July 2002
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benzyl bromide in 31% yield, mp 125—126 °C (triturated with EtOH/Et2O). acidified with 35% aqueous HCl. The precipitates were collected by filtra-
1H-NMR (DMSO-d6) d: 2.15 (3H, s), 3.79 (3H, s), 5.15 (2H, s), 7.27—7.47, tion and dissolved in MeOH. The solution was concentrated, and the crys-
7.47—7.60 (5H, m), 7.78 (1H, s), 7.92 (1H, s), 9.58 (1H, s). Anal. Calcd for talline precipitates were collected by filtration and dried to give 39.6 g (84%)
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C17H16ClNO4: C, 61.18; H, 4.83; Cl, 10.62; N, 4.20. Found: C, 60.97; H,
of 28 as a colorless crystal, mp 210—213 °C. H-NMR (DMSO-d6) d: 2.15
(3H, s), 3.77 (3H, s), 7.71 (1H, s), 7.76 (1H, s), 9.55 (1H, s). Anal. Calcd for
4.88; Cl, 10.84; N, 4.12. MS: m/z, 334 (MHϩ). IR cmϪ1: 3352, 3333, 1707,
1684, 1605, 1580, 1411, 1238. 2) 23e (colorless crystal) was obtained from C10H10ClNO4: C, 49.30; H, 4.14; Cl, 14.55; N, 5.75. Found: C, 49.27; H,
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22e in 80% yield, mp 190—191 °C. H-NMR (DMSO-d6) d: 5.09 (2H, s), 4.22; Cl, 14.43; N, 5.66. MS: m/z, 244 (MHϩ). IR cmϪ1: 3369, 3260, 1720,
6.08 (2H, s), 6.53 (1H, s), 7.25—7.45, 7.45—7.6 (5H, m), 7.62 (1H, s), 1693, 1604, 1582, 1522, 1450, 1408, 1337, 1240.
11.94 (1H, s). Anal. Calcd for C14H12ClNO3·1/4H2O: C, 59.58; H, 4.46; Cl,
12.56; N, 4.96. Found: C, 59.78; H, 4.35; Cl, 12.48; N, 4.95. MS: m/z, 278 4-amino-5-chloro-2-ethoxybenzoic acid28) (23b, 2.6 g, 12 mmol), HCHO
(MHϩ). IR cmϪ1: 3470, 3323, 3285, 1701, 1626, 1593, 1441, 1400, 1229.
(37% solution in H2O, 8 ml, 0.11 mol), NaBH3CN (95%, 1.9 g, 27 mmol),
5-Chloro-4-dimethylamino-2-ethoxybenzoic Acid (29b) A mixture of
4-Amino-2-butoxy-5-chlorobenzoic Acid (23f) In a similar manner to and MeCN (40 ml) was stirred at room temperature for 6 h. After addition of
that described above, 1) 22f (colorless fine needle) was prepared from 21 HCHO (37% solution in H2O, 4 ml, 54 mmol) and NaBH3CN (95%, 1.0 g,
1
and BuI in 43% yield, mp 105.5—107 °C (EtOH/hexane). H-NMR d: 0.98
14 mmol), the mixture was restirred at room temperature for 16 h. The sol-
(3H, t, Jϭ7), 1.42—1.63 (2H, m), 1.74—1.89 (2H, m), 2.27 (3H, s), 3.78 vent was evaporated, and the residue was acidified with 10% aqueous HCl.
(3H, s), 4.07 (2H, t, Jϭ6), 7.75 (1H, br s), 7.88 (1H, s), 8.27 (1H, s). Anal. The precipitates were collected by filtration and recrystallized from EtOH to
Calcd for C14H18ClNO4: C, 56.10; H, 6.05; Cl, 11.83; N, 4.67. Found: C,
give 1.7 g (58%) of 29b as a white crystal, mp 144—145 °C. 1H-NMR
(DMSO-d6) d: 1.33 (3H, t, Jϭ7.0), 2.83 (6H, s), 4.12 (2H, q, Jϭ7.0), 6.66
55.85; H, 6.04; Cl, 11.70; N, 4.66. MS: m/z, 300 (MHϩ). IR cmϪ1: 3283,
1699, 1676, 1574, 1412, 1248. 2) 23f (colorless fine needle) was obtained (1H, s), 7.64 (1H, s), 12.29 (1H, br s). Anal. Calcd for C11H14ClNO3: C,
from 22f in 94% yield, mp 124.5—125 °C. 1H-NMR (DMSO-d6) d: 0.92
54.22; H, 5.79; Cl, 14.55; N, 5.75. Found: C, 54.00; H, 5.81; Cl, 14.62; N,
(3H, t, Jϭ7.4), 1.38—1.54 (2H, m), 1.62—1.74 (2H, m), 3.92 (2H, t, 5.57. MS: m/z, 244 (MHϩ). IR cmϪ1: 3294, 1717, 1605, 1406, 1238.
Jϭ6.4), 6.03 (2H, s), 6.44 (1H, s), 7.57 (1H, s), 11.77 (1H, br s). Anal. Calcd 5-Chloro-4-dimethylamino-2-methoxybenzoic Acid (29a) In a similar
for C11H14ClNO3: C, 54.22; H, 5.79; Cl, 14.55; N, 5.75. Found: C, 53.86; H, manner to that described above, 29a (colorless crystal) was prepared from 4-
5.72; Cl, 14.53; N, 5.70. MS: m/z, 244 (MHϩ). IR cmϪ1: 3497, 3381, 3267,
1724, 1620, 1591, 1441, 1410, 1230.
amino-5-chloro-2-methoxybenzoic acid (23a) in 55% yield, mp 150—
151.5 °C. H-NMR (DMSO-d6) d: 2.85 (6H, s), 3.83 (3H, s), 6.67 (1H, s),
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5-Chloro-2-isopropoxy-4-methylaminobenzoic Acid (25) 1) NaH 7.65 (1H, s), 12.39 (1H, br s). Anal. Calcd for C10H12ClNO3: C, 52.30; H,
(60% dispersion in mineral oil, 5.9 g, 0.15 mol) was added portionwise to a 5.27; Cl, 15.44; N, 6.10. Found: C, 52.36; H, 5.26; Cl, 15.36; N, 5.95. MS:
mixture of methyl 4-acetylamino-5-chloro-2-isopropoxybenzoate20) (22c, m/z, 230 (MHϩ). IR cmϪ1: 1686, 1597, 1244.
10.3 g, 36 mmol), MeI (30.6 g, 0.22 mol), and anhydrous THF (60 ml) at ca.
5-Chloro-4-formylamino-2-methoxybenzoic Acid (30) A mixture of
5 °C. The reaction mixture was stirred at room temperature for 16 h and con- Ac2O (55.7 g, 0.55 mol) and HCO2H (99%, 100.6 g, 2.2 mol) was heated at
centrated to dryness. After careful addition of H2O, the precipitates were 50 °C for 1 h. After addition of 23a (11.0 g, 55 mmol), the whole was heated
collected by filtration, washed with H2O, and dried to give 8.1 g (75%) of at 65 °C for 2 h and cooled to room temperature. The reaction mixture was
methyl 4-(N-acetyl-N-methyl)amino-5-chloro-2-isopropoxybenzoate (24) as poured into cold H2O, and the precipitates were collected by filtration,
a colorless crystal, mp 91—92.5 °C. 1H-NMR (DMSO-d6) d: 1.39 (6H, d,
Jϭ6.1), 1.85 (3H, s), 3.19 (3H, s), 3.91 (3H, s), 4.55 (1H, hep, Jϭ6.1), 6.88
(1H, s), 7.88 (1H, s). Anal. Calcd for C14H18ClNO4: C, 56.10; H, 6.05; Cl,
washed with H2O, and dried to give 10.6 g (85%) of 30 as a gray powder, mp
207—208 °C. H-NMR (DMSO-d6) d: 3.79 (3H, s), 7.75 (1H, s), 8.15 (1H,
s), 8.44 (1H, s), 10.08 (1H, s), 12.76 (1H, s). Anal. Calcd for C9H8ClNO4: C,
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11.83; N, 4.67. Found: C, 56.14; H, 6.11; Cl, 11.85; N, 4.55. MS: m/z, 300 47.08; H, 3.51; Cl, 15.44; N, 6.10. Found: C, 46.99; H, 3.53; Cl, 15.41; N,
(MHϩ). IR cmϪ1: 1715, 1666, 1599, 1244, 1105. 2) A mixture of 24 (4.5 g, 6.00. MS: m/z, 230 (MHϩ). IR cmϪ1: 3323, 3275, 1717, 1678, 1609, 1583,
15 mmol) and 20% aqueous NaOH (60 ml) was heated to reflux for 15 h and 1518, 1447, 1418, 1271.
cooled to ca. 5 °C. After acidification with 10% aqueous HCl, the precipi-
4-Amino-5-bromo-2-ethoxybenzoic Acid (33a) 1) A solution of
tates were collected by filtration and recrystallized from MeOH to give 3.5 g methyl 4-acetylamino-2-ethoxybenzoate28,29) (31, 10.0 g, 42 mmol) and NBS
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(96%) of 25 as a colorless crystal, mp 154—155 °C. H-NMR (DMSO-d6) (8.2 g, 46 mmol) in N,N-dimethylformamide (DMF) (60 ml) was heated at
d: 1.29 (6H, d, Jϭ6.1), 2.82 (3H, d, Jϭ4.8, NMe), 4.71 (1H, hep, Jϭ6.1), 80 °C for 3.5 h and cooled to room temperature. After addition of H2O
6.19 (1H, q, Jϭ4.8, NH), 6.21 (1H, s), 7.52 (1H, s), 11.73 (1H, br s, CO2H). (100 ml), the precipitates were collected by filtration, washed with H2O, and
Anal. Calcd for C11H14ClNO3: C, 54.22; H, 5.79; Cl, 14.55; N, 5.75. Found: dried to give 12.5 g (94%) of methyl 4-acetylamino-5-bromo-2-ethoxyben-
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C, 53.97; H, 5.84; Cl, 14.41; N, 5.72. MS: m/z, 243 (Mϩ). IR cmϪ1: 3396, zoate (32a) as a white fine needle, mp 172—173 °C. H-NMR (DMSO-d6)
1713, 1607, 1454, 1389.
d: 1.31 (3H, t, Jϭ7), 2.13 (3H, s), 3.76 (3H, s), 4.04 (2H, q, Jϭ7), 7.64 (1H,
5-Chloro-4-ethylamino-2-methoxybenzoic Acid (27) 1) Methyl 4- s), 7.86 (1H, s), 9.44 (1H, s). Anal. Calcd for C12H14BrNO4: C, 45.59; H,
acetylamino-5-chloro-2-methoxybenzoate (22a, 10.0 g, 39 mmol) was added 4.46; Br, 25.27; N, 4.43. Found: C, 45.57; H, 4.48; Br, 25.38; N, 4.43. MS:
portionwise to a suspension of NaH (60% dispersion in mineral oil, 4.7 g, m/z, 315 (Mϩ). IR cmϪ1: 3231, 2988, 1690, 1665, 1572, 1408, 1389, 1252.
0.12 mol) in anhydrous tetrahydrofuran (THF) (75 ml) under ice-cooling. 2) A mixture of 32a (4.1 g, 13 mmol), NaOH (3.5 g, 88 mmol), MeOH
The mixture was warmed to room temperature and stirred for 1 h. After the
(12 ml), and H2O (16 ml) was heated to reflux for 4 h and cooled to ca. 5 °C.
mixture was recooled to ca. 5 °C, EtI (31 ml, 0.39 mol) was added, and The reaction mixture was acidified with 25% aqueous H2SO4, and the pre-
the whole was stirred at room temperature overnight. The reaction mixture cipitates were collected by filtration and recrystallized from MeOH to afford
was poured carefully into cold H2O, and the volatiles were evaporated. The 3.3 g (98%) of 33a as a colorless crystal, mp 179—181 °C. 1H-NMR
aqueous solution was washed with CHCl3, acidified with 35% aqueous HCl,
and extracted with CHCl3. The extract was washed with brine and concen-
(DMSO-d6) d: 1.33 (3H, t, Jϭ7.0), 3.98 (2H, q, Jϭ7.0), 5.99 (2H, br s,
NH2), 6.44 (1H, s), 7.73 (1H, s), 11.79 (1H, br s, CO2H). Anal. Calcd for
trated to dryness to give ca. 10 g of 4-(N-acetyl-N-ethyl)amino-5-chloro-2- C9H10BrNO3: C, 41.56; H, 3.88; Br, 30.72; N, 5.39. Found: C, 41.20; H,
methoxybenzoic acid (26) as a pale yellow amorphous solid, which was used
in the next step without further purification. H-NMR (DMSO-d6) d: 1.02 1628, 1585, 1447, 1402.
(3H, t, Jϭ7.1), 3.11 (3H, s), 3.46 (1H, dq, Jϭ7.1, 13.6), 3.77 (1H, dq,
3.87; Br, 30.50; N, 5.23. MS: m/z, 259 (Mϩ). IR cmϪ1: 3489, 3327, 1699,
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4-Amino-2-ethoxy-5-iodobenzoic Acid (33b) 1) A solution of 31
Jϭ7.1, 13.6), 3.85 (3H, s), 7.26 (1H, s), 7.78 (1H, s), 13.09 (1H, br s). IR (5.0 g, 21 mmol) and ICl (3.8 g, 23 mmol) in DMF (25 ml) was stirred at
cmϪ1: 1717, 1647, 1600, 1227. MS: m/z, 272 (MHϩ). 2) In a similar manner
room temperature for 0.5 h, heated at 80 °C for 2 h, and cooled to room tem-
to that described above, 27 was obtained from 26 in 63% yield from 22a. An perature. After addition of H2O (100 ml), the precipitates were collected by
analytical sample of 27 was obtained by recrystallization from filtration and recrystallized from acetone to give 3.6 g (47%) of methyl 4-
acetone/hexane, mp 128—130 °C. 1H-NMR (DMSO-d6) d: 1.21 (3H, t, acetylamino-2-ethoxy-5-iodobenzoate (32b) as a colorless fine needle, mp
1
Jϭ7.5), 3.28 (2H, q, Jϭ7.5), 3.83 (3H, s), 6.00 (1H, br), 6.27 (1H, s), 7.64 188—189 °C. H-NMR (DMSO-d6) d: 1.32 (3H, t, Jϭ7), 2.10 (3H, s), 3.77
(1H, s), 11.98 (1H, br s). Anal. Calcd for C10H12ClNO3: C, 52.30; H, 5.27; (3H, s), 4.04 (2H, q, Jϭ7), 7.42 (1H, s), 8.06 (1H, s), 9.36 (1H, s). Anal.
Cl, 15.44; N, 6.10. Found: C, 52.11; H, 5.27; Cl, 15.21; N, 5.93. MS: m/z,
Calcd for C12H14INO4: C, 39.69; H, 3.89; I, 34.95; N, 3.86. Found: C, 39.88;
H, 3.93; I, 34.83; N, 3.67. MS: m/z, 363 (Mϩ). IR cmϪ1: 3221, 2984, 1684,
1665, 1566, 1406, 1387, 1252. 2) In a similar manner to that described
above, 32b was hydrolyzed to give 33b as a colorless crystal in 91% yield,
mp 190—193 °C. 1H-NMR (DMSO-d6) d: 1.32 (3H, t, Jϭ7.0), 3.98 (2H, q,
230 (MHϩ). IR cmϪ1: 3427, 3281, 1707, 1606, 1425, 1323.
4-Acetylamino-5-chloro-2-methoxybenzoic Acid (28) A suspension of
22a (50.0 g, 0.19 mol) and NaOH (9.0 g, 0.23 mol) in a mixture of MeOH
(80 ml) and H2O (150 ml) was heated at 60 °C for 1 h and cooled to room
temperature. After evaporation of MeOH, the resulting aqueous solution was Jϭ7.0), 5.87 (2H, br s, NH2), 6.42 (1H, s), 7.93 (1H, s), 11.75 (1H, br s).