2636 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 8
Breschi et al.
procedure described above for the preparation of 4b. The crude
product was purified by column chromatography eluting with
AcOEt/n-hexane (7:3) to give 4d (148 mg, 0.24 mmol, 25% yield)
as a white solid: mp 70-72 °C. MS (m/z) 552 (M+ - ONO2, 6%);
Anal. C31H30ClN7O5.
2,6-Dimethyl-3-[(nitrooxy)methyl]benzoate of Losartan (5).
Compound 5 was synthesized from 12 (200 mg, 0.47 mmol)
following the same procedure described above for the preparation
of 4b. This compound was purified by column chromatography
eluting with AcOEt/n-hexane (3:7) to give 5 (101 mg, 0.16 mmol,
34% yield) as a white solid: mp 105-107 °C. MS (m/z) 566 (M+
- ONO2, 20%); Anal. C32H32ClN7O5.
phase was dried, and the solvent was evaporated to give 11c (206
mg, 1.0 mmol, yield 81%) as a yellow solid: mp 90-92 °C. MS
(m/z): 211 (M+, 2%); 149 (M+ - ONO2, 100%); Anal. C9H9NO5.
4-[(2-Nitrooxy)ethyl]benzoic Acid (11d). Compound 11d was
synthesized from 22 (268 mg, 1.6 mmol) following the same
procedure described above for the preparation of 11c. The crude
product was purified by precipitation with n-hexane from AcOEt
to give 11d (100 mg, 0.5 mmol, yield 30%) as a white solid. MS
(m/z): 149 (M+ - ONO2, 100%); Anal. C9H9NO5.
2,6-Dimethyl-3-[(nitrooxy)methyl]benzoic Acid (12). Com-
pound 12 was synthesized from 24 (730 mg, 3.7 mmol) following
the same procedure described above for the preparation of 11b.
The crude product was triturated with CHCl3 (20 mL) and filtered
to remove the unreacted silver nitrate and AgCl. The solvent was
evaporated to give 12 (740 mg, 3.3 mmol, yield 90%) as a white
6-[(Nitrooxy)methyl]pyridine-2-carboxylate of Losartan (6).
Compound 6 was synthesized from 13 (270 mg, 1.36 mmol)
following the same procedure described above for the preparation
of 4b. This compound was purified by column chromatography
eluting with CHCl3/MeOH (9:1) to give 6 (343 mg, 0.57 mmol,
solid: mp 123-125 °C. MS (m/z): 225 (M+, 6%); 163 (M+
ONO2, 85%); Anal. C10H11NO5.
-
42% yield) as a solid: mp 102-104 °C. MS (m/z) 166 (M+
O2NOCH2Py, 100%); Anal. C29H27ClN8O5.
-
6-[(Nitrooxy)methyl]pyridine-2-carboxylic Acid (13). A solu-
tion of 27 (300 mg, 2.0 mmol) in Ac2O (2 mL) was added to a
solution of HNO3 (0.55 mL) and Ac2O (1.15 mL) cooled at -10
°C. The mixture was stirred at -10 °C for 2 h. Then the solvent
was evaporated to give 13 (277 mg, 1.4 mmol, yield 69%) as a
white solid: mp 58-63 °C. MS (m/z): 107 (M+ - NO2, - CO2,
100%); 123 (M+ - CH2ONO2, 69%); Anal. C7H6N2O5.
3-Hydroxybenzyl Nitrate (14). A solution of 3-hydroxy-benzyl
chloride 29 (608 mg, 4.3 mmol) in a small amount of CH3CN was
added to a stirred solution of AgNO3 (2.90 g, 17.1 mmol) in CH3-
CN (14 mL). Stirring was continued over 1 h at room temperature
in the dark, and then the precipitate (silver salt) was filtered off,
and the solvent was evaporated. The crude product was purified
by column chromatography eluting with hexane/AcOEt (3:1) to give
14 (232 g, 1.4 mmol, 32% yield) as a yellow oil. MS m/z:170 (M+,
11%); 107 (100%, - ONO2); Anal. C7H7NO4.
3-(Hydroxymethyl)benzyl Nitrate (15a). Compound 15a was
synthesized from 32a (638 mg, 4.08 mmol) following the same
procedure described above for the preparation of 11b. The crude
product was triturated with CHCl3 (20 mL) and filtered to remove
the unreacted silver nitrate and AgCl. The solvent was evaporated
to give 15a (681 mg, 3.72 mmol, yield 91%) as a yellow oil. MS
(m/z): 183 (M+, 15%); 121 (M+ - ONO2, 100%); Anal. C8H9-
NO4.
4-(Hydroxymethyl)benzyl Nitrate (15b). Compound 15b was
synthesized from 32b (454 mg, 2.90 mmol) following the same
procedure described above for the preparation of 11b. The crude
product was triturated with CHCl3 (10 mL) and filtered to remove
the unreacted silver nitrate and AgCl. The solvent was evaporated
to give 15b (390 mg, 2.13 mmol, yield 74%) as a yellow oil. MS
(m/z): 183 (M+, 10%); 121 (M+ - ONO2, 100%); Anal. C8H9-
NO4.
3-(1-Hydroxyethyl)benzoic Acid (21). A solution of 3-acetyl-
benzoic acid (19) (400 mg, 2.4 mmol) in THF (2 mL) was added
to a solution of 1 M LiAlH4 in THF (2.44 mL, 2.4 mmol) cooled
at 0 °C. The mixture was stirred at 0 °C for 1 h, then the solvent
was evaporated, and water was added. The aqueous phase was
acidified with 1 M HCl and extracted with AcOEt. The organic
phase was dried, and the solvent was evaporated to give 21 (341
mg, 2.1 mmol, 84% yield) as a yellow solid: mp 90-92 °C. Anal.
C9H10O3.
3-[(Nitrooxy)methyl]phenyl Ester of EXP 3174 (7). A solution
of DCC (161 mg, 0.8 mmol) in dry THF (5 mL) was added
dropwise to a stirred solution of 2 (283 mg, 0.6 mmol), 14 (110
mg, 0.6 mmol), and DMAP (6 mg) in dry THF (6.6 mL). The
suspension was stirred at room temperature for 12 h, then the
precipitate was removed by filtration, and the filtrate was concen-
trated. The solid was triturated with acetone, and the solvent was
evaporated. The crude product was purified by column chroma-
tography eluting with hexane/AcOEt (1:1) to give 7 (46 mg, 0.08
mmol, 12% yield) as a yellow solid. MS m/z: 588 (M+, 2%); Anal.
C29H26ClN7O5.
3-[(Nitrooxy)methyl]benzoate of EXP 3174 (8a). Compound
8a was synthesized from 15a (105 mg, 0.57 mmol) following the
same procedure described above for the preparation of 7. This
compound was purified by column chromatography eluting with
AcOEt and then by precipitation with n-hexane from AcOEt. The
solid was collected to give 8a (79 mg, 0.131 mmol, 24% yield) as
a white solid: mp 56-58 °C. MS m/z: 602 (M+, 0.2%); Anal.
C30H28ClN7O5.
4-[(Nitrooxy)methyl]benzoate of EXP 3174 (8b). Compound
8b was synthesized from 15b (66 mg, 0.36 mmol) following the
same procedure described above for the preparation of 8a. This
compound was purified by column chromatography eluting with
AcOEt and then by precipitation with n-hexane from AcOEt. The
solid was collected to give 8b (58 mg, 0.097 mmol, 27% yield) as
a white solid: mp 72-74 °C. MS m/z: 602 (M+, 0.6%); Anal.
C30H28ClN7O5.
Nitrooxy Ester of Losartan (9). Compound 9 was synthesized
from losartan 1 (200 mg, 0.5 mmol) following the same procedure
described above for the preparation of 11c. The crude product was
purified by precipitation with n-hexane from AcOEt to give 9 (140
mg, 0.3 mmol, yield 55%) as a yellow solid: mp 92-95 °C. MS
(m/z): 467 (M+, 3%); Anal. C22H22ClN6O2.
5-(Nitrooxy)pentanoic Acid (10). Preparation of 10 and char-
acterization data have already been reported.19
3-[(Nitrooxy)methyl]benzoic Acid (11a). Preparation of 11a and
characterization data have already been reported.19
4-[(Nitrooxy)methyl]benzoic Acid (11b). A solution of 4-(chlo-
romethyl)benzoic acid (18) (1.00 g, 5.3 mmol) in a small amount
of CH3CN (5 mL) was added to a stirred solution of AgNO3 (3.59
g, 21.2 mmol) in CH3CN (19 mL). Stirring was continued over 2
h at room temperature in the dark, and then the precipitate (silver
chloride) was filtered off, and the solvent was evaporated. The crude
product was triturated with CHCl3 (20 mL) and filtered off to
remove the unreacted silver nitrate and AgCl. The solvent was
evaporated to give 11b (563 mg, 2.9 mmol, yield 54%). MS (m/z):
197 (M+, 3%); 135 (M+ - ONO2, 46%); Anal. C8H7NO5.
3-[(2-Nitrooxy)ethyl]benzoic Acid (11c). A solution of 21 (200
mg, 1.2 mmol) in Ac2O (2 mL) was added to a solution of HNO3
(0.34 mL) and Ac2O (0.70 mL) cooled at -10 °C. The mixture
was stirred at -10 °C for 2 h. Then water was added, and the
resulting aqueous phase was extracted with AcOEt. The organic
4-(1-Hydroxyethyl)benzoic Acid (22). Compound 22 was
synthesized from 20 (500 mg, 3.0 mmol) following the same
procedure described above for the preparation of 21. The crude
product was purified by crystallization from CHCl3/n-hexane to
yield 22 (251 mg, 1.5 mmol, yield 50%) as a solid. MS (m/z): 167
(M+, 2%), 123 (M+ - CO2, 31%); Anal. C9H10O3.
2,6-Dimethyl-3-(chloromethyl)benzoic Acid (24). Paraformal-
dehyde (7.9 g) and HClconc (15.9 mL) were added to a solution of
2,6-dimethylbenzoic acid (23) (1.60 g, 10.0 mmol) in AcOH glac.
(15.9 mL). The resulting suspension was heated at 80 °C for 5 h.
Then water was added, and the solid precipitate was collected to
give 24 (1.47 g, 7.4 mmol, yield 74%): mp 55-57 °C. Anal.
C10H11ClO2.