Beilstein J. Org. Chem. 2015, 11, 1509–1513.
Supporting Information
Supporting Information File 1
Experimental procedures, spectroscopic and analytical data,
and copies of NMR spectra for all described compounds.
References
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3. Hand, T. H.; Marek, G. J.; Seiden, L. S. Psychopharmacology (Berlin)
Figure 3: The ORTEP diagram for X-ray analysis of compound (S)-7.
4. van der Burg, W. J.; Gisors, J. D. Polycyclic piperazines. U.S. Patent
US3,534,041, Oct 13, 1970.
In order to obtain standards for HPLC analysis, racemic deriva-
tives 7–10 and 1 were made (Scheme 1). Compounds 7–9 were
insoluble in hexane/2-propanol mixture, a typical mobile phase
for HPLC analysis on an OD-H column. Therefore chromato-
graphic analysis was done for amines 10 and 1 only. For
mianserin satisfactory resolution conditions were found that
confirmed the optical purity of the final product (S)-1 [17].
5. van der Burg, W. J.; Bonta, I. L.; Delobelle, J.; Ramon, C.; Vargaftig, B.
6. Jackson, R. W.; Subasinghe, K. R. Resolution of optically-active
compounds. WO Patent WO99/16769, April 8, 1999.
7. Pawłowska, J.; Czarnocki, Z.; Wojtasiewicz, K.; Maurin, J. K.
Tetrahedron: Asymmetry 2003, 14, 3335–3342.
8. Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Synthesis 2012, 241–246.
The preparation of optically pure amine 7 allows also for its
transformation to epinastine (2). The synthesis is presented in
Scheme 2 and is based on the modified procedure described by
Schneider [18]. The reaction of (S)-(+)-7 with hydrazine led to
derivative 13 with deprotected amine function. Subsequent con-
densation with cyanogen bromide gave (S)-(+)-epinastine (2) in
nearly quantitative yield.
9. ter Laak, A. M.; Venhorst, J.; Donné-Op den Kedler, G. M.;
Timmerman, H. J. Med. Chem. 1995, 38, 3351–3360.
10.Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
11.Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102.
12.Roszkowski, P.; Maurin, J. K.; Czarnocki, Z. Tetrahedron: Asymmetry
13.Roszkowski, P.; Czarnocki, Z. Mini-Rev. Org. Chem. 2007, 4, 190–200.
Conclusion
In summary, we have presented a simple enantioselective syn-
thesis of (S)-(+)-mianserin and (S)-(+)-epinastine. Chirality was
introduced in a key step by asymmetric transfer hydrogenation.
This synthetic procedure could be used for the preparation of
other compounds variously substituted at the aryl rings.
14.Czarnocki, S. J.; Wojtasiewicz, K.; Jóźwiak, A. P.; Maurin, J. K.;
Czarnocki, Z.; Drabowicz, J. Tetrahedron 2008, 64, 3176–3182.
15.Moffett, R. B. J. Heterocycl. Chem. 1980, 17, 341–350.
Scheme 2: Enantioselective synthesis of (S)-(+)-epinastine.
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