Organic Process Research & Development 1998, 2, 226−229
Development of a Continuous Homogeneous Metal Complex Catalyzed,
Asymmetric Hydrogenation under High Pressure (270 bar)
Shaoning Wang* and Frank Kienzle
F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland
Table 1. Influence of pressurea
Abstract:
A kinetic model and simulation as well as a continuous stirred
tank reactor (CSTR) system for the synthesis of (S)-2-(4-
fluorophenyl)-3-methylbutanoic acid, an important optically
active intermediate in the synthesis of mibefradil (POSICOR,
a new type of calcium antagonist), by asymmetric hydrogenation
of 2-(4-fluorophenyl)-3-methylbut-2-enoic acid under high pres-
sure (270 bar) are described. It was demonstrated that a
continuous, homogeneous metal complex catalyzed, enantiose-
lective hydrogenation under high pressure is not only feasible
but also a very attractive possibility. Using such a CSTR system
one may achieve a space-time yield of 5.0 kg/L/day. Compared
to a batch mode under high pressure, the CSTR reactor system
has a more favourable space-time yield, is safer, would need
less investment, and allows easier temperature control.
pressure [bar ]
conversion [%]
ee [%]
180
93.7
89.8
230
99.1
91.3
270
99.7
92.1
270 (20 °C)
90.9
94.2
a 30 min, at 30 °C.
Table 2. Influence of temperaturea
temperature [°C ]
conversion [%]
ee [%]
20
26.5
100
91.5
30
100
90.5
96.54
93
a 60 min, at 180 bar.
Table 3. Influence of rpma
rpm [1/min]
conversion [%]
ee [%]
800
100
89.9
1200
100
90.5
1. Introduction
a 60 min, at 30 °C, P ) 180 bar.
The (S)-2-(4-fluorophenyl)-3-methylbutanoic acid (2) is
an important optically active intermediate in the synthesis
of mibefradil (POSICOR), a new type of calcium antagonist
which is being marketed in several countries.1 In the choice
between a synthesis of 2 by asymmetric hydrogenation or
resolution, the design of an appropriate high-pressure equip-
ment plays a crucial rule.
Mathematical modeling for investigating and developing
a technical process in the basic chemical and petrochemical
industry has been widely applied.2 However, for the
production of pharmaceuticals, where much smaller volumes
are required and generally most processes are run batchwise,
this is rarely the case. In the past, the costs of producing
pharmaceutical products have been considered unimportant;
as a consequence, the cost of goods has been usually rather
high. With the increasing public pressure to lower the ever-
rising costs for medical care, decreasing the prices for
pharmaceuticals and, hence the costs for their production
becomes an important goal. The availability of reliable
mathematical models could therefore be of great help to
develop economic processes.
hydrogenation of 2-(4-fluorophenyl)-3-methylbut-2-enoic
acid (1) under high pressure with the [Ru((R)-MeOBIPHEP)-
(OAc)2]-catalyst1 in a continuous stirred tank reactor (CSTR)
system are described. The following procedure has thereby
been employed: designing first a mathematical kinetic model
estimated from experimental data obtained in batch experi-
ments and using then this model to simulate a continuous
process (applying a continuous stirred tank reactor model).
On the basis of the simulation, continuous experiments were
then carried out. Using this method, not only starting
material and solvents could be saved but also the develop-
ment time could be shortened, too, because the flow rate for
the continuous operation can be calculated in advance and
does not have to be determined by experimentation.
2. Investigation of the Basic Reaction Conditions
To optimize the process, the influence of pressure,
temperature, rpm, and solvents on the reaction rate and
enantiomeric excess (ee) was investigated. The experiments
were carried out mainly in 30 mL autoclaves with magnetic
stirring (S/C ) 1000, 30% in MeOH, 0.6 mol Et3N). The
results are given in Tables 1-3, where the conversion and
ee were analyzed by GC (Perkin-Elmer model AutoSystem;
column SE 54 for conversion and column OV-61/P-DiMe-
B-CD for ee).
In this investigation the mathematical models and simula-
tion as well as the design of a suitable reactor system for
the synthesis of (S)-acid 2 by continuous asymmetric
* Author to whom correspondence should be addressed. Tel. +41-61-6886156.
Fax +41-61-6881670. E-mail shaoning.wang@roche.com.
(1) Crameri, Y.; Foricher, J.; Hengartner, U.; Jenny, C.; Kienzle, F.; Ramuz,
H.; Scalone, M.; Schlageter, M.; Schmid, R.; Wang, S. Chimia 1997, 51,
303.
As the temperature is increased, the reaction rate in-
creases; however, the ee decreases. If one increases the
(2) Baerns, M.; Hofmann, H.; Renken, A. Chemische Reaktionstechnik; Georg
Thieme Verlag: Stuttgart, 1987.
226
•
Vol. 2, No. 4, 1998 / Organic Process Research & Development
S1083-6160(98)00007-3 CCC: $15.00 © 1998 American Chemical Society and Royal Society of Chemistry
Published on Web 05/02/1998