Sep-Oct 2001
Synthesis of Regioisomeric 2,5-Bis-substituted-Aza-Benzothiopyranoindazoles
1165
eluent. The initial eluent was 5:1 with gradual changes to 1:1,
which eluted the product. Concentration of the product fractions
led to 52b (50%), mp 168-170°; H nmr (deuteriochloroform): δ
(d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.88 (br s, 1H), 4.38
(t, J = 6.9 Hz, 2H), 3.32 (d, J = 5.4 Hz, 4H), 2.86 (t, J = 6.9 Hz,
2H), 2.33 (s, 6H), 1.49 (s, 9H).
1
Anal. Calcd. for C H N O S C, 60.77; H, 6.65; N, 18.49.
Found: 60.54; H, 6.42; N, 18.90.
8.39 (d, J = 5.0 Hz, 1H), 7.85 (br s, 1H), 7.77 (d, J = 5.0 Hz, 1H),
7.39 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 5.43 (br s, 1H),
4.37 (t, J = 6.8 Hz, 2H), 4.00 (d, J = 5.9 Hz, 2H), 2.82 (t, J = 6.8
Hz, 2H), 2.30 (s, 6H), 1.52 (s, 9H).
23 30
6 2
N'-[2-(Dimethylamino)ethyl]-2H-pyrido[3',2':5,6]thiopyrano-
[4,3,2-cd]indazol-5-yl-1,2-ethanediamine Trihydrochloride (56a).
Anal. Calcd. for C H N O S: C, 58.96; H, 6.02; N, 17.94.
23 28
6 3
Using method C, 45a was converted into 56a (95%), mp
Found: 58.72; H, 5.93; N, 17.94.
1
>260°; H nmr (deuterium oxide): δ 8.23 (dd, J = 4.8, 1.4 Hz,
1,1-Dimethylethyl [2-[[2-(Dimethylamino)ethyl]-2H-pyrido-
[3',4':5,6]-thiopyrano-[4,3,2-cd]indazol-5-yl]amino]-2-
oxoethyl]carbamate (53c).
1H), 8.09 (dd, 7.8, 1.4 Hz, 1H), 7.26 (dd, J = 7.8, 4.9 Hz, 1H),
7.13 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 5.9
Hz, 2H), 3.79 ( t, J = 5.9 Hz, 2H), 3.59 (t, J = 6.2 Hz, 2H), 3.34
(t, J = 6.2 Hz, 2H), 3.05 (s, 6H).
Analogue 21c was converted into 53c using Method I. After
Anal. Calcd. for C H N S•3HCl•2H O: C, 43.25; H, 5.85;
18 22
6
2
purification over silica gel using methanol:ethyl acetate (1:1)
N, 16.81. Found: C, 43.02; H, 5.63; N, 16.72.
1
53c (43%) was obtained, mp 155-156°; H nmr (deuterio-
chloroform): δ 9.17 (s, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.70
(br s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 5.4 Hz, 1H),
7.00 (d, J = 8.8 Hz, 1H), 5.21 ( br s, 1H), 4.40 (t, J = 6.9 Hz,
2H), 3.99 (d, J = 6.0 Hz, 2H), 2.84 (t, J = 6.9 Hz, 2H), 2.33 (s,
6H), 1.48 (s, 9H).
N'-[(2-Hydroxyethyl]amino]-2H-pyrido[3':2':5,6]thiopyrano-
[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine Dihydrochloride (57a).
Using Method C, 46a was converted into 57a (quantitatively);
H nmr (deuterium oxide): δ 8.22 (dd, J = 4.7, 1.5 Hz, 1H), 8.14
1
(dd, J = 7.8, 1.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.9
Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 7.8 Hz, 4.7 Hz,
1H), 4.40 (t, J = 4.8 Hz, 2H), 4.03 ( t, J = 4.8 Hz, 2H), 3.48 (t, J =
5.9 Hz, 2H), 3.20 ( t, J = 5.9 Hz, 2H).
Anal. Calcd. for C H N O S: C, 58.96; H, 6.02; N, 17.94.
23 28
6 3
Found: C, 58.72; H, 6.35; N, 17.86.
N'-[2-(Dimethylamino)ethyl-2H-pyrido[3',2':5,6]thiopyrano-
[4,3,2-cd]indazole-5-yl]-N-methyl-1,2-ethanediamine (54a).
Anal. Calcd. for C H N OS•2HCl: C, 48.00; H, 4.78; N,
16 17
5
17.71. Found: C, 48.18; H, 5.11; N, 17.56.
(Method K). To a suspension of lithium aluminum hydride
(0.040 g, 1.05 mmoles) in tetrahydrofuran (5.0 ml), 51a (0.10 g,
0.21 mmole) was added as a solution in tetrahydrofuran (2 ml).
The resultant suspension was heated at reflux for 5 hours. The
mixture was cooled in an ice bath, quenched with water and
sodium potassium tartrate was added. The products were
extracted with dichloromethane (5 ml), the extracts dried over
magnesium sulfate and concentrated to dryness. The resultant
crude orange solid was purified by flash chromatography over
silica gel initially eluting with methanol:dichloromethane 7:93 to
afford 45a (0.010 g, 13%). The second part of the eluent led to a
N'-[2-[(Aminoethyl)-2H-pyrido[3',2':5,6]thiopyrano[4,3,2-
cd]indazol-5-yl]-1,2-ethanediamine Trihydrochloride (58a).
Following Method C 47a was quantitatively converted into
1
58a; H nmr δ 7.87 (dd, J = 4.5, 1.6 Hz, 1H), 7.58 (dd, J = 7.6, 1.6
Hz, 1H), 7.28 (d, J = 9.1 Hz, 1H), 6.98 (dd, J = 7.6, 4.5 Hz, 1H),
6.55 (d, J = 9.1 Hz, 1H), 4.25 (m, 4H), 3.35 (m , 4H).
Anal. Calcd. for C H N S•3HCl•H 0: C, 42.25; H, 5.11; N,
16 18
6
2
18.52. Found: C, 42.31: H, 5.011; N, 18.04.
N'-[2-[2-(Dimethylamino)ethyl-2H-pyrido[4',3':5,6]thiopyrano-
[4,3,2-cd]indazol-5-yl]-1,2-ethanediamine Trihydrochloride (59b).
1
product (Figure 6) (0.020 g, 26%), mp 150-152°; H nmr
(deuteriochloroform): δ 8.33 (dd, J = 4.6, 1.7 Hz, 1H), 8.22
(dd, J = 7.8, 1.7 Hz, 1H), 7.21 (d, J = 8,8 Hz, 1H), 7.13 (dd, J =
7.8, 4.6 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.38 (s, 1H), 4.39 ( t, J
= 6.9 Hz, 2H), 3.83 (t, J = 7.7 Hz, 2H), 3.60 (t, J = 7.7 Hz, 2H),
2.81 (J, J = 6.9 Hz, 2H), 2.30 (s, 6H). The third fractions which
eluted with methanol:dichloromethane:ammonium hydroxide
Protected analogue 48b was converted to 59b (98%) using
method C; 'H nmr (deuterium oxide): δ 8.57 (s, 1H), 8.42 (d, J =
5.7 Hz, 1 H), 7.97 (d, J = 5.7 Hz, I H), 7.31 (d, J = 8.9 Hz, 1 H),
7.23 (d, J = 8.5 Hz, I H), 4.85 (t, J = 5.8 Hz, 1 H), 3.87 (t, J = 5.8
Hz, I H), 3.63 (t, J = 5.8 Hz, 2H), 3.35 (t, J = 5.8 Hz, 2), 3.0 (s, 6H).
.
.
Anal. Calcd for C H N S 3HCl 2H O: C, 43.25; H, 5.85; N,
18 22
6
2
1
50:50:1 led to 54a (0.030 g, 38%), mp 114-115°; H nmr
16.81. Found: C, 43.13; H, 5.92; N, 16.51.
(deuteriochloroform): δ 8.27 (dd, J = 4.7, 1.8 Hz, 1H), 8.14 (dd,
J = 7.8, 1.8 Hz, 1H), 7.08 (dd, J = 7.8, 4.7 Hz, 1H), 6.89 (d, J =
8.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.34 (t, J = 7.1 Hz, 2H),
3.30 (t, J = 5.7 Hz, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.80 (t, J = 7.1
Hz, 2H), 2.47 (s, 3H), 2.30 (s, 6H).
N'-[2-Hydroxyethyl]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-cd]-
indazol-5-yl]-1,2-ethanediamine Dihydrochloride (60c).
1
Treatment of 49c as in method C led to 60c (98%); H nmr
(deuteriium oxide): δ 8.75 (s, 1H), 7.68 (d, J = 5.3 Hz, 1H), 7.54
(d, J = 8.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 5.3 Hz,
1H), 4.39 (t, J = 4.8 Hz, 2H), 4.07 (t, J = 4.8 Hz, 2H), 3.45 (t, J =
5.9 Hz, 2H), 3.15 (t, J = 5.9 Hz, 2H).
Anal. Calcd. for C
H N S: C, 61.59; H, 7.07; N, 22.68.
19 26 6
Found: C, 61.48; H, 6.75; N, 22.48.
1,1-Dimethylethyl [2-[[2-(2-Dimethylaminoethyl)-2H-
pyrido[3',4':5,6]-thiopyrano[4,3,2]indazol-5-yl]amino]ethyl]-
carbamate (55c).
Anal. Calcd. for C H N OS•2HCl•H O: C, 45.95; H, 5.06;
16 17
5
2
N. 16.75. Found: C, 46.21; H, 5.31; N, 17.01.
N'-[2-(Aminoethyl)amino]-2H-pyrido[3',4':5,6]thiopyrano[4,3,2-
cd]indazol-5-yl]-1,2-ethanediamine Dihydrochloride (61c).
Following method J, 53c led to crude 55c which was purified
by column chromatography over silica gel using methanol:-
chloroform as the eluent to yield 55c (30%) as a yellow solid; mp
Following method C, 50c was converted into 61c (quanti-
1
1
123-125°; H nmr (deuteriochloroform): δ 9.10 (s, 1H), 8.25
tatively); H nmr (deuterium oxide): δ 8.79 (d, J = 6.5 Hz,
(d, J = 5.4 Hz, 1H), 7.35 (br s, 1H), 7.11 (d, J = 5.4 Hz, 1H), 6.95
1H), 8.23 (d, J = 6.5 z, 1H), 7.76 (d, J = 6.5 Hz, 1H), 7.21