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Vol. 52, No. 8
water (20 mlꢀ2) and then dried over Na2SO4. Solvent was evaporated in
vacuo to get solid crude material 0.94 g (mp 181—186 °C). The crude prod-
uct was purified on silica gel column (hexane : ethyl acetate 40 : 60 (v/v) to
obtain pure 17b-hydroxy-17a-methylandrostan-3-one (0.88 g, 88%) mp
190—192 °C, [a]D25 ꢁ10.5° (CHCl3). IR (KBr) cmꢂ1: 3433, 1699, 1150. H-
1
NMR (400 MHz, CDCl3) d: 2.38—2.23 (3H, overlapping m), 2.11—2.09
(2H, m), 1.81—1.70 (3H, overlapping m), 1.61—1.24 (7H, overlapping m),
1.21 (3H, s), 1.03 (3H, s), 0.91 (1H, m), 0.87 (3H, s), 0.71 (1H, dt, Jꢃ3.68,
14.6 Hz). 13C-NMR (CDCl3) d: 212.0 (C3), 81.6 (C17), 53.7 (C13), 50.4
(C4), 46.7 (C9), 45.4 (C14), 44.6 (C2), 38.9 (C10), 38.5 (C5), 38.1 (C16),
36.2 (C1), 35.7 (C8), 31.5 (C7), 31.3 (C12), 28.8 (C6), 25.7 (C11), 23.2
(C20), 21.0 (C18), 13.9 (C15), 11.4 (C19), Anal. Calcd for C20H32O2: C,
78.90; H, 10.59. Found: C, 78.88; H, 10.52. FABꢁ-MS m/z: 305 (Mꢁ1).
Synthesis of 17b-Hydroxy-17a-methyl-D1-androsten-3-one (3) from
17a-Methyl Androstan-3b,17b-diol (1) Using 2-Iodoxy Benzoic Acid
(IBX) 17a-Methylandrostan-3b,17b-diol (1) (1 g, 3.27 mmol) was dis-
solved in 15 ml of DMSO. To this solution 2-iodoxy benzoic acid (IBX)
(2.28 g, 8.16 mmol) was added in one lot. The solution was heated at 65 °C
for 24 h and reaction was monitored by TLC. The reaction mixture was
cooled to room temperature and diluted with 50 ml of diethyl ether. The or-
ganic layer was separated and washed with 5% NaHCO3 solution (20 mlꢀ2),
water (20 mlꢀ2) and then dried over Na2SO4. Solvent was evaporated in
vacuo to get 0.90 g of brown colored solid crude material (91%, mp 125—
130 °C). The crude product was purified by column chromatography (Silica
gel, eluted with hexane/ethyl acetate 50 : 50 (v/v)) to obtain pure 17b-hy-
droxy-17a-methyl-D1-androsten-3-one (3) (0.72 g, 74%), mp 154—155 °C
(lit.5) mp 153—154 °C, [a]D25 ꢁ23° (EtOH). IR (KBr) cmꢂ1: 3517, 3030,
1663, 1066. 1H-NMR (400 MHz, CDCl3) (d: 7.15 (1H, d, Jꢃ10.04 Hz), 5.85
(1H, d, Jꢃ10.24 Hz), 2.37 (1H, dd, Jꢃ3.4, 14.6 Hz), 2.22 (1H, dd, Jꢃ4.16,
14.6 Hz), 1.84—1.70 (6H, overlapping m), 1.59—1.23 (8H, overlapping m),
1.22 (3H, s), 1.03 (3H, s), 0.89 (3H, s). 13C-NMR (CDCl3) d: 200.1 (C3),
158.3 (C1), 127.3 (C2), 81.4 (C17), 50.5 (C13), 49.9 (C4), 45.6 (C9), 44.3
(C14), 40.9 (C10), 38.9 (C5), 38.8 (C16), 36.4 (C8), 31.4 (C7), 30.9 (C12),
27.4 (C6), 25.8 (C11), 23.1 (C20), 20.8 (C18), 14.0 (C15), 12.9 (C19). Anal.
Calcd for C20H30O2: C, 79.42; H, 10.00. Found: C, 79.39; H, 9.98. FAB-MS:
302.224 (Mꢁ). 10% of Methyltestosterone 4 was present as by product. mp
161—162 °C (lit. 161—165 °C).
Synthesis of 17b-Hydroxy-17a-methylandrostan-3-one (2) Using
NaOCl/TBABr 17a-Methylandrostan-3b,17b-diol (1) (1 g, 3.2 mmol)
was taken in 14 ml of acetic acid (glacial). Added tetrabutyl ammonium bro-
mide (2 mg) and cooled the reaction mixture to 15 °C in water bath and avoiding the multiple step of oxidation, bromination and de-
added sodium hypochlorite 0.5 M (8.4 ml) drop-wise while maintaining the
temperature of waterbath 15—18 °C. Stirred the reaction mixture at same
temperature for 16 h. After completion of reaction (TLC) evaporated the
acetic acid in vacuo and then coevaporated with ethanol/water (70 : 30 v/v).
The solid was crystallized using ethanol : water (70 : 30) as a solvent to get 2
(0.67 g, 68%), mp 188—190 °C.
Synthesis of 7b-Hydroxy-17a-methylandrostan-3-one (2) Using
H2O2/Na2WO4/CTMAHSO4 17a-Methylandrostan-3b,17b-diol (1) (1 g,
starting material and directly converted it into 17b-hydroxy-
3.2 mmol) was taken in 80 ml of toluene. Added Na2WO4 (0.25 g) and
cetyltrimethylammonium hydrogensulphate (CTMAHSO4) (0.28 g). Cooled
the reaction mixture in ice bath and added H2O2 (30% solution) (4.2 ml,
4.8 mmol) drop-wise with fast mechanical stirring (1000 rpm). After addi-
tion of H2O2, the reaction mixture was slowly heated to 95 °C. Reaction mix-
ture was stirred at same temperature for 24 h. After completion of reaction
ferent approach for the synthesis of 3.6) They first brominated
(TLC), toluene was completely removed in vacuo. Solid product obtained
Chart 2. Oxidation of 17a-Methylandrostan-3b,17b-diol 1 with IBX (2.5
Equivalent)
larly enticing. Aqueous H2O2 is an ideal oxidant when cou-
pled with a tungstate complex and quaternary ammonium hy-
drogen sulfate as an acidic phase transfer catalyst. Hence we
have used NaOCl and H2O2/Na2WO4 under phase transfer
conditions for the oxidation of 1.
17a-Methylandrostan-3b,17b-diol (1) was obtained by the
reaction of MeMgI with epiandrosterone using a standard
procedure.17) 1 on oxidation with iodoxybenzoic acid in di-
methyl sulfoxide gave 17b-hydroxy-17a-methylandrostan-3-
one (2) in very high yield in 2 h. When the same reaction was
done with higher amount of IBX (2.5 equivalent), dehydro-
genated product 17b-hydroxy-17a-methyl-D1-androsten-3-
one (3) is obtained in high yield. In this method, 10—15%
methyltestosterone 4 is also formed (Chart 2). The products
3 and 4 were isolated by column chromatography. Formation
of 3 in major amount in this method indicate that after oxida-
tion of hydroxyl group the abstraction of hydrogen (dehydro-
genation) from a,b-position to carbonyl group by bulky 2-io-
doxybenzoic acid take place from the less sterically hindered
side of the reactant. The approach of 2-iodoxybenzoic acid to
carbon C1 and C2 will be comparatively easier to that of C4
and C5. It is interesting that by this reagent we can directly
convert 17a-methylandrostan-3b,17b-diol 1 to 17b-hydroxy-
17a-methyl-D1-androsten-3-one (3) in single step reaction,
hydrobromination and thus obtaining 3 in much higher yield
and easier way.
Desai et al. have reported the synthesis of 17b-hydroxy-
17a-methyl-D1-androsten-3-one using IBX as reagent for
dehydrogenation.5) They have started from mestanolone
while we have used 17a-methylandrostan-3b,17b-diol as
17a-methyl-D1-androsten-3-one. Hence one step is reduced
in our synthetic procedure and secondly 17a-methyl an-
drostan-3b,17b-diol is less costly. Reduction of one step
leads to increase in overall yield. Cabaj et al. have used a dif-
the mestanolone regioselectively and then dehydrobromi-
nated the intermediate to give product 3. The earlier reported
procedures are multiple step reactions and molecular
bromine, a highly harmful chemical was used for the synthe-
sis. The overall yield of product 3 was low. In this report
was crystallized from water : t-butanol (3 : 50 v/v), first refluxing the mixture
to clear solution and then cooling at 4 °C to afford 2 (3.65 g, 80%) mp 190—
192 °C.
Result and Discussion
Despite their ubiquity and utility in organic chemistry the (Chart 2), we have eliminated the multiple steps, used mild
synthesis of Oxandrolone is tedious and involve challenging and environment friendly reagents and overall yield is higher
transformations. Several methods to effect this operation to that of earlier reports.
have been developed over the years. Most of these protocols
Oxidation of 1 with sodium hypochlorite has been re-
rely on highly toxic reagents and laborious low yielding pro- ported with very low yield of the mestanolone.18) Lee et al.
cedures. Our recent explorations for a cheap and non-toxic used the sodium hypochlorite with phase transfer catalyst for
oxidizing reagent led us to propose the IBX as a suitable can- the oxidation of alcohols and amines and has reported high
didate to effect the oxidation of 1 to 2 and 3. Since IBX is yield of the oxidized product.19) Oxidation of 1 with sodium
known to oxidize alcohols, the prospect of accomplishing hypochlorite under phase transfer condition gave the 100%
multiple oxidative processes in one operation was particu- conversion of 1 but after crystallization the mestanolone was