Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis of 5-Cyano-2-formylbenzoic Acid

Article abstract of DOI:10.1021/acs.oprd.9b00180

Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) as a key intermediate for various biologically important compounds has been achieved from isopropyl 2-bromo-5-cyanobenzoate (8c) by means of continuous flow-flash chemistry using flow microreactors. It was found that Br/Li exchange reaction of 8c, bearing both a carboisopropoxy group and a cyano group, with BuLi took place within 0.1 s at -50 °C, and the resulting highly reactive aryllithium intermediate underwent formylation with DMF to afford 1, which is extremely difficult to achieve by a conventional batch process. Optimization of the continuous flow-flash reaction conditions and modification of the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without purification by column chromatography. The results suggest that phthalaldehydic acid derivatives bearing electrophilic group(s) can be synthesized conveniently from the corresponding 2-bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors.

Full text of DOI:10.1021/acs.oprd.9b00180

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Full Paper
Application of Continuous Flow-Flash Chemistry to
Scale-up Synthesis of 5-Cyano-2-formylbenzoic acid
Masaki Seto, Shinichi Masada, Hirotsugu Usutani, David G. Cork, Koichiro Fukuda, and Tetsuji Kawamoto
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00180 • Publication Date (Web): 30 May 2019
Downloaded from http://pubs.acs.org on June 4, 2019
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Application of Continuous Flow-Flash Chemistry to
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Scale-up Synthesis of 5-Cyano-2-formylbenzoic acid
Masaki, Seto,*,‡Shinichi Masada,‡ Hirotsugu Usutani,§,∥ David G. Cork,§,  Koichiro Fukuda,‡,†
and Tetsuji Kawamoto*,‡,†
‡ Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Ltd.,
26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
§ Process Chemistry, Pharmaceutical Sciences, Takeda Pharmaceutical Company Ltd., 26-1,
Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan
Present Address
† Chemistry Research Division, Axcelead Drug Discovery Partners, Inc. 26-1, Muraoka-Higashi
2-chome, Fujisawa, Kanagawa 251-0012, Japan (K.F. and T.K.)
∥Kyoto University Original Co., Ltd., Kyoto University, Yoshida-Hommachi, Sakyo-ku, Kyoto
606-8501, Japan (H.U.)
2-4-56 Ueno Higashi, Toyonaka, Osaka, 560-0013, Japan (D.G.C.)
1
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TOC figure
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2 Electrophilic functional groups
Flash Chemistry !!
 = 0.25 mm
9
NC
CO2iPr
Br
Residence time
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= 0.030 sec
 = 0.25 mm
897 g
0.4 M in THF
30 mL/min
O
O
NC
NC
OH
H
nBuLi
1.6 M in hexane
9 mL/min
O
OH
O
DMF
7 mL/min
Flow 237 g, 40%
O
CO2iPr
oC＞
NC
＜- 60
Batch
Br
CN
Total 270 min
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Abstract: Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer
6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) as a key intermediate for various biologically
important compounds has been achieved from isopropyl 2-bromo-5-cyanobenzoate (8c) by means of
continuous flow-flash chemistry using flow microreactors. It was found that Br/Li exchange
reaction of 8c, bearing both a carboisopropoxy group and a cyano group, with BuLi took place
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o
within 0.1 sec at - 50 C and the resulting highly reactive aryllithium intermediate underwent
formylation with DMF to afford 1, which is extremely difficult to be achieved by a conventional
batch process. Optimization of the continuous flow-flash reaction conditions and modification of
the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without
purification by column chromatography. The results suggest that phthalaldehydic acid derivatives
bearing electrophilic group(s) can be synthesized conveniently from the corresponding
2-bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors.
KEYWORDS: flow synthesis, flash chemistry, flow microreactor, 5-cyano-2-formylbenzoic acid,
alkoxycarbonyl group, cyano group
■ INTRODUCTION
Phthalaldehydic acid1 derivatives have been used widely as key intermediates for various
heterocyclic compounds of biological importance, such as isoindolin-1-one,2 dihydroisoindolo[2,1-a]
quinolin-11-one,3 benzo[c]thiophen-1(3H)-one,4 phthalazin-1(2H)-one,5 6H-isochromeno[4,3-b]
pyridin-6-one6 and 2-benzofuran-1(3H)-one7 derivatives. Among them 5-cyano-2-formylbenzoic
acid or the cyclic 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) derivatives2e,f,g,3a,b have been
reported to be employed as key intermediates for synthesis of the 3-cyano-dihydroisoindolo[2,1-a]
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O
O
OH
O
O
O
H
NH
OH
N
NC
NC
N
N
N
O
NC
NC
O
O
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(1)
(2)
(3)
CF3
H
N
N
Me
N
CN
CN
O
N
N
O
N
Me
N
O
N
NC
N
F3C
O
O
O
N
N
N
O
(5)
(6)
(4)
Figure 1. Biologically important compounds derived from 5-cyano-2-formylbenzoic acid or
6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1)
quinolin-11-one derivative (2)3 as an inhibitor of tyrosyl-DNA phosphodiesterase I (Tdp1) and
topoisomerase I (Top1) and they would also be potential key intermediates for various biologically
active compounds bearing an isoindolin-1-one pharmacophore substituted at the C(6) position with a
cyano group (3)8a and (4)8d or a 1,2,4-oxaziazol-3-yl group (5)9a and (6)9c (Figure 1).
It is well known that various phthalaldehydic acid derivatives are synthesized conveniently from
2-bromobenzaldehyde protected with lithium morpholide1c or 2-bromobenzoic acid2a,b,c,4b,10
derivatives through their treatments with BuLi followed by carboxylation or formylation of the
resulting aryllithium intermediates with CO2 or DMF, respectively.
However, the above methods
have generally been limited to the syntheses of phthalaldehydic acid derivatives without electrophilic
functional group(s) because highly reactive aryllithium intermediates bearing electrophilic functional
group(s) are very difficult to be generated.
Therefore, some of the phthalaldehydic acid
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derivatives2d,e,f,g,3a,b involving (1) have been synthesized via the corresponding phthalide derivatives
through their bromination, followed by hydrolysis of the resulting 3-bromophthalide derivatives
(Scheme 1).
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Scheme 1. Conventional synthesis of 1 from 7 and investigation of efficient synthesis of 1
from 8 by means of flow-flash chemistry using flow microreactors
O
OH
i)
ii)
Br
O
H
O
O
OH
OR
NC
NC
NC
NC
Flow
O
O
O
(7)
(1)
(8)
i) Bromination followed by hydrolysis3) ; ii) BuLi then DMF (Flow)
Yoshida et al reported that by means of flow-flash chemistry11 using flow microreactors, aryl
bromides bearing alkoxycarbonyl,12 nitro,13 cyano14 and other electrophilic functional groups,15
generate highly reactive aryllithium intermediates through Br/Li exchange reaction on treatment with
BuLi, which can then react with various electrophiles without affecting the electrophilic functional
groups and giving compounds that are generally difficult to obtain by conventional batch processes.
The method was anticipated to be applicable for an efficient synthesis of 1 from
2-bromo-5-cyanobenzoic acid ester (8) by Br/Li exchange reaction followed by formylation of the
resulting highly reactive aryllithium intermediate with DMF and its scale-up synthesis through the
continuous operation of flow-flash synthesis using flow microreactors (Scheme 1). Generation and
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reaction of aryllithium compounds bearing an alkoxycarbonyl12 or a cyano14 group have been
reported so far, however, flow-flash syntheses of those possessing both an alkoxycarbonyl and a
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cyano group have not been reported.
From these points of view, it should be intriguing to
investigate Br/Li exchange reactions of 8 followed by formylation of the resulting aryllithium
intermediate with DMF for efficient synthesis of 1.
The present paper describes investigation of efficient synthesis of 5-cyano-2-formylbenzoic acid
or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1), from 2-bromo-5-cyanobenzoic
acid ester (8) as well as scale-up synthesis using continuous flow-flash chemistry with flow
microreactors.
■ RESULTS AND DISCUSSION
Investigation of continuous flow-flash synthesis of 1 from 8 using flow microreactors
To investigate synthesis of 1 from 8 by means of flow-flash chemistry using flow microreactors, a
flow-flash chemistry reaction system composed of two T-shaped mixers (M1 and M2) and two
microtube reactors was set up (Figure 2).
Initially, continuous streams of solutions of a series of 2-bromo-5-cyanobenzoic acid ester (8a-d,
0.2 M in THF) and BuLi (0.22 M in hexane) were delivered into T-shaped mixer (M1) by syringe
pumps and the resulting highly reactive phenyl lithium intermediate was provided into T-shaped
mixer (M2) for formylation with a solution of DMF (2.0 M in THF), provided by a syringe pump at
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- 50 C. The reaction solution obtained from tube reactor (L2) was treated with aqueous 1 N HCl
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8
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solution at 0 C before measurements of the ratios of 8, 1, 9, and by-products including 10 and 11
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were carried out by HPLC. The results are shown in Table 1.
L1
( i.d. = 1.0 mm)
 (msec)
8a
8b
8c
: R = Me
NC
CO2R
Br
: R = Et
i
: R = Pr
t
8d:
R = Bu
L2
A
C
( i.d. = 1.0 mm)
M in THF
M1
( i.d. = 0.25 mm)
B
mL/min
n-BuLi
9a
9b
9c
: R = Me
NC
CO2H NC
CHO
CO2R
CHO
M2
M in hex
mL/min
: R = Et
D
( i.d. = 0.5 mm)
i
: R = Pr
(1.1 eq.)
t
9d:
R = Bu
9
1
DMF
E M in THF
O
C
F
mL/min
(10 eq.)
< - 50 °C >
NC
CO2R
H
NC
CO2R
CN
1 N HCl
Br
11
0 o
C
10
by-products
Figure 2. Set-up of the lithiation-formylation flow-flash reaction system for synthesis of 1 and 9
from 8
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Table 1. Feasibility Study for Synthesis of 1 and 9 from 8 by Flow-Flash Chemistry using Flow
Microreactorsa
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b
substrate
C
D
F
HPLC area (%)c
A


entry
(msec)
(M) mL/min (M) mL/min (M) mL/min
8x
1
9x
By-
productsd
1
2
3
4
5
6
8a
8b
8b
8c
8c
8d
0.1
0.1
0.1
0.2
0.2
0.2
10
10
5.0
6
0.1
0.1
10
10
1.0
1.0
1.0
2.0
2.0
0.2
10
10
80
80
30
36
14
13
6
0
0
62
50
66
10
21
-
12
14
42
0.1
5.25
6.0
6.0
6.0
10
160
160
240
240
0
0.22
0.22
0.2
6.0
6.0
6.0
9
6.0
6.0
N.D. 30
3
1.5
8
58
aat - 50 C (bath temperature). Residence time. cProducts and by-products were not isolated. dTotal
of by-products 10 and 11, identified by their HPLC retention time. Various amounts of unidentified
by-products were also produced.
o
b
o
It was found that the flow-flash chemistry reactions at - 50 C gave rise to almost completion of
the Br/Li exchange reaction of 8 within 240 msec, to afford a mixture of 1 and 9 concomitant with
by-products including 10 and 11 depending on the alkoxycarbonyl group of 812: Compounds 8a and
8b gave 1 in lower yield than 8c, with significant formation of by-products even in the Br/Li
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exchange reactions of 80 and 160 msec at - 50 oC (entries 1-3).
5
6
7
8
9
On the other hand, 8d was found to afford 9d as the major product (entry 6), which would need
purification by column chromatography on silica gel. Considering that 8c is available more easily
than 8d as a substrate for scale-up synthesis and purification of 1 without column chromatography is
possible by back extraction of the reaction mixture and crystallization, flow-flash synthesis of 1 from
8c using flow microreactors was investigated for a scale-up synthesis.
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Thus, continuous streams of solutions of 8c (0.2 M in THF) and BuLi (0.2 M in hexane) were
delivered into a T-shaped mixer (M1,  i.d. = 0.25 mm) and the resulting aryllithium intermediate was
provided into a second T-shaped mixer (M2) under varying reaction conditions (reaction
Table 2. Effects of Reaction Temperature and Residence Time on Flow-Flash Synthesis of 1
and 9c from 8c using Flow Microreactorsa
L1
H
( i.d.
=
mm)
 (msec)
NC
CO2iPr
Br
8c
L2
( i.d. = 1.0 mm)
M1
0.2 M in THF
G
mL/min
( i.d. = 0.25 mm)
n-BuLi
NC
CO2H
CHO
NC
CO2iPr
CHO
M2
0.2 M in hex
G
mL/min
I
( i.d.
=
mm)
(1.0 eq.)
9c
1
DMF
2 mL/min
O
C
<Temp.>
NC
CO2iPr
H
NC
CO2iPr
CN
1 N HCl
Br
0 o
C
11c
10c
by-products
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entry Temp
(oC)b
G
Hc
(mL/min) (mm)
Ie
(mm)
1.0
HPLC area (%)
d
(msec)
70.7
35.3
70.7
70.7
70.7
17.7
8.8
8c
1
9c
By-productsf
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1
2
3
4
5
6
7
0
0
10
20
10
10
10
10
20
1.0
1.0
1.0
1.0
1.0
0.5
0.5
N.D.
N.D.
N.D.
N.D.
28.8
53.2
16.5
3.8
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
12.6
13.1
13.4
21.1
17.5
9.9
1.0
9.6
-
-
-
-
-
25
50
80
80
80
1.0
14.6
36.8
15.8
14.1
24.0
1.0
1.0
0.5
0.5
N.D.
18.5
a[8c] = 0.2 M in THF; [BuLi] = 0.2 M in hexane; [DMF] = neat, 2.0 mL/min. Bath temperature.
b
d
cInner diameter of microtube reactor (L1). Residence time. eInner diameter of microreactor (M2).
fTotal of by-products 10c and 11c, identified by their HPLC retention time. Various amounts of
unidentified by-products were also produced.
temperature, reaction tube (L1), residence time (), and T-shaped mixer (M2)) where a continuous
stream of DMF was delivered without dilution to enhance formylation of the aryllithium
intermediate with DMF. The reaction solution was treated with an aqueous 1 N HCl solution at 0
oC before measurements of the ratios of 8c, 1, 9c, and by-products including 10c and 11c were
carried out by HPLC. The results are shown in Table 2.
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The Br/Li exchange reactions of 8c with BuLi have been found to be completed within 100 msec
o
at 0 C to afford 1 concomitant with by-products (entry 1). The flow-flash reaction with higher
flow rates of the solutions of 8c and BuLi (entry 2) and those at lower reaction temperature, brought
about increased yield of 1 (entries 2 - 4). Significant recovery of 8c was observed for the flow-flash
reaction at – 80 oC, with decreased yield of 1 (entry 5), and the reaction using tube reactor (L1) and
flow micromixer (M2) with smaller diameter, resulted in increased recovery of 8c and similar yield
of 1 to that for entry 5 (entry 6). Higher flow rate of the solutions of 8c and BuLi at the same
temperature enhanced the Br/Li exchange reaction to give 1 in better yield than for the entries 5 and
6 (entry 7), which was lower than that in entry 4. Therefore, further optimization of the reaction
condition for flow-flash synthesis of 1 from 8c using flow microreactors was investigated, based on
the experimental result in entry 4, for a scale-up synthesis.
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Optimization of the reaction condition for continuous flow-flash synthesis of 1 and 9c from 8c
using flow microreactors
To improve the productivity of the flow-flash synthesis of 1 from 8c using flow microreactors,
higher concentrations of the solutions of 8c and BuLi than those used in the experiments in Tables 1
o
and 2 were employed and optimization of the flow-flash reaction condition at – 50 C was
investigated. To deliver the highly reactive aryllithium intermediate rapidly into T-shaped mixer
(M2) for formylation with DMF, a reaction tube (L1) with a smaller diameter ( i.d. = 0.5 mm) was
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employed. Thus, continuous streams of varying concentration of solution of 8c in THF and a
solution of BuLi (1.6 M in hexane) were delivered into T-shaped mixer (M1) by syringe pumps and
the resulting highly reactive phenyl lithium intermediate was provided into T-shaped mixer (M2) for
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o
formylation with DMF provided by a syringe pump at - 50 C. The reaction solution was treated
o
with aqueous 1 N HCl solution at 0 C before measurements of the ratios of 1, 9c, and by-products
including 10c and 11c were carried out by HPLC. The results are shown in Table 3.
Table 3. Effects of the Concentrations of the 8c and BuLi Solutions and Residence Times on the
Flow-Flash Synthesis of 1 and 9c from 8c using Flow Microreactorsa
L1
N
O
( i.d.
=
mm, cm)
NC
CO2iPr
Br
 (msec)
8c
L2
( i.d. = 1.0 mm)
M1
J
L
M in THF
K
mL/min
( i.d. = 0.25 mm)
n-BuLi
NC
CO2H
CHO
NC
CO2iPr
CHO
M2
M in hex
M
mL/min
( i.d. = 0.5 mm)
(1.0 eq.)
9c
1
DMF
2 mL/min
O
C
<- 50 °C >
NC
CO2iPr
H
NC
CO2iPr
CN
1 N HCl
Br
0 o
C
11c
10c
by-products
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entry
J
K
L
M
Nb
Oc
HPLC area (%)
1
9c By-productse
d
(M) (mL/min) (M) (mL/min) (mm) (cm) (msec)
8c
70.7 N.D. 36.8 N.D.
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1f
2
3
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5
6
0.2
0.2
0.2
0.4
0.4
10
10
10
10
20
10
0.2
1.6
1.6
1.6
1.6
1.6
10
1.25
1.25
2.5
5
1.0
0.5
3.0
3.0
21.1
16.4
12.2
12.2
18.3
11.3
31.4
131
4.6 27.0 2.2
N.D. 16.7 2.6
1.5 28.4 2.0
0.5 12.5
0.5
0.5
0.5
3.0
3.0
3.0
28.3
14.1 N.D. 33.5 5.1
23.6 1.5 10.1 3.3
0.8
5
aat - 50 C (bath temperature); DMF (neat), 2.0 mL/min. Inner diameter of microtube reactor (L1).
cLength of microtube reactor (L1). dResidence time. e Total of by-products 10c and 11c, identified by
their HPLC retention time. Various amounts of unidentified by-products were also produced. fData
from Table 2 entry 4.
o
b
Although 8c was almost totally consumed in the flow-flash reactions using a higher concentration
BuLi solution (1.6 M in hexane), lower yields of 1 and 9c than those of entry 1 were observed in the
experiments with shorter and longer residence times for the Br/Li exchange reactions of 8c (entries 2
and 3). Higher concentration of the 8c solution (0.4 M in THF) gave 1 and 9c in as low yield as
those for entry 2 (entry 4) and higher flow rates of the solutions brought about similar yields of 1 and
9c to those in entry 1 (entry 5). In contrast to these results, higher concentration of the 8c solution
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(0.8 M in THF) than used in entries 4 and 5 resulted in significant decrease in the yield of 1 (entry 6).
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Scale-up Synthesis of 1 from 8c by means of Continuous Flow-Flash Chemistry using flow
microreactors
Considering the experimental results of the optimization studies in Table 3, scale-up synthesis of 1
from 8c by means of continuous flow-flash chemistry using flow microreactors was investigated.
Thus, continuous streams of solutions of 8c (0.4 M in THF) and BuLi (1.6 M in hexane) were
delivered into a T-shaped mixer (M1,  i.d. = 0.25 mm) at flow rates of 40 mL/min and 12 mL/min,
respectively, by gear pumps and the resulting highly reactive aryllithium intermediate was provided
into a T-shaped mixer (M2,  i.d. = 0.25 mm) for formylation with DMF, provided at a flow rate of
o
9.0 mL/min by a gear pump at - 50 C. The reaction solution was treated with aqueous 2 N HCl
o
solution at 0 C before measurements of the ratios of 8c, 1, 9c, and by-products including 10c and
11c were carried out by HPLC. The results are shown in Table 4.
In preliminary experiments for continuous flow-flash synthesis of 1 at - 50 oC, a significant rise in
temperature of the cooling bath and increase in internal pressure of the flow-flash reaction system
was observed (entries 1 and 2). Therefore, to address safety concerns for the flow-flash reaction
system, continuous streams of the solutions of 8c, BuLi and DMF were delivered at lower flow rates
o
into flow microreactors at - 60 C for all subsequent continuous flow-flash syntheses of 1, while
employing longer operation times (entries 3 – 5). The collected reaction mixture was extracted with
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aqueous saturated NaHCO3 solution and the aqueous layer was acidified with aqueous 2 N HCl
solution at pH = 2 under cooling, before it was extracted back with EtOAc. It was found that 9c
was converted easily into 1 during the treatment, to afford crude 1 as crystals in ca. 40% yield with
sufficient purity (> 98% HPLC area) for use in the subsequent step.
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Table 4. Scale-up Synthesis of 1 from 8c by means of Continuous Flow-Flash Chemistry
using flow microreactorsa
L1
( i.d. = 0.5 mm, 10 cm)
 (msec)
NC
CO2iPr
Br
8c
L2
( i.d. = 1.0 mm)
M1
0.4
P
M in THF
mL/min
( i.d. = 0.25 mm)
n-BuLi
NC
CO2H
CHO
NC
CO2iPr
CHO
M2
1.6
Q
(1.1 eq.)
M in hex
mL/min
( i.d. = 0.25 mm)
9c
1
DMF
R
mL/min
O
C
<- 60 °C >
NC
CO2iPr
H
NC
CO2iPr
CN
2 N HCl
Br
0 o
C
11c
10c
by-products
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b
entry 8c Operation
P
Q
R
HPLC area (%)
Yiel
6
7
8
(g)
time
(mL/min) (mL/min) (mL/min) (msec)
d
8c
1
9c
By-
9
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productsc
(min)
1 (g,
(%)d)
6.9
1e
2e
3f
4f
22.3
53.6
197
216
5.2
12.5
61
40
40
30
30
12
12
9
9
9
9
7
22.6
22.6
30.2
30.2
11. 17.9 19.1
11.7
11.0
10.7
10.9
0
(47)
15.2
(44)
46
7.1 18.7 14.9
6.8 18.1 16.6
(36)
55
68
9
6.8 16.1 16.3
(39)
5f
408
124
30
9
7
30.2
4.0 16.3 17.2
9.9
114
(42)
a[8c] = 0.4 M, [BuLi] = 1.6 M, DMF (neat). Residence time. Total of by-products 10c and 11c,
identified by their HPLC retention time. Various amounts of unidentified by-products were also
produced. dIsolated yield. eat - 50 oC (bath temperature). f at - 60 oC (bath temperature)
b
c
Thus, scale-up synthesis of 1 to give 237 g from 897 g of 8c was achieved in 270 min by means of
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flow-flash chemistry using flow microreactors, without purification by column chromatography,
which was then provided to drug research and development programs.
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■ CONCLUSIONS
Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer
6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) as a key intermediate for various biologically
important compounds, has been achieved from isopropyl 2-bromo-5-cyanobenzoate (8c) by means
of continuous flow-flash chemistry using flow microreactors.
It was found that the Br/Li
exchange reaction of 8c bearing both a carboisopropoxy group and a cyano group with BuLi took
place within 0.1 sec at - 50 oC and the resulting highly reactive aryllithium intermediate underwent
formylation with DMF to afford 1, which is extremely difficult to be achieved in a conventional
batch process. Optimization of the continuous flow-flash reaction conditions and modification of
the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without
the need for purification by column chromatography.
The results suggest that further optimization of the continuous flow-flash reaction conditions
should give rise to even higher yields of 1 from 8c for its practical synthesis and phthalaldehydic
acid derivatives bearing electrophilic group(s) can be synthesized conveniently from the
corresponding 2-bromobenzoic acid esters by means of flow-flash chemistry using flow
microreactors, as key intermediates for biologically important compounds, which will facilitate
enhanced drug research and development programs.
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■ EXPERIMENTAL SECTION
9
General. 1H NMR spectra were recorded on a Bruker AVANCE III (300 MHz), chemical shifts are
given in parts per million (ppm) downfield from tetramethysilane (δ) as the internal standard in
deuterated solvent and coupling constants (J) are in Hertz (Hz). Data are reported as follows:
chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, dd = doublet of doublet, brs = broad singlet) and coupling constants. All solvents and
reagents were obtained from commercial suppliers and used without further purification. LC-MS
analysis was performed on a Shimadzu UFLC-Mass Spectrometer System, operating in ESI (+ or −)
ionization mode. Analyses were obtained using a linear gradient of 0.05% TFA containing
water/acetonitrile, 0.1% TFA containing water/acetonitrile or 5 mM ammonium acetate containing
water/acetonitrile mobile phase. The purities of compounds were determined by LC-MS analysis
(detection at 220 or 254 nm). HPLC was performed on an Agilent 1200 series instrument (Column:
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o
ZORBAX (SB-C18,  4.6× 50 mm, 1.8 µm, 40 C)). Flow rate = 1.0 mL/min. Mobile phase =
0.05% TFA in CH3CN and 0.05% TFA in H2O.
Ethyl 2-bromo-5-cyanobenzoate (8b). A mixture of 2-bromo-5-iodobenzoic acid (5.0 g, 15.29
mmol), iodoethane (1.479 mL, 18.35 mmol) and K2CO3 (3.17 g, 22.94 mmol) in DMF (50 mL) was
stirred at room temperature for 16 h. Water was added to the reaction mixture at room temperature
and the mixture was extracted with EtOAc. The organic layer was washed with water, aqueous
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saturated NaHCO3 solution/water (v/v, 1:1), water and brine, and was dried over Na2SO4. The
solution was concentrated in vacuo to give ethyl 2-bromo-5-iodobenzoate (5.40 g, 15.20 mmol,
99 %) as a pale yellow oil.
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A mixture of ethyl 2-bromo-5-iodobenzoate (3.0 g, 8.45 mmol), zinc cyanide (0.590 mL, 9.30
mmol), Pd(Ph3P)4 (0.195 g, 0.17 mmol) in DMF (dry) (30 mL) was stirred at 70 °C under Ar for 17
h. Water was added to the reaction mixture at room temperature and undissolved materials were
removed by filtration. The filtrate was extracted with EtOAc. The organic layer was washed with
water three times and brine, and was dried over Na2SO4. The solution was concentrated in vacuo.
The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in
hexane) to give ethyl 2-bromo-5-cyanobenzoate (8b, 1.820 g, 7.16 mmol, 85 %) as a white
amorphous solid.16)
1H NMR (400 MHz, CDCl3) δ 1.43 (3H, t, J = 7.1 Hz), 4.44 (2H, q, J = 7.3 Hz), 7.58 (1H, dd, J =
8.3, 2.0 Hz), 7.80 (1H, d, J = 8.3 Hz), 8.07 (1H, d, J = 2.0 Hz). 13C NMR (101 MHz, CDCl3) δ 14.1,
62.4, 111.7, 117.2, 127.2, 133.8, 134.7, 134.8, 135.6, 164.3.
Isopropyl 2-bromo-5-cyanobenzoate (8c). To a mixture of 2-bromo-5-iodobenzoic acid (2.0 kg, 6.12
mol) and potassium carbonate (2.52 kg, 18.41 mol) in DMF (7.7 L), was added a solution of
2-iodopropane (920 mL, 9.18 mol) in DMF (3.0 L) at room temperature over the period of 1.5 h and the
mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and
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extracted with EtOAc (3 times). The combined organic layers were washed with water, aqueous
saturated sodium bicarbonate solution and brine before being dried over Na2SO4. The solvent was
removed by evaporation under reduced pressure to give crude isopropyl-2-bromo-5-cyanobenzoate (2.0
kg, 89%) as a red oil.
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To a solution of crude isopropyl-2-bromo-5-cyanobenzoate (3.0 kg, 8.13 mol) in DMF (30 L) was
added zinc cyanide (992.8 g, 8.45 mol) at room temperature and the mixture was flushed with N2 for
1 h before (triphenylphosphine)palladium(0) (187.8 g, 0.162 mol) was added at room temperature.
The mixture was stirred at 70 °C for 16 h under N2 and the reaction mixture was diluted with water
and EtOAc. The undissolved materials were removed by filtration and the solid was washed with
EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc (3
times). The combined organic layers were washed with water and brine solution before being dried
over Na2SO4. The solvent was removed by evaporation under reduced pressure to give crude
compound. The crude compound was purified by flash column chromatography on silica gel
(100-200 mesh) (eluted with 3-5% EtOAc/Petrol) to afford isopropyl 2-bromo-5-cyanobenzoate (8c,
1.247 kg, 57%) as a white solid.
1H NMR (300 MHz, Me2SO-d6) δ 1.36 (6H, d, J = 6.3 Hz), 5.18 (1H, spt, J = 6.3 Hz), 7.93 (1H, dd,
13
J = 8.3, 2.0 Hz), 7.98 (1H, dd, J = 8.3, 0.5 Hz), 8.20 (1H, dd, J = 2.0, 0.5 Hz). C NMR (75 MHz,
Me2SO-d6) δ 21.4, 70.1, 111.0, 117.3, 125.4, 133.8, 134.4, 135.0, 135.6, 163.9. Anal Calcd for
C11H10BrNO2: C, 49.28; H, 3.76; N, 5.22. Found: C, 49.21; H, 3.93; N, 5.49. mp 47.0 – 48.9 °C.
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tert-Butyl 2-bromo-5-cyanobenzoate (8d). 1,1-Di-tert-butoxytrimethylamine (24.88 mL, 104.00
mmol) was added dropwise to a solution of 2-bromo-5-iodobenzoic acid (8.5 g, 26.00 mmol) in
toluene (40 mL) at 80 °C under N2. The mixture was stirred at 80 °C under N2 for 28 h. The
solvent was removed in vacuo and the residue was purified by column chromatography (NH silica
gel, eluted with 5% - 40% EtOAc in hexane) to give tert-butyl 2-bromo-5-iodobenzoate (9.26 g,
24.18 mmol, 93 %) as a colorless oil.
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A mixture of tert-butyl 2-bromo-5-iodobenzoate (9.26 g, 24.18 mmol), Pd(Ph3P)4 (0.559 g, 0.48
mmol) and zinc cyanide (1.611 mL, 25.39 mmol) in DMF (dry) (90 mL) was stirred at 70 °C under
Ar for 18 h. Water and EtOAc were added to the reaction mixture at room temperature and
undissolved materials were removed by filtration. The filtrate was separated, and the aqueous layer
was extracted with EtOAc. The organic layer was washed with water and brine before being dried
over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 10% - 60% EtOAc in hexane) to give tert-butyl 2-bromo-5-cyanobenzoate
(8d, 5.77 g, 20.45 mmol, 85 %) as a white amorphous solid.17)
1H NMR (400 MHz, CDCl3)  1.62 (9H, s), 7.54 (1H, dd, J = 8.3, 2.2 Hz), 7.76 (1H, d, J = 8.3 Hz),
7.96 (1H, d, J = 2.0 Hz). 13C NMR (101 MHz, CDCl3)  28.1, 84.0, 111.6, 117.3, 126.6, 134.3,
134.3, 135.3, 135.5, 163.6. HRMS (m/z): [M(-C4H9)-H]- calcd. for C8H4NO2Br , 223.9353; found
223.9376.
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Typical procedure for feasibility study of synthesis of 1 and 9 from 8 by flow-flash chemistry
using flow microreactors (Table 1. entry 5). The flow-flash reaction system in Figure 2 was set
up according to reports in the literature,11 composed of precooling loops (stainless tube, id = 1.0
mm, L = 50 cm), T-shaped mixers (M1, stainless tee pieces,  i.d. = 0.25 mm, Sannkouseikikougyou)
and (M2 ( i.d. = 0.5 mm, Shimadzu-GLC tee piece, part no. 6010-72357), microtube reactors
(stainless tube, id = 1.0 mm, L1 (3.0 cm) and L2 (283 cm)), syringe pumps (ISIS Ltd., Osaka Japan,
Fusion 100), and a cooling bath (PSL-2000, EYELA). Continuous streams of solutions of 8c and
BuLi (0.2 M in THF and 0.22 M in hexane, respectively) were provided into the T-shaped mixer
o
(M1) at flow rates of 6.0 mL/min, respectively, by the syringe pumps at - 50 C. The resulting
solution of 2-bromophenyllithium intermediate was delivered into the next T-shaped mixer (M2) for
formylation with a continuous stream of a solution of DMF (2.0 M in THF), provided at a flow rate
of 6.0 mL/min by the syringe pump, at - 50 oC. The reaction solution obtained from L2 was poured
into aqueous 1 N HCl at - 0 oC and extracted with EtOAc. The organic layer was concentrated and
subjected to an HPLC analysis to determine the ratio of 8c, 1, 9c, and by-products.
Typical procedure for optimization of reaction condition of continuous flow-flash synthesis of 1
and 9c from 8c using flow microreactors (Table 3. entry 4). The above described flow-flash
reaction system was set up, composed of precooling loops (stainless tube, id = 1.0 mm, L = 50 cm),
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T-shaped mixers (M1, stainless tee pieces,  i.d. = 0.25 mm, Sannkouseikikougyou) and (M2 ( i.d.
=
5
6
7
8
9
0.5 mm, Shimadzu-GLC tee piece, part no. 6010-72357), microtube reactors (stainless tube, L1 (id =
0.5 mm, 3.0 cm) and L2 (id = 0.5 mm, 283 cm), syringe pumps (ISIS Ltd., Osaka Japan, Fusion
100), and a cooling bath (PSL-2000, EYELA). Continuous streams of solutions of 8c and BuLi
(0.4 M in THF and 1.6 M in hexane, respectively) were provided into the T-shaped mixer (M1), at
flow rates of 10 and 2.5 mL/min, respectively, at - 50 oC by syringe pumps. The resulting solution
of 2-bromophenyllithium intermediate was delivered into the next T-shaped mixer (M2) for
formylation with a continuous stream of DMF (neat) provided at a flow rate of 2 mL/min, at - 50 oC
by a syringe pump. The reaction solution obtained from L2 was poured into aqueous 1 N HCl at - 0
oC and extracted with EtOAc. The organic layer was concentrated and subjected to an HPLC
analysis to determine the ratio of 8c, 1, 9c, and by-products.
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5-Cyano-2-formylbenzoic acid
entry 4). The above described flow-flash reaction system was set up composed of precooling loops
(stainless tube, id = 1.0 mm, L = 50 cm), T-shaped mixers (M1 and M2, stainless tee pieces,  i.d.
(6-cyano-3-hydroxy-2-benzofuran-1(3H)-one, 1) (Table 4.
=
0.25 mm, Sannkouseikikougyou), microtube reactors (stainless tube, L1 (id = 0.5 mm, 10 cm) and
L2 (id = 1.0 mm, 300 cm), gear pumps equipped with mass flow meters (mini-CORI-Flow,
Bronkhost), and a cooling bath (PSL-2000, EYELA). Continuous streams of solutions of 8c and
BuLi (0.4 M in THF and 1.6 M in hexane, respectively) were provided into the T-shaped mixer
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(M1), at flow rates of 30 and 9.0 mL/min, respectively, by gear pumps equipped with mass flow
meters, at - 60 oC. The resulting solution of 2-bromophenyllithium intermediate was delivered into
the next T-shaped mixer (M2) for formylation with a continuous stream of a solution of DMF (4.0 M
in THF), provided at a flow rate of 20 mL/min by the gear pumps equipped with mass flow meters,
at - 60 oC. The reaction solution obtained from L2 was poured into aqueous 2 N HCl solution at 0
oC and extracted with EtOAc (3060 mL). The separated organic layer was extracted with aqueous 1
N NaOH solution (1632 mL), aqueous 1 N NaOH solution (408 mL) and water (400 mL x 2). The
combined aqueous layers were made acidic with aqueous 6 N HCl solution (408 mL) and extracted
back with EtOAc (2040 mL). The organic layer was washed with brine and dried over anhydrous
MgSO4. The solvent was removed in vacuo to give crude 5-cyano-2-formylbenzoic acid
(6-cyano-3-hydroxy-2-benzofuran-1(3H)-one, 1, 82 g, 57.4 %) as a dark red solid. The crude solid
was treated with a mixture of IPE (240 mL) and EtOAc (40 mL) and collected by filtration. The
obtained solid was washed with IPE and dried to give 5-cyano-2-formylbenzoic acid
(6-cyano-3-hydroxy-2-benzofuran-1(3H)-one, 1, 55.0 g, 314 mmol, 38.5 %)3a,b as an orange solid.
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■ ASSOCIATED CONTENT
* S Supporting Information
Copies of 1H and 13C NMR spectra for compounds 1, 8b, 8c, and 8d.
■ AUTHOR INFORMATION
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Corresponding Authors
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* E-mail: masaki.seto@takeda.com. Phone: +81-466-32-1194 (M.S.).
E-mail: tetsuji.kawamoto@takeda.com. Phone: +81-466-32-1193 (T.K.).
ORCID
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Tetsuji Kawamoto: 0000-0002-4319-6934
Present Address
† Chemistry Research Division, Axcelead Drug Discovery Partners, Inc. 26-1, Muraoka-Higashi
2-chome, Fujisawa, Kanagawa 251-0012, Japan (S.M., K.F., and T.K.)
∥Kyoto University Original Co., Ltd., Kyoto University, Yoshida-Hommachi, Sakyo-ku, Kyoto
606-8501, Japan (H.U.)
2-4-56 Ueno Higashi, Toyonaka, Osaka, 560-0013, Japan (D.G.C.)
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We are grateful to Mr. Shotaro Miura for his helpful discussion regarding preparation of the
manuscript.
■ ABBREVIATIONS
BuLi, n-butyl lithium; DMF, N,N-dimethylformamide; IPE, Diisopropyl ether.
■ REFERENCES
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