ORDER
REPRINTS
Improved Synthesis of [11C]Raclopride
1905
temperature. The reaction mixture was concentrated to residue which was
treated with 2 M aqueous NaOH. The solution was stirred at room temperature
for 30 min and subsequently acidified with concentrated aqueous HCl.
Repeated extractions with EtOAc, drying of the combined organic phases
with Na2SO4 and concentration yielded the crude product in the form of
yellow crystals. The crude product was re-dissolved in a small quantity of
water, made alkaline with concentrated aqueous NH4OH, and repeatedly
extracted with EtOAc. The combined organic phases were dried over
Na2SO4 and the residue obtained after concentration was purified by silica
gel flash column chromatography (90 : 10 CH2Cl2 : CH3OH) to give the
pure compound 1 in the form of a yellow oil (1.50 g, 71%), Rf ¼ 0.50
1
(7 : 3 CH2Cl2 : CH3OH). RT ¼ 4.10 min (anal. HPLC). H NMR (400 MHz,
CDCl3): d 1.12–1.16 (t, J ¼ 6.6 Hz, 3H, CH3CH2), 1.85–4.20 (m, 11H),
3.92 (s, 3H, OCH3), 7.49 (s, 1H, Ph-H), 8.88 (bs, 1H, OH).
(S)-(2)-3,5-Dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dihydroxy-
benzamide hydrobromide (4). To a solution of compound 1 (0.66 g,
1.89 mmol) in HOAc (2 mL), HBr in HOAc (5.0 M, 1.0 mL, 5.0 mmol) was
added and the reaction solution was stirred under nitrogen at 608C for 2 hr.
The solution was then concentrated under repeated addition of toluene to
obtain the crude product in the form of brownish crystals. Recrystallization
from EtOH/heptane afforded the pure hydrobromide salt 4 as a solid
1
(0.42 g, 54%). RT ¼ 2.01 min (anal. HPLC). H NMR (400 MHz, DMSO-
d6): d 1.08–1.12 (t, J ¼ 6.8 Hz, 3H, CH3CH2), 1.60–3.60 (m, 11H), 7.54
(s, 1H, Ph-H), 9.20 (bs, 1H), 9.40 (s, 1H).
(S)-(2)-3,5-Dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dihydroxy-
benzamide (desmethyl-raclopride, 5). An aliquot of the hydrobromide salt
4 (100 mg, 0.24 mmol) was dissolved in H2O (15 mL). The pH of the solution
was adjusted to 8–9 with aqueous NH4OH and repeatedly extracted with
EtOAc. The combined organic phases were dried over MgSO4 and concen-
trated to yield the pure precursor desmethyl-raclopride 5 as a fine, yellowish
1
powder (68 mg, 85%). RT ¼ 2.06 min (anal. HPLC). H NMR (400 MHz,
DMSO-d6): d 1.35–1.42 (t, J ¼ 6.8 Hz, 3H, CH3CH2), 1.83–3.98 (m, 11H),
7.50 (s, 1H, Ph-H), 9.20 (bs, 1H), 9.40 (s, 1H).
[11C]Raclopride (1). 11CO2 was produced by the 14N(p, a)11C nuclear
reaction in small volume (12.3 cm3) aluminum gas target (CTI) from
11 MeV proton cyclotron on research purity nitrogen (þ3% O2) in a Siemens
radionuclide delivery system (RDS-112). Precursor 5 (0.1 mg) was dissolved
in acetone (400 mL). To this solution was added aqueous NaOH (4 mL, 6 M
solution). The mixture was transferred to a small volume, three-neck reaction
tube. [11C]Methyl triflate that was produced by the GPP method from 11CO2
through 11CH4 and 11CH3Br was passed into the air-cooled reaction tube at
2158C to 2208C, which was generated by a Venturi cooling device powered