S. C. Schou
reaction mixture was stirred under an argon atmosphere at 801C added and the solution was degassed and flushed with argon
for 1 h, cooled to rt, added sat. NaHCO3 (20 mL) and extracted again. The reaction mixture was stirred at 801C for 1 h affording
with ethyl acetate (4 ꢀ 10 mL). The organic phase was dried a yellow solution. The reaction mixture was cooled to rt, added
(Na2SO4), filtered and concentrated in vacuo affording 594 mg of H2O (5 mL) and extracted with ethyl acetate (3 ꢀ 5 mL). The
brown oil. The oil was purified by silica gel chromatography (5 g organic phase was dried (MgSO4), filtered and concentrated in
SiO2) using a gradient of heptane:ethyl acetate [100:0!75:25] vacuo. The residue was purified by silica gel chromatography
affording the desired product as pale yellow crystals in 89% (2 g SiO2) using a gradient of heptane:ethyl acetate:acetic acid
1
yield (83 mg, 0.69 mmol, 1.36 GBq). H NMR (d6-DMSO) d = 7.37 [100:0:0!67:33:1] as eluent affording the desired product as off-
(d, J = 7.8, 1H), 7.29 (t, J = 7.8, 1H), 6.78 (d, J = 8.4, 1H), 6.59 white crystals in 77% yield (16 mg, 0.11 mmol, 203 MBq). 1H NMR
(t, J = 7.5, 1H), 5.99 (s, 2H). 13C NMR (d6-DMSO) d = 151.96, 134.32, (d6-DMSO) d = 8.09 (d, J = 8.2, 1H), 7.98 (d, J = 8.2, 1H). 13C NMR
132.79, 116.28, 115.56, 93.79.
(d6-DMSO) d = 166.07, 132.67, 131.44, 129.92, 115.01.
2-Amino-benzoic acid-[carboxyl-14C] (3)
Terephthalic acid-[monocarbonyl-14C] (9)
2-Amino-benzonitrile-[cyano-14C] (2) (78 mg, 0.65mmol, 1.29GBq)
and KOH (1.8 g, 32.5 mmol, 50 eq) were weighed in a 100 mL
round bottom flask. H2O was added in the flask (30 mL) and
stirred at reflux (1151C) for 5 h affording a clear brown solution.
The reaction mixture was cooled to rt and pH was adjusted to
pH = 3–4 using conc. HCl, whereby precipitation occurred. The
reaction mixture was extracted with ethyl acetate (5 ꢀ 15 mL).
The organic phase was dried (Na2SO4), filtered and concentrated
in vacuo affording the desired product as beige/light
brown crystals in 96% yield (87 mg, 0.64 mmol, 1.23 GBq, SA:
1.97 GBq/mmol)).
Cyano-benzoic acid-[cyano-14C] (8) (11 mg, 0.078 mmol, 154 MBq)
was dissolved/suspended in H2O (10 mL) in a round bottom flask.
KOH (215mg, 3.85mmol) was added and the reaction mixture
was stirred at reflux (1151C) for 5 h affording a brown solution.
The reaction mixture was cooled to rt and pH was adjusted to
pH= 3–4 using conc. HCl, whereby precipitation occurred. The
reaction mixture was extracted with ethyl acetate (4 ꢀ 10mL). The
organic phase was dried (MgSO4), filtered and concentrated in
vacuo affording the desired product as off-white crystals in 89%
yield (11.6 mg, 0.069 mmol, 137 MBq, SA: 1.98GBq/mmol).
4-Hydroxy-benzonitrile-[cyano-14C] (5)
3-[2-Chloro-4-(2,4-difluoro-phenylamino)-benzoyl]-4-methyl-ben-
zonitrile-[cyano-14C] (11)
4-Hydroxyiodobenzene (4) (33 mg, 0.149 mmol) was dissolved in
dry DMF (1 mL) in a dry flask charged with argon. The solution
was degassed (vacuum) and flushed with argon. Zn(CN)2
(8.8 mg, 0.073 mmol, 289 MBq) and Pd(PPh3)4 (8 mg, 0.007 mmol)
were added and the solution was degassed and flushed with
argon again. The reaction mixture was stirred at 801C for 1 h,
then cooled to rt, added H2O (5 mL) and extracted with ethyl
acetate (3 ꢀ 5 mL). The organic phase was dried (MgSO4), filtered
and concentrated in vacuo. The residue was purified by silica gel
chromatography (2 g SiO2) using a gradient of heptane:ethyl
acetate [100:0!75:25] as eluent affording the desired product
as off-white crystals in 63% yield (11 mg, 0.09 mmol, 183 MBq).
1H NMR (d6-DMSO) d = 7.62 (d, J = 8.7, 2H), 6.89 (d, J = 8.7, 2H).
13C NMR (d6-DMSO) d = 161.99, 134.23, 116.50, 100.65.
Method A: [2-Chloro-4-(2,4-difluoro-phenylamino)-phenyl]-(5-
iodo-2-methyl-phenyl)-methanone (10) (72 mg, 0.149 mmol)
was dissolved in dry DMF (500 mL) in a dry flask charged with
argon. The solution was degassed (vacuum) and flushed with
argon. Zn(14CN)2 (9 mg, 0.074 mmol, 293 MBq) and Pd(PPh3)4
(8 mg, 0.074 mmol) were added and the solution was degassed
and flushed with argon again. The red-brown solution was
stirred at 801C for 1 h. The reaction mixture was cooled to rt,
added H2O (10 mL) and extracted with ethyl acetate (4 ꢀ 10 mL).
The organic phase was dried (MgSO4), filtered and concentrated
in vacuo. The residue was purified by silica gel chromatography
(5 g SiO2) using
a
gradient of heptane:ethyl acetate
[100:0!50:50] as eluent affording the desired product as
off-white crystals in 92% yield (52 mg, 0.135 mmol, 269 MBq)).
1H NMR (d6-DMSO) d = 8.85 (s, 1H), 7.88 (dd, J = 1.5, 7.9, 1H), 7.73
(s, 1H), 7.55 (d, J = 8.0, 1H), 7.48–7.38 (m, 3H), 7.13 (t, J = 7.6, 1H),
6.82 (d, J = 1.5, 1H), 6.78 (dd, J = 1.7, 8.7, 1H), 2.34 (s, 3H). 13C
NMR (d6-DMSO) d = 193.44, 159.38 (dd, J = 11.4, 244.2), 156.29
(dd, J = 12.7, 248.8), 150.43, 142.25, 141.20, 134.78, 134.60,
134.07, 132.53, 131.94, 127.15 (d, J = 9.6), 125.66, 124.38 (dd,
J = 3.3, 12.1), 115.35, 112.44 (dd, J = 3.4, 22.2), 112.28, 109.21,
105.50 (dd, J = 24.5, 26.5), 20.16.
Method B: Pd(OAc)2 (7 mg, 0.064 mmol, 0.07eq) and solid
supported PPh3 (23 mg, 0.137 mmol, 0.15 eq, 3 mmol/g) were
weighed in a dry microwave tube charged with argon and
dissolved in dry DMF (2 mL). The solution was stirred at rt for
2 h affording an orange mixture. [2-Chloro-4-(2,4-difluoro-
phenylamino)-phenyl]-(5-iodo-2-methyl-phenyl)-methanone (10)
(440 mg, 0.91 mmol) and Zn(14CN)2 (108 mg, 0.91 mmol, 3.7 GBq)
were added, the microwave tube was sealed and exposed to
4-Hydroxy-benzoic acid-[carbonyl-14C] (6)
4-Hydroxy-benzonitrile-[cyano-14C] (5) (9.5 mg, 0.078 mmol,
155 MBq) was dissolved/suspended in H2O (10 mL) in a round
bottom flask. KOH (224 mg, 4 mmol) was added and the reaction
mixture was stirred at reflux (1151C) for 5 h affording a brown
solution. The reaction mixture was cooled to rt and pH was
adjusted to pH = 3–4 using conc. HCl, whereby precipitation
occurred. The reaction mixture was extracted with ethyl
acetate (4 ꢀ 10 mL). The organic phase was dried (MgSO4),
filtered and concentrated in vacuo affording the desired product
as off-white crystals in 98% yield (11 mg, 0.077 mmol, 153 MBq,
SA: 1.94 GBq/mmol).
Cyano-benzoic acid-[cyano-14C] (8)
4-Iodobenzoic acid (7) (37 mg, 0.149 mmol) was dissolved in dry microwaves, 1401C for 50 min. The reaction mixture was cooled
DMF (500 mL) in a dry flask charged with argon. The solution was to rt, added H2O (50 mL) and extracted with ethyl acetate
degassed (vacuum) and flushed with argon. Zn(14CN)2 (8 mg, (4 ꢀ 25 mL). The organic phase was dried (Na2SO4), filtered and
0.067 mmol, 263 MBq) and Pd(PPh3)4 (8 mg, 0.007 mmol) were concentrated in vacuo affording the desired product as light
J. Label Compd. Radiopharm 2009, 52 173–176
Copyright r 2009 John Wiley & Sons, Ltd.