3742 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20
Duggan et al.
2H), 6.93 (d, J ) 9 Hz, 2H), 6.57 (t, J ) 5 Hz, 1H), 5.53 (br m,
1H), 4.20 (t, J ) 5 Hz, 2H), 3.88 (s, 3H) 3.88 (overlapped t,
2H).
1.8 mmol) was added and the mixture was stirred for 16 h,
concentrated, and purified by flash chromatography (silica, 5%
Et2O/hexane) provided 4-3 (5.8 g, 29.9 mmol, 90%) as a yellow
oil: Rf 0.47 (silica, 10% EtOAc/hexane); H NMR (300 MHz,
CDCl3) δ 8.00 (d, J ) 8 Hz, 2H), 7.55 (d, J ) 8 Hz, 2H), 4.38
(q, J ) 7 Hz, 2H), 3.22 (s, 1H), 1.40 (t, J ) 7 Hz, 3H).
1
4-[2-(P yr im id in -2-yla m in o)eth yloxy]ben zoic Acid (3-
4). Pyrimidine ester 3-3 (3.31 g, 12.1 mmol) was combined with
1 N NaOH (30 mL, 30 mmol) in 50 mL EtOH. After 2 h at 60
°C the mixture was cooled and 30 mL 1 N HCl was added (final
pH 5). The resulting white precipitate was collected on a frit,
washed with water, and dried providing 3-4 (2.0 g, 7.9 mmol,
65%): Rf 0.67 (silica, 10:1:1 EtOH/NH4OH/H2O); 1H NMR (300
MHz, DMSO) d 9.02 (d, J ) 5 Hz, 2H), 8.60 (d, J ) 9 Hz, 2H),
8.05 (t, J ) 6 Hz, 1H), 7.76 (d, J ) 9 Hz, 2H), 7.32 (t, J ) 5
Hz, 1H), 4.89 (t, J ) 6 Hz, 2H), 4.38 (q, J ) 6 Hz, 2H), 4.06 (s,
1H).
3-{4-[2-(P yr im idin -2-ylam in o)eth yloxy]ben zoylam in o}-
2(S)-ben zen esu lfon yla m in op r op ion ic Acid ter t-Bu tyl Es-
ter (3-5). Acid 3-4 (0.770 g, 2.97 mmol), amine 1-4 (1.0 g, 2.97
mmol), NMM (1.14 µL, 10.4 mmol) and HOBT (0.522 g, 3.86
mmol) were combined in 30 mL DMF, cooled to 0 °C, and EDC
(0.740 g, 3.86 mmol) was added. The mixture was stirred at
room temperature for 3 days, diluted with ethyl acetate,
washed twice with water, saturated NaHCO3, and brine, dried
(MgSO4), and concentrated. Flash chromatography (silica, 80%
EtOAc/hexanes) provided 3-5 (1.1 g, 2.0 mmol, 67%) as a waxy
solid: Rf 0.23 (silica, 80% EtOAc/hexane); 1H NMR (300 MHz,
CDCl3) δ 8.31 (d, J ) 5 Hz, 2H), 7.85 (d, J ) 7 Hz, 2H), 7.73
(d, J ) 9 Hz, 2H), 7.60-7.45 (m, 3H), 6.90 (d, J ) 9 Hz, 2H),
6.67 (br m, 1H), 6.57 (t, J ) 5 Hz, 1H), 5.94 (d, J ) 8 Hz, 1H),
5.68 (br m, 1H), 4.17 (t, J ) 5 Hz, 2H), 4.00-3.83 (m, 4H),
3.59 (m, 1H), 1.28 (s, 9H).
Eth yl 4-[2-(2-Am in op yr id in -6-yl)eth yl]ben zoa te (4-4).
2-Amino-6-bromopyridine (0.38 g, 2.4 mmol; available from
Davos), 4-3 (0.35 g, 2.0 mmol), Et3N (1.0 mL, 7.2 mmol), (Ph3P)
2PdCl2 (76 mg, 0.11 mmol), an CuI (26 mg, 0.14 mmol) were
combined in 5 mL CH3CN, sealed in a glass pressure tube and
heated to 100 °C for 3 h. The mixture was diluted with EtOAc,
washed with water and brine, dried (MgSO4), concentrated,
and purified by flash chromatography (silica, 5% acetone/hex-
ane), to give 4-4 (293 mg, 1.1 mmol, 55%) as a tan solid: Rf
0.45 (silica, 10% acetone/hexane); 1H NMR (300 MHz, CDCl3)
δ 8.03 (d, J ) 8 Hz, 2H), 7.64 (d, J ) 8 Hz, 2H), 7.44 (t, J ) 8
Hz, 1H), 6.95 (d, J ) 7 Hz, 1H), 6.50 (d, J ) 8 Hz, 1H), 4.55
(br s, 2H), 4.39 (q, J ) 7 Hz, 2H), 1.40 (t, J ) 7 Hz, 3H).
4-[2-(2-Am in op yr id in -6-yl)eth yl]ben zoa te (4-5). A mix-
ture of ester 4-4 (700 mg, 2.63 mmol) 10% Pd/C (350 mg) and
EtOH were stirred under 1 atm H2. After 20 h, the reaction
was filtered through a Celite pad and then concentrated to
provide the crude ester as a brown oil: TLC Rf ) 0.23 (silica,
40% EtOAc/hexanes). A suspension of ester (650 mg, 2.31
mmol) in 6 N HCl (12 mL) was heated to 60 °C. After ∼20 h,
the reaction was concentrated to give acid 4-5 (650 mg, 2.33
mmol, 91%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 7.96
(d, 2H, J ) 8 Hz), 7.80 (m, 1H), 7.33 (d, 2H, J ) 8 Hz), 6.84 (d,
1H, J ) 9 Hz), 6.69 (d, 1H, J ) 7 Hz), 3.09 (m, 4H).
3-{4-[2-(P yr im idin -2-ylam in o)eth yloxy]ben zoylam in o}-
2(S)-ben zen esu lfon yla m in op r op ion ic Acid (3-6). Ester 3-5
(1.05 g, 1.86 mmol) and anisole (0.40 mL, 3.7 mmol) were
dissolved in CH2Cl2 (9 mL), cooled to 0 °C, and TFA (9 mL)
was added. After 2 h at 0 °C and 16 h at 20 °C, the reaction
was concentrated, azeotroped with toluene, and triturated with
Et2O providing 3-6 (1.1 g, 1.8 mmol, 95%) as a white solid: Rf
0.30 (silica, 22:20:1:1 EtOAc/EtOH/NH4OH/H2O). 1H NMR
(400 MHz, CD3OD) δ 8.45 (br, 2H), 7.82 (dt, J ) 7, 2 Hz, 2H),
7.72 (d, J ) 9 Hz, 2H), 7.50 (tm, J ) 7 Hz, 1H), 7.42 (tm, J )
8 Hz, 2H), 6.99 (d, J ) 9 Hz, 2H), 6.82 (t, J ) 5 Hz, 1H), 4.25
(t, J ) 5 Hz, 2H), 4.18 (dd, J ) 9, 5 Hz, 1H), 3.88 (t, J ) 5 Hz,
2H), 3.71 (dd, J ) 14, 5 Hz, 1H), 3.48 (m, 1H).
3-[4-(6-Am in op yr id in -6-yleth yn yl)ben zoyla m in o]-2(S)-
ben zen esu lfon yla m in op r op ion ic Acid ter t-Bu tyl Ester
(4-6a ). Acid 4-5 (234 mg, 0.98 mmol), 1-4 (351 mg, 0.98 mmol),
EDC (225 mg, 1.2 mmol), HOBT (159 mg, 1.2 mmol) and NMM
(323 µL, 2.9 mmol) were combined in 5 mL DMF. After 16 h
the mixture was diluted with EtOAc, washed with water,
saturated NaHCO3 and brine, dried (MgSO4), concentrated and
chromatographed (silica, 80% EtOAc/hexane) providing 4-6a
1
(410 mg, 0.78 mmol, 83%): Rf 0.53 (EtOAc, silica); H NMR
(300 MHz, CDCl3) δ 7.86 (d, J ) 8 Hz, 2H), 7.76 (d, J ) 9 Hz,
2H), 7.62 (d, J ) 9 Hz, 2H), 7.57-7.41 (m, 4H), 6.95 (dd, J )
7,1 Hz, 1H), 6.86 (br m, 1H) 6.50 (dd, J ) 8, 1H, 1H), 5.92 (br
m, 1H), 458 (br s, 2H), 4.00-3.84 (m, 2H), 3.36-3.00 (m, 5H),
1.29 (s, 9H).
3-{4-[2-(3,4,5,6-Tetr a h yd r op yr im id in -2-yla m in o)eth yl-
oxy]ben zoyla m in o}-2(S)-ben zen esu lfon yla m in op r op ion -
ic Acid (3). Pyrimidine 3-6 (1.05 g, 1.75 mmol) was dissolved
in a mixture of acetic acid (50 mL) and concentrated HCl (4.5
mL). After addition of 10% Pd/C (450 mg) the mixture was
shaken on a Parr hydrogenator under 45 psi H2 pressure for
2 h. The reaction mixture was filtered, concentrated, azeo-
troped with toluene, and purified by flash chromatography
(silica 20:1:1 then 8:1:1 EtOH/NH4OH/H2O) providing 3 (0.66
g, 1.3 mmol, 75%) as a white solid: Rf 0.35 (8:1:1, EtOH/NH4-
OH/H2O); 1H NMR (300 MHz, CD3OD + DCl) δ 7.84 (d m, J )
7 Hz, 2H), 7.74 (d, J ) 9 Hz, 2H), 7.50-7.40 (m, 3H), 7.02 (d,
J ) 9 Hz, 2H), 4.22-4.17 (m, 3H), 3.72 (dd, J ) 14, 5 Hz, 1H),
3.60 (t, J ) 5 Hz, 2H), 3.49 (dd, J ) 14, 9 Hz, 1H), 3.38 (t, J
) 5 Hz, 4H), 1.95 (qn, J ) 6 Hz, 2H); HRMS (FAB, M + 1)
calcd 490.1760, found 490.1759. Anal. (C22H27N5O6S‚1.2H2O)
C, H, N.
4-Tr im eth ylsila n yleth yn ylben zoic Acid Eth yl Ester (4-
2). TMS-acetylene (5.0 mL, 35.5 mmol), ethyl 4-bromobenzoate
(4-1) (58 mL, 35.5 mmol) and Et3N (20 mL, 144 mmol) were
combined in 50 mL CH3CN in a glass pressure tube. (Ph3P)2-
PdCl2 (198 mg, 0.28 mmol) and CuI (100 mg, 0.53 mmol) were
added, and the reaction was sealed and heated at 100 °C for
18 h. Dilution with EtOAc, washing twice with water, then
brine, drying and concentration provided 4-2 (8.2 g, 33.2 mmol,
93%) as a brown liquid: Rf 0.60 (silica, 10% EtOAc/hexane);
1H NMR (300 MHz, CDCl3) δ 7.97 (d, J ) 8 Hz, 2H), 7.51 (d,
J ) 9 Hz, 2H), 4.37 (q, J ) 7 Hz, 2H), 1.40 (t, J ) 7 Hz, 3H),
0.26 (s, 9H).
3-{4-[2-(6-Am in opyr idin -6-yl)eth yl]ben zoylam in o}-2(S)-
4-iod oben zen esu lfon yla m in op r op ion ic Acid Eth yl Ester
(4-6b). A solution of acid 4-5 (400 mg, 1.43 mmol), amine 1-6
(686 mg, 1.57 mmol), EDC (358 mg, 1.86 mmol), HOBT (252
mg, 1.86 mmol), NMM (632 µL, 5.72 mmol) in DMF (10 mL)
was stirred for ∼20 h. The reaction was diluted with EtOAc
and then washed with saturated NaHCO3, brine, dried (Mg-
SO4) and concentrated. Flash chromatography (silica, EtOAc
then 5% 2-propanol/EtOAc) provided amide 4-6b (430 mg, 0.69
mmol, 48%) as a white solid: TLC Rf ) 0.4 (silica, 10%
2-propanol/EtOAc); 1H NMR (300 MHz, CD3OD) δ 7.79 (d, 2H,
J ) 9 Hz) 7.61 (d, 2H, J ) 8 Hz), 7.52 (d, 2H, J ) 9 Hz), 7.29
(m, 1H), 7.27 (d, 2H, J ) 8 Hz), 4.20 (m, 1H), 3.95 (q, 2H, J )
7 Hz), 3.66 (dd, 1H, J ) 6 Hz, 14 Hz), 3.49 (dd, 1H, J ) 8 Hz,
13 Hz), 3.01 (m, 2H), 2.86 (m, 2H), 1.08 (t, 3H, J ) 7 Hz).
3-{4-[2-(6-Am in opyr idin -6-yl)eth yl]ben zoylam in o}-2(S)-
ben zen esu lfon yla m in op r op ion ic Acid (4). Ester 4-6a (375
mg, 0.72 mmol), was dissolved in 1:1 CH2Cl2/TFA (7.2 mL).
After 2 h the reaction was concentrated, azeotroped with
toluene, and triturated with 10:1:1 EtOH/NH4OH/H2O, provid-
ing 4 (160 mg, 0.34 mmol, 48%) as a light yellow solid: 1H
NMR (300 MHz, D2O + NaOD) δ 7.73 (d, J ) 8 Hz, 2H), 7.52
(d, J ) 9 Hz, 2H), 7.34 (d, J ) 8 Hz, 2H), 7.30-7.15 (m, 3H),
6.67 (d, J ) 7 Hz, 1H), 6.62 (d, J ) 8 Hz, 1H), 3.80-3.68 (m,
2H), 3.35-3.05 (m, 5H); HRMS (FAB, M + 1) calcd 469.1546,
found 469.1559. Anal. (C23H24N4O5S‚0.4H2O) C, H, N.
3-{4-[2-(6-Am in opyr idin -6-yl)eth yl]ben zoylam in o}-2(S)-
4-iod oben zen esu lfon yla m in op r op ion ic Acid (7). A solu-
tion of ester 4-6b (200 mg, 0.3213 mmol) and 6 N HCl (30 mL)
was heated to 60 °C. After ∼20 h, the reaction mixture was
4-Eth yn ylben zoic Acid Eth yl Ester (4-3). Ester 4-2 (8.2
g, 33.2 mmol) was dissolved in 100 mL EtOH, K2CO3 (0.25 g