Development of optimised synthesis of 4-amino-N-(4-carbamoylphenyl) benzamide for industrial application

Article abstract of DOI:10.1007/s11164-012-0753-0

An efficient two-step synthetic route for preparation of the important Pigment Yellow 181 intermediate 4-amino-N-(4-carbamoylphenyl)benzamide is described. The synthetic pathway reflects requirements that are important for industrial applications. Optimis

Full text of DOI:10.1007/s11164-012-0753-0

Res Chem Intermed (2013) 39:2237–2244
DOI 10.1007/s11164-012-0753-0
Development of optimised synthesis of 4-amino-N-(4-
carbamoylphenyl)benzamide for industrial application
•
Vladimır Pejchal Ales Imramovsky
´
ˇ
´
Received: 2 June 2012 / Accepted: 28 July 2012 / Published online: 14 August 2012
ꢀ Springer Science+Business Media B.V. 2012
Abstract An efficient two-step synthetic route for preparation of the important
Pigment Yellow 181 intermediate 4-amino-N-(4-carbamoylphenyl)benzamide is
described. The synthetic pathway reflects requirements that are important for
industrial applications. Optimisation of the reaction steps was performed to improve
yields and procedures. The overall yield was higher than 78 %.
Keywords Organic technology Á Pigment Yellow 181 Á N-(4-carbamoylphenyl)-4-
nitrobenzamide Á 4-Amino-N-(4-carbamoylphenyl)benzamide Á Catalytic reduction
Introduction
Pigment Yellow 181 (P.Y. 181) is an extremely heat stable, very light-fast reddish
yellow pigment. Its main area of application is in plastics, especially polyolefins. It
is a suitable pigment for other polymers which are processed at high or very high
temperatures. The list includes polyester, polyacetal, and various other technical
plastics. P.Y. 181 is also frequently used to colour spin-dyed viscose rayon and
viscose cellulose. In these media the pigment satisfies the particularly stringent
specifications regarding light-fastness and weather-fastness for use in automobile
interiors. This is a purpose for which only very few organic yellow pigments are
suited [1].
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-012-0753-0) contains supplementary material, which is available to authorized users.
´
V. Pejchal Á A. Imramovsky (&)
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology,
´
University of Pardubice, Studentska 573, Pardubice, Czech Republic
e-mail: ales.imramovsky@upce.cz
123

´
V. Pejchal, A. Imramovsky
2238
4-Aminobenzoylbenzamide (4-amino-N-(4-carbamoylphenyl)benzamide) is an
important intermediate in the production of P.Y. 181. Suitable methodology for
laboratory preparation of this compound is available in the literature [2]. This
synthetic pathway, however, includes reduction of polymer-bound nitroarenes,
which is unsuitable for the industrial production, because of low yields, and the use
of toxic N,N-dimethylformamide as solvent [2]. Hence, a two-step, safe, inexpen-
sive, and high-yield industrial synthetic pathway has been developed and tested for
synthesis of 4-aminobenzoylbenzamide.
Results and discussion
The synthetic pathway is shown in Scheme 1. The synthesis of 4-aminobenzoyl-
benzamide II was designed as a two-step reaction with isolation of N-(4-
carbamoylphenyl)-4-nitrobenzamide I as intermediate.
The first step is the preparation of N-(4-carbamoylphenyl)-4-nitrobenzamide I. It
was decided to prepare this compound by direct reaction of 4-nitrobenzoyl chloride
(4-NBC) and 4-aminobenzoyl amide (4-ABA). The synthesis of intermediate I is
described in the literature [3]. This synthetic pathway is not suitable for industrial
production. For formation of this type of amide bond, a procedure known from the
literature was chosen. In generally, formation of this bond is realised in
dichloromethane in the presence of a base, for example triethylamine (TEA) [4,
5] or pyridine (Py) and sodium hydrogen carbonate [6], and eventually in Py [7].
Because of health risks associated with dichloromethane, in some studies this
solvent was substituted with tetrahydrofuran and sodium hydrogen carbonate [8].
However, tetrahydrofuran is also not suitable for technological use because of the
possibility of formation of unstable peroxides and its high flammability.
For the purpose of this study, toluene was chosen as solvent for the reaction, and
N,N-dimethylaniline (DMA), TEA, and Py were tested as bases. Individual
experiments were performed under the same conditions and using the same amounts
of starting materials. All experiments and their results are listed in Table 1. The
procedure was performed as follows: 4-ABA, toluene, and a base were placed in a
reactor (V = 1.5 L). To this suspension solid 4-NBC was slowly added (temper-
ature was maintained at 40 ꢁC). After addition of the chloride, the reaction mixture
was heated to 80 ꢁC. The product was collected by use of hot filtration. When DMA
2
O2N
H2N
H2, Pd/C
3
O2N
H2N
+
Pyridine
s: TOL,
O
O
2
O
O
4
5
s: DMA
50 °C
3
HN
HN
5
100 °C, 2 h
Cl
NH2
I
II
O
O
4
NH2
NH2
Scheme 1 Developed synthetic pathway. Grey numbers are used for assignment of proton resonances in
the ‘‘Experimental’’ section
123

Synthesis of 4-amino-N-(4-carbamoylphenyl)benzamide
2239
Table 1 Conditions used in optimisation of the preparation of the N-(4-carbamoylphenyl)-4-nitroben-
zamide I
Exp. Reactants and solvents
no.
Addition
Finishing
Yield Yield
(%)
temp (ꢁC) temp (ꢁC) (g)
4-ABA 4-NBC Toluene Base (g) EtOH
(mol)
(mol)
(mL)
(mL)
1
2
3
4
5
6
0.316
0.316
0.316
0.316
0.316
0.316
0.372
0.372
0.372
0.372
0.372
0.372
400
400
400
400
400
400
50.5DMA
40.0TEA
33.0Py
33.0Py
33.0Py
–
60
40
40
60
60
80
80
80
0
0
1,000
1,000
500
14.6
68.7
73.4
72.4
69.9
16.2
76.3
81.5
80.5
77.6
80
100
100
100
500
33.0Py
500
DMA N,N-dimethylaniline; TEA triethylamine; Py pyridine
was used as the base, it was not possible to isolate the product by filtration, and this
experiment was terminated. This base was not used subsequently.
In other experiments, in which TEA or Py was used, the crude product was easily
isolated by filtration and then suspended in water to remove hydrochloride salts.
After this operation, NMR spectroscopy of the isolated products was performed.
When TEA was used, the desired product I was produced in 20 % yield whereas Py
gave a product in approximately a 70 % yield. Other compounds, for example
4-ABA and 4-nitrobenzoic acid, products of hydrolysis of 4-NBC, and other,
unknown, impurities were also detected. To refine the product, ethanol was used.
The crude product I was suspended in hot ethanol for 15 min. The product was
filtered while hot and this material was dried and analysed by NMR spectroscopy.
Compound I was obtained without any impurities. The unsuccessful step of
purification with hot water was performed again in the future experiments. Py was
identified as an optimum base for this reaction and hot ethanol was used to eliminate
pyridinium hydrochloride from the reaction mixture.
The next stage of the research focussed on modification of the reaction
conditions. First, the temperature during addition of 4-NBC was increased to 60 ꢁC
and the temperature at the end of the reaction was increased to 100 ꢁC. The yield of
this experiment increased to 81 % whereas experiments at lower temperatures gave
yields of 76 %. A further increase in temperature (addition temperature 80 ꢁC and
finishing temperature 100 ꢁC) did not change the yield or purity of the compound.
In experiments 4, 5, and 6, the amount of ethanol used during refining was
reduced from 1 L to 500 mL. In experiment 6, addition of 4-NBC as a solution in
toluene was also investigated. Both changes were without any significant effect on
the reaction yields of product I. All the experiments and their results are listed in
Table 1.
The second step of the synthesis was reduction of intermediate I to the final
´
product, 4-aminobenzoylbenzamide 2. The classic Bechamp reduction process [9]
could not be used because of the production of a large amount of wastewater
containing iron oxides. Therefore, attention was focussed on Pd-catalytic reduction
using hydrogen. The optimum solvent for this reaction was investigated. It should
123

´
V. Pejchal, A. Imramovsky
2240
Table 2 Solubility of 4-amino-N-(4-carbamoylphenyl)benzamide II, and toxicity and boiling points of
solvents
Solvent
Solubility of II
LD50 (mg/kg)a
Boiling point (ꢁC)
Toluene
Insoluble
Slightly soluble
Insoluble
Insoluble
Insoluble
Soluble
3–8.41
10,300
1,650
111
Ethanol
78.1
66
Tetrahydrofuran
Butanol
3,500
117.7
101
Dioxane
4,200
14–28 9 103
Dimethyl sulfoxide
N-methylpyrrolidone
N,N-dimethylformamide
N,N-dimethylacetamide
189
Soluble
3,914
204.3
153
Soluble
2,800
Soluble
4,250
166.1
a
ORL-RAT
be an inexpensive and non-toxic solvent in which compound II is soluble. The most
commonly used solvents for reductions are ethanol [10], tetrahydrofuran [11],
toluene, 1,4-dioxane [12], dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimeth-
ylformamide [13], and N,N-dimethylacetamide (DMAC) [14]. Regeneration should
be possible by single distillation or other conventional methods. For the purpose of
this study, most of the solvents commonly used for catalytic reductions are not
suitable, because of their toxicity or the lack of solubility of the starting material. In
Table 2, possible solvents are listed, together with their important properties.
The relatively non-toxic DMAC was chosen as the optimum solvent. The
solubility of II is high, and the solvent can be regenerated by distillation. All
experiments were performed in this solvent. Reductions were performed under
hydrogen pressure (1.5 MPa) in a non-corrosive autoclave (V = 1 L). Palladium
Table 3 Investigation of reaction conditions and yields of the reduction of N-(4-carbamoylphenyl)-
4-nitrobenzamide I in DMAC as solvent
Exp. Reagents
no.
Reaction
conditions
Product II
Compd DMAC c I 3 %
I (g) (g/100 mL) Pd/C (g)
H2
(L)
Temp Time Yield Yield HPLC
(%)
(ꢁC)
(min) (g)
area
220 nm
(%)
7
10
300
300
300
300
450
450
450
3.33
8.33
3
2.3 50–55 60
6.5 50–65 45
7.27 81.4
99
8
25
5
20.7
29.3
92.4
96.2
93
9
34
11.33
16.67
9.93
5
9
50–65 60
95.6
99.6
98.17
98.22
98.77
10
11
12
13
50
4
12.5 50–75 30
12.0 60–80 15
12.5 70–80 45
9.31 20.8
44.7
50
3
36.9
92.2
94.4
93.3
11.11
11.11
1.5
42.3
41.8
50
1.5* ? 0.5 13.5 60–80 65
* Catalyst was separated from experiment 6 and 0.5 g of fresh catalyst was used
123

Synthesis of 4-amino-N-(4-carbamoylphenyl)benzamide
2241
Table 4 Time dependence of hydrogen consumption of chosen experiments 11, 12 and 13
Exp. no. Time (min) Temperature (ꢁC)
Pressure (Mpa)
Hydrogen consumption (L)
Reactor Thermostat Reactor H2 tank Change
Total
11
0
1
51
60
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
68
0
0
60
60.4
61.8
80
67
1.0
1.0
3.5
2.5
4.0
0
1.0
2
64.3
69.5
71.6
81.1
79.8
79.8
69.3
83
66
2.0
5
62.5
60
5.5
8
80
8.5
15
25
70
0
80
56
12.5
12.5
12.5
0
80
56
80
56
0
12
80
35
0
4
80
31
4.0
5.0
2.0
0.5
1.0
0
4.0
9
81.8
79
80
26
9.0
15
25
35
45
55
100
0
80
24
11.0
11.5
12.5
12.5
12.5
12.5
0
79
80
23.5
22.5
22.5
22.5
22.5
44
79.9
79.9
79.9
79.8
59.4
79.3
81.4
81.2
81.0
80.8
80.8
80.8
80.8
80
80
80
0
80
0
13
66
0
9
76.6
80.6
80.8
80.8
80.8
80.8
80.8
80.8
37.5
35
6.5
2.5
3.0
1.0
0.5
0
6.5
15
25
35
45
55
65
115
9.0
32
12.0
13.0
13.5
13.5
13.5
13.5
31
30.5
30.5
30.5
30.5
0
0
(3 %) in activated carbon as a 50 % paste with water was used as catalyst.
Hydrogen consumption was monitored by the pressure decrease in the 1-L hydrogen
high-pressure tank. The optimum concentration of I, the amount of catalyst, and the
temperature course of reduction was investigated. The experimental conditions and
yields are summarised in Table 3.
Table 3 shows that the concentrations of the starting material increased from
3.33 g/100 mL DMAC in experiment 1, to 16.67 g/100 mL of DMAC in
experiment 4. The highest concentration is the maximum solubility of I and the
starting material crystallised in the reaction mixture. The optimum concentration of
the starting material I is approximately 11 g in 100 mL of DMAC. Half of the
amount of catalyst used in experiment 6 was used. In comparison with experiment 5,
the reaction time was extended. The yield of the desired product II was then higher
123

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V. Pejchal, A. Imramovsky
2242
15.0
12.5
10.0
7.5
Experiment 11
Experiment 12
Experiment 13
5.0
2.5
0.0
0
10
20
30
40
50
Time of reduction [min]
Fig. 1 Graphical representation of the time-dependence of hydrogen consumption
than 90 %. In experiment 7, the catalyst isolated from experiment 6 was used with
0.5 g new catalyst. The yield of this experiment was also comparable with that of
experiments 5 and 6. The purity of isolated products was monitored using HPLC,
and the optimum concentration was higher than 98 % for all experiments.
The course of hydrogenation in experiments 11, 12, and 13 was monitored. The
time dependence of hydrogen consumption is shown in Table 4.
The course of hydrogenation in these experiments is shown graphically in Fig 1.
It was concluded that use of half the amount of catalyst in experiment 13 does not
dramatically affect the reaction rate (green line).
In all of the experiments, the same procedure was used for isolation of product II.
When hydrogenation complete, the reaction mixture was stirred for 1 h at 80 ꢁC.
The catalyst was then removed by filtration and washed with DMAC (100 mL,
55 ꢁC). Part of the solvent was removed at low pressure. Cooling of the mixture and
the addition of distilled water caused precipitation of the desired product II. This
was isolated by filtration and dried at 80 ꢁC to constant weight. This material was
1
then analysed by use of HPLC and H and 13C NMR spectroscopy.
Conclusion
A short and efficient synthesis of 4-amino-N-(4-carbamoylphenyl)benzamide II
has been described. This study provides new ideas for synthesis of this important
intermediate. The developed procedure also helped to eliminate undesirable
impurities, which can be a major problem with low-quality products. The overall
yield was higher than 78 %, and the prepared compound can be used directly into
123

Synthesis of 4-amino-N-(4-carbamoylphenyl)benzamide
2243
the next step of the synthesis of P.Y. 181. The developed methodology is now ready
for industrial application.
Experimental
General information
All reagents and solvents were purchased from commercial sources and were
technical grade. NMR spectra were measured in DMSO-d6 solutions at ambient
1
temperature on a Bruker Avance 500 (500 MHz for H, 125.77 MHz for 13C).
Coupling constants are presented in Hz. Proton chemical shifts in DMSO-d6 are
referenced to the middle of the solvent multiplet (d = 2.50). 13C NMR spectra were
measured by using an APT pulse sequence. Carbon chemical shifts are referenced to
the middle of the solvent multiplet (d = 39.5 in DMSO-d6). A LaChrom Merck
Hitachi HPLC separation module and a LaChrom Merck Hitachi L7450 photodiode
array detector were used. A Symmetry Shield RP-18 5 lm, 4.0 mm 9 150 mm,
chromatographic column was used. A mixture of MeOH p.a. (40 %) and Milli-Q
HPLC-grade H2O (60 %) was used as mobile phase; the flow rate was 1.0 mL/min,
the injection volume 10 lL, and the column temperature 25 ꢁC, all at ambient
sample temperature. The detection wavelength was 220 nm.
General procedure for preparation of compound I, and its characterisation
N-(4-Carbamoylphenyl)-4-nitrobenzamide (I) (experiment no. 5). Toluene (400 mL),
4-ABA (43 g, 0.316 mol), and Py (33 g, 0.417 mol) were placed in a nitrogen-
flushed autoclave (V = 1.5 L). The mixture was heated to 60 ꢁC and 4-NBC (69 g,
0.372 mol) was slowly added. The reaction mixture was than heated to 100 ꢁC and
stirred at this temperature for 2 h. The precipitate was isolated by filtration and
washed with hot toluene (200 mL, 80 ꢁC). Crude intermediate I was put back in the
autoclave and 96 % ethanol (500 mL) was added. The suspension was heated to
reflux and then stirred for 2 h. The product was isolated by filtration while hot and
washed with hot ethanol (200 mL, 70 ꢁC). The product was dried in an oven
(80 ꢁC) to constant weight, to give 72.4 g of desired intermediate I with purity
higher than 99 % (HPLC).
1
White solid, yield 70.7 %. H NMR (500,13 MHz, DMSO-d6): d 10.84 (1H, s,
NH–CO); 8.39 (2H, d, J = 8,7 Hz, H2); 8.19 (2H, d, J = 8,7 Hz, H3); 8.04 (1H, s,
NH2–CO); 7.92 (2H, d, J = 8,7 Hz, H5); 7.86 (2H, d, J = 8,7 Hz, H4); 7.33 (1H, s,
NH2–CO). 13C NMR (125,77 MHz, DMSO-d6) : d• 168.1; 164.8; 149.6; 141.7;
140.7; 129.9; 129.8; 128.7; 124.0; 120.1.
General procedures for preparation of compound II, and its characterisation
4-Amino-N-(4-carbamoylphenyl)benzamide (II) (experiment no. 12). N-(4-Carba-
moylphenyl)-4-nitrobenzamide I (50 g), DMAC (400 mL) and Pd/C 3 % (water
paste 1.5 g) were placed in a non-corrosive pressure autoclave (V = 1 L).
123

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V. Pejchal, A. Imramovsky
2244
The reaction mixture was heated to 50 ꢁC and hydrogen was introduced under the
surface of the mixture (the pressure of hydrogen was constant at 1.5 MPa during the
operation). The temperature of reaction mixture was maintained between 60 and
80 ꢁC. When hydrogen consumption was constant for more than hour, reduction
was terminated. The reaction mixture was filtered through a pressure filter to
remove the catalyst and the isolated catalyst was washed with DMAC (50 mL,
55 ꢁC). DMAC (280 g) was removed from the filtrates under reduced pressure
(26 mBar). The content of the autoclave was cooled to 30 ꢁC and distilled water
(200 mL) was slowly added. The reaction mixture was stirred for another 1 h.
Precipitated product II was isolated by filtration, washed with water (100 mL), and
dried in oven (80 ꢁC) to constant weight, to give 42.3 g of desired 4-amino-N-
(4-carbamoylphenyl)benzamide II with purity higher than 98 % (HPLC).
1
White solid, yield 94.4 %. H NMR (500,13 MHz, DMSO-d6) : d 10.06 (1H, s,
NH–CO); 8.00 (1H, s, NH2–CO); 7.84 (4H, m, H4, H5); 7.75 (2H, d, J = 8,6 Hz,
H3); 7.26 (1H, s, NH2–CO); 6.66 (2H, d, J = 8,6 Hz, H2); 5.80 (2H, s, NH2). 13C
NMR (125,77 MHz, DMSO-d6): d 168.5; 166.3; 152.8; 142.9; 130.1; 130.0; 128.6;
121.1; 119.8; 113.2.
Acknowledgments This study was supported by the institutional support of The Ministry of Education,
Youth, and Sports of the Czech Republic and by the University of Pardubice, Faculty of chemical
Technology.
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