September 2009
P., Huang B., Sinha U., Park G., Reed A., Scarborough R. M., Zhu
B.-Y., Bioorg. Med. Chem. Lett., 12, 1651—1655 (2002).
8) Jia Z. J., Wu Y., Huang W., Clizbe L. A., Zhang P., Goldman E. A.,
Sinha U., Arfsten A. E., Edwards S. T., Alphonso M., Hutchaleelaha
A., Park G., Scarborough R. M., Zhu B.-Y., Bioorg. Med. Chem. Lett.,
14, 1221—1227 (2004).
9) Jia Z. J., Wu Y., Huang W., Zhang P., Song Y., Woolfrey J., Sinha U.,
Arfsten A. E., Edwards S. T., Hutchaleelaha A., Hollenbach S. J.,
Lambing J. L., Scarborough R. M., Zhu B.-Y., Bioorg. Med. Chem.
Lett., 14, 1229—1234 (2004).
10) Baskin J. M., Wang Z., Org. Lett., 4, 4423—4425 (2002).
11) Levy L. A., Synth. Commun., 13, 639—648 (1983).
12) Zhu Z., Drach J. C., Townsend L. B., J. Org. Chem., 63, 977—983
(1998).
13) Hoey M. D., Dittmer D. C., J. Org. Chem., 56, 1947—1948 (1991).
14) Jung F., Molinc M., Van Den Elzen R., Durst T., J. Am. Chem. Soc.,
96, 935—936 (1974).
15) Charlton J. L., Durst T., Tetrahedron Lett., 25, 5287—5290 (1984).
16) Durst T., Charlton J. L., Can. J. Chem., 64, 246—249 (1986).
17) Attardo G., Wang W., Kraus J.-L., Belleau B., Tetrahedron Lett., 35,
4743—4746 (1994).
1007
water to quench the reaction, followed by addition of 100 ml DCM.
The mixture was stirred for 1 h. The organic phase was separated and
washed with brine twice. The organic phase was dried and concen-
trated in vacuo. The residue was then treated with 10 ml TFA at 50 °C
for 1 h. The mixture was concentrated in vacuo and directly subjected
to reverse phase preparative HPLC to isolate compound 5 (47 mg, 51%
yield). Compound 29 was prepared using the same procedure. Com-
pounds 6 and 30 were prepared using the same procedure without the
TFA treatment step.
22) Compound 5: MS found for C28H22ClFN4O5S2 as [MꢃH]ꢃ 613.2 with
pattern of 1 chlorine; HR-MS (ESI) m/z calcd for [MꢃH]ꢃ 613.0782,
found: 613.0782; 1H-NMR (CD3OD) d: 8.59 (1H, s), 8.13 (1H, d,
Jꢄ2.0 Hz), 7.97 (1H, s), 7.96—7.92 (2H, m), 7.61 (1H, dd, Jꢄ8.4,
2.0 Hz), 7.48—7.44 (2H, m), 7.39 (1H, td, Jꢄ7.6, 1.6 Hz), 7.17 (1H,
dd, Jꢄ7.2, 1.2 Hz), 7.10 (1H, dd, Jꢄ11.2, 1.6 Hz), 7.01 (dd, Jꢄ8.8,
1.6 Hz), 6.92 (1H, s), 3.00 (3H, s), 2.32 (3H, s) ppm. Compound 6:
MS found for C29H23ClFN3O5S2 as [MꢃH]ꢃ 612.2 with pattern of 1
chlorine; HR-MS (ESI) m/z calcd for [MꢃH]ꢃ 612.0830, found:
612.0830; 1H-NMR (CD3OD) d: 8.71 (1H, s), 8.24 (1H, d, Jꢄ2.0 Hz),
8.12 (1H, dd, Jꢄ7.6, 1.6 Hz), 8.08 (1H, s), 8.04 (1H, d, Jꢄ8.8 Hz),
7.74—7.67 (2H, m), 7.61 (1H, td, Jꢄ8.0, 1.6 Hz), 7.36 (1H, dd, Jꢄ7.2,
1.6 Hz), 7.25 (1H, dd, Jꢄ11.2, 2.0 Hz), 7.13 (1H, dd, Jꢄ8.0, 2.4 Hz),
7.04 (1H, s), 3.12 (3H, s), 2.72 (3H, s), 2.43 (3H, s) ppm. Compound
29: MS found for C28H22ClFN4O5S2 as [MꢃH]ꢃ 613.3 with pattern of
1 chlorine; HR-MS (ESI) m/z calcd for [MꢃH]ꢃ 613.0782, found:
613.0782; 1H-NMR (CD3OD) d: 8.63 (1H, s), 8.07 (1H, d, Jꢄ8.8 Hz),
7.99 (1H, d, Jꢄ2.4 Hz), 7.95 (1H, dd, Jꢄ8.0, 1.2 Hz), 7.92 (1H, s),
7.59 (1H, dd, Jꢄ9.2, 2.4 Hz), 7.48—7.44 (2H, m), 7.39 (1H, td, Jꢄ7.6,
1.6 Hz), 7.17 (1H, dd, Jꢄ7.2, 1.2 Hz), 7.10 (1H, dd, Jꢄ11.6, 2.0 Hz),
7.01 (dd, Jꢄ8.4, 1.2 Hz), 6.93 (1H, s), 3.00 (3H, s), 2.32 (3H, s) ppm.
Compound 30: MS found for C29H23ClFN3O5S2 as [MꢃH]ꢃ 612.3
with pattern of 1 chlorine; HR-MS (ESI) m/z calcd for [MꢃH]ꢃ
18) Lucas H. J., Kennedy E. R., Org. Syn., Coll. Vol. II, 351—352 (1943).
19) Preparation of compound 7: To the solution of compound 26A
(430 mg, 1.0 mmol) in 10 ml DMSO were added sodium methane-
sulfinate (Aldrich #433063, 400 mg, 4.0 mmol), copper(I) trifluo-
romethanesulfonate benzene complex (Aldrich #407240, 250 mg,
0.5 mmol) and N,Nꢀ-dimethylethylenediamine (55 ml, 0.5 mmol). The
mixture was stirred for 3 h in 115 °C bath. After cooling to RT, the
mixture was treated with 10 ml 1N HCl solution for a few minutes. The
mixture was diluted using 250 ml ethyl acetate and washed with brine
three times. The organic phase was dried, concentrated and subjected
to silica flash column using 20% ethyl acetate in hexane to isolate
compound 7 (192 mg, 49% yield). Compound 7B was prepared using
compound 26B by the same procedure.
1
612.0830, found: 612.0842; H-NMR (CD3OD) d: 8.75 (1H, s), 8.17
(1H, d, Jꢄ8.4 Hz), 8.11 (1H, dd, Jꢄ8.0, 1.6 Hz), 8.08 (1H, d,
Jꢄ2.0 Hz), 8.03 (1H, s), 7.72—7.66 (3H, m), 7.60 (1H, td, Jꢄ8.0,
1.6 Hz), 7.35 (1H, dd, Jꢄ7.6, 1.6 Hz), 7.25 (1H, dd, Jꢄ11.6, 2.0 Hz),
7.13 (1H, dd, Jꢄ8.0, 2.4 Hz), 7.04 (1H, s), 3.11 (3H, s), 2.71 (3H, s),
2.43 (3H, s) ppm. The ESI-HR-MS experiments were performed by
HT Laboratories, Inc., 9823 Pacific Heights Blvd, Suite F, San Diego,
CA 92121, U.S.A.
20) Compound 7: MS found for C18H17ClN2O4S as [MꢃH]ꢃ 393.1 with
1
pattern of 1 chlorine; H-NMR (CDCl3) d: 8.58 (1H, s), 7.98 (1H, d,
Jꢄ2.0 Hz), 7.86 (1H, s), 7.80 (1H, d, Jꢄ8.8 Hz), 7.58 (1H, dd, Jꢄ8.8,
2.0 Hz), 6.82 (1H, s), 4.08 (2H, q, Jꢄ7.0 Hz), 2.96 (3H, s), 2.33 (3H,
s), 1.04 (3H, t, Jꢄ7.0 Hz) ppm; NOE: irradiation at 8.58 ppm caused
positive response at 7.98 (d, Jꢄ2.0 Hz) ppm; irradiation at 7.98 ppm
caused positive response at 8.58 (s) ppm. Compound 7B: MS found
23) Basha A., Lipton M., Weinreb S. M., Tetrahedron Lett., 18, 4171—
4172 (1977).
1
for C18H17ClN2O4S as [MꢃH]ꢃ 393.1 with pattern of 1 chlorine; H-
NMR (CDCl3) d: 8.70 (1H, s), 8.01 (1H, d, Jꢄ8.8 Hz), 7.90 (1H, d, 24) Quan M. L., Liauw A. Y., Ellis C. D., Pruitt J. R., Carini D. J., Bostrom
Jꢄ1.6 Hz), 7.84 (1H, s), 7.63 (1H, dd, Jꢄ8.8, 1.6 Hz), 6.87 (1H, s),
3.01 (3H, s), 4.12 (2H, q, Jꢄ7.0 Hz), 2.38 (3H, s), 1.10 (3H, t,
Jꢄ7.0 Hz) ppm; NOE: irradiation at 8.70 ppm caused positive re-
sponse at 8.01 (d, Jꢄ8.8 Hz) ppm.
L. L., Huang P. P., Harrison K., Knabb R. M., Thoolen M. J., Wong P.
C., Wexler R. R., J. Med. Chem., 42, 2752—2759 (1999).
25) The fXa IC50 values were determined by the method described in:
Sinha U., Ku P., Malinowski J., Zhu B. Y., Scarborough R. M., Mar-
lowe C. K., Wong P. W., Lin P. H., Hollenbach S. J., Eur. J.
Pharmacol., 395, 51—59 (2000).
26) The fXa Ki values were determined by the method described in: Betz
A., Wong P. W., Sinha U., Biochemistry, 38, 14582—14591 (1999).
27) For description of our human plasma-based thrombin generation assay,
see: Sinha U., Lin P. H., Edwards S. T., Wong P. W., Zhu B., Scarbor-
ough R. M., Su T., Jia Z. J., Song Y., Zhang P., Clizbe L., Park G.,
Reed A., Hollenbach S. J., Malinowski J., Arfsten A. E., Arterioscler.
Thromb. Vasc. Biol., 23, 1098—1104 (2003). This is an in vitro func-
tional assay run in human plasma to measure the overall anticoagulant
activity of a fXa inhibitor. The assay result (2ꢂTG) is expressed by the
required concentration of this inhibitor to extend the time for reaching
the maximum thrombin generation point by one fold. The targeted
2ꢂTG values for our fXa inhibitors were 1.0 mM or less.
21) Preparation of compound 5: Ethyl ester 7 (60 mg, 0.15 mmol) and ani-
line 27 (100 mg, 0.31 mmol) were dissolved in 10 ml dichloromethane
(DCM). To this solution was added trimethylaluminum (2.0 M solution
in hexane, Aldrich #268569, 0.45 ml, 0.90 mmol), and the mixture was
stirred for 1 d at RT. To it was carefully added 10 ml of a saturated so-
lution of Rochelle’s salt (potassium sodium tartrate tetrahydrate) in