Carboxamide CJ -13,454
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 3 725
4-Acetyl-4-(3-flu or o-5-h yd r oxyp h en yl)-3,4,5,6-tetr a h y-
d r o-2H-p yr a n (19). Step 1. 4-Hyd r oxym eth yl-4-[5-(ben zyl-
oxy)-3-flu or oph en yl]-3,4,5,6-tetr ah ydr o-2H-pyr an . Lithium
aluminum hydride (0.16 g, 4.3 mmol) was added in three
portions to a stirred solution of ethyl 4-[5-(benzyloxy)-3-
fluorophenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (24,
1.54 g, 4.3 mmol) in Et2O (150 mL). The resulting suspension
was stirred at room temperature under a nitrogen atmosphere
for 20 min. The excess hydride was hydrolyzed by adding
saturated sodium sulfate. The mixture was diluted with 10%
aqueous sulfuric acid (100 mL), and the layers were separated.
The organic layer was washed with water (100 mL), saturated
aqueous sodium bicarbonate (100 mL), and brine (100 mL),
then dried (MgSO4), and finally concentrated to dryness to
afford the desired compound as white solids (1.28 g, 94%): 1H
NMR (CDCl3) δ 7.44-7.33 (m, 5 H), 6.78-6.58 (m, 3 H), 5.05
(s, 2H), 3.84-3.73 (2m, H), 3.62-3.48 (m, 4 H), 2.13-2.00 (m,
2 H), 1.95-1.82 (m, 2 H), 1.09 (t, 1 H, J ) 7 Hz).
St ep 2. 4-F or m yl-4-[5-(b en zyloxy)-3-flu or op h en yl]-
3,4,5,6-tetr a h yd r o-2H-p yr a n . Tetra-n-propylammonium per-
ruthenate (70 mg, 0.2 mmol) was added to a stirred mixture
of 4-hydroxymethyl-4-[5-(benzyloxy)-3-fluorophenyl]-3,4,5,6-
tetrahydro-2H-pyran (1.28 g, 4.0 mmol), N-methylmorpholine
N-oxide (0.70 g, 6.0 mmol), and powdered 3 Å molecular sieves
(2.0 g) at room temperature under a nitrogen atmosphere.
After 20 min, tetra-n-propylammonium perruthenate (30 mg,
0.085 mmol) and N-methylmorpholine N-oxide (0.30 g, 2.6
mmol) were added and the mixture was stirred for an ad-
ditional 30 min. The mixture was chromatographed (ethyl
acetate-n-hexane (1:3)) to give the desired compound as a
colorless liquid (1.08 g, 86%): 1H NMR (CDCl3) δ 9.38 (s, 1
H), 7.44-7.32 (m, 5 H), 6.70-6.58 (m, 3 H), 5.03 (s, 2 H), 3.89
(ddd, 2 H, J ) 4, 4, 12 Hz), 3.62-3.51 (m, 2 H), 2.38-2.28 (m,
2 H), 2.09-1.97 (m, 2 H).
Step 3. 4-(1-Hyd r oxyeth yl)-4-[5-(ben zyloxy)-3-flu or o-
p h en yl]-3,4,5,6-tetr a h yd r o-2H-p yr a n . A 0.96 M solution of
methylmagnesium bromide (5.3 mL, 5.1 mmol) was added in
a dropwise manner to a stirred solution of 4-formyl-4-[5-
(benzyloxy)-3-fluorophenyl]-3,4,5,6-tetrahydro-2H-pyran (1.08
g, 3.4 mmol) in THF (16 mL) at room temperature under a
nitrogen atmosphere. The mixture was stirred overnight,
diluted with saturated aqueous ammonium chloride (40 mL),
and extracted with dichloromethane (2 × 40 mL). The com-
bined organic layers were washed with water (40 mL) and then
brine (40 mL), dried (MgSO4), and finally concentrated to
dryness. Purification by column chromatography (40-60%
ethyl acetate in n-hexane) afforded the desired compound as
a colorless liquid (0.71 g, 63%): 1H NMR (CDCl3) δ 7.47-7.32
(m, 5 H), 6.73-6.70 (m, 1 H), 6.67-6.60 (m, 2 H), 5.05 (s, 2
H), 3.85-3.75 (m, 2 H), 3.64 (dt, 1 H, J ) 7, 7 Hz), 3.47-3.27
(m, 2 H), 2.28-2.20 (m, 1 H), 2.06-2.00 (m, 1 H), 1.93-1.78
(m, 2 H), 1.11 (d, 1 H, J ) 7 Hz), 0.90 (d, 3 H, J ) 7 Hz).
Step 4. 4-(1-Hyd r oxyeth yl)-4-(3-flu or o-5-h yd r oxyp h en -
yl)-3,4,5,6-tetr a h yd r o-2H-p yr a n . The desired compound was
obtained according to the procedure described for the prepara-
tion of 4-(3-fluoro-5-hydroxyphenyl)-4-hydroxy-3,4,5,6-tetrahy-
dro-2H-pyran (15) using 4-(1-hydroxyethyl)-4-[5-(benzyloxy)-
3-fluorophenyl]-3,4,5,6-tetrahydro-2H-pyran: 1H NMR (DMSO-
d6) δ 9.70 (br s, 1 H), 6.60-6.52 (m, 2 H), 6.40 (ddd, 1 H, J )
2, 2, 11 Hz), 4.62 (br d, 1 H, J ) 5 Hz), 3.77-3.61 (m, 2 H),
3.54-3.41 (m, 1 H), 3.30-3.12 (m, 2 H), 2.11-2.00 (m, 1 H),
1.95-1.72 (m, 3 H), 0.70 (d, 3 H, J ) 6 Hz).
3.85 (ddd, 2 H, J ) 4, 4, 12 Hz), 3.59 (ddd, 2 H, J ) 2, 9, 12
Hz), 2.40-2.29 (m, 2 H), 2.19-2.18 (m, 2 H, m), 1.97 (s, 3 H).
Eth yl 4-(3-Flu or o-5-h ydr oxyph en yl)-3,4,5,6-tetr ah ydr o-
2H-p yr a n -4-ca r boxyla te (20). The desired compound was
obtained according to the procedure described for the prepara-
tion of 4-(3-fluoro-5-hydroxyphenyl)-4-hydroxy-3,4,5,6-tetrahy-
dro-2H-pyran (15) using ethyl 4-[5-(benzyloxy)-3-fluorophenyl]-
3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (24): 1H NMR
(CDCl3) δ 6.72-6.62 (m, 2 H), 6.47 (ddd, 1 H, J ) 2, 2, 10 Hz),
5.40 (br s, 1 H), 4.17 (q, 2 H, J ) 7 Hz), 3.98-3.89 (m, 2 H),
3.61-3.49 (m, 2 H), 2.50-2.41 (m, 2 H), 2.00-1.86 (m, 2 H),
1.24, (t, 3 H, J ) 7 Hz).
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Step 5. 4-Acetyl-4-(3-flu or o-5-h yd r oxyp h en yl)-3,4,5,6-
tetr a h yd r o-2H-p yr a n (19). The desired compound was ob-
tained according to the procedure described for the preparation
of 4-formyl-4-[5-(benzyloxy)-3-fluorophenyl]-3,4,5,6-tetrahydro-
2H-pyran using 4-(1-hydroxyethyl)-4-(3-fluoro-5-benzyloxy-
phenyl)-3,4,5,6-tetrahydro-2H-pyran: 1H NMR (CDCl3) δ 6.61
(d, 1 H, J ) 2, 2, 10 Hz), 6.55-6.47 (m, 2 H), 5.90 (br s, 1 H),
(12) Mano, T.; Stevens, R. W.; Ando, K.; Nakao, K.; Okumura, Y.;
Sakakibara, M.; Okumura, T.; Tamura, T.; Miyamoto, K. Design
and synthesis of a novel orally active 5-lipoxygenase inhibitor,
CJ -13,610. Manuscript in preparation.
J M0303554