Vol. 65, No. 12 (2017)
Chem. Pharm. Bull.
1165
(
33.7mg, 70.7µmol) was added to the reaction mixture and it (CDCl , 400MHz) δ: 1.91–2.02 (4H, m), 2.21 (6H, s), 2.23 (6H,
3
was refluxed for additional 8.5h. After addition of water and s), 2.40 (2H, t, J=7.0Hz), 2.41 (2H, t, J=7.0Hz), 3.90 (2H, t,
EtOAc, the reaction mixture was filtered through cotton and J=7.0Hz), 3.97 (2H, t, J=7.0Hz), 6.87–6.95 (5H, m), 6.99–7.07
the mixture was extracted with EtOAc. The combined organic (3H, m), 7.12–7.19 (3H, m), 7.30 (1H, d, J=2.2Hz), 7.32 (1H,
13
layer was washed with sat. aq. NaHCO followed by brine, dd, J=8.2, 2.2Hz); C-NMR (CDCl , 75MHz) δ: 25.1, 25.3
3
3
filtered and concentrated in vacuo. The resulting residue was 45.5, 45.7, 113.8 115.6, 115.8, 120.7, 122.3, 122.5, 123.0, 124.1,
purified by column chromatography (hexane–EtOAc=20:1 125.0, 125.1, 125.6, 125.9, 127.2, 127.4, 127.6, 127.9, 133.3,
then 5:1 (v/v)) and product 7 (1.57g, 3.16mmol, 90%) was 135.7, 139.2, 143.7, 145.1, 145.7, 146.3; HR-MS (ESI-TOF) m/z:
1
+
obtained as pale yellow amorphousness: H-NMR (CDCl3, Calcd for C H ClN S ([M+H] ) 601.2226. Found 601.2207;
34
38
4 2
3
00MHz, 50°C) δ: 1.32 (12H, s), 1.42 (9H, s), 2.01 (2H, quint, IR (KBr) 751, 806, 931, 1039, 1105, 1132, 1168, 1219, 1244,
−1
J=6.7Hz), 2.78 (3H, s), 3.33 (2H, t, J=6.7Hz), 3.92 (2H, t, 1457, 1573, 2765, 2940cm .
J=6.7Hz), 6.79–6.91 (2H, m), 7.06–7.17 (3H, m), 7.29 (1H, Di-tert-butyl{[8′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
13
s), 7.37 (1H, d, J=7.7Hz); C-NMR (CDCl , 75MHz, 50°C) 2-yl)-10H,10′H-(2,3′-biphenothiazine)-10,10′-diyl]-
3
δ: 24.7, 25.4, 28.3, 34.3, 44.5, 46.4, 79.1, 83.6, 115.5, 121.1, bis(propane-3,1-diyl)}bis(methylcarbamate) (9) Chloride
122.3, 125.2, 126.8, 127.1, 127.3, 129.0, 129.5, 144.6, 145.0, 8 (200mg, 259µmol) was converted to 9 as similar to con-
1
55.7; HR-MS (ESI-TOF) m/z: Calcd for C H BN NaO S version of 2 to 7, and product 9 (195mg, 225µmol, 87%)
2
7
37
2
4
+
1
(
8
[M+Na] ) 519.2465. Found 519.2446; IR (neat) 668, 684, 751, was obtained as yellow amorphousness: H-NMR (CDCl3,
23, 855, 966, 1051, 1109, 1145, 1247, 1353, 1410, 1456, 1552, 300MHz, 50°C) δ: 1.34 (12H, s), 1.41 (9H, s), 1.43 (9H, s),
−
1
1593, 1697, 2869, 2934, 2976, 3061, 3479cm .
2.06 (4H, quint, J=6.8Hz), 2.78 (3H, s), 2.81 (3H, s), 3.25–3.45
13
Di-tert-butyl {[8′-Chloro-10H,10′H-(2,3′-biphenothiazine)- (4H, m), 3.90–4.10 (4H, m), 6.82–7.45 (13H, m); C-NMR
1
0,10′-diyl]bis(propane-3,1-diyl)}bis(methylcarbamate) (8) (CDCl , 75MHz, 50°C) δ: 24.9, 25.6, 25.7, 28.5, 34.5, 34.6,
3
K CO (1.61g, 11.7mmol) and Pd(PPh ) (93.6mg, 81.0µmol) 44.8, 46.6, 79.4, 83.9, 113.9, 115.8, 120.9, 121.2, 122.7, 125.7,
2
3
3 4
were added to a solution of substrates 3 (782mg, 1.62mmol) 125.8, 127.0, 127.2, 127.6, 127.7, 129.2, 135.3, 139.6, 144.5,
and 7 (883mg, 1.78mmol) in DME (51.4mL) and H O 144.6, 145.2, 145.8, 155.8; HR-MS (ESI-TOF) m/z: Calcd for
2
+
(
17.0mL), and the obtained mixture was refluxed overnight. C H BN NaO S ([M+Na] ) 887.4023. Found 887.4009; IR
After addition of water and EtOAc, the reaction mixture was (KBr) 751, 809, 1147, 1249, 1356, 1393, 1417, 1458, 1578, 1693,
filtered through cotton and the mixture was extracted with 2929, 2977cm .
EtOAc. The combined organic layer was washed with brine, Di-tert-butyl
dried over Na SO , filtered and concentrated in vacuo. The amino]propyl}-8″-chloro-10H,10′H,10″H-[2,3′:8′,3″-
4
8
61
4
6 2
−1
[(10′-{3-[(tert-Butoxycarbonyl)(methyl)-
2
4
resulting residue was purified by column chromatography terphenothiazine]-10,10″-diyl)bis(propane-3,1-diyl)]-
hexane–EtOAc=6:1 then 4:1 (v/v)) and dimerized product 8 bis(methylcarbamate) (10) Dimer 9 (100mg, 116µmol) was
1.10g, 1.42mmol, 88%) was obtained as yellow amorphous- coupled with bromide 3 (46.8mg, 96.7µmol) to generate tri-
(
(
1
ness: H-NMR (CDCl , 300MHz, 50°C) δ: 1.41 (9H, s), 1.44 mer 10 as similar to coupling of 7 and 3. In this case NaHCO3
3
(
9H, s), 1.97–2.11 (4H, m), 2.78 (3H, s), 2.81 (3H, s), 3.35 (4H, was employed instead of K CO . Product 10 (90.6mg,
2 3
t, J=6.7Hz), 3.86 (2H, t, J=6.7Hz), 3.94 (2H, t, J=6.7Hz), 79.3 µmol, 82%) was obtained as yellow amorphousness:
13
1
6
.80–7.32, 13H, m); C-NMR (CDCl , 75MHz, 50°C) δ: 25.4,
H-NMR (CDCl , 300MHz, 50°C) δ: 1.41 (18H, s), 1.44 (9H,
3
3
25.5, 28.3, 34.5, 44.7, 44.8, 46.3, 46.5, 79.2, 79.3, 113.7, 115.6, s), 1.95–2.18 (6H, m), 2.79 (3H, s), 2.81 (3H, s), 2.83 (3H, s),
1
15.7, 115.8, 120.8, 122.4, 122.5, 123.4, 124.6, 125.4, 125.6, 3.22–3.45 (6H, m), 3.90 (2H, t, J=6.8Hz), 3.90–4.25 (4H, m),
13
125.5, 125.8, 127.1, 127.4, 127.6, 127.9, 133.3, 135.8, 139.1, 6.82–7.39 (19H, m); C-NMR (CDCl , 75MHz, 50°C) δ: 24.9,
3
1
43.6, 144.9, 145.6, 146.1, 155.6; HR-MS (ESI-TOF) m/z: Calcd 25.4, 25.6, 25.7, 28.5, 34.5, 34.7, 44.8, 44.9, 46.6, 79.4, 79.5,
+
for C H ClN NaO S ([M+Na] ) 795.2781. Found 795.2762; 114.0, 115.8, 115.9, 121.0, 121.1, 122.6, 122.7, 125.8, 125.9,
IR (neat) 732, 909, 1151, 1247, 1393, 1455, 1573, 1688, 2872, 126.0, 127.3, 127.6, 127.7, 127.8, 128.1, 133.5, 135.6, 139.5,
42
49
4
4 2
−
1
2930, 2975cm .
143.9, 144.5, 144.8, 145.2, 145.6, 145.8, 146.3, 155.9; HR-MS
+
3
,3′-[8′-Chloro-10H,10′H-(2,3′-biphenothiazine)-10,10′- (ESI-TOF) m/z: Calcd for C H ClN NaO S ([M+K] )
63
73
6
6 3
diyl]bis(N,N-dimethylpropan-1-amine) (1 (n=2)) Hydro- 1179.4079. Found 1179.4088; IR (KBr) 749, 808, 1150, 1247,
−1
gen chloride in 1,4-dioxane (4M, 2.0mL) was added to Boc 1394, 1457, 1569, 1692, 2930, 2975cm .
derivative 8 (100mg, 129µmol), and the obtained mixture was
3, 3′, 3″-[8 ″- Ch loro -10H,10′H,10 ″H- (2 , 3′:8′, 3″-
stirred for 3h. Following to addition of sat. aq. NaHCO , the terphenothiazine)-10,10,′10″-triyl]tris(N,N-dimethylpropan-
3
mixture was extracted with CH Cl and the obtained organic 1-amine) (1 (n=3)) Boc derivative 10 (25.0mg, 21.9µmol)
2
2
layer was washed with brine and dried over Na SO . After re- was converted to CPZ trimer 1 (n=3) as similar to conversion
2
4
moval of the solvent in vacuo, the crude residue was dissolved of 8 to 1 (n=2), and product 1 (n=3) (16.8mg, 19.0µmol, 87%
1
in CH Cl (3.0mL). Then formalin (aq. formaldehyde, 37% over 2 steps) was obtained as yellow amorphousness: H-NMR
2
2
(
w/w), 137µL, 5.16mmol), NaBH(OAc)3 (109mg, 516µmol), (CDCl , 400MHz) δ: 1.90–2.08 (6H, m), 2.21 (6H, s), 2.22
3
and AcOH (157µL, 2.75mmol) were added to the CH Cl solu- (6H, s), 2.23 (6H, s), 2.38–2.48 (6H, m), 3.91 (2H, t, J=6.8Hz),
2
2
tion. Following to stirring for 14h and subsequent addition of 3.98 (2H, t, J=6.8Hz), 4.00 (2H, t, J=7.2Hz), 6.87–6.97 (6H,
sat. aq. NaHCO , the mixture was extracted with CH Cl . The m), 7.00–7.09 (5H, m), 7.12–7.19 (4H, m), 7.29–7.36 (4H, m);
3
2
2
13
combined organic layer was washed with brine, dried over
C-NMR (CDCl , 75MHz) δ: 25.1, 25.3, 29.7, 45.6, 57.0, 57.2,
3
Na SO , and concentrated in vacuo. The product was purified 113.8, 115.7, 115.9, 120.7, 120.8, 122.3, 122.5, 123.0, 123.6,
2
4
by column chromatography (CHCl –MeOH–Et N=100:1:1 124.0, 125.1, 125.2, 125.4, 125.6, 125.7, 125.8, 126.0, 127.2,
3
3
(
2
v/v/v)), and CPZ dimer 1 (n=2) (68.4mg, 114µmol, 88% over 127.4, 127.6, 127.7, 127.9, 133.4, 135.3, 135.7, 139.4, 143.8,
1
steps) was obtained as yellow amorphousness: H-NMR 144.3, 145.1, 145.5, 145.7, 146.3; HR-MS (ESI-TOF) m/z: Calcd