A Practical synthesis of (7-methoxynaphth-l-yl)acetic acid

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A Practical Synthesis of (7-
Methoxynaphth-1-yl)acetic Acid
Jia-Deng Tang a & Jun-Da Cen a
a Department of Chemistry , Shanghai Institute of Pharmaceutical
Industry , Shanghai, PR, China
Published online: 22 Apr 2009.
To cite this article: Jia-Deng Tang & Jun-Da Cen (2009) A Practical Synthesis of (7-Methoxynaphth-1-
yl)acetic Acid, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 41:2, 164-168, DOI: 10.1080/00304940902802347
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164
Tang and Cen
4. N. Viswanathan, B. S. Joshi, D. H. Gawad, U. B. Gokhale, A. R. Sidhaye and G. R. Rajasekariah,
Indian J. Chem., Section B, 24B, 730 (1985); Chem. Abstr., 105, 172352 (1985).
5. V. V. Korshak, A. A. Izyneev, D. M. Mognonov, V. P. Mazurevskii, Zh. P. Mazurevskaya, I. S.
Novak, G. F. Slezko, A. I. Prokosova and A. D. Markov, Akad. Nauk SSSR, 143 (1971); Chem.
Abstr., 78, 110732 (1971).
6. A. A. Joshi and C. L. Viswanathan, Bioorg. Med. Chem. Lett., 16, 2613 (2006).
7. None of the previous references has reported a melting point for this compound.
Organic Preparations and Procedures International, 41:164–168, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802347
A Practical Synthesis
of (7-Methoxynaphth-1-yl)acetic Acid
Jia-Deng Tang and Jun-Da Cen
Department of Chemistry, Shanghai Institute of Pharmaceutical Industry,
Shanghai, P. R. China
The neurohormone melatonin (5-methoxy-N-acetyltryptamine, 1), which is mainly secreted
from the pineal gland or chemically synthesized, is putatively involved in several physio-
logical processes including circadian rhythms, retinal physiology, seasonal breeding, and
cardiovascular regulation.1–3 Since the therapeutic efficacy of melatonin is limited by its
short biological half-life, analogs of melatonin were designed and synthesized. It is known
that naphthalenic ligands have a high affinity for the melatonin receptor.4 Among these
ligands, agomelatine (N-[2-(7-methoxynaphth-1-yl) ethyl]acetamide, 2), which contains
the naphthalene moiety instead of indole nucleus, is currently in clinical trial.5
(7-Methoxynaphth-1-yl)acetic acid (6), a key intermediate to 2, has been prepared in
three steps using substituted tetralone 3 as starting material6 (Scheme). Treatment of 3 with
BrCH2CO2Et through a Reformatsky reaction afforded 4b whose extranuclear double bond
Submitted July 14, 2008.
Address correspondence to Jia-Deng Tang, Department of Chemistry, Shanghai Institute of
Pharmaceutical Industry, Shanghai 200437, P. R. China. E-mail: blueskytang2003@yahoo.com.cn

Practical Synthesis of (7-Methoxynaphth-1-yl)Acetic Acid
165
was indicated by the ultraviolet absorption; it was dehydrogenated with sulfur at 215◦C to
give compound 5 which was hydrolyzed to afford compound 6 in 56% overall yield from
3.7 This method suffers from drawbacks such as the use of noxious benzene as solvent and
sulfur for dehydrogenation at high temperatures. Actually, the product of this Reformatsky
reaction is a mixture of 4a and 4b as reported by Ferraz;7 the isolated yields of 4a and 4b
were 56% and 13%, respectively (4a:4b = 4.3:1). It was speculated that the intranuclear
double bond of 4a tends to make aromatization more facile than for the extranuclear double
bond of 4b. As we expected, when 4a and 4b were separated by chromatography and arom-
atized, 4a can be dehydrogenated easily with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in CH2Cl2 at room temperature for 1 hour, whereas 4b cannot be dehydrogenated
with DDQ at reflux in CH2Cl2 after 24 hours. Herein, we report a practical synthesis of
compound 6 in high yields. The Wittig-Horner reaction is applied in the preparation of
compound 4a and 4b. Treatment of 3 with diethyl ethoxycarbonylmethanephosphonate
in the presence of NaOEt in tetrahydrofuran (THF) under reflux for 12 hours affords a
mixture of 4a and 4b in 99% yield with 4a:4b in a ratio of 9.4:1. It is noteworthy that, when
ethanol was used as solvent instead of THF under reflux, the reaction was incomplete after
24 hours.
Reformatsky Reaction Conditions:7a) BrCH2CO2Et, Zn, I2, benzene, 74%; b) sulfur,
215◦C 80%; c) 10%NaOH, ethanol, reflux, 94%. Total yield of 6: 56% (based on 3).
Wittig-Horner Reaction Conditions: a) (EtO)2P(=O)CH2CO2Et, NaOEt, THF, reflux,
99%, 4a:4b = 9.4:1; b) DDQ, CH2Cl2, 15◦C; c) NaOH/EtOH, reflux. Total yield of 6: 76%
(based on 3).
The product of the Wittig-Horner reaction, in which the intranuclear double bonded 4a
predominates, was subjected directly to the subsequent dehydrogenation with DDQ under
mild conditions to afford a high yield of ester 5 which could be hydrolyzed in the next step
without purification. Refluxing of 5 in ethanolic sodium hydroxide solution gave, after the
removal of solvent, a residue that was dissolved in water and acidified by 10% hydrochloric
acid to afford the target compound 6 as a crystalline solid in an overall yield of 76% from
3 compared to 56% for the Reformatsky reaction.

166
Tang and Cen
Experimental Section
All melting points are uncorrected. 1H NMR data were recorded on an Inova-400 spectrom-
eter in CDCl3 or DMSO-d6 using TMS as an internal standard. Mass spectra were performed
on Micro Mass Q-Tof Micro MS. Diethyl ethoxycarbonylmethanephosphonate was pre-
pared in 80% yield according to Wu et al.8 as a colorless liquid, bp. 129–131◦C/6mmHg
(lit.8 bp.142–145◦C/1.2kPa, yield 89%).
Ethyl (7-Methoxy-3,4-dihydronaphthalen-1-yl)acetate (4a) and Ethyl (7-Methoxy-1,2,3,
4-tetrahydro-1-naphthalenylidene)acetate (4b)
Sodium (1.38 g, 60 mmol) was dissolved in dry ethanol (50 ml) and after complete removal
of ethanol under reduced pressure, the residual sodium ethoxide was taken up in dry THF
(50 ml). Diethyl ethoxycarbonylmethanephosphonate (13.44 g, 60 mmol) was added at
room temperature and the mixure stirred for 10 minutes, then 3 (5.28 g, 30 mmol) was
added in one portion and the mixture was refluxed for 12 hours. The mixture was cooled
to room temperature and the solvent was removed under reduced pressure. The residue
was dissolved in ethyl acetate (150 ml), washed with water (30 ml × 3) and brine (50
ml), dried over MgSO4 and the solvent was removed under reduced pressure to provide
10.6 g of a red oil, which was used for the subsequent dehydrogenation without further
purification.
Separation and Analysis of 4a and 4b
For identification of 4a and 4b, the above crude mixture was chromatographed on silica gel
using petroleum ether (bp. 60–90◦C)/ethyl acetate (60:1) as eluent, give 4a (6.6 g, 89%) as
a colorless oil, ESI-MS (m/z): 269.00 ([M+Na]). 1H NMR (CDCl3, 400M): δ 1.24 (t, J =
7.4 Hz, 3 H), 2.27–2.32 (m, 2 H), 2.72 (t, J = 8.0 Hz, 2 H), 3.40 (s, 1 H), 3.41 (s, 1 H), 3.78
(s, 3 H), 4.14 (q, J = 7.1 Hz, 2 H), 6.02 (t, J = 4.4 Hz, 1 H), 6.68 (dd, J = 2.8 Hz and 8.0
Hz, 1 H), 6.80 (d, J = 2.4 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H).
Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.30; H, 7.25.
4b (0.7 g, 9.5%) as a colorless oil, ESI-MS (m/z): 269.03 ([M+Na]). 1H NMR (CDCl3,
400 M): δ 1.32 (t, J = 7.2 Hz, 3 H), 1.84 (t, J = 6.0 Hz, 2 H), 2.73 (t, J = 6.4 Hz, 2 H),
3.15–3.18 (m, 2 H), 3.82 (s, 3 H), 4.21 (q, J = 7.2 Hz, 2 H), 6.29 (s, 1 H), 6.87 (dd, J = 2.4
Hz and 8.4 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 1 H), 7.15 (d, J = 2.4 Hz, 1 H).
Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found: C, 73.26; H, 7.19.
The overall yield of 4a and 4b was 99%.
Ethyl (7-Methoxynaphth-1-yl)acetate (5).
a) Using a Mixture of 4a and 4b as Starting Material
To a solution of 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ, 8.12 g, 36 mmol) in
anhydrous CH2Cl2 (100 ml) was added dropwise a solution of the above isolated red oil
(10.6 g, about 30 mmol of 4a and 4b) in anhydrous CH2Cl2 (50 ml) at about 15◦C. After
addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture was
filtered and the precipitate was washed by CH2Cl2 (50 ml), the combined organic phase

Practical Synthesis of (7-Methoxynaphth-1-yl)Acetic Acid
167
was washed successively with a saturated NaHCO3 solution (50 ml × 3), water (50 ml)
and brine (50 ml), dried over MgSO4. The solvent was removed under reduced pressure to
afford crude 5 (9.0 g, 95%) as a red oil, which was used directly in the next step without
further purification.
Analytically pure 5 was obtained as a colorless oil by silica gel chromatography using
petroleum ether (bp. 60∼90◦C)/ethyl acetate (60:1) as eluent. 1H NMR (CDCl3,400 M): δ
1.18 (t, J = 6.8 Hz, 3 H), 3.88 (s, 3 H), 4.08 (s, 2 H), 4.13 (q, J = 6 Hz, 2 H), 7.20 (dd, J
= 2.4 Hz and 8.8 Hz, 1 H), 7.27–7.33 (m, 2 H), 7.40 (d, J = 6.8 Hz, 1 H), 7.78 (d, J = 8.0
Hz, 1 H), 7.86 (d, J = 9.2 Hz, 1 H).
Anal. Calcd for C15H16O3: C, 73.75; H, 6.60. Found: C, 73.60; H, 6.45.
b) Using 4a as Starting Material
To a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 1.38g, 6.1 mmol) in
anhydrous CH2Cl2 (20 ml) was added dropwise a solution of 4a (1.0 g, 4.07 mmol) in
anhydrous CH2Cl2 (10 ml) at about 15◦C. After addition, the mixture was stirred at room
temperature for 1 hour. The mixture was filtered and the precipitate was washed by CH2Cl2
(10 ml), the combined organic phase was washed successively with saturated a NaHCO3
solution (10 ml × 3), water (10 ml) and brine (10 ml), dried with MgSO4. The solvent was
removed under reduced pressure to afford a colorless oil (0.9 g, 91%) which was identified
as compound 5 by TLC and 1H NMR.
When 4b was used instead of 4a for dehydrogenation with DDQ. Compound 5 was
not detected by TLC even after 24 hours.
(7-Methoxynaphth-1-yl)acetic Acid (6)
To a solution of sodium hydroxide (2.95 g, 73.8 mmol) in ethanol (100 ml) was added 9.0
g (about 30 mmol) of crude 5. After reflux for 2 hours, the solvent was removed under
reduced pressure and the residue was dissolved in water (50 ml). The aqueous solution was
cooled in an ice-water bath and 10% hydrochloric acid was added to pH 1–2. After stirring
for 1 hour, the solid was collected, washed four times with water and dried at 70◦C to afford
6 as a beige powder (4.9 g, 76% overall yield), mp. 150–152◦C(lit.7 mp. 149.5–150◦C).
ESI-MS (m/z): 215.24 ([M-H]), 1H NMR (CDCl3, 400 M): δ 3.88 (s, 3 H), 3.99 (s, 2 H),
7.2 (dd,J = 2.4 Hz and 8.8 Hz, 1 H), 7.28–7.32 (m, 2 H), 7.39 (d, J = 6.4 Hz, 1 H), 7.77 (d,
J = 8.4 Hz, 1 H), 7.86 (d,J = 8.8 Hz, 1 H).
Anal. Calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 72.11; H, 5.42.
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Organic Preparations and Procedures International, 41:168–171, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902802370
A Simple and Convenient Synthesis of Triprolidine
G. Venkateswara Rao, B. Narayana Swamy,
P. Hareesh Kumar, and G. Chandrasekara Reddy
Vittal Mallya Scientific Research Foundation, Bangalore, India
Triprolidine (3)1 is an anti-histamine drug belonging to 1,1-diaryl-2-propyleneamine class1
having trade names ActidilTM and MyodilTM. It is a very popular first-generation anti-
histamine used for coughs and colds. In combination with pseudo-ephedrine, it is being sold
under the brand name ActifedTM. Recently Bolser,2 Pratter, and Abouzgheib3 reported that
for coughs associated with the common cold, first-generation anti-histamine decongestants
would be more effective than newer nonsedative antihistamines. This observation together
with continuous demand for first-generation anti-histamines prompted us to search for
nonhazardous commercially viable alternate synthesis of triprolidine.
The carbon-carbon double bond in propyleneamines such as Acrivastine,4–7 Pyrrobu-
tamine,8,9 Triprolidine, Zimeldine10 have been built by dehydration of corresponding
alcohols11–14 or by the Wittig method.15 n-Butyllithium has been employed in both the Wit-
tig condensation and in the preparation of the tertiary alcohol (Scheme 1) at around −70◦C.
However, large-scale preparations of these compounds employ the dehydration method
rather than the Wittig method because no efficient method was available for preparation of
the intermediates such as 2-(N,N-dialkylaminoethyl)triphenylphosphonium bromides and
2-aroylpyridines. Having developed commercially viable methods for the preparation of
2-(p-toloyl)pyridine (1)16 and 2-(N-pyrrolidinoethyl)triphenylphosphonium bromide (2)17
we now report the preparation of triprolidine (3) without the use of n-butyllithium.
The existing industrial scale preparation of triprolidine11–14 involves the con-
densation of 2-bromopyridine with β-pyrrolidino-4-methylpropiophenone using alkyl-
lithium at around −70◦C followed by dehydration using sulfuric acid between 140
Submitted August 29, 2008.
Address correspondence to G. Chandrasekara Reddy, P. O. Box 406, K. R. Road, Bangalore
560004, India. E-mail: gcreddy@vmsrf.org