Safe and Efficient Phosgenation Reactions in a Continuous Flow

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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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Organic Process Research & Development

Safe and Efficient Phosgenation Reactions in a Continuous Flow Reactor Hiroaki Yasukouchi*, Akira Nishiyama, and Masaru Mitsuda

Pharma Research Group, Pharma & Supplemental Nutrition Solutions Vehicle, KANEKA CORPORATION 1-8, Miyamae-cho, Takasago-cho, Takasago, Hyogo 676-8688, Japan

ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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.

KEYWORDS. flow reactor, phosgene reaction, tributylamine, pharmaceutical intermediate


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INTRODUCTION 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, N-carboxyanhydride, and carbamoyl chloride can be easily synthesized using phosgene.2-6 However, large-scale 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. Continuous flow reactors, especially micro- 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 less-toxic triphosgene as a phosgene surrogate is a valuable approach to mitigate safety risks



associated with hazardous materials. 18 For example, Fuse et al. successfully conducted safe triphosgene-mediated peptide synthesis in a microflow reactor.19-22 Consequently, we believe that flow methodology employing triphosgene will provide a drastic improvement in process safety for the aforementioned phosgene reactions. 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 T-junction mixer and residence line while controlling the reaction temperature using a refrigerant, and the desired product is continuously obtained. This system allows on-demand 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.

Figure 2. Phosgene reactions employing triphosgene and amine.

Table 1. Solubility tests of amine HCl salts in several solvents.a Solvent THF

AcOiPr

Acetone

CH3CN

Toluene

Counter

Triethylamine S

S

S

S

S

amine

Tributylamine C

C

C

C

C

i

a

Pr2NEt

S

S

C

C

O

DBU

S

S

C

C

O

2,6-Lutidine

S

S

S

S

S

“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 T-junction 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 T-junction 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. Initially, 9-fluorenylmethanol (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



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. 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. N-carboxy 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). 26-28 In this study, flow reactions employing 3a–5a as the starting



materials were performed using the same triphosgene/tributylamine system as that depicted in Table 3.

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.



First, the N-carboxy 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). 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 t-1 and t-2 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). Finally, a scale-up 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.



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 scale-up processes. A wide variety of phosgene reactions, such as chloroformate, N-carboxyanhydride, 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.

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 5C18-AR-II (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.

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



as the mobile phase at a flow rate of 0.7 mL/min, providing a retention time for 5b of 10 min.

General procedure of solubility test of amine HCl salts in several solvents. HCl in n-propanol (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 (YSP-101, YMC. Co., Ltd.), a T-junction mixer (JTF-320, EYLA, i.d.: 2.0 mm) and a PTFE residence line (i.d.: 2.0 mm). The T-junction 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 T-junction 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.

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 (YSP-101, YMC. Co., Ltd.), two T-junction mixers (JTF-320, EYLA, i.d.: 2.0 mm) and two PTFE residence lines (i.d.:2.0 mm). The T-junction 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 T-junction 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 T-junction 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 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.

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 T-junction mixers (Swagelok, i.d.: 2.4 mm) and two PTFE residence lines (i.d.:3.0 mm). The T-junction 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 T-junction 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 T-junction 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.

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



Tel: +81 79 445 2409; fax: +81 79 445 2692

Email address: [email protected]

Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit 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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Safe and Efficient Phosgenation Reactions in a Continuous Flow

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