Organic Process Research & Development
Communication
column chromatography (hexane/ethyl acetate = 100/0 to 0/
Hz, 1H), 8.09 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz,
1H), 4.36 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 6.4 Hz, 2H), 2.77 (s,
3H), 2.23−2.19 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.09 (d, J =
6.8 Hz, 6H).
1
00) to yield 4a (611 mg from the solid and 405 mg from the
filtrate; 91% yield in total) as an off-white solid. The NMR
4
spectrum was consistent with that reported previously.
Second-Generation C−H Arylation: Reaction Screen-
ing (Table 1). Ethyl 2-(3-Cyano-4-isobutoxyphenyl)-4-
methylthiazole-5-carboxylate (4b). To a three-neck flask,
2-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-
carboxylic Acid (Febuxostat, 1). To a three-neck flask were
added 4b (25.0 g, 72.6 mmol), THF (25 mL), and ethanol
(175 mL). The mixture was warmed to 40−50 °C, and 8 N
aqueous NaOH (10.9 mL, 87.1 mmol) was added to the
mixture. The mixture was stirred at the same temperature until
the conversion reached 99.5%. Water (76.2 mL) was added to
the mixture, and the resulting mixture was stirred for 1 h at the
same temperature, followed by quenching with 1 M aqueous
HCl (95.8 mL, 95.8 mmol) to adjust the pH to below 3.5. To
the mixture was added water (62.5 mL) at 60−70 °C, and the
resulting mixture was then heated to the reflux temperature,
stirred for 30 min, and cooled to 30−40 °C. The resulting
slurry was filtered, and the wet cake was washed with warm
3
b (1.71 g, 10.0 mmol), 2 (2.54 g, 10.0 mmol), palladium
catalyst, di-tert-butyl(cyclohexyl)phosphine, additive, K CO
2
3
(
2.90 g, 21.0 mmol), and xylene (10 mL) were added under
2
N . The mixture was stirred at 140−145 °C and periodically
monitored by HPLC.
C−H Arylation: Role of the Reagents (Table 2). Ethyl
-(3-Cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carbox-
2
ylate (4b). N was vigorously flowed into a sealed tube, to
2
which 3b (2.14 g, 12.5 mmol), 2 (2.54 g, 10.0 mmol), PdCl2
(
(
4.4 mg, 0.025 mmol), di-tert-butyl(cyclohexyl)phosphine
22.8 mg, 0.10 mmol), isobutyric acid (8.8 mg, 0.10 mmol),
copper(I) bromide−dimethyl sulfide complex (206 mg, 1.00
mmol), K CO (2.90 g, 21.0 mmol), and/or xylene (7.5 mL)
water (625 mL) and dried in vacuo at 75−85 °C to give 1
1
(22.5 g, 98%) as a whitish solid. H NMR (400 MHz, CDCl
):
3
2
3
were added. The tube was quickly closed, and the mixture was
δ 8.20 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 9.0 Hz, 2.4 Hz, 1H),
7.03 (d, J = 9.0 Hz, 1H), 3.91 (d, J = 6.6 Hz, 2H), 2.80 (s,
3H), 2.23−2.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H).
stirred in an aluminum block at 140 °C for 24 h. CAUTION!
The internal pressure greatly increases because of CO and water
2
evolution! The mixture was diluted and measured by HPLC.
Optimized C−H Arylation: Ethyl 2-(3-Cyano-4-iso-
butoxyphenyl)-4-methylthiazole-5-carboxylate (4b). To
a mixture of potassium tert-butoxide (11.8 g, 105 mmol) and
toluene (100 mL) was added 2-methyl-1-propanol (8.15 g, 110
mmol) dropwise. The mixture was stirred for 5 min, and
approximately two-thirds of the mixture removed at 60 °C
AUTHOR INFORMATION
■
*
ORCID
Notes
under reduced pressure. N was then back-filled into the vessel,
2
and the mixture was stirred in an ice bath. To the resulting
mixture of potassium isobutoxide was added 8 (20.0 g, 100
mmol) in toluene (50 mL) dropwise as the internal
temperature was maintained between 5 and 10 °C. The
mixture was warmed to room temperature and stirred for 2 h.
After reaction completion, the mixture was washed sequentially
with 20 wt % citric acid (50 mL) and water (50 mL, twice).
The resulting organic layer was concentrated at 60 °C under
reduced pressure to give 71.6 g of 2 (53 mL of toluene was
theoretically assayed).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Ms. Miki Murata and Mr. Takahiro Takeuchi for
analytical support and Mr. Tomohide Ida, Dr. Tomohiro
Shimada, Dr. Shiro Kondo, and Mr. Akira Nakano for helpful
discussions.
REFERENCES
■
To the solution of 2 in a three-neck flask with a Dean−Stark
(
1) (a) Osada, Y.; Tsuchimoto, M.; Fukushima, H.; Takahashi, K.;
1
6
trap were added 3b (18.0 g, 105 mmol), PdCl (18 mg, 0.10
Kondo, S.; Hasegawa, M.; Komoriya, K. Hypouricemic Effect of the
Novel Xanthine Oxidase Inhibitor, TEI-6720, in Rodents. Eur. J.
Pharmacol. 1993, 241, 183. (b) Komoriya, K.; Osada, Y.; Hasegawa,
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Hypouricemic Effect of Allopurinol and the Novel Xanthine Oxidase
Inhibitor TEI-6720 in Chimpanzees. Eur. J. Pharmacol. 1993, 250,
2
mmol), di-tert-butyl(cyclohexyl)phosphine (55 mg, 0.24
mmol), isobutyric acid (35 mg, 0.40 mmol), copper(I)
bromide (143 mg, 1.00 mmol), KHCO (21.0 g, 210 mmol),
3
and toluene (23 mL, in addition to the aforementioned 53
mL) under N . After 5 min of stirring at room temperature, the
2
4
55. (c) Horiuchi, H.; Ota, M.; Kobayashi, M.; Kaneko, H.; Kasahara,
mixture was warmed and stirred at the reflux temperature for
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the Hypouricemic Activity and Potency in Renal Xanthine Calculus
Formation of Two Xanthine Oxidase/Xanthine Dehydrogenase
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Inhibitor of Xanthine Oxidoreductase. J. Biol. Chem. 2003, 278, 1848.
1
5 h. After reaction completion, the mixture was cooled to an
internal temperature of 90 °C. The insoluble species were then
filtered off (remaining at this temperature) and washed with
hot toluene (25 mL). The filtrate was then partially
concentrated at 60 °C under reduced pressure. To the
concentrated mixture (53 mL of toluene was assayed),
additional toluene (23 mL) and 90% aqueous EtOH (178
mL) were added. The mixture was dissolved at 85 °C and then
cooled to 60−68 °C, inducing precipitation. The mixture was
stirred at the same temperature for 1 h, cooled to 0 °C over 2
h, and stirred at 0 °C for 1.5 h. The resulting slurry was filtered,
and the wet cake was washed with 80% aqueous EtOH (76
(
e) Takano, Y.; Hase-Aoki, K.; Horiuchi, H.; Zhao, L.; Kasahara, Y.;
Kondo, S.; Becker, M. A. Selectivity of Febuxostat, a Novel Non-
purine Inhibitor of Xanthine Oxidase/Xanthine Dehydrogenase. Life
Sci. 2005, 76, 1835.
(2) (a) Hande, K. R.; Noone, R. M.; Stone, W. J. Severe Allopurinol
Toxicity. Description and Guidelines for Prevention in Patients with
Renal Insufficiency. Am. J. Med. 1984, 76, 47. (b) Mayer, M. D.;
Khosravan, R.; Vernillet, L.; Wu, J.-T.; Joseph-Ridge, N.; Mulford, D.
J. Pharmacokinetics and Pharmacodynamics of Febuxostat, a New
mL) and dried in vacuo at 80 °C to give 4b (31.3 g, 91%) as a
1
whitish solid. H NMR (400 MHz, CDCl ): δ 8.18 (d, J = 2.4
3
E
Org. Process Res. Dev. XXXX, XXX, XXX−XXX