CHART 1
Gr een Ch em istr y Ap p r oa ch to th e
Syn th esis of N-Su bstitu ted P ip er id on es
Margaret M. Faul, Michael E. Kobierski, and
Michael E. Kopach*
Lilly Research Laboratories, A Division of Eli Lilly and
Company, Chemical Process Research and
Development Division, Eli Lilly and Co.,
Indianapolis, Indiana 46285-4813
kopach_michael@lilly.com
Received December 13, 2002
Abstr a ct: An efficient green chemistry approach to the
synthesis of N-substituted piperidones and piperidines was
developed and applied to the synthesis of 1-(2-pyridinyl-
methyl)-piperidin-4-one, 1, a key starting material for the
synthesis of LY317615, an antiangiogenic agent currently
under development at Eli Lilly and Company (Chart 1).1 The
general utility of this methodology, which presents signifi-
cant advantages over the classical Dieckman approach to
this class of compounds, was also demonstrated by the direct
synthesis of a series of substituted piperidones and pip-
eridines, including potential dopamine D4 receptor antago-
nists 2 and 3, that have been evaluated in the clinic as
antipsychotic agents (Chart 2).2
CHART 2
SCHEME 1
To support clinical evaluation of LY317615, multiki-
logram quantities of 1-(2-pyridinyl-methyl)-piperidin-4-
one, 1, were required (Chart 1). A synthesis of 1 in 50%
yield was reported by Hosken via a classical three-step
sequence, involving a bis-Michael addition of 2-(amino-
methyl)-pyridine, 4, with ethyl acrylate, 5, to generate 6
followed by Dieckman cyclization and base-catalyzed
decarboxylation (Scheme 1).3 This method represents the
most general approach to the synthesis of N-substituted
piperidones reported in the literature.4
Our initial scale-up of the Dieckman cyclization se-
quence to produce kilogram quantities of 1 resulted in
significant processing problems that included (1) a need
for a large excess of ethyl acrylate (7 equiv) to ensure
complete formation of the bis-Michael adduct 6; (2) long
reaction times (7-10 days); (3) a need to completely
remove residual ethyl acrylate from 6 prior to the
Dieckman cyclization, otherwise the yield and quality of
1 were significantly reduced; and (4) significant problems
in isolation of 1, following decarboxylation, and partition-
ing of 1 into organic solvents proved to be a significant
challenge due its high aqueous solubility. In fact, five
extractions of the aqueous layer with CH2Cl2 were
required to achieve efficient isolation of 1 in 70% yield.5
Furthermore, a competing side reaction with CH2Cl2
produced a troublesome chloroiminium salt impurity.6
Overall the Dieckman process for preparing 1 was
inefficient and required multiple solvents and cumber-
some aqueous workups. In addition, the dilute reaction
conditions required for scale-up resulted in large genera-
tion of solvent and reagent waste streams that were
environmentally undesirable.
An alternate approach to N-substituted piperidones
developed by Kuehne has some advantages over the
classical Dieckman conditions.7 Mainly, the troublesome
bis-Michael addition is avoided since the desired piperi-
done is prepared by an exchange reaction between 4-oxo-
piperidinium iodide, 7, and a primary amine (Scheme 2).
However, shortcomings of this approach are (1) exchange
reactions frequently do not go to completion; (2) the
approach is not applicable to systems where quaternary
amine salts cannot be easily formed; and (3) it lacks the
* Corresponding author.
(1) (a) Faul, M. M., Gillig, J . R.; J irousek, M. R.; Ballas, L. M.;
Schotten, T.; Kahl, A.; Mohr, M. Bioorg. Med. Chem. Lett. 2003, 13,
1857. (b) Faul, M. M.; Grutsch J . L.; Kobierski, M. E.; Kopach, M. E.;
Krumrich, C. A.; Staszak, M. A.; Sullivan, K. A.; Udodong, U.; Vicenzi,
J . T. Tetrahedron. In press.
(2) (a) Belliotti, T. R.; Blankley, C. J .; Kestemn, S. R.; Wise, L. D.;
Wustrow, D. J . U.S. Patent 5,945,421, August 31, 1999. (b) Maryanoff,
C. A.; Reitz, A. B.; Scott, M. K. U.S. Patent, 8 pp, Continuation-in-
part of U.S. Patent 5,314,885.
(3) Hosken, G. D.; Hancock, R. D. J . Chem. Soc., Chem. Comm. 1994,
1363.
(4) (a) Schaefer, J . P.; Bloomfield J . J . Org. React. 1967, 15, 1. (b)
McElvain, S. M. J . Am. Chem. Soc. 1926, 48, 2179. (c) Leonard; N. J .;
Barthel, E., J r. J . Am. Chem. Soc. 1950, 72, 3632. (d) McElvain, S.
M.; Stork, G. J . Am. Chem. Soc. 1946, 68, 1049. (e) Reed; Cook. J .
Chem. Soc. 1945, 399. (f) Dickerman; Lindwall. J . Org. Chem. 1949,
14, 530. (g) Bolyard, N. W.; McElvain, S. M. J . Am. Chem. Soc. 1929,
51, 922. (h) Elpern, B.; Wetterau, W.; Carabateas, P.; Grumbach, L.
J . Am. Chem. Soc. 1958, 80, 4916.
(5) Partition coefficients: CH2Cl2 k ) 8.6, EtOAc k ) 0.9, MTBE k
) 0.8.
(6) Hansen, S. H.; Nordholm, L. J . Chromatogr. 1981, 204, 97.
(7) (a) Kuehne, M.E.; Muth R. S. J . Org. Chem. 1991, 56, 2701. (b)
Kuehne, M.E.; Matson, P. A.; Bornmann, W. G. J . Org. Chem. 1991,
56, 513. (c) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.;
Dolling, U.; Frey, L.; Karady, S., Shi, Y.; Verhoeven, T. R. J . Org. Chem.
1995, 60, 4324. (d) Tortolani, D.; Poss, M. Org. Lett 1999, 1, 1261.
10.1021/jo026848i CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003
J . Org. Chem. 2003, 68, 5739-5741
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