Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin Paul Bowles, † Steven J. Brenek, † Ste ́ phane Caron, † Nga M. Do, † Michele T. Drexler, † Shengquan Duan, † Pascal Dube ́ , †,§ Eric C. Hansen, † Brian P. Jones, † Kris N. Jones, † Tomislav A. Ljubicic, † Teresa W. Makowski, † Jason Mustakis, † Jade D. Nelson,* ,† Mark Olivier, ‡ Zhihui Peng, † Hahdi H. Perfect, † David W. Place, † John A. Ragan, † John J. Salisbury, ‡ Corey L. Stanchina, † Brian C. Vanderplas, † Mark E. Webster, † and R. Matt Weekly † † Chemical Research and Development, ‡ Analytical Research and Development, Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States * S Supporting Information ABSTRACT: A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa- bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-D-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with L-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality. ■ INTRODUCTION The synthetic C-aryl glycoside ertugliflozin 1 is a sodium glucose cotransporter 2 (SGLT2) inhibitor currently in clinical development for the potential treatment of type 2 diabetes mellitus (Figure 1). 1-4 A medicinal chemistry synthesis of 1 was designed to enable the preparation of analogues on gram scale during candidate selection, but was undesirable for large, multikilogram scale manufacture. 5,6 This first-generation syn- thesis involved 13 linear steps from D-glucose, performed in an overall yield of 0.3% and required HPLC purification to isolate 1 from a mixture of C4 epimers. The key step in the route involved arylation of Weinreb amide 2 with aryllithium 3 (Scheme 1, Approach A). This general strategy involving arylation of an open-chain gluconamide was potentially applicable for large scale synthesis of 1, but a more expeditious approach to the point of convergency would be required. Furthermore, it was clear that the C5 tertiary alcohol of 2 needed to be protected prior to introduction of the aryl anion. Not only does the free hydroxyl consume one equivalent of the anion, it contributes to epimerization at C2, presumably via intramolecular deprotona- tion of ketone 4 through a six-membered transition state. As the ertugliflozin program transitioned into clinical develop- ment, an attractive alternative synthesis was reported by the medicinal chemistry team. 7 This stereoselective route provided 1 in a much-improved 26% overall yield from diacetone-α-D- mannofuranose. This approach was also deemed unsuitable for large scale application, however, primarily due to a lack of crystalline isolable intermediates and the requirement for cryogenic reaction temperatures in setting key stereochemistry. A more recent report 8 describes the second-generation synthesis developed and implemented for manufacture of API in support of early clinical studies. Although this process was successfully scaled to produce tens of kilograms of ertugliflozin in a pilot plant setting, the significantly larger quantities of API required for phase 3 and beyond, prompted development of a more efficient, scale-friendly process. Evaluating Synthetic Approaches to the Carbohy- drate Core. Among the published syntheses of SGLT2 inhibitor candidates under pharmaceutical evaluation, the direct arylation of protected gluconolactones of type 5 is most prevalent (Scheme 1, Approach B). 8-13 This strategy provides rapid access to the target compounds and is highly convergent. Recent advances, such as protection of the gluconolactone hydroxyls as labile TMS ethers, 14,15 have made this general approach particularly attractive for large scale, since a dedicated protecting group removal step is unnecessary. On the basis of this precedent, the initial strategy to 1 targeted utilization of the analogous approach C (Scheme 1). Thus, fully protected D- gluconolactone analogues, with an additional hydroxymethyl substituent at C5 (i.e., 7), were required for further conversion to compounds 8 via aryl anion addition to the lactone carbonyl. Received: October 7, 2013 Published: December 20, 2013 Figure 1. Structure of SGLT2 inhibitor candidate ertugliflozin (1). Article pubs.acs.org/OPRD © 2013 American Chemical Society 66 dx.doi.org/10.1021/op4002802 | Org. Process Res. Dev. 2014, 18, 66-81