Synthesis Etorphine Dihydroetorphine
J. Chin. Chem. Soc., Vol. 58, No. 1, 2011 105
sure to afford a crude product which was purified by col-
umn chromatography on basic alumina to afford the title
compound as a pure white solid (6) (1.00 g, 2.62 mmol,
72%). 1H NMR (400 MHz, CDCl3, d): 6.62-6.60 (d, J = 8.2
Hz, 1H), 6.53-6.51 (d, J = 8.1 Hz, 1H), 5.57-5.55 (d, J = 8.8
Hz, 1H), 5.56 (d, J = 1.2 Hz, 1H), 3.80 (s, 3H), 3.58 (s, 3H),
3.23-3.17 (m, 1H), 2.91-2.90 (t, J = 2.4 Hz, 1H), 2.49-2.38
(m, 2H), 2.34 (s, 3H), 2.23-2.19 (m, 2H), 2.17 (s, 3H),
1.96-1.81 (m, 1H), 1.38-1.31 (m, 1H). 13C NMR (100.6
MHz, CDCl3, d): 209.3, 148.2, 142.0, 136.1, 134.2, 128.1,
126.2, 119.6, 113.6, 95.4, 81.4, 60.1, 56.8, 53.7, 50.8, 47.7,
45.7, 43.7, 43.4, 33.6, 30.7, 30.1, 22.6.
Synthesis of etorphine 9
In a magnetically stirred mixture of the compound 7
(212 mg, 0.5 mmol), PhSH (51.2 mL, 0.5 mmol) and K2CO3
(34.5 mg, 0.25 mmol) in dry NMP (1.0 mL) was heated
220-230 ºC under Ar for 30 minutes. The cold reaction
mixture was neutralized with saturated aqueous NH4Cl and
extracted with CH2Cl2. The combined extracts were dried
over anhydrous magnesium sulfate. Concentration of the
solvents under reduced pressure afforded crude product
which was purified by flash column chromatography using
neutral silica gel as the stationary phase and ethyl ace-
tate-hexane as a mobile phase to yield etorphine (89 mg,
43%). 1H NMR (400 MHz, CDCl3, d): 6.61-6.59 (d, J = 8.1
Hz, 1H), 6.48-6.46 (d, J = 8.0 Hz, 1H), 5.95-5.93 (d, J = 8.8
Hz, 1H), 5.44-5.41 (d, J = 8.9 Hz, 1H), 4.88 (s, 1H), 4.57 (s,
1H), 3.74 (s, 3H), 3.22-3.17 (d, J = 18.5 Hz, 1H), 3.12-3.11
(d, J = 6.5 Hz, 1H), 2.82-2.75 (m, 1H), 2.39 (s, 3H), 2.50-
2.30 (m, 1H), 2.00-1.80 (m, 2H), 1.60-1.10 (m, 2H), 1.99-
1.84 (m, 1H), 1.55-1.15 (m, 3H), 0.90 (s, 3H), 0.82-0.77 (t,
J = 8.1 Hz, 1H), 0.82-0.77 (m, 1H). IR (KBr): 3433, 3242,
2955, 2930, 1716, 1635, 1606, 1455, 1159, 785 cm-1. MS
m/z: 411.2 (M+, 100), 324.2 (83), 297.1 (26), 250.2 (18),
215.1 (96), 164.1 (50), 121.1 (22). HRMS-EI (m/z): [M]+
calcd for C25H33NO4, 411.2410; found, 411.2415.
Synthesis of 19-propylthevinol 7
Bromopropane (1.5 mL, 16.79 mmol) was slowly
added to a suspension mixture of magnesium (0.26 g, 10.5
mmole) in anhydrous ditheyl ether (25 mL) under an argon
atmosphere, and was then refluxed for 30 min. After cool-
ing to room temperature, a solution of compound thevinone
(1.00 g, 2.6 mmol) in benzene (25 mL) was added drop-
wise, and the contents were stirred at room temperature for
1 h. The reaction mixture was poured into a saturated am-
monium chloride solution, and then basified using a satu-
rated sodium bicarbonate solution. The resulting basic so-
lution was extracted with diethyl ether (3 ´ 15 mL) and the
combined extracts were dried over anhydrous magnesium
sulfate. Concentration of the solvents under reduced pres-
sure afforded crude product which was purified by flash
column chromatography using basic Al2O3 as the station-
ary phase and ethyl acetate/hexanes as a mobile phase to
yield pure 19-propylthevinol 7 (0.55 g, 49%) as a white
solid. 1H NMR (400 MHz, CDCl3, d): 6.63-6.61 (d, J = 8.1
Hz, 1H), 6.52-6.50 (d, J = 8.2 Hz, 1H), 5.98-5.96 (d, J = 9.0
Hz, 1H), 5.45-5.43 (d, J = 8.9 Hz, 1H), 4.90 (s, 1H), 4.55 (s,
1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.24-3.19 (d, J = 18.6 Hz,
1H), 3.12-3.11 (d, J = 6.5 Hz, 1H), 2.84-2.79 (m, 1H),
2.40-2.34 (m, 1H), 2.37 (s, 3H), 1.99-1.84 (m, 1H), 1.55-
1.15 (m, 3H), 0.96 (s, 3H), 0.92-0.88 (t, J = 7.2 Hz, 1H),
0.80-0.77 (m, 1H). 13C NMR (100.6 MHz, CDCl3, d):
148.1, 141.7, 135.2, 134.3, 128.4, 125.2, 119.2, 113.7,
98.9, 84.1, 74.9, 60.0, 56.8, 55.2, 47.1, 46.7, 45.5, 43.6,
43.3, 42.8, 33.6, 30.6, 24.1, 22.2, 15.9, 14.8. IR (KBr):
3492, 2936, 2837, 2798, 1625, 1598, 1498, 781, 754 cm-1.
MS m/z: 425.3 (M+, 59), 338.2 (100), 311.1 (33), 296.1
(19), 250.2 (47), 229.1 (31), 189.1 (22), 164.1 (44).
HRMS-EI (m/z): [M] + calcd for C26H35NO4, 425.2566;
found, 425.2568.
4.3. Preparatipn of dihydroetorphine 13
Synthesis of 1-(4,5-epoxy-3,6-dimethoxy-17-methyl-
6,14-ethano-morphinan-7-yl)-ethanone 10
A 10% of Pd/C (60 mg, 10 wt%) was weighed in a
Parr glass vessel and carefully wet with methanol. A solu-
tion of 6 (0.10 g, 0.26 mmol) in methanol (5 mL) was added
and then flushed three times with hydrogen gas. The vessel
was finally charged with hydrogen gas (60 psi) and shaken
mechanically for 56 h. After completion of the reaction
(TLC, 12 h), the reaction mixture was filtered through a
pad of celite and washed with excess methanol (2 × 5 mL).
The filtrate was concentrated under reduced pressure to af-
ford a crude product which was purified by using basic alu-
minum oxide as the stationary phase and ethyl acetate-hex-
1
anes as mobile phase (1:4) to give 10 (45 mg, 45%). H
NMR (400 MHz, CDCl3, d): 6.71-6.69 (d, J = 8.1 Hz, 1H),
6.59-6.57 (d, J = 8.1 Hz, 1H), 4.47 (s, 1H), 3.86 (s, 3H),
3.43 (s, 3H), 3.11-3.01 (m, 2H), 2.72-2.65 (m, 2H), 2.44-
2.32 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.05-1.97 (m, 1H),
1.78-1.62 (m, 2H), 1.55-1.45 (m, 2H), 1.33-1.21 (m, 1H),
0.78-0.64 (m, 1H). 13C NMR (100.6 MHz, CDCl3, d):
210.8, 146.7, 141.8, 132.4, 128.7, 119.2, 113.9, 94.6, 61.3,