ACS Chemical Neuroscience
Research Article
Qing Dao Marine Chemical Factory, Qingdao, China). All reactions
were monitored by thin-layer chromatography (TLC) and LCMS. 1H
NMR spectra were recorded on a Bruker Avance III 400 MHz and
Varian Mercury Plus 400 MHz, and TMS was used as an internal
standard. LCMS was taken on a quadrupole mass spectrometer on an
Agilent LC/MSD 1200 Series (column: BP-C18 (50 mm × 4.6 mm, 5
μm) operating in ES (+) or (−) ionization modes; T = 30 °C; flow
rate = 1.5 mL/min; detected wavelength = 254 nm).
Reagents and conditions: (a) Ac2O, pyridine, DCM, 0 °C, 3 h; (b)
AlCl3, 180 °C, 3 h; (c) H2SO4, HNO3, 0 °C, 30 min; (d) BnBr,
K2CO3, ACN, 70 °C, overnight; (e) DMSO, NH3·H2O, 50 °C, 2 h;
(f) DCM, BBr3, rt, 2 h; (g) 4-formylbenzonitrile, DMF, NaH, rt, 5 h;
(h) DMSO, I2, 130 °C, 1 h; (i) DMF, TFAA, rt, 3 h; (j) MeOH, Fe,
50 °C, overnight.
Preparation of CF3CN (Figure 1B). R 2. To a solution of R 1
(200 g, 1.57 mol) in DCM (2 L), pyridine (155 g, 1.96 mol) and
Ac2O (200 g, 1.96 mol) were added at 0 °C. The mixture was stirred
at 0 °C for 3 h. Ice−water (2 L) was added. The mixture was
extracted with DCM (1000 mL × 2), and the combined organic layer
was washed with brine, dried over Na2SO4, and evaporated in a
vacuum to give R 2 (190 g, yield 69%) as a red oil. 1H NMR (CDCl3,
400 MHz): δ (ppm) 2.29 (s, 3H), 6.84−6.96 (m, 3H), 7.29−7.37 (m,
1H).
R 8. To a solution of compound 7 (3 g, 15.3 mmol) in DMF (30
mL), NaH (1.8 g, 45.9 mmol) was added batchwise at 0 °C, and the
mixture was stirred at room temperature for 0.5 h. The solution of 4-
formylbenzonitrile (3.93 g, 30 mmol) in DMF (5 mL) was added to
the above solution dropwise at 0 °C. The mixture was stirred at r.t for
3 h. The mixture was quenched with water and filtered, the filtrate
cake was dried in vacuum to give R 8 (2.2 g, yield 49%) as a yellow
1
solid. H NMR (CDCl3, 400 MHz): δ (ppm) 6.49−6.52 (d, J = 9.2
Hz, 1H), 7.68 (s, 2H), 7.82−7.86 (d, J = 15.2 Hz, 1H), 7.93−7.95 (d,
J = 8 Hz, 2H), 8.07−8.12 (m, 3H), 8.23−8.25 (d, J = 9.2 Hz, 1H).
R 9. To a solution of compound 8 (2.2 g, 7.12 mmol) in DMSO
(10 mL), I2 (270 mg, 1.07 mmol) was added in one batch. The
mixture was stirred at 130 °C for 1 h. The mixture was cooled to
room temperature and quenched with ice−water (100 mL). The
precipitate was filtered, and the filtrate cake was triturated with
MeOH (10 mL × 2) to give R 9 (1.1 g, yield 50%) as a yellow solid.
1H NMR (CDCl3, 400 MHz): δ (ppm) 6.99−7.02 (d, J = 9.2 Hz,
1H), 7.23 (s, 1H), 7.87−7.90 (d, J = 9.2 Hz, 2H), 8.07−8.09 (d, J =
8.8 Hz, 2H), 8.21−8.23 (d, J = 8.8 Hz, 2H).
R 10. To a mixture of compound 9 (500 mg, 1.63 mmol) in
pyridine (10 mL), TFAA (1.03 g, 4.89 mmol) was added dropwise at
0 °C, and the mixture was stirred at room temperature for 2 h. The
mixture was diluted with water (10 mL) and extracted with EtOAc
(10 mL × 2). The organic layer was washed with HCl (0.5 M, 10 mL)
and brine (100 mL), dried over Na2SO4, and concentrated in vacuum
to give R 10 (405 mg, yield 66.7%) as a yellow solid. 1H NMR
(CDCl3, 400 MHz): δ (ppm) 7.38 (s, 1H), 7.74−7.76 (d, J = 8.4 Hz,
1H), 8.09−8.17 (m, 4H), 8.28−8.30 (d, J = 8.8 Hz, 1H).
CF3CN. To a solution of R 10 (405 mg, 1.09 mmol) and Fe (304
mg, 5.4 mmol) in MeOH (10 mL), HAc (5 mL) was added in
portions. The mixture was stirred at 50 °C for 2 h. The mixture was
filtered; the filtrate was poured into water (20 mL) and extracted with
EtOAc (20 mL × 2). The combined organic layer was washed with
water (20 mL × 2) and brine (20 mL x 2), dried over Na2SO4, and
filtered. The filtrate was concentrated to give crude product which was
purified by prep-HPLC to give CF3CN (300 mg, yield 77.9%) as a
yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.33 (s, 1H),
7.75−7.77 (d, J = 8.8 Hz, 1H), 7.98−8.00 (d, J = 8.8 Hz, 1H), 8.10−
8.12 (d, J = 8.4 Hz, 2H), 8.37−8.39 (d, J = 7.6 Hz, 2H); purity > 98%
at 220 nm, MS (ESI) m/z = 356.1 [M + H]+.
R 3. A mixture of R 2 (190 g, 1.23 mol) and AlCl3 (295 g, 2.22
mol) was stirred at 180 °C for 3 h under N2 atmosphere. The mixture
was cooled to room temperature and cold water (1 L) was added, it
was extracted with DCM (1000 mL × 2). The combined organic layer
was washed with brine (1000 mL), dried over Na2SO4, and
evaporated in vacuum to give the crude product which was purified
by column chromatography on silica gel to give R 3 (104 g, yield
67.5%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 2.62
(s, 3H), 6.63−6.69 (m, 2H), 7.73−7.79 (m, 1H), 12.60 (s, 1H).
R 4. To a solution of concentrated (conc.) H2SO4 (400 mL), R 3
(100 g, 0.65 mmol) was added at 0 °C. The conc. HNO3 (66 mL)
was added to the mixture dropwise at 0 °C for 30 min. After addition,
ice−water (2 L) was added. The mixture was extracted with EtOAc
(500 mL × 2). The combined organic layer was washed with brine
(1000 mL), dried over Na2SO4, and evaporated in vacuum to give the
residue which was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 10/1−3/1) to give R 7 (45
1
g, yield 35%) as a yellow solid. H NMR (CDCl3, 400 MHz): δ
(ppm) 2.67 (s, 3H), 6.77−6.83 (t, J = 9.0 Hz, 1H), 7.90−7.95 (dd, J
ASSOCIATED CONTENT
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= 9.0, 6.3 Hz, 1H), 13.30 (s, 1H).
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* Supporting Information
The Supporting Information is available free of charge at
R 5. A solution of R 4 (10 g, 0.05 mol), K2CO3 (13.8 g, 0.1 mol),
and BnBr (9.35 g, 0.055 mol) in ACN (100 mL) was stirred at 70 °C
overnight. The mixture was concentrated and then diluted with water
(100 mL). The mixture was extracted with EtOAc (100 mL × 2). The
combined organic layer was washed with water (200 mL) and brine
(200 mL), dried over Na2SO4, and evaporated in vacuum to give R 5
CF3CN selectively protects human TrkB stably trans-
fected BR6 cells but not SH-SY5Y cells, CF3CN
selectively binds to TrkB LRM and CC2 domains,
CF3CN decreases Aβ plaque deposition in 5xFAD mice,
CF3CN elicits TrkB and downstream signaling activation
in 5xFAD mice, 12 weeks treatment with CF3CN
demonstrates no toxic effect on tissue and blood, plasma
stability half-life data summary, microsomal intrinsic
clearance data summary, heptatocyte stability half-life
data summary, Caco-2 permeability data summary, BBB-
PAMPA permeability data summary, turbidimetric
solubility screen data summary, human plasma protein
binding data summary, mouse plasma protein binding
data summary, and percent reduction of hERG current
1
(6 g, yield 41.4%) as yellow solid. H NMR (CDCl3, 400 MHz): δ
(ppm) 2.56 (s, 3H), 5.06 (s, 2H), 7.08−7.11 (t, J = 8.7 Hz, 1H),
7.36−7.41 (m, 5H), 7.77−7.82 (dd, J = 9.0, 6.3 Hz, 1H).
R 6. To a solution of R 5 (10 g, 34.6 mmol) in DMSO (50 mL),
NH3.H2O was added dropwise at rt. The reaction was stirred at 50 °C
for 1 h. The mixture was poured into water (60 mL) and extracted
with EtOAc (50 mL × 2). The combined organic layer was washed
with water (100 mL × 3) and brine (100 mL × 2), dried over
Na2SO4, and filtered. The filtrate was concentrated to give crude R 6
1
(7.2 g, yield 83.6%) as a red oil. H NMR (CDCl3, 400 MHz): δ
(ppm) 2.52 (s, 3H), 5.00 (s, 2H), 5.35 (s, 2H), 6.58−6.60 (d, J = 8.8
Hz, 1H), 7.37−7.44 (m, 5H). 7.69−7.70 (d, J = 8.8 Hz, 1H).
R 7. To the solution of R 6 (8 g, 28 mmol) in DCM (80 mL),
boron tribromide was added dropwise at −78 °C. The reaction was
stirred at rt for 2 h. MeOH was added dropwise to the above mixture
at 0 °C. The reaction was diluted with water (100 mL) and extracted
with EtOAc (50 mL × 2). The organic layer was washed with water
(100 mL) and brine (100 mL), dried over Na2SO4, and concentrated
in vacuum to give crude product which was triturated with EtOAc to
AUTHOR INFORMATION
■
Corresponding Author
1
Keqiang Ye − Department of Pathology and Laboratory
Medicine, Emory University School of Medicine, Atlanta,
give R 7 (3 g, yield 37%) as a yellow solid. H NMR (CDCl3, 400
MHz): δ (ppm) 2.70 (s, 3H), 8.01−8.04 (d, J = 12.2 Hz, 2H).
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ACS Chem. Neurosci. 2021, 12, 2448−2461
Chen, Chun
