Journal of Medicinal Chemistry
Article
7.42 (m, 0.67 H), 7.16−7.27 (m, 3.33 H), 7.01−7.15 (m, 2 H), 6.88−
6.98 (m, 1.34 H), 6.79−6.87 (m, 1.67 H), 6.72−6.78 (m, 0.33 H),
5.02−5.07 (m, 0.67 H), 4.96−5.02 (m, 1.33 H), 4.72−4.77 (m, 0.67
H), 4.66−4.71 (m, 1.33 H), 4.18−4.34 (m, 1.33 H), 3.96 (s, 2 H), 3.90
(s, 1 H), 3.11−3.25 (m, 1.33 H), 2.91−3.00 (m, 0.67 H), 2.66−2.73
(m, 0.67 H). 13C NMR (CDCl3) (2 conformers): δ 163.48, 163.47,
161.9, 161.8, 159.5, 159.4, 157.7, 157.6, 157.5, 155.9, 150.5, 149.7,
149.4, 146.7, 145.8, 138.6, 137.7, 128.58, 128.55, 128.4, 128.2, 127.3,
126.7, 126.2, 125.2, 122.9, 122.5, 121.5, 121.2, 120.8, 115.3, 113.0,
112.4, 112.1, 112.0, 66.1, 66.0, 65.1, 64.9, 56.5, 56.0, 55.8, 55.5, 29.7,
29.6.
crystallized from diethyl ether/hexane. The solid material was
collected, washed with cold diethyl ether/hexane, and dried under
high vacuum to give 2-(4-bromophenyl)-malonic acid dimethyl ester
(74.1 g, 79%) as beige crystals; mp 76−77 °C; Rf (silica gel,
heptane:ethyl acetate 1:1) 0.7, shows decomposition. LC-MS: this
compound is not stable under HPLC conditions. 1H NMR (CDCl3): δ
3.76 (s, 6 H), 4.61 (s, 1 H), 7.25−7.30 (m, 2 H), 7.46−7.51 (m, 2 H).
13C NMR (CDCl3): δ 53.4, 57.3, 122.9, 131.2, 131.7, 132.0, 168.2.
A solution of 2-(4-bromophenyl)-malonic acid dimethyl ester
(11.73 g, 40.9 mmol) in methanol (100 mL) was added at 0 °C to a
solution of sodium (2.83 g, 0.118 mmol) in methanol (100 mL). The
mixture was stirred for 18 h at rt before formamidine hydrochloride
(4.10 g, 50.9 mmol) was added. The suspension was stirred at rt for 4
h. The solvent was removed, and the residue was suspended in 10% aq
citric acid (100 mL) and stirred for 10 min. The white precipitate was
collected, washed with 10% aq citric acid, water, evaporated three
times from cyclohexane, and dried under high vacuum at 40 °C to give
5-(4-bromophenyl)-pyrimidine-4,6-diol (9.90 g, 91%) as a pale-beige
powder; Rf (silica gel, heptane:ethyl acetate 1:1) at start. LC-MS: tR =
0.52 min, [M + H]+ = 267.08. 1H NMR (DMSO-d6): 7.43−7.48 (m, 2
H), 7.50−7.55 (m, 2 H), 8.13 (s, 1 H), 12.1 (s br, 2 H). 13C NMR
(DMSO-d6): δ 101.4, 119.3, 130.6, 132.9, 133.2, 148.7, 163.2.
Potassium (N-Propylsulfamoyl)amide (13). Chlorosulfonyl
isocyanate (9, 28.3 g, 0.2 mol) was dissolved in DCM (100 mL)
and cooled to 0 °C before a solution of tert-BuOH (18.8 mL; 0.2 mol)
in DCM (100 mL) was added over 30 min. Stirring was continued
without cooling for additional 30 min. The mixture was then carefully
added over 1 h to a solution of n-propylamine (16.5 mL, 0.2 mol) and
triethylamine (42 mL, 0.3 mol) in DCM (400 mL) at 0 °C. Stirring
was continued without cooling for additional 16 h. The reaction
mixture was concentrated in vacuo, and the residue was dissolved in
EtOAc (1 L) and washed with water (100 mL) and brine (40 mL).
The organic layer was dried over MgSO4 and concentrated under
reduced pressure to give 11. 1H NMR (CDCl3): δ 0.97 (t, J = 7 Hz, 3
H), 1.51 (s, 9 H), 1.62 (m, 2 H), 3.04 (q, J = 6 Hz, 2 H), 5.12 (t br, J =
5 Hz, 1 H), 7.17 (s br, 1 H). 13C NMR (CDCl3): δ 11.6, 22.8, 28.4,
46.0, 84.1, 150.3. The residue was dissolved in dioxane (100 mL)
followed by the addition of HCl in dioxane (4M; 250 mL). Stirring
was continued for 4 h at rt. The solvent was evaporated under reduced
pressure, and the residue was dried under HV to give sulfamide 12. 1H
NMR (DMSO-d6; 300 MHz; Varian): δ 0.87 (t, 3H), 1.43 (m, 2H),
2.81 (q, 2H), 3.09 (m, 1H; NH), 6.42 (s, 2H; NH2). 13C
NMR(CDCl3): δ 11.6, 23.1, 45.7. The residue was dissolved in
MeOH (200 mL), and KOtBu (22.4 g; 0.2 mol) was added. The
solvent was removed under reduced pressure. The residue was taken
up in diethylether (500 mL), and the precipitate was filtered off,
washed with cold ether, and dried at HV to give potassium (N-
propylsulamoyl)amide (13) (32.4 g, 92%) as an off-white powder.
5-(4-Bromophenyl)-4,6-dichloropyrimidine (14).42 To a sol-
ution of 4-bromophenylacetic acid (73.9 g, 0.34 mol) in methanol
(400 mL), thionyl chloride (49.05 g, 30 mL, 0.41 mol) was added
dropwise while the temperature of the reaction mixture was kept at 0−
5 °C. Upon complete addition, the cooling was removed and the
mixture was allowed to warm to rt. Stirring was continued for 3 h
before the solvent was removed in vacuo. The yellow oil was dissolved
in benzene and evaporated. The residue was dissolved in ethyl acetate
and washed with brine, 2 N aq Na2CO3, and again brine. The organic
extract was dried over MgSO4 and evaporated and dried under high
vacuum at 85 °C for 30 min to give 4-bromophenylacetic acid methyl
ester (74.9 g, 95%) as a yellow oil. LC-MS: tR = 0.93 min, [M + H]+ =
To a suspension of 5-(4-bromophenyl)-pyrimidine-4,6-diol (43.0 g,
0.16 mmol) in POCl3 (500 mL) was carefully added N,N-
dimethylaniline (50 mL). The mixture was heated to 130 °C for 2
h. The dark-brown solution was evaporated, and the residue was
dissolved in dichloromethane (200 mL). Water (500 mL) was slowly
added, and the mixture was stirred at rt for 30 min before the organic
phase was separated. The aqueous phase was extracted two more times
with dichloromethane. The organic extracts were washed with water
and 1 N aq HCl, treated with charcoal, dried over MgSO4, filtered, and
evaporated. The product was purified by crystallization from 2-
propanol. The crystals were collected, washed with cold 2-propanol
and dried under high vacuum to give 14 (39.8 g, 81%) as beige
crystals; mp 100−101 °C; Rf (silica gel, heptane:ethyl acetate 1:1)
1
0.79. LC-MS: tR = 0.92 min, [M + H + CH3CN]+ = 344.0. H NMR
(CDCl3): δ 8.81 (s, 1 H), 7.68 (dt, Jd = 8.9 Hz, Jt = 2.4 Hz, 2 H), 7.22
(dt, Jd = 9.0 Hz, Jt = 2.4 Hz, 2 H). 13C NMR (CDCl3): δ 124.1, 131.0,
131.7, 132.3, 157.1, 161.4.
N-5-(4-Bromophenyl)-6-chloro-4-pyrimidinyl-N′-propylsul-
famide (15). To a solution of 14 (760 mg; 2.50 mmol) in DMSO (5
mL), the sulfamide potassium salt 13 (529 mg; 3.00 mmol) was added.
The mixture was stirred at rt for 48 h, diluted with brine (25 mL), and
extracted three times with ethyl acetate (3 × 25 mL). The combined
organic extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was crystallized form
methanol to give 15 (706 mg, 69%) as a white solid; Rf (silica gel,
heptane:ethyl acetate 1:1) 0.49. LC-MS: tR = 0.89 min, [M + H]+ =
404.98. 1H NMR (CDCl3): δ 0.96 (t, J = 7.6 Hz, 3 H), 1.50−1.66 (m,
2 H), 2.94−3.03 (m, 2 H), 5.52 (s br, 1 H), 6.90 (s br, 1 H), 7.16−
7.21 (m, 2 H), 7.68−7.74 (m, 2 H), 8.65 (s, 1 H). 13C NMR (CDCl3):
δ 11.6, 22.7, 46.1, 118.6, 125.0, 128.9, 131.2, 133.6, 156.6, 157.0, 159.9.
N-5-(4-Bromophenyl)-6-(2-hydroxyethoxy)-4-pyrimidinyl-
N′-propylsulfamide (16). Ethylene glycol (58.7 g, 53 mL; 946
mmol) was dissolved in dimethoxyethane (80 mL), and KOtBu (8.80
g; 78 mmol) was added. The temperature rose to 40 °C. After stirring
for 10 min, monochloride 15 (10.55 g; 26 mmol) was added and
stirring was continued at 100 °C for 70 h. The reaction mixture was
carefully added to a 1:1 mixture of water:10% aq citric acid solution.
The product was extracted with ethyl acetate (2 × 120 mL), the
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduce pressure. The crude product was purified
by flash column chromatography (silicagel, heptanes:ethyl acetate 1:1)
to give alcohol 16 (9.65 g, 86%) as a white solid; Rf (silica gel,
heptane:ethyl acetate 1:1) 0.20. LC-MS: tR = 0.88 min, [M + H]+ =
430.98. 1H NMR (CDCl3): δ 0.95 (t; J = 7.6 Hz, 3 H), 1.60 (h, J = 7.6
Hz, 2 H), 2.98 (t, J = 7.0 Hz, 2 H), 3.82−3.86 (m, 2 H), 4.47−4.51
(m, 2 H), 5.70 (s br, 1 H), 7.13−7.22 (m, 2 H), 7.61−7.67 (m, 2 H),
8.48 (s, 1 H). 13C NMR (CDCl3): δ 11.6, 22.7, 46.1, 61.9, 69.8, 104.8,
123.8, 128.1, 131.6, 133.2, 155.9, 156.4, 166.6.
1
not detectable. H NMR (DMSO-d6): δ 3.60 (s, 3H), 3.67 (s, 2H),
7.22 (d, J = 8.5, 2H), 7.50 (d, J = 8.5, 2H). 13C NMR (CDCl3): δ 40.9,
52.5, 121.4, 131.2, 131.9, 133.1, 171.6.
NaH (24.0 g, 0.82 mol, 60% in mineral oil) was suspended twice in
THF (75 mL), and the solvent was decanted. The remaining slurry
was diluted with THF (500 mL) and heated to 35−40 °C. A solution
of 4-bromophenylacetic acid methyl ester (74.9 g, 0.33 mol) in THF
(200 mL) was carefully added dropwise. Gas evolution started after
about half of the phenylacetic acid ester had been added and the
mixture became slightly warm. The addition was continued at 45 °C.
Upon completion of the addition, stirring was continued at 40 °C for 5
min before the mixture was allowed to cool to rt. The evolution of gas
had stopped before dimethylcarbonate (117.9 g, 1.31 mol) was added
dropwise. Evolution of gas started, and the mixture became warm (32
°C). Upon completion of the addition, stirring of the mixture was
continued for 24 h before it was cooled to 0 °C and acidified by adding
25% aq HCl (100 mL) and diluted with water (150 mL). The organic
solvent was removed under reduced pressure, and the remaining
aqueous mixture was extracted three times with ethyl acetate (3 × 200
mL). The organic extracts were washed with 1 N aq HCl and brine,
dried over MgSO4, filtered, and concentrated. The crude product was
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dx.doi.org/10.1021/jm3009103 | J. Med. Chem. 2012, 55, 7849−7861