41 indicated some erosion of chiral integrity had occurred
(d.r. = 86:14 as determined by chiral HPLC). Efforts are
ongoing in our laboratory to identify alternative base catalysts
for use with this substrate class which minimize epimerization.
We also examined alternative phosphazene bases in the
reaction (Figure 3).14 The bases P1-tBu (42) and BTPP (43)
are around a third of the price of 6 and may offer a cost-
effective alternative when conducting these reactions on a
larger scale.14 Using either P1-tBu or BTPP for the con-
version of 1 to 3 under the optimized conditions developed
above furnished the desired product in 93 and 82% yields,
respectively.
Figure 4. Preparation of an AMPA receptor potentiator.
known amino alcohol 4718 and 38 which furnished the
protected amide intermediate 48 in 70% isolated yield,
illustrating an example of the process using a secondary
alcohol moiety. Subsequent acidic cleavage of the Boc
group delivered the active entity in 75% yield.
Figure 3. Alternative phosphazene bases examined.
In the last phase of our study, we sought to apply our
methodology to the preparation of some medicinally
relevant compounds. In the first instance, we targeted the
synthesis of the R-amino-3-hydroxy-5-methylisoxazole-4-
propionic acid (AMPA) receptor potentiator Org 26576
(46, Figure 4),15 a nootropic agent in clinical trials for
Attention Deficit Hyperactivity Disorder. An unpro-
tracted route starting from the commercially available
nicotinic derived methyl ester 44 and (S)-prolinol (14)
afforded the requisite intermediate amide 45 in 87%
yield (which increases to 98% when carrying out the reac-
tion at 40 °C).
Figure 5. Synthesis of midodrine.
In summary, through reaction screening and statistically
drivenoptimization we have developed a robust and highly
general set of conditions for the base-mediated synthesis of
amido alcohols. In addition, we have been able to exem-
plify the methodology in the preparation of bioactive
compounds and anticipate it can be further utilized in this
valuable context. Current work is focused on enhancing
the substrate scope of the reaction, identification of addi-
tional base catalysts, and the mechanistic aspects of the
process, and these will be reported in due course.
In a previous synthesis,16 nicotinamide derivative 45 was
prepared using the corresponding nicotinic acid derivative
with stoichiometric amounts of the coupling reagent N,N0-
dicyclohexylcarbodiimide (DCC) combined with the ad-
ditive 1-hydroxybenzotriazole (HOBt) in 86% yield, de-
monstrating the comparative utility of the current method.
Following the base mediated amide formation subsequent
SNAr chemistry realized the target compound 46 in 97%
yield.
Acknowledgment. We thank the EPSRC and Astra-
Zeneca for financial support and are indebted to Professor
W. J. Kerr, Dr A. J. B. Watson, and Professor N. C. O.
Tomkinson (University of Strathclyde) for invaluable dis-
cussions. We are also grateful to the EPSRC National
Mass Spectrometry Service (Swansea, U.K.) for the provi-
sion of high resolution mass spectra.
In a second example, we targeted the synthesis of the
R1-receptor agonist midodrine 49 (Figure 5) which is utilized
clinically for the treatment of orthostatic hypotension.17
concise synthetic route was implemented starting from the
A
(15) Bursi, R.; Erdemli, G.; Campbell, R.; Hutmacher, M. M.;
Kerbusch, T.; Spanswick, D.; Jeggo, R.; Nations, K. R.; Dogterom,
P.; Schipper, J.; Shahid, M. Psychopharmacology 2011, 218, 713.
(16) Schultz, A. G.; Flood, L.; Springer, J. P. J. Org. Chem. 1986, 51,
838.
(17) Oldenburg, O.; Kribben, A.; Baumgart, D.; Philipp, T.; Erbel,
R.; Cohen, M. V. Curr. Opin. Pharmacol. 2002, 2, 740. Compound 49 is
marketed as the racemate.
(18) Epifani, E.; Lapucci, A.; Macchia, B.; Macchia, F.; Tognetti, P.;
Breschi, M. C.; Del Tacca, M.; Martinotti, E.; Giovannini, L. J. Med.
Chem. 1983, 26, 254. Compound 47 is commercially available from
Fluorochem UK, Ltd.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all products. This
material is available free of charge via the Internet at
The authors declare no competing financial interest.
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