Safe and Efficient Phosgenation Reactions in a Continuous Flow Reactor

Article abstract of DOI:10.1021/acs.oprd.7b00353

Phosgene is widely used in organic synthesis owing to its high reactivity, utility, and cost efficiency. However, the use of phosgene in batch processes on the industrial scale is challenging owing to its toxicity. An effective method to minimize reaction volumes and mitigate the safety risks associated with hazardous chemicals is the use of flow reactors. Consequently, we have established a flow reaction system using triphosgene and tributylamine, which affords a homogeneous reaction that avoids clogging issues. In addition, we have demonstrated that this methodology can be applied to a wide variety of phosgene reactions, including the preparation of pharmaceutical intermediates, in good to excellent yields.

Full text of DOI:10.1021/acs.oprd.7b00353

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Communication
Safe and Efficient Phosgenation Reactions in a Continuous Flow Reactor
Hiroaki Yasukouchi, Akira Nishiyama, and Masaru Mitsuda
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00353 • Publication Date (Web): 22 Jan 2018
Downloaded from http://pubs.acs.org on January 22, 2018
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Safe and Efficient Phosgenation Reactions in a
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Continuous Flow Reactor
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Hiroaki Yasukouchi*, Akira Nishiyama, and Masaru Mitsuda
Pharma Research Group, Pharma & Supplemental Nutrition Solutions Vehicle,
KANEKA CORPORATION 1ꢀ8, Miyamaeꢀcho, Takasagoꢀcho, Takasago, Hyogo
676ꢀ8688, Japan
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ABSTRACT. Phosgene is widely used in organic synthesis owing to its high reactivity,
utility, and cost efficiency. However, the use of phosgene in batch processes on the
industrial scale is challenging owing to its toxicity. An effective method to minimize
reaction volumes and mitigate the safety risks associated with hazardous chemicals is the
use of flow reactors. Consequently, we have established a flow reaction system using
triphosgene and tributylamine, which affords a homogeneous reaction that avoids
clogging issues. In addition, we have demonstrated that this methodology can be applied
to a wide variety of phosgene reactions, including the preparation of pharmaceutical
intermediates, in good to excellent yields.
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KEYWORDS. flow reactor, phosgene reaction, tributylamine, pharmaceutical
intermediate
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INTRODUCTION
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The inexpensive gaseous phosgene is utilized as a versatile reagent in organic synthesis
from the laboratory to the industrial scale owing to its high reactivity.1 It is well known
that a wide variety of building blocks such as isocyanate, urea, chloroformate,
Nꢀcarboxyanhydride, and carbamoyl chloride can be easily synthesized using
phosgene.2ꢀ6 However, largeꢀscale batch system reactions of phosgene, especially those
that are exothermic, present significant safety issues because of the high toxicity of
phosgene.7 Thus, minimizing phosgene reaction volumes to enhance manufacturing
safety is desirable.
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Continuous flow reactors, especially microꢀ and mesofluidic flow reactors, provide
small reaction volume and equipment size. This allows significant reductions in the
reaction volumes of hazardous chemicals in the reactor as well as facilitating equipment
segregation. Furthermore, heat control for exothermic reactions is readily accomplished
owing to the excellent heat removal efficiency. Thus, the safety of hazardous reactions
can be dramatically improved with respect to that of conventional batch procedures using
the flow reactor approach, and several research groups have reported the safety benefits
of flow techniques for hazardous reactions.8–17 Moreover, the utilization of lessꢀtoxic
triphosgene as a phosgene surrogate is a valuable approach to mitigate safety risks
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associated with hazardous materials. 18 For example, Fuse et al. successfully conducted
safe triphosgeneꢀmediated peptide synthesis in a microflow reactor.19ꢀ22 Consequently,
we believe that flow methodology employing triphosgene will provide a drastic
improvement in process safety for the aforementioned phosgene reactions.
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In this study, we established a flow reactor system for a wide variety of phosgenation
reactions using triphosgene and amines, as depicted in Figure 1. In this system,
triphosgene in solvent (feed A) and a mixture of an amine and the substrate in solvent
(feed B) are transferred by two pumps. The substrate and the phosgene generated from
triphosgene exothermically react in the Tꢀjunction mixer and residence line while
controlling the reaction temperature using a refrigerant, and the desired product is
continuously obtained. This system allows onꢀdemand generation and utilization of
poisonous phosgene within a compact and closed system. Additionally, any excess of
phosgene in the reaction mixture is immediately destroyed upon quenching. Thus, the
manufacturing safety of phosgenation reactions is dramatically enhanced using this
approach.
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Figure 1. Illustration of the flow system for phosgene reactions used in this study.
RESULTS AND DISCUSSION
Solubility study of amine HCl salts.
Phosgene reactions employing triphosgene and amines give the amine HCl salt as a
byproduct, which can result in the unwanted precipitation of a solid (Figure 2). Solid
generation often leads to problematic clogging issues for flow reactions. 23,24 Thus, to
circumvent this serious issue, a homogenous reaction mixture must be obtained.
Consequently, it is crucial to adopt a suitable combination of amine and solvent. For
example, Fuse et al. achieved homogeneous phosgene reactions in flow mode by
adopting polar solvents (i.e., CH2Cl2, DMF, and CH3CN).18,19 We examined a wide
selection of amine/solvent combinations, including versatile and green solvents, to enable
phosgene reactions in a continuous flow reactor. A solubility study of amine HCl salts
revealed that no precipitation was formed by tributylamine in any of the tested solvents
(Table 1). It is expected that tributylamine gives a homogeneous reaction in phogenation
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while overcoming serious clogging issues in continuous flow system. Therefore, we
concluded that tributylamine is a suitable amine for the phosgene reaction in flow mode.
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Figure 2. Phosgene reactions employing triphosgene and amine.
Table 1. Solubility tests of amine HCl salts in several solvents.a
Solvent
THF
Triethylamine S
Tributylamine C
AcOiPr
Acetone
CH3CN
Toluene
Counter
amine
S
C
S
S
S
S
S
S
C
C
C
S
C
C
C
S
C
O
O
S
iPr2NEt
S
S
S
DBU
2,6ꢀLutidine
a “C” indicates a clear solution, “O” indicates oiling out, and “S” indicates a slurry.
Chloroformate reaction in flow mode.
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We initially chose the chloroformate reaction as a model phosgene reaction for
continuous flow experiments. The chroloformate compounds 1b and 2b were prepared
using the triphosgene/tributylamine system, which is described in Table 2. In this system,
reaction part consisted of Tꢀjunction mixer and a residence line comprising a coiled
PTFE, both of which were immersed in a water bath. Triphosgene in toluene and the
tributylamine/substrate mixture in toluene were combined at the Tꢀjunction mixer before
passing into the coiling tube by two syringe pumps. The mixture emerging from the
residence line was continuously quenched in a flask containing a phosphoric acid solution
with stirring at 0 °C.
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Initially, 9ꢀfluorenylmethanol (1a) was utilized as the substrate. The desired product 1b
was obtained in 90% yield with a residence time of 1 min at 0 °C (Run 1). Moreover, no
clogging problems were encountered during the reaction with tributylamine. We assumed
that the main reaction of phosgene and alcohol with moderate nucleophilicity is a late
limiting step in this flow synthesis because the phosgene generation from triphosgene
must be extremely rapid. To improve main reaction conversion, the residence time was
optimized. When the residence time was extended to 4 min, 98% yield was achieved (Run
2). Additionally, the yield under flow conditions was ca. 40% higher than that in the
corresponding batch mode because product decomposition during the reaction was
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mitigated owing to the shorter reaction time (98%, Run 2 vs 60%, Run 3). It was found
that the flow condition gives the advantage in reaction yield compared to the batch
process.
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Next, (ꢀ)ꢀmenthol (2a) was selected as the substrate. Chloroformate compound 2b was
furnished in excellent yield under mild temperature conditions with a short residence time
without precipitation issues (99%, Run 4). These experiments revealed that the
chloroformate reaction was compatible with continuous flow conditions using the
triphosgene/tributylamine system.
Table 2. Chloroformate reactions in flow conditions using the triphosgene/tributylamine
system.a
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Preparation of pharmaceutical intermediates by the phosgene reaction in flow.
A variety of pharmaceutical intermediates were synthesized using our flow reaction
system to demonstrate its range of application. Nꢀcarboxy anhydride (3b), urea (4b), and
carbamoyl chloride (5b), which are precursors of imidapril,25 relebactam,26 and
solifenacin, 27 respectively, were selected as the target compounds. It has been reported
that the desired products 3b–5b can be prepared from 3a–5a by phosgene reactions under
batch mode (Scheme 1). 26ꢀ28 In this study, flow reactions employing 3a–5a as the starting
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materials were performed using the same triphosgene/tributylamine system as that
depicted in Table 3.
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Scheme 1. Synthesis of pharmaceutical intermediates employing the phosgene reaction.
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Table 3. Synthesis of pharmaceutical intermediates using the flow reaction system.
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First, the Nꢀcarboxy anhydride synthesis was performed in flow mode. Product 3b was
successfully obtained in moderate yield at 35 °C with a residence time of 4 min (69%,
Run 1). To improve the reaction yield, the reaction temperature and residence time were
examined. When the reaction temperature was 60 °C, an increase in yield was observed
(76%, Run 2). However, increasing the residence time did not improve the results (76%,
Run 3).
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Next, urea synthesis was performed in the same manner. Compound 4b was furnished
in good yield at 25 °C with a residence time of 2 min (80%, Run 4). To improve the
reaction yield, additional optimizations of the reaction temperature and residence time
were conducted. An increase in yield was achieved by decreasing the reaction
temperature (85%, Run 5). However, increasing the residence time caused a decrease in
the yield (72%, Run 6).
Finally, carbamoyl chloride 5b was prepared under flow reaction conditions. In the
case of Method A, a low yield was obtained due to the generation of an undesired
byproduct (45%, Run 7). We envisaged that the preparation of a sufficient amount of
phosgene prior to the main reaction would lead to a decrease in the amount of impurity.
Consequently, we evaluated the effectiveness the new setup depicted as Method B for the
synthesis of 5b. In this flow setup, phosgene in toluene was prepared by combining
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triphosgene and tributylamine at the first mixer and residence line. The solution emerging
from the first reaction tube was mixed with 5a in toluene at the second mixer. When the
residence times tꢀ1 and tꢀ2 were set as 4 and 2 min, respectively, the desired product 5b
was obtained in 90% yield without the formation of undesired byproducts (Run8). To
optimize the reaction condition, both residence times were examined. As the result of
investigations, it was demonstrated that residence time of 5–10 s was sufficient to afford
an excellent reaction yield (94%, Run9).
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Finally, a scaleꢀup study was performed with a high flow rate (total: 158 ml/min,
throughput of 5a: 53 mmol/min, ~40 times vs Run9) and the wide diameter tube (3.0mm,
6 times vs Run9) under Method B condition in Run 10. The process run for 4.5 min
successfully afforded to total 64 g of the target product 5b in organic solution without
compromising reaction yield after quenching and phase separation (98%, Run10)
Thus, it was found that our flow reaction system is applicable to the preparation of a
wide variety of pharmaceutical intermediates and is amenable to large scale experiment.
CONCLUSIONS
In summary, we have established
a
flow reactor system employing
triphosgene/tributylamine for phosgene reactions while increasing process efficiency.
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The selection of tributylamine contributes considerably to avoid precipitation/clogging
issues in this system. Furthermore, the system enables hazardous phosgene to be handled
easily and safely, allowing its application to scaleꢀup processes. A wide variety of
phosgene reactions, such as chloroformate, Nꢀcarboxyanhydride, urea as well as
carbamoyl chloride syntheses, are compatible with our flow reactor system. Furthermore,
it was demonstrated that various pharmaceutical intermediates can be successfully
synthesized in continuous flow in good yields. To further improve reaction yields, the
optimization of reaction conditions including residence time, temperature, and flow rate
is now in progress in our laboratory.
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EXPERIMENTAL SECTION
HPLC methods.
HPLC analysis was performed on a Shimazu LC20. The method was altered depending
on the substrate.
Analysis of 1b: A CHIRALPAC IA (250 × 4.6 mm) analytical column was used at 30
°C. The UV detector was set at 254 nm. Hexane/ethanol (85:15, v/v) was utilized as the
mobile phase at a flow rate of 1.0 mL/min, providing a retention time for 1b of 6 min.
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Analysis of 2b: A COSMOSIL 5C18ꢀARꢀII (250 × 4.6 mm) analytical column was used
at 30 °C. The UV detector was set at 210 nm. Mobile phase 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 10% to 60% over 10 min, from 60% to 80% over 12 min, maintained at 80%
for 5 min, and increased linearly from 80% to 90% over 3 min, providing a retention time
of 28 min for 2b.
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Analysis of 3b: A CHIRALPAC IA (250 × 4.6 mm) analytical column was used at 30
°C. The UV detector was set at 254 nm. Hexane/ethanol (85:15, v/v) was utilized as the
mobile phase at a flow rate of 0.8 mL/min, providing a retention time for 3b of 12 min.
Analysis of 4b: A Zorbax Eclipse Plus C18 (50 × 4.6 mm) analytical column was used
at 40 °C. The UV detector was set at 210 nm. Mobile phase A (0.1% phosphoric acid) and
B (acetonitrile) were utilized as the mobile phase at a flow rate of 1.0 mL/min. Mobile
phase B was increased linearly from 5 to 95% over 15 min, providing a retention time for
4b of 9 min.
Analysis of 5b: A CHIRALCEL OD (250 × 4.6 mm) analytical column was used at 35
°C. The UV detector was set at 220 nm. Hexane/isopropyl alcohol (98:2, v/v) was utilized
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as the mobile phase at a flow rate of 0.7 mL/min, providing a retention time for 5b of 10
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min.
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General procedure of solubility test of amine HCl salts in several solvents.
HCl in nꢀpropanol (ca. 33 wt%, 1.1 eq. vs. amine) was added to the amine diluted with
the appropriate solvent (approximately 10 ml) in a flask with stirring at room
temperature. This mixture (0.5–0.7 mol/L) was agitated for 1 h at the same temperature.
After stirring, the dissolution state of the mixture was evaluated.
General procedure for phosgene reactions in flow mode (preparation of 1b to 5b under
Method A)
The flow reactor system was composed of two syringe pumps (YSPꢀ101, YMC. Co.,
Ltd.), a Tꢀjunction mixer (JTFꢀ320, EYLA, i.d.: 2.0 mm) and a PTFE residence line (i.d.:
2.0 mm). The Tꢀjunction mixer and residence line were immersed in a water bath.
Disposable syringes were filled with triphosgene in solvent (solution A, approximately
70 mM) and the tributylamine/substrate in solvent (solution B, approximately 120 mM).
Solutions A (2 mL/min) and B (2 mL/min) were transferred to the residence line via the
Tꢀjunction mixer. The reaction mixture was continuously quenched in 13% phosphoric
acid solution with stirring at 0 °C. Once the syringes were empty, the residual reaction
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mixture in the PTFE tube was flushed with solvent at the same flow rate. Next, the
quenched solution was stirred for 30 min, and the organic phase which contained the
desired product was obtained after phase separation. The yield was calculated from the
concentration of the desired product in the organic phase by using HPLC analysis.
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General procedure for phosgene reactions in flow mode (Preparation 5b under Method
B, small scale)
The flow reactor system was composed of three syringe pumps (YSPꢀ101, YMC. Co.,
Ltd.), two Tꢀjunction mixers (JTFꢀ320, EYLA, i.d.: 2.0 mm) and two PTFE residence
lines (i.d.:2.0 mm). The Tꢀjunction mixers and residence lines were immersed in a water
bath. Three disposable syringes were filled with triphosgene in toluene (solution A,
approximately 0.34 M), tributylamine in toluene (solution B, approximately 1.1 M), and
5a in toluene (solution C, approximately 0.47 M). Solutions A (1 mL/min) and B (1
mL/min) were transferred to the first residence line via a Tꢀjunction mixer to prepare the
phosgene/toluene solution. Solution C (2 mL/min) and the phosgene/toluene solution (2
mL/min) were transferred to the second residence line via the second Tꢀjunction mixer.
The reaction mixture was continuously quenched in 2N HCl solution with stirring at 0 °C.
After solutions A, B, and C were exhausted, the residual reaction mixtures in the PTFE
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tubes were flushed by solvent at the same flow rate. Next, the quenched solution was
stirred for 30 min, and the organic phase which contained the desired product was
obtained after phase separation. The yield was calculated from the concentration of
desired product in the organic phase by using HPLC analysis.
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General procedure for phosgene reactions in flow mode (Preparation 5b under Method
B, large scale)
The flow reactor system was composed of three diaphragm pumps (SIMDS 10, KNF
Japan Co., Ltd.), two Tꢀjunction mixers (Swagelok, i.d.: 2.4 mm) and two PTFE
residence lines (i.d.:3.0 mm). The Tꢀjunction mixers and residence lines were immersed
in a water bath. Triphosgene in toluene (solution A, ~0.34 M), tributylamine in toluene
(solution B, ~1.1 M), and 5a in THF (solution C, ~0.47 M) were prepared. Solutions A
(39.5 mL/min) and B (39.5 mL/min) were transferred to the first residence line via a
Tꢀjunction mixer to prepare the phosgene/toluene solution. Solution C (79 mL/min) and
the phosgene/toluene solution (79 mL/min) were transferred to the second residence line
via the second Tꢀjunction mixer. The reaction mixture was continuously quenched in 2N
HCl solution with stirring at 0 °C. After solutions A, B, and C were exhausted, the
residual reaction mixtures in the PTFE tubes were flushed using toluene at the same flow
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rate. Next, the quenched solution was stirred for 30 min, and the organic phase that
contained the desired product was obtained after phase separation. The yield was
calculated from the concentration of desired product in the organic phase via HPLC
analysis.
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ASSOCIATED CONTENT
Supporting Information
a. General Information
b. Experimental Procedures
1. General procedure of solubility test of amine HCl salts in several
solvents
2. Preparation of chloroformate compounds
2.1 Typical procedure for 1b in flow mode
2.2 Typical procedure for 2b in flow mode
2.3 Typical procedure for 1b in batch mode
3. Preparation of pharmaceutical intermediates (Method A)
3.1 Typical procedure for 3b in flow mode
3.2 Typical procedure for 4b in flow mode
3.3 Typical procedure for 5b in flow mode
4. Preparation of pharmaceutical intermediate 5b (Method B)
4.1 Small scale experiment
4.2 Large scale experiment
Author Information
Corresponding Author
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Tel: +81 79 445 2409; fax: +81 79 445 2692
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Email address: Hiroaki.Yasukouchi@kaneka.co.jp
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Funding Sources
This research did not receive any specific grant from funding agencies in the public,
commercial, or notꢀforꢀprofit sectors.
ACKNOWLEDGMENT
The authors wish to express our gratitude to Toshihiro Takeda and Makoto Funabashi
in our Process Research Group for all of their valuable discussions and advice throughout
this study.
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Table of Contents graphic
90x30mm (300 x 300 DPI)
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