Design and Optimization of a Continuous Stirred Tank Reactor

Jun 21, 2019 - Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α- ...
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Cite This: Org. Process Res. Dev. 2019, 23, 1359−1368

Design and Optimization of a Continuous Stirred Tank Reactor Cascade for Membrane-Based Diazomethane Production: Synthesis of α‑Chloroketones Michaela Wernik,†,‡ Peter Poechlauer,§ Christoph Schmoelzer,§ Doris Dallinger,*,†,‡ and C. Oliver Kappe*,†,‡

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†

Center for Continuous Flow Synthesis and Processing (CCFLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria ‡ Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria § Patheon Austria GmbH & Co KG, Sankt-Peter-Straße 25, 4020 Linz, Austria S Supporting Information *

ABSTRACT: The development of a continuous diazomethane generator comprising a continuous stirred tank reactor (CSTR) cascade and membrane separation technology is reported. This reactor concept was applied for the telescoped three-step synthesis of a chiral α-chloroketone, a key building block for many HIV protease inhibitors, via a modified Arndt−Eistert reaction starting from N-protected L-phenylalanine. The initial mixed anhydride was generated in a coil reactor and directly introduced into the CSTR diazomethane cascade. The use of a semipermeable Teflon membrane (AF-2400) allowed the generation of anhydrous diazomethane, which diffuses through the membrane into the CSTR where it is immediately consumed by the anhydride to furnish the corresponding diazoketone. The subsequent halogenation with concentrated HCl was performed downstream in batch and allowed production of the α-chloroketone on a multigram scale, with a productivity of 1.54 g/h (5.2 mmol/h). KEYWORDS: anhydrous diazomethane, membrane separation, CSTR, α-chloroketone synthesis

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INTRODUCTION Since the late 1990s, the Food and Drug Administration has approved a series of highly effective, orally bioavailable protease inhibitors for the treatment of HIV, such as atazanavir, palinavir, or lopinavir, that contain a chiral amino alcohol as a key building block (Scheme 1).1,2 This central moiety is generally introduced by a nucleophilic ring opening of the respective N-protected aminoepoxide via the amino functionality of the C-terminal building block. The chiral aminoepoxide is usually obtained by selective reduction of the corresponding halomethyl ketone, which is readily available via halomethylation of an N-protected amino acid.2 This most direct and cost-effective route involves an Arndt−Eistert type reaction of an activated amino acid with anhydrous diazomethane (CH2N2) to the α-diazoketone, followed by an α,αsubstitution with a hydrogen halide to furnish the corresponding α-halo ketone (Scheme 1). CH2N2 is a versatile C1 building block for numerous reactions,3,4 with the advantage that those transformations are generally fast, clean (often nitrogen is the sole byproduct), and can be carried out under mild conditions. On the other hand, as with many alkylating reagents, CH2N2 is extremely toxic and a potent carcinogen.5 Because of high volatility and extreme sensitivity to explosive decomposition, it is also challenging to handle or to store CH2N2.6 Diazomethane is usually prepared by base-mediated decomposition of an N-methyl-N-nitroso amine precursor such as Diazald.6−8 To generate anhydrous CH2N2, classical distillation techniques have historically been © 2019 American Chemical Society

employed, and special distillation kits were developed to codistill an ethereal CH2N2 solution.6,9 As an alternative to the distillation procedures, a nitrogen stream can be employed to transport the CH2N2 into the gas phase and further into the substrate-containing receiver flask.10 Since the interest in diazo-compounds has increased in recent years, the development of safer techniques for the preparation of CH2N2 is in constant progress. Over the last few years, different methods to generate CH2N2 in continuous flow systems have been developed.3,11−16 This allows the in situ ondemand generation of CH2N2 without the hazards of storage, isolation, or accumulation of large amounts of material. For instance, a recent approach by Lehmann applied a microreactor and a liquid−liquid phase separator for continuous CH2N2 generation and purification on a 95−117 mmol/h scale.17 A safe method to generate pure, anhydrous CH2N2 is the use of membrane technology, which allows continuous separation/ isolation of gaseous CH2N2 from the basic aqueous stream. A number of different reactor types have been developed using microporous, semipermeable membranes, which are chemically and mechanically stable and selectively allow the transport of low-molecular hydrophobic molecules.18−24 Two examples of these reactor types were introduced by our group: the tube-intube20,21 and the tube-in-flask reactor,22−24 both of them Received: March 13, 2019 Published: June 21, 2019 1359

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Scheme 1. Synthesis of α-Haloketones from CH2N2 and N-Protected Amino Acids

relying on a commercially available Teflon AF-2400 membrane as separation and purification tool. The fully continuous tubein-tube reactor, which was initially developed by Ley to saturate a liquid phase with gas,25 was used to generate CH2N2 in an aqueous inner stream. Subsequently, the gaseous CH2N2 diffused through the membrane into an outer substrate stream which was enclosed within a thick walled impermeable outer tubing. In an attempt to further simplify the setup with respect to the handling of solids, concentrations, and scale-up, a tubein-flask reactor was developed where the membrane is coiled inside a glass flask, which allows the gaseous CH2N2 to diffuse into the flask where it is immediately consumed by the substrate solution.22,23 Both set-ups have been employed by our group for the multistep synthesis of α-chloroketones starting from Nprotected amino acids.21,24 In the tube-in-tube reactor, CH2N2 was generated from Diazald as the precursor,21 whereas the tube-in-flask protocol started from cheap and benign N-methyl urea and sodium nitrite.24 Although the tube-in-tube reactor operates fully continuously, its limitation is a very low productivity (1.25 mmol/h) especially when slow reactions such as the intended diazoketone synthesis are considered. A larger throughput can be obtained with the semibatch tube-in-flask reactor, in particular by simple parallelization of the membranes.22 Nevertheless, this approach still has its limits with regard to scale-up as the size of the flask, for safety reasons, cannot be increased to a commercially relevant volume. In consideration of a higher throughput, we report here the design of a tube-inCSTR, which is a fully continuous version of the tube-in-flask model. In a proof-of-concept study, the three-step synthesis of an α-chloroketone from N-protected L-phenylalanine and anhydrous CH2N2 was performed continuously employing the tube-in-CSTR setup. For reaction control and monitoring of the CH2N2 generation, respectively, in-line FTIR was implemented as a PAT tool.

Figure 1. Schematic overview of the tube-in-flask reactor for initial optimization studies (see also Figure S1, Supporting Information).

semipermeable membrane was connected to standard gastight perfluoroalkoxy alkane (PFA) tubing (1/16 in. OD) on both sides. The inlet tubing was fed with the CH2N2 solution that was generated in situ from Diazald and KOH solutions. The two streams were combined in a Y-mixer. Precipitation and blockages at the mixing point were avoided by immersing the Y-mixer into a water bath at 30 °C. The outlet tubing was connected to a back pressure regulator (BPR) and further led into a quench solution (e.g., acetic acid). The glass flask was filled with 50 mL of solution (solvent/substrate) which was stirred by a Teflon-coated stirring bar and cooled in an ice bath to 0 °C. Although CH2N2 is best soluble in diethyl ether,22 its use as a solvent is strongly discouraged, if not forbidden, in industrial laboratories.26 Therefore, methyl tert-butyl ether (MTBE) was considered a more appropriate solvent despite the lower CH2N2 solubility.22 All reactions were monitored with in situ FTIR spectroscopy (Mettler Toledo ReactIR 15 with a silicon probe). The probe was inserted into the flask via a screw-cap adapter. The described reactor (Figure 1) was the standard setup for the subsequent experiments. Generation of Anhydrous Diazomethane. Access to anhydrous CH2N2 is crucial for the modified Arndt−Eistert reaction and therefore for the synthesis of the amino alcohol building block of HIV protease inhibitors. Previous reports describe the reaction of acyl chlorides (e.g., benzoyl chloride) with CH2N2 as an indicator of anhydrous reaction conditions.20,22 Consequently, the water sensitivity of benzoyl chloride was examined. As it turned out, the expected benzoic acid was only detectable via GC-FID upon addition of at least 50 vol % of water, showing that this method was not sufficiently sensitive to prove the generation of anhydrous CH2N2. Hence, other methods to determine the water content

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RESULTS AND DISCUSSION Before the tube-in-CSTR concept was implemented, the tubein-flask setup (Figure 1) was used for simplicity reasons to execute a thorough evaluation of the membrane performance with respect to the anhydrous nature of CH2N2, the mass balance, and the throughput. A commercially available AF2400 membrane tubing (0.8 mm ID, 1.0 mm OD) was coiled inside a standard 250 mL GLS 80 wide necked glass flask (Ø neck: 80 mm, Ø: 95 mm, h: 105 mm), as previously reported.22,23 A custom-made safety screw cap was attached to the glass flask (see Figure S1, Supporting Information). The 1360

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in the organic CH2N2 solution inside the flask were explored. FTIR spectroscopy could in principle be used to monitor the characteristic absorption spectrum of water at ca. 3400 cm−1,27 but unfortunately, the absorption of water is in the blind spot area of the silicon probe used in this study. Ultimately, the water content was determined by Karl Fischer titration. A 0.1 M solution of CH2N2 in anhydrous MTBE (0.0003% H2O) was generated inside the flask and subsequently quenched with benzoic acid. A reference Karl Fischer titration was performed for a benzoic acid solution in MTBE, and the value was subtracted from the one of the quenched CH2N2 solution. The Karl Fischer titration proved our concept of anhydrous CH2N2 generation by revealing 347 ± 7 ppm of water in the quenched solution. FTIR Monitoring. As recently reported by our group, FTIR spectroscopy allows accurate monitoring of the generation and consumption of CH2N2 based on the characteristic CN2 stretch at 2100 cm−1.22 By employing the Mettler Toledo iCQuant software, the factual concentration of CH2N2 in the flask could be determined in real time. Therefore, CH2N2 was generated by pumping 10 mL of a 1 M solution of Diazald in DMF and a 2 M KOH solution in MeOH/H2O (1:2) with a flow rate of 200 μL/min each through the AF-2400 membrane tubing (3.5 m). The flask was filled with 50 mL of anhydrous MTBE, and samples were taken in definite intervals. The conversion of a stoichiometric amount of benzoic acid to methyl benzoate was determined via HPLC−UV/vis peak integration at 215 nm and used for an external calibration. This allowed to directly convert the peak area of the CN2 stretch at 2100 cm−1 into the CH2N2 concentration in the flask over time (Figure 2). As can be seen in Figure 2b, the CH2N2 concentration increases linearly until it reaches a plateau at a maximum concentration of 0.10 M, which correlates to 50% CH2N2

diffusion into the flask, after 48 min. After ca. 55 min a quench with acetic acid was performed, upon which the concentration of CH2N2 drops to zero. The calculated values from the iCQuant software (0.104 M) were in good agreement with the experimental values from the external calibration (0.110 M). The collected reference data were directly converted into a quantitative model, which enabled the direct measurement of the CH2N2 concentration without an external control reaction with benzoic acid. This CH2N2 quantification concept was implemented in the membrane performance studies described below for experiments where only pure solvent was contained inside the flask. Membrane Performance/Mass Balance Evaluation. In order to achieve a high diffusion of CH2N2 through the membrane tubing into the solution inside the flask, in-depth optimization studies were performed with respect to substrates/type of CH2N2 consumption, residence time/flow rates, and throughput. Significant emphasis was put on the careful determination of the mass balance. Standard conditions for the membrane performance studies were based on those we have reported previously for the tube-in-flask reactor.22,23 A total of 10 mL of a 1 M Diazald solution (10 mmol) in DMF and a 2 M KOH solution in MeOH/H2O (1:2) were pumped through the AF-2400 membrane (3.5 m, 1.75 mL residence volume) at equal flow rates. The mass balance is based on complete conversion of Diazald to CH2N2. The diffusion of CH2N2 into pure MTBE was compared to the diffusion into a reaction mixture containing an equimolar amount of benzoic acid, with respect to Diazald and thus CH2N2, inside the flask. The final CH2N2 yield was determined after the complete consumption of the Diazald solution. For no-substrate-containing studies, CH2N2 was quantified via FTIR (vide supra). In the other case, the conversion of benzoic acid to methyl benzoate inside the flask (HPLC analysis) provided information on the CH2N2 yield. In addition, CH2N2, which did not diffuse through the membrane tubing, was analyzed in the waste solution. The aqueous outlet stream was directed into a solution of benzoic acid in MTBE that was equimolar to the employed Diazald. The corresponding methyl ester that was extracted into the organic phase was determined by HPLC. In the process of CH2N2 generation from Diazald, potassium p-toluenesulfonate (PPTS) is formed as byproduct,15 which in turn might be further converted to methyl p-toluenesulfonate (MPTS) by the reaction with CH2N2 in the MeOH/H2O/ DMF environment inside the membrane tubing (Scheme 2). This pathway was corroborated by independent experiments treating PPTS with CH2N2 (see Supporting Information). MPTS was therefore expected in the waste solution, and indeed its presence was confirmed by GC-MS and HPLC versus reference material (Figures S2−S8, Supporting Information). To take MPTS into account for the mass balance of CH2N2, it was quantified via HPLC. To investigate the impact of the residence time in the membrane on CH2N2 yield and mass balance, solutions of Diazald and KOH were pumped through the reactor at varying flow rates. As can be seen in Figure 3, by applying longer residence times, the amount of both CH2N2 and MPTS in the waste stream decreased. Conversely, unrecovered CH2N2 (Δ), most likely due to decomposition under aqueous conditions, increased with prolonged residence times: This outcome is not surprising since previous studies report a half-life of 750 s for CH2N2 in water.14 No-substrate (Figure 3a) and substrate-

Figure 2. Correlation of CH2N2 concentration (HPLC analysis) with (a) FTIR peak area of the CN2 stretch at 2100 cm−1 and (b) time. 1361

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Scheme 2. CH2N2 Generation from Diazald and KOH and Its Potential Consumption Pathwaysa

a

For more details, see the Supporting Information.

Figure 3. CH2N2 mass balance with respect to residence times/flow rates. (a) CH2N2 was generated with pure MTBE inside the flask. (b) CH2N2 was generated with benzoic acid dissolved in MTBE inside the flask. DM: diazomethane. (c) Flowchart of CH2N2 pathway and mass balance based on the experimental data shown in panel b (4.4 min residence time).

Scheme 3. Synthesis of α-Chloroketone 4 Used for the Proof-of-Concept Study of the Tube-in-CSTR Reactor

vs 28% CH2N2 in the waste), by doubling the residence time to 8.8 min a 23% higher CH2N2 yield could be achieved when the substrate was contained inside the flask. This corresponds exactly to the difference of CH2N2 that remains unrecovered (33% vs 10%, Figure 3), which leads to the conclusion that at some point decomposition will prevail over diffusion if the CH2N2 is not immediately consumed by a substrate (see 17.6 min residence time, Figure 3a). Approximately 3−11% of the

containing (Figure 3b) reactions in the tube-in-flask system show comparable trends for the mass balance in the waste stream. However, higher CH2N2 yields inside the flask could be achieved when benzoic acid was present directly in the flask. Because of the concentration gradient that is maintained, the diffusion of CH2N2 from the membrane into the flask is favored, according to Le Chatelier’s principle. Whereas the results for a residence time of 4.4 min are fairly comparable for the two approaches (52% vs 64% CH2N2 in the flask and 29% 1362

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throughput (3.8 mmol CH2N2/h), we decided on a 4 min residence time in the membrane and 50 mL of MTBE in the flask for the CSTR experiments. Temperature Screening. Initially, the tube-in-flask reactor was operated at 0 °C to minimize the risks associated with CH2N2. At this temperature, no CH2N2 was detectable in the headspace as measured by FTIR. To simplify the setup for the CSTR approach, we aimed to operate the flask at slightly higher, potentially even ambient, temperatures. As mentioned above, CH2N2 is extremely sensitive to explosion, therefore, generating a concentrated solution of CH2N2 in MTBE at 25 °C should be avoided. Instead, a stoichiometric amount of benzoic acid was added to the flask in order to directly consume the CH2N2. While increasing the temperature in a stepwise manner from 0 to 25 °C, no CH2N2 was detected in the headspace at any temperature, not even at 24 °C where MTBE was observed (Figure S10, Supporting Information). In addition, a headspace experiment at 20 °C for the slower reaction of CH2N2 with Boc-L-Phe mixed anhydride 2 was performed, and also here, no CH2N2 was detected in the headspace (Figure S11, Supporting Information). Presumably, CH2N2 is sufficiently soluble in MTBE to remain in the liquid phase. Therefore, experiments could be performed at 15−20 °C, without the risk of having gaseous CH2N2 in the headspace. CSTR Cascade. As described above, the tube-in-tube and tube-in-flask reactors both have their limitations considering scale-up. In continuation with our development of larger scale diazomethane generators, we decided to employ a CSTR concept, which can be considered as a continuous version of the tube-in-flask reactor. The three-step synthesis of αchloroketone 4 starting from Boc-L-Phe 1 was used as a proof of concept of the tube-in-CSTR (see, Scheme 3). The first step (activation of amino acid 1) was conducted in flow employing a coil reactor, as previously reported by Pinho et al.21 The synthesis of diazoketone 3 was performed in a CSTR cascade in a continuous flow approach, and finally the αchloroketone synthesis was done in batch. The first CSTR unit (Scheme 4) consisted of a 5 m AF-2400 Teflon membrane inside a double-walled 250 mL CSTR, which was cooled to 15−20 °C and equipped with a Teflonbladed mechanical stirrer. A nylon net was employed to hold

CH2N2 inside the membrane react with PPTS to furnish MPTS. Since the reaction of CH2N2 and benzoic acid is considered to be essentially instantaneous, also the mass balance for the reaction of N-Boc-L-phenylalanine (Boc-L-Phe) anhydride 2 and CH2N2 (Scheme 3) was determined, which is known to proceed at a slower reaction rate.21,24 Compound 2 was generated inside the flask by adding 1 equiv of Bu3N and 1.5 equiv of ClCO2Et to a solution of 5 mmol Boc-L-Phe in 50 mL of MTBE at 0 °C. Excess CH2N2 is necessary for this modified Arndt−Eistert reaction, and therefore 3 equiv of Diazald was employed. Similar results for the mass balance as described above (Figure 3) were obtained: With a residence time of 4 min inside the membrane, 15−20% of CH2N2 did not diffuse through the membrane and thus could be detected in the waste and ca. 5% of CH2N2 reacted with PPTS to MPTS. These results show that, even if the reaction in the flask is slower, the concentration gradient is not affected by the rate of CH2N2 consumption, and hence a similar membrane performance can be attained. In view of the envisaged scale-up in a CSTR, a throughput screening was additionally performed aiming for maximum diffusion of CH2N2 in correlation with time and expenditure of starting material. Again, different residence times in the membrane were tested, but now, the correlation with different filling volumes inside the flask was examined (Table 1), which Table 1. CH2N2 Throughput Screeninga entry

residence time (min)

MTBE in flask (mL)

CH2N2 yield (%)

CH2N2 conc (mol/L)

CH2N2 throughput (mmol/h)

1 2 3 4 5

2 4 8 4 8.4

50 50 50 100 150

51 71 93 80 92

0.10 0.14 0.19 0.08 0.06

3.9 3.8 3.3 1.2 1.0

a

Conditions: 10 mL (1 M solution in DMF) of Diazald and 20 mL (2 M solution in MeOH/H2O 1:2) of KOH were pumped at equal flow rates, 5 m AF-2400, 10 mmol of benzoic acid dissolved in MTBE at 0 °C, yield of CH2N2 determined by conversion of benzoic acid to methyl benzoate and monitored by HPLC peak area % integration.

should provide information about the impact of dilution and headspace. The same conditions with respect to Diazald and KOH were applied as described above. We have shown that a higher concentration gradient of CH2N2 can be maintained with the substrate-in-flask approach (Figure 3b), which in turn leads to higher CH2N2 yields, and hence it was also applied for this study. While, as anticipated, the CH2N2 yield increases from 51 to 93% by increasing the residence time from 2 to 8 min (Table 1, entries 1−3), the throughput is only affected marginally, as it decreases by only 15%. The solvent volume in the flask and thus the concentration of CH2N2, on the other hand, has a stronger effect on the throughput (Table 1, entries 2−5). Similar yields were obtained independently of the filling volume, resulting in a decrease of the throughput due to higher dilution. In addition, this observation implies that the headspace does not have an effect on the reaction outcome, indicating that CH2N2 does not accumulate in the headspace under these conditions. Since the conditions shown in entry 2 (Table 1) represent a good compromise between material consumption, total reaction time (40 min), CH2N2 yield (71%), and thus

Scheme 4. Tube-in-CSTR Unit with Continuous Substrate Feed and Goose Neck Outleta

a

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substrate feedthus the Diazald/CH2N2 to substrate ratio and the residence time inside the CSTR. As described above, the best conditions with respect to throughput and total reaction time involve a residence time of 4 min inside the membrane which relates to a total flow rate of 0.626 mL/min. Our studies started with the optimum conditions that were determined in the tube-in-flask setup which necessitated 3 equiv of Diazald for full conversion of the mixed anhydride 2 to diazoketone 3. The residence time in the CSTR therefore was 72 min, and 3 was detected in only 90% conversion (entry 1, Table 2). Applying more than 3 equiv of Diazald (entries 2−

the fragile membrane tubing in place inside the CSTR. In addition, this design also provided protection from the stirrer blades. Similar to the tube-in-flask setup, the membrane was connected to standard PFA tubing (1/16 inch OD) on both sides. The custom-made Teflon lid (Figure S13, Supporting Information) was equipped with appropriate ports to introduce the inlet and outlet fittings. The inlet tubing was connected to two syringe pumps via a Y-mixer, which was immersed into a 30 °C water bath. For these experiments, the same conditions as described above were applied: solutions of Diazald (1 M in DMF) and KOH (2 M in MeOH/H2O 1:2) were pumped through the membrane tubing at equal flow rates. The outlet tubing was directed to a quench solution (either benzoic acid for mass balance or acetic acid). In contrast to the tube-in-flask reactor, the BPR was omitted in the tube-in-CSTR setup, since the BPR blocked at ambient temperatures when being used for a longer period of time (>3 h). Membrane performance tests revealed that the applied 4−5 bar back pressure had no effect on the performance of the membrane. Therefore, to avoid a potential bottleneck, the BPR was removed from the setup. It should be noted, however, that without the BPR the actual residence time is shorter due the formation of gaseous CH2N2. The substrate feed entered through the Teflon lid of the CSTR and was directed to the bottom near the stirrer blades. To maintain both a constant solvent level in the CSTR and a constant flow rate by simply using gravity, a goose neck was installed. A Teflon tubing (2.4 mm ID, 3.2 mm OD) was connected to the bottom outlet of the CSTR and then to a Ypiece (13.6 μL inner volume, thru-hole 2 mm) which was kept at the same height as the desired solvent height in the CSTR. On one side of the Y-piece another Teflon tubing was attached as outlet. The third opening of the Y-piece was left open and enlarged by simply drilling a larger hole (3 mm, see Figure S13b, Supporting Information). To test the setup, the mass balance for the CSTR unit was determined using a stoichiometric amount of benzoic acid dissolved in 50 mL of MTBE inside the CSTR. Similar results as in the tube-in-flask reactor (see, Figure 3b) were obtained, with a 68−77% CH2N2 yield, 15−20% CH2N2 in the waste, and ca. 5% MPTS generation. As mentioned before, the unrecovered 3−8% CH2N2 probably decomposes in the aqueous environment due to the short half-life of CH2N2. This shows that the transfer of the tube-in flask setup to the CSTR does not affect the performance of the AF-2400 membrane. In accordance with the previously reported conditions for the continuous flow approach toward activation of the amino acid,21 a solution of ClCO2Et (0.45 M in MTBE, 1.50 equiv) was combined in a Y-mixer with a premixed equimolar solution of Boc-L-Phe (1) and Bu3N (0.3 M in MTBE, 1.00 equiv). The solutions were pumped through a PFA coil reactor (9.7 m, 0.8 mm ID, 4.85 mL residence volume) at equal flow rates (0.348 mL/min, 7 min residence time) at 20 °C to reach a conversion of 97% to the desired mixed anhydride 2. As previously reported,21 the remaining 3% of 1 could not be converted to the anhydride. Starting with one CSTR unit, several optimization experiments were performed for the diazoketone synthesis. First, the amount of Diazald required to convert the mixed anhydride 2 to the corresponding diazoketone 3 was screened. Similar to the tube-in-tube reactor, all other parameters depend on the CH2N2 production efficiency. The residence time in the AF2400 membrane therefore also determines the flow rate of the

Table 2. Optimization Studies for the Generation of Diazoketone 3 in One or Two CSTRsa tres (min) entry 1 2 3 4 5

eq Diazald

CSTR 1 CSTR 2 CSTR 1 CSTR 2 72 77 84 48 72

48 72

3 3.2 3.5 2 3

1.2 0.5

DK 3 (%)b

AH 2 (%)b

90 91 90 85 98

10 9 10 15 2

a

CSTR 1:1 M solution of Diazald in DMF and 2 M solution of KOH in MeOH/H2O 1:2, total flow rate: 0.626 mL/min, tres: 4 min, 50 mL MTBE at 20 °C. CSTR 2:0.5 M solution of Diazald in DMF and 1 M solution of KOH in MeOH/H2O 1:2, total flow rate: 0.2 mL/min, tres: 4 min, 50 mL MTBE at 20 °C. Anhydride synthesis: 0.3 M Boc-L-Phe and Bu3N in MTBE and 0.45 M ClCO2Et in MTBE, total flow rate: 0.696 mL/min, tres: 7 min. Conversions measured after 4 CSTR volumes of the first and second CSTR, respectively bConversions of anhydride 2 (AH) to diazoketone 3 (DK) determined by HPLC peak area % integration, 3% Boc-L-Phe-OMe from the first step is not included.

3, Table 2) had no significant effect on the conversion. The residual 3% of the protected amino acid 1 from the previous step was converted to the corresponding methyl ester. The remaining 9−10% of anhydride 2 can be explained by the broad residence time distribution, which is typical for a CSTR. Hence, achieving full conversion within a single CSTR is challenging. To overcome this issue, a second CSTR was installed in series as an additional residence time unit. The outlet of the goose neck attached to the first CSTR was therefore directed into the second reactor. At the outlet of the second CSTR, another goose neck was installed to allow a residence time of 14 min and a constant flow rate of 0.696 mL/ min over both units. Unfortunately, the reaction 2 → 3 did not proceed further, even with a total residence time of 86 min. Therefore, we concluded that a second residence time unit was not required. Ultimately, to reach higher conversion, a second CH2N2 generator was installed in the second CSTR (Scheme 5). The CH2N2 generator in this unit was constructed similarly to the first, with minor adjustments. Since a glass lid was used, the inlet and outlet of the 3.2 m AF-2400 membrane were connected via PFA tubing through a septum (see Figure S14, Supporting Information). An 0.5 M solution of Diazald (in DMF) and a 1 M solution of KOH (in MeOH/H2O 1:2) was used in this CH2N2 generator. Since considerably less CH2N2 would be needed to complete the reaction in the second CSTR, the concentration of the Diazald solution was minimized to 0.5 M to increase the flow rate to 0.2 mL/min and thus prevent blockage of the membrane. By applying lower 1364

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Scheme 5. Synthesis of Diazoketone 3 in the CSTR Cascade with Two Separate CH2N2 Generatorsa

a

See also Figure S12, Supporting Information.

flow rates, occasional precipitation of Diazald and/or PPTS was noticed. Each of the two CSTRs was filled with 50 mL of MTBE. We first considered that lower amounts of Diazald could be used in the CSTR cascade, which would entail the advantage of a dramatically decreased residence time of 48 min in each CSTR by applying a total flow rate of 1.04 mL/min (entry 4, Table 2). Unfortunately, only 85% of the anhydride could be converted to the diazoketone, leaving 15% unreacted anhydride. Best results were obtained with 3 equiv of Diazald in the first reactor and an additional 0.5 equiv in the second (this corresponds to 3 equiv based on the 10% remaining anhydride 2), which gave a 98% conversion to the desired diazoketone 3 (entry 5, Table 2) within a residence time of 72 min in each CSTR. Therefore, these conditions were employed for the steady state experiment. It should be noted, that, compared to the tube-in-tube approach,21 a 1.4 times lower amount of Diazald was required for the synthesis of diazoketone 3. By conducting a residence time distribution (RTD) experiment (tracer experiment monitored by FTIR), it was determined that 5 reactor volumes of CSTR 2 are required to reach steady state (see Figure S15, Supporting Information). This corresponds to a start-up time of 6 h. The FTIR was placed in the second CSTR and used for monitoring the formation of diazoketone 3 at 2107 cm−1. Unfortunately, the concentration of CH2N2 could not be determined via FTIR since the characteristic stretches of CH2N2 (2097 cm−1) and diazoketone 3 overlap. The FTIR spectrum shown in Figure 4 indicates that, as predicted by the RTD calculations, after ca. 6 h a steady state is reached. Product was collected in fractions for 4 h, while the system was at steady state and HPLC analysis revealed 96−98% diazoketone. The last step in the synthesis toward α-chloroketone 4 requires the addition of HCl to the diazoketone 3 solution. We opted for aqueous (concentrated) HCl as a cost efficient reagent, as has already been described for the tube-in-flask approach.24 However, attempts for a fully continuous synthesis of α-chloroketone 4 using the CSTR cascade were unsuccessful. The goose neck was not reliable, since the

Figure 4. FTIR spectrum of the steady state run for the synthesis of diazoketone 3 employing the CSTR cascade. Diazoketone 3 was monitored at 2107 cm−1.

surface tension of water is too high, which resulted in a rising solvent level in the CSTR. Additionally, aqueous HCl accumulated in the dead volume (15 mL) of the CSTR, resulting in a phase separation even with vigorous stirring, which was detrimental to the reaction performance. Because of these issues, the α-chloroketone synthesis was conducted in batch by quenching the collected fractions with 3 equiv of concentrated HCl at room temperature (10 min stirring). Thus, diazoketone 3 is fully converted to α-chloroketone 4, and additionally any excess CH2N2 is destroyed. Applying more than 3 equiv of concentrated HCl led to deprotection of the α-chloroketone. For the activation of the amino acid, generally an amine base (Et3N or Bu3N) is used as a HCl scavenger which could be challenging for both a continuous process and the isolation of the α-chloroketone. The insolubility of the Et3N·HCl salt in MTBE disqualified Et3N as suitable base for a continuous flow process. As previously reported in the fully continuous chloroketone synthesis, Bu3N·HCl is soluble in THF, but 1365

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separation by column chromatography was necessary.21 Switching the solvent from THF to MTBE allowed us to remove the Bu3N·HCl by a simple extraction procedure. An acidic (1 M HCl) and basic (saturated NaHCO3) washing step and evaporation of the solvent afforded α-chloroketone 4 in 80−85% yield. In the 1H NMR, the only detectable side product is the Boc-L-Phe methyl ester (2%), which is a result of unconverted amino acid 1 reacting with CH2N2. In total, 7.4 g of α-chloroketone 4 could be isolated from the steady state run, which corresponds to a productivity of 1.54 g/h (5.2 mmol/h).

importantly, concomitant generation of anhydrous CH2N2 is under investigation in our laboratories. While various ways to provide the required membrane area for scale-up are known and have been realized on larger scale,12,17 there is still a need to provide sufficient contact time for substrates reacting more slowly with diazomethane. For such substrates, the use of stirred tank cascades is among the cheapest and best-understood ways to provide the required contact time.

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EXPERIMENTAL SECTION General. 1H NMR spectra were recorded on a Bruker 300 MHz instrument. 13C NMR spectra were recorded on the 300 MHz instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. The letters s, d, dd, t, q, and m are used to indicate singlet, doublet, doublet of doublets, triplet, quadruplet, and multiplet. Analytical HPLC (Shimadzu LC20) analysis was carried out on a C18 reversedphase (RP) analytical column (150 mm × 4.6 mm, particle size 5 μm) at 37 °C using mobile phases A (H2O/MeCN (90:10 v/v) + 0.1% TFA) and B (MeCN + 0.1% TFA) at a flow rate of 1.5 mL/min. The following gradient was applied: linear increase from 30% B to 100% B within 10 min. GC-MS spectra were recorded using a ThermoFisher Focus GC coupled with a DSQ II (EI, 70 eV). A TR-5MS column (30 m × 0.25 mm × 0.25 μm) was used, with helium as the carrier gas (1 mL min−1 constant flow). The injector temperature was set to 280 °C. After 1 min at 50 °C, the temperature was increased by 25 °C min−1 to 300 °C and kept at 300 °C for 3 min. In-line FTIR analysis (software package iC IR 7.0) was performed using a Mettler Toledo ReactIR 15 with a AgX Fiber Conduit with an integrated attenuated total reflectance (ATR) gold-sealed silicon sensor and a mercury cadmium telluride (MCT) detector. Melting points were obtained in a Stuart SMP3 melting point apparatus in open capillary tubes. The water content was analyzed by an automatic Metrohm Titrando 831 KF coulometric Karl Fisher titration method (EN ISO 12937:2000) in triplicate. All solvents and chemicals were obtained from standard commercial vendors and were used without any further purification. Diazald was synthesized following a literature procedure.28 All compounds synthesized herein are known in the literature. Proof of purity was obtained by 1H NMR and HPLC−UV/vis spectroscopy. CAUTION: CH2N2 is mutagenic, carcinogenic, toxic, and explosive. All reactions should be carried out in an ef f icient f umehood with the sash closed, and laboratory personnel working with CH2N2 MUST familiarize themselves with the potential hazards and prevention measures. Excess CH2N2 should be destroyed by the addition of acetic acid. Preparation of α-Chloroketone 4 from N-Boc-LPhenylalanine (1) in a CSTR Cascade. The setup shown in Scheme 5 was used. A 1 M Diazald (225 mmol) solution in DMF (feed A) and a 2 M KOH (450 mmol) solution in MeOH/H2O 1:2 (feed B) were prepared. For the second CH2N2 generator, a 0.5 M Diazald (37.5 mmol) solution in DMF (feed C) and a 1 M KOH (75 mmol) solution in MeOH/H2O 1:2 (feed D) were prepared. CSTR 1 and CSTR 2 were each filled with 50 mL of anhydrous MTBE. Both CSTRs were water cooled to 15−20 °C. For feed E, Boc-L-Phe (75 mmol) and Bu3N (75 mmol) were dissolved in 250 mL of MTBE (0.3 M). For feed F, ethyl chloroformate (112.5 mmol) was dissolved in 250 mL of MTBE (0.45 M). Feeds E and F were pumped into a Y-mixer (1.7 μL, 0.5 mm thru-hole) at 20

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CONCLUSION In conclusion, we have developed a laboratory-scale multistep process to synthesize α-chloroketone 4, an important key element of HIV protease inhibitors, from Boc-L-Phe with multigram-per-day productivity. The synthetic pathway using anhydrous CH2N2 is a cost-effective and straightforward approach to this building block. A modified Arndt−Eistert reaction was performed in a continuous setup with two consecutive CH2N2 generators housed in a CSTR for the synthesis of diazoketone 3. The continuous on-site-on-demand generation and immediate consumption of CH2N2 eliminates the need to store and transport this hazardous reagent. Subsequent treatment of the diazo compound with HCl allowed synthesis of the α-chloroketone 4 in good yields (80− 85%) with a purity of 98%. With the setup described in this work, an α-chloroketone 4 throughput of 1.54 g/h could be reached. Compared to the tube-in-tube reactor, the productivity could be increased by a factor of 4.2. The tube-in-CSTR cascade represents a productive continuous alternative to the tube-in-flask reactor previously developed. Initial studies in the tube-in-flask reactor allowed the development of a robust setup with the two CSTRs in series, which ran for several hours without intervention. The same membrane was used for all the optimization studies in the CSTR and the steady state run, which totals 70 h of reliable use. Moreover, by optimizing the reaction conditions in the anhydride activation step, we were able to simplify the purification process of the final product from chromatography to extraction. Potentially, the reactor could be scaled up to reach a higher productivity by parallelization of the membrane in the CSTRs. As demonstrated by our group previously in the tube-in-flask setup, the productivity could be increased 4-fold with four membraneseach 4 m in length (2 mL residence volume) wrapped in parallel.22 Theoretically, with more membranes housed inside the CSTR, a higher substrate concentration could be used since more CH2N2 is generated at the same time. This could be achieved by introducing the substrate at a higher flow rate, which would in turn also reduce the residence time inside the CSTR cascade and thus the time until steady state is reached. By adjusting the number of membrane tubings used per CSTR, the throughput could be adjusted as needed: e.g., four membranes with the same characteristics employed in parallel for CH2N2 generation would potentially lead to ca. 50 g of α-chloroketone 4 within one working day (8 h, excluding the time needed for reaching steady state) which corresponds to a throughput of 6.2 g/h. Another, yet more favorable, option to increase productivity is the application of membranes with a higher CH2N2 diffusion rate, which allows the processing of higher substrate concentrations. A membrane screening with respect to increased CH2N2 diffusion capabilities and, 1366

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°C and further through a 9.7 m PFA tubing (1.6 mm OD, 0.8 mm ID. 4.85 mL internal volume) by a syringe pump (Syrris Asia) at flow rates of 0.348 mL/min each. The resulting anhydride solution was directed into CSTR 1. Seven minutes after starting the anhydride synthesis, the CH2N2 generation in both CSTRs was started by switching from pure DMF to Diazald. Feeds A and B were pumped into a Y-mixer (1.7 μL, 0.5 mm thru-hole) that was immersed in a water bath at 30 °C by two syringe pumps (Syrris Asia) at flow rates of 0.313 mL/ min each. The mixture was directed through a short PFA tubing (1.6 mm OD, 0.8 mm ID, 110 μL) and then further through a 5 m AF-2400 Teflon membrane (1.0 mm OD, 0.8 mm ID, 2.5 mL). Feeds C and D were also pumped into a Ymixer that was immersed in a water bath at 30 °C, by two syringe pumps (Syrris Asia) at flow rates of 0.100 mL/min each. The stream then was directed through a 3.2 m AF-2400 Teflon membrane (1.0 mm OD, 0.8 mm ID, 1.6 mL). The aqueous streams leaving the membranes were quenched with AcOH. The product stream was collected for 4 h (50 mL fractions) once steady state was reached (after 6 h). The 4 × 50 mL fractions were quenched by dropwise adding concentrated HCl (22.5 mmol). After 10 min under vigorous magnetic stirring at room temperature, the reaction to the desired α-chloroketone was complete. Each fraction was extracted with 1 M HCl (50 mL) and saturated NaHCO3 (50 mL). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure. 1.80−1.90 g (80−85%) of a white solid was isolated. mp. 100−102 °C (lit.29 102−103 °C); 1H NMR (300 MHz, CDCl3) δ 7.31− 7.20 (m, 3H), 7.14−7.11(m, 2H), 5.02−4.99 (d, J = 5.01 Hz 1H), 4.65−4.58 (m, 1H), 4.13 (d, J = 4.13 Hz, 1H), 3.94 (d, J = 3.94 Hz, 1H) 3.08−2.97 (m, 2H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 201.5, 155.3, 135.7, 129.3, 129.1, 127.5, 80.7, 58.6, 47.7, 37.8, 28.4

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.9b00115. Additional experimental information, supplementary figures and 1H and 13C NMR spectra (PDF)

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Article

AUTHOR INFORMATION

Corresponding Authors

*(D.D.) E-mail: [email protected]. *(C.O.K.) E-mail: [email protected]. ORCID

Doris Dallinger: 0000-0003-1649-0465 C. Oliver Kappe: 0000-0003-2983-6007 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The CC Flow Project (Austrian Research Promotion Agency FFG No. 862766) is funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Science, Research and Economy (BMWFW), and the State of Styria (Styrian Funding Agency SFG). 1367

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