Process Intensification and Integration Studies for the Generation of a

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Process Intensification and Integration Studies for the Generation of a Key Aminoimidazole Intermediate in the Synthesis of Lanabecestat Desiree Znidar, David Cantillo, Phillip Inglesby, Alistair Boyd, and C. Oliver Kappe Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00089 • Publication Date (Web): 26 Apr 2018 Downloaded from http://pubs.acs.org on April 26, 2018

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Organic Process Research & Development

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Process Intensification and Integration Studies for the Generation of a Key Aminoimidazole Intermediate in the Synthesis of Lanabecestat

Desiree Znidar,†,‡ David Cantillo,†,‡ Phillip Inglesby,§ Alistair Boyd,§ and C. Oliver Kappe*,†,‡

†

Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria

‡

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

AstraZeneca, Silk Road Business Park, Macclesfield SK10 2NA, United Kingdom

____________________ * Corresponding author. E-mail: [email protected] 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

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ABSTRACT An improved synthetic procedure for the multistep synthesis of aminoimidazole 6, a key intermediate in the preparation of lanabecestat (AZD3293/LY3314814), is described. Under intensified conditions (high temperature and elevated pressure) the overall processing time and required amount of reagents could be significantly reduced, thus potentially minimizing manufacturing costs and improving the sustainability footprint. Process integration of three sequential steps starting from ketone intermediate 2 has been attempted to set the stage for a potential multistep continuous manufacturing route. The process consists of initial formation of imine 3 by treatment of ketone 2 with ammonia and Ti(iPrO)4, a cyclocondensation of 3 with thioamide 4 to form thiol 5 and an aminolysis using ammonia and Zn(OAc)2 allowing the target building block 6 to be accessed in 48% overall yield.

Keywords: BACE inhibitors; microwave chemistry; process intensification; process integration



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4 INTRODUCTION Alzheimer’ disease (AD) is a growing health issue due to an aging population worldwide. It is the most common cause of dementia and therefore the World Health Organization (WHO) has recognized this neurodegenerative disorder as a public health priority.1,2 Worldwide, Alzheimer’s disease affects around 50 million people with nearly 10 million new cases every year. Currently, no therapy exists to cure the disorder or to stop its progress. AD is thought to be caused by the accumulation of amyloid plaques, mainly composed of neurotoxic ß amyloid peptides (Aß), in the brain.3 The Aß fragments are formed by cleavage of amyloid precursor proteins (APPs) induced by two enzymes, namely ß-site amyloid precursor protein cleaving enzyme (BACE-1) and γ-secretase. BACE-1 activity induces the first step in the processing of APP to Aß peptides, and thus its inhibition is a key therapeutic target to stop or reduce the formation and build-up of Aß.2,4 Lanabecestat (AZD3293/LY3314814), co-developed by AstraZeneca and Eli Lilly and Co., is currently in Phase III clinical trials as an investigational treatment for early AD by inhibiting BACE-1.5 In August 2016 the strategic AstraZenecaLilly BACE alliance announced that they received U.S. Food and Drug Administration (FDA) Fast Track designation which is particularly designed to promote the development and review of promising new therapies to treat serious conditions and tackle unmet medical needs.6 The manufacturing route to lanabecestat currently used, as outlined in the patent literature,7 utilizes indanone 1 as the starting material and includes the formation of the imine intermediate 3 from ketone 2 and a subsequent cyclocondensation between imine 3 and thioamide 4 to produce mercaptoimidazole 5 (Scheme 1). Mercaptoimidazole 5 is then converted to aminoimidazole 6 via aminolysis with ammonia in the presence of a hydrogen sulfide scavenger, such as zinc acetate. A classical resolution with (+)-camphorsulfonic acid, taking advantage of the newly installed basic nitrogen, provides 7 as a (+)-camphorsulfonic acid salt with 99% enantiomeric excess. The final step is a C─C bond formation via Suzuki cross coupling with pyridylboronic acid 8 to afford lanabecestat.7,8


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5 Scheme 1. Synthetic Route to Lanabecestat

The reported batch manufacturing process is relatively time-, labor- and resource consuming, as several work-up procedures are required between the reaction steps.9 Additionally, an overall reaction time of several days, without considering the time required for isolation and purification between each of the steps, is a major drawback and intensification of the process would be highly desirable. Flow chemistry and continuous processing have been shown as ideal tools for the design and execution of integrated multistep syntheses.10,11 The ease with which several reaction steps, including purification steps, can be combined in a single reaction stream is attracting considerable attention from the pharmaceutical industry towards the implementation of continuous operations for the preparation of active pharmaceutical ingredients (API).11 This shift is largely driven by a focus of the pharmaceutical manufacturing industry on process intensification, safety, costeffectiveness, sustainability, product quality, and atom-efficiency.12 In addition, the ability of scaling this technology can drastically reduce the discovery-to-manufacturing time frame.13 Continuous reactors in general provide a wide temperature window, high pressure resistance and accurate residence time control which makes them perfect tools to employ intensified conditions.10 Our group has recently developed continuous, intensified processes for the synthesis of two of the key intermediates in the synthesis of lanabecescat (i.e., the synthesis of intermediates 4 and 8).14 As a continuation of this work, we decided to also evaluate an integrated, fully continuous procedure for the synthesis of intermediate 6 over three steps ACS Paragon Plus Environment


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6 starting from ketone 2. Integration of these steps into a single telescoped process would not only be economically and environmentally beneficial, but could also help to reduce the technical complexity of the process. Unstable, humidity sensitive intermediates such as iminium salt 3 could be directly telescoped into further transformations reducing the risk of degradation or hydrolysis. In addition, a telescoped flow synthesis could greatly reduce the overall processing time compared to the current batch procedure. Herein, we describe the optimization and intensification of each of the three individual reaction steps mainly using microwave batch conditions for the synthesis of aminoimidazole intermediate 6 (imine formation, cyclization, aminolysis).15 In addition, an evaluation of a one-pot three-step procedure has also been examined as preliminary assessment of a fully integrated continuous protocol.

RESULTS AND DISCUSSION One-Pot Imine Formation and Cyclization Reaction to Mercaptoimidazole 5. The described batch procedure for the generation of imine 3 from ketone 2 (Scheme 1) consists of treatment of the ketone 2 with ammonia using Ti(iPrO)4 as water scavenger and Lewis acid mediator.7 The reaction mixture is then heated at 65-70 °C in an autoclave reactor for 15 h under nitrogen atmosphere. Before elimination of excess of ammonia, all inorganics are removed by filtration with activated carbon. The resulting imine 3 is then treated with hydrogen chloride in a non-aqueous solvent in an additional step to afford the corresponding iminium salt after filtration in 89% yield. The subsequent synthesis of mercaptoimidazole 5 involves heating of the isolated imine hydrochloride intermediate 3 and thioamide 4 in isopropanol at 60 °C for 10 h in the presence of CH(OMe)3 as water scavenger and DIPEA under an argon atmosphere (cf. Scheme 1).7 Typically 70 - 80% of the desired product 5 is obtained accompanied by approximately 20 - 30% of thione 5b as impurity (Scheme 2), with the desired compound 5 being isolated in 63% yield after a laborious work-up including solvent switch, filtration, washing, etc.7 In order to avoid the elaborate isolation of intermediate 3 and to shorten the reaction time we evaluated a one-pot procedure in which imine 3 is generated under intensified conditions and then directly cyclized to 4. The investigation commenced with an evaluation of the stability of the starting material 2 in solution as a potential feedstock for a continuous process. HPLC monitoring of a 0.5 M solution of ketone 2 revealed that it is stable over 26 h at room temperature and 60 °C, both with and without the addition of 1.5 equiv of Ti(iPrO)4


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7 (for details see Supporting Information). The substrate showed poor solubility in methanol at room temperature, while it was fully dissolved under gentle heating (99%) and conversion (97%). A pressure of ca. 5 bar was generated in the sealed vessel, as observed in a pressure-monitored microwave experiment carried out under the same conditions. Moreover, the amount of Ti(iPrO)4 which acts as a water scavenger and Lewis acid mediator, could be reduced to 1.5 equiv under intensified conditions. Importantly, the reaction mixture appeared fully homogenous at temperatures above 60 °C and thus suitable for flow processing. It should be noted that further improvements could be expected under continuous flow conditions, as the lack of headspace maximizes the amount of ammonia dissolved in the liquid reaction phase.17 Under optimal conditions (Table 1, entry 17) the desired imine 3 was isolated as the hydrochloride salt in nearly quantitative yield (98%) after adding a solution of HCl in dioxane (see Experimental Section for details). Both the imine and the isolated iminium salt are moisture sensitive, and need to be stored under inert atmosphere. Attempts to replace stoichiometric amounts of Ti(iPrO)4 by a combination of trimethyl orthoformate as water scavenger and catalytic amounts of other metal-based Lewis acid catalysts such as ZnCl2, Zn(OAc)2, Yb(OTf)3 or Sc(OTf)3 resulted in very poor conversions (99% purity). Aminoimidazole 6 Starting from Crude Mercaptoimidazole 5. To a 10 mL microwave process vial, equipped with a magnetic stirring bar, were added crude isolated mercaptoimidazole 5 (797 mg, 0.74 mmol), Zn(OAc)2 (330 mg, 1.5 mmol, 1.75 equiv) and 5 mL ammonia in methanol (7 M, 35 equiv). The vial was sealed with a crimp top cap and heated for 20 min at 150 °C under microwave irradiation. After cooling down to room temperature, an aliquot of the reaction mixture was taken for yield determination by calibrated HPLC (97%yield, >99% purity and 47% yield of 6 over all steps).

ACKNOWLEDGEMENT 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 by the State of Styria (Styrian Funding Agency SFG). We gratefully acknowledge Robert Woodward (AstraZeneca) his scientific contributions to this work.

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental details (optimization studies, 1H-NMR and 13C-NMR spectra of all products)

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Process Intensification and Integration Studies for the Generation of a

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