Synthetic Approaches To The New Drugs 2012

This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.. Administered by inh

Synthetic approaches to the 2012 new drugs

Hong X Dinga, , Carolyn A Leverettb,à, Robert E Kyne Jr.b,§, Kevin K.-C Liuc,–, Subas M Sakyad,k,

Andrew C Flickb,  , Christopher J O’Donnellb,⇑

a PharmaPhase Co., Ltd, Beijing 100193, China

b

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

c

Lilly China Research and Development Center, Shanghai 201203, China

d

BioDuro Co., Ltd, Shanghai 200131, China

a r t i c l e i n f o

Article history:

Received 27 December 2013

Revised 11 February 2014

Accepted 13 February 2014

Available online 25 February 2014

Keywords:

Synthesis

New drug molecules

New chemical entities

Medicine

Therapeutic agents

a b s t r a c t

New drugs introduced to the market every year represent a privileged structure for a particular biological target These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011

Ó 2014 Elsevier Ltd All rights reserved

Contents

1 Introduction 2006

2 Aclidinium bromide (Tudorza PressairÒ, Eklira GenuairÒ, Bretaris GenuaiÒ) 2006

3 Allisartan isoproxil 2006

4 Anagliptin (BeskoaÒ, SuinyÒ) 2006

5 Axitinib (InlytaÒ) 2009

6 Azilsartan (AzilvaÒ) 2010

7 Bedaquiline fumarate (SirturoÒ) 2012

http://dx.doi.org/10.1016/j.bmc.2014.02.017

0968-0896/Ó 2014 Elsevier Ltd All rights reserved.

Abbreviations: 1,2-DAP, 1,2-diaminopropane; 1,2-DCE, 1,2-dichloroethane; Ac, acetyl; aq, aqueous; B 2 (pin) 2 , bis(pinacolato)diboron; BINAP, 2,2 0 -bis(diphenylphosphino)-1,1 0 -binaphthyl; BOP, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophospate; CDI, N,N 0 -carbonyldiimidazole; DAP, diaminopropane; DBU, 1,5-diazabi-cycolo[4.3.0]non-5-ene; DCC, 1,3-dicyclohexylcarbodiimide; DCM, dichloromethane; DIC, 1,3-diisopropylcarbodiimide; DIEA/DIPEA, diisopropylethylamine; DMA, dimeth-ylacetamide; DMAP, 4-dimethylaminopyridine; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; EDC, N-(3-dimethylaminopropal)-N 0 -ethylcarbodiimide; Fmoc, 9-fluorenylmethoxycarbonyl; HBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HOBT, 1-hydroxybenzotriazole hydrate; IPAc, isopropyl acetate; LAH, lithium aluminum hydride; LHMDS, lithium bis(trimethylsilyl)amide; LDA, lithium diisopropylamide; MEK, methyl ethyl ketone; MIBK, 4-methyl-2-pentanone; NBS, N-bromosuccinimide; NMM, N-methylmorpholine; NMP, N-methyl-2-pyrrolidone; Pd 2 (dba) 3 , tris(dibenzyl-ideneacetone)dipalladium(0); Pd(dppf)Cl 2 , [1,1 0 -bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh 3 ) 4 , tetrakis(triphenylphosphine)palladium(0); pin, pinacol;

Py, pyridine; RT, room temperature; STAB-H, sodium triacetoxyborohydride; TBAF, t-butyl ammonium fluoride; TFA, trifluoroacetic acid; THF, tetrahydrofuran; TMSCl, trimethylsilyl chloride; XantPhos, 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.

⇑ Corresponding author Tel.: +1 860 715 4118.

E-mail addresses: Hongxia.ding@gmail.com (H.X Ding), carolyn.a.leverett@pfizer.com (C.A Leverett), robert.kynejr@pfizer.com (R.E Kyne), Liu_kang_zhi_kevin@lilly.com

(K.K.-C Liu), subas.sakya@bioduro.com (S.M Sakya), andrew.flick@pfizer.com (A.C Flick), christopher.j.odonnell@pfizer.com (C.J O’Donnell).

  Tel.: +86 10 8484 8357.

à Tel.: +1 860 441 3936.

§

Tel.: +1 860 441 1510.

–

Tel.: +86 21 2080 5590.

k Tel.: +86 38139788x3904.

   Tel.: +1 860 715 0228.

Contents lists available atScienceDirect

Bioorganic & Medicinal Chemistry

j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / b m c

8 Bosutinib hydrate (BosulifÒ) 2013

9 Cabozantinib (S)-malate (CometriqÒ) 2015

10 Carfilzomib (KyprolisÒ) 2015

11 Dapagliflozin propanediol hydrate (ForxigaÒ, EmplicitiÒ, EdistrideÒ, AppebbÒ) 2016

12 Enzalutamide (XtandiÒ) 2016

13 Iguratimod (CareramÒ, IremodÒ) 2017

14 Imrecoxib (HengyangÒ) 2019

15 Ingenol mebutate (PicatoÒ) 2020

16 Ivacaftor (KalydecoÒ) 2021

17 Lorcaserin hydrochloride hydrate (BelviqÒ) 2021

18 Omacetaxine mepesuccinate (SynriboÒ) 2022

19 Pasireotide (SigniforÒ) 2022

20 Perampanel hydrate (FycompaÒ) 2024

21 Pixantrone dimaleate (PixuvriÒ) 2024

22 Ponatinib hydrochloride (IclusigÒ) 2025

23 Radotinib hydrochloride (SupectÒ) 2026

24 Regorafenib hydrate (StivargaÒ) 2026

25 Tafamidis meglumine (VyndaqelÒ) 2027

26 Teneligliptin hydrobromide hydrate (TeneliaÒ) 2028

27 Teriflunomide (AubagioÒ) 2028

28 Tofacitinib citrate (XeljanzÒ) 2029

29 Vismodegib (ErivedgeÒ) 2029

References and notes 2029

1 Introduction

‘The most fruitful basis for the discovery of a new drug is to start

with an old drug.’ – Sir James Whyte Black, winner of the 1988

No-bel Prize in medicine.1

This annual review was inaugurated eleven years ago2–11and

presents synthetic methods for molecular entities that were

launched in various countries during the past year Given that

drugs tend to have structural homology across similar biological

targets, it is widely believed that the knowledge of new chemical

entities and their syntheses will greatly enhance the ability to

de-sign new drugs in shorter periods of time The pharmaceutical

industry enjoyed a banner year in 2012, with a total of 36 new

products, including new chemical entities, biological drugs and

diagnostic agents having reached the worldwide market for the

first time Although an additional 22 new products were approved

for the first time in 2012, these were not launched before year

end,12

and therefore this review focuses on the syntheses of 26

drugs that were launched or approved in 2012 and two additional

drugs that was launched at the end of 2011 (Fig 1) New

indica-tions for previously launched medicaindica-tions, new combinaindica-tions,

new formulations of existing drugs, and drugs synthesized purely

via bio-processes or peptide synthesizers have been excluded from

this review Although the scale of the synthetic routes were not

explicitly disclosed in most cases, this review covers, perceptibly,

the most scalable routes based on published or patent literature

Drugs are covered in alphabetical order by the drug’s generic name

2 Aclidinium bromide (Tudorza PressairÒ, Eklira GenuairÒ,

Bretaris GenuaiÒ)

Aclidinium bromide was approved by the U.S Food and Drug

Administration (FDA) in July 2012 for the treatment of chronic

obstructive pulmonary disease (COPD).13Marketed by Forest

Phar-maceuticals, aclidinium bromide selectively binds to five human

muscarinic receptors (M1–M5), and posesses a subnanomolar

bind-ing affinity for these particular targets Administered by inhalation,

this medicine has demonstrated favorable onset and duration of

action, and its safety profile is an improvement over competitor

therapies.14While no manufacturing route has been disclosed to

date,15 the most scalable published synthesis is described in

Scheme 1.16Dimethyl oxalate (1) was initially treated with two equivalents of Grignard 2 to give bis-thiophenoate 3 in 36% yield Subsequent transesterification with (R)-quinuclidinol (4) gave rise

to the quinuclidine-containing ester 5 in 50% yield Aclidinium mide (I) could be accessed by two different methods involving bro-moalkyl phenyl ether 6: an excess of bromide in the presence of an acetonitrile/chloroform mixture gave the drug in 89% isolated yield, or with fewer equivalents of electrophile (1.25 equiv) during exposure to refluxing acetophenone, has reportedly delivered (I) quantitatively on multi-gram scale.17 From commercial 2,18 the multi-gram synthesis of Aclidinium bromide (I) was completed

in 17.8% over three steps

3 Allisartan isoproxil Allisartan isoproxil, a member of a new class of selective angio-tensin II-1 receptor antagonists, was approved by the Chinese Food and Drug Administration (CFDA) for the treatment of hypertension

in July 2012.19At time of publication, there is no trade name asso-ciated with this drug Allisartan was discovered and developed by the Chinese biomedical company Allist Pharmaceuticals Allisartan isoproxil is a prodrug which is readily hydrolyzed to active metabolite EXP3174, which is also the active metabolite of losartan (des-triphenylmethyl-9, Scheme 2).20 Although several synthetic routes have been reported within two patents,21,22the most likely scalable process route is described in Scheme 2 Commercial 2-butyl-4-chloro-5-(hydroxymethyl)-imidazole (7) was alkylated with N-triphenylmethyl-5-(40 -bromomethylbiphenyl-2-yl)tetra-zole (8) under basic conditions in warm DMF, providing alcohol 9

in 90% yield This alcohol was then oxidized to the corresponding carboxylic acid 10 with KMnO4 in 88% yield Etherification of acid 10 with isopropyl chloromethyl carbonate (11) followed by de-tritylation of the tetrazole group under acidic conditions gave allisartan isoproxil (II) in 69% yield.22

4 Anagliptin (BeskoaÒ, SuinyÒ) Anagliptin, which is marketed as Beskoa or Suiny, is a dipeptidyl peptidase-IV (DPP-4) inhibitor which was approved in September

2012 and launched in November 2012 in Japan for the treatment

of Type II diabetes The drug was co-developed by three Japanese

O

OHSS

O

HN

NN

NN

OHO

ONONHO

IV Axitinib V Azilsartan VI Bedaquiline fumarate

NO

O

HNCN

O

OO

O

Cl

HOHOOHOH

O

OHOH

H2O

IX Carfilzomib X Dapagliflozin propanediol hydrate

NN

HS

H

OO

NO

XIV Ingenol mebutate XV Ivacaftor XVI Lorcaserin hydrochloride hydrate

N

ONOOH

NH

Cl

HCl1/2 H2O

N

Br

OPh

H3C

OHN

HO2C

CO2HH

O HO

O

HO

NHOOOO

OHO

HO

XVII Omacetaxine mepesuccinate XVIII Pasireotide

XIX Perampanel hydrate XX Pixantrone dimaleate

NN

O

O

OHN

HN

NH2

NH22COOH

O

HCl

O

HNN

N

NN

N

CF3

NN

H2O

XXIII Regorafenib hydrate XXIV Tafamidis meglumine

ON

OHO

Cl

Cl

HHO

OH

OHOH

OH

N

NHNHHN

HNOOOO

Ph

OOPh

OOHN

H2N

OBn

H2N

NH

H( )3

N NNNNHNO

S2.5 HBr

HOOC

XXVII Tofacitinib citrate XXVIII Vismodegib

XXV Teneligliptin hydrobromide hydrate XXVI Teriflunomide

NH

companies; Kowa, Sanwa Kagaku and JW pharmaceutical

Anaglip-tin, which is more selective against several recombinant human

proteases by comparison to sitagliptin and vildagliptin,23has more

than 10,000-fold selectivity over the structurally homologous

DPP-8 and DPP-9 enzymes

The most likely process-scale synthesis is depicted inScheme 3.24

Commercially available

(S)-1-(2-chloroacetyl)-pyrrolidine-2-carboni-trile (12) was alkylated with t-butyl (2-amino-2-methyl-1-propyl)

carbamate (13), giving rise to (S)-t-butyl

(2-((2-(2-cyanopyrrolidin-1-yl)-2-oxoethyl)amino)-2-methylpropyl)carbamate (14) This

Boc-pro-tected system was subsequently treated with strong acid to give the

ethylene diamine derivative 15 in 96% yield Activation of 15 with

CDI followed by coupling with commercially available

2-methylpy-razolo[1,5-a] pyrimidine-6-carboxylic acid (16) gave anagliptin (III)

in 90% yield

5 Axitinib (InlytaÒ)Sold under the brand name InlytaÒby Pfizer, Inc., axitinib wasapproved by the FDA in January 2012 for the treatment of ad-vanced renal cell carcinoma (RCC), specifically after the failure ofother systemic treatments.25Axitinib slows cancer cell prolifera-tion by inhibition of the vascular endothelial growth factor(VEGF)/VEGF receptor tyrosine (RTK) signaling pathway In partic-ular, axitinib is a potent inhibitor of VEGF/RTK 1–3, which selec-tively slows angiogenesis, vascular permeability, and blood flow

in solid tumors.26,27While numerous patents and papers have beendisclosed on the synthesis of axitinib,28–37 a recently publishedmanuscript details the development of the manufacturing route,and this route is depicted inScheme 4.38The synthesis began withMigita coupling of commercial iodide 17 with thiophenol 18

MeO

OMeOO

1

Et2O,−30 °C36%

SMgBr

OOOH

SS

Br

-N+ON

OHN

Scheme 1 Synthesis of aclidinium bromide (I).

NN

Cl

90%

+Br

NN

N NCPh3

NN

ClOH

NN

0 °C to 50 °C, 88%

NN

ClOH

NN

ClO

NN

O

OOO

3 4N HCl, dioxane, RT

Scheme 2 Synthesis of allisartan isoproxil (II).

Interestingly, this transformation’s efficiency relied upon attention

to the number of equivalents of base and an inert atmosphere in

the reaction vessel, conditions which minimized catalyst poisoning

during the reaction Without isolation, indazole 19 was iodinated

to afford diarylthioether 20 in 85–90% yield over the two steps

Protection of the indazole within 20 as its acetamide preceeded a

Heck reaction with 2-vinylpyridine, and then subsequent removal

of the indazole protection followed by a series of recrystallizations

yielded axitinib (IV) in a combined 62% yield over the final 4 steps

6 Azilsartan (AzilvaÒ)

Azilsartan is an orally active angiotensin II blocker which was

approved and launched in Japan for the treatment of arterial

hypertension in May 2012.39Azilsartan, which is marketed under

the trade name AzilvaÒ, was discovered and developed by

Take-da—the same firm which had developed and launched a prodrug

of azilsartan (azilsartan kamedoxomil, EdarbiÒ) in 2010 Azilsartan

exhibits higher potency and slower off-rate kinetics for type 1

angiotensin II receptors, which contributes to azilsartan’s

compar-atively improved blood pressure lowering effect.40

The most likely process-scale synthetic route mimics thatwhich is disclosed in Takeda’s patents, and this is described in

Scheme 541,42 Commercially available benzoic acid 21 was vated as the corresponding acyl azide and underwent a Curtiusrearrangement to give carbamate 22 in 57% yield (three steps fromcompound 21) The resulting aniline 22 was alkylated with com-mercial 4-(bromomethyl)-2’-cyanobiphenyl (23) to give benzyl-amine 24 in 85% yield Nitroamine 24 was then exposed tomildly acidic conditions to affect Boc-removal prior to reductionvia ferric chloride hydrate in the presence of hydrazine hydrate.The resulting diamine 25 arose in 64% yield across the two-step se-quence Interestingly, it was found that metal catalysts under con-ventional hydrogenation conditions caused partial debenzylation,which led the authors to arrive at the hydrazine/ferric chlorideconditions Next, benzimidazole formation was achieved upontreatment of diamine 25 with ethyl orthocarbonate in acetic acid.The resulting ethoxylbenzimidazole 26 was procured in 86% yield,and this benzonitrile was further reacted with hydroxylaminehydrochloride and sodium methoxide to provide amidoxime 27

acti-in 90% as a white powder Next, activation with ethyl bonate gave 28 followed by heating in refluxing xylene to give

O

HN

III Anagliptin

ClN

12

OO

13

NHN

NNN

OOH

H2N

HN

OO

Scheme 3 Synthesis of anagliptin (III).

HN

HNS

19

I2, NMP, aq KOH85-90% f or 2 steps

HNNS

3 1,2-DAP, THF, polishing filter

4 NMP, THF, 62% for 4 steps

HNS

N

OO

OCN

26

NN

OO

O

27

OHNHOH•HCl, NaOMe/MeOH

DMSO, 90 °C, 90%

Et3N, RT

OOOEt

xylenes,↑↓

23% for 2 steps

29

NN

OO

ONONH

OHO

ONONHO

OO

ONONHO

30

NN

aq NaOH

V Azilsartan

NN

OHO

ONONHO

50 °C, 88-90%

OOO

oxadiazolone 29 in 23% yield from hydroxyamidine 27 Finally,

ester 29 was saponified with 2 N LiOH in methanol to give

azilsartan (V) in 84% yield

An improved scalable route (Scheme 6) to azilsartan was

re-ported and features reproducibly better yields.43Hydroxyamidine

30 was treated with dimethyl carbonate and sodium methoxide,

which triggered they key cyclization along with concomitant

transesterification to deliver 29 Milder aqueous sodium hydroxide

hydrolysis converted this methyl ester 29 to azilsartan (V) in88–90% yield

7 Bedaquiline fumarate (SirturoÒ)Bedaquiline fumarate is a diarylquinone drug developed byJanssen Pharmaceutical which is marketed under the trade nameSirturoÒ.44 The drug, which was approved in 2012 for the

• HCl

aq NaOH, 60 °C98%

N

Br

O CH3Ph

N

Br

OPh

H3C

OHN

H3C

OHN

Scheme 7 Synthesis of bedaquiline fumarate (VI).

H3CO

O

NHN

NaI, DME, ↑↓, 77%

O

ONN

ClCl

43

37

O

ONN

NN

O

H2O

NN

OHNC

O

Cl

ClNC

O

treatment of multidrug-resistant tuberculosis (MDR-TB), was

developed in partnership with Johnson & Johnson and represents

the first new tuberculosis therapy approved in over four decades.44

Bedaquiline is the first member of a new class of diarylquinoline

compounds whose mechanism of action inhibits Mycobaterium

tuberculosis ATP synthase which deprives bacterium of energy.44

Of the relatively few synthetic approaches to bedaquiline (or its

fumarate salt) that have been reported,45–47the most likely

pro-cess-scale route is that described by Porstmann and co-workers

from Janssen Pharmaceutical, and this route is outlined in

Scheme 7.48The synthesis was initiated by first treating

commer-cially available dimethylaminoketone 31 with sodium hydroxide

to provide naphthylone 32 in nearly quantitative yield Treatment

of commercially available quinoline 33 with LDA and subsequent

trapping with naphthylone 32 provided a mixture of

diastereo-mers, whereby the major diastereomer obtained from this reaction

corresponded to the bedaquiline geometry The minor

diastereo-mer was resolved through multiple recrystallizations and seeding

techniques.48 This racemate of the major diastereomer

subse-quently underwent a chiral resolution upon treatment with BINAP

derivative 34 in refluxing DMSO Cooling and subjection to

aqueous base in warm toluene furnished bedaquiline 35, bearing

the requisite (R,S)-configuration of the two vicinal chiral centers

corresponding to that of the drug The overall yield of the

conversion of 33 to enantiopure 35 was 39% Aminoquinolinol 35

was then prepared as the corresponding fumarate salt upon

treatment with fumaric acid in the presence of isopropanol, andthis salt formation delivered bedaquiline fumarate (VI) in 82%yield.49

8 Bosutinib hydrate (BosulifÒ)BosulifÒ(Bosutinib hydrate), also known as (SKI-606), is a novel4-phenylamino-3-quinolinecarbonitrile kinase inhibitor approvedfor treatment of adults with chronic, accelerated, or blast phasePhiladelphia chromosome-positive chronic myeloid leukemia(Ph+CML).50Bosutinib is an orally-dosed, dual Src/Abl kinase inhib-itor51,52which provides an alternative treatment to patients exhib-iting immunity to imatinib and other kinase inhibitors utilized forthis treatment.53,54 In contrast to competitor tyrosine inhibitors,bosutinib inhibits autophosphorylation of both Srs and Abl kinases,leading to decreased cell growth and apoptosis.51 Bosutinib wasoriginally developed by Wyeth and continues to be marketed byPfizer after the merger of Wyeth and Pfizer in 2009.55

Several synthetic routes to bosutinib have been reported,including synthetic work for scale up and processing to obtain puresalt forms of bosutinib for pharmaceutical applications.56–59Thecurrent manufacturing route begins with reaction of 2-methoxy-5-nitrophenol (36) and 1-bromo-3-chloropropane (37) to providearyl chloroether 38 in 82% yield.58Reaction of 38 with N-methylpi-perazine (39) and NaI in refluxing DME provided the functionalizedaryl-nitro-piperazine 40 (77% yield), which was converted directly

NO

O

OHPOCl3, CH3CN

NO

O

O

NH2

NO

OHO

O

OH75%

to aniline 41 under hydrogenolysis conditions Aniline 41 was then

reacted with triethyl orthoformate and aryl cyanoamide 42, which

was generated in one step from 2,4-dichloro-5-methoxy-aniline

(44), 1,3-diisopropylcabodiimide (DIC), and cyanoacetic acid (45)

under refluxing conditions, to yield advanced intermediate 43

(93% over 2 steps).58,59Finally, conversion of 43 to bosutinib wasfacilitated by a POCl3-promoted cyclization in the presence of sul-folane As shown inScheme 8, employment of carefully optimizedconditions for the isolation of bosutinib hydrate (VII) providedmaterial in 75–82% yields and >99% purity.59

H

CO2MeO

BocHN

NO

H

CO2Me

OH

O

NO

H

CO2H

OH

ONO

H2NOO

NO

HN

OH

ONO

O

OO

BOP, HOBT, DMF

1 TFA, DCM, 0 °C

1 TFA, DCM

1 KI, THFmorpholine

1 59, HBTU, HOBT, DMF, DIPEA, 0 °C

2 ClCH2C(O)Cl

DMF, DIPEA, 0 °C67% for 2 steps

2 LiOH, MeOH

0 °C to 5 °C 87% for 2 steps

2 Recrystallization from MeOH/H2O75% for 2 steps

BocHN

O

MgBrTHF, 5 °C, 81%

9 Cabozantinib (S)-malate (CometriqÒ)

Cabozantinib (S)-malate (CometriqÒ), which was discovered

and developed by Exelixis, gained approval by the U.S FDA in

November 2012 The drug’s indication is for the treatment of

med-ullary thyroid cancer (MTC), and is the second drug for this disease

after AstraZeneca’s vandetanib (CaprelsaÒ) The drug was

success-fully launched on January 24, 2013.60,61Cabozantinib inhibits

mul-tiple receptor tyrosine kinases including RET, MET, VEGFR-1, -2

and -3, KIT, TRKB, FLT-3, AXL, and TIE-2.62 It is currently also

undergoing clinical trials for the treatment of prostate, ovarian,

brain, melanoma, breast, non-small cell lung, pancreatic,

hepato-cellular and kidney cancers Of the three syntheses of cabozantinib

reported,63–66the kilo-gram scale process route65,66is described in

Scheme 9

The preparation began with 6,7-dimethoxy-quinoline-4-ol (46)

which upon treatment with POCl3 provided chloride 47 in 70%

yield Exposure of 47 to 4-aminophenol under basic conditions

using t-BuONa furnished diaryl ether 48 in 72% yield This aniline

was then coupled with amidoacid chloride 51 (which arose from

the activation of commercial diacid 49 to the corresponding

mono-chloride, coupling with p-fluoroaniline, and subsequent exposure

to oxalyl chloride to furnish the transient acid chloride) to

con-struct cabozantinib as the free base 52 in 95% yield Salt formation

of cabozantinib 52 was carried out with (S)-malic acid, which

ulti-mately delivered the final product of cabozantinib (S)-malate (VIII)

in 75% yield.65,66

10 Carfilzomib (KyprolisÒ)Carfilzomib is an irreversible inhibitor of the chymotrypsin-likeprotease in the proteasome and was approved in the U.S for thetreatment of multiple myeloma.67,68Carfilzomib was discovered

by Proteolix, which was later acquired by Onyx Therapeutics,who completed the development of this drug Carfilzomib is alsoundergoing clinical evaluation for additional oncology indicationssuch as relapsed solid tumors, lymphoma, prolymphocytic leuke-mia, acute myeloid leukemia and acute lymphocytic leukemia Car-filzomib is an analog of the natural product epoxomicin which wasfirst synthesized in the laboratories of Professor Crews at Yale Uni-versity.69Subsequent development of the SAR led to the discovery

of YU-101 in which 3 of the amino acids of this pentapeptide weremodified to improve the potency of the molecule.70After licensingthe molecule to Proteolix, the introduction of the morpholinogroup was found to improve the solubility of the drug while main-taining efficient interaction with the target The most scalableroute to carfilzomib closely resembles the original route developedtoward epoximicin and is described herein.71,72

The synthesis was initiated with the amide coupling of phenylalanine methyl ester (53) and N-Boc leucine (54) using standardcoupling reagents to afford dipeptide 55 in high yield (Scheme 10).Acidic removal of the amine protecting group, followed by a secondamide coupling reaction with N-Boc homophenyl alanine, providedtripeptide 56 in 85% yield for the two steps Acidic removal of theamine protecting group and subsequent acylation with chloroace-

O

Cl

HOHOOHOH

O

OHOH

H2O

X Dapagliflozin propanediol hydrate

OHOHOOHOH

63

TMSOTMSOOTMSOTMS

67

O

Cl

HOHOOHOH

2 Ac2O, pyridineDMAP, DCM55% f or 2 steps

1 aq LiOHTHF, H2O

tyl chloride yielded b-chloro amide 57 in 67% yield Reaction of 57

with morpholine in the presence of catalytic amounts of potassium

iodide followed by saponification of the methyl ester with lithium

hydroxide led to acid 58 in 87% yield for the two steps Finally,

amide coupling between acid 58 and keto-epoxyamine 59 (whose

preparation is described inScheme 11) using HOBT as the coupling

reagent and recrystallization of the resulting product ultimately

gave carfilzomib (IX) in 75% yield

Keto-epoxyamine 59 was prepared from N-Boc leucine (54) as

described inScheme 11 Reaction of 54 with isobutyl

chlorofor-mate followed by N,O-dimethylhydroxylamine provided Weinreb

amide 60 in 94% yield Grignard addition of isopropenylmagnesium

bromide (60) provided enone 62 in 81% yield Epoxidation of 62

with calcium hypochlorite provided a mixture of epoxides giving

41% yield of the desired isomer (presumably isolated by

chroma-tography), and subsequent treatment with TFA liberated the

amine, providing the TFA salt of ketoepoxy amine 59 in 92% yield

11 Dapagliflozin propanediol hydrate (ForxigaÒ, EmplicitiÒ,

EdistrideÒ, AppebbÒ)

Dapagliflozin propanediol hydrate, an orally active sodium

glu-cose cotransporter type 2 (SGLT-2) inhibitor, was developed by

Bristol–Myers Squibb (BMS) and AstraZeneca for the once-daily

treatment of type 2 diabetes As opposed to competitor SGLT-2

inhibitors, dapagliflozin was not associated with renal toxicity or

long-term deterioration of renal function in phase III clinical

tri-als.73The drug exhibits excellent SGLT-2 potency with more than

1200-fold selectivity over the SGLT-1 enzyme.74

The most likely process-scale synthesis has been described in a

literature publication and patent, and this is summarized in

Scheme 12below.74,75The synthesis began with global silylation

glucolactone 63 to form tetrasiloxide 64 In parallel, commercial

5-bromo-2-chlorobenzoyl acid (65) was converted to the sponding acid chloride with oxalyl chloride Subsequently, thisacid chloride was subjected to Friedel–Crafts acylation with ethylphenyl ether (‘phenetole’) in the presence of aluminum trichloride

corre-at low tempercorre-ature to give benzophenone 66 in 91% yield Next,the carbonyl functionality within 66 was removed upon treatmentwith triethylsilane and boron trifluoride-etherate, producing5-bromo-2-chloro-40-ethoxydiphenylmethane (67) in 75% yield asthe aglycon partner Aryl bromide 67 was subjected to lithium hal-ogen exchange conditions and subsequent exposure to lactone 64,provided a mixture of lactols which were then immediately sub-jected to methanesulfonic acid, leading to glucol 68 in 85% yield.The anomeric methoxy group of 68 was reduced with triethylsilaneand boron trifluoride-etherate followed by peracetylation to deli-vera-C-glycoside tetraacetate 69 in 55% (two steps) after recrys-talliaztion in ethanol Hydrolysis of polyacetate 69 with lithiumhydroxide gave dapagliflozin in quantitative yield, and upon treat-ment with propanediol in water, dapagliflozin propanediol hydrate(X) was produced

12 Enzalutamide (XtandiÒ)

In August 2012, the FDA approved enzalutamide, marketed byMedivation and Astellas Pharma U.S for the treatment of meta-static castration-resistant prostate cancer (CRPC), specifically forthose patients who had previously received docetaxel.76Enzaluta-mide is an inhibitor of androgen receptors (AR)—whose increasedexpression has been closely linked with castration-resistant pros-tate cancer (CRPC), thus, AR inhibitors have seen increased recentattention from the medicinal chemistry community Phase I/IItrials were particularly promising for enzalutamide, as 43% ofpatients showed >50% sustained suppression of a key serumbiomarker.77 Of the several patents and papers describing

CO2H

FBr

SOCl2, IPAc

FBr

OCl

CH3NH2, IPAc, 2 °C to 35 °C90% for 2 steps

FBr

ONHMe

FNHMeO

NOMeO

MeI, 30 °C to 40 °C95%

synthetic approaches,78–81a 2011 patent represents the most likely

scale production route to enzalutamide, and this is described in

Scheme 13.82

Commercially available carboxylic acid 70 was first converted

to the corresponding acid chloride 71, followed by amide

forma-tion with methylamine to furnish benzamide 72 in 90% yield over

two steps Bromide 72 was then coupled with amine 73 using

cop-per(I) catalysis to afford trisubstituted benzene 74 in 76% isolated

yield Esterification of 74 to 75 with iodomethane furnished one

fragment for the key ring-forming event Isothiocyanate 76,

avail-able in one step from the corresponding aniline 77, was then

ex-posed to aminoester 75 in the presence of warm isopropyl

acetate, resulting in construction of the lynchpin thiohydantoin

and delivering enzalutamide (XI) in an impressive 78% yield This

5-step process has successfully generated multi-gram quantities

of the drug in 50.7% overall yield

13 Iguratimod (CareramÒ, IremodÒ)

Iguratimod, which was discovered by Toyama Pharmaceuticals

and jointly co-developed with Eisai in Japan, was approved by the

PMDA (Pharmaceuticals and Medical Devices Agency) of Japan on

June 29, 2012 for the treatment of rheumatoid arthritis.83This drug

was also independently developed by Simcere PharmaceuticalGroup and is marketed as IremodÒin China The drug exhibitedinhibitory effects on granuloma inflammation, and was shown to

be efficacious for the prevention of joint destruction in adjuvantarthritis.84,85While several synthesis of iguratimod have been pub-lished,86 the most likely scale synthesis, which does not requirechromatographic purification, is described inScheme 14.87

The synthesis began with commercially available chloro anisole (78) which was reacted with potassium phenoxide(generated from phenol and potassium t-butoxide at 110 °C) toprovide the corresponding nitrophenyl ether which was subse-quently reduced and sulfonylated to furnish sulfonamide 79 Next,this diphenyl ether was submitted to a Friedel–Crafts reaction withaminoacetonitrile hydrochloride which gave rise to aminomethy-lacetophenone 80 in 90% yield This aminoketone was then formy-lated with formic trimethylacetic anhydride 81 at roomtemperature to afford formamide 82 in 91% yield, and this materialwas immediately subjected to O-demethylation conditions withaluminum trichloride and sodium iodide in acetonitrile to givethe phenol 83 in 95% yield Finally, treatment of the aminomethylacetophenone phenol 83 with N,N-dimethylformamide dimethyl-acetal in DMF at low temperatures furnished iguratimod (XII) in87% yield

3-nitro-4-O

O2NCl

1 PhOH,t-BuOK, DMF, 110 °C, 84%

2 Fe/4N HCl, EtOH, 65 °C to 70 °C, 72%

3 MeSO2Cl•Py, 0 °C to RT, 82%

OH

80

OHOO

81

OH

O

S

ONOH

OHH

O

S

ONOH

OO

OO

SOO

NO

O HOO

HO

OO

HO HO

HO

OO

HO HO

HO

HOHO

HOHO

Scheme 16 Synthesis of ingenol mebutate (XIV).

3.L-(+)-tartaric acid, acetone /H2O

4 Recrystallization from acetone/H2O27% for 4 steps

3 HCl (gas), 0 °C to 5 °C90% for 3 steps

• 1/2 H2O

2 SOCl2, DMA, PhCH3, 65 °C71% for 2 steps

92

H2SO4, HNO3DCM, 0 °C to RT57%

OOEtO

O2N

93

1 Pd/C, H2, MeOH

2 94, Et3N, DCM, RT53% f or 2 steps

NH

ONOOOEtO

95

KOH, MeOH96%

N

ONOOH

XV Ivacaftor

N

OClO

94

Scheme 17 Synthesis of ivacaftor (XV).