methoxy-1-methylethyl)-1H-1,2,4-triazole-3-carboxylate (5c).
Without further purification 5c was allowed to react with ketone
3 to obtain the corresponding N-protected S-1360 derivative
(6c) with good yield as crystals that were isolated directly by
crystallization from the reaction mixture. The obtained crude
6c was purified by recrystallization from MeOH. The purified
6c was completely deprotected in aqueous acetone at 50–60
°C in the presence of a catalytic amount of acid to afford purified
7 as crystals without further purification.
s), 5.67 (1H, dd, J ) 2.8 and 9.6 Hz), 6.47 (1H, d, J ) ∼4
Hz), 6.93 (1H, s), 7.18 (2H, t, J ) 8.8 Hz), 7.34 (2H, dd, J )
5.5 and 8.7 Hz), 7.53 (1H, d, J ) 3.5 Hz), 8.93 (1H, s). H
NMR (keto): (500 MHz, DMSO-d6) δ 1.58 (2H, m), 1.69 (1H,
m), 1.95 (1H, m), 2.02 (1H, m), 2.12 (1H, m), 3.69 (1H, m),
3.96 (1H, m), 4.15 (2H, s), 4.52 (2H,s) 5.67 (1H, dd, J ) 2.8
and 9.6 Hz), 6.47 (1H, d, J ) ∼4 Hz), 7.18 (2H, t, J ) 8.8
Hz), 7.34 (2H, dd, J ) 5.5 and 8.7 Hz), 7.53 (1H, d, J ) 3.5
Hz), 8.93 (1H, s). 13C NMR (enol): (125 MHz, DMSO-d6) δ
1
The present new protective method has the following
advantages compared with the THP method. (1) Carcinogenic
by-product 9 (R ) Cl) was eliminated. (2) Final crystals of 7
are obtained directly from the reaction mixtures without the
recrystallization procedure. (3) For clinical use the final step
involves filtration to remove insoluble particulates. As a result
of the four times higher solubility of 6c compared to that of 7,
a high concentration procedure (high throughout) was per-
formed. As a result, final recrystallization volume was reduced
by quarter.
21.3, 24.3, 29.2, 32.8, 66.8, 85.2, 94.4, 110.4, 115.3 (d, JC-F
)
21 Hz), 119.7, 130.5 (d, JC-F ) 7.9 Hz), 133.0 (d, JC-F ) 3.0
Hz), 145.3, 148.8, 157.0, 160.7, 161.0 (d, JC-F ) 242 Hz), 171.9,
177.5. 13C NMR (keto): (125 MHz, DMSO-d6) δ 21.3, 24.3,
29.2, 32.8, 49.5, 66.8, 85.2, 110.4, 115.3 (d, JC-F ) 21 Hz),
119.7, 130.5 (d, JC-F ) 7.9 Hz), 133.0 (d, JC-F ) 3.0 Hz), 145.3,
148.8, 157.0, 160.7, 161.4 (dd, JC-F ) 242 Hz), 181.4, 187.3.
IR (ATR) 1625, 1602, 1505, 1453, 1278, 1214, 1195, 1081
cm-1. Anal. Calcd for C21H20FN3O4: C, 63.47; H, 5.07; F, 4.78;
N, 10.57. Found: C, 63.40; H, 4.91; F, 4.41; N, 10.47.
(Z)-1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-
1,2,4-triazol-3-yl)propenone (S-1360). First campaign pro-
cedure. To a stirred slurry of N-protected S-1360 (6b) (25.0
kg, 62.9 mol) and 2-propanol (192.1 kg) was added concentrated
HCl (32.8 kg, 315 mol). The mixture was warmed at 60 °C for
2 h and cooled at 25 °C for 1 h to crystallize. The slurry was
filtered and washed with 2-propanol (98.2 kg) to give hydro-
chloride salt of S-1360 (7·HCl). The obtained wet hydrochloride
salt was dissolved in THF (76.3 kg) and H2O (12 kg), and then
the solution was filtered with a Teflon membrane filter to
remove insoluble particulates. THF (15.3 kg) was added to the
filtrate as a rinse, and H2O (160 kg) was added for crystalliza-
tion. The slurry was stirred at 25 °C for 1 h and at 10 °C for
1 h. The slurry was filtered and washed with H2O (342 kg).
The obtained crystals were dried at 70 °C (jacket temperature)
under vacuum to obtain 16.3 kg of S-1360 (7) in 82.6% yield.
Mp 183 °C (TG-DTA). 1H NMR (enol): (500 MHz, DMSO-
d6) δ 4.15 (2H, s), 6.48 (1H, d, J ) 3.6 Hz), 6.95 (1H, s), 7.18
(2H, t, J ) 8.8 Hz), 7.35 (2H, dd, J ) 5.7 and 8.5 Hz), 7.53
(1H, br), 8.78 (1H, br), 14.73 (1H, brs), 15.6(1H, brs). 1H NMR
(keto): (500 MHz, DMSO-d6) δ 4.09 (2H, s), 4.54 (2H, s), 6.42
(1H, d, J ) 3.6 Hz), 7.16 (2H, t, J ) 8.8 Hz), 7.31 (2H, dd, J
) 5.7 and 8.5 Hz), 7.53 (1H, br), 8.31 (1H, br), 15.2 (1H, br).
13C NMR (enol): (125 MHz, DMSO-d6) δ 32.9, 94.2, 110.5,
115.4 (d, JC-F ) 21 Hz), 119.5, 130.6 (d, JC-F ) 8 Hz), 133.1
Conclusion
The protecting group on the triazole ring is essential for the
Claisen reaction, and a ketal protecting group on the triazole
ring can be completely deprotected compared with the acetal
group. By selection of the protective groups on the triazole ring,
we developed an efficient process for manufacturing 7 that
realizes a high throughput procedure without the need for a
final recrystallization process.
Experimental Section
General. The 1H and 13C NMR spectra were measured on
a Varian Gemini 300 MHz FT NMR spectrometer and/or
Varian Inova 500 MHz FT NMR spectrometer. The FT-IR
spectra were recorded on a Bruker Vertex 70 spectrometer.
Melting points were measured on a Büchi B-545 melting point
apparatus.
1-[5-(4-Fluorobenzyl)-2-furyl]-3-[1-tetrahydropyranyl-
1,2,4-triazol-3-yl]propan-1,3-dione (6b). To a stirred slurry
of ethyl 1H-1,2,4-triazole-3-carboxylate (4) (20 kg, 142 mol),
benzenesulfonic acid hydrate (600 g, 3.41 mol) and dry THF
(53.3 kg) was added 3,4-dihydropyran (13.1 kg, 156 mol)
dropwise while maintaining the reaction temperature under 45
°C, and then THF (8.9 kg) was added as a rinse. The solution
was stirred at 45 °C for 1 h. 5-(4-Fluorobenzyl)-2-furyl methyl
ketone (3) (30.9 kg, 142 mol) was added at 15 °C to the solution,
28% sodium methoxide (35.6 kg, 185 mol) in MeOH was added
dropwise under 25 °C, and then the obtained brownish solution
was stirred at 65 °C for 3 h. MeOH (79.1 kg) was added, and
the mixture was cooled at 15 °C. Aqueous 13.7% acetic acid
solution (92.7 kg, 211 mol) was added dropwise to neutralize
to pH ) 6. The mixture was stirred at 20 °C for 1 h to
crystallize, and then the slurry was stirred at 5 °C for 1 h, filtered
and washed with aqueous 60% MeOH solution (85.3 kg). The
obtained yellow crystals were dried at 45 °C (jacket temperature)
under vacuum to obtain 48.4 kg of N-protected S-1360 (6b) in
85.8% yield. Mp 122.6–123.2 °C. 1H NMR (enol): (500 MHz,
DMSO-d6) δ 1.58 (2H, m), 1.69 (1H, m), 1.95 (1H, m), 2.02
(1H, m), 2.12 (1H, m), 3.69 (1H, m), 3.96 (1H, m), 4.15 (2H,
(d, JC-F ) 3 Hz), 145.4, 148.8, 157.4, 160.5, 161.1 (d, JC-F
)
242 Hz), 173.0, 177.3. 13C NMR (keto): (125 MHz, DMSO-
d6) δ 32.9, 49.6, 109.8, 115.4 (d, JC-F ) 21 Hz), 121.7, 130.6
(d, JC-F ) 8 Hz), 133.0 (d, JC-F ) 3 Hz), 145.4, 150.7, 157.4,
160.6, 161.1 (d, JC-F ) 242 Hz), 181.6, 187.6. IR (KBr)
3100–3200, 1621, 1601, 1510, 1219, 1081, 770 cm-1. Anal.
Calcd for C16H12FN3O3: C, 61.34; H, 3.86; F, 6.06; N, 13.41.
Found: C,61.48; H, 3.83; F, 6.07; N, 13.40.
(Z)-1-[5-(4-Fluorobenzyl)furan-2-yl]-3-hydroxy-3-(1H-
1,2,4-triazol-3-yl)propenone (S-1360). Second campaign pro-
cedure. To a stirred slurry of N-protected S-1360 (6b) (16.5
kg, 41.5 mol) and MeOH (65.2 kg) was added concentrated
HCl (6.5 kg, 62.4 mol), and the mixture was warmed at 60 °C
to dissolve. Additionally, concentrated HCl (15.1 kg, 145 mol)
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