2300 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Hamby et al.
used in subsequent reactions without further purification: 1H
NMR (DMSO-d6) δ 8.64 (s, 1H, 4-H), 7.66 (s, 1H, 5-H), 6.66
(br s, 2H, 2-NH2), 6.66-6.58 (br s, 2H, 7-NH2), 6.58 (s, 2H,
butyl isocyanate (0.108 g, 1.09 mmol), 4d was prepared as
described above for 4a . The crude product was purified by
medium-pressure liquid chromatography, eluting over silica
gel with EtOAc:CHCl3 (1:1) to afford 0.050 g (46% yield) of 4d
as a white solid: mp >300 °C; 1H NMR (CDCl3) δ 10.14 (s,
1H, NHCONH-t-Bu), 8.77 (s, 1H, 4-H), 7.55 (s, 1H, 5-H), 7.06
(s, 1H, H-4′), 6.57 (br s, 1H, NHCONH-t-Bu), 5.41 (br s, 2H,
NH2), 2.26 (s, 6H, 2′,6′-CH3), 2.26 (s, 6H, 3′,5′-CH3), 1.49 (s,
9H, t-Bu H’s); HPLC tR ) 17.02 min; MS (CI) m/ z 393 (MH+).
Anal. (C22H28N6O‚0.41CHCl3) C, H, N.
2′,6′-H), 6.58 (m, 1H, 4′-H), 3.34 (s, 6H, OCH3); HPLC tR
)
11.10 min, MS (CI) m/ z 298 (MH+). Anal. (C15H15N5O2‚
0.16Et2O) C, H, N.
1-(2-Am in o-6-ph en ylpyr ido[2,3-d]pyr im idin -7-yl)-3-ter t-
bu tylu r ea (4a ). The starting material for this reaction, 3a ,
was prepared according to the method of Davoll.22 To a stirred
slurry of 3a (0.25 g, 1.04 mmol) in DMF (5 mL) at room
temperature was added 60% NaH (0.048 g, 1.2 mmol) in
portions. After 1 h of stirring, tert-butyl isocyanate (0.11 g,
1.12 mmol) was added and the reaction mixture stirred at
ambient temperature for 18 h. The reaction mixture was
filtered, and the insoluble salts were washed with DMF. The
filtrate was evaporated under high vacuum and the residue
diluted with water. The insoluble product was collected by
filtration, washed with water and then ether, and dried in air
on the filter. Purification by medium-pressure liquid chro-
matography over silica gel, eluting with a solvent gradient of
EtOAc:CHCl3 (1:1) to EtOAc (100%) afforded 0.010 g (30%
1-[2-Am in o-6-(3,5-d im eth oxyp h en yl)p yr id o[2,3-d ]p yr i-
m id in -7-yl]-3-ter t-bu tylu r ea (4e). Starting from 3e (0.5 g,
1.68 mmol), 60% NaH (0.078 g, 1.94 mmol), and tert-butyl
isocyanate (0.178 g, 1.80 mmol), 4e was prepared as described
above for 4a . The crude product was purified by medium-
pressure liquid pressure chromatography over silica gel,
eluting with a solvent gradient of 1-2% MeOH in CH2Cl2 to
afford 0.265 g (40% yield) of 4e as an off-white solid: mp >250
1
°C dec; H NMR (DMSO-d6) δ 10.04 (s, 1H, NHCONH-t-Bu),
8.93 (s, 1H, 4-H), 8.00 (s, 1H, 5-H), 7.19 (s, 2H, H-2′,6′), 7.10
(s, 1H, H-4′), 6.64 (br s, 3H, NHCONH-t-Bu, NH2), 3.80 (s, 6H,
OCH3), 1.38 (s, 9H, t-Bu H’s); MS (CI) m/ z 397 (MH+). Anal.
(C20H24N6O3) C, H, N.
1
yield) of 4a as a pale yellow solid: mp >250 °C dec; H NMR
(DMSO-d6) δ 10.06 (s, 1H, NHCONH-t-Bu), 8.94 (s, 1H, 4-H),
7.99 (s, 1H, 5-H), 7.58-7.49 (m, 5H, Ph-H’s), 7.20 (br s, 2H,
NH2), 7.01 (br s, 1H, NHCONH-t-Bu), 1.4 (s, 9H, t-Bu H’s);
HPLC tR ) 13.87 min; MS (CI) m/ z 337 (MH+). Anal.
(C18H20N6O‚0.5CHCl3‚1.0EtOAc‚2.25H2O) C, H, N.
1-[2-Am in o-6-(2,6-d ich lor op h en yl)p yr id o[2,3-d ]p yr im i-
d in -7-yl]-3-eth ylu r ea (4f). Starting from 3b (2.0 g, 6.5
mmol), 60% NaH (0.261 g, 6.5 mmol), and ethyl isocyanate
(0.464 g, 6.5 mmol), 4f was prepared as described above for
4a . The crude product was purified by radial chromatography,
eluting with a solvent gradient of EtOAc:CHCl3 (70:30) to
CHCl3 (100%) to afford 1.8 g (71% yield) of 4f as a white solid:
mp 185-187 °C; 1H NMR (DMSO-d6) δ 10.12 (t, 1H, J ) 5.67,
7.23 Hz, NHCONHEt), 8.94 (s, 1H, 4-H), 8.21 (s, 1H, NHCON-
HEt), 7.98 (s, 1H, 5-ArH), 7.64-7.62 (app d, 2H, 3′,5′-ArH),
7.54-7.52 (app t, 1H, 4′-ArH), 7.38 (br s, 2H, NH2), 3.29 (dq,
2H, J ) 5.67, 7.23 Hz, NHCH2CH3), 1.15 (t, 3H, J ) 7.23 Hz,
NHCH2CH3); MS (CI) m/ z 377 (M+). Anal. (C16H14N6-
Cl2O‚0.15EtOAc) C, H, N.
1-[2-Am in o-6-(2,6-d ich lor op h en yl)p yr id o[2,3-d ]p yr im i-
d in -7-yl]-3-ter t-bu tylu r ea (4b) a n d Dia cyla ted Byp r od -
u ct. To a slurry of 3b (3.0 g, 9.8 mmol) from above in 45 mL
of DMF was added 50% NaH (0.48 g, 10.0 mmol) in portions.
The mixture was stirred for 1 h, tert-butyl isocyanate (1.0 g,
10.09 mmol) added, and the reaction mixture stirred at
ambient temperature for 16 h. The reaction mixture was
filtered to remove a small amount of insoluble material and
the filtrate diluted with 500 mL of water. The insoluble
product was collected by filtration, washed with water and
then ether, and dried in air on the filter. The product was
purified by silica gel chromatography, eluting with a gradient
of 0-1% MeOH in CHCl3 to afford, after crystallization from
EtOH, 0.7 g (14% yield) of the bis-acylated byproduct 1-tert-
butyl-3-[7-(3-tert-butylureido)-6-(dichlorophenyl)pyrido[2,3-d]-
pyrimidin-2-yl]urea as a white solid: mp >200 °C dec; 1H NMR
(DMSO-d6) δ 9.89 (s, 1H, NH), 9.41(s, 1H, NH), 9.20 (s, 1H,
4-H), 8.93 (s, 1H, NH), 8.23 (s, 1H, 5-H), 8.19 (s, 1H, NH),
7.68-7.65 (m, 2H, H-3′,5′), 7.60-7.52 (m, 1H, H-4′), 1.41(s,
9H, t-Bu H’s), 1.39 (s, 9H, t-Bu H’s); MS (APCI) m/ z 506 (M+).
Anal. (C23H22Cl2N7O2‚0.1H2O) C, H, N.
6-(2,6-Dich lor op h en yl)-N2-[3-(d ieth yla m in o)p r op yl]p y-
r id o[2,3-d ]p yr im id in e-2,7-d ia m in e (5a ). A mixture of 3b
(3.0 g, 9.8 mmol), sulfamic acid (0.66 g, 6.82 mmol), and
3-(diethylamino)propylamine (10 mL) was refluxed for 24 h.
The warm reaction mixture was partitioned between water
and hexane. The insoluble crude product was filtered, washed
with water, and dried in air to afford 2.48 g of the intermediate
5a as an off-white solid. The crude product was used in the
next step without further purification. An analytical sample
was obtained by trituating the crude compound in hot diiso-
propyl ether, filtering, and recrystallizing the insoluble mate-
rial twice from EtOAc: mp 220-230 °C; 1H NMR (DMSO-d6)
δ 8.62 (br s, 1H, 4-H), 7.61-7.58 (m, 3H, 5-H and 3′,5′-H), 7.47
(app t, 1H, 4′-H), 7.36 (br s, 1H, 2-NH), 6.58 (br s, 2H, 7-NH2),
3.36 (br s, 4H, NHCH2CH2CH2NEt2), 2.45 (q, 4H, J ) 7.23
Hz, NH(CH2CH3)2), 1.70-1.66 (m, 2H, NHCH2CH2CH2NEt2),
0.95 (t, 6H, J ) 7.23 Hz, NH(CH2CH3)2); MS (APCI) m/ z 419
(M+). Anal. (C20H24N6Cl2) C, H, N.
Continued elution afforded 1.5 g (38% yield) of the desired
product (4b) as a white solid after crystallization from EtOH:
mp 335 °C; 1H NMR (CDCl3) δ 10.06 (s, 1H, NHCONH-t-Bu),
8.81 (s, 1H, 4-H), 7.69 (s, 1H, 5-ArH), 7.49-7.47 (app d, 2H,
H-3′,5′), 7.39-7.36 (app t, 1H, H-4′), 6.42 (br s, 1H, NHCONH-
t-Bu), 5.56 (br s, 2H, NH2), 1.5 (s, 9H, t-Bu H’s); MS (CI) m/ z
405 (M+). Anal. (C18H18Cl2N6O‚0.5H2O) C, H, N.
6-(2,6-Dich lor op h en yl)-N2-[4-(d ieth yla m in o)bu tyl]p y-
r id o[2,3-d ]p yr im id in e-2,7-d ia m in e (5b). A mixture of 3b
(25.4 g, 0.13 mol), sulfamic acid (40 g, 0.26 mol), and 4-(di-
ethylamino)butylamine (205 mL, 1.82 mol) was heated with
stirring at 150 °C for 28 h. Excess amine was removed on a
rotoevaporator at 95 °C under high vacuum (1.0 mmHg). After
being cooled to 25 °C, the residue was suspended in water,
and aqueous saturated NaHCO3 solution was added to make
the suspension alkaline. The suspension was extracted several
times with CH2Cl2, and the combined organic layers were
washed several times with saturated NaHCO3 solution fol-
lowed by several washings with a saturated solution of NaCl.
The organic layer was dried over MgSO4 and filtered, and the
filtrate was evaporated under reduced pressure. The residue
was washed several times with Et2O and then crystallized from
EtOAc. The product was further purified by column chroma-
tography, eluting first with EtOAc:MeOH:Et3N (85:14:1) fol-
lowed by EtOAc:EtOH:Et3N (9:2:1) to afford 36.2 g (64% yield)
of the intermediate 5b as a pale yellow solid: mp 228-232
°C; 1H NMR (CDCl3) δ 8.63 (s, 1H, 4-H), 7.53 (s, 1H, 5-H), 7.48
(d, 2H, H-3′, 5′), 7.49-7.45 (m, 1H, H-4′), 5.77 (br s, 1H,
1-[2-Am in o-6-(2,6-d im et h ylp h en yl)p yr id o[2,3-d ]p yr i-
m id in -7-yl]-3-ter t-bu tylu r ea (4c). Starting from 3c (0.5 g,
1.88 mmol), 60% NaH (0.075 g, 1.88 mmol), and tert-butyl
isocyanate (0.168 g, 1.88 mmol), 4c was prepared as described
above for 4a with the following exceptions: After removal of
the reaction solvent (DMF) under high vacuum, the residue
was partitioned between EtOAc and water. The aqueous layer
was extracted twice with EtOAc, and the organic layers were
combined, dried (MgSO4), and evaporated under reduced
pressure. The crude product was purified by radial chroma-
tography, eluting with a solvent gradient of 3-5% MeOH in
CHCl3 to afford 0.120 g (25% yield) of 4c as an off-white solid:
1
mp 203-205 °C; H NMR (CDCl3) δ 10.07 (s, 1H, NHCONH-
t-Bu), 8.79 (s, 1H, 4-H), 7.60 (s, 1H, 5-H), 7.29-7.25 (app t,
1H, H-4′), 7.18-7.16 (app d, 2H, H-3′,5′), 6.57 (br s, 1H,
NHCONH-t-Bu), 5.66 (br s, 2H, NH2), 2.05 (s, 6H, 2′,6′-CH3),
1.5 (s, 9H, t-Bu H’s); MS (CI) m/ z 365 (MH+). Anal.
(C20H24N6O‚0.17H2O) C, H, N.
1-[2-Am in o-6-(2,3,5,6-tetr a m eth ylp h en yl)p yr id o[2,3-d ]-
p yr im id in -7-yl]-3-ter t-bu tylu r ea (4d ). Starting from 3d
(0.3 g, 1.02 mmol), 60% NaH (0.047 g, 1.18 mmol), and tert-