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Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in API Step Ian S. Young, Eric M. Simmons, Michael David B. Fenster, Jason Zhu, and Kishta Katipally Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00022 • Publication Date (Web): 29 Mar 2018 Downloaded from http://pubs.acs.org on March 29, 2018
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Organic Process Research & Development
Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in API Step Ian S. Young,† Eric M. Simmons,* Michaël D. B. Fenster,* Jason J. Zhu and Kishta R. Katipally Chemical and Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, U.S.A.
* To whom correspondence
[email protected] should
be
addressed.
E-mail:
[email protected],
† Current address: Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
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Organic Process Research & Development
ABSTRACT The final two steps used to prepare greater than 1 kg of a compound evaluated as a treatment for type 2 diabetes are reported. The application of a palladium catalyzed C–O coupling presented significant challenges due to the nature of the reactants, impurities produced, and non-crystalline coupling intermediate. Process development was able to address these limitations and enable production of kg quantities of API in greater efficiency than a Mitsunobu reaction for formation of the key bond. The development of a sequence that telescopes the coupling with the subsequent ester hydrolysis to yield the active pharmaceutical ingredient (API), as well as the workup and final product crystallization necessary to produce high-quality drug substance without the need of column chromatography are discussed.
Key Words: C–O Coupling, Ligand Screening, Impurity Control, High-Throughput Experimentation, Crystallization Development
INTRODUCTION Type 2 diabetes is a progressive metabolic disorder that results in elevated levels of blood sugar due to the body’s inability to efficiently utilize insulin.1 The World Health Organization estimated that there were over 422 million cases of diabetes worldwide in 2014.2 The long-term effects of untreated high blood sugar can be severe, and may include reduced cardiac function (heart disease), as well as blindness, kidney failure and poor circulation. The need to aid the large population of individuals suffering from this disease is a driver to develop better treatments, and our Discovery Chemistry colleagues identified a lead molecule (1, Scheme 1) that is a potent agonist of the GPR40 receptor.3 Compound 1 was found to promote both gut peptide and glucose-dependent insulin secretion in a variety of animal models, and >1 kg of material was required to allow for a more thorough toxicology evaluation. The final two steps of the synthetic sequence are presented, as the route used for prior smallscale preparations was deemed unsuitable for scale-up. The Mitsunobu reaction employed by Discovery Chemistry to join fragments 3 and 4 to produce penultimate 2 (Scheme 1, Path A) was considered a potential scale-up liability due to the formation of
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significant amounts of alkene impurities (7), the challenges associated with removing the Mitsunobu byproducts (in this case requiring column chromatography), and the thermal hazards associated with the use of azodicarboxylates.4 Recent advances in transition metal-catalyzed heteroatom/aryl couplings5 prompted us to consider forming the C(sp2)–O bond of 2 via union of fragments 56 and 63b (Scheme 1, Path B). We were encouraged by a report from Buchwald and co-workers that demonstrated the Pdcatalyzed coupling of simple secondary alcohols and aryl halides in moderate to good yields (39-82%).7 However, there were several key differences between the previously reported couplings and the proposed disconnection to prepare 2. First, the reported examples utilized 2 equivalents of the secondary alcohol, a requirement which we hoped to avoid due to the complexity of alcohol 5. Also, in contrast to the literature examples, 5 contains a methyl group adjacent to the hydroxyl functionality, thereby introducing additional steric shielding which we anticipated would further complicate this transformation.8
Scheme 1. Mitsunobu versus C–O Cross-Coupling Retrosynthesis for the Preparation of Drug Substance 1
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Organic Process Research & Development
C–O Coupling Optimization and Impurity Identification Our initial attempts to couple 5 and 6 drew upon our experience from evaluation of an earlier GPR40 agonist candidate in which we identified the combination of a bulky biaryl monophosphine ligand (tBuBrettPhos9 or RockPhos7), K3PO4 base, and cyclopentyl methyl ether (CPME), toluene or trifluorotoluene solvent, as effective conditions for the C–O coupling of the nitrile analog of ester 6 with analogs of 5 lacking the methyl group adjacent to the hydroxyl moeity.10 Unfortunately, while tBuBrettPhos and RockPhos did promote the coupling of 5 and 6 in our preliminary experiments, they also led to the formation of biaryl ether 12 (see Scheme 2) in roughly equal amounts to 2.11 Biaryl ether 12 likely arises from an initial Pd-catalyzed hydroxylation of 6 with adventitious water present in the K3PO4 base, followed by C–O coupling of the resulting phenol with a second equivalent of 6.12 We subsequently found that the formation of 12 could be minimized by using K3PO4 that had been dried under vacuum at 110-150 °C, but even with rigorously dried base we still observed a ca. 4:1 ratio of 2:12. Due to the modest rejection of the daughter impurity of 12 in the final crystallization, as well as the requirement of using thoroughly dried base and solvent, these conditions were ultimately deemed unsuitable for scale-up. 5 ACS Paragon Plus Environment
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To identify scalable conditions for the coupling of 5 and 6, we conducted a high-throughput (HTP) ligand survey with a variety of ligands using K3PO4 as base and CPME, trifluorotoluene, toluene, and heptane as solvents at 90 °C. As shown in Figure 1, the majority of ligands that were examined proved to be ineffective for this transformation. However, we were pleased to find that Ad-BippyPhos (8), recently reported by Beller as an effective ligand for the C–O coupling of aryl bromides and chlorides with primary alcohols,13 gave >50 liquid chromatography area percent (AP) of the desired C–O product 2 in all four solvents tested, whereas all of the other ligands tested gave
