LATLI ET AL.
563
filter funnel for 2 hours and then transferred to a flask to give
400 mg (50 mCi) of a white solid in 48% yield.
5.3.3 |
(2R,4S)‐7‐((((S)‐3‐Acetoxy‐2‐phenylpropanoyl‐1‐14C)
oxy)‐9‐butyl‐9‐methyl‐3‐oxa‐9‐azatricyclo[3.3.1.02,4]nonan‐9‐
ium bromide (13)
5.2.2.8
|
(S)‐3‐Hydroxy‐2‐phenyl‐propionic‐1‐14C acid (l‐tropic
A solution of (12) (220 mg, 0.97 mmol) in anhydrous chloro-
form (6 mL) was treated with N‐butylscopoline bromide (11)
(200 mg, 0.7 mmol) and heated to 40°C for 5 hours. HPLC of
the mixture showed the desired product. The reaction solu-
tion was cooled to room temperature and concentrated in
vacuo to give 460 mg of a residue, which was used as is in
the next step.
acid‐carboxyl‐14C) (10)
To a mixture of the salt (9) (400 mg, 1.05 mmol) in IPAC
(6 g) was added concentrated aqueous HCl (112 μL, 12 N).
The mixture was heated to 60°C and stirred for 30 minutes
and then cooled to room temperature for more than 2 hours.
The mixture was filtered and washed twice with IPAC
(2.5 mL × 2), and the IPAC solution was concentrated in
vacuo to give 163 mg of a white solid in 92% yield. Total
activity = 45.7 mCi and specific activity = 45.7 mCi/mmol.
HPLC method B: Rt = 4.1 minutes, 97.2% ee, 98.6% radio-
chemical purity.
5.3.4
|
[14C]‐Buscopan
A solution of the acetate derivative (13) (450 mg, 0.93 mmol)
was treated with water (2 mL) and concentrated HCl (0.5 mL,
6 mmol). The mixture was stirred overnight. HPLC analysis
showed that the starting material was converted to both the
tropic acid and Buscopan. The reaction was extracted with
ether, and the aqueous layer was frozen in liquid nitrogen
and then lyophilized to give 310 mg of viscous oil. This
residue was dried under reduced pressure and then dissolved
in acetonitrile (0.2 mL), and anhydrous ether (3 mL) was
added while heating. The cloudy mixture was seeded with
few crystals of unlabeled Buscopan and left to crystallize at
0°C for 2 hours. The solution was pipetted out and concen-
trated in vacuo to give 112 mg (30 mCi) of crude (S)‐tropic
acid (76% yield). The solid, carbon‐14 Buscopan, was dried
to give 252 mg of a white solid in 20% yield. Total
activity = 7.83 mCi. HPLC method C: Rt = 4.44 minutes,
98.5% radiochemical purity, and 97.1% ee with a specific
activity of 42.4 mCi/mmol (117.7 μCi/mg); Rt of (R)‐
5.3 | Hydrolysis of Buscopan
5.3.1
| (2R,4S)‐9‐Butyl‐7‐hydroxy‐9‐methyl‐3‐oxa‐9‐azatricyclo
[3.3.1.02,4]nonan‐9‐ium bromide, N‐butyl scopoline (11)
To a suspension of Buscopan (6.61 g, 15 mmol) in methanol
(22 mL) was added a solution of sodium methoxide (1.3 mL,
0.65 mmol, 0.5M in MeOH), and the mixture was heated to
40°C. The resulting colorless solution was stirred at this
temperature for 3 hours. LCMS showed only 40% conver-
sion. A solution of sodium methoxide (0.43 mL, 0.5M in
MeOH) was added, and stirring was continued for another
5 hours. HPLC showed about 60% conversion at 254 nm. A
solution of acetic acid (0.1 mL in 1.0 mL of isopropyl alco-
hol) was added and stirred for 10 minutes. Then, IPAC
(77 mL) was added to give a suspension that was stirred at
40°C for 30 minutes. The reaction was cooled to room tem-
perature and stirred overnight. Stirring was stopped, and the
mixture was left to settle. The mixture was filtered, and the
solid was washed with i‐PrOAc (80 mL) and dried in vacuo
to give 2.81 g of a white solid in 64% yield. LCMS:
Rt = 0.21 minutes, M+–Br = 212.6 (100%). 1H NMR
(DMSO‐d6) δ: 5.07 (t, J = 4.1 Hz, 1H), 4.15 (m, 2H), 3.98
(m, 1H), 3.55 (m, 2H), 3.28 (s, 2H), 2.97 (s, 3H), 2.51 (m,
2H), 2.46 (t, J = 6.1 Hz, 1H), 1.79 (d, J = 16.1 Hz, 1H),
1.65 (m, 2H), 1.26 (m, 2H), 0.91 (t, J = 8.1 Hz, 3H).
1
Buscopan 3.57 minutes. H NMR (DMSO‐d6) δ: 7.36 (m,
5H), 5.09 (t, J = 4.1 Hz, 1H), 5.03 (t, J = 6.1 Hz, 1H),
4.18 (m, 2H), 3.91 to 4.01 (m, 2H), 3.75 to 3.82 (m, 2H),
3.71 (m, 1H), 3.51 to 3.58 (m, 2H), 3.04 (s, 3H), 2.55 to
2.71 (m, 2H), 1.91 (d, J = 16.1 Hz, 1H), 1.77 (d,
J = 16.1 Hz, 1H), 1.65 (m, 2H), 1.24 (m, 2H), 0.90 (t,
J = 8.1 Hz, 3H).
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5.3.2
|
(S)‐3‐Chloro‐3‐oxo‐2‐phenylpropyl‐3‐14C acetate (12)
A mixture of (S)‐tropic acid (10) (163 mg, 0.97 mmol) and
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