W.W.K.R.Mederski, M.Germann / Bioorg.Med.Chem.Lett.13 (2003) 3715–3718
3717
Scheme 2. General synthesis of carbamoyl semicarbazide 5a.
potency in comparison to the d-amino acid series
caused us to suspend the synthesis of further 2-alkyl
semicarbazides.
7. Dutta, A. S.; Morley, J. S. J.Chem.Soc,. Perkin Trans.1
1975, 1712.
8. (a) Ronco, K.; Erlenmeyer, H. Helv.Chim.Acta 1956, 39,
1045. (b) Ronco K., Prijs B., Erlenmeyer, H. Helv.Chim.Acta
1956, 39, 1253.
In conclusion, we have described the selective and effi-
cient three step synthesis of a 2-propyl-4-aryl semi-
carbazide and the subsequent condensation to
carbamoyl analogue 5a which gave rise to a moderately
active factor Xa inhibitor. Although some more alkyl
derivatives have been prepared the application to other
2-alkyl and/or 4-aryl compounds has to be confirmed.
9. O’Donnell, M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron
Lett. 1978, 30, 2641.
10. Schreder, M. E.; Erker, T. J.Heterocyclic Chem. 2000, 37, 349.
11. Experimental procedure for 1-diphenlymethylen-4-[4-(3-
oxo-4-morpholinyl)-phenyl]-semicarbazide 10: A mixture of 4-
(4-amino-phenyl)-morpholin-3-one 7 (2.0 g, 10.4 mmol), 4-
nitro-phenyl chloroformate (2.1 g, 10.4 mmol), pyridine (0.84
mL, 10.4 mmol), and dichloromethane (50 mL) was stirred at
ambient temperature for 1 h. This mixture was treated with
benzophenone hydrazone 9 (2.04 g, 10.4 mmol) and ethyl-di-
isopropyl-amine (5.3 mL, 31.2 mmol). The resulting suspen-
sion was allowed to stir at room temperature for 2 h. On
diluting with ethyl acetate (100 mL) the organic phase was
washed with sodium hydroxide (0.5 N, 100 mL) and dried over
sodium sulfate. The organic solution was evaporated under
reduced pressure and the residue was purified by recrystalliza-
tion from ethyl acetate to yield 10 (3.94 g, 79%) as a colourless
solid: mp 241–243 ꢀC; 1H NMR (DMSO-d6) d 9.20 (s, 1H),
8.71 (s, 1H), 7.65–7.54 (m, 5H), 7.56 (d, J=8.9 Hz, 2H), 7.40–
7.31 (m, 5H), 7.29 (d, J=8.9 Hz, 2H), 4.18 (s, 2H), 3.96 (dd,
J=3.8 and 4.7 Hz, 2H), 3.70 (dd, J=3.8 and 4.9 Hz); MS (EI)
m/z 414 (8, M+), 165 (100). HRMS calcd for C24H22N4O3
(M+) m/e 414.1692, found m/e 414.1687.
References and Notes
1. (a) Harker, L. A.; Hanson, S. R.; Kelly, A. B. Thromb.
Haemostasis 1995, 74, 464. (b) Hara, T.; Yokoyoma, A.;
Tanabe, K.; Ishihara, H.; Iwamoto, M. Thromb.Haemostasis
1995, 74, 635.
2. Ewing, W. R.; Pauls, H. W.; Spada, A. P. Drugs Future
1999, 24, 771.
3. Dorsch, D.; Mederski, W.; Tsaklakidis, C.; Barnes, C.;
Gleitz, J. PCTInt. Appl. WO 0248099. Chem.Abstr. 2002,
137, 47128.
4. (a) Gante, J. Synthesis 1989, 405. (b) Gante, J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699.
5. For the synthesis of compound 7, see: Straub, A.; Lampe,
T.; Pernerstorfer, J.; Perzborn, E.; Pohlmann, J.; Roehrig, S.;
Schlemmer, K.-H. PCTInt. Appl. WO 0300256. Chem.Abstr.
2003, 138, 89797.
6. (a) Shevchenko, V. V.; Vasilevskaya, G. A.; Grekov, A. P.
J.Org.Chem.USSR 1971, 7 (Engl. Transl.), 1175. (b) Zinner,
G.; Dorschner, K. Arch.Pharm 1973, 306, 35.
12. Experimental procedure for 1-diphenlymethylen-4-[4-(3-
oxo-4-morpholinyl)-phenyl]-2-propylsemicarbazide 11: A sus-
pension of semicarbazide 10 (1.0 g, 2.4 mmol) and cesium
carbonate (0.98 g, 3.0 mmol) in acetonitrile (30 mL) was stir-
red at room temperature for 0.5 h. This mixture was treated
with 1-iodo-propane (0.29 mL, 3.0 mmol) and stirred for
additional 7 h. After treatment with cold water (150 mL) the