X. Zhao et al. / European Journal of Medicinal Chemistry 182 (2019) 111625
9
and all other solvents and chemical reagents were purchased from
4.5. The synthesis of 4b
The compound 2b (352 mg, 2 mmol) was dissolved in anhydrous
commercial sources and without further purification or treatment.
All performed reactions were carried out under an atmosphere of
nitrogen.
CH
2
Cl2. EDCI (765 mg, 4 mmol) and HoBt (540 mg, 4 mmol) was
1
ꢁ
Instruments: The H NMR spectra were measured on a Bruker
added. The reaction was stirred at 0 C for 3 h. Then 3b (450 mg,
AVANCE III 400 MHz NMR instrument at 298 K by using CDCl
3
or
3
3 mmol) and Et N (486 mg, 4 mmol) was added to the solution. The
DMSO‑d as solvent. Chemical shifts are expressed in ppm relative
6
reaction was stirred at room temperature overnight. the mixture
was washed with an aqueous HCl solution, the organic layer was
dried with MgSO4, filtered and concentrated under reduced press.
The mixture was further purified by column chromatography. The
to tetramethylsilane (TMS) (0 ppm). HRMS analyses were carried
out on LC-QTOF-MS (G6520B/G6520B). Electronic absorption
spectra were recorded on the Hitachi UH4150 UV-Visible-NIR
Spectrophotometer. Fluorescence spectra were recorded on F-
product was isolated as a white viscous solid. Yield 414 mg,67.2%.
1
4
600 Hitachi Fluorescence Spectrometer. The used Microplate
H NMR (400 MHz, CDCl
3
)
d
7.77e7.69 (m, 4H), 7.26 (t, J ¼ 2.8 Hz,
@
reader was SpectraMax i3x. The mentioned confocal laser scan-
ning microscopy (CLSM) images were performed on an Olympus
FV1000-IX81 CLSM and a Leica TCSSP confocal system (Leica,
Germany).
2H), 6.95 (dd, J ¼ 8.7, 2.2 Hz, 2H), 6.87 (s,1H), 4.72 (d, J ¼ 2.4 Hz, 2H),
3.54 (d, J ¼ 5.7 Hz, 2H), 3.17 (t, J ¼ 5.3 Hz, 2H), 2.55 (t, J ¼ 2.5 Hz, 1H),
13
3
2.39 (s, 3H). C NMR (101 MHz, CDCl ) d 167.81, 160.09, 143.48,
136.60, 129.78, 128.98, 126.95, 126.88, 114.53, 78.00, 76.17, 55.81,
þ
4
3
2.99, 39.90, 21.50. HRMS (ESI) m/z calcd C19
95.1041, found 395.1036.
H
20
N
2
O
4
S [MþNa] :
4.2. The synthesis of 1b
4.6. The synthesis of 5b
The methyl 4-hydroxybenzoate (0.913 g, 6 mmol) was dissolved
in acetone (100 ml). Then anhydrous K
2
CO
3
(2.484 g, 18 mmol) and
Compound 4b (246 mg, 0.8 mmol) and 2-(2-(2-azidoethoxy)
ethoxy) ethan-1-ol (140 mg, 0.8 mmol) was dissolved in THF (5 ml).
The mixture of CuSO O (15 mg) and sodium ascorbate (30 mg)
were added in EtOH (0.5 ml) and water (0.5 ml). The reaction
mixture stirred for 24 h at room temperature. After completed, the
reaction was extracted with CH Cl and H O three times and the
2 2 2
organic layer was evaporatd under reduced pressure. The residue
was further purified by silica gel column chromatography using
propargyl bromide (0.857 g, 7.2 mmol) were added. The reaction
refluxed overnight under nitrogen atmosphere. After it was
completed, the mixture was concentrated under reduced pressure
4
ꢂ5H
2
and the crude product was washed with CH
times. The organic phase was dried over anhydrous Na
removal of Na SO by filtration, the filtrate was concentrated under
reduced pressure, then the crude product was further purified by
column chromatography using CH Cl as eluent. The product was
isolated as a white solid. Yield: 1.130 g, 69.5%. H NMR (400 MHz,
CDCl
2
Cl
2
and H
2
O three
2
SO
4
. After
2
4
2
2
CH
colorless oily substance. Yield: 301 mg, 78.0%. H NMR (400 MHz,
CDCl
7.90 (s, 1H), 7.72 (dd, J ¼ 8.5, 3.9 Hz, 4H), 7.24 (d, J ¼ 7.9 Hz,
2H), 7.09 (t, J ¼ 4.5 Hz, 1H), 6.95 (d, J ¼ 8.4 Hz, 2H), 5.30 (s, 1H), 5.23
s, 2H), 4.57 (t, J ¼ 4.9 Hz, 2H), 3.88 (t, J ¼ 4.9 Hz, 2H), 3.70 (t,
J ¼ 4.6 Hz, 2H), 3.58 (s, 4H), 3.53 (q, J ¼ 7.0, 5.9 Hz, 4H), 3.16 (t,
2
Cl
2
: MeOH ¼ 10:1 as mobile phase. The product was isolated as
1
1
3
)
d
8.01 (d, J ¼ 8.8 Hz, 2H), 7.00 (d, J ¼ 8.4 Hz, 2H), 4.75 (s, 2H),
3
) d
3
.89 (s, 3H), 2.55 (t, J ¼ 2.2 Hz, 1H).
(
1
3
4.3. The synthesis of 2b
J ¼ 5.4 Hz, 2H), 2.38 (s, 3H). C NMR (126 MHz, CDCl
3
) d 167.85,
1
60.72, 143.36, 143.17, 136.81, 129.72, 129.07, 126.91, 126.68, 124.70,
The compound 1b (1.620 g, 6 mmol) was dissolved in 100 ml
114.43, 72.45, 70.41, 70.09, 69.18, 61.65, 61.48, 50.31, 42.97, 39.86,
þ
methol. Sodium hydroxide (1.200 g, 30 mmol) in 4 ml water was
21.45. HRMS (ESI) m/z calcd for C25
H N
33 5
O
7
S [MþNa] :570.1998,
ꢁ
added into the reaction mixture. The reaction stirred at 80 C under
found: 570.1989.
2
N atmosphere for 8 h. The volatiles was evaporated under reduced
pressure. The residue was mixed with water, and then the pH of the
mixture was adjusted to 1 with HCl solution. The mixture was
4.7. The synthesis of 6b
washed with ethyl acetate and H
2
O three times. The organic phase
. After removal of Na SO by
Erlotinib (0.944 mg, 2.4 mmol) and 2-(2-(2-azidoethoxy)
ethoxy) ethan-1-ol (420 mg, 2.4 mmol) was dissolved in THF
was dried over anhydrous Na SO
2
4
2
4
filtration, the filtrate was concentrated under reduced pressure,
then the crude product was purified by using ethyl acetate as eluent
through column chromatography. The product was isolated as a
(10 ml). The mixture of CuSO
bate (240 mg) were added in EtOH (1.0 ml) and water (1.0 ml). The
reaction mixture was stirred for 24 h at room temperature. After
4
ꢂ5H
2
O (120 mg) and sodium ascor-
white solid. Yield: 1.004 g, 95.0%. 1H NMR (400 MHz, DMSO‑d
)
6
2 2 2
the reaction was completed, it was extracted with CH Cl and H O
d
2
12.66 (s, 1H), 7.91 (d, J ¼ 7.2 Hz, 2H), 7.07 (d, J ¼ 7.6 Hz, 2H), 4.89 (s,
three times and the organic layer was evaporatd under reduced
pressure. The residue was further purified by silica gel column
H), 3.62 (d, J ¼ 2.5 Hz, 1H).
chromatography using CH
2
Cl
2
: MeOH ¼ 10:1(v/v) as mobile phase.
The product was isolated as yellow oily substance. Yield: 1.268 g,
1
4
.4. The synthesis of 3b
93.0%. H NMR (400 MHz, CDCl 8.56 (s, 1H), 8.16 (s, 1H), 7.97 (d,
3
) d
J ¼ 8.2 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J ¼ 7.6 Hz, 1H), 7.54 (s, 1H), 7.42
(d, J ¼ 7.9 Hz, 1H), 7.22 (s, 1H), 4.59 (t, J ¼ 4.4 Hz, 2H), 4.38e4.33 (m,
2H), 4.28e4.23 (m, 2H), 3.89 (d, J ¼ 4.1 Hz, 2H), 3.84 (s, 4H),
3.81e3.77 (m, 2H), 3.66 (d, J ¼ 1.7 Hz, 4H), 3.64e3.59 (m, 2H),
3.50e3.45 (m, 6H).
The ethylenediamine (1.500 g, 25 mmol) was dissolved in
CH Cl (100 ml). TsCl (0.953 g, 5 mmol) in CH Cl (20 ml) was added
2 2 2 2
dropwise over 2 h. The reaction stirred at room temperature
overnight. The reaction was monitored by TLC. After the reaction
was completed, the mixture was concentrated under reduced press.
The residue was purified by column chromatography using CH
2
Cl
2
:
4.8. The synthesis of PEG-Pc
MeOH ¼ 10:1(v/v) as eluent. The product was isolated as a white
1
solid. Yield: 846 mg, 79.0%. H NMR (400 MHz, CDCl
3
)
d
7.76 (d,
A mixture of silicon (IV) phthalocyanine dichloride (122 mg,
0.20 mmol), Triethylene glycol monomethyl ether (328 mg,
2.00 mmol), and NaH (23 mg, 1.00 mmol) in toluene (15 mL) was
J ¼ 7.4 Hz, 2H), 7.27 (d, J ¼ 7.6 Hz, 2H), 4.80 (s, 3H), 3.04 (d,
J ¼ 4.6 Hz, 2H), 3.01e2.91 (m, 2H), 2.39 (s, 3H).