Synthesis of Vildagliptin Utilizing Continuous Flow and Batch

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Synthesis of Vildagliptin utilizing continuous flow and batch technologies Laurent Pellegatti, and Joerg Sedelmeier Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 25 Mar 2015 Downloaded from http://pubs.acs.org on March 26, 2015

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Organic Process Research & Development

Synthesis of Vildagliptin utilizing continuous flow and batch technologies Laurent Pellegatti and Jörg Sedelmeier* Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland.

*Corresponding Author [email protected]

ACS Paragon Plus Environment

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ABSTRACT The preparation and utilization of the Vilsmeier reagent (VR) is well-known in the literature with its usefulness and scope being frequently demonstrated in organic synthesis. However, it is an irritant and has a high thermal energy of decomposition consequently these factors lead to operational issues on larger scale which suggests approaches whereby the reagent is not isolated. Herein, we report the in-line formation and instantaneous consumption of VR utilizing both conventional batch and flow technologies. The approach is demonstrated by way of the synthesis of Vildagliptin, thereby mitigating potential safety and hygiene hazards.

KEYWORDS Vildagliptin, Galvus, Continuous Manufacturing, Vilsmeier reagent.


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Vildagliptin (6), is an oral anti-diabetic (anti-hyperglycemic) drug of the dipeptidyl peptidase-4 (DPP-4) inhibitor class developed and marketed by Novartis Pharma (Scheme 1).[1] The synthesis of Vildagliptin involves three linear chemical steps starting from the readily available L-proline amide 1 and chloro-acetyl chloride (2). The N-acylated adduct 3 consecutively undergoes dehydration of the amide functionality mediated by VR to yield the cyanopyrrolidine 4. Alkylation of hydroxyl amino adamantane (HAAD) 5 with 4 in the presence of base provides Vildagliptin (6).

Scheme 1. Synthesis scheme of Vildagliptin (6).

The synthesis for intermediate 4 from N-acylated proline amide (3) utilizes the VR as dehydrating agent, which is known to be most commonly prepared from either DMF/phosphorus oxychloride (POCl3), DMF/thionyl chloride (SOCl2) or DMF/oxalyl chloride ([COCl]2) but requires special consideration with respect to transportation, storage, handling and process safety.[2] Even though the use of VR has been extensively investigated,[3] the application of this highly reactive and moisture sensitive compound on large scale requires special precautions to mitigate the risks of potentially dangerous incidences such as physical exposure or runaway reactions. Calorimetry investigations report that both, the formation of Vilsmeier reagent as well as its consumption possess specific thermal hazards accompanied with large and rapid increases


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in temperature and pressure.[2b-d, 2f] Given these facts, the development of a chemical process for a reliable and safe synthesis of the cyanopyrrolidine 4 utilizing VR as dehydration agent is highly desirable. We focused our attention toward continuous flow technology anticipating that the identified hygiene issues associated with intermediates 3 and 4 as well as safety concerns of the Vilsmeier reagent can be adequately addressed. Flow chemistry principles[4] allow for the safer on-site generation and rapid in-line consumption of Vilsmeier reagent (VR), while operating at reduced reaction holdup (volume) compared to conventional batch vessels. Furthermore, the closed flow reactor system facilitates the safe and contained handling of the hazardous compounds and protects the operator from exposure. Implementation of simply constructed flow reactors (e.g. T-shaped mixers and empty tubing) into an existing batch infrastructure has been anticipated to result in process intensification at low investment costs. The continuous manufacturing setup used for our investigation integrates pre-cooling loops for each reagent stream, tubular perfluoroalkoxy (PFA) reactors, PFA T-pieces,[5] syringe pumps,[6] pressure sensors[7] and a mass flow controller unit[8] to monitor the overall flow rate (Figure 1). The hardware modules are software-controlled[9] allowing for on-line monitoring of relevant process parameters. The integrated control features enable automatic emergency actions based upon user predefined parametersa thereby increasing the overall reliability of the chemical operation.

a

Minimum (2.0 bar) and maximum (5.0 bar) operational pressure is defined. A blockage or leakage results in a pressure deviation, which consequently leads to shut-down of the pump modules and emergency cooling (5 °C) of the reactor. Same safety measures apply for deviation in the overall mass-flow.


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From initial small scale batch experiments the flow compatibility of reaction mixtures resulting from combinations of DMF and the chlorinating agents POCl3, SOCl2 and (COCl)2 were investigated. The VR formation prepared from oxalyl chloride and DMF appears highly violent with vigorous outgassing of CO2 and CO being observed. The resulting heavy suspension and gas evolution rated this approach unsuitable for flow. However, it was noted that reactions of POCl3 and SOCl2 with DMF preceded smoothly resulting in clear solutions and therefore being in principle well-suited for flow chemistry application. Due to the highly acidic pH of the reaction solution and the associated corrosiveness, PFA was selected as the reactor material. Based on the preliminary solubility assessment, a consideration of reaction kinetics and the potential formation of N,N-dimethylcarbamoyl chloride (DMCC), a known carcinogen,[1e,10] the generation of VR in continuous flow mode was optimized using the reagent combination DMF/POCl3 as precursors, with reagent concentration, stoichiometry, reaction temperature and residence time being determined. Optimal conditions for the preparation of VR was achieved by mixing neat phosphorous oxychloride (4.0 mL/min; 1.0 equiv) and DMF (5.0 mL/min; 1.5 equiv) in a simple T-shaped mixer (id=1.6 mm; PFA) with the combined stream being directed through a perfluoroalkoxy (PFA) coiled tubing reactor (id=1.6 mm, 4.5 mL) with a residence time of 30 sec at 22 °C bath temperature (Figure 1). The formation of VR was quantified by quench with L-proline amide 3 and consecutive HPLC analysis, tracking the conversion to intermediate 4 relative to naphthalene as an internal standard. A calculated adiabatic temperature rise (∆Tad) of 16 °Cb for a 4.8 M solution at a bath temperature of 22 °C gave an estimated internal reaction temperature (IT) of about 40 °C (313 K) which is below the onset

b

∗∆

Calculated using formula: ∆ad = ∗∁ , based on literature value[2b]


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decomposition temperature of 67 °C (340 K)[2b]. Operating under these reaction conditions can be justified due to the minimal reactor holdup (4.5 mL), minimized residence time and built-in software safety features, mitigating the overall risk of a run-away reaction and exposure. Figure 1. Reactor setup for the preparation of Vilsmeier reagent.

We next focused our attention towards the development of the reaction conditions for the direct conversion of N-acylated proline amide 3 to the cyanopyrrolidine 4 by in-line quenching freshly prepared VR (Figure 2). The reaction 1+2[3] was performed using existing batch equipment (Reactor 1), with the reactor containing the crude reaction solution 3 serving as a feedstock tank (stream 1; 1.5 M). Stream 2 providing the VR was prepared as previously described (4.8 M, 9 mL/min). For optimization of the dehydration reaction (34) we investigated the effect of stoichiometry (flow rate ratio), residence time, solubility of intermediates and reaction temperature. Under optimal reaction conditions a 1.5 M solution of


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intermediate 3 (26.0 mL/min; 0.9 equiv) in DMF (Stream 1) was mixed at a T-piece (id=1.6 mm; PFA) with a 4.8 M solution of VR (9.0 mL/min; 1.0 equiv) in DMF (Stream 2). The resulting mixture containing 4 (1.11 M, 35 mL/min) was then directed to a PFA coiled tubing reactor (id=5 mm; 50 mL; PFA) filled with glass beads (d=2 mm) for improved mixing to give a residence time of 90 sec at 22 °C bath temperature. The conversion to the cyanopyrrolidine (4) was quantified by HPLC analysis (w/w%) based on naphthalene as internal standard. Upon exiting the loop-reactor, the output containing intermediate 4 (stream 3, 1.11 M, 35 mL/min) was then collected in a batch vessel (Reactor 2) for consecutive workup in traditional batch mode. Figure 2. Reactor setup for the preparation of cyanopyrrolidine 4 and Vildagliptin (6).


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The work up consisted of reducing the crude reaction mixture by 75wt% under high vacuum (5 mbar, 60 °C) followed by crystallization from DMF/n-pentanol/n-heptane (volume ratio 1/2/2) delivering 4 in 79.4% yield and 99% purityc. With the telescoped flow process generating intermediate 4 in hand, we turned our attention towards a longer-duration experiment considering this to be an important indicator for potential blockages or fouling of the flow reactor system. The flow setup ran for 60 min under steady stated, thereby generating multigram quantities of the desired cyanopyrrolidine 4, while the online monitoring of reaction parameters and available safety featuresa ensured a safe operation and conversion of 2.34 moles 3 (1.56 L stock solution, throughput of 5.8 kg*hr-1*L-1)e. As an extension of this work we were attracted by the opportunity to synthesis Vildagliptin 6 in a fully continuous flow mode without isolation of reaction intermediates. Following a semibatch strategy, issues with reactivity and pH adjustmentf were encountered. It was revealed that for successful transformation of 46 a neutralization and purification of moiety 4 is required prior to the reaction with HAAD (5). We concluded that crystallization of 4 from the crude flow stream appeared to be the most practical solution allowing us to follow-up with the reaction 4+56 as planned in existing batch vessels. Scheme 2. Batch-wise transformation of cyanopyrrolidine 4 to Vildagliptin (6).

c

Due to the irritant nature of compound 4 the filter cake has always been handled as a wet solid to mitigate the risk of exposure.

d

After two times the residence time (2*120 sec) the steady state experiment was started.

e

Throughput of product (space-time-yield) has been normalized to production time [1 h] and reactor volume [1 L].

f

Significant amounts of K2CO3 (12.5 equiv) are required for the reaction 4+56 to occur, which is not attractive from an operational point of view.


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Cyanopyrrolidine 4 originating from the flow process was crystallized in reactor 2 followed by filtration and washing of the filter cake with n-heptane. The DMF-containing crude 4 was redissolved in DMF in reactor 2 and combined with HAAD (5) (1.2 equiv) in the presence of K2CO3 (5.5 equiv). Vildagliptin (6) was isolated from the reaction mixture by crystallization from isopropanol/TBME (volume ratio 1:20).[1b] The alkylation of HAAD (5) with cyanopyrrolidine 4 was successfully accomplished yielding Vildagliptin (6) in 79% yield based on proline amide (1) within the required analytical specification for drug substance release. CONCLUSION: Driven by the desire to mitigate the risks associated with the utilization of Vilsmeier reagent on scale and the potential benefits of its on-demand synthesis and immediate consumption, we investigated a two-step flow process delivering the key intermediate 4 of the Vildagliptin synthesis. We successfully demonstrated the technical and chemical feasibility of the continuous manufacture of compound 4 as well as the process effectiveness. The closed continuous flow setup enabled us to safely handle irritant compounds including intermediates 3, 4 and the Vilsmeier reagent. Even though the attempts to run a fully continuous process 36 were not successful we showed the implementation of simply constructed flow equipment into an existing batch facility to be an attractive concept for process intensification. Overall, an economical and


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safe two-step flow process for Vildagliptin intermediate 4 has been developed and scaled-up delivering 4 with a throughput of 5.8 kg*hr-1*L-1.

ACKNOWLEDGMENT We thank Dr. Mark Meisenbach, Dr. Donatienne Denni-Dischert, Stefanie Knobloch, Prof. Dr. G. Sedelmeier, Dr. Friedrich Schürch, Dr. Christian Mathes, Bernard Linder, Flavien Susanne, Dr. Jutta Polenk, Dr. Benjamin Martin, Dr. Stephan Abel and Dr. Berthold Schenkel for their valuable contributions and support.

SUPPORTING INFORMATION AVAILABLE Experimental procedures and full characterization (1H and

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C NMR data and spectra) for all

compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

ABBREVIATIONS DPP-4, dipeptidyl peptidase-4; VR, Vilsmeier reagent; HAAD, hydroxy amino adamantane; PFA, perfluoralkoxy; DMCC, N,N-dimethylcarbamoyl chloride; IT, inner temperature.

REFERENCES (1) a) Villhauer, E. B. N-substituted 2-cyanopyrrolidines. WO9819998, 1998; b) Schäfer, F.; Sedelmeier, G. Processfor the preparation of N-substitueted 2-cyanopyrrolidens. WO04092127, 2004. c) Holmes, D. G. Combinination of organic compounds. WO05049088, 2005; d) Pfeffer,


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Synthesis of Vildagliptin Utilizing Continuous Flow and Batch

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