Journal of Medicinal Chemistry
ARTICLE
Et2Oꢀhexanes to yield 18a (0.6 g, 91%). Mp 186ꢀ187 ꢀC. 1H NMR
(DMSO-d6, δ): 2.2 (m, 2H, J = 7 Hz), 3.7 (s, 3H), 3.8 (t, 2H, J = 7 Hz),
4.15 (t, 2H, J = 7 Hz), 7.0ꢀ7.1 (m, 3H), 7.8 (d, 2H, J = 7.8 Hz), 8.0 (d,
1H). LCMS m/z: 279 (M þ 1).
(m, 1H), 4.14 (t, 2H, J = 5.9 Hz), 5.45 (br s, 1H), 7.06 (m, 3H), 7.85 (d,
2H, J = 8.4 Hz), 8.03 (d, 1H, J = 9.7 Hz), 10.09 (br s, 1H). LCMS m/z:
344 (M þ 1).
6-{4-[3-((R)-2-Hydroxymethylpyrrolidin-1-yl)propoxy]-
phenyl}-2-methyl-2H-pyridazin-3-one Hydrochloride (20c).
Yield 50%, purity 99%. Mp 166ꢀ167 ꢀC (HCl salt, acetonitrileꢀhexanes).
1H NMR (DMSO-d6 δ): 1.78 (broad m, 1H), 1.90 (broad m, 1H), 2.07
(broad m, 1H), 2.10 (broad m, 1H), 2.24 (broad m, 2H), 3.12ꢀ3.20
(broad m, 2H), 3.59 (broad m, 3H), 3.68 (m, 1H), 3.72 (s, 3H), 3.75 (m,
1H), 4.14 (t, 2H, J = 5.9 Hz), 5.45 (broad s, 1H), 7.06 (m, 3H), 7.85 (d,
2H, J = 8.7 Hz), 8.03 (d, 1H, J = 9.7 Hz), 10.09 (broad s, 1H). LCMS m/z:
344 (M þ 1).
2-Methyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]-
phenyl}-2H-pyridazin-3-one (19a). A mixture of 18a (1.5 g,
5.4 mmol), K2CO3 (2.2 g 16.2 mmol), NaI (0.8 g, 5.4 mmol), (R)-2-
methylpyrrolidineꢀHCl (1.3 g, 10.8 mmol) in CH3CN (30 mL) was
heated under N2 at 90 ꢀC for 2 days. The mixture was filtered and
concentrated. The residue was dissolved in EtOAc and washed with 2 N
Na2CO3, NaCl solution, dried (MgSO4), and concentrated. The
product was purified by ISCO silica gel chromatography (95:5 DCM/
MeOH). The fractions were combined and concentrated to yield 19a
(0.85 g, 48%, free base). The HCl salt was prepared by adding a 1 N
HClꢀether solution to the base in ether. The white solid was collected
and crystallized from CH3CNꢀether. Mp 183ꢀ185 ꢀC. 1H NMR
(DMSO-d6, δ): 1.38 (d, 3H, J = 5.2 Hz), 1.62 (m, 1H), 1.92ꢀ1.97
(m, 2H), 2.1ꢀ2.3 (m, 3H), 3.1 (m, 2H), 3.4 (m, 2H), 3.6 (m, 1H), 3.7
(m, 1H), 3.7 (s, 3H), 4.15 (m, 2H), 7.0ꢀ7.17 (m, 3H), 7.8 (d, 2H, J =
8.6 Hz), 8.0 (d, 1H, J = 9.6 Hz), 10.1 (s, 1H). LCMS m/z: 328 (M þ 1).
Compounds 19b-e and 20aꢀc were synthesized using the methods
for 19a.
5-{4-[3-((R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-2H-
pyridazin-3-one (21). To a round-bottom flask was added 12 (3.3 g,
9.5 mmol), 2-hydroxymethyl-5-iodo-2H-pyridazin-3-one (2.3 g, 9.1 mmol),
tetrakis(triphenylphosphine)palladium(0) (2.1 g, 1.8 mmol), potassium
carbonate (6.3 g, 45.2 mmol), 1,2-dimethoxyethane (80 mL), and water
(40 mL). The reaction mixture was flushed with nitrogen for 30 min and was
heated at reflux for 48 h. The mixture was cooled to room temperature, filtered,
and concentrated. The residue was purified by column chromatography
(CH2Cl2/MeOH/i-PrNH2, 9:1:0.1) to give 21 (3.3 g, 63% yield, 98% purity).
Mp 166ꢀ169 ꢀC. 1H NMR (DMSO-d6, δ): 1.00 (d, 3H, J =
4 Hz), 1.27ꢀ1.3.6 (m, 1H), 1.56ꢀ1.72 (m, 1H), 1.87 (m, 3H), 1.98ꢀ2.29
(m, 3H), 2.84ꢀ2.98(m, 1H), 3.03ꢀ3.13 (m, 1H), 4.09 (t, 2H, J= 6 Hz), 7.06
(m, 2H), 7.78 (m, 3H), 8.29 (m, 2H), 13.0 (s, 1H). LCMS m/z:314(Mþ 1).
1-Bromo-4-(3-chloropropoxy)benzene (23). 4-Bromophenol
22 (10 g, 57.8 mmol), 3-bromo-1-chloropropane (9.6 g, 60.7 mmol),
and K2CO3 (8.0 g, 63.6 mmol) in acetone was stirred at reflux for 18 h.
The mixture was cooled to room temperature, filtered, and concentrated
at reduced pressure. The resulting oil was dissolved in ether (100 mL)
and washed with 1 N NaOH solution (2 ꢁ 25 mL), water, NaCl solution
and dried over MgSO4 to give 23 (13.3 g, 92%) as a clear oil that
solidified on standing. 1H NMR (DMSO-d6, δ): 2.21 (m, 2H), 3.73 (t,
2H, J = 6.1 Hz), 4.08 (t, 2H, J = 5.7 Hz), 6.78 (d, 2H, J = 8 Hz), 7.37 (d,
2H, J = 8 Hz). LCMS m/z: 250 (M þ 1).
2-Ethyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-
2H-pyridazin-3-one (19b). Yield 96% free base, purity 97%. Mp
1
58ꢀ62 ꢀC (L-tartrate salt, acetoneꢀether). H NMR (DMSO-d6 δ):
1.19 (d, 3H, J = 5.6 Hz), 1.29ꢀ1.33 (t, 3H, J = 7.1 Hz), 1.4 (m, 1H), 1.7
(m, 2H), 2.0 (m, 4H), 2.8 (m, 2H), 3.0 (broad, 1H), 3.2 (broad, 1H),
6.99ꢀ7.06 (m, 3H), 7.84 (d, 1H, J = 8.9 Hz), 7.99 (d, 2H, J = 9 Hz).
LCMS m/z: 342 (M þ 1).
2-Isopropyl-6-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]-
phenyl}-2H-pyridazin-3-one (19c). Yield 88% free base, purity
98%. Mp 60ꢀ64 ꢀC (L-tartrate salt, CHCl3ꢀetherꢀhexane). 1H NMR
(CDCl3, δ): 1.09 (d, 3H, J = 5.8 Hz), 1.43 (d, 6H, J = 6.6 Hz), 1.7ꢀ1.9
(m, 2H), 1.9ꢀ2.4 (m, 7H), 2.8 (m, 1H), 3.0 (broad, 1H), 4.06ꢀ4.1 (m,
2H), 5.37 (m, 1H), 6.94ꢀ6.99 (m, 3H), 7.59 (d, 1H, J = 9.7 Hz), 7.73 (d,
2H, J = 8.7 Hz). LCMS m/z: 358 (M þ 1).
(R)-1-[3-(4-Bromophenoxy)propyl]-2-methylpyrrolidine (24).
A mixture of 22 (2.0 g, 8.0 mmol), (R)-2-methylpyrrolidineꢀHCl (1.2 g,
9.6 mmol), K2CO3 (2.2 g, 16 mmol), and NaI (0.6 g, 4 mmol) in acetonitrile
(35 mL) was stirred at reflux 48 h. The mixture was cooled to room
temperature. Water was added and the solution extracted with ether (3 ꢁ
25 mL). The ether layer was washed with water, NaCl solution and dried over
MgSO4 to give 23 (2.3 g, 97%) as a clear oil. The HCl salt was prepared
by adding a 1 N HClꢀether solution to the base in ether. Mp 157ꢀ159 C (HCl
salt, MeOHꢀether). 1HNMR(CDCl3, δ): 1.07 (d, 3H, J = 6 Hz), 1.39ꢀ1.43
(m, 1H), 1.66ꢀ1.79 (m, 2H), 1.87ꢀ2.00 (m, 3H), 2.06ꢀ2.21 (m, 2H),
2.26ꢀ2.31 (m, 1H), 2.92ꢀ2.99 (m, 1H), 3.14ꢀ3.18 (m, 1H), 3.97ꢀ4.0 (m,
2H), 6.77 (d, 2H, J= 8 Hz), 7.35 (d, 2H, J=8Hz). LCMSm/z:299(Mþ 1).
2-{4-[3-((R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-2H-
pyridazin-3-one (25). A mixture of 24 (560 mg, 1.87 mmol), 2H-
pyridazin-3-one (180 mg, 1.87 mmol), K2CO3 (775 mg, 5.61 mmol), copper
powder (120 mg, 1.87 mmol) in pyridine (75 mL) was stirred at reflux under
nitrogen for 18 h. The mixture was cooled to room temperature and
concentrated at reduced pressure. The residue was absorbed onto Fluorosil
for elution and purification by ISCO silica gel chromatography (95:5:1/
DCM, MeOH, i-PrNH2). The fractions containing pure product were
collected and concentrated. The solid was crystallized from Et2Oꢀhexanes
to give 25 (210 mg, 36%, 97% purity) as a white solid. Mp 106ꢀ107 ꢀC. The
HCl salt was prepared by dissolving the base in MeOH and adding 1 N
Et2OꢀHCl. After concentration the product was crystallized using
MeOHꢀether. Mp 175ꢀ177 ꢀC (MeOHꢀEt2O). 1H NMR (CDCl3, δ):
1.10 (d, 3H, J = 5.2 Hz), 1.42 (m, 1H), 1.70ꢀ1.79 (m, 2H), 1.79ꢀ1.92 (m,
3H), 2.11ꢀ2.30 (m, 3H), 2.98 (m, 1H), 3.18 (m, 1H), 4.06 (m, 2H), 6.98 (d,
2H, J = 8 Hz), 7.04 (d, 1H, J = 9 Hz), 7.21ꢀ7.24 (m, 1H), 7.50 (d, 2H, J = 8
Hz), 7.87 (s, 1H). LCMS m/z: 314 (M þ 1).
2-Phenyl 6-{4-[3-((R)-2-Methylpyrrolidin-1-yl)propoxy]-
phenyl}-2H-pyridazin-3-one (19d). Yield 88% purity 96%. Mp
82ꢀ86 ꢀC (CH2Cl2). 1H NMR (DMSO-d6, δ): 1.36 (m, 3H), 1.59 (m,
1H), 1.91 (m, 2H), 2.14 (m, 3H), 3.09 (m, 2H), 3.39 (m, 2H), 3.59 (m,
1H), 4.13 (t, 2H, J = 4.5 Hz), 7.06 (d, 2H, J = 8.5 Hz,), 7.16 (d, 1H, J = 9.8
Hz,), 7.44 (t, 1H, J = 6.9 Hz,), 7.53 (t, 2H, J = 7.9 Hz,), 7.65 (d, 2H, J =
8.3 Hz,), 7.88 (d, 2H, J = 8.5 Hz,), 8.13 (d, 1H, J = 9.8 Hz,). LCMS m/z:
390 (M þ 1).
2-Benzyl-6-{4-[3-((R)-2-Methylpyrrolidin-1-yl)propoxy]-
phenyl}-2H-pyridazin-3-one (19e). Yield 88% free base, purity
96%. Mp 228ꢀ230 ꢀC (HCl salt, MeOHꢀether). 1H NMR (DMSO-d6,
δ): 1.37 (d, 3H, J = 6.2 Hz), 1.62 (m, 1H), 1.94 (m, 2H), 2.15 (m, 3H),
3.12 (m, 2H), 3.44 (m, 2H), 3.62 (m, 1H), 4.13 (t, 2H, J = 5.8 Hz), 5.31
(s, 2H), 7.07 (m, 3H), 7.31 (m, 3H), 7.35 (d, 2H, J = 4.1 Hz), 7.85 (d,
2H, J = 8.7 Hz), 8.04 (d, 1H, J = 9.5 Hz), 9.53 (broad s, 1H). LCMS m/z:
404 (M þ 1).
2-Methyl-6-[4-(3-piperidin-1-yl-propoxy)phenyl]-2H-pyr-
idazin-3-one (20a). Yield 71%, purity 98%. Mp 200ꢀ201 ꢀC (HCl
1
salt, MeOHꢀether). H NMR (CDCl3, δ): 1.58ꢀ161 (br m, 6H),
2.00ꢀ2.04 (m, 2H), 2.4 (b, 4H), 2.47ꢀ2.51 (m, 2H), 3.86 (s, 3H), 4.06
(m, 2H), 6.95ꢀ7.0 (m, 3H), 7.63 (d, 1H, J = 9.7 Hz), 7.70 (d, 2H, J =
7 Hz). LCMS m/z: 328 (M þ 1).
6-{4-[3-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)propoxy]-
phenyl}-2-methyl-2H-pyridazin-3-one Hydrochloride (20b).
Yield 53%, purity 99%. Mp 169 ꢀC (HCl salt, acetonitrileꢀhexanes). 1H
NMR (DMSO-d6 δ): 1.78 (broad m, 1H), 1.90 (broad m, 1H), 2.07
(broad m, 1H), 2.10 (broad m, 1H), 2.25 (broad m, 2H), 3.09ꢀ3.20
(broad m, 2H), 3.58 (broad m, 3 H), 3.68 (m, 1H), 3.72 (s, 3H), 3.78
4789
dx.doi.org/10.1021/jm200401v |J. Med. Chem. 2011, 54, 4781–4792