7
726 Li et al.
Asian J. Chem.
was added to keep the pH of the solution was 7-8. The residue
EXPERIMENTAL
was extracted with 60 mL of CH
by flash chromatography (ethyl acetate) to afford compound
2 2
Cl . The crude was purified
All the chemicals were purchased from Guangfu
1
Technology Development Co., Ltd., Tianjin (China) and Chase
Sun Pharmaceutical Co., Ltd., Tianjin (China) unless otherwise
stated. All reagents were used as purchased from commercial
suppliers without further purification. Solvents were dried and
purified according to standard procedures before use. The
course of reactions was monitored by TLC (silica gel GF254s),
Flash chromatography was performed using 200~300 mesh
3
3 (3.91 g, 75 %) dense yellow oil. H NMR (400 MHz, CD OD)
δ: 9.87 (s, 1 H), 8.93 (d, J = 5.8 Hz, 1 H), 8.72 (s, 1 H), 8.61
(d, J = 7.3 Hz, 2 H), 7.92 (t, J = 7.4 Hz, 1 H), 4.14 (s, 1 H),
3.78 (d, J = 11 Hz, 1 H), 3.66-3.50 (m, 1 H), 3.40 (d, J = 16.5
13
3
Hz, 2 H), 2.18-1.56 (m, 5 H). C NMR (100 MHz, CD OD)
δ: 25.12, 30.46, 47.69, 49.47, 50.87, 62, 124.20, 130.17,
131.45, 134.51, 136.13, 136.72, 137.68, 140.17, 149.80.
(R)-6H-1-(5-Isoquinolinesulfonyl)-2-carboxyl-1-pyrro-
lidine (4#): Isoquinoline sulfonyl chloride hydrochloride (2
g, 7.60 mmol) was dissolved in 25 mL ice water to keep the
temperature at 0-5 °C. To solution of isoquinoline sulfonyl
chloride hydrochloride was added dropwise to L-proline (1 g,
8.69 mmol) and sodium carbonate (1.11 g, 10.4 mmol) in 25
mL ice water. The reaction was keep to 0-5 °C for 2 h. The
aqueous layer was concentrated. The residue was extracted
1
13
silica gel. H and C NMR spectra were recorded on INOVA
00/600 Hz spectrometer with TMS as an internal standard.
HR-MS was recorded on MicroOTOF-Q II.
4
Fasudil nitrogen oxides (1#): Fasudil hydrochloride (5 g,
3.7 mmol) was slowly added to a saturated sodium bicar-
1
bonate solution (2.50 g, 20 mmol), the pH of the solution was
kept at 5-6. The mixture was stirred for 0.5 h and extracted
2 2
with 80 mL of CH Cl . The organic layer was dried over anhy-
drous Na SO , filtered and concentrated. The M-chloropero-
2
4
3
with 30 mL CH OH. The crude was purified by flash chroma-
xybenzoic acid (2.50 g, 14.5 mmol) was added dropwise to
the organic layer in 35 mL dichloromethane. The reaction
mixture was stirred at 30 °C for 1 h. The organic layer was
tography (ethyl acetate) to afford compound 4 (0.23 g, 14 %)
1
dense yellow oil; H NMR (600 MHz, CDCl ) δ: 9.47 (s, 1H),
3
8.87-8.62 (d, J = 9.6 Hz, 2H), 8.67 (s, 1H), 8.55 (d, J = 10.8
Hz, 1H), 8.37 (s, 1H), 7.86 (t, J = 11.7 Hz, 1H), 4.27 (t, J =
11.4 Hz, 1H), 3.5 (m, 1H), 2.47-2.45 (m, 2 H), 2.16-2.13 (m,
2 4
dried over anhydrous Na SO , filtered and concentrated. The
crude was purified by flash chromatography (ethyl acetate) to
1
afford compound 1 (4.49 g, 82.17 %) yellow oil. H NMR
13
3
2H), 2.13-2.09 (m, 2H). C NMR (150 MHz, CDCl ) δ: 25.86,
(
400 MHz, CDCl
3
) δ: 9.42 (s, 1 H), 8.74 (s, 2 H), 8.49 (d, J =
.3 Hz, 1 H), 8.29 (d, J = 8.1 Hz, 1 H), 7.78 (t, J = 7.8 Hz,
H), 3.97-3.82 (m, 1 H), 3.71 (d, J = 11.4, 4.9 Hz, 2 H), 3.56-
32.25, 53.44, 61.93, 123.94, 130.04, 131.25, 135.25, 136.27,
137.76, 139.81, 149.95, 174.07, 175.26.
7
1
3
(S)-6H-1-(5-Isoquinolinesulfonyl)-2-carboxyl-1-
pyrrolidine (5#): Following similar compound 4 procedure,
compound 5 was prepared from D-proline. The crude was
purified by flash chromatography (ethyl acetate) to afford
13
.32 (m, 2 H), 1.99-1.70 (m, 3 H), 1.66-1.51 (m, 1 H).
) δ: 14.79, 21.38, 25.13, 30.53, 61.78,
04.15, 127.04, 129.33, 131.52, 134.22, 134.28, 136.16,
37.20, 173.24.
S)-6H-1-(5-Isoquinolinesulfonyl)-2-hydroxymethyl-1-
pyrrolidine (2#): Isoquinoline sulfonyl chloride hydrochloride
5 g, 18.9 mmol) was slowly added to a saturated sodium
C
NMR (100 MHz, CDCl
3
1
1
1
compound 5 (0.23 g, 14 %) dense yellow oil; H NMR (600
(
3
MHz, CDCl ) δ: 9.47 (s, 1H), 8.87-8.82 (d, J = 9.6 Hz, 2H),
8.67 (s, 1H), 8.55 (d, J = 10.8 Hz, 1H), 8.37 (s, 1H), 7.86 (t,
J = 11.7 Hz, 1H), 4.27 (t, J = 11.4 Hz, 1H), 3.5 (m, 1H), 2.47-
(
13
bicarbonate solution (2.52 g, 30 mmol), the pH of the solution
was kept at 5-6. The mixture was stirred 0.5 h and extracted
2.45 (m, 2 H), 2.16-2.13 (m, 2H), 2.13-2.09 (m, 2H). C NMR
(150 MHz, CDCl ) δ: 25.86, 32.38, 53.39, 61.84, 123.73,
3
with 20 mL CH
concentrated. The residue dissolved in 20 mL CH
added dropwise to the flask containing D-prolinol (2.29 g,
2.6 mmol) and triethylamine (1.91 g, 18.9 mmol). The
2
Cl
2
. The organic layers were dried and
130.04, 131.25, 135.25, 136.17, 137.62, 139.76, 149.92,
174.07, 175.26.
2
Cl was
2
(R)-6H-1-(5-Isoquinolinesulfonyl)-2-fluorinated-
methyl-1-pyrrolidine (6#): To a solution of methanesulfonyl
chloride (1.71 g ,15 mmol) was added dropwise to (R)-6H-1-
(5-isoquinolinesulfonyl)-2-hydroxymethyl-1-pyrrolidine
(3.80 g, 13 mmol) and triethylamine (1.85 g, 18.3 mmol) in
40 mL dichloromethane. The reaction mixture was stirred at
0-5 °C for 2 h. The organic layer was washed with 20 mL
water for twice. And then the organic layer was dried and
concentrated, afford yellow oil (4.30 g, 90.3 %); to solution
the tetrabutylammonium fluoride (1.88 g, 7.2 mmol) was added
dropwise to the yellow oil (4.30 g, 11.6 mmol) dissolved in
30 mL tetrahydrofuran. The reaction mixture was stirred at 65
°C for 8 h and then tetrabutylammonium fluoride was distilled.
The crude was purified by flash chromatography (ethyl acetate:
petroleum ether = 2:1, v/v) to afford compound 6 (0.92 g, 27
2
mixture was stirred at 0-5 °C for 2 h. Then it was concentrated
and the residue was dissolved in 50 mL ethyl acetate. The
organic layer was washed with 20 mL water for three times.
After dried and concentrated, the residue was purified by flash
chromatography (ethyl acetate) to afford compound 2 (5.29
1
g, 95 %) yellow oil. H NMR (400 MHz, CDCl
3
) δ: 9.42 (s,
1
1
1
1
5
1
H), 8.74 (s, 2H), 8.49 (d, J = 7.3 Hz, 1H), 8.29 (d, J = 8.1 Hz,
H), 7.78 (t, J = 7.8 Hz, 1H), 3.97-3.82 (m, 1H), 3.71 (dd, J =
1.4, 4.9 Hz, 2H), 3.56-3.32 (m, 2H), 1.99-1.70 (m, 2H), 1.66-
13
.51 (m, 2H). C NMR (100 MHz, CDCl ) δ: 25.27, 29.39,
3
0.44, 62.70, 65.04, 124.31, 130.13, 131.35, 134.52, 136.42,
36.71, 137.41, 139.97, 149.74.
(
S)-6H-1-(5-Isoquinolinesulfonyl)-2-chloromethyl-1-
1
pyrrolidine (3#): Compound 2 (5 g, 0.02 mol) was added to
thionyl chloride (20 mL, 0.27 mol) and the reaction mixture
was stirred at 40 °C for 8 h. And then thionyl chloride was
distilled. The saturated aqueous solution of sodium bicarbonate
%) dense yellow oil; m.p.: 178.2-179.1 °C. H NMR (600 MHz,
CDCl ) δ: 10.23 (d, J = 10.7 Hz, 1H), 9.25 (d, J = 6.8 Hz, 1H),
3
8.97-8.65 (m, 2H), 8.11 (t, J = 7.8 Hz, 1H), 7.28 (s, 1H), 4.34
(m, 1H), 4.20 (m, 1H), 3.75-3.67 (m, 2H), 2.13-2.10 (m, 2H),