4-nitrophenethylamine, biotransformation
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SYNTHETIC COMMUNICATIONS
Vol. 33, No. 11, pp. 1829–1832, 2003
A Convenient Synthesis of
4-Nitrophenethylamine Hydrochloride
Uday M. Joshi, Balu S. Kobal, and Hemant V. Joshi
*
Discovery Chemistry, Glenmark Research Centre,
MIDC, Mahape, Navi-Mumbai, India
ABSTRACT
A short, convenient, and e/cient synthesis of 4-nitrophenethylamine
hydrochloride is described. The key step involved removal of water from
4-nitrophenylalanine monohydrate followed by decarboxylation.
Key Words: Amino acid decarboxylation.
*Correspondence: Hemant V. Joshi, Discovery Chemistry, Glenmark Research
Centre, A-607, T.T.C. Industrial Area, MIDC, Mahape, Navi-Mumbai 400 709,
India; E-mail: hemant_joshi@glenmarkindia.com.
1829
DOI: 10.1081/SCC-120020191
0039-7911 (Print); 1532-2432 (Online)
Copyright & 2003 by Marcel Dekker, Inc.
www.dekker.com
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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
1830
Joshi, Kobal, and Joshi
INTRODUCTION
4-Nitrophenethylamine due to its bifunctionality finds wide application
in the pharmaceutical industry and was needed as an intermediate in our
drug discovery program.
A number of methods have been reported
[1–4]
in theliteraturewhich
includes the nitration of phenylacetonitrile followed by reduction.
[1–3]
Other methods included the acetylation of phenethylamine followed by
nitration, separation of isomers, and deacetylation.
[4]
All these methods
either involve reduction or are cumbersome and give low yields.
Herein we wish to report a very simple and convenient synthesis of
4-nitrophenethylamine hydrochloride which does not involve reduction
or purification methods.
RESULTS AND DISCUSSION
L
-4-Nitrophenylalanine 2 was prepared by nitration of
L
-phenylalanine 1
according to theliteratureprocedure
[5,6]
except that thecrudeproduct was
recrystallized once from water with a yield of 47%. It was necessary to remove
the water before carrying out the next step. This presumably is to facilitate
imine formation with the added ketone which is essential for subsequent
decarboxylation. Water was removed using Dean–Stark assembly and
benzene as solvent. The amount of water was below 0.6% (by KF analysis).
Decarboxylation of 2 in diphenylether in the presence of catalytic
amount of methyl ethyl ketone followed by bubbling dry HCl gas
resulted in formation 4-nitrophenethylamine hydrochloride 3 with
excellent yields as shown in Sch. 1.
EXPERIMENTAL
Commercial solvents and reagents were used without further purifica-
tion.
1
H NMR spectra were recorded on a Varian 300 MHz spectrometer.
Scheme 1.
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4-Nitrophenethylamine Hydrochloride
1831
Melting points are uncorrected. Elemental analysis was performed on a
Perkin–Elmer analyzer. The purity of the final product was checked using
an Agilent 1100 HPLC system. A reverse phase C18 Hypersil BDS
2504.6 mm 5 m column was used. A solvent system containing 85% acet-
onitrile and 15% phosphate buffer with pH adjusted to 2.5 was employed
at flow rateof 1.0 mL/min [¼280 nm].
4-Nitrophenyl-
L
-alanine Monohydrate 2: The Bergel and Stock
[5]
procedure was used except that the crude product obtained was recrystal-
lized from water to give a yield of 47%.
4-Nitrophenethylamine HCl 3: To a suspension of 2 (5.0 g, 23.81 mM)
in 50 mL of diphenylether was added methyl ethyl ketone (MEK) 0.17 g
(2.37 mM). This was heated at 220
C for 3 h resulting in a clear dark red
solution. This solution was diluted with 50 mL of diethyl ether and cooled
in ice bath. HCl gas was bubbled through the solution to obtain a dark red
precipitate which was filtered off. This residue was stirred in EtOAc and
filtered to obtain the desired product 3 as a brown solid with a yield of
3.75 g (78%), m.p. 200
C decomp. IR (KBr): 2956, 2911, 1623, 1608, 1598,
1524, 1345, 1250, 1108, 856, 746 cm
1
. NMR (d-
6
, DMSO): 3.07 (4H, br
s), 7.56 (2H, d, J ¼8.4 Hz), 8.18 (2H, d, J ¼8.4 Hz), 8.17–8.19 (3H,
embedded peaks). Anal. calcd. for C
8
H
10
N
2
O
2
HCl: C, 47.42; H, 5.47;
N, 13.82. Found: C, 47.45; H, 5.59; N, 13.48. HPLC purity>99%.
ACKNOWLEDGMENTS
Theauthors thank Dr. B. Gopalan, Dr. C. V. Srinivasan for helpful
discussions, and Dr. M. A. Khan for analytical support.
REFERENCES
1. Umino, N.; Iwakuma, T.; Itoh, N. Sodium acyloxyborohydrideas
new reducing agents. II. reduction of nitriles to the corresponding
amines. Tetrahedron Lett. 1976, 33, 2875–2876.
2. Suzuki, S.; Imai, Z.; Suzuki, Y.; Sato, T.; Miyaji, Y. Ger. Offen. 1970,
GWXXBX DE 2008443 19700224.
3. Mash, L.I.; Gerasimova, N.E. USSR Patent, URXXAF SU 620476
1,978,0825, 1978.
4. Johnson, T.B.; Guest, H.H. Synthesis of 4-nitrophenyl ethyl amine
and 2,4 dinitrophenyl ethyl amine. Am. Chem. J. 1910, 43, 310–
322.
M
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1832
Joshi, Kobal, and Joshi
5. Bergel, F.; Stock, J. Cytoactive amino acid and peptide derivatives. I.
substituted phenylalanines. J. Chem. Soc. 1954, 2409–2417.
6. Houghten, R.A.; Rapoport, H. Synthesis of pure p-Chlorophenyl-
L
-
alaninefrom
L
-phenylalanine. J. Med. Chem. 1974, 17, 556–558.
Received in the Netherlands July 20, 2002
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