chloroform. The combined chloroform solutions were washed with
water and brine, dried over anhydrous magnesium sulfate, and
concentrated to afford 1.45 g (100%) of 7: IR (KBr) 1733, 1604, 1584,
1547, 1510 cm-1; 1H NMR (CDCl3) δ 1.40-1.65 (m, 2, aliphatic CH2),
1.74-2.00 (m, 2, aliphatic CH2), 2.07 (s, 3, OCOCH3), 2.38 (t, J ) 7.4
Hz, 2, NCH2CH2), 2.49 (t, J ) 5 Hz, 4, piperazine CH2), 3.50 (t, J )
5 Hz, 4, piperazine CH2), 5.74 (t, J ) 6.9 Hz, 1, CHOAc), 6.53 (d, J )
9 Hz, 1, pyridine H-3), 6.98-7.07 (m, 2, ArH), 7.29-7.35 (m, 2, ArH),
7.52 (dd, J ) 9, 2.5 Hz, 1, pyridine H-4), 8.18 (d, J ) 2.5 Hz, 1, pyridine
H-6); 13C NMR (CDCl3) δ 21.4, 22.9 34.2, 45.3, 53.0, 58.3, 75.5, 108.1,
108.8, 115.6, 116.1, 128.7, 128.9, 136.8, 136.9, 140.2, 149.0, 158.5,
centrated, and chromatographed on silica gel using ammonium
hydroxide solution:methanol:chloroform (1:8:40, v/v) to afford 1.78 g
(71%) of 3: IR (KBr) 3435, 2954, 2823, 1677, 1600, 1507 cm-1
;
1H
NMR (CDCl3) δ 1.85-2.02 (m, 2, aliphatic CH2), 2.35-2.60 (m, 6,
NCH2), 2.80-3.05 (m, 6, COCH2 and NCH2), 3.25-3.36 (m, 1, NH),
7.05-7.20 (m, 2, ArH), 7.95-8.10 (m, 2, ArH).
1-(4-F lu or op h en yl)-4-[4-(5-n itr o-2-p yr id in yl)-1-p ip er a zin yl]-
1-bu ta n on e (13) fr om 3sTo a solution of 880 mg (3.52 mmol, 1
equiv) of 3 and 715 mg (3.52 mmol, 1 equiv) of 2-bromo-5-nitropyridine
in 5-mL of isoamyl alcohol was added 373 mg (3.52 mmol, 1 equiv) of
anhydrous sodium carbonate. The mixture was refluxed, with
continuous removal of water with a Dean Stark trap, for 3 h. The
solvent was removed by distillation under reduced pressure. The
residue was dissolved in chloroform, washed with water, sodium
bicarbonate solution and brine, dried over anhydrous magnesium
sulfate, concentrated, and chromatographed on a silica gel column
using methanol:chloroform (1:19, v/v) to afford 772 mg (59%) of 13.
160.5, 165.4, 171.0; exact mass spectrum calculated for C21H25
BrFN3O2 449.1116, found 449.1115.
-
1-(4-F lu or op h en yl)-4-[4-(5-br om o-2-p yr id in yl)-1-p ip er a zin yl]-
1-(ter t-bu tyld im eth ylsiloxy)bu ta n e (8)sTo a solution of 408 mg
(1 mmol, 1 equiv) of 6 in 2-mL of anhydrous N,N-dimethylformamide
(DMF) was added 170 mg (2.5 mmol, 2.5 equiv) of imidazole. The
mixture was stirred at 25 °C for 5 min, and 226 mg (1.5 mmol, 1.5
equiv) of tert-butyldimethylsilyl chloride was added. The solution was
stirred at 25 °C for 18 h. The mixture was diluted with ethyl acetate
and washed thoroughly with water. The combined aqueous phase
was extracted once with ethyl acetate, and the combined ethyl acetate
solutions were washed with brine, dried over anhydrous magnesium
sulfate, concentrated, and chromatographed on silica gel using ethyl
acetate:hexane (1:1, v/v) to afford 450 mg (86%) of 8: IR (TF) 2952,
1-(4-F lu or op h en yl)-4-[4-(5-h yd r oxy-2-p yr id in yl)-1-p ip er a zin -
yl]-1-bu ta n on e (16)sTo a solution of 372 mg (1 mmol, 1 equiv) of
13 in 30-mL of methanol was added 50 mg of 10% palladium on
carbon. The mixture was stirred under 50 psi of hydrogen at 25 °C
for 6 h. The catalyst was removed by filtration through Celite, and
the filtrate was concentrated to afford the crude amine (14). The
amine (14) was dissolved in 10-mL of water containing 0.5-mL of
concentrated sulfuric acid. The mixture was cooled to 0 °C; 83 mg
(1.2 mmol, 1.2 equiv) of sodium nitrite in 1-mL of water was added
dropwise; and stirring was continued at 0-5 °C for 15 min. The
solution of the diazonium salt (15) was slowly added to a refluxing
solution of 10-mL of concentrated sulfuric acid and 1.5 g of anhydrous
sodium sulfate in 10-mL of water. The mixture was refluxed for 3 h.
The solution was cooled, and the acid was neutralized first by adding
a 20% sodium hydroxide solution and subsequently by adding sodium
bicarbonate. The mixture was extracted with chloroform. The
combined chloroform solutions were washed with sodium bicarbonate
solution and brine, dried over anhydrous magnesium sulfate, con-
centrated, and chromatographed on a silica gel column using metha-
nol:chloroform (1:5, v/v) to afford 80 mg (23%) of 16: IR (KBr) 3540
2885, 2856, 1605, 1584, 1548, 1509 cm-1 1H NMR (CDCl3) δ -0.15
;
(s, 3, CH3Si), 0.03 (s, 3, SiCH3), 0.88 (s, 9, SiC(CH3)3), 1.40-1.75 (m,
4, aliphatic CH2), 2.34 (t, J ) 7.2 Hz, 2, aliphatic NCH2), 2.48 (t, J )
5.1 Hz, 4, piperazine CH2), 3.49 (t, J ) 5.1 Hz, 4, piperazine CH2),
4.66 (t, J ) 6.3 Hz, 1, CHOTBS), 6.53 (d, J ) 9 Hz, 1, pyridine H-3),
6.90-7.03 (m, 2, ArH), 7.22-7.29 (m, 2, ArH), 7.52 (dd, J ) 9, 2.5
Hz, 1, pyridine H-4), 8.18 (d, J ) 2.5 Hz, 1, pyridine H-6); 13C NMR
(CDCl3) δ -4.87, -4.59, 18.3, 22.7, 25.9, 38.9, 45.4, 53.1, 58.8, 74.5,
108.0, 108.8, 115.1, 115.5, 127.7, 127.9, 140.2, 141.8, 141.8, 149.0,
158.6, 159.0, 164.8. Anal.sCalculated for C25H37BrFN3SiO: C, 57.46,
H, 7.14. Found: C, 57.42; H, 7.16.
1-(5-Nitr o-2-p yr id in yl)p ip er a zin e (12)sTo a solution of 860 mg
(10 mmol, 2 equiv) of piperazine (11) and 1.02 g (5 mmol, 1 equiv) of
2-bromo-5-nitropyridine in 5-mL of isoamyl alcohol was added 530
mg (5 mmol, 1 equiv) of anhydrous sodium carbonate. The mixture
was refluxed under a Dean Stark trap for 2 h. The mixture was
cooled, the solids were removed by filtration, and the clear filtrate
was concentrated and chromatographed on silica gel using methanol:
chloroform (1:5, v/v) to afford 880 mg (85%) of 12: IR (KBr) 3346,
2953, 2900, 2834, 1607, 1568, 1525 cm-1; 1H NMR (CDCl3) δ 1.78 (s,
1, NH), 2.99 (t, J ) 5.1 Hz, 4, piperazine CH2), 3.75 (t, J ) 5.1 Hz, 4,
piperazine CH2), 6.57 (d, J ) 9.5 Hz, 1, pyridine H-3), 8.20 (dd, J )
9.5, 2.7 Hz, 1, pyridine H-4), 9.04 (d, J ) 2.7 Hz, 1, pyridine H-6).
1-(4-F lu or op h en yl)-4-[4-(5-n itr o-2-p yr id in yl)-1-p ip er a zin yl]-
1-bu ta n on e (13) fr om 12sTo a solution of 416 mg (2 mmol, 1 equiv)
of 12 and 8.02 mg (4 mmol, 2 equiv) of 4-chloro-1-(4-fluorophenyl)-
1-butanone in 10-mL of n-butanol was added 212 mg (2 mmol, 1 equiv)
of anhydrous sodium carbonate and 150 mg (1 mmol, 0.5 equiv) of
sodium iodide. The mixture was refluxed under a nitrogen atmo-
sphere for 20 h, and the solvent was removed by distillation under
reduced pressure. The residue was diluted with chloroform, washed
with water, sodium bicarbonate solution and brine, dried over
magnesium sulfate, concentrated, and chromatographed on silica gel
using methanol:chloroform (1:19, v/v) to afford 180 mg (24%) of 13:
IR (KBr) 2949, 1689, 1595, 1510 cm-1; 1H NMR (CDCl3) δ 1.95-2.05
(m, 2, aliphatic CH2), 2.40-2.60 (m, 6, NCH2), 3.03 (t, J ) 6.9 Hz, 1,
ArCOCH2), 3.71 (t, J ) 4.6 Hz, 4, piperazine NCH2), 6.56 (d, J ) 9.5
Hz, 1, pyridine H-3), 7.14 (t, J ) 8.5 Hz, 2, ArH), 7.99-8.10 (m, 2,
ArH), 8.18 (dd, J ) 9.5, 2.7 Hz, 1, pyridine H-4), 9.01 (d, J ) 2.7 Hz,
1, pyridine H-6); 13C NMR (CDCl3) δ 21.5, 36.2, 45.0, 52.9, 57.8, 105.0,
116.0, 116.4, 131.1, 131.2, 133.5, 134.1, 135.3, 147.1, 160.9, 163.7,
(br), 2835, 1680, 1590 cm-1 1H NMR (CDCl3) δ 1.90-2.10 (m, 2,
;
aliphatic CH2), 2.48 (t, J ) 7.2 Hz, 2, aliphatic NCH2), 2.59 (br s, 4,
piperazine CH2), 3.00 (t, J ) 6.9 Hz, 2, COCH2), 3.34 (br s, 4,
piperazine CH2), 6.57 (d, J ) 9.2 Hz, 1, pyridine H-3), 7.00-7.20 (m,
3, pyridine H-4 and ArH), 7.82 (d, J ) 2.9 Hz, 1, pyridine H-6), 7.90-
8.20 (m, 2, ArH); 13C NMR (CDCl3) δ 21.2, 36.3, 46.7, 53.1, 57.9, 109.6,
115.9, 116.3, 127.2, 131.1, 131.3, 135.2, 147.2, 155.0, 163.8. 168.9,
199.2.
1-(4-Flu or oph en yl)-4-[4-(5-acetoxy-2-pyr idin yl)-1-piper azin yl]-
1-bu ta n on e (17)sTo a solution of 26 mg (0.076 mmol, 1 equiv) of 16
in 0.5-mL of pyridine was added 15.5 mg (15 µL, 0.152 mmol, 2 equiv)
of acetic anhydride and 2 mg (0.015 mmol, 0.2 equiv) of 4-(N,N-
dimethylamino)pyridine. The mixture was stirred at 25 °C for 18 h.
The solvent was removed under reduced pressure. The residue was
dissolved in chloroform, washed with a saturated solution of sodium
bicarbonate and brine, dried over anhydrous sodium bicarbonate,
concentrated, and chromatographed on silica gel using methanol:
chloroform (1:10, v/v) to afford 22 mg (76%) of 17: IR (KBr) 1750,
1680, 1595 cm-1 1H NMR (CDCl3) δ 1.90-2.10 (m, 2, aliphatic H),
;
2.29 (s, 3, OCOCH3), 2.47 (t, J ) 7 Hz, 2, aliphatic NCH2), 2.55 (t, J
) 5 Hz, 4, piperazine CH2), 3.02 (t, J ) 7 Hz, 2, COCH2), 3.50 (t, J )
5 Hz, 4, piperazine CH2), 6.63 (J ) 9.2 Hz, 1, pyridine H-3), 7.14 (t,
J ) 8.5 Hz, 2, ArH), 7.27 (dd, J ) 9.2, 2.5 Hz, 1, pyridine H-4), 7.95-
8.10 (m, 3, ArH and pyridine H-6). Anal.sCalculated for C21H24
-
FN3O2: C, 65.44, H, 6.28. Found: C, 65.22; H, 6.33.
1-(4-F lu or op h en yl)-4-[4-(5-h yd r oxy-2-p yr id in yl)-1-p ip er a zin -
yl]-1-bu ta n ol (10) fr om 17sTo a solution of 20 mg (0.05 mmol, 1
equiv) of 17 in 3-mL of ether:tetrahydrofuran (2:1, v/v) at 0 °C was
slowly added a solution of 8 mg (0.20 mmol, 8 equiv) of lithium
aluminum hydride in 1-mL of ether. The mixture was stirred at 25
°C for 30 min and carefully hydrolyzed by adding a drop of water.
The precipitate was removed by filtration and washed thoroughly with
ether. The combined filtrate was washed with water and brine, dried
over anhydrous magnesium sulfate, concentrated, and chromato-
graphed on silica gel using methanol:chloroform (1:5, v/v) to afford
199.1. Anal.sCalculated for
C19H21FN4O3: C, 61.28, H, 5.68.
Found: C, 61.33; H, 5.68.
1-(4-F lu or op h en yl)-4-(1-p ip er a zin yl)-1-bu ta n on e (3)sTo a so-
lution of 2.0 g (10 mmol, 1 equiv) of 4-chloro-1-(4-fluorophenyl)-1-
butanone and 1.72 g (20 mmol, 2 equiv) of piperazine (11) in 10-mL
of isoamyl alcohol was added 1.06 g (10 mmol, 1 equiv) of anhydrous
sodium carbonate. The mixture was refluxed under a Dean Stark
trap for 3 h. The solution was concentrated. The residue was
dissolved in chloroform, washed with water, sodium bicarbonate
solution and brine, dried over anhydrous magnesium sulfate, con-
17 mg (94%) of 10: IR (KBr) 3432, 3104, 2937, 1605, 1577, 1498 cm-1
;
1H NMR (CDCl3) δ 1.70-2.10 (m, 4, aliphatic CH2), 2.45-2.90 (m, 6,
aliphatic and piperazine CH2), 3.20-3.40 (m, 4, piperazine CH2),
4.65-4.75 (m, 1, CHOH), 6.34 (d, J ) 8.8 Hz, 1, pyridine H-3), 6.92-
82 / Journal of Pharmaceutical Sciences
Vol. 85, No. 1, January 1996