Ligandless Heck coupling between a halogenated aniline and acrylonitrile catalyzed by Pd/C: Development and optimization of an industrial-scale Heck process for the production of a pharmaceutical intermediate

Article abstract of DOI:10.1021/op8000383

The aniline derivative 3 is a key building block of rilpivirine (TMC278) 2, a new potent NNRTI compound under clinical evaluation. In this paper we describe the development of a new synthesis of 3 based on a Heck coupling between a halogenated aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as catalyst. This resulted in a process which has been successfully transferred into production on 2400 mol-scale (6000 L reactor)

Full text of DOI:10.1021/op8000383

Organic Process Research & Development 2008, 12, 530–536
Ligandless Heck Coupling between a Halogenated Aniline and Acrylonitrile
Catalyzed by Pd/C: Development and Optimization of an Industrial-Scale Heck
Process for the Production of a Pharmaceutical Intermediate
Didier Schils,*,†,2 Fred Stappers,† Geoffrey Solberghe,†,O Richard van Heck,† Michelle Coppens,† Dirk Van den Heuvel,‡
Peter Van der Donck,§ Tom Callewaert,§ Frank Meeussen,§ Erika De Bie, Kristof Eersels,¶ and Ellen Schouteden¶
Johnson and Johnson Pharmaceutical Research and DeVelopment, a DiVision of Janssen Pharmaceutica, API DeVelopment,
Turnhoutseweg 30, B-2340 Beerse, Belgium
Abstract:
The aniline derivative 3 is a key building block of rilpivirine
(TMC278) 2, a new potent NNRTI compound under clinical
evaluation. In this paper we describe the development of a new
synthesis of 3 based on a Heck coupling between a halogenated
aniline and acrylonitrile using low loading of Pd/C (0.5 mol %) as
catalyst. This resulted in a process which has been successfully
transferred into production on 2400 mol-scale (6000 L reactor)
Figure 1. Structures of etravirine and rilpivirine
Introduction
Since its discovery in the early 70s by Mizoroki and Heck,
the commonly called “Heck reaction” is one of the most
powerful tools to create C-C bonds by reacting halogenated
aromatics and olefins.1 In the past decade, new generations of
homogeneous catalysts such as palladacycles, pincer-ligands,
and more recently bulky electron-rich ligands have extended
the scope of the reaction to all aromatic halides, even the poorly
reactive aryl chlorides.2 Nevertheless, from the perspective of
process development, homogeneous catalysis suffers from
several drawbacks. First, ligands are required to form the active
catalyst. These ligands may be expensive, not available in bulk
or privileged. Also, the removal of the catalyst (the ligand, the
metal or the complex) from the product can be challenging as
the residual palladium at the API level has to be consistently
under 10 ppm. For these reasons, only few Heck processes are
used at production scale in the pharmaceutical industry.3 In this
article, we would like to report the development of a Heck
Scheme 1
process which has been successfully transferred into production
at full-scale (2400 mol/6000 L reactor).
As part of our HIV program at Johnson & Johnson, two
new non-nucleoside reversed transcriptase inhibitors (NNRTIs)
are under active development: the recently FDA approved
Intelence (etravirine, TMC125) 1 and rilpivirine (TMC278) 24
(Figure 1).
For the commercial synthesis of TMC278, the intermediate
3 was required. This intermediate was first synthesized in a four-
step sequence from the commercially available 4-bromo-2,6-
dimethylaniline 44b and our goal became to develop a more
efficient and cost-effective synthesis. Therefore we have decided
to develop a Heck coupling between the halogenated aniline
derivatives 4 or 5 and acrylonitrile that would provide 3 in a
single step (Scheme 1).
* Corresponding author. E-mail: dschils@euroscreen.com.
† Chemical Process Research.
‡ Chemical Process Control.
§ Pilot Plant.
Safety Testing Laboratory.
¶ Chemical Production (Geel site, Belgium).
2 Current address: Euroscreen SA (47, Rue Adrienne Bolland, B-6041
Gosselies, Belgium).
O Current address: UCB Pharma SA (Chemin du Foriest, B-1420 Braine-l’
Alleud, Belgium).
Results and Discussion
Initial Screening. In order to gain an understanding of the
reactivity of our aniline derivatives, the commercially available
(1) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44,
581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320. (c)
Review: Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100,
3009-3066 and references therein.
(2) (a) Review: Littke, A.; Fu, G. Angew. Chem., Int. Ed. 2002, 41,
4176-4211. (b) Review: Whitecombe N. J.; Hii, K.; Gibson, S.
Tetrahedron 2001, 57, 7449-7476. (c) Review oriented towards
Process Chemistry: Farina, V. AdV. Synth. Catal. 2004, 346, 1553-
1582.
(3) (a) Beller, M.; Zapf, A.; Ma¨gerlein, W. Chem. Eng. Technol. 2001,
24, 575–582. (b) de Vries, J. G. Can. J. Chem. 2001, 79, 1086–1092.
(c) Prashad, M. Top. Organomet. Chem. 2004, 6, 181–203.
(4) (a) Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.; de Jonge,
M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier,
E.; Kukla, M.; Ludovici, D.; Andries, K.; de Bethune, M.-P.; Pauwels,
R.; Das, K.; Clark, A. D., Jr.; Frenkel, Y. V.; Hughes, S. H.; Medaer,
B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams,
P.; Stoffels, P. J. Med. Chem. 2005, 48, 1901–1909. (b) Medicinal
Chemistry synthesis of 3, unpublished results.
530
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Vol. 12, No. 3, 2008 / Organic Process Research & Development
10.1021/op8000383 CCC: $40.75
2008 American Chemical Society
Published on Web 05/16/2008

Table 1. Screening Heck reaction conditions of bromo- and
Interestingly, results obtained with bromo- and iodo-deriva-
tives 4 and 5 (entries 5a-d) showed that both halides can be
used for the synthesis of the desired intermediate 3. For these
two anilines, we have not observed any Michael addition of
the aniline with acrylonitrile (compared to entry 4b). Presumably
the two flanking methyl groups are sterically impeding this
competing reaction.
On the basis of these preliminary results, it was decided to
develop processes with 4 and 5 in parallel in order to evaluate
which one would be most suitable to be transferred to chemical
production.
Conditions for a Heck Reaction with 4-Iodo-2,6-dim-
ethylaniline (5). Catalyst Loading. Palladium on charcoal (10%
Pd/C, wet) is sufficient to catalyze the reaction, no supplemen-
tary ligand or salt being required (Table 1, entry 5c). The
reaction is very selective, the main side products 6 (from
dehalogenation) and 7 (double Heck product) were each formed
in less than 1%, and we have found that it was possible to reach
more than 99% conversion by using only 0.1 mol % of catalyst,
although we have typically used loadings of 0.5 mol % to ensure
robustness (Scheme 3, Table 2).
iodo-derivatives with acrylonitrile
entry
R
R1
X
cond. yield (E + Z)a
E/Za
1a
1b
1c
1d
H
H
Br
A
B
A
B
5.6
72.9
92.8
99.0
74/26
72/28
78/22
76/24
I
2a
2b
2c
2d
NO2
OMe
NH2
NH2
H
H
H
Br
I
A
B
A
B
100
100
91.8
100
74/26
75/25
80/20
75/25
3a
3b
3c
3d
Br
I
A
B
A
B
4.1
73/27
75/25
77/23
75/25
75.2
96.8
99.9
4a
4b
4c
4d
Br
I
A
B
A
B
6.5
29.9b
93.6
99.7
76/24
76/24
78/22
79/21
5a
5b
5c
5d
Me Br
I
A
B
A
B
3.0
87.5
100
94.3
80/20
80/20
79/21
80/20
a Yield (%) of products (E+Z isomers) from GLC analysis using an internal
standard (diethylene glycol di-n-butyl ether). b Yield was 40% after
but
Scheme 3
4
h
decreased with time as the Heck product reacts with acrylonitrile to give the
corresponding Michael adduct (detected by GLC-MS).
bromo derivative 4 and the easily synthesized iodo derivative
55 were compared as potential starting materials. Both homo-
geneous and heterogeneous Heck conditions6 were evaluated
(Scheme 2, Table 1).
Table 2. Heck reaction of 3 with different catalyst loading
(10% Pd/C, wet)
Scheme 2a
entry
cat. loading (mol %)
3a
5a
Σ restb
1
2
3
4
5
0.5
0.4
0.2
0.1
0.05
96.2
94.2
91.5
96.3
84.0
0.4
3.4
5.8
8.5
3
-
-
0.7
12.9
3.1
a A: 10% Pd/C wet (0.05 equiv), DMA, NaOAc, 140°C, 20 h. B: Pd(OAc)2
(0.05 equiv), tri-o-tolylphosphine (0.10 equiv), DMA, NaOAc, 140°C, 20 h.
a Determined by HPLC analysis (area
remaining impurities determined by HPLC analysis (area % at 254 nm).
%
at 254 nm). b Sum of the total
As previously reported in the literature, all the Heck reactions
with acrylonitrile afforded a mixture of E/Z-olefins in ratio ∼75/
25 to 80/20. The iodides and the activated bromide reacted
quantitatively using Pd/C as catalyst (entries 1 to 5/c,d and 2a,b).
The nonactivated bromides gave low conversion (3-6.5%) with
Pd/C (entries 1,3,4,5/a) but high conversion (75-87%) with
the homogeneous system Pd(OAc)2/tri-o-tolylphosphine (entries
1,3,4,5/b).
Reaction Safety. The initial scale-up of this reaction revealed
significant exothermic behavior. When all the compounds were
mixed together and the mixture heated to 140 °C, the temper-
ature rose from 110 to 150 °C in one minute. A common way
to manage the exothermicity is to operate via a controlled
addition of the reagents. RC1 experiment showed that addition
of a solution of 5 and acrylonitrile in DMA (over 2 h) onto a
warm suspension (140 °C) of Pd/C, NaOAc in DMA effectively
controlled the exothermicity and allowed complete conversion
after 17 h at 140 °C (Table 3).
(5) Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.; Okamoto,
T. Bull. Chem. Soc. Jpn. 1988, 61, 600.
(6) (a) Homogeneous conditions adapted from: Herrmann, W.; Brossmer,
C.; Ofele, K.; Reisinger, C. P.; Priermeier, T.; Beller, M.; Fischer, H.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1844-1847. (b) Heterogeneous
conditions adapted from: Ko¨hler, K.; Heidenreich, R.; Krauter, J.;
Pietsch, J. Chem. Eur. J. 2002, 8, 622-631.
Table 3. Conversion observed during the RC1 experiment
(1.2 mol scale)
timea (h)
3b
5b
Σ restc
(7) Tr: reaction mixture temperature, Tj: jacket temperature, Qr: heat of
reaction, Qb: baseline for Qr. The reaction enthalpy (∆Hr) is calculated
by integration as the area between the Qr curve and the baseline Qb
(∆Hr ) (Qr – Qb)·dt). The thermal conversion (R(t)) is calculated from
the integral of Qr and normalized to 100%. Thermal conversion at the
time (t) is given by R(t) ) ∆Hr(t)/∆Hr(E) x 100 where ∆Hr(t) )
reaction enthalpy from start to time t and ∆Hr(E) ) reaction enthalpy
over the entire reaction time (In this case, initial time is dosing start).
3
76.2
91.3
96.2
21.8
5.7
0.4
2.0
2.8
3.4
6
17
a Including dosing time of 5. b Determined by HPLC analysis (area % at 254
nm). c Sum of the total remaining impurities determined by HPLC analysis (area %
at 254 nm).
Vol. 12, No. 3, 2008 / Organic Process Research & Development
•
531

Figure 2. Temperature profile during the Heck reaction7 (RC1, 2-L glass reactor, Hastelloy Tr sensor, HC calibration probe, HC
large propeller stirrer, and Ritter TG1 gas meter).
By using this mode of addition, the reaction can be safely
performed at Pilot-Plant and Production scale. The reaction
shows a medium exotherm (191 kJ/mol), and the accumulation
at the end of the dosing is only 26% (Figure 2).
Leaching and Residual Palladium. The amount of residual
palladium at the level of intermediates 3 or 8 was assessed as
part of our strategy for the control of the palladium content on
the final API. We anticipated that the use of a heterogeneous
“pre-catalyst” would be advantageous as the reactive palladium
nanoparticles8 would agglomerate back onto the support surface
upon completion of the reaction, allowing Pd removal by
filtration of the catalyst.9 This assumption was confirmed by
our results (Scheme 4).
The leaching reached ∼27% (1340 ppm palladium in
Figure 3. Ligand screening for the Heck coupling (conversion
solution at 75% conversion) but decreased to only 10% (500
ppm) in the DMA solution after removal of the catalyst by
filtration. The level of palladium can be further reduced by a
simple treatment of the organic layer with activated charcoal
(20 ppm of Pd remained in 3) which will ensure less than 5
ppm on the isolated product 8.
based on HPLC results - area %).
Scheme 4
Conditions for a Heck Reaction with 4-Bromo-2,6-
dimethylaniline (4). Catalyst Screening. A ligand screening
for the bromoaniline derivative 4 using 5 mol % Pd (Pd/L: 1/2),
DMA, NaOAc, 140 °C for 24 h showed that two phosphines,
tri-o-tolylphosphine and tri-tert-butylphosphine, provided more
than 90% conversion (Figure 3). We chose these two phosphines
for further development.
From the pioneer work of Jeffery on the influence of
tetraalkylammonium salts on the Heck-type reaction, it is known
that these salts can enhance the reactivity as well as the stability
(8) For palladacycles, pincers and several heterogeneous Pd catalysts, the
Heck coupling occurs at high temperature (120-160 °C). At these
temperatures, they have tendency to form soluble Pd0 nanoparticles
which are the true catalytic species. For more detailed discussion, see
de Vries, J. G. Dalton Trans. 2006, 421–429 and references therein.
(9) Review see: (a) Ko¨hler, K.; Pro¨ckl, S.; Kleist, W. Current Org. Chem.
2006, 10, 1585–1601, Review: (b) Phan, N.; Van Der Sluys, M.; Jones,
C. AdV. Synth. Catal. 2006, 348, 609–679. (c) Thathagar, M.; ten
Elshof, J.; Rothenberg, G. Angew. Chem., Int. Ed. 2006, 45, 2886–
2890.
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Table 4. Screening Heck reaction conditions using
Pd(OAc)2, P(o-tol)3 or P(t-Bu)3.HBF4, Bu4N+Cl-
Pd(OAc)2 P(o-tol)3 P(t-Bu)3 · Bu4NCla time conv.b
entry (mol %) (mol %) HBF4(mol %) (equiv) (h) (area %)
ligand, the following system was chosen for scale-up in the
Pilot Plant: Pd/C (2.5 mol %)/P(o-tol)3 (5 mol %)/Bu4N+Cl-
(1 equiv) in DMA at 140 °C with NaOAc as base.
Reaction Safety. The reaction with 4 is much less exothermic
than the reaction with the iodoaniline 5 derivative and can be
safely performed in batch mode in the Pilot Plant. This was
confirmed by RC1 experiment where complete conversion was
obtained after heating the reaction mixture for 20 h at 140 °C.
Heck Processes with Bromo- and Iodo-Derivatives 4 and
5. Work-Up and Isolation. Isolation of the reaction product is
an important part of a good process. For both reactions (with 4
or 5), removal of the catalyst by filtration, aqueous workup
followed by a salt formation allowed us to isolate the hydro-
chloride salt 8 in 60-70% yield and high purity (HPLC > 98%)
(Scheme 5).
1
5
10
10
8
–
–
1
24
24
48
48
48
24
24
4
94.2
91.5
99.7
94.9
91.0
77.8
67.7
99.2
94.1
76.6
73.2
2
5
1.5
1
3
4
–
4
3
6
–
1
5
2
4
–
1
6
1
2
–
1
7
1
2
–
0.5
1
8
5
–
10
2
9
1
–
1
48
48
48
10
11
0.5
0.25
–
1
0.5
1
–
1
a Tetrabutylammonium chloride used is 95% purity (technical grade).
b determined by HPLC analysis (area % at 254 nm).
of the catalyst.10 For the reaction of 4 with acrylonitrile (NaOAc,
DMA, 140 °C), it was found that the use of Bu4N+Cl– 11 was
beneficial with both phosphines (Table 4).
Scheme 5
With one equivalent of Bu4N+Cl-, complete conversion was
obtained (entries 1,3,8,9) while using 1.5 equiv (entry 2) or 0.5
equiv (entry 7) showed reduced efficiency. Regarding the
residual palladium content,12 we considered the use of a
heterogeneous source of palladium in combination with a
phosphine ligand. This concept has been extensively investi-
gated by Lipshutz for Ni/C with external phosphine ligands and
more recently by Merck researchers for Suzuki coupling with
Pd/C13 Not surprisingly, we obtained similar results in the Heck
coupling (Table 5).
It is worth noting that during the salt formation, the E/Z ratio
can be increased from 80/20 to 98/2. This is not due to an
isomerization but rather to the selective destruction of the
Z-isomer by Michael reaction with the solvent (Michael adduct
is soluble in ethanol) and also to the higher solubility of the Z-
isomer in ethanol.
Pilot-Plant Campaigns. These processes were implemented
in our Pilot Plant, and several campaigns afforded more than
400 kg of 8 (250 kg from 5 and 150 kg from 4). Nevertheless,
an issue in the isolation protocol was identified during the scale-
up. In the laboratory filtration proceeded well mainly due to
the fact that 8 forms agglomerates. However in the Pilot Plant,
pressure filtration was changed to centrifugation, and the
agglomerates were broken into very fine particles (8 µm) which
obstructed the centrifugation bag, resulting in slower centrifuga-
tion and a less efficient washing effect.14
Table 5. Screening Heck reaction conditions using Pd/C
(10% Pd/C, wet), P(o-tol)3 or P(t-Bu)3.HBF4 and Bu4N+Cl-
conv.b
Pd/C P(o-tol)3 P(t-Bu)3 ·HBF4 Bu4NCla time (area
Entry (mol %) (mol %)
(mol %)
(equiv) (h) %)
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
1.25
0.5
5
5
–
–
1
20 99
5
1c
0.5
1
4
98
5
1
2.5
1
–
–
–
24 87d
48 86
–
–
1
24 96.4
–
1
24
9.4
10
1
1
24 99
24 88
0.5
1
a Unless specified, tetrabutylammonium chloride used is 95% purity (technical
grade). b determined by HPLC analysis (area at 254 nm). c 98% purity
%
tetrabutylammonium chloride (not usable in Plant due to high cost and low bulk
availability).The reaction is faster because the technical grade tetrabutylammonium
chloride contains up to 5% of tetrabutylammonium which is less reactive and
slows down the reaction (see ref 11). d 12.5% (area %) double Heck product 7
observed.
For the Heck process using iodo derivative 5, the residual
palladium content was well under control (average 30 ppm with
a maximum of 58 ppm). On the other hand, the bromo
derivative 4 gave much higher residual Pd content with one
case above 1000 ppm (96 to 1196 ppm) necessitating a rework.15
The extreme value (1196 ppm) is the result of bad centrifugation
On the basis of results of table 4 and 5, and taking into
consideration the availability and the cost of the additive and
(10) Review Jeffery, T. Tetrahedron 1996, 52, 10113–10130.
(11) Other tetrabutylammonium salts were also tested and the reactivity is
-
the following: AcO- ≈ F- > Cl- > Br- > HSO4 . I-. Lithium
chloride gives 50% conversion while ammonium fluoride gives less
than 10% conversion. For economical reasons, we selected the
tetrabutylammonium chloride salt (technical grade 95% purity).
(12) First results with homogeneous system (10 mol % Pd used) afforded
8 containing 6600 ppm of residual Pd.
(14) Interestingly these fine particles (8 µm) were observed only when the
salt formation started from an 80/20 E/Z mixture (3). If the salt
formation is performed on the pure E-isomer (E > 98%), much bigger
crystals are obtained (average 250 µm), as determined by Lasentec
experiments. All our efforts to improve the particle size of 8 starting
from the 80/20 E/Z mixture 3 were unsuccessful.
(15) Rework consisted of neutralization of the hydrochloride salt to liberate
the base, extraction of the free base in toluene, treatment of the toluene
phase with Silica-thiol followed by a solvent switch to ethanol and
salt formation (yield: 80%).
(13) (a) Lipshutz, B.; Blomgren, P. J. Am. Chem. Soc. 1999, 121, 5819–
5820. (b) Lipshutz, B.; Tasler, S.; Chrisman, W.; Spliethoff, B.; Tesche,
B. J. Org. Chem. 2003, 68, 1177–1189. (c) Conlon, D.; Pipik, B.;
Ferdinand, S.; LeBlond, C.; Sowa, J.; Izzo, B.; Collins, P.; Ho, G.;
Williams, J.; Shi, Y.; Sun, Y. AdV. Synth. Catal. 2003, 345, 931–935.
Vol. 12, No. 3, 2008 / Organic Process Research & Development
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533

and poor washing effect. So for the bromo derivative 4
significant work would be needed for successful and robust
transfer to production.
to 80%.18 The final process was first scaled-up in the Pilot then
successfully transferred in production at full scale in 6000 L
reactors (Scheme 6).
Selection of the Final Process. Comparison of the two
processes is given in Table 6.
Scheme 6
Table 6. Comparison of Heck processes using the
bromo-aniline 4 or the iodo-aniline 5
iodoaniline
process
bromoaniline
process
parameter
yield
same (∼65%)
same (>98%)
58 ppm
same
purity
max. residual Pd
processability
process Cost
cost of aniline
cost of catalytic system
potential for cost decrease
1196 ppm
same
high
low
high
low
high
low
Both processes have comparable yield, quality, processabil-
ity, and cost. However two parameters are in favor of iodoa-
niline process 5. First this process was deemed more robust
allowing easy and reliable control of the residual palladium
content. Second, another advantage of the iodoaniline process
is its potential for cost decrease. Although both processes are
equivalent in cost, the cost drivers are different. For the
iodoaniline process, the major part of the cost is the iodoaniline
5 (80% of the total process cost). For the bromoaniline process,
the cheap bromoaniline 4 represents only 20% of the cost, while
the catalytic system, which will remain constant, is contributing
for more than 70% (higher Pd loading, phosphine ligand, and
ammonium salt required). This means that any price decrease
of 5 (which is expected with increasing scale) will have a high
impact of the total process cost, rendering the iodoaniline
process more attractive.16 Our example illustrates the fact that
it is sometimes easier and cheaper to adapt the substrate (choice
of iodoaniline 5) to an inexpensive catalyst (Pd/C) rather than
to spend significant resources to find a catalytic system able to
perform the same transformation on a cheap and commercially
available aryl bromide (or chloride).
We were delighted to notice that the exothermicity was
completely under control, even when the reaction was per-
formed at full scale in our production facilities. It is also
important to mention that no emission of acrylonitrile has been
detected during these campaigns.19 The results of the pilot plant
and production campaigns show the robustness and the ef-
ficiency of the process. In four production batches more than
1.3 ton of 3 has been produced (Table 7).
Table 7. Overview of Pilot Plant batches (260 mol) and
Chemical Production batches (2388 mol)
entry
mol-scale
conc.a
purityb
yieldc
residual Pdd
1
2
3
4
5
6
7
8
260
260
21.9
21.9
21.5
21.3
21.1
20.9
20.5
21.3
93.7
94.6
93.0
93.4
94.6
95.3
94.7
94.7
75.7
81.8
79.3
80.9
82
56
40
260
28
260
35
2388
2388
2388
2388
<5
<5
<5
<5
81
80
82
a 3 in the NMP solution (w/w %). b HPLC purity (w/w %). c Active yield of 3
(%) in the NMP solution. d determined by AAS (ppm).
For these reasons, the iodoaniline 5 was selected for the final
synthesis of rilpivirine.
Conclusion
A robust and high-yielding Heck process for the production
of 3, a key intermediate in the synthesis of rilpivirine 2, has
been developed. The use of the more reactive iodoaniline
derivative 5 allowed us to perform the reaction without ligand
and with low loading of Pd/C as catalyst (0.5 mol %). It is also
worth noting that on production scale the reaction can be safely
performed by controlled addition of the reagents, that the
residual Pd content on 3, after a simple activated charcoal
treatment, is always less than 5 ppm, and that no acrylonitrile
emission in the atmosphere has been detected.
Final Process Implemented in Chemical Production. In
addition to the benefits mentioned above, the iodoaniline 5
afforded pure enough 3 (low Pd level) that we could use in the
next step of the synthesis.17 This allowed us to avoid the difficult
isolation of 8 while increasing the overall yield of the reaction
(16) As mentioned before in this article, at the beginning of the project,
the 4-iodo-2,6-dimethylaniline 5 was not commercially available. After
one year, two suppliers were found. Until now, more than seven
suppliers have been evaluated. At the time we had to select the process,
the price of 5 had already decreased by more than 15 times since our
first order. Since then, significant decrease occurred again, confirming
our assumption made about the potential of cost decrease. The
iodoaniline process (cost for production of 3) is now 25% cheaper
than the bromoaniline process.
(18) The Heck product 3 is an oily residue which solidifies on standing.
For ease of handling, and as the next step of the synthesis occurred in
NMP, 3 is stored in NMP. This solution is stable over the time
(confirmed by suitable stability experiments).
(17) The starting E/Z ratio of the aniline (80/20 for 3 or 98/2 for 8) is of
little importance since a thermodynamic ratio (E/Z: 85/15) is obtained
in the reaction conditions of next step of the synthesis.
(19) Acrylonitrile is considered as a carcinogenic substance (R 45). The
emission in the atmosphere is strictly regulated in Belgium and in
Europe (emission <2 mg/m3 since September 2007).
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Experimental Section
The filtrate was transferred in a separation funnel, and after
decantation, the layers were separated. The water layer was
extracted with 600 mL of toluene, and the combined organic
layers were washed with 600 mL water in the presence of 14.8 g
of filter aid. After filtration (paper filter), the filtrate was
transferred in a separation funnel, and after decantation, the
layers were separated. The organic layer was washed a second
time with 600 mL and then treated with 14.82 g of sodium
sulfate anhydrous and 14.82 g Norit A Supra. The suspension
was stirred for 2 h at room temperature and then filtered (paper
filter) to give the final toluene layer. The toluene layer was
concentrated under reduced pressure (rotavap: 10 mbars/ 90 °C).
The oily residue obtained was diluted with 600 mL of
N-methylpyrrolidinone (NMP) to give 3 in NMP
Small-scale experiments were carried out using standard
glassware, while the experiments on scale were carried out in
glass-lined or stainless steel reactors. In the small-scale reactions,
the used reagents and solvents were standard technical grade
reagents and solvents used without any purification, while Pilot
Plant and Production scale experiments were carried out with
bulk reagents and solvents. The phosphine ligands used in the
screening experiments were purchased from Acros, Aldrich or
Strem and used without any purification. The tri-o-tolylphos-
phine was purchased from Rhodia and used without any
purification. The palladium on charcoal used in laboratory and
production was purchased from Degussa (10% Pd/C, wet) and
was used without any purification or treatment. This Pd/C
containing in average 50% of water, the quantity of catalyst is
calculated on the basis of 10 mol% Pd present on the dry
support (i.e.: 1.06 g catalyst contains 5 × 10-4 mol of Pd). The
activated charcoal used in laboratory and production (for the
removal of residual palladium) was purchased from Norit
Americas Inc., type Norit A Supra and was used without any
purification or treatment. At the beginning we used the 4-bromo-
2,6-dimethylaniline 4 from Acros or Aldrich and 4-iodo-2,6-
dimethylaniline 5 synthesized according to literature method.5
Then bulk 4 and 5 from different suppliers were used in the
laboratory and on scale without further purification (HPLC assay
>97 w/w %). For analytical purpose, pure 7, 3 (E-isomer) and
3 (Z-isomer) were synthesized.
Physical yield: 802.7 g of NMP solution containing 3.
ActiVe yield: concentration of 3 is 21.3 w/w % f 170.97 g
of 3 (0.9927 moles, 82.73%).
1
3 (mixture 80/20 of E/Z-isomers). H NMR (400 MHz,
CDCl3): δ ) 7.49 (s, Z-isomer), 7.22 (d, J ) 16.3 Hz,
E-isomer), 7.05 (s, E-isomer), 6.91 (d, J ) 12.4 Hz, Z-isomer),
5.59 (d, J ) 16.8 Hz, E-isomer), 5.11 (d, J ) 12.0 Hz,
Z-isomer), 4.04 (br s, E+Z-isomers), 2.21 (s, Z-isomer), 2.19
(s, E-isomer).
The E/Z ratio was determined by integration of the olefinic
protons at δ ) 5.59 (d, J ) 16.8 Hz, E-isomer) and 5.11 (d, J
) 12.0 Hz, Z-isomer).
3 (pure E-isomer) and 3 (pure Z-isomer) were obtained from
the 80/20 E/Z mixture after separation by preparative HPLC
(preparative Chiralcel OJ column, 100% ethanol).
HPLC analyses were performed on reversed-phase columns
(waters XTerra RP 3.5 µm, 4.6 mm × 50 mm) in gradient mode
(ammonium acetate buffer to acetonitrile) with UV detection
(254 nm). GLC analysis were performed on Hewlett-Packard
5890 series II (capillary column HP 5, 10 m) in temperature
gradient mode (50 to 300 °C, rate 10 °C/min.) with FID
detection. High resolution mass were performed on Jeol-JMS-
T100LP (DART ionization). NMR spectra were recorded on a
Bruker AV 400 and 360 instrument. Palladium determination
were performed by AAS on a Varian SpectrAA-880.
3 (pure E-isomer): 1H NMR (360 MHz, CdCl3): δ ) 7.21
(d, J ) 16.4 Hz, 1H), 7.04 (s, 2H), 5.58 (d, J ) 16.5 Hz, 1H),
3.96 (br s, 2H), 2.18 (s, 6H); 13C NMR (90 MHz, CDCl3): δ )
150.9, 146.2, 128.0, 123.3, 121.5, 119.6, 90.2, 17.5. High
resolution mass confirms the elemental composition.
3 (pure Z-isomer): 1H NMR (360 MHz, CDCl3): δ ) 7.46
(s, 2H), 6.89 (d, J ) 12.5 Hz, 1H), 5.10 (d, J ) 12.1 Hz, 1H),
3.98 (br s, 2H), 2.19 (s, 6H); 13C NMR (90 MHz, CDCl3): δ )
148.7, 145.9, 129.8, 123.6, 121.2, 118.8, 88.7, 17.5. High
resolution mass spectrometry confirms the elemental composition.
Industrial synthesis (2388 mol) of 3-(4-amino-3,5-di-
methylphenyl)acrylonitrile (3). A 6000 L glass-lined reactor
(reactor 1) was inertised with nitrogen then charged with 25.5
kg (12 mol, 0.005 equiv) of 10% Pd/C (wet) and 1400 kg DMA.
The suspension was stirred and 235 kg sodium acetate (2865
mol, 1.2 equiv) were added. The suspension was heated to
140 °C (range ( 5 °C).
The quantitative analytical results (HPLC w/w %, AAS for
palladium determination) of Pilot Plant and Production batches
were performed by the Chemical Process Control Department
according to GLP procedures using validated methods.
Synthesis (1.2 mol-scale) of 3-(4-Amino-3,5-dimethyl-
phenyl)acrylonitrile (3). In a four-necked RBF with mechanical
stirrer were placed 118.13 g sodium acetate (1.44 mol, 1.2
equiv), 12.77 g 10% palladium on charcoal, wet (6.00 mmol,
0.005 equiv) and 750 mL dimethylacetamide (DMA). The
suspension was heated to 140 °C. At this temperature a solution
of 296.49 g of 5 (1.20 mol, 1 equiv), 119 mL acrylonitrile (1.80
mol, 1.5 equiv) and 450 mL DMA was added dropwise to the
reaction mixture over 2 h. After 21 h at 140 °C, the reaction
mixture was cooled to room temperature. After addition of 6.4 g
of filter aid, the reaction mixture was stirred for 1 h at room
temperature, and then filtered (paper filter); the filter cake was
washed with 60 mL of toluene, and the filtrate was concentrated
under reduced pressure (rotavap: 10 mbar/90 °C) to give an
oily residue (711 g). To this residue was added 1.2 L of water,
1.2 L of toluene, and 14.8 g of filter aid. The suspension was
stirred for 1 h at room temperature and then filtered (paper filter).
A 6000 L stainless steel reactor (reactor 2) was inertised
with nitrogen then charged with 190 kg (3581 mol, 1.5 equiv)
of acrylonitrile, 700 kg DMA and 590 kg (2388 mol, 1 equiv)
4-iodo-2,6-dimethylaniline 5. The solution was stirred for 1 h
30 min at room temperature. This solution was transferred via
a 500 L glass addition flask onto the warm suspension in reactor
1 over 2 h (Tmin 137 °C, Tmax 140 °C). Reactor 2 was rinsed
with 150 kg of DMA also transferred into reactor 1. After the
addition, the suspension in the reactor 1 was stirred at 140 °C
for 17 h, then cooled to room temperature: IPC check for
complete conversion was performed before the workup (<1%
5 by HPLC); 11.9 kg of filter aid was added, and the reaction
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535

mixture was stirred for 30 min and then filtered through filter
plates (three filters in parallel). The filtrate was transferred to
reactor 2 (which was first cleaned using toluene). Reactor 1
was rinsed three times with 200 L of toluene, also transferred
to reactor 2 via each plate filter used. (Reactor 1 was washed
with water for the removal of the residual palladium on charcoal
from the wall). In reactor 2, the reaction mixture was concen-
trated by vacuum distillation of the solvents (industrial vacuum,
reactor temperature 142 °C). The residue was cooled to
100 °C, and then 2400 L of toluene was added, followed by
addition of 2400 L of water and 29.2 kg of filter aid. The
solution was stirred vigorously for 30 min and transferred into
reactor 1 via a mobile plate filter. In reactor 1, the layers were
separated after decantation. The water layer was transferred in
reactor 2 (while the organic layer stayed in reactor 1), washed
with 2400 L of toluene, and then discarded. The organic layers
were combined in the reactor 2. To the combined organic layers
were added 1200 L water and 28.6 kg filter aid. The mixture
was stirred vigorously for 30 min and transferred into reactor
1 via a mobile plate filter. After decantation, the layers were
separated, and the water layer was discarded; 1200 L of water
was added, and the mixture was stirred vigorously for 30 min.
After decantation, the layers were separated, and the water layer
was discarded. The resulting organic layer was treated with 28.6
kg of sodium sulfate and 28.6 kg of Norit A Supra. After 2 h
30 min stirring at room temperature it was transferred into
reactor 2 (previously cleaned with water) via a mobile plate
filter: IPC before removal of the toluene (<50 ppm Pd by AAS).
Toluene was removed by vacuum distillation (industrial vacuum,
reactor temperature 94 °C), and the warm residue of 3 was
diluted with 1225 kg of N-methylpyrrolidone (NMP). The NMP
solution of 3 was cooled to room temperature and transferred
in metallic drums of 200L.
determined by GLC, area %) then allowed to cool down to
room temperature. The reaction mixture was filtered through a
Dicalite pad. The filtrate was transferred in a separation funnel
and partitioned with 150 mL of water and 100 mL of toluene.
After phase separation, the obtained organic layer was treated
with Norit A Supra, filtered, and concentrated under vacuum
to give 5 g of a dark brown oily residue. 7 (0.9 g, 0.0031 mol,
30.9% yield, GC purity >99%) was obtained by crystallization
from ethyl acetate/hexane (1/2).
7: 1H NMR (360 MHz, CDCl3): δ ) 7.05 (s, 2H), 6.92 (s,
2H), 5.36 (s, 1H), 3.84 (br s, 4H), 2.18 (s, 6H), 2.14 (s, 6H);
13C NMR (90 MHz, CDCl3): δ ) 163.9, 145.1, 144.5, 130.1,
129.1, 126.9, 121.1, 121.0, 119.9, 88.3, 17.6. High resolution
mass spectrometry confirms the elemental composition.
Synthesis (0.3 mol-scale) of (2E)-3-(4-Amino-3,5-dimeth-
ylphenyl)acrylonitrile Hydrochloride (8). The crude oily
residue 3 obtained after standard workup and concentration of
the toluene layer (rotavap: 10 mbars/ 90 °C) was transferred in
a 1 L RBF with mechanical stirrer. To this residue was added
450 mL of ethanol (denaturated with 2% methanol). The
solution was heated at 60 °C, and 55 mL of a solution of HCl
in isopropanol (6 N, 1.1 equiv) was added dropwise over 1 h
(T range: 60 °C ( 5 °C). After addition of 10 mL of the HCl
solution, seeding material 8 was added (crystallization occurred
after addition of 25 mL of HCl solution). After complete
addition, the reaction mixture (heterogeneous) was stirred for
1 h at 60 °C and then allowed to reach spontaneously 25 °C.
The reaction mixture was filtered (paper filter), and the pale
yellow solid was washed with 50 mL of isopropanol. The solid
was dried at 50 °C under reduced for 16 h to afford 40.4 g of
8 (64.5% yield).
HPLC purity: 98% (w/w). E/Z ratio: 98/2
1
8: H NMR (360 MHz, DMSO-d6): δ ) 9.12 (br s, 3H),
Physical yield: 1591 kg of in NMP solution containing 3.
ActiVe yield: concentration of 3 is 20.9 w/w % f 332.5 kg
of 3 (1931 mol, 81%).
7.48 (d, J ) 16.5 Hz, 1H), 7.35 (s, 2H), 6.30 (d, J ) 16.5 Hz,
1H), 2.31 (s, 6H); 13C NMR (100 MHz, DMSO-d6): δ )150.6,
143.6, 128.1, 124.3, 123.6, 119.7, 90.8, 17.7.
Residual Pd content: <5 ppm
Based on these results, this Heck reaction will become the
industrial process for the production of 3.
Synthesis
of
3,3-Bis(4-amino-3,5-dimethylphenyl)
acrylonitrile 7.20 In a 100 mL RBF with magnetic stirrer were
placed 1.7 g of 3 (0.01 mol, 1 equiv), 4.9 g of 5 (0.02 mol, 2
equiv), 112.3 mg of palladium acetate (0.0005 mol, 0.05 equiv),
3.5 g of tetra-n-butylammonium bromide (0.011 mol, 1.1 equiv)
and 30 mL of DMA. The reaction mixture was heated at
80 °C for 44 h (at this moment the conversion is ca. 85%,
Acknowledgment
We thank Luc Vrins for the preparative separation of the E-
and Z-isomers of 3, Paul Moons for the determination of residual
Pd and Ludwig Goetelen for the HRMS analyses.
Received for review February 21, 2008.
OP8000383
(20) Conditions adapted from Masllorens, J.; Moreno-Man˜as, M.; Pla-
Quintana, A.; Pleixats, R.; Roglans, A. Synthesis 2002, 1903–1911.
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