1424
Vol. 57, No. 12
bined organic extracts were dried and concentrated to afford pure product 10
4H), 1.83—1.80 (q, Jꢃ7.4 Hz, 2H), 1.71—1.65 (m, 2H), 0.95—0.91 (t,
Jꢃ7.4 Hz, 3H). 13C-NMR (100.6 MHz, CDCl3) d: 174.6, 141.3, 138.0,
131.3, 129.2, 128.5, 128.2, 127.7, 127.0, 70.5, 63.0, 61.6, 58.0 (m), 50.0,
33.1, 30.7, 9.5.
as colorless solid (90 mg, 93%). mp 120—122 °C. IR (KBr): 3160, 2923,
2826, 2345, 2065, 1655, 1594, 1486, 1373, 1250, 1057, 769, 705, 692 cmꢀ1
.
1H-NMR (400 MHz, CDCl3) d: 7.42—7.37 (m, 3H), 7.16—7.14 (m, 2H),
7.11—7.10 (dd, Jꢃ5.1, 1.1 Hz, 1H), 6.91—6.89 (dd, Jꢃ5.1, 3.4 Hz, 1H),
6.79—6.78 (d, Jꢃ2.8 Hz, 1H), 5.17 (b, 1H), 4.04—4.03 (d, Jꢃ3.8 Hz, 2H),
2.98—2.94 (t, Jꢃ7.4 Hz, 2H), 2.81—2.78 (m, 2H), 2.63—2.60 (t, Jꢃ8.2 Hz,
2H), 2.30—2.24 (t, Jꢃ11.7 Hz, 2H), 2.07—2.04 (dd, Jꢃ13.1, 1.8 Hz, 2H),
1.91—1.86 (q, Jꢃ7.4 Hz, 2H), 1.65—1.60 (dt, Jꢃ12.2, 2.6 Hz, 2H), 0.94—
0.98 (t, Jꢃ7.4 Hz, 3H). 13C-NMR (100.6 MHz, CDCl3) d: 176.7, 142.5,
140.5, 130.2, 129.3, 128.5, 126.6, 124.6, 123.5, 66.7, 63.77, 59.8, 50.4,
32.7, 30.6, 27.8, 9.6.
2-(Thiophen-2-yl)ethyl Methanesulfonate To a solution of 2-(thio-
phen-2-yl)ethanol (3.00 g, 23.7 mmol) in CH2Cl2 (45 ml) in a 250 ml flask
was added triethylamine (3.63 ml, 26.0 mmol) and the clear solution was
stirred at room temperature for 30 min. It was then cooled to 0—5 °C with
ice-salt bath and methanesulfonyl chloride (1.92 ml, 24.9 mmol) was added
dropwise in 10 min. The resulting white slurry was then allowed to warm to
room temperature. After completion of the reaction (TLC, 1 h), NaHCO3 so-
lution (30 ml) was added and the organic layer was separated. The aqueous
layer was extracted again with CH2Cl2 (25 ml). The combined organic ex-
tracts were dried over MgSO4, filtered and concentrated under reduced pres-
sure to afford 2-(thiophen-2-yl)ethyl methanesulfonate as a colorless liquid
Acknowledgment The authors thank National Bureau of Controlled
Drugs, Department of Health, Taiwan, Republic of China, for financially
supporting this work under Contract DOH97-NNB-1002, and National Sci-
ence Council of the Republic of China (NSC 96-2811-M-259-011) fellow-
ship for supporting this work (Dr. S. Srimurugan).
(4.53 g, 94%). IR (KBr): 3650, 2938, 1353, 1169, 959, 903, 799, 704 cmꢀ1
.
1H-NMR (400 MHz, CDCl3) d: 7.20—7.19 (dd, Jꢃ5.1, 1.2 Hz, 1H), 6.97—
6.95 (dd, Jꢃ5.1, 3.5 Hz, 1H), 6.92—6.91 (m, 1H), 4.44—4.40 (t, Jꢃ6.6 Hz,
2H), 3.29—3.26 (t, Jꢃ6.6 Hz, 2H), 2.92 (s, 3H). 13C-NMR (100.6 MHz,
CDCl3) d: 138.2, 127.1, 126.3, 124.6, 69.8, 37.4, 29.8.
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Norsufentanil (8) A mixture of 10% Pd/C (500 mg, 10 wt%) and 20%
Pd(OH)2/C (500 mg, 10 wt%) were weighed in a Parr glass vessel and care-
fully wet with methanol. A solution of 7 (5.30 g, 14.8 mmol) in methanol
(32 ml) was added and then flushed three times with hydrogen gas. The ves-
sel was finally charged with hydrogen gas (60 psi) and shaken mechanically
for 12 h. After completion of the reaction (TLC, 12 h), the reaction mixture
was filtered through a pad of celite and washed with excess methanol
(2ꢂ30 ml). The filtrate was concentrated under reduced pressure to afford
the product as a colorless liquid (3.68 g, 92%) which was immediately used
for the final step. The same procedure was followed for debenzylation of 11,
12 and 13. [2H3]-7 was reacted in a similar fashion to afford [2H3]-8.
Sufentanil (9) To a solution of norsufentanil 8 (4.28 g, 15.5 mmol) in
acetonitrile (45 ml) in a 100 ml two-neck flask with a condenser were added
K2CO3 (214 mg, 1.6 mmol), 2-(thiophen-2-yl)ethyl methanesulfonate
(3.51 g, 17.1 mmol) and KI (77 mg, 0.47 mmol). Et3N (4.32 ml, 31.0 mmol)
was added to the slurry at room temperature and the contents were heated
under reflux overnight. After completion of the reaction, the flask was
cooled and the solvent was pumped off under reduced pressure. Water was
added and the mixture was extracted with EtOAc (3ꢂ20 ml). The combined
organic extracts were dried over MgSO4, filtered and concentrated under re-
duced pressure to afford crude product as a colorless liquid. Purification by a
short path column chromatography on alumina using EtOAc–hexane as a
mobile phase afforded pure product 9 which crystallized on cooling in an
ice-bath to colorless solid (4.80 g, 80%). [2H3]-8 was reacted in a similar
fashion to afford [2H3]-9. mp 103—104 °C; GC, tRꢃ28.2 min. MS (EI,
70 eV): m/z (%): 384.2 (1), 357.2 (1), 341.2 (1), 289.1 (100), 187.1 (2),
158.1 (4), 140.1 (23), 110.1 (11), 93.1 (24). IR (KBr): 3082, 2982, 2920,
2809, 2728, 1655, 1488, 1358, 1251, 1117, 774, 702 cmꢀ1 1H-NMR
.
(400 MHz, CDCl3) d: 7.30—7.23 (m, 5H), 7.05—7.03 (dd, Jꢃ5.1, 1.1 Hz,
1H), 6.85—6.82 (dd, Jꢃ5.1, 3.4 Hz, 1H), 6.73—6.72 (dd, Jꢃ3.4, 0.6 Hz,
1H), 4.03 (s, 2H), 3.38 (s, 3H), 2.92—2.88 (t, Jꢃ7.4 Hz, 2H), 2.64—2.61
(m, 2H), 2.55—2.52 (t, Jꢃ7.4 Hz, 2H), 2.20—2.15 (m, 4H), 1.81—1.76 (q,
Jꢃ7.3 Hz, 2H), 1.71—1.65 (m, 2H), 0.91—0.87 (t, Jꢃ7.3 Hz, 3H). 13C-
NMR (100.6 MHz, CDCl3) d: 174.6, 142.7, 141.2, 131.3, 128.6, 127.8,
126.6, 124.6, 123.4, 70.3, 61.5, 60.1, 59.2, 50.2, 33.2, 30.7, 27.8, 9.5.
Data for [2H3]-9: mp 103—104 °C; GC, tRꢃ27.5 min. MS (EI, 70 eV): m/z
(%): 387.2 (1), 341.2 (1), 292.1 (100), 187.1 (2), 158.1 (3), 143.1 (20),
111.1 (12), 93.1 (10). IR (KBr): 2934, 2811, 2351, 2181, 2052, 1647, 1594,
1
1491, 1374, 1250, 1130, 703 cmꢀ1. H-NMR (400 MHz, CDCl3) d: 7.34—
7.26 (m, 5H), 7.10—7.09 (dd, Jꢃ4.4, 0.6 Hz, 1H), 6.90—6.88 (dd, Jꢃ5.1,
3.5 Hz, 1H), 6.78—6.77 (m, 1H), 4.06 (s, 2H), 2.97—2.93 (t, Jꢃ7.5 Hz,
2H), 2.69—2.65 (m, 2H), 2.61—2.57 (t, Jꢃ7.6 Hz, 2H), 2.26—2.18 (m,
4H), 1.85—1.80 (q, Jꢃ7.4 Hz, 2H), 1.74—1.71 (m, 2H), 0.95—0.91 (t,
Jꢃ7.4 Hz, 3H). 13C-NMR (100.6 MHz, CDCl3) d: 174.7, 142.7, 141.2,
131.3, 128.6, 127.8, 126.6, 124.6, 123.4, 70.4, 61.5, 60.0, 58.0 (m, very
weak signal), 50.1, 33.1, 30.7, 27.8, 9.5.
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98—107 (2006).
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Thijsen J., Drug Metab. Dispos., 15, 905—913 (1987).
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matogr. B, 804, 375—387 (2004).
Desmethylsufentanil (10) Sufentanil 9 (100 mg, 0.26 mmol) was dis-
solved in dry CH2Cl2 (2 ml) in a two-neck flask under argon atmosphere.
The reaction mixture was cooled to ꢀ78 °C and BBr3 (0.26 ml, 1.0 M solu-
tion) was added dropwise for a period of 15 min. The contents were further
stirred at the same temperature for 15 min and warmed to room temperature
and stirred 3 h. After the completion of the reaction, water was added fol-
lowed by 2 N NaOH solution and extracted with CH2Cl2 (2ꢂ5 ml). The com-