Investigation into an Unexpected Impurity: A Practical Approach to Process Development for the Addition of Grignard Reagents to Aldehydes Using Continuous Flow Synthesis

Article abstract of DOI:10.1021/acs.oprd.9b00515

This work presents a case study of process development using continuous flow synthesis. In developing a process for manufacturing drug substances in batch reactors, we unexpectedly obtained a significant amount of a trimerized byproduct on addition of MeMgBr to an aldehyde. Consideration of a plausible generation mechanism for the byproduct indicated that it arose from a reaction between the starting material and the Mg salt of the target product. This led us to try applying continuous flow synthesis to the process to shorten the time during which the starting material coexists with the Mg salt of the target product. This led to drastic suppression of the byproduct under very mild conditions and the establishment of a more robust process than that for batch reactors.

Full text of DOI:10.1021/acs.oprd.9b00515

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Full Paper
Investigation into an Unexpected Impurity: a Practical
Approach to Process Development for the Addition of Grignard
Reagents to Aldehydes Using Continuous Flow Synthesis
Masahiro Hosoya, Shogo Nishijima, and Noriyuki Kurose
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00515 • Publication Date (Web): 11 Feb 2020
Downloaded from pubs.acs.org on February 11, 2020
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Investigation into an Unexpected Impurity: a
Practical Approach to Process Development for the
Addition of Grignard Reagents to Aldehydes Using
Continuous Flow Synthesis
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Masahiro Hosoya,* Shogo Nishijima, Noriyuki Kurose
API R&D Laboratory, CMC R&D Division, Shionogi and Co., Ltd., 1-3, Kuise Terajima 2-
chome, Amagasaki, Hyogo 660-0813, Japan
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TOC
5
Batch Reactor
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61%
10.2%
O
OMe
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9
O
O
OMe
OH
MeMgBr
in THF
H
O
OMe
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O
MeO
HO
OH
O
O
OMe
91%
0.3%
Flow Reactor
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ABSTRACT
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This work presents a case study of process development using continuous flow synthesis. In
developing a process for manufacturing drug substances in batch reactors, we unexpectedly
obtained a significant amount of a trimerized byproduct on addition of MeMgBr to an aldehyde.
Consideration of a plausible generation mechanism for the byproduct indicated that it arose from
a reaction between the starting material and the Mg salt of the target product. This led us to try
applying continuous flow synthesis to the process to shorten the time during which the starting
material coexists with the Mg salt of the target product. This led to drastic suppression of the
byproduct under very mild conditions and the establishment of a more robust process than that
for batch reactors.
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KEYWORDS: process development, Grignard reagent, aromatic aldehyde, trimerized
byproduct, continuous flow synthesis, fast mixing
INTRODUCTION
This work suggests a practical approach using continuous flow synthesis, which was
established during process development for the addition of Grignard reagents.
Grignard reagents offer a versatile synthetic strategy to construct C–C bonds.1 In contrast with
organic lithium reagents, which work in a similar manner,2 Grignard reagents can generally be
stored at room temperature whereas organic lithium reagents often need to be stored at low
temperature.3 Also, while organic lithium reagents are used under cryogenic conditions, Grignard
reagents are used at relatively mild temperatures without the need for excess cooling.4 However,
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establishing a high yield with a Grignard reagent at room temperature is often still challenging.
Pursuing milder reaction conditions on the application of Grignard reagents remains meaningful.
Although Grignard reagents are useful for constructing C–C bonds, the generation of Grignard
reagents with halides and metal magnesium is a highly exothermic reaction and can be
troublesome for a large-scale batch.5 Knochel et al. reported a method for preparing a variety of
organomagnesium reagents under mild conditions via metal-halogen exchange.6 This
methodology can facilitate preparation of highly functionalized Grignard reagents, which can be
used to synthesize complex molecules, such as active pharmaceutical ingredients.
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Addition of Grignard reagents to benzoyl moieties can provide important structural units of
drug substances. As shown in Figure 1, lusutrombopag,7 aprepitant8 and lorlatinib9 have this unit,
and the development of this reaction procedure should greatly aid the manufacturing of drug
substances.
O
O
S
N
O
CH3
Cl
H
HN
N
CH3
CO2H
N
N
CF3
H
N
O
H
OCH3
CH3
H
Cl
H3C
O
CF3
lusutrombopag
F
aprepitant
O
CH3
N
H
CH3
N
F
CH3
N
O
CN
H2N
N
lorlatinib
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Figure 1. Structures of drug substances bearing a unit which can be constructed by addition of
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Grignard reagents to benzoyl moieties.
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Recently, regulatory agencies have recommended the application of continuous manufacturing,
including continuous flow synthesis, for pharmaceutical production.10, 11 From the viewpoint of
organic synthesis, continuous flow synthesis has three advantages12: 1) precise temperature
control can be conducted easily due to high heat exchange efficiency; 2) fast mixing can be done
using a micromixer; and 3) residence time can be strictly controlled by setting the flow rates and
internal volumes of reactors. These advantages can help improve the quality of drug substances
and the robustness of manufacturing processes. However, continuous manufacturing of drug
substances with continuous flow synthesis has been limited despite the possible wide range of
applications.13 One of the issues is insufficient discussion about whether the effectiveness and
robustness of continuous flow synthesis are actually superior to those of batch synthesis.
Therefore, the applicability of continuous flow synthesis directed toward manufacturing drug
substances needs to be examined on a regular basis.
Herein we report the generation of an unexpected byproduct during addition of MeMgBr to
methyl 4-formyl benzoate during the development of a process for manufacturing drug
substances. We found that this byproduct could be suppressed under very mild conditions using
continuous flow synthesis.14 We then examine the robustness of the continuous flow system and
the generality of the application of this system for versatile substrates.
RESULTS AND DISCUSSION
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In manufacturing drug substances, addition reaction of MeMgBr to methyl 4-formyl benzoate
(1a) bearing an ester group, which can be converted to other functional groups, has been
developed. During our development of the process for batch reactors, addition of a solution of
MeMgBr in THF to a solution of 1a in THF gave a significant amount of an unexpected
byproduct 3a (Scheme 1). Extensive investigation including 1H NMR, 13C NMR, 2D NMR (1H-
1H COSY, 1H-13C HSQC, and 1H-13C HMBC), and mass spectroscopy of the isolated byproduct
showed that it had a trimerized structure with the methyl ester group tolerated.15 A plausible
generation mechanism for the trimerized byproduct 3a is shown in Scheme 1. During addition of
MeMgBr, the starting material 1a and the Mg salt of the target product 2a coexist in the reaction
mixture in batch reactors. Therefore, Oppenauer oxidation of the Mg salt of 2a with 1a gave the
resulting ketone 4a and benzyl alcohol 5a.16 The ketone 4a was further converted into the
trimerized byproduct 3a via aldol reaction twice.17 To the best of our knowledge, this is the first
report of a trimerized byproduct generated consecutively during addition of Grignard reagents to
aldehydes. The evidence that the ketone 4a and benzyl alcohol 5a were detected on HPLC in
comparison with authentic samples supports our mechanism considerations.
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Addition of a solution of 1a in THF to MeMgBr gave a moderate yield of 2a, and the residual
amount of 1a increased because MeMgBr was consumed by addition of MeMgBr to the methyl
ester in 2a. The extended reaction time increased the amount of 3a since the residual starting
material 1a reacted with the Mg salt of the target product 2a (entry 1, Table 1). Simultaneous
addition of 1a and MeMgBr did not suppress the reaction between the starting material 1a and
the Mg salt of the target product 2a (entry 2, Table 1).18 The addition time of MeMgBr had a
great impact on the generation of 3a. When the addition time was extended to 60 minutes, 3a
increased to 21.5%, whereas ultrafast addition of 10 seconds minimized 3a to 4.4% at room
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temperature (entries 3-5, Table 1) by shortening the time of coexistence of 1a and the Mg salt of
2a. When the reaction temperature was decreased, the yield of 2a gradually increased (entries 4,
6, 7, Table 1). Furthermore, 2a was obtained almost quantitatively and the generation of 3a was
suppressed below 1% under cryogenic conditions (entry 7, Table 1).
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Table 1. Screening of Reaction Conditions in Batch Reactors
O
OMe
O
O
OH
OMe
MeMgBr (1.0 equiv)
THF
OMe
O
H
MeO
HO
O
OH
O
O
1a
2a
OMe
3a
entrya
internal
addition order
reaction time
HPLC (%)b
temperature
addition time
1a
RRTc
1.17
28
13
32
18
1
2a
3a
–
RRT
1.48
3.0
1
2
3
4
25°C
25°C
25°C
25°C
1a to MeMgBr
10 min
1 min
60
55
49
45
92
91
60
61
10 min
1 min
13.2
14.4
25.6
4.8
simultaneous
10 min
1 min
MeMgBr to 1a
10 sec
10 min
1 min
0
4.4
MeMgBr to 1a
10 min
0
11.6
10.2
10 min
0
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25°C
MeMgBr to 1a
60 min
1 min
0
28
28
77
77
85
85
84
>99
22.3
21.5
7.8
8.5
0.8
0.8
0.8
0.7
10 min
1 min
0
−10°C
−60°C
MeMgBr to 1a
10 min
1
10 min
1 min
1
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MeMgBr to 1a
10 min
16
14
16
1
10 min
30 min
+ 10 min
Heated to 5°C
a
Reaction conditions: 0.50 g (3.05 mmol) – 1.10 g (6.70 mmol) of 1a, 1.0 equiv of MeMgBr
b
and 19–22 vol of THF based on 1a. Reaction mixtures were assayed, and yields were
determined by HPLC analysis using an authentic sample. RRT: Relative retention time. RRT
was calculated based on the retention time of 2a.
c
Scheme 1. Plausible Mechanism for the Generation of the Trimerized Byproduct.
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O
Plausible Mechanism
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OMe
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OH
2a
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O
work-up
+ H+
O
OMe
O
H
OMe
OMe
H
1a
O
O
OMgBr
Oppenauer oxidation
Me MgBr
1a
O
OMe
Br
Mg
O
4a
O
O
O
O
work-up
MeO
OMe
H
+ H+
H
OMe
OMe
O
O
OH
OMgBr
5a
Base
Me MgBr
MeO
OH
O
O
O
and/or
O
OMe
2
H
OMe
O
O
2 Bases
OMe
MeO
OMgBr
and/or
HO
O
O
O
Aldol reaction
(twice)
O
4a
OMe
3a
then work up
+ H+
OMe
OMgBr
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Although the byproduct 3a could be reduced under cryogenic conditions in conventional batch
reactors, the equipment for cooling to cryogenic conditions is very limited due to the low-
availability. Also, avoiding such conditions would help conserve energy costs. An alternative
process to reducing the byproduct 3a was ultrafast addition of MeMgBr at room temperature,
although the scale-up to batch manufacturing would be difficult. Calorimetry analysis using
RC1e19,20 revealed that the total heat of reaction was 184 kJ/mol (Table 2), and the addition time
of MeMgBr was estimated by simulations for the transition of internal temperature based on this
calorimetry result for a variety of manufacturing scales (Table 3). Addition of MeMgBr could be
completed within a few minutes on a 5.0 g scale of charge amount (entry 1, Table 3). Even for a
charge amount of 10 kg, the addition time was estimated to be 30 minutes to maintain an internal
temperature at 25±5°C due to high heat generation (entry 2, Table 3). As for a charge amount of
300 kg, the addition time would be at least 90 minutes (entry 4, Table 3). Based on these
simulations, this reaction cannot be conducted at room temperature in batch manufacturing
because when a larger manufacturing scale is used, a longer addition time is needed. Thus, we
propose that using continuous flow synthesis would be a practical approach to solving this
problem, and the fast mixing,21 which is one advantage of continuous flow synthesis, would be
effective for suppressing the byproduct 3a regardless of the manufacturing scale.
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Table 2. Calorimetry Analysis Using RC1e
O
O
OMe
MeMgBr (1.0 equiv)
THF
OMe
H
O
OH
1a
2a
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charge amount of 1a
reaction mass
temperature
(°C)
enthalpy
the total heat of
reaction
(g)
(kg)
(kJ)
(kJ/mol)
184
5.0
0.048
25
5.6
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Table 3. Estimation of Addition Time of MeMgBr by Simulation of Internal Temperature
entrya
charge amount of required addition time
1a
(min)
(kg)
1
2
3
0.005
10
2
30
45
90
50
4
300
a
Assumption; overall heat transfer coefficient is 150 J/m2·K·s (measured with our
manufacturing equipment). The jacket temperature is set as −20°C. The internal temperature is
maintained at 25±5°C. See Supporting Information for the simulation details.
In a preliminary study of continuous flow synthesis, the inner diameter and internal volume of
the tube reactor were fixed, and various flow rates were examined (Table 4). When the total flow
rate was 1.66 mL/min, the largest amount of the starting material 1a remained (20.7%, entry 1,
Table 4). This revealed that the flow rate has an impact on mixing efficiency, and a low flow rate
leads to low conversion in spite of a long residence time.22 4.98 mL/min (entry 2, Table 4), 8.30
mL/min (entry 3, Table 4) and 13.27 mL/min (entry 4, Table 4) for total flow rates provided
approximately 90% yield. Therefore, conversion to the target product 2a could be almost
completed within a few seconds when the total flow rate was higher than 4.98 mL/min. In all
these cases, the trimerized byproduct 3a was drastically suppressed to 0.1% at room temperature
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by the introduction of continuous flow synthesis compared with 10.2% under the standard
conditions in batch reactors. The fast mixing by the application of continuous flow synthesis led
to a short coexistence time of 1a and the Mg salt of 2a, which was effective for suppressing the
byproduct 3a as expected.
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Table 4. Preliminary Screening of Flow Rate Using Continuous Flow Synthesis
Pump A
O
Jacket temperature: 25°C
OMe
Inner diameter: 1.0 mm
Internal volume: 0.22 mL
H
O
1a
T-Mixer
through hole:
1.27 mm
0.559 mmol/mL
Pump B
MeMgBr
1.07 mmol/mL
(1.00 equiv)
O
OMe
OH
2a
entry
pump A
residence
molecular ratio (%)b
time
pump B
5a
2a
1a
4a
3a
(sec)
(mL/min)a
RRTc
0.87
1.3
–
RRT RRT RRT
1.17 1.21 1.48
1
2
1.09
0.57
3.27
1.71
8
3
77.2
88.9
20.7 0.7
0.1
1.0
9.6
0.5
0.1
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5.45
2.85
8.72
4.55
–
2
1
–
0.9
91.0
90.4
60.7
7.6
8.5
0.2
0.5
0.4
0.1
0.1
4
0.7
0.1
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5d
15.9
10.2
a Flow rates of pump A and pump B were adjusted so that the equivalent of MeMgBr would be
adjusted to 1.00 equiv. b Molecular ratio (1a,2a,3×3a,4a,5a and other impurities) was calculated
by HPLC with sensitivity corrections for continuous flow synthesis. Other impurities of more
than 1.0 area% were detected as the sensitivity equivalent to 2a. Note that 3a is composed of 3
molecules of 1a. c RRT: Relative retention time. RRT was calculated based on the retention time
of 2a. d Result for batch conditions as reference; MeMgBr was added to a solution of 1a at 25°C
over 10 min. The reaction mixture was assayed, and yield was determined by HPLC analysis
using an authentic sample.
This preliminary result encouraged us to examine the robustness of this continuous flow
system for manufacturing purposes. Standard conditions were set as follows: 1.00 equiv of
MeMgBr, 8.30 mL/min for total flow rate, 29 seconds of residence time, 25°C for jacket
temperature, 0.559 mmol/mL for concentration of 1a, and 1.07 mmol/mL for concentration of
MeMgBr. We evaluated the acceptable ranges of the variable parameters (flow rate, temperature
and concentration of reagents) (Table 5). When the residence time was 2 seconds, 29 seconds
and 57 seconds, more than 90% yield was obtained. An extended residence time led to slightly
higher amounts of the trimerized byproduct 3a but the level remained suppressed at 0.5%
(entries 1, 2, 3, Table 5). When the equivalents of MeMgBr were adjusted to 1.05 equiv and 1.10
equiv by adjustment of the flow rate of MeMgBr, the starting material was correspondingly
consumed (entries 4, 5, Table 5), resulting in maximizing of the yield of the target product 2a to
98.0% (entry 5, Table 5). Continuous flow synthesis at 40°C also resulted in near completion of
the reaction (entry 6, Table 5). The concentration and inner diameter of the tube reactor did not
have a great impact on the reaction conversion and the amount of the byproduct 3a (entries 7, 8,
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9, Table 5). These results clearly showed that the trimerized byproduct 3a was generally
suppressed to not more than 0.5% in the confirmed ranges of variable parameters with
continuous flow synthesis, while temperature and addition time of MeMgBr had a great impact
on generation of the trimerized byproduct 3a in batch reactors. Furthermore, these results
indicated that application of continuous flow synthesis successfully improved the process
robustness compared with batch reactors. However, strict control of the flow rate is a key factor
for controlling the equivalent ratio and maintaining stable reaction conversion in manufacturing
by continuous flow synthesis.
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Table 5. Evaluation of Process Robustness with Continuous Flow Synthesis
Pump A
O
Jacket temperature: 25-40°C
OMe
Inner diameter: 1.0-2.18 mm
H
Internal volume: 0.22-7.85 mL
O
1a
T-Mixer
through hole:
1.27 mm
Pump B
MeMgBr
O
OMe
OH
2a
entry pump A
pump B
concentration jacket
of 1a
residence molecular ratio (%)b
temperature timea
5a
2a
1a
4a
3a
concentration (°C)
(sec)
RRTc
–
RRT RRT RRT
(mL/min)
of MeMgBr
inner
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(mmol/mL)
diameter
(mm)
25
0.87
0.9
1.17 1.21 1.48
1
2
5.45
0.559
1.07
2
91.0 7.6
0.5
0.1
0.3
2.85
(1.00
equiv)
1.0
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5.45
2.85
0.559
1.07
25
29
1.0
1.1
0.7
0.4
0.4
0.9
91.0e 7.2 e 0.6
1.0
(1.00
equiv)
3
4
5
6
7
5.45
2.85
0.559
1.07
25
57
29
28
29
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94.4 3.5
96.0 2.7
98.0 0.1
97.2 0.1
93.6 5.0
0.5
0.4
0.1
0.0
0.4
0.5
0.2
0.0
0.0
0.2
1.0
(1.00
equiv)
5.45
2.99
0.559
1.07
25
1.0
(1.05
equiv)
5.45
3.14
0.559
1.07
25
1.0
(1.10
equiv)
5.45
2.85
0.559
1.07
40
1.0
(1.00
equiv)
4.96
2.85
0.615
1.07
25
1.0
(1.00
equiv)
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8
5.97
2.85
0.511
1.07
25
27
29
–
1.1
89.2 8.9
91.8 6.2
60.7 0.2
0.6
0.6
0.1
0.1
1.0
(1.00
equiv)
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9
5.45
2.85
0.559
1.07
25
1.1
0.3
2.18
(1.00
equiv)
10d
–
–
25
15.9
10.2
a The internal volume was 4.04 mL (entries 2, 4–9), 0.22 mL (entry 1) and 7.85 mL (entry 3). b
Molecular ratio (1a, 2a, 3×3a, 4a, 5a and other impurities) was calculated by HPLC with
sensitivity corrections in continuous flow synthesis. Other impurities of more than 1.0 area%
were detected as the sensitivity equivalent to 2a. Note that 3a is composed of 3 molecules of 1a c
RRT: Relative retention time. RRT was calculated based on the retention time of 2a. d Result for
batch conditions as reference; MeMgBr was added to a solution of 1a at 25°C over 10 min.
Reaction mixture was assayed, and the yield was determined by HPLC analysis using an
authentic sample. e Isolated yield was also confirmed in entry 2. The yield of 2a and recovery of
1a were 91% and 8%, respectively.
Running for a long duration was demonstrated to confirm the robustness of this continuous
flow system. The transition of the reaction conversion was analyzed in running for 6 hours as
shown in Table 6. The reaction conversions did not change for 6 hours, which indicated that this
continuous flow system has an acceptable robustness.
Table 6. Transition of the reaction conversion in running for a long duration
entrya running time
(min)
molecular ratio (%)b
5a
2a
1a
4a
3a
RRTc
0.87
–
RRT RRT RRT
1.17 1.21 1.48
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5
0.4
0.5
0.2
0.3
0.3
0.3
0.3
96.8 0.1
96.2 0.2
96.5 0.1
96.7 0.1
97.0 0.1
96.8 0.1
96.9 0.1
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
60
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350
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a Jacket temperature was 25°C, inner diameter was 1.0 mm, internal volume was 2.14 mL, and
T-mixer (through hole 1.27 mm) was used. Flow rate of pump A (solution of 1a, 0.559
mmol/mL) was 3.27 mL/min, Flow rate of pump B (MeMgBr) was 1.97 mL/min in the case of
1.02 mmol/mL, and 1.90 mL/min in the case of 1.06 mmol/mL (1.10 equiv). The residence time
b
was calculated as 25 sec. Molecular ratio (1a, 2a, 3×3a, 4a, 5a and other impurities) was
calculated by HPLC with sensitivity corrections in continuous flow synthesis. Other impurities
of more than 1.0 area% were detected as the sensitivity equivalent to 2a. Note that 3a is
composed of 3 molecules of 1a c RRT: Relative retention time. RRT was calculated based on the
retention time of 2a.
The productivity of the target product 2a using this continuous flow system was estimated.
When the maximum flow rate as shown in entry 4 in Table 4 is demonstrated, the fed amount of
1a is estimated to be 1.2 kg/day, which gives 1.2 kg/day of 2a.23 If ten pieces of this continuous
flow system are connected in parallel, the productivity will be 12 kg/day, which has an
appropriate productivity for pilot manufacturing in an early phase. Further investigations into
running for a longer duration, and scale-up such as lager tubes, higher flow rates or larger
dimensions of mixers are ongoing.
This reaction system was applied to other similar reactions (Table 7). The difference of yield
between batch and flow procedures was evaluated. First, benzaldehyde derivatives containing a
variety of functional groups were examined. An electron-rich substrate bearing methoxy group
1b resulted in high yields for both batch and flow procedures since Oppenauer oxidation was
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suppressed even under batch conditions (entry 2, Table 7). With 4-cyanobenzaldehyde 1c and 4-
nitrobenzaldehyde 1d, batch procedures provided a moderate yield to low yield due to the
complex mixtures, and precipitation was observed in batch procedures (entries 3 and 4, Table 7),
for which the flow procedure could not be evaluated. Examining 4-bromo benzaldehyde 1e and
methyl (p-formylphenyl) acetate 1f bearing α-hydrogen showed that application of the flow
procedure improved the yield of 2e and 2f by approximately 20% (entries 5 and 6, Table 7).
When 1f was used as the substrate, approximately 10% of the residual starting material was
observed, probably due to deprotonation at the α-position by MeMgBr (entry 6, Table 7). Next,
Grignard reagents were examined. iPrMgBr was allowed to react with methyl 4-formyl benzoate
(1a), and the generation of byproducts derived from Oppenauer oxidation was suppressed by the
application of a flow condition, resulting in improvement of the yield of 2g (27% (Batch) to 51%
(Flow)). However, the reduction of 1a could not be suppressed sufficiently by application of
flow procedure to give the target product 2g in a moderate yield (51%, entry 7, Table 7) since
reduction of 1a by β-hydride reduction24 was competitive with the addition of iPrMgBr to 1a. For
addition of PhMgBr, application of continuous flow synthesis also improved the yield compared
with the batch procedure, and the flow procedure afforded nearly the quantitative yield of 2h
(entry 8, Table 7). Consequently, the application of continuous flow synthesis generally provided
improvement of yields for addition of Grignard reagents to aromatic aldehydes compared with
the batch procedure, which should be a practical approach to these reaction systems.25
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Table 7. Application of Continuous Flow Synthesis in a Variety of Substrates and Grignard
5
6
Reagents
7
8
9
R1
R1
R2-MgBr (1.00 equiv)
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H
R2
THF
O
OH
1a-f
2a-h
entry
1
substrate
Grignard
reagent
product
procedurea yield
(%)b
O
O
MeMgBr
Batch
Flow
61
91
OMe
OMe
H
O
2a
2b
2c
1a
OH
OH
OMe
CN
OMe
2
3
4
5
MeMgBr
MeMgBr
MeMgBr
MeMgBr
Batch
Flow
88
92
H
O
1b
1c
CN
NO2
Br
Batch
Flow
50
c
H
H
H
–
O
O
O
OH
OH
OH
NO2
Batch
Flow
3
c
–
1d
1e
2d
2e
Br
Batch
Flow
77
97
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MeMgBr
iPrMgBr
PhMgBr
Batch
Flow
57
79
COOMe
COOMe
H
O
OH
1f
2f
O
O
O
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Batch
Flow
27
51
OMe
OMe
OMe
H
H
1a
2g
2h
O
O
OH
O
Batch
Flow
79
99
OMe
Ph
OH
1a
a Batch; Grignard reagents were added to a solution of 1a-f at 25°C over 10 min. Flow: jacket
temperature was 25°C, inner diameter was 1.0 mm, internal volume was 4.04 mL, and T-mixer
(through hole 1.27 mm) was used. Batch: Reaction mixture was assayed, and yield was
determined by HPLC analysis using an authentic sample. Flow: Isolated yield. Not conducted
due to precipitation.
b
c
CONCLUSION
In conclusion, we established a practical synthetic approach for addition of MeMgBr to methyl
4-formyl benzoate (1a) using continuous flow synthesis. The unexpected trimerized byproduct
3a was drastically suppressed to not more than 0.5%, and the yield was greatly improved to 98%
at room temperature. In the ranges of variable parameters, the trimerized byproduct 3a was
generally suppressed, and the robustness of this procedure was confirmed. This approach was
widely applied to other addition reactions of Grignard reagents to aromatic aldehydes, with
confirmation of a general improvement of the yield using the proposed procedure. It can be
widely used when byproducts are generated by reaction between the starting material and the
target product in batch manufacturing during addition of a reagent; the key to success is
reduction of the addition time. Our next challenge is to apply in-line monitoring to control
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reaction rate by in-situ Fourier Transform Infrared Spectroscopy (FT-IR) in a flow system and to
use internal temperature monitoring to enable reliable internal temperature simulations26 for
process safety. Our final goal is the realization of continuous manufacturing of drug substances
by continuous flow synthesis.
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EXPERIMENTAL SECTION
General Information
All reactions were run under a nitrogen atmosphere. Solvents and reagents were purchased
i
from commercial sources and used without further purification. 1a and PrMgBr in THF were
purchased from Tokyo Chemical Industry Co., Ltd. MeMgBr in THF and PhMgBr in THF were
purchased from Kanto Chemical Co., Inc. Because a metallic precipitate was often observed in
commercial Grignard reagents, the precipitate should be dissolved carefully at 40°C before using
commercial Grignard reagents to avoid an unexpected clogging in continuous flow synthesis.
High performance liquid chromatographic (HPLC) analysis was carried out using a Shimadzu
1
13
LC-2010CHT. The heat of reaction was measured using Mettler Toledo RC1e. H NMR, C
NMR, and 2D NMR spectra were recorded on a Bruker Avance ΙΙΙ HD 400 MHz. LCMS were
recorded on a Shimadzu LCMS-2010EV. A T-shape mixer was purchased by M&S Instruments
Inc. (P-633, through hole 0.05 inch (= 1.27 mm)). The Vapourtec V-3 is a peristaltic pump.
Flow rates were calibrated manually as follows: the weight of the fed amount was measured
for 1 minute using THF in the case of pump A and MeMgBr in THF (1.07 mmol/mL) in the case
of pump B. The measured weight was converted to the volume using the density.
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Dimethyl
4,4'-(1,3-dihydroxy-2-(4-(methoxycarbonyl)benzoyl)propane-1,3-
5
6
diyl)dibenzoate (3a)
7
8
9
Two solutions were fed by the Vapourtec V-3; solution A was a solution of 1a in 10 volumes
of THF (0.559 mmol/mL) and solution B was MeMgBr in THF (1.07 mmol/mL). Flow rate of
solution A was set as 1.09 mL/min, and that of solution B was set as 0.57 mL/min so that the
equivalent of MeMgBr would be adjusted to 1.00 equiv. Two solutions were poured into a 4-
neck flask containing THF (10 mL) with a stirring bar at 25°C for 11 minutes. Input amount of
the starting material 1a was defined as 1.10 g (0.559 mmol/mL × 1.09 mL/min × 11 min ×
164.16 mg/mmol). The reaction mixture was stirred for 90 minutes and poured into the mixture
of ethyl acetate (80 mL) and aqueous solution of citric acid prepared from citric acid
monohydrate (2.0 g) and water (38 mL) at 0°C. The organic phase was separated, and the
organic phase was washed with water (20 mL). The organic phase was evaporated, and the
residue was purified by flash column chromatography on silica gel (eluent: n-hexane/ethyl
acetate 75/25 (v/v) to 60/40 (v/v)) to afford 3a (74.2 mg, 95.2 area%, containing ethyl acetate (1
wt%) and n-hexane (2 wt%) from 1H-NMR). 1H NMR (400 MHz, CDCl3) δ 7.93–7.90 (6H, m),
7.68–7.66 (2H, m), 7.41–7.39 (4H, m), 5.02 (2H, dd, J = 6.3, 6.3 Hz), 4.08 (1H, t, J = 6.2 Hz),
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13
3.89 (3H, s), 3.87 (6H, s), 3.78 (2H, d, J = 6.5 Hz). C NMR (100 MHz, CDCl3) δ 205.77,
166.76, 166.13, 146.82, 141.63, 134.17, 129.99, 129.95, 129.69, 128.21, 126.01, 74.17, 59.25,
52.27, 52.25. MS (ESI+) m/z 529 [M+Na]+.
Calorimetry analysis procedure
Two solutions were fed by the Vapourtec V-3; solution A was a solution of 1a in 10 volumes
of THF (0.559 mmol/mL) and solution B was MeMgBr in THF (1.07 mmol/mL). Flow rate of
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solution A was set as 5.45 mL/min, and that of solution B was set as 2.85 mL/min so that the
equivalent of MeMgBr would be adjusted to 1.00 equiv. Two solutions were mixed at a T-shape
mixer, and the combined solution was passed through PFA tube reactors (inner diameter 1.0 mm,
internal volume 7.85 mL). The flow system consisting of the T-mixer and the tube reactor was
put in RC1e and RC1e was filled with water (475 mL). The filled water was adjusted to 25°C,
and heat generation was measured for 10 minutes. Input amount of the starting material 1a was
defined as 5.00 g (0.559 mmol/mL × 5.45 mL/min × 10 min × 164.16 mg/mmol)
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General procedure of continuous flow synthesis to synthesize 2a in Table 4
Two solutions were fed by the Vapourtec V-3; solution A was a solution of 1a in 10 volumes
of THF (0.559 mmol/mL) and solution B was MeMgBr in THF (1.07 mmol/mL). Flow rate of
solution A was set as 1.09 mL/min to 8.72 mL/min, and that of solution B was set as 0.57
mL/min to 4.55 mL/min so that the equivalent of MeMgBr would be adjusted to 1.00 equiv. Two
solutions were mixed at a T-shape mixer in a bath of 25°C, and the combined solution was
passed through PFA tube reactors (inner diameter 1.0 mm, internal volume 0.22 mL). After
reaching a steady state (running for 3 minutes), the reaction mixture was poured into MeCN/H2O
(80/20 (v/v)) containing 0.1 vol% of HCOOH directly and diluted in a measuring flask to
measure the molecular ratio (1a, 2a, 3×3a, 4a, 5a and other impurities).
Isolating procedure of 2a–h using continuous flow synthesis
Two solutions were fed by the Vapourtec V-3; solution A was a solution of 1a–f in THF
(adjusted to 0.559 mmol/mL) and solution B was MeMgBr in THF (1.07 mmol/mL), iPrMgBr in
THF (1.0 mmol/mL) or PhMgBr in THF (1.07 mmol/mL). Flow rate of solution A was fixed as
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i
5.45 mL/min, and that of solution B was adjusted so that the equivalent of MeMgBr, PrMgBr
and PhMgBr would be adjusted to 1.00 equiv. Two solutions were mixed at a T-shape mixer in a
bath of 25°C, and the combined solution was passed through PFA tube reactors (inner diameter
1.0 mm, internal volume 4.04 mL). After reaching a steady state (running for 3 minutes), the
reaction mixture was poured into the mixture of ethyl acetate (100 mL) and aqueous solution of
citric acid prepared from citric acid monohydrate (0.96 g) and water (100 mL) at 0°C for 2
minutes. The organic phase was separated, and the aqueous phase was extracted with ethyl
acetate (50 mL). The combined organic phases were evaporated, and the residue was purified by
flash column chromatography on silica gel (eluent: n-hexane/ethyl acetate 90/10 (v/v) to 70/30
(v/v)) to afford the target product 2a–h. Input amount of the starting materials depends on
molecular weight (0.559 mmol/mL × 5.45 mL/min × 2 min × molecular weight mg/mmol)
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Methyl 4-(1-hydroxyethyl)benzoate (2a)
Input amount of the starting material: 1000.2 mg. Isolated amount of recovery 1a and 2a were
80.2 mg (8%, 92 area%, containing 8 area% of 5a) and 1002.0 mg (91%, 99.3 area%),
respectively. 1H NMR (400 MHz, CDCl3) δ 7.99–7.96 (2H, m), 7.42–7.40 (2H, m), 4.92 (1H, qd,
J = 6.5, 3.0 Hz), 3.89 (3H, s), 2.48 (1H, d, J = 3.1 Hz), 1.48 (3H, d, J = 6.6 Hz). 13C NMR (100
MHz, CDCl3) δ 167.13, 151.17, 129.90, 129.19, 125.38, 69.97, 52.16, 25.34. MS (ESI+) m/z 163
[M−OH]+.
ASSOCIATED CONTENT
Supporting Information
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HPLC Methods for preparation of 2a–h and 3a, procedures of batch synthesis to synthesize 2a,
1H NMR spectra and 13C NMR spectra of 2a–h and 3a. 2D-NMR (COSY, HSQC, HMBC)
spectra of 3a, heat flow about addition of MeMgBr and data for justification of calorimetry
analysis combined with continuous flow system and RC1e, simulation details based on the heat
of reaction, a detailed description of the equipment used for continuous flow synthesis,
procedure of running for a long duration
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AUTHOR INFORMATION
Corresponding Author
* E-mail: masahiro.hosoya@shionogi.co.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors are grateful to Dr. Kazuya Okamoto, Mr. Hiroyuki Otaka, Dr. Nobuaki Fukui, Dr.
Yoshitomo Nagasawa, Dr. Yusuke Maegawa, Dr. Shuichi Yanagisawa and our other laboratory
members for their encouraging and helpful discussions.
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