3
in 67% yield (two steps) by employing the same two step
sequences used for the preparation of (R)-mexiletine (1).
Subsequently, palladium carbon catalyzed controlled reductive
ring opening of R-8 [H2 (50 psi), 10 % Pd/C, MeOH, 45 min.]
afforded the amine derivative R-9 in 72 % yield. To introduce,
chloroethyl moiety on nitrogen, we first alkylated the secondary
amine R-9 with ethylbromoacetate in the presence of potassium
carbonate as a base to obtain a tertiary amine product R-10 in
66% yield. Finally, compound R-10 was reduced using lithium
aluminiumhydride to give amino alcohol R-11 in which the
hydroxyl group was replaced by a chloride using thionyl chloride
to afford (R)-Phenoxybenzamine. HCl (2) in over all yield 10.5%
(ee >99%). The structure of (R)-phenoxybenzamine. HCl (2) was
confirmed by means of IR, 1H NMR, 13C NMR and mass
spectroscopic analysis.
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Conclusion:
In conclusion, we have developed a concise and efficient route
for the synthesis of active enantiomer of antiarrhythmic drug (R)-
mexiletine (1) and an antihypertensive agent (R)-
phenoxybenzamine. HCl (2) via controlled reductive ring
opening of chiral aziridine intermediate as a key step. Simple
procedures, ready availability of the starting materials and good
overall yields are some of the salient features of this approach.
Further, this strategy is being exploited for the preparation of
other optically active mexiletine and phenoxybenzamine
analogues, in our laboratory.
Acknowledgements
V.N. thanks the UGC, New Delhi for a research fellowship. The
authors thank Dr. Pradeep Kumar for his constant support and
Mrs. S. S. Kunte for chiral HPLC analysis. Financial support
from the CSIR Network projects (CSC0130, CSC0108 and
BSC0121) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at
8. (a) Mujahid, M.; Kunte, S. S.; Muthukrishnan, M.
Tetrahedron Lett., 2014, 55, 3223; (b) Reddi, A.; Mujahid,
M.; Sasikumar, M.; Muthukrishnan, M. Synthesis, 2014, 46,
1751; (c) Mujahid, M.; Muthukrishnan, M. Chirality, 2013,
25, 965; (d) Mujahid, M.; Mujumdar, P.; Sasikumar, M.;
Kunte, S. S.; Muthukrishnan, M. Tetrahedron: Asymmetry,
2012, 23, 1512; (e) Muthukrishnan, M.; Mujahid, M.;
Sasikumar, M.; Mujumdar, P. Tetrahedron: Asymmetry,
2011, 22, 1353.
9. (a) Nikalje, M. D.; Sasikumar, M.; Muthukrishnan, M.
Tetrahedron: Asymmetry, 2010, 21, 2825; (b) Sasikumar, M.;
Nikalje, M. D.; Muthukrishnan, M. Tetrahedron: Asymmetry,
2009, 20, 2814; (c) Muthukrishnan, M.; Garud, D. R.; Joshi,
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R.A.; Garud, D.R.; Muthukrishnan, M.; Joshi, R.R.; Gurjar,
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