Synthetic Approaches to New Drugs Approved During 2016 - Journal


2 days ago - This annual review describes the most likely process-scale synthetic approaches to nineteen new chemical entities (NCEs) that were approv...
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Synthetic Approaches to New Drugs Approved During 2016 Andrew Flick, Hong Xia Ding, Carolyn A Leverett, Sarah J. Fink, and Christopher J. O'Donnell J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.8b00260 • Publication Date (Web): 05 Apr 2018 Downloaded from http://pubs.acs.org on April 6, 2018

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Journal of Medicinal Chemistry

Synthetic Approaches to the New Drugs Approved During 2016 Andrew C. Flick,1 Hong X. Ding,2 Carolyn A. Leverett,3 Sarah J. Fink,4 Christopher J. O’Donnell5* 1,3,5

Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, CT 06340, United States 2

4

Abstract:

Pharmacodia (Beijing) Co., Ltd., Beijing, 100085, China

BioDuro, 11011 Torreyana Road, San Diego, CA 92121, United States.

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 nineteen new chemical entities that were approved for the first time in 2016.

1

Email: [email protected]; tel: 404-849-4280

2

Email: [email protected]; tel: 8610-8282-6195

3

Email: [email protected]; tel: 860-441-3936

4

Email: [email protected]; tel: 631-635-0516

5

Email: [email protected]; tel: 860-303-1138 1

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Key Words: Synthesis, New Drug Molecules, New Chemical Entities, Medicine, Therapeutic Agents.

1. Introduction “The most fruitful basis for the discovery of a new drug is to start with an old drug.” ─ Sir James Whyte Black, winner of the 1988 Nobel Prize in medicine.1 Inaugurated fifteen years ago2, this annual review presents synthetic methods for molecular entities that were approved for the first time by governing bodies within various countries during 2016.

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 review describes the most likely

process-scale synthetic approaches to the 19 small-molecule NCEs that were approved for the first time in 2016 by a governing body anywhere in the world (Fig.1) and each section will only contain a limited introduction to the pharmacology of the drug as more detailed reviews on this topic are readily available.3

New indications for previously launched medications, new combinations or

formulations of existing drugs, and drugs synthesized purely via bio-processes or peptide synthesizers have been excluded from this review.

Drugs presented in this review are divided into

the

anti-infective,

following

seven

therapeutic

categories:

gastrointestinal, metabolic, oncology, and ophthalmology. drug coverage follows alphabetical order by generic name.

neuroscience,

dermatologic,

Within each of these therapeutic areas, 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.

However, the synthetic sequences presented in this review have all been published in

2

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the public domain and represent scalable routes that originate from commercially available starting materials (determined by explicit statement in the description or by experimental detail).

Figure 1.

Structures of 19 NCEs approved in 2016

3

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Oncology Drugs

O N

O N N H

H N

N H

S

N

O

O O S OH N H

F

N

Olmutinib (XVI)

O

HN

Rucaparib camsylate (XVII)

HN N O N

N

NO2

O HN S O O

NH O

Cl Venetoclax (XVIII)

Ophthalmologic Drugs

Cl

N

O

O

SO2CH3 N H

Cl

OH O

O Lifitegrast (XIX)

2. Anti-Infective Drugs 2.1 Beclabuvir (Ximency®) Beclabuvir is a non-nucleoside, nonstructural protein 5B (NS5B) polymerase inhibitor approved in Japan as part of a fixed-dose combination product for the treatment of hepatitis C virus (HCV). Upon administration and after intracellular uptake, the drug binds to the allosteric, non-catalytic “Thumb 1” site of NS5B resulting in a decreased rate of viral RNA synthesis and replication.4 Beclabuvir is combined with asunaprevir and declatasvir (both approved in 2014) and was 6

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discovered and developed by Bristol-Myers Squibb.4 The syntheses of asunaprevir and declatasvir were described in an earlier review article.2m The synthesis to produce 10-100 grams of beclabuvir is described in Scheme 1.5 Condensation of indole-6-carboxylic acid (1) with cyclohexanone under basic conditions gave acid 2 in quantitative yield. Hydrogenation of the double bond in 2 using Pearlman’s catalyst was followed by esterification to give ester 3 in high yield.6 Bromination of the indole at the 2-position was accomplished with pyridinium tribromide, and this was followed by saponification to provide acid 4. Treatment of 4 with carbonyldiimidazole (CDI) followed by N,N-dimethylsulfamide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave compound 5 in 74% yield. Suzuki coupling of 5 with commercial boronic acid 6 provided intermediate 7, which converted to hemiaminal 8 upon continued

heating

in

61%

2-(dimethoxyphosphoryl)acrylate

yield. (9)

Compound to

affect

8 a

was tandem

then

treated

conjugate

with addition

methyl and

Horner-Wadsworth-Emmons (HWE) olefination to give ester 10. Alternatively, the Suzuki coupling reaction of 5 with 6 could be stopped at the intermediate 7 which could be treated with 9 to promote the tandem conjugate addition/HWE to give 10. Corey-Chaykovsky cyclopropanation of 10 using sodium hydride and trimethylsulfoxonium iodide followed by chiral separation provided cyclopropane 11 in good yield and >99% enantiomeric excess (ee). Saponification of the methyl ester of 11 followed by coupling with 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (12) gave beclabuvir (I) in high yield.

Scheme 1. Synthesis of beclabuvir (I)

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2.2 Elbasvir/Grazoprevir (Zepatier®) Discovered and developed by Merck, the combination of elbasvir and grazoprevir was approved by the United States Food and Drug Administration (USFDA) for the treatment of adults 8

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with chronic hepatitis C virus (HCV) genotype 1 or 4 infection.7 drugs is approved as a separate medication.

Interestingly, neither of these

In clinical trials, the two drugs were co-administered

as separate tablets and administered as a fixed-dose combination tablet, with the primary endpoint being the sustained virological response rate twelve weeks post-treatment (SVR12); patients exhibited a 95% SVR12 rate overall.7

Elbasvir inhibits HCV NS5A, which is necessary for viral

RNA replication and virion assembly.7

Grazoprevir inhibits HCV NS3/4A protease, which is

essential for the proteolytic cleavage of the HCV encoded polyprotein and viral replication.7

For

the purpose of this review, the synthesis of elbasvir and grazoprevir for HCV treatment, will be discussed separately. Elbasvir possesses a particularly interesting molecular architecture consisting of two identical N-Moc-valine-linked pyrrolidinoimidazole subunits appended to a 2-arylindolyl hemiaminal spacer. A clever process-scale synthesis of elbasvir, as described by researchers at Merck in both a 2014 publication and a patent application, relies upon a stereochemical relay approach to set the challenging hemiaminal stereogenic center.8

The synthetic route began with esterification of

commercially available 2,5-dibromoacetic acid (13) with 3-bromophenol (14)—a reaction that proceeded through the corresponding acyl halide of 13 en route to ester 15 (Scheme 2). Fries rearrangement was employed to effect ester-to-ketone transposition.

Next, a

Exposure of 15 to a

mixture of methanesulfonic acid and methanesulfonic anhydride at elevated temperatures gave rise to acetophenone 16.

Although the authors do not explicitly comment about the regiochemical

considerations of this reaction, presumably the meta-arylbromide provides sufficient steric hindrance to favor ketone formation at the position para- to the bromide substituent.

Ketone 16 was

subsequently converted to the corresponding imine 17 upon condensation with ammonia in methanol. At this point, the stage was set for a critical stereochemical relay strategy for the construction of the 9

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hemiaminal geometry within elbasvir.

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This chirality establishing sequence ultimately began with

an asymmetric reduction of imine 17, in which ruthenium-catalyzed transfer hydrogenation conditions utilizing a metal-ligand complex, originally described by Wills,9 delivered branched amine 18 in excellent yield and enantioselectivity.

This was followed by an intramolecular

copper-mediated amination reaction to furnish indoline 19.

This indoline, which possessed a

stereogenic center unlikely to epimerize under strongly acidic conditions, was treated with benzaldehyde

in

warm

TFA

and

acetonitrile

to

facilitate

smooth

conversion

tetrahydrooxazinoindole 20 in excellent yield and remarkable 99:1 diastereomeric ratio (dr).

to

From

dibromoarene 20, Miyaura conditions were employed to convert both aryl bromides to the corresponding bis-pinacol borane (Scheme 3), and this reaction was followed by a cross-coupling with pyrrolidino bromoimidazole 21 (whose preparation is described in Scheme 4). with p-nitrobenzoic acid furnished azacycle 22 in 82% overall yield from 20.

Salt formation

Coincidentally, this

two-step sequence also resulted in oxidation of the indoline ring, establishing the 2,3-indolyl π-bond within 22. Next, exposure to potassium carbonate followed by reaction with methanolic HCl removed both Boc groups, converted 22 to diamine 23, which was immediately coupled with commercially-available methyl carbamate (Moc)-substituted valine (24) under standard amide bond-forming conditions. Recrystallization in warm ethanol completed the assembly of elbasvir (II) in 80% yield from 23.8 Pyrrolidino bromoimidazole 21 was derived from oxidation of commercially available S-Boc-prolinol (25, Scheme 4) followed by exposure to ammonia and glyoxal to secure the imidazole ring to give 26.

Perbromination of 26 and subsequent reduction completed the

construction of key bromide coupling partner 21.8 Scheme 2. Synthesis of dibromoarene fragment 20 for elbasvir 10

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Scheme 3. Synthesis of elbasvir (II)

Scheme 4. Synthesis of pyrrolidino bromoimidazole fragment 21 for elbasvir

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Grazoprevir hydrate is one of several structurally-related macrocycles developed for the treatment of patients with HCV. The structure of the drug presents considerable complexity given the numerous stereocenters both within and external to the macrocyclic array. Several different approaches to the construction of grazoprevir have been reported.10 Interestingly, the original synthetic approach used by the discovery team proceeded through the use of a ring-closing olefin metathesis to produce the macrocyclic ring.10a,b However, this route suffered from low yield in the key macrocycle forming step, necessitating development of an alternative strategy on scale, which hinges

upon

a

macrolactamization

disconnection.

Toward

this

end,

grazoprevir

was

retrosynthetically subdivided into three key fragments: chloroquinoxaline 29, cyclopropanol ent-32, and amine 38. The synthesis and union of these three fragments represents the most likely process-scale entry to this structurally complex drug, given that the patent application exemplified the synthetic sequence on kilogram scale, and is described in Schemes 5-8.11 The synthesis of chloroquinoxaline 29 started with the acid-mediated condensation of 4-methoxy-1,2-benzenediamine dihydrochloride salt (27) with oxalic acid followed by bis-chlorination to provide the corresponding dichloroquinoxaline (Scheme 5).11a Upon exposure to SNAr conditions (DBU, DMA) in the presence of commercially available hydroxyproline 28, chloroquinoxaline 29 was isolated in 68% yield. This three-step reaction sequence delivered the product with 95:5 selectivity for the desired regioisomer which could be further purified by recrystallizing from MTBE/heptanes. 12

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Scheme 5. Synthesis of chloroquinoxaline fragment 29 for grazoprevir

13

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The cyclopropanol ent-32 was prepared using a strategy that relied on enzymatic resolution (Scheme 6).11b A diastereoselective cyclopropanation of a vinyl boronate resembling 30 was attempted, but low yields and difficult purification prompted the authors to consider a racemic cyclopropanation. On 34.3 kg scale, commercially available vinyl boronate 30 was subjected to trifluoroacetic acid-modified cyclopropanation conditions developed by Shi and coworkers (ICH2ZnO2CCF3), which gave higher conversion and a cleaner impurity profile than classic Simmons-Smith conditions (Zn(CH2I)2).12

The product was isolated as a solution in heptane (96%

yield) and treated directly with 10 M sodium hydroxide and aqueous hydrogen peroxide to provide racemic cyclopropanol rac-31, which was carried forward crude as a solution in MTBE.

Direct

displacement of the chloride with lithium acetylide-ethylene diamine complex was optimized to generate terminal alkyne rac-32.

Safety considerations surrounding the use of lithium

acetylide-ethylene diamine on scale were closely examined due to the risk of uncontrolled release of acetylene gas.

To minimize acetylene gas evolution, pre-treatment of rac-31 with 1.2 equiv of

n-hexyllithium (HexLi) formed the alkoxide prior to addition of 1.1 equiv of lithium acetylide-ethylene diamine at 50 ºC.

This procedure was used successfully to synthesize rac-32 on

16.1 kg scale from the bulk stream of rac-31. Next, acylation of crude rac-32 in MTBE gave rise to ester rac-33, the key substrate for the enzymatic hydrolysis step.

Optimized conditions

employed Novozyme 435 in MTBE with 0.1 M aqueous potassium phosphate dibasic.

While all

previous steps could be carried through without isolation or purification, chromatography was required to isolate ent-32 (desired) from ent-33 and all other impurities generated through the five-step process. from 30.

At 40% conversion, ent-32 could be isolated in 96% ee and 19% overall yield

An alternate gram-scale synthesis of this fragment has recently been reported by

researchers at Merck using a route that avoids the use of lithium acetylide and enzymatic 14

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resolution.11c Scheme 6. Synthesis of chiral cyclopropanol fragment ent-32 for grazoprevir

With chloroquinaxoline 29 and cyclopropanol ent-32 in hand, assembly of the macrocycle commenced (Scheme 7).11a,

11d

Ent-32 was reacted with CDI and DIPEA followed by slow

addition of L-tert-leucine (34) to give carbamate 35, which was isolated as a solution in cyclopentyl methyl ether (CPME) and used without further purification.

After extensive optimization, the

Sonogashira cross-coupling product of alkyne 35 and chloroquinoxaline 29 was isolated in 98% HPLC purity following aqueous workup, and carried forward without purification.

The resulting

alkyne was subjected to catalytic hydrogenation conditions to furnish the macrocyclization precursor 36, which was also not isolated.

Phenylsulfonic acid-mediated Boc removal followed by direct

addition of excess DIPEA and slow addition of the mixture to a solution of HATU in acetonitrile resulted in intramolecular lactam formation with minimal dimerization byproducts (<2%). Macrocycle 37 was the first crystalline intermediate to be isolated in this sequence and was obtained in 65% yield in analytically pure form.

Careful saponification utilizing LiOH was followed by

amidation with amine 38 (the synthesis of which is described in Scheme 8) under conditions designed to minimize proline carboxylate epimerization (EDC, pyridine, MeCN) to give grazoprevir. 15

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Grazoprevir hydrate (III) was then generated by recrystallization from acetone and water at 50 ºC and the last three steps were completed in 44% overall yield. Scheme 7. Synthesis of grazoprevir hydrate (III)

Aminovinylcyclopropane 38 was generated in one step from the commercially available Boc-protected derivative (39, Scheme 8) by treatment with TsOH.11a, 13

Interestingly, this same

stereogenic vinyl cyclopropane subunit has been incorporated into a number of other recently-approved antiviral drugs.

A description of its synthesis, originally developed by 16

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Journal of Medicinal Chemistry

researchers at Bristol-Myers Squibb (BMS), has been summarized in our previous review for the synthesis of asunaprevir.2m

Scheme 8. Synthesis of aminovinylcyclopropane fragment 38 for grazoprevir

2.3 Narlaprevir (Arlansa®) Narlaprevir was approved as a treatment for genotype 1 HCV and serves as a class 2 HCV NS3 serine protease inhibitor.14

In clinical trials, it showed a rapid and steady decline in

HCV-RNA levels in both previously-treated and treatment-naïve patients when used in combination with ritonavir and PEG-IFN-α.15

This combination ultimately led to ≥ 50% of patients with

undetectable HCV-RNA levels after a second period of treatment.15

Narlaprevir also has

demonstrated activity against HCV mutations resistant to other treatments such as boceprevir and telaprevir.16

The unique activity of this drug can be attributed to a critical electrophilic

α-keto-amide “warhead” which covalently reacts with an HCV NS3 protease active-site serine residue involved in the HCV viral replication process.16-17

Because of their essential roles in viral

replication, HCV NS3 and NS5B proteases have recently become key targets for HCV drug development.17

Strategically, the development of narlaprevir stems specifically from the pursuit of

a single-diastereomer, second generation HCV protease inhibitor which would provide in vitro potency and pharmacokinetic profile improvements over the structurally-related anti-viral drug boceprevir,2j which exists as a mixture of diastereomers.17-18 After the R-Pharm pharmaceutical 17

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Page 18 of 80

group obtained the license to manufacture narlaprevir from Merck in 2012, further development of the drug was realized through collaborations with Schering-Plough and Texas Liver Institute.14 A kilogram-scale synthetic route to narlaprevir has been reported, and proceeds strategically through the union of urea 45, bicyclic amine intermediate 46, and amine salt 48 (Schemes 9-10).19 Preparation of urea 45 begins with commercial cyclohexanecarboxylic acid methyl ester (40), which was treated with freshly-prepared LDA and TMSCl in THF to provide silyl enol ether 41 (Scheme 9). This

intermediate

was

immediately

reacted

with

commercial

2-[(chloromethyl)thio]-2-methyl-propane (42) under Lewis acid conditions (ZnBr2) to provide ester 43 in 58% yield over the two-step process.18-19

A solution of crude 43 was subjected to

saponification conditions (NaOH, H2O, MeOH) and sulfide oxidation with Oxone® in DCM/MeOH, leading to the target sulfone 44 in 66% yield.

From 44, a Curtius rearrangement delivered an

isocyanate intermediate which could be trapped with L-tert-leucine, forming the desired urea 45 in 53% over the two-step sequence.18-19 Coupling 45 with commercially available bicyclic amine 46 under peptide coupling conditions (EDC, HOBt, NMM) led to the desired amide in 79% yield, which was then saponified with aqueous NaOH in 2-methyltetrahydrofuran (2-MeTHF) to provide acid intermediate 47 (84% yield).

This intermediate was coupled with amine salt 48 (synthesis of

48 is described in Scheme 10) with EDC and HOBt, providing the penultimate intermediate to narlaprevir.

Completion of the synthesis relied upon installation of the essential α-keto-amide

functionality, which was accomplished by α-hydroxy amide oxidation using TEMPO-catalyzed conditions. A final recrystallization from acetone/water completed synthesis of narlaprevir (IV) in 83% yield.19a

It is worth noting that this overall route was used to generate >1 kg of narlaprevir and

required no chromatographic separation steps.17-19

18

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Scheme 9. Synthesis of narlaprevir (IV)

Amine salt 48 was prepared by first subjecting commercially available pentanal (49) to Knoevenagel condensation conditions using malonic acid, followed by conversion of the resulting acid to the corresponding t-butyl ester 50 by reaction with H2SO4 and isobutylene (Scheme 10).19a The key transformation for establishing the requisite stereocenter in intermediate 48 relied on an asymmetric conjugate addition of a bis-protected lithiated amine followed by enolate trap with an electrophilic

source

of

oxygen.

In

practice,

treatment

of

α-methyl-N-(phenylmethyl)-(αS)-benzenemethanamine (51) with n-hexyllithium resulted in 19

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stereoselective 1,4-addition, followed by subjection of lithium enolate intermediate 52 to (1S)-(+)-(10-camphorsulfonyl)oxaziridine (53), which furnished the α-hydroxyl group and delivered the syn-amino alcohol derivative 54 in 81% yield for the two-step protocol.20 removal was realized by exposure of 54 to TFA in warm toluene.

Tert-butyl ester

Subsequent coupling of the

resulting acid with cyclopropylamine (55) utilizing EDC and HOBt conditions provided cyclopropyl amide 56 in 71% yield from 54.

Finally, hydrogenolytic removal of the benzyl groups from the

β-amine followed by subjection of the product to refluxing HCl provided amine salt 48 in 83% yield.19a

Scheme 10. Synthesis of cyclohexane amino fragment 48 for narlaprevir

HN

1. malonic acid py, 25-35 °C

O H

Ot-Bu

2. isobutylene heptane, H2SO4

49

O O O

THF, -60 °C

50

67% for 2 steps

N

51 n-HexLi, 51, THF

O

S O O

N 53 OH N

t-Bu -55 °C to -65 °C

Li

81% for 2 steps

54

OH

1. TFA, tol, 50 °C

55

N O

H N

1. Pd/C, HOAc, MeOH, H2, 60 °C 2. MTBE, HCl, 3 °C

to

OH H2N • HCl

H N

O

83% for 2 steps

NH2

71% for 2 steps

t-Bu

O

52

2. 55, DIPEA, EDC HOBt, 2-MeTHF 25 °C to 35 °C

O

56

48

20

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2.4 Nemonoxacin (Taigexyn®) Nemonoxacin is a novel non-fluorinated quinolone and broad-spectrum antibiotic for the treatment of drug-resistant bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA) and quinolone-resistant MRSA as well as quinolone-resistant Streptococcus pneumonia.21 The drug

was originally discovered by Procter & Gamble Pharmaceuticals (P&GP).22

It was

co-developed by TaiGen Biotechnology for development in Asia and by Warner Chilcott for development in the United States and Europe, and was first approved by the China Food and Drug Administration (CFDA).22,23 Although several synthetic approaches to marketed quinolone antibiotics similar in structure to nemonoxacin have been reported,23 two dedicated synthetic routes to nemonoxacin have been reported.24

The route depicted in Scheme 11, which has been disclosed by workers at Warner

Chilcott, not only describes a process route to the pharmaceutically active ingredient, but also describes the preparation and examination of several salt forms under consideration for intravenous and/or oral dosing approaches.24d

Condensation of commercial 2,4-difluoroacetophenone (57) with

ethylene glycol furnished ketal 58 in 86% yield.

This was followed by fluorine-directed

o-lithiation with n-butyllithium and trimethylborate quench.

Acidification followed by oxidation of

the boron species rendered hydroxyketone 59 in 79% yield from 58.

Next, phenol methylation with

dimethyl sulfate followed by deprotonation and reaction with diethyl carbonate (60) gave rise to the keto-ester intermediate, which underwent condensation with dimethylformamide-dimethylacetal (DMF-DMA) in refluxing toluene to provide the corresponding vinylogous amide 61.

An

addition-elimination reaction with cyclopropylamine (55) and subjection of this intermediate to acetimidate 62 in refluxing toluene presumably facilitated alkene isomerization with concomitant cyclization to produce the quinolinone derivative 63 in 82% yield over five steps.

Acidic 21

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Page 22 of 80

hydrolysis followed by treatment with diboron trioxide and acetic anhydride generated the triacetoxyborate 64, which served as a unique protecting group for the next step of the synthesis. Exposure of 64 to aminopiperidine 65 (whose synthesis is described in Scheme 12) under SNAr conditions provided aniline derivative 66.

This was followed by base-mediated borate removal,

acidic quench with concomitant Boc deprotection, and basification to furnish nemonoxacin (V) in 79% yield from 64.24d Scheme 11. Synthesis of nemonoxacin (V)

For the preparation of the aminopiperidine fragment 65 of nemonoxacin, commercial proline 22

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Journal of Medicinal Chemistry

derivative 67 was converted to the corresponding ester 68 in 52% yield prior to treatment with Bredereck’s reagent to give enamine 69 (Scheme 12).

Next, catalytic hydrogenation of 69 using a

Pfaudler reactor and 5% Pd/C converted the vinylogous amide to the corresponding methyl group, delivering 70 in nearly quantitative yield and 93:7 diastereomeric excess in favor of the desired geometry.

Further reduction of 70 using NaBH4 followed by treatment with calcium chloride

dihydrate gave the corresponding diol 71 in 66% yield.

Mesylation of diol 71 followed by

cyclization with benzylamine and hydrogenation to remove the N-benzyl group provided aminopiperidine 65.24c The yields of the last three steps were not reported.

Scheme 12. Synthesis of aminopiperidine fragment 65 for nemonoxacin

2.5 Tenofovir alafenamide fumarate (Vemlidy®)) Tenofovir alafenamide fumarate is an oral phosphonoamidate prodrug of the reverse transcriptase inhibitor tenofovir.

It was approved by the USFDA for the treatment of chronic

hepatitis B virus infection with compensated liver disease.

Tenofovir alafenamide fumarate was 23

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discovered and developed by Gilead as a potentially safer form of the previously approved tenofovir disoproxil fumarate (Viread®).25 A multi-kilogram synthesis of tenofovir alafenamide fumarate was described in a Gilead patent.26

Additional process improvements on specific steps of the Gilead process have been

reported on 100 gram scale and these will be noted throughout the description of the synthesis.

The

synthesis was initiated with the alkylation of adenine (72) with (R)-propylene carbonate (73) to give hydroxypropyl adenine 74 in 75% yield (Scheme 13).

It should be noted that sodium hydroxide

can be replaced by potassium bases with increased yields on 100 g scale.27 Alkylation of 74 with diethyl p-toluenesulfonyloxymethylphosphonate (75) gave intermediate 76, which was not isolated. Hydrolysis of the phosphonate esters with trimethylsilylbromide followed by recrystallization from water gave phosphonic acid 77 in 50% yield.

Interestingly, replacing Mg(Ot-Bu)2 with

PhMgCl/t-BuOH led to improved yields for the alkylation step (74  76) on a 100 g scale.27 Additionally, the authors note that conditions for hydrolyzing that phosphonate ester can be modified using HCl or HBr for improved yields on smaller scale.28

Dicyclohexylcarbodiimide (DCC)

coupling of 77 with phenol produced phosphonate 78 in 51% yield.

This step was also reported to

proceed in higher yield on smaller scale by changing the solvent to cyclopentylmethyl ether.28 Mono-phosphonate ester 78 was treated with thionyl chloride followed by (L)-alanine isopropyl ester (79) and triethylamine to give tenofovir alafenamide rac-80 as a mixture of phosphonate diastereomers in 47% yield.

The diastereomers were separated using simulated moving bed

chromatography29 to give the desired diastereomer ent-80 in 47% yield and 99% diastereomeric purity.

The diastereomers could also be separated using a crystallization-induced dynamic

resolution of rac-80.30

Tenofovir alafenamide fumarate (VI) was prepared from ent-80 and

fumaric acid in 83% yield. 24

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Scheme 13. Synthesis of Tenofovir alafenamide fumarate (VI)

2.6 Velpatasvir/Sofosbuvir (Epclusa®) In 2016, velpatasvir was approved in the US, Europe, and Canada as a once-daily oral treatment for chronic HCV genotypes 1-6 when used as a combination therapy with the recently approved HCV inhibitor sofosbuvir (SOVALDI).2l While velpatasvir functions as an HCV NS5A protein 25

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Page 26 of 80

inhibitor, sofosbuvir serves as an inhibitor of HCV NS5B RNA polymerase, both of which play a key role in inhibiting HCV replication.31

The combination, developed by Gilead, has been shown

to provide very high rates of sustained virological responses (SVRs) in a variety of clinical trials31a, 32

and exhibits full antiviral activity against resistance-associated variants developed by other HCV

inhibitors with varying mechanisms of action.31 The velpatasvir/sofosbuvir combination has been classified as pangenotypic,32a demonstrating antiviral activity for all known HCV genotypes, and joins a class of direct-acting antivirals (DAAs) that can also be used for patients suffering from severe liver failure, who were previously contraindicated for treatment with standard interferon- and ribavirin-based regimens.32a, 33 The synthetic strategy for the preparation of velpatasvir involves a series of bi-directional functionalizations that require the preparation and union of several structural subunits.

Although

several routes to velpatasvir intermediates have been recently published,34 including a potential alternate process route,35 the most likely process-scale route to the drug target has been described in a 2015 patent application authored by scientists at Gilead; this patent also describes several alternative routes to the drug’s key building blocks.36

It is important to note that no yields are

reported throughout the patent, and only the route to pyrrolidine 91 was exemplified on multi-kilogram scale.36-37

Synthesis of the central tetracyclic intermediate in the velpatasvir

synthesis, tetralone 86, began with commercial 2-bromo-5-iodo-benzenemethanol (81), which underwent iodide-metal exchange and subsequent quench with acetamide 82 (Scheme 14).36 Mesylation of the resulting alcohol followed by treatment with LiBr furnished benzyl bromide 83, which was then subjected to nucleophilic attack by commercial 7-hydroxytetralone (84) in the presence of K2CO3/MeCN to provide ether 85.

An innovative use of an intramolecular

Pd-mediated C-H activation reaction catalyzed by Pd(OAc)2/PPh3 secured the central tetracyclic 26

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core, which then underwent bis-α-keto-bromination with pyridinium tribromide in MeOH/DCM at room temperature to furnish tetralone 86.36

Scheme 14. Synthesis of tetralone fragment 86 for velpatasvir

The preparation of the ethereal pyrrolidine subunit 91 began with formylation of commercial glutamate 87 followed by an intramolecular cyclocondensation reaction facilitated by TFA to secure dihydropyrrole 88 (Scheme 15).36

It should be noted that while TFA was used to affect the

formation of enamine 88, the reported route indicates no loss of Boc or t-Bu ester protecting groups in this transformation, and no further discussion was provided by the authors.36-37 Reduction of the enamine (H2, Pd/C, HOAc) and ester (NaBH4, H2O/THF) moieties present in 88 yielded pyrrolidine 89 as a mixture of diastereomers.

Global deprotection of this mixture using room temperature HCl

in methanol generated the free amino acid, which was immediately subjected to mono reprotection with Boc anhydride to allow isolation of the Boc-protected amino acid intermediate 90.

Final steps

of the synthesis of 91 included alkylation with methyl iodide and dicyclohexylamine salt formation, 27

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Page 28 of 80

enabling isolation of the desired cis-isomer after crystallization. Finally, subjection to NaOH in MTBE/H2O provided the desired ethereal pyrrolidine 91.36

Scheme 15. Preparation velpatasvir ethereal pyrrolidine 91

Construction of the final building block, methylpyrrolidine 96, began with a ring-opening reaction

to

convert

N-Boc-pyrrolidinone

92

to

ketone

93,

followed

Boc-deprotection/ring-closing reductive amination sequence (Scheme 16).36

by

a

one-pot

This step resulted in

stereoselective hydride addition from the face opposite the ethyl ester,37 leading to the desired syn product, which was isolated as tosylate salt 94 after heating with p-toluenesulfonic acid monohydrate. Subsequent coupling with commercially available valine derivative 95 under standard peptide coupling conditions (HATU, DIPEA) and ester saponification with LiOH/MeOH furnished methyl pyrrolidine 96.36

Scheme 16. Synthesis of methyl pyrrolidine fragment 96 for velpatasvir

28

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The final approach to the velpatasvir synthesis proceeded linearly, starting with the central tetralone core and building outward (Scheme 17).36 Alkylation of dibromide 86 first with acid 91 and secondly with acid 96 resulted in the transient bis-ketoester intermediate 97, which was converted to bis-imidazole 98 using ammonium acetate followed by DDQ oxidation.

Finally, introduction of

fragment 99 relied upon on Boc-deprotection with HCl/MeOH and subsequent neutralization of the resulting HCl salt to enable crystallization as the triphosphate salt.

A second neutralizing step (aq.

NH4OH) and CDMT/NMM-mediated coupling of the free amine with commercially available phenylacetic acid derivative 99 provided velpatasvir (VII).36

Scheme 17. Synthesis of velpatasvir (VII)

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2.7 Zabofloxacin D-aspartate (Zabolante®) Zabofloxacin is a quinolone antibiotic originally developed by Dong Wha Pharmaceuticals and licensed to Pacific Beach Biosciences in 2007.38

In March 2015, Korea’s Ministry of Food and

Drug Safety (MFDS) approved zabofloxacin for the treatment of acute bacterial exacerbation of 30

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Journal of Medicinal Chemistry

chronic obstructive pulmonary disease (ABE-COPD).39

In 2016, zabofloxacin gained approval

from the USFDA for the treatment of community-acquired pneumonia. ABE-COPD is caused by respiratory tract and pulmonary parenchyma that cause chronic pulmonary inflammation and obstruction in the respiratory tract and lead to irreversible damage.

In the non-clinical evaluation

process, zabofloxacin showed strong antibiotic activity on respiratory germs (e.g. Streptococcus pneumonia, S. haemophilus, S. moraxella) and was the most potent antibacterial agent against penicillin-resistant S. pneumoniae (PRSP) in the murine systemic infection model.40 The

synthesis

of

zabofloxacin

leverages

the

wide

commercial

availability

of

chloronaphthyridinone acid 106 to essentially reduce the task to the construction of functionalized diazaspirocyclic pyrrolidine 105 (Scheme 18).41

As described in a series of patents from

researchers at Dong Wha who have exemplified the synthesis on multi-kilogram scale, the route began with first converting the commercially available ketone 100 to the corresponding oxime followed by formylation to give oximyl alcohol 101. Next, mesylation of the alcohol was followed by conversion of the nitrile to the corresponding amine 103.

An intramolecular ring closing step

then occurred to secure the azetidine using aqueous sodium hydroxide. Salt formation with phthalic acid furnished 104 in good yield. Next, Boc-protection of the azetidine followed by hydrogenative CBz removal and treatment with succinic acid resulted in the formation of amine salt 105, and this was followed by a substitution reaction with 106 to deliver the Boc-protected zabofloxacin structure 107. Lastly, removal of Boc via TFA followed by basification and subjection to D-aspartate in warm ethanol furnished zabofloxacin D-aspartate (VIII) in 56% yield for the three-step sequence. Scheme 18. Synthesis of zabofloxacin D-aspartate (VIII)

31

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O CBz N

1. NH2OMe-HCl py, MeOH, 28 °C 2. aq. HCHO, 28 °C

CN

O N

NaBH4, LiCl EtOAc, EtOH

O N OMs NH2

3. D-aspartate EtOH, 60 °C

OMs CN

DCM, 25 °C, 90% 102

1. aq. NaOH, EtOH DCM, 78 °C

CBz N

O N

HO2C

.

CBz N

HO2C

2. phthalic acid MeOH, 25 °C

NH 104

92% for 2 steps

O O N

106, aq. NaOH EtOH, MeCN

NH HO2C

.

25 °C, 94% N Boc

O

F O N

N

OH N

N

CO2H N Boc

105

92% for 3 steps

1. TFA, EtOH 0-5 °C 2. aq. NaOH EtOH, 25 °C

CBz N

101

90% for 3 steps

103

3. succinic acid MeOH, 25 °C

MsCl, Et3N

OH CN

25 °C, 82%

1. aq. NaOH Boc2O, 25 °C 2. H2, 10% Pd/C MeOH, 20-30 °C

O N

CBz N

3. 7 N HCl 100

Page 32 of 80

O

O O

F O N HN

58% for 3 steps

N

107

OH N

F

O OH

N Cl

. NH2 HO2C

N

N 106

CO2H

Zabofloxacin D-aspartate (VIII)

3. CNS Drugs 3.1 Brivaracetam (Briviact®) Brivaracetam, a novel oral antiepileptic drug with a high affinity for synaptic vesicle protein 2A (SV2A), was approved in Europe and the US as an adjunctive therapy for the treatment of partial onset seizures with or without secondary generalization in patients aged sixteen or older.42 Brivaracetam is very closely related to levetiracetam—an antiepileptic treatment whose immediate release formulation has been available in the United States as a generic drug since 2008, but whose 32

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extended release formulation is under patent protection until 2028.

The two drugs, which were

both developed by UCB Pharma, are structurally similar, with brivaracetam having an n-propyl group at the C-4 position of the pyrrolidinone ring and levetiracetam having a hydrogen at this same position.

A systematic investigation of the various substitutions of levetiracetam resulted in the

identification of more potent and selective SV2A ligands and ultimately culminated in the discovery of brivaracetam, which has greater affinity for SV2A, improved selectivity, more rapid brain penetration, and faster onset of action against seizures than levetiracetam.43,44 Regarding the large scale synthetic approach to brivaracetam, stereocontrolled installation of the 4-n-propyl group stands as the central challenge in the assembly of the molecule. routes have been published that require chiral separation.44-45 been

reported,

one

employing

an

enzymatic

(R)-(-)-epichlorohydrin as a chiral starting material.47

Several

Two enantioselective routes have

resolution46

and

the

other

utilizing

The route detailed in Scheme 19, which

involves an enzymatic resolution, is the only kilogram-scale route disclosed in the literature to date and reportedly permits the production of brivaracetam within the required commercial quality specifications.

However, the authors note that the development of this route for commercial

purposes has been stopped.46 tert-butyl-2-bromoacetate.

Commercial dimethyl n-propylmalonate 108 was first alkylated with

The resulting product underwent Krapcho decarboxylation to afford

racemic succinate derivative 109 in 94% yield over the two steps.46

Optimized conditions for the

key enzymatic resolution employed protease C from Bacillus subtilis type 2 at 30 ºC for 18 hours to resolve ester 109 and provide the acid enantiomer 110.

This biocatalytic process allowed for

residual unreacted diester 109 to be washed away with cyclohexane at pH 9 (adjusted with 0.5 M NaOH), and the desired acid 110 could be isolated upon lowering the pH (~1) and extracting with isopropyl acetate (42% yield, 97% ee).

The transformation of acid 110 into propyllactone 111 33

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proceeded in nearly quantitative yield by a three-step sequence – activation of the acid with ethyl chloroformate, reduction to the alcohol with sodium borohydride, and cyclization upon acidic workup with TFA.

Exposure of 111 to HBr in acetic acid followed by esterification of the resulting

acid generated bromoester 112.

Finally, TBAI-catalyzed alkylation of 112 with commercial

(S)-2-aminobutanamide (113) in refluxing isopropyl acetate introduced the n-butylamide moiety while facilitating lactamization.

Addition of MTBE followed by filtration and recrystallization

from isopropyl acetate to afford brivaracetam (IX) in 32% yield and 96% ee. Scheme 19. Synthesis of brivaracetam (IX)

3.2 Opicapone (Ongentys®) Opicapone is a selective and reversible catechol O-methyltransferase (COMT) inhibitor which was developed by the Portuguese pharmaceutical firm Bial and sold to Neurocrine Biosciences.48 34

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The

drug

was

approved

by

the

USFDA

as

adjunctive

treatment

to

levodopa

(L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations.49

In 14- to

15-week double-blind, multinational trials and in one-year, open-label extension studies in this patient population, opicapone was an effective and generally well-tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapies.49

During the double-blind phase, adjunctive

opicapone (50 mg once daily) provided significantly greater improvements in motor fluctuations than placebo, and no new unexpected safety concerns were identified after treatment with opicapone over a 1.4-year period.49 Furthermore, no serious cases of hepatotoxicity were reported in clinical trials, which represents a significant safety profile improvement over existing standard-of-care COMT inhibitors enticapone, tolcapone, and nebicapone.48-49 Although several synthetic approaches to opicapone or opicapone subunits have been disclosed,50 a synthetic approach described by Bial was exemplified on a scale capable of producing 14.4 kg of the active pharmaceutical ingredient (API).47e Commercial 2,4-pentanedione (114) was condensed with cyanoacetamide in warm methanol to give rise to cyanopyridone 115 in excellent yield (Scheme 20).

Chlorination with sulfuryl chloride in chilled acetonitrile followed by treatment

with phosphorous oxychloride resulted in the dichloropyridine 117.

Next, treatment with

hydroxylamine in aqueous methanol converted nitrile 117 to the corresponding N-hydroxyamidine 118, and this was followed by exposure to pyridine and acid chloride 119 (whose preparation is described in Scheme 21).

These operations facilitated a cyclization reaction which furnished the

key oxadiazole 120 in good yield.

Subjection of 120 to urea hydrogen peroxide (UHP) in

dichloromethane to establish the pyridine N-oxide functionality within opicapone preceded methyl ether cleavage through the use of aluminum trichloride in warm pyridine to furnish opicapone (X) in 35

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53% yield for the two-step sequence. Scheme 20. Synthesis of opicapone (X)

The preparation of acid chloride 119 involved the nitration of commercially available benzoic acid 121 followed by thionyl chloride-mediated conversion of the resulting nitrobenzoic acid 122 to acid chloride 119 (Scheme 21).

Interestingly, although the nitration step is low-yielding and

involves nitric acid, the authors report an operationally simple isolation method that has been exemplified on multiple kilogram scale.

No yield was reported for the conversion of 122 to 119.

Scheme 21. Synthesis of acid chloride fragment 119 for opicapone

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3.3 Pimavanserin tartrate (Nuplazid®) Pimavanserin, developed by San Diego-based Acadia Pharmaceuticals, is a selective and potent serotonin 2A (5-HT2A) receptor inverse agonist.51

The USFDA approved this once-daily drug to

treat the delusions and hallucinations associated with psychosis as a function of Parkinson's disease.52

Pimavanserin has a unique mechanism of action relative to other antipsychotics,

behaving as a selective inverse agonist of the serotonin 5-HT2A receptor while exhibiting 40-fold selectivity over the 5-HT2C receptor and having no significant affinity or activity with the 5-HT2B or dopamine receptors.53 Three patent applications filed by Acadia described the process-scale synthetic approach to pimavanserin.54

The kilogram-scale synthesis (Scheme 22) began with the alkylation of

commercially available 4-hydroxybenzaldehyde (123) with isobutyl bromide (124) under basic conditions. Condensation of the resultant benzaldehyde 125 with hydroxylamine furnished the corresponding oxime 126 in 63% yield from 123.

Hydrogenation of 126 catalyzed by Pd/C under

acidic conditions produced benzylamine 127 which was isolated as the acetate salt in 41% yield. This compound underwent sodium hydroxide workup followed by reaction with HCl gas and phosgene to deliver isocyanate 128.

Nucleophilic attack of this isocyanate by benzylamine 129

(prepared from reductive amination of commercially available N-methylpiperid-4-one 130 with 4-fluorobenzylamine 131, Scheme 23) followed by salt formation using tartaric acid in aqueous isopropyl acetate and THF completed the synthesis of pimavanserin tartrate (XI) in 50% yield over the two-step protocol and a 10.6% overall yield from 123.54c

Scheme 22. Synthesis of pimavanserin tartrate (XI)

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Scheme 23. Synthesis of benzylamine fragment 129 for pimavanserin

3.4 Pitolisant hydrochloride (Wakix®) Pitolisant hydrochloride, a first-in-class inverse agonist of the histamine H3 receptor, was approved in the EU for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy with or without cataplexy.55 The drug, which was developed by Bioprojet and has orphan drug designation in the EU and US, enhances wakefulness by increasing histaminergic 38

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neuron activity.

With once daily oral administration in the morning, patients taking pitolisant

exhibited significantly reduced EDS versus placebo, but not versus modafinil.56

Plasma levels of

the drug are reduced at the end of the day such that its waking effect is minimized at night (plasma t1/2 10-12h).

Several articles have been published detailing the discovery of pitolisant.57

The most likely scale preparation of pitolisant hydrochloride consists of only four synthetic steps, starting with the mesylation of commercial 3-(4-chlorophenyl)propan-1-ol (132, Scheme 24).58

Displacement

of

the

mesylate

with

the

sodium

salt

of

commercial

3-(piperidin-1-yl)propan-1-ol (133) in warm DMA assembled the parent drug in 97% yield over two steps.59

Salt formation was affected by pH adjustment to 3-4 using HCl gas in EtOAc.

Recrystallization from ethyl acetate and isopropanol provided pitolisant hydrochloride (XII) on kilogram scale in 78% overall yield across the short four-step protocol.60

Scheme 24. Synthesis of pitolisant hydrochloride (XII)

4. Dermatologic Drugs 4.1 Crisaborole (Eucrisa®) Crisaborole is a phosphodiesterase-4 (PDE4) inhibitor that was approved by the USFDA for the treatment of mild to moderate atopic dermatitis (AD) in patients aged two years and older.61 The 39

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drug, which was developed by Anacor Pharmaceuticals and later acquired and marketed by Pfizer, is delivered as a 2% ointment which is applied topically.61

The unique employment of boron within

the chemical structure of the drug is designed to enable selective engagement of PDE4 (an enzyme involved in the conversion of cAMP into AMP which signals for downstream inflammatory events), effective penetration of the drug through human skin, and rapid clearance to limit systemic circulation.62

During in vitro experiments, the drug demonstrated significantly reduced cytokine

production from peripheral blood mononuclear cells in a pattern similar to other PDE4 inhibitors and distinct from corticosteroids.62 In phase 1 and 2 clinical studies, crisaborole ointment was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms.62 Several

disclosures

describing

synthetic

approaches

to

ethereal

boron-containing

anti-inflammatory compounds have been published by Anacor.64,65 A scalable synthetic route to crisaborole is described in Scheme 25 and closely follows an approach to the drug reported in the public literature by researchers at Anacor.65 Commercially available bromobenzaldehyde 134 was protected as the corresponding acetal upon subjection to warm ethylene glycol in the presence of catalytic p-toluenesulfonic acid.

This was followed by nucleophilic aromatic substitution involving

4-fluorobenzonitrile and subsequent acetal deprotection to furnish diaryl ether 136.

Although

multiple approaches to crisaborole have been reported from this intermediate diaryl ether 136,64b,64c,65 the published literature approach involves the following sequence: reduction of the aldehyde with sodium borohydride followed by THP protection to furnish bromobenzene 137 which then underwent lithium-halogen exchange prior to quench with triisopropyl borate and acidification to arrive at crisaborole (XIII).65 Alternatively, patents from Anacor describe a general approach employing a Miyaura coupling of 136 enabling the installation of the corresponding pincacol borane, 40

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which could then be exposed to reduction conditions using sodium borohydride followed by boric acid wash, aqueous workup, and lyophilization to furnish XIII.64b, 64c Scheme 25. Synthesis of crisaborole (XIII)

5. Gastrointestinal Drugs 5.1 Obeticholic Acid (Caliva®) Obeticholic acid is a potent and selective farnesoid X receptor agonist that promotes the flow of bile in the liver.63

The drug was approved by the USFDA for the treatment of the rare chronic liver

disease primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response to UDCA, or as a single agent therapy in adults unable to tolerate UDCA.64

Obeticholic acid was discovered at the Università de Perugia and developed by Intercept

Pharmaceuticals. Obeticholic acid has also been granted orphan drug designation for the treatment of primary sclerosing cholangitis and primary biliary cirrhosis and has received breakthrough therapy designation for the treatment of patients with non-alcohol steatohepatitis (NASH) with liver fibrosis. The

synthesis

of

obeticholic

acid

was

initiated

from

commercial

3α-hydroxy-7-keto-5β-cholan-24-oic acid (138) and is described in Scheme 26.65

Fischer 41

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esterification of 138 provided methyl ester 139, which was treated with trimethylsilyl chloride and triethylamine to protect the secondary alcohol.

Reaction of the protected alcohol with lithium

diisopropylamine and trimethylsilyl chloride gave silyl enol ether 140. Aldol condensation with acetaldehyde and boron trifluoride etherate followed by saponification of the methyl ester produced enone 141.

Hydrogenation of the olefin followed by heating to reflux to epimerize the resulting

ethyl group produced the α-ethyl ketone 142, in 62% yield from compound 138. Reduction of the ketone in 142 with sodium borohydride and subsequent crystallization from phosphoric acid and water gave obeticholic acid (XIV) in 90% yield. Scheme 26. Synthesis of obeticholic acid (XIV)

6. Metabolic Drugs 42

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6.1 Migalastat hydrochloride (GalafoldTM) Migalastat, which is marketed by Amicus Therapeutics,

received approval in the EU for the

treatment of Fabry disease in adults and adolescents aged 16 or older.66

Fabry disease is caused by

mutations of the enzyme α-galactosidase A (α-GAL A) that cause protein mis-folding, and prevents efficient metabolism of the glycosphingolipid globotriaosylceramide (GL3).67

Accumulation of

GL3 in lysosomes, blood vessels, and various tissues ultimately leads to significant heart, kidney, and dermatological problems.67

Migalastat functions as a molecular chaperone to α-GAL A,

engaging the enzyme and enabling it to adopt the proper conformation allowing for efficient breakdown of GL3.66 Because the standard of care prior to 2016 for treating Fabry disease was enzyme replacement therapy (ERT), migalastat’s approval in the EU represents an important advance for patients suffering from this disorder.66 Several

unique

synthetic

approaches

to

migalastat,

which

is

D-1-deoxygalactonojirimycin (DGJ), have been reported in the literature.68

also

known

as

Although the most

likely commercial-scale preparation of this drug proceeds through a microbial fermentation process disclosed in a 2015 patent,69 a kilogram-scale synthesis of the drug outlined in Scheme 27 has been described in a 2008 patent application filed by Amicus.

This route closely resembles a procedure

disclosed in 1999 by Uriel and Santoyo-Gonazlez68i,70 that presented handling and safety concerns.68i Commercial D-galactose (143) was treated with five equivalents of pivaloyl imidazole (144),71q followed by triflation, treatment with Hünig’s base, and exposure to sodium nitrite to furnish the tetrapivaloyl altofuranose triflate 145 after recrystallization from heptane.

Next, stereospecific

azide displacement of the triflate successfully delivered azidofuranose 146 in 65-70% yield.

This

reaction generated over 3 kg of the desired alkyl azide after recrystallization from ethanol and water. Lastly, palladium-catalyzed hydrogenolysis in the presence of sodium methoxide, a methanolic 43

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acidification step, and then a subsequent acidification step using HCl in THF furnished migalastat hydrochloride (XV) in 70-75% yield over the three-step sequence from 146. Scheme 27. Synthesis of migalastat hydrochloride (XV)

7. Oncology Drugs 7.1 Olmutinib (Olita®) Olmutinib, co-developed by Boehringer Ingelheim and Hanmi Pharmaceutical Co., was approved by the Korean Ministry of Food and Drug Safety (MFDS) for treatment of locally advanced or metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC).71 Olmutinib serves as a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), being used as an oral therapy for patients who have previously been treated with an alternate EGFR TKI.71a

First and second-generation EGFR TKIs, which bind reversibly and

irreversibly to the TK domain, respectively, are both generally effective at onset of treatment but result in development of resistance within the first year of treatment.71b, 72

Third-generation EGFR

TKIs such as olmutinib have demonstrated the ability to covalently bind to the kinase domain of EGFR while sparing wild-type EGFR, leading to irreversible inhibition of both EGFR mutations and 44

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the T790M mutation, which is linked to EGFR TKI resistance.71b, 73 Synthetically,

olmutinib

can

be

accessed

in

two

steps

beginning

with

2,4-dichloro-thieno[3,2-d]pyrimidine (147, Scheme 28), which is commercially available and can be prepared in two steps from urea and 3-aminothiophene 2-carboxylate.74

Nucleophilic addition of

N-(3-hydroxyphenyl)-2-propenamide (148) to 147 proceeded with complete regioselectivity via treatment with K2CO3 in warm DMSO, smoothly providing the desired diaryl ether 149 in 87% yield after crystallization from isopropanol and water.74b, 75

From 149, substitution with commercially

available piperazinyl aniline 150 under acidic heating conditions (DMA, IPA, TFA, 90 °C) provided olmutinib in 82% yield.

After recrystallization, olmutinib (XVI) was obtained in 60% overall yield

and 99.1% purity.75 Scheme 28. Synthesis of olmutinib (XVI)

7.2 Rucaparib camsylate (Rubraca®) Rucaparib was approved in the US as an oral treatment for advanced ovarian cancer.76 45

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Development of rucaparib began with collaborations between Cancer Research UK and Agouron Pharmaceuticals (later acquired by Pfizer).

Global development rights for rucaparib were

ultimately granted to Clovis Oncology via a licensing agreement from Pfizer.76

To qualify for

treatment with rucaparib monotherapy, patients must demonstrate deleterious breast cancer (BRCA) mutation (germline and/or somatic) associated advanced ovarian cancer and also must have previously been treated with two or more chemotherapy regimens.77

Rucaparib functions as a

small molecule poly(ADP-ribose) polymerase (PARP) inhibitor which plays an important role in DNA repair.77-78

This newly-approved drug displays nanomolar potency against PARP-1, -2, and -3

enzymes,79 which translates into improved efficacy over alternative therapies such as olaparib or niraparib.80

Furthermore, rucaparib is also known to cause vasodilation, which is thought to induce

tumor perfusion and increased accumulation of the drug in cancer cells.81 While rucaparib shows higher cytotoxicity in cancer cells with mutation of BRCA1/2 genes and other DNA repair genes,76, 82 reduced tumor growth was observed in mouse xenograft models of human cancers with and without BRCA mutations.76

Rucaparib is also being pursued as a treatment for breast cancer83 and has

displayed promising initial results in trials for pancreatic cancer.84 Synthesis of rucaparib camsylate begins from commercially available phthalimide acetal 151 (Scheme 29).85

Unveiling of the aldehyde via treatment with aqueous HCl and precipitation from

toluene provided aldehyde 152 in 62% yield.

To avoid polymerization, 152 was immediately

subjected to 6-fluoro-1H-indole-4-carboxylic acid methyl ester (153) under reductive conditions in the presence of acid to give rise to tryptamine derivative 154.

After considerable research, optimal

conditions for this transformation (triethylsilane in DCM/TFA)86 were found that were successful on up to 15.7 kg scale, enabling clean separation of the aldehyde reduction byproduct following crystallization.85

Conversion of the phthalimide within 154 to the corresponding amine using 46

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aqueous methylamine at room temperature was accompanied by an intramolecular cyclization reaction to secure the intermediate lactam as a solid in 89% isolated yield.

This was followed by a

high-yielding bromination reaction (83%) at the indole C-2 position employing pyridinium tribromide, providing access to indoloazepinone 155.

After screening various catalysts for the

coupling of bromide 155 and commercial boronic acid 156, Pd(dppf)Cl2•DCM was found to reliably deliver the desired coupling product with reasonable rates of reaction.

Thus, after development of

an extensively optimized reaction protocol,85 Suzuki coupling of 155 and 4-formylphenylboronic acid (156) with Pd(dppf)Cl2•DCM and Na2CO3 in DMA at 90 °C generated the desired 2-arylated indole 157 in high yield (92%) after trituration and re-slurry with methanol.

Conversion of

aldehyde 157 to amine 158 necessitated a two-pot procedure designed to limit the formation of dimerization and aldehyde reduction products that generally arise under conventional one-pot reductive amination conditions and have traditionally been problematic on scale.

Toward this end,

subjection of aldehyde 157 to a methylamine solution in EtOH/MeOH/THF and wash of the resulting reaction solids with methanol led to efficient isolation of pure imine intermediate, which could be immediately reduced with NaBH4 in THF/MeOH, providing hydrochloride salt 158 upon acidic workup in 76% over two steps.

The two remaining steps for conversion to the drug involve

a salt-swap, first breaking the HCl salt with NaOH in MeOH, then treatment with (S)-camphorsulfonic acid/IPA/H2O at 70 °C.

Filtration and washing of the cake with water

generated rucaparib camsylate (XVII) in 95% yield.85 Scheme 29. Synthesis of rucaparib camsylate (XVII)

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7.3 Venetoclax (Venclexta®) Venetoclax, co-developed by AbbVie (previously Abbott Laboratories) and Genentech/Roche, was approved in the US for treatment of patients with chronic lymphocytic leukemia (CLL). To meet qualifications for venetoclax treatment, patients must have received prior therapy and possess the 17p deletion genetic mutation, as determined by USFDA testing.87 Venetoclax functions as a selective inhibitor of B cell lymphoma subtype 2 (BCL-2), which is often overexpressed on malignant cells and thus leads to impairment of the apoptotic pathway.88 Along these lines, the orally-dosed small molecule drug restores the ability of malignant cells to undergo apoptosis as its mechanism of action.89 While other BCL-2 inhibitors are known, development of similar agents such as navitoclox have been pursued and halted due to undesired inhibition of BCL-XL, leading to 48

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Journal of Medicinal Chemistry

significant thrombocytopenia and demonstrating the need for more selective inhibitors.88b Venetoclax is also currently being considered for approval in Europe and Canada for similar indications and is in various stages of development for treatment of non-Hodgkin lymphomas (NHL), acute myeloid leukemia (AML), multiple myeloma (MM), and several other disorders, either as a combination therapy or a stand-alone treatment.88a The manufacturing route to venetoclax takes place by coupling of three key structural subunits: azaindole 162, sulfonamide 165, and piperazine 172.90

The first of these subunits was generated in

two steps from commercially available 4-bromo-2-fluoro-1-iodo-benzene (159, Scheme 30). Grignard formation of iodide 159 (i-PrMgCl) followed by quench with Boc2O provided the desired tert-butyl ester 160 without the need for chromatographic purification.

Aromatic substitution of

crude 160 with azaindole 161 provided access to 162 in 86% yield after recrystallization from EtOAc/heptane. Separately, as shown in Scheme 31, sulfonamide 165 was formed in 91% yield and 99.9% purity via aromatic substitution of commercially available 163 with amine 164 at 80 °C (DIPEA, MeCN).90a

Scheme 30. Synthesis of azaindole fragment 162 for venetoclax

Scheme 31. Synthesis of sulfonamide fragment 165 for venetoclax 49

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Synthesis of the third venetoclax subunit, piperazine amine hydrochloride salt 172, began with commercial cyclohexanone 166 (Scheme 32).90a Vilsmeier-Haack formylation of the sterically more accessible enol tautomer of 166 delivered vinyl chloride 167 in quantitative yield. Coupling of this chloride with commercial aryl boronate 168 gave rise to transient enal 169 in 87% assay yield, which was not isolated. Crude 169 was then carried into a reductive amination reaction with commercial N-Boc piperazine (170). Precipitation and recrystallization from acetonitrile ultimately furnished piperazinyl alkene 171 in 74% yield from 167. Finally, subunit 172 was obtained via Boc removal with concentrated HCl in IPA at 65 °C and subsequent filtration, conditions that provided a 95% yield of high purity intermediate 172 (>99.5%).90a Scheme 32. Synthesis of piperazine hydrochloride amine fragment 172 for venetoclax (HO)2B

Cl 168

POCl3, DMF , quant.

O 166

HN

Pd(OAc)2, TBAB Cl

CHO

CHO

aq. K2CO3 DME, MeCN Cl

167

169

N Boc 170

N

conc. HCl, IPA

N

NH

65 °C, 95%

NaBH(OAc)3 tol, THF 74% from 167

N Boc

• 2 HCl Cl

171

Cl 172

50

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Journal of Medicinal Chemistry

The final approach to venetoclax involved a palladium-catalyzed coupling of amine 172 with aryl bromide 162, ester hydrolysis, and coupling of the resulting carboxylic acid with sulfonamide 165 (Scheme 33).90

In practice, Buchwald-Hartwig amination of 162 with 172 proceeded smoothly

and relied upon workup with cysteine to enable cleansing of residual palladium from the reaction mixture. This reaction gave rise to advanced intermediate 173 in 89% yield after crystallization from cyclohexane. Treatment of 173 with t-BuOK/H2O/2-MeTHF at 55 °C provided the corresponding free acid, which was immediately activated with EDC/DMAP/Et3N to promote coupling with sulfonamide 165 at room temperature. The final drug target could be accessed by crystallization from EtOAc and washing with 1:1 DCM/EtOAc, yielding venetoclax (XVIII) in free base form90-91 in 71% over the two final steps.90a,89b, 90

This synthetic route was capable of fashioning the drug

target in 52% overall yield based on the longest linear sequence (7 steps).90b Scheme 33. Synthesis of venetoclax (XVIII)

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8. Ophthalmologic Drugs 8.1 Lifitegrast (Xiidra®) Lifitegrast, initially designed and developed by SARcode Bioscience (which was acquired by Shire in 2013),14 is a novel tetrahydroisoquinoline derivative that is marketed as a 5% ophthalmic solution.92

The drug was approved by the USFDA for the treatment of dry eye disease.14

As a

small-molecule integrin antagonist, lifitegrast reduces inflammation through binding inhibition of the proteins lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1), influencing T-cell activation and cytokine (protein) release.

Lifitegrast

represents the first LFA-1/ICAM-1 interaction inhibitor approved globally, making it a first-in-class therapy for the treatment of dry-eye disease by this mechanism.92,93,94 The most likely synthetic approach capable of delivering lifitegrast on scale is described in Scheme 34 beginning with commercial 3-bromo-L-phenylalanine (174) as the starting material.95 After Boc protection, reaction with sodium methanesulfinate in the presence of copper iodide, K2CO3, and L-proline gave rise to sulfonate 176.

Esterification of 176 with benzyl alcohol

followed by removal of the Boc group within 177 yielded the corresponding HCl salt of the aminoester 178. Amide bond coupling with acid 179 (prepared as shown in Scheme 35) furnished amide 180, which was then subjected to 4N HCl in dioxane resulting in trityl removal and arrival at HCl salt 181 in 88% yield over two steps.

Tetrahydroisoquinoline 181 was then coupled with

commercial benzofuranyl acid 182 to give rise to lifitegrast benzyl ester in 90% yield.

Finally,

saponification delivered lifitegrast (XIX) in 88% yield.95c Scheme 34. Synthesis of lifitegrast (XIX)

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Tetrahydroisoquinoline-6-carboxylic acid 179 was prepared starting from commercial 3,5-dichlorobenzaldehyde 183 (Scheme 35).

Reductive amination with 1-chloro-2-aminoethane

184 gave chloroethyl amine 185, which underwent an efficient intramolecular Friedel-Crafts reaction using AlCl3 to generate the corresponding tetrahydroisoquinoline 186 in 91% yield.

N-Tritylation

of 186 proceeded in 89% yield, and this was followed by a directed o-metallation reaction and carbon dioxide quench to furnish the requisite acid 179 in 75% yield. Scheme 35. Synthesis of tetrahydroisoquinoline-6-carboxylic acid fragment 179 for lifitegrast

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9. Conclusion In summary, the pharmaceutical industry collectively enjoyed a productive 2016 – a year that saw the introduction of these 19 new and important small molecule medicines to the marketplace. Innovative synthetic chemistry, particularly new methods for bond construction and the assembly of complex molecular architectures that can be effectively applied not only in the discovery setting but on process scale as well, will continue to permit access to challenging and/or novel chemical space. As the discipline continues to advance, the discovery of new synthetic methodologies and expansion of the limits of known bond-making technologies to new substrates through deeper mechanistic understanding will play an increasingly important role in the discovery and development of new medicines.

This review continues to highlight the application of such technology and innovation

toward the production of important treatments for disease and hopefully will provide inspiration to researchers worldwide in the continued discovery of new drugs.

10. Acknowledgments The authors would like to thank Dr. Matthew Perry for helpful and insightful discussions 54

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regarding crisaborole.

The authors would also like to thank Dr. Emma McIntuff and Dr. John

Ragan for helpful discussions and suggestions.

ABBREVIATIONS Ac = Acetyl Ad = Adamantyl aq. = Aqueous Bn = Benzyl Boc = N-tert-Butoxycarbonyl Bu, n-Bu = Butyl, n-butyl cat = Catalytic Cbz = Benzyloxycarbonyl CDI = N,N'-Carbonyldiimidazole CDMT = 2-Chloro-4,6-dimethoxy-1,3,5-triazine CPME = Cyclopentyl methyl ether CSA = Camphorsulfonic Acid Cy = Cyclohexyl dba = Dibenzylideneacetone DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC = 1,3-Dicyclohexylcarbodiimide DCE = Dichloroethane DCM = Dichloromethane DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone 55

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DIPEA = Diisopropylethylamine DMA = Dimethylacetamide DMAP = 4-Dimethylaminopyridine DME = 1,2-Dimethoxyethane DMF = N,N-Dimethylformamide DMF-DMA = Dimethylformamide – dimethylacetal DMPU = 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO = Dimethyl sulfoxide DPPA = Diphenyl phosphoryl azide dppf = 1,1’-Ferrocenediyl-bis(diphenylphosphine) dr = Diastereomeric ratio EDC = N-(3-Dimethylaminopropal)-N-ethylcarbodiimide EDTA = Ethylenediaminetetraacetic acid ee = Enantiomeric excess Et = Ethyl EtOAc = Ethyl acetate HATU = N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methyl methanaminium hexafluorophosphate N-oxide Hex, n-Hex = Hexyl HMDS = Hexamethyldisilazane HOBt = 1-Hydroxybenzotriazole hydrate HWE = Horner-Wadsworth-Emmons i-Pr = Isopropyl 56

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IPA = Isopropyl alcohol IPAc = Isopropyl acetate LAH = Lithium aluminum hydride LDA = Lithium diisopropylamide Me = Methyl MeCN = Acetonitrile MEK = Methyl ethyl ketone Moc = Methoxycarbonyl Ms = Methylsulfonyl, mesyl MTBE = Methyl tert-butyl ether NBS = N-Bromosuccinimide NMM = N-Methyl morpholine NMP = N-Methyl-2-pyrrolidone Ph = Phenyl Pin = Pinacolato Piv = Pivaloyl p-TsOH = p-Toluenesulfonic acid Py = Pyridine rac = Racemic rt = Room temperature TBAB = tert-Butyl ammonium bromide TBAF = Tetrabutylammonium fluoride TBAH = Tetrabutylammonium hydroxide 57

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TBAI = Tetrabutylammonium iodide TBTU = O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate t-Bu = tert-Butyl TEA = Triethylamine TES = Triethylsilane TEMPO = 2,2,6,6-Tetramethylpiperidine 1-oxyl Tf = Triflic, trifluoromethanesulfonyl TFA = Trifluoroacetic acid TFAA = Trifluoroacetic acid anhydride THF = Tetrahydrofuran THP = Tetrahydropyranyl TMEDA = N,N,N′,N′-Tetramethylethylenediamine TMS = Trimethylsilyl tol = Toluene Tr = Trityl, triphenylmethyl Ts = p-Toluenesulfonyl UHP = Urea hydrogen peroxide

Author Information Corresponding Author *Phone:

860-303-1138.

Email: [email protected]

ORCID Christopher J. O’Donnell:

0000-0003-1004-7139 58

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Notes The Authors declare no competing financial interest. Biographies Andrew C. Flick earned a B. A. in Chemistry from Lake Forest College and then he joined Abbott Laboratories’ Diagnostics Group in Abbott Park, Illinois. He then moved to Array BioPharma in Longmont as a Research Associate in their Process Chemistry Group. In 2003, he joined Professor Albert Padwa’s laboratory at Emory University in where he successfully demonstrated a Michael addition-Nitrone dipolar cycloaddition approach for the total synthesis of the marine natural alkaloid cylindricine C. After obtaining his Ph. D. in 2008, he joined the Medicine Design group at Pfizer in Groton, CT where he has been involved with numerous discovery projects within the Neurosciences, Rare Diseases, and Inflammation & Immunology therapeutic areas. Andy has authored over 30 peer-reviewed publications and patents.

Hongxia (Sheryl) 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 co-founder and

Chief Executive Officer of PHARMACODIA, a company founded in 2013, which is an online platform (http://www.pharmacodia.com) providing big data and information service in pharmaceutical R&D field. Biotech company.

In 2010-2013, Hongxia joined Shenogen Pharma Group, a China-based

As senior director of R&D department, Hongxia is responsible for the CMC

development of a novel ER-α36 targeted Phase II candidates drugs, named Icaritin (SNG162) and the discovery and development of second-generation small molecular based on the structure optimization of SNG162.

Before Shenogen, Hongxia worked in BioDuro since 2006, as senior

group leader and senior research scientist. 59

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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 Applied Synthesis Technologies group, where she is involved in the discovery of biocatalytic routes to support various chemistry therapeutic areas. Carolyn is a native of North Carolina and obtained her B.S. in chemistry from North Carolina State University. She completed her doctoral studies with Professor Albert Padwa at 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

post-doctoral fellow working with Professor Daniel Romo at Texas A&M University, exploring new applications of nucleophile-catalyzed aldol lactonization reactions.

Sarah Fink is a Senior Manager for Integrated Programs at BioDuro and is based in the Boston area. She 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. work focused on the total synthesis of aplyronine C.

Her thesis

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 to Boston in early 2017; in her current role, she provides medicinal

chemistry and scientific project management support for collaborations with pharma and biotech.

Christopher J. O’Donnell obtained a B.S. in Chemistry from the University of Illinois in Urbana/Champaign and a Ph.D. in Organic Chemistry from the University of Wisconsin, Madison. After postdoctoral research at the University of California-Irvine, he joined the Neuroscience 60

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Medicinal Chemistry group at Pfizer.

As a scientist, project leader, and manager he has led teams

to the nomination of over 10 clinical candidates and he is the inventor of the Phase 2 AMPA PAM, PF-04958242 for schizophrenia. Chris moved to the Oncology Medicinal Chemistry group to build the Antibody Drug Conjugate chemistry group and his team nominated 14 conjugates for clinical development.

In 2017 Chris built the Applied Synthesis Technology group at Pfizer. Chris is an

author/inventor of 70 peer-reviewed journal articles and patents.

61

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