Development of a Continuous-Flow Sonogashira Cross-Coupling

Full Paper

Development of a Continuous-Flow Sonogashira Cross-Coupling Protocol using Propyne Gas under Process Intensified Conditions Desiree Znidar, Christopher Hone, Phillip Inglesby, Alistair Boyd, and C. Oliver Kappe Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 29 May 2017 Downloaded from http://pubs.acs.org on June 3, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 19

Organic Process Research & Development

1 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

Development of a Continuous-Flow Sonogashira Cross-Coupling Protocol using Propyne Gas under Process Intensified Conditions

Desiree Znidar,† Christopher A. Hone, †,‡ Phillip Inglesby,§ Alistair Boyd,§ and C. Oliver Kappe*,†,‡

†

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

‡

Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria §

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

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

ACS Paragon Plus Environment


Page 2 of 19

2 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

Graphical contents entry


Page 3 of 19


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

Abstract The development of a continuous-flow Sonogashira cross-coupling protocol using propyne gas for the synthesis of a key intermediate in the manufacturing of a β-amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, currently undergoing late stage clinical trials for a disease-modifying therapy of Alzheimer’s disease, is described. Instead of the currently used batch manufacturing process for this intermediate which utilizes TMS‐propyne as reagent, we herein demonstrate the safe utilization of propyne gas, as a cheaper and more atom efficient reagent, using an intensified continuous-flow protocol under homogeneous conditions. The flow process afforded the target intermediate with a desired product selectivity of ~91% (vs bis-adduct) after a residence time of 10 min at 160 °C. The continuous-flow process compares favorably with the batch process, which uses TMSpropyne, requires overnight processing, TBAF as an additive, and a significantly higher loading of Cu co-catalyst.

Keywords: BACE inhibitors; continuous-flow; gas-liquid transformations; propyne; scale-up, Sonogashira cross-coupling



Page 4 of 19

4 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

INTRODUCTION Alzheimer’s disease (AD) is a progressive neurodegenerative disease resulting in personality and behavioral disturbances, impaired memory loss in ability to perform daily tasks and death.1 AD affects an estimated 47 million patients and their families worldwide,2 and this number is expected to rise to 115 million by 2050.3 Alzheimer’s disease is caused through the accumulation of β-amyloid proteins into plaques outside neurons in the brain.4 It is thought that soluble forms of this protein are neurotoxic and are the main cause of deterioration seen in Alzheimer patients. The soluble protein fragments are made through the cutting of larger proteins, namely the amyloid precursor protein (APP), by two enzymes, β-site amyloid cleaving enzyme (BACE) and γ-secretase. Notably, BACE-1 inhibitors have shown promise as potentially disease-modifying treatments for AD.5 The novel, potent BACE-1 inhibitor AZD3293 (LY3314814; Figure 1, 1) is a brain-permeable, orally active compound with a slow off-rate from its target enzyme BACE-1, which robustly reduced plasma, CSF, and brain Aβ40, Aβ42, and sAβPPβ concentrations in multiple non-clinical species and in elderly subjects and patients with AD.6,7 Eli Lilly and Co. and AstraZeneca are currently studying AZD3293 in phase 3 clinical trials.8

Figure 1. Structure of Eli Lilly/AstraZeneca BACE1 inhibitor AZD3292 (+)-camsylate and of the 3-propynylpyridine fragment common to several BACE1 inhibitors. A key step in the manufacturing of compound 1 is the Pd-catalyzed Sonogashira crosscoupling reaction between 1-trimethylsilyl(TMS)-propyne and 3,5-dibromopyridine (2) leading to the 3-propyne-pyridine intermediate 3 (Scheme 1),9 a common fragment in several bioactive BACE1 inhibitors.5 The batch manufacturing process for the Pd-catalyzed Sonogashira cross-coupling reaction shown in Scheme 1 involves heating at reflux overnight to proceed to >99% conversion, and typically affords approximately 80% of the desired product 3 and 19% bis-adduct as an impurity (HPLC area%), with the desired compound 3 being isolated in 66% yield.9 The subsequent step in the manufacturing route is a lithiation/borylation sequence (Scheme 1); the resulting intermediate is then coupled with the right-hand part of the target molecule using Suzuki-type cross-coupling chemistry.9 ACS Paragon Plus Environment

Page 5 of 19


5 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

Scheme 1. Sonogashira coupling and lithiation/borylation chemistry towards AZD3293.

We wanted to assess the feasibility of using propyne as a greener, less expensive and more efficient alternative to TMS-propyne for the Sonogashira cross-coupling reaction. Propyne is a valuable three carbon atom building block for organic synthesis, but is a gas at room temperature (bp = −23.2 °C) and is highly hazardous due to its potential flammability and explosive properties under certain conditions, and high reactivity.10 Thus, the use of gas surrogates is often favored at a laboratory scale for ease of handling. For instance, Abraham and Suffert reported the treatment of (E/Z)-1-bromopropene (1.92 mmol scale) with n-BuLi and water in THF at −78 °C.11 Propyne was liberated in situ and subsequently used in a Sonogashira cross-coupling, circumventing the direct use of propyne gas and the need for specialized equipment for gas dissolution. However, the use of surrogates is typically more expensive and atom inefficient, therefore on larger scale the direct use of propyne gas is often a preferred option.12 There are unique process challenges with handling gas-liquid reactions, in the case of large-scale batch reactors: (i) much of the gas is in the headspace and therefore the reactor needs to be pressurized to maximize the amount of gas in solution and reduce mass transfer effects; and (ii) there is a large inventory of highly reactive gas and potentially flammable mixture within the reactor. Typical commercial batch reactors can operate between 2 to 6 barg, thus higher pressures require more specialized equipment. Many of the safety and process challenges involving gas-liquid reactions can be better addressed by using continuous processing.13,14 There is a current paradigm shift in the pharmaceutical industry from traditional batch manufacturing to continuous processing for the preparation of Active Pharmaceutical Ingredients (API).14 This shift is reflected by a focus in the fine chemicals and pharmaceutical sector on process intensification, safety, cost, sustainability, product quality



Page 6 of 19

6 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

and energy usage.15 The small channel dimensions of continuous-flow reactors provide a high surface-to-volume ratio enabling the generated heat to be dissipated quickly and an exquisite control of reaction temperature.16 In addition, there is only a small inventory of gas within the reactor at any one time due to the small reactor volumes, thus gases can be handled in a safer and more controlled manner.13 Furthermore, flow reactors provide precise residence time control which may enable the reduction of overreaction products. Notably, process intensified conditions (“extreme process windows”) are easily realized in flow with continuous-flow reactors safely being pressurized to increase the solubility of gases in the liquid phase.17 Given the importance of Pd-catalyzed coupling reactions in modern organic synthesis and pharmaceutical manufacturing, many protocols have been reported to perform these transformations using continuous-flow reactors,18 including Sonogashira cross-coupling reactions.19 The aim of the research described in this article was to develop a safe and scalable continuous-flow process with propyne gas for the preparation of key intermediate 3 under process intensified conditions. The continuous-flow protocol should provide a more cost effective alternative to the currently employed batch manufacturing routine employing TMSpropyne as a propyne surrogate.

RESULTS AND DISCUSSION Microwave Experiments Employing 1-Hexyne. We commenced our investigation with a feasibility study using 1-hexyne as a propyne mimic cross-coupling partner in small-scale microwave batch experiments. Initial screening experiments were performed with 1.0 mmol of 3,5-dibromopyridine (2) and 1-hexyne in a sealed borosilicate glass vessel (maximum filling volume 6 mL, total volume 10 mL). 1-Hexyne has a boiling point of ca. 71 °C, therefore it is a liquid at room temperature, making it easier to handle than propyne. The vessels were sealed, heated using microwave dielectric heating and stirred (600 rpm) using a Monowave 300 single-mode microwave reactor. A fiber optic sensor was used for internal temperature control and the “as-fast-as-possible” heating mode was used.20 The TMS-propyne Sonogashira cross-coupling protocol reported in the original patent and published literature (see Scheme 1)9,21 was slightly adapted for these preliminary screening experiments. Instead of reflux heating at 110 °C overnight, sealed vessel microwave heating at 160 °C for 10 min was employed. Tetra-n-butylammonium iodide (TBAI) was used instead of tetra-nbutylammonium fluoride (TBAF) because it displayed better solubility in a range of organic solvents. CuI concentration was lowered from 30 mol% to 10 mol% to reduce the loading ACS Paragon Plus Environment

Page 7 of 19


7 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

down to more acceptable levels for commercial manufacture.22 Since homogeneous reaction mixtures are highly preferable for continuous-flow processing, initial batch screening reactions were performed to identify solvents which provided good solubility for all the reaction components. Gratifyingly, moderate to good selectivity for the desired monosubstituted product 4 was observed by GC-MS analysis (area%) for all solvents studied (48 to 85%, Table 1), however, it is noteworthy that the selectivity is impacted by the conversion. MTBE and toluene produced a heterogeneous mixture before reaction and gave only moderate formation of the desired product at 54% and 59%, respectively. THF, Me-THF and DME provided homogeneous solutions before the reaction after gentle pre-heating. However, precipitation of amine salts at the end of the reaction was observed. THF and Me-THF showed the lowest reactivity even with a higher excess (2 equiv) of 1-hexyne. DME as solvent resulted in significant dehalogenation to provide 3-bromopyridine (13%) as a minor product. Pd black formation was observed with MeCN, which is indicative of some catalyst deactivation. Notably, homogeneous mixtures throughout could be achieved with either DMF, DMA or NMP, with DMA providing the best conversions and selectivities (2:

Development of a Continuous-Flow Sonogashira Cross-Coupling

Recommend Documents