Synthesis of Dimemorfan from Dextromethorphan
217
(
(
m, 1H), 3.78 (s, 3H), 3.84 (m, 1H), 4.12 (q, 2H), 4.31 (m, 1H), 6.71 (m, 1H), 6.82
C
C
d, 1H), 7.00 (t, 1H). MS (ESI, m/z): 330 (MCH ), 659 (2MCH ).
(
C)-3-Trifluoromethylsulfonyloxy-N-ethoxycarbonylmorphinan (4)
To a solution of crude carbamate 3 (85.2 g, 0.26 mol) in dichloromethane (600 mL) in a
ꢀ
round bottom flask (2 L) and cooled to 0 C, was added slowly boron tribromide (97.7 g,
ꢀ
0
.39 mol) so as to maintain the reaction temperature below 5 C. The reaction mixture
was stirred until TLC (hexane-ethyl acetate, 10:1) showed the reaction to be complete.
Then the mixture was transferred slowly to a solution of ammonium hydroxide in ice
(2 L) with stirring. After stirring for 30 min, the resulting mixture was extracted with
dichloromethane (3 L). The organic layer was dried over sodium sulfate, and filtered.
The solution was used without further purification in the next step (crude 82.0 g in 3.5 L).
A solution of the demethylated intermediate in dichloromethane prepared as
ꢀ
described above was charged to a round bottom flask (5 L) and cooled to 0 C. Triethyl-
amine (30.4 g, 0.30 mol) and N-phenyltrifluoromethanesulfonimide (103 g, 0.29 mol)
were added. The reaction mixture was allowed to warm to ambient temperature and
stirred for 5 h, at which point TLC (hexane-ethyl acetate, 10:1) showed complete con-
sumption of the starting material. The mixture was diluted with dichloromethane (1.5 L),
and the solution was washed with 1M HCl (3 L £ 2), saturated sodium bicarbonate (3 L
£
2) and water (3 L £ 2). The organic layer was dried over sodium sulfate, filtered, and
concentrated on a rotary evaporator. The resulting material was used without further puri-
fication to the next step (crude 94.0 g, 81%). An analytical sample was purified by col-
umn chromatography on silica gel (hexane-ethyl acetate, 10:1) to afford 4 as a colorless
1
oil. H NMR (300 MHz, CDCl ): d 0.98 (m, 1H), 1.25–1.35 (m, 7H), 1.44–1.86 (m, 5H),
3
2
.32 (m, 1H), 2.56 (m, 1H), 2.74 (m, 1H), 3.13 (m, 1H), 3.86 (m, 1H), 4.13 (q, 2H), 4.46
C
C
(m, 1H), 7.06 (m, 1H), 7.25–7.38 (m, 2H). MS (ESI, m/z): 448 (MCH ), 895 (2MCH ).
Anal. Calcd for C H F NO S*H O: C, 51.61; H, 5.63; N, 3.01. Found: C, 51.48; H,
2
0
24
3
5
2
5
.61; N, 2.83.
(
C)-3-Methyl-N-ethoxycarbonylmorphinan (5)
A slurry of of bis(triphenylphosphine)palladium chloride (17.5 g, 25 mmol), lithium
chloride (67.8 g, 1.6 mol), and triphenylphosphine (32.8 g, 125 mmol) in dry DMF (1 L)
were charged to a round bottom flask (2 L) under nitrogen. A solution of compound 4
(93.9 g, 0.21 mol) in dry DMF (500 mL) was added. After the reaction mixture was
stirred for 10 min at room temperature, tetramethyltin (75.1 g, 0.42 mol) and 2,6-di-t-
ꢀ
butyl-4-methyl- phenol (0.1 g) were added. The reaction mixture was stirred at 120 C
until TLC (hexane-ethyl acetate, 10:1) showed the reaction to be complete. The volatiles
were removed by evaporation in vacuo, and the residue was partitioned between dichloro-
methane (3 L) and saturated sodium bicarbonate (3 L). The combined organic extracts
were washed with 10% KF (3 L), dried over potassium carbonate, filtered, and concen-
trated on a rotary evaporator. The crude product was purified by column chromatography
on aluminum oxide (hexane-ethyl acetate, 10:1) to afford 50.1 g (76%) of 5 as a colorless
1
oil. H NMR (300 MHz, CDCl ): d 1.01 (m, 1H), 1.21–1.38 (m, 7H), 1.52–1.68 (m, 5H),
3
2
4
.32 (s, 3H), 2.41 (m, 1H), 2.58–2.71 (m, 2H), 3.10 (m, 1H), 3.84 (m, 1H), 4.13 (q, 2H),
C
C
.47 (m, 1H), 6.96 (m, 2H), 7.07 (s, 1H). MS (ESI, m/z): 314 (MCH ), 627 (2MCH ).
Anal. Calcd for C H NO : C, 76.64; H, 8.68; N, 4.47. Found: C, 76.49; H, 8.87; N,
2
0
27
2
4
.35.