Efficient and Practical Deacylation Reaction System in a Continuous Packed-Bed Reactor

Article abstract of DOI:10.1021/acs.oprd.8b00393

The ester deacylation reaction is widely applied in organic synthesis for preparing desired hydroxy compounds, as the acyl group is often used for protecting the hydroxyl group. This reaction is usually performed by acid, base, or enzyme catalysts, which have to be removed by complicated workups such as extraction or filtration in batch mode. Therefore, a simple deacylation process is desirable to improve productivity, especially at the industrial scale. In this work, we established an efficient and practical packed-bed reactor system for undertaking the deacylation reaction using an anion-exchange resin that provides a simple process compared with batch processing. We also demonstrated that this technique is applicable to the preparation of a wide variety of desired pharmaceutical intermediates containing hydroxy groups in good to excellent yields.

Full text of DOI:10.1021/acs.oprd.8b00393

Communication
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
pubs.acs.org/OPRD
Efficient and Practical Deacylation Reaction System in a Continuous
Packed-Bed Reactor
Hiroaki Yasukouchi,* Koji Machida, Akira Nishiyama, and Masaru Mitsuda
,
†
†
†
‡
†
‡
Pharma Research Group, Pharma & Supplemental Nutrition Solutions Vehicle, and Biotechnology Research Laboratories, Kaneka
Corporation, 1-8 Miyamae-cho, Takasago-cho, Takasago, Hyogo 676-8688, Japan
*
S Supporting Information
this system enables acceleration of the reaction because of
higher exposure of the catalyst while achieving excellent heat
and mass transfer. This provides easy scale-up compared with a
conventional batch system. Several research groups that have
harnessed packed-bed flow reactor systems have reported their
studies and outlined the many advantages stemming from the
ABSTRACT: The ester deacylation reaction is widely
applied in organic synthesis for preparing desired hydroxy
compounds, as the acyl group is often used for protecting
the hydroxyl group. This reaction is usually performed by
acid, base, or enzyme catalysts, which have to be removed
by complicated workups such as extraction or filtration in
batch mode. Therefore, a simple deacylation process is
desirable to improve productivity, especially at the
industrial scale. In this work, we established an efficient
and practical packed-bed reactor system for undertaking
the deacylation reaction using an anion-exchange resin
that provides a simple process compared with batch
processing. We also demonstrated that this technique is
applicable to the preparation of a wide variety of desired
pharmaceutical intermediates containing hydroxy groups
in good to excellent yields.
11−18
use of these systems.
For example, Sibasaki-Kitagawa and
19−21
22
co-workers
and Hirano and co-workers successfully
performed transesterification using packed-bed and fixed-bed
reactor systems with ion-exchange resins for the production of
biodiesel whose composition included a desired fatty acid
ester. In these cases, hydroxy compounds were absorbed on
the ion-exchange resin, and solvent flushing was required after
the main reaction to obtain them with high purity. We believe
that packed-bed flow reactor systems employing an ion-
exchange resin as a catalyst will provide an efficient and
practical deacylation process.
KEYWORDS: packed-bed reactor, deacylation,
anion-exchange resin, pharmaceutical intermediate,
hydroxy compounds
In this study, we established a continuous flow system for
the deacylation reaction using an inexpensive and commer-
cially available anion-exchange resin, as depicted in Figure 1.
The anion-exchange resin in the column is activated by the
displacement of chloride into methoxide form prior to the
main reaction. The substrate 1 in methanol is pumped into the
column at a controlled reaction temperature, producing a
continuous stream of the desired alcohol 2 without the
necessity for extraction and catalyst filtration. Additionally,
when the methyl ester byproduct 3 has a low boiling point (i.e.,
R = Me, Bu), both 3 and methanol can be easily removed by
evaporation. Thus, it is expected that the productivity of the
deacylation process can be dramatically improved by using the
flow process compared with the conventional batch mode.
INTRODUCTION
■
Hydroxy compounds are found in many chemical products,
such as pharmaceuticals, agrochemicals, and other fine
chemicals. In general, the hydroxyl group, which has high
reactivity, is protected to avoid undesired reactions during
multistep synthesis. Since acyl groups are often utilized as the
2
t
1
−3
protecting group for hydroxyl groups,
the development of a
deacylation process that enables a simple reaction and workup
is highly desirable. It has been reported that deacylation
reactions of esters can be achieved by hydrolysis or alcoholysis
with acid, base, or enzyme catalysts in liquid−liquid and
RESULTS AND DISCUSSION
■
4
−9
liquid−solid systems.
However, deacylation in batch mode
Feasibility Study. As a preliminary study, we chose some
commercially available substrates (4−6) with simple structures
and performed the deacylation reaction in the packed-bed
system, as depicted in Table 1. An anion-exchange resin
(DIAION PA 308, produced by Mitsubishi Chemical Co.,
Ltd.) was filled into the column as the catalyst. The reaction
temperature was controlled by an HPLC column oven. Prior to
the main reaction, sodium methoxide in methanol or aqueous
sodium hydroxide was fed into the column using a transfer
requires complicated processes including extraction and
4
−9
filtration to remove the catalyst prior to the next step.
Furthermore, it is predicted that product loss might be
observed at the liquid−liquid separation step in the case of
10
highly water-soluble hydroxy compounds. Process improve-
ment and development of the deacylation reaction in batch
mode, especially large-scale production, is desirable in terms of
productivity.
We realized a simple system for the deacylation process by
using a continuous packed-bed flow reactor. Desired hydroxy
compounds can be readily obtained by feeding acyl
compounds into a column loaded with the catalyst, thus
avoiding the need for extraction and filtration. Furthermore,
Special Issue: Japanese Society for Process Chemistry
Received: November 30, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.8b00393
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Figure 1. Illustration of the packed-bed flow reactor system used for the deacylation process.
a
Table 1. Deacylation Reaction with an Anion-Exchange Resin in a Packed-Bed Reactor
a
b
4
.7 mL of resin was filled into an Omnifit column, and 3 g of substrate was used. In method A, NaOMe was used. In method B, NaOH was used.
d
c
Determined by HPLC analysis. The residence time was determined as the resin volume in the column (in mL) divided by the flow rate (in mL/
e
f
h). Reaction conversion was examined after stabilization in flow. The stabilization time was more than 30 min. The result of batch conditions
using 4.7 mL of resin and 3 g of 4. Reaction time in batch. The result for a reaction time of 15 min is indicated in parentheses.
g
h
pump, causing the chloride to exchange to methoxide. This
was performed to activate the catalyst before its use in the
main reaction. The methanol solution of the substrate was
supplied to the column packed with the catalyst at a space
velocity (SV) of 4 h . The solution emerging from the
reaction site was then collected in the flask.
First, benzyl acetate (4) was used as the starting material,
and the cleavage of acetyl groups was conducted in the flow
process at 25 °C. As the result, an excellent yield (98%) of the
desired product, benzyl alcohol, was obtained (run 1). To
examine the effect of the pretreatment procedure, the activated
methoxide type resin was prepared with sodium hydroxide
flow reaction process. In method B, hydroxide of the resin was
transformed into methoxide by methanol after sodium
hydroxide treatment. It was found that a comparable reaction
yield (97%) was obtained in spite of the difference in the
pretreatment method (run 2). Additionally, the comparative
batch reaction was performed using the same concentration
and ratio of 4 and active resin. The desired product was
obtained in comparable reaction conversion and yield to flow
mode (run 3). However, a prolonged reaction time was
necessary to achieve excellent reaction conversion because of
the insufficient exposure of the catalyst in the batch reaction.
Furthermore, poor filterability of the resin was observed in the
purification process. It was confirmed that the deacylation
efficiency was highly improved by the use of the packed-bed
−
1
(
method B in the Experimental Section) instead of sodium
methoxide (method A in the Experimental Section) before the
B
DOI: 10.1021/acs.oprd.8b00393
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Scheme 1. Synthesis of Pharmaceutical Intermediates by Deacylation Reactions
reactor system and that this system gives good operability over
the conventional batch conditions.
Table 2. Screening of Anion-Exchange Resins for the
a
Deacylation Reaction
Next, the flow reaction was carried out under the same
conditions as in run 1 using benzyl isobutyrate (5), which has a
more bulky structure. As a result, a decrease in the reaction
yield was observed (75%; run 4). An improvement in the
reaction yield was observed when the reaction temperature was
increased from 25 to 50 °C (90%; run 5). Additionally, good
results were also obtained in the case of benzyl butyrate (6) at
higher reaction temperature (93%; run 6). Moreover, it was
confirmed that byproducts such as methyl acetate, isopropyl
acetate, and propyl acetate were completely removed by
evaporation in all of the experiments. These studies revealed
that a packed-bed reactor system employing an anion-exchange
resin is applicable to several deacylation reactions to produce
the desired hydroxy compounds while eliminating byproducts
without the need for a complicated purification step.
anion-exchange resin
ion-
cross-
exchange
capacity
linking
density yield
(%)
b
run
1
name
type
(equiv/L)
(%)
DOWEX 1X2
(100−200 mesh)
gel
0.6
2
92
Preparation of Pharmaceutical Intermediates by
Deacylation Reaction in a Flow Reactor. It has been
reported that the chiral compounds 7b and 8b described in
Scheme 1 are key intermediates of efinaconazole and
2
3
4
5
DIAION PA306s
DIAION PA308
DIAION HPA25L
AMBERLITE
IRA900J
porous
porous
highly porous
MR
≥0.8
≥1.0
≥0.5
≥1.0
3
4
25
87
74
49
58
2
3−26
atorvastatin.
As the next step, we addressed the
no data
preparation of these hydroxy compounds from the correspond-
ing precursors 7a and 8a containing pivaloyl and acetyl groups,
respectively, in a packed-bed reactor system to expand the
range of applications.
a
4
.2 mL of resin was filled in an Omnifit column, and 2 g of 7a was
used. Determined by HPLC analysis.
b
First, the optimal anion-exchange resin for this reaction was
investigated by using 7a as the starting material in continuous
flow mode (Table 2). Several basic resins with different
physical properties (Table 2) were chosen for this study. The
resin was displaced from chloride to methoxide ion. The
methanol solution of 7a was subsequently supplied to the
packed-bed reactor with SV = 1 h at 40 °C. The results
revealed that resins with lower cross-linking density tended to
give better reaction yields, with the DOWEX 1X2 (100−200
mesh) affording the best result (92% yield; run 1). Presumably,
the low cross-linking density of the resin might provide wide
reaction sites with substrates and methoxide ion, resulting in
higher reactivity. However, it was found that the unit cost of
this resin is very high compared with other tested resins, thus
making it not ideal for scaled processing. Therefore, we chose
DIAION PA 306s as the optimal anion-exchange resin for this
study in terms of the economics and availability for bulk scale,
despite the fact that the reaction yield was slightly lower
compared with that using DOWEX 1X2.
To achieve an excellent reaction yield, we examined the
optimal reaction conditions required for the preparation of 7b
using DIAION PA 306s in continuous flow mode, and the
results are shown in Table 3. Initially, the methanol solution of
−
1
−
1
7a was fed into the column with SV = 5 h at 25 °C. The
results indicated that the deacylation reaction hardly
proceeded (8% yield; run 1). To improve the reaction yield,
the SV and temperature were examined. The results showed
that decreasing the SV, which enables prolonged residence
time, and increasing the reaction temperature led to an
excellent yield (98% yield; run 4). Similarly, the synthesis of 8b
in continuous flow mode was investigated to show the broad
applicability of our system. An excellent yield was obtained
C
DOI: 10.1021/acs.oprd.8b00393
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
a
Table 3. Preparation of Pharmaceutical Intermediates Using a Packed-Bed Reactor System with DIAION PA 306s Resin
a
b
c
Resin was filled into an Omnifit column; 2 g of 7a and 3 g of 8a were used. The result of run 2 in Table 2. Resin was filled into a large column,
d
and 42 g of 7a was used. Determined by HPLC analysis.
when the same conditions as in Run 1 were used (98% yield;
run 7). It was noteworthy that the acetyl group was selectively
deacylated in this system, while cleavage of the tert-butyl ester
was avoided. In addition, in run 5 a large-scale experiment was
performed using a wide inner diameter (22 mm, ca. 2.4 times
that of run 4) and high throughput (198 mL/h throughput of
7
b: 72 mmol/hr, ca. 51 times that of run 4) to showcase the
scalability of this process. A large-sized glass column with a
jacket was prepared, and 198 mL of resin (ca. 51 times that of
run 4) was filled into the column. After catalyst activation, 7a
dissolved in methanol was transferred into the large column
using a diaphragm pump with SV = 1 h− at 50 °C. A total of
1
3
2 g of the desired product 7b was successfully obtained in a
yield comparable to that in the small-scale experiment without
a high-pressure drop. Thus, we demonstrated that our packed-
bed reactor system with an anion-exchange resin for
deacylation reactions is applicable to the synthesis of high-
value pharmaceutical intermediates as well as being compatible
with large-scale processes.
Figure 2. Durability study of the base catalyst in continuous flow
mode.
conversion due to deactivation of the resin was observed.
Presumably, the deactivation of the catalyst occurred over an
extended reaction period because the methoxide ion, which is
an active species, was replaced by an inactive pivalate ion
stemming from the pivaloyl group in 7a.
We tried to regenerate the deactivated catalyst using the
following procedures. A sodium hydroxide solution was
supplied to the column packed with deactivated resin to
exchange the pivalate ions into hydroxide ions on the resin,
Finally, we studied the durability of the basic resin used as
the catalyst during continuous flow operation for several days.
The reaction conversion was examined following the supply of
a methanol solution of 7a to a DIAION PA 306s column with
−
1
SV = 1 h at 50 °C for 7 days. As shown in Figure 2 (blue
line), it was found that high catalytic performance was
maintained for 94 h, after which a decrease in the reaction
D
DOI: 10.1021/acs.oprd.8b00393
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
followed by water flushing to remove the residual sodium
hydroxide in the reaction site. Finally, methanol was used to
flush and replace the hydroxide with methoxide and to remove
the water. The methanol solution of 7a was fed into the
column, and the reaction conversion was examined again. It
was found that the reaction conversion increased to 99.9%.
The methanol solution of 7a was pumped into a column filled
with regenerated resin with SV = 1 h− at 50 °C for 10 days,
after which the reaction conversion was examined again. As
shown in Figure 2 (red line), it was confirmed that the catalyst
was efficiently recycled and that catalytic performance
increased compared with that of the first trial. According to
these results, we concluded that catalyst activation from
chloride to methoxide ions under the current pretreatment
procedure was insufficient. Thus, the optimal methodology for
activation to achieve high catalytic performance will be
investigated in the near future.
containing an anion-exchange resin (Cl type) was filled with
methanol, and the inner temperature was maintained at 25 °C
by the column oven. Sodium methoxide dissolved in methanol
(1 M, 2.5 volumes/resin volume) was fed into the column
using a transfer pump with SV = 4 h . Finally, methanol (3.0
volumes/resin volume) was fed into the column at the same
flow rate to remove the sodium methoxide.
−
1
1
Method B. A glass column (Omnifit column, 10 mm i.d.)
containing an anion-exchange resin (Cl type) was filled with
water, and the inner temperature was maintained at 25 °C by
the column oven. Sodium hydroxide (1 M, 2.5 volumes/resin
volume) was fed into the column using a transfer pump with
−
1
SV = 4 h . Next, water (4.5 volumes/resin volume) was fed
into the column at the same flow rate to remove the sodium
hydroxide. Finally, methanol (4.5 volumes/resin volume) was
−
1
fed into the column with SV = 10 h .
General Procedure for the Deacylaion Reaction in
the Packed-Bed Reactor (Preparation of 7b). The
substrate solution in methanol (ca. 0.4 M) was prepared in a
bottle. The solution was then transferred into the column filled
with the methoxide-type resin using a diaphragm pump
Through these studies, we demonstrated that the DIAION
PA 306s has high durability for the deacylation reaction of 7a
and that regeneration of the catalysts is readily achievable.
(
SIMDOS 10, KNF Japan Co., Ltd.) at a temperature of 50
CONCLUSIONS
■
−1
°
C (SV = 1 h ). Once the bottle was empty, the residual
We have established an efficient and practical packed-bed
reactor system with an anion-exchange resin as a catalyst for
deacylation reactions. This simple system produces the desired
hydroxy compounds, including pharmaceutical intermediates,
without time-consuming purification steps such as extraction
and filtration. Moreover, we have demonstrated that this
system can be easily scaled-up and provides excellent yields
across a number of reactions. It was confirmed that the catalyst
is highly durable and readily regenerable. To establish a
manufacturing process, more efforts are currently being
investigated in our laboratory to optimize the method for
large-scale production.
reaction mixture in the column was flushed with methanol at
the same flow rate, and the collected solution was concentrated
in vacuo. Finally, the reaction yield was calculated from the
concentration of the desired product in the concentrate using
HPLC analysis.
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.8b00393.
General Information and experimental procedures
(PDF)
EXPERIMENTAL SECTION
■
AUTHOR INFORMATION
Corresponding Author
Phone: +81 79 445 2409. Fax: +81 79 445 2692. E-mail:
Hiroaki.Yasukouchi@kaneka.co.jp.
ORCID
Hiroaki Yasukouchi: 0000-0003-3722-2566
Notes
HPLC Methods. HPLC analysis was performed on a
Shimazu LC20 chromatograph. The method was altered
according to the substrate used.
Analysis of Benzyl Alcohol. A Shiseido Capcell Pak C18
type MG (250 mm × 4.6 mm) analytical column was used at
■
*
3
(
0 °C. The UV detector was set at 220 nm. Mobile phases A
0.1% phosphoric acid) and B (acetonitrile) were utilized at a
flow rate of 1.0 mL/min. Mobile phase B was increased linearly
from 25% to 95% over 25 min and maintained at 95% for 3
min, providing a retention time of 8.5 min for benzyl alcohol.
Analysis of 7b. A Shiseido Capcell Pak C18 type MG (250
mm × 4.6 mm) analytical column was used at 30 °C. The UV
detector was set at 210 nm. Mobile phases A (0.1% phosphoric
acid) and B (acetonitrile) were utilized at a flow rate of 1.0
mL/min. Mobile phase B was maintained at 30% for 15 min,
increased linearly from 30% to 60% over 10 min, maintained at
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors express their gratitude to Dr. Yoshihiko Yasohara
at Biotechnology Research Laboratories, Kaneka Corporation,
for all of his valuable discussions and advice throughout this
study.
REFERENCES
6
0% for 20 min, increased linearly from 60% to 90% over 5
■
(
1) Ishihara, K.; Kurihara, H.; Yamamoto, H. An Extremely Simple,
Convenient, and Selective Method for Acetylating Primary Alcohols
min, and maintained at 90% for 10 min, providing a retention
time of 5 min for 7b.
in the Presence of Secondary Alcohols. J. Org. Chem. 1993, 58, 3791−
Analysis of 8b. YMC-Pack ODS-A A-303 (250 mm × 4.6
mm) analytical column was used at 30 °C. The UV detector
was set at 210 nm. An acetonitrile/water mixture (40:60 v/v)
was utilized as the mobile phase at a flow rate of 1.0 mL/min,
providing a retention time of 22 min for 8b.
3
793.
(
2) Spivey, A. C.; Arseniyadis, S. Nucleophilic Catalysis by 4-
Dialkylamino)pyridines RevisitedThe Search for Optimal Reac-
tivity and Selectivity. Angew. Chem., Int. Ed. 2004, 43, 5436−5441.
3) Robins, M. J.; Hawrelak, S. D.; Kanai, T.; Siefert, J. M.; Mengel,
(
(
General Preparation of Methoxide-Type Resins.
Method A. The glass column (Omnifit column, 10 mm i.d.)
R. Transformations of Adenosine to the First 2′,3′-Aziridine-Fused
Nucleosides, 9-(2,3-Epimino-2,3-dideoxy-β-D-ribofuranosyl)adenine
E
DOI: 10.1021/acs.oprd.8b00393
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
and 9-(2,3-Epimino-2,3-dideoxy-β-D-lyxofuranosyl)adenine. J. Org.
Chem. 1979, 44, 1317−1322.
(21) Yamazaki, K.; Shibasaki-Kitakawa, N.; Nakashima, K.;
Yonemoto, T. Effectiveness of Adjustable-Volume Packed-Bed
Reactor with an Ion-Exchange Resin Catalyst for Continuous
Production. J. Chem. Eng. Jpn. 2016, 49, 668−672.
(
4) Matos, M. C.; Murphy, P. V. Synthesis of Macrolide-Saccharide
Hybrids by Ring-Closing Metathesis of Precursors Derived from
Glycitols and Benzoic Acids. J. Org. Chem. 2007, 72, 1803−1806.
(22) Ito, T.; Kakuta, Y.; Hirano, K.; Kojima, T. Study on Continuous
Production of Biodiesel Using Fixed Bed Reactors Filled with Anion-
Exchange Resins. Energy Environ. Res. 2014, 4, 47−54.
(
5) Yokoyama, H.; Otaya, K.; Kobayashi, H.; Miyazawa, M.;
Yamaguchi, S.; Hirai, Y. Palladium(II)-Catalyzed Cyclization of
Urethanes and Total Synthesis of 1-Deoxymannojirimycin. Org.
Lett. 2000, 2, 2427−2429.
(23) Tamura, K.; Kumagai, N.; Shibasaki, M. An Enantioselective
Synthesis of the Key Intermediate for Triazole Antifungal Agents;
Application to the Catalytic Asymmetric Synthesis of Efinaconazole
(
6) Xu, D.; Edgar, K. J. TBAF and Cellulose Esters: Unexpected
(
Jublia). J. Org. Chem. 2014, 79, 3272−3278.
24) Cheng, W.; Li, Y.; Xue, J.; Zhang, T.; Zhang, X. Preparation
method of atorvastatin calcium. CN101805279, August 18, 2010.
25) Beck, G.; Jendralla, H.; Kesseler, K. Practical Large Scale
Deacylation with Unexpected Regioselectivity. Biomacromolecules
012, 13, 299−303.
7) Suhara, Y.; Nihei, K.; Kurihara, M.; Kittaka, A.; Yamaguchi, K.;
(
2
(
(
Fujishima, T.; Konno, K.; Miyata, N.; Takayama, H. Efficient and
Versatile Synthesis of Novel 2α-Substituted 1α,25-Dihydroxyvitamin
D3 Analogues and Their Docking to Vitamin D Receptors. J. Org.
Chem. 2001, 66, 8760−8771.
Synthesis of tert-Butyl (3R,5S)-6-Hydroxy-3,5-O-isopropylidene-3,5-
dihydroxyhexanoate: Essential Building Block for HMG-CoA
Reductase Inhibitors. Synthesis 1995, 1995, 1014−1018.
(26) Fan, W.; Li, W.; Ma, X.; Tao, X.; Li, X.; Yao, Y.; Xie, X.; Zhang,
(
8) Yang, X.; Reinhold, A. R.; Rosati, R. L.; Liu, K. K. Enzyme-
Z. Ru-Catalyzed Asymmetric Hydrogenation of γ-Heteroatom
Substituted β-Keto Esters. J. Org. Chem. 2011, 76, 9444−9451.
Catalyzed Asymmetric Deacylation for the Preparation of Lasofox-
ifene (CP-336156), a Selective Estrogen Receptor Modulator. Org.
Lett. 2000, 2, 4025−4027.
(
9) Singh, S. K.; Sharma, V. K.; Bohra, K.; Olsen, C. E.; Prasad, A. K.
Biocatalytic Deacylation Studies on Tetra-O-acyl-β-D-xylofuranosyl
Nucleosides: Synthesis of xylo-LNA Monomers. J. Org. Chem. 2011,
7
(
6, 7556−7562.
10) Machida, K.; Yasukouchi, H.; Nishiyama, A. Method for
producing alcohol compound. WO2018124172 A1, Dec 28, 2016.
(
11) Tsubogo, T.; Ishiwata, T.; Kobayashi, S. Asymmetric Carbon−
Carbon Bond Formation under Continuous-Flow Conditions with
Chiral Heterogeneous Catalysts. Angew. Chem., Int. Ed. 2013, 52,
6
(
590−6604.
12) Zaborenko, N.; Linder, R. J.; Braden, T. M.; Campbell, B. M.;
Hansen, M. M.; Johnson, M. D. Development of Pilot-Scale
Continuous Production of an LY2886721 Starting Material by
Packed-Bed Hydrogenolysis. Org. Process Res. Dev. 2015, 19, 1231−
1
(
243.
13) Constantinou, A.; Wu, G.; Corredera, A.; Ellis, P.; Bethell, D.;
Hutchings, G. J.; Kuhn, S.; Gavriilidis, A. Continuous Heteroge-
neously Catalyzed Oxidation of Benzyl Alcohol in a Ceramic
Membrane Packed-Bed Reactor. Org. Process Res. Dev. 2015, 19,
1
(
973−1979.
14) Seayad, A. M.; Ramalingam, B.; Chai, C. L. L.; Li, C.; Garland,
M. V.; Yoshinaga, K. Self-Supported Chiral Titanium Cluster (SCTC)
as a Robust Catalyst for the Asymmetric Cyanation of Imines under
Batch and Continuous Flow at Room Temperature. Chem. - Eur. J.
2
(
012, 18, 5693−5700.
15) Andrade, L. H.; Kroutil, W.; Jamison, T. F. Continuous Flow
Synthesis of Chiral Amines in Organic Solvents: Immobilization of E.
coli Cells Containing Both ω-Transaminase and PLP. Org. Lett. 2014,
1
(
6, 6092−6095.
16) Andrade, L. H.; Sousa, B. A.; Jamison, T. F. Confining a
Biocatalyst for Highly Efficient and Selective Synthesis of Carbox-
amide Derivatives under Continuous-Flow Conditions. J. Flow Chem.
2
(
016, 6, 67−72.
17) Dencic, I.; de Vaan, S.; Noel, T.; Meuldijk, J.; de Croon, M.;
̌
́
̈
Hessel, V. Lipase-Based Biocatalytic Flow Process in a Packed-Bed
Microreactor. Ind. Eng. Chem. Res. 2013, 52, 10951−10960.
(
18) Meunier, S. M.; Rajabzadeh, A. R.; Williams, T. G.; Legge, R. L.
Methyl Oleate Production in a Supported Sol-Gel Immobilized Lipase
Packed Bed Reactor. Energy Fuels 2015, 29, 3168−3175.
(
19) Shibasaki-Kitakawa, N.; Honda, H.; Kuribayashi, H.; Toda, T.;
Fukumura, T.; Yonemoto, T. Biodiesel production using anionic ion-
exchange resin as heterogeneous catalyst. Bioresour. Technol. 2007, 98,
4
(
16−421.
20) Shibasaki-Kitakawa, N.; Kanagawa, K.; Nakashima, K.;
Yonemoto, T. Simultaneous production of high quality biodiesel
and glycerin from Jatropha oil using ion-exchange resins as catalysts
and adsorbent. Bioresour. Technol. 2013, 142, 732−736.
F
DOI: 10.1021/acs.oprd.8b00393
Org. Process Res. Dev. XXXX, XXX, XXX−XXX