N. Harada et al.
chromatography (n-heptane/EtOAc, 90/10 ! 40/60) gave 13 (610 mg,
97%). 1H-NMR (CDCl3): d 1.68 (s, 9H), 2.42 (s, 3H), 3.74 (t, 2H, J = 4.8 Hz),
3.78 (t, 2H, J = 4.8 Hz), 4.18 (t, 2H, J = 4.8 Hz), 4.41 (t, 2H, J = 4.8 Hz), 5.22
(s, 2H), 6.82 (d, 1H, J = 8.8 Hz), 7.30 (d, 1H, J = 8.0 Hz), 7.66 (dd, 1H, J = 2.4
and 8.8 Hz), 7.76 (s, 1H), 7.79 (d, 2H, J = 8.0 Hz), 8.18 (s, 1H). HRMS: Calcd
for C25H31ClN3O7S [(M + H)+] 552.1565, found 552.1576.
Synthesis of {6-[4-(tetrahydro-pyran-2-yloxy)-butoxy]-pyridin-3-yl}-
methanol (8)
Compound 8 was synthesized by the same procedure as for 7 starting from
6 (3 g, 8.58mmol). Chromatographic purification on silica gel (n-heptane/
EtOAc = 70/30 ! 30/70) gave 8 (2.3g, 94%) as a pale yellow oil. 1H-NMR
(CDCl3): d 1.50–1.54 (m, 4H), 1.67–1.87 (m, 6H), 2.99 (br, 1H), 3.41–3.59 (m,
2H), 3.76–3.88 (m, 2H), 4.31 (t, 2H, J= 6.8Hz), 4.57 (s, 3H), 6.70 (d, 1H,
J = 8.8Hz), 7.59 (dd, 1H, J= 2.4 and 8.8Hz), 8.04 (s, 1H).
Synthesis of toluene-4-sulfonic acid 4-[5-(1-tert-butyl-5-chloro-6-
oxo-1,6-dihydropyridazin-4-yloxymethyl)-pyridin-2-yloxy]-butyl
ester (14)
Synthesis of 2-tert-butyl-4-chloro-5-(6-{2-[2-(tetrahydro-pyran-2-
yloxy)-ethoxy]ethoxy}-pyridin-3-ylmethoxy)-2H-pyridazin-3-one (9)
Compound 14 was prepared by the same procedure as 13 from 12
(400 mg, 1.04 mmol). Purification of crude product by silica gel column
chromatography (n-heptane/EtOAc, 95/5) gave 14 (458 mg, 82%).
1H-NMR (CDCl3): d 1.64 (s, 9H), 1.82 (t, 4H, J = 2.8 Hz), 2.44 (s, 3H), 4.10
(s, 2H), 4.09–4.12 (m, 2H), 4.26 (d, 1H, J = 6.0 Hz), 5.21 (s, 2H), 6.74 (d, 1H,
J = 8.4 Hz), 7.33 (d, 2H, J = 7.6 Hz), 7.66 (dd, 1H, J = 2.4 Hz, 8.8 Hz), 7.75
(s, 1H), 7.89 (d, 2H, J = 8.8 Hz), 8.15 (s, 1H). HRMS: Calcd for C25H31ClN3O6S
[(M + H)+] 536.1616, found 536.1626.
To a mixture of 1 (1.43 g, 7.04mmol), 7 (2.3g, 7.74mmol), and PPh3 (2.77 g,
10.6mmol) in THF (100 mL) was added diisopropyl azodicarbooxylate
(2.09mL, 10.6mmol) under an argon atmosphere. After stirring for 16 h
at 25ꢁC, the reaction mixture was supplemented with H2O and extracted
with EtOAc. The organic layer was washed with saturated NaCl, dried over
anhydrous MgSO4, and concentrated under reduced pressure. Sequential
purification by silica gel chromatography (heptane/EtOAc = 90/10–60/40
then CHCl3/CH3OH = 99/1) gave 9 (2.7g, 80%). 1H-NMR (CDCl3): d 1.65
(9H, s), 1.52–1.83 (m, 15H), 3.48–3.50 (m, 1H), 3.60–3.66 (m, 1H), 3.72–3.75
(m, 2H), 3.84–3.91 (m, 4H), 4.48–4.51 (m, 2H), 4.64 (t, 1H, J= 4.0Hz), 5.22
(s, 2H), 6.84 (d, 1H, J = 8.8Hz), 7.65 (dd, 1H, J = 2.4 and 8.8Hz), 7.75 (s, 1H),
8.17 (d, 1H, J= 2.4Hz).
Synthesis of 2-tert-butyl-4-chloro-5-{6-[2-(2-fluoro-ethoxy)-ethoxy]-
pyridin3-ylmethoxy}-2H-pyridazin-3-one (BCPP-EF)
Compound 13 (110 mg, 0.2 mmol) was added to 0.6 mL of TBAF (1.0 mol/
L in THF, 0.6 mmol) and stirred for 16 h at 25ꢁC. After evaporation of the
solvent under reduced pressure, the residue was purified by silica gel
chromatography (n-heptane/EtOAc = 90/10 ! 50/50) to give BCPP-EF
(70 mg, 88%). 1H-NMR (CDCl3): d 1.64 (s, 9H), 3.77 (t, 1H, J = 4.0 Hz), 3.84
(d, 1H, J = 4.0 Hz), 3.89 (t, 2H, J = 4.8 Hz), 4.51–4.54 (m, 3H), 4.65
(d, 1H, J = 4.0 Hz), 5.22 (s, 2H), 6.85 (d, 1H, J = 8.8 Hz), 7.65 (dd, 1H,
J = 2.4 Hz, 8.8 Hz), 7.75 (s, 1H), 8.17 (d, 1H, J = 2.4 Hz). HRMS: Calcd for
Synthesis of 2-tert-butyl-4-chloro-5-{6-[4-(tetrahydro-pyran-2-yloxy)-
butoxy]pyridin-3-ylmethoxy}-2H-pyridazin-3-one (10)
Compound 10 was prepared by the same procedure as for 9 starting
from 8 (2.18 g, 7.74 mmol). Crude product was purified by silica gel
chromatography (heptane/EtOAc = 95/5 ! 60/40) to give 10 (6.2 g,
84%). 1H-NMR (CDCl3): d 1.57 (s, 9H), 1.75 (dd, 2H, J = 6.4, 14.4 Hz), 1.87
(dd, 2H, J = 6.4, 14.4 Hz), 3.73 (t, 2H, J = 6.4 Hz), 4.35 (t, 2H, J = 6.4 Hz),
5.22 (s, 2H), 6.78 (d, 1H, J = 8.8 Hz), 7.66 (dd, 1H, J = 2.4, 8.8 Hz), 7.76 (s,
1H), 8.18 (d, 1H, J = 2.4 Hz).
C
18H24ClFN3O4 [(M + H)+] 400.1433, found 400.1449.
Synthesis of 2-tert-butyl-4-chloro-5-[6-(4-fluoro-butoxy)-pyridin-3-
ylmethoxy]2H-pyridazin-3-one (BCPP-BF)
The BCPP-BF was prepared by the same procedure as BCPP-EF from 14
(70 mg, 0.13 mmol). Crude product was purified by silica gel
chromatography (n-heptane/EtOAc = 97/3 ! 80/20) to give BCPP-BF
(35 mg, 70%). 1H-NMR (CDCl3): d1.64 (s, 9H), 1.81–1.94 (m, 4H), 4.35
(t, 2H, J = 5.8 Hz), 4.46 (t, 1H, J = 5.8 Hz), 4.58 (s, 1H), 5.22 (s, 2H), 6.72
(d, 1H, J = 8.8 Hz), 7.66 (dd, 1H, J = 2.6 and 8.8 Hz), 7.76 (s, 1H), 8.18 (s,
1H). HRMS: Calcd for C18H24ClFN3O3 [(M + H)+] 384.1484, found 384.1500.
Synthesis of 2-tert-butyl-4-chloro-5-{6-[2-(2-hydroxy-ethoxy)-
ethoxy]-pyridin3-ylmethoxy}-2H-pyridazin-3-one (11)
A mixture of 9 (96mg, 7.2mmol) and p-toluene sulfonic acid monohydrate
(2mg, 0.01 mmol) in CH3OH (1mL) was stirred for 16h at 25ꢁC. After
evaporation of the solvent under reduced pressure, chromatographic
purification of the residue on silica gel (heptane/EtOAc= 70/30 ! 20/80)
gave 11 (96.9mg, 99%) as a colorless solid. H-NMR (CDCl3): d 1.64 (s, 9H),
3.65–3.67 (m, 2H), 3.75 (s, 1H), 3.87 (t, 2H, J = 4.8Hz), 4.51 (t, 2H,
J = 4.8Hz), 5.22 (s, 2H), 6.85 (d, 1H, J = 8.4 Hz), 7.67 (dd, 1H, J = 2.0 and
8.4Hz), 7.75 (s, 1H), 8.17 (d, 1H, J= 2.0Hz). Calcd for C18H25ClN3O5
[(M + H)+] 398.1477, found 398.1493.
Synthesis of 2-tert-butyl-4-chloro-5-{6-[2-(2-methoxy-ethoxy)-
ethoxy]-pyridin3-ylmethoxy}-2H-pyridazin-3-one (BCPP-EM)
In a sealed tube, a solution of 11 (80 mg, 0.2 mmol) in 1,4-dioxane (2 mL)
was added to NaH (60% in mineral oil, 12 mg, 0.3 mmol) at 0ꢁC under an
argon atmosphere. 125 mL of CH3I (2 mmol) was added to the solution
and stirred for 1 h at 25ꢁC. After cooling to room temperature, H2O was
added to the reaction mixture and extracted with EtOAc. Organic layer
was washed with saturated NaCl and dried over MgSO4. Evaporation of
the solvent under reduced pressure and purification by silica gel
chromatography (n-heptane/EtOAc = 70/30 ! 30/70) gave BCPP-EM
(62 mg, 75%). 1H-NMR (CDCl3): d 1.64 (s, 9H), 3.38 (s, 3H), 3.65–3.67
(m, 2H), 3.69–3.72 (m, 2H), 3.86 (t, 2H, J = 4.8 Hz), 4.50 (t, 2H, J = 4.8 Hz),
5.22 (s, 2H), 6.84 (d, 1H, J = 8.8 Hz), 7.65 (dd, 1H, J = 2.4 and 8.8 Hz), 7.75
(s, 1H), 8.16 (s, 1H). HRMS: Calcd for C19H27ClN3O5 [(M + H)+] 412.1633,
found 412.1649.
Synthesis of 2-tert-butyl-4-chloro-5-[6-(4-hydroxy-butoxy)-pyridin-
3-ylmethoxy]- 2Hpyridazin-3-one (12)
Compound 12 was prepared by the same procedure as 11 from 10
(126 mg, 0.2 mmol). Chromatographic purification of crude product on
silica gel (heptane/EtOAc = 70/30 ! 30/70) gave 12 (64 mg, 84%) as a
colorless oil. 1H-NMR (CDCl3): d 1.57 (s, 9H), 1.75 (dd, 2H, J = 6.4 and
14.4 Hz), 1.87 (dd, 2H, J = 6.4 and 14.4 Hz), 3.73 (t, 2H, J = 6.4 Hz), 4.35 (t,
2H, J = 6.4 Hz), 5.22 (s, 2H), 6.78 (d, 1H, J = 8.8 Hz), 7.66 (dd, 1H, J = 2.4
and 8.8 Hz), 7.76 (s, 1H), 8.18 (d, 1H, J = 2.4 Hz).
Synthesis of toluene-4-sulfonic acid 2-{2-[5-(1-tert-butyl-5-chloro-6-
oxo-1,6dihydro-pyridazin-4-yloxymethyl)-pyridin-2-yloxy]-
ethoxy}-ethyl ester (13)
Measurement of the distribution coefficient (log D7.4
)
BCPP-EF and BCPP-EM
A mixture of 11 (450 mg, 1.13 mmol), Et3N (1.58 mL, 11.3 mmol), and
4-dimethylamino-pyridine (13.8 mg, 0.11 mmol) in CH2Cl2 (10 mL) was CH3CN solution (500 mL) of BCPP-EF (750 mM) or BCPP-EM (534 mM) was
supplemented with p-toluenesulfonyl chloride (0.32 g, 1.69 mmol) below dispensed into an Eppendorf pipette and evaporated. Each compound
ꢂ10ꢁC and then stirred for 16 h. H2O was added to the reaction mixture was dissolved in 1 ml of octanol, mixed with 1 ml of 0.1 M potassium
and extracted twice with CH2Cl2. The combined organic layer was phosphate buffer (pH 7.4), and vortexed for 5 min. After centrifugation
washed with saturated NaCl, dried over anhydrous MgSO4, and at 12,000 rpm for 5 min, the two phases were separated. The octanol
concentrated in vacuo. Purification of the residue by silica gel column layer was diluted 10-fold with CH3CN, and the buffer layer was directly
J. Label Compd. Radiopharm 2013, 56 553–561
Copyright © 2013 John Wiley & Sons, Ltd.