WEN ET AL.
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2.2.2 | Synthesis of 18F-FHep-α-L-Glu
precursor compound 6
proceed under stirring and RT for 24 hours. After that,
the mixture was diluted with water, extracted with dic-
hloromethane (3 * 100 mL). Then the organic layer was
washed with 10% citric acid solution (200 mL), satu-
rated sodium bicarbonate solution (200 mL), water
(200 mL) ,and saturated sodium chloride solution
(200 mL) in turn. At last, the organic layer was dried
over Na2SO4, the solvent removed from filtrate on a
rotary evaporator under vacuum, and the crude product
purified by silica gel column chromatography to give
To a solution of L-glutamic acid (14.7 g, 100 mmol) in
tert-butyl acetate (66 mL) was slowly added perchloric
acid at 0ꢀC. The mixture was stirred for 48 hours at RT
and then quenched with saturated sodium bicarbonate.
The mixture was extracted with EtOAc, and the organic
layer was washed with citric acid (10%), water and satu-
rated sodium chloride solution, respectively. Light yellow
oily compound 2 obtained by vacuum concentration
1
compound 6 (2.20 g, 81%). H-NMR (600 MHz, CDCl3)
1
(6.64 g, 26%). H-NMR (400 MHz, CDCl3) δ 3.33 (dd,
δ 7.79 (d, J = 7.7 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H),
4.14-3.83 (m, 3H), 3.35 (dd, J = 48.0, 32.2 Hz, 1H), 2.87
(dd, J = 13.6, 8.1 Hz, 1H), 2.45 (s, 3H), 2.35-1.91 (m,
4H), 1.59-1.52 (m, 1H), 1.44 (s, 27H), 1.37-1.17 (m,
7H).13C-NMR (101 MHz, CDCl3) δ 171.43, 169.48,
169.29, 154.31, 154.07, 143.66, 132.15, 128.81, 126.85,
80.24, 80.12, 79.44, 79.34, 79.24, 78.75, 75.75, 69.52,
69.45, 59.31, 58.76, 47.54, 46.57, 31.12, 30.88, 28.67,
28.09, 27.81, 27.35, 27.09, 27.01, 26.76, 25.48, 25.36,
24.43, 24.14, 23.80, 20.61.
J = 8.2, 5.3 Hz, 1H), 2.35 (t, J = 7.6 Hz, 2H), 2.05-1.71 (m,
2H), 1.46 (d, J = 7.9 Hz, 18H).
Compound c and sodium triacetoxyborohydride were
added to a solution of compound 2 (5.20 g, 20 mmol) in
1,2-dichloroethane solution in sequence at 0ꢀC, and the
mixture reacted at RT overnight. The solution was
quenched with 200 mL water and extracted with dic-
hloromethane. The organic layer was washed with water
and saturated sodium chloride solution and was dried
with anhydrous sodium sulfate. At last, the crude product
3 was obtained by rotary evaporator under vacuum
heating conditions.
To crude compound 3 in 100 mL dichloromethane
was added di-tert-butyl dicarbonate, and the mixture was
stirred overnight at RT. Then, the organic phase was
removed with a rotary evaporator. Next, the residual mix-
ture was purified by silica gel column chromatography to
afford compound 4.
2.2.3 | Synthesis of 18F-FHep-α-L-Glu
standard compound 8
To the solution of compound 6 (800 mg, 1.30 mmol) in
anhydrous acetonitrile, tetrabutylammonium fluoride
(1 N) in tetrahydrofuran was dropwise added. The mix-
ture was heated to reflux for 5 hours. After the reaction
finished, the solvent was removed from filtrate on a
rotary evaporator. Then, the residuum was diluted with
20 mL water and extracted with EtOAc. The organic layer
was washed with 50 mL water and 50 mL saturated
sodium chloride solution and was dried over Na2SO4. At
last, the solvent was removed by rotary evaporator, and
the residue was purified by silica gel column chromatog-
raphy to give compound 7 (450 mg, 75%).
To compound 4 in 100 mL methanol was added 20%
Pd (OH)2/C, and the mixture was stirred overnight with
hydrogen (1 atm) flow at RT. After the reaction finished,
the reaction solution was filtrated with diatomite, and
then the filter residue was washed with methanol. The
solvent was removed from filtrate on a rotary evaporator
under reduced pressure to give crude compound 5. The
pure compound 5 (2.42 g, 27%) was obtained by silica gel
1
column chromatography. H-NMR (400 MHz, CDCl3) δ
1H-NMR (400 MHz, CDCl3) δ 4.43 (dt, J = 47.4,
5.6 Hz, 2H), 4.15-3.83 (m, 1H), 3.50-3.26 (m, 1H), 3.00-
2.84 (m, 1H), 2.36-2.20 (m, 3H), 2.10-1.93 (m, 1H),
1.761.53 (m, 4H), 1.45 (d, J = 5.7 Hz, 27 H), 1.31 (ddd,
J = 22.1, 14.0, 4.2 Hz, 4H).
4.18-4.04 (m, 1H), 3.87 (d, J = 4.6 Hz, 1H), 3.63 (d,
J = 5.6 Hz, 2H), 3.53-2.83 (m, 2H), 2.41-1.92 (m, 4H),
1.65-1.52 (m, 4H), 1.45 (d, J = 5.1 Hz, 27H), 1.39-1.24 (m,
4H). 13C-NMR (101 MHz, CDCl3) δ 172.49, 171.18,
170.54, 170.33, 155.40, 155.20, 81.81, 81.26, 81.13, 80.47,
80.32, 79.72, 67.00, 62.70, 62.66, 62.43, 60.38, 60.30, 59.78,
48.43, 47.69, 32.65, 32.56, 32.16, 31.92, 29.27, 28.66, 28.48,
28.35, 28.21, 28.08, 28.01, 27.77, 26.87, 26.37, 25.56, 25.44,
25.38, 25.14, 24.79, 21.01, 14.16.
To the solution of compound 5 (2.04 g, 4.44 mmol),
4-dimethylaminopyridine (0.20 g, 1.64 mmol),
triethylamine (0.90 g, 8.89 mmol), and dichloromethane
(70 mL) were added p-toluenesulfonyl chloride (PTSC)
(1.02 g, 5.37 mmol). The reaction was allowed to
13C-NMR (101 MHz, CDCl3) δ 172.46, 170.52, 170.33,
155.36, 155.09, 84.82, 83.18, 81.23, 81.11, 80.44, 80.33,
80.24, 79.74, 60.32, 59.79, 48.67, 47.66, 32.14, 32.03, 31.88,
30.46, 30.26, 29.30, 29.20, 28.53, 28.37, 28.08, 28.01, 27.82,
26.70, 26.64, 25.42, 24.99, 24.93, 24.80.
19F-NMR (376 MHz, CDCl3) δ −217.95 to −218.45 (m,
1 F).
Compound 7 (400 mg, 1.10 mmol) was added to
trifluoroacetic acid (TFA, 30 mL) and dichloromethane
(3 mL) mixture, and the reaction mixture was kept