Synthetic Approaches To The New Drugs 2018

pubs.acs.org/jmc Perspective Synthetic Approaches to New Drugs Approved during 2018 Andrew C Flick, Carolyn A Leverett, Hong X Ding, Emma McInturff, Sarah J Fink, Christopher J Helal, Jacob C DeForest, Peter D Morse, Subham Mahapatra, and Christopher J O’Donnell* Downloaded via UNIV OF EXETER on July 15, 2020 at 16:28:41 (UTC) See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles Cite This: https://dx.doi.org/10.1021/acs.jmedchem.0c00345 ACCESS Read Online Metrics & More Article Recommendations ABSTRACT: New drugs introduced to the market every year represent privileged structures for particular biological targets These new chemical entities (NCEs) provide insight into molecular recognition while serving as leads for designing future new drugs This annual review describes the most likely process-scale synthetic approaches to 39 new chemical entities approved for the first time globally in 2018 INTRODUCTION The most fruitful basis for the discovery of a new drug is to start with an old drug only a discovery-scale or a general synthetic approach capable of delivering the active pharmaceutical ingredient (API) has been made available Nonetheless, the synthetic sequences described in this review have all been previously reported in either patent or public chemical literature and, to the best of our assessment, represent scalable routes originating from commercially available starting materials (as determined by explicit statement or inferred by experimental detail) Sir James Whyte Black, Winner of the 1988 Nobel Prize in Medicine1 Because drugs can have structural homology across similar biological targets, it is widely believed that the knowledge of new chemical entities and approaches to their construction will enhance the ability to discover new drugs more efficiently This annual review, which is now in its 17th installment,2 presents synthetic routes for 39 new molecular entities that were approved for the first time by a governing body anywhere in the world during the 2018 calendar year (Figure 1).3 Each drug is prefaced by a brief introduction summarizing the relevant pharmacology or differentiating features of the medicine.4 New indications for previously launched medications, new combinations or formulations of existing drugs, and drugs synthesized entirely by biological processes or peptide synthesizers have been excluded from coverage For organizational purposes, drugs presented in this review are categorized into the following therapeutic areas: antibiotic and antifungal, anti-infective, cardiovascular and hematologic, gastrointestinal, inflammation and immunology, metabolic, oncology, ophthalmologic, rare disease, reproductive, and urinary tract Within each of these therapeutic areas, drugs are ordered alphabetically by generic name It is important to note that a drug’s process-scale synthetic approach is often not explicitly disclosed at the time of this review’s publication In some cases, © XXXX American Chemical Society ANTIBIOTIC AND ANTIFUNGAL DRUGS 2.1 Eravacycline (Xerava) Eravacycline belongs to the tetracycline class of antibiotics and was approved by the United States Food and Drug Administration (USFDA) for the treatment of complicated intra-abdominal infections in patients aged 18 years and older Eravacycline is a fully synthetic broad-spectrum antibiotic that exhibits potent activity against both Gram-positive and Gram-negative bacterial strains, including many that have acquired tetracycline-specific resistant mechanisms.5 Eravacycline was discovered and developed by Tetraphase Pharmaceuticals and was Received: February 26, 2020 Published: April 27, 2020 A https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Figure continued B https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Figure continued C https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Figure Structures of 39 NCEs approved in 2018 licensed to Everest Medicines for commercialization in many eastern Asian countries Two other tetracycline antibiotics, sarecycline and omadacycline, were also approved this year, but both molecules were prepared from previously approved tetracyclines that were ultimately obtained via fermentation Eravacycline is a fully synthetic tetracycline, and a highly convergent route for its preparation was first described by the laboratory of Professor D https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Figure Retrosynthetic approach to eravacycline Scheme Preparation of Eravacycline Isoxazole (4·Tartrate) Andrew Myers at Harvard University.6 This route was later refined at Tetraphase Pharmaceuticals, leading to the discovery and development of eravacycline.7 The route described has been published in the primary and patent literature on multikilogram scale.8 Retrosynthetically, eravacycline (I) was envisioned to be derived via a Michael addition−Dieckmann cyclization reaction between the anion of compound and Michael acceptor (Figure 2) Tricyclic intermediate was envisioned to come from addition of the anion of isoxazole to the aldehyde 3, followed by an intramolecular Diels−Alder reaction to set the carbon framework of Isoxazole was envisioned to come from dimethyl maleate, and the chiral vinyl amine stereocenter was set via an Ellman sulfinamide auxiliary The preparation of the chiral isoxazole is described in Scheme 1.8c Dimethyl maleate (5) was treated with bromine in the presence of azo-bis(isobutyronitrile) (AIBN) and ultraviolet light to give dibromide in 92% yield Condensation of with hydroxyurea in the presence of potassium tert-butoxide provided isoxazole in 66% yield Benzylation of the hydroxy group of followed by DIBAL reduction of the ester gave aldehyde in high yield over the two steps Condensation of with (S)-tert-butylsulfinylamide (Ellman’s auxiliary) in the presence of copper(II) sulfate provided chiral sulfinimine in 85% yield After reaction optimization, was treated with vinylmagnesium chloride in the presence of methyllithium and zinc chloride to give 10 in 95% yield (99.3:0.7 dr) The tertbutylsulfinyl group was removed under acidic conditions The resulting primary amine was treated with formaldehyde in the presence of sodium acetate and then reduced using a picoline− borane complex to give the dimethylamine coupling partner in 88% yield for the two-step sequence (96.0% ee) The ee was enhanced to 99.0% by tartrate salt formation, giving 4·tartrate in 91% yield The preparation of the tricyclic Michael acceptor enone is described in Scheme 2.8b Treating 4·tartrate with sodium hydroxide provided the free base 4, which was reacted with tetramethylpiperidine (TMP) magnesium chloride−lithium chloride complex to effect the direct magnesiation of on the oxazole ring, with no competing allylic metalation This intermediate was reacted with aldehyde to give alcohols 11a/ 11b in 95% yield (3.57:1 dr) Heating the mixture of 11a/11b in DMSO, DIPEA, butylated hydroxytoluene, and isopropyl acetate effected the intramolecular Diels−Alder reaction to give a mixture of endo products (12a/12b), arising from 11a, and a mixture of exo products (12c/12d), arising from 11b This mixture of alcohols 12a−d was oxidized with sulfur trioxide pyridine complex to give ketones 13a/13b in 99.1:0.9 dr and 74% overall yield from 11a/b Treating 13a/13b with boron trichloride efficiently effected demethylation of the methyl enol ether, which spontaneously underwent ring E https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme Construction of Eravacycline Tricyclic Michael Acceptor Enone Scheme Preparation of Dibenzyl Amine Protected Coupling Partner ether gave nitroarene 18 Reduction of the nitro group with sodium bisulfite provided aniline 19 in 83% from compound 15 Amine 19 was reacted with benzyl bromide to produce the dibenzylamine-protected coupling partner in 80% yield The completion of the synthesis of eravacycline (I) is described in Scheme 4.8a Compound was treated with LDA followed by compound to promote the desired intermolecular Michael addition The resulting Michael adduct was then treated with lithium bis(trimethylsilyl)amide (LHMDS) to induce an intramolecular Dieckmann cyclization, which gave compound 20 in 94% yield The silyl protecting group was opening to provide enone 14 in high yield Protection of the resulting alcohol as its tributylsilyl ether followed by recrystallization from isopropyl alcohol provided the tricyclic Michael acceptor coupling partner in 88% yield The preparation of intermediate is described in Scheme 3.6c Compound 15 was treated initially with LDA and then quenched with methyl iodide to give arene 16 Formation of the acid chloride of 16 followed by reaction with phenol provided the corresponding ester, making way for methyl ether cleavage with boron tribromide to provide phenol 17 Nitration of 17 and protection of the phenol as a benzyl F https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme Final Assembly of Eravacycline (I) Scheme Synthesis of Ravuconazole (35) removed using hydrofluoric acid, and the resulting intermediate was treated with hydrogen and palladium on carbon These conditions resulted in the removal of the dibenzylamine and benzyl ether protecting groups, which further gave rise to G https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme Synthesis of Fosravuconazole L-Lysine Ethanolate (II) Scheme Synthesis of Omadacycline III the opening of the oxazole ring to ultimately arrive at compound 21 in 89% yield for the two step sequence Compound 21 was then reacted with acid chloride 22 to furnish eravacycline I in 89% yield 2.2 Fosravuconazole L-Lysine Ethanolate (Nailin) Fosravuconazole L-lysine ethanolate (F-RVCZ) is an orally administered, broad-spectrum antifungal drug approved in Japan for the treatment of onychomycosis in 2018.9 F-RVCZ is a prodrug of ravuconazole with improved solubility and oral bioavailability.10 Originally discovered by Eisai,11 ravuconazole was licensed to Bristol-Myers Squibb (BMS) for worldwide development, excluding Japan, in 1996 However, BMS terminated development of the drug in 2004, and Eisai reacquired the worldwide development, manufacturing, and marketing rights The antifungal activities of ravuconazole, like other azole drugs, derive from the inhibition of ergosterol biosynthesis and block the 14α-demethylation pathway present in many strains of yeasts and molds.10 The lowering of ergosterol levels leads to accumulation of 14α-methyl sterols, which impairs normal structure and functions of cell membranes, ultimately resulting in growth inhibition or death of fungal cells F-RCVZ exhibited higher efficacy (higher initial cure rates and lower recurrence rates), an improved safety-profile (lower hepatic functional disorders), and improved dosing regimen (once daily for 12 weeks) over existing standards of care such as terbinafine and itraconazole.12 In addition to several disclosures describing the gram-scale synthesis of ravuconazole and related precursors,13 a robust plant-scale preparation has been described by researchers at BMS (Scheme 5).14 This route utilized lactate 23 as a starting material for the preparation of arylpropanone 26 First, methyl ester 23 was converted to a morpholine amide in the presence of catalytic sodium methoxide The alcohol was subsequently protected to generate tetrahydropyranyl ether 24 Use of realtime infrared reaction monitoring allowed for safe formation of Grignard reagent 25 from the corresponding bromide, which was then reacted with amide 24 to furnish aryl ketone 26 after aqueous acetic acid quench Corey−Chaykovsky epoxidation and subsequent epoxide opening were performed in a singlestep, telescoped process Once epoxidation was complete, heating the reaction mixture to 90 °C triggered a triazolemediated epoxide-opening sequence to form alcohol 28 The stereochemical outcome of the epoxide-forming step is H https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme Synthesis of Plazomicin (IV) Paratek Pharmaceuticals, omadacycline was licensed to Bayer, Merck, and Novartis over the course of its clinical development Ultimately the rights were returned to Paratek, who collaborated with Zai Lab (Shanghai) Co., Ltd to commercialize the drug in China.17 A number of syntheses of omadacycline have been published, and the largest scale route is described in Scheme This route advantageously began with minocycline (38, Scheme 7) which is a tetracyclic antibiotic drug first patented in 1961 Minocycline was condensed with N(hydroxymethyl)phthalimide (39) in the presence of triflic acid to give a mixture of the 9-phthalimidomethyl analogs 40 and 41 in approximately a 60:40 ratio This mixture was treated with methylamine, which resulted in hydrolysis of the phthalimide to give an unreported distribution of methylamine analogs 42 and 43 This mixture was then treated with pivaldehyde under catalytic hydrogenation conditions to affect the reductive amination at position N-9, followed by concomitant removal of the hemiaminal group on the amide, furnishing omadacycline (III) in 15−18% yield for the overall process after conversion to the tosylate salt 2.4 Plazomicin (Zemdri) Originally discovered by California-based Ionis Pharmaceuticals and later developed by Achaogen, plazomicin was approved by the USFDA in 2018 for the treatment of patients 18 years of age or older with complicated urinary tract infections (cUTI), including pyelonephritis The drug, a next-generation aminoglycoside dictated by the adjacent chiral center, providing 27 in 8.6:1 dr Removal of the tetrahydropyranyl protecting group within 28 generated an intermediate diol which was converted to trisubstituted epoxide 29 via selective mesylation of the secondary alcohol Generation of lithium cyanide in situ from acetone cyanohydrin 30 and LHMDS followed by subsequent addition to epoxide 29 delivered the α-cyano alcohol 31 in 90% yield, which was subsequently converted to thioamide monohydrate salt 33 by treatment with diethyl dithiophosphate 32 and sulfuric acid Condensation of the thioamide 33 with 2-bromo-4′-cyanoacetophenone 34 in hot ethanol resulted in thiazole formation which completed the preparation of ravuconazole (35) Conversion of ravuconazole to the highly water-soluble prodrug fosravuconazole L-lysine ethanolate (II) has been described by the scientists at Eisai (Scheme 6).15 First, ravuconazole (35) was O-alkylated with di-tert-butyl chloromethylphosphate 36 to furnish phosphate ester 37 Subjection of ester 37 to trifluoroacetic acid (TFA) and aqueous sodium hydroxide provided the free acid, which was subsequently converted to fosravuconazole L-lysine ethanolate (II) 2.3 Omadacycline (Nuzyra) Omadacycline belongs to the aminomethylcycline class of tetracycline antibiotics and was approved by the USFDA for the treatment of acute bacterial skin and skin structure infections and communityacquired bacterial pneumonia.16 Discovered and developed by I https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme Synthesis of Sarecycline Hydrochloride (V) Scheme 10 Assembly of Baloxavir Piperazine Heterocyclic Core 59 completed the development and launch of the drug before rights were acquired by Almarall S.A in 2018.22 To date, there are no publications describing the discovery of sarecycline The only reported synthetic route to the drug, performed on small scale by Paratek, is described in Scheme 9.23 Iodination of commercially available sancycline 51 with Niodosuccinimide followed by HPLC purification provided iodosancycline 52 as the trifluoroacetate salt (no yield reported) Carbonylation of 52 in the presence of palladium acetate and Xantphos followed by treatment with triethylsilane provided the corresponding aldehyde, which was treated with trifluoracetic acid to provide formylsancycline trifluoroacetate 53.24 Condensation of 53 with N,O-dimethylhydroxylamine hydrochloride, reduction with sodium cyanoborohydride, and treatment with hydrochloric acid provided sarecycline hydrochloride (V) in 23% yield for the three-step sequence that is delivered by injection, was acquired by Cipla as part of an auction of Achaogen assets after the American firm filed for chapter 11 bankruptcy.19 As a structural derivative of the antiinfective aminoglycoside sisomycin, plazomicin is a neoglycoside that is highly active against a variety of bacterial pathogens, including many of the Gram-negative rods that are implicated in cUTIs Plazomicin is not affected by most aminoglycoside-modifying enzymes and retains activity against multidrug-resistant (MDR) isolates known as carbapenemresistant enterobacteriaceae (CRE).20 Two synthetic routes to plazomicin have been reported, both of which originate from commercial sisomicin (44, Scheme 8) and vary only by differential protection of the sisomicin amines.21 Sisomicin was treated with an ionexchange resin which furnished trifluoroacetamide 45 after reaction with ethyl trifluorothioacetate Zinc acetate and benzyloxycarbonyl succinimide provided the corresponding Cbz-protected intermediate 46 in a 35% yield from 44 Amide coupling and removal of the trifluoroacetate group yielded glycoside 48, which then underwent reductive amination, benzoyl ester cleavage, and global Cbz removal under hydrogenative conditions to give rise to plazomicin (IV).21c,d 2.5 Sarecycline Hydrochloride (Seysara) Sarecycline belongs to the tetracycline class of antibiotics and was approved by the USFDA for the oral treatment of inflammatory lesions of non-nodular, moderate-to-severe acne vulgaris in patients at least years old Sarecycline was discovered at Paratek Pharmaceuticals and licensed to Warner Chilcott, which was later acquired by Allergan Allergan ANTI-INFECTIVE DRUGS 3.1 Baloxavir Marboxil (Xofluza) In 2018, baloxavir marboxil received its first approval by the Pharmaceuticals and Medical Devices Agency of Japan (PMDA) for the treatment of influenza A or B virus infections.25 Later the same year, the drug was also approved by the USFDA for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 h.26 Baloxavir marboxil was discovered by Shionogi, who licensed their rights to Roche in February 2016 for development and commercialization except in Taiwan and Japan (Shionogi maintained its rights in these two J https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme 64 Synthesis of Omidenepag Isopropyl (XXXVI) Scheme 65 Synthesis of Omidenepag Isopropyl Chloromethylpyridine 361 OPHTHALMOLOGIC DRUGS 9.1 Omidenepag Isopropyl (Eybelis) Omidenepag isopropyl, which is administered as a 0.002% ophthalmic solution, was approved in Japan in 2018 for the treatment of glaucoma and ocular hypertension.194 Discovered and developed by Santen, the drug was designed as an isopropyl ester to allow for increased passive permeability to the corneal epithelium, where the physiologic pH of this compartment would convert the molecule to the corresponding carboxylate, revealing a potent and selective prostaglandin E2 (h-EP2) receptor agonist.195 Omidenpag isopropyl, also referred to as OMDI, lowered intraocular pressure (IOP) in preclinical trials at significantly low concentrations (0.0006%) in a dosedependent manner in monkeys, suggesting that the drug could offer an alternative treatment option to prostaglandin F (FP) receptor agonists.195 The drug, whose structure evolved from a small-molecule EP2 agonist originally published by researchers at Pfizer,196 is currently undergoing clinical trial investigation in the United States as a 0.002% once-daily solution, in comparison to a twice-daily 0.5% timolol maleate solution, for the treatment of ocular hypertension.194 Two patent applications disclosed by the Japanese firm Ube Industries, Ltd have described a process synthesis of omidenepag isopropyl.197 Reacting p-cyanofluorobenzene (357) with pyrazole in the presence of base, borane reduction of the nitrile, and acid−base workup led to 358 in 83% across the three-step sequence (Scheme 64) Next, subjection of sulfonic acid 359 to triflic anhydride prior to exposure to 358 under basic conditions yielded sulfonamine 360 Lastly, reaction with 361 (arising from exposure of 362 in Scheme 65 to sulfonic acid in warm aqueous isopropanol, giving 363 and subsequent treatment with thionyl chloride and aqueous base) under basic conditions in refluxing acetonitrile furnished omidenepag isopropyl (XXXVI) in an impressive 98% yield It should be noted in Scheme 65 that although tert-butyl nicotinate 362 is commercially available, the source of this starting material was not specified in the Ube patent.197b 10 RARE DISEASES DRUGS 10.1 Tezacaftor (Symdeko) In 2018, the USFDA approved tezacaftor as a combination therapy with ivacaftor (a USFDA approved drug in 2012)2k,198 for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del gene mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor.199 Discovered and developed by Vertex Pharmaceuticals, tezacaftor is a broad-acting CFTR corrector that facilitates the cellular processing and trafficking of normal CFTR and multiple mutant CFTR, including F508del, thereby increasing the amount of CFTR protein at the cell surface.200 Ivacaftor is a CFTR potentiator that enhances chloride ion transport by potentiating the channel gating activity of CFTR protein Ivacaftor potentiates the CFTR protein delivered to the cell surface by tezacaftor, leading to further enhancement of chloride ion transport than either agent can achieve alone.200a One of the major differentiators of tezacaftor over other CFTR correctors is that tezacaftor is not a CYP3A4 enzyme inducer and does not interfere with ivacaftor’s metabolic pathways.201,202 In June 2019, the USFDA approved tezacaftor/ivacaftor combination therapy for the treatment of pediatric patients aged years and older with CF who have certain genetic mutations.203 Multiple patent applications have been filed by scientists at Vertex describing the preparation of tezacaftor, and all of which outline similar reaction sequences.204 The route depicted here has been chosen based on higher reported scale, better efficiency, and lesser step counts.204f The convergent synthetic strategy utilizes a late-stage amide bond formation to unite two key fragments Preparation of the acid AM https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme 66 Synthesis of Tezacaftor Cyclopropylacetic Acid 368 Scheme 67 Synthesis of Tezacaftor (XXXVII) Scheme 68 Synthesis of Tezacaftor Alkyne 373 authors A Sonogashira coupling between aryl bromide 372 and terminal alkyne 373 (whose synthesis is described in Scheme 68) followed by a Larock-type cyclization completed the preparation of aminoindole subunit 374 To unite key subunits 368 and 374, the carboxylic acid 368 was first converted to an acid chloride and then reacted with aminoindole 374 to deliver bis-benzyl protected tezacaftor Finally, global deprotection via palladium-catalyzed hydrogenation furnished tezacaftor (XXXVII) in 68−84% yield (based on 374) Preparation of alkyne 373 is described in Scheme 68 First, propargyl alcohol 375 was converted to propargyl chloride 376 by treatment with aqueous HCl A Grignard reagent was generated from chloride 376 and subsequently alkylated with benzyl chloromethyl ether 377 Removal of the trimethylsilyl moiety generated the terminal alkyne 373 fragment 368 commenced with the palladium-catalyzed decarboxylative arylation involving ethyl cyanoacetate 365 with aryl bromide 364 in the presence of a bulky phosphine ligand (Scheme 66) The reaction yielded benzonitrile 366 in 66% yield after acidification Cyclopropanation of 366 via double alkylation of ethylene fragment 367 in the presence of a phase transfer catalyst followed by basic hydrolysis delivered carboxylic acid 368, which was purified by recrystallization from hot toluene Synthesis of the indole subunit began with regioselective bromination of 3-fluoro-4-nitroaniline (369) to arene 370 (Scheme 67) Lewis acid-catalyzed epoxide ring opening of (R)-glycidyl benzyl ether (371) by aniline 370 followed by reduction of the nitro group furnished hydroxy p-phenylenediamine 372, which was isolated as the p-TsOH salt The salt was treated with aqueous NaHCO3 in DCM to generate free base 372 prior to the next step It should be noted that the yields for conversion of 370 to 372 were not reported by the AN https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme 69 Synthesis of Segesterone Acetate (XXXVIII) Scheme 70 Synthesis of Vibegron Progenitor Aminoalcohol 386 11 REPRODUCTIVE DRUGS 11.1 Segesterone Acetate (Annovera) Segesterone acetate is a progestin hormonal contraceptive that was developed by The Population Council and has been available since 2000 In 2018, it was approved as a combination therapy with ethinyl estradiol, marketed under the brand name Annovera.205 This drug represents the first in a new class of contraceptives, as it is administered as a silicone ring that can be inserted by the patient and does not require refrigeration and whose duration of action lasts for an entire year.206 These factors are all especially beneficial for providing effective contraception in limited-resource settings and developing nations.207 Although detailed synthetic routes to segesterone acetate are sparsely available, a 1997 paper from The Population Council208 cited earlier work by Mehrof et al.209 and Schwars et al.210 for a general synthetic approach to the compound A 2013 patent by the same group disclosed an updated and concise synthesis involving nucleophilic addition of an acetylene equivalent into a ketone followed by hydration to obtain the desired functionality.211 The route began with 19norandrostenedione (378, Scheme 69) In a two-step, one-pot procedure, the enone was converted to the enol ether using trimethyl orthoformate, followed by formylation of the remaining ketone to provide 379 in an 80% yield over two steps Next, trimethysilylacetylene was deprotonated using LiHMDS in THF prior to subjection to 379 After the addition was complete, the reaction was allowed to warm to room temperature, and the TMS group was removed with potassium carbonate to generate 380 The alkyne was then hydrated under acidic conditions to the corresponding ketone 381 The next series of reactions enabled inversion of configuration at the congested C-17 center Treatment of alcohol 381 with phenylsulfuryl chloride resulted in chloride displacement and a 2,3-sigmatropic rearrangement to arrive at sulfoxide 382 Subjection of the enone of 382 to trimethoxyphosphine and triethylamine, followed by treatment with hypochlorous acetic anhydride conditions, induced a Mislow−Evans rearrangement to complete the preparation of segesterone acetate (XXXVIII) 12 URINARY TRACT DRUGS 12.1 Vibegron (Beova) Vibegron is a selective β3 adrenergic receptor (β3AR) agonist approved in Japan during 2018 for the treatment of overactive bladder (OAB).212 The drug, originally discovered by Merck,213 was developed jointly by Kyorin Pharmaceutical Co., Ltd and Kissei Pharmaceutical Co., Ltd and is currently undergoing clinical trials for OAB in the United States and Europe.212 Vibegron represents the third AO https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Perspective Scheme 71 Synthesis of Vibegron (XXXIX) β3AR agonist to be examined in clinical trials for OAB, the other two being Astellas’ mirabegron (approved in 2012) and GSK and AltheRx’s solabegron (currently in phase II trials).213 Vibegron differentiates from mirabegron such that it offers an enhanced safety profile (reportedly driven by its selectivity against other adrenergic receptors and CYP3A4 and CYP2D6 inhibition/induction) and offers an improved dosing regimen in comparison to solabegron (once daily versus twice daily, which was used in a phase II efficacy study).213,214 Vibegron evolved from structural modifications to a previously discovered Merck β3AR agonist, MK-0634, which progressed into preclinical studies for the treatment of obesity in the early 2000s and has since been discontinued Vibegron differs from previously reported acyclic β-hydroxylamine β3AR agonists in that it possesses a unique cis-pyrrolidine moiety linking the C-2 and C-5 substituents, resulting in improved pharmacological properties,213 but simultaneously increases the complexity of the drug structure and synthesis Several reports describing the construction of vibegron have been published.213,215 A concise manufacturing-scale synthesis of the drug was reported by Merck in 2018 in which the authors engineered a dynamic kinetic resolution (DKR) that efficiently established a challenging amino alcohol stereorelationship within an early stage intermediate (386, Scheme 70) and later influenced the incumbent C-2 and C-5 pyrrolidine stereocenters within the API structure.215a This elegant synthetic approach is described in Schemes 70 and 71 Oxidation of commercial pentynol 383 (Scheme 70) followed by a Strecker reaction and Boc-protection furnished racemic aminonitrile 384.216 Grignard addition to the nitrile followed by acidic workup generated racemic ketones 385 in 95% Because epimerization of the Boc-protected amine stereocenter within 385 was observed under basic conditions, a ketoreductase (KRED-p301) was engineered to selectively facilitate reaction of cofactor sodium nicotinamide adenine dinucleotide phosphate (NADPNa) with (R)-385 within a pH range capable of facilitating both epimerization and reduction of the ketone.215a In practice, the catalytic conditions developed efficiently converted (R)-385 to amino alcohol 386 The reaction proceeded in 95% conversion with >99.4% ee and with a diastereomeric ratio greater than 100:1 Subjection of 386 to Sonagashira conditions followed by treatment with acid delivered disubstituted alkyne 387 as the corresponding HCl salt Warming 387 in the presence of Hunig’s base facilitated an intramolecular cyclization reaction to produce crude pyrrolidinol 388 which was converted to the corresponding silyl ether prior to hydrogenation The authors reason that the bulky silyl ether imparted good selectivity (95:5 dr) during the hydrogenation step Upon workup of the hydrogenation, the silyl functionality was removed, resulting in an overall conversion of 387 to 390 in 80% yield.215a Reaction of aniline 390 with commercial carboxylate 391 under conventional amide-bond forming conditions secured vibegron (XXXIX) in 93% yield 13 CONCLUSION In summary, the pharmaceutical industry continued its trend of considerable productivity with respect to annual small molecule drug approvals These 39 new medicines (which include highly functionalized macrocycles, compounds containing multiple asymmetric centers, and complex heterocyclic systems) represent an architecturally diverse set of molecules that address disease states worldwide across a wide range of therapeutic areas Fascinatingly, the scale preparation of these drugs relied upon synthetic methodologies spanning the full breadth of known chemical reactions ranging from engineered biocatalytic reactions aided by molecular modeling technologies to transformations first discovered in the 19th century Clever utility of metal-catalyzed reactions proved critical to establishing structural motifs within the 2018 class of drugs, further emphasizing the expanding importance of this technology particularly toward the scale preparation of API and to an expanded scope of bonds that are capable of being fashioned in this manner The architectural complexity within these drugs gives clear evidence that medicinal chemists are becoming empowered to explore structurally challenging motifs in the early discovery stages, further reinforcing the industry’s embrace of complex chemical space As we embark upon a new decade of drug discovery, new biological targets and opportunities will emerge As this expansion continues, the demands to reach higher levels of complexity more quickly will be asked of the modern medicinal and process chemist AP https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc Innovative synthetic technologies and creative, artistic approaches will continue to inspire and deliver the medicines of the future Emory University in Atlanta, GA, working on total synthesis of several piperidine-based natural products and the alkaloid minfiensine Prior to joining Pfizer she was a Postdoctoral Fellow working with Professor Daniel Romo at Texas A&M University, exploring new applications of nucleophile-catalyzed aldol lactonization reactions ■ AUTHOR INFORMATION Corresponding Author Perspective Hong X Ding obtained a B.S in Pharmaceutics in 2001 and a Ph.D in Medicinal Chemistry in 2006 from Zhejiang University in Hangzhou, China Hongxia is the cofounder and Chief Executive Officer of Pharmacodia, a leading pharmaceutical big data company in China, which is an online platform (http://www.pharmacodia.com) providing big data and information service in the pharmaceutical R&D field In 2010−2013, Hong Xia joined Shenogen Pharma Group, a China-based biotech company as a senior director of the R&D department Before Shenogen, Hong Xia worked in BioDuro since 2006, as senior group leader and senior research scientist Christopher J O’Donnell − Groton Laboratories, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States; orcid.org/0000-0003-1004-7139; Phone: 860-405-4976; Email: christopher.j.odonnell@ pfizer.com Authors Andrew C Flick − Takeda California, Inc., San Diego, California 92121, United States Carolyn A Leverett − Groton Laboratories, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States Hong X Ding − Pharmacodia (Beijing) Co., Ltd., Beijing 100085, China Emma McInturff − Groton Laboratories, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States; orcid.org/0000-0003-0426-3089 Sarah J Fink − Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts 02142, United States Christopher J Helal − Biogen, Cambridge, Massachusetts 02142, United States Jacob C DeForest − Groton Laboratories, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States Peter D Morse − Groton Laboratories, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States Subham Mahapatra − Groton Laboratories, Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States Complete contact information is available at: https://pubs.acs.org/10.1021/acs.jmedchem.0c00345 Emma McInturff obtained a B.S in Chemistry from Boise State University and a Ph.D from the University of Texas at Austin, working in the laboratory of Professor Mike Krische on ruthenium catalyzed carbonyl addition methodology development She joined Pfizer process chemistry in Groton, CT, in 2014 Sarah J Fink obtained a B.A in Chemistry and English literature from Williams College, followed by a Ph.D in Organic Chemistry from the University of Cambridge with Professor Ian Paterson Her thesis work focused on the total synthesis of aplyronine C After a fellowship for young international scientists at Shanghai Institute of Materia Medica, Sarah joined BioDuro in Shanghai in 2014, where she was a scientist and chemistry group leader for integrated drug discovery projects in multiple therapeutic areas She relocated with BioDuro to Boston in early 2017, where she provided medicinal chemistry and scientific project management support for collaborations with pharma and biotech as an associate director for integrated programs Sarah recently joined Takeda’s Rare Disease Drug Discovery Unit Christopher J Helal received his B.S in Chemistry at the Ohio State University in 1991 and carried out his doctoral studies at Harvard University with Professor Elias J Corey He joined Pfizer in 1997 in Groton, CT, working in neuroscience medicinal chemistry He supported the metabolic disease research area and led an enabling technologies team that included biocatalysis, flow chemistry, singleelectron chemistry, reaction optimization, and parallel synthesis He currently leads the medicinal chemistry group at Biogen, focusing on neuroscience indications Notes The authors declare no competing financial interest Biographies Andrew C Flick earned a B.A in Chemistry from Lake Forest College After associate-level appointments at Abbott Laboratories and Array BioPharma, he joined Professor Albert Padwa’s laboratory at Emory University After completing his Ph.D studies on dipolar cycloaddition approaches to alkaloid natural product total synthesis, he joined Pfizer where he was involved with numerous medicinal chemistry projects within the Neurosciences, Rare Diseases, and Inflammation & Immunology therapeutic areas As a synthesis team lead, his contributions led to the discovery of the transcription factor inhibitor PF-06763809, which is currently undergoing clinical trials for the treatment of psoriasis Andy recently joined Takeda California’s GI Drug Discovery Unit and has authored over 40 peer-reviewed publications and patents Jacob C DeForest received his B.A in Chemistry from Pepperdine University under the supervision of Professor Matt Joyner in 2012 He completed his Ph.D in Chemistry at the University of California, Irvine, in 2017 working with Professor Scott Rychnovsky on the total synthesis of alkaloid natural products He is currently a process chemist at Pfizer Peter D Morse obtained a B.Sc in Structural Biology and Chemistry from the University of Connecticut in 2010 He then obtained his Ph.D at the University of North Carolina at Chapel Hill, working with Professor David Nicewicz in 2015 After postdoctoral studies with Professor Timothy Jamison at MIT, he joined the Applied Synthesis Technology group at Pfizer in 2017 Carolyn Leverett began her career at Pfizer in 2012, focusing on the development of microtubule inhibitor-based payloads for use as antibody−drug conjugates She currently works in the Discovery Sciences research group, exploring the use of protein degrader-based therapies for treating a variety of disease areas Carolyn obtained her B.S in Chemistry from North Carolina State University She completed her doctoral studies with Professor Albert Padwa at Subham Mahapatra received his M.Sc in Chemistry from Indian Institute of Technology Bombay, Mumbai, and earned his Ph.D from Oregon State University, Corvallis, where he completed the first total syntheses of natural products amphidinolides C and F Subsequently, Subham’s postdoctoral research with Professor Barry Trost at Stanford University was focused on the development of a new C− AQ https://dx.doi.org/10.1021/acs.jmedchem.0c00345 J Med Chem XXXX, XXX, XXX−XXX Journal of Medicinal Chemistry pubs.acs.org/jmc H activation method for the generation of π-allyl intermediates Later, Subham picked up a second postdoctoral position in the laboratory of Professor Seth Herzon at Yale University where he worked on the total synthesis of lomaiviticin A Subham joined Pfizer in 2017 Currently, he is a Senior Scientist (medicinal chemistry) in the Internal Medicine Department and his research focuses on cardiovascular and metabolic disease areas NIS, N-iodosuccinimide; NMM, N-methylmorpholine; NMO, N-methylmorpholine N-oxide; NMP, N-methyl-2-pyrrolidone; PBS, phosphate buffered saline; PCC, pyridinium chlorochromate; Ph, phenyl; PhCH3, toluene; Pin, pinacolato; PLP, pyridoxal-5-phosphate; PPA, polyphosphoric acid; PPTS, pyridinium p-toluenesulfonate; p-TsOH, p-toluenesulfonic acid; py, pyridine; rt, room temperature; Su, succinimide; SFC, supercritical fluid chromatography; T3P, 1-propanephosphonic acid cyclic; TBAB, tetrabutylammonium bromide; TBAC, tetrabutylammonium chloride; TBAF, tetrabutylammonium fluoride; TBAHS, tetrabutylammonium hydrogen sulfate; TBAI, tetrabutylammonium iodide; TBS, tert-butyldimethylsilyl; TBTU, O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate; t-Bu, tert-butyl; TEMPO, 2,2,6,6-tetramethylpiperidine 1-oxyl; Tf, triflic, trifluoromethanesulfonyl; TFA, trifluoroacetic acid; TFAA, trifluoroacetic acid anhydride; TFE, 2,2,2-trifluoroethanol; THF, tetrahydrofuran; THP, tetrahydropyranyl; TMEDA, N,N,N′,N′tetramethylethylenediamine; TMP, tetramethylpiperidine; TMS, trimethylsilyl; Tr, trityl, triphenylmethyl; Ts, ptoluenesulfonyl Christopher J O’Donnell obtained a B.S in Chemistry from the University of Illinois UrbanaChampaign and a Ph.D in Organic Chemistry from the University of Wisconsin After postdoctoral research at the University of CaliforniaIrvine, he joined Pfizer in 1999 in the Neuroscience Medicinal Chemistry group As a scientist, project leader, and manager in these areas, he has led project teams to the nomination of over 10 clinical candidates In 2010, Chris moved to the Oncology Medicinal Chemistry group to build the Antibody Drug Conjugate chemistry group, and his team has nominated 11 conjugates for clinical development In 2018, Chris moved to the Pfizer Ventures team where he makes and manages equity investments for Pfizer Chris is an author/inventor of 75 peerreviewed journal articles and patent applications ■ ■ ABBREVIATIONS USED Ac, acetyl; ADDP, 1,1′-(azodicarbonyl)dipiperidine; AIBN, 2,2′-azobis(isobutyronitrile); aq, aqueous; BHT, butylated hydroxytoluene; BINAP, 2,2′-bis(diphenylphosphino)-1,1′dinaphthalene; Bn, benzyl; Boc, N-tert-butoxycarbonyl; 2,2′bpy, 2,2′-bipyridyl; Bu, butyl; n-Bu, n-butyl; TTBP·HBF4, tritert-butylphosphonium tetrafluoroborate; cat., catalytic; Cbz, benzyloxycarbonyl; CDI, N,N′-carbonyldiimidazole; COD, 1,5-cyclooctadiene; conc, concentrated; CPME, cyclopentyl methyl ether; CSA, camphorsulfonic acid; Cy, cyclohexyl; dba, dibenzylideneacetone; DBU, 1,8-diazabicyclo[5.4.0]undec-7ene; DCC, 1,3-dicyclohexylcarbodiimide; DCE, dichloroethane; DCM, dichloromethane; de, diastereomeric excess; dr, diastereomeric ratio; DIBAL, diisobutylaluminum hydride; DIC, N,N′-diisopropylcarbodiimide; DIPEA, diisopropylethylamine; DIP-Cl, B-chlorodiisopinocampheylborane, (+)-Ipc2BCl; DMA, dimethylacetamide; DMAP, 4-dimethylaminopyridine; DME, 1,2-dimethoxyethane; DMF, N,N-dimethylformamide; DMF−DMA, dimethylformamide−dimethylacetal; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; dppb, 1,4-bis(diphenylphosphino)butane; dppf, 1,1′ferrocenediyl-bis(diphenylphosphine); dr, diastereomeric ratio; dtbpf, 1,1′-bis(di-tert-butylphosphino)ferrocene; EDCI, N-(3dimethylaminopropal)-N-ethylcarbodiimide; ee, enantiomeric excess; EEDQ, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; Et, ethyl; HATU, 1-[bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HBTU, (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; Hex, hexyl; n-Hex, n-hexyl; HMDS, hexamethyldisilazane; HOAc, acetic acid; HOAt, 1-hydroxy-7azabenzotriazole; HOBt, 1-hydroxybenzotriazole hydrate; i-Pr, isopropyl; i-PrOH, isopropyl alcohol; KOTMS, potassium trimethylsilanolate; LAH, lithium aluminum hydride; LHMDS, lithium bis(trimethylsilyl)amide; LDA, lithium diisopropylamide; m-CPBA, 3-chloroperoxybenzoic acid; Me, methyl; MeCN, acetonitrile; MEK, methyl ethyl ketone; MeTHF, 2methyltetrahydrofuran; MIBK, methyl isobutyl ketone; Ms, methylsulfonyl, mesyl; MS, molecular sieves; MTBE, methyl tert-butyl ether; n-Pr, n-propyl; NADP, nicotinamide adenine dinucleotide phosphate; NADPNa, sodium nicotinamide adenine dinucleotide 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