Development of a scaleable synthesis for 1,2-bis(2-aminophenylthio)ethane (APO-Link) used in the production of bismaleimide resin

Article abstract of DOI:10.1021/op700122q

The diamine reagent 1,2-bis(2-aminophenylthio)ethane is no longer commercially available but is still required for the synthesis of the bismaleimide resin, APO-BMI, used in syntactic foams. In this work, we examined the hydrolysis of benzothiazole followed by reaction with dichloroethane or dibromoethane. The deprotonation of 2-aminothiophenoI followed by reaction with dibromoethane was also investigated and later optimized for scale-up by scrutinizing all aspects of the reaction conditions, work-up, and recrystallization. On bench-scale, the optimized procedure consistently produced a 75-80% overall yield of finely divided, high purity product (>95%). The material was also produced on both a 100 Ib scale and a 200 Ib scale using the optimized process, giving high quality material in excellent yield.

Full text of DOI:10.1021/op700122q

Organic Process Research & Development 2007, 11, 996–1003
Development of a Scaleable Synthesis for 1,2-Bis(2-aminophenylthio)ethane
(APO-Link) Used in the Production of Bismaleimide Resin
,
†
§
§
†
)
‡
Crystal G. Densmore,* Hilary Wheeler, Rebecca Cohenour, Thomas W. Robison, Dawud Hasam, Blossom J. Cordova,
‡
O
O
O
Peter C. Stark, Edward N. Fuller, Charles J. Cook, and Holly A. Weber
Chemistry DiVision, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, U.S.A., and National Nuclear Security
Adminstration’s Kansas City Plant Operated by Honeywell FM&T, LLC, Kansas City, Missouri 64141, U.S.A.
Abstract:
The diamine reagent 1,2-bis(2-aminophenylthio)ethane is no longer
commercially available but is still required for the synthesis of
the bismaleimide resin, APO-BMI, used in syntactic foams. In this
work, we examined the hydrolysis of benzothiazole followed by
reaction with dichloroethane or dibromoethane. The deprotonation
of 2-aminothiophenol followed by reaction with dibromoethane
was also investigated and later optimized for scale-up by scrutiniz-
ing all aspects of the reaction conditions, work-up, and recrystal-
lization. On bench-scale, the optimized procedure consistently
produced a 75–80% overall yield of finely divided, high purity
product (>95%). The material was also produced on both a 100
lb scale and a 200 lb scale using the optimized process, giving high
quality material in excellent yield.
Figure 1. Structures of 4,4′-bismaleimidodiphenylmethane
(BMI) bismaleimide resin and methylenedianiline (MDA).
Introduction
Aromatic diamine reagents have been used for decades in
weapon systems as starting materials for urethane elastomers
and bismaleimide resins. In the 1970s, two commonly used
aromatic diamines, methylenedianiline (MDA; Figure 1) and
Figure 2. Structures of Adiprene L-100 prepolymer and
4
,4′-methylenebis(2-chloroaniline) (MOCA or MBOCA).
4
,4′-methylenebis(2-chloroaniline) (MOCA or MBOCA; Figure
1
2) were ruled to be possible carcinogens. At the time, a three-
phase syntactic foam called Kerimid 601 was used and consisted
of a mixture of MDA, 4,4′-bismaleimidodiphenylmethane
(
BMI; Figure 1) bismaleimide resin and glass microballons
2–5
(GMB). Uncured Kerimid 601 consisted of a weight ratio of
2
approximately 6.7 parts BMI to 1 part MDA. In addition, an
important urethane elastomer system based on MOCA and
Adiprene L-100 prepolymer (Figure 2) was widely used. The
carcinogen rulings led to extensive replacement programs for
both materials.
Figure 3. Structure of 1,2-bis(2-aminophenylthio)ethane.
During the late 1970s, research indicated that 1,2-bis(2-
aminophenylthio)ethane, known commercially as APOCure-
601 (Figure 3), was a promising replacement for MOCA in
*
To whom correspondence should be addressed. E-mail: cgd@lanl.gov.
Phone: (505) 664-0248.
†
Chemical Sciences and Engineering Group (C-CSE), Chemistry Division,
6
Los Alamos National Laboratory.
some urethane systems. In the early 1980s, 1,2-bis(2-ami-
‡
Advanced Diagnostics and Instrumentation Group (C-ADI), Chemistry
nophenylthio)ethane, then known as Cyanacure, was used as a
diamine curing agent for urethane adhesives containing Adi-
Division, Los Alamos National Laboratory.
§
Organic Materials and Polymer Production Group, National Nuclear Security
Adminstration’s Kansas City Plant Operated by Honeywell FM&T.
7
prene L-100. During this same period, 1,2-bis(2-aminophen-
)
Plastics Engineering Group National Nuclear Security Adminstration’s
ylthio)ethane was also used as the diamine reagent for the
Kansas City Plant Operated by Honeywell FM&T.
O
Analytical Group, National Nuclear Security Adminstrationµs Kansas City
Plant Operated by Honeywell FM&T.
(4) Whinnery, L. L.; Goods, S. H.; Tootle, M. L.; Neuschwanger, C. L.
TEPICsA New High Temperature Structural Foam (SAND98-8246);
Sandia National Laboratories: Albuquerque, NM, 1998.
(5) Young, D. A. Scale Up of Process for Producing Polyaminobisma-
leimide (BDX-613-1886); Bendix Kansas City Plant: Kansas City, KS,
1977.
(6) Quant, A. J.; Drummond, D. D.; Lagasse, R. R. APOCure 601 - A
MOCA Replacement (SAND79-0630); Sandia National Laboratories:
Albuquerque, NM, 1979.
(
1) Domeier, L.; Keifer, P.; Hunter, M. Urethane Elastomers: DeVelopment
of TDI-Free Replacement Materials for EN-7 (SAND2000-8224);
Sandia National Laboratories: Albuquerque, NM, 2000.
(
2) Jamieson, D. R. Synthesis of Polyaminobismaleimide BDX-613-1480;
Bendix Kansas City Plant: Kansas City, KS, 1975.
3) Jamieson, D. R. Pilot Plant Process for Producing Polyaminobisma-
leimide Resin (BDX-613-1854); Bendix Kansas City Plant: Kansas
City, KS,1977.
(
9
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Vol. 11, No. 6, 2007 / Organic Process Research & Development
10.1021/op700122q CCC: $37.00  2007 American Chemical Society
Published on Web 10/19/2007

Scheme 1. Synthesis of APO-BMI resin from 1,2-bis(2-aminophenylthio)ethane (APO-Link) and maleic anhydride
formation of the new bismaleimide resin, APO-BMI, the
replacement for Kerimid 601 (Scheme 1). American Cyanamid
(ATP) with sodium ethoxide.11–13 A typical procedure involves
adding dibromoethane dropwise to a refluxing solution of
2-aminothiophenol and sodium in anhydrous ethanol. The
mixture is then allowed to cool to room temperature and added
to ice–water to precipitate the crude material. Following
crystallization in ethanol, the purified yield is typically 70–80%.
For scale-up, there are obvious concerns with using sodium in
ethanol followed by precipitation in water. An important note
8
sold 1,2-bis(2-aminophenylthio)ethane under the trade name
9
Cyanacure until 1989 when it was discontinued. In the 1990s,
1,2-bis(2-aminophenylthio)ethane reappeared on the market
under the name Versalink C138 from Air Products, but was
once again discontinued. Currently, 1,2-bis(2-aminophenylthio)-
ethane is not commercially available in any significant quantity.
Because the material is no longer commercially available,
it will be manufactured in-house at Honeywell’s Kansas City
Plant (KCP). In this work, we have focused on the bench-scale
optimization of 1,2-bis(2-aminophenylthio)ethane in preparation
for scale-up in the Polymer Production Facility at KCP. The
diamine reagent has been granted yet another name, APO-Link,
and will be used in the production of the bismaleimide resin,
APO-BMI.
The goal of the synthetic development of APO-Link was to
optimize a procedure that was suitable to a 100 gallon or larger
scale. Important factors for scale-up included utilizing practical
methods, reducing processing time, reducing reaction volumes,
increasing yields, minimizing equipment requirements, and
taking ES&H concerns into account.
14,15
is that the pK
a
of 2-aminothiophenol is 6.6–6.8,
which means
that it is possible to replace sodium ethoxide with other bases
in this approach.
By altering the starting materials and reaction conditions,
we pursued five basic reaction paths (Scheme 2) toward the
synthetic optimization of APO-Link. Synthesis work was
completed in laboratory glassware at Los Alamos National
Laboratory (LANL) as well as a fully instrumented 1 L reaction
calorimeter at KCP.
Results and Discussion
Prior to our synthetic work, we conducted a detailed
characterization of 1,2-bis(2-aminophenylthio)ethane samples
previously available from American Cyanamid as “Cyanacure”
and later from Air Products as “Versalink C138” to provide
baseline data (Figure 6). A detailed discussion of our results
can be found in the Supporting Information.
Because the synthesis of APO-Link will be scaled to a 100
gallon or larger reactor, every aspect of the bench-scale synthesis
was scrutinized and optimized if possible. The goal was to
maximize the yield using an efficient process where reagents,
solvents, waste, and corrosion were minimized. Table 1
summarizes the results of bench-scale APO-Link reactions
performed at LANL and KCP.
There are two basic approaches to the synthesis of 1,2-bis(2-
aminophenylthio)ethane (APO-Link). The first approach is
documented in a U.S. Patent from 1975 and involves the
hydrolysis of benzothiazole with sodium hydroxide followed
10
by reaction with dichloroethane. Although the crude yield is
reported to be 98%, the purified yield and crystallization solvent
were not reported. An alternate approach is reported in the
literature and involves deprotonation of 2-aminothiophenol
(
7) Caruthers, D. J. Adhesion of Adiprene L-100/Cyanacure to Cable
Materials (BDX-613-3086); Bendix Kansas City Plant: Kansas City,
KS, 1984.
(11) Chhikara, B. S.; Mishra, A. K.; Tandon, V. Heterocycles 2004, 63,
1057–1065.
(8) Jamieson, D. R. Nontoxic Polyimides (BID-A193); Bendix Kansas City
(12) Cannon, R. D.; Chiswell, B.; Venanzi, L. M. J. Chem. Soc. A 1967,
1277–1281.
Plant: Kansas City, KS, 1981.
(
9) Wilson, M. H. Characterization Studies of Lower and Non-TDI
Polyurethane Encapsulants (KCP-613-5282); Allied-Signal: Kansas
City Plant, Kansas City, KS, 1993.
(13) Kumar, M.; Sharma nee Bhalla, V.; Sharma, P. J. Chem. Res. 2000,
10, 492–493.
(14) Chuchani, G.; Frohlich, A. J. Chem. Soc. B 1971, 7, 1417–1420.
(15) Danehy, J. P.; Noel, C. J. Am. Chem. Soc. 1960, 82, 2511–2515.
(
10) Hirosawa, F. N.; Lee, M. H. U.S. Patent 3,920,617, 1975.
Vol. 11, No. 6, 2007 / Organic Process Research & Development
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997

Scheme 2. Synthesis of APO-Link from the hydrolysis of benzothiazole or deprotonation of 2-aminothiophenol (ATP) followed
by reaction with dichloroethane (DCE) or dibromoethane (DBE)
Table 1. Purity values of bench-scale APO-Link reactionsa
work-up
method
crude
yield (%)
rextal
method
GC/MS
%APO-Link
GPC
%APO-Link
reaction
condition
A
B
C
D
E
F
Path 1
Path 1
Path 1
Path 1
Path 1
1
2
2
3
2
4
5
5
4
4
4
5
5
4
4
4
4
4
5
5
5
5
5
5
56
80
80
60
79
90
b
70
89
89
89
93
90
92
93
93
83
92
88
88
b
1
1
3
2
2
4
5
5
4
4
5
6
6
5
5
96.23
94.57
98.44
87.40
90.57
87.56
Path 1 (w/DBE)
G (2.0 mol benzothiazole)
Path 1
96.00
93.90
H (2.0 mol benzothiazole)
Path 1
I
Path 2
85.82
89.12
93.70
J
Path 2
K
Path 2
L (2.0 mol ATP)
M (6.0 mol ATP)
N
Path 2
92.30
93.82
Path 2
Path 3
98.38
97.21
71.62
96.56
97.25
98.07
97.77
99.3
O
Path 3
c
P
Path 4
5
Q
Path 4 (w/DCE)
Path 4
5
5
5
R (1.0 mol ATP)
S (2.0 mol ATP)
T (2.0 mol ATP)
U (2.0 mol ATP)
V (2.0 mol ATP)
W (2.0 mol ATP)
X (2.0 mol ATP)
94.6
c
Path 5 (DBE addn. 45 min)
Path 5 (DBE addn. 45 min)
Path 5
Path 5 (DBE addn. 60 min)
Path 5 (DBE addn.180 min)
Path 5 (DBE addn. 60 min;
rextal after 2nd rinse)
97.22
97.95
97.80
97.42
95.43
95.79
6
6
6
6
6
b
b
b
98.04
96.76
98.04
a
Reaction scales are based on 0.10 moles benzothiazole or ATP unless otherwise noted. Crude yield percentage is based on calculated theoretical yield. b Total crude
c
product was not isolated and dried. After dropwise addition of water, the recrystallization solution was stirred during cooling.
Synthesis Process. The initial work focused on the hydroly-
sis of benzothiazole using sodium hydroxide followed by the
reaction with dichloroethane (Path 1). The reaction was
conducted at reflux and is described in U.S. Patent 3,920,617
from 1975. We used dichloroethane but also studied this reaction
using a more reactive reagent, dibromoethane. Replacing
dichloroethane with dibromoethane increased the yield and
purity of the crude product. Other synthetic options were
considered due to the corrosive nature of Path 1. An alternate
approach reported in the literature, involves deprotonation of
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2
-aminothiophenol (ATP) with sodium ethoxide.11–13 For scale-
up, the use of elemental sodium in ethanol is not practical. The
Recrystallization/Purification. Another processing hurdle
involved purification of the crude product via recrystallization.
In U.S. Patent 3,920,617, example 2 (using Path 1 chemistry)
does not report the recrystallization solvent or yield. In early
Path 1 reactions, the crude product was recrystallized from
14,15
pK
a
of 2-aminothiophenol is 6.6–6.8,
allowing for the
replacement of sodium ethoxide with more mild bases using
this approach. Example 1 of U.S. Patent 3,920,617 describes
the deprotonation of ATP with sodium hydroxide followed by
reaction with dichloroethane. We successfully used both
sodium hydroxide and sodium carbonate to deprotonate ATP.
In comparison to Path 1, this approach is more attractive,
requiring less base and completely consuming all starting
11–13
ethanol based on additional literature references.
However,
10
ethanol was not a very efficient solvent for recrystallization
because the crude product was fairly soluble at room temper-
ature. Additional solubility and recrystallization information can
be found in the Supporting Information. Using typical bench-
scale recrystallization techniques, the purified APO-Link crys-
tallized in a dense, crystalline cake. In this form, the material
would have been impossible to remove from a large-scale
reactor, costing both time and yield. Solvent combinations and
techniques were used to yield a slurry of recrystallized product
that could be transferred for filtration and drying, thus avoiding
“caking” of the purified product. A considerable amount of time
was devoted to devising a recrystallization method that would
minimize solvent, give high purity, and yield a material
consistency conducive for transfer, processing, and drying. We
also wanted to purify the material in the same reactor used for
synthesis and extraction, thus reducing the need for material
transfer. Both denatured and nondenatured ethanol resulted in
successful recrystallizations. Recrystallization of the crude
material was investigated using six different solvent conditions:
1. 100% Ethanol. Although used in the literature, ethanol
is not a very efficient solvent for large-scale recrystallization
because the crude product is fairly soluble at room temperature.
Although the purity levels were good, the yield of the first crop
of material was only about 25–35% based on the amount of
crude used. Several crops of material must be isolated from
the solution to maximize the overall yield, making the recrys-
tallization very time intensive.
2 3
materials. Using sodium carbonate (Na CO ) is appealing
because it is less corrosive than sodium hydroxide. However,
from a scale-up standpoint, the overall volume of the reaction
can be reduced by using NaOH because it has a higher solubility
in water. At 20 °C the solubility of NaOH is 111 g/100 mL,
2 3
whereas the solubility of Na CO in water is 30 g/100 mL. Thus,
corrosion issues were outweighed by production scale limits.
We further reduced the corrosive nature of the reaction by
lowering the reaction temperature to 80–85 °C from reflux.
Work-Up/Extraction. One processing hurdle involved the
work-up or extraction of the crude product. The crude material
quickly solidified into a hard, yellow wax (mp 50–65 °C), thus
presenting major complications when conventional bench-scale
work-up methods (such as a separatory funnel extraction) were
employed. A considerable amount of time was devoted to
devising a work-up method that would minimize solvent
amounts and the loss of the crude material while effectively
removing salts from the thick, molten wax. Five methods for
work-up/extraction were studied during bench-scale work.
Details of each method can be found in the Supporting
Information. The five methods were the following: (1) boiling
water extraction in separatory funnel; (2) organic/aqueous
extraction with methyl ethyl ketone (MEK) and water; (3) water
extraction at room temperature; (4) repeat extraction and
cooling; (5) hot water extraction in reactor with drain.
2. Ethanol/Water 95/5 (V/V). The crude product is still
considerably soluble in this solvent combination at room
temperature.
Method 5 was the most practical for scale-up. For reactions
performed in the 1 L reaction calorimeter or jacketed cylindrical
reactor, work-up was completed in the reactor because a bottom
outlet drain was available. When the second reaction was
completed, the layers were allowed to separate, while the reactor
temperature set point was maintained at approximately 85 °C.
Due to the high salt content, the aqueous layer was on the
bottom and was drained from the reactor. Hot water was added
to the reactor for the rinsing step. Following phase separation,
the organic crude material (now bottom layer) was quickly
drained from the reactor and then returned after the aqueous
portion was removed. This process was repeated to give a total
of three rinses. Although this method of extraction is fairly
common in plant facilities, the hard, waxy nature of the crude
material provided the potential for significant complications
during large-scale extraction and transfer. An understanding of
the material’s behavior during bench-scale optimization proved
extremely valuable when preparing for large-scale optimization.
Equipment modifications accounted for the need to keep the
dense waxy material molten and piping was designed to prevent
solidification during transfer. Our method provides an optimized
extraction of salts from the molten wax with minimal hot water
and no organic solvents.
3. Ethanol/Water 50/50 (V/V). Approximately 900 mL of
hot 50/50 (v/v) ethanol/water was required for the recrystalli-
zation of about 11 g of crude product. Although the purity levels
were quite good, the ratio of solvent to crude product is too
large to be practical for scale-up.
4. Ethanol/Water 80/20 (V/V). The crude product is largely
insoluble at room temperature but dissolves in a reasonable
amount of hot solvent. When 80/20 (v/v) ethanol/water was
used, the yield of the first recrystallized crop from the crude
material was improved to approximately 70% compared to only
25–35% yield for the first recrystallized crop from 100% ethanol
or 95/5 (v/v) ethanol/water.
5. Ethanol Followed by Dropwise Addition of Water.
Attempts to further reduce the total solvent volume were made
by dissolving the crude material in a minimal amount of hot
ethanol and seeding the crystallization by adding water drop-
wise. This method worked quite well, however, the problem
of “caking” was still observed.
6. Constant Agitation Method. Although good recrystallized
recovery and purities were achieved with the previous two
methods, it was still imperative to obtain the purified material
in a form that could be easily transferred and dried on large
Vol. 11, No. 6, 2007 / Organic Process Research & Development
•
999

Figure 5. Major impurities in crude APO-Link products from
path 1.
Table 2. Metal content of APO-Link samples prepared in
a
Hastelloy vessel
Sample
Ni (mg/kg)
Mo (mg/kg)
Cr (mg/kg)
b
KCP - 04062005
KCP - 05182005
86.0
136.8
37.4
8.8
nd
nd
b
1
Figure 4. H NMR of crude APO-Link product A (Path 1) and
a
Concentration is average of triplicate analyses. b nd ) not detected.
product I (Path 2) and identification of impurities.
scale. Stirring during recrystallization is contrary to conventional
bench-scale chemistry techniques but is a normal method for
large-scale crystallizations. Using the optimized solvent com-
bination, rapid stirring of the solution during cooling allowed
for uniform temperature distribution and yielded a slurry of
recrystallized APO-Link. The slurry could be efficiently trans-
ferred, filtered, and dried. Both 80/20 ethanol/water by weight
(
Paths 2–5) appear to be 2-aminophenyldisulfide and 3,4-
dihydro-2H-benzo[1,4]thiazine.
Corrosion Study of APO-Link Synthesis. A major concern
of this synthetic process was the corrosive nature of the APO-
Link reactions, especially Paths 1 and 2, where concentrated
aqueous sodium hydroxide solutions at reflux are used. During
early bench-scale development at KCP, equipment constructed
of glass was damaged due to base corrosion. In addition, crude
APO-Link samples synthesized in a nickel alloy reactor clearly
showed evidence of nickel and molybdenum (Table 2).
The existing 100 gallon reactors at KCP’s Polymer Produc-
tion Facility are lined with glass. Reactor A is lined with
Pfaudler 3115 multipurpose glass, and reactor D is lined with
DeDietrich 3009 multipurpose glass. Glass coupons of each type
were acquired from the manufacturer and exposed to the bench-
scale reaction conditions. Worst-case scenario glass lifetime
estimates were calculated based on thickness measurements.
Under Path 1 conditions, the effects of corrosion were substan-
tial, and the worst-case lifetime of the Pfaudler 3115 glass was
determined to be approximately 8 years. Under Path 2 condi-
tions, the effects of corrosion were less pronounced. The worst-
case lifetime of the Pfaudler 3115 glass was roughly 35–40
years. The DeDietrich 3009 glass did not show any discernible
thinning under Path 2 conditions; thus, the lifetime was
unlimited. Because our final optimization uses sodium hydrox-
ide at 85 °C (Path 5), there are even fewer concerns over reactor
corrosion and damage. Reactor D lined with DeDietrich 3009
multipurpose glass was chosen for APO-Link production.
Reaction Calorimetry Data for Scale-Up. Power com-
pensation calorimetry was also used to study the optimized
bench-scale procedure to provide additional data for scale-up.
Prior to scale-up of Path 5 chemistry, power compensation
calorimetry was used to accurately measure the molar heat of
reaction during the addition of ATP (1st reaction) and the
addition of 1,2-dibromoethane (2nd reaction). During the
addition of ATP in the first reaction, the molar heat of reaction
was 43.23 kJ/mol. During the addition of dibromoethane in the
second phase of the reaction, the molar heat of reaction was
214.79 kJ/mol. This information was needed prior to full-scale
production in order to assess heat removal requirements.
Addition Rate and Rinsing. The addition rate of DBE was
investigated prior to scale-up (Table 1) because the addition of
(w/w) and by volume (v/v) were used in the bench-scale
development, with no observable differences in the final product.
Because it is more practical to weigh large amounts of solvents,
the weight percent method for preparation of 80/20 ethanol/
water solution was chosen for synthesis scale-up. In terms of
feasibility for scale-up, the constant agitation method was a
considerable improvement over more conventional bench-scale
methods examined and consistently yielded high purity material
in 75–80% overall yield. On bench-scale, the recrystallization
slurry was cooled to 0 °C in order to maximize product
recovery. Existing equipment in the Polymer Production Facility
does not have the capability to conveniently cool to this
temperature; therefore, the temperature dependence of the
product recovery was studied. It was found that the majority
of the purified APO-Link crystallized at 40 °C (see Supporting
Information). Therefore, for the full-scale production, existing
equipment was used to cool the recrystallization slurry to 25
°C with constant agitation and resulted in 75% overall reaction
yield on both the 100-lb and the 200-lb scale. The effect of
cooling rate on the APO-Link material was also examined.
There was not a considerable difference in the particle size of
the material when cooled at a very fast rate (50°/h) versus a
very slow rate (3°/h) with similar agitation conditions.
APO-Link Impurities. Both GC/MS and NMR spectros-
copy (Figure 4) were used to characterize the starting materials,
crude products, recrystallized products, and organic material
remaining in aqueous extracts. The major impurities arising
from the hydrolysis of benzothiazole followed by reaction with
dichloroethane (Path 1) appear to be unreacted benzothiazole,
2-aminophenyldisulfide and 3,4-dihydro-2H-benzo[1,4]thiazine
(
Figure 5). The crude materials from reactions with 2-ami-
1
nothiophenol (Paths 2–5) were also examined. Using H NMR,
there was no evidence of the starting material, 2-aminothiophe-
nol. The major impurities arising from the deprotonation of
2-aminothiophenol followed by reaction with dibromoethane
1
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dibromoethane. The molten crude product is rinsed multiple
times with hot water and then recrystallized with 80/20 (w/w)
ethanol/water solution. Our optimized procedure consistently
gives 75–80% overall yield of product, with a purity greater
than 95% purity by GC/MS. Our work has provided valuable
characterization information for the material specification along
with a scalable procedure for APO-Link production. APO-Link
has been produced on both 100 lb and 200 lb scales, using the
optimized process, giving high quality material in excellent
yield. The synthetic optimization of APO-Link involved col-
laboration between chemistry and engineering from the initial
development. Our work clearly illustrates the importance of
constant collaboration between laboratory and pilot-plant to
develop a practical synthetic process for scale-up.
1
Figure 6. H NMR spectra of Versalink (formerly available
Experimental Section
General. Benzothiazole (Aldrich, 96%), 2-aminothiophenol
(Aldrich 99% or Alfa Aesar 98%), 1,2-dichloroethane (Aldrich
from Air Products), recrystallized product X from optimized
bench-scale procedure, and recrystallized product from 100 lb
and 200 lb production scale.
9
9%), 1,2-dibromoethane (Aldrich 99+%), sodium hydroxide
DBE is the most exothermic portion of the synthetic process.
In V, DBE was added over 60 min, and in W, DBE was added
over 180 min. There was no significant difference in the overall
yield and purity between the two reactions. Thus, a 60 min
addition time of DBE was recommended to reduce overall
processing time. In X, the third water rinse was eliminated to
determine if the overall cycle time could be reduced. Because
the yield and purity of the recrystallized product following the
second rinse were quite good, it may be possible to eliminate
the third hot water rinse during large-scale production. Although
not surprising, we also found that the purity of the recrystallized
product could be increased slightly simply by carrying out an
additional rinse of the recrystallized product with chilled 80/20
(Fisher 99% or Acros 98%), sodium carbonate (Fisher 99%),
methyl ethyl ketone (Acros 99+%), and ethanol (AAPER,
nondenatured, Absolute 200 proof or 190 proof). All reagents
were used as received without additional purification.
For nuclear magnetic resonance spectroscopy (NMR),
samples were prepared by dissolving approximately 30 mg of
APO-Link sample in 0.8 mL of deuterated chloroform (CDCl3
99.8 atom % D with 1% v/v TMS). A Bruker Avance 400
spectrometer was used for proton and carbon NMR analysis
1
13
(operating at 400.13 MHz for H and 100.62 MHz for C).
1
13
For H, 16 scans were collected and for C, at least 176 scans
were collected. All spectra were referenced against TMS at 0
ppm. For Fourier transform infrared spectroscopy (FT-IR),
samples for solution FT-IR were prepared by dissolving
approximately 50 mg of sample in 3.0 mL of carbon tetrachlo-
(w/w) ethanol/water. This option may be useful if the material
requires large-scale rework to meet material specifications.
Scale-Up. The synthesis of APO-Link was scaled up using
Path 5 conditions in a 100 gallon reactor lined with DeDietrick
ride (CCl , 99.9% ACS reagent). The solution was then injected
into a SL-3 KBr solution cell with a 0.1023 mm pathlength
4
3
009 multipurpose glass. The material was produced on
(International Crystal Laboratories). A Mattson 5000 Series FT-
IR spectrometer was used for the analysis. Before spectra were
collected, a background spectrum of carbon tetrachloride was
collected and stored. All spectra were collected with 16 scans
approximately 100 lb (batches 061115 and 061213) and 200
lb (batch 070308) scales. The material was recrystallized with
agitation within the same 100 gallon glass-lined reactor. The
slurry was transferred to a 50 gallon Pfaudler Nutsche filter
dryer for filtration and final drying. The thick product slurry
was transferred using a streamlined transfer design with 2-in
diameter piping. The overall yields of the large-scale production
batches were approximately 75% of free-flowing, finely divided
material, with a purity of 96–99%, using both GPC and GC/
MS. We also used NMR spectroscopy to verify the high quality
of APO-Link material produced on both bench scale and
-1
-1
-1
from 4000 cm to 850 cm , with a resolution of 2 cm . After
analysis of each sample, the solution cell was thoroughly rinsed
with carbon tetrachloride and evacuated to prevent cross-
contamination of samples. Samples for solid FT-IR analysis
were prepared by fabricating a solid potassium bromide pellet
using approximately 7 mg of sample and 350 mg of KBr. A
Mattson 5000 FT-IR spectrometer was used for the analysis.
Before spectra were collected, a background spectrum was
1
-1
production scale (Figure 6). The H NMR spectra are identical
for the optimized bench-scale sample X, the 100 lb scale
production batch 061213, and the 200 lb production scale batch
collected and stored. All spectra were collected from 4000 cm
-1
-1
to 400 cm , with a resolution of 2 cm and 16 scans. For gas
chromatography coupled with mass spectrometry (GC/MS),
samples were prepared by dissolving 0.20 g of sample in 9.7 g
of acetonitrile with 0.1 g of a 1% diglyme internal standard
solution in acetonitrile. An Agilent 5890 gas chromatograph
with a 5971 mass spectrometer was used. The separation of
APO-Link components resulted in a total ion chromatograph
(TIC). The peaks were identified through retention time
matching and comparison to mass spectra. The GC/MS column
was a Restek Rtx-5 30 m × 0.25 mm i.d. × 0.25 µm film. The
1
070308. Furthermore, the spectra match H NMR of Cyanacure
and Versalink samples that were previously commercially
available.
Conclusion
The recommended procedure for the scaled-up synthesis of
APO-Link is based on the deprotonation of 2-aminothiophenol,
with sodium hydroxide at 80–85 °C, followed by addition of
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•
1001

injection port temperature was 250 °C. The sample was injected
with split injection mode, consisting of a 1 µL injection with
an 8:1 split flow ratio. The oven temperature was 50 °C, with
a ramp of 10 °C/min to 280 °C followed by an isotherm at 280
General Reaction Conditions with 2-Aminothiophenol
(Paths 2 and 3). A mixture of 2-aminothiophenol (ATP, 0.100
mol), sodium hydroxide or sodium carbonate (NaOH/Na CO ,
2 3
0.103 mol), and 60 mL of deionized water was heated to reflux
for 30 min. The mixture was allowed to cool to 60–65 °C, and
dibromoethane (DBE, 0.050 mol) was added dropwise over
20–30 min. The mixture was then heated to reflux for 1.5–2 h.
Following work-up, the crude product was recrystallized and
characterized.
For experiments conducted at KCP in the reaction calorim-
eter, 215 mL of demineralized water and sodium hydroxide
NaOH, 2 mol) were charged to the 1 L reactor vessel.
-Aminothiophenol (ATP, 2 mol) was added to the reactor over
a period of 30 min. The reaction progressed for 30 min at 116
C. Dichloroethane or dibromoethane (DCE/DBE, 1 mol) was
°C for 20 min. The MS transfer temperature was 280 °C. The
relative area % quantitation was performed by summing all the
peak areas and then dividing the area of each peak by the total
peak area. This gives a relative concentration and requires no
standards. Using these conditions, the retention time of APO-
Link was approximately 26.8 min. For gel permeation chro-
matography (GPC), samples were prepared by dissolving
approximately 20 mg of sample in 10 mL of tetrahydrofuran
(
2
(THF stabilized with BHT). Stabilized THF was used as the
mobile phase with three Waters high-resolution HR0.5 columns
arranged in series. The molecular weight range for this type of
high-resolution column is 0–1000 g/mol. The high-resolution
columns are cross-linked styrene/divinyl benzene with ∼60 Å
pore size. As with GC/MS, the GPC quantitation was performed
using a relative area % method. For inductively coupled plasma
spectroscopy (ICP), approximately 250 mg of sample was
digested under agitation at ambient temperature in 10 mL of
°
then fed to the reactor vessel over a period of 60 min. The
reaction progressed for 1.5 h at 105 °C. Following work-up,
the crude product was recrystallized and characterized.
General Reaction Conditions with 2-Aminothiophenol
(
Paths 4 and 5). A mixture of 2-aminothiophenol (ATP, 0.100
mol), sodium hydroxide or sodium carbonate (NaOH/Na CO
.103 mol), and 60 mL of deionized water was heated at 80–85
C for 30 min. Without additional cooling, dibromoethane
DBE, 0.050 mol) was added dropwise over 20–30 min. The
2
3
,
0
°
(
3
50% (v/v) concentrated HNO for approximately 24 h. The
sample was filtered first through a 5 µm syringe filter and then
filtered a second time through a 0.45 µm syringe filter. The
sample was diluted with deionized water to give a final sample
concentration of either 0.25 mg/mL or 10 mg/mL (1% sample).
The sample was analyzed for Cr, Fe, Mo, and Ni content against
a certified multi-element reference standard. A nonquantitative
survey scan for 66 other metals was also performed. A Thermo
Jarrell Ash Corporation IRIS Inductively Coupled Argon Plasma
Emission Spectroscopy system was used for the analysis. The
argon plasma was operated at 1.0 kW power, with a plasma
flow rate of 15.0 L/min and a nebulizer flow rate of 1.5 L/min.
The vertical and horizontal slits were set at 300 and 50 mm.
The viewing height above the load coil was set at 15 mm for
all species. Data from the spectrometer was collected by TJA
ThermoSpec-CID software. Three replicate analyses were
performed for each sample, with the mean concentration
reported.
mixture was then heated at 80–85 °C for 1.5–2 h. Following
work-up, the crude product was recrystallized and characterized.
For experiments conducted at KCP in the reaction calorim-
eter, 215 mL of demineralized water and sodium hydroxide
NaOH, 2 mol) were charged to the 1 L reactor vessel.
-Aminothiophenol (ATP, 2 mol) was added to the reactor over
a period of 30 min. The reaction progressed for 30 min at 85
C. Dichloroethane or dibromoethane (DCE/DBE, 1 mol) was
(
2
°
then fed to the reactor vessel over a period of 60 min. The
reaction progressed for 1.5 h at 85 °C. Following work-up, the
crude product was recrystallized and characterized.
Detailed Optimized Procedure Based on Path 5. The
optimized procedure intended for scale-up was carried out on
the bench scale to verify the full-scale formulation and
procedure. Deionized water (225 mL) was added to a 1 L, four-
neck, cylindrical, jacketed reactor with bottom outlet. Sodium
hydroxide (2.02 mol, Acros Organics 98%, 82.42 g) was
transferred slowly with stirring to dissolve. The reactor jacket
temperature was adjusted to maintain a solution temperature
of 85 ( 5 °C. 2-aminothiophenol (2.0 mol, Aldrich 99%, 252.88
g) was transferred to a pressure-equalizing funnel for addition.
The ATP was added to the sodium hydroxide solution over 30
min while maintaining the temperature at 85 ( 5 °C. Following
the addition of ATP, the mixture was allowed to stir at 85 ( 5
General Reaction Conditions with Benzothiazole (Path
1
). For experiments conducted at LANL in laboratory glassware,
a mixture of benzothiazole (0.100 mol), sodium hydroxide
NaOH, 0.205 mol), and 23 mL of deionized water was heated
to reflux for 4–4.5 h. The mixture was allowed to cool to 60–65
C, and dichloroethane (DCE, 0.050 mol) was added dropwise
(
°
over 20–30 min. The mixture was then heated to reflux for 2 h.
Following work-up, the crude product was recrystallized and
characterized.
°
C for 30 min. 1,2-Dibromoethane (1.0 mol, Aldrich 99%,
For experiments conducted at KCP in the reaction calorim-
eter, 250 mL of demineralized water and sodium hydroxide
1
87.74 g, 87.04 mL) was transferred into a graduated pressure-
equalizing addition funnel. 1,2-Dibromoethane (DBE) was
added to the reaction mixture over 60 min while maintaining
the temperature at 85 ( 5 °C. This step was noticeably more
exothermic; therefore, the temperature and addition rate were
closely monitored. Following the addition of DBE, the mixture
reacted with agitation at 85 ( 5 °C for 90 min. Agitation was
stopped, and the phases were allowed to separate. During phase
separation and work-up, the temperature was maintained at 85
(NaOH, 2.27 mol) were charged to the 1 L reactor vessel.
Benzothiazole (1.13 mol) was fed to the reactor over a period
of 15 min. The reaction progressed for 4 h at 116 °C.
Dichloroethane or dibromoethane (DCE/DBE, 0.57 mol) was
then added to the reactor over a period of 20 min. The reaction
progressed for 2 h at 105 °C. Following work-up, the crude
product was recrystallized and characterized.
1
002
•
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(
5 °C to keep the crude product molten. Due to the high salt
perature, the mixture was poured into a Buchner funnel and
vacuum filtered. During filtration, the solid was rinsed with
approximately 500 mL of chilled (approximately 5 °C) 80/20
(w/w) ethanol/water. The material was transferred to a large
dish and dried under reduced pressure at 45 °C for 48 h. The
final dried material was a powdery, light-yellow solid (ap-
proximately 80% overall yield).
content of the aqueous phase, the organic fraction is the top
layer in the initial phase separation. The aqueous layer was
drained from the reactor and discarded. Approximately 260 mL
of hot deionized water was added to the reactor, and the mixture
was agitated for approximately 15 min (first rinse). Agitation
was stopped, and the phases were allowed to separate for 5–10
min. The organic crude material (now bottom layer) was quickly
drained and then returned to the reactor after the aqueous portion
was removed. This process was repeated two more times to
give a total of three rinses. The organic crude product was stirred
in the reactor at a temperature of approximately 75 °C to keep
the crude molten. For recrystallization, approximately 500 mL
of 80/20 (w/w) ethanol/water was heated near boiling. The hot
solvent was carefully poured into the reactor to dissolve the
crude material. The solution was stirred for approximately 45
min to ensure complete dissolution. The temperature of the
recirculating water in the reactor jacket was adjusted to 20.0
APO-Link characterization: FW (calcd) 276.42 g/mol,
1
generally light-yellow granular powder; H NMR (400 MHz,
3 2 2
CDCl ) δ (ppm) 2.85 (s, 2H, CH ), 4.33, (s, 2H, NH ), 6.63,
6.64, 6.66, 6.67, 6.68, 6.70 (mult, 2H, aromatic H at positions
4 and 5), 7.09, 7.11, 7.13 (t, 1H, aromatic H at position 3),
13
7.30, 7.31, 7.32, 7.33 (dd, 1H, aromatic H at position 6);
C
NMR (100 MHz, CDCl ) δ (ppm) 34.4 (CH ), 114.9 (aromatic
3
2
C at position 3), 116.6 (aromatic C at position 6), 118.5
(aromatic C at position 4), 129.9 (aromatic C at position 5),
136.1 (aromatic C at position 1), 148.5 (aromatic C at position
-1
2); IR (KBr pellet, cm ) 3366, 3358, 3290, 3182, 2062, 2931,
1617, 1583, 1479, 1446, 1423, 1316, 1304, 1288, 1249, 1206,
1164, 1096, 1058, 962, 938, 858, 837, 749, 700.
°C so the reactor would begin to cool. The temperature of the
recrystallization solution and recirculating water were monitored
as the solution cooled and crystallization began. Rapid stirring
was maintained throughout the cooling and crystallization so
that the purified product would not “cake out” within the reactor.
When the recrystallization solution reached approximately 60
Supporting Information Available
Additional information and spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
°C, finely dispersed solid began to come out of solution. At
approximately 40 °C, the mixture was a relatively thick slurry
of fine, light-yellow solid. The slurry was cooled to ap-
proximately 20–25° while stirring. Upon reaching room tem-
Received for review June 1, 2007.
OP700122Q
Vol. 11, No. 6, 2007 / Organic Process Research & Development
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1003