Synthesis of 11C-/ 13C-Amides
SCHEME 2a
SCHEME 3a
a
Ar ) phenyl, R′ ) isopropyl and R′′ ) H (32a ), Ar
)
a
R ) 3-pyridyl (30a ), R ) 1-isoquinolyl (30b).
4
-nitrophenyl, R′ ) isopropyl and R′′ ) H (32b), Ar ) 4-chlorophen-
yl, R′ ) isopropyl and R′′ ) H (32c), Ar ) 4-methoxyphenyl, R′ )
isopropyl and R′′ ) H (32d ), Ar ) 4-methylphenyl, R′ ) isopropyl
and R′′′′ ) H (32e), Ar ) 2-naphthyl, R′) isopropyl and R′′ ) H
(32f), Ar ) phenyl and R′ ) R′′ ) n-propyl (32g), Ar ) phenyl,
R′) benzyl and R′ ) methyl (32h ), Ar ) 2-chlorophenyl, R′) allyl
and R′′ ) H (32i).
of 4 mL/min. An automated synthesis system15 was used for
LC injection and fraction collection.
Radioactivity was measured in an ion chamber. For coarse
estimations of radioactivity during production and for safety,
a portable dose-rate meter was used.
For the determination of yields and purity of the products,
unlabeled reference substances were used for comparison when
LC runs were performed. Identities of precursors and reference
TABLE 2. Ch em ica l Yield s a n d Meltin g P oin ts of th e
Refer en ce Com p ou n d s
1
13
compounds were determined using H and C NMR and GC-
entry
products
yields (%)
mp (°C)
MS. NMR spectra were recorded on a 400 MHz NMR instru-
1
2
3
4
5
6
7
8
9
30a
30b
32a
32b
32c
32d
32e
32f
32g
32h
32i
92
87
90
66
91
89
91
84
95
93
94
83 (lit.21 85-85.5)
1
ment. Tetramethylsilane or chloroform-d was used as the
88 (lit.2 85)
2
internal standard. LC-MS was performed using an instru-
ment with electrospray ionization (ESI+). An autosampler and
an ODS C18 (5 µm, 100 × 4.6 mm i.d.) column were used.
Mobile phases were D and B. GC-MS was performed with a
mass spectrometer coupled to a GC.
2
3
95 (lit. 99-103)
153 (lit.2 151-153)
4
25
142 (lit. 144)
25
123 (lit. 120-122)
25
133 (lit. 131-132)
All of the triflates, except 3-pyridyl, 2- and 4-chlorophenyl
26
170 (lit. 168.5-169.5)
,
and 1-isoquinolyl triflates, and all of the amines used in this
colorless oil
colorless oil
work were commercially available. The triflate, 3-pyridyl
trifluoromethanesulfonate (21), was prepared by the reaction
of 3-hydroxypyridine with trifluoromethanesulfonic anhy-
10
11
2
7
66
1
6
dride. This compound was prepared previously by different
1
7
methods. The preparation of 2- and 4-chlorophenyl trifluo-
chloride, lithium bromide, tetrakis(triphenylphosphine)pal-
ladium(0), Ph As, and Pd (dba) were commercially available
1
6
romethanesulfonates (16 and 20) and isoquinolin-1-yl tri-
3
2
3
1
8
fluoromethanesulfonate (22) has been described previously,
and the same procedure was followed. Two of the reference
compounds, N-phenylbenzamide and N-phenylnicotinamide,
were commercially available. Reference compounds 30a and
and used without further purification. THF was distilled under
nitrogen from sodium/benzophenone. Pyridine was distilled
2
under nitrogen from CaH .
1
1
Syn th esis of [Ca r bon yl- C]Am id es. Gen er a l P r oce-
d u r e. Tetrakis(triphenylphosphine)palladium(0) (5.0 mg, 4.3
µmol) was placed in a vial (1 mL) which was flushed with
nitrogen and dissolved in THF (250 µL). Aryl triflate (22.1
µmol) and LiBr (5 µL of 0.46 M solution in THF, 2.3 µmol)
were added. The mixture was shaken until the solution was
homogeneous. Amine (117.4 µmol) was added, and the result-
ing mixture was injected into the injection loop of the synthesis
apparatus. The appropriate volume (200 µL) was then trans-
ferred under pressure (35 Mpa) to the micro-autoclave pre-
3
0b were synthesized from the corresponding carboxylic acids
1
9
and benzylamine using method A (Scheme 2), and compounds
3
2a -i were synthesized from the corresponding acid chlorides
20
and different amines using method B (Scheme 3). The yields
were 65-95% (Table 2). Analytical data to identify the
2
1
22
23
24
25
25
reference compounds 30a , 30b, 32a , 32b, 32c, 32d ,
3
2
5
26
27
2e, 32h , and 32i were compared with the literature
values. No such data for compounds 32f and 32g are available
in the literature and presented here. The reagents lithium
1
1
charged with [ C]carbon monoxide in helium. The micro-
autoclave was heated (150 °C) for 5 min. The crude product
was transferred to a preevacuated, septum-fitted vial (5 mL).
The micro-autoclave was filled with THF (200 µL) and emptied
into the collection vial. The radioactivity was measured before
and after the vial was purged with nitrogen. The solvent
volume was reduced to less than 0.2 mL by heating at 75 °C
and purging with nitrogen. Acetonitrile/water: 1/1 (2 mL) was
added, and the resulting solution was injected onto the
semipreparative LC. Solvent A-B (70:30) linear gradient to
(
15) Bjurling, P.; Reineck, R.; Westerberg, G.; Gee, A. D.; Sutcliffe,
J .; Långstr o¨ m, B. Proceedings of the VIth workshop on targetry and
target chemistry; TRIUMF: Vancouver, Canada, 1995; pp 282-284.
(
16) Creary, X.; Benage, B.; Hilton, K. J . Org. Chem. 1983, 48, 2887-
2
891.
17) (a) Dolle, R. E.; Schmidt, S. J .; Kruse, L. I. J . Chem. Soc., Chem.
(
Commun. 1987, 904-905. (b) Wentworth, A. D.; Wentworth, P., J r.;
Mansoor, U. F.; J anda, K. D. Org. Lett. 2000, 2, 477-480.
(
18) Crisp, G. T.; Papadopoulos, S. Aust. J . Chem. 1989, 42, 279-
2
6
85.
(
19) Vaughan, J . R., J r.; Osato, R. L. J . Am. Chem. Soc. 1952, 74,
2
1
1
R
0:80 in 10 min, flow 4 mL/min, t ) 9.1, 10.3, 11.5, 9.3, 10.6,
76-678.
2.4, 12.2, 12.8, 12.7, 9.6, 8.6, 8.4 and 14.6 min for products
, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13, respectively. The
(20) White, E. Organic Syntheses; Wiley: New York, 1973; Collect.
Vol. V, pp 336-337.
21) Pop, I. E.; Deprez, B. P.; Tartar, A. L. J . Org. Chem. 1997, 62,
594-2603.
22) Benincori, T.; Brenna, E.; Sannicolo, F. J . Chem. Soc., Perkin
Trans. 1 1993, 675-680.
23) Murphy, J . A.; Roome, S. J . J . Chem. Soc., Perkin Trans. 1 1995,
1, 1349-1358.
24) Hegarty, A. F.; Eustace, S. J .; Tynan, N. M.; Pham-Tran, N.-
N.; Nguyen, M. T. J . Chem. Soc., Perkin Trans. 2 2001, 1239-1246.
(
identity and radiochemical purity of the collected fraction were
2
assessed by analytical LC: solvent A-C (70:30) linear gradient
(
to 0:100 in 10 min, flow 1.5 mL/min, wavelength 254 nm, t )
R
4
.7, 5.8, 6.2, 5.2, 5.8, 7.3, 8.0, 7.8, 7.2, 5.1, 4.5, 4.0, and 9.1
(
min for products 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13,
respectively.
1
(
MS(ESI+) m/z ) 164, 209, 198, 194, 178, 214, 206, 226, 198,
(
25) Cavert, D. J .; O’Connor, C. J . Aust. J . Chem. 1979, 32, 337-
1
8
96, 213, 199, and 263 (M + 1) for products 1, 2, 3, 4, 5, 6, 7,
, 9, 10, 11, 12, and 13, respectively.
3
43.
(
26) (a) Tokitoh, N.; Okazaki, R. Bull. Chem. Soc. J pn. 1987, 60,
Syn th esis of N-Ben zylisoqu in olin e-1-(13C)ca r boxa m -
3
6
291-3298. (b) Schulthess, A. H.; Hansen, H.-J . Helv. Chim. Acta 1981,
4, 1322-1336.
id e. Tetrakis(triphenylphosphine)palladium(0) (15.0 mg, 13.8
µmol) was placed in a vial (1 mL), flushed with nitrogen, and
(27) Agwada, V. C. J . Chem. Eng. Data 1984, 29, 231-235.
J . Org. Chem, Vol. 68, No. 9, 2003 3561