A new route for the preparation of 5-hydroxyisophthalic acid

Article abstract of DOI:10.1021/op0100302

A new, simple and practical, two-stage process for the preparation of 5-hydroxyisophthalic acid (5-HIPA) from isophthalic acid is described. In the first stage, isophthalic acid is brominated by bromine in oleum, in the presence of an iodine catalyst, to give crude 5-bromoisophthalic acid (5-BIPA). In the second stage the crude 5-BIPA is hydrolyzed with aqueous NaOH, in the presence of a copper catalyst, to give crude 5-HIPA, with a purity of ca. 98%. Both stages of the process were optimized. A single crystallization of the crude 5-HIPA from water gives the product in a purity of more than 99%. The overall yield of pure 5-HIPA is 65-70%.

Full text of DOI:10.1021/op0100302

Organic Process Research & Development 2002, 6, 591−596
Articles
A New Route for the Preparation of 5-Hydroxyisophthalic Acid
Mark Gelmont* and Jakob Oren
IMI (TAMI) Institute for Research and DeVelopment, Ltd., P.O. Box 10140, Haifa Bay 26111, Israel
Abstract:
Scheme 1. Industrial method for the preparation of
-HIPA
5
A new, simple and practical, two-stage process for the prepara-
tion of 5-hydroxyisophthalic acid (5-HIPA) from isophthalic
acid is described. In the first stage, isophthalic acid is bromi-
nated by bromine in oleum, in the presence of an iodine catalyst,
to give crude 5-bromoisophthalic acid (5-BIPA). In the second
stage the crude 5-BIPA is hydrolyzed with aqueous NaOH, in
the presence of a copper catalyst, to give crude 5-HIPA, with a
purity of ca. 98%. Both stages of the process were optimized.
A single crystallization of the crude 5-HIPA from water gives
the product in a purity of more than 99%. The overall yield of
pure 5-HIPA is 65-70%.
Scheme 2. New method for the preparation of 5-HIPA
KOH at 250 °C9a and from 6-bromo-3-methoxy-5-oxo-
cyclohepta-1,3,6-trienecarboxylic acid, with aqueous KOH
at 200 °C, (5) from hydroxyanthraquinones with KOH, in
the melt, for example, from rufigallic acid (1,2,3,5,6,7-
Introduction
1
0a
5-Hydroxyisophthalic acid (5-HIPA) is used as a starting
hexahydroxy anthraquinone) or from chrysophanic acid
1
0b
material for a variety of products such as drugs, agrochemi-
cals, and polymers. Lately, the interest in 5-HIPA as an
intermediate for drugs has increased, as it is used in the
production of X-ray contrast materials (radiopaques) for
example, iomeprol.2
(dihydroxy-2-methyl-anthraquinone).
1
Among the prior art processes, the one based on sulfona-
tion and caustic fusion appears to be the most effective, and
it is used as an industrial process for manufacturing 5-HIPA
(Scheme 1).
-5
Various methods for the preparation of 5-HIPA are
described in the literature. The main published methods for
The main feature of this process is the need for a high
reaction temperature together with a strong basic medium.
Such severe reaction conditions lead to corrosion of the
equipment and the necessity for its frequent replacement.
The aim of this work was to develop a simple, economi-
cal, and practical process, with industrial potential, for the
preparation of 5-HIPA in a high yield and with a high purity,
which can be carried out under relatively mild temperature
conditions.
preparing 5-HIPA include (1) sulfonation of isophthalic acid
6
(
IPA) followed by caustic fusion, (2) a method based on
7
the diazotization of 5-aminoisophthalic acid, and (3) oxida-
tion of a substituted xylene. (4) Alkaline rearrangement of
8
tropone-carboxylic acids, for example, from 6-methoxy-3-
oxo-cyclohepta-1,4,6-trienecarboxylic acid, with aqueous
*
To whom correspondence should be addressed. Telephone: +972-4-
5-HIPA was prepared by the bromination of IPA to obtain
8
469567. Fax: +972-4-8469320. E-mail: mark@tami-imi.co.il.
(
(
(
(
(
(
1) Sasaki, S.; et al. JP 63,122,668, JP 62,99,371, and WP 195,402.
2) Davies, A.; Felder, E.; Tirone, P. Drugs Fut. 1990, 15, 1074-1076.
3) . DD 291990, 18 July, 1991,
5-bromoisophthalic acid (5-BIPA), followed by hydrolysis
to 5-HIPA and purification of the final product (Scheme 2).
This method is new and was patented by us in 1997.11
Preparation of 5-BIPA. Literature Search. A literature
review has been carried out on the preparation of 5-BIPA.
4) p.A.). EP 185130, 25 June, 1986.
5) E.R. and Sons, Inc.). U.S. Patent 3,914,294, 21 October, 1975.
6) (a) Lonnies, H. Chem. Ber. 1880, 13, 703-706. (b) Heine, K. Chem. Ber.
1
880, 13, 491-497. (c) ( Eastman Kodak). U.S. Patent 2,756,149. 1954.
d) Cake, W. R. Continuous Fusion Apparatus. (Alliance Color and Chemical
Corp.). U.S. Patent 3,285,706, 26 September, 1960; Chem. Abstr. 1966,
(
(8) Aoyama, T.; Ishihara, F. (Mitsubishi Gas Chemical Co., Ltd. Japan). Jpn
Kokai JP 51108030, 25 September, 1976 Showa; Chem. Abstr. 1977, 86,
106181a.
3
0405r. (e) Gensler, W. J.; Solomon, P. H. J. Org. Chem. 1973, 38, 1726-
1
731; Chem. Abstr. 1973, 78, 159893a. (f) Minami, K.; Takahashi, S.;
Furikado, K. (Taoka Dyestuffs Mfg. Co., Ltd., Japan). Japan Kokai JP
1052142, 8 May, 1976, Showa; Chem. Abstr. 1977, 86, 16407z. (g)
Takahashi, S.; Furikado, K.; Minati, K. (Taoka Chemical Co., Ltd. Japan).
(9) (a) Johns, R. B.; Johnson, A. W.; Langemann, A.; Murray, J. J. Chem. Soc.
1955, 309-313. (b) Johns, R. B.; Johnson, A. W.; Murray, J. J. Chem.
Soc. 1954, 198-202.
(10) (a) Schreder, J. Monatsh Chem 1 1880, 431-441. (b) Leger, M. E. Hebd.
Seances Acad. Sci. 1912, 154, 281-296; J. Pharm Chim. 1912, (7), 5, 286-
288.
5
Japan Tokkyo Koho JP 60035332 B4, 14 Aug 1985; Chem. Abstr. 1986,
1
04, 33857d. (h) Ueno, R.; Sakota, K.; Naito, Y.; Kishimoto, M. Eur. Pat.
Appl. EP 92772 A1, 2 November, 1983 (Kabushiki Kaisha Eiyaku Oyo
Kenyujo, Japan); Chem. Abstr. 1994, 100, 87657z.
7) Beyer, B. J. Prakt. Chem. 1882, (2) 25, 505-517.
(11) Gelmont, M.; Bercovici, Y.; Oren, J. Process for the Preparation of
5-Hydroxyisophthalic Acid. U.S. Patent 5,703,274, 1997.
(
1
0.1021/op0100302 CCC: $22.00 © 2002 American Chemical Society
Vol. 6, No. 5, 2002 / Organic Process Research & Development
•
591
Published on Web 07/30/2002

Scheme 3. Main products of IPA bromination
Table 1. Influence of the quantity of iodine catalyst and the
temperature on the reaction (IPA 50 g, 0.3 mol; oleum 239
3 2
g, 20% SO ; Br /IPA molar ratio 0.64; washing with 0.8 L
of H O at 80-90 °C)
2
composition, GC, %
iodine %
expt w/w IPA
temp,
°C
time,
h
IPA BIPA IIPA DBIPAb
1a
2
3
4
5
-
102-105
102-105
102-105
102-105
79-80
5.0 89.0
9.8
3.6 82.2
1.0 81.7
0.9 81.0
-
-
1.0
5.0
4.0
3.0
0.5
12.5
15.5
15.1
2.6
2.0
3.0
2.0
1.1
2.2
0.8
0.7
1.7
1.6
5.0 15.5 81.1
1
4.0
9.0
5.0 88.2
7.9 85.9
5.9 87.2
6.1
4.4
4.8
The main methods are (1) bromination of IPA in oleum, to
6
3.0
84-88
12
yield predominantly 4-bromoisophthalic acid. If, however,
a small amount of iodine and a compound of copper, silver,
lead, or mercury are present, the bromination occurs selec-
11.5
a
% CuSO
4
. b Herein and below, DBIPA represents the sum of DBIPA-1
5
and DBIPA-2.
tively at the 5-position. The amount of I
from 0.02 to 2 mol % of the IPA. The oleum initially contains
from 25 to 65% SO , and 4.5-8.5 parts by weight of oleum
can be used. The reaction is carried out at 100 °C over 5 h
when I is present, or 24 h without I . (This publication is
only an abstract and does not give any additional details).
2) 5-BIPA was prepared in 40% yield by diazotizing
2
or metal can be
Table 2. Influence of the quantity of oleum and the
temperature on the reaction (IPA 50 g, 0.3 mol; oleum
20% SO
0-90 °C)
3
3 2 2
; I 2% w/w IPA; washing with 0.8 L of H O at
8
2
2
composition, GC, %
oleum/IPA Br2/IPA
expt w/w IPA mol. ratio
temp, time,
(
°C
h
IPA BIPA IIPA DBIPA
dimethyl 5-aminoisophthalic acid and then reacting the
diazonium salt with copper bromide and HBr (the Sandmeyer
3
5
7
8
9
4.8
4.8
5.6
3.2
2.8
0.64
0.64
0.64
0.64
0.55
102-105
79-80
4
5
6
9
4
1.0 81.7 1.1
15.5 81.1 0.8
9.8 84.8 0.8
15.3 79.9 1.4
1.2 89.2 1.7
15.5
2.6
4.6
3.4
7.1
1
3
reaction). (3) The dimethyl ester of 5-BIPA was obtained
from dimethyl 5-aminoisophthalate in a manner similar to
that described previously,13 in a yield of ca. 50%. (4)
86-89
118-123
102-105
14
a
5
-BIPA was obtained by the bromination of IPA with
a
3
The oleum concentration was 40% SO .
bromine and silver sulfate, in concentrated sulfuric acid. The
silver was employed in an equimolar quantity. The bromi-
nation was carried out at 100-110 °C over 32 h.
1
5
in the subsequent hydrolysis stage. Additional impurities
formed, in very small amounts (<1%, GC area), during the
bromination, are bromoiodoisophthalic acids and tribromoiso-
phthalic acid. Their structures were determined by GC/MS
analyses.
Results and Discussion
Bromination Stage. Our investigations commenced with
optimization of the temperature, required amounts of I and
catalyst, and the quantity and concentration of oleum.
The criterion of a “good” bromination was maximum
reaction conversion with a minimum amount of dibrominated
by-products. In the hydrolysis stage, the latter leads to the
formation of both a certain quantity of IPA, with the resulting
crude 5-HIPA being a darker color. The main product of
the bromination in all the experiments is 5-BIPA. Two
isomers of dibromoisophthalic acid are obtained together with
2
Several experiments were carried out to study the influ-
ence of the quantity of I
Table 1).
Attempts to carry out the bromination with a CuSO
catalyst, but without iodine, were unsuccessful, due to the
slow reaction rate (expt no. 1). On the other hand, the use
of CuSO
experiments were carried out without CuSO
The use of 1% I leads to a slow reaction rate and
incomplete conversion (expt no. 2). The same results were
obtained when the reaction temperature was reduced (expt
nos. 5 and 6).
2
and the temperature of the reaction
(
4
4
turned out to be unnecessary, and all further
4
.
5-BIPA. These dibromo products were separated by prepara-
2
1
tive HPLC and identified by H NMR spectra. One of them
was shown to be 2,5-dibromoisophthalic acid (DBIPA-1),
while the other is 4,5-dibromoisophthalic acid (DBIPA-2)
(Scheme 3). It is worth mentioning that the solubility of the
It seems that the optimum, after consideration of the
2,5-isomer in water is higher than that of the 4,5-isomer. In
2
reaction time and cost of raw materials, is to use 2% I at
addition, a small amount of iodoisophthalic acid (IIPA) is
formed by iodination of the IPA. However, IIPA does not
present a problem as an impurity, since it also gives 5-HIPA
102-105 °C (expt no. 3).
A number of experiments were carried out at different
temperatures, studying the influence of the quantity of oleum
on the bromination products (Table 2). The aim of these
investigations was to find the minimum quantity of oleum
required to obtain crude 5-BIPA with the specified impurity
content.
(
(
12) McGrath, H. Res. Discl. 1976, 146, 51-52; Chem. Abstr. 1976, 85, 123510d.
13) Gumbley, J. S.; Stewart, R. J. Chem. Soc., Perkin Trans. 1984, 2, 529-
5
31.
(14) Boots, S. G.; Franklin, M. A.; Dunlavey, B. J.; Costello, J.; Lipsits, C.;
Boots, M. R.; Rogers, K. S. Proc. Soc. Exp. Biol. Med. 1976, 151, 316-
In expt no. 3, (at 102-105 °C and an oleum/IPA weight
ratio of 4.8) a satisfactory result was obtained. An attempt
3
20.
(15) Crandall, E. W.; Harris, L. Org. Prep. Proced. Int. 1969, 1, 147-156.
5
92 Vol. 6, No. 5, 2002 / Organic Process Research & Development
•

Table 3. Influence of oleum concentration and temperature
on the reaction (IPA 50 g, 0.3 mol; oleum/IPA molar ratio
20-25 kg of 20% H
2 4
SO together with organic impurities,
Na SO and NaBr, per kg of 5-BIPA). (b) Filtration of the
2
4
2 2
4.8; I 2% w/w IPA; washing with 0.8 L of H O at
precipitated, crude 5-BIPA was carried out at 80-90 °C.
The wet, crude 5-BIPA cake was washed on the filter with
80-90 °C)
concentration, GC, %
fresh H
case, the crude 5-BIPA contained ca. 0.5-1.0% IPA, 83-
6% 5-BIPA, 1.4-1.6% IIPA, and 13-16% DBIPA. The
amount of acid wastes in this method was less than in method
(a) and amounted to ca. 12-15 kg of 30% H SO (together
with organic impurities, Na SO and NaBr) per kg of
-BIPA. (c) The reaction mixture was fed into H O at 80-
O was used than in methods (a) and (b).
2
O at 80-90 °C without additional treatment. In this
oleum
Br2/IPA
temp
°C
time
h
expt concn % mol. ratio
IPA 5-BIPA IIPA DBIPA
8
10
11
12
13
14
15
16
65
40
30
20
15
15
10
0.55
0.55
0.60
0.64
0.64
0.64
0.64
102-105 2.0 0.8 86.7
102-105 3.0 1.5 90.1
102-105 4.0 1.5 89.2
102-105 4.0 1.0 81.5
102-105 4.5 3.1 82.9
120-125 3.0 1.9 80.1
120-125 7.5 60.6 36.9
1.7
1.6
0.7
1.0
1.0
1.5
1.9
10.7
6.3
7.5
15.3
12.8
16.0
0.6
2
4
2
4
5
2
100 °C. Less H
2
Filtration of the precipitated, crude 5-BIPA was carried out
at 40-50 °C. The wet, crude 5-BIPA cake was washed on
to reduce the DBIPA formation by reduction of the reaction
temperature was carried out in expt no. 5, but it resulted in
both a slow reaction rate and low conversion. A similar result
was obtained at a temperature of 86-89 °C and an oleum/
IPA weight ratio of 5.6 (expt no. 7).
Reduction of the oleum/IPA weight ratio to 3.2, even at
a higher temperature, results in a reduction of both the
reaction rate and conversion (expt no. 8).
the filter with fresh H O at 40-50 °C. The impurity content
2
in the crude 5-BIPA by this method was similar to that in
method (b), but the quantity of acid waste by this method
was less than in methods (a) and (b) and amounted to ca.
8
2 4
-10 kg of 40% H SO (together with organic impurities,
sodium sulfate and sodium bromide) per kg of 5-BIPA.
Precipitation by Feeding the Reaction Mixture into Water
Followed by Neutralization. A few experiments were carried
out to neutralize the reaction mixture after precipitation. This
was to reduce the potential corrosion of the equipment.
Aqueous solutions of NaOH were used. After the usual
precipitation procedure, aqueous 40% NaOH was added to
the reaction mixture at 80-90 °C to pH ) 2.4. The product
was filtered at 80 °C and washed with hot water (at 80-90
The best results were obtained when 40% oleum was used.
In this case, only 7.1% DBIPA was obtained at 102-105
°
C and an oleum/IPA weight ratio of 2.8.
A number of experiments were carried out to study the
influence of the oleum concentration on the bromination
products. The results (presented in Table 3) show the
following: (a) A high IPA conversion (>97%) cannot be
reached at a temperature of 102-105 °C when the oleum
°
1
C). The dry, crude product contained ca. 83.2% 5-BIPA,
.0% IPA, 6.0% Na SO , 8.5% DBIPA, and 1.4% IIPA.
Filtration of the Precipitated Crude 5-BIPA from Cooled
2
4
concentration is less than 20% free SO
DBIPA by-products is reduced when the oleum concentration
is increased from 20 to 40% free SO and then increased
again at 65%. The best result was obtained when 40% free
SO oleum was used.
3
. (b) The quantity of
Oleum Solution and Use of RecoVered Filtrate in the Next
Bromination (Procedure Proposed by Y. BercoVici, IMI).
After the bromination, the reaction mixture was cooled to
3
3
2
0-30 °C, and the crude 5-BIPA which precipitated was
filtered. The obtained cake contained ca. 50% crude 5-BIPA
ca. 91.2% 5-BIPA, 0.7% IPA, 5.5% DBIPA, 1.4% IIPA)
Work-Up of the Bromination Mixture. The procedure
for the work-up of the bromination mixture appears to have
a significant effect on the IPA and DBIPA content of the
product. Various work-up procedures were checked. The
yield of crude BIPA by all methods was ca. 77-83% based
on IPA.
(
and 50% oleum. The cake may be used directly in the next
hydrolysis stage without further treatment. The filtrate,
containing ca. 82% oleum (<8% free SO
3
) and 18% crude
5-BIPA (ca. 69.2% 5-BIPA, 3.6% IPA, 25.4% DBIPA, 1.3%
Precipitation by Feeding the Reaction Mixture into the
Water. The first attempted work-up method involved pouring
IIPA), may be used in the next bromination experiment. The
main advantages of this work-up method are the reduction
of the amount of oleum required for the production of a unit
of 5-BIPA and a considerable reduction in the quantity of
waste.
Preparation of Crude 5-HIPA. 5-HIPA was prepared
by the hydrolysis of crude 5-BIPA with aqueous NaOH, in
an autoclave, in the presence of a copper catalyst. The starting
material, crude 5-BIPA, as shown above, is a composition
of main product, 5-BIPA (85-94%), together with several
by-products, IPA (0.3-1.0%), IIPA (1.5-2.0%), and DBIPA
(4-12%).
the reaction mixture into H O at 80-100 °C, followed by
2
filtration of the precipitated crude 5-BIPA at 40-90 °C. The
filtration was fast in comparison with precipitation in cold
water. Three variations of the work-up continuation were
checked. (a) Filtration of the precipitated, crude 5-BIPA was
carried out at 80-90 °C. The wet, crude 5-BIPA cake was
2
boiled for 1 h with a fresh batch of H O and then filtered at
80-90 °C. This work-up method gave crude 5-BIPA
containing 0.3-1.0% IPA, 88-94% 5-BIPA, 1.5-2.0%
IIPA, and 5-10% dibrominated products. A relatively small
content of DBIPA was present, due to the higher solubility
of DBIPA in H
of DBIPA in the crude 5-BIPA essentially depends on the
quantity of H O used, both for the first precipitation stage
and the following re-slurry stage. A serious disadvantage of
this work-up method is the large amount of acid wastes (ca.
2
O in comparison with 5-BIPA. The content
Different copper compound catalysts, such as Cu, CuCl,
CuO, CuBr , CuSO , Cu O, and so forth, may be used. After
2 4 2
full conversion was achieved, the autoclave was cooled to
room temperature and opened, and the reaction mixture was
filtered to remove the catalyst. The filtrate was acidified to
2
Vol. 6, No. 5, 2002 / Organic Process Research & Development
•
593

Scheme 4. Hydrolysis of crude 5-HIPA
Table 4. Influence of the temperature on the hydrolysis of
crude 5-BIPA (crude BIPA 55 g; H O 175 g; NaOH/5-BIPA
2
2
molar ratio ) 5; Cu O 2% w/w of the crude 5-BIPA)
composition, GC, %
temp time
expt °C
h
5-BIPA 5-HIPA DHBA DHIPA IPA
1
120
1.5
23.8
3.8
N.D.
N.D.
N.D.
N.D.
N.D.
71.1
93.0
96.0
98.6
98.6
98.3
98.3
-
-
4.4
2.8
3.1
0.2
-
-
-
0.4
0.6
0.7
0.9
1.1
1.4
1.7
3.0
2
3
4
5
6
140
160
170
180
210
1.5
1.5
1.5
1.0
1.0
0.2
0.3
0.3
0.3
-
Table 5. Influence of the NaOH/5-BIPA molar ratio on the
hydrolysis of crude 5-BIPA (crude BIPA - 55 g; H
2
O - 175
g; Time - 1.5 h; Temp. - 170 °C; Cu
2
O - 2% w/w of the
crude 5-BIPA)
composition, GC, %
expt NaOH/5-BIPA 5-BIPA 5-HIPA DHBA DHIPA IPA
molar ratio
7
8
9
0
3
4
5
6
4.2
86.5
97.5
99.0
98.3
-
-
0.1
0.4
5.2
1.2
-
-
3.8
1.3
0.9
1.3
N.D.
N.D.
N.D.
pH ) 1 with H
C, and the crude 5-HIPA precipitate was filtered.
At full conversion, the main product of the hydrolysis
2
SO
4
or HCl at 60-80 °C and cooled to 20
1
°
was 5-HIPA. By-products of the reaction were IPA (some
present in the starting material and some formed by hydro-
genolysis of 5-BIPA and DBIPA), two isomers of dihy-
droxybenzoic acid, formed by the decarboxylation of dihy-
droxyisophthalic acid, and two isomers of dihydroxyisophthalic
acid (DHIPA), formed by the hydrolysis of DBIPA (Scheme
Table 6. Influence of the quantity of catalyst on the reaction
(crude BIPA 55 g; H O 175 g; time 1.5 h; temp 170 °C;
NaOH/5-BIPA molar ratio 5)
2
composition,GC, %
expt w/w 5-BIPA 5-BIPA 5-HIPA DHBA DHIPA IPA
2
Cu O
4
). The structure of the impurities was determined on the
11
0.001
0.2
1.0
2.0
3.0
13.2
N.D.
N.D.
N.D.
N.D.
83.7
97.1
98.3
98.4
98.5
-
1.3
1.3
0.2
0.3
0.2
1.8
1.4
1.2
1.0
1.0
1
1
1
1
2
3
4
5
0.2
basis of GC/MS analysis.
0.3
0.3
0.3
Most of the DHIPA formed from DBIPA decomposes into
benzoic acid derivatives and further into fractions nonde-
tected in crude 5-HIPA.
To find the optimum reaction conditions, the influence
of the temperature, NaOH/5-BIPA molar ratio, and amount
of catalyst on the reaction rate and selectivity was studied.
The crude 5-BIPA used in these experiments consisted of
11-15 illustrate the effect of using different amounts of
Cu O catalyst on the hydrolysis of crude 5-BIPA, at constant
temperature and catalyst concentration (Table 6).
2
5
0
-BIPA, 92.1%; IPA, 0.4%; IIPA, 2.2%; DBIPA1/DBIPA2,
.9/4.4.
As seen from the data in Table 6, full conversion of the
5-BIPA was achieved in all the experiments, except in expt
Examples 1-6 illustrate the effect of the temperature on
no. 11, when only 0.001% Cu
2
O was used. The problem in
the hydrolysis of crude 5-BIPA in the presence of a copper
catalyst (Cu O), at a constant NaOH/5-BIPA molar ratio
Table 4).
The results presented in Table 4 show the following: (a)
using a small quantity of Cu O is that the DHIPA remains
2
2
in the crude 5-HIPA. In addition, when <2% catalyst is used,
more IPA is present in the crude 5-HIPA.
(
Purification of Crude 5-HIPA. A single crystallization
A certain amount of IPA is formed during the hydrolysis,
perhaps as a result of the debromination of 5-BIPA and
DBIPA. (b) An increase in the temperature leads to an
increase in the hydrolysis rate of 5-BIPA and to decomposi-
tion of the DHIPA but also to an increase in the amount of
IPA formed.
Examples 7-10 illustrate the effect of changing the ratio
of base to crude 5-BIPA, at a constant temperature and
catalyst concentration (Table 5).
2
of crude 5-HIPA from H O gives a product with a purity of
>99%. The yield of the crystallization stage is 93%.
Summary
A method was developed by which 5-HIPA was prepared
with a purity of >99% and an overall yield of 65-70%,
using two chemical steps and one crystallization.
The recommended conditions for the first bromination
step are as follows: bromine/IPA molar ratio, 0.55-0.65;
As can be seen from the results, the selectivity of the
hydrolysis depends on the molar ratio of NaOH/5-BIPA. The
best results were obtained at a molar ratio of 5. Examples
oleum, 20-40% free SO
the oleum concentration: 4.3 kg of oleum/kg of IPA for
oleum with 20% free SO , and 2.7 kg of oleum/kg of IPA
3
. The quantity used depends on
3
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for oleum with 40% free SO
The reaction is carried out at 102-107 °C for 6 h. Three
3
. I
2
(2-3%) catalyst is used.
(trimethylsilyl)trifluoroacetamide (Aldrich) for 1 min at 70-
90 °C. H NMR spectra were measured with a Bruker
1
options for the reaction mixture work-up were investigated:
WP200 spectrometer using TMS as an internal standard.
Bromination of IPA with Work-Up Comprising Pre-
cipitation by Feeding Brominated Reaction Mixture into
Water. Into a 3-L flask were introduced 199.7 g of (1.2 mol)
(
1) the precipitation of brominated organics from the reaction
mixture by adding to H O, followed by filtration; (2) the
precipitation of the brominated organics from the reaction
mixture by adding to H O, followed by neutralization of the
formed H SO solution with NaOH and filtration; and (3)
2
2
IPA, 4 g of I , and 450 mL of 20% oleum. The mixture was
2
2
4
stirred without heating to dissolve the IPA in the oleum. The
filtration of the precipitated crude 5-BIPA from the cooled
oleum solution and recycling the filtrate to the next bromi-
nation. All these work-up methods give crude material
containing 0.3-1.0% IPA, 85-94% 5-BIPA, 1.5-2.0%
reaction mixture was then heated to 103-106 °C and stirred
vigorously; then 121 g (0.756 mol) of Br was added
2
dropwise over 4 h. Heating and stirring were continued for
an additional 2 h, and a sample was removed to check the
reaction conversion (if the product contains >0.8-1.0% IPA,
5-IIPA, and 4-12% dibrominated products. The crude
5-BIPA was used for the hydrolysis stage without additional
an additional quantity of Br
mixture was transferred, by means of a peristaltic pump, into
a 3-L flask containing 1500 mL of H O at 70 °C. The product
2
must be added). The reaction
treatment.
Two different schemes may be used for the hydrolysis
step. The first one, which makes it possible to increase the
loading of the pressure reactor, is based on hydrolysis with
2
precipitated. The speed of the transfer was restricted due to
the temperature of the contents of the flask rising to boiling
point. The precipitation was carried out with vigorous
stirring. The product was filtered at 80-90 °C and washed
35% NaOH, followed by transfer of the reaction mixture to
an additional reactor, dilution to dissolve precipitated salts,
and then filtration from the catalyst. According to the second
route, the hydrolysis is performed with 20% NaOH. Under
this condition, most of the salts obtained during the reaction
are dissolved, and the reaction mixture may be filtered
without prior dilution; thus, the additional reactor is not
necessary. The disadvantage of this route is the lower loading
of the pressure reactor. The duration of the hydrolysis is
affected by the DBIPA content in the crude 5-BIPA. When
the crude 5-BIPA contains a large quantity of DBIPA
with 500 mL of hot H
was placed in 1500 mL of of H
stirred at 90-100 °C for 1 h. The product was filtered at
0-90 °C and washed with 500 mL of hot H O (at 80-90
C) to give, after drying, 255 g of an off-white powder. The
2
O (at 80-90 °C). The crude product
2
O, and the mixture was
8
2
°
5
8
-BIPA content, by GC, was 86-90%. The yield was about
0%.
Bromination of IPA with Work-Up Comprising Pre-
cipitation by Feeding the Brominated Reaction Mixture
into Water, Followed by Neutralization with NaOH. Into
a 1-L flask were introduced 100 g (0.6 mol) of IPA, 2 g of
I and 480 g of 20% oleum (Fertilizers & Chemicals Ltd.).
2
The mixture was stirred without heating to dissolve the IPA
(
>10%), the reaction time must be increased. The work-up
comprises catalyst filtration, precipitation by acidification
with H SO
2
4
to pH 1.0-1.5 at ∼80 °C, filtration of the crude
product at 20 °C, and washing at 20 °C. The filtration
temperature, the washing temperature, and the quantity of
washing H O may be changed within a small range,
2
depending on the quantity of DBIPA in the crude 5-BIPA.
The recommended conditions for the hydrolysis stage are
in the oleum. The reaction mixture was then heated to 103-
1
06 °C and stirred vigorously; then 61.4 g (0.38 mol) of Br
2
was added dropwise over 6 h. Heating and stirring were
continued for an additional 2 h, and then a sample was
removed to check the reaction conversion (if the product
contains >0.8-1.0% IPA, an additional quantity of Br must
2
be added). The reaction mixture was transferred, by means
of a peristaltic pump, into a 2-L flask containing 800 mL of
2
H O at 70 °C. The product precipitated. The velocity of the
transfer was restricted due to an increase in the temperature
of the contents of the flask to boiling point. The precipitation
was carried out with vigorous stirring. Aqueous 40% NaOH
2
0-35% aqueous NaOH solution; NaOH/5-BIPA molar
ratio, 4.5-5.0; Cu O catalyst, 2-3% w/w of the crude
-BIPA; temperature/time, 160 °C/6-8 h.
A single crystallization of the crude 5-HIPA from H
2
5
2
O
gives a product with a purity of >99%. The yield of the
crystallization stage is 93%.
In conclusion, a practical process, with industrial potential,
was developed, which may compete with existing industrial
processes.
(
ca. 1 kg) was added to the reaction mixture at 80-90 °C to
pH ) 2.4. The product was filtered at 80 °C and washed
with 800 mL of hot H O (at 80-90 °C). The crude product
after drying weighed about 135 g and contained: 83%
5-BIPA, 1.0% IPA, 6% Na SO , 8% DBIPA, and 1.5% IIPA.
The overall yield was 77%.
Experimental Section
GC analyses were conducted on a Hewlett-Packard 5890
series II apparatus. A 30 m capillary column, Rtx-20, was
used for analysis of the 5-BIPA. A 30 m capillary column,
DB-5, was used for analysis of the 5-HIPA. GC/MS analyses
were conducted on a Hewlett-Packard 5890 series II ap-
paratus equipped with a 5970 series mass selective detector,
using a 10 m capillary column (i.d. ) 0.25 mm), Rtx-1, for
analysis of 5-BIPA and a 20 m capillary column (i.d. ) 0.18
mm), Rtx-1, for analysis of 5-HIPA. For GC and GC/MS
analyses the products were silylated by reacting a sample
2
2
4
Bromination of IPA with Work-Up Comprising Fil-
tration of the Precipitated Crude 5-BIPA from Cooled
Oleum Solution. Into a 1-L flask were introduced 100 g
2
(0.6 mol) of IPA, 2 g of I and 430 g of 20% oleum
(Fertilizers & Chemicals Ltd.). The mixture was stirred
without heating to dissolve the IPA in the oleum. The
reaction mixture was then heated to 103-106 °C and stirred
(20 mg) with an excess of the silylating agent (1 mL) bis-
Vol. 6, No. 5, 2002 / Organic Process Research & Development
•
595

vigorously; then 61.4 g (0.38 mol) bromine was added
dropwise over 6 h. Heating and stirring were continued for
an additional 2 h, and a sample was removed to check the
reaction conversion (if the product contains >0.8-1.0% IPA,
cooling to 20 °C the product was filtered and washed with
100 mL of H O at 20 °C. After drying, 123 g of a cream-
colored solid, with a purity of 98.2%, was obtained (93%
yield, based on 5-BIPA).
2
an additional quantity of Br
2
must be added). The reaction
Purification of crude 5-HIPA. 5-HIPA (100 g dry, crude,
mixture was cooled to 20 °C, and the precipitated product
2
purity 98%) and 900 mL of H O were placed into a 2-L
was filtered. The obtained cake (186 g) contained 50% crude
flask and heated to 100 °C, with stirring, for 1 h. The solution
was then cooled to 20 °C with vigorous stirring, and the
precipitated product was filtered and washed with 150 mL
5
-BIPA (91.2% BIPA, 0.7% IPA, 5.5% DBIPA, 1.4% IIPA)
and 50% oleum (<8% free SO ). The cake may be used
directly in the hydrolysis stage without further treatment. The
filtrate (336 g), containing 82% oleum (<8% free SO ) and
8% crude 5-BIPA (72.2% 5-BIPA, 2.6% IPA, 23.4%
3
2
of H O at 20 °C. After drying, 93 g (93% yield, based on
3
5-HIPA) of an off-white solid was obtained.
The NMR, GC, and GC/MS spectra may be requested, if
required.
1
DBIPA, 1.3% IIPA) may be used in the next bromination
experiment.
Preparation of 5-HIPA. H
crude 5-BIPA (196 g, 0.8 mol), and Cu
2
O (640 g), NaOH (160 g),
O (3.9 g, 0.027 mol)
Acknowledgment
2
We are grateful to Mr. I. Gozlan and Ms. I. Keidar for
their help and support in providing the analytical results and
to Ms. D. Alon and Ms. C. Henry for technical assistance.
Special thanks to Dr. R. Effenberger for helpful discussions.
We are grateful to BCL for financial support.
were placed into a 1-L autoclave. The autoclave was sealed
and heated to 140 °C. Full conversion was achieved after
90 min. The autoclave was cooled to room temperature and
opened, and the reaction mixture was filtered to remove the
catalyst. The reaction mixture was transferred to a dropping
funnel and added dropwise, with vigorous stirring, to 820
mL of 15% HCl (prepared from 332 mL of 37% HCl and
Received for review March 29, 2001.
OP0100302
488 mL of water) placed in a 3-L flask at 60-70 °C. After
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