Journal of Medicinal Chemistry
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yields (60 mg, 0.200 mmol). 1H NMR (400 MHz, CDCl3): δ 8.38 (t,
1H, J = 1.6 Hz), 8.27 (m, 1H), 7.92 (m, 1H), 7.64 (t, 1H, J = 8.0 Hz),
3.95 (s, 3H), 3.73 (m, 4H), 3.00 (m, 4H). ESI-MS: 286.1 [M + H]+.
The methyl 3-(morpholinosulfonyl) benzoate 25 (120 mg, 0.421
mmol) was reacted with hydrazine hydrate (17.53 mg, 0.547 mmol) in
methanol (5 mL) and was refluxed for 12 h at 65 °C. After completion
of the reaction, solvents were removed by vacuum and the obtained
crude material was purified by Companion Rf to give 28 (90 mg, 0.315
mmol, 75%). 1H NMR (400 MHz, CDCl3): δ 8.16 (m, 1H), 8.12 (m,
1H), 8.04 (m, 1H), 7.85 (m, 1H), 7.63 (t, 1H, J = 8.0 Hz), 4.19 (m,
2H), 3.71 (m, 4H), 2.97 (m,4H). ESI-MS: 286.1 [M + H]+.
in the presence of acetic acid as a catalyst, and then the reaction
mixture was heated via microwave irradiation to 120 °C for 30 min.
Reaction was monitored by TLC. After completion of the reaction,
following cooling, the solvent was removed by vacuum and the
resulting crude material was purified by Companion Rf with 1%
CH3OH/CH2Cl2, afforded the title compound 14 as a solid (15 mg,
18%). 1H NMR (400 MHz, acetone-d6): δ 8.29 (m, 2H), 8.01 (d, 1H,
J = 8.4 Hz), 7.83 (t, 1H, J = 8.4 Hz), 7.62 (d, 1H, J = 2.4 Hz), 7.32
(dd, 1H, J = 2.4 and 8.8 Hz), 6.96 (d, 1H, J = 8.8 Hz), 2.73 (s, 6H),
2.58 (s, 3H). ESI-MS: 396.0 [M + H]+. LC-MS purity of compound
14 was found to be >95%.
In the final step, either the ester compound 25 or 3-
(morpholinosulfonyl) benzoic acid 27 was utilized for the preparation
of series of benzohydrazide compounds. In one example starting with
1-(5-chloro-2-hydroxyphenyl) ethanone 23 (25.2 mg, 0.147 mmol)
and hydrazine 28 (4.72 mg, 0.147 mmol) was refluxed in methanol (5
mL) in the presence of catalytic acetic acid for 1 h. In certain examples,
the microwave heating to 120 °C for 30 min was performed. After
completion of the reaction, the solvents was removed by vacuum and
the resulting crude material was purified by Companion Rf with 2%
CH3OH/CH2Cl2 affording the title, in this case the compound 12 as a
white solid (85%). 1H NMR (400 MHz, DMSO-d6): δ 13.31 (s, 1H),
11.69 (s, 1H), 8.27 (d, 1H, J = 7.6 Hz), 8.18 (s, 1H), 7.96 (d, 1H, J =
7.6 Hz), 7.83 (t, 1H, J = 7.6 Hz), 7.65 (d, 1H, J = 2.4 Hz), 7.33 (dd,
1H, J = 2.4 and 8.4 Hz), 6.94 (d, 1H, J = 9.2 Hz), 3.62 (m, 4H), 2.90
(m, 4H), 2.49 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 164.0,
158.4, 158.1, 135.5, 134.8, 133.7, 131.7, 131.5, 1.30.5, 128.6, 127.8,
122.8, 121.4, 119.8, 65.9, 46.6, 15.1. HRMS: expected 438.0885 [M +
H], observed 438.0898 [M + H]. LC-MS purity of compound 12 was
found to be >95%.
5.2.5. (Z)-N′-(1-(5-Chloro-2-hydroxyphenyl)propylidene)-3-
(morpholinosulfonyl)benzohydrazide (15). 3-(Morpholinosulfonyl)-
benzohydrazide 28 (40 mg, 0.140 mmol) and 1-(5-chloro-2-
hydroxyphenyl)propan-1-one 32 (25.9 mg, 0.140 mmol) was dissolved
in methanol (volume: 4 mL) in the presence of acetic acid as a catalyst,
and then the reaction mixture was heated via microwave irradiation to
120 °C for 30 min. Reaction was monitored by TLC. After completion
of the reaction, following cooling, the solvent was removed by vacuum
and the resulting crude material was purified by Companion Rf with
2% CH3OH/CH2Cl2, affording the title compound 15 as a solid (20
1
mg, 31.6%). H NMR (400 MHz, acetone-d6): δ 8.26 (m, 2H), 8.00
(d, 1H, J = 7.6 Hz), 7.84 (t, 1H, J = 8.0 Hz), 7.64 (d, 1H, J = 2.4 Hz),
7.33 (m, 1H), 6.98 (d, 1H, J = 9.2 Hz), 3.69 (m, 4H), 3.10 (q, 2H, J =
7.6 Hz), 2.99 (m, 4H), 1.26 (t, 3H, J = 7.6 Hz). ESI-MS: 452.1 [M +
H]+. LC-MS purity of compound 15 was found to be >95%.
5.2.6. (E)-N′-(1-(3-Chloro-2-fluorophenyl)ethylidene)-3-
(morpholinosulfonyl)benzohydrazide (16). 1-(3-Chloro-2-
fluorophenyl)ethanone 33 (20 mg, 0.116 mmol) and 3-(morpholino-
sulfonyl) benzohydrazide 28 (33.1 mg, 0.116 mmol) was dissolved in
methanol (4 mL) in the presence of acetic acid as a catalyst, and then
the reaction mixture was heated via microwave irradiation to 120 °C
for 30 min. Following cooling, the solvent was removed by vacuum,
and the resulting crude material was purified by Companion Rf with
2% CH3OH/CH2Cl2, affording the title compound 16 as a white solid
Similar experimental procedures were employed for the preparation
of list of compounds given in Table 2, and their NMR and mass
spectral data confirms the title compounds.
5.2.3. (E)-N′-(1-(2,5-Dichlorophenyl)ethylidene)-3-
(morpholinosulfonyl)benzohydrazide (13). 1-(2,5-Dichlorophenyl)-
ethanone 29 (20 mg, 0.106 mmol) and 3-(morpholinosulfonyl)
benzohydrazide 28 (30.2 mg, 0.106 mmol) was dissolved in methanol
(volume: 4 mL) in the presence of acetic acid as a catalyst, and then
the reaction mixture was heated via microwave irradiation to 120 °C
for 30 min. Following cooling, the solvent was removed by vacuum
and the resulting crude material was purified by Companion Rf with
1% CH3OH/CH2Cl2, affording the title compound 13 as a solid (10
1
(22 mg, 43.2%). H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.37
(m, 1H), 8.16 (m, 1H), 7.87 (d, 1H, J = 7.2 Hz), 7.65 (m, 1H), 7.41
(m, 1H), 7.10 (t, 1H, J = 8.0 Hz), 3.71 (m, 4H), 2.95 (m, 4H), 2.38 (s,
3H). ESI-MS: 440.1 [M + H]+. LC-MS purity of compound 16 was
found to be >95%.
5.2.7. (E)-N′-(1-(2,6-Dihydroxyphenyl)ethylidene)benzohydrazide
(17). 1-(2,6-Dihydroxyphenyl)ethanone (100 mg, 0.657 mmol) 34 and
benzohydrazide 24 (89 mg, 0.657 mmol) was dissolved in methanol (4
mL) in the presence of acetic acid as a catalyst, and then the reaction
mixture was heated via microwave irradiation to 120 °C for 30 min.
Following cooling, the solvent was removed by vacuum and the
resulting crude material was purified by Companion Rf with 2%
CH3OH/CH2Cl2, affording the title compound 17 as a white solid
1
mg, 21%). H NMR (400 MHz, CDCl3): δ 8.29 (m, 1H), 8.09 (m,
1H), 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 7.26 (m, 2H), 3.52
(m, 4H), 2.91 (m, 4H), 2.28 (s, 3H). ESI-MS: 456.1 [M + H]+. LC-
MS purity of compound 13 was found to be >95%.
5.2.4. (Z)-3-(2-(1-(5-Chloro-2-hydroxyphenyl)ethylidene)-
hydrazinecarbonyl)-N,N-dimethylbenzenesulfonamide (14). 3-
(N,N-Dimethylsulfamoyl)benzoic acid (200 mg, 0.872 mmol) was
refluxed in the presence of conc H2SO4 (5.64 mg, 0.044 mmol) in
methanol at 70 °C for overnight, and after completion of the reaction,
solvent was removed by vacuum and then compound was purified by
Companion Rf with 1% CH3OH/CH2Cl2, affording the methyl 3-
1
(100 mg, 56.3%). H NMR (400 MHz, CD3OD): δ 7.59 (m, 2H),
7.49 (m, 1H), 7.39 (m, 2H), 7.11 (t, 1H, J = 8.0 Hz), 6.45 (m, 2H),
2.35 (s, 3H). ESI-MS: 271.1 [M + H]+. LC-MS purity of compound
17 was found to be >95%.
5.2.8. (E)-N′-(1-(2-Chloropyridin-4-yl)ethylidene)-3-
(morpholinosulfonyl)benzohydrazide (18). 1-(2-Chloropyridin-4-yl)-
ethanone 35 (20 mg, 0.129 mmol) and 3-(morpholinosulfonyl)-
benzohydrazide 28 (36.7 mg, 0.129 mmol) was dissolved in methanol
(4 mL) in the presence of acetic acid as a catalyst, and then the
reaction mixture was heated via microwave irradiation to 120 °C for 30
min. Following cooling, the solvent was removed by vacuum and the
resulting crude material was purified by Companion Rf with 1%
CH3OH/CH2Cl2, affording the title compound 18 as a solid (32.6 mg,
1
(N,N-dimethylsulfamoyl)benzoate 30 as a solid (125 mg, 58.9%). H
NMR (400 MHz, CDCl3): δ 8.42 (s, 1H), 8.27 (d, 1H, J = 8.0 Hz),
7.97 (d, 1H, J = 7.2 Hz), 7.65 (t, 1H, J = 8.0 Hz), 3.96 (s, 3H), 2.74 (s,
6H). ESI-MS: 244.0 [M + H]+.
Methyl 3-(N,N-dimethylsulfamoyl)-benzoate 30 (150 mg, 0.617
mmol) was added to the hydrazine (29.6 mg, 0.925 mmol) in
methanol and refluxed for 8 h at 65 °C. Following cooling, reaction
was monitored by TLC. After completion of the reaction, solvent was
removed by vacuum and then compound was purified by Companion
Rf with 1% CH3OH/CH2Cl2, affording the 3-(hydrazinecarbonyl)-
N,N-dimethylbenzenesulfonamide 31 as a solid (60 mg, 40%). 1H
NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 8.01 (d, 1H, J = 8.4 Hz),
7.92 (d, 1H, J = 8.0 Hz), 7.65 (t, 1H, J = 8.0 Hz), 2.73 (s, 6H). ESI-
MS: 244.0 [M + H]+.
1
60%). H NMR (400 MHz, CDCl3): δ 9.43 (m, 1H), 8.39 (m, 2H),
8.15 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J = 7.6 Hz), 7.70 (t, 1H, J= 7.6
Hz), 7.52 (m, 1H), 3.73 (m, 4H), 3.02 (m, 4H), 2.35 (s, 3H). ESI-MS:
423.1 [M + H]+. LC-MS purity of compound 18 was found to be
>95%.
5.2.9. (Z)-3-Bromo-4-chloro-N′-(1-(5-chloro-2-hydroxyphenyl)-
ethylidene)benzohydrazide (19). 3-Bromo-4-chlorobenzoic acid
(200 mg, 0.849 mmol) was refluxed in the presence of conc H2SO4
(5.49 mg, 0.042 mmol) in methanol at 70 °C for overnight, and after
3-(Hydrazinecarbonyl)-N,N-dimethylbenzenesulfonamide 31 (50
mg, 0.206 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone 23
(35.1 mg, 0.206 mmol) was dissolved in methanol (volume: 4 mL)
J
dx.doi.org/10.1021/jm400870h | J. Med. Chem. XXXX, XXX, XXX−XXX