Organic Chemistry of Drug Synthesis. Volume 7

enantiomer of this compound is far more active than its antipode both
in vitroandin vivo. One of several methods for preparing the substituted
thiazole^25 comprises displacement of the mesylate group in benzothiazole
( 173 ) by the free amine in protected aminopiperidine ( 172 ). Hydrolysis
then removes the protecting group to reveal the free piperidine amine
( 175 ). In a convergent step, the anion from difluorophenol ( 176 ) is reacted
with chiral epichlorohydrin ( 177 ) to afford 178. This reaction proceeds
with overall retention of configuration whether initial attack is on chlorine
or the epoxide. Reaction of this intermediate with the piperidine ( 175 )
affords the product with a linkage reminiscent of ab-blocker. This com-
pletes the synthesis of the (S)-isomer oflubeluzole( 179 ).^26

REFERENCES

1. C. Mellin, U.S. Patent 5,854,282 (1998). Note this patent describes the chem-
   istry up to phenol 8. The alkylation step is conjectural though well
   precedented.


2. Anon,Drugs Future 25 , 620 (2000).


3. K.-H. Buchheit, R. Gamse, R. Giger, D. Hoyer, F. Klein, E. Klopner,
   H.-J. Pfannkuche, H. Mattes,J. Med. Chem. 38 , 2331 (1995).


4. E.C. Haley et al.,Stroke 36 , 1006 (2005).


5. R.D. Fabio, A. Cugola, D. Donati, A. Ferari, G. Gariraghi, E. Ratti,
   D.G. Trists, A. Reggiani,Drugs Future 23 , 61, (1998).


6. S.D. Draheim et al.,J. Med. Chem. 39 , 5159 (1996).


7. M.C. Van Zandt et al.,J. Med. Chem. 48 , 3141 (2005).


8. C.P. Miller, H.A. Harris, B.S. Komm,Drugs Future 27 , 117 (2002).


9. Anon,Drugs Future 24 , 367 (1999).


10. P.R. Brodfuehrer et al.,J. Org. Chem. 62 , 9192 (1997).


11. J.C. McKew, S.Y. Tam, K.L. Lee, L. Chen, P. Thakker, F.-W. Sum,
    M. Behnke, B. Hu, J.D. Clark, U.S. Patent 6,797,708 (2004).


12. L. Sun, N. Tran, H. App, P. Hirth, G. McMahon, C. Tan,J. Med. Chem. 41 ,
    2588 (1998).


13. L. Sun et al.,J. Med. Chem. 46 , 1116 (2003).


14. G.P. Stack, R.F. Mewshaw, B.A. Bravo, Y.H. Kang, U.S. Patent 5,962,465
    (1999).


15. P. Hewawasam et al.,Bioorg. Med. Chem. Lett. 12 , 1023 (2002).


16. G.W. Muller, R. Chen, S.-Y. Huang, L.G. Corral, L.M. Wong, R.T. Patterson,
    Y. Chen, G. Kaplan, D.I. Stirling,Bioorg. Med. Chem. Lett. 9 , 1625 (1999).


17. D.C. Dean et al.,J. Med. Chem. 39 ,1767(1996).

160 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING