1-Amino-4-benzylphthalazines
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 13 3965
Anal. RP-HPLC tR ) 9.44 min (method 1). HR-MS (m/z, MH+):
measd 475.1838, calcd 475.1858.
8.11 (t, J ) 7.6 Hz, 1H), 7.29-7.37 (m, 4H), 7.22-7.28 (m, 1H),
4.77 (s, 2H), 4.23-3.27 (m, 2H), 4.14 (t,
J ) 6.1
Hz, 2H), 3.67-3.71 (m, 2H), 3.41-3.46 (m, 2H), 2.39 (q, J ) 5.6
4-{4-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]phthalazin-1-
ylmethyl}benzoic Acid Methyl Ester (37). 37 was synthesized from
30 and 4-(bromomethylzinc)benzoic acid methyl ester in 50% yield
according to the general coupling procedure. 4-(Bromomethylz-
inc)benzoic acid methyl ester was prepared as described for
4-(trifluoromethyl)benzylzinc bromide and was used immediately.
1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J ) 2.4 Hz, 1H),
8.24-8.17 (m, 2H), 7.99-7.90 (m, 3H), 7.88 (d, J ) 8.2 Hz, 2H),
7.48 (d, J ) 8.2 Hz, 2H), 7.04 (d, J ) 9.2 Hz, 1H), 4.69 (s, 2H),
4.00-3.93 (m, 4H), 3.82 (s, 3H), 3.56-3.46 (m, 4H). Anal. RP-
HPLC tR ) 8.63 min (method 1, purity 92.92%/100%). HR-MS
(m/z, MH+): measd 465.2032, calcd 465.2039.
4-{4-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]phthalazin-1-
ylmethyl}benzoic Acid (38). Compound 37 (60 mg, 0.129 mmol)
and MeOH (2 mL) were added to a 10 mL round-bottom flask.
NaOH (0.775 mL, 1 M, 0.775 mmol) was then added, and the
mixture was stirred at room temperature for 24 h. The MeOH was
removed in vacuo, the flask was placed in an ice bath, and the
remaining solution was acidified to pH ∼3.0 with acetic acid. The
organics were extracted with DCM, washed with water followed
by brine, dried over Na2SO4, filtered, and concentrated. The residue
was purified by trituration with EtOAc to afford the title compound
as an off-white solid (36 mg, 62%). 1H NMR (400 MHz, DMSO-
d6) δ 12.79 (s, 1H), 8.54 (d, J ) 2.4 Hz, 1H), 8.26-8.17 (m, 2H),
7.99-7.89 (m, 3H), 7.86 (d, J ) 8.2 Hz, 2H), 7.45 (d, J ) 8.2 Hz,
2H), 7.04 (d, J ) 9.1 Hz, 1H), 4.68 (s, 2H), 4.00-3.93 (m, 4H),
3.54-3.47 (m, 4H). Anal. RP-HPLC tR ) 8.50 min (method 1).
HR-MS (m/z, MH+): measd 451.1896, calcd 451.1882.
Hz, 2H). MS (m/z, MH+): 319.2.
1-Benzyl-4-((S)-3-methylpiperazin-1-yl)phthalazine (41b). Solid
Na2CO3 (400 mg, 3.8 mmol) was added to a solution of 1-benzyl-
4-chlorophthalazine (250 mg, 0.98 mmol) and (S)-2-methylpipera-
zine (400 mg, 4.0 mmol) in dioxane (5 mL). The resulting
suspension was heated at 100 °C for 48 h. The reaction mixture
was then concentrated, and EtOAc (50 mL) and water (15 mL)
were added. The organic fraction was washed with H2O and then
brine, dried over Na2SO4, and concentrated in vacuo to afford the
1
title compound as a white solid (200 mg, 64%). H NMR (400
MHz, CDCl3) δ 7.97 (d, J ) 7.1 Hz, 1H), 7.89 (d, J ) 8.2 Hz,
1H), 7.68-7.58 (m, 2H), 7.28-7.24 (m, 2H), 7.22-7.14 (m, 2H),
7.11-7.06 (m, 1H), 3.69 (d, J ) 12.4 Hz, 2H), 3.61 (s, 2H),
3.03-3.20 (m, 4H), 2.74 (dd, J ) 12.6, 10.2 Hz, 1H), 1.07 (d, J )
6.3 Hz, 3H). MS (m/z, MH+): measd 319.1.
1-Benzyl-4-((R)-3-methylpiperazin-1-yl)phthalazine (41c). 41c
was synthesized from 6a and (R)-methylpiperazine in 58% yield
according to the procedure described for 41b. 1H NMR (400 MHz,
CDCl3) δ 8.08 (d, J ) 7.1 Hz, 1H), 8.00 (d, J ) 7.7 Hz, 1H),
7.79-7.69 (m, 2H), 7.39-7.34 (m, 2H), 7.32-7.25 (m, 2H), 7.20
(d, J ) 7.2 Hz, 1H), 4.65-4.61 (m, 2H), 3.82-3.76 (m, 2H),
3.30-3.13 (m, 4H), 2.85 (dd, J ) 12.6, 10.2 Hz, 1H), 1.17 (d, J )
6.3 Hz, 3H). MS (m/z, MH+): measd 319.1.
6-[4-(4-Benzylphthalazin-1-yl)[1,4]diazepan-1-yl]nicotinoni-
trile (42). 42 was synthesized from 6-chloronicotinonitrile and 41a
in 34% yield according to general procedure B. 1H NMR (400 MHz,
CDCl3) δ 8.40 (d, J ) 2.5 Hz, 1H), 7.97-8.03 (m, 2H), 7.68-7.75
(m, 2H), 7.60 (dd, J ) 10.4, 2.0 Hz, 2H), 7.32 (d, J ) 7.1 Hz,
2H), 7.25 (t, J ) 7.6 Hz, 2H), 7.17 (t, J ) 7.1 Hz, 1H), 6.59 (d, J
) 9.1 Hz, 1H), 4.60 (s, 2 H), 4.11 (br s, 2H), 3.88-3.94 (m, 4H),
3.67 (t, J ) 5.6 Hz, 2H), 2.19 (q, J ) 5.6 Hz, 2H). Anal. RP-
HPLC tR ) 7.21 min (method 1, purity 100.00%/92.50%). HR-
MS (m/z, MH+): measd 421.2142, calcd 421.2141.
6-{4-[7-Chloro-4-(4-fluorobenzyl)phthalazin-1-yl]piperazin-1-
yl}nicotinonitrile and 6-{4-[6-Chloro-4-(4-fluorobenzyl)phthalazin-
1-yl]piperazin-1-yl}nicotinonitrile (39a,b). 39a,b were synthesized
from 31a,b and 4-fluorobenzylzinc chloride in 81% yield as a 1:1
1
mixture of regioisomers. H NMR (1:1 mix of 39a and 39b) (400
MHz, CDCl3) δ 8.38 (m, 1H), 7.98 (m, 1H), 7.88 (m, 1H),
7.69-7.59 (m, 2H), 7.21 (m, 2H), 6.91 (m, 2H), 6.64 (m, 1H),
4.51 (s, 1H), 4.49 (s, 1H), 3.89 (m, 4H), 3.56 (m, 4H). Anal. RP-
HPLC tR ) 6.44, 6.54 min (regioisomers elute separately) (method
1). HR-MS (m/z, MH+): measd 459.1483, calcd 459.1500.
6-[(S)-4-(4-Benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nico-
tinonitrile (43). Solid Na2CO3 (50 mg, 0.47 mmol) was added to a
solution of 6-chloronicotinonitrile (50 mg, 0.36 mmol) and 41b
(100 mg, 0.31 mmol) in DMF (1 mL) and dioxane (2 mL) in a
microwave vial. The vial was sealed and irradiated in the microwave
at 180 °C (high absorption setting) for 30 min. The reaction mixture
was concentrated in vacuo and then diluted with CH2Cl2. This
solution was washed with H2O and then brine. The organics were
dried over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified via flash chromatography on silica gel (50-90%
EtOAc/hexanes) to afford the title compound as a white solid (30
4-[4-(5-Cyanopyridin-2-yl)piperazin-1-yl]-1-(4-fluoroben-
zyl)phthalazine-6-carbonitrile and 1-[4-(5-Cyanopyridin-2-yl)pip-
erazin-1-yl]-4-(4-fluorobenzyl)phthalazine-6-carbonitrile (40a,b).
To a solution of 39a and 39b (46 mg, 0.1 mmol, 1:1 mix of
regioisomers) in DMF (2 mL) was added Zn(CN)2 (24 mg, 0.2
mmol), Pd2(dba)3 (9.2 mg, 0.1 equiv), and X-phos (6 mg, 0.125
equiv). The mixture was degassed by bubbling N2 through the
solution for 5 min and then heated in the microwave (high
absorption setting) at 120 °C for 45 min. EtOAc (4 mL) was added,
and the mixture was passed through a plug of silica. The filtrate
was washed with water, brine, dried over Na2SO4, and concentrated
in vacuo. The residue was purified via flash chromatography on
silica gel (25% heptane in EtOAc) gave the title compounds as a
1
mg, 23%). H NMR (400 MHz, CDCl3) δ 8.39 (d, J ) 2.3 Hz,
1H), 8.09 (d, J ) 8.7 Hz, 1H), 7.97 (d, J ) 7.8 Hz, 1H), 7.77-7.71
(m, 1H), 7.77-7.66 (m, 1H), 7.60 (dd, J ) 9.0, 2.3 Hz, 1H),
7.30-7.25 (m, 2H), 7.23-7.16 (m, 2H), 7.14-7.09 (m, 1H), 6.60
(d, J ) 9.0 Hz, 1H), 4.77-4.67 (m, 1H), 4.56 (s, 2H), 4.31 (d, J
) 13.1 Hz, 1H), 3.90 (d, J ) 11.9 Hz, 1H), 3.75 (dt, J ) 12.8, 2.1
Hz, 1H), 3.53 (ddd, J ) 12.7, 3.5 Hz, 1H), 3.36 (dd, J ) 12.7, 3.6
Hz, 1H), 3.20 (td, J ) 12.5, 3.5 Hz, 1H), 1.42 (d, J ) 6.3 Hz, 3H).
Anal. RP-HPLC tR ) 9.03 min (method 1). HR-MS (m/z, MH+):
measd 421.2151, calcd 421.2141.
1
yellow powder (41 mg, 91%, 1:1 mix of regioisomers). H NMR
(1:1 mix of 40a and 40b) (400 MHz, CDCl3) δ 8.37 (m, 0.5H),
8.36 (s, 1H), 8.26 (m, 0.5H), 8.14 (d, J ) 8.6 Hz, 0.5H), 8.02 (d,
J ) 8.6 Hz, 0.5H), 7.91 (m, 0.5H), 7.87 (m, 0.5H), 7.61 (m, 1H),
7.20 (m, 2H), 6.90 (m, 2H), 6.63 (m, 1H), 4.53 (s, 2H), 3.90 (m,
4H), 3.58 (m, 4H). Anal. RP-HPLC tR ) 6.28 min (regioisomers
coelute) (method 1, purity 90.3%/93.8%). HR-MS (m/z, MH+):
measd 450.1840, calcd 450.1842.
1-Benzyl-4-[1,4]diazepam-1-ylphthalazine (41a). 1-Benzyl-4-
chlorophthalazine (1.11 g, 4.35 mmol) and homopiperazine (2.20
g, 21.7 mmol) were added to a microwave vial, followed by NMP
(5 mL) and triethylamine (1.84 mL, 13.1 mmol). The vial was sealed
and irradiated in the microwave at 180 °C (high absorption setting)
for 30 min. The mixture was diluted with H2O, and the organics
were extracted with CH2Cl2. The combined organic fractions were
dried over MgSO4 and then concentrated in vacuo to afford the
title compound as a yellow oil (640 mg, 42%). 1H NMR (400 MHz,
CDCl3) δ 8.47 (t, J ) 9.1 Hz, 2H), 8.19 (dt, J ) 8.6, 1.0 Hz, 1H),
6-[(R)-4-(4-Benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nico-
tinonitrile (44). 44 was synthesized from 6-chloronicotinonitrile and
1
41c in 42% yield according to the procedure described for 43. H
NMR (400 MHz, CDCl3) δ 8.39 (d, J ) 2.0 Hz, 1H), 8.09 (d, J )
7.5 Hz, 1H), 7.97 (d, J ) 7.7 Hz, 1H), 7.76-7.66 (m, 2H), 7.59
(dd, J ) 9.0, 2.3 Hz, 1H), 7.30-7.24 (m, 2H), 7.22-7.16 (m, 2H),
7.14-7.08 (m, 1H), 6.60 (d, J ) 9.1 Hz, 1H), 4.76-4.68 (m, 1H),
4.59-4.54 (m, 2H), 4.30 (d, J ) 13.0 Hz, 1H), 3.94-3.86 (m,
1H), 3.78-3.71 (m, 1H), 3.53 (td, J ) 12.7, 3.4 Hz, 1H), 3.35
(dd, J ) 12.8, 3.7 Hz, 1H), 3.20 (td, J ) 12.5, 3.5 Hz, 1H), 1.44
(d, J ) 6.7 Hz, 3H). Anal. RP-HPLC tR ) 9.01 min (method 1).
HR-MS (m/z, MH+): measd 421.2153, calcd 421.2141.
6-((R)-3-Methylpiperazin-1-yl)nicotinonitrile (45a). Triethyl-
amine (5.51 g, 4 mL, 54.6 mmol) was added to a solution of