Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles

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A Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles – Towards the Continuous Production of Daclatasvir Paula F Carneiro, Bernhard Gutmann, Rodrigo Octavio Mendonça Alves de Souza, and C. Oliver Kappe ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.5b01191 • Publication Date (Web): 08 Nov 2015 Downloaded from http://pubs.acs.org on November 16, 2015

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Article

A Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles – Towards the Continuous Production of Daclatasvir Paula F. Carneiro,† Bernhard Gutmann,*,† Rodrigo O. M. A. de Souza‡ and C. Oliver Kappe*,†

†

Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria

‡

Biocatalysis and Organic Synthesis Group, Chemistry Institute, Federal University of Rio de Janeiro, CEP 22941 909, Rio de Janeiro, Brazil

* Bernhard Gutmann. E-mail: [email protected] * C. Oliver Kappe. E-mail: [email protected].

ACS Paragon Plus Environment


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ABSTRACT: Herein we present a high-temperature/high-pressure continuous flow synthesis of 1H-4-substituted imidazoles starting from α-bromoacetophenones and carboxylic acids. 1H-4aryl imidazoles are key building blocks in the synthesis of NS5A inhibitors, including daclatasvir as the most prominent example. The reaction sequence started with the generation of the αacyloxy ketone from α-bromoacetophenone and the carboxylic acid. The subsequent condensation to the 1H-4-substituted imidazole was performed with ammonium acetate in a hightemperature stainless steel coil reactor. High-temperature operation (> ~150 °C) was essential for this reaction to form the desired imidazole in high purity. Intensification of chemical reactions in continuous flow reactors has emerged as key enabling technology for process enhancement and for reducing the environmental impact of chemical processes. The continuous flow setup allowed rapid heating of the reaction mixture to the desired temperature. Furthermore, operation at elevated pressure (~ 17 bar) eliminated headspace and increased the concentration of volatile compounds in the liquid phase. The imidazole formation was completed in the coil reactor after residence times of only 2 to 5 min. The products were isolated after the two step reaction sequence in high purity by a simple extraction procedure. Imidazoles derived from chiral amino acids were obtained as the optically pure compounds.

KEYWORDS: Flow chemistry, Microwave chemistry, Process intensification, Pharmaceuticals, Sustainable manufacturing


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INRODUCTION In 2015 the World Health Organization (WHO) estimated that worldwide 130–150 million people are infected with the hepatitis C virus (HCV).1 Approximately 80% of all HCV infections become chronic, and about one third of the people who become chronically infected develop cirrhosis of the liver or liver cancer.1,2 Extensive efforts from the pharmaceutical industry have been initiated to discover effective and well-tolerated, oral therapeutics for the treatment of HCV. From these efforts several successful drugs, directed against various targets in the life cycle of the hepatitis C virus, have recently emerged, including the protease inhibitors telaprevir, boceprevir and simeprevir, and the RNA polymerase inhibitor sofosbuvir.2 These antiviral drugs are applied in combination with peg-interferon-α and ribavirin for the treatment of chronic HCV infection.2 These combinations provide significantly higher cure rates, fewer side effects, and reduced duration of therapy compared to traditional treatments based on pegylated interferon and ribavirin alone. The most recent member in the family of antiviral drugs for HCV therapy is daclatasvir (Figure 1).3 It has been approved in the European Union in 2014 and in the United States in 2015. At present it is listed by the WHO as an Essential Medicine for a basic health care system. Daclatasvir is an inhibitor of the viral phosphoprotein NS5A.4-7 Despite extensive research, the precise role of NS5A in the life cycle of the virus is not fully understood.8 The protein has no known enzymatic activity, but it is critical for the viability of the hepatitis C virus.8 NS5A inhibitors initiate a rapid decline in viral load, and NS5A has emerged as one of the most promising targets for HCV therapy.4-7 Drugs developed for NS5A inhibition frequently contain a 4-phenyl imidazole moiety derived from L-proline, and 1H-4-substituted imidazoles of the general structure 4 are typically key intermediates in the synthesis of NS5A inhibitors (Figure 1).3-7 It has been assumed that the functionalized imidazole moiety is the crucial structural element for binding to the dimeric NS5A protein.7 Specifically, daclatasvir is composed of a C2-symmetric biphenyl bisimidazole motif (Figure 1). A general, inexpensive and scalable process for the production of 1H-4-substituted imidazoles 4 is thus critically important. In the last decade, continuous flow technology has emerged as one of the most significant tools for process intensification.9-12 In fact, in the context of API (Active Pharmaceutical Ingredient) synthesis continuous processing was recently identified as one of the “key green engineering research areas for sustainable manufacturing”.13,14 The distinct features of continuous flow processes are fast heat and mass transfer, an improved safety profile, and the ACS Paragon Plus Environment


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potential for process automation and process integration. In continuous flow reactors, temperatures far above the atmospheric boiling point of the solvent become accessible easily and safely (“Novel Process Windows”).15 The high reaction rates at elevated temperatures increase throughput and reactor efficiency, or allow a reduction of the reactor size and consequently reactor cost. Furthermore, elimination of headspace in pressurized continuous flow reactors keeps volatile reagents in the liquid phase and consequently increases reaction rate as well as reaction purity.16-18 A continuous flow process for the high-temperature synthesis of an 1H-4-aryl imidazole was employed in 2012 by chemists from Eli Lilly (Figure 1).18 For their synthesis the α-bromoketone was converted to the corresponding amine by a nucleophilic substitution of the bromine with sodium azide and subsequent reduction of the azide with triphenyl phosphine. Acetylation of the amine with the acid yielded the ketoamide which cyclizes with ammonium acetate to the imidazole. While the cyclization of the ketoamide proceeded satisfactorily on a small scale in a sealed tube, the reaction rate decreased significantly upon scale-up in traditional glassware and multiple charges of ammonium acetate were required to compensate for loss of ammonia from the reaction mixture at elevated temperatures.18 In contrast, the reaction proceeded well at 140 °C in a stainless steel flow reactor (residence time 90 min).18 Herein we describe the continuous flow synthesis of 1H-4-substituted imidazoles 4 starting from the corresponding α-halo ketones 1. Nucleophilic substitution of the bromine with a suitably N-protected L-proline and subsequent condensation with ammonium acetate provides the imidazoles 4 directly without the need to generate an intermediate ketoamide (Figure 1).4-7 This reaction was first described in 1937 as a side reaction accompanying the formation of oxazoles,19 but it has been developed into a valuable and general method for the synthesis of imidazoles since then.20,21 However, the condensation to the imidazole is usually very slow and requires reaction times of many hours at the boiling point of high boiling solvents such as xylene.4-7 The two-step continuous flow protocol described herein afforded the imidazoles within residence times of only 4-10 min employing acetonitrile as solvent. The desired products were isolated with high purity by a simple extraction procedure.


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O

OMe O N

H N

N

N N

N H

O

HN

Daclatasvir

O OMe

ketoamide route O Br 1

X

R

1) NaN3 2) PPh3 3) RCO2H 2

O

N

H N

R O

X

NH

NH4OAc 4

X

acyloxy ketone route

R

O

O Br RCO H 2 2

X

1

N O

X

3

R

NH

NH4OAc

O

X

4

Figure 1. Synthesis of 1H-4-aryl imidazoles 4.

RESULTS AND DISCUSSION Preliminary Batch Experiments. The reaction sequence was initially explored in a laboratory scale batch microwave reactor22-24 using α-bromoacetophenone 1a and acetic acid as model substrates. The addition of 1.2 equivalents of acetic acid to the α-bromoketone (1 mmol) in the presence of 2 equivalents of triethyamine (Et3N) as a base proceeded to completion within 20 min at 60 °C in acetonitrile as solvent (see Table S1 in the Supporting Information). Essentially pure α-acetoxy acetophenone 3a was isolated from a reaction on a 10 mmol scale in 89% product yield after basic extraction. The direct cyclization of α-acyloxy ketones to the corresponding imidazoles is commonly performed with ammonium acetate.4-7 Ammonium acetate is both reagent and catalyst in this reaction. However, since the ideal amount of ammonia and acetic acid is not necessarily the same, we initially contemplated the use of gaseous ammonia as reagent together with a suitable acidic catalyst. For the envisaged flow process, ammonia from a gas cylinder would be combined with the catalyst and with the solution carrying the α-acyloxy ketone. The condensation of αacyloxy ketone 3 with ammonia to the imidazole 4 would then proceed in a high-temperature coil reactor. Continuous flow reactors are virtually ideally suited for reactions involving gaseous reagents.9 Gases can be dosed into the flow system with precise stoichiometry using mass flow ACS Paragon Plus Environment


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controllers and intense mixing with the liquid phase can be achieved. Furthermore, high pressure operation minimizes headspace and increases the concentration of the gaseous reagent in the liquid phase.9 Preliminary high-temperature batch experiments in a sealed vessel microwave reactor revealed that the imidazole formation is slow employing 1 equivalent of acetic acid and 5 equivalents of ammonia in MeCN/dioxane as solvent. A conversion of 28% was obtained after a reaction time of 15 min at 240 °C (see entry 1 in Table 1). The only side product detected in the reaction mixture in significant amounts was the 2,4-oxazole 5a. Increasing the amount of acetic acid increased the reaction rate significantly. However, also the amount of oxazole increased concomitantly (see entry 1 to 4 in Table 1). A further increase in the stoichiometry of ammonia did not reduce oxazole formation appreciably (entry 5 to 9 in Table 1). Furthermore, the oxazole is not converted to the imidazole upon further heating. Indeed, separate reactions with the isolated oxazole 5a demonstrated that the oxazole is stable under the reaction conditions. These experiments indicate that the 2,4-oxazole is not an intermediate in this reaction, but an actual side product. The results are in good agreement with the proposed mechanism for the formation of substituted 2,4-oxazoles and imidazoles from α-acyloxy ketones.20,21 The reaction of ammonia with the acyloxy ketone 3a initially provides an imine in equilibrium with the enamine (Scheme 1). Intramolecular condensation of the enamine yields the oxazole side-product 5a, while a fast intramolecular acyl transfer prior to the condensation provides the desired 1H-4-phenyl imidazole 4a (Scheme 1). Interestingly, with trifluoroactic acid instead of acetic acid, the 2,4-oxazole 5a was obtained as the mayor product. Only 2% of the imidazole 4a was formed in this reaction.

Scheme 1. Imidazole Formation from Acyloxy Ketones 3a with NH3/AcOH


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After increasing the concentration of the ammonia solution to 3 M in MeCN as solvent, the imidazole was finally obtained with 95% selectivity after a reaction time of 15 min at 180 °C (11 bar internal pressure). The one-pot-two-step reaction sequence, comprising reaction of acetic acid with α-bromoacetophenone to the acyloxy ketone and subsequent cyclization with ammonia, afforded the 1H-4-phenyl imidazole 4a in 85% yield after extraction. The corresponding reaction with benzoic acid proceeded with a HPLC purity of 98% and the product was isolated in 93% yield. Table 1. Optimization of Imidazole Formation from Acyloxy Ketone 3a with NH3/AcOHa

acyloxy imidazole 4a oxazole 5a ketone 3a (%)b (%)b b (%) 1 1 5 72 25 3 2 2 5 41 49 11 3 3 5 2 78 20 4 6 5 5 72 23 5 3 6 14 73 14 6 3 7 4 83 13 7 3 8 8 80 12 8 3 9 9 80 11 9 3 10 9 80 11 a Conditions: 0.1 mmol of acyloxy ketone 3a in 2 mL MeCN, AcOH and the corresponding amount of a 0.5 M solution of NH3 in dioxane were heated in a sealed vessel microwave reactor for 15 min to 240 °C. bHPLC-UV/VIS peak area integration at 215 nm. For a general experimental procedure, see the experimental section. AcOH (equiv)

NH3 (equiv)

As expected, also the reaction of α-bromoacetophenone with N-Boc-L-proline 2b to the αacyloxy ketone 3b proceeded fast and cleanly. However, the subsequent condensation of the αacyloxy ketone to the imidazole 4b yielded more side products in addition to the 2,4-oxazole 5b. These side products were identified as the corresponding N-acetyl-imidazole 4b’ and N-acetyloxazole 5b’. These products are evidently formed by Boc-deprotection and subsequent acetylation. Decreasing the amount of acetic acid reduced the deprotection rate (Table 2). Coincidentally, the best results were obtained with about equal amounts of acetic acid and



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ammonia (entry 5 and 6 in Table 2). Thus, subsequent reactions were directly performed with ammonium acetate as readily available and inexpensive reagent/catalyst. Table 2. Optimization of Imidazole Formation from Acyloxy Ketone 3b with NH3/AcOHa

AcOH (equiv)

acyloxy imidazole oxazole 5b N-acetyl- N-acetylothers ketone 3b 4b (%)b (%)b imidazole oxazole (%)b b b b (%) 4b’ (%) 5b’ (%) 1 50 4 3 6 68 18 1 2 40 4 11 6 60 11 8 3 30 3 27 8 56 6 4 20 4 41 7 40 3 5 5 10 10 70 2 12 6 6 5 9 69 11 3 8 7 0 30 59 1 10 a Conditions: 0.4 mmol of acyloxy ketone 3b, AcOH in 2 mL MeCN and 0.93 mL of a 3 M solution of NH3 in MeCN (7 equivalents of NH3) were heated in a sealed vessel microwave reactor for 15 min to 180 °C (11 bar). bHPLC-UV/VIS peak area integration at 215 nm. See the experimental section for further details.

Continuous Flow Synthesis of 1H-4-substituted Imidazoles 4. Formation of the α-acyloxy ketone from α-bromoketones and N-Boc-L-proline 2b was then re-optimized in a flow reactor (Scheme 2). For these reactions, a 1.3 M solution of Et3N was pumped by a high pressure syringe pump (Syrdos) into a Y-shaped mixer (Upchurch Scientific). A solution containing αbromoacetophenone 1a (0.25 M) and 1.05 equivalents of the amino acid 2b was pumped into the mixer from an injection loop by a HPLC pump. The combined mixture went through a 7.5 mL coil reactor made from PFA (perfluoroalkoxy alkane; 1.6 mm o.d.; 0.8 mm i.d.). The processed mixture finally left the system through a 17 bar back-pressure regulator (Upchurch Scientific). These reactions revealed that the substitution of the bromine by proline is indeed completed after a reaction time of only 2 min at 60 °C with 1.9 equivalents of Et3N (Table S2 in the Supporting Information). Without a base, no appreciable conversion to the α-acyloxy ketone 3b was observed. ACS Paragon Plus Environment

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Scheme 2. Continuous Flow Formation of Acyloxy Ketone 3ba

a

Conditions: Feed A (1.6 mL of a 0.25 M solution of 1a and 1.05 equivalents of 2b in MeCN)

and feed B (1.3 M solution of Et3N in MeCN) were pumped through a 7.5 mL PFA reactor at 60 °C.

Optimization of the imidazole formation was performed in a 20 mL stainless steel coil reactor (1.6 mm o.d.; 1 mm i.d.) heated on an aluminum heating block (Uniqsis FlowSyn). Initial experiments were performed under conditions similar to those developed in the sealed vessel batch microwave reactor.24 However, ammonium acetate was used for these flow reactions instead of ammonia/acetic acid. For these experiments, the α-acyloxy ketone 3b was prepared as described above from the α-bromoacetophenone and N-Boc-proline in a microwave reactor, and the reaction mixture was then immediately used for the subsequent flow reaction. The α-acyloxy ketone solution was filled into an injection loop, and the mixture was pumped from the loop into the reactor by a HPLC pump. In the reactor the α-acyloxy ketone was combined with an 8.6 M aqueous solution of ammonium acetate, and the mixture then passed through a coil reactor at 180 °C (Table 3). The mixture was finally cooled in a 1 mL stainless steel tubing in a water bath, and collected after the back pressure regulator. To prevent the MeCN from boiling, a 34 bar back pressure was employed. With a flow rate of 1.3 mL/min for the feed solution containing the acyloxy ketone 3b (feed A) and a flow rate of 0.2 mL/min for the ammonium acetate feed solution (feed B), 7.3 equivalents of NH4OAc with respect to the acyloxy ketone and a residence time of 13.3 min in the heated coil reactor were obtained. The desired imidazole 4b was formed with a selectivity of 78% (entry 1 in Table 3). Reducing the residence time in the reactor to 5 min increased the selectivity appreciably without decreasing conversion (entry 1 to 3 in Table 3). A reduction of the amount of NH4OAc decreased the purity of the reaction, while larger amounts did not further improve selectivity (see Table S3 in the Supporting Information). At a constant



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residence time of 5 min, the temperature was reduced to 150 °C, still affording complete conversion of the α-acyloxy ketone 4b (entries 4 to 6 in Table 3). Interestingly, the purity of the reaction decreased significantly upon further decrease of the reaction temperature (entry 7 to 9 in Table 3). A similar observation was also made by May and co-workers for the cyclization of a ketoamide with ammonium acetate.18 Low temperatures favored oligomerization, while at temperatures above 100 °C cyclization to the imidazole was preferred pathway.18 Rapid heating to the desired temperature was crucial for this reaction to maximize reaction purity.18 We finally decided for a reaction temperature of 160 °C. At this temperature, the residence time required to achieve full conversion was 2 min (see Table S3 in the Supporting Information). Importantly, only 1% of the oxazole 5b and none of the N-acetyl compounds 4b’ and 5b’ were detected in the reaction mixture (see Figure 2). Table 3. Continuous Flow Formation of Imidazole 4b from Acyloxy Ketone 3ba

residence flow rate flow rate imidazole oxazole acyloxy others time feed A feed B ketone 3b 4b 5b (%)b (min) (mL/min) (mL/min) (%)b (%)b (%)b 1 180 13 1.3 0.2 78 1 21 2 180 10 1.75 0.27 84 1 15 3 180 5 3.45 0.53 1 94 1 4 4 170 5 3.45 0.53 97 1 2 5 160 5 3.45 0.53 97 1 2 6 150 5 3.45 0.53 1 95 1 3 7 140 5 3.45 0.53 92 0 8 8 130 5 3.45 0.53 1 89 10 9 120 5 3.45 0.53 10 69 21 a Conditions: Feed A (0.4 mmol solution of acyloxy ketone 3b in MeCN; prepared in a microwave reactor) and feed B (8.6 M solution of NH4OAc in H2O) were pumped through a 20 mL stainless steel reactor (~7.3 equivalents of NH4OAc). bHPLC-UV/VIS peak area integration at 215 nm. rt = room temperature. Temp (°C)


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Figure 2. HPLC-UV/Vis (215 nm) of the reaction mixture after a reaction time of 5 min at 160 °C in the continuous flow reactor (entry 5 in Table 3). Both steps were finally combined to afford the desired 1H-4-phenyl imidazole in a continuous two-step reaction sequence (Scheme 3). For these transformations, the solution of αbromoacetophenone 1a (2 mmol) and N-Boc-L-proline 2b (1.05 equivalents) was mixed with the solution of Et3N in a Y-mixer. The resulting mixture passed through a 6.5 mL PFA tubing at 60 °C to form α-acyloxy ketone 3b, and the mixture was subsequently combined with aqueous NH4OAc in a second mixer. After the solution passed through a 7.5 mL stainless steel reactor at 160 °C it was cooled in a heat exchanger and left the system through a back-pressure regulator. Since the vapor pressure of MeCN at 160 °C is only ~7 bar, the back pressure was reduced from 34 to 17 bar for these experiments (Scheme 3). The processed mixture left the flow reactor as a two phase water/MeCN solution. The aqueous phase was removed and discarded, and the solvent from the organic phase was removed under reduced pressure. The crude product was dissolved in ethyl acetate and extracted into 1 M HCl. Neutralization with NaHCO3 and re-extraction into ethyl acetate provided the product as a yellow solid after evaporation of the solvent in 81% yield. The total reaction time in the reactor was only ~4 min, allowing a throughput of 0.15 g/min of product in a reactor with a total residence volume of ~14 mL. Importantly, the imidazole was isolated as the pure S-product 4b, confirming that no racemization is occurring during the synthesis (see Figure S2 in the Supporting Information).



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Scheme 3. Two Step Flow Synthesis of Imidazole 4ba O

O NBoc

OH

feed A 2.4 mL/min 6.5 mL PFA

Br

+

2b (0.26 M) + 1a (0.25 M) in MeCN

7.5 mL stainless steel

N

17 bar

Boc N NH

Et3N 1.3 M in MeCN

feed B 0.87 mL/min

2 min 160°C

2 min 60°C

1 mL rt

4b (81%)

feed C 0.5 mL/min NH4OAc 8,6 M in H2O

a

Conditions: 8 mL of a 0.25 M solution of 1a and 1.05 equivalents of Boc-L-proline 2b were combined with a 1.3 M solution of Et3N at flow rates of 2.4 mL/min and 0.87 mL/min, respectively. The solution passed through a first residence reactor at 60 °C before it was combined with the feed solution of NH4OAc pumped at a flow rate of 0.5 mL/min. The mixture passed through the second residence reactor and was subsequently cooled in a heat exchanger. For a detailed description of the flow setup see Figure S1 in the Supporting Information. The scope of this imidazole-forming reaction was subsequently explored using the optimized conditions described above employing a variation of different α-bromoketones and carboxylic acids. Satisfactory results were achieved with a range of bromoketones of varying reactivity (Figure 3). The protocol proved also suitable for different carboxylic acids, including N-Cbz-Lproline (4f), N-Cbz-glycine (4i), and N-Boc-L-phenylalanine (4l). Imidazoles derived from glycine 4i are the intermediates in the synthesis of certain heteroaryl derivatives of 7-chloro-4aminoquinolines.25 These compounds are related to chloroquine and amodiaquine and show promising antimalarial activity.25 They are furthermore the crucial intermediates in the synthesis of

imidazolopiperazines,

compounds

also

explored

for

their

antimalarial

activity.26

Phenylimidazoles derived from L-phenylalanine are motifs in molecules studied for their antithrombotic activity (structure 4l in Figure 3).27,28 All products shown in Figure 3 were isolated in high purity (>95%) by a simple extraction procedure (for 1H-NMR and spectra of these products see the Supporting Information).


13

C NMR

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Figure 3. Continuous flow synthesis of various imidazoles. Flow rates for feed A, B and C were: 2.4 mL/min, 0.87 mL/min and 0.5 mL/min, respectively (cf. Scheme 3 and the Experimental Section). aFlow rates were reduced to 1.2 mL/min, 0.44 mL/min and 0.25 mL/min. bCyclization at 200 °C. cFlow rates were reduced to 0.96 mL/min, 0.35 mL/min and 0.20 mL/min.

Synthesis of Biphenyl Bisimidazole 4m. The developed reaction sequence was finally applied for the synthesis of the symmetrical core unit of daclatasvir (Figure 1). The dibromo intermediate was prepared in dichloromethane from commercially available 4,4′-diacetylbiphenyl and Nbromosuccinimide (NBS) following a literature procedure.29 After batch reaction with a reaction time of 30 min at 80 °C the dibromo derivative 1m was isolated by recrystallization in 78% yield. The dibromo compound 1m itself is not soluble at the desired concentration in MeCN as solvent. However, the dibromo intermediate is quickly transformed to the soluble acyloxy-derivative 3m upon stirring with N-Boc-L-proline 2b at room temperature. Since the formation of the acyloxy ketone 3m is fast at room temperature, no attempts were made to translate this reaction step to a ACS Paragon Plus Environment


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continuous flow process, and only the imidazole formation was performed in the continuous flow reactor. For these experiments, the dibromo intermediate was stirred with 2.1 equivalents of NBoc-L-proline and 4 equivalents of Et3N for 10 min at room temperature, and the resulting homogenous solution was then introduced into the flow reactor at a flow rate of 2.15 mL/min (Scheme 4). In the Y-mixer the mixture was combined with the aqueous solution of ammonium acetate, pumped at a flow rate of 0.33 mL/min, and the resulting mixture passed through the stainless steel reactor at 160 °C. Complete conversion of the bisacyloxy ketone 3m was obtained after a residence time of 3 min at 160 °C. The water phase of the bi-phasic reaction mixture was removed and discarded. The organic phase was concentrated in vacuum and extracted with EtOAc and aqueous NaHCO3. The desired biphenyl bisimidazole 4m was isolated from the organic phase in a yield of 71%. The yield of the isolated product is comparable to those previously reported for batch procedures.5 However, the reaction time of the intensified continuous flow process is one to two orders of magnitude lower than the reaction times reported in the literature (respectively 2 and 14 hours for imidazole formation at reaction temperatures of 140 and 100 °C).3,5 Scheme 4. Two Step Flow Synthesis of Bisimidazole 4m a

a

Conditions: 1 mmol of dibromo compound 1m, 2.1 mmol of Boc-proline and 4 mmol of trimethylamine were stirred in 10 mL acetonitrile for 10 min at room temperature. The mixture was then converted to the bisimidazole 4m in the continuous flow reactor (see Experimental Section for details). ACS Paragon Plus Environment

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CONCLUSION In conclusion we have demonstrated a continuous flow high-temperature synthesis of 1H-4substituted imidazoles starting from the corresponding α-bromoacetophenones and carboxylic acids. These compounds are building blocks in the synthesis of a variety of active pharmaceutical ingredients. Most importantly, the imidazoles derived from N-Boc-L-proline are the key building blocks for the synthesis of NS5A inhibitors such as daclatasvir. The desired products were formed in two steps by nucleophilic substitution of the bromine of the α-bromoacetophenone with the acid in the presence of triethylamine as a base and subsequent condensation to the 1H-4substituted imidazole in a high temperature coil reactor. Imidazole formation at temperatures below ~150 °C resulted in the formation of significant amounts of unidentified side products. In contrast, high-temperature operation at a back pressure of 17 bar afforded the desired products in high purity. The imidazole formation was completed in a stainless steel coil reactor after residence times of 2 to 5 min, and the products were isolated after the two step reaction sequence in high purity by a simple extraction procedure. Green and sustainable chemical processes rely not only on effective chemistry but also on the implementation of novel reactor technologies, which enhance reaction performance and overall safety.10 A continuous flow reactor allows rapid heating of the reaction mixture to the desired temperature. Furthermore, high-pressure operation eliminates headspace and increases the concentration of volatile compounds in the liquid phase.

EXPERIMENTAL PROCEDURES General: 1H-NMR spectra were recorded on a Bruker 300 MHz instrument.

13

C-NMR spectra

were recorded on the same instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. The letters s, d, t, q, and m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet. Analytical HPLC (Shimadzu LC20) analysis was carried out on a C18 reversed-phase (RP) analytical column (150 × 4.6 mm, particle size 5 µm) at 37 °C using a mobile phase A (water/acetonitrile 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 solution 30% B to 100 % B in 17 min. All solvents and chemicals were obtained from standard commercial vendors and were used without any further purification. The purity of all compounds synthesized in the present study was ≥ 95% as determined by HPLC-UV/Vis analysis at 215 nm. ACS Paragon Plus Environment


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General Procedure for Microwave Batch Experiments (Table 2). Into a 10 mL microwave process vial equipped with a magnetic stir bar were placed the acyloxy ketone 3b (0.4 mmol), the respective amounts of AcOH in 2 mL MeCN and 0.93 mL of a 3 M solution of NH3 in MeCN (7 equivalents of NH3). The vials were sealed by a snap-cap with PTFE coated silicone septum, and the samples were irradiated in a Monowave 300 (Anton Paar) for 15 min at 180 °C (stirring speed 600 rpm). General Procedure for the Continuous Flow Synthesis of Imidazoles 4a to 4l. The αbromoacetophenone 1 (2 mmol) and the respective acid 2 (2.1 mmol) were dissolved in 7.5 mL MeCN (feed A; 0.25 M solution of bromoacetophenone 1). 16 mmol (2.2 mL) of triethlyamine were dissolved in 10 mL acetonitrile (feed B; 1.3 M), and 110.7 mmol (8.52 g) of ammonium acetate were dissolved in 6 mL water (feed C; 8.6 M). For the flow reactions feed A and feed B first carried MeCN while feed C carried water (see Scheme 3; for a description of the flow setup see Figure S1 in the Supporting Information.). The flow rates for feed A, feed B, and feed C were as indicated in Figure 3. When a reaction was started, feed B was switched from MeCN to the triethylamine solution and feed C was switched from water to the ammonium acetate solution. The bromoacetophenone solution (feed A) was introduced into the flow reactor from an injection loop. Feed A and feed B were mixed in a Y-shaped mixer (Upchurch Scientific) and the combined mixture went through a 6.5 mL PFA tubing at 60 °C (perfluoroalkoxy alkane, 1.6 mm o.d.; 0.8 mm i.d.). The mixture was combined with the feed C solution in a second mixer, and the mixture went through a 7.5 mL stainless steel tubing at 160 °C (1.6 mm o.d.; 1.0 mm i.d.). The processed solution was cooled in a heat exchanger (1 mL stainless steel tubing; 1.6 mm o.d.; 1 mm i.d.), and finally left the system through a back pressure regulator (17 bar; Upchurch Scientific). The processed mixture left the flow reactor as a two phase water/MeCN solution. The aqueous phase was removed and discarded, and the solvent from the organic phase was removed under reduced pressure. The crude product was dissolved in ethyl acetate and extracted into 1 M HCl. Neutralization with NaHCO3 and re-extraction into ethyl acetate provided the imidazoles 4 after drying with MgSO4 and evaporation of the solvent. 2-Methyl-5-phenyl-1H-imidazole (4a). Yellow solid (211 mg, 67%); mp 158-160 °C; 1H NMR (300 MHz, DMSO) δ 7.71 (d, J = 7.2 Hz, 2H), 7.40 (s, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 2.33 (s, 3H). 13C NMR (75 MHz, DMSO) δ 144.98, 128.90, 126.26, 124.41, 14.33, 14.31.


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tert-Butyl (S)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4b). Yellow solid (505 mg, 81%); mp 135 - 137 °C; 1H NMR (300 MHz, DMSO) δ 11.85 (d, J = 19.9 Hz, 1H), 7.74 (d, J = 7.4 Hz, 2H), 7.46 (s, 1H), 7.31 (t, J = 7.4 Hz, 2H), 7.14 (t, J = 7.1 Hz, 1H), 4.80 (d, J = 20.1 Hz, 1H), 3.54 (s, 1H), 3.39 (s, 1H), 2.32 – 2.08 (m, 1H), 2.03 – 1.69 (m, 3H), 1.28 (d, J = 71.8 Hz, 9H). 13C NMR (75 MHz, DMSO) δ 154.21, 153.87, 150.84, 139.90, 135.58, 129.22, 128.75, 126.17, 124.60, 124.26, 112.54, 112.16, 79.01, 78.63, 55.74, 55.16, 47.01, 46.74, 33.78, 28.62, 28.32, 24.25, 23.56. tert-Butyl (R)-2-(5-phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (R-4b). Yellow solid (482 mg, 77%); mp 137 - 139 °C; 1H NMR (300 MHz, DMSO) δ 11.87 (s, 1H), 7.72 (d, J = 7.1 Hz, 2H), 7.44 (s, 1H), 7.32 (t, J = 7.4 Hz, 2H), 7.24 – 7.09 (m, 1H), 4.81 (dd, J = 23.0, 4.6 Hz, 1H), 3.54 (s, 1H), 3.37 (s, 1H), 2.31 – 2.11 (m, 1H), 2.05 – 1.75 (m, 3H), 1.46 – 1.11 (m, 9H). 13C NMR (75 MHz, DMSO) δ 153.84, 128.82, 126.24, 124.54, 79.03, 78.61, 55.67, 55.10, 46.75, 33.77, 32.28, 28.63, 28.32, 24.25, 23.56. 2,5-Diphenyl-1H-imidazole (4c). White solid (412 mg, 94%); mp 268 - 271 °C; 1H NMR (300 MHz, DMSO) δ 8.34 – 8.26 (m, 3H), 8.08 – 8.00 (m, 2H), 7.70 – 7.63 (m, 3H), 7.59 – 7.50 (m, 2H), 7.46 (ddd, J = 7.4, 3.6, 1.2 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 144.79, 134.30, 132.38, 129.67, 129.60, 129.43, 127.97, 127.46, 126.45, 123.66, 117.04. tert-Butyl

(S)-2-(5-(4-Fluorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(4d).

Yellow solid (474 mg, 72%); mp 134 - 139 °C; 1H NMR (300 MHz, DMSO) δ 11.88 (s, 1H), 7.85 – 7.68 (m, 2H), 7.54 – 7.33 (m, 1H), 7.25 – 7.05 (m, 2H), 4.90 – 4.69 (m, 1H), 3.64 – 3.45 (m, 1H), 3.39 (s, 1H), 2.28 – 2.07 (m, 1H), 2.02 – 1.73 (m, 3H), 1.41 – 1.10 (m, 9H). 13C NMR (75 MHz, DMSO) δ 162.71, 159.51, 153.85, 126.35, 126.24, 115.68, 115.42, 111.95, 79.04, 78.63, 55.67, 46.74, 33.74, 32.28, 28.60, 28.30, 24.26, 23.55. tert-Butyl (S)-2-(5-(p-Tolyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4e). White solid (417 mg, 64%); mp 174 - 176 °C; 1H NMR (300 MHz, DMSO) δ 11.81 (s, 1H), 7.61 (d, J = 7.5 Hz, 2H), 7.35 (s, 1H), 7.13 (d, J = 7.7 Hz, 2H), 4.80 (d, J = 26.0 Hz, 1H), 3.53 (s, 1H), 3.37 (s, 1H), 2.28 (s, 3H), 2.26 – 2.11 (m, 1H), 2.07 – 1.75 (m, 3H), 1.25 (d, J = 16.0 Hz, 9H). 13C NMR (75 MHz, DMSO) δ 153.85, 135.23, 129.41, 124.51, 79.00, 78.59, 55.69, 55.11, 46.75, 33.77, 32.27, 28.63, 28.32, 24.28, 23.56, 21.21, 21.18. Benzyl (S)-2-(5-Phenyl-1H-imidazol-2-yl)pyrrolidine-1-carboxylat (4f). Yellow solid (352 mg, 51%); mp 146 – 148 °C; 1H NMR (300 MHz, DMSO) δ 11.94 (d, J = 22.3 Hz, 1H), 7.81 – 7.60 (m, 2H), 7.48 (d, J = 7.0 Hz, 1H), 7.35 (dd, J = 17.9, 6.0 Hz, 5H), 7.15 (d, J = 4.4 Hz, 2H), ACS Paragon Plus Environment


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7.02 (q, J = 14.9 Hz, 1H), 4.98 (ddd, J = 26.5, 17.4, 9.9 Hz, 3H), 3.62 (s, 1H), 3.46 (s, 1H), 2.26 (dt, J = 18.6, 10.1 Hz, 1H), 1.89 (ddd, J = 40.3, 20.1, 10.5 Hz, 3H). 13C NMR (75 MHz, DMSO) δ 154.34, 150.25, 140.08, 137.48, 135.46, 128.79, 128.49, 128.19, 127.91, 127.70, 127.00, 126.28, 124.65, 112.67, 66.34, 65.94, 55.82, 55.57, 47.36, 46.79, 33.68, 32.40, 24.21, 23.35. tert-Butyl

(S)-2-(5-(4-Chlorophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(4g).

1

Yellow solid (332 mg, 48%); mp 154 - 157 °C; H NMR (300 MHz, DMSO) δ 11.91 (d, J = 19.6 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.53 (s, 1H), 7.33 (t, J = 14.1 Hz, 2H), 4.78 (d, J = 20.3 Hz, 1H), 3.58 (d, J = 31.5 Hz, 1H), 3.45 – 3.30 (m, 1H), 2.26 (dd, J = 15.5, 13.7 Hz, 1H), 1.87 (dd, J = 39.5, 23.5 Hz, 3H), 1.42 – 1.09 (m, 9H). 13C NMR (75 MHz, DMSO) δ 153.81, 151.07, 138.75, 134.52, 130.39, 128.76, 126.21, 112.79, 78.64, 55.66, 46.75, 33.73, 28.60, 28.30, 23.55. tert-Butyl

(S)-2-(5-(4-Methoxyphenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate

(4h).

1

Yellow solid (427 mg, 62%); mp 153 - 156 °C; H NMR (300 MHz, DMSO) δ 11.76 (s, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.24 (d, J = 37.9 Hz, 1H), 6.96 (dd, J = 32.2, 7.2 Hz, 2H), 4.90 – 4.69 (m, 1H), 3.75 (s, 3H), 3.52 (d, J = 6.3 Hz, 1H), 3.34 (d, J = 16.3 Hz, 2H), 2.28 – 2.06 (m, 1H), 2.01 – 1.72 (m, 3H), 1.42 – 1.11 (m, 9H). 13C NMR (75 MHz, DMSO) δ 158.07, 153.87, 128.30, 125.79, 114.26, 79.01, 78.60, 55.47, 55.43, 46.75, 33.78, 32.28, 28.62, 28.32, 24.25, 23.58. Benzyl ((5-Phenyl-1H-imidazol-2-yl)methyl)carbamate (4i). White solid (238 mg, 39%); mp 171 - 174 °C; 1H NMR (300 MHz, DMSO) δ 7.82 (t, J = 5.5 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.56 (s, 1H), 7.42 – 7.30 (m, 6H), 7.21 (t, J = 7.4 Hz, 1H), 5.05 (d, J = 12.2 Hz, 2H), 4.32 (d, J = 5.8 Hz, 2H). 13C NMR (75 MHz, DMSO) δ 156.74, 146.29, 137.66, 137.45, 133.45, 129.01, 128.80, 128.24, 126.90, 124.73, 115.26, 66.04, 38.49. tert-Butyl (S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4j). Yellow solid (334 mg, 43%); mp 149 - 153 °C; 1H NMR (300 MHz, DMSO) δ 11.92 (d, J = 17.9 Hz, 1H), 7.72 (dd, J = 19.6, 5.6 Hz, 2H), 7.49 (d, J = 8.0 Hz, 3H), 4.90 – 4.68 (m, 1H), 3.53 (s, 1H), 3.35 (s, 1H), 2.30 – 2.08 (m, 1H), 2.06 – 1.74 (m, 3H), 1.43 – 1.11 (m, 9H). 13C NMR (75 MHz, DMSO) δ 138.75, 131.66, 126.56, 78.63, 55.66, 46.80, 33.72, 28.61, 28.30, 23.56. tert-Butyl (S)-2-(5-(4-Cyanophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4k). Yellow solid (295 mg, 44%); mp 92 - 95 °C; 1H NMR (300 MHz, DMSO) δ 7.95 (d, J = 8.2 Hz, 2H), 7.90 – 7.68 (m, 3H), 5.04 – 4.72 (m, 1H), 3.55 (s, 1H), 3.37 (s, 1H), 2.32 – 2.14 (m, 1H), 2.00 – 1.78 (m, 3H), 1.26 (d, J = 72.8 Hz, 9H). 13C NMR (75 MHz, DMSO) δ 172.44, 154.18, 153.61, 151.93, 151.27, 138.30, 133.02, 125.16, 119.60, 116.80, 108.71, 79.26, 78.87, 55.21, 54.82, 47.07, 46.79, 45.85, 33.65, 32.27, 28.55, 28.25, 24.31, 23.62, 21.51 ACS Paragon Plus Environment

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tert-Butyl (S)-(2-Phenyl-1-(5-phenyl-1H-imidazol-2-yl)ethyl)carbamate (4l). White solid (459 mg, 63%); mp 189 - 192 °C; 1H NMR (300 MHz, DMSO) δ 14.96 (s, 2H), 8.04 (s, 1H), 7.93 – 7.84 (m, 2H), 7.73 (d, J = 6.9 Hz, 1H), 7.51 (t, J = 7.4 Hz, 2H), 7.46 – 7.38 (m, 1H), 7.25 (q, J = 5.7 Hz, 4H), 5.17 (q, J = 7.4 Hz, 1H), 3.38 (d, J = 12.8 Hz, 1H), 3.24 (dd, J = 13.3, 9.0 Hz, 1H), 1.31 (s, 6H).

13

C NMR (75 MHz, DMSO) δ 155.31, 148.83, 136.75, 132.93, 129.64, 129.58,

128.79, 127.37, 127.26, 125.83, 115.23, 79.53, 49.50, 28.44. Procedure for the Continuous Flow Synthesis of Bisimidazole 4m. 1 mmol (396 mg) of 4,4'bis(2-bromoacetyl)biphenyl (1m),29 2.1 mmol (451.5 mg) of N-Boc-L-proline (2b) and 3.8 mmol (540 µL) of triethylamine were added to a 10 mL sample of acetonitrile. The mixture was stirred for 10 min at room temperature. During this time the solution becomes homogeneous. The mixture was introduced into the injection loop of the continuous flow reactor (feed A). The mixture was pumped from the injection loop into the Y-mixer at a flow rate of 2.15 mL/min. In the mixer the solution was combined with the ammonium acetate solution at a flow rate of 0.33 mL/min (feed B; 8.6 M solution of ammonium acetate in water). The mixture passed through the stainless steel reactor at 160 °C (3 min residence time). The mixture was cooled in the heat exchanger and left the flow system through the back pressure regulator. The processed mixture left the flow reactor as a two phase water/MeCN solution. The aqueous phase was removed and discarded, and the solvent from the organic phase was removed under reduced pressure. The crude product was dissolved in ethyl acetate and extracted with sat. NaHCO3. The organic phase was separated and dried with MgSO4. Evaporation of the solvent provided 446 mg (71%) of ditert-butyl

2,2'-([1,1'-biphenyl]-4,4'-diylbis(1H-imidazole-5,2-diyl))(2S,2'S)-bis(pyrrolidine-1-

carboxylate) (4m). Yellow solid (446 mg, 71%); mp 180-185 °C; 1H NMR (300 MHz, DMSO) δ 12.00 (s, 2H), 7.81 (d, J = 7.9 Hz, 4H), 7.68 (d, J = 7.6 Hz, 4H), 7.50 (s, 2H), 4.82 (d, J = 18.8 Hz, 2H), 3.55 (s, 2H), 3.36 (s, 2H), 2.23 (s, 2H), 1.94 (d, J = 34.2 Hz, 6H), 1.28 (d, J = 73.1 Hz, 18H).

13

C NMR (75 MHz, DMSO) δ 154.23, 153.84, 151.20, 137.69, 126.74, 125.06, 79.09,

78.67, 55.65, 55.12, 46.79, 33.78, 32.31, 28.63, 28.33, 24.28, 23.60.

ACKNOWLEGMENTS C.O.K acknowledges the Science without Borders program (CNPq, CAPES) for a “Special Visiting Researcher” fellowship. P. F. C. thanks CNPq for a postdoctoral scholarship (200566/2014-8/PDE). We are indebted to Dr. Michael Fuchs for chiral HPLC measurements. ACS Paragon Plus Environment


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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at 10.1021/acssuschemeng.xxxxxx. Further experimental results, description of the continuous flow setup, 1H and 13C NMR spectra of the compounds 4a to 4m.

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A Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles – Towards the Continuous Production of Daclatasvir

Paula F. Carneiro,† Bernhard Gutmann,*,† Rodrigo O. M. A. de Souza‡ and C. Oliver Kappe*,†

SYNOPSIS: An intensified flow process yields 1H-4-aryl imidazoles in residence times of < 10 min in a continuous two-step reaction sequence.


Process Intensified Flow Synthesis of 1H-4-Substituted Imidazoles

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