6170 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Ferguson et al.
Ethyl 5-cyano-4-methyl-6-oxo-1-(4-(trifluoromethyl)phenyl)-1,6-
dihydropyridazine-3-carboxylate (12g). Yield 40%. 1H NMR
(CDCl3) δ 7.80 (m, 4H, ArH), 4.44 (q, 2H, J ) 7.1 Hz, CH2), 2.77
(s, 3H, CH3), 1.41 (t, 3H, J ) 7.1 Hz, CH3). MS m/z 352.2 (M +
H+).
Ethyl 5-cyano-4-methyl-1-(4-nitrophenyl)-6-oxo-1,6-dihydropy-
ridazine-3-carboxylate (12h). Yield 42%. mp 173-175 °C. 1H
NMR (CDCl3) δ 8.36 (dt, 2H, J ) 9.1 Hz, J ) 2.0, 2.8 Hz, ArH),
7.94 (dt, 2H, J ) 9.1 Hz, J ) 2.0, 2.8 Hz, ArH), 4.45 (q, 2H, J )
7.1 Hz, CH3), 2.77 (s, 3H, CH3), 1.41 (t, 3H, J ) 7.1 Hz, CH3).
MS m/z 329.2 (M + H+).
General Procedure (A) for Thienopyridazines. To a suspension
of 1,6-dihydropyridazine-3-carboxylate (1.69 g, 5.65 mmol) and
elemental sulfur (0.28 g, 8.77 mmol) in ethanol (5 mL), morpholine
(0.97 mL, 11.12 mmol) was added. The reaction mixture was stirred
and heated at reflux temperature (90 °C) for 6 h. The reaction
mixture was allowed to cool to room temperature and water was
added until a precipitate developed. The precipitate was collected
by filtration under reduced pressure, washed with water and the
crude product was recrystallized from ethanol to afford the target
compound.
General Procedure (B) for Thienopyridazines. To a suspension
of 1,6-dihydropyridazine-3-carboxylate (181 mg, 0.58 mmol) and
elemental sulfur (27 mg, 0.85 mmol) in ethanol (2 mL), morpholine
(0.1 mL, 1.14 mmol) was added. The reaction vessel was sealed
and placed in a microwave reactor, prestirred (1 min) and reacted
at 150 °C for 10 min. A precipitate developed and the reaction
mixture was diluted with water. The precipitate was collected by
filtration under reduced pressure, air-dried and recrystallized from
ethanol to afford the target compound.
162.4, 158.4, 158.3, 133.7, 132.4, 127.5, 126.2, 113.6, 104.1, 103.0,
61.20, 55.3, 14.0. HRMS (ESI+) calcd for C16H16N3O4S+ 346.0856,
found 346.0877. Anal. (C16H15N3O4S) C, H, N.
Ethyl 5-amino-3-(4-iodophenyl)-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (13f). Procedure A. Yield 100%. mp
1
196-198 °C. H NMR (DMSO-d6) δ 7.83 (d, 2H, J ) 8.6 Hz,
ArH), 7.63 (br s, 2H, NH2), 7.35 (d, 2H, J ) 8.6 Hz, ArH), 7.11
(s, 1H, CH), 4.33 (q, 2H, J ) 7.1 Hz, CH2), 1.30 (t, 3H, J ) 7.1
Hz, CH3). 13C NMR (DMSO-d6), δ 163.3, 162.3, 160.3, 158.1,
140.5, 137.2, 133.1, 128.1, 125.9, 103.7, 92.7, 61.3, 14.0. HRMS
(ESI+) calcd for C15H12IN3NaO3S+ 463.9536, found 463.9529.
Anal. (C15H12IN3O3S) C, H, N.
Ethyl 5-Amino-4-oxo-3-(4-(trifluoromethyl)phenyl)-3,4-dihy-
drothieno[3,4-d]pyridazine-1-carboxylate (13g). Procedure A. Yield
99%. mp 180-184 °C. 1H NMR (DMSO-d6) δ 7.82 (br s, 4H,
ArH), 7.68 (br s, 2H, NH2), 7.13 (br s, 1H, CH), 4.33 (q, 2H, J )
6.8, 6.9 Hz, CH2), 1.31 (t, 3H, J ) 6.8, 6.9 Hz, CH3). 13C NMR
(DMSO-d6) δ 163.6, 162.2, 158.1, 144.0, 133.6, 127.2 (q, J ) 32.1
Hz), 125.7, 125.5 (q, J ) 3.8 Hz), 124.0 (q, J ) 272.2 Hz), 104.0,
103.7, 61.4, 14.0. HRMS (ESI+) calcd for C16H12F3N3NaO3S+
406.0444, found 406.0452. Anal. (C16H12F3O3S) C, H, N.
Ethyl 5-Amino-3-(4-nitrophenyl)-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (13h). Procedure A. Yield 87%. mp
1
259-261 °C. H NMR (DMSO-d6) δ 8.33 (dt, 2H, J ) 2.1, 2.9,
9.2 Hz, ArH), 7.90 (dt, 2H, J ) 2.1, 2.9, 9.2 Hz, ArH), 7.75 (br s,
2H, NH2), 7.15 (s, 1H, CH), 4.35 (q, 2H, J ) 7.1 Hz, CH2), 1.32
(t, 3H, J ) 7.1 Hz, CH3). 13C NMR (DMSO-d6), δ 164.0, 162.1,
158.0, 145.9, 145.2, 134.0, 125.9, 125.5, 123.8, 104.6, 103.3, 61.5,
14.0. MS m/z 361.0 (M + H+). Anal. (C15H12N4O5S) C, H, N.
Ethyl 3-(4-Acetoxyphenyl)-5-amino-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (13i). To a suspension of 13d (100 mg,
0.30 mmol), triethylamine (56 µL, 0.40 mmol) and 4-dimethylami-
nopyridine (26 mg, 0.22 mmol) in CH2Cl2 (10 mL), acetic anhydride
(38 µL, 0.41 mmol) was added. The reaction mixture was stirred
at room temperature for 5.5 h. After this period TLC (hexane/
EtOAc, 4:6, Rf ) 0.44) showed complete conversion. The reaction
mixture was diluted with H2O (20 mL) and extracted with EtOAc
(2 × 20 mL). The organic extracts were combined, washed with 1
M HCl (10 mL), saturated NaHCO3 (20 mL) and H2O (20 mL).
The organic layer was dried (MgSO4), filtered and evaporated to
afford the product as a yellow solid (0.10 g, 0.25 mmol, 84%). 1H
NMR (DMSO-d6) δ 7.61 (br s, 2H, NH2), 7.54 (d, 2H, J ) 8.8 Hz,
ArH), 7.23 (d, 2H, J ) 8.8 Hz, ArH), 7.12 (s, 1H, CH), 4.33 (q,
2H, J ) 7.1 Hz, CH2), 2.30 (s, 3H, OCOCH3), 1.30 (t, 3H, J ) 7.1
Hz, CH3). 13C NMR (DMSO-d6) δ 169.1, 163.2, 162.3, 158.2,
149.2, 138.1, 132.9, 127.3, 126.0, 121.8, 103.8, 103.5, 61.3, 26.8,
14.0. MS m/z 374.2 (M + H+). Anal. (C17H15N3O5S) C, H, N.
Ethyl 5-amino-4-oxo-3-(4-(trifluoromethylsulfonyloxy)phenyl)-
3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylate (13j). A solution
of 13d (205 mg, 0.62 mmol), N-phenyltriflimide (0.22 g, 0.62
mmol) and K2CO3 (251 mg, 1.82 mmol) in THF (1.5 mL) was
placed in a sealed vessel and into microwave reactor. The reaction
was prestirred (1 min) and then heated at 120 °C for 6 min, followed
by rapid cooling. The reaction mixture was diluted with water and
extracted with ethyl acetate. The organic extracts were combined,
dried (MgSO4), filtered and evaporated to afford the title compound
(28 mg, 100%). mp 153-155 °C. 1H NMR (DMSO-d6) δ 7.75
(dt, 2H, J ) 2.2, 3.2, 9.1 Hz, ArH), 7.66-7.61 (m, 4H, ArH and
NH2), 7.14 (s, 1H, CH), 4.34 (q, 2H, J ) 7.1 Hz, CH2), 1.31 (t,
3H, J ) 7.1 Hz, CH3). 13C NMR (DMSO-d6) δ 162.9, 162.1, 159.3,
148.1, 140.5, 134.4, 127.5, 126.9, 121.6, 118.9 (q, J ) 321 Hz),
106.5, 105.3, 62.2, 14.3. HRMS (ESI+) calcd for C16H12-
F3N3NaO6S2+ 486.0012, found 486.0017. Anal. (C16H12F3N3O6S2) C,
H, N.
Ethyl 5-Amino-4-oxo-3-phenyl-3,4-dihydrothieno[3,4-d]pyridazine-
1-carboxylate (13a). Procedure A. Yield 55%. mp 196-198 °C.
1H NMR (DMSO-d6) δ 7.61 (br s, 2H, NH2), 7.52-7.45 (m, 4H,
ArH), 7.40-7.38 (m, 1H, ArH), 7.11 (s, 1H, CH), 4.33 (q, 2H, J
) 7.1 Hz, CH2), 1.30 (t, 3H, J ) 7.1 Hz, CH3). 13C NMR (DMSO-
d6) δ 163.2, 162.4, 158.3, 140.7, 132.8, 128. 5, 127.3, 126.3, 126.0.
103.9, 103.3, 61.3, 14.0. HRMS (ESI+) calcd for C15H13N3NaO3S+
338.0570, found 338.0562. Anal. (C15H13N3O3S) C, H, N.
Ethyl 5-amino-3-(3-chlorophenyl)-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (13b). Procedure B. Yield 94%. mp
164-166 °C. 1H NMR (DMSO-d6) δ 7.65 (br s, 3H, NH2 and ArH),
7.55-7.51 (m, 2H, ArH), 7.48-7.43(m, 1H, ArH), 7.12(s, 1H, CH),
4.34 (q, 2H, J ) 7.1 Hz, CH2), 1.31 (t, 3H, J ) 7.1 Hz, CH3). 13
C
NMR (DMSO-d6) δ 163.4, 162.3, 158.1, 141.9, 133.3, 132.5, 130.1,
127.2, 126.0, 125.9, 124.7, 103.8, 103.7, 61.4, 14.0. HRMS (ESI+)
calcd for C15H12ClN3NaO3S+ 372.0180, found 372.0173. Anal.
(C15H12ClN3O3S) C, H, N.
Ethyl 5-Amino-4-oxo-3-(3-(trifluoromethyl)phenyl)-3,4-dihy-
drothieno[3,4-d]pyridazine-1-carboxylate (13c). Procedure B. Yield
1
100%. mp 176-178 °C. H NMR (DMSO-d6) δ 7.96 (br s, 1H,
ArH), 7.88-7.86 (m, 1H, ArH), 7.75-7.73 (m, 2H, ArH), 7.68
(br s, 2H, NH2), 7.13 (br s, 1H, CH), 4.34 (q, 2H, J ) 7.1 Hz,
CH2), 1.31 (t, 3H, J ) 7.1 Hz, CH3). 13C NMR (DMSO-d6) δ 162.9,
162.0, 159.4, 141.2, 134.4, 131.6 (q, J ) 32.8 Hz), 129.3, 129.1,
124.2 (q, J ) 3.7 Hz), 123.9 (q, J ) 272 Hz), 122.9 (q, J ) 3.9
Hz), 106.6, 105.3, 62.2, 14.3. HRMS (ESI+) calcd for
C16H12F3N3NaO3S+ 406.0444, found 406.0453. Anal. (C16H12F3-
N3O3S) C, H, N.
Ethyl 5-Amino-3-(4-hydroxyphenyl)-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (13d). Procedure A. Yield 80%. mp
253-256 °C. 1H NMR (DMSO-d6) δ 9.64 (s, 1H, OH), 7.56 (br s,
2H, NH2), 7.25 (d, 2H, J ) 8.7 Hz, ArH), 7.07 (s, 1H, CH), 6.83
(d, 2H, J )8.7 Hz, ArH), 4.31 (q, 2H, J ) 7.1 Hz, CH2), 1.29 (t,
3H, J ) 7.1 Hz, CH3). HRMS (ESI+) calcd for C15H13N3NaO4S+
354.0519, found 354.0526. Anal. (C15H13N3O4S) C, H, N.
Ethyl 5-Amino-3-(4-methoxyphenyl)-4-oxo-3,4-dihydrothieno[3,4-
d]pyridazine-1-carboxylate (13e). Procedure A. Yield 81%. mp
General Procedure for Thienopyridazine Carboxylic Acids. To
a solution of the ethyl thieno[3,4-d]pyridazine-1-carboxylate (0.38
mmol) in ethanol, was added NaOH (16 mg, 0.40 mmol). The
reaction mixture was stirred and heated at reflux for 3 h. The
reaction mixture was allowed to cool to room temperature, diluted
with H2O followed by the addition of concentrated HCl until a
precipitate developed (pH 3). The precipitate was collected by
1
173-175 °C. H NMR (DMSO-d6), δ 7.58 (br s, 2H, NH2), 7.41
(d, 2H, J ) 8.6 Hz, ArH), 7.09 (s, 1H, CH), 7.01 (d, 2H, J ) 8.6
Hz, ArH), 4.31 (q, 2H, J ) 7.0 Hz, CH2), 3.80 (s, 3H, COCH3),
1.29 (t, 3H, J ) 7.0 Hz, CH3). 13C NMR (DMSO-d6), δ 163.0,