10.1002/cmdc.201700447
ChemMedChem
FULL PAPER
detection: UV 254 nm]: tR (min): 13.4–15.6 (enantiomer 1: compound 32;
ESI-HRMS: m/z [M + H]+ calcd for C18H19FN5O2S: 388.1243, found:
388.1241), 15.6–18.5 (enantiomer 2: BAY 1143572).
physicochemical properties. M. Bergmann and K. Greenfield are
acknowledged for valuable technical support with the manuscript.
The activities of the LDC have been co-funded by the Max-
Planck Foundation, on behalf of the Max-Planck Society, as well
as by a grant from the Ministry for Research and Technology
(BMBF, grant number 0315326).
(R)-4-(4-Fluoro-2-methoxyphenyl)-N-{3-[(S-methylsulfonimidoyl)-
methyl]phenyl}-1,3,5-triazin-2-amine (BAY 1143572)
Mp: 165 °C; []58920 = –14.0 ± 0.40 (c = 1 in DMSO); 1H NMR (600 MHz,
[D6]DMSO): = 2.81 (br s, 3H), 3.57 (s, 1H), 3.88 (br s, 3H), 4.29–4.40
(m, 2H), 6.90 (td, 1H), 7.09 (dd, 1H), 7.13 (d, 1H), 7.36 (t, 1H), 7.62–8.09
(m, 3H), 8.75–8.83 (m, 1H), 10.34 ppm (s, 1H); 13C NMR (125 MHz,
[D6]DMSO): = 40.9, 56.2, 62.3, 100.4, 106.7, 120.2, 122.8, 122.9, 125.8,
128.4, 130.9, 133.2, 138.5, 160.0, 163.1, 164.5, 166.2, 171.1 ppm; IR
Keywords: PTEFb • CDK • antitumor agents • sulfoximines •
drug design
References:
(KBr): = 3325–3246, 3013, 2960–2918, 1616–1403, 1284–1103 cm–1
;
ESI-HRMS: m/z [M + H]+ calcd for C18H19FN5O2S: 388.1243, found:
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388.1246.
(R)-N-[(3-{[4-(4-Fluoro-2-methoxyphenyl)-1,3,5-triazin-2-yl]amino}-
benzyl)(methyl)oxido-6-sulfanylidene]acetamide (33)
Acetyl chloride (22 mg, 0.28 mmol) was added dropwise to a solution of
BAY 1143572 (100 mg, 0.26 mmol) in TEA (31 mg, 0.31 mmol) and DCM
(3.0 mL) at 0 °C. The ice bath was removed and the mixture was stirred
at RT for 3 h. Then, the mixture was diluted with water and extracted with
DCM (3 ×). The combined organic phases were filtered using a Whatman
filter and concentrated. The residue was purified by preparative HPLC
(acidic conditions) to give 33 as a white solid (63 mg, 0.15 mmol, 57%):
1H NMR (600 MHz, [D6]DMSO): = 2.14 (s, 3H), 3.05 (s, 3H), 3.94 (s,
3H), 4.67 (d, 1H), 4.80 (d, 1H), 6.74–6.83 (m, 2H), 7.17 (d, 1H), 7.42 (t,
1H), 7.82 (br s, 2H), 7.97 (br s, 1H), 8.03 (br s, 1H), 8.83 ppm (s, 1H);
ESI-HRMS: m/z [M + H]+ calcd for C20H21FN5O3S: 430.1349, found:
430.1346.
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X-ray structure determination of 33
Single crystals of 33 were obtained by slow evaporation of an ethyl
acetate solution of 33 at RT. A single crystal was mounted on a
CryoLoop using inert oil. Data collection was carried out using a Bruker
diffractometer equipped with an APEX II CCD area detector, an IS
microsource with Cu K radiation, mirrors as monochromator and a
Kryoflex low temperature device (T = 110 K). The program APEX II
v.2011.8-0 was used for data collection and reduction.[29] Absorption
correction and scaling was performed using SADABS.[30] The crystal
structure solution was achieved using direct methods as implemented in
SHELXTL version 6.14[31] and visualized using the XP program[31]
.
Missing atoms were subsequently located from difference Fourier
synthesis and added to the atom list. Least-squares refinement on F2
using all measured intensities was carried out using the program
SHELXTL version 6.14.[31] All non-hydrogen atoms were refined including
anisotropic displacement parameters. Final data collection and structure
refinement parameters: = 1.54178 Å, T = 110 K, space group = P2(1),
a = 10.3041(8) Å, b = 7.9030(9) Å, c = 12.8716(11) Å , = 108.990(5)°, Z
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= 2, reflections collected = 6794, independent reflections = 1261 (Rint
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Acknowledgements
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We thank K. Sauvageot-Witzku, R. Golde, A. Glowczewski, C.
Pakebusch, N. Gallus and R. Droschinski for technical support,
O. Schenk for HPLC separations, S. Gründemann and G. Depke
for analytical support, and U. Ganzer for the measurement of
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16
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