Development of a grignard-type reaction for manufacturing in a continuous-flow reactor

Article abstract of DOI:10.1021/op500290x

This paper describes the scale-up of a highly exothermic and fast reaction from a microreactor with an internal volume of less than 1 mL to a mesoreactor with an internal volume of 13.5 mL. The development of a continuous process for manufacturing a keton

Full text of DOI:10.1021/op500290x

Article
pubs.acs.org/OPRD
Development of a Grignard-Type Reaction for Manufacturing in a
Continuous-Flow Reactor
Fabrice G. J. Odille,†,§,∥ Anna Stenemyr, and Fritiof Ponten
†,§
*,‡
́
†
Pharmaceutical Development R&D, Chemical Science, AstraZeneca, SE-151 85 So
Innovative Medicines, Cardiovascular and Metabolic Diseases, Medicinal Chemistry, AstraZeneca R&D, Pepparedsleden 1, SE-431
3 Molndal, Sweden
SP Process Development, Forskargatan 20, SE-151 36 So
̈ ̈
dertalje, Sweden
‡
8
§
̈
̈
̈
dertalje, Sweden
ABSTRACT: This paper describes the scale-up of a highly exothermic and fast reaction from a microreactor with an internal
volume of less than 1 mL to a mesoreactor with an internal volume of 13.5 mL. The development of a continuous process for
manufacturing a ketone from an ester using a Grignard reagent is described. The different steps undertaken and the
considerations made to be able to operate in continuous mode and achieve a product output of ca. 0.5 kg are presented.
INTRODUCTION
reactors have a well-defined working volume, the reaction
residence) time can be accurately controlled by adjustment of
■
(
Herein we describe a simple approach for the development and
scale-up of a Grignard reaction realizing the opportunity offered
by micro- and mesoreactors. It also includes the ways in which
significant challenges posed by precipitation and fast and highly
exothermic reactions were addressed. The chemical trans-
formation under consideration is a Grignard reaction where an
ester starting material 1 is subjected to a Grignard reagent
leading to the formation of ketone 2 (Scheme 1). Ketone 2 is
an intermediate in the synthesis of drug candidates in the early
development phase.
the flow rate(s). These possibilities frequently result in better
reaction profiles and increased yields. Thus, the use of
continuous processing can lead to distinct improvements in
efficiency that, for obvious reasons, provide an added value to
the fine chemicals and pharmaceutical industries. To date,
several examples using microreactors have been reported in the
3
literature, including DIBAL-H reductions and organometallic
4
reactions.
RESULTS AND DISCUSSION
The chemistry described in this paper was originally
developed for processing in a batch reactor following the
protocol developed by Ikuo and Tadahika. This procedure
■
In this specific case, it was realized that the use of a flow reactor
could potentially decrease the amount of unwanted aldol
product 4. Indeed, this technology opens the opportunity to
have a more rapid quench reaction because of more efficient
addition of acid.
1
consumes 2 equiv of MeMgBr in combination with 6 equiv of
triethylamine in order to generate the enolate form in situ,
which avoids further reaction of ketone 2 with excess MeMgBr
leading to tertiary alcohol 3. Quenching of the reaction with
acid gives a mixture of ketone 2 and the aldol condensation
product 4. In the original procedure, this mixture was treated
with sodium hydroxide at 45 °C to promote the retro-Aldol
reaction, giving ketone 2 as the sole product. However, this
approach was not viable in our specific case since 2
decomposed under basic conditions at elevated temperature.
Medicinal chemistry experience indicated that the formation of
aldol 4 could not be controlled when the reaction was
performed in a 100 mL round-bottom flask. It was noted that
the results fluctuated dramatically with isolated yields of 2 from
Two different systems were used to investigate the reaction.
For early screening, a Sigma-Aldrich glass chip with an internal
volume of 630 μL (Figure 1a) was used. For further
development, an ART PR37 reactor, designed by Alfa Laval
5
AB (Figure 1b), was used. This can be equipped with plates
6
with different channel sizes.
The reaction was initially screened to understand the
influence of temperature and amount of reactant on the
product distribution between unreacted starting material 1, the
desired ketone 2, tertiary alcohol 3, and aldol product 4. The
initial screening was made in a simple setup using a double
syringe pump imposing identical flow rates connected to a
Sigma-Aldrich glass chip (Figure 1a). Furthermore, the reaction
was quenched in a semibatch mode by collecting the discharge
from the flow reactor into a large excess of acid at 0 °C. The
3
0% to 60% and with 4 as the main by-product. Residual ester 1
and tertiary alcohol 3 contributed less than 10% of the total
amount of product. The aldol product 4 inhibited crystal-
lization of ketone 2, and chromatography was required to
obtain the desired quality.
1
procedure from Ikuo and Tadahika was followed by mixing the
Continuous-flow micro- or mesoreactors have a superior
surface-area-to-volume ratio and hence an improved hea2t
transfer capacity compared with conventional batch reactors.
This offers advantages such as the possibility of maintaining
temperature control even when the reaction in question is fast
and highly endo- or exothermic. Furthermore, since the
Grignard reagent with Et N prior to the reaction. One syringe
3
Special Issue: Continuous Processes 14
Received: September 11, 2014
©
XXXX American Chemical Society
A
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Organic Process Research & Development
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Scheme 1. Ester 1 is reacted with MeMgBr, leading to the formation of ketone 2, which can undergo various transformations to
generate compounds 3 and 4
Figure 1. Pictures of (a) the Sigma-Aldrich glass chip and (b) the ART PR37 reactor.
was loaded with a solution of ester 1 in 2-MeTHF at different
concentrations (see Table 1). The other syringe was loaded
of tertiary alcohol 3 and aldol 4. However, reducing the
reaction temperature to −20 °C (entries 5 and 6) did not give
any significant advantages. Increasing the concentration of the
ester 1 solution from 0.6 to 0.8 M (entry 7) resulted in an
unstable system and blockage due to precipitation before steady
state could be reached and any sample could be collected.
with a solution of MeMgBr and Et N in toluene/2-MeTHF.
3
The different amounts of the Grignard reagent and Et N were
3
obtained by varying the concentrations of the reagents loaded
in the syringes.
First, the amount of MeMgBr was varied from 1.2 to 1.5
equiv (Table 1, entries 1−3). Increasing the amount of
Replacing Et N with TMEDA (entry 8) gave poor results with
3
low conversion and over-reaction to giv the tertiary alcohol.
Shortening the residence time gave a similar reaction
outcome but better throughput (vide supra). Therefore, the
conditions given in Table 1 entry 4 were used to convert 160 g
of ester 1 to 100 g of ketone 2 (after chromatography),
corresponding to an isolated yield of 68% after 5.5 h of
processing in the chip reactor.
This initial screening encouraged us to further optimize the
process to identify conditions suitable for manufacture of larger
amounts. To increase the throughput of the process, it was
decided to further investigate some parameters such as the
quenching procedure, flow rate and the composition of the
Table 1. Results of the screening using the Sigma-Aldrich
glass chip and a semibatch quench
equivalents of
HPLC yield (area %)
a
entry MeMgBr Et N t (s)
T (°C)
1
2
3
4
3
b
1
2
3
4
5
1.2
1.4
1.5
1.4
1.3
1.3
1.1
1.4
3.6
4.2
4.5
5.2
4.0
4.0
3.4
4.6
13
13
13
6
0
0
9
9
1
3
5
5
80
79
76
85
80
80
6
5
5
9
5
4
4
b
b
b
b
c
7
14
7
0
0
13
13
13
13
−20
−20
0
11
11
6
d
7
no sample could be taken
starting solution. For simplicity it was decided that the Et N
3
e
c
8
0
26 43 23
8
would be mixed with the solution of ester 1 instead of using the
1
a
b
c
original procedure.
Time in the chip reactor. HOAc/H O/MeTHF quench. Acetic acid
2
d
e
quench. 0.8 M in 1 and 1 M HCl(aq)/2-MeTHF quench. TMEDA
The ART PR37 reactor offered opportunities to add an
additional solution to quench the reaction while maintaining
full temperature control. The larger volume of this reactor also
made it possible to use a higher flow rate. To avoid the
formation of a large amount of triethylammonium salt, it was
decided to quench the reaction in situ with as small an excess of
acid as possible. Therefore, it was attempted to quench the
reaction with 1.2 equiv of pure acetic acid and also 1.2 equiv of
HCl in an aqueous solution (Table 2, entries 1 and 2). Both
solutions resulted in immediate clogging of the reactor. In the
as an additive and HOAc/2-MeTHF quench.
MeMgBr resulted in better conversion (less of the unreacted
ester 1) but at the cost of more tertiary alcohol 3. It could be
concluded that 1.5 equiv of MeMgBr was the upper limit to be
used since the yield of tertiary alcohol 3 was already at 14%.
Shortening the reaction time from 13 to 6 s while keeping the
temperature at 0 °C (entry 4) gave better conversion of ester 1
(
but within experimental error) while maintaining the amounts
B
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Table 2. Results of the screening using the ART PR37 reactor with different plate volumes at 0°C
HPLC yield (area%)
entry
ART plate size (PL37/X-X-C22)
equiv of MeMgBr
residence time (s)
1
2
3
4
a
1
0.8-2.2
0.8-2.2
0.8-2.2
3-12
1.2
1.2
1.2
20
20
20
24
2.9
22.3
4.1
70.7
b
2
no sample could be taken
c
3
1.5
0
93
4
1.5
2.1
c
4
1.4
85.1
12.8
a
b
c
Quench in the ART PR37 with 1.2 equiv of pure acetic acid. Quench in the ART PR37 with 1.2 equiv of HCl. Quench in the ART PR37 with a
equivolume solution of acetic acid, water, and 2-MeTHF (1:1:1 v/v/v, 15.6 equiv of AcOH).
Figure 2. Schematic setup for the continuous processing in the Aldrich chip reactor and continuous syringe pump.
first case (entry 1), a sample could be taken, and it showed a
significant increase in the yield of aldol product 4 (up to 71%).
From earlier experiments it was known that quenching the
reaction with a equivolume mixture of acetic acid, water, and 2-
MeTHF (one-phase solution) resulted in a clear solution. It
was therefore decided to implement this quenching in the flow
reactor using a 1:1:1 (v/v/v) mixture of acetic acid, water, and
quench solution to back-flush the system when the pressure
was above 5 bar. The cleaning cycle was repeated every 45 min,
and the process was restarted after every such cycle. Since the
cleaning procedure and restart was not fully optimized this
caused loss of material, resulting in a total yield of less than 50%
even though the conversion reflected the results in Table 2,
entry 4.
2
-MeTHF (Table 2 entry 3). This approach solved the
More material of the API and ketone 2 was required for
extended toxicity studies, but as the ART PR37 setup was not
available, a system based on Aldrich chip reactors (Figure 1a)
was designed. To accommodate an in situ quench, two glass
chip reactors from Sigma-Aldrich (Figure 1a) were used. The
first one was used to add the Grignard reagent, and the second
one was employed to quench the reaction (Figure 2). A
modified Vapourtec R-Series reactor system was used to feed
precipitation issue and gave significantly better results with
higher conversion and better selectivity. These results indicated
that a practical approach was to mix Et N with ester 1 and react
3
it with 1.2 equiv of MeMgBr at 0 °C for 20 s before quenching
the reaction at 0 °C with a 1:1:1 (v/v/v) mixture of acetic acid,
water and 2-MeTHF.
In order to rapidly convert the 580 g of ester 1 needed for
the next campaign, the reaction was scaled up by using the ART
PR37 reactor (Figure 1b) equipped with a plate of larger
internal volume so that the total flow rate could be increased
from 7 to 25 mL/min while keeping a similar residence time.
The amount of MeMgBr was also increased to 1.4 equiv (Table
both the ester 1/Et N solution and the quench solution. The
3
Grignard reagent solution was fed by a double syringe pump
fitted with two 2.5 mL gastight syringes. By means of a
combination of check valves, when one syringe was adding the
Grignard solution the other syringe was refilled, and therefore,
the syringe pump could be used to continuously feed the
solution containing the Grignard reagents (Figure 2). The
injection loop of the Vapourtec reactor was used to introduce
the wash solution when the pressure rose above 5 bar. The
2, entry 4) to ensure complete reaction. This was based on
strategic judgment, as it was known that the residual tertiary
alcohol 3 did not compromise the crystallization of ketone 2
while unreacted ester 1 had been observed to create issues at a
later stage in the reaction sequence.
ester 1 solution (0.46 M in 2-MeTHF with 3.5 equiv of Et N)
3
On the basis of the above results, the reaction conditions
from Table 2, entry 4 were chosen to manufacture the required
amount of ketone 2. During the continuous processing of 580 g
of ester 1, precipitation occurred, as evidenced by a pressure
increase that soon resulted in a blockage of the reactor. This
necessitated the implementation of a cleaning cycle using the
and the MeMgBr solution (1.4 M in toluene/THF from
Aldrich) were reacted in the first chip reactor immersed into an
ice bath after a short precooling path in the chip. The process
stream was then immediately quenched in the second chip
(also immersed in an ice bath at 0 °C) by reaction with 1:1:1
(v/v/v) HOAc/water/2-MeTHF. Finally, the process stream
C
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was collected in a batch reactor containing toluene and brine at
allowing good productivity for this process in a microreactor
(300 g of ester in 12 h).
1
0 °C (Figure 2). Monitoring of the temperature in the chip
with a Pt100 sensor showed that without stirring in the ice
bath, the temperature in the chip reached 8 °C within 5 min.
Knowledge accumulated from earlier development indicated
that a short residence time would give an acceptable reaction
profile and reasonable throughput. The plan was to use
between 1.2 and 1.7 equiv of MeMgBr. A key objective, as
mentioned before, was to keep the residual ester 1 and aldol
condensation product 4 at a low level (<1%). As can been seen
in Table 3, entry 3, this requirement was fulfilled when 1.7
equiv of MeMgBr was used.
On the basis of measurements of the temperature in the chip,
this reaction appears to be highly exothermic and could be
expected to cause processing issues if scaled up in a
conventional stirred batch reactor.
It has been demonstrated that such a challenging reaction is
not sensitive to the type of flow reactor used, since similar
results were obtained in both the Sigma-Aldrich glass chip
reactor and in the ART PR37 plate reactor with two different
channel sizes and geometries. The difference in residence time
(
7 s vs 20 s) in the addition step indicates that the initially
formed complex is formed quickly and is stable enough at the
reaction temperature.
Table 3. Results of the screening using different ratios of
MeMgBr and residence times in two Sigma-Aldrich chip
reactors
This procedure can be used as an alternative to the Weinreb
ketone synthesis and reduces the synthesis by at least one step
(
synthesis of the Weinreb amide).
residence
time (s)
HPLC yield (area%)
EXPERIMENTAL SECTION
Ketone 2, Method 1. Solution A. Ethyl 2-(3-chlorophen-
yl)-2H-tetrazole-5-carboxylate (1) (75.3 g, 0.30 mol) was
dissolved in 2-MeTHF (430 mL), and the resulting solution
was filtered to give a 0.6 M solution.
■
entry equiv of MeMgBr chip 1 chip 2
1
2
3
4
1
2
3
1.2
1.5
1.7
5.4
6.3
6.9
2.8
3.0
3.2
10
5
85
87
90
5
<1
<1
<1
7
<1
10
Solution B. MeMgBr (123 mL, 1.4 M in toluene/THF) was
Under the reaction conditions depicted in Table 3, entry 3,
00 g of ester 1 could be converted within 12 h. After
mixed with Et N (87 mL, 1.17 mol).
3
3
Solution C. The quench solution was made of equal volumes
separation of the collected process stream and washing once
with brine, the organic phase was evaporated to dryness and
was then crystallized from 2:1 IPA/water to give ketone 2 in
of acetic acid, water, and 2-MeTHF.
Example Procedure (Table 1, entry 4). Solutions A and B
were charged at a flow rate of 3 mL/min each into the Sigma-
Aldrich glass chip at 0 °C, and the discharge was collected in a
vessel containing stirred solution C.
Ketone 2, Method 2. Solution A. Ethyl 2-(3-chlorophen-
yl)-2H-tetrazole-5-carboxylate (1) (301 g, 1.19 mol) was
6
3% isolated yield (167 g). A final crop of 25 g was isolated
after chromatographic purification of the mother liquor, giving
a total yield of 72%. Similar issues with precipitation occurred
during this manufacture, and the cleaning cycle was run every
4
5 min. As can be observed in Figure 3, the precipitation
dissolved in 2-MeTHF, and Et N (0.58 L, 4.17 mol) was
3
occurred right after the mixing zone.
added. The resulting solution was filtered and then diluted to a
total volume of 2.59 L, giving an ester 1 concentration of 0.46
M.
Solution B. MeMgBr (Aldrich, 1.4 M in toluene/THF) was
used as supplied.
Solution C. The quench solution was made of equal volumes
of acetic acid, water, and 2-MeTHF.
Example Procedure (Table 2, entry 3). Solutions A, B, and
C were charged at flow rates of 5, 2, and 6.2 mL/min,
respectively.
Example Procedure (Table 2, entry 4). Solutions A, B, and
C were charged at flow rates of 17.9, 8.0, and 22.1 mL/min,
respectively.
CONCLUSION
■
The formation of by-product 4 could be suppressed below 1%
by quenching the reaction in the flow reactor. The procedure
developed for the flow reactor requires less than 2 equiv of
MeMgBr, representing an improvement compared with the
1
original procedure of Ikuo and Tadahika, which required 2
equiv of MeMgBr. However, to reach full conversion of ester 1,
a small excess of Grignard reagent (1.2−1.7 equiv) had to be
used. This excess led to a minor loss of yield at the cost of
tertiary alcohol 3, but this was a minor issue for the overall
process. The residence time could be reduced to less than 7 s,
Figure 3. Picture of the Sigma-Aldrich glass chip reactor used for the mixing of MeMgBr and solution of ester 1/Et N.
3
D
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Example Procedure (Table 3, entry 3). Solutions A, B, and
C were charged at flow rates of 3.5, 2.0, and 6.2 mL/min,
respectively.
AUTHOR INFORMATION
Corresponding Author
E-mail: fritiofponten@me.com.
■
*
Notes
The authors declare no competing financial interest.
∥
F.G.J.O.: Phone: +46 (0)5166504. E-mail: Fabrice.Odille@sp.
se.
REFERENCES
■
(
(
(
1) Ikuo, K.; Tadahika, Y. Synthesis 1980, 877−878.
2) Watts, P.; Wiles, C. Chem. Commun. 2007, 443−467.
3) Durcy, L.; Roberge, D. M. Org. Process Res. Dev. 2008, 12, 163−
167.
(
4) Aiichiro, N.; Heejin, K.; Yuya, M.; Chika, M.; Jun-ichi, Y.
Chem.Eur. J. 2010, 16, 11167−11177. Brodmann, T.; Koos, P.;
Metzger, A.; Knochel, P.; Ley, S. Org. Process Res. Dev. 2012, 16,
1
(
102−1113.
5) The ART PR37 plate reactor consists of a series of cassettes. The
core of each of these is a specially designed process channel plate into
which the process and utility channels are machined. These are
designed to promote optimum mixing and heat transfer performance.
Different numbers of these cassettes can be stacked vertically and held
together in a frame. The reactor frame holds the plates together in
compression, thus sealing the fluid channels. This frame is spring-
loaded, which ensures that the correct sealing force is maintained at all
times, even when extreme temperatures are involved.
(
6) Each plate has one process inlet and one process outlet port.
Secondary ports that make it possible to add specific reactants or to
insert measuring and monitoring devices are positioned along the
length of the plate and provide access to the main process channel.
The process channels are connected in series to ensure the required
residence time. Four different sizes are available and fit in the PR37
reactor frame: PL37\0.8-2.2-C22 (volume per plate = 3.5 mL; cross
2
2
section: min = 0.85 mm , max = 1.8 mm ); PL37\3-12-C22 (volume
2
2
per plate = 13.6 mL; cross section: min = 3 mm , max = 6 mm );
PL37\12-46-C22 (volume per plate = 24.9 mL; cross section: min = 6
2
2
mm , max = 12 mm ); PL37\12-46-C22 (volume per plate = 47.7 mL;
2
2
cross section: min = 12 mm , max = 24 mm ).
E
dx.doi.org/10.1021/op500290x | Org. Process Res. Dev. XXXX, XXX, XXX−XXX