April 2001
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35 as a pale yellow viscous oil. MS m/z: 351, 353 (Mϩ, 3 : 1). IR n (KBr)
cmϪ1: 1694, 1644. 1H-NMR (CDCl3): 1.65—2.30 (9H, m), 2.28 (3H, s),
3.60—3.75 (2H, m), 4.02 (3H, s), 4.30—4.45 (1H, m), 7.82 (1H, br s), 8.21
(1H, s), 8.34 (1H, s), 8.40—8.50 (1H, m).
by filtration and the filtrate was evaporated. The resulting residue was dis-
solved in 10% HCl and the insoluble substance was removed by filtration.
The filtrate was basified with K2CO3 and the precipitate was collected by fil-
tration, washed with water and dried to give 9.90 g (100%) of 41d as a color-
less amorphous solid, which was converted to the hydrochloride in the usual
manner. The hydrochloride was recrystallized from EtOH to afford colorless
needles, mp Ͼ300 °C. Anal. Calcd for C17H22N4O·HCl: C, 60.98; H, 6.92;
N, 16.73. Found: C, 60.77; H, 7.01; N, 16.55. MS m/z: 298 (Mϩ). IR n
(KBr) cmϪ1: 1640. 1H-NMR (DMSO-d6): 1.25—2.65 (10H, m), 3.35 (1H,
br s), 3.55—3.95 (2H, m), 4.13 (3H, s), 4.25—4.80 (1H, m), 7.15—7.80
(3H, m), 8.05—8.35 (1H, m), 8.40—9.40 (1H, m).
Ethyl endo-3-[(4-Acetylamino-5-chloro-2-methoxybenzoyl)amino]-8-
azabicyclo[3.2.1]octane-8-acetate (36) A mixture of 35 (8.00 g, 22.7
mmol), ethyl bromoacetate (4.18 g, 25.0 mmol) and K2CO3 (3.46 g, 25.0
mmol) in DMF (50 ml) was stirred at 60 °C for 2 h. After the addition of
water, the reaction mixture was extracted with AcOEt. The extract was
washed with water, dried and evaporated. The resulting residue was washed
with iso-Pr2O to give 5.20 g (52%) of 36 as a colorless crystal, which was re-
crystallized from EtOH to afford colorless prisms, mp 144—145 °C. Anal.
Calcd for C21H28ClN3O5: C, 57.60; H, 6.44; N, 9.60. Found: C, 57.45; H,
6.32; N, 9.49. MS m/z: 437, 439 (Mϩ, 3 : 1). IR n (KBr) cmϪ1: 1738, 1704,
1640. 1H-NMR (CDCl3): 1.29 (3H, t, Jϭ7 Hz), 1.65—2.45 (9H, m), 2.28
(3H, s), 3.26 (2H, s), 3.30—3.50 (2H, m), 4.02 (3H, s), 4.21 (2H, q,
Jϭ7 Hz), 4.25—4.40 (1H, m), 7.80 (1H, br s), 8.21 (1H, s), 8.34 (1H, s),
8.35—8.50 (1H, m).
Ethyl endo-3-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-8-azabi-
cyclo[3.2.1]octane-8-acetate (37) A mixture of 36 (4.60 g, 10.5 mmol)
and 10% ethanolic hydrochloride (30 ml) in EtOH (10 ml) was refluxed for
1 h. The reaction mixture was evaporated and water was added to the result-
ing residue. The aqueous layer was washed with AcOEt and then adjusted to
pH 9 with 10% aqueous K2CO3. The resulting crystals were collected by fil-
tration and washed with water and iso-Pr2O to give 4.09 g (98%) of 37 as a
pale yellow crystal, which was recrystallized from EtOH to afford colorless
crystals, mp 187—188 °C. Anal. Calcd for C19H26ClN3O4: C, 57.65; H, 6.62;
N, 10.61. Found: C, 57.57; H, 6.52; N, 10.42. MS m/z: 395, 397 (Mϩ, 3 : 1).
IR n (KBr) cmϪ1: 1748, 1640. 1H-NMR (CDCl3): 1.28 (3H, t, Jϭ7 Hz),
1.60—2.50 (8H, m), 3.26 (2H, s), 3.25—3.50 (2H, m), 3.93 (3H, s), 4.20
(2H, q, Jϭ7 Hz), 4.20—4.40 (1H, m), 4.41 (2H, br s), 6.31 (1H, s), 8.10
(1H, s), 8.20—8.35 (1H, m).
endo-3-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-8-azabicy-
clo[3.2.1]octane-8-acetic Acid (38) A mixture of 37 (3.60 g, 9.09 mmol)
and 2 N aqueous NaOH solution (9.1 ml) in MeOH (36 ml) was refluxed for
1 h. The reaction mixture was concentrated and the resulting residue was
dissolved in a small amount of water. The solution was adjusted to pH 1
with 10% HCl. The resulting precipitate was collected by filtration and
washed with water to give crude crystals, which were recrystallized from
water to afford the hydrochloride (3.19 g, 81%) of 38 as a pale yellow crys-
tal, mp 254—256 °C (dec.). Anal. Calcd for C17H22ClN3O4·HCl·3/2H2O: C,
47.34; H, 6.08; N, 9.74. Found: C, 47.36; H, 5.96; N, 9.79. MS m/z: 367,
369 (Mϩ, 3 : 1). IR n (KBr) cmϪ1: 1736, 1628. 1H-NMR (DMSO-d6): 1.95—
2.60 (8H, m), 3.85 (3H, s), 3.95—4.15 (1H, m), 4.01 (2H, s), 5.90 (2H, br),
6.56 (1H, s), 7.65 (1H, s), 8.05—8.20 (1H, m).
Method D. endo-N-(9-Benzyl-9-azabicyclo[3.3.1]non-3-yl)-1-methyl-
1H-indazole-3-carboxamide (40d) A mixture of endo-3-amino-9-benzyl-
9-azabicyclo[3.3.1]nonane (13.8 g, 59.9 mmol), Et3N (6.60 g, 65.2 mmol)
and 1-methyl-1H-indazole-3-carbonyl chloride 39d (10.2 g, 52.2 mmol) in
CH2Cl2 (150 ml) was stirred at room temperature for 2 h. The reaction mix-
ture was washed with water, dried and evaporated. The resulting residue was
purified by column chromatography (SiO2, CHCl3) and crystallized from
iso-Pr2O to give 14.75 g (73%) of 40d as a colorless crystal, which was re-
crystallized from MeOH to afford colorless needles, mp 161—162 °C. Anal.
Calcd for C24H28N4O: C, 74.20; H, 7.26; N, 14.42. Found: C, 74.15; H, 7.32;
N, 14.41. MS m/z: 388 (Mϩ). IR n (KBr) cmϪ1: 1672. 1H-NMR (CDCl3):
0.75—2.25 (8H, m), 2.25—2.75 (2H, m), 2.90—3.35 (2H, m), 3.87 (2H, s),
4.09 (3H, s), 4.50—4.95 (1H, m), 6.70—6.95 (1H, m), 7.05—7.65 (8H, m),
8.35—8.55 (1H, m).
Compounds 41e, f were prepared in a manner similar to that described
above. 41e: mp 232—236 °C (dec., aqueous EtOH). Anal. Calcd for
C17H21N3O·H2O: C, 67.75; H, 7.69; N, 13.94. Found: C, 67.85; H, 7.76; N,
1
13.86. MS m/z: 283 (Mϩ). IR n (KBr) cmϪ1: 1606. H-NMR (DMSO-d6):
0.90—2.35 (10H, m), 2.95—3.55 (2H, m), 3.80—4.50 (1H, m), 6.90—7.55
(4H, m), 7.99 (1H, s), 8.00—8.25 (1H, m), 11.39 (1H, br s). 41f: mp 218—
219 °C (EtOH). Anal. Calcd for C18H23N3O: C, 72.70; H, 7.80; N, 14.13.
Found: C, 72.54; H, 7.84; N, 13.96. MS m/z: 297 (Mϩ). IR n (KBr) cmϪ1
:
1614. 1H-NMR (CDCl3): 1.00—2.10 (8H, m), 1.90 (1H, s), 2.10—2.60 (2H,
m), 3.20—3.55 (2H, m), 3.80 (1H, s), 4.00—4.60 (1H, m), 5.60—5.95 (1H,
m), 7.10—7.50 (3H, m), 7.67 (1H, s), 7.80—8.05 (1H, m).
Ethyl endo-3-[[(1-Methyl-1H-indazol-3-yl)carbonyl]amino]-9-azabicy-
clo[3.3.1]nonane-9-acetate (42d) A mixture of 41d (2.50 g, 8.38 mmol),
ethyl bromoacetate (1.54 g, 9.22 mmol) and K2CO3 (1.16 g, 8.39 mmol) in
DMF (20 ml) was stirred at 70 °C for 4.5 h. After the addition of water, the
reaction mixture was extracted with Et2O. The extract was washed with
water, dried and evaporated. The residue was purified by column chromatog-
raphy [SiO2, CH2Cl2] to afford 2.69 g (84%) of 42d as a pale yellow viscous
oil. High resolution MS m/z: Calcd for C21H28N4O3: 384.2161. Found:
384.2173. MS m/z: 384 (Mϩ). IR n (KBr) cmϪ1: 1748, 1662. 1H-NMR
(CDCl3): 0.90—2.25 (8H, m), 1.28 (3H, t, Jϭ7.5 Hz), 2.25—2.80 (2H, m),
3.05—3.45 (2H, m), 3.49 (2H, s), 4.08 (3H, s), 4.17 (2H, q, Jϭ7.5 Hz),
4.20—4.80 (1H, m), 6.65—6.95 (1H, m), 7.10—7.60 (3H, m), 8.20—8.50
(1H, m).
Compounds 42e, f were prepared in a manner similar to that described
above and their physicochemical data were summarized in Table 3.
endo-3-[[(1-Methyl-1H-indazol-3-yl)carbonyl]amino]-9-azabicyclo-
[3.3.1]nonane-9-acetic Acid (43d) A mixture of 42d (2.00 g, 5.20 mmol)
and 2 N aqueous NaOH solution (5.2 ml) in MeOH (20 ml) was refluxed for
1 h. The reaction mixture was evaporated and the resulting residue was dis-
solved in a small amount of water. The solution was adjusted to pH 2 with
10% aqueous HCl. The resulting precipitate was collected by filtration to af-
ford 1.50 g (67%) of 43d as a colorless amorphass solid. Anal. Calcd for
C19H24N4O3·HCl·2H2O: C, 53.21; H, 6.81; N, 13.06. Found: C, 53.34; H,
1
6.66; N, 13.04. MS m/z: 357 (Mϩϩ1). IR n (KBr) cmϪ1: 1744, 1652. H-
NMR (DMSO-d6): 1.25—2.70 (10H, m), 3.70—4.05 (2H, m), 4.14 (3H, s),
4.18 (2H, s), 4.35—5.05 (1H, m), 7.10—7.85 (3H, m), 8.00—8.50 (2H, m).
Compounds 43e, f were prepared in a manner similar to that described
above and their physicochemical data was summarized in Table 3.
Method E. Methyl 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-
1-piperidineacetate (44) To a suspension of 19 (5.00 g, 14.6 mmol) in
MeOH (75 ml) was added concentrated sulfuric acid (1.80 g). The mixture
was refluxed for 16 h. After cooling, the solvent was evaporated to give the
residue, which was basified (pHϭ9) with aqueous K2CO3 and extracted with
CH2Cl2. The extract was washed with saturated aqueous NaCl, dried and
evaporated to afford 3.82 g (74%) of 44 as pale brown residue, which was re-
crystallized from MeOH to afford 2.95 g of pale brown prisms, mp 196—
197 °C. Anal. Calcd for C16H22ClN3O4: C, 54.01; H, 6.23; N,11.81. Found:
C, 53.80; H, 6.14; N, 11.83. MS m/z: 355, 357 (3 : 1, Mϩ). IR n (KBr) cmϪ1
:
Compounds 40e, f were prepared in a manner similar to that described
above. 40e: mp 212—214 °C (CH2Cl2–MeOH). Anal. Calcd for C24H27N3O:
C, 77.18; H, 7.29; N, 11.25. Found: C, 77.08; H, 7.34; N, 11.24. MS m/z:
373 (Mϩ). IR n (KBr) cmϪ1: 1620. 1H-NMR (DMSO-d6): 0.70—2.75 (10H,
m), 2.85—3.30 (2H, m), 3.83 (2H, s), 4.05—4.85 (1H, m), 6.90—7.60 (9H,
m), 7.99 (1H, d, Jϭ3 Hz), 8.10—8.30 (1H, m), 11.38 (1H, br s). 40f: mp
210—211 °C (EtOH). Anal. Calcd for C25H29N3O: C, 77.49; H, 7.54; N,
10.84. Found: C, 77.45; H, 7.57; N, 11.10. MS m/z: 387 (Mϩ). IR n (KBr)
cmϪ1: 1614. 1H-NMR (CDCl3): 0.80—2.20 (8H, m), 2.30—2.80 (2H, m),
3.00—3.30 (2H, m), 3.76 (3H, s), 3.86 (2H, s), 4.25—5.10 (1H, m), 5.70—
5.80 (1H, m), 7.10—7.50 (8H, m), 7.63 (1H, s), 7.80—8.15 (1H, m).
endo-N-(9-Azabicyclo[3.3.1]non-3-yl)-1-methyl-1H-indazole-3-carbox-
amide (41d) A mixture of 40d (12.9 g, 3.32 mmol), Pearlman’s catalyst
(2.0 g) and acetic acid (25 ml) in MeOH (225 ml) was stirred at room tem-
perature and atmospheric pressure of H2 for 3 h. The catalyst was removed
3400, 3320, 3216, 1756. 1H-NMR (DMSO-d6): 1.45—1.55 (2H, m), 1.75—
1.85 (2H, m), 2.30—2.35 (2H, m), 2.70—2.80 (2H, m), 3.23 (2H, s), 3.62
(3H, s), 3.70—3.85 (1H, m), 3.85 (3H, s), 5.80 (2H, br s), 6.50 (1H, s), 7.67
(1H, s), 7.68 (1H, d, Jϭ7.5 Hz).
n-Propyl 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineac-
etate (45) A solution of n-propyl bromide (1.78 g, 14.5 mmol) in DMF
(15 ml) was added to a suspension of 19 (4.50 g, 13.2 mmol) and K2CO3
(2.00 g, 14.5 mol) in DMF (135 ml) at 60 °C over 1 h. The mixture was
stirred at 60 °C for 2 h. After cooling, the reaction mixture was added to
water and extracted with toluene. The extract was washed with saturated
aqueous NaCl, dried and evaporated to afford colorless residue. The residue
was washed with n-heptane to afford 3.94 g (78%) of the crude 45, which
was converted to the mesylate in the usual manner. The mesylate of 45 was
recrystallized from iso-PrOH to give a colorless crystal, mp 209—210 °C.