New synthesis of 4-methoxyisophthalic acid

Article abstract of DOI:10.1134/S1070428017030241

A new synthetic route to 4-methoxyisophthalic acid, the key intermediate in the synthesis of Picotamide, is reported. The new protocol starts from commercially available and cheap 4-methylphenol and includes four steps: esterification, Fries rearrangement, methylation, and oxidation; the overall yield is 49%. Unlike the traditional Blanc chloromethylation/oxidation scheme, the proposed procedure avoids using volatile and corrosive hydrochloric acid.

Full text of DOI:10.1134/S1070428017030241

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2017, Vol. 53, No. 3, pp. 459–461. © Pleiades Publishing, Ltd., 2017.
1
New Synthesis of 4-Methoxyisophthalic Acid
a
a
b
a
a
X. J. Liu ,* Y. N. Yan , S. Q. Wang , X. Li , and X. G. Liu **
a
School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin, 300384, P.R China
e-mail: *liuxiujie@hotmail.com; **xuguangliu@yahoo.com
b
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, P.R. China
Received November 22, 2016
Abstract—A new synthetic route to 4-methoxyisophthalic acid, the key intermediate in the synthesis of
Picotamide, is reported. The new protocol starts from commercially available and cheap 4-methylphenol and
includes four steps: esterification, Fries rearrangement, methylation, and oxidation; the overall yield is 49%.
Unlike the traditional Blanc chloromethylation/oxidation scheme, the proposed procedure avoids using volatile
and corrosive hydrochloric acid.
DOI: 10.1134/S1070428017030241
Picotamide (1), also known as N,N′-bis(3-picolyl)-
-methoxyisophthalamide, is an antiplatelet drug with
ficult to handle but it also causes corrosion of the
experimental equipment. Storage of a large volume of
waste acid is also troublesome when the reaction is
carried out on a large scale. Moreover, it is dangerous
to use Blanc chloromethylation for industrial process
because of using a large volume of bubbling hydrogen
chloride. Direct oxidation of 2,4-dimethylphenol with
potassium permanganate to produce 4-methoxyiso-
phthalic acid was also reported; however, the yield is
low (25%), and 2,4-dimethylpenol is a relatively ex-
pensive reagent [10]. Herein, we would like to intro-
duce a new and safer method to synthesize 4-methoxy-
isophthalic acid using Fries rearrangement as the key
step (Scheme 3). The proposed procedure allows pre-
paration of 4-methoxyisophthalic acid on a large scale
without using chromatographic purification, and the
overall yield is 49% based on 4-methylphenol.
4
dual inhibitory effects [1, 2]. Picotamide can inhibit
thromboxane A (TXA ) receptors and the synthesis of
2
2
TXA , and it has no influence on the endothelial
2
prostacyclin (PGI ) production [3, 4]. We have report-
2
ed the synthesis of a series of structural analogs 2 of
Picotamide by replacing its two 3-picolyl groups by
substituted phenyl groups. Some of these analogs
exhibited higher antiplatelet aggregation activities than
Picotamide itself [5–8]. 4-Methoxyisophthalic acid (3)
is the key intermediate in the synthesis of Picotamide
and its analogs [5–8] (Scheme 1).
The most common method to synthesize 4-me-
thoxyisophthalic acid is Blanc chloromethylation/
methylation/oxidation sequences using anisole [9],
2
-methylanisole, or 4-methylanisole [10] as starting
materials (Scheme 2). A drawback of these methods is
the use of volatile hydrogen chloride in the Blanc
chloromethylation. Hydrogen chloride is not only dif-
As shown in Scheme 3, 4-methylphenol (4) was
used as starting material. Acetylation of 4 with acetic
anhydride gave 4-methylphenyl acetate (5) which was
Scheme 1.
OMe
O
OMe
OMe O
N
R
H
COOH
N
N
H
O
N
H
R
COOH
O
N
H
N
Picotamide (1)
4-Methoxyisophthalic acid (3)
Picotamide analogs (2)
1
The text was submitted by the authors in English.
4
59

4
60
LIU et al.
Scheme 2.
OMe
OAc
Me
OMe
(
(
1) Blanc chloromethylation
2) Oxidation
COOH (1) Fries rearrangement
(2) Oxidation
Traditional methods
This work
COOH
4
-Methoxyisophthalic acid (3)
Scheme 3.
OH
OAc
OH
Me
OMe
OMe
(
MeO) SO
2 2
COMe
COMe
COOH
Ac O
2
AlCl3
NaOH, TBAB
KMnO4
70%
9
0% over 2 steps
78.5%
Me
Me
Me
COOH
4
5
6
7
3
1
subjected to Fries rearrangement to 5-methyl-2-hy-
spectrometer (400 MHz for H) using tetramethyl-
silane as internal standard. The IR spectra were
recorded on a Perkin Elmer 157 spectrometer. The
mass spectra (electrospray ionization) were measured
on Agilent 6310 Ion Trap and Shimadzu LC-MS
instruments.
droxyacetophenone (6) in the presence of AlCl [11].
3
The yield was 90% over two steps. Compound 6
reacted with dimethyl sulfate in aqueous sodium hy-
droxide using tetrabutylammonium bromide (TBAB)
as catalyst to produce 2-methoxy-5-methylaceto-
phenone (7) in 78.5% yield. Oxidation of the methyl
and acetyl groups in 7 afforded the target 4-me-
thoxyisophthalic acid (3) which can be isolated in
the pure state by recrystallization from ethanol. The
structure of 4-methoxyisophthalic acid was fully
characterized.
4
-Methylphenyl acetate (5) and 1-(2-hydroxy-5-
methyl)ethanone (6). A mixture of 4-methylphenol (4)
37.0 mmol, 4.0 g) and acetic anhydride (38.2 mmol,
.6 mL, 3.9 g) was refluxed for 3 h. Aluminum
trichloride (44.0 mmol, 6.0 g) and 36% hydrochloric
acid (129.3 mmol, 4.0 mL, 4.7 g) were then added to
the resulting solution, and the mixture was heated at
(
3
This new synthesis of 3 has several advantages.
First of all, all steps are chromatography-free, and
intermediate products 5, 6, and 7 can be used in the
following steps without purification; therefore, the
procedure is readily scalable. Moreover, the Fries
rearrangement gives 6 as the only product. The known
Blanc chloromethylation procedures usually give mix-
tures of mono- and disubstituted products. The new
route reported in this paper avoids using difficult-to-
handle gaseous hydrogen chloride which might cause
corrosion of the equipment and environmental
problems.
1
10°C for 8 h. The mixture was cooled and extracted
with methylene chloride, the extract was dried over
anhydrous magnesium sulfate and filtered, and the
solvent was removed under reduced pressure to give
.95 g (36.7 mmol, 90%) of yellow crude product 6.
Compound 6 was used directly in the following step
4
without further purification.
1-(2-Methoxy-5-methylphenyl)ethanone (7).
A 150-mL round bottom flask was charged with
compound 6 (35.3 mmol, 5.3 g), sodium hydroxide
36.0 mmol, 1.4 g), and dimethyl sulfate (47.1 mmol,
.2 g) in aqueous ethanol (15 mL), and tetrabutyl-
(
5
EXPERIMENTAL
ammonium bromide (3.5 mmol, 1.1 g) was then added
as catalyst. The mixture was stirred first at 40°C for
30 min and then at 75°C for 4.5 h and extracted with
ethyl acetate, and the extract was washed with 15 ml of
5% aqueous NaOH and 50 mL of water three times in
succession. The organic layer was dried with anhy-
drous magnesium sulfate and filtered, and the solvent
was removed under reduced pressure to leave 4.55 g
All reagents were purchased from Aladdin
Industrial Corporation (P.R. China), Shanghai Darui
Fine Chemical (P.R. China), and Tianjin Kewei (P.R.
China) and used without further purification. The
melting points were determined with a Kofler micro
melting point apparatus and are uncorrected. The
1
1
H NMR spectra were recorded with a Bruker AM 400
(78.5%) of crude compound 7. H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017

NEW SYNTHESIS OF 4-METHOXYISOPHTHALIC ACID
461
(
3
7
CDCl ), δ, ppm: 2.31 s (3H, CH ), 2.63 s (3H, CH ),
Science and Technology of Tianjin of China
(15JCZDJC33100), and the Tianjin University of
Technology for financial support.
3
3
3
.89 s (3H, OCH ), 6.87 d (1H, Harom, J = 8.2 Hz),
3
.27 d.d (1H, Harom, J = 2.0, 8.2 Hz), 7,54 d (1H, Harom
,
J = 2.0 Hz). Compound 7 was used in the next step
without further purification. The H NMR spectrum of
1
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1
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6
3
7
8
.20 d (1H, Harom, J = 8.8 Hz), 8.03 d.d (1H, Harom, J =
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1
1
3
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6
C
1
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–
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 53 No. 3 2017