A convenient one-pot synthesis of 1,8-naphthyridones

Article abstract of DOI:10.1021/jo034321f

In this paper, we disclose an efficient one-pot procedure for the preparation of substituted 1,8-naphthyridin-4-one analogues. Previous efforts to effect this type of transformation were complicated by the formation of benzene tricarboxylate. Via the use of excess base, the impurity formation was completely inhibited. This allowed for the clean preparation of the desired intermediate and subsequent formation of naphthyridone analogues in a single flask, which could then be crystallized directly from the reaction mixture in good yield and high purity.

Full text of DOI:10.1021/jo034321f

SCHEME 1
A Con ven ien t On e-P ot Syn th esis of
1,8-Na p h th yr id on es
Shawn A. Springfield,* Karen Marcantonio,
Scott Ceglia, J ennifer Albaneze-Walker,
Peter G. Dormer, Todd D. Nelson, and J erry A. Murry
SCHEME 2
Department of Process Research, Merck & Co. Inc.,
P.O. Box 2000, Rahway, New J ersey 07065-0900
shawn_springfield@merck.com
Received March 11, 2003
Abstr a ct: In this paper, we disclose an efficient one-pot
procedure for the preparation of substituted 1,8-naphthyri-
din-4-one analogues. Previous efforts to effect this type of
transformation were complicated by the formation of ben-
zene tricarboxylate. Via the use of excess base, the impurity
formation was completely inhibited. This allowed for the
clean preparation of the desired intermediate and subse-
quent formation of naphthyridone analogues in a single
flask, which could then be crystallized directly from the
reaction mixture in good yield and high purity.
that involves the condensation of 2-chloronicotinoyl
chloride with ethyl-3,3-dimethylaminoacrylate followed
by in situ reaction with a variety of anilines to provide
the desired 1,8-naphthyridone in a single flask.
We recently required a facile method for the prepara-
tion of 1,8-naphthyridone analogues on a large scale.
While the existing methodology allowed access to a
variety of these compounds, they suffered from high
temperatures and or messy reaction mixtures that re-
quired tedious purification and were not immediately
amenable to multi-kilogram scale. We envisioned a one-
pot process that would allow for a convenient way of
varying substitution, while providing pure material in
good yield by direct crystallization of the product from
the crude reaction mixture.
Our initial experiments involved heating 2-chloroni-
cotinoyl chloride with dimethylamino acrylate in aceto-
nitrile to provide the desired intermediate (2).10 These
reactions were complicated by the excessive formation
of the corresponding triethyl 1,3,5-benzenetricarboxylate
from trimerization of the acrylate (Scheme 1). We rea-
soned that this reaction was acid catalyzed and investi-
gated the effect of base on the yield of the proposed
reaction. It was found that the amount of trimer was
inversely proportional to the amount of base. By taking
advantage of this observation and using 4 equiv of base,
the trimerization was completely inhibited in acetonitrile
and the 3,3-(dimethylamino)-2-[2-chloronicotinyl]acrylic
acid ethyl ester intermediate (2) was formed in high
purity without the need to isolate. This allowed for the
1,8-Naphthyridin-4-ones are a group of heterocycles
that demonstrate biological activity toward numerous
important targets. As a result there are many recent
examples of preparing these compounds.1
Most of the documented chemistry for the formation
of this particular class of naphthyridones utilizes one of
two common approaches toward their synthesis. The first
method involves the preparation of an alkyl 1-substituted-
2-[2-substituted nicotinyl]acrylic acid ethyl ester inter-
mediate (2), followed by base-catalyzed ring closure to
form the desired naphthyridone. Of the several ways of
preparing this intermediate many are labor intensive.
They require the formation of a 2-substituted pyridinyl
acetate typically prepared via malonic ester acylation
with 2-chloronicotinoyl chloride, followed by decarboxy-
lation and then subsequent reaction with either di-
methylamino dimethyl acetal, triethylorthoformate/acetic
anhydride, or an iminochlorothioformate.2-6 A second
option is to employ the use of a thermal rearrangement/
cyclization that requires temperatures as high as 350
°C.7-9 In this paper, we disclose a new, one-pot method
(1) For a review, see: Stanforth, S. P. Comprehensive Heterocyclic
Chemistry II; Elsevier Science Ltd.: New York, 1996; pp 527-559.
(2) J acquet, J .-P.; Bouzard, D.; Di Cesare, P.; Dolnic, N.; Massoudi,
M.; Remuzon, P. Heterocycles 1992, 34 (12), 2301.
(3) Bouzard, D.; Di Cesare, P.; Essiz, M.; J acquet, J . P.; Ledoussal,
B.; Remuzon, P.; Kessler, R. E.; Fung-Tomc, J . J . Med. Chem. 1992,
35, 518.
(4) Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Gracey, E.
H.; Pernet, A. G. J . Med. Chem. 1986, 29, 2363.
(5) Yoon, S. J .; Chung, Y. H.; Lee, C. W.; Oh, Y. S.; Choi, D. R.;
Kim, N. D.; Lim, J . K.; J in, Y. H.; Lee, D. K.; Lee, W. Y. J . Heterocycl.
Chem. 1997, 34, 1021.
(6) Chu, D. T. W.; Claiborne, A. K. J . Heterocycl. Chem. 1990, 27,
1191.
(7) Hermecz, I.; Horvath, A. J . Heterocycl. Chem. 1992, 29, 559.
(8) Chen, K.; Kuo, S.-C.; Hsieh, M.-C.; Mauger, A.; Lin, C. M.;
Hamel, E.; Lee, K.-H. J . Med. Chem. 1997, 40, 2266.
(9) Hirose, T.; Mishio, S.; Matsumoto, J .-I.; Minami, S. Chem.
Pharm. Bull. 1982, 30, 2399.
(10) Chemistry involving the use of 3,3-dimethylaminoacrylate to
form a 2-benzoylacrylic carboxylate was demonstrated in the follow-
ing: Grohe, K. U.S. Patent 2 699 992, 1987. Bose, P.; Kumar, N.;
Kiyoto, T. W.O. Patent 01 66512 A1, 2001. Neither utilized this
chemistry for preparing 1,8-naphthyridin-4-ones.
(11) HPLC samples were quenched with n-propylamine, and con-
sumption of starting material was considered complete when less than
3 liquid chromatography area percent n-propyl-2-chloronicotinamide
was detected.
10.1021/jo034321f CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003
4598
J . Org. Chem. 2003, 68, 4598-4599

TABLE 1
With a successful one-pot method in hand, we next
decided to investigate the scope of the reaction with
respect to the nature and structure of the aniline (Table
1). Entries a and c demonstrate that both the electron-
poor and electron-rich anilines behaved similarly. Thus,
the electronic nature of the aniline does not seem to affect
the reaction. However, the steric nature of the substi-
tuted anilines affected both reaction rate and yield.
Differentially substituted bromoanilines were investi-
gated in this reaction (entries b, d , and e). While 3- and
4-substitution gave similar yields within ordinary reac-
tion times (∼18 h), the analogous o-bromoaniline, entry
e, which should be electronically similar, required more
time to completely react (∼24 h) and provided a lower
yield. This observation was further supported by the
results of the o-tert-butylaniline, entry f, which gave only
a 26% isolated yield and required more then a week to
completely react.
In conclusion, we have developed a synthetically useful,
operationally simple and general synthesis of 1,8-naph-
thyridin-4-ones that allows for the preparation of a
variety of important naphthyridone intermediates. Im-
portant to the success of this methodology was the
observation of the acid-catalyzed trimerization of the
aminoacrylate, and the need for excess base to inhibit
the formation of this impurity to effect the desired
transformation cleanly. The products were prepared from
readily available starting materials in one pot and were
isolated directly from the reaction mixture in high purity
and in good to moderate yield.
Su p p or tin g In for m a tion Ava ila ble: General procedure
for the preparation of compound 3a and characterization data
for compounds 3a -f. This material is available free of charge
via the Internet at http://pubs.acs.org.
in situ addition of a given aniline to prepare the desired
1,8-naphthyridone.
J O034321F
J . Org. Chem, Vol. 68, No. 11, 2003 4599