Synthesis of a Sodium-Hydrogen Exchange Type 1 Inhibitor: An Efficient Cu-Catalyzed Conjugated Addition of a Grignard Reagent to an Acetyl Pyridinium Salt Wenjun Tang, † Nitinchandra D. Patel, Xudong Wei,* Denis Byrne, Ashish Chitroda, Bikshandarkoil Narayanan, Alexander Sienkiewicz, Laurence J. Nummy, Max Sarvestani, Shengli Ma, Nelu Grinberg, Heewon Lee, Soojin Kim, Zhibin Li, Earl Spinelli, Bing-Shiou Yang, Nathan Yee, and Chris H. Senanayake Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, United States * S Supporting Information ABSTRACT: A facile and economical five-step process for the synthesis of a sodium-hydrogen exchange type I inhibitor (NHE-1) was developed from readily available starting materials in 43% overall yield. Key transformations included a highly efficient copper-catalyzed conjugate addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts, a facile hydrogenation of 4-aryl dihydropyridines, a regioselective aromatic bromination, an efficient palladium-catalyzed carbonylation of aryl bromides, and a high-yielding acyl guanidine formation. A safe and scalable protocol for preparation of 2-trifluoromethyl phenyl Grignard reagent was developed, and a facile method for controlling the palladium content with N-acetyl-L-cysteine as the scavenger was demonstrated. Process issues in controlling the formation of a key diacylation side product during acyl guanidine formation are also addressed. ■ INTRODUCTION Sodium-hydrogen exchangers (NHEs) are ion transporters expressed in a variety of cells that maintain intracellular pH homeostasis by the electroneutral exchange of intracellular hydrogen for extracellular sodium. 1 Among the nine identified isoforms of NHEs, NHE type 1 (NHE-1) as the major subtype in myocardial cells is known to be deeply involved in ischemic and reperfusion injury. The NHE-1 inhibitors are proven to improve myocardial contractility and metabolic status as well as to reduce arrhythmia, apoptosis, necrosis, and intracellular overload of sodium and calcium ions. They can be effectively used for prevention and treatment of ischemic heart diseases such as acute myocardial infarction, arrhythmia, angina pectoris, etc., and they are also promising candidates for heart-protecting agents applied to reperfusion therapy or cardiac surgery including coronary artery bypass graft and percutaneous transluminal coronary angioplasty. 2 Our research department has recently discovered a potent NHE-1 inhibitor 1 for preclinical development to fully define safety and pharmaco- logical properties. An efficient and economical process to acyl guanidine 1 was thus required in order to supply ample drug substances for preclinical studies. The original synthetic route to compound 1 from Medicinal Chemistry 3 (Scheme 1) consisted of 14 synthetic steps and, while suitable for medicinal chemistry’s requirements, had a low overall yield (∼20%). In addition to the requirement of several chromatographic purifications, some costly reagents such as triflimide 3, octamethyl-2,2′-bi(1,3,2-dioxaborolane), and Boc- protected guanidine were also employed. We herein report an efficient and highly convergent synthesis of compound 1 from the readily available starting material 2-bromobenzotrifluoride (7) in only five synthetic steps and in 42% overall yield. Key transformations including an efficient copper-catalyzed con- jugated addition of 2-trifluoromethylphenyl Grignard reagents to acetyl pyridinium salts, a facile hydrogenation of 4-aryl dihydropyridines, a regioselective aromatic bromination, an efficient carbonylation of aryl bromides, and a high-yielding acyl guanidine formation are described at multikilogram scales, and the key process issues are addressed. ■ RESULTS AND DISCUSSION Choice of Synthetic Strategy. The original synthesis of NHE-1 inhibitor 1 from Medicinal Chemistry adopted a key Suzuki coupling reaction 4 between vinyl boronic ester 6 and trisubstituted aryl bromide 10 followed by a transfer hydro- genation to construct its 4-aryl piperidine framework. Although the Suzuki coupling was facile and proceeded in high yield (85%), the preparation of both vinyl boronic ester 6 and aryl bromide 10 were tedious and required several synthetic steps from readily available starting materials. Thus, this synthetic strategy was not ideal for further scale-up activity of compound 1. Several alternative methods for the synthesis of 4-aryl piperidines were studied on the basis of the availability of starting materials and practicality (Scheme 2). These included Received: November 14, 2012 Article pubs.acs.org/OPRD © XXXX American Chemical Society A dx.doi.org/10.1021/op300331b | Org. Process Res. Dev. XXXX, XXX, XXX-XXX