Novel and gram-scale green synthesis of flutamide

Article abstract of DOI:10.1080/00397910500464848

Isobutyric acid in the presence of cyanuric chloride and N-methylmorpholine was converted into active ester 3 at 0-5°C, and it was subsequently treated with 3-aminobenzotrifluoride 4 at 25°C to furnish corresponding amide 5. This amide finally, on nitration, produced the desired product flutamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propionamide 6 in good yield. By-product 2,4,6-trihydroxy-1,3,5-triazine 7 was converted into the useful starting material cyanuric chloride 1 by refluxing with N,N-diethylamine and POCl₃. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500464848

This article was downloaded by: [University of Connecticut]
On: 06 November 2012, At: 01:09
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Novel and Gram‐Scale Green Synthesis of
Flutamide
a
a
B. P. Bandgar & S. S. Sawant
a
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramananad Teerth Marathwada University, Nanded, India
Version of record first published: 16 Aug 2006.
To cite this article: B. P. Bandgar & S. S. Sawant (2006): Novel and Gram‐Scale Green Synthesis of Flutamide,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:7, 859-864
To link to this article: http://dx.doi.org/10.1080/00397910500464848
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

w
Synthetic Communications , 36: 859–864, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500464848
Novel and Gram-Scale Green Synthesis
of Flutamide
B. P. Bandgar and S. S. Sawant
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramananad Teerth Marathwada University, Nanded, India
Abstract: Isobutyric acid in the presence of cyanuric chloride and N-methylmorpho-
line was converted into active ester 3 at 0–5 8C, and it was subsequently treated
with 3-aminobenzotrifluoride 4 at 25 8C to furnish corresponding amide 5. This
amide finally, on nitration, produced the desired product flutamide, 2-methyl-N-
[
4-nitro-3-(trifluoromethyl)phenyl]propionamide 6 in good yield. By-product 2,4,6-tri-
hydroxy-1,3,5-triazine 7 was converted into the useful starting material cyanuric
chloride 1 by refluxing with N,N-diethylamine and POCl
3
.
Keywords: Cyanuric chloride, flutamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)
phenyl]propionamide, nonsteroidal drug
INTRODUCTION
The amide unit is one of the most widely occuring functional groups. It is
present as a key feature in many important natural products and manmade
[
1]
compounds. The amide functionality is highly thermostable and is one of
the most important factors to be considered in designing photoelectric
[
2]
[3]
materials, liquid crystal devices, and drugs. Flutamide is a nonsteroidal
drug with specific antiandrogenic but no other hormonal activity. Its active
metabolite, 2-hydroxyflutamide comparatively blocks androgen action on
accessory sex organs as well as on pituitary glands and increases LH secrea-
tion by blocking inhibitors. Plasma testosterone level increases in males,
Received in India September 13, 2005
Address correspondence to B. P. Bandgar, Organic Chemistry Research Laboratory,
School of Chemical Sciences, Swami Ramananad Teerth Marathwada University,
Nanded 431 606, India. E-mail: bandgar_bp@yahoo.com
8
59

8
60
B. P. Bandgar and S. S. Sawant
which partially overcomes the direct antiandrogenic action of flutamide.
Synthetic androgen and antiandrogens have therapautic value in the
treatment of various androgen-dependent conditions such as regulation of
male fertility. Androgen antagonists are potentially useful for treatment of a
number of hormone-dependent conditions ranging from acne and hirsutism
[
4]
to prostate cancer. Currently both steroidal and nonsteroidal agents such
as flutamide have shown clinical benefit in the treatment of prostate cancer.
RESULTS AND DISCUSSION
Flutamide is a nonsteroidal antiandrogen. Because of the importance of
flutamide as an anticancer agent, various methods are reported in the literature
for its preparation. Most of the methods involved condensation of isobutyric
acid chloride with 3-(trifluoromethyl)aniline in the presence of a base as the
hydrogen chloride acceptor. 2-Methyl-N-[3-(trifluoromethyl)phenyl]propio-
namide thus formed was further nitrated using a nitrating agent to yield
flutamide. Flutamide was synthesized by acylation of 3-trifluoromethyl-
aniline with Me CHCOCl in the presence of NaHCO , followed by nitration
2
3
[
5,6]
[7]
with fuming HNO /H SO
or NaNO in oleum or 95% HNO in 24%
3 3
3
2
4
[
olium. It was also prepared in four steps starting from 3-trifluoromethyl-
8]
[
9]
benzene in low yield (46.4%). Flutamide was prepared
[10]
from trifluoroto-
luene in five steps with a total yield of 43.7%. A mixture of Me CHCOCl in
2
pyridine and 4-nitro-3-trifluoromethylaniline on heating for 1.5 h in a steam
[12]
[
11]
[5,6]
[11]
bath yielded flutamide.
NaHCO3,
pyridine,
and Et N
3
are
generally used has bases for HCl acceptor in flutamide synthesis. All the
methods reported in the literature for the synthesis of flutamide involved use
of isobutyric acid chloride. Therefore, conversion acid to acid chloride is
required, using hazardous SOCl and reflux conditions. Therefore, it is of
2
interest to develop an alternative, rapid, mild, practical, and convenient
method for the synthesis of flutamide, starting from isobutyric acid.
Over the past few years there has been considerable interest in the use of
[
13,14]
cyanuric chloride or its derivatives in organic synthesis.
recently reported the use of 2-chloro-4,6-dimethoxy-1,3,5-triazine for the
We have
[15]
[16]
direct conversion of carboxylic acids into acyl azides,
[
2-oxazolines,
We now report here a convenient and
17]
and monoacylated piperazines.
green chemistry route for gram-scale synthesis of flutamide involving
cyanuric chloride (Scheme 1).
The present procedure is based on the reaction of 2,4,6-trichloro-1,3,5-
triazine 1 and N-methylmorpholine to furnish a complex that was
subsequently treated with a isobutyric acid 2 to yield 2,4,6-triacyloxy-1,3,5-
triazine 3. This acylated derivative was reacted with 3-(trifluomethyl)aniline
to furnish 2-methyl-N-[3-trifluoromethyl)phenyl]propionamide 5 in good
yield. The amide obtained was subsequently nitrated using mixture of conc.
HNO and H SO to obtain flutamide 6 in good yield.
3
2
4

Green Synthesis of Flutamide
861
Scheme 1.
Although the formation of by-products resulting from undesirable side
reactions can be avoided by improving reaction conditions, formation of co-pro-
ducts (i.e. accompanying reaction leading to desired product) is inevitable.
Unless isolation and conversion of such co-products into other useful
compounds are very easy, they become waste material. To be useful on an indus-
trial scale it is particularly important to avoid column chromatography in the
isolation procedure. Thus, development of an effective and efficient method
for recovery and reuse of co-products is very desirable from both an environ-
mental and economic perspective. 2,4,6-Trihydroxy-1,3,5-triazine 7 was
formed as a co-product of the present procedure, and this co-product was
treated with POCl and N,N-diethylaniline under reflux conditions to furnish
3
cyanuric chloride 1. In comparison with other methods, our method is superior
because the isobutyric acid can be directly converted to the amide moiety in a
one-photosynthesis at room temperature without converting the carboxylic
acid to an acyl chloride, and the co-product, 2,4,6-trihydroxy-1,3,5-triazine, is
recycled in the process after converting it into cyanuric chloride.
EXPERIMENTAL
1 13
H NMR spectra and C NMR spectra were recorded on Brucker AC 300-
MHz and 75-MHz instruments respectively using CDCl3 as a solvent.
Chemical shifts are expressed in parts per million downfield from TMS. UV
(MeOH) spectra were recorded on a Shimadzu UV-visible spectrophotometer,
UV-2450 (pc)s, and IR (KBr) spectra were recorded on a Perkin-Elmer FTIR
spectrometer, spectrum one model, respectively. Melting points were deter-
mined on a Veego MP-D apparatus.

8
62
B. P. Bandgar and S. S. Sawant
2
-Methyl-N-[3-(trifluoromethyl)phenyl] propionamide (4) N-methyl-
morpholine (11.5 g, 0.114 mol) was added to a solution of cyanuric chloride
6.97 g, 0.038 mol) in methylene dichloride (300ml) at 0–5 8C with continueous
(
stirring. A white suspension was formed, to which a solution of the isobutyric
acid (10 g, 0.114 mol) was added, and the stirring was continued at the same
temperature for 5 h. The reaction mixture was filtered, and to this filtrate 3-ami-
nobenzotrifluoride (18.5g, 0.115 mol) was added. Stirring was continued for 3 h
at room temperature. After completion of reaction (TLC), reaction mixture was
washed with a saturated solution of sodium bicarbonate (2 Â 25ml) and then
with water (2 Â 30ml). The organic layer was dried with Na SO , concentrated,
2
4
and recrystallized from n-hexane to furnish 4 (20.0 g, 76%). Mp ¼ 115–120 8C;
UV (CH OH): lmax ¼ 243.50nm (Abs. 3.113); IR (KBr): 663.23, 638.09,
3
7
1
80.38, 892.90, 1069.21, 1107.99, 1252.96, 1275.11, 1389.02, 1466.72,
21
1
657.60, 1665, 1781.25, 2986.62, 3253.28 cm
;
H NMR (300MHz),
CDCl ): d 1.2 [d, 6H, (CH ) ], 2.6 [m, 1H, CH(CH ) ], 7.3 (m, 2H, Ar-H),
3
3 2
3 2
1
3
7
.7 (d, 1H, Ar-H), 7.95 (m, 1H, Ar-H), 8.85 (s, 1H, Ar-H); C NMR
75 MHz, CDCl ): d 19.349, 36.283, 117.300, 120.679, 123.633, 129.270,
(
3
138.863, 177.071. Anal. calcd. for C H F NO: C, 57.14; H, 5.19; F, 24.67;
11 12 3
N, 6.06, Found: C, 57.09; H, 5.15; F, 24.72; N, 6.11.
2
-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl] propionamide (5).
mixture of conc. sulfuric acid (5.2 ml, 0.098 mol) and conc. nitric acid (4 ml,
.095 mol) was added dropwise to a solution of 2-methyl-N-[3-(trifluoro-
methyl)phenyl]propionamide 4 (20 g, 0.087 mol) in conc. sulfuric acid
100 ml) at 0 to 5 8C and further stirred for 3 h at the same temperature. After
A
0
(
completion of the reaction (TLC), the reaction was quenched with water, and
the crude product was filtered at the suction and washed with sodium bicarbon-
ate solution. The crude compound was crystallized from toluene to furnish pure
product
5
(19.0 g, 79%). Mp ¼ 111.5–112 8C; UV (CH OH):
3
l max ¼ 205.50 nm (Abs. 2.125); IR (KBr): 478.3, 659.71, 713.37, 755.10,
8
1
3
39.73, 852.91, 903.03, 1041.24, 1103.42, 1173.99, 1244.59, 1275.11,
391.66, 1495.36, 1541.36, 1596.68, 1611.00, 1716.20, 1804.22, 2585.05,
2
360.86 cm ; H NMR (300 MHz), CDCl ): d 1.25 [d, 6H, (CH ) ], 2.65
1 1
3
3 2
(
1
m, 1H, .CH), 7.95 (m, 2H, Ar-H), 8.1 (s, 1H, Ar-H), 8.35 (s, 1H, NH);
3
C NMR (75 MHz, CDCl ): d 19.275, 36.845, 116.574, 122.476, 125.046,
3
1
2
42.812, 176.400; Anal. calcd for C H F N O : C, 47.83; H, 4.01; F,
1
1 11 3 2 3
0.63; N, 10.14. Found: C, 47.88; H, 4.06; F, 20.55; N, 10.09.
Procedure for Recovery of Cyanuric Chloride
A mixture of 2,4,6-trihydroxy-1,3,5-triazine (10.0 g, 0.078 mol) and
N,N-diethylaniline (19 g, 0.127 mol) dissolved in phosphoryl chloride
(
178 ml) was refluxed for 3 h. After removal of the excess phosphoryl
chloride at 35 8C/45 mm Hg, the residue was poured into icewater and

Green Synthesis of Flutamide
863
stirred for 50 min. The resulting mixture was extracted with CHCl , and the
3
organic layer was washed successively with dilute HCl, NaHCO3, and
brine. The organic layer was dried with anhydrous sodium sulfate, and
removal of the solvent under reduced pressure furnished the crude product,
which was purified by recrystallization from chloroform. The yield of pure
cyanuric chloride was 10 g (90%).
REFERENCES
1. (a) Beekwith, A. L. The Chemistry of Amides: Synthesis of Amide; Zabicky, J., Ed.;
Interscience: New York, 1970, 96; (b) North, M. Contemp. Org. Synth. 1994, 1,
475.
2. Lai, L. L.; Lin, H. C. Liq. Cryst. 2000, 27, 707.
3. (a) Ravina, E.; Teran, C.; Santana, L.; Garcia, N.; Estevez, I. Heterocycles 1990,
31, 1967; (b) Ohnishi, A.; Ishizaki, E. J. Clin. Pharmacol. 1988, 28, 113;
(
(
c) Koo, J.; Avakian, S.; Martin, G. J. J. Am. Chem. Soc. 1955, 77, 5373;
d) Desai, M.; Watthey, J. W. H.; Zuckerman, M. Org. Prep. Proceed. Int.
1976, 8, 85; (e) Butora, G.; Blaha, L.; Rajsner, M.; Helfert, I. Collect. Czech.
Chem. Commun. 1992, 57, 1967; (f) Boschi, D.; Stilo, A. D.; Fruttero, R.;
Medana, C.; Sorba, G.; Gasco, A. Arch. Pharm. (Weinheim. Ger.) 1994, 327,
661; (g) Althuis, T. H. H.; Hess, H. J. J. Med. Chem. 1977, 20, 146;
(
h) Manoury, P. M.; Binet, J. L.; Dumas, A. P.; Lefevre-Borg, F.; Cavero, I.
J. Med. Chem. 1986, 29, 19; (i) Campell, S. F.; Davey, M. J.; Hardstone, J. D.;
Lewis, B. N.; Plamer, M. J. J. Med. Chem. 1987, 30, 49; (j) Hokanen, E.;
Pippuri, A.; Kairisalo, P.; Thaller, H.; Kolvisto, M.; Taomi, S. J. Heterocycl.
Chem. 1980, 17, 797; (k) Hese, H. J. US Pat. 3,511,836, 1970; (l) Winn, M.;
Kyncl, J US Pat. 4093,726, 1978; (m) Campell, S. F. US Pat. 4,188,390, 1980;
(
4
n) Manoury, P. N. US Pat. 4,315,007, 1982; (o) Roteman, R. US Pat.
,251,532, 1981; (p) Igarashi, T. Eur. Pat. 209,089, 1986; (q) Schlager, L. H
Eur. Pat. 225,886, 1986; (r) Koning, J Ger. Pat. 3,419,223, 1984.
. Rasmusson, G. H. Ann. Rep. Med. Chem. 1996, 21, 179.
. Wang, S.; Liu, X. Hecheng Huaxue 2001, 9(3), 256.
. Wang, S.; Wang, H.; Yi, Z. Shenyang Yaoke Daxue Xuebao 2000, 17 (1), 38.
. Konieczny, M.; Potrykus, A. J. Polish Patent 167,850, 1990.
. Bal’on, Y. G.; Varga, S. V.; Vakulenko, L. I. Khimiko-Farmatserticheskii Zhurnal
4
5
6
7
8
1991, 25 (12), 53.
9. Li, J.; Guo, M. Guangdong Yaoxuebao 1995, 11 (2), 74.
10. Xia, P.; Zhou, X.; Shem, Y.; Zheng, Y. Zhongguo Yiyao Congye Zazhi 1989,
20 (8), 341.
1
1
1. Neri, R.; Topliss, J. G. Swedish Patent FI 62,058, 1982.
2. Baker, J. W.; Bachman, G. L.; Schumacher, I.; Roman, D. P.; Tharp, A. L. J. Med.
Chem. 1967, 10 (1), 93.
1
3. (a) Falorni, M.; Porcheddu, A.; Toddei, M. Tetrahedron Lett. 1999, 40, 4395;
(
b) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taldei, M. J. Org. Chem. 1999,
64, 8962; (c) Falchi, A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett
2000, 2, 1275; (d) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001,
66, 2534; (e) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3,
1519; (f) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 3041;
(
g) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553; (h) De

8
64
B. P. Bandgar and S. S. Sawant
Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 5152; (i) De
Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272;
(
j) Deluca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem. 2003,
8, 4999.
4. (a) Kumishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani, S. Tetrahedron 2001,
7, 1551; (b) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tetra-
6
1
5
hedron Lett. 1999, 40, 5327; (c) Kunishima, M.; Morita, J.; Kawachi, C.;
Iwasaki, F.; Terao, K.; Tani, S. Synlett 1999, 8, 1255; (d) Luo, G.; Xu, L.;
Poindexter, G. S. Tetrahedron Lett. 2002, 43, 8909; (e) De Luca, L.;
Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66, 7907;
(f) Kaminska, J. E.; Kaminski, Z. J.; Gora, J. Synthesis 1999, 4, 593;
(g) Kaminski, Z. J.; Kolesingka, B.; Markowicz, S. W.; Pokrzeptowicz, K.
Polish J. Chem. 1999, 73, 1965; (h) Lee, H.-W.; Kang, T. W.; Cha, K. H.;
Kim, E.-N.; Choi, N.-H.; Kim, J.-W.; Hong, C. Synth. Commun. 1999, 28 (8),
1
339.
1
1
1
5. Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2002, 43, 3413.
6. Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2003, 44, 2331.
7. Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett. 2003, 44, 3855.