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Synthetic Approaches to the New Drugs Approved During 2017 Andrew C Flick, Carolyn A Leverett, Hong Xia Ding, Emma L McInturff, Sarah J. Fink, Christopher J. Helal, and Christopher J. O'Donnell J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.9b00196 • Publication Date (Web): 02 Apr 2019 Downloaded from http://pubs.acs.org on April 2, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Journal of Medicinal Chemistry

Synthetic Approaches to the New Drugs Approved During 2017

1 2

Andrew C. Flick,1 Carolyn A. Leverett,2 Hong X. Ding,3 Emma McInturff,4 Sarah J. Fink,5

3

Christopher J. Helal,6 Christopher J. O’Donnell7*

4

1 Seattle

5 2,4,6,7

6

Genetics, Inc. 21823 30th Drive SE, Bothell, WA 98021, United States

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

7

3 Pharmacodia

8

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

1

Email: [email protected]; tel: 425-527-4755

2


3


4


5


6


7


1

ACS Paragon Plus Environment

Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

5 BioDuro,

1

Page 2 of 117

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

2

3

Abstract:

New drugs introduced to the market every year represent privileged structures for

4

particular biological targets. These new chemical entities (NCEs) provide insight into molecular

5

recognition while serving as leads for designing future new drugs. This annual review describes the

6

most likely process-scale synthetic approaches to thirty-one new chemical entities approved for the

7

first time globally in 2017.

8 9

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

10

1. Introduction

11

“The most fruitful basis for the discovery of a new drug is to start with an old drug.” ─ Sir James

12

Whyte Black, winner of the 1988 Nobel Prize in medicine.1

13

Because drugs can have structural homology across similar biological targets, it is widely believed

14

that the knowledge of new chemical entities and approaches to their construction will enhance the

15

ability to discover new drugs more efficiently. This annual review, which is now in its seventeenth

16

installment,2 presents synthetic routes for 31 new molecular entities that were approved for the first

17

time by a governing body anywhere in the world during the 2017 calendar year (Fig.1).3 For each

18

drug, a description of the most likely process-scale synthetic approach, or in some cases the only

19

publicly disclosed synthetic approach, is prefaced by a brief introduction summarizing the relevant

20

pharmacology or differentiating features of the medicine.4 In all cases, descriptions of the syntheses

21

begin with commercially available starting materials. New indications for previously launched 2


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1

medications, new combinations or formulations of existing drugs, and drugs synthesized entirely by

2

biological processes or peptide synthesizers have been excluded from coverage. For organizational

3

purposes, drugs presented in this review are categorized into the following eight therapeutic areas:

4

anti-infective, CNS (neuroscience), gastrointestinal, hematologic, metabolic, musculoskeletal,

5

oncology, and ophthalmology. Within each of these therapeutic areas, drugs are ordered alphabetically

6

by generic name. It is important to note that a drug’s process-scale synthetic approach is often not

7

explicitly disclosed at the time of this review’s publication. In some cases, only a discovery-scale or a

8

general synthetic approach capable of delivering the active pharmaceutical ingredient (API) has been

9

made available. Nonetheless, the synthetic sequences presented in this review have all been previously

10

reported either in patent or public chemical literature and, to the best of our assessment, represent

11

scalable routes originating from commercially available starting materials (determined by explicit

12

statement or inferred by experimental detail).

13

Figure 1.

Structures of 31 NCEs approved in 2017

3



Page 4 of 117

Anti-Infective Drugs O

S

O O

O

NH

H N

N

N

N

O

N N

NO2

O

Benznidazole (II)

Amenamevir (I)

O

O F

OH OH

OH

N

N H

N Cl

HO

F

N

OH OH OH

H 2N F Delafloxacin meglumine (III) F F O

N N F NC

H N

O O

Br

HN

Na+

Cl

S OO

Cl

O

O

F

N-

HN

F

O

O

N O O

O

O NH S O

Elsulfavirine (IV)

Glecaprevir (V) O

F O

HO

CF3

N N

N

F

N

N

F F

F F

O

N

Letermovir (VI) HN

N

N O O

O NH

O N

N N

N

OH

O 2N

1

H N

O

Secnidazole (VIII)

O N H

O O

Pibrentasvir (VII)

4


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Journal of Medicinal Chemistry F F N O

O

N

O

O

S

HN

HN

O

N B

HO

F

CO2H

O

HN

F

O O

O

O NH S O Voxilaprevir (X)

Vaborobactam (IX)

CNS Drugs D3CO

O N

D3CO

N

O

H

H

O

O

Deutetrabenazine (XI)

O

2 p-TsOH

H 2N Valbenazine (XII) Hematologic Drugs

Gastrointestinal Drugs

Cl

O O N OH

• TsOH

HN O O

O

HO

OH

N H NH

N

CO2H CO2H

O

N

N

N

NH

Naldemedine (XIII)

Betrixaban (XIV)

Metabolic Drugs O

O

HO

O

O

HO

N

OEt Cl OH

O

N

OH

O HN

HO2C

O

OH O

1

Ertugliflozin - L-pyroglutamic acid (XV)

Pemafibrate (XVI)

5



Page 6 of 117

Musculoskeletal Drugs O

O S

N N N

CN

N N H

N

Baricitinib (XVII) Oncology Drugs O N

N HN

F

N

H 2N

N H

N

N

N F

N

O

N N

Acalabrutinib (XIX) O

H N

O

N N

N

N

N

Abemaciclib (XVIII) O

N

N

Cl

N

NH

N N

N

O N

HN

P O

N

NH2

N F3C

N

N

N N

N

N H

CF3

MsOH

O

Enasidenib (XXII)

Copanlisib (XXI)

Brigatinib (XX)

OH

HN

O G-544 (anti-CD22)

O

N H

Me O Me Me Me O

I O Me HO MeO

O OH

Me S

N O

OMe OH OMe Me O

1

N S H S O Me HN O HO O Et O N MeO

HO

O NHCOOMe

O H

~6

Inotuzumab Ozogamicin (XXIII)

2

6


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Journal of Medicinal Chemistry Oncology Drugs H N

O N O

N

O

O O

N

O H

HN

Cl

HN

N

N

CN

EtO

N

Neratinib (XXV) Midostaurin (XXIV)

O

• TsOH • H 2O

NH2

N

NH

N

H N

N

N

HN Ribociclib (XXVII)

Niraparib (XXVI)

O -

O

Cl

N H

O

O

N

N

N

N

NH2 N

N

NH3+

CF3 N

N O Cl

O

H N

CH3 N O

O

O

O

O

H N

• HCl

O

N

Telotristat Ethyl (XXVIII)

Tivozanib (XXIX)

Ophthalmologic Drugs HO

O

O

ONO2

O

O HO

 2 MsOH

OH

H N

H 2N O

1

Latanoprostene bunod (XXX)

N

Netarsudil (XXXI)

2 7



1 2

Page 8 of 117

2. Anti-Infective Drugs 2.1 Amenamevir (Amenalief®)

3

Originally discovered by Astellas and co-developed with Maruho Co., Ltd., amenamevir is an

4

antiviral agent approved for the first time in Japan in 2017 for the treatment of herpes zoster

5

(shingles).5 The non-nucleoside drug inhibits helicase-primase and offers an improved

6

pharmacokinetic profile over existing therapies acyclovir and valacyclovir.6 Researchers from Astellas

7

attribute amenamevir’s differentiated profile to an improved absorption ratio (not hepatic availability)

8

and slower rates of metabolism relative to acyclovir/valacyclovir.5 Perhaps unsurprisingly, the primary

9

metabolic pathway in rodents involves oxidation of the methyl groups affixed to the central aniline

10

ring along with conversion of the oxadiazole to the corresponding amidine residue.5 The half-life of

11

the drug in human plasma was found to be 8 hours, which translates into a once-daily dosing regimen,

12

whereas acyclovir/valacyclovir have dosing regimens ranging from 2-5 doses per day.5

13

While three separate patent applications describe preparative approaches to amenamevir, only

14

general synthetic approaches to the drug structure have been reported to date.7 Although yields,

15

spectral characterization, or crystallization conditions of intermediates or API were not detailed, a

16

representative synthetic approach was reported and this route is described in Scheme 1.7a, 8 Aniline 1

17

was alkylated with ethyl bromoacetate and the resulting product was immediately subjected to acid

18

chloride 3 and pyridine giving rise to aniline 4. Ester saponification of 4 followed by activation with

19

EDCI and coupling with commercially available aniline 59 resulted in amenamevir (I).

20

Scheme 1.

Synthesis of amenamevir (I)

8


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Journal of Medicinal Chemistry O

O

Cl

NH2

S

HN

ethyl bromoacetate

O

1

S

3

O

1. 3, py, DCM, rt 2. 1N HCl, CHCl3, rt

K2CO3, DMF, 

O

O

2 O

O

S

O

1. 1N NaOH, rt, then 1N HCl O

N

CO2Et

2. 5, EDCI, CHCl3, rt H 2N

4

H N

N O

N

1

O

5

N

N N

O

O

Amenamevir (I)

2 3 4

2.2 Benznidazole (Rochagan®)

5

Benznidazole was first disclosed almost 50 years ago in a patent10 by Hoffman-La Roche

6

demonstrating anti-infective properties. It was subsequently found to be particularly effective at

7

treating Chagas disease (a.k.a. American trypanosomiasis), which is caused by the parasite

8

Trypanosoma cruzi. In 2017, benznidazole was approved for the first time by the United States Food

9

and Drug Administration (USFDA) under its accelerated approval program to treat Chagas disease in

10

children ages 2 to 12 years old; its registration was led by Chemo Research. While Chagas disease is

11

predominantly found in rural Latin America, it is estimated that up to 300,000 people may be infected

12

in the United States. Chronic infection can lead to heart damage.11 Benznidazole oxidizes nucleotides

13

incorporated into the parasite’s DNA, resulting in lethality.12

14

The original two-step synthesis of benznidazole has been improved upon in a recent patent that

15

discloses a highly efficient one-pot process route that avoids isolating intermediates and introduces a

16

procedure to cleanly crystallize the product on gram scale (Scheme 2).13 Alkylation of 2-

17

nitroimidazole (6) was affected with ethyl bromoacetate using potassium carbonate as base in 9



Page 10 of 117

1

anhydrous ethanol at 70 °C. These conditions minimized hydrolysis, afforded 7 in good conversion,

2

and represent an improvement over the originally reported protocol which required DMF and sodium

3

methoxide at temperatures exceeding 100 °C. The mixture was directly treated with benzylamine (3.0

4

equivalents) and warmed to 50 °C, followed by addition of water and filtration to yield benznidazole

5

in 87% yield over two steps. Recrystallization by first solubilizing in acetone-methanol-water (1:1:0.1),

6

distilling at atmospheric pressure, adding water, cooling to 0 to 5 °C while stirring, and filtration

7

conveniently yielded benznidazole (II) in 91% yield. The simplicity of the method suggests that larger

8

scale application would be viable. Scheme 2.

9

Synthesis of benznidazole (II)

10 O N

NH NO2

11

O

ethyl bromoacetate K2CO3, EtOH, 70 °C

N

N

2. acetone, H2O MeOH

NO2

6

7

O

1. benzylamine 50 °C

79% for 3 steps

NH N

N NO2 Benznidazole (II)

12 13

2.3 Delafloxacin Meglumine (BaxdelaTM)

14

Delafloxacin meglumine is a fluoroquinolone antibiotic that targets DNA topoisomerase. It was

15

approved by the USFDA in 2017 for the treatment of acute bacterial and skin structure infections.14

16

Delafloxacin was discovered at Wakunaga Pharmaceutical Co. and licensed to Abbott Laboratories

17

for further development. It was acquired by Rib-X (later renamed to Melinta Therapeutics), which

18

completed its development and launch. Delafloxacin is currently in Phase III clinical studies for the

19

treatment of community-acquired pneumonia.

20

The synthesis of delafloxacin is similar to that of other fluoroquinolone antibiotics, but is unique

21

in that the introduction of the chlorine to the C8 position of the quinolone occurred at a later stage of 10


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1

the synthetic sequence. Many routes have been published in the patent literature and the multi-

2

kilogram route disclosed by Abbott is described in Scheme 3.15 Ketoester 8 (whose synthesis is

3

described in Scheme 4) was condensed with triethylorthoformate to give ethoxymethylene ester 9.

4

This intermediate was not isolated but was instead directly treated with 2,6-diamino-3,5-

5

difluoropyridine (10, whose synthesis is described in Scheme 5) to give vinylogous amide 11 in 93%

6

yield. Complexation of 11 with lithium chloride in N-methylpyrrolidone (NMP) followed by reaction

7

with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) effected cyclization to quinolone 12. Intermediate 12

8

was not isolated but was treated with 3-hydroxyazetidine hydrochloride (13, Scheme 6) and DBU,

9

resulting in displacement of the fluorine in the 7-position of the quinolone. Exposure of the resulting

10

alcohol to isobutyric anhydride followed by crystallization from citric acid gave quinolone 14 in 93%

11

yield. Chlorination of the 8-position of the quinolone was effected by treatment with N-

12

chlorosuccinimide (NCS) and sulfuric acid.15b Hydrolysis of both the ester and the carbonate in the

13

resulting product gave delafloxacin 15 in 90% yield. Salt formation with N-methyl-d-glycamine

14

followed by crystallization provided delafloxacin meglumine (III) in 73% yield.

15

Scheme 3. Synthesis of delafloxacin meglumine (III)

11


Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 31 32 2 33 34 35 3 36 37 4 38 39 40 5 41 42 43 6 44 45 46 47 48 49 50 7 51 52 8 53 54 9 55 56 57 10 58 59 60

O

O

F F

F

CH(OEt)3

OEt

Ac2O, 

F

H 2N

O

O

F

OEt

N

NH2 F

NMP, MeCN, 93%

F

F

F

O

O

10

OEt

F

Page 12 of 117

OEt NH

F

F

N 8

9

F DBU, LiCl, NMP

F

13

O

N 1. 2. 3. 4.

F

N H 2N F

13, DBU (i-PrCO)2O EtOAc citric acid

i-PrO

OEt

N

N

O

F

N H 2N F

93% from 11 14

12

O

O

F O 1. NCS, EtOAc MeAc, H2SO4 17 °C

O

F

2. 4% KOH, i-PrOH 50 °C

N Cl

F

N

N-methyl-dglycamine, H2O

HO

N Cl

F

N

H 2N

60 to 0 °C, 73%

F OH OH

H 2N

90% for 2 steps

OH

N OH

N HO

O

F

HO

OEt

F

O

NH·HCl

O

O

H 2N

11

N H

F 15

OH OH OH

Delafloxacin meglumine (III)

Ketoester 8 was prepared in 94% yield from commercial 2,3,5-trifluorobenzoic acid (16) in two steps: reaction with thionyl chloride to generate the corresponding acid chloride and then treatment with the reagent derived from potassium ethyl malonate and magnesium chloride (Scheme 4).15b Scheme 4.

Synthesis of delafloxacin meglumine ketoester fragment 8 O

F

OH

F

F 16

O

1. SOCl2, DMF, PhCH3, 60 °C

F

2. KO2CCH2CO2Et, Et3N, MgCl2 THF, PhCH3, 0 to 50 °C

F

94% for 2 steps

O OEt

F 8

Diamine 10 was prepared as described in Scheme 5.15c 2,3,5,6-Tetrafluoropyridine (17) was reacted with benzylamine to give 2,6-dibenzylamino-3,5-difluoropyridine (18). Hydrogenolysis using catalytic palladium hydroxide on carbon and formic acid provided diamine 10 in 86% yield. 12


Page 13 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Scheme 5.

1 F

N

F

F

F

Synthesis of delafloxacin meglumine diaminopyridine 10

BnNH2, K3PO4

BnHN

NMP, 50 to 165 °C

F

17

2

N

Pd(OH)2/C i-PrOAc

NHBn F

18

HCO2H, 50 °C

H 2N

N

NH2

F

86% for 2 steps

F 10

3

Hydroxyazetidine 13 was prepared as described in Scheme 6.15c Epichlorohydrin (19) was treated

4

with benzylamine to give azetidine 20 in quantitative yield. Catalytic hydrogenation of 20 using

5

palladium hydroxide on carbon followed by salt formation with hydrochloric acid gave 3-

6

hydroxyazetidine hydrochloride (13) in 49% yield. Scheme 6.

7

O

8

Cl

Synthesis of delafloxacin meglumine azetidine fragment 13 N

BnNH2, H2O 0 °C, 100%

19

HO

1. H2, Pd(OH)2/C AcOH, 55 to 65 °C 2. HCl

20

49% for 2 steps

NH·HCl HO 13

9 10

2.4 Elsulfavirine (Elpida®)

11

Elsulfavirine is an acyl sulfonamide prodrug of the non-nucleoside reverse-transcriptase (NNRT)

12

inhibitor VM1500A (28, Scheme 7), which is used for the treatment of HIV-AIDS. It was approved

13

in Russia in June 2017 for use in combination with existing retroviral medications. Originally

14

discovered by Roche,16 the rights for elsulfavirine were transferred to Viriom, which led its

15

development. In efficacy trials, elsulfavirine demonstrated non-inferiority to efavirenz in both viral

16

load and HIV RNA reduction at 12 weeks with superior tolerability. An assessment of human

17

pharmacokinetics showed that elsulfavirine was rapidly converted (t1/2 = ca. 2 h) to VM1500A, which

18

has a very long half-life (t1/2 > 5 days).17 Development of once-weekly elsulfavirine oral and

19

subcutaneous once-monthly VM1500A dosage forms, presumably enabled by the long t1/2, is

20

underway to enhance patient compliance and efficacy.18 13



Page 14 of 117

1

Although the exact synthesis of elsulfavirine has not been reported, the synthesis of structurally

2

similar compounds have been exemplified in a patent disclosed by Roche.16 In Scheme 7, reactions

3

with yields are those that have specifically been exemplified in the Roche patent. Reaction conditions

4

for the last steps of the synthesis (26 to 28 to elsulfavirine (IV)) were reported only in a generalized

5

approach.16 Because these final steps were not specifically exemplified with the bromine atom within

6

elsulfavirine in place, no yields could be reported for these steps. The route is linear in nature and

7

utilizes multiple site-selective nucleophilic aromatic substitution reactions to efficiently prepare the

8

drug. The synthesis commenced with the interesting selective mono-chloride displacement reaction of

9

21 with sodium methoxide, likely facilitated by the electron-deficient nature of the aromatic system,

10

followed by lithium iodide-mediated demethylation to afford phenol 22 in approximately 80% yield

11

over two steps (Scheme 7). A second SNAr reaction of the sodium salt of 22 with 2,3,4-

12

trifluoronitrobenzene (23) proceeded in an ortho-selective manner at low temperature to yield diaryl

13

ether 24 in 82% yield. Introduction of the acetate unit was affected by a two-step process: SNAr

14

reaction of ethyl tert-butyl malonate at the position para to the nitro group followed by TFA-mediated

15

Boc removal/decarboxylation, afforded 25 in 83% yield for the two steps. Conversion of the nitro

16

group to the corresponding bromide was accomplished by iron-mediated reduction of 25 to the

17

corresponding aniline (87% yield) and subsequent diazotization/bromination with tert-butyl nitrite in

18

the presence of copper (I) bromide (53% yield) to give 26. A reported general three-step sequence of

19

(a) hydrolysis of ester 26 to acid, (b) conversion of acid to acid chloride, and (c) acylation of aniline

20

27, without isolation of intermediates, was most likely used to convert 26 to 28 (VM1500A).

21

Preparation of the acyl sulfonamide precursor likely used propionic anhydride (29) with catalytic

22

DMAP, which afforded elsulfavirine (IV) upon treatment with a sodium base.19

23

Scheme 7.

Synthesis of elsulfavirine (IV) 14


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Journal of Medicinal Chemistry F F

F Cl 1. NaOMe, DMF rt, 86%

NC

2. LiI, collidine 170 °C, 94%

Cl

OH

O 2N

O

NaOt-Bu, THF 0 °C, 82%

Cl

F O O 2N

F

CO2Et

NaH, NMP, rt 2. TFA, DCE, 75 °C

O 2N

83% for two steps

Cl 24

1. LiOH, EtOH, H2O, rt 2. (COCl)2, DMF (cat.) DCM, rt CO2Et

F

1. Fe, NH4Cl, EtOH CO2Et H2O, 80 °C, 87%

NC

O

3.

Br

2. CuBr, t-BuONO2 70oC, 53%

Cl

1. t-BuO2C

F NC

23

22

21

NC

NC

Cl

Cl

25

H 2N

26

27 SO2NH2

acetone, H2O, NaHCO3, rt 1. F NC

H N

O Br

O

Cl

Cl

O

O

29

O THF, DCE, DMAP SO2NH2 2. Na-Base (not reported)

F NC

Br

O

Cl

Cl

28 (VM1500A)

1

H N

O

Na N S O O O

Elsulfavirine (IV)

2

Glecaprevir/Pibrentasvir (MavyretTM)

3

2.5

4

Discovered and developed in a joint effort between Abbvie and Enanta Pharmaceuticals, the

5

combination of glecaprevir and pibrentasvir was approved by the USFDA in 2017 for the treatment of

6

adults with chronic hepatitis C virus (HCV) genotypes 1-6 with no or mild cirrhosis, who have

7

previously been treated with either an NS5A inhibitor or an NS3/4A inhibitor, but not both.20 Similar

8

to Merck’s introduction of the HCV combination therapy Zepatier® to the market in 2016, neither

9

glecaprevir nor pibrentasvir have been previously approved as a separate medication prior to 2017.21

10

Glecaprevir inhibits the serine protease NS3/4A, while pibrentasvir inhibits NS5A, which is a zinc-

11

binding hydrophilic phosphoprotein involved in viral RNA replication.21 In clinical trials,

12

glecaprevir/pibrentasvir was found to be effective against all six known HCV genotypes.20 The

13

following side effects were commonly observed during clinical trials: headache, nausea, diarrhea, and

15



Page 16 of 117

1

hepatitis B reactivation.20 For the purpose of this review, the synthesis of each component of the

2

combination therapy will be discussed separately.

3

No explicit report of a process-scale synthetic approach to glecaprevir has been published to date.

4

However, a route capable of preparing milligram quantities of glecaprevir has been disclosed in a

5

patent application from researchers at Enanta.22 In this approach, glecaprevir’s macrocyclic structure

6

was retrosynthetically divided into three subunits—quinoxaline 34, allyl ether 38, and

7

cyclopropylamine 44. The preparation of these subunits are described in Schemes 8-10, and their final

8

assembly to furnish the API is described in Scheme 11.

9

Scheme 8. Synthesis of glecaprevir quinoxaline subunit 34 1. In powder ethyl glyoxylate PhCH3, DMF, rt

F F Br

F F O

2. NMO, TPAP DCM, rt

30

EtO

1. 1,2-benzenediamine Et3N, EtOH, rt

O 31

2. POCl3, DMF, 65 °C 45% for 4 steps

OH

F F N

F F

N

EtO

N

33 Boc

N

O

O N

Cl

32

NaOt-Bu, THF, DMF 0 °C to rt, 82%

N

EtO

Boc O 34

10 11

Allyl bromide 30 underwent a Barbier reaction with ethyl glyoxylate through activation with

12

indium powder at room temperature,23 and the resulting alcohol was subjected to a Ley-Griffith

13

oxidation facilitating construction of oxopentanoate 31 (Scheme 8).24 Condensation with 1,2-

14

benzenediamine under mild conditions with base and subsequent treatment with phosphorous

15

oxychloride converted 31 to chloroquinoxaline 32 in 45% yield from the starting allylic difluoride

16

system 30. Treatment of 32 with prolinol 33 in the presence of sodium t-butoxide resulted in ether

17

formation to secure 34 in good yield.

16


Page 17 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

The construction of allyl ether 38 (Scheme 9) began with monoacylation of trans-pentanediol (35)

2

which was followed by a selective saponification by lipase resolution, allylation, and finally lithium-

3

hydroxide mediated removal of the acetyl protecting group to furnish enantiopure allyl ether 36. Yields,

4

specific lipase conditions, and enantioselectivities were not reported for this particular sequence but

5

were instead described as a general procedure in the patent. Carbamate formation through initial

6

exposure of 36 to phosgene and aminoester 37 in THF, followed by treatment with aqueous sodium

7

hydroxide and subsequent acidification provided allyl ether 38. This sequence was described as a

8

general approach having no reported yields or stereoselectivity data. Scheme 9. Synthesis of glecaprevir allyl ether 38

9

HO

1. DMAP, Ac2O, py, DCM, rt 2. NaOH, H2O, lipase, rt

HO

3. NaH, allyl bromide, DMF, rt 4. LiOH, MeOH, THF, rt 35

40% for 4 steps

1. COCl2, THF, rt NH2 MeO O HO

O

O

2. aq NaOH, dioxane, rt then aq HCl

36

10

O

37 HN

O

HO O 38

11

A clever approach to cyclopropylamine 44 (Scheme 10) has been described by researchers from

12

Gilead in a 2014 patent.25 Interestingly, this same structural subunit is incorporated into the structure

13

of voxilaprevir (X), whose synthesis is described vide infra. Knoevenagel condensation of hemiacetal

14

39 with diethyl malonate utilizing cerium trichloride and sodium iodide followed by Corey-

15

Chaykovsky cyclopropanation gave racemic cyclopropane diester 40.26 Next, esterase resolution

16

presumably delivered an enantioenriched carboxylic acid which then underwent Curtius

17

rearrangement giving rise to aminoester 41. This aminoester could be further resolved

18

chromatographically to obtain the desired enantiomer in higher purity (exact purities and yields were

19

not disclosed). Lastly, reaction of 41 with lithium hydroxide followed by mild acid quench and

20

subsequent coupling of the resulting acid 42 with sulfonamide 43 furnished cyclopropylamine 44. 17



Page 18 of 117

Scheme 10. Preparation of glecaprevir cyclopropylamine 44

1 F HO

F

F

1. CeCl3, NaI, diethyl malonate, EtOH, 65 °C

OEt

2. Me3SOI, t-BuOK, DMF, rt

F

EtO O O EtO

39

1. Esterase ES46.5K H2O, 30 °C 2. HCl, pH ~ 3

F F

3. DPPA, Et3N, t-BuOH PhCH3, 30 to 90 °C

OEt

40

F 1. LiOH, MeCN, rt 2. citric acid, H2O pH ~4.5, rt

2

F

NHBoc O

1. EDCI, Et3N, DMAP DCM, 0 °C O NH2 S O 43 2. 4N HCl, dioxane, rt

OH 42

NHBoc O

41

F F

NH2 O O NH S O 44

3

The final assembly of glecaprevir commenced with the union of quinoxaline 36 and allyl ether 40

4

through amide bond formation (Scheme 11). Acidic removal of the Boc group within 34 followed by

5

HATU-mediated amide formation with acid 38 resulted in the diallyl species 45. Next, a ring-closing

6

metathesis involving the Zhan 1B catalyst (46) secured macrocycle 47.27 Exposure of 47 to methanolic

7

lithium hydroxide and subsequent amide bond formation with cyclopropylamine 44 ultimately

8

furnished glecaprevir (V).

9

Scheme 11. Synthesis of glecaprevir (V)

18


Page 19 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 31 32 2 33 34 35 3 36 37 4 38 39 40 5 41 42 43 6 44 45 7 46 47 48 8 49 50 9 51 52 53 10 54 55 56 11 57 58 12 59 60


F F

O

N

F F N

N

O

+ HN

O

Boc

N

O

O HN

O

O

O

2. HATU, DIPEA DMF, rt

HO

N

EtO

1. 4N HCl, dioxane DCM, rt

O

EtO

O

O

34

O

N

38

45 F F O

N F F

46, PhCH3

N

1. LiOH, aq MeOH THF, rt 2. 44, HATU, DIPEA DCM, rt

O

N

O

O

80 °C

HN

F

O

F O

O

44

O NH S O

47

O

N

F NH2

O

O HN

F

O

N EtO

N

HN

O O

O

O NH S O Glecaprevir (V)

-

Cl

Ru

N

O iPr ClN

46

The synthetic route to pibrentasvir has been reported in the patent literature and proceeded as shown in Schemes 12 and 13.28 Substitution of 1,2,3-trifluoro-5-nitrobenzene (48) with 1,4-dioxa-8azaspirol[4.5]decane (49) in the presence of potassium carbonate was followed by acid-mediated acetal removal to give the corresponding N-arylated 4-piperidone in 74% yield (Scheme 12). Deprotonation with LiHMDS followed by treatment with N-phenyl triflimide then delivered the corresponding enol triflate 50 in 81% yield. Suzuki coupling of triflate 50 with 4fluorobenzeneboronic acid (51) furnished piperidine 52 in 54% yield. Hydrogenation of 52 reduced the olefin and the p-nitro group simultaneously to give the corresponding anilino piperidine in 99% yield. This compound was then reacted with bis-mesylate 53 (whose synthesis is described in Scheme 14) to form pyrrolidine 54 in 51% yield. Scheme 12. Synthesis of pibrentasvir pyrrolidine core 54 19



Page 20 of 117 F

TfO F

F

1. K2CO3, DMSO, 100 °C 2. HCl, acetone, H2O, 50 °C

O

F

+

O NH

NO2

N

3. PhN(Tf)2, LiHMDS THF, -78 °C

NO2

50

49

B(OH)2

Pd(PPh3)4, 2M Na2CO3 LiCl, DME, 100 °C, 54%

F

60% for 3 steps 48

51

F

F F 1. H2, Pd/C, THF, 99% 2. 53, DIPEA, MeCN, 75 °C, 51% F

N

MsO N

F

F

Cl

Cl

F

OMs NO2

O 2N

NO2

Cl

F O 2N

N

53

F

Cl F 54

52

1

F O 2N

2 3

The final approach to pibrentasvir is outlined in Scheme 13. Buchwald amidation of bis-aryl

4

chloride 54 with amide 55 generated the corresponding bis-amide 56 in 54% yield. Reduction of the

5

nitro groups followed by acid-mediated benzimidazole formation and removal of the Boc groups

6

furnished compound 57. Bis-coupling with carboxylic acid 58 ultimately generated pibrentasvir (VI)

7

in excellent yield.

8

Scheme 13. Synthesis of pibrentasvir (VI)

9

20


Page 21 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry F F

O N

F O 2N

Cl

N

F O 2N

N

F

Cl

N

F

H N

NH2 Boc

F

F

55

F

Pd2(dba)3, Xantphos Cs2CO3 dioxane 100 °C, 54%

N O NO2

Boc

N

3. 2N HCl dioxane, rt

HN

F

58% for 3 steps

NO2

O

N Boc

54

1. H2, PtO2, THF EtOH 2. HOAc, PhCH3 70 °C

56 F

F HO O N

F

H N F

F F

N

N

O N H

O N

O

F

HATU, DIPEA, DMF rt, 98%

N

HN

N

N O O

O NH

O N

HN N NH

H N F

F

58 N H

F

N 57

O

1

O N H

O O Pibrentasvir (VI)

2 3

Preparation of the bis-mesylate intermediate 53 (Scheme 14) began with conversion of benzoic

4

acid 59 to the corresponding methyl ketone 60 via the intermediate acyl chloride. Bromination

5

followed by a dimerization reaction utilizing conditions originally described by Kulinkovich gave 1,4-

6

diketone 62 in 74% yield over two steps.29 Asymmetric bis-reduction using the CBS reduction system

7

provided diol 63 in 97% yield (ee not reported).30 Finally, treatment of 63 with methanesulfonyl

8

chloride in the presence of base delivered intermediate 53 in excellent yield.28

9

Scheme 14. Preparation of pibrentasvir dimesylate 53

21



F

F

1. (COCl)2, DMF DCM, rt

OH Cl

2. MeMgBr, ZnBr2 Pd(PPh3)4, THF -78 °C to rt, 74%

O O 2N

Page 22 of 117

pyridinium bromide

Cl

perbromide, THF rt, 96%

O O 2N

59

60 F O

F Br Cl

F

ZnCl2, Et3N t-BuOH, benzene rt, 77%

O O 2N

Cl

NO2

O O 2N

61

Cl

(R)-(+)-,-diphenyl-2pyrrolidinemethanol BH3•PhNEt2, B(OMe)3 THF, 0 °C to rt, 97%

62

F

F

HO F

MsO Cl

Cl OH

NO2

F

MsCl, Et3N DCM, 0 °C, 98%

Cl

O 2N

1

Cl

OMs

NO2

O 2N 63

53

2 3 4

2.6 Letermovir (PrevymisTM) Letermovir was approved in 2017 in the US and Canada for the treatment of cytomegalovirus (CMV)

5

infection and disease in CMV-seropositive adults who have received an allogeneic hematopoietic stem

6

cell transplant (HSCT).31 Initially developed by the German firm AiCuris and later licensed to Merck,

7

letermovir differs in mechanism of action relative to existing treatments for CMV.32 As such, the drug

8

shows potent activity as a viral terminase inhibitor of CMV DNA-terminase complexes pUL51,

9

pUL56, and pUL89, all of which play a role in processing and packaging viral DNA.32a Existing

10

medicines previously approved for CMV serve as DNA polymerase inhibitors and have been

11

associated with drug resistance and significant adverse effects.32b, 33 The drug demonstrates activity

12

against viral populations resistant to existing standard of care treatments while exhibiting no cross-

13

resistance.31-32 Letermovir received fast-track status by the USFDA and was approved based on the

14

results of several clinical trials,31 including those where post-HSCT individuals receiving letermovir

15

demonstrated significantly lower rates of clinically-significant CMV infection than individuals on 22


Page 23 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

placebo.34 The approval of letermovir, therefore, represents a significant advance for patients suffering

2

from CMV, as the drug provides an alternative to other traditional DNA polymerase-based therapies.

3

Letermovir has furthermore received a positive opinion from the European Medicines Agency (EMA)

4

and is under review in several additional countries.31

5

Researchers at Merck have recently reported a scale-up route to letermovir, which also constitutes

6

the first reported asymmetric route to the drug (Schemes 15, 16, and 17).35 This synthetic approach

7

relies on the union of building blocks 74 and 75 and use of an asymmetric Phase-Transfer-Catalyzed

8

(PTC) aza-Michael reaction of an advanced guanidine intermediate (74) to install the necessary chiral

9

center (Scheme 15). Toward this end, synthesis of guanidine 74 began with a Heck reaction involving

10

2-bromo-6-fluoroaniline (64) and methyl acrylate (65) on kilogram scale, providing acrylate 66 in an

11

unisolated 99% yield. Acrylate 66 was then converted to phenyl carbamate 68 with phenyl

12

chloroformate (67) under Schotten-Baumann conditions. This carbamate was immediately reacted

13

with 2-methoxy-5-(trifluoromethyl)aniline (69) to afford urea 70, which was isolated via

14

crystallization in high yield (87% over the one-pot, 3-step sequence from 64). Dehydration of urea 70

15

was achieved with PCl5 and 2-picoline in warm toluene, giving rise to intermediate carbodiimide 71,

16

which was further reacted without isolation with piperazine 72 under basic conditions (Et3N,

17

toluene/H2O) providing 74 in free base form. Subsequent treatment with salicyclic acid (73) enabled

18

the isolation of the desired guanidine salicylate salt in 90% yield from 70. The authors comment that

19

utilization of toluene as a solvent in the guanidine-formation reaction was essential for suppression of

20

undesired cyclization products.35

21

Scheme 15. Preparation of letermovir guanidine 74

23


Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 1 33 2 34 35 36 3 37 38 39 4 40 41 5 42 43 44 6 45 46 47 7 48 49 8 50 51 52 9 53 54 10 55 56 57 58 59 60

Page 24 of 117 CO2Me

Br CO2Me

+

NH2

Cl

(t-Bu)3P-Pd G2 c-Hex2NMe i-PrOAc, 80 °C

F 64

O

67 OPh

Na2HPO4 i-PrOAc, H2O

NH2 F 66

65

CF3 CO2Me

69 OMe

O N H

F

CO2Me

H 2N

OPh

DMAP, i-PrOAc, 80 °C 87% for 3 steps

F

N H

PhCH3, 40 °C, 92%

N H

OMe

70

• 2 HCl

HN N

CO2Me OMe •

PCl5, 2-picoline

O

68

N

CF3

OMe

72

MeO CO2Me

Et3N, PhCH3, H2O

N

CO2H • OH

N N

CO2H CF3 OH 71

N

then

F

CF3

HN

F

73

90% for 3 steps

OMe 74

The key step in the synthesis of letermovir relied upon on the intramolecular aza-Michael reaction of 74 to install the stereogenic acetate and dihydroquinazoline core present in the final drug target (Scheme 16).35 Subjection of salicylate salt 74 to biphasic basic conditions (K3PO4 in toluene/H2O) and Cinchona-alkaloid-based PTC 75 (prepared on multi-kilogram scale in two steps from cinchonidine (79, Scheme 17)) provided dihydroquinazoline 76 in nearly quantitative conversion and 76% ee as a solution in toluene. Optical enrichment of this solution was made possible by treatment with di-p-toluoyl-(S,S)-tartaric acid (DTTA, 77), ultimately enabling production of 78 in 99.6% ee and 82% yield after filtration. Finally, free base formation (MTBE, Na2HPO4) and ester saponification

24


Page 25 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

(NaOH, 70 C) converted intermediate 78 to the drug target letermovir (VII) after precipitation from

2

acetone/H2O (94% yield over 2 steps).35 Scheme 16. Synthesis of letermovir (VII)

3

O

MeO CO2Me

CO2H

CF3

HN N

•

N

Me O

MeO K3PO4, PhCH3, H2O

N F

CF3

N

then 75, K3PO4 PhCH3, H2O, 0 °C

OH

N

N

F

N

98%, 76% ee OMe

74

76

O O HO O O p-Tol

O

OH O

Me O

MeO

O

77 (DTTA) p-Tol

CF3

N N

PhCH3, EtOAc

OMe

N

F

• DTTA • EtOAc

N

82% for 3 steps 99.6% ee 78

O

Me O

HO

CF3

N

Na2HPO4 then NaOH (aq), MTBE

N F

OMe

N N

94% for 2 steps OMe

4

Letermovir (VII)

5 6 7

Scheme 17. Preparation of letermovir auxiliary 75

25



Page 26 of 117

CF3 80 Br N

CF3

MeCN, i-PrOH, 50 °C

OH

then

N 79

CF3

OH CF3

Br

N 81

CF3 75

70 °C, 91%

1 2

N

CF3

2.7 Secnidazole (SolosecTM)

3

Secnidazole is a nitroimidazole antimicrobial agent approved for the treatment of bacterial

4

vaginosis (BV) in adult women.36 Although the drug has been commercially available for more than

5

three decades within Europe, Asia, South America, and Africa, the USFDA approved the drug for the

6

first time in 2017 after it underwent priority review as an antibacterial agent intended to treat serious

7

or life-threatening infections.36 Structurally, secnidazole differs from other nitroimidazole

8

antimicrobial agents metronidazole and tinidazole in N-1 substitution. The modest differences in

9

structure likely account for physiochemical and biochemical differences (e.g., tissue distribution,

10

metabolic pathways). Interestingly, the antimicrobial and antiprotozoal activity of this class of

11

compounds is largely attributed to the nitro group attached directly to the 2-position of imidazole ring

12

system, which is structurally conserved throughout this class of drugs.36 Secnidazole and other 5-

13

nitroimidazoles induce bactericidal activity by first diffusing into the organism, where the inactive

14

parent compound (prodrug) undergoes nitro reduction to produce cytotoxic metabolites, which lead to

15

DNA helix damage, disruption of bacterial protein synthesis and replication, and ultimately

16

cytotoxicity.36

26


Page 27 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

A single-step process-scale synthesis of secnidazole reported in the patent literature proceeded

2

as depicted in Scheme 18.37 2-Methyl-5-nitroimidazole (82) was alkylated with 1-bromine-2-propanol

3

(83) in the presence of base to give secnidazole (VIII) in 88% yield.37b

4

Scheme 18. N NH

+

Synthesis of secnidazole (VIII) OH

Br

 88%

O 2N 82

5

N K2CO3, acetone

OH

N O 2N

83

Secnidazole (VIII)

6 7

2.8 Vaborbactam (Vabomere®, Vaborbactam/Meropenem combination)

8

Discovered by Rempex Pharmaceuticals and subsequently developed and marketed by The

9

Medicines Company, vaborbactam is an inhibitor of the carbapenem-deactivating serine protease

10

Klebsiella pneumoniae carbepenemase (KPC). Intravenous dosing of vaborbactam in combination

11

with the previously-approved carbapenem antibiotic meropenem was approved by the USFDA in 2017

12

for the treatment of complicated urinary tract infections including pyelonephritis.38 Key in the design

13

of vaborbactam is the use of a cyclic boronate to engender potent, reversible interactions with the

14

catalytic serine hydroxyl group in KPC, and also to reduce affinity to mammalian proteases that

15

accommodate linear substrates.39 In human trials, vaborbactam/meropenem demonstrated clinical

16

efficacy

17

Enterobacteriaceae (CRE) infections.16, 40

superior

to

the

best

available

treatment

in

addressing

carbapenem-resistant

18

The main challenge in the synthesis of vaborbactam is construction of the relative cis-

19

stereochemistry of the N-acyl and N-acetate groups at the 3- and 6-positions of the oxiborinane ring

20

system in an asymmetric fashion. The absolute stereochemistry was established in an efficient 3-step

21

process by enantioselective lipase resolution of the (R)-enantiomer of racemic ester 84, base-mediated

22

acetate hydrolysis, and hydroxyl silylation to afford 85 in 40% yield and >99% ee (Scheme 19). 27



Page 28 of 117

1

Iridium-catalyzed hydroboration gave boronate 86 in high yield followed by exchange of pinacol with

2

pinanediol 87 to give pinene boronate 88. Elegant utilization of a Matteson homologation (88 to 89)

3

established the chiral center vicinal to boron. Originally reported as a batch step at -95 oC yielding an

4

85:15 ratio of desired to undesired diastereomers, a flow-based method has been reported at higher

5

temperatures (-60 to -70 ºC) resulting in improved d.r. (95:5), yield (>90%), and reaction

6

reproducibility.41 The flow approach has reportedly delivered more than 1,000 kilograms of 89 under

7

GMP conditions.41 Conversion of the stereodefined chloride in 89 to acylated amine 90 was achieved

8

with lithium hexamethyldisilazide followed by treatment of crude hexamethylsilazane with 2-

9

thiopheneacetic acid and amide coupling reagents (EDCI, HOBT, NMM) in good yield. Subjection of

10

90 to HCl in dioxane affected concomitant deprotection of the alcohol, hydrolysis of the boronate

11

ester, and intramolecular cyclization to yield vaborbactam (IX) as a white solid. Scheme 19.

12

O OH O

Synthesis of vaborbactam (IX)

1. PS-Amano Lipase pentane, 30 °C 2. K2CO3, MeOH, rt 3. TBSCl, imidazole DCM, rt 40%, >99% ee

O TBS

O

84

[Ir(COD)Cl]2 pinacol borane

O

O B

dppb, DCM rt, 96%

O

O TBS

85

O

O

86

OH 87 H

OH

THF, rt, 91%

H O

O B

1. n-BuLi, heptane THF, DCM -60 to 70 °C

O TBS

O

2. ZnCl2, THF, -20 °C

O

90% for 2 steps

Cl O

B O

H

O TBS

O

O

89

88 S

O

S 1. LiHMDS, THF, -78 °C 2. 2-thiopheneacetic acid EDCI, HOBT, NMM 70%

B O

H

13

O

HN O

3N HCl, dioxane O

TBS

O

 64%

O

90

HN HO

B

O

CO2H

Vaborobactam (IX)

28


Page 29 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1 2

2.9 Voxilaprevir (Vosevi®)

3

First approved by the USFDA and the EU in 2017, voxilaprevir was approved as part of a threefold

4

combination therapy involving sofosbuvir and velpatisvir for the treatment of chronic HCV genotype

5

1–6 infection in adults, including those who have previously received direct-acting antiviral (DAA)

6

therapy.2o,

7

through

8

sofosbuvir/velpatasvir/voxilaprevir in DAA-naive patients without compensated cirrhosis is shorter

9

than sofosbuvir/velpatasvir (8 vs 12 weeks).43 This shorter treatment period may improve patient

10

adherence to treatment. Furthermore, treatment with sofosbuvir/velpatasvir/voxilaprevir does not

11

require ribavirin, a drug that is teratogenic and increases pill burden as well as the likelihood of mild

12

anemia when used in combination with DAAs.43

42,2o

The drug, which is sold by Gilead, reversibly inhibits the HCV NS3/4A protease

non-covalent

interactions.

The

approved

treatment

duration

with

13

A 2015 patent application published by workers at Gilead describes a process for the preparation

14

of voxilaprevir and structurally-related antiviral agents.44 Although the Gilead patent exemplifies the

15

reactions depicted in Schemes 20-23 in thorough detail on scales capable of supporting delivery of

16

multigram quantities the API (and in many examples describe conditions for recrystallization or

17

precipitative isolation of intermediates), no yields were reported in the patent. Voxilaprevir possesses

18

significant structural homology to glecaprevir. Coincidentally, both HCV NS3/4A inhibitors utilize

19

cyclopropylamine 44 for their preparation (see Scheme 10).25 The macrocyclic structure of

20

voxilaprevir was subdivided into four main subunits: pyrrolidinol 95, cyclopropyl carbamate 100,

21

quinoxaline 105, and cyclopropylamine 44—and the synthesis hinged upon a critical ring-closing

22

metathesis (RCM)-hydrogenation approach strategically similar to glecaprevir.22, 25, 27a, 45

29



Page 30 of 117

1

The preparation of pyrrolidinol 95 began with subjection of pyrrolidinone 91 to DMF-DMA in

2

warm dichloromethane. The resulting enaminone was treated with methylmagnesium bromide to

3

furnish an unspecified mixture of E/Z enones 92 (Scheme 20). Hydrogenation of the olefin delivered

4

excellent diastereoselectivity of the resulting product, presumably due to approach of the catalyst from

5

the face opposite the preexisting t-butyl ester, allowing for arrival at ethyl pyrrolidinone 93. Next,

6

stereoselective reduction of the carbonyl group was facilitated by treatment with zinc chloride, which

7

likely biased delivery of hydride from the same face as the ester. Isolation of the product upon

8

treatment with citric acid furnished alcohol 94 as the major product. No diastereoselectivity ratios

9

were reported for this transformation. Transesterification through the use of tosic acid necessitated

10

reinstallation of the Boc group to produce pyrrolidinol 95.

11

Scheme 20. Preparation of voxilaprevir pyrrolidinol 95

12 O

O N

O

Boc

O

N

1. DMF-DMA, DCM, 45 °C O

2. MeMgBr, Et2O, 2-MeTHF -12 °C

O

O

HO N

O

13

93

H2, Pd on activated charcoal PhCH3, 20 °C > 50:1 dr

92

91

O

Boc

1. ZnCl2, CPME, 95 °C 2. NaBH4, CPME, 25 °C Boc

3. citric acid, H2O, 0 °C

N O

HO

1. p-TsOH, MeOH 25 to 60 °C 2. MTBE, 40 °C Boc

O

94

3. Boc2O, Et3N DCM, 25 °C

N O

Boc

O 95

14 15

Cyclopropyl carbamate 100 was prepared by first converting cyclopropanol 96 to carbonate 98

16

using bis-succinimide reagent 97 (Scheme 21). Next, coupling with tert-leucine (99) proceeded in the

30


Page 31 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

presence of aqueous potassium phosphate. This step was followed by pH adjustment to allow for

2

isolation of carbamate 100. Scheme 21. Preparation of voxilaprevir cyclopropyl carbamate 100

3

NH2

O

HO

N

O

O +

O O N

HO

O

O

1. py, DMF, 45 °C 2. H2O, 0 °C O

O N

O O

O 96

4

97

99 O

O 1. aq K3PO4, 99, 25 °C HO 2. 6N HCl, then 2.5 N NaOH, then 6N HCl, 25 °C

HN

O

O

98

100

5

Preparation of quinoxaline 105 started with acid 101, which conveniently incorporated the

6

difluoromethylene group into the molecule at a very early stage of the synthesis (Scheme 22).

7

Subjection of this pentenoic acid to aniline in the presence of triphenylphosphine and CCl4 converted

8

101 to the corresponding amide. This was followed by exposure to POCl3 and subsequently potassium

9

cyanide to form iminonitrile 102 (E/Z selectivity not reported). Reaction with o-phenylenediamine

10

103 in acetic acid followed by treatment with base established the quinoxaline core. Sandmeyer

11

conditions were employed to transform the amine to the corresponding chloride, giving rise to

12

quinoxalyl chloride 105. Scheme 22. Preparation of voxilaprevir quinoxaline 105

13

1. HOAc, PhCH3 20 to 30 °C NH2 1. aniline, PPh3, CCl4, Et3N, 5 °C 2. POCl3, DCM, 25 °C

F F HO

3. 40% aq K3PO4, 20 °C 4. KCN, MeCN, 25 °C

O 101

F F

14

103 O

NH2

2. 3N NaOH, pH ~9

CN 102

N O

F F N

N

NH2

F F

1. BCl3, DCM, 5 °C, then t-BuNO2 2. 5% aq NaHCO3, 25 °C 3. i-PrOH, 40 to 25 °C then H2O, 5 °C

104

N O

N

Cl

105

15 31


Journal of Medicinal Chemistry 1 1 2 3 2 4 5 6 3 7 8 4 9 10 11 5 12 13 14 6 15 16 17 7 18 19 8 20 21 22 9 23 24 10 25 26 27 11 28 29 30 12 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 117

Final assembly of the voxilaprevir subunits is depicted in Scheme 23. Substitution of chloride 105 with alcohol 95 established the alkyl-aryl ether linkage. This was followed by tosic acid-mediated removal of the Boc group to give tosylate salt 106. The amine salt was then immediately coupled with carboxylic acid 100 using EDCI as the activating reagent. Next, the key RCM reaction was facilitated by the Zhan IIa catalyst (108) to deliver the ring-closed product with impressive functional group tolerance.27b Subsequent platinum-mediated hydrogenation secured macrocycle 109.45b Lastly, saponification of the methyl ester followed by amide bond formation with cyclopropylamine 44 delivered voxilaprevir (X). Although the Gilead patent exemplifies API isolation conditions as using chromatography,44 a separate patent application by the Chinese firm Sunshine Lake Pharma Co., Ltd. describes API solid form and crystallization conditions of macrocycles similar in structure to that of voxilaprevir.27a Scheme 23.

Synthesis of voxilaprevir (X)

32


Page 33 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of Medicinal Chemistry F F HO

1. Cs2CO3, DMA 100 to 110 °C 2. i-PrOH, H2O, 40 °C

F F N

+

N

Boc

O

O

O

O

N

3. p-TsOH, 2-MeTHF 20 to 60 °C, then MTBE, 15 to 20 °C

Cl

N

N O

N H H

O O

95

105

O HN

F F N

N

HO

O O

106

F F O

N

HN

HN

O

N

2. Pt/C, H2 i-PrOAc, 20 °C

O

O

O

107

O

O

109

F F N

N

NH2 N

O

O 44

O

O

O

N

1. 108, PhCH3 20 to 110 °C

N

O

F F

O

O

O

100

1. 100, EDCI, DMF NMM, 0 to 100 °C 2. NaHCO3, PhCH3, H2O, -5 to 25 °C

OTs

O NH S O

O

O HN

O

S

O

O

N

1. LiOH, i-PrOH, 40 °C, then 1N HCl (pH ~3), then 5% EtOH/heptane

F F

2. 44, HATU, DIPEA, DMAP DMF, 20 °C, then 2N HCl

HN

O O

O

O NH S O

Cl N

Ru

O i-Pr Cl N

108

Voxilaprevir (X)

1 2 3 4

3. CNS Drugs 3.1

Deutetrabenazine (Austedo®)

5

Deutetrabenazine, a reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2),

6

was approved by the USFDA for the treatment of chorea (abnormal involuntary movements)

7

connected with Huntington’s disease.46 As the second drug approved in the US for this indication,

8

deutetrabenazine represents an improvement over its non-deuterated counterpart, tetrabenazine (118, 33



Page 34 of 117

1

Figure 2), which has been used for the same indication since its approval in 2008.47 While

2

tetrabenazine provides effective treatment, the drug is quickly metabolized, necessitating frequent

3

dosing, which contributes to issues with patient non-compliance.46, 47b, 48 The strategic incorporation

4

of six deuterium atoms into tetrabenazine enables a more favorable pharmacokinetic profile due to the

5

increased strength of C-D versus C-H bonds, lowering the rate of metabolism. This improves half-life

6

and decreases dosage, and ultimately reduces adverse events compared to tetrabenazine.46, 49 As the

7

first deuterated drug approved by the USFDA, deutetrabenazine represents a successful incorporation

8

of deuterium to modulate pharmacokinetic profile, establishing proof-of-concept for other deuterated

9

compounds currently in clinical trials for a variety of indications.47a, 50 The drug consists as a racemic

10

mixture of R,R and S,S isomers, which are converted to two major active metabolites, - and β-

11

dihydrodeutetrabenazine.46, 48 Even though the exact mechanism of action is unknown, the drug is

12

believed to suppress levels of monoamines such as dopamine, serotonin, norepinephrine, and

13

histamine, with the circulating active metabolites of the drug leading to decreased monoamine uptake

14

into synaptic vesicles.46

15

While several synthetic routes to (±)-deutetrabenazine and (±)-tetrabenazine have been

16

reported,51 the majority of these routes, including the route reported by Auspex Pharmaceuticals

17

described herein,51c, 52 rely on a single-step transformation to install the benzoquinoline core from the

18

corresponding dihydroisoquinoline 114.52-53 Synthesis of 114 is shown in Scheme 24, beginning with

19

dopamine hydrochloride (110). Condensation of 110 with ethyl formate (111) in the presence of

20

sodium t-butoxide provided formamide 112 in 85% yield. From 112, phenol alkylation with CD3I

21

provided the deuterated 3,4-bis-methoxy analog 113, which then underwent a Bischler-Napieralski

22

cyclization to generate dihydroisoquinoline 114 in 44% yield over the 2-step sequence.52 The key step

23

in the synthesis of deutetrabenazine is the final transformation, which was achieved by reaction of 114 34


Page 35 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

and quaternary ammonium salt 115 (whose preparation is outline in Scheme 25) with K2CO3 under

2

heating conditions.52 This transformation presumably proceeded through a tandem Mannich reaction-

3

Hofmann elimination-Michael addition sequence,54 which has been previously employed in the

4

synthesis of tetrabenazine51e, 55 and has also been reported successfully on kilogram scale with similar

5

substrates.54a This cyclization sequence provided the racemic product as the cis-diastereomer55b, 56 of

6

deutetrabenazine (XI) in 67% yield after washing of the crude product with hot ethanol.52

7

Quaternary ammonium salt 115 can be synthesized on multi-kilogram scale starting from 5-

8

methylhexan-2-one (116, Scheme 25).51c Treatment of 116 with paraformaldehyde and dimethylamine

9

hydrochloride under refluxing conditions provided intermediate 117, which was converted to the

10

corresponding ammonium salt 115 in 87% yield via treatment with iodomethane.51c Furthermore, an

11

alternate approach to XI has recently been reported by reacting CD3OD with a catechol intermediate

12

under Mitsunobu conditions.51e This approach may offer a more cost-effective means of deuterium

13

introduction relative to the CD3I displacement approach described in Scheme 24. Scheme 24.

14

Synthesis of deutetrabenazine (XI) O

HO

NH2 • HCl

HO

EtO

H

111

NaOt-Bu 25 to 60 °C, 85%

H N

HO

O

HO

H N

H O

D3CO

CD3I, 35 °C

115, K2CO3 MeOH, H2O

D3CO

25 to 45 °C, 81%

D3CO

D3CO

POCl3 MeCN, 

N

D3CO

• HCl

44% for 2 steps 113

acetone, K2CO3

112

110

D3CO

H

114

N H O

()-Deutetrabenazine (XI)

15 16 17

Scheme 25.

Synthesis of piperidone-forming reagent 115 for deutetrabenazine (XI) 35



O

O

O

(Me)2NH HCl paraformaldehyde EtOH, HCl, , 36%

MeI, DCM 5 °C, 87%

Me2N

116

1

Page 36 of 117

Me3N

I 115

117

2 3

3.2

Valbenazine (Ingrezza®)

4

Valbenazine was developed by Neurocrine Biosciences and approved by the USFDA for treatment

5

of adults with tardive dyskinesia, a movement disorder characterized by repetitive, purposeless, and

6

involuntary movements caused by exposure to dopamine receptor-blocking agents that are prescribed

7

as antipsychotics, some antidepressants, and antiemetics.57 Valbenazine is a selective VMAT2

8

inhibitor that demonstrates superior potency over current standard of care, tetrabenazine (118, Figure

9

2), requiring less frequent administration.58 Valbenazine bears significant structural homology to

10

tetrabenazine, deutetrabenazine (XI), and R,R,R-dihydrotetrabenazine (R,R,R-DHTBZ, 119). It was

11

found to have superior selectivity and potency relative to the other four possible hydroxyl metabolite

12

isomers resulting from non-selective reduction of (±)-tetrabenazine by carbonyl reductase.59

13

Valbenazine was designed as a valine ester prodrug of R,R,R-DHTBZ, enabling slower release of the

14

active metabolite in the liver.60

15

Figure 2. Structures of (±)-tetrabenazine 118, R,R,R,-DHTBZ 119, and valbenazine (XII) MeO MeO MeO

MeO N H

Me

MeO

MeO N H

Me

H

Me

Me O

N

Me OH

Me O H 2N

O Me Me

16

(±)-Tetrabenazine 118

R,R,R-DHTBZ 119

Valbenazine XII

17

Patent literature from Neurocrine Biosciences suggests that valbenazine is accessed by a four-

18

step synthetic route beginning with commercial (±)-tetrabenazine 118, as shown in Scheme 26. 36


Page 37 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

Although (±)-tetrabenazine is commercially available, a likely scale route has also been described

2

which resembles the approach used for construction of deutetrabenazine (Scheme 24).53 While

3

deutetrabenazine is a mixture of cis-enantiomers, valbenazine’s construction requires tetrabenazine as

4

a single enantiomer. Toward this end, a resolution of racemic 118 was developed using (-)-O,O’-di-p-

5

toluoyl-L-tartaric acid.61 Treatment of the salt with aqueous ammonium hydroxide in ethanol provided

6

resolved amine (+)-120 in 67% yield and 97-98% chiral purity. Borane reduction of the ketone

7

furnished the requisite (R,R,R)-alcohol 121. This transformation can also be accomplished using a

8

ruthenium-catalyzed transfer hydrogenation protocol, albeit in lower reported yields. Esterification of

9

121 with Boc-L-valine followed by subjection to excess tosic acid resulted in bis-tosylate salt

10

formation and arrival at valbenazine (XII). The precipitated product could be isolated via filtration,62

11

which represented an improvement over earlier patents describing an esterification using CBz-L-

12

valine, and relied upon column chromatography for isolation of final product.63 Scheme 26. Synthesis of valbenazine (XII)

13 MeO N

MeO

1. (-)-O,O'-Di-ptoluoyl-L-tartaric acid, acetone

Me

H

MeO MeO

N H

2. NH4OH, EtOH

Me O

67% for 2 steps 97-98% chiral purity

(±)-Tetrabenazine 118

Me

1. BH3•THF, THF -15 °C

Me 2. NH4OH, 35 °C O

80% for 2 steps

(+)-120 MeO MeO

MeO MeO

N H

Me Me

OH

1. Boc-L-Val-OH, EDCI DMAP, 2-MeTHF 2. p-TsOH 47% for 2 steps

121

N

Me

H

Me O H 2N

O

2 p-TsOH Me

Me Valbenazine XII

14 15 16

4. Gastrointestinal Drugs 37



1

4.1

Page 38 of 117

Naldemedine (Symproic®)

2

Naldemedine was approved by the USFDA in March 2017 for the treatment of opioid-induced

3

constipation in adult patients with chronic non-cancer pain, and subsequently in Japan for the treatment

4

of opioid-induced constipation in patients with cancer and non-cancer pain.64 It is a third-in-class,

5

orally active, peripherally-acting µ-opioid receptor antagonist (PAMORA) developed by Shionogi &

6

Co., Ltd. Constipation is a common side effect of opioid treatment, occurring in 40-80% of patients;65

7

naldemedine blocks the effect of opioids at peripheral µ-opioid receptors localized in the

8

gastrointestinal tract tissue. Naldemedine is structurally similar to naltrexone, an opioid receptor

9

antagonist approved for treatment of alcohol or opioid dependence, with a side chain designed to limit

10

blood-brain barrier (BBB) penetration by increasing molecular weight and topological polar surface

11

area. This structural modification results in minimal or no effect on CNS opioid activity (analgesia)

12

and minimizes adverse effects associated with opioid withdrawal.20 Naldemedine is also a

13

permeability glycoprotein (P-gp) efflux substrate.

14

The synthesis of naldemedine commenced with commercial naltrexone hydrochloride (122,

15

Scheme 27). Acylation of the phenol followed by CuCl2-mediated reaction with isocyanate 123

16

(whose synthesis is described in Scheme 28) generated carbamate 124 in 89% yield.66 Subjection of

17

124 to KOH induced a 1,4-intramolecular acyl transfer reaction that proceeded with concomitant

18

removal of the phenolic acetate. Treatment with tosic acid followed by crystallization from methanol

19

and isopropyl acetate afforded naldemedine tosylate (XIII) in 66% yield from 124.

20

Scheme 27. Synthesis of naldemedine (XIII)

38


Page 39 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 1 23 24 2 25 26 27 3 28 29 30 4 31 32 5 33 34 35 6 36 37 7 38 39 40 41 42 43 44 45 46 47 48 49 50 8 51 52 9 53 54 10 55 56 57 11 58 59 60


O

N N

N OH • HCl O

HO

N HN O O

1. Ac2O, Et3N, EtOAc, 40 °C 2. 123, CuCl2, H2O, EtOAc, rt O

O

C

N

N

AcO

O N

123

89% for 2 steps

122

3. MeOH, i-PrOAc

• TsOH

HN O

HO

O

124

N OH 1. aq KOH, i-PrOH, 80 °C 2. p-TsOH, i-PrOH

O

O O OH

N N

66% for 3 steps Naldemedine (XIII)

Isocyanate 123 was synthesized in 4 steps from N-Boc 2-amino-2-methylpropanoic acid (125, Scheme 28).66 Chloroformate-mediated oxadiazole formation with 126 and Boc deprotection proceeded in 93% yield over two steps. Carbamate formation with methyl chloroformate and subsequent treatment with boron trichloride and triethylamine gave isocyanate 123, which was carried forward without isolation. Scheme 28. Synthesis of naldemedine isocyanate intermediate 123 N

OH NH2 126

1. DIPEA, n-PrOAc, isobutyl chloroformate, 0 °C then 126, n-PrOAc, 95 °C 2. aq HCl BocHN

CO2H

3. methyl chloroformate, aq K2CO3, PhMe, 50 °C 4. BCl3, Et3N, PhMe, 50 °C

125

93% from 125

O

C

N

N O N 123

5. Hematologic Drugs 5.1 Betrixaban (Bevyxxa®) 39



Page 40 of 117

1

Discovered by Millenium Pharmaceuticals and later developed by Portola Pharmaceuticals, Inc.

2

(originally in collaboration with Merck) as a selective serine protease factor Xa (FXa) inhibitor,

3

betrixaban is an anticoagulant approved in 2017 by the USFDA for the treatment of

4

thromboprophylaxis in hospitalized patients that have risk factors for venous thromboembolisms (such

5

as deep vein thrombosis and pulmonary embolisms).67 Some of these risk factors include acute medical

6

illness, hospitalization, age and a history of the condition.67 Betrixaban binds to the active site of FXa

7

thereby decreasing prothrombinase activity and thrombin generation.68 Betrixaban belongs to a class

8

of FXa inhibitors known as non-vitamin K antagonist oral anticoagulants (NOACs), which provide an

9

alternative therapy to vitamin K antagonists, such as warfarin.69

10

Researchers at Millennium Pharmaceuticals described the design and discovery of the

11

anthranilamide-containing drug,70 and a modular synthetic approach to the API has been reported in

12

the patent literature.71 Although alternative preparations have been available in the public literature,

13

the route depicted in Scheme 29 was demonstrated on kilogram scale.72 Starting from 5-methoxy-2-

14

nitrobenzoic acid (127), conversion to the corresponding acid chloride then reaction with 5-

15

chloropyridin-2-amine (128) formed amide 129. Nitro group reduction followed by coupling with 4-

16

cyanobenzoyl chloride (131) to 130 established the core structure 132. Conversion of nitrile 132 to

17

amidine 133 using dimethylamine and hexyl lithium completed the synthesis of the parent compound

18

which was isolated as the maleate salt to arrive at betrixaban (XIV).

19

Scheme 29. Synthesis of betrixaban (XIV)

40


Page 41 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 1 30 31 2 32 33 34 3 35 36 4 37 38 39 5 40 41 6 42 43 44 7 45 46 47 8 48 49 9 50 51 52 10 53 54 11 55 56 57 12 58 59 60

Journal of Medicinal Chemistry Cl

O MeO

H 2N

OH

N

MeO

POCl3, py, MeCN 25 °C, 88%

NO2 127

N H NO2

O

Cl

O N H NH2

2. EtOH 90% for 2 steps

131

MeO

N H NH

CN

N

Cl

O

THF, py, 19 to 30 °C, 75%

N HNMe2 in THF, n-HexLi THF, -3 to 10 °C, 77%

O

130

CN

132

Cl

O MeO

1. H2, Pt/C, DCM

N

129

Cl

MeO

Cl

O

128

N H NH

MeO

N

N H NH

maleic acid, EtOH, H2O Me N Me NH

O

Cl

O

19 to 25 °C, 85%

O

CO2H

N

CO2H Me N Me NH

Betrixaban (XIV)

133

6. Metabolic Drugs 6.1 Ertugliflozin (Steglatro®) Ertugliflozin, an oral sodium glucose transporter type 2 (SGLT2) inhibitor discovered by Pfizer and co-developed by Pfizer and Merck, was approved by the USFDA in 2017 and by the European Medicines Agency (EMA) in 2018 for the treatment of type II diabetes mellitus.73 SGLT2 inhibitors block glucose reabsorption in the kidney, resulting in increased glucose excretion and reduced glucose blood levels, body weight, and blood pressure.74 Fixed-dosage forms of ertugliflozin/sitagliptin (DDPIV inhibitor) and ertugliflozin/metformin (hepatic glucogenesis inhibitor) have also been approved. Four other SGLT2 inhibitors have been approved by the FDA and EMA: dapagliflozin, ipragliflozin, empagliflozin, and canagliflozin.75 Ertugliflozin contains a bridged oxabicyclic ring system that 41



Page 42 of 117

1

presented synthetic challenges.76 A number of routes have been used over the course of ertugliflozin’s

2

development,77 with a commercially viable route recently reported.78 The key challenge was the

3

introduction of the hydroxymethyl group at the C1 position. The additional steric hindrance of this

4

quaternary stereocenter led to reactivity patterns that required creative solutions and surveying

5

multiple potential starting materials. Furthermore, ertugliflozin and most related intermediate

6

carbohydrate structures are non-crystalline, which made non-chromatographic purification difficult,

7

leading to a strategy of telescoping steps, screening intermediates that were structurally different yet

8

equivalent in reactivity for desired solid form properties, and developing a co-crystal of ertugliflozin

9

as the final pharmaceutical form.

10

The synthesis started with oxidation of benzylated glucose derivative 134 (Scheme 30) with

11

DMSO/acetic anhydride at ambient temperature to afford gluconolactone 135 in high yield. This

12

intermediate was carried directly into an amidation with methylpiperazine (136), affording amide 137

13

as a solid that was readily isolated and also allowed for potential salt formation. Oxidation of the

14

secondary alcohol of 137 under Parikh-Doering conditions with SO3-pyridine yielded ketone 138

15

which could be directly reacted with different hydroxymethyl anion equivalents to generate the key

16

C1 quaternary stereocenter within 142. Two methods were identified from different organomagnesium

17

reagents: 1) derived from (chloromethyl)(isopropoxy)dimethylsilane followed by Tamao-Fleming

18

oxidation (KF, H2O2) (140 as 3:2 mixture of diastereomers), and 2) derived from iodomethyl pivalate

19

followed by methoxide-mediated pivalate removal (141 as 95:5 mixture of diasteromers). Protection

20

of the hindered diol in 142 was achieved with 2,2-dimethoxypropane and methanesulfonic acid.

21

Formation of the oxalate salt 143 afforded an isolable solid. Importantly, the ratio of C1 diastereomers

22

did not impact subsequent chemistry at this point.

42


Page 43 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

The free base of 143 was generated (toluene, aqueous NaHCO3) and the organic layer was

2

concentrated, serving to azeotropically dry 143 in preparation for the addition of the aryl anion

3

(Scheme 31). The precursor to the aryl anion (144, Scheme 32) was identified based upon both good

4

yield in synthesis, physical properties (highest melting point), and performance in the subsequent

5

chemistry. Another series of telescoped steps started with metalation of 144 (n-hexyl lithium, 2-

6

MeTHF, toluene, -15 °C) to give ketone 145. Concomitant removal of the acetonide protecting group

7

and reductive hydrogenolysis of the benzhydryl ether led to 146 as a mixture of diastereomers.

8

Hydrogenation under acidic conditions removed the benzyl protecting groups and catalyzed the

9

convergence of the diastereomers to ertugliflozin. To enhance the purity of ertugliflozin for final co-

10

crystal formation, peracetylation (acetic anhydride, pyridine) gave highly crystalline 147 that allowed

11

for effective purging of impurities to low levels in good yield over five steps (58% average yield).

12

Acetate removal with catalytic sodium methoxide in methanol provided an ertugliflozin solution of

13

good purity that was concentrated, taken up in isopropanol, heated to 60 oC, and treated with water

14

followed by a solution of L-pyroglutamic (L-PGA) in water to yield crystalline ertugliflozin-L-

15

pyroglutamic acid (XV) (MP = 142.5 °C) in high yield (88% average yield over two steps).

16

Scheme 30. Synthesis of amide 143 towards ertugliflozin-L-pyroglutamic acid (XV)

17

43



OBn

OBn O

OH

BnO

OBn

20 to 25 °C. 92%

BnO

OBn

3. 138, CpMeO, -20 °C

KF H2O2 (35%) NaHCO3 MeOH

OiPr SiMe2 OHOBn O

20 °C N

OH NMe

OHOBn O N

140

NMe 1.

OBn OBn OBn

O O

138

I 139

i-PrMgCl, THF -75 °C 2. 138, PhCH3, -60 °C

OPiv

OBn OBn OBn

2. (CO2H)2, MTBE, 50 °C 60 to 70% from 137

1

Scheme 31.

NaOMe PhCH3

OHOBn O N

1. 2,2-dimethoxypropane MsOH, CpMeO 20 to 25 °C

2

5 °C, 90%

137, isolated precipitate

OBn OBn OBn

N

NMe

77% for 2 steps

OBn O

OBn OBn OBn

OBn OBn OBn

135

1. Mg, Br(CH2)2Br THF, 65 °C 2. i-PrO-Si(Me)2CH2Cl 65 °C

O

N

PhCH3, 20 to 25 °C

OBn

SO3•py, DIPEA DMSO

OH OBn O

O

OBn

134

NMe 136

HN O

Ac2O, DMSO

Page 44 of 117

NMe

142

0 to 5 °C NMe

141

O O

OBn O • (CO2H)2

N OBn OBn OBn

NMe

143

Synthesis of ertugliflozin-L-pyroglutamic acid (XV)

44


Page 45 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 1 25 26 27 2 28 29 30 3 31 32 33 4 34 35 36 37 5 38 39 40 41 42 43 44 45 46 6 47 48 7 49 50 51 8 52 53 9 54 55 56 10 57 58 11 59 60


• (CO2H)2

O O

OBn O N

OBn OBn OBn

NMe

1. aq NaHCO3 PhCH3 20 to 25 °C

O O

2. 144, n-HexLi 2-MeTHF PhCH3, -15 °C

OBn O

OBn

OBn OBn OBn

143

BnO

TFA

Cl

Et3SiH PhCH3, rt

OEt

O

BnO

O

H2, Pd/C HCl, THF MeOH, 25 °C

OBn

146

OEt

O

AcO

Ac2O, py

Cl

HO

Cl

OBn

145

HO

OEt

O

PhCH3, 5 to 20 °C

OH OH

O

OAc OAc

Ertugliflozin

147

HO

O

OEt

O

HO

•

Cl

2. L-PGA, i-PrOH, H2O 88% for 2 steps

Cl

AcO

58% from 143

1. NaOMe, MeOH

OEt

O

O HN

HO2C

OH OH

Ertugliflozin - L-pyroglutamic acid XV

Intermediate 144 was prepared as described in Scheme 32. Addition of Grignard reagent 149 to aldehyde 148 followed by etherification of the resulting alcohol gave 144 in 75% yield. Scheme 32.

Synthesis of benzyl ether intermediate 144 for ertugliflozin-L-pyroglutamic acid 1. BrMg

Cl H

Br O

OEt 149

Cl

OEt

2-MeTHF, 0 °C 2. H2SO4, BnOH  75%

Br

148

OBn 144

6.2 Pemafibrate (Parmodia®) Pemafibrate is an orally-delivered peroxisome proliferator activated receptor agonist (PPAR)- that was developed by Kowa Pharmaceuticals America, Ltd.79 The drug, which is also named K-877 and (R)-K-13675, received approval for the treatment of hyperlipidemia from Japan’s Pharmaceutical 45



Page 46 of 117

1

and Medical Devices Agency in 2017.79 Pemafibrate acts by binding to PPAR-, which is a nuclear

2

hormone receptor primarily expressed in the liver, thereby regulating the expression of target genes

3

that modulate lipid metabolism resulting in the increased amount of high-density lipoprotein

4

cholesterol levels (HDL-C) and decreased plasma triglyceride levels.80 Pemafibrate exhibits

5

remarkable selectivity for PPAR- (>2000x) over PPAR- and PPAR- amongst other receptors,

6

which likely contributes to its improved adverse-event (AE) profile over existing fibrate drugs such

7

as bezafibrate, fenofibrate, and gemfibrozil which are weaker PPAR agonists with poor selectivity.80a,

8

81

9

Kowa has disclosed three different synthetic approaches to pemafibrate—an initial synthesis, an

10

improved enantioselective approach, and a kilogram-scale procedure.80b, 82 The kilogram scale route

11

described in Scheme 33 relied upon a critical ethereal bond establishment between optically pure

12

triflate ester 153 and phenol 152.82a Conjugate addition of 4-methoxyphenol (150) to acrylonitrile was

13

followed by borane-THF reduction to arrive at amine 151 in good yield. Next, reductive amination

14

with commercial 3-hydroxybenzaldehyde followed by substitution with 2-chlorobenzoxazole gave

15

rise to 2-aminobenzoxazole 152 in 62% yield across the two-step sequence. After considerable study,

16

the SN2 reaction between phenol 152 and triflate ester 153 (Scheme 34) proceeded with complete

17

inversion of configuration using potassium carbonate and acetonitrile at ambient temperature. The

18

authors reason that the trifluoromethanesulfonate group is critical to ensuring an efficient alkylation

19

reaction in this case; racemization of the -carboxylate stereocenter was observed with other

20

alkylsulfonate leaving groups such as mesylate and tosylate.82b Finally, saponification of the n-butyl

21

ester proceeded in good yield to give pemafibrate (XVI) in 75% yield from 152.

22

The preparation of triflate 153 began from enantiopure (S)-2-hydroxybutyrolactone 154.82b An

23

interesting ring-opening reaction involving trimethylsilyl iodide converted 154 to iodide 155. The 46


Page 47 of 117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1

authors speculate that the mechanism of this reaction first involved activation of the ester carbonyl by

2

the trimethylsilyl group to form an intermediate oxonium species which then underwent attack by a

3

stoichiometric equivalent of n-butanol. The resulting tetrahedral intermediate participated in SN2

4

displacement by the iodide ion, and this was followed by ejection of trimethylsilanol, resulting in n-

5

butyl ester 155.82b Hydrogenative reduction of the iodide followed by triflate formation through the

6

use of 2,6-lutidine allowed for conversion of 155 to triflate 153 with complete stereocontrol and no

7

loss of stereointegrity across the three-step sequence.82b Scheme 33. Synthesis of pemafibrate (XVI)

8 O

1. aq benzyltrimethylammonium hydroxide, acrylonitrile, 80 °C OH

O

2. BH3•THF, THF, 65 °C, then 4N NaOH, rt 68% for 2 steps

150

NH2 2. 2-chlorobenzoxaxole Et3N, DMF, 75 °C

151

O N

1. 3-hydroxybenzaldehyde NaBH4, aq MeOH, 0 °C

O

62% for 2 steps

N

TfO

O

O

O OH

N

OnBu

O

N

OH

153 O

1. 153, K2CO3, MeCN, rt

O

2. 4N aq NaOH, EtOH, rt 75% for 2 steps O

O Pemafibrate (XVI)

152

9 10

Scheme 34. Synthesis of pemafibrate triflate 153

11

O

O HO

12

O

TMSI, n-BuOH DCM, -20 °C, 81%

154

HO

OnBu I 155

1. H2, 10% Pd/C Et3N, EtOH, rt

O TfO

OnBu

2. Tf2O, 2,6-lutidine DCM, -20 °C 68% for 2 steps

153

13 14

7. Musculoskeletal Drugs

15

7.1 Baricitinib (Olumiant®) 47



Page 48 of 117

1

Baricitinib is an inhibitor of Janus family tyrosine kinase (JAK)-1 and -2 approved by the USFDA

2

in 2017 as monotherapy or in combination with methotrexate for the treatment of adults with moderate

3

to severe active rheumatoid arthritis.83 Baricitinib was discovered by Incyte and co-developed with Eli

4

Lilly. It is also in clinical trials for the treatment of atopic dermatitis, systemic lupus erythematosus,

5

and giant cell arteritis.

6

Numerous synthetic routes to baricitinib have been reported in the patent literature.28 The largest

7

scale synthesis was reported by Incyte and is described in Schemes 35-37.28a Horner-Emmons reaction

8

between tert-butyl 3-oxoazetidine-1-carboxylate (156) and diethyl cyanomethyl phosphonate (157)

9

gave cyanomethylene azetidine 158 in 61% yield (Scheme 35). Acidic removal of the Boc protecting

10

group was followed by treatment with ethanesulfonyl chloride to give the sulfonamide subunit of

11

baricitinib 159 in 91% yield. Scheme 35.

12

NC O

NBoc 156

Synthesis of baricitinib azetidine sulfonamide 159

O P(OEt)2 157

NC

t-BuOK, THF -5 to -10 °C, 61%

NBoc 158

1. HCl, MeCN

NC

2. EtSO2Cl, DIPEA MeCN, 0 to 5 °C

O N S O 159

91% over 2 steps

13 14 15

The synthesis of baricitinib was completed as described in Scheme 36. Deprotonation of

16

chloropyrrolopyrimidine

160

with

sodium

hydride

followed

by

treatment

with

17

trimethylsilylethoxymethyl chloride gave the SEM protected chloropyrrolopyrimidine 161 in 89%

18

yield. Suzuki coupling with commercially available boronic ester 162 followed by acidic removal of

19

the ethoxyethyl protecting group gave pyrazole 163 in 87% yield. 1,4-Addition of pyrazole 163 to

20

cyanomethylazetidine 159 was accomplished in the presence of DBU to give SEM-protected

21

baricitinib 164 in high yield. Finally, treatment of 164 with lithium tetrafluoroborate followed by 48


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1

ammonium hydroxide gave baricitinib (XVII) in 81% yield. An alternative synthesis of baricitinib

2

that avoids the use of the ethoxylethyl and SEM protecting groups and changes the order of the 1,4-

3

addition and Suzuki coupling steps has also been reported on large scale and is described in Scheme

4

37.28b, 84 Scheme 36.

5

Synthesis of baricitinib (XVII)

6 N N

O

B O

OEt

162 Cl

Cl SEMCl, NaH

N N

N H

1. 162, K2CO3, Pd(PPh3)4 1-butanol, H2O, 

N

DMA, 0 to 5 °C, 89%

N NH

N SEM

N

N

2. aq HCl, THF

160

161

NC

O

O N S O 159

163

O S

O

N N N

O S

N CN

DBU, MeCN, 97%

1. LiBF4, MeCN H2O, 80 °C

N N

CN

2. aq NH4OH 81% for 2 steps

N N

N SEM 164

7

N SEM

N

82% for 2 steps

N N

N H

Baricitinib (XVII)

8 9

Scheme 37.

Alternative synthesis of baricitinib (XVII)

49



O

O N S O

O

B

DBU, DMF O

O S

O

N N

CN

70 °C, 87% O

B

O S

N

N

N NH NC

Page 50 of 117

160, PdCl2(dcypf)

N N

CN

K2PO4, THF, H2O 90 °C, 90% O

N N H Baricitinib (XVII) N

1

159

165

166

2

8. Oncology Drugs

3

8.1 Abemaciclib (Verzenio®)

4

Abemaciclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor developed by Eli Lilly &

5

Company for the treatment of breast cancer. CDK4/6 inhibitors impact signaling mechanisms for cell

6

cycle progression by inhibiting phosphorylation of retinoblastoma 1 (RB1) gene that prompts

7

transition from G1 to S phase in cell growth.85 Abemaciclib has shown greater efficacy than other

8

chemotherapeutic agents in multi-drug resistant hormone receptor (HR) positive breast cancer cells.86

9

The USFDA awarded approval for abemaciclib in combination with fulvestrant (a selective estrogen

10

receptor degrader) in patients with HR-positive, human epidermal growth factor receptor 2 (HER2)-

11

negative breast cancer that had progressed while receiving endocrine therapy,87 as well as in

12

combination with a non-steroidal aromatase inhibitor for postmenopausal patients with advanced HR-

13

positive, HER2-negative breast cancer.88

14

A convergent approach to the assembly of abemaciclib was disclosed in a 2014 patent application

15

from Lilly.89 In the sequence shown in Schemes 38 and 39, in which some reactions were exemplified

16

on kilogram scale, the molecule was subdivided synthetically into three distinct subunits—

17

aminopyridine 170, chloropyrimidine 176, and benzimidazole 175. This efficient synthetic strategy

18

avoids the use of protecting groups and chromatographic purification across the entire sequence, which

19

is particularly noteworthy considering the use of palladium in the final three steps of the sequence. 50


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1

Aminopyridine 170 was accessed in two steps, beginning with the reductive amination of 6-

2

bromonicotinaldehyde (168) with ethylpiperizine 167 to form bromopyridine 169 (Scheme 38). This

3

compound was then converted to aminopyridine 170 through an Ullman coupling employing ammonia

4

and copper oxide. Scheme 38. Synthesis of abemaciclib aminopyridine 170

5

Br N N

NH

+

20 to 30 °C quantitative

O

6

167

168

Br

NaBH(OAc)3 DCM

N

N

N

NH3, CuO MeOH 65 to 75 °C 54%

169

N

N

NH2

N 170

7 8

A Vilsmeier-type reagent was formed by the addition of N-isopropylacetamide (172) to

9

phosphorous oxychloride (Scheme 39). Upon exposure to 4-bromo-2-5-fluoroaniline 171, amidine

10

173 was formed, which then underwent base-induced intramolecular cyclization in warm DMF to

11

form benzamidazole 174. Miyaura borylation converted 174 to the corresponding boronic ester 175,

12

which then underwent Suzuki coupling with commercial aryl dichloride 176 giving rise to the

13

penultimate chloropyrimidine 177. Finally, a palladium catalyzed Buchwald-Hartwig amination with

14

aminopyridine 170 using Pd2(dba)3 in combination with Xantphos completed the synthesis of

15

abemaciclib (XVIII) in five steps in the longest linear sequence, with seven steps overall.89

16

Scheme 39. Synthesis of abemaciclib (XVIII)

51


Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 32 2 33 34 35 3 36 37 4 38 39 40 5 41 42 43 6 44 45 7 46 47 48 8 49 50 9 51 52 53 10 54 55 56 11 57 58 59 60

O

Br

F NH2 F

Br

172

N H

F

F N

N H

F

171

70 to 75 °C, 73%

N

Br

173

Cl

N O

176

N

B O

174

N

F

PCy3, KOAc DMSO, 90 °C

N

KOt-Bu, DMF

Et3N, POCl3 PhMe, 110 °C, 99%

B2pin2, Pd(OAc)2

Page 52 of 117

N

N Cl

Pd(PPh3)2Cl2 Na2CO3, DME, H2O 84 °C 64% for 2 steps

175

F

F N

Cl N

N F 177

N HN N

170, Pd2(dba)3 Cs2CO3, Xantphos dioxane, 110 °C, 88%

F N F

N

N N

N

Abemaciclib (XVIII)

8.2

Acalabrutinib (Calquence®)

Acalabrutinib is a small molecule drug developed by Netherlands-based Acerta Pharma (now a subsidiary of AstraZeneca) for the treatment of adults with mantle cell lymphoma (MCL) who have received at least one prior therapy.90 The drug, which received approval in October 2017 from the USFDA, is an irreversible inhibitor of Bruton’s Tyrosine Kinase (BTK) and achieves a half maximal inhibitory concentration (IC50) of 3 nM against purified BTK in vitro.90 The drug exhibited a higher selectivity for BTK than ibrutinib in a competitive binding assay, and—in contrast to ibrutinib—does not inhibit EGFR, ITK or TXK.91 Acalabrutinib was designated by the USFDA as a breakthrough therapy and clinical trials for chronic lymphocytic leukemia (CLL) are currently underway.90

52


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1

Several small-scale synthetic approaches to the synthesis of acalabrutinib have been reported.92

2

An efficient and creative process preparation has been reported in two 2017 patents by the Chinese

3

firm Suzhou Mingrui Pharmaceutical Technology Co., Ltd. and is described in Scheme 40.93

4

Conversion of 4-bromobenzoic acid (178) to the corresponding acid chloride preceded amide-bond

5

formation with 2-aminopyridine. This step was immediately followed by Miyaura borylation with

6

catalytic Pd(dppf)Cl2. Subsequent hydrolysis through the use of hydrochloric acid with sodium

7

periodate in aqueous THF furnished boronic acid 179. Next, a clever use of a Petasis reaction involving

8

commercial pyrazinyl aldehyde 180 in the presence of ammonia in aqueous 1,4-dioxane yielded

9

racemic branched amine 181 in 81% overall yield from 178.94 At this stage, establishment of the core

10

heterocycle took place through a modified Filmier cyclization. Although typically this reaction

11

encompasses the preparation of imidazopyridines, the approach in this case has been extended to the

12

construction of imidazopyrazine 183.95,96 To this end, amidation of amine 181 and proline derivative

13

182 proceeded via the corresponding acid chloride. Exposure of the resulting product to phosphorous

14

oxychloride in acetonitrile at elevated temperatures gave rise to chloroimidazopyrazine 183. Lastly,

15

treatment of 183 with ammonia in isopropanol facilitated a SNAr reaction to furnish acalabrutinib

16

(XIX) in 86% overall yield from 181.

17

Scheme 40. Synthesis of acalabrutinib (XIX)

53



O

Page 54 of 117 O

1. POCl3, 2-aminopyridine, py, rt 2. B2(pin)2, Pd(dppf)Cl2, AcOK, PhCH3, 110 °C

HO

N

N H

OH B OH

3. NaIO4, aq THF, rt, then aq HCl, rt

Br 178

179

O Cl H

N O

180

N

N

N

O

Cl

N H

NH2 181

81% from 178

O N

N N

N O

N

N H

H 2N

86% from 181

N N

rt to 120 °C

183

8.3

2. Et3N, DCM, 30 to 50 °C 3. POCl3, MeCN, 80 to 100 °C

N NH3, i-PrOH

182

1. 182, Et3N, SOCl2, 30 to 40 °C

O

Cl

N H

OH

N N

NH3, 2,4-pentanedione dioxane, H2O, 90 °C

O

N O

N

Acalabrutinib (XIX)

Brigatinib (Alunbri®)

Brigatinib, an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Ariad Pharmaceuticals, a subsidiary of Takeda Pharmaceutical Company, was granted accelerated approval by the USFDA in April 2017 for the treatment of patients with metastatic ALK-positive non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.97 A majority of patients treated with first-generation ALK inhibitors like crizotinib develop disease progression within one to two years post-treatment and acquire resistance.98 Brigatinib has demonstrated in vitro activity against a panel of 17 ALK mutants that confer resistance to first-generation inhibitors, as well as substantial and durable responses in Phase I/II and ALTA clinical trials after progression on crizotinib. Unique to 54


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1

brigatinib’s architecture is its dimethylphosphine oxide moiety, which serves as a hydrogen-bond

2

acceptor designed to drive potency, selectivity, and favorable ADME properties.99

3

Brigatinib was readily synthesized in five steps, with an assembly strategy consisting of a metal-

4

catalyzed reaction to introduce the phosphine oxide functional group and three SNAr reactions.99-100

5

Although reaction yields were not reported, the largest scale route was exemplified in a patent

6

published by Ariad in 2017 and this sequence is depicted in Scheme 41.100e Phosphine oxide 185 was

7

prepared from 2-iodoaniline (184) and dimethylphosphine oxide under modified Hirao conditions

8

employing palladium acetate and Xantphos. Remarkably, this reaction represents one of the few

9

reported examples of P-arylation of aryl halides involving a dialkyl- or diaryl-phosphine oxide in the

10

presence of an unsubstituted aniline.101 Trichloropyrimidine 186 next underwent sequential

11

nucleophilic aromatic substitution reactions, first with aniline 185 to give intermediate 187, and then

12

with aniline 188 (preparation in Scheme 42) to afford brigatinib (XX).

13

Scheme 41. Synthesis of brigatinib (XX)

14 15

Cl

I

N

NH2

NH2

dimethylphosphine oxide K3PO4, Pd(OAc)2, Xantphos DMF, 120 °C

184

Cl

Cl

P O

N

186 N

Cl

P O 187

185

N

N

N

O NH2

H N

N

188 N

Brigatinib (XX)

16

N N

Cl NH

N

2.5 M HCl, EtOH, DME, 20 °C

Cl NH

K2CO3, n-Bu4NHSO4 DMF, 65 °C

O

N

P O

17 55



1 2

Page 56 of 117

Aniline 188 was prepared in two steps via an SNAr displacement of fluoronitroarene 189 with piperidine 190 followed by hydrogenative nitro reduction (Scheme 42). No yields were reported. Scheme 42. Synthesis of brigatinib aniline 188

3

1. O

NH2

N NO2

N

190

N

K2CO3, MeCN, 

F

2. H2, Pd/C, EtOH, rt 189

4

O

NH

N N

188

5 6

8.4

Copanlisib Hydrochloride (Aliqopa®)

7

Copanlisib is an inhibitor of pan-class I phosphoinositide 3-kinase (PI3K) approved by the

8

USFDA for the treatment of adults with relapsed follicular lymphoma who have received at least two

9

prior systemic therapies.102 The drug was developed and launched by Bayer in 2017. It is also currently

10

in Phase III trials for the treatment of relapsed/refractory diffuse large B-cell lymphoma and it is under

11

evaluation in patients with relapsed indolent B-cell non-Hodgkin’s lymphoma in combination with

12

rituximab or rituximab-based chemotherapy or standard immunochemotherapy.103 The drug is

13

administered as an intravenous infusion on a weekly but intermittent schedule (three weeks on and

14

one week off), and is currently approved only in the United States.103

15

Although multiple synthetic approaches to copanlisib have been reported in the patent

16

literature,104 the most likely large scale synthesis of copanlisib follows a linear sequence disclosed in

17

a patent from Bayer and is described in Scheme 43.104a Nitration of 4-formyl-2-methoxyphenyl acetate

18

(191) gave nitroarene 192. Next, saponification of the acetate within 192 followed by acidic pH

19

adjustment and lastly benzylation furnished aldehyde 193, which then underwent condensation with

20

ethylene diamine (194) to arrive at imidazoline 195. Selective nitro reduction of 196 followed by

21

treatment with cyanogen bromide in base secured the key tricyclic core of the drug’s substructure 197. 56


Page 57 of 117 1 1 2 3 2 4 5 6 3 7 8 4 9 10 11 5 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 6 47 48 7 49 50 8 51 52 53 9 54 55 56 10 57 58 11 59 60


Interestingly, the catalytic hydrogenation conditions which reduced the nitro group did not remove the benzyl ether protecting group, presumably necessitating resubjection of 197 to a second hydrogenation to liberate phenol 198. Next, base-mediated alkylation installed the morpholine side chain. This was followed by coupling with acid 201 to ultimately provide copanlisib (XXI) in 96% yield. Scheme 43. Synthesis of copanlisib (XXI) OAc

OAc H

conc. H2SO4

O

H

HNO3, DCM, 0 °C

O

O O

OBn

1. K2CO3, MeOH, 30 °C 2. aq HCl, DCM, < 30 °C

H

3. BnBr, K2CO3, DMF, 30 °C

NO2

O O

NO2

60% for 4 steps 191

192

H 2N

NH2

194

193

OBn

1. DCM, 20 °C

N

2. NBS, 22 °C

OBn H2, Pt/Fe/C, THF

O NH

81% for 2 steps

H2O, 45 °C, 99%

NO2

N

O N

60 °C, 65%

N

. HCl 199

K2CO3, n-BuOH, DMF H2O, 90 °C, 86%

NH2

197

198

N

O O

N

O N

HO

O

NH2

O

N

N O

201

EDCI, DMAP, DMF 20 °C, 96%

NH2

N N

N

HN

O N

NH2 N

O Copanlisib (XXI)

200

8.5

O Cl

N

NH2

N

DCM, 22 °C, 95%

NH2 196

H2, Pd/C, DMF

N

N

NH

OH

O N

Et3N, BrCN

O

195

OBn N

N

Enasidenib (Idhifa®)

Enasidenib is a selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) that was developed by Agios and later licensed to Celgene. The drug was approved by the USFDA for the treatment of patients with relapsed or refractory acute myeloid leukemia with IDH2 mutation.105 IDH2 catalyzes 57



Page 58 of 117

1

the conversion of isocitrate to α-ketoglutarate (α-KG) in the citric acid cycle.105 The mutant enzyme

2

reduces α-KG further to R-2-hydroxyglutarate (2-HG), which leads to hypermethylation of histones

3

and DNA.106 Elevated levels of 2-HG have been used as a biomarker for IDH1 or IDH2 mutated

4

cells.106 Likely due to enasidenib’s high selectivity for mutant IDH2, the drug was well-tolerated in

5

clinical trials and did not exhibit significant off-target cytotoxicity.107

6

The only reported synthesis of enasidenib was described in a 2015 patent application filed by

7

Agios which involves a linear seven-step process to construct the API (no yields were reported for any

8

of the transformations in this disclosure).108 Although it is possible that this route could have been one

9

of the first-generation approaches to the drug, the procedure avoids the use of protecting groups. 2-

10

(Trifluoromethyl)pyridine 202 (Scheme 44) underwent metalation with n-BuLi followed by carbon

11

dioxide quench to prepare the carboxylic acid intermediate, which was converted to methyl ester 203

12

using acetyl chloride in methanol. Next, triazine dione 205 was formed by condensation of 203 with

13

carbamyl urea 204 in the presence of sodium ethoxide in ethanol. This reaction was followed by

14

chlorination using phosphorous pentachloride and phosphorous oxychloride to generate 206.

15

Dichlorotriazine 206 underwent two sequential SNAr reactions, first with aminopyridine 207, and then

16

with ethanolamine 209 to access enasidenib 210 as the free base. Subjection of this compound to

17

methanesulfonic acid in acetone yielded enasidenib mesylate (XXII).

18

Scheme 44. Synthesis of enasidenib (XXII)

19

58


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F3C

1. n-BuLi then CO2(g) Et2O, hexanes -65 to 5 °C

N

O

O N

F3C

H 2N

OMe

2. AcCl, MeOH 65 to 70 °C

HN N

F3C

203

N P2Cl5, POCl3

F3C

N

N

H 2N Cl

206

209

NaHCO3, THF 75 to 80 °C

N F3C

N

CF3

N F3C

N

N N

O

N N H

CF3

208

OH

HN N

N H

N N

OH

HN

OH

207

NaHCO3, THF 75 to 80 °C

105 to 110 °C

N

Cl

N N

NH

205

Cl

acetone CF3

MsOH, 0 °C

210

1

N H

O

204 NH2

Na, EtOH, 75 to 80 °C

202

H 2N

O

N F3C

N

N N

N N H

CF3 MsOH

Enasidenib (XXII)

2 3

8.6

Inotuzumab Ozogamicin (Besponsa®)

4

Inotuzumab ozogamicin is an antibody drug conjugate (ADC) approved by the USFDA for the

5

treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia

6

(ALL).109 Inotuzumab ozogamicin consists of a conjugate of an anti-CD22 monoclonal antibody with

7

the potent DNA double strand cleaving payload, N-acetyl--calicheamicin.110 The payload is linked

8

through lysines on the antibody using a hydrolytically cleavable linker that releases the payload in the

9

acidic environment of the lysosome after internalization of the ADC. There are approximately 6

10

payload molecules/antibody. Inotuzumab ozogamicin was discovered in the Lederle laboratories of

11

American Cyanamid. After the merger between American Cyanamid and American Home Products

12

the combined company was eventually renamed Wyeth. In 2009, Wyeth was acquired by Pfizer where

13

the development and launch of inotuzumab ozogamicin was completed. Pfizer also completed the re-

14

launch of Mylotag™ (gemtuzumab ozogamicin)—an ADC that incorporates the same calicheamicin 59



Page 60 of 117

based linker-payload conjugated to an anti-CD33 antibody and is approved to treat a certain type of acute myeloid leukemia (AML).111 The synthesis of the linker of inotuzumab ozogamicin began with the 1,4-addition of (4methoxyphenyl)methanethiol (211) to methyl 3-methylbut-2-enoate (212) followed by basic hydrolysis of the resulting ester to give thioether 213 in 89% yield (Scheme 45).112 Activation of the acid with 1,1’-carbonyldiimidazole (CDI) followed by treatment with hydrazine monohydrate gave hydrazide 214 in 97% yield. Condensation of hydrazide 214 and ketone 215 using acetic acid provided hydrazone 216, which was treated with trifluoroacetic acid and anisole to give thiol 217 in 94% yield. The mixed anhydride of the carboxylic acid group of 217 was generated by treatment with pivaloyl chloride and triethyl amine and the resulting anhydride was reacted with N-hydroxysuccinimide (NHS) to give the NHS ester 218 in 92% yield. Scheme 45.

Synthesis of the inotuzumab ozogamicin linker fragment 218

60


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Journal of Medicinal Chemistry 1. Bu4NF, 2-MeTHF CO2Me 212

SH

2. aq NaOH, then HCl

MeO

2. H2NNH2•H2O

N H

NH2

215, HOAc

N H

S MeO

214

65 to 70 °C, 94%

N H

HS

CO2H

N

O

O HS

1

N H

1. PivCl, Et3N, THF 92% for 2 steps

O O

O

N O

N

N

2. N-hydroxysuccinimide 217

O

CO2H

216

O

O

TFA, anisole

O

O MeOH

MeO

97% for 2 steps

213

O S

1. CDI, THF

MeO

89% for 2 steps

211

CO2H

S

O

CO2H 215

218

2

The completion of the synthesis of inotuzumab ozogamicin is described in Scheme 46.

3

Calicheamicin (219) was obtained from the fermentation of micromonospora echinospora ssp.

4

calichenis113 and was aceylated to give N-acetyl-calicheamicin 220 in 80% yield.114 The linker 218

5

was coupled to 220 in the presence of EDCI and triethylamine to give the disulfide containing linker-

6

payload 221 in 60% yield.112 The linker-payload was conjugated to the anti-CD22 mAb G-544 using

7

the conditions described in Scheme 46 to give inotuzumab ozogamicin (XXIII) in 60% yield based

8

on the amount of protein with approximately 6 linker/payloads per antibody.115

9

Scheme 46.

Synthesis of inotuzumab ozogamicin (XXIII)

61



HO Me O I O Me HO MeO

Me

S

O Me HN O HO O O

OMe OH OMe

O

O NHCOOMe

S S

O

S

Page 62 of 117

Ac2O, MeOH, 0 °C to rt O H

80%

EtHN MeO

OH

219 HO Me O I O Me HO MeO

Me S

S S S O Me HN O HO O Et O N MeO

O

OMe OH OMe

O

Me

OH

O

O NHCOOMe

218, EDCI, Et3N MeCN, 60%

O H

220 O N

O O

O

Me O Me Me

O Me O I O Me HO MeO

O

Me S

N O

OMe OH OMe Me

OH

O


HO

G-544 (anti-CD22 mAb)

O NHCOOMe

PBS, propylene glycol, 1 M NaOH 1 M caprylic acid, pH 7.4 >60% protein yield, ~6 drugs/mAb

O H

221

O G-544 (anti-CD22)

O

N H

Me O Me Me Me O

I O Me HO MeO

O

Me S

N O

OMe OH OMe Me

OH

O


HO

O NHCOOMe

O H

~6

Inotuzumab Ozogamicin (XXIII)

1 2 3

8.7

Midostaurin (Rydapt®)

4

Midostaurin is a natural product-based multi-targeted kinase inhibitor approved in 2017 for the

5

treatment of FMS-like tyrosine kinase 3 (FLT3) mutation-positive Acute Myeloid Leukemia 62


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1

(AML).116 The approval includes use as a combination therapy with standard chemotherapy treatments

2

such as daunorubicin and cytarabine.116 Midostaurin represents the first multi-kinase inhibitor therapy

3

approved for FTL3-mutant AML.117 Although originally studied as an inhibitor of protein kinase C,

4

in 2001 midostaurin became the topic of collaborations between Novartis and the Dana-Farber Cancer

5

Institute to identify inhibitors of mutant FLT3-positive AML.116b In clinical trials, combination therapy

6

of midostaurin with chemotherapy resulted in 80% complete response amongst patients and led to

7

significantly increased survival time versus placebo.118 The activity of midostaurin against AML relies

8

on a reversible binding event with a variety of kinases, including stem cell factor receptors (c-KIT)

9

and mutated and wild-type FLT3 kinases, overall resulting in inhibition of cell signaling pathways and

10

leading to diminished cell growth and apoptosis.118

11

While the drug was approved as a combination therapy for FLT3-positive AML, midostaurin was

12

also approved as a monotherapy for more rare blood disorders such as Aggressive Systemic

13

Mastocytosis (ASM), Systemic Mastocytosis with associated hematological neoplasm (SM-AHN),

14

and Mast Cell Leukemia (MCL).116, 118

15

Midostaurin was generated via semi-synthesis119 from the natural product staurosporine,120 which

16

can be produced via a variety of fermentation processes.121 Acylation of staurosporine 222 (Scheme

17

47) with benzoic anhydride (223) provided midostaurin (XXIV) in 82% yield.122

18

Scheme 47. Synthesis of midostaurin (XXIV) from staurosporine (222)

63



Page 64 of 117 H N

H N

O

O

O

O O

N

O

N

223

N H

EtOH, H2O, 60 °C, 82%

O

O O

O

N H

N

HN 222 Midostaurin (XXIV)

1 2 3

8.8

Neratinib (Zykadia®)

4

Neratinib was approved by the USFDA in 2017 for the extended adjuvant treatment of HER2-

5

positive breast cancer following adjuvant treatment with trastuzumab, a humanized HER2 monoclonal

6

antibody, based upon a statistically significant impact on invasive disease free survival.123 Discovered

7

by Wyeth and currently marketed by Puma Biotechnology, Inc., neratinib is an irreversible inhibitor

8

of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)

9

kinases, the latter being overexpressed in 20-25% of breast cancer patients.124 An interesting feature

10

of the neratibib structure involves the terminal dimethylamino functionality in proximity to a 2-

11

butenoyl group. By design, the terminal amine functions as a base to deprotonate a nucleophilic active-

12

site cysteine residue (Cys773 (EGFR) and Cys805 (HER2)), thereby catalyzing a 1,4-addition to the

13

2-butenoyl group resulting in covalent linkage between the inhibitor and the kinase.

14

Three patents were published by Wyeth detailing the process-scale approach to the drug—two

15

focusing on various routes to neratinib125 and one emphasizing methods to introduce the 4-

16

dimethylamino-2-butenoyl side chain.126 Starting with aniline 224, an addition-elimination reaction

17

with ethyl 2-cyano-3-ethoxyacrylate (225) in warm toluene afforded vinylogous amide 226 in high

18

yield (Scheme 48). Subsequent heating of 226 at elevated temperature (approx. 250 C) led to a 64


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1

cyclization reaction providing quinolone 227 in modest efficiency (42% yield). Treatment of 227 with

2

POCl3 at reflux converted the hydroxyl group to the corresponding chloride 228, thereby completing

3

the synthesis of the cyanoquinoline core. The anilino-sidechain 229 (which is synthesized as described

4

in Scheme 49) was introduced via SNAr reaction with 228. As scale increased for this transformation,

5

catalytic methanesulfonic acid was found to be important for optimal yields of 230. Intermediate 230

6

was carried directly into the acetyl hydrolysis step (2.7 N HCl in water, reflux) and subsequent

7

neutralization (K2CO3, MeOH) to afford 231 in 86% conversion from 228. Lastly, introduction of the

8

4-dimethylamino-2-butenoyl side chain required significant optimization due to stability issues of the

9

acid chloride on scale. One method that proved highly effective involved conversion of the commercial

10

acid 232 to the acid chloride-HCl salt 233 with oxalyl chloride and catalytic DMF. The selection of

11

isopropyl acetate as solvent was critical in promoting precipitation of 233 as an isolable solid. Addition

12

of aniline 231 to acid chloride 233 in chilled NMP afforded neratinib in improved yield (85-98% vs.

13

60-75%) and purity (96-98% vs. 85-90%) when compared to using a solvent such as THF. Dissolving

14

neratinib and malic acid (1:1) in n-propanol/water (9:1) with heating provided neratinib maleate (XXV)

15

following isolation.

16

Scheme 48.

Synthesis of neratinib maleate (XXV)

65



EtO

O

EtO

HN EtO

O

O CN

225

PhCH3, 90 °C 90%

NH2

Page 66 of 117

O

HN

NC

EtO

N H

224

CO2Et

Dowtherm 250 °C 42%

EtO

HN

CN

EtO

O

229, cat. MsOH

HN

N 1. 2.7 N HCl, H2O, 

Cl

HN

EtOH, 70 to 75 °C

N

100 °C 65%

N 227

O Cl

POCl3 diglyme

CN

226

O

OH

HN

CN

EtO

2. K2CO3, MeOH 86% for 3 steps

N

228

230

O

Me2N O HN

N

O

232; X = OH 233; X = Cl (HCl salt)

(COCl)2, DMF i-PrOAc, 15 °C

Cl

H 2N

NMe2

X

CN

O

HN

HN

N

Cl CN

233, NMP, 0 °C, 85% EtO

N

EtO

N

231

Neratinib

NMe2 O O

malic acid n-PrOH/H2O (9:1) 40 to 50 °C, 88%

HN

HN

Cl

COOH

CN

EtO

COOH

N

Neratinib maleate (XXV)

1 2

N

Side chain 229 arose from exposure of fluoroarene 234 to 2-pyridyl methanol (235) with flake

3

KOH in acetonitrile followed by platinum-mediated hydrogenation (Scheme 49). 229 was carried

4

forward as a solution. Scheme 49.

5 Cl

HO F

234

Cl

N

KOH, MeCN 35 to 40 °C, 93%

O 2N

6

235

Synthesis of neratinib anilino sidechain 229 Cl O

N

THF 25 to 30 °C

O 2N

O

Pt/C, H2

236

N

H 2N 229

7 66


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1


8.9

Niraparib (Zejula®)

2

Niraparib was approved by the USFDA in March 2017 for the maintenance treatment of adult

3

patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a

4

complete or partial response to platinum-based chemotherapy.127 Niraparib is an oral poly (ADP-

5

ribose) polymerase (PARP)-1 and PARP-2 inhibitor discovered by Merck and developed by Tesaro,

6

and is the first approved PARP inhibitor that does not require BRCA or other biomarker testing.

7

PARP-1 and PARP-2 play a role in DNA repair, with inhibition resulting in DNA damage, apoptosis,

8

and cell death.128

9

Researchers from Merck have published several approaches to niraparib.129 The route in Schemes

10

50 and 51—while not the largest scale reported in the patent literature—is potentially the most scalable,

11

relying upon a late stage C-N bond coupling between aryl bromide 244 and indazole 246, along with

12

a key transaminase-mediated asymmetric synthesis of the piperidine substructure within 244.129b An

13

earlier, fit-for-purpose process chemistry route, which was reportedly used to provide kilogram-scale

14

material to support early development work, was deemed unsuitable for further development due to

15

the use of chiral chromatography and azide-containing reagents.129c Details associated with the

16

asymmetric transaminase reaction to establish chirality within piperidine 244 along with the merits

17

and challenges of various routes to niraparib (as well as other PARP inhibitors) have been nicely

18

reviewed by Hughes.129d

19

Bearing a challenging chiral center at the 3-position, piperidine 244 was prepared asymmetrically

20

in nine steps and an impressive 44% overall yield (Scheme 50).129b, 129d, 129g, 129h Solvent-free Friedel-

21

Crafts acylation of bromobenzene (237) with succinic anhydride (238) and subsequent esterification

22

afforded isopropyl ester 239. The choice of the isopropyl group proved important as the corresponding

23

methyl and ethyl esters were prone to hydrolysis during the transaminase step. One-carbon 67



Page 68 of 117

homologation was next affected by an epoxidation/rearrangement sequence involving the subjection of 239 to Me3SOI followed by ZnBr2 that gave aldehyde 240 as a solution in toluene. As this aldehyde was unstable and not crystalline, it was converted to bisulfite adduct 241, which could be partitioned into the aqueous layer and was used directly without isolation. Optimized conditions for the transaminase reaction were found to employ enzyme ATA-302, pyridoxal-5-phosphate (PLP, 242) as co-catalyst, and isopropylamine as an amine donor at pH 10.5 in aqueous DMSO. After filtration and solvent switch to isopropyl acetate, -arylvalerolactam 243 was crystallized in 84% yield. Reduction of the carboxyl group (NaBH4, BF3.THF) followed by Boc N-protection afforded coupling partner 244. Scheme 50.

Synthesis of niraparib piperidinyl aryl bromide 244

1. AlCl3, 5 °C to rt O O O 238 Br

2. conc. H2SO4 i-PrOH, 

237

O 1. Me3SOI, KOt-Bu DMSO, THF, rt Br

CO2i-Pr 239

86% for 2 steps

CHO

O

HO

NaHSO3 H2O, rt

Br

CO2i-Pr

68% for 3 steps

Br

240

O

ATA-302 enzyme 242, i-PrNH2

ONa

pH 10.5 buffer DMSO, 45 °C, 84%

CO2i-Pr

1. NaBH4, BF3•THF THF, 0 °C to rt 2. TsOH•H2O, i-PrOH 50 °C to rt 3. Boc2O, aq NaOH MTBE, 100 °C

243

S O

241

H N

Br

2. ZnBr2, PhCH3, rt

92% for 3 steps

O P O OH OH O

Boc N N OH

Br

242 (PLP) 244

68


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1

Aryl bromide 244 was then coupled to indazole 246, which was synthesized from indazole-7-

2

carboxylic acid (245) by amidation with t-butylamine (Scheme 51). The C-N coupling of 244 and 246

3

was the focus of extensive optimization. The conditions ultimately identified (CuBr, K2CO3, DMA,

4

8-hydroxyquinoline at 110 ºC) afforded product 247 in 94% yield. The t-butyl amide within 246 was

5

designed to influence regiochemical N-arylation at the desired N-2 position, and indeed excellent

6

selectivity over the undesired N-1 counterpart (99% ee). After considerable optimization, carboxylic acid 285 was then carefully converted to

7

isoquinoline amide 288 through unusual conditions involving 6-aminoisoquinoline (286), collidine,

8

and 2,2,2-trichloro-1,1-dimethylethylchloroformate (287). The authors claim that the use of dimethyl

9

chloroformate 287 in this reaction is the first report of its use as an amide coupling reagent (although

10

other chloroformates have been utilized as coupling reagents). In this case, 287 was particularly

11

effective at minimizing epimerization of the -carboxylate stereocenter relative to other reagents and

12

other chloroformates.146b The final dimesylate salt of the drug substance was generated upon the

13

removal of the Boc group in 288 using methanesulfonic acid at ambient temperature. The final product

14

netarsudil (XXXI) was purified by recrystallization from isopropanol and heptane.

15

Scheme 59. Synthesis of netarsudil (XXXI)

16

79



Page 80 of 117

NHBoc N

O

N N

O

N

O 283

Bn

LiHMDS, THF

O

-70 to -30 °C 68%, 96:4 d. r.

O

O

282

O

N

BocHN

O

O

O Bn

aq LiOH, H2O2

O

THF, H2O 90%, > 99% ee

BocHN

O

O 285

284

O N

O O

286

O

NH2 Cl

O

OH

CCl3

O

1. MsOH, DCM, rt 287

H N

BocHN O

2. i-PrOH, heptane N

90% for 2 steps

2 MsOH H N

H 2N O

N

collidine, DMF, 0 °C, 60% 288

1

Netarsudil (XXXI)

2 3

10. Conclusion

4

In summary, the industry at large enjoyed a productive year during 2017 as evidenced by the

5

substantial number of small molecules comprising the overall total: 46 new drugs were approved by

6

the USFDA in 2017 including antibodies and other modalities. Noteworthy contributions this year

7

include the first-ever approved deuterated compound, a chiral alkyl boronate, a dozen oncology

8

medicines (including the fourth antibody drug conjugate), and two separate nitroimidazole prodrugs.

9

Structural complexity continued to increase—highly functionalized macrocycles, asymmetric centers,

10

and complex heterocyclic systems can be found in many of the structures of these important new

11

medicines—and we can expect that trend to persist within future approvals. The development of

12

innovative and creative chemistry was certainly required not only to deliver these 31 medicines on

13

scale, but ostensibly during the initial discovery stages as well. As opportunities for new targets,

14

medicines, and modalities continue to increase, so will the synthetic obstacles facing organic chemists

80


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1

become more challenging and complex, prompting the continuing demand for development of

2

innovative and efficient synthetic technologies.

3 4

ABBREVIATIONS

5

Ac = Acetyl

6

Ad = Adamantyl

7

AIBN = 2,2’-azobisisobutyronitrile

8

aq = Aqueous

9

BINAP = 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene

10

Bn = Benzyl

11

Boc = N-tert-Butoxycarbonyl

12

Bu, n-Bu = Butyl, n-butyl

13

cat = Catalytic

14

Cbz = Benzyloxycarbonyl

15

CDI = N,N'-Carbonyldiimidazole

16

CDMT = 2-Chloro-4,6-dimethoxy-1,3,5-triazine

17

conc = Concentrated

18

CPME = Cyclopentyl methyl ether

19

CSA = Camphorsulfonic Acid

20

Cy = Cyclohexyl

21

dba = Dibenzylideneacetone

22

DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene

23

DCC = 1,3-Dicyclohexylcarbodiimide 81



1

DCE = Dichloroethane

2

DCM = Dichloromethane

3

DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

4

DIPEA = Diisopropylethylamine

5

DMA = Dimethylacetamide

6

DMAP = 4-Dimethylaminopyridine

7

DME = 1,2-Dimethoxyethane

8

DMF = N,N-Dimethylformamide

9

DMF-DMA = Dimethylformamide – dimethylacetal

10

DMPA = Dimethylolpropionic acid

11

DMPU = 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

12

DMSO = Dimethyl sulfoxide

13

DPPA = Diphenyl phosphoryl azide

14

dppb = 1,4-Bis(diphenylphosphino)butane

15

dppf = 1,1’-Ferrocenediyl-bis(diphenylphosphine)

16

dr = Diastereomeric ratio

17

EDCI = N-(3-Dimethylaminopropal)-N-ethylcarbodiimide

18

EDTA = Ethylenediaminetetraacetic acid

19

ee = Enantiomeric excess

20

Et = Ethyl

21

EtOAc = Ethyl acetate

22

HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid

23

Page 82 of 117

hexafluorophosphate 82


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1

HBTU = (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

2

Hex, n-Hex = Hexyl

3

HMDS = Hexamethyldisilazane

4

HOBt = 1-Hydroxybenzotriazole hydrate

5

HWE = Horner-Wadsworth-Emmons

6

i-Pr = Isopropyl

7

L-PGA = L-Pyroglutamic acid

8

LAH = Lithium aluminum hydride

9

LDA = Lithium diisopropylamide

10

Me = Methyl

11

MeCN = Acetonitrile

12

MEK = Methyl ethyl ketone

13

Moc = Methoxycarbonyl

14

Ms = Methylsulfonyl, mesyl

15

MTBE = Methyl tert-butyl ether

16

n-Pr = n-Propyl

17

NBS= N-Bromosuccinimide

18

NMM = N-Methyl morpholine

19

NMO = N-Methyl morpholine-N-oxide

20

NMP = N-Methyl-2-pyrrolidone

21

PBS = Phosphate-buffered saline

22

Ph = Phenyl

23

PhCH3 = toluene 83



1

Pin = Pinacolato

2

Piv = Pivaloyl

3

PLP = Pyridoxal-5-phosphate

4

p-TsOH = p-Toluenesulfonic acid

5

py = Pyridine

6

rac = Racemic

7

rt = Room temperature

8

SEM = 2-(Trimethylsilyl)ethoxymethyl

9

TBAB = Tetrabutylammonium bromide

10

TBAF = Tetrabutylammonium fluoride

11

TBAH = Tetrabutylammonium hydroxide

12

TBAI = Tetrabutylammonium iodide

13

TBS = t-Butyldimethylsilyl

14

TBTU = O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyluronium tetrafluoroborate

15

t-Bu = tert-Butyl

16

TEA = Triethylamine

17

TES = Triethylsilane

18

TEMPO = 2,2,6,6-Tetramethylpiperidine 1-oxyl

19

Tf = Triflic, trifluoromethanesulfonyl

20

TFA = Trifluoroacetic acid

21

TFAA = Trifluoroacetic acid anhydride

22

THF = Tetrahydrofuran

23

THP = Tetrahydropyranyl

Page 84 of 117

84


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1

TMEDA = N,N,N’,N’-Tetramethylethylenediamine

2

TMS = Trimethylsilyl

3

TPAP = Tetrapropylammonium perruthenate

4

Tr = Trityl, triphenylmethyl

5

Ts = p-Toluenesulfonyl

6

UHP = Urea hydrogen peroxide

7

Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

8 9

Author Information

10

Corresponding Author

11

*Phone:

12

ORCID

13

Christopher J. O’Donnell:

14

Notes

15

The Authors declare no competing financial interest.

16

Biographies

17

Andrew C. Flick earned a B. A. in Chemistry from Lake Forest College. After brief appointments

18

at Abbott Laboratories and Array BioPharma, he joined Professor Albert Padwa’s laboratory at Emory

19

University. After obtaining his Ph.D. in organic chemistry in 2008, he joined Pfizer where he was

20

involved with numerous medicinal chemistry projects within the Neurosciences, Rare Diseases, and

21

Inflammation & Immunology therapeutic areas. As a team leader, his contributions led to the

22

discovery of the transcription factor inhibitor PF-06763809 which is currently undergoing Phase I

860-405-4976.

Email:

[email protected]

0000-0003-1004-7139

85



Page 86 of 117

1

trials for the treatment of psoriasis. Andy has recently joined Seattle Genetics’ Chemistry Research

2

group, and has authored over 40 peer-reviewed publications and patents.

3 4

Carolyn Leverett began her career at Pfizer in 2012, focusing on the development of microtubule

5

inhibitor-based payloads for use as antibody-drug conjugates. She currently works in the Discovery

6

Sciences research group, exploring the use of protein degrader-based therapies for treating a variety

7

of disease areas. Carolyn is a native of North Carolina and obtained her B.S. in chemistry from North

8

Carolina State University. She completed her doctoral studies with Professor Albert Padwa at Emory

9

University in Atlanta, GA, working on total synthesis of several piperidine-based natural products and

10

the alkaloid minfiensine. Prior to joining Pfizer she was a post-doctoral fellow working with Professor

11

Daniel Romo at Texas A&M University, exploring new applications of nucleophile-catalyzed aldol

12

lactonization reactions.

13 14

Hongxia (Sheryl) Ding obtained a B.S. in Pharmaceutics in 2001 and a Ph.D. in Medicinal

15

Chemistry in 2006 from Zhejiang University in Hangzhou, China. Hongxia is the co-founder and Chief

16

Executive Officer of PHARMACODIA, a company founded in 2013, which is an online platform

17

(http://www.pharmacodia.com) providing big data and information service in pharmaceutical R&D

18

field. In 2010-2013, Hongxia joined Shenogen Pharma Group, a China-based Biotech company. As

19

senior director of R&D department, Hongxia is responsible for the CMC development of a novel ER-

20

36 targeted Phase II candidates drugs, named Icaritin (SNG162) and the discovery and development

21

of second-generation small molecular based on the structure optimization of SNG162. Before

22

Shenogen, Hongxia worked in BioDuro since 2006, as senior group leader and senior research scientist.

23 86


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1

Emma McInturff obtained a B.S. in chemistry from Boise State University and a Ph.D. from the

2

University of Texas at Austin, working in the laboratory of Professor Mike Krische on ruthenium

3

catalyzed carbonyl addition methodology development. She joined Pfizer process chemistry in Groton,

4

CT in 2014.

5 6

Sarah Fink is a Senior Manager for Integrated Programs at BioDuro and is based in the Boston

7

area. She obtained a B.A. in Chemistry and English literature from Williams College, followed by a

8

Ph.D. in Organic Chemistry from the University of Cambridge with Professor Ian Paterson. Her thesis

9

work focused on the total synthesis of aplyronine C. After a fellowship for young international

10

scientists at Shanghai Institute of Materia Medica, Sarah joined BioDuro in Shanghai in 2014, where

11

she was a scientist and chemistry group leader for integrated drug discovery projects in multiple

12

therapeutic areas. She relocated to Boston in early 2017; in her current role, she provides medicinal

13

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

14 15

Christopher J. Helal received his B.S. in chemistry at the Ohio State University in 1991 and

16

carried out his doctoral studies at Harvard University with Professor Elias J. Corey. He joined Pfizer

17

in 1997 in Groton, CT, working in neuroscience medicinal chemistry. He currently is Senior Director

18

of Medicinal Chemistry, supporting the metabolic disease research area and leading an enabling

19

technologies team that includes biocatalysis, flow chemistry, single-electron chemistry, reaction

20

optimization, and parallel synthesis.

21 22

Christopher J. O’Donnell obtained a B.S. in Chemistry from the University of Illinois in

23

Urbana/Champaign and a Ph.D. in Organic Chemistry from the University of Wisconsin, Madison. 87



Page 88 of 117

After postdoctoral research at the University of California-Irvine, he joined Pfizer’s Neuroscience Medicinal Chemistry group in 1999. 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 eleven 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 peer-reviewed journal articles and patent applications.

88


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Latanoprostene Bunod, a Dual-Acting Nitric Oxide Donating Prostaglandin Analog for Lowering of

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Nitrooxy Derivatives for the Treatment of Glaucoma. WO 2005068421, 2005. (b) Vittitow, J. L.;

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Cavet, M. E. Nitric Oxide Releasing Prostaglandin Derivatives for Treating Normal Tension

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Glaucoma. WO 2018087092, 2018.

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Table of Contents Graphic OBn O BnO

OH OBn

OBn

O

• (CO2H)2

O OBn O

HO

N OBn OBn OBn

NMe

O

OEt

O

HO

Cl OH

O

HN HO2C

OH Ertugliflozin - L-Pyroglutamic acid XV

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Plus the 30 other New Drugs marketed in 2017

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Synthetic Approaches to the New Drugs Approved ... - ACS Publications

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