyl) group in similar bis-hydroxylations. AlA. J.Med. Chem. 1993,36,1120. though we have previously been able to epoxidize the (4) The letter-indicators in the compound numbers refer to the A,B,C-ring moieties of the steroid structures as depicted in Chart 1. C16,C17 double bond of methoxyoxazolinyl compound 5c Note that this moiety may change during a reaction, for example the (X = i t turned out t h a t the dienol ether group of Sa dienol ether group of the a series will hydrolyse with H30e to the enone is affected by the conditions of bis-hydroxylation (KMn04 function of the b series. Scheme 1 relates to the a series only. Representatives of the other series appear in Table 1 and Scheme 2. ( 5 ) (a) Carruthers, N. I.; Garshasb, S.; McPhail, A. T. J.Org.Chem. 1992,57,961.(b) Batist, J.N. M.; Ma=, A. F.; van Zoest, W. J.; Kapur, J. C. European patent EP 263,569,1987; Chem. A k t r . 1988, 109, 1294603.. (6)Wovcha, M.G.; Antosz, F. J.; Knight, J. C. Komineck, L. A.; Pyke, T. R. Biochim. Biophys. Acta 1978,539,308. See also ref 4. (7)Lednicer, D.;Mitcher, L. A. in The Organic Chemistry of Drug Synthesis. Vol I, Wiley, New York, 1977,p 201.
(8)( a )Bematein, S.; Lenhard, R, H.; Allen, W. S.; Heller, M.; Littell, R.; Stolar, S. M.; Feldman, L. I.; Blank, R. H. J.Am. Chem. SOC.1959, 81, 1689.(b) Heller, M.; Stolar, S. M. ; Bernstein, S. J. Ow. - Chem. 1961,26,5044. (9)Gardi,R.; Ercoli, A. in Organic Reactions in Steroid Chemistry, Fried, J.; Edwards, J. A. Eds., Vol I, Chapter 7,Reinhold, New York 1972.
0022-326319411959-7534$04.50/00 1994 American Chemical Society
J . Org. Chem., Vol. 59, No. 24, 1994 7535
Notes
Scheme 2. Synthesis of Triamcinolone Acetonide (6) from 9-Hydroxy-3-methoxy-17-(2-methoxy3-oxazolin-4-yl)androsta-3,5,16-triene (5a)'
2a
Me0
- -
7-0 N+
'0
4a
(84?0')
Chart 1. Structures of the bB,C-RingMoieties, Denoted by the Letters a-h, of the Steroid Derivatives 2-5 and 7-14
(84%)
do& & d'oJ# '0
a
[5c X = H]
' 0 &=OH
H30el (75%)
r~
b
o&
0
d
10b 10d llb 12d
I
X = OH, Y = OCHO X = H, Y = OCHO X=Y=OH X = H, Y =
7b 7d 8b 9b 9d
Me2CO/Hep7Y0)
x = OH, y = OCHO
EHO. 13b
1
X=H,Y=OCHO X=Y=OH X = OH, Y = OCOCH3 X = H, Y = OCOCH3
14f
1
OCHO
HOBr (92%)
.
€0
base
Br
-16 Y = OCHO I17 Y = O q
15
1-
HF (79%)
@-Fo< w - F 0
