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M. Wang et al. / Steroids 75 (2010) 967–973
was added. The reaction mixture was continued to stir at room
temperature for 0.5 h, and then heated at 80 ◦C overnight. The
The combined organic layer was washed with brine, dried over
Na2SO4, and filtered. The solvent was evaporated in vacuo, and the
crude product was purified by preparative TLC plate, eluting with
CH2Cl2/MeOH (100:3) to afford 17 (50 mg, 47%) as a pale brown
solid, m.p. 129–130 ◦C (lit. 128–130 ◦C [7]). 1H NMR (CDCl3) ı: 6.83
(s, 1H, Ph-H), 6.57 (s, 1H, C CH), 3.96 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 3.82 (d, J = 2.0 Hz, 3H, NCH3), 2.63 (s, 3H,
CH3).
According to the procedure for preparation of 20a, compound
20c (640 mg, 46%) was prepared from PPA (20 g) and 19c (1.5 g,
6.3 mmol) as a pale yellow solid, m.p. 186–187 ◦C (lit. 187–189 ◦C
[7]). 1H NMR (CDCl3) ı: 9.38 (br s, 1H, NH), 6.89 (d, J = 8.5 Hz, 1H,
Ph-H), 6.53 (d, J = 9.0 Hz, 1H, Ph-H), 6.42 (s, 1H, C CH), 3.92 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 2.65 (d, J = 1.0 Hz, 3H, CH3).
2.2.22. 8-Methoxy-1,4-dimethylquinolin-2(1H)-one (21a)
To a suspension of compound 20a (120 mg, 0.63 mmol) in DMF
(2 mL) was added NaH (60% dispersion in mineral oil, 31.6 mg,
0.79 mmol). The reaction mixture was stirred and heated at 40 ◦C
for 1 h. The mixture was cooled to room temperature, and CH3I
(0.16 mL, 2.52 mmol) was added. After stirring at room temperature
for 0.5 h and at 60 ◦C overnight, the reaction mixture was poured
into ice water and extracted with CH2Cl2. The combined organic
layer was washed with brine, dried over Na2SO4, and filtered. The
solvent was evaporated in vacuo, and the crude product was puri-
fied by preparative TLC plate, eluting with hexanes/EtOAc (1:1) to
afford 21a (65 mg, 50%) asayellow solid, m.p. 71–72 ◦C (lit. 72–74 ◦C
[7]). 1H NMR (CDCl3) ı: 7.30 (dd, J = 1.5, 8.0 Hz, 1H, Ph-H), 7.18 (t,
J = 8.0 Hz, 1H, Ph-H), 7.09 (dd, J = 1.5, 8.0 Hz, 1H, Ph-H), 6.62 (s, 1H,
2.2.16. N-(2-Methoxyphenyl)-3-oxobutanamide (19a)
A mixture of o-anisidine 18a (3.0 g, 24.4 mmol) and methyl ace-
toacetate (2.63 mL, 24.4 mmol) in toluene (50 mL) was stirred and
refluxed using a Dean-Stark apparatus for 24 h. The solvent was
evaporated in vacuo, and the crude product was purified by col-
umn chromatography, eluting with hexanes/EtOAc (2.5:1) to afford
19a (1.3 g, 26%) as a yellow solid, m.p. 82–83 ◦C (lit. 82–84 ◦C [7]).
1H NMR (CDCl3) ı: 9.23 (br s, 1H, NH), 8.32 (dd, J = 1.5, 8.0 Hz, 1H,
Ph-H), 7.06 (dt, J = 1.5, 8.0 Hz, 1H, Ph-H), 6.95 (dt, J = 1.0, 8.0 Hz, 1H,
Ph-H), 6.89 (dd, J = 1.0, 8.5 Hz, 1H, Ph-H), 3.91 (s, 3H, OCH3), 3.60 (s,
2H, C(O)CH2C(O)), 2.33 (s, 3H, CH3).
C
CH), 3.93 (s, 3H, OCH3), 3.90 (s, 3H, NCH3), 2.43 (s, 3H, CH3).
According to the procedure for preparation of 21a, compound
21b (139 mg, 65%) was prepared from 20b (200 mg, 0.91 mmol),
NaH (60% dispersion in mineral oil, 45.6 mg, 1.14 mmol), and
CH3I (0.23 mL, 3.64 mmol) as a yellow solid, m.p. 158–160 ◦C (lit.
157–159 ◦C [7]). 1H NMR (CDCl3) ı: 6.71 (d, J = 3.0 Hz, 1H, Ph-H),
6.68 (d, J = 3.0 Hz, 1H, Ph-H), 6.66 (s, 1H, C CH), 3.91 (s, 3H, OCH3),
3.89 (s, 3H, OCH3), 3.87 (s, 3H, NCH3), 2.41 (d, J = 1.0 Hz, 3H, CH3).
2.2.17. N-(2,4-Dimethoxyphenyl)-3-oxobutanamide (19b)
According to the procedure for preparation of 19a, compound
19b (9.2 g, 59%) was prepared from 2,4-dimethoxyaniline 18b
(10.0 g, 65.0 mmol) and methyl acetoacetate (7.05 mL, 65.0 mmol)
as a beige solid, m.p. 91–92 ◦C (lit. 92–44 ◦C [7]). 1H NMR (CDCl3)
ı: 9.02 (br s, 1H, NH), 8.18 (d, J = 9.0 Hz, 1H, Ph-H), 6.49–6.45 (m,
2H, Ph-H), 3.88 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.58 (s, 2H,
C(O)CH2C(O)), 2.33 (s, 3H, CH3).
According to the procedure for preparation of 21a, compound
21c (121 mg, 57%) was prepared from 20c (200 mg, 0.91 mmol),
NaH (60% dispersion in mineral oil, 45.6 mg, 1.14 mmol), and
CH3I (0.23 mL, 3.64 mmol) as a yellow solid, m.p. 186–187 ◦C (lit.
187–189 ◦C [7]). 1H NMR (CDCl3) ı: 7.03 (d, J = 9.0 Hz, 1H, Ph-H),
6.63 (d, J = 9.0 Hz, 1H, Ph-H), 6.50 (s, 1H, C CH), 3.84 (s, 6H, OCH3),
3.82 (s, 3H, NCH3), 2.60 (d, J = 0.5 Hz, 3H, CH3).
2.2.18. N-(2,5-Dimethoxyphenyl)-3-oxobutanamide (19c)
According to the procedure for preparation of 19a, compound
19c (11.7 g, 75%) was prepared from 2,5-dimethoxyaniline 18c
(10.0 g, 65.0 mmol) and methyl acetoacetate (7.05 mL, 65.0 mmol)
as a pale yellow solid, m.p. 68–70 ◦C (lit. 70–72 ◦C [7]). 1H NMR
(CDCl3) ı: 9.25 (br s, 1H, NH), 8.06 (d, J = 3.0 Hz, 1H, Ph-H), 6.80 (d,
J = 8.5 Hz, 1H, Ph-H), 6.59 (dd, J = 3.0, 9.0 Hz, 1H, Ph-H), 3.87 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 3.59 (s, 2H, CH2, C(O)CH2C(O)), 2.33 (s,
3H, CH3).
2.3. Synthesis of [11C]casimiroin ([11C]11) and its
carbon-11-labeled analogues [11C]17 and [11C]21a–c
2.2.19. 8-Methoxy-4-methylquinolin-2(1H)-one (20a)
[
11C]CO2 was produced by the 14N(p,␣)11C nuclear reaction in
To a preheated PPA (10 g) was added compound 19a (800 mg,
3.9 mmol) at 100 ◦C. After stirring at the same temperature for 2 h,
the reaction mixture was poured into ice water and neutralized
with 5N NaOH. The mixture was extracted with CH2Cl2. The com-
bined organic layer was washed with brine, dried over Na2SO4,
and filtered. The solvent was evaporated in vacuo, and the crude
product was purified by column chromatography, eluting with
CH2Cl2/MeOH (100:2.5) to afford 20a (200 mg, 27%) as a white solid,
m.p. 189–190 ◦C (lit. 188–190 ◦C [7]). 1H NMR (CDCl3) ı: 9.33 (br s,
1H, NH), 7.28 (d, J = 1.0, 1H, Ph-H), 7.17 (t, J = 8.0 Hz, 1H, Ph-H), 7.00
(dd, J = 0.5, 8.0 Hz, 1H, Ph-H), 6.56 (d, J = 1.0 Hz, 1H, C CH), 3.98 (s,
3H, OCH3), 2.49 (d, J = 1.5 Hz, 3H, CH3).
small volume (9.5 cm3) aluminum gas target (CTI) from 11 MeV
proton cyclotron on research purity nitrogen (+1% O2) in a Siemens
radionuclide delivery system (Eclipse RDS-111). The precursor
10, 16, 20a, 20b, or 20c (0.1–0.3 mg) was dissolved in CH3CN
(300 L). To this solution was added NaH (0.5–1 mg). The mixture
was transferred to a small reaction vial. No-carrier-added (high
specific activity) [11C]CH3OTf that was produced by the gas phase
production method [25] from [11C]CO2 through [11C]CH4 and
[
11C]CH3Br with silver triflate (AgOTf) column was passed into the
reaction vial until radioactivity reached a maximum (∼2 min), and
then the reaction vial was isolated and heated at 80 ◦C for 3 min.
The contents of the reaction vial were diluted with NaHCO3 (0.1 M,
1 mL), and injected onto the semi-preparative HPLC column with
2 mL injection loop. The product fraction was collected, the solvent
was removed by rotatory evaporation under vacuum, and the final
product, [11C]11, [11C]17, [11C]21a, [11C]21b, or [11C]21c, was for-
mulated in saline, sterile-filtered through a sterile vented Millex-GS
0.22 m cellulose acetate membrane, and collected into a sterile
vial. Total radioactivity was assayed and total volume was noted
for tracer dose dispensing. The overall synthesis, purification and
2.2.20. 6,8-Dimethoxy-4-methylquinolin-2(1H)-one (20b)
According to the procedure for preparation of 20a, compound
20b (320 mg, 23%) was prepared from PPA (20 g) and 19b (1.5 g,
6.3 mmol) as a yellow solid, m.p. 230–231 ◦C (lit. 232–234 ◦C [7]).
1H NMR (DMSO-d6) ı: 10.48 (br s, 1H, NH), 6.80 (d, J = 2.5 Hz, 1H,
Ph-H), 6.72 (d, J = 2.5 Hz, 1H, Ph-H), 6.42 (d, J = 1.0 Hz, 1H, C CH),
3.88 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.40 (d, J = 1.0 Hz, 3H, CH3).