Organic Process Research & Development 2007, 11, 885–888
An Alternate Route to 2-Amino-3-nitro-5-bromo-4-picoline: Regioselective Pyridine
Synthesis via 2-Nitramino-picoline Intermediate
,
†
,‡
,§
§
§
§
Apurba Bhattacharya,* Vikram C. Purohit,* Prashant Deshpande,* Annie Pullockaran, John A. Grosso, John D. DiMarco,
§
and Jack Z. Gougoutas
Department of Chemistry, Texas A&M UniVersity-KingsVille, KingsVille, Texas 78363, Department of Chemistry, Texas A&M
UniVersity-College Station, Texas 77842, and Bristol-Myers Squibb Pharmaceutical Institute, 1 Squibb DriVe, New Brunswick,
New Jersey 08903, U.S.A.
Abstract:
to the 3- and 5-nitro isomer during the nitration of 2-amino-
pyridine derivatives. Conceivably, by halting the nitration at
4
The 2-nitramino functionality in 2-nitramino-4-picoline was suc-
cessfully exploited not only as a protecting group but also as a
directional handle to afford an efficient, atom-economic, and
regioselective synthesis of 2-amino-5-bromo-3-nitro-4-picoline (4),
a precursor for a drug candidate in development.
the intermediate 2-nitraminopicoline stage and exploiting the
steric influence of the bulky 2-nitramino functionality, bromine
could be selectively introduced to the 5-position. Subsequent
rearrangement of the resulting 5-bromo-2-nitramino-pyridine
would then produce the desired product provided the integrity
of the 2-nitramino functionality remained intact during the entire
sequence of operations. These expectations were fully realized,
resulting in a simple, efficient, and regioselective synthesis of
Introduction
As part of our ongoing industry–university collaborative
research program, established between Texas A&M
University-Kingsville and the Process R&D department
at Bristol-Myers Squibb Co., we required an expeditious
route to 2-amino-5-bromo-3-nitro-4-picoline (4), a precur-
sor for a key intermediate, starting from the readily
2
-amino-5-bromo-3-nitro-4-picoline (4) whereby the 2-nitra-
mino functionality in the intermediate 2-nitramino-4-picoline
5) served a dual role, not only as a masking group but also as
(
a directional handle (Scheme 2).
1
available 4-picoline (1). Only one synthesis of 4 is
2
known. Our initial bench-scale synthesis for the produc-
Results and Discussion
tion of 4 involved nitration of 2-amino-4-picoline (1),
producing a mixture of 3- and 5-nitro isomers in an
unfavorable 1:4 ratio. Isolation of the desired minor isomer
Initially we had sought to modify the traditional nitration
chemistry of 2-amino-4-picoline (1) in order to optimize the
selectivity of the desired 3-nitro isomer 3. Nitration of 2-amino-
3
by tedious steam distillation (or sublimation) followed
by bromination produced 4, albeit in low (<10%) overall
yield (Scheme 1).
4-picoline (1) utilizing the established procedure (H
2 4
SO 5 g/g
3
of substrate and HNO 1.3 g/g of substrate) proceeded via the
3
In short, this process was encumbered by poor yield,
unwanted byproducts, and a difficult isolation and was not
amenable to pilot plant scale-up.
A hint of a promising solution to this problem was found in
an earlier report by Seide et. al. describing the formation of
corresponding 2-nitramino-4-picoline intermediate 5, which
subsequently underwent acid-catalyzed rearrangement at room
temperature over 60 h, producing as expected the desired 3-
and undesired 5-nitro isomers in a 1:4 ratio. The intermediate
formation was complete in 1 h at 0 °C as evidenced by HPLC
2-nitramino-pyridine as a discrete intermediate that rearranged
2 4
and MS analysis. High dilution conditions (H SO 50 g/g of
substrate and HNO 1.3 g/g of substrate) resulted in improved
3
*
To whom correspondence should be addressed: Email: (A.B.)
kfab002@tamuk.edu; (V.C.P.) vpurohit@mail.chem.tamu.edu; (P.D.)
prashant.deshpande@bms.com.
product selectivity from 1:4 to 1.6:1 in the favor of the
regioisomer 3. The improved ratio under high dilution could
be attributed to an intramolecular mechanism, as has been
†
Texas A&M University-Kingsville.
Texas A&M University-College Station.
Bristol-Myers Squibb Pharmaceutical Institute.
‡
§
5
suggested by some mechanistic studies. Additional optimization
(
1) Process Chemistry Collaboration, Education Concentrate. Chem. Eng.
News 2001, July 23, 41.
studies, involving modification of several reaction variables (e.g.,
(
2) For a patented synthesis of 2-amino-5-bromo-3-nitro-4-picoline (1)
see: Igarashi et al. U.S. Patent 5,290,943, 1992 [EP0530524]. The
synthesis involves protection of the amine function of 2-aminopicoline
via N-acetylation followed by bromination of the resulting NH-acetyl
derivative. Nitration and aqueous hydrolysis of the acetamido group
produced the desired compound.
3) (a) Partial solubility of the product in water made the isolation even
more difficult after the steam distillation. (b) For sublimative isolation
of the product, see: Grozinger, K. G.; Fuchs, V.; Hargrave; Maudlin,
S.; Vitous, J.; Campbell, S.; Adams, J. J. Heterocycl. Chem. 1995,
(4) (a) Seide, O. Chem. Ber. 1924, 57 (791), 1802. (b) Seide, O. J. Russ.
Phys.-Chem. Soc. 1924, 50, 534.
(5) (a) Deady, L. W.; Grimmett, M. R.; Potts, C. H. Tetrahedron 1979,
35, 2895. (b) White, W. N. Mechanism of Molecular Migrations;
Thyaagrajan, B. S., Ed.; Wiley-Interscience: New York, 1971, Vol.
3, p 109. (c) Williams, D. L. H. ComprehensiVe Chemical Kinetics;
Bamford, C. H., Tipper, C. F. H., Eds.; Elsevier: Amsterdam, 1972;
Vol. 31, p 433. (d) Thomas, A.; Tomasik, P.; Herman-Matusiak, G.
Bull. Acad. Polon. Sci., Ser. Sci. Chim. 1975, 23, 311. (e) Kokocinska,
H.; Thomas, A.; Tomasik, P.; Zalewski, R. Bull. Acad. Polon. Sci.
Ser. Sci. Chim. 1976, 24, 535. (f) White, W. N.; Klink, J. R. J. Org.
Chem. 1970, 35, 965.
(
3
2, 259. (c) Marcello, M. M. P.; Jose da Silva, V. G.; Clive, D. L. J.;
Coltart, D. M.; Hof, F. A. J. Hetereocycl. Chem. 1999, 36, 653. (d)
Burton, A. G.; Frampton, R.D.; Johnson, C.D.; Katritzky, A. R.
J. Chem. Soc., Perkin Trans. 1972, 2, 1940.
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0.1021/op700114d CCC: $37.00
2007 American Chemical Society
Vol. 11, No. 5, 2007 / Organic Process Research & Development
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Published on Web 07/31/2007