S. Aki et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2317–2320
2319
media, underwent thioamidation reaction in satisfactory
yields (Table 2, entries 7–10).
2041. (b) Notzel, M. W.; Labahn, T.; Es-Sayed, M.; De Mei-
jere, A. Eur. J. Org. Chem. 2001, 3025. (c) Ito, K.; Glen, S. W.;
Yamada, A.; Toshima, M.; Kato, M. Chem. Abstr. 2001, 135,
180630t. Jpn. Kokai Tokkyo Koho, JP2001 220,375. (d) Ishi-
zuka, N.; Nagata, K.; Yamamori, T.; Sakai, K. Chem. Abstr.
2001, 135, 190413p. Jpn. Kokai Tokkyo Koho, JP2001
233,767. (e) Yu, D. T.; Macina, O. T.; Sircar, I.; Sircar, J. C.;
Riviello, C. M. Chem. Abstr. 2001, 134, 29412g. U.S. Patent,
US6,156,776.
6. (a) Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. Bull. Soc.
Chim. Belg. 1978, 87, 229. (b) Yde, B.; Yousif, N. M.; Ped-
ersen, U.; Thomsen, I.; Lawesson, S.-O. Tetrahedron 1984, 40,
2047. (c) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697 and
references therein.
7. (a) Sastry, S.; Kudav, N. A. Indian J. Chem., Sect. (B)
1979, 18B, 455. (b) Feiring, A. E. J. Org. Chem. 1976, 41, 148.
(c) Papadopoulos, E. P. J. Org. Chem. 1976, 41, 962.
8. Becke, F.; Hagen, H. Chem-Ztg. 1969, 474.
9. These yields were for 1,2-dimethoxybenzene (4b: veratrol),
1,3-dimethoxybenzene (resorcinol dimethyl ether), and anisole
(4c) as starting materials; see: ref 7a.
In conclusion, we have developed a facile and practical
method in good yield for preparing the benzthioamide
derivative 2a, which is the key intermediate for the
synthesis of OPC-6535, by taking advantage of Friedel–
Crafts reaction using potassium thiocyanate in meth-
anesulfonic acid at ambient temperature. This method
could be done by using inexpensive starting materials
and reagents in ordinary reaction vessels and could be
extended to otheractivated aromatic compounds having
alkoxy groups, especially toward the important com-
pounds such as 2c, in the field of medicinal chemistry.
Typical experimental procedure for the preparation of
2a is as follows: Potassium thiocyanate (33.60 g, 345.8
mmol) was added to a solution of 4a (50.00 g, 300.8
mmol) in methanesulfonic acid (371 mL) with ice-cool-
ing bath. After stirring at room temperature (about
30 ꢁC) for 4.3 h, the reaction mixture was poured into
cold water (1.0 L). The precipitates were filtered and
dried to give crude 2a (65.62 g). The crude 2a was
recrystallized from ethyl acetate (522 mL) to give 57.53
g of 2a (85% yield).11 The aqueous filtrate was extracted
with dichloromethane. The combined dichloromethane
extract and mother liquid of the recrystallization was
purified by SiO2 column chromatography (methanol/
dichloromethane=1/20; Rf=0.56, methanol/dichloro-
methane=1/9) to give further 5.39 g of 2a (total 62.92 g,
93% yield).
10. 99.87% purity on HPLC analysis; Column: Tosoh TSKgel
ODS-80Ts; eluent: CH3CN/aqueous 10 mM Na2SO4 solution/
H3PO4 (500/500/1) phase; detection: 254 nm. Flow rate: 1.0
mL/min, Rt=4.0 min.
11. Mp 151.5–153.0 ꢁC (lit.:3b 157–158 ꢁC); IR (KBr): 1271,
1592, 1630, 3273, 3317 cmꢀ1; 1H NMR (300 MHz, DMSO-d6)
d 1.33 (3H, t, J=6.9 Hz), 1.34 (3H, t, J=6.9 Hz), 4.06 (4H, q,
J=6.9 Hz), 6.95 (1H, d, J=9.1 Hz), 7.6 (1H, d, J=1.9 Hz),
7.62 (1H, dd, J=9.6, 1.9 Hz), 9.31 (1H, br.s), 9.64 (1H, br.s);
13C NMR (75 MHz, DMSO-d6) d 14.7, 14.8, 64.0, 64.2, 111.8,
113.1, 121.4, 131.4, 147.1, 151.4, 198.8.
12. Mp 190.5–191.5 ꢁC; IR (KBr): 850, 1270, 1595, 1641, 3336
;
cmꢀ1 1H NMR (300 MHz, DMSO-d6) d 3.79 (3H, s), 3.80
(3H, s), 6.98 (1H, d, J=8.4 Hz), 7.60 (1H, d, J=1.7 Hz), 7.62
(1H, dd, J=8.4, 1.7 Hz), 9.34 (1H, br.s), 9.67 (1H, br.s); 13C
NMR (75 MHz, DMSO-d6) d 55.7, 55.8, 110.7, 111.4, 121.3,
131.5, 147.7, 151.8, 198.8.
Caution: Concerning the use of potassium thiocyanate,
it is reported that cyanic acid is discharged from thio-
cyanic acid when the solution is eitherhot orin high
concentration.17 During our production campaign, no
cyanic acid was detected; however, it is recommended to
prepare an alkaline trap.
13. Mp 151.5–152.0 ꢁC (lit.:3a 148.5–149.5 ꢁC); IR (KBr): 887,
1258, 1597, 1626, 3276, 3365 cmꢀ1 1H NMR (300 MHz,
;
DMSO-d6) d 3.80 (3H, s), 6.95 (2H, d, J=8.8 Hz), 7.96 (2H, d,
J=8.8 Hz), 9.33 (1H, br.s), 9.66 (1H, br.s); 13C NMR
(75 MHz, DMSO-d6) d 55.5, 113.1 (ꢂ 2), 129.5 (ꢂ 2), 131.5,
162.0, 198.8.
1
Acknowledgements
14. This H NMR spectrum was identical with that reported
in lit.; see: Chihiro, M.; Komatsu, H.; Tominaga, M.; Yabuuchi,
Y. Chem. Abstr. 1993, 118, 191726d. WO92 09,586, 1992. It
was recrystallized from toluene to give an analytical sample;
mp 107.7–108.3 ꢁC (lit. 107–109 ꢁC; see: Uhlendorf, J.; Betz-
ing, H.; Winkelmann, J. Chem. Abstr. 1983, 98, 160703e. Ger-
man Patent, DE3,128,452); IR (KBr): 868, 1277, 1518, 1626,
We thank Ms Kyoko Sejiyama at ourAnalytical Sec-
tion forskillful analysis.
3158, 3279, 3328 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.09
;
References and Notes
(1H, dd, J=5.0, 3.9 Hz), 7.51 (1H, dd, J=3.9, 1.1 Hz), 7.57
(1H, dd, J=5.0, 1.1 Hz), ca. 7.15 (1H, br.s), ca. 7.51 (1H,
br.s); 13C NMR (75 MHz, CDCl3) d 126.8, 128.3, 134.0, 144.7,
192.1.
1. (a) Chihiro, M.; Nagamoto, H.; Takemura, I.; Kitano, K.;
Komatsu, H.; Sekiguchi, K.; Tabusa, F.; Mori, T.; Tominaga,
M.; Yabuuchi, Y. J. Med. Chem. 1995, 38, 353. (b) Chihiro,
M.; Komatsu, H.; Tominaga, M.; Yabuuchi, Y. Chem. Abstr.
1994, 121, 9391c. WO93 24,472, 1993.
2. Hantzsch, A.; Weber, J. H. Chem. Ber. 1887, 20, 3118.
3. (a) Taylor, E. C.; Zoltewicz, J. A. J. Am. Chem. Soc. 1960,
82, 2656. (b) Chaudhari, D. T.; Sabnis, S. S.; Patel, M. R.;
Deliwala, C. V. Bull. Haff. Instt. 1976, 4, 8. (c) Lin, P.-Y.; Ku,
W.-S.; Shiao, M.-J. Synthesis 1992, 1219.
4. Aki, S.; Ishigami, M.; Fujioka, T.; Minamikawa, J. Jpn.
Kokai Tokkyo Koho. Chem. Abstr. 2000, 133, 177026d.
JP2000 229,920.
5. Forercent examples, see (a) Einsiedel, J.; Thomas, C.;
Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2000, 10,
1
15. This H NMR spectrum was identical with that reported
in lit.; see (a) Chihiro, M.; Komatsu, H.; Tominaga, M.;
Yabuuchi, Y. Chem. Abstr. 1993, 118, 191726d. WO92 09,586,
1992. (b) Papadopoulos, E. P. J. Org. Chem. 1973, 38, 667. It
was recrystallized from toluene to give an analytical sample;
mp 158.0–159.7 ꢁC (lit. 162–164 ꢁC; see: Papadopoulos, E. P.
J. Org. Chem. 1973, 38, 667.); IR (KBr): 841, 1537, 1630, 3176,
3279, 3332 cmꢀ1; 1H NMR (300 MHz, CDCl3) d 6.31 (1H, dd,
0
J=2.6, 2.6 Hz, H-4 orH-4 ), 6.32 (1H, dd, J=2.6, 2.6 Hz,
0
H-40 orH-4), 6.64 (1H, dd, J=2.6, 1.3 Hz, H-3 orH-3 ), 6.65
(1H, dd, J=2.6, 1.3 Hz, H-30 orH-3), 6.94 (1H, br.s, NH or
2
NH02), 6.98 (1H, br.s, NH02 orNH 2), 7.04 (1H, dd, J=2.6, 1.3
Hz, H-5 orH-5 ), 7.05 (1H, dd J=2.6, 1.3 Hz, H-50 orH-5),
0