Stereoselective and Economical Methods for Chemical Synthesis of Essential Medicines

Executive Summary: Innovation in synthetic chemistry enables pharmaceutical research and development by allowing the exploration of diverse chemical space during drug discovery, and by encouraging the development of economical and sustainable solutions in active pharmaceutical ingredient (API) manufacturing. For a given API, a single stereoisomer often displays preferable chemical and pharmacological properties including potency, stability, solubility, or toxicity. Methods for diastereo- or enantioselective synthesis are highly desirable, for exploration of biological properties of different stereoisomers, or for driving efficiency during drug manufacturing. In this thesis, synthesis of small molecule drugs emtricitabine, lamivudine, bedaquiline, and diazepam was investigated. Stereoselective strategies and cost-of-goods reduction more broadly are described. Lastly, a perspective on reproductive health safety in the chemical laboratory is presented. Chapter 1: Diazotization of S-Sulfonyl-Cysteines. We report the synthesis of enantiomerically enriched -thio--hydroxy and -chloro carboxylic acid and ester building blocks by diazotization of S-sulfonyl-cysteines. Within these pharmaceuticallyrelevant building blocks, the thiosulfonate protecting group demonstrated resistance to oxidation and attenuation of sulfur’s nucleophilicity. The key transformation was optimized by a 2² factorial design of experiment, highlighting the unique reactivity of cysteine derivatives in comparison with aliphatic amino acids. Chapter 2: Synthesis of Emtricitabine and Lamivudine by Chlorotrimethylsilane- -Sodium Iodide-Promoted Vorbrüggen Glycosylation. By simply adding water and sodium iodide (NaI) to chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl–NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for N -glycosylation of silylated cytosine derivatives, leading to cis oxathiolane products with up to 95% yield and >20:1 d.r.. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of (±)-FTC/3TC from a tartrate diester. Chapter 3: Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline. Bedaquiline is a crucial drug in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. A focus on reproducibility and mechanistic understanding led to optimized conditions that double the previously reported yields of racemic bedaquiline simply by changing the lithium amide base and including a salt additive. We anticipate facile implementation of these improvements on manufacturing scale that will increase throughput of this essential medication. Chapter 4: Synthesis of a Key Precursor to Benzodiazepines by Copper Hydride Reduction of 2,1-benzo[c]isoxazole. Benzodiazepines are used broadly for the treatment of anxiety disorders and for general anaesthesia. Herein we describe a new method for synthesis of diazepam precursor 2-amino-5-chlorobenzophenone by N,Oreduction of 5-chloro-3-phenylbenzo[c]isoxazole using copper hydride. The desired compound is prepared in >80% isolated yield by optimizing reaction parameters to prevent overreduction of the product. We outline future directions including continuous flow processing and purification by recrystallization. Chapter 5: A Call for Increased Focus on Reproductive Health within Lab Safety Culture. The approach to reproductive health and safety in academic laboratories requires increased focus and a shift in paradigm. Our analysis of the current guidance from more than 100 academic institutions’ Chemical Hygiene Plans (CHPs) indicates that the burden to implement laboratory reproductive health and safety practices is often placed on those already pregnant or planning conception. We also found inconsistencies in the classification of potential reproductive toxins by resources generally considered to be authoritative, adding further confusion. In the interest of human health and safe laboratory practice, we suggest straightforward changes that institutions and individual laboratories can make to address these present deficiencies: Provide consistent and clear information to laboratory researchers about reproductive health and normalize the discussion of reproductive health among all researchers. Doing so will promote safer and more inclusive laboratory environments.Ph.D

Diazotization of S-sulfonyl-cysteines

We report the preparation of enantiomerically enriched β-thio-α-hydroxy and α-chloro carboxylic acid and ester building blocks by diazotization of S-sulfonyl-cysteines. The thiosulfonate protecting group demonstrated resistance to oxidation and attenuation of sulfur's nucleophilicity by the anomeric effect. The key transformation was optimized by a 22 factorial design of experiment, highlighting the unique reactivity of cysteine derivatives in comparison with aliphatic amino acids.National Science Foundation Graduate Research Fellowship Program (grant no. 1122374

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane-Sodium Iodide Promoted Vorbrüggen Glycosylation

By simply adding water and sodium iodide (NaI) to chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for N-glycosylation of silylated cytosine derivatives, leading to cis ox-athiolane products with up to 95% yield and >20:1 dr. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of (±)-FTC/3TC from an achiral tartrate ester

Synthesis of (±)-Emtricitabine and (±)-Lamivudine by Chlorotrimethylsilane–Sodium Iodide-Promoted Vorbrüggen Glycosylation

By simple combination of water and sodium iodide (NaI) with chlorotrimethylsilane (TMSCl), promotion of a Vorbrüggen glycosylation en route to essential HIV drugs emtricitabine (FTC) and lamivudine (3TC) is achieved. TMSCl-NaI in wet solvent (0.1 M water) activates a 1,3-oxathiolanyl acetate donor for N-glycosylation of silylated cytosine derivatives, leading to cis-oxathiolane products with up to 95% yield and >20:1 dr. This telescoped sequence is followed by recrystallization and borohydride reduction, resulting in rapid synthesis of (±)-FTC/3TC from a tartrate diester

Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline**

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication

Application of Chiral Transfer Reagents to Improve Stereoselectivity and Yields in the Synthesis of the Antituberculosis Drug Bedaquiline

Bedaquiline (BDQ) is an important drug for treating multidrug-resistant tuberculosis (MDR-TB), a worldwide disease that causes more than 1.6 million deaths yearly. The current synthetic strategy adopted by the manufacturers to assemble this molecule relies on a nucleophilic addition reaction of a quinoline fragment to a ketone, but it suffers from low conversion and no stereoselectivity, which subsequently increases the cost of manufacturing BDQ. The Medicines for All Institute (M4ALL) has developed a new reaction methodology to this process that not only allows high conversion of starting materials but also results in good diastereo- and enantioselectivity toward the desired BDQ stereoisomer. A variety of chiral lithium amides derived from amino acids were studied, and it was found that lithium (R)-2-(methoxymethyl)pyrrolidide, obtained from d-proline, results in high assay yield of the desired syn-diastereomer pair (82%) and with considerable stereocontrol (d.r. = 13.6:1, e.r. = 3.6:1, 56% ee), providing BDQ in up to a 64% assay yield before purification steps toward the final API. This represents a considerable improvement in the BDQ yield compared to previously reported conditions and could be critical to further lowering the cost of this life-saving drug

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use