Design of new reaction conditions for the Sugasawa reaction based on mechanistic insights

Article abstract of DOI:10.1021/op0340659

A process to prepare 2-propionyl-4-bromoaniline by ortho acylation of 4-bromoaniline under Sugasawa conditions was developed. Upon scale-up in a pilot plant, the process gave lower yields than in the laboratory in four out of five plant runs. Analysis of

Full text of DOI:10.1021/op0340659

Organic Process Research & Development 2003, 7, 723−732
Design of New Reaction Conditions for the Sugasawa Reaction Based on
Mechanistic Insights‡
Kapa Prasad,* George T. Lee, Apurva Chaudhary, Michael J. Girgis, James W. Streemke, and Oljan Repicˇ
Process Research and DeVelopment, NoVartis Institute for Biomedical Research, One Health Plaza,
East HanoVer, New Jersey 07936, U.S.A.
Abstract:
to give the acylated product in 9% yield. By switching from
refluxing benzene to refluxing toluene, we improved the yield
to 50%. Using this acylation as a key step, we developed a
two-step process for producing 6-bromo-4-ethylquinazoline
3 in 44% isolated yield (Scheme 2; see method A in the
Experimental Section); the final step, as before, comprises
the reaction of 2 with formamidine acetate to give 3.
The process based on these experiments was scaled-up
by a factor of about 800 in a pilot plant, but gave the product
in lower yield, on scale-up, in four out of five pilot-plant
batches. The causes for the lower yields were then investi-
gated, and these studies led to a development of modified
reaction conditions that made the reaction more rugged,
reproducible, and higher-yielding compared to the classical
mix-reflux conditions.
A process to prepare 2-propionyl-4-bromoaniline by ortho
acylation of 4-bromoaniline under Sugasawa conditions was
developed. Upon scale-up in a pilot plant, the process gave lower
yields than in the laboratory in four out of five plant runs.
Analysis of the pilot-plant data, in conjunction with reaction
calorimetric experiments, showed that expulsion of HCl from
the reaction medium was key for obtaining high product yields.
New reaction conditions were subsequently developed for
carrying out ortho acylation of 4-bromoaniline (1). The reaction
mixture containing aniline/BCl3/AlCl3/C2H5CN was added to a
refluxing solution of toluene to allow for substantial HCl
expulsion and thus obtain the optimum yield of the desired
product. Aniline hydrochlorides were also shown to be suitable
starting materials under these conditions. Mechanistic implica-
tions of these findings are discussed. The new reaction condi-
tions significantly increased the yield.
Results and Discussion
Conversion of 1 to 2. Initial process development efforts
focused on enhancement of the reactivity of 1 to obtain
reasonable product yields. By changing the addition sequence
and the stoichiometry of various reagents, and performing
the reaction in xylenes at reflux (Table 1, item E), an efficient
process to produce 2 in 50% yield was developed. Upon
reaction of 2 with formamidine acetate, 3 was obtained in
an overall yield of 44% (based on 1). A key finding was
that the order of reagent addition was not critical. Conse-
quently, it was possible to develop a safer process wherein
controlled addition of liquid reagents (see below) was
performed for the highly exothermic steps vs the classical
Sugasawa conditions, in which the highly exothermic addi-
tion of solid AlCl3 to the aniline/BCl3/nitrile mixture is
performed (Table 1, item A).
Although all the initial experiments were done in refluxing
xylenes, refluxing toluene gave similar yields, and the
optimized procedure was developed using toluene as the
solvent. At the optimal conditions, a solution of 1 in toluene
at room temperature was added to a suspension of AlCl3 in
toluene at -10 °C. Pressurized BCl3 was then added as a
liquid at -10 °C, followed by propionitrile addition at about
-5 °C. The reaction mixture was heated to reflux (103-
107 °C) and held at reflux for 3 h to produce the cyclic
precursor to product 2. HCl evolution occurred during this
process. After cooling to room temperature, the reaction
mixture was poured slowly into a vessel containing water,
thus hydrolyzing the cyclic precursor to give 2. After
allowing the reaction mixture to settle into two layers at 55
°C, the lower aqueous layer was removed. The desired
Introduction
Ortho acylation of anilines by condensation with a nitrile
in the presence of BCl3 and AlCl3 is a powerful method in
organic synthesis and is commonly referred to as the
Sugasawa reaction.1 This transformation has gained greater
synthetic importance as o-acyl anilines are preferred precur-
sors in building a variety of medicinally useful heterocycles.2-4
In one of our antifungal projects5 we needed an efficient
synthesis for making multikilogram quantities of quinazoline
3 which was made from o-acyl aniline 2.
The o-acyl aniline 2 has been made from 3′-bromopro-
piophenone (Aldrich price >$2000/kg) in two steps2 as
shown in Scheme 1. As the starting material is expensive
and the reaction conditions are not conducive to large-scale
manufacturing, we explored the ortho acylation of readily
available 4-bromoaniline 1 using propionitrile/BCl3/AlCl3 and
Sugasawa reaction conditions. Ortho acylation of 4-bromo-
aniline 1 with propionitrile mediated by BCl3 with AlCl3 as
the auxiliary Lewis acid had been reported in the literature6
‡ Dedicated to Professor Andrea Vasella on the occasion of his 60th birthday.
(1) Sugasawa, T.; Toyoda, T.; Adachi M.; Sasakura, K. J. Am. Chem. Soc.
1978, 100, 4482.
(2) Earley, J. V.; Gilman, N. W. Synth. Commun. 1985, 15, 1271-1276.
(3) Houpis, I. N.; Molina, A.; Douglas, A. W.; Xavier, L.; Lynch, J.; Volante,
R. P.; Reider, P. J. Tetrahedron Lett. 1994, 35, 6811-6814.
(4) Tabuchi, S.; Ito, H.; Sogabe, H.; Kuno, M.; Kinoshita, T.; Katumi, I.;
Yamamoto, N.; Mitsui, H.; Satoh, Y. Chem. Pharm. Bull. 2000, 48, 1-15.
(5) Nussbaumer, P. WO 9628430, 1996.
(6) Yaegashi, T.; Sawada, S.; Nagata, H.; Furuta, T.; Yokokura, T.; Miyasaka,
T. Chem. Pharm. Bull. 1994, 42, 2518-2525.
10.1021/op0340659 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/01/2003
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723

Scheme 1
Table 1. Initial experiments to enhance the yield of 2
molar ratio
(1:C2H5CN:BCl3:AlCl3)
addition sequence of reactants and reagents
yield (%)
A. 1:2:1.1:1.2
Add BCl3/xylene into 1/C2H5CN solution, then add AlCl3 & reflux
Add 1/C2H5CN solution into BCl3/xylene then add AlCl3 & reflux
Same as B, but use more 1 and more AlCl3 & reflux
Same as B, but use 1 HCl salt
Add 1/C2H5CN solution into a mixture of AlCl3 and BCl3/xylene solution & reflux
Add C2H5CN into BCl3/xylene, add 1 at room temperature, then add AlCl3 & reflux.
50
44
21
47
44
47
B. 1:4.6:1.1:1.2
C. 1.3:4.7:1:1.4
D. 1:4.6:1.1:1.2
E. 1:4.6:1.1:1.2
F. 1:1.2:1.05:1.26
Table 2. Process data from scale-up reactions
plant batches
3
lab process
1
2
4
5
Isolated yield of 3, %
HPLC: area % of 2
time to heat, h:min
reflux time, h:min
amount distilled, L
no. of distillate returns
batch temperature, °C
jacket temperature,°C
44
53.6
1:50
3:00
35
47.1
1:30
4:00
64
1
103-104
103-105
38
50.0
2:00
4:00
135
3
102-104
104-105
38
40
50
50.0
1:00
4:00
96
49.9
1:30
5:00
101
10
104
105
58.0
2:20
5:00
232
10
105-107
112
N/A
total reflux
105-107
107-110
2
103-104
104-106
Scheme 2
yield of 3 obtained when isolated 2 was used and (b) HPLC
analyses of ortho acylation reaction mixture for 2. The low
yield of Sugasawa reaction was, in turn, related to two
factors: (a) incomplete conversion of the starting material
1 and (b) formation of a competing amidine byproduct 4 as
shown in Scheme 2.
Pilot-Plant Scale-Up. Five batches were prepared in the
pilot plant based on the above procedure. Unlike the
laboratory procedure, the ortho acylation step was not
performed under total-reflux conditions. Instead, the vapors
were directed to a separate vessel for condensation, the
contents of which were returned to the reactor periodically.
This modification was prompted by concerns over the
possible breakage of the glass condenser on top of the reactor,
which might result in a violent reaction between the ethylene
glycol condenser coolant and BCl3 and AlCl3 in the reactor.
Process data, including the isolated 3 yields from the pilot-
plant runs, are summarized in Table 2. In comparison to the
laboratory yield, the isolated yields of 3 in batches 1-4 were
lower, whereas that of batch 5 was higher. HPLC analyses
of the ortho acylation hydrolysis mixture, performed to allow
separate determination of the yield of 2 and thus decouple
the scale-up performance of the two steps, indicated that
lower yields of 3 in batches 1-4 were correlated with lower
yields of 2.
product 2 was in the organic phase, and 1 and 4 were in the
aqueous phase.
Although pure 2 could be isolated by evaporation of the
solvent, the process was streamlined to allow production of
3 without the isolation of 2. First, a vacuum distillation of
the organic layer was performed to remove toluene, excess
propionitrile, and water. Formamidine acetate and ethylene
glycol solvent were added, and the mixture was heated to
reflux (105-120 °C) to give 3. Ammonia was formed during
the reaction. A vacuum distillation was then performed to
remove additional toluene. Product 3 precipitated by the
addition of water to the reaction mixture and cooling to 0-5
°C; the mixture was held at this temperature for 1.5 h, and
3 was isolated by filtration and drying. An overall yield of
44% of 3 was obtained.
Examination of the data shows that the key process
variable that was changed in batch 5 was the jacket
temperature at reflux (viz., 112 vs e 106 °C in the first four
This rather low yield was attributed primarily to low yield
of the ortho acylation reaction based on (a) the near 90%
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batches). The higher jacket temperature at reflux in batch 5
is expected to result in greater heat-input rate to the reaction
mixture according to the following equation
Q ) UA(Tj - Tr)
(1)
where:
Q ) heat input rate, W
U ) overall heat transfer coefficient between jacket and
reaction mixture, W/(m2‚°C)
A ) heat transfer area, m2
Figure 1. Schematic diagram of RC1 apparatus.
Tj,Tr ) jacket and batch temperatures, respectively, °C
HPLC to quantify reactant conversion and product yields
and selectivities as functions of reaction time.
With a greater heat input rate at reflux, where the batch
temperature hardly changes, the boilup rate increases, as
evidenced by the greater amount of condensed vapors
collected in batch 5 relative to the other batches (232 vs e
135 L). Heat-input rates in the plant batches were estimated
for batches 4 and 5 using measured values of 375 W/(m2‚
°C) for the overall heat transfer coefficient U in the plant
reactor.7 Although the latter value was determined in
experiments with water in the reactor, it was nevertheless
useful to calculate an upper bound for U, and thus the heat-
input rate. The heat transfer area (2.12 m2) was determined
from knowledge of the wetted area at two fill-volumes, viz.,
1.83 m2 at 300 L and 3.02 m2 at 600 L, and linear
interpolation at the actual reaction volume. From these
results, the heat-input rates per unit mass in batches 4 and 5
were determined to be 5.7 and 15.2 W/kg, respectively. Thus,
in batch 5, the heat input rate per unit mass was more than
2.5 times greater than for the previous batches. Evidently,
the reaction performance depended on the heat-input rate at
reflux, and hence the boilup rate.
The boilup rate per se, however, cannot account for the
lower yield in the first four batches, since the rate of a reac-
tion depends on reactant concentrations and temperature,
neither of which changed appreciably in the plant batches
(Table 2). However, the boilup rate could affect the concen-
tration of a volatile component in solution that impacts pro-
duct selectivity. The most obvious such component is the
HCl formed as a byproduct, most of which is produced as an
offgas. It was thus necessary to investigate more thoroughly
the role of heat-input rate and its impact on the boilup rate,
the HCl-removal rate, and the selectivity to 2 vs 4.
An experiment was first performed in which a heat-input
rate corresponding approximately to that of batch 5 was used.
In the latter experiment, when the batch temperature ap-
proached 105 °C, the temperature control mode in the RC1
was changed from batch to jacket temperature control to
simulate the pilot plant’s temperature control method. The
jacket temperature was then increased gradually to maintain
an average temperature difference of about 2.5 °C between
the jacket and the batch temperatures, giving an average heat-
input rate of 16.5 W/kg (vs 15 W/kg in batch 5). Temperature
and concentration profiles are shown Figure 2. The figure
indicates that when the reaction is terminated after a 3-h hold
at a batch temperature of 105-107 °C, the fractional molar
yield of 2 is 0.559 (i.e., about 56%), with an amidine 4 yield
of 0.222 and incomplete conversion of 1. A good mass
balance closure is obtained (96%). Furthermore, the rate of
amidine 4 formation during reflux is lower than that of 2.
For example, at a reaction time of 2.3 h, the yield of 2 and
amidine 4 molar yields are 0.195 and 0.120 respectively; at
a reaction time of 5.1 h, the yield of 2 triples (0.557), whereas
that of amidine 4 barely doubles (0.222).
To evaluate how a lower heat-input rate impacts yields
relative to the base case illustrated in Figure 2, a subsequent
experiment was performed using a lower jacket temperature
to give a heat-input rate more similar to that in plant batch
4 (Figure 3), namely, 7 W/kg. The lower heat-input rate also
resulted in a slightly lower batch temperature (<2.5 °C)
during reflux. Similar lower batch temperatures were also
observed at lower jacket temperatures in plant batches 1-4
(Table 2).
Follow-up Experiments: Impact of Heat-Input Rate.
Subsequent experiments were performed using a Mettler-
Toledo RC1 reaction calorimeter to measure the effect of
the heat-input rate on reaction selectivity. A schematic
diagram of the apparatus is given in Figure 1; details are
given in the Experimental Section. In the RC1, the quantity
UA, comprising the product of the overall heat transfer
coefficient U and the heat transfer area A, was determined
as part of the experiment, and the batch and jacket temper-
atures were continuously data-logged. The heat-input rate
could thus be calculated directly from eq 1. Additionally,
the reaction mixture composition was determined using
The lower heat-input rate did not affect the overall
consumption of 1 significantly (Figure 4), but had a large
impact on the molar yield of 2 (Figure 5), the latter being
significantly lower (0.414 vs 0.559) at the lower heat-input
rate. The yield of 2 at the lower heat-input rate is 74% that
of the base case value, and the change is comparable to plant
results, where batch 4 value was about 80% that of batch 5.
Thus, the lower yield of 2 when using a lower heat-input
rate per unit mass was replicated in the laboratory. Note that
the yield comparisons are done at the same 5-h reaction time,
corresponding to about 3 h at reflux. Figure 5 also shows
that longer time at reflux did not impact yield of 2
significantly at lower heat-input rate.
(7) Streemke, J. W.; Khan, S. Unpublished results.
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Figure 2. Temporal temperature and concentration profiles of compounds 1, 2, and 4 in experiment corresponding to same heat
input rate as pilot-plant batch 5.
Figure 3. Heat input rate profiles in experiments to simulate pilot-plant batches 4 and 5.
The results in Figures 4 and 5 are in agreement with the
greater yields of 2 obtained in plant batch 5 relative to those
in the other plant batches. As mentioned earlier, the heat
input rate does not appear to impact consumption rate of 1
greatly. Thus, its impact on selectivity indicates that it must
affect another factor. With a greater heat input rate, it is
hypothesized that the reflux rate is greater, allowing more
HCl to be evolved per unit time, and thus keeping less HCl
in solution. Using a wet test meter placed at the exit of the
RC1 reactor vessel, the gas-evolution rate could be deter-
mined (see Experimental Section). Figure 6 shows clearly
that a greater off-gas evolution rate is obtained in the
experiment at the higher heat-evolution rate. With more HCl
left in the liquid phase, with conversion being minimally
impacted, lower selectivity for 2 results.
selectivity, two additional experiments were performed: In
the first, the reactor was closed during the reaction. Thus,
any HCl gas evolved escaping from the liquid-phase ac-
cumulated in the headspace. The resulting greater pressure
increases HCl concentration in the liquid-phase according
to Henry’s Law:8
Pi ) Hxi
where:
Pi ) partial pressure of component i
H ) Henry’s Law coefficient
Follow-up Experiments: Impact of HCl Removal
Rate. To probe further the impact of HCl offgas on product
xi ) liquid-phase mole fraction of component i
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Figure 4. Conversion of 1 at two different heat input rates corresponding to pilot-plant batches 4 and 5.
Figure 5. Yields of 2 at two different heat input rates corresponding to plant batches 4 and 5.
In the second experiment, the toluene solvent (bp 111 °C)
was replaced by higher-boiling xylenes (bp 137-144 °C),
and the reaction mixture was heated to 107 °C. This
temperature corresponds to the upper temperature reached
during the reaction in toluene. With toluene as solvent, reflux
occurs at 103-107 °C because propionitrile, which boils at
97 °C, is present in the reaction mixture. Because of the
higher boiling point of xylene, less reflux should occur, and
therefore the HCl gas evolution rate will be diminished. In
both these experiments, then, the HCl concentration in the
liquid phase is expected to be greater than that in the previous
set of experiments, and on the basis of the results in Figure
5, one should expect a lower selectivity of 2.
tration, arising from either a sealed reactor or a lower boilup
rate due to absence of reflux, does not impact conversion of
1, but that it decreases substantially the yield of 2 and
increases that of the amidine. Since conversion of 1 is hardly
impacted, this means that a greater liquid-phase concentration
decreases selectivity of 2 while increasing that of amidine
4.
Mechanistic Interpretations. The published9 reaction
mechanism (Scheme 3) for the Sugasawa reaction, which
was inferred on the basis of NMR spectroscopic examination
of various intermediates, involves formation of a supercom-
plex by reaction of two initial complexes, one comprising
the aniline and BCl3 and the other the nitrile and the auxiliary
Lewis acid. With AlCl3 as the auxiliary acid, HAlCl4 is
eliminated from the supercomplex with the formation of the
ortho-functionalized intermediate. Low conversions are typi-
The results from these experiments are compared in
Figures 7, 8, and 9 to those from the low-heat input run.
The figures indicate that a greater HCl liquid-phase concen-
(8) Sandler, S. I. Chemical and Engineering Thermodynamics; John Wiley and
(9) Douglas, A. W.; Abramson, N. L.; Houpis, I. N.; Karady, S.; Molina, A.;
Sons: New York, 1977.
Xavier, L. C.; Yasuda, N. Tetrahedron Lett. 1994, 35, 6807-6810.
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Figure 6. Impact of heat evolution rate on HCl offgas rate.
Figure 7. Reactivity of 1 in three experiments: (a) low heat input rate, (b) sealed reactor, (c) with xylenes as solvent.
Scheme 3. Published reaction mechanism of the Sugasawa reaction9
cally attributed to the generation of the anilinium hydro-
chloride salt of the starting aniline.3
conditions; (c) the formation of the supercomplex and the
following ortho functionalization is independent of the order
of mixing the reagents; and (d) the expulsion of HCl from
the reaction mixture is required to increase the ortho acylation
yield compared to the amidine formation.
To understand the basics of this ortho acylation process
and to facilitate the design of proper reaction conditions, we
performed a series of experiments listed in Table 3, varying
On the basis of the results discussed so far in our work,
the following fundamental observations became clear: (a)
aniline HCl salt is as effective as the corresponding aniline
in the Sugasawa reaction without affecting the yield of ortho-
functionalized product as evidenced by entry D in Table 1;
(b) 1 equiv of HCl is liberated during these reaction
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Figure 8. Molar yield of 2 in three experiments:: (a) base case, (b) closed reactor, (c) with xylenes as solvent.
Figure 9. Amidine (4) yield in three experiments: (a) base case, (b) closed reactor, (c) with xylenes as solvent.
Table 3. Role of AlCl3 and BCl3 in ortho acylation of
4-bromoaniline 1
Table 4. Effect of time from 80 °C to reflux on the yield of
2
reaction conditions
1 [%] 2 [%] amidine 4 [%]
heating time from
80 °C to reflux, [min]
yield, of 2 after
3-h hold at reflux [%]
no BCl3, no AlCl3, reflux, 3 h
no BCl3, 100 °C, 5 min
no AlCl3, 101 °C, 0.5 h
no AlCl3, 101 °C, 3 h
99.8
0
62
45
0
0
16
15
0
100
22
5
30
60
61
56
48
40
conditions) there is no noticeable ortho acylation or amidine
formation.
the described process conditions. In the absence of BCl3 and
AlCl3 (entry 1) aniline 1 and propionitrile are quite stable to
refluxing toluene conditions. When BCl3 was excluded from
the reaction mixture, amidine formation was almost quantita-
tive by the time internal temperature reached 100 °C. In the
absence of AlCl3, amidine formation predominated over ortho
acylation. At 3 h refluxing, amidine 4 was formed in 44%
yield compared to the ortho-acylated 2 formed in 15% yield.
It is interesting to see that the combination of BCl3 and AlCl3
in fact suppresses the amidine 4 formation. In addition, we
observed that in a mixture of aniline 1, propionitrile, BCl3,
and AlCl3 when heated at 80 °C in toluene (nonrefluxing
Knowing that there is no significant formation of ortho
acylation or amidine formation up to 80 °C, experiments were
performed in which the time from 80 °C to reflux was
increased (Table 4). The reaction mixture was held for 3 h
in each case. The results in Table 4 show clearly that as the
time to reach reflux is prolonged, the yield of 2 decreases,
implying further that the fast HCl removal is critical for
higher yield of ortho acylation and for a reproducible process.
The New Process. With this information in hand and
knowing that the expulsion of HCl from the reaction mixture
and the time needed to take the reaction mixture to reflux
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729

Figure 10. Relative product composition as a function of reflux time.
Scheme 4. Modified mechanism involving the expulsion of HCl
Table 5. Propionylation of other nilines
were crucial for the preferred ortho acylation, we designed
new reaction conditions by combining all the reagents and
reactants below 70 °C and adding this mixture to refluxing
toluene10 (see Method B in the Experimental Section). Time
taken for the addition is not critical, but it is important to
maintain refluxing conditions inside the reactor throughout
the addition period.
X
yield using our new process [%] lit. yield [%]
Under these new reaction conditions, 2 was isolated in a
60% yield, the best result thus far using 1. Figure 10 shows
the results of such an experiment (HPLC area as a function
of time at reflux).
On the basis of our observations that the elimination of
HCl from the medium is crucial for the progress of ortho
acylation, and that the order of mixing the reagents and
reactants was not critical for the formation of the supercom-
plex, and taking into account the earlier NMR studies from
the literature,9 we propose a modified mechanism (Scheme
4).
Application of New Procedure to the Acylation of
Other Anilines. The new procedure for ortho propionylation
described above was tested with other anilines. These results
were compared with the literature yields, and in each case
the yields with the new conditions are superior (Table 5).
3-Br
2-Br
4-Cl
4-Cl, 5-Cl
4-CH3
72
71
62
36
71
71
46
-
10
4
60
-
4-CH3 (HCl salt)
Conclusions
The ortho acylation of 4-bromoaniline was studied in great
detail with respect to optimization of yields and mechanistic
details. The order of mixing of BCl3, AlCl3, C2H5CN, and
aniline in toluene has no effect in the formation of super-
complex and the subsequent yield of the acylation product.
Analysis of pilot-plant data following process scale-up and
subsequent RC1 experiments showed that a higher jacket
temperature at reflux, and thus a higher heat input rate, gave
substantially higher product yield. These results, coupled with
additional experiments in which greater liquid-phase HCl
concentrations were obtained by either sealing the reactor
(10) Sparging with an inert gas such as nitrogen could be an alternative way for
HCl expulsion, but it was not tried during this study.
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Table 6. Sources and purities of materials used
Procedure. 6-Bromo-4-ethylquinazoline, 3 (Method A).
Thoroughly flush the 1-L vessel with dry nitrogen. Charge
the reactor under nitrogen with 52.06 g of aluminum chloride
and add (not exothermic) 148.79 g of toluene. Cool the slurry
to ∼10 °C and add (slightly exothermic, 20 W/kg) a solution
(22 °C) of 55.23 g of 4-bromoaniline in 168.25 g of toluene
at a rate of 4.47 g/min into the mixture at ∼10 °C over 50
min. Rinse the addition funnel with 28.00 g of toluene. Add
(not exothermic) 45.00 g of boron trichloride to the mixture
at ∼10 °C over 5 min, and purge the gas line with dry
nitrogen through the scrubber. Add (exothermic, 50 W/kg)
at a rate of 0.82 g/min, 73.88 g (95.70 mL) of propionitrile
at ∼10 °C over 90 min. Heat the contents at 1 C/min to 107
°C, under reflux and constant flow of nitrogen. As the batch
temperature approaches 100 °C, gas evolution increases with
a maximum rate of 150 mL/min, accompanied by an
endotherm. Hold the reaction mixture at 107 °C for 3 h at
reflux to obtain a yellow-brown homogeneous mixture. The
cumulative amount of off-gas formed is 7.57 L. Cool the
reaction mixture to 60 °C, stop the agitator, and let the
reaction mixture separate into two layers. Take a sample of
the bottom layer for analysis. Empty the reactor into a 2-L
Erlenmeyer flask and rinse the reactor with 14.20 g of
toluene.
Charge the MP10 reactor with 332.40 g of water. Heat
the water to 55 °C and hold. Add the reaction mixture with
stirring over a 2-h period from the 2-L Erlenmeyer flask into
the MP10 reactor containing water under efficient stirring
conditions. Maintain the batch temperature at 55 °C. The
quench is exothermic and produces 0.47 L of HCl off-gas.
Withdraw the contents of the MP-10 reactor and rinse the
reactor and the dosing line thoroughly with 47.63 g of toluene
and 110 g of water for 5 min. Transfer the reactor contents
and toluene/water rinse into a 2-L LabMax glass reactor.
Stir the mixture at 55 °C for 15 min. Stop the agitator to
obtain two layers. Discard the bottom aqueous layer in a
proper fashion. Take a sample from top layer. Wash the top
organic layer three times with a total of 330 g of water.
Transfer the organic layer to a 500-mL, four-necked, round-
bottomed flask. Concentrate at 60-65 °C (20-100 mbar)
to a final volume of 165 mL to obtain a light brown viscous
oil (∼37 g of 2 and 100 g of toluene). Cool to room
temperature. Add 44.2 g of formamidine acetate and 128 g
of ethylene glycol under nitrogen. Heat the suspension to
105 °C over 1 h to obtain a two-layer mixture, then distill
off water, ammonia (byproduct) and toluene under atmo-
spheric pressure to raise the internal temperature from 105
to 120 °C over 0.5 h. Ammonia evolution occurs when the
batch temperature reaches about 70 °C. The cumulative
amount of ammonia evolved is 10.79 L. The maximum flow
rate of ammonia is about 210.6 mL/min, and occurs at a
batch temperature of about 110 °C.
compound
purity (%)
source
4-bromoaniline
aluminum trichloride 99
98
GIC
Aldrich
boron trichloride
propionitrile
toluene
formamidine acetate
ethylene glycol
99.9
Scott Specialty Gases
97, water <0.2 Aldrich
99
99
99
Aldrich
SKW Trostberg
Aldrich
or using a higher-boiling solvent, demonstrated that expulsion
of HCl from the reaction medium was of critical importance
for achieving higher and reproducible acylation yields. On
the basis of these findings, a new procedure involving the
addition of mixture of reagents and reactants to refluxing
toluene with a specific heat input was designed, and higher
yields were achieved compared to those from the previous
methods. A modified mechanism incorporating the expulsion
of HCl was also proposed.
Experimental Section
Equipment and Materials. Reaction experiments were
performed using laboratory glassware or a Mettler-Toledo
RC1 reaction calorimeter. The RC1 reaction calorimeter was
equipped with a 1.0-L glass MP-10 vessel and pitched-blade
agitator (Figure 1). Calorimeter principles are discussed
elsewhere.11 All metallic inserts in the vessel were made of
Hastelloy C. Liquid BCl3, obtained as a pressurized liquid
in a stainless steel cylinder at 50 psig initial pressure under
He, was metered into the reaction mixture by placing the
cylinder on a balance and controlling the addition to the
reactor with a metering valve. The reactor outlet was attached
to a condenser. The volume of HCl gas formed in the reaction
was measured using a Ritter model TG05 wet test meter
connected after the condenser. The wet test meter was filled
with paraffinic white oil (Aldrich mineral oil, white, light,
catalog no. 33,077-9) to minimize dissolution of HCl and
thus measure gas volume accurately. The outlet of the test
meter was directed to two scrubbers containing aqueous
NaOH and attached in series. The wet test meter was attached
to a data-logging system to allow automatic data collection.
The offgas rate during reaction was calculated as follows.
Prior to the experiment, the rate of N2 purge gas, which was
set to constant value with a mass flow controller (Brooks
model 5850i), was determined by numerical differentiation
of the wet test meter output, which measures the cumulative
gas volume. During the experiment, which was performed
with N2 purge gas, the rate of HCl offgas was determined
by taking the difference of the total offgas flow rate during
reaction (viz., N2 + HCl) and that of the purge gas. The
total offgas rate was also determined by numerical dif-
ferentiation. The cumulative HCl volume was subsequently
determined by numerical integration of the HCl flow rate.
Sources and purities of all materials used are given in Table
6. All materials were used as received.
Reflux the homogeneous mixture at 119-120 °C by
distilling off the azeotropic mixture of toluene, water and
ethylene glycol, using a Dean-Stark trap continuously and
maintain at 120 °C for 3 h. Take a sample when the reaction
mixture is at 110 °C and analyze by HPLC. Add 15 mL of
ethylene glycol into the pot containing a two-layer mixture
(11) Girgis, M. J.; Kiss, K.; Ziltener, C. A.; Prashad, M.; Har, D.; Yoskowitz,
R. S.; Basso, B.; Repicˇ, O.; Blacklock. T. J.; Landau, R. N. Org. Process
Res. DeV. 1997, 1, 339-349.
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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731

(top layer is 3 in toluene and bottom layer is ethylene glycol).
Concentrate the contents at 60 °C (40-50 mbar) to distill
off 45 mL of toluene. Cool the mixture to 20 °C and stir at
room temperature to obtain a hazy mixture. Add 27 mL of
water into the pot, then cool the suspension to 2 °C and
maintain at 0-5 °C for 1.5 h. Filter off the solids at 0-5 °C
through a polypropylene pad on a Bu¨chner funnel. Rinse
the flask with one-third of the cold filtrate, then wash the
filter cake four times with a total amount of 240 mL of water.
Hold the filter cake under vacuum (200 mbar) to dry for 2
h, then dry at 35 °C (30 mbar) for 2 days to afford 32.7 g of
3 (44% yield based on 1) as a straw-yellow granular solid,
mp 61.5-62.5 °C.
6-Bromo-4-ethylquinazoline, 3 (Method B). Charge a 1-L,
three-necked, round-bottom flask (reactor A) under nitrogen
with 49.00 g of aluminum chloride, then add 250 g of
toluene. Cool the slurry to -10 °C and add 64.37 g of
4-bromoaniline 1 in portions (exothermic addition). Add (not
exothermic) 47.23 g of boron trichloride to the mixture at
-10 to -5 °C over 5 min and purge the gas line with dry
nitrogen through the scrubber. Add (very exothermic!) 92.60
g (120 mL) of propionitrile into the reactor A (containing
1/AlCl3/BCl3/toluene mixture) and allow the temperature to
rise to no greater than 45 °C. Heat the reaction mixture to
63 °C over 10 min and maintain at 60-65 °C for 5 min to
give a homogeneous solution.
Charge 213 g of toluene into reactor B under dry nitrogen.
Heat to reflux (112 °C), distill off 24 mL (21 g) of solvent
(toluene and water), and maintain the toluene solution at
reflux. Add the solution from reactor A to the refluxing
toluene over 45 min. Reflux the mixture vigorously at 106
°C for an additional 4 h to obtain a yellow-brown homoge-
neous mixture. It is important to maintain heat input rate at
a value of 116 ( 10 W/kg of reaction mixture during hold
period to remove HCl gas which is generated as a reaction
byproduct (Figure 5). Total amount of HCl gas generated
was estimated to be 7.23 L.
layer to a 500-mL, four-necked, round-bottomed flask and
concentrate at 60-65 °C (20-100 mbar) to a final volume
of 165 mL to obtain a light-brown viscous oil. Add 63.60 g
of formamidine acetate and 173 g of ethylene glycol. Heat
the suspension to 112 °C over 1 h to obtain a two-layer
mixture, then distill off water, ammonia (byproducts), and
toluene under atmospheric pressure to raise the internal
temperature from 112 to 127 °C over 1 h. Reflux the
homogeneous mixture at 127-131 °C by distilling off the
azeotropic mixture of toluene, water, and ethylene glycol
using a Dean-Stark trap and maintain at this temperature
for 2 h. Cool the reaction mixture to 60 °C. Add 22 g (20
mL) of ethylene glycol and concentrate the contents at 60-
70 °C (40-50 mbar) to distill off the toluene. Cool the
mixture to 20 °C and add (slightly exothermic) 40 mL of
water. Add seeds of 3, cool the suspension to 2 °C, and
maintain at 0-5 °C for 1.5 h. Filter off the solids at 0-5 °C
through a polypropylene pad on a Bu¨chner funnel. Rinse
the flask with one-third of the cold filtrate (5 °C), then wash
the filter cake four times with a total amount of 325 mL of
water. Dry the filter cake at 40-45 °C (30 mbar) to afford
47.8 g of 3 (54% yield over two steps) as a straw-yellow
solid; mp 61.5-62.5 °C.
Analytical Chemistry. The ortho acylation reaction
mixture was analyzed using a Hewlett-Packard 1100 series
HPLC. Known amounts of samples (by weight) were
withdrawn periodically during the reaction and quenched
immediately in a 50:50 mixture of methanol:water. The
quenched mixture was diluted and then injected in the HPLC.
The concentrations of 1, 2, and 4 in the sample were
determined from the peak area and measured response factors
of 1, 2, and 4, determined using external reference standards.
The amounts of 1, 2, and 4 in the reaction mixture were
calculated by multiplying the concentrations with the total
weight of the reaction mixture. From the latter and the
amount of 1 charged to the reactor, conversion of 1 and molar
yields of 2 and 4 were calculated.
Add the reaction mixture to a 2-L reactor containing 500
g of water under efficient stirring over 0.5 h. Allow the
temperature of the reaction mixture to rise to 45 °C from
the heat released during the quenching procedure. Rinse the
first reactor with 225 g of toluene and add to the quench
mixture. Heat the mixture to 55 °C and stir the batch at 50-
55 °C for 15 min. Some HCl gas (∼1.5 L) is also released
during this step. Stop the agitation and allow the mixture to
separate into two layers. Wash the top organic layer three
times with a total of 360 g of water. Transfer the organic
After gaining more experience using this analytical
technique, it was found that the HPLC area-% values of 1,
2, and 4 obtained from direct analysis of crude ortho
acylation reaction mixture were also a good measure of
reaction performance as these values correlated well with
the isolated yield of 2.
Received for review May 28, 2003.
OP0340659
732
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