Journal of Medicinal Chemistry
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1
185.3−186.4 °C. H NMR (300 MHz, CDCl3) δ 9.46 (s, 2H, NH),
dry dichloromethane (3 mL). The reaction was monitored by TLC,
and after 1 h, if any 5 remained, an additional 0.5 equiv of diacid
chloride in dry dichloromethane (1 mL) was added to the solution and
the reaction mixture was stirred for an additional 2−5 h at room
temperature. The reaction mixture was partitioned between ethyl
acetate (30 mL) and aqueous sodium hydroxide (30 mL, 1 M). The
organic layer was separated and the aqueous layer was extracted with
ethyl acetate (3 × 30 mL). The combined organic layers were washed
with water (2 × 30 mL) and saturated brine (30 mL), dried over
anhydrous sodium sulfate, filtered, and evaporated to dryness in vacuo,
yielding a yellow oil. The product was purified by preadsorption onto
coarse silica, followed by flash column chromatography. Compounds
were typically purified with 1−3 columns (refer to specific
experimental description for details of eluent).
8.54 (d, J = 2.3 Hz, 2H, H9′), 7.78 (m, 2H, H1′/H4′), 7.44−7.37 (m,
4H, H3′/H2′ and H4′/H1′), 7.36 (d, J = 8.6 Hz, 2H, H6′), 7.15 (m,
2H, H2′/H3′), 7.13 (dd, J = 8.5, 2.4 Hz, 2H, H7′), 3.57 (m, 8H, H2″
and H6″), 2.68 (m, 8H, H3″ and H5″), 2.39 (s, 6H, CH3), 2.25 (m,
4H, H2 and H5), 1.67 (m, 4H, H3 and H4). 13C NMR (75 MHz,
CDCl3) δ 170.6 (C), 153.9 (C), 141.9 (C), 133.8 (C), 132.8 (C),
128.3 (CH), 126.9 (C), 124.6 (CH), 123.7 (CH), 122.7 (CH), 121.9
(CH), 120.8 (CH), 116.3 (C), 110.7 (CH), 54.8 (CH2), 49.4 (CH2),
46.4 (CH3), 37.8 (CH2), 24.8 (CH2). HPLC: tR 9.72 min, >99% purity
(method 1). LCMS (m/z): 793.1 [M + H]+, 397.2 [M + 2H]2+.
+
HRMS (m/z): C42H47Cl2N10O2 requires [M + H]+ 793.3255; found
793.3256.
4,4′-(Piperazine-1,4-diyl)bis{N-[8-chloro-11-(4-methylpiperazin-
1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-yl]-4-oxobutanamide} (12a).
4,4′-(Piperazine-1,4-diyl)bis(4-oxobutanoic acid) (11a, 0.090 g, 0.316
mmol) and oxalyl chloride were reacted, followed by the addition of 2
(0.191 g, 0.558 mmol) and pyridine (70 μL, 0.867 mmol) as per
general procedure B. Additional 4,4′-(piperazine-1,4-diyl)bis(4-oxobu-
tanoyl chloride) (0.052 g, 0.161 mmol) was added. Column
chromatography conditions: 1% ammonia/4% methanol/chloroform.
Yield: 12a as an off-white foam (0.063 g, 0.067 mmol, 24%). 1H NMR
(400 MHz, CDCl3) δ 9.70 (s, 2H, NH), 8.56 (s, 2H, H9″), 7.79 (ddd,
J = 8.2, 0.9, 0.9 Hz, 2H, H1″/H4″), 7.42−7.36 (m, 4H, H3″/H2″ and
H4″/H1″), 7.36 (d, J = 8.5 Hz, 2H, H6″), 7.15 (m, 2H, H2″/H3″), 7.13
(dd, J = 8.5, 2.4 Hz, 2H, H7″), 3.59 (m, 8H, H2‴ and H6‴), 3.55−
3.46 (m, 4H, piperazine spacer), 3.42−3.36 (m, 4H, piperazine
spacer), 2.69 (m, 8H, H3‴ and H5‴), 2.64 (s, 8H, H2′ and H3′), 2.40
(s, 6H, CH3). 13C NMR (101 MHz, CDCl3, mixture of amide
rotamers)36 δ 170.3 (C), 170.1 (C), 170.0 (C), 153.9 (C), 141.9 (C),
133.9 (C), 132.9 (C), 128.2 (CH), 126.9 (C), 124.8 (CH), 123.7
(CH), 122.6 (CH), 121.8 (CH), 120.7 (CH), 116.4 (C), 110.7 (CH),
54.8 (CH2), 49.4 (CH2), 46.3 (CH3), 45.2 (CH2), 45.0 (CH2), 41.53
(CH2), 41.45 (CH2), 32.7 (CH2), 32.6 (CH2), 28.0 (CH2). HPLC: tR
7.22 min, 96% purity (method 2). LCMS (m/z): 933.2 [M + H]+,
N1,N6-Bis{3-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-
piperazin-1-yl]propyl}adipamide (9a). 1,6-Hexanedioic acid (6a)
(0.027 g, 0.184 mmol) and oxalyl chloride were reacted, followed by
the addition of 5 (0.130 g, 0.352 mmol) and pyridine (0.040 mL, 0.496
mmol) as per general procedure C. Additional 1,6-hexanedioyl
dichloride (0.016 g, 0.089 mmol) was added. Column chromatography
conditions: 10% methanol/chloroform. Yield: 9a as a yellow foam
(0.068 g, 0.080 mmol, 46%). 1H NMR (400 MHz, CDCl3) δ 7.29 (m,
2H, H3‴), 7.24 (dd, J = 7.7, 1.4 Hz, 2H, H1‴), 7.08 (br t, J = 5.0 Hz,
2H, CONH), 7.05 (d, J = 2.4 Hz, 2H, H9‴), 7.00 (ddd, J = 7.6, 7.5,
1.0 Hz, 2H, H2‴), 6.86 (dd, J = 8.0, 0.6 Hz, 2H, H4‴), 6.82 (dd, J =
8.3, 2.4 Hz, 2H, H7‴), 6.66 (d, J = 8.3 Hz, 2H, H6‴), 5.26 (s, 2H,
H5‴), 3.47 (m, 8H, H3″ and H5″), 3.29 (td, J = 5.8, 5.8 Hz, 4H, H1′),
2.58 (m, 8H, H2″ and H6″), 2.52 (t, J = 6.4 Hz, 4H, H3′), 2.17 (m, 4H,
H2 and H5), 1.69 (app p, J = 6.5 Hz, 4H, H2′), 1.64 (m, 4H, H3 and
H4). 13C NMR (101 MHz, CDCl3) δ 172.9 (C), 163.1 (C), 153.1
(C), 141.7 (C), 140.8 (C), 132.2 (CH), 130.3 (CH), 129.1 (C), 126.8
(CH), 123.5 (CH), 123.3 (C), 123.2 (CH), 120.4 (2 × CH), 57.2
(CH2), 53.0 (CH2), 47.3 (CH2), 39.1 (CH2), 36.5 (CH2), 25.3 (CH2),
25.2 (CH2). HPLC: tR 7.93 min, >99% purity (method 1). LCMS (m/
z): 849.2 [M + H]+, 425.2 [M + 2H]2+. HRMS (m/z):
+
467.2 [M + 2H]2+. HRMS (m/z): C48H55Cl2N12O4 requires [M +
+
C46H55Cl2N10O2 requires [M + H]+ 849.3881; found 849.3881.
H]+ 933.3841; found 933.3803.
Synthesis of Monovalent Ligands. 1-[8-Chloro-11-(4-meth-
ylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-yl]decan-1-one
(15). Compound 1 (0.103 g, 0.315 mmol) was dissolved in dry
dichloromethane (3 mL), at room temperature, under a
nitrogen atmosphere. Pyridine (37 μL, 0.459 mmol) and
N,N-diisopropylethylamine (80 μL, 0.459 mmol) were added
to the stirred solution, followed by decanoyl chloride (127 μL,
0.612 mmol). After 2 h, the reaction mixture was diluted with
dichloromethane (30 mL) and washed with aqueous hydro-
chloric acid (30 mL, 1 M). The organic layer was separated and
the aqueous layer was further extracted with dichloromethane
(2 × 30 mL). The combined organic layers were then washed
with aqueous sodium hydroxide (3 × 30 mL), water (2 × 30
mL), and saturated brine (30 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The crude
yellow oil was purified by flash column chromatography
(column 1, 5% methanol/chloroform; column 2, 1%
ammonia/4% methanol/chloroform) to give the pure title
compound 15 as a pale yellow oil (0.055 g, 0.114 mmol, 36%).
1H NMR (400 MHz, CDCl3, 320 K) δ 7.49 (ddd, J = 8.0, 7.0,
1.8 Hz, 1H, H3′), 7.40−7.30 (m, 3H, H1′, H2′, and H4′), 7.15
(d, J = 2.4 Hz, 1H, H9′), 7.10 (d, J = 8.3 Hz, 1H, H6′), 6.96
(dd, J = 8.3, 2.3 Hz, 1H, H7′), 3.70 (m, 2H, H2″a and H6″a),
3.48 (m, 2H, H2″b and H6″b), 2.46 (m, 2H, H3″a and H5″a),
2.36 (m, 2H, H3″b and H5″b), 2.32−2.24 (m, 4H, NCH3,
H2a), 2.17 (m, 1H, H2b), 1.55 (m, 2H, H3), 1.33−1.17 (m,
12H, H4−H9), 0.87 (t, J = 7.0 Hz, 3H, H10). 13C NMR (101
MHz, CDCl3, 320 K) δ 173.7 (C), 160.5 (C), 146.3 (C), 145.0
(C), 133.9 (C), 133.6 (C), 131.9 (CH), 129.0 (CH), 127.7
(CH), 127.6 (CH), 126.9 (C), 126.1 (2 × CH), 123.1 (CH),
54.9 (CH2), 46.9 (CH2), 46.0 (CH3), 33.5 (CH2), 31.8 (CH2),
29.3 (CH2), 29.21 (CH2), 29.19 (2 × CH2), 25.1 (CH2), 22.6
(CH2), 14.0 (CH3). HPLC: tR 9.10 min, >99% purity (method
Ethane-1,2-diyl bis(4-{[8-chloro-11-(4-methylpiperazin-1-yl)-5H-
dibenzo[b,e][1,4]diazepin-5-yl]amino}-4-oxobutanoate) (14). 4,4′-
[Ethane-1,2-diylbis(oxy)]bis(4-oxobutanoic acid) (13, 0.090 g, 0.343
mmol) and oxalyl chloride were reacted, followed by the addition of 2
(0.204 g, 0.596 mmol) and pyridine (76 μL, 0.942 mmol) as per
general procedure B. Column chromatography conditions: column 1,
0.5% ammonia/2.5% methanol/chloroform; column 2, gradient
elution from 2% to 5% methanol/chloroform, increasing in 1%
increments. Yield: 14 as an off-white foam (0.124 g, 0.136 mmol,
1
46%). H NMR (400 MHz, CDCl3) δ 9.64 (s, 2H, NH), 8.52 (d, J =
2.3 Hz, 2H, H9″), 7.78 (ddd, J = 8.3, 0.9, 0.9 Hz, 2H, H1″/H4″), 7.43−
7.36 (m, 4H, H3″/H2″ and H4″/H1″), 7.36 (d, J = 8.5 Hz, 2H, H6″),
7.14 (ddd, J = 8.1, 6.3, 1.8 Hz, 2H, H2″/H3″), 7.12 (dd, J = 8.5, 2.4 Hz,
2H, H7″), 4.16 (s, 4H, H1 and H2), 3.58 (m, 8H, H2‴ and H6‴), 2.72
(m, 8H, H3‴ and H5‴), 2.66 (m, 4H, H2′/H3′), 2.57 (m, 4H, H3′/
H2′), 2.42 (s, 6H, CH3). 13C NMR (101 MHz, CDCl3) δ 172.3 (C),
169.4 (C), 153.7 (C), 141.8 (C), 133.6 (C), 132.7 (C), 128.3 (CH),
126.9 (C), 124.6 (CH), 123.7 (CH), 122.6 (CH), 121.8 (CH), 120.7
(CH), 116.3 (C), 110.6 (CH), 62.3 (CH2), 54.6 (CH2), 49.2 (CH2),
46.1 (CH3), 32.2 (CH2), 28.9 (CH2). HPLC: tR 10.17 min, >99%
purity (method 1). LCMS (m/z): 909.1 [M + H]+, 455.2 [M + 2H]2+.
+
HRMS (m/z): C46H51Cl2N10O6 requires [M + H]+ 909.3365; found
909.3328.
General Procedure C for Preparation of Clozapine Propylamine
Bivalent Ligands (9a−g). All glassware used in the following
procedure was flame-dried and cooled under nitrogen. The
dicarboxylic acid (6a−g) (0.169−0.184 mmol) was suspended in dry
dichloromethane (2 mL) at room temperature, under a nitrogen
atmosphere. Oxalyl chloride (2.2 equiv) and N,N-dimethylformamide
(1 drop) were added to the solution, which was stirred for 1 h at room
temperature. To this mixture was added a solution of 5 (2.0 equiv) and
pyridine (2.8−6.8 equiv), and in some cases N,N-diisopropylethyl-
amine (2.5 equiv) or anhydrous potassium carbonate (2.0 equiv), in
1631
dx.doi.org/10.1021/jm201420s | J. Med. Chem. 2012, 55, 1622−1634