An easy access to 7-methyl-2-naphthalenecarbonitrile

Article abstract of DOI:10.1248/cpb.53.448

A practical and cost-effective procedure has been developed for the synthesis of 7-methyl-2-naphthalenecarbonitrile, the precursor of the anticoagulant agents YM-60828 or YM-96765. This new route generates the key intermediate in only two steps from readily available 3-cyanopropionaldehyde dimethyl acetal and m-tolualdehyde, without requiring chromatographic purification. The synthesis involves condensation of the cyano derivative with the aldehyde and subsequent cyclodehydration.

Full text of DOI:10.1248/cpb.53.448

448
Notes
Chem. Pharm. Bull. 53(4) 448—450 (2005)
Vol. 53, No. 4
An Easy Access to 7-Methyl-2-naphthalenecarbonitrile
*
Hiroyuki KOSHIO, Tsukasa ISHIHARA, Hiroyoshi YAMADA, Fukushi HIRAYAMA, Yuzo MATSUMOTO, and
Isao YANAGISAWA
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd.; 21 Miyukigaoka, Tsukuba, Ibaraki
305–8585, Japan. Received December 27, 2004; accepted January 12, 2005; published online January 21, 2005
A practical and cost-effective procedure has been developed for the synthesis of 7-methyl-2-naphthalenecar-
bonitrile, the precursor of the anticoagulant agents YM-60828 or YM-96765. This new route generates the key
intermediate in only two steps from readily available 3-cyanopropionaldehyde dimethyl acetal and m-tolualde-
hyde, without requiring chromatographic purification. The synthesis involves condensation of the cyano deriva-
tive with the aldehyde and subsequent cyclodehydration.
Key words inhibitor; bicyclic compound; nitrile; condensation; cyclization
acid, yields a substituted naphthalene product.11) Although
Thromboembolic diseases continue to be a leading cause
this method is limited to activated benzaldehydes such as
methoxybenzaldehyde, we adapted it for our target com-
pound using a weakly activated benzaldehyde, m-tolualde-
hyde (Chart 1). Condensation of 2 with 3 in the presence of
LDA (lithium diisopropylamide) gave intermediate alcohol 4,
and the crude alcohol was then refluxed in 20% aqueous sul-
furic acid to afford compound 1 in 43% yield after chromato-
graphic purification (Chart 1, Entry 1). The more hindered
cyclization product, 5-methyl-2-naphthalenecarbonitrile, was
not observed.
Several different reaction conditions were used in optimiz-
ing the reaction for multi-gram preparations, and the re-
sults are summarized in Chart 1. Sodium amide,12) n-butyl-
lithium,13—15) a combination of di-n-butylboryl triflate and
diisopropylamine,16) potassium t-butoxide,17) and a combina-
tion of proazaphosphatrane and magnesium sulfate18) have
been used as condensation reagents for acetonitrile with ben-
zaldehyde. Our attention was drawn to the reaction in the
presence of potassium t-butoxide, since it has the following
advantages: (1) potassium t-butoxide is readily available
from commercial sources, and (2) it does not cause evolution
of gas from the reaction mixture. However, condensation of 3
with 2 in the presence of potassium t-butoxide followed by
cyclization in 20% aqueous sulfuric acid gave compound 1
with an overall yield of 34% (Chart 1, Entry 2); hence, the
application of potassium t-butoxide as a base resulted in a
disappointingly low yield. In contrast, use of Bradsher’s
reagent as a cyclodehydration agent19) gave good results. Cy-
clization of the crude coupling product 4 with aqueous hy-
drobromic acid in acetic acid afforded the target compound 1
with an overall yield of 66% (Chart 1, Entry 3). Moreover,
the crystalline naphthalene derivative 1 precipitated from the
resulting reaction mixture, and simple filtration allowed iso-
of morbidity and mortality in the developed world, and the
use of anticoagulant drugs is a primary clinical strategy to
treat and prevent these diseases. Factor Xa inhibitors have the
potential to be superior anticoagulant agents, and thus the
search for novel factor Xa inhibitors has emerged as one of
the most active areas of current drug discovery.
Several potent factor Xa inhibitors containing naphthyl-
amidine moieties have been reported,1—5) and representative
structures of these inhibitors are shown in Fig. 1. These
drugs have a common precursor, 7-methyl-2-naphthalenecar-
bonitrile (1), and several methods have been reported for
preparation of this compound.6—10) Earlier syntheses of com-
pound 1 are multi-step procedures6,8) or require high temper-
ature (flame-heating or heating to 400 °C),7,9) and hence they
are impractical and unsuitable for commercial exploitation.
More recently, Yokoyama et al. have described the prepara-
tion of compound 1 in four steps, in which 2,7-dimethyl-
naphthalene was used as the starting material.10) However,
2,7-dimethylnaphthalene is not readily available from com-
mercial sources, and this method also involves a selective
transformation of a symmetrical starting material to an asym-
metrical target compound. These two problems contribute to
decreased synthetic efficacy. Due to the high worldwide mar-
ket value of factor Xa inhibitors, development of an effective
synthetic procedure for the synthesis of the key precursor 1
remains as an important and challenging task. Herein, we
present a practical and efficient synthesis of 7-methyl-2-
naphthalenecarbonitrile (1) starting from two common, read-
ily available starting materials: m-tolualdehyde (2) and 3-
cyanopropionaldehyde dimethyl acetal (3).
Teague et al. have reported that condensation of a 3-
cyanopropionaldehyde dialkyl acetal with a methoxy-acti-
vated aromatic aldehyde, followed by treatment with sulfuric
Fig. 1. Representative Structures of Factor Xa Inhibitors and Their Precursor 1
∗ To whom correspondence should be addressed. e-mail: koshio@yamanouchi.co.jp
© 2005 Pharmaceutical Society of Japan

April 2005
449
Condition
Entry
Yield (%)
Condensation process
Cyclodehydration process
1
2
3
4
LDA, THF, ꢀ78 °C to r.t.
KOt-Bu, THF, ꢀ78 °C to r.t.
LDA, THF, ꢀ78 °C to r.t.
LDA, THF, ꢀ78 °C to r.t.
20% sulfuric acid, 100 °C
20% sulfuric acid, 100 °C
48% hydrobromic acid, AcOH, 100 °C
48% hydrobromic acid, AcOH, 100 °C
43a)
34a)
66a)
49b)
a) Yield after chromatographic purification. b) Isolated by filtration of the reaction mixture.
Chart 1. Synthesis of 7-Methyl-2-naphtalenecarbonitrile (1)
then brine, dried over magnesium sulfate, and concentrated in vacuo to yield
a pale yellow oil (191.74 g). A mixture of the resulting oil (191.74 g), glacial
AcOH (769 ml), and hydrobromic acid (48 wt% in water; 601 ml) was stirred
at 100 °C for 2 h. The reaction mixture was cooled to ambient temperature
and the resulting precipitate was filtered. The collected solid was washed
lation of the pure target compound (Chart 1, Entry 4). These
conditions abridged the work-up procedures of the reaction
and furnished compound 1 with excellent reproducibility,
which led us to conclude that this procedure is practical for
multi-gram preparation. We subsequently confirmed that the with a mixture of glacial AcOH and H2O (1 : 1 by volume) and then H2O,
and dried at 40 °C under reduced pressure to yield the title compound as a
method is applicable for scale-up to as much as 63 g of com-
pound 1.
beige solid.
Yield: 63.2 g (49%); mp 136—137 °C (lit.10) mp 132.4—133.3 °C). IR
In conclusion, we have successfully established a simple,
practical, and cost-effective synthesis of 7-methyl-2-naph-
thalenecarbonitrile. The key features of this procedure are (1)
an efficient condensation of 3-cyanopropionaldehyde di-
methyl acetal with m-tolualdehyde; and (2) reliable cyclode-
hydration of the intermediate alcohol. This method will be
useful for synthesis of naphthalene derivatives from weakly
activated benzaldehydes such as m-tolualdehyde, compared
with strongly activated benzaldehydes such as methoxyben-
zaldehyde derivatives. The final target compound can be iso-
lated without chromatographic purification, and we anticipate
that this new and straightforward procedure will be of great
utility in the preparation and production of anticoagulant
agents.
(KBr): 2227, 916, 848 cmꢀ1. 1H-NMR (400 MHz, DMSO-d6): d 2.51 (s, 3H,
CH3), 7.56 (d, 1H, Jꢁ8.0 Hz, H-6), 7.70 (d, 1H, Jꢁ8.4 Hz, H-4), 7.79 (s, 1H,
H-8), 7.94 (d, 1H, Jꢁ8.0 Hz, H-5), 8.04 (d, 1H, Jꢁ8.4 Hz, H-3), 8.42 (s, 1H,
H-1). 13C-NMR (100 MHz, DMSO-d6) d 21.16, 108.34, 119.22, 125.39,
127.06, 127.76, 128.97, 131.37, 132.03, 132.54, 133.48, 137.27. EI-MS:
m/zꢁ167 [M]ꢂ. Anal. Calcd for C12H9N: C, 86.20; H, 5.43; N, 8.38. Found:
C, 86.17; H, 5.47; N, 8.34.
The analysis of the first condensation product by TLC on silica gel (n-
hexane–ethyl acetate, 2 : 1) gave the following results; a spot, which was
weakly UV-active, was detected upon exposure to iodine vapor at an Rf value
of 0.23. The analysis of the title compound by TLC on silica gel (n-
hexane–ethyl acetate, 8 : 1) gave the following results; a spot, which was
strongly UV-active, was detected upon exposure to iodine vapor at an Rf
value of 0.38.
Acknowledgements We would like to express our gratitude to Dr. Mi-
noru Okada for helpful support in the preparation of this manuscript, and we
are also grateful to the staff of the Division of Analytical Science Laborato-
ries for the elemental analysis and spectral measurements.
Experimental
Melting points were determined using a Yanaco MP-500D melting point
apparatus, and are uncorrected. IR absorption spectra were obtained using a
Horiba FT-720 spectrometer. 1H-NMR spectra were recorded on a JEOL References
EX400 spectrometer (400 MHz). 13C-NMR spectra were recorded on a
JEOL EX400 spectrometer (100 MHz). The chemical shifts (d) are ex-
pressed in ppm relative to tetramethylsilane, and spectra were recorded in
DMSO-d6. MS spectra were recorded on a Fisons TRIO1000 spectrometer
using electron impact ionization at 70 eV. Elemental analysis was performed
with a Yanaco MT-5 microanalyzer (C, H and N). Analytical thin-layer chro-
matography (TLC) were performed on a glass plates precoated with silica
gel (Merck Silica gel 60 F254). Visualization was accomplished by UV light
(254 nm) and iodine vapor. 3-Cyanopropionaldehyde dimethyl acetal and m-
tolualdehyde were purchased from Tokyo Kasei Kogyo Co., Ltd. and were
used without further purification. A solution of lithium diisopropylamide in
cyclohexane was purchased from Aldrich Chemical Co. All solvents em-
ployed in these experiments were reagent grade obtained from Kanto Chem-
ical Co. and were used without further purification.
1) Nagahara T., Yokoyama Y., Inamura K., Katakura S., Komoriya S., Ya-
maguchi H., Hara T., Iwamoto M., J. Med. Chem., 37, 1200—1207
(1994).
2) Hirayama F., Koshio H., Katayama N., Kurihara H., Taniuchi Y., Sato
K., Hisamichi N., Sakai-Moritani Y., Kawasaki T., Matsumoto Y.,
Yanagisawa I., Bioorg. Med. Chem., 10, 1509—1523 (2002).
3) Hirayama F., Koshio H., Ishihara T., Watanuki S., Hachiya S., Kaizawa
H., Kuramochi T., Katayama N., Kurihara H., Taniuchi Y., Sato K.,
Sakai-Moritani Y., Kaku S., Kawasaki T., Matsumoto Y., Sakamoto S.,
Tsukamoto S., Bioorg. Med. Chem., 10, 2597—2610 (2002).
4) Hirayama F., Koshio H., Katayama N., Ishihara T., Kaizawa H., Tani-
uchi Y., Sato K., Sakai-Moritani Y., Kaku S., Kurihara H., Kawasaki
T., Matsumoto Y., Sakamoto S., Tsukamoto S., Bioorg. Med. Chem.,
11, 367—381 (2003).
7-Methyl-2-naphthalenecarbonitrile (1) In a three-necked round bot-
tom flask equipped with stirrer, a solution of lithium diisopropylamide (1.5 M
in cyclohexane; 616 ml, 924 mmol) and tetrahydrofuran (740 ml) was taken
and cooled to ꢀ78 °C under argon. To the mixture was added dropwise 3-
cyanopropionaldehyde dimethyl acetal (3) (105 ml, 806 mmol) and the
whole was stirred for 1 h. To the reaction mixture m-tolualdehyde (2)
(90.0 ml, 763 mmol) was added dropwise at ꢀ78 °C. The whole was stirred
for 0.5 h, and allowed to warm to ambient temperature and then stirred for a
further 2 h. After addition of H2O (500 ml) at 0 °C, the reaction mixture was
extracted with ethyl acetate (300 ml). The extract was washed with H2O and
5) Koshio H., Hirayama F., Ishihara T., Taniuchi Y., Sato K., Sakai-Mori-
tani Y., Kaku S., Kawasaki T., Matsumoto Y., Sakamoto S.,
Tsukamoto S., Bioorg. Med. Chem., 12, 2179—2191 (2004).
6) Adcock W., Wells P. R., Aust. J. Chem., 18, 1351—1364 (1965).
7) Gore P. H., Siddiquei A. S., Thorburn S., J. Chem. Soc., Perkin Trans.
1, 1972, 1781—1788 (1972).
8) Yamaguchi H., Yamada K., Kanetani N., Yokoyama Y., JP05078344
(1993) [Chem. Abstr., 119, 95314 (1993)].
9) Sagi K., Hasebe R., Saito N., JP07285923 (1996) [Chem. Abstr., 124,
201801 (1996)].

450
Vol. 53, No. 4
10) Yokoyama Y., Sato T., Takeda K., JP08268990 (1997) [Chem. Abstr.,
126, 31180 (1997)].
11) Teague S. J., Roth G. P., Synthesis, 1986, 427—429 (1986).
12) Lettre H., Meiners G., Wichmann H., Naturwissenschaften, 33, 157—
158 (1946) [Chem. Abstr., 41, 7373 (1947)].
13) Clouse D. N., Seebach D., Chem. Ber., 101, 3113—3121 (1968).
14) Kaiser E. M., Hauser C. R., J. Org. Chem., 33, 3402—3404 (1968).
15) Kauffmann T., Kieper H., Pieper H., Chem. Ber., 125, 899—906
(1992).
16) Hamada H., Sugasawa T., Chem. Lett., 1982, 1401—1404 (1982).
17) Koenig T. M., Mitchell D., Tetrahedron Lett., 1994, 1339—1342
(1994).
18) Kisanga P., Mcleod D., D’sa B., Verkade J., J. Org. Chem., 64, 3090—
3094 (1999).
19) Wolinska-Mocydlarz J., Canonne P., Leitch L. C., Synthesis, 1974,
566—568 (1974).