Page 13 of 22
Journal of Medicinal Chemistry
and 1.31 (CH3, 3H, t, JCH3-CH2 = 7.1Hz). MS : M+H+ = 195.0
(exact mass of C9H10N2OS : 194.05).
0.96 (CH2cPr, 4H, m). HRMS
C11H10FN2OS : 237.0492 and mass found : 237.0498.
: Mass calculated for
1
2
3
4
5
6
7
8
Characterization
of
N-(benzothiazol-2-
N-(6-methylbenzothiazol-2-
yl)cyclopropanecarboxamide 17 to 26.
yl)cyclopropanecarboxamide (23). Yield : 47%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.55 (NH,
N-(6-ethylbenzothiazol-2-
1H, br), 7.74 (H7, 1H, d, J7-5 = 1.3Hz), 7.61 (H4, 1H, d, J4-5
=
yl)cyclopropanecarboxamide (17). Yield : 52%. Purity
8,1Hz), 7.24 (H5, 1H, dd, J5-4 = 8.1Hz and J5-7 = 1.3Hz), 2.40
(CH3, 3H, s), 1.98 (CHcPr, 1H, m) and 0.94 (CH2cPr, 4H, m).
HRMS : Mass calculated for C12H13N2OS : 233.0743 and mass
found : 233.0742.
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.54 (NH,
1H, br), 7.77 (H7, 1H, d, J7-5 = 1.6Hz), 7.63 (H4, 1H, d, J4-5
=
9
8.3Hz), 7.27 (H5, 1H, dd, J5-4 = 8.3Hz and J5-7 = 1.6Hz), 2.69
(CH2, 2H, q, JCH2-CH3 = 7.6Hz), 1.99 (CHcPr, 1H, m), 1.22 (CH3,
3H, t, JCH3-CH2 = 7.6Hz) and 0.95 (CH2cPr, 4H, m). HRMS :
Mass calculated for C13H15N2OS : 247.0900 and mass found
247.0905.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(6-methoxybenzothiazol-2-
yl)cyclopropanecarboxamide (24). Yield : 54%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.46 (NH,
1H, br), 7.62 (H4, 1H, d, J4-5 = 8.8Hz), 7.55 (H7, 1H, d, J7-5
=
N-(6-isopropylbenzothiazol-2-
2.5Hz), 7.02 (H5, 1H, dd, J5-4 = 8.8Hz and J5-7 = 2.5Hz), 3,80
(OMe, 3H, s), 1,97(CHcPr, 1H, m) and 0.93 (CH2cPr, 4H, m).
HRMS : Mass calculated for C12H13N2O2S : 249.0701 and
mass found 249.0692. mp (ºC): 205.3.
yl)cyclopropanecarboxamide (18). Yield : 61%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.54 (NH,
1H, br), 7.81 (H7, 1H, d, J7-5 = 1.8Hz), 7.64 (H4, 1H, d, J4-5
=
8.3Hz), 7.31 (H5, 1H, dd, J5-4 = 8.3Hz and J5-7 = 1.8Hz), 2.99
(CHiPr, 1H, sx, JCHiPr-CH3 = 7.1Hz), 1.98 (CHcPr, 1H, m) 1.25
(CH3, 6H, d, JCH3-CHiPr = 7.1Hz) and 0.95 (CH2cPr, 4H, m).
HRMS : Mass calculated for C14H17N2OS : 261.1056 and mass
found 261.1051. mp (ºC): 168.8.
N-(6-nitrobenzothiazol-2-
yl)cyclopropanecarboxamide (25). Yield : 15%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 13.05 (NH,
1H, br), 9.03 (H7, 1H, d, J7-5 = 1.6Hz), 8.27 (H5, 1H, dd, J5-4
=
9.2Hz and J5-7 = 1.6Hz), 7.88 (H4, 1H, d, J4-5 = 9.2Hz), 2.04
(CHcPr, 1H, m) and 0.99 (CH2cPr, 4H, m). HRMS : Mass
calculated for C11H10N3O3S : 264.0437 and mass found :
264.0444.
N-(6-(tert-butyl)benzothiazol-2-
yl)cyclopropanecarboxamide (19). Yield : 71%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.53 (NH,
1H, br), 7.94 (H7, 1H, d, J7-5 = 1.8Hz), 7.64 (H4, 1H, d, J4-5
=
8.6Hz), 7.48 (H5, 1H, dd, J5-4 = 8.6Hz and J5-7 = 1.8Hz), 1.99
(CHcPr, 1H, m), 1.33 (CH3, 9H, s) and 0.95 (CH2cPr, 4H, m).
HRMS : Mass calculated for C15H19N2OS : 275.1213 and mass
found : 275.1220.
N-(6-(trifluoromethyl)benzothiazol-2-
yl)cyclopropanecarboxamide (26). Yield: 59%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.88 (NH,
1H, br), 8.47 (H7, 1H, d, J7-5 = 1.7Hz), 7.89 (H4, 1H, d, J4-5
=
8,6Hz), 7.73 (H5, 1H, dd, J5-4 = 8.6Hz and J5-7 = 1.7Hz), 2.02
(CHcPr, 1H, m) and 0.99 (CH2cPr, 4H, m). HRMS : Mass
calculated for C12H10F3N2OS : 287.0460 and mass found :
287.0464.
N-(6-(trifluoromethoxy)benzothiazol-2-
yl)cyclopropanecarboxamide (20). Yield : 59%. Purity
(LC-MS) > 95%. NMR : 1H (DMSO, 400MHz) : 12.75 (NH,
1H, br), 8.10 (H7, 1H, d, J7-5 = 1.8Hz), 7.81 (H4, 1H, d, J4-5
= 8.8Hz), 7.42 (H5, 1H, dd, J5-4 = 8.8Hz and J5-7 = 1.8Hz),
2.01 (CHcPr, 1H, m) and 0.97 (CH2cPr, 4H, m). HRMS :
Mass calculated for C12H10F3N2O2S : 303.0410 and mass
found : 303.0414.
General
Synthesis
protocol
of
N-
substituted(benzothiazol-2-yl) 27 to 30.
To an ice-cold solution of aminobenzothiazole (1 eq.) in
DCM (0.13M) were successively added triethylamine (3 eq.)
and acyl chloride (1.5 eq.). After stirring from 1h to 24h, the
mixture was diluted in 10mL of brine and ex-tracted with
DCM. The organic layers were combined, washed with a
saturated solution of NaHCO3, dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude was
N-(6-ethoxybenzothiazol-2-
yl)cyclopropanecarboxamide (21). Yield: 34%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.47 (NH,
1H, br), 7.61 (H4, 1H, d, J4-5 = 8.8Hz), 7.52 (H7, 1H, d, J7-5
=
2.5Hz), 7.00 (H5, 1H, dd, J5-4 = 8.8Hz and J5-7 = 2.5Hz), 4.06
(CH2, 2H, q, JCH2-CH3 = 7.1Hz), 1.97 (CHcPr, 1H, m), 1.34 (CH3,
3H, t, JCH3-CH2 = 7.1Hz) and 0.94 (CH2cPr, 4H, m). HRMS :
Mass calculated for C13H15N2O2S : 263.0849 and mass found
: 263.0857.h
purified
by
chromatography
eluting
with
cyclohexane/EtOAc.
N-(6-chlorobenzothiazol-2-yl)butyramide (27). Yield :
28%. Purity (LC-MS) > 95%. NMR : 1H (DMSO, 400MHz) :
12.40 (NH, 1H, br), 8.11 (H7, 1H, d, J7-5 = 2.2Hz), 7.72 (H4,
1H, d, J4-5 = 8.8Hz), 7.44 (H5, 1H, dd, J5-4 = 8.8Hz and J5-7
2.2Hz), 2.47 (CH2CO, 1H, t, JCH2CO-CH2CH3= 7.2Hz), 2.03
(CH2CH3, 2H, sx) and 0.92 (CH3, 3H, d, J = 7.5Hz).
N-(6-fluorobenzothiazol-2-
=
yl)cyclopropanecarboxamide (22). Yield : 51%. Purity
1
(LC-MS) > 95%. NMR : H (DMSO, 400MHz) : 12.65 (NH,
CH3-CH2
1H, br), 7.87 (H7, 1H, dd, J7-F = 8.7Hz and J7-5 = 2.7Hz), 7.74
(H4, 1H, dd, J4-5 = 8.8Hz and J4-5 = 4.8Hz), 7.27 (H5, 1H, td,
J5-4 and 5-F = 8.7Hz and J5-7 = 2.7Hz), 1.99 (CHcPr, 1H, m) and
HRMS: Mass calculated for C11H11ClN2OS : 255.0353 and
mass found 255.0352.
13
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