min. The resulting yellow solution was stirred at room
temperature for 40 min, powdered potassium carbonate (287
mg, 2.07 mmol) was added, and the mixture was stirred at
(60.0 g, 0.166 mol, 1.0 equiv) in NMP (180 mL) (made by
dissolving the solid in cold NMP and keeping the solution
cold to avoid dimerization of the imidoyl chloride) over 50
min. The addition funnel was rinsed with NMP (60 mL),
and the mixture was stirred 1 h at room temperature. To the
stirred mixture was added milled potassium carbonate (91.8
g, 4.0 equiv, 0.664 mol), the slurry was heated to 90-95 °C
40 °C for 4 h. The reaction was cooled to room temperature
and added slowly to 10 mL of stirred water. The resulting
solid was filtered and dried at 40 °C (30 mmHg) overnight
to afford imidate 16a as an off-white solid (540 mg, 87%
1
yield, 98% HPLC purity). H NMR (CDCl
3
) δ 2.4 (s, 3H),
2
under N , and the reaction was followed by HPLC. After
2
.5 (m, 4H), 3.2 (m, 4H), 3.5 (s, 2H), 6.2 (s, 1H), 7.05 (d,
completion of the cyclization (4 h), the mixture was cooled
in a water bath, and cold water (600 mL) was added slowly.
After stirring for 15 min the slurry was filtered. The solid
was suspended in MeOH (350 mL), stirred at room temper-
ature for 30 min, and filtered. The light-tan solid was dried
in vacuo (40 °C, 30 mmHg) overnight to afford indazole
J ) 7 Hz, 2H), 7.2 (m, 3H), 7.8 (d, J ) 7 Hz, 2H).
Amidine 16a from 14 (Tertiary Amine Added). The
procedure was the same as the above procedure, except that
the imidoyl chloride 14 solution was added to a mixture of
the piperazine and the tertiary amine (see Table 1) in NMP.
Preparation of 4-[6-Fluoro-1-[(4-methylphenyl)sul-
fonyl]-1H-indazol-3-yl]-1-cyanomethylpiperazine (18a) from
18b (52.8 g, 76.8% yield, 99% HPLC purity): mp 146-
1
148 °C. H NMR (CDCl
3
) δ 2.3 (s, 3H), 2.4 (s, 3H), 2.6 (m,
1
6a. A mixture of amidine 16a (89.4 g, 0.199 mol corrected
4H), 3.5 (m, 4H), 7.0 (dt, J ) 9, 2 Hz, 1H), 7.2 (d, J ) 8
Hz, 2H), 7.6 (dd, J ) 9,5 Hz, 1H), 7.75 (d, J ) 8 Hz, 2H),
7.9 (dd, J ) 9,2 Hz, 1H).
Preparation of 4-[6-Fluoro-1-[(4-methylphenyl)sul-
fonyl]-1H-indazol-3-yl]-1-phenylmethylpiperazine (18c).
To a stirred mixture of 1-benzylpiperazine (2.68 g, 15.2
mmol) and 1,4-diazabicyclo[2.2.2]octane (0.7 equiv, 1.09 g,
for purity) and milled potassium carbonate (55.3 g, 0.4 mol,
2
N
was diluted with water (540 mL, 6:1 v/v NMP) over 15 min,
and the resulting slurry was cooled to 10 °C and filtered
after 1 h. The solid was washed with cold water (2 × 300
mL) and dried in a vacuum oven at 85 °C to afford indazole
equiv) in NMP (270 mL) was heated to 90-95 °C under
for 4 h and cooled to room temperature. The mixture
2
2
9.7 mmol) in dry NMP (5 mL) under N was added dropwise
1
8a as a light tan solid (78.8 g, 95.8% yield): mp 170-171
a cold solution of imidoyl chloride 14 (5.00 g, 13.8 mmol)
in NMP (15 mL) (made by dissolving the solid in cold NMP
and keeping the solution cold to avoid dimerization of the
imidoyl chloride) over 12 min. The addition funnel was
rinsed with NMP (5 mL), and the dark green/brown mixture
was stirred for 2 h at room temperature. To the stirred
mixture was added milled potassium carbonate (7.66 g, 4.0
equiv, 55.4 mmol), and the slurry was heated to 90-95 °C
1
°
C; external standard HPLC 99.8% w/w purity. H NMR
(CDCl ) δ 2.4 (s, 3H), 2.75 (m, 4H), 3.55 (m, 4H), 3.6 (s,
3
2
1
H), 7.0 (dt, J ) 7,1 Hz, 1H), 7.2 (d, J ) 7 Hz, 2H), 7.6 (m,
H), 7.75 (d, J ) 7 Hz, 2H), 7.8 (dd, J ) 7, 1 Hz, 1H).
Preparation of 4-[6-Fluoro-1-[(4-methylphenyl)sul-
fonyl]-1H-indazol-3-yl]-1-cyanomethylpiperazine (18a) from
4. To a stirred mixture of 1-cyanomethylpiperazine 15a
22.9 g, 183 mmol, 1.1 equiv) and 1,4-diazabicyclo[2.2.2]-
octane (0.7 equiv, 13.0 g, 0.116 mol) in dry NMP (60 mL)
under N was added dropwise a cooled (0 °C) solution of
imidoyl chloride 14 (60.0 g, 0.166 mol, 1.0 equiv) in NMP
180 mL) (made by dissolving the solid in cold NMP and
1
(
2
under N for 4 h. The mixture was cooled in a water bath,
and cold water (50 mL) was added slowly. After stirring for
10 min the slurry was filtered. The solid was suspended in
MeOH (30 mL), stirred at room temperature for 30 min, and
filtered. The light-tan solid was dried in vacuo (40 °C, 30
2
(
keeping the solution cold to avoid dimerization of the imidoyl
chloride) over 60 min. The addition funnel was rinsed with
NMP (60 mL), and the mixture was stirred for 1 h at room
temperature. To the stirred mixture was added milled
potassium carbonate (91.8 g, 4.0 equiv, 0.664 mol), the slurry
mmHg) overnight to afford indazole 18c (4.55 g, 70.9%
1
yield): mp 165-167 °C. H NMR (CDCl
3
) δ 2.4 (s, 3H),
2.6 (m, 4H), 3.5 (m, 4H), 3.6 (s, 2H), 6.9 (dt, J ) 7,1,Hz,
1H), 7.2 (d, J ) 7 Hz, 2H), 7.3 (m, 5H), 7.5 (m, 1H), 7.75
(d, J ) 7 Hz, 2H), 7.8 (dd, J ) 7,1 Hz, 1H).
was heated to 90-95 °C under N
followed by HPLC. After completion of the cyclization (4
h), the mixture was cooled in a water bath, and cold water
2
, and the reaction was
Preparation of 4-[1-[(4-Methylphenyl)sulfonyl]-6-fluoro-
1H-indazol-3-yl]-1-piperazinecarboxylic Acid Ethyl Ester
(18d). To a mixture of 1-carboethoxypiperazine (470 g, 2.97
mol, 1.1 equiv), and 1,4-diazabicyclo[2.2.2]octane (227 g,
2.02 mol, 0.75 equiv) in NMP (1950 mL) cooled to 0-2 °C
was added slowly a cooled (0 °C) solution of 14 (1.35 mol,
0.5 equiv, 488 g) in cold NMP (1460 mL) over 75 min.
Another cooled solution of 14 (1.35 mol, 0.5 equiv, 488 g)
in cold NMP (1460 mL) was prepared and added slowly to
the cooled mixture. During the addition the mixture became
acidic; therefore, another portion of DABCO (15.2 g, 0.05
equiv) was added. After the addition, the mixture was
allowed to warm to room temperature overnight. Milled
potassium carbonate (3.0 equiv, 1120 g) was added, and the
mixture was heated to 100-105 °C until the cyclization was
complete (2.5 h). The mixture was allowed to cool to room
(600 mL) was added slowly. After stirring for 15 min, the
resulting slurry was filtered, and the solid was washed with
cold water (2 × 120 mL). The solid was suspended in MeOH
(350 mL), stirred at room temperature for 40 min, and
filtered. The light-tan solid was dried in vacuo (40 °C, 30
mmHg) overnight to afford indazole 18a (48.8 g, 70.9%
yield, 99.8% HPLC purity).
Preparation of 4-[6-Fluoro-1-[(4-methylphenyl)sul-
fonyl]-1H-indazol-3-yl]-1-methylpiperazine (18b). To a
stirred mixture of 1-methylpiperazine (22.8 g; 1.1 equiv,
0
.182 mol) and 1,4-diazabicyclo[2.2.2]octane (0.7 equiv, 13.0
g, 0.116 mol) in NMP (180 mL) under N , was added
dropwise a cooled to 0 °C solution of imidoyl chloride 14
2
182
•
Vol. 5, No. 2, 2001 / Organic Process Research & Development