Ethoxyacetanilide synthesized by reductive acetylation of ethoxynitrobenzene on palladium catalysts

Full text of DOI:10.1023/A:1020836908866

Pharmaceutical Chemistry Journal
Vol. 36, No. 6, 2002
ETHOXYACETANILIDE SYNTHESIZED BY REDUCTIVE ACETYLATION
OF ETHOXYNITROBENZENE ON PALLADIUM CATALYSTS
M. G. Abdullaev1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 6, pp. 40 – 41, June, 2002.
Original article submitted February 26, 2002.
Phenacetin, or 4-ethoxyacetanilide (I), has been known
for a long time and is used as an antipyretic, analgesic, and
antiinflammatory drug [1], entering into a number of com-
bined preparations such as citramon, asphen, and caficyl.
However, the administration of phenacetin alone has been re-
stricted because of side toxicity manifestations related to an
admixture of p-chloroacetanilide present in the as-synthe-
sized parent compound [2]. In this context, the search for
new effective methods for the synthesis of compound I free
of toxic impurities is still important.
mass is poured into water and the precipitated technical-pu-
rity compound I is separated by filtration and recrystallized
from water.
However, even these commercially adopted optimum
schemes are not free of disadvantages. The main drawbacks
are related to a large number of intermediate stages, each in-
volving a certain loss of the main component and leading to
reduced total yield of the target compound. The relatively
low yield of the pharmacopoeial product is caused not only
by the presence of impurities of the initial substances and in-
termediate products: an additional negative factor is the ap-
pearance of products of incomplete reduction of the nitro
group. The amount and rate of formation of these products
depend on the conditions of reduction of II, and (to an even
greater extent) on the nature of the reducing agent.
There are several pathways to the target compound I.
Most widely used are the two schemes of synthesis proceed-
ing from phenol [3] and p-nitrochlorobenzene [4]. In both
cases, a key stage is the reduction of p-ethoxynitrobenzene
(
II) to p-phenetidine (III). The latter compound is subse-
quently distilled in vacuum and acetylated with acetic alde-
hyde or a 80 % aqueous acetic acid. Finally, the reaction
The above drawbacks can be completely or at least partly
eliminated using the proposed method of one-stage synthesis
of I from from II, based on the reductive acetylation of II on
palladium catalysts according to the following scheme:
1
Derbent Branch, Dagestan State University, Derbent, Dagestan, Russia.
Catalyst, H ,(CH CO) O (or 80% CH COOH)
2
3
2
3
II
I
–
2H O,CH COOH (or – 3H O)
2 3 2
TABLE 1. Effective Reaction Rate Constants (K , M/sec;
eff
±
15 – 27%) and Yields of Phenacetin (I) for the Reductive
Acetylation of p-ethoxynitrobenzene (II) on Various Palladium Cat-
alysts in Ethanol*
The catalysts represented a heterogeneous supported
Pd/C system and palladium-containing anion exchangers
AN-1 and AV-17-8 (AN-1-Pd and AV-17-8-Pd, respec-
tively). The high efficiency of the latter catalysts in reactions
of the type under consideration (including hydrogenation of
the nitro group without formation of products of incomplete
reduction) was repeatedly demonstrated in the previous pa-
pers [5 – 7].
In order to optimize the reaction conditions, it was pre-
liminarily established that the reductive acetylation of II pro-
ceeds in the kinetic region and is a first-order process with
respect to the catalyst and a zero-order process with respect
to the substrate.
Pd/C
yield, %
AN-1-Pd
AV-17-8-Pd
Experi-
ment No.
K
eff
K
eff
yield, %
K
eff
yield, %
1
0.17
0.19
0.15
0.15
0.16
0.18
0.16
62.5
64.1
64.4
65.3
61.7
60.8
65.2
0.08
0.07
0.07
0.09
0.08
0.09
0.07
77.6
78.1
79.3
78.5
78.0
79.0
78.8
0.14
0.12
0.13
0.14
0.14
0.12
0.14
85.0
85.5
85.1
87.3
86.6
87.8
85.9
2
3
4
5
6
7
*
Process conditions: solvent volume, 10 – 70 ml; acid or acetic an-
hydride concentration, 0.1 – 0.5 M; hydrogen pressure, ~1 atm;
temperature, 45°C; catalyst weight, 0.4 g; Pd content, 4 wt.% (parti-
cle size, d = 0.075 – 0.192 mm); concentration of II, 0.1 – 0.8 M.
Data on the reaction kinetics (Fig. 1) obtained by gas
chromatography showed that the reductive acetylation of II
to the target product I under selected conditions proceeds
324
0
091-150X/02/3606-0324$27.00 © 2002 Plenum Publishing Corporation

Ethoxyacetanilide Synthesized by Reductive Acetylation of Ethoxynitrobenzene
325
Concentration, mol.%
00
Concentration, mol.%
100
à
1
I
I
II
5
0
5
0
III
III
6
0
120
180
240
300
360
3
0
60
Concentration, mol.%
00
90
120
150
180
Reaction time, min
Reaction time, min
Fig. 2. Time variation of the concentration of the initial reagent III
and the product I during acetylation on an AV-17 – 8-Pd catalysts.
The process conditions are indicated in Table 1 (except for hydro-
gen).
b
1
II
I
superior to the metal – polymer catalysts with respect to ac-
5
0
tivity (K ), while offering a lower selectivity (percentage
eff
yield of I). Apparently, the relatively low selectivity of the
reaction proceeding on the heterogeneous Pd/C catalyst is
related to side reactions taking place in this system:
alkylation of the amino group of III by the solvent (ethanol)
and hydrolysis of the ethoxy group. Which of the two side re-
actions dominates depends on the process conditions. For ex-
ample, the process of reductive acetylatrion in benzene,
while excluding alkylation of the amino group, shows a de-
crease in the yield of I, which is evidence of a significant de-
crease in the selectivity (Table 2).
III
4
0
80
120
160
200
240
Reaction time, min
Fig. 1. Time variation of the concentration of the initial reagent II,
the intermediate product III, and the target product I during the
reductive acetylation on (a) Pd/C and (b) AV-17 – 8-Pd catalysts.
The reaction conditions are indicated in Table 1.
The variation of the activity of catalysts in response to a
change of the solvent (ethanol versus benzene) is rather am-
biguous. Indeed, the rate constants of the reaction on Pd/C in
the two cases are virtually the same (Tables 1 and 2). In con-
trast, the rate of reductive acetylation on the metal – polymer
without the formation of a significant amount of products of
incomplete reduction of the nitro group. However, the accu-
mulation of p-phenetidine (III) in the reaction mass indicates
that a process other than hydrogenation of II is the limiting
stage of the reductive acetylation process. The accumulation
of III in a significant amount is due to the possibility of the
acetylation reaction proceeding via two pathways: (i)
reductive acetylation and (ii) acetylation of the primary
amine III formed in situ.
TABLE 2. Effective Reaction Rate Constants (K , M/sec;
eff
±
10 – 22%) and Yields of Phenacetin (I) for the Reductive
Acetylation of p-ethoxynitrobenzene (II) on Various Palladium Cat-
alysts in Benzene *
In order to determine which of the two pathways domi-
nates in a reaction mixture, we performed experiments on the
acetylation of III in a hydrogen-free medium in the presence
of various catalysts (Fig. 2). It was established that the rate of
formation of product I, and especially the product yield from
the equilibrium acetylation process, are significantly lower
as compared to the case of reductive acetylation. Therefore,
we may suggest that the first pathway is dominating.
Pd/C
yield, %
AN-1-Pd
AV-17-8-Pd
Experi-
ment No.
K
eff
K
eff
yield, %
K
eff
yield, %
1
0.15
0.14
0.13
0.14
0.14
0.15
0.13
58.4
59.6
57.7
58.0
58.5
60.0
59.3
0.06
0.05
0.05
0.06
0.05
0.05
0.06
70.2
70.5
70.8
73.3
71.8
71.6
72.7
0.08
0.08
0.07
0.07
0.07
0.08
0.08
80.0
80.1
80.5
81.7
83.8
80.5
81.4
2
3
4
5
6
7
The effective rate constants of the reaction of reductive
acetylation of II to I, calculated per kilogram of catalyst, are
presented in Table 1. As can be seen from these data, Pd/C is
*
For the reaction conditions, see Table 1.

3
26
M. G. Abdullaev
catalysts changes more significantly (drops) on passage from
ethanol to benzene where the degree of polymer swelling is
much lower as compared to that in ethanol [8]. With respect
to stability, the catalyst systems reported here, as well as
those studied previously [5 – 8], can be arranged in the fol-
lowing order: AV-17-8-Pd > AN-1-Pd > Pd/C
agent grade was additionally purified by recrystallization
from ethanol. The degree of purity (98.7%) of the synthe-
sized 4-ethoxyacetanilide (I) with m.p. = 134 – 136°C was
evaluated by TLC and gas chromatography.
REFERENCES
Thus, the synthesis of phenacetin (I) via reductive
acetylation of p-ethoxynitrobenzene (II) should be carried
out in ethanol at 45°C on AV-17-8-Pd or AN-1-Pd catalysts.
These catalysts exceed the Pd/C system with respect to both
selectivity and stability of operation. The proposed sin-
gle-stage synthesis of I from II eliminates contamination of
the target product by the main toxic impurity, p-chloroaceta-
nilide.
1
. USSR State Pharmacopoeia (Xth Edition) [in Russian],
Meditsina, Moscow (1968), p. 510.
2. M. D. Mashkovskii, Drugs [in Russian], Novaya Volna, Moscow
(1996), p. 202.
3. G. A. Melent’eva, Pharmaceutical Chemistry [in Russian],
Meditsina, Moscow (1968).
4
. USSR State Pharmacopoeia (Xth Edition) [in Russian],
Meditsina, Moscow (1968), p. 509.
5. M. G. Abdullaev, A. A. Nasibulin, and M. V. Klyuev, Zh. Org.
Khim., 33, 1759 – 1760 (1997).
EXPERIMENTAL PART
6
7
. M. G. Abdullaev, Khim.-Farm. Zh., 35(1), 42 – 45 (2001).
. M. G. Abdullaev, Khim.-Farm. Zh., 35(10), 30 – 33 (2001).
The preparation of catalysts, the reaction procedures, and
the chromatographic conditions have been described in detail
elsewhere [6]. The initial p-ethoxynitrobenzene (II) of re-
8. M. V. Klyuev, A. A. Nasibulin, and M. G. Abdullaev,
Neftekhimiya, 34(5), 413 – 420 (1994).