JOURNAL OF CHEMICAL RESEARCH 2017 269
disappeared (TLC, benzene:acetone = 12:1). The mixture was cooled
to 20 °C and stirring was maintained for 1 h after water (100 mL) was
added. The reaction mixture was poured into a solution of ice and
sodium carbonate (0.1%, 5000 mL). The precipitate was collected
by centrifugation, washed with absolute alcohol (100 mL) and dried
at 30–35 °C to give compound 3 as: Yellow solid; m.p. 114–118 °C
(decomposed); yield 527.4 g (96%); 1H NMR (400 MHz, CDCl3):
Δ 5.49 (s, 1H), 5.24–5.25 (m, 1H), 5.15 (s, 1H), 3.73–3.81 (m, 2H),
2.41–2.59 (m, 4H), 1.87–2.39 (m, 7H), 1.54–1.64 (m, 3H), 1.22–1.35
(m, 3H), 1.14 (s, 3H), 0.86 (s, 3H); 13C NMR (100.6 MHz, CDCl3): Δ
154.9, 144.9, 139.2, 124.3, 116.8, 115.0, 98.9, 62.4, 49.9, 46.4, 37.3, 36.3,
33.5, 32.3, 31.9, 27.4, 25.7, 22.9, 14.8, 14.0, 13.8; MS-ESI (m/z): 313.2
[M + H]+.
= 4.0, 1H), 4.91 (d, J = 8.0, 1H), 4.77 (d, J = 8.0, 1H), 2.46–2.58 (m,
1H), 2.44–2.45 (m, 2H), 2.24–2,37 (m, 6H), 2.18 (s, 3H), 2.08–2.17
(m, 2H), 2.09 (s, 1H), 1.98–2.01 (m, 1H), 1.53–1.55 (m, 1H), 1.34 (s,
3H), 1.11–1.15 (m, 1H), 0.91 (s, 3H); 13C NMR (100.6 MHz, CDCl3): Δ
199.3, 192.6, 170.5, 169.5, 154.2, 145.3, 143.7, 124.2, 119.3, 68.5, 51.1,
47.0, 41.2, 40.9, 38.2, 35.1, 34.4, 33.8, 32.8, 31.9, 26.3, 20.6, 18.5, 16.0.
MS-ESI (m/z): 382.5 [M + H]+.
Synthesis of 21-acetoxy-16 (17) α-epoxy-16-methylpregna-4,9(11)-
diene-3,20-dione (7)
Compound 6 (100 g, 0.261 mol) was dissolved in CH2Cl2 (500 mL) and
the solution was cooled to −5–0 °C. m-CBPA (54.1 g, 0.314 mol) was
added in five portions every 20 min, then the mixture was stirred for
6 h at 0°C (TLC, benzene:acetone = 6:1) and then filtered. The solution
was washed with sodium carbonate solution (1%, 300 mL) and the
CH2Cl2 was removed under reduced pressure. Dioxane (300 mL) was
added and the solution of 7 was used directly for the next step.
Synthesis of 3-ethoxy-16α-methylandrosta-3,5,9(11)-diene-17-one (4)
A solution of diisopropylamine (148.6 mL, 1.06 mol) and HMPA
(80 mL, 0.43 mol) in tetrahydrofuran (400 mL) was cooled to
−40°C under argon, and a solution of n-butyllithium in hexanes (1.6 M,
60 mL, 1.5 equiv.) was added slowly (<−20 °C) over 0.5–1.0 h. Then,
the resulting LDA solution was cooled to −40 °C, 3 (200 g, 0.64 mol)
was added in three portions and methyl bromide (100 g, 1.05 mol,
dissolved in 100 mL THF) was added (<−40 °C). The mixture was
stirred for 3 h from −40 °C to r.t. After reaction completion (TLC,
benzene:acetone = 12:1), water (50 mL) was added to quench the
reaction followed by acetic acid (30 mL). The organic solvent was
evaporated under reduced pressure at 50 °C, more water (500 mL)
was pumped in and the slurry was stirred for 0.5 h at 0–5 °C. The
precipitate was collected and washed with water, added to methanol
(200 mL) and the slurry was heated to 40–45 °C for 30 min, cooled to
0–5 °C for another 1 h, filtered and dried at 30–35 °C to give product 4
as: White solid; m.p. 123–125 °C (decomposed); yield 192.2 g (92%);
1H NMR (400 MHz, CDCl3): Δ 5.50–5.51 (m, 1H), 5.27 (s, 1H), 5.16
(s, 1H), 3.73–3.83 (m, 2H), 2.23–2.58 (m, 3H), 1.58–2.18 (m, 10H),
1.37–1.48 (m, 3H), 1.10–1.26 (m, 6H), 0.88 (s, 3H); 13C NMR (100.6
MHz, CDCl3): Δ 155.0, 145.0, 139.4, 117,0, 115.3, 99.0, 62.5, 47.3, 47.1,
40.1, 37.4, 33.9, 33.3, 32.3, 32.0, 31.3, 31.1, 27.4, 25.8, 17.0, 14.8, 14.3;
MS-ESI (m/z): 327.2 [M + H]+.
Synthesis of 21-acetoxy-17α-hydroxy-16-methylenepregna-4,9(11)-
diene-3,20-dione (8)
A solution of 7 in dioxane was stirred at r.t. (25–30 °C). Aqueous
hydrobromic acid (40%, 100 mL) was added dropwise into P2O5 and
anhydrous hydrobromic acid was bubbled into the solution over 1 h
(<35 °C). The solution was stirred for another 4 h and then cooled to
0–5 °C. Pyridine (40 mL, 0.523 mol) was added dropwise at 0–5 °C
to neutralise the reaction (TLC, benzene:acetone = 6:1), the resulting
mixture (pH = 6–7) was poured into ice water (1000 mL) and the slurry
was filtered at 0–5 °C. The wet product was added to methanol (100
mL) and the slurry was stirred at r.t. for 30 min, cooled to 0–5 °C for
another 1 h, filtered and dried at 30–35 °C to yield compound 8 (with
the isomer 18) as: Yellow solid; yield 60.4 g (two steps, 58%).
Synthesis of 21-acetyloxy-17α-hydroxy-16β-methylpregna-4,9(11)-
diene-3,20-dione (9)
Compound 8 (20 g, 0.05 mol) was dissolved in anhydrous ethyl acetate
(400 mL). A rhodium catalyst (Wilkinson’s catalyst RhCl(PPh3)3,
0.60 g) was added to the mixture under nitrogen. The reaction mixture
was then stirred under hydrogen (1 atm, hydrogen balloon) at 60–65 °C
for 6–8 h. The solution was washed with water (200 mL) and the ethyl
acetate was removed under reduced pressure. Crystallisation at 0–5 °C
gave compound 9 as: Yellow solid; m.p. 208–212°C (lit.19 210–214 °C);
yield 16.5 g (82%); 1H NMR (400 MHz, CDCl3): Δ 5.72 (s, 1H), 4.56
(d, J = 8.2, 1H), 4.32 (d, J = 8.2, 1H), 3.35 (m, 2H), 2.46–2.58 (m, 1H),
2.45–2.48 (m, 4H), 2.11–2.32 (m, 8H), 1.90 (m, 1H), 1.61–1.72 (m, 4H),
1.39 (s, 3H), 1.09 (d, J = 3.2, 3H), 1.08 (m, 1H), 0.96 (s, 3H); 13C NMR
(100.6 MHz, CDCl3): Δ 202.8, 199.5, 171.3, 124.1, 89.7, 65.3, 60.3, 50.4,
48.2, 48.1, 44.7, 44.6, 39.6, 35.9, 34.6, 34.0, 31.4, 31.2, 29.5, 26.0, 23.7,
23.6, 20.1, 17.7; MS-ESI (m/z): 401.1 [M + H]+.
Synthesis of 20-chloro-3-keto-16α-methylpregna-4,9(11),17(20)-
triene-21-al (5)
Anhydrous THF (400 mL) and 2-chloro-1-ethoxyethylene (36 g,
0.338 mol) were cooled to −45 °C under nitrogen. n-BuLi in hexanes
(400 mL) was added over 30 min (−30 °C). The mixture was stirred
for about 15 min. Compound 4 (100 g, 0.306 mol) was added at once
and the solution was stirred for 3 h at approximately −40–−45 °C The
mixture was then poured into hydrochloric acid (6 N, 300 mL) and
stirring was maintained at 15–20 °C for 2 h (TLC, benzene:acetone
= 10:1). The THF was removed under reduced pressure and water
(500 mL) was added. The slurry was filtered at 5–10 °C and
recrystallisation from ethyl acetate gave compound 5 as: White solid;
m.p. 145–147 °C; yield 101.1 g (92%); 1H NMR (400 MHz, CDCl3): Δ
9.76 (s, 1H), 5.75 (s, 1H), 5.55 (d, J = 4.0, 1H), 3.59 (m, 1H), 2.89–2.94
(dd, J1 = 7.9, J2 = 2.9, 1H), 2.11–2.59 (m, 10H), 1.73 (m, 4H), 1.74 (s,
3H), 1.25–1.27 (m, 4H), 1.02 (s, 3H); 13C NMR (100.6 MHz, CDCl3):
Δ 199.2, 184.6, 175.6, 169.2, 145.3, 126.5, 124.3, 118.9, 48.3, 47.6, 46.4,
41.2, 41.1, 38.4, 36.0, 35.9, 33.9, 32.7, 32.6, 32.0, 26.3, 14.4. MS-ESI
(m/z): 359.1 [M + H]+.
Synthesis of 21-acetoxy-17α-hydroxy-9β,11β-epoxy-16β-methylpregna-
4-ene-3,20-dione (10)
Compound 9 (20 g, 0.05 mol) was suspended in acetone (300 mL)
and H2O (30 mL) at 0 °C, and HClO4 (70%, 1.52 g) was added to the
mixture. This was followed by the addition of DBH at 0–5 °C over
about 30 min. The mixture was stirred for 2 h at 0–5 °C. Potassium
carbonate solution (20%, 200 mL) was then added dropwise and
the temperature of the slurry was allowed to rise to r.t. (25–30 °C)
for 2 h (TLC, benzene:acetone = 4:1). Acetic acid was then added to
modify the pH to 6–7. The solvents were removed by distillation under
reduced pressure, and the resulting slurry was cooled to about 0 °C,
filtered and dried at 50 °C to provide compound 10 as: White solid;
m.p. 212–214 °C (lit.8 212–216 °C); yield 19.9 g (96%); 1H NMR (400
MHz, CDCl3): Δ 5.75 (s, 1H), 4.99 (d, J = 7.6, 1H), 4.80 (d, J = 7.6,
1H), 3.40 (s, 1H), 3.01 (s, 1H), 2.46–2.47 (m, 3H), 2.13–2.15 (m, 6H),
1.83–1.87 (m, 2H), 1.56–1.62 (m, 3H), 1.40 (s, 3H), 1.09–1.01 (m, 4H),
0.9 (s, 3H); 13C NMR (100.6 MHz, CDCl3): Δ 204.7, 199.4, 170.0, 170.8,
124.2, 89.0, 69.4, 65.3, 65.2, 60.4, 48.6, 48.2, 44.9, 39.6, 35.9, 34.7, 31.4,
31.0, 29.5, 26.1, 23.7, 20.7, 20.0, 17.3; MS-ESI (m/z): 417.2 [M + H]+.
Synthesis of 21-acetoxy-16-methylpregna-4,9(11),16-triene-3,20-dione
(6)
Anhydrous sodium acetate (60 g, 0.73 mol) and DMF (300 mL)
containing acetic anhydride (12 mL, 0.13 mol) were stirred and heated
to 115 °C under nitrogen. Compound 5 (100 g, 0.279 mol) dissolved in
DMF (300 mL) was added dropwise over 0.5 h, and the mixture was
stirred for 1.5 h at 115 °C (TLC, benzene:acetone = 10:1). Some of the
DMF was removed under reduced pressure and the remaining solution
was poured into ice water (1000 mL). The precipitate was collected by
filtration to give compound 6 as: Brown solid; m.p. 166–169 °C; yield
1
93.8 g (88%); H NMR (400 MHz, CDCl3): Δ 7.73 (s, 1H), 5.51 (d, J