Borate reduction of nitrophenols

A process for the direct production of aminophenol and N-acetyl-p-aminophenol from nitrophenols using a borate ion additive during hydrogenation to eliminate undesirable by-products and color formation.

FIELD OF INVENTION 
This invention relates to the production of aminophenols and 
N-acetyl-p-aminophenol. 
BACKGROUND OF INVENTION 
Aminophenols are generally known to be useful as dye intermediates, 
particularly for the so-called azo and sulfur dyes. Aminophenols are 
intermediates for pharmaceuticals, such as for amino salicyclic acid or 
APAP. In addition, aminophenols are used as oil additives, as photographic 
developers and as antioxidants. 
N-acetyl-p-aminophenol (APAP) is a known compound widely used as an 
analgesic and anti-pyretic agent in various therapeutic preparations. A 
commercial method for preparing N-acetyl-p-aminophenol involves reduction 
of p-nitrophenol to p-aminophenol and then acetylation wherein the 
p-aminophenol is dispersed in a non-aqueous solvent and/or excess 
anhydride. 
The conventional process for the reduction of p-nitrophenol to produce 
p-aminophenol involves catalytically hydrogenating the p-nitrophenol in 
the presence of strong acids such as sulfuric, hydrochloric and phosphoric 
acids as shown in U.S. Pat. No. 2,198,249. Other acids such as oxalic or 
sulfonic acids as disclosed in U.S. Pat. No. 2,525,515 have also been 
used. Metal catalysts used for reduction include aluminum as in U.S. Pat. 
No. 2,525,515; platinum, palladium or noble metal catalysts and their 
oxides as described in U.S. Pat. Nos. 2,947,781; 3,076,030; 3,079,435; 
3,328,465; 3,383,416; 3,654,365 and 3,383,416; and molybdenum sulfide or 
platinum sulfide-on-carbon as in U.S. Pat. No. 3,953,309. 
In all of these methods, the p-aminphenol which is obtained is relatively 
impure and requires substantial purification before it can be further used 
in the production of APAP. Unfortunately, by-products are formed in the 
reduction of the p-nitrophenol and in the acetylation which lead to 
off-color and impure APAP thus requiring further purification and 
crystallization steps to produce an acceptable product as described in 
U.S. Pat. Nos. 3,658,905; 3,694,508; 3,703,598; 3,717,680; 3,845,129; 
3,876,703 and 3,953,283. 
Attempts to overcome the discoloration and by-product formation by various 
techniques have not been entirely successful or economical. The use of a 
reducing atmosphere and non-oxidizing acids is described in U.S. Pat. Nos. 
3,177,250; 3,042,719 and 3,223,727. More recently simultaneous reduction 
of p-nitrophenol and acetylation of the p-aminophenol product while using 
an acetic acid solvent or acetic anhydride solvent system without prior 
isolation of the p-aminophenol has been reported as in U.S. Pat. Nos. 
3,076,030 and 3,341,587. 
The principle method for the preparation of p-nitrophenol begins with 
nitration and chlorination of benzene to produce p-chloronitrobenzene. The 
p-chloronitrobenzene then is subjected to alkaline hydrolysis to produce 
the p-nitrophenol. The p-nitrophenol must be purified and separated from 
the hydrolysate before it can be used to prepare acceptable APAP according 
to the conventional processes. Heretofore in the preparation of 
N-acetyl-p-aminophenol (APAP) it has been necessary to follow expensive 
and laborious purification procedures for p-nitrophenol, p-aminophenol and 
the APAP to insure an acceptably pure APAP product for therapeutic 
preparations. 
SUMMARY OF THE INVENTION 
In accordance with this invention, a process is provided for the production 
of aminophenol which comprises the steps of hydrolysing halonitrobenzene 
to form a hydrolysate product containing the corresponding nitrophenol, 
hydrogenating the hydrolysate product in the presence of borate ion to 
convert the nitrophenol to aminophenol and recovering the aminophenol. 
In another embodiment, the present invention is directed to a process for 
the production of N-acetyl-p-aminophenol which comprises the steps of 
hydrolysing p-chloronitrobenzene to form a hydrolysate product containing 
p-nitrophenol, hydrogenating the hydrolysate product in the presence of 
borate ion to convert said p-nitrophenol to p-aminophenol, treating the 
p-aminophenol with acetic anhydride to affect acetylation of said 
p-aminophenol and recovering the N-acetyl-p-aminophenol from the final 
reaction product. 
It has unexpectedly been found that impure p-nitrophenol hydrolysate can be 
directly hydrogenated in the presence of borate ion without the formation 
of undesirable by-products and color and that a highly purified 
N-acetyl-p-aminophenol (APAP) may thereby be produced. Moreover, according 
to this invention boric acid is the superior acid for the reduction of 
nitrophenols which avoids interference of undesirable side reactions that 
accompany direct hydrogenation of nitrophenol hydrolysates using previous 
methods. The elimination of the purification step for the p-nitrophenol 
containing hydrolysate (i.e. from hydrolysis of p-chlorobenzene) thus 
providing direct hydrogenation and acetylation to produce a high purity 
N-acetyl-p-aminophenol (APAP) in a commercially significant development. 
DESCRIPTION OF PREFERRED EMBODIMENTS 
The present invention enables the use of the nitrophenol obtained directly 
from the hydrolysis of halonitrobenzene for the production of aminophenols 
by subjecting the nitrophenol to hydrogenation without prior separation 
and purification procedures. According to this invention, the presence of 
the borate ion during the reduction of the nitrophenol containing total 
hydrolysate from the hydrolysis of halonitrobenzenes, such as the 
chlorine, fluorine, or bromine derivatives, eliminates interference and 
side reactions caused by the presence of undesirable by-products and 
leading to impurities and color formation. 
Another embodiment of the present invention relates to the production of 
N-acetyl-p-aminophenol (APAP) directly from p-nitrophenol produced by the 
hydrolysis of p-chloronitrobenzene without the need for extensive 
separation and purification procedures. It has unexpectedly been found 
that the presence of borate ion during reduction of p-nitrophenol permits 
the production of highly pure N-acetyl-p-aminophenol without laborious 
purification steps for the p-nitrophenol or the p-aminophenol. 
Since the mechanisms involved in the hydrolysis of halobenzenes and the 
production of N-acetyl-p-aminophenol from chloronitrobenzene are 
complicated, applicant does not wish to be bound by any theory. 
Nevertheless, it appears that borate ion forms some complex with 
by-products produced in the hydrolysis of halonitrobenzenes and that the 
borate complex avoids undesirable side effects and discolorations that 
normally occur in the subsequent hydrogenation. It is, therefore, further 
believed that there are at least two sources for impurities and 
discoloration during the production of N-acetyl-p-aminophenol, i.e. one 
sourse arising during hydrolysis of the p-chloronitrobenzene and the other 
originating during hydrogenation of the p-nitrophenol. 
The commercial rate to the production of N-acetyl-p-aminophenol involves 
the following steps: 
(1) Hydrolysis of p-chloronitrobenzene to produce p-nitrophenol, 
(2) Separation and purification of p-nitrophenol, 
(3) Reduction of the p-nitrophenol to p-aminophenol, 
(4) Separation and purification of the p-aminophenol, 
(5) Acetylation of the p-aminophenol to produce N-acetyl-p-aminophenol, and 
(6) Separation and purification of the N-acetyl-p-aminophenol. 
As previously discussed, it has been found that if unpurified p-nitrophenol 
is the starting material for the reduction and acetylation, then an impure 
N-acetyl-p-aminophenol is produced. It would be desirable if one could 
proceed directly from p-chloronitrobenzene without separation and 
purification of the p-nitrophenol produced in the hydrolysis step. 
Therefore, according to the process of the instant invention, a source of 
borate ion, such as boric acid may be added to the p-nitrophenol before 
the hydrogenation and acetylation for production of 
N-acetyl-p-aminophenol. Preferably, the boric acid is added to the 
p-chloronitrobenzene before or during the subsequent hydrolysis and the 
p-nitrophenol containing hydrolysate used directly in acetylation for 
production of highly purified APAP. 
The alkaline hydrolysis of p-nitrochlorobenzene produces a suspension of 
sodium-p-nitrophenol in a sodium chloride solution. To insure uniformity 
in the composition prior to reduction, the sodium-para-nitrophenate 
preferably may be centrifuged and reconstituted for reduction. Nitrites 
produced in the hydrolysis are preferably destroyed by addition of 
sulfamic acid and the neutralization of the sodium salt may be 
accomplished by addition of sulfuric acid. Similarly the p-nitrophenol may 
be treated with charcoal before hydrogenation. In conventional processes, 
the soluble by-products remain with the p-nitrophenol solution and result 
in formation of undesirable reactants and color bodies if the 
p-nitrophenol is not further purified as by distillation or 
crystallization before hydrogenation and acetylation. Moreover, the use of 
various conventional acids during reduction, such as sulfuric, 
hydrochloric, phosphoric, or milder organic acids such as oxalic or acetic 
do not overcome the deleterious effect of direct hydrogenation of the 
p-nitrophenol produced as thus described. Unexpectedly it has been found 
that addition of borate ion in the form of boric acid or boric acid salts 
to the thus produced non-purified p-nitrophenol followed by reduction and 
acetylation overcomes the undesirable side reactions and permits 
production of an acceptable highly pure N-acetyl-p-aminophenol product. 
The amount of borate ion used must be sufficient to complex by-products 
that lead to undesirable side reactions and color formation. Thus, from 
about 0.5 to about 20 mole percent boric acid based on p-nitrophenol may 
be used. Preferably, from about 10 to about 15 mole percent boric acid 
based on p-nitrophenol is used when proceeding from the 
p-chloronitrobenzene hydrolysate. The borate ion may be introduced at 
different points in the APAP synthesis. For example, it may be added 
before, during or after the hydrolysis of the p-chloronitrobenzene. For 
elimination of undesirable reactions and color formation, borate ion must 
be present during the hydrogenation stage of the process of this 
invention, and to provide maximum benefit of the complexing activity. 
Therefore, according to this invention, conventional acid catalysts may be 
used when proceeding from a total hydrolysate of p-nitrophenol and will 
result in high purity N-acetyl-p-aminophenol only if the borate ion is 
also present. 
The hydrogenation catalyst preferred for the reduction of the p-nitrophenol 
to p-aminophenol is palladium-on-carbon. Other hydrogenation catalysts may 
be used without affecting the overall process of this invention. For 
example, nickel, platinum, palladium or noble metal catalysts and their 
oxides may be used. During hydrogenation the temperature is preferably 
held below 110.degree. C. and most preferably from about 95.degree. C. to 
about 100.degree. C. The process may be carried out at a hydrogen pressure 
from slightly above atmospheric pressure to several hundred atmospheres. 
Preferably a hydrogen pressure of from about 60 to about 80 psi is used. 
After the available p-nitrophenol has been completely hydrogenated to 
p-aminophenol, the reaction mixture is preferably filtered to recover 
catalyst. The p-aminophenol may be recovered at this stage. However, 
according to the teaching of this invention, one may acetylate the 
p-aminophenol without prior separation or purification. Direct acetylation 
of the reduction product and minimization of undesirable side effects is 
possible operating preferably at a temperature of from about 60.degree. C. 
to about 80.degree. C. Thus a high purity APAP is obtained using an 
aqueous solvent system. 
In determining purity of the N-acetyl-p-aminophenol, the caustic test and 
granulation test were employed. In the caustic test 100 mg. of 
N-acetyl-p-aminophenol is placed in a 5.0 ml. volumetric flask and diluted 
to volume with a 10% sodium hydroxide solution. A completely colorless 
solution upon the dissolution of the N-acetyl-p-aminophenol indicates 
acceptable pharmaceutical quality. 
In the granulation test 10.0 gm. of N-acetyl-p-aminophenol (ground to 100 
mesh) is placed in a 50 ml. beaker and 10.0 ml. of water is added to make 
a level paste. The paste is heated for 21/2 hours at 50.degree.-55.degree. 
C. and then cooled to room temperature. No discoloration of the hardened 
mass indicates acceptable pharmaceutical grade purity. Any pink, yellow or 
gray discoloration indicates impure N-acetyl-p-aminophenol. 
Thus, as previously described, if the N-acetyl-p-aminophenol product is 
discolored, it is impure. A white product or colorless product solution 
indicates purity, but not necessarily an acceptable purity for a 
pharmaceutical grade material. For a pharmaceutical grade purity, the 
N-acetyl-p-aminophenol product should be white and also pass the caustic 
test and the granulation test as set forth in the above description.

The invention is illustrated by the following examples which, however, are 
not to be taken as limiting in any respect. 
EXAMPLE I 
Boric Acid Reduction 
In calculation of the crude yield of the following examples, the actual 
weight in grams of the recovered APAP is divided by the theoretical yield 
of APAP in grams. The theoretical yield is calculated by multiplying the 
weight in grams of the starting material (p-nitrophenol) by the ratio of 
the molecular weight of APAP to the molecular weight of p-nitrophenol. 
Similarly the weight in grams of the APAP recovered from recrystalization 
divided by the theoretical yield provides the recrystalized yield. 
The following example shows the use of boric acid during hydrogenation of 
p-nitrophenol and acetylation of the p-aminophenol product: 
47 lbs. of p-chloronitrobenzene in 118 lbs. of water was mixed with 50 lbs. 
of 50% NaOH and heated at 170.degree.-175.degree. C. for 3 hours to 
hydrolyze the p-chloronitrobenzene to p-nitrophenol. 
34.9 lbs. of the total hydrolysis mixture (containing 6.5 lbs. of 
p-nitrophenol) was charged into a jacketed reaction vessel. Excess caustic 
and sodium-p-nitrophenolate was then neutralized by adding 695 g. of 50% 
sulfuric acid. Then, 65.5 g. (5 mole percent based on p-nitrophenol) of 
boric acid and 14 g. of 5% palladium-on-carbon catalyst was added. The 
charged vessel was purged with hydrogen, sealed, heated to a temperature 
of about 100.degree. C. at 60-80 psi and maintained at 
95.degree.-100.degree. C. throughout the hydrogenation. A total of 3576 g. 
of 50% sulfuric acid was fed into the reaction during hydrogenation. 
Hydrogenation was completed in 3 hours. The product was filtered to 
recover the catalyst and then the filtrate acetylated with acetic 
anhydride by the conventional procedure. 
Quality of the APAP was much improved over reductions conducted using no 
boric acid and was only slightly off-color. 
EXAMPLE II 
Reduction of Total Hydrolysate 
This comparative experiment demonstrates the necessity of boric acid for 
production of high quality N-acetyl-p-aminophenol beginning with total 
hydrolysate from p-chloronitrophenol hydrolysis: 
______________________________________ 
N-acetyl-p-aminophenol 
Caustic 
Granulation 
Acid Yield % Color Test Test 
______________________________________ 
H.sub.2 SO.sub.4 
86 Off White Fail Poor 
Acetic 85 Pink Fail Poor 
H.sub.3 PO.sub.4 
83 Gray Fail Poor 
H.sub.2 SO.sub.4 + Boric 
87 White Pass Pass 
______________________________________ 
As can be seen from the above results, the presence of the borate ion 
results in a high purity colorless product without decreasing the overall 
product yield. 
EXAMPLE III 
This example demonstrates the combined boric/sulfuric acid reduction of 
total hydrolysate from p-chloronitrophenol. 
47 lbs. of p-chloronitrobenzene in 118 lbs. of water was mixed with 50 lbs. 
of 50% NaOH and heated at 170.degree.-175.degree. C. for 3 hours to 
hydrolyze the p-chloronitrobenzene to p-nitrophenol. 
34.9 of the total hydrolysis mixture (containing 6.5 lbs. of p-nitrophenol) 
was charged into a jacketed reaction vessel. Excess caustic and 
sodium-p-nitrophenolate was then neutralized by adding 695 g. of 50% 
sulfuric acid. Then, 131 g. (10 mole percent based on p-nitrophenol) of 
boric acid and 14 g. of 5% palladium-on-carbon catalyst was added. The 
charged vessel was purged with hydrogen, sealed, heated to a temperature 
of about 100.degree. C. at 60-80 psi and maintained at 
95.degree.-100.degree. C. throughout the hydrogenation. A total of 3576 g. 
of 50% sulfuric acid was fed into the reaction during hydrogenation. 
Hydrogenation was completed in 3 hours. The product was filtered to 
recover the catalyst and then the filtrate acetylated with acetic 
anhydride. 
An acceptable and colorless N-acetyl-p-aminophenol solution was recovered. 
Upon recrystallization from 3 parts of water, a high quality white 
pharmaceutical grade N-acetyl-p-aminophenol was obtained at 87.2% yield. 
EXAMPLE IV 
This experiment relates to a large scale process and to the production of 
an acceptable pharmaceutical quality APAP. 
A 30 gal. jacketed vessel is charged with 25.15 lbs. of 
p-nitrochlorobenzene, 26.8 lbs. of 50% sodium hydroxide and 63 lbs. of 
water. The charge is heated at 170.degree.-175.degree. C. for 3 hours to 
effect hydrolysis to p-nitrophenol. Thereafter, the charge is cooled and 
18 lbs. of 50% sulfuric acid, 0.98 lbs. of boric acid (10 mole % on 
p-nitrophenol), and 50 g. of 5% palladium-on-carbon catalyst are added. 
The mixture is heated to 100.degree.-105.degree. C. under a hydrogen 
pressure of 70 psig and 17 lbs. of 50% sulfuric acid are fed during the 
course of the hydrogenation. After the theoretical quantity of hydrogen is 
absorbed, the catalyst is filtered and the filtrate is acetylated with 17 
lbs. of acetic anhydride. Thereafter, the batch is cooled and 
crystallized. The crystals are filtered yielding 20.7 lbs. of crude APAP 
corresponding to a 85.8% of the theoretical yield. 
Upon one recrystallization from 43 lbs. of water containing 0.4 lbs. of 
sodium hydrosulfite glistening white crystals of pharmaceutical grade APAP 
are obtained in 92% recovery. 
EXAMPLE V 
The following runs demonstrate the use of boric acid as the sole acid 
catalyst during reduction of p-nitrophenol and the preparation of highly 
pure N-acetyl-p-aminophenol therefrom. 
In the following runs, boric acid was added to p-nitrophenol in water and 
the mixture hydrogenated to completion in the presence of a 
palladium-on-carbon catalyst at 65.degree.-78.degree. C. and 68-72 psig. 
The p-aminophenol reaction product was filtered to recover the catalyst 
and then subjected to acetylation. 
__________________________________________________________________________ 
p-nitro- 5% Pd on 
Boric 
Hydrogenation 
Acetic 
Crude 
Recrystal. 
Granula- 
Phenol 
Carbon 
Carbon 
Acid 
Temp. Time 
Anhydride 
Yield 
Yield Caustic 
tion 
Run 
lbs. 
oz. gms. lbs. 
.degree.C. 
PSIG 
Hrs. 
lbs. % % Test 
Test 
__________________________________________________________________________ 
A 38 8 140 6 68-70 
68-72 
8.5 
20 -- -- Pass 
Pass 
B 38 8 140 3 69-70 
70-72 
9.0 
28 67 56 Pass 
Slt. Pink 
C 38 8 80 3 68-72 
68-72 
7.0 
28 80 75 Pass 
Pass 
D 38.sup.b 
8 80 3 70 68-72 
4.0 
28 69 60 Pass 
Slt. Gray 
E 38 8 80 3 68-70 
68-70.sup.c 
4.0 
28 91 80 Pass 
Pass 
F 38 8 80 3 65-78 
68-72 
4.0 
28 73 -- Pass 
Pass 
__________________________________________________________________________ 
.sup.a 5% Palladium on Charcoal 50% water wet. 
.sup.b Neutralized 55.5 lbs. of sodium pnitrophenate to pH 1.0 with 14.5 
lbs. 93% sulfuric to give the equivalent 38 lbs. pnitrophenol. 
.sup.c After 60% of hydrogen was absorbed, pressure was reduced to 22 PSI 
to control feed rate of hydrogen. 
EXAMPLE VI 
Analysis of APAP Compared to Purity Standards 
The following analysis compares a typical APAP product produced by the 
boric acid process of this invention with USP Standards: 
______________________________________ 
ANALYTICAL RESULTS USP STANDARDS 
______________________________________ 
Caustic Soln. 
Clear, Colorless 
Report 
Solubility Passes To Pass 
Melting Range 
168.1-169.1.degree. C. 
168-172.degree. C. 
pH 5.5 5.3-6.5 
Residue on Ignition 
Nil 0.1% Max. 
Sulfide Trace No Trace 
Heavy Metals Passes 10 ppm Max. 
1/10 Ethanol Soln. 
Clear, Colorless 
Clear & Colorless 
McNeil Limits 
of Color 0.030 0.030A Max. 
Sat. Water Soln. 
Colorless Report 
ADDITIONAL 
STANDARDS 
Granulation Satisfactory Report 
______________________________________ 
While the invention has been described in connection with specific 
embodiments thereof, it will be understood that it is capable of further 
modifications and this application is intended to cover any variations, 
uses or adaptations of the invention and including such departures from 
the present disclosure as come within known or customary practice in the 
art to which this invention pertains and as may be applied to the 
essential features hereinbefore set forth, and as fall within the scope of 
the invention.