Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 20 6321
4-(3-bromophenyl)-4-[4-(trifluoromethoxy)phenyl]-1,3-thia-
zolidine-2,5-dithione (0.86 g, 98%) as a clear oil: MS m/e 464
over sodium sulfate, filtered, and concentrated. Purification by
flash chromatography (silica, 95:5:0.25 methylene chloride/
methanol/concentrated ammonium hydroxide) afforded
8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-
2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (37 entry;
Table 2) as a white solid (0.042 g, 56% yield): mp 120-125 °C;
MS m/e 470 (M þ H)þ; 1H NMR (500 MHz, CD3OD) δ 1.87 (m,
2H), 3.48 (m, 2H), 3.69 (t, J=5.9 Hz, 2H), 7.23 (d, J=8.7 Hz,
2H), 7.49-7.37 (m, 6H), 7.53 (m, 1H), 8.04-7.98 (m, 1H), 8.15
(dd, J=4.8, 1.1 Hz, 1H). Anal. (C24H19F4N5O) C, H, N.
Generation of the Enantiomers of Key Compounds Using
Chiral HPLC Techniques. (8R)-8-(3-Pyrimidin-5-ylphenyl)-8-[4-
(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyri-
midin-6-amine [(R)-35] and (8S)-8-(3-Pyrimidin-5-ylphenyl)-
8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-
a]pyrimidin-6-amine [(S)-35]. Racemic 8-(3-pyrimidin-5-ylphe-
nyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo-
[1,5-a]pyrimidin-6-amine (1.30 g, 2.87 mmol) was separated into
its enantiomers using a Chiralpak AD 5 cm ꢀ 50 cm column
(90:10:0.1 heptane/ethanol/diethylamine). The first eluting peak
(tR=35 min) was collected and concentrated to give a pale-yellow
oil. The residue was redissolved in a minimal amount of methy-
lene chloride, and a solid was precipitated by the addition of
hexanes. This solid was collected by filtration and dried under
vacuum for 24 h to afford to afford (R)-35 as an off-white solid
(0.55 g): Rf=0.38 (95:5:0.25 methylene chloride/methanol/con-
centrated ammonium hydroxide); mp 128-131 °C; [R]25D -10.1°
1
(M þ H)þ; H NMR (300 MHz, CDCl3) δ 3.70 (s, br, 1H),
7.86-7.10 (m, 8H).
Step e. 8-(3-Bromophenyl)-8-[4-(trifluoromethoxy)phenyl]-3,
4,7,8-tetrahydroimidazo[1,5-a]pyrimidine-6(2H)-thione (22;
R1 = 4-OCF3, R2 = 3-Br). A mixture of 4-(3-bromophenyl)-
4-[4-(trifluoromethoxy)phenyl]-1,3-thiazolidine-2,5-dithione
(0.60 g, 1.30 mmol) and propane-1,3-diamine (0.40 g, 3.91
mmol) in ethanol (6 mL) was heated at 70 °C for 1.5 h and then
cooled to room temperature. The solvents were evaporated, and
the residue was partitioned between ethyl acetate (60 mL) and
water (30 mL). The organic layer was separated and washed with
brine (50 mL), dried over sodium sulfate, filtered, and concen-
trated. Purification by flash chromatography (silica, 4:1 hex-
anes/ethyl acetate) afforded 8-(3-bromophenyl)-8-[4-(trifluoro-
methoxy)phenyl]-3,4,7,8-tetrahydroimidazo[1,5-a]pyrimidine-
6(2H)-thione (0.45 g, 54%) as a white solid: MS m/e 456 [M þ
H]þ; 1H NMR (300 MHz, CDCl3) δ 3.87 (t, J=8.5 Hz, 2H), 4.46
(t, J=8.5 Hz, 2H), 7.59-7.19 (m, 8H), 8.50 (s, 1H).
Step f. 8-(3-Bromophenyl)-8-[4-(trifluoromethoxy)phenyl]-
2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (23; R1 = 4-
OCF3, R2 = 3-Br). A mixture of 8-(3-bromophenyl)-8-[4-(tri-
fluoromethoxy)phenyl]-3,4,7,8-tetrahydroimidazo[1,5-a]pyrimi-
dine-6(2H)-thione (0.200 g, 0.438 mmol) and tert-butyl
hydroperoxide (0.79 g of a 70% solution in water, 8.80 mmol)
in methanol (20 mL) and concentrated aqueous ammonium
hydroxide (4 mL) was stirred overnight at room temperature.
The mixture was then concentrated. Purification by flash chro-
matography (silica, 95:5:0.25 methylene chloride/methanol/
concentrated ammonium hydroxide) afforded 8-(3-bromophe-
nyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo-
[1,5-a]pyrimidin-6-amine (0.16 g, 81%) as a white solid: MS m/e
453 [M þ H]þ; 1H NMR (300 MHz, CD3OD) δ 1.86 (t, J=5.7
Hz, 2H), 3.47 (t, J = 5.5 Hz, 2H), 3.69 (t, J = 6.0 Hz, 2H),
7.26-7.19 (m, 3H), 7.34-7.30 (m, 1H), 7.46-7.39 (m, 3H), 7.52
(t, J=1.8 Hz, 1H). Anal. (C19H16BrF3N4O) C, H, N.
General Methods of Suzuki and StilleCouplingsforCompounds
Illustrated in Schemes 1 and 2. 8-(3-Pyrimidin-5-ylphenyl)-
8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-
a]pyrimidin-6-amine (24; R1 = 4-OCF3, R2 = 3-Pyrimidin-
5-ylphenyl). A mixture of 8-(3-bromophenyl)-8-[4-(trifluorome-
thoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine
(0.25 g, 0.55 mmol), 5-pyrimidineboronic acid (0.082 g, 0.66
mmol), tetrakis(triphenylphosphino)palladium(0) (0.064 g,
0.054 mmol), and potassium carbonate (0.23 g, 1.65 mmol) in
5:1 dioxane/water (7.2 mL) was heated at 100 °C for 3.5 h. The
mixture was then cooled to room temperature and concentrated
and the crude product purified by flash chromatography (silica,
95:5:0.25 methylene chloride/methanol/concentrated ammo-
nium hydroxide) to 8-(3-pyrimidin-5-ylphenyl)-8-[4-(trifluo-
romethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-
6-amine (35 entry, Table 2) as a white solid (0.16 g, 60% yield):
mp 214-218 °C; MS m/e 453 (M þ H)þ; 1H NMR (500 MHz,
CD3OD) δ 1.88 (t, J=6.5 Hz, 2H), 3.52(t, J=6.0 Hz, 2H), 3.71(t,
J=6.2 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 7.47-7.43 (m, 2H),
7.54-7.51 (m, 2H), 7.69-7.65 (m, 2H), 9.01 (s, 2H), 9.11 (s, 1H).
Anal. (C23H19F3N6O) C, H, N.
1
(c 0.50, MeOH); MS m/e 453 (M þ H)þ; H NMR (300 MHz,
CD3OD) δ 1.91(t, J=5.7, 5.4 Hz, 2H), 3.55 (t, J=5.4 Hz, 2H),
3.75 (t, J=5.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.48-7.44 (m,
2H), 7.57-7.51 (m, 2H), 7.70-7.67 (m, 2H), 9.02 (s, 2H) 9.12 (s,
1H). HPLC (Chiralpak AD analytical column) >99% (AUC),
tR=15.44 min. Anal. (C23H19F3N6O) C, H, N.
The second eluting peak (tR = 48 min) was collected and
concentrated to give a pale-yellow oil. The oil residue was
redissolved in a minimal amount of methylene chloride and
then triturated with hexanes and filtered. The product was dried
under vacuum for 24 h to afford (S)-35 as an off-white solid (0.58
g): Rf = 0.38 (95:5:0.25 methylene chloride/methanol/concen-
trated ammonium hydroxide); mp 123-130 °C; [R]25D þ9.9° (c,
1
0.50, MeOH); MS m/e 453 (M þ H)þ; H NMR (300 MHz,
CD3OD) δ 1.91 (tt, J=5.7, 5.4 Hz, 2H), 3.55 (t, J=5.4 Hz, 2H),
3.75 (t, J=5.7 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.46-7.48 (m,
2H), 7.51-7.57 (m, 2H), 7.67-7.70 (m, 2H), 9.02 (s, 2H), 9.12 (s,
1H). HPLC (Chiralpak AD analytical column) >99% (AUC),
tR=19.11 min. Anal. (C23H19F3N6O) C, H, N.
(8R)-8-[3-(2-Fluoropyridin-3-yl)phenyl]-8-[4-(trifluorometho-
xy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine
[(R)-37] and (8S)-8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluo-
romethoxy)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-
6-amine [(S)-37]. A racemic mixture of 8-[3-(2-fluoropyridin-
3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-tetrahydro-
imidazo[1,5-a]pyrimidin-6-amine (0.74 g, 1.57 mmol) was
placed on a Chiralpak AD 5 cm ꢀ 50 cm column (90:10:0.1
heptane/ethanol/diethylamine as eluent). The first eluting peak
(tR=19 min) was collected and concentrated to a pale-yellow oil.
The oil residue was redissolved in a minimal amount of methy-
lene chloride, triturated with hexanes, and filtered. The filter
cake is dried under vacuum for 24 h to (S)-37 as an off-white
solid (0.315 g): Rf=0.49 (90:10:0.5 methylene chloride/metha-
nol/concentrated ammonium hydroxide); mp 124-128 °C;
[R]25D þ12.6° (c 0.5, MeOH); MS m/e 470 (M þ H); 1H NMR
(500 MHz, CD3OD) δ 1.90-1.85 (m, 2H), 3.49 (t, J=5.4 Hz,
2H), 3.70 (t, J=6.0 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.40-7.37
(m, 1H), 7.44-7.41 (m, 1H), 7.49-7.45 (m, 3H), 7.55-7.52 (m,
1H), 7.58 (s, 1H), 8.03-7.98 (m, 1H), 8.16 (dd, J=4.8, 1.1 Hz,
1H). HPLC (Chiralpak AD analytical column) >99% (AUC),
tR=8.47 min. Anal. (C24H19F4N5O) C, H, N.
8-[3-(2-Fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)-
phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine [24;
R1 = 4-OCF3, R2 = 3-(2-fluoropyridin-3-yl)phenyl]. A mixture
of 8-(3-bromophenyl)-8-[4-(trifluoromethoxy)phenyl]-2,3,4,8-
tetrahydroimidazo[1,5-a]pyrimidin-6-amine (0.072 g, 0.159
mmol), 2-fluoro-3-(tributylstannanyl)pyridine (0.092 g, 0.24
mmol), and dichlorobis(triphenylphosphino)palladium(II)
(0.006 g, 0.008 mmol) in DMF (2.5 mL) was degassed and then
heated at 150 °C in a sealed tube for 1.5 h. The mixture was then
cooled to room temperature and diluted with ethyl acetate (50
mL) and 5% aqueous LiCl (20 mL). The organic layer was
separated and washed with 5% aqueous LiCl (2 ꢀ 10 mL), dried
The second eluting peak (tR = 26 min) was collected and
concentrated to a pale-yellow oil. The oil residue is redissolved