550
TU ET AL.
vacuum to give the crude product. The pale yellow crystal 7
3.10 | D9‐1‐[bis‐3′,5′‐(N,N‐dimethylcarbamoyloxy)‐
phenyl]‐2‐(t‐butylamino)ethanone (12)
(6.5 g, 70.2%) was obtained through recrystallization by
1
isopropyl ether. H NMR (600 MHz, CDCl3) δ ppm 4.33
To a stirred solution of 11 (3.7 g, 10.0 mmol) in chloro-
form (40 mL) at reflux state was added the D9‐tert‐
Butylamine (1.6 g, 20.0 mmol) over 30 minutes. The
reaction mixture was stirred for 6 hours, while white solid
generating. Then, the mixture was filtered, and the filtrate
was washed with water, which was dried over anhydrous
magnesium sulfate and concentrated in vacuum to give
solid. The solid was washed with isopropyl ether to give
(s, 2H), 5.24 (s, 2H), 8.03 (d, J = 1.5 Hz, 1H), 8.09
(d, J = 1.8 Hz, 1H). LC‐MS: [M − H]− m/z 318.
3.7 | D9‐1‐(3‐amino‐5‐chloro‐4‐trifluoromethylphenyl)‐
2‐(t‐butylamino)ethanone (8)
A dry 100 mL 3‐necked flask with a reflux condenser was
charged with 7 (2.0 g, 6.2 mmol) and chloroform (25 mL).
The solution was heated to 65°C and remained 30 minutes;
then the D9‐tert‐Butylamine (1.0 g, 12.0 mmol) was
injected slowly over 30 minutes. The reaction mixture
was stirred for 2 hours while some white solid was gener-
ated. After cooling, the mixture was filtered and to filtrate
was added an isopropanol solution of hydrochloric acid
giving a turbid solution. The pale yellow solid powder
8 (1.1 g, 27.5% based on D9‐tert‐Butylamine) was obtained
by filtration. 1H NMR (600 MHz, CDCl3) δ ppm 4.62
(s, 2H), 8.12 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.2 Hz, 1H).
LC‐MS: [M + H]+ m/z 318.
1
12 (2.4 g, 31.5 % based on D9‐tert‐Butylamine). H NMR
(600 MHz, CDCl3) δ ppm 2.98 ~ 3.07 (s, 12H), 3.77
(s, 2H), 7.16 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 2H).
LC‐MS: [M + H]+ m/z 375.
3.11 | D9‐Bambuterol (13)
To a solution of 12 (2.4 g, 6.3 mmol) and water (20 mL) in
ethanol (20 mL) at 0°C was added sodium borohydride
(1.0 g, 25.2 mmol) gradually. The reaction mixture was stirred
for 4 hours at r.t and then added water (30 mL) and ethyl
acetate (40 mL). The layers were separated, and the organic
layers was washed with water (20 mL × 2), dried over anhy-
drous magnesium sulfate, and concentrated in vacuum to yield
white solid 13 (1.9 g, 81.3%). 1H NMR (600 MHz, CDCl3) δ
ppm 2.94 ~ 3.02 (m, 12H), 2.85 ~ 3.20 (m, 2H), 5.35 (s, 1H),
6.90 (t, J = 2.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 2H), 8.09
(br, 1H), 9.80 (br, 1H). LC‐MS: [M + H]+ m/z 377.
3.8 | D9‐Mabuterol (9)
To a stirred suspension of 8 (1.1 g, 3.5 mmol) and water
(5 mL) in methanol (10 mL), sodium borohydride (0.6 g,
15.9 mmol) in water (1 mL) was added gradually at 0°C.
The system was stirred for 2 hours at r.t, adjusted to acid-
ity by 6 N hydrochloric acid. After stirring overnight,
sodium borohydride (0.6 g, 15.9 mmol) in water (1 mL)
was added slowly into the solution. Adjusted the pH to
2 ~ 5 by 6 N hydrochloric acid, the system was filtered
and to the filtrate was added ammonia until no white
precipitate appeared. The white solid 9 (0.9 g, 80.0%)
was obtained by filtration. 1H NMR (600 MHz, CDCl3)
δ ppm 2.53 (d, J = 0.6 Hz, 1H), 2.87 (d, J = 1.2 Hz, 1H),
4.53 (m, 1H), 4.60 (s, 1H), 7.36 (s, 1H), 7.47 (s, 1H). LC‐MS:
[M + H]+ m/z 320.
3.12 | 1‐(4‐amino‐3‐bromophenyl)ethan‐1‐one (15)
The 1‐(4‐aminophenyl)ethan‐1‐one 14 (4.1 g, 30.0 mmol)
and toluene (50 mL) were added to a round‐bottom flask
equipped with a reflux condenser. N‐bromosuccinimide
(5.3 g, 30.0 mmol) was added to the solution over 10 minutes.
Stirring was continued for 10 minutes at 35°C. After
completion of reaction, the organic layers were successively
washed with a solution of 5% NaHCO3 (50 mL) and water
(50 mL × 2). Removal of the solvent under vacuum yielded
a dark brown oil. The water was added into the crude prod-
uct, which was dissolved in ethanol, as the white crystal
appearing. Then 15 was collected by filtration (5.9 g,
3.9 | 1‐[bis‐3′,5′‐(N,N‐dimethylcarbamoyloxy)‐phenyl]‐
2‐bromoethanone (11)
1
91.2%). H NMR (600 MHz, CDCl3) δ ppm 2.51 (s, 3H),
To a suspension of 10 (8.8 g, 30.0 mmol) and CuBr2
(13.4 g, 60.0 mmol) in CHCl3 (80 mL) and ethyl acetate
(80 mL) at 70°C was added ethanol (40 mL) over 30
minutes. The reaction mixture was stirred for 2 hours, then
filtered. The cake was washed with ethyl acetate (40 mL),
and the filtrate was washed with water until no white
precipitate. The organic layer was dried over anhydrous
magnesium sulfate and removed in vacuum and crystallized
in chloroform to give a yellow solid 11 (8.4 g, 75.4% ).
1H NMR (600 MHz, CDCl3) δ ppm 3.00 ~ 3.08
(s, 12H), 4.41 (s, 2H), 7.25 (t, J = 1.2 Hz, 1H), 7.57
(d, J = 1.8 Hz, 2H). LC‐MS: [M + H]+ m/z 374.
4.57 (brs, 2H), 6.74 (d, J = 12.6 Hz, 1H), 7.74 (dd,
J = 3.0, 3.0 Hz, 1H), 8.07 (d, J = 3.0 Hz, 1H). LC‐MS:
[M − H]− m/z 212.
3.13 | 5‐acetyl‐2‐aminobenzonitrile (16)
Cuprous cyanide (1.8 g, 20.0 mmol) was added to a mixture
of 15 (3.6 g, 16.6 mmol) dissolved in N,N‐
dimethylformamide (20 mL). The mixture was stirred at
160°C under nitrogen for 6 hours. The progress of the
reaction was monitored using thin‐layer chromatography
(hexane : ethyl acetate = 2:1). The resulting mixture was