Acotiamide hydrochloride hydrate AcofideÒ Acotiamide hydrochloride trihydrate is the first drug to be approved in Japan for the treatment of functional dyspepsia FD.. The drug was discover
Trang 1Synthetic approaches to the 2013 new drugs
Hong X Dinga, , Carolyn A Leverettd,à, Robert E Kyne Jr.d,§, Kevin K.-C Liub,–, Sarah J Finkc,k,
Andrew C Flickd, , Christopher J O’Donnelld,⇑
a Pharmacodia (Beijing) Co., Ltd, Beijing 100085, China
b
Lilly China Research and Development Center, Shanghai 201203, China
c
BioDuro Co., Ltd, Shanghai 200131, China
d
Pfizer Worldwide Research and Development, Groton Laboratories, 445 Eastern Point Road, Groton, CT 06340, United States
Article history:
Received 5 January 2015
Revised 20 February 2015
Accepted 26 February 2015
Available online 6 March 2015
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 privileged structures for particular biological targets These new chemical entities (NCEs) provide insight into molecular recognition and also serve
as leads for designing future new drugs This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review
Ó 2015 Elsevier Ltd All rights reserved
Contents
1 Introduction 1896
2 Acotiamide hydrochloride hydrate (AcofideÒ) 1896
3 Afatinib dimaleate (GiotrifÒ, GilotrifÒ) 1896
4 Canagliflozin hydrate (InvokanaÒ) 1897
5 Cetilistat (ObleanÒ) 1898
http://dx.doi.org/10.1016/j.bmc.2015.02.056
0968-0896/Ó 2015 Elsevier Ltd All rights reserved.
Abbreviations: 1,2-DAP, 1,2-diaminopropane; 1,2-DCE, 1,2-dichloroethane; Ac, acetyl; aq, aqueous; Bn, benzyl; Bz, benzoyl; Boc, t-butoxycarbonyl; B 2 (pin) 2 , bis(pinacolato)diboron; BINAP, 2,2 0 -bis(diphenylphosphino)-1,1 0 -binaphthyl; BSA, N,O-bistrimethylsilyl acetamide; CDI, N,N 0 -carbonyldiimidazole; CDMT, 2-chloro-4, 6-dimethoxy-1,3,5-triazine; DAP, diaminopropane; Dba, dibenzylideneacetone; DBU, 1,5-diazabicycolo[4.3.0]non-5-ene; DCC, 1,3-dicyclohexylcarbodiimide; DCE, dichloroethane; DCM, dichloromethane; DIAD, diisopropyl azodicarboxylate; DIC, 1,3-diisopropylcarbodiimide; DIEA/DIPEA, diisopropylethylamine; ()-DIP-chloride, ()-diisopinocampheyl chloroborane; DMA, dimethylacetamide; DMAP, 4-dimethylaminopyridine; DME, dimethoxyethane; DMF, N,N-dimethylformamide; DMSO, dimethyl sulfoxide; DPPA, diphenylphosphoryl azide; EDCI, N-(3-dimethylaminopropyl)-N 0 -ethylcarbodiimide; EDTA, ethylenediaminetrteaacetic acid; EEDQ, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; HBTU, 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HMDS, bis(trimethylsilyl)amide; HOBT, 1-hydroxy-benzotriazole hydrate; IPA, isopropyl alcohol; IPAc, isopropyl acetate; LAH, lithium aluminum hydride; LHMDS, lithium bis(trimethylsilyl)amide; MIBK, methyl isobutyl ketone; MsOH, methansulfonic acid; MsCl, methanesulfonic chloride; MTBE, methyl tert-butyl ether; NaHMDS, sodium bis(trimethylsilyl)amide; NBS, N-bromosuccinimide; NMM, N-methylmorpholine; NMP, N-methyl-2-pyrrolidone; pin, pinacol; Py, pyridine; rt, room temperature; TBAB, tetrabutylammonium bromide; TBAF, t-butyl ammonium fluoride; TFA, trifluoroacetic acid; TFAA, trifluoroacetic anhydride; THF, tetrahydrofuran; TMEDA, tetramethylethylenediamine; TMP, 2,2,6,6-tetramethylpiperidine; TMSCl, trimethylsilyl chloride; TMSI, trimethylsilyl iodide; TBDPS, tert-butyl diisopropylsilyl; Ts, tosyl(p-toluenesulfonyl).
⇑ Corresponding author Tel.: +1 860 715 4118.
E-mail addresses: Sheryl.ding@pharmacodia.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), Sarah.fink@bioduro.com (S.J Fink), andrew.flick@pfizer.com (A.C Flick), christopher.j.odonnell@pfizer.com (C.J O’Donnell).
Tel.: +86 10 8282 6195.
à Tel.: +1 860 441 3936.
§
Tel.: +1 860 441 1510.
–
Tel.: +86 21 2080 5590.
k Tel.: +86 21 3175 2858.
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
Trang 26 Cobicistat (TybostÒ) 1898
7 Dabrafenib mesylate (TafinlarÒ) 1900
8 Dolutegravir sodium (TivicayÒ) 1901
9 Efinaconazole (JubliaÒ) 1902
10 Elvitegravir (VitekaÒ) 1904
11 GemigliptinL-tartrate hydrate (ZemigloÒ) 1906
12 Ibrutinib (ImbruvicaÒ) 1908
13 Istradefylline (NouriastÒ) 1909
14 Levomilnacipran hydrochloride (FetzimaÒ) 1910
15 Lomitapide mesylate (JuxtapidÒ) 1912
16 Macitentan (OpsumitÒ) 1912
17 Olodaterol hydrochloride (Striverdi RespimatÒ) 1914
18 Ospemifene (OsphenaÒ) 1914
19 Pomalidomide (PomalystÒ) 1914
20 Riociguat (AdempasÒ) 1914
21 Saroglitazar (LipaglynÒ) 1916
22 Simeprevir (OlysioÒ; SovriadÒ) 1917
23 Sofosbuvir (SovaldiÒ) 1917
24 Topiroxostat (UriadecÒ; TopiloricÒ) 1917
25 Trametinib dimethyl sulfoxide (MekinistÒ) 1918
26 Trastuzumab emtansine (KadcylaÒ) 1918
27 Vortioxetine (BrintellixÒ) 1919
28 Conclusion 1919
References and notes 1920
1 Introduction
‘The most fruitful basis for the discovery of a new drug is to start
with an old drug.’–Sir James Whyte Black, winner of the 1988
Nobel Prize in medicine.1
This annual review was inaugurated twelve years ago2–12and
presents synthetic methods for molecular entities that were
approved for the first time 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 design new drugs more efficiently The
pharmaceuti-cal industry enjoyed a banner year in 2013, with a total of 56 new
products including new chemical entities, biological drugs, and
diagnostic agents having reached the worldwide market for the
first time Although an additional 19 new products were approved
for the first time in 2013, some were not launched before the end
of the year,13and therefore this review focuses on the syntheses of
twenty-four NCEs that were approved and launched for the first
time in 2013 It also includes two additional drugs that although
were initially approved in 2012, were not included in our prior
review (Fig 1).12 New indications for previously launched
med-ications, new combinations, new formulations of existing drugs,
and drugs synthesized purely via bio-processes or peptide
synthe-sizers 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 that have
been disclosed within published or patent literature beginning
from commercially available starting materials Drugs presented
in this review are ordered alphabetically by generic name
2 Acotiamide hydrochloride hydrate (AcofideÒ)
Acotiamide hydrochloride trihydrate is the first drug to be
approved in Japan for the treatment of functional dyspepsia (FD)
The drug was discovered by Zeria Pharmaceuticals and jointly
developed with Astellas Pharmaceuticals.14The drug blocks
mus-carinic receptors and inhibits peripheral acetylcholine esterases,
thereby increasing the concentration of acetylcholine,14ultimately
improving the impaired gastric motility and delayed gastric
emptying along with the additional symptoms associated with
FD, such as post prandial fullness, upper abdominal bloating and early satiation.14–16 Although multiple synthetic approaches to the drug have been reported,17,18 the synthesis highlighted in
Scheme 1 and described below represents the largest scale reported to date in a patent application.18
Commercial 3,4,5-trimethoxybenzoic acid (1) was first con-verted to the corresponding acid chloride 2, which was isolated
by co-distillation with hexane In refluxing dichloroethane (DCE), the acid chloride was coupled with the commercially available thiazole amine (3) to give the desired amidothiazole 4 in 89% yield From this intermediate, amide linkage, selective demethylation of the 2-methoxy group, salt formation, and recrystallization were accomplished in the following sequence: the thiazole ester 4 was reacted with N,N-diisopropyl ethylenediamine (5) in DMA at ele-vated temperatures Upon cooling, the mixture was dissolved in n-butanol and washed with aqueous sodium hydroxide Subsequent treatment with HCl gas in isopropanol gave the corresponding HCl salt as crystals that could be collected by filtra-tion The product obtained was further crystallized from 4:1 iso-propanol and water to give the desired product acotimide (I) as the hydrochloride trihydrate in 71% yield
3 Afatinib dimaleate (GiotrifÒ, GilotrifÒ) Afatinib dimaleate was approved by the U.S Food and Drug Administration (FDA) in 2013 for the treatment of non-small cell lung cancer (NSCLC).19 Specifically, it was approved for patients presenting with metastatic NSCLC tumors which contain epider-mal growth factor receptor (EGFR) exon 19 deletions or exon 21 mutations.19Afatinib dimaleate is a covalent inhibitor of ErbB tyr-osine kinases (tyk), which downregulates ErbB signaling by irre-versible binding of EGFR tyk binding sites.19 While no manufacturing route has been disclosed to date,20–24the most scal-able published route likely derives from two Boehringer Ingelheim patents (Scheme 2).25,26
Nitroquinazolinone (6), which is commercially available, was first chlorinated with phosphorous oxychloride (POCl3) followed
by treatment with commercial 3-chloro-4-fluoroaniline (7) to afford SNAr adduct 8 in 90% yield over two steps Sulfonylation to
Trang 3afford 9 (86%) and subsequent displacement with
(S)-tetrahy-drofuran-3-ol gave 10 in 90% yield.25 Raney–Nickel reduction
of the nitro group delivered 11 in 97% yield, which set the stage
for the final side-chain functionalization 2-(Diethoxyphosphoryl)
acetic acid and N,N0-carbonyldiimidazole (CDI) were pre-mixed
and added to aniline 11 to afford 12 in 70% isolated yield Next, a
Horner–Wadsworth–Emmons homologation gave the (E)-olefin
13 in quantitative yield, followed by maleate salt formation
(92%) to deliver the final API The final five steps of this synthesis
have been successfully demonstrated on multi-kilogram scale.24,25
4 Canagliflozin hydrate (InvokanaÒ)
Canagliflozin, an orally active and selective sodium–glucose
cotransporter 2 (SGLT2) inhibitor, was co-developed by
Mitsubishi Tanabe Pharma and Johnson & Johnson (J&J) for the
treatment of type 2 diabetes mellitus (T2DM) and obesity The
drug was approved in March by the U.S FDA and launched in
April 2013 in the U.S SGLT2 is involved in the glucose
re-absorp-tion pathway in the kidney, and its inhibire-absorp-tion increases urinary
glucose excretion, and reduces plasma glucose and HbA1c levels.27
In addition, canagliflozin is safe in combination with other
com-monly used antidiabetic agents and has a significant effect on body
weight reduction.28 A recently published process patent fromScinoPharm Taiwan describes the synthesis of canagliflozin Thepreparation of the drug involves a convergent strategy wherebythe union of the aglycone and glycoside components of the mole-cule ultimately secure the atomic framework of the API—the syn-thesis of each region and their union are described inScheme 3.29Synthesis of the aglycone region of canagliflozin was described
in a separate patent by first condensing commercially available bromo-2-methylbenzoyl chloride (14) and 2-(4-fluorophenyl)-thiophene (15) under Friedel–Crafts acylation conditions to giveketone 16 in 69% yield as a crystalline solid.29Ketone 16 was thenreduced with triethylsilyl hydride in the presence of BF3Et2O atlow temperature to give aglycone bromide 17 in 70% yield Theprecursor for the glycoside moiety, commercially available gly-coside triol 18, was selectively treated with t-butyldiphenylsilylchloride (TBDPSCl) in THF in the presence of imidazole to givethe bis-silyl ether 19 in 81% yield Next, a unique, stereospecificb-C-arylglucosidation was developed to secure the union of theaglyone- and glycoside-containing portions of canagliflozin.Bromide 17 was subjected to magnesium powder under standardGrignard conditions prior to treatment with AlCl3in THF in situ.This resulting mixture was then exposed to a solution of com-pound 19 in PhOMe which had been pre-treated with n-BuLi, and
F
N N H
O
O
O N
COOH
1/2 H2O
O HO HO OH OH
O N O
O
N O
N H
O
N
S O
N
O N S
O
N N O
CH3O
O
-H H
O
F F
Na +
OH O
O
N
N O HN N
HCl 3 H2O
H FS O O F
F
S N
N N
NH2
. CH3SO3H
HO N N N N F
F
Figure 1 Structures of 26 NCEs covered in this review.
Trang 4the entire mixture was then warmed to 150 °C for 5 h to ultimately
give the b-anomer 20 in 56% yield Finally, removal of the silyl
groups within 20 with tetrabutyl ammonium fluoride (TBAF) in
THF delivered canagliflozin hydrate (III) in 73% yield (Scheme 3)
5 Cetilistat (ObleanÒ)
Cetilistat is a selective pancreatic lipase inhibitor which was
approved in Japan in September 2013 for the treatment of obesity
The drug was discovered by Alizyme PLC and later co-developed
with Takeda Cetilistat demonstrated a lower incidence of adverse
gastrointestinal events during a 12 week clinical trial, and the
degree of weight loss associated with cetilistat is comparable to
that of other approved antiobesity therapies.30The most likely
pro-cess-scale preparation of cetilistat is described below in
Scheme 4.31
Commercially available hexadecanol (21) was treated with
phosgene in THF/toluene to give the corresponding chloroformate
(22), which was immediately subjected to commercial
2-amino-5-methylbenzoic acid (23) in pyridine Subsequent slow addition of
methyl chloroformate at room temperature resulted in the tion of cetilistat (IV), which was produced in 31% overall yield fromhexadecanol.31
forma-6 Cobicistat (TybostÒ)Cobicistat, a selective, mechanism-based CYP3A inhibitor, wasdiscovered and developed by Gilead Sciences, Inc In 2013,European Medicines Agency (EMA) approved cobicistat (TybostÒ)for the treatment of HIV-1 infection in combination with proteaseinhibitors (PIs) atazanavir or darunavir Interestingly, cobicistatdoes not interact with HIV directly, but instead serves as apharmacokinetic enhancer to boost the anti-HIV effect of atazana-vir or darunavir through blockade of CYP3A.32 Cobicistat slowsCYP-mediated metabolism of atazanavir and darunavir, resulting
in prolonged systemic exposure of the drug(s).32Cobicistat is alsoavailable as part of a fixed-dose combination tablet (StribildÒ) offour additional drugs with CYP3A liabilities (elvitegravir, cobicistat,emtricitabine and tenofovir disoproxil fumarate), which wasapproved in U.S in 2012, and subsequently approved in Europe
N N
N N
NH 2
N O
OPh
N N O
N
O O
O
N
NH2HCl
.
XIII Levomilnacipran hydrochloride
Br
N N
H S N O O
O NH2
F F
OH
OH O OH O
HO
1.5 H2O F
Cl
N OH
O OH O O
HN
F 3 C
N O
N O
O
NH O O
XVI Olodaterol hydrochloride
OH
HCl
•
Fig 1 (continued)
Trang 5and Japan in 2013 Although several synthetic routes have been
reported,33–37 the improved process route by Gilead Sciences is
described inSchemes 5 and 6.37
Commercial L-methionine (24) was treated with bromoacetic
acid at elevated temperatures to afford aminolactone salt 25 in
70% yield This material was then reacted with methyl
aminomethylthiazole (26) in the presence of CDI and lethylamine to arrive at urea 27 in 91% yield Next, lactone 27underwent a ring-opening sequence upon exposure to trimethylsi-lyl iodide (TMSI) giving intermediate 28 The iodide was then dis-placed by morpholine, followed by treatment with oxalic acid todeliver the -thiazole morpholine ethyl ester as the oxalate salt
diisopropy-XX Saroglitazar
O
H N N
O O O
N S
N MeO
XXI Simeprevir XIX Riociguat
hydrobromide
trastuzumab
O O O
3.5
O O
O N
O
N OH O O
Cl
H
N O O S
N N N F
N N
H2N
NH 2
N O
O
O
O N S
S N H
HBr
N N N
N O
Me F
HO
N NH O
O PhO
O O
Me O
OH O
O O O
O O O
N
N O OEt
N
H2N
OH O
O
N
N O HN N
Scheme 1 Synthesis of acotiamide hydrochloride hydrate (I).
Trang 629 in 71% yield for the sequence Base-mediated hydrolysis of ethyl
ester 29, followed by treatment of carboxylate 30 with
mono-car-bonate hydrochloride 31 in the presence of EDCI and HOBT,
pro-vided cobicistat (V) in 76% yield for two steps
Of note, the preparation of mono-carbonate hydrochloride 31
arose from commercially available (S)-2-benzylaziridine (32)
which was first condensed with N,N-dimethylsulfamoyl chloride
to obtain N-tosyl-protected aziridine 33 in 77% yield (Scheme 6)
Next, a unique base-induced dimerization reaction was employed
to convert aziridine 33 to alkene 34 Presumably this proceeded
through initial deprotonation at the methylene carbon within
azir-idine 33 upon exposure to lithium 2,2,6,6-tetramethylpiperazir-idine
(LiTMP) resulting in an unstable trans-R-lithiated terminal
aziri-dine This lithiate then underwent nucleophilic attack onto another
molecule of 33 followed by elimination to give the
2-ene-1,4-dia-mine 34 in 72% yield.37–39 Removal of the sulfonyl groups with
1,3-diaminopropane followed by hydrogenation of the alkene
pro-vided diamine 36 in quantitative yield Conversion to the diamine–
dihydrogen chloride 37 through the use of HCl in dioxane was
followed by a treatment with a single equivalent of base and
5-thiazolylmethyl carbonate 38 (prepared from
bis-(4-nitro-phenyl)-carbonate (39) with 5-hydroxymethylthiazole) This
sequence furnished amino carbamate 31, which then participated
in the coupling with carboxylate fragment 30 to prepare cobicistat
as described above
7 Dabrafenib mesylate (TafinlarÒ)Dabrafenib mesylate, sold by GlaxoSmithKline under the tradename TafinlarÒ, was approved by the U.S FDA in May 2013 forthe treatment of metastatic BRAF-mutant melanoma Dabrafenibreversibly inhibits the BRAF(V600E) mutant kinase as a selectiveATP-competitive inhibitor which results in tumor regression.40While the process-scale route has not yet been disclosed,41–43thelargest scale route to date is represented inScheme 7.44
Commercially available fluoroaniline 4042was first converted tosulfonamide 42 in 91% yield by treatment with 2,5-difluoroben-zenesulfonyl chloride (41) in the presence of pyridine Next, depro-tonation of 2-chloro-4-methylpyrimidine (43) with lithiumbis(trimethylsilyl)amide (LHMDS) followed by addition to ester
42 afforded chloropyrimidine 44 in 72% yield Bromination lowed by thiazole formation through the use of 2,2-dimethyl-propanethioamide gave the penultimate target 45 in 80% overtwo steps Chloropyrimidine 45 was subjected to S Ar conditions
fol-HN N O
Cl
NO2
1 POCl3, Et3N
CH3CN, 80 °C 2.
NH 2
F Cl 90% for 2 steps
N N NH
Cl
NO2
F Cl
N N NH
SO2Ph
NO2
F Cl DMF, rt to 90 °C 86%
O HO
t-BuOH, DMF, THF
KOt-Bu, 20 °C to 45 °C
90%
N N
NH
NO 2
F Cl
O
O
Raney-Ni, DMF
NH 4 Cl, 40 °C 97%
N N
NH
NH 2
F Cl
CDI, THF, 40 °C to 20 °C 70%
N N
NH H
O
O
O
P OEt O OEt
F Cl
N N
NH H
O
O O
F Cl
-5 °C to 30 °C
maleic acid EtOH, 70 °C, 92%
O
O
O N
Trang 7with ammonium hydroxide to furnish the aminopyrimidine in 88%
yield, and this was followed by exposure to methanesulfonic acid
to afford dabrafenib mesylate (VI) in 85% yield.44
8 Dolutegravir sodium (TivicayÒ)
Dolutegravir sodium (TivicayÒ), developed and marketed by
GlaxoSmithKline,45was approved by the FDA in August 2013 as a
novel integrase inhibitor for the treatment of HIV infection.46
Dolutegravir was fast-tracked by the FDA in February 2012,47and
joins an important class of drugs known as Integrase Strand
Transfer inhibitors (INSTi’s).48 INSTi’s are characterized by their
two-metal-chelating scaffolds, which are known to chelate Mg2+
cofactors in the enzyme active site,49,50l interrupting function of
HIV-1 integrase, which is essential for replication of viral DNA into
host chromatin.49–52 Other drugs in this class, raltegravir andelvitegravir, are known to require either high dosages53 or PKboosting agents,54 respectively, with raltegravir also exhibitingsubstantial loss of potency in several major HIV-1 integrase muta-tion pathways.55Dolutegravir was pursued with the goal of devel-oping a novel INSTi with a once-daily, low-dosage treatment withimproved resistance profile and without the need for the use of a
PK boosting agent.51,56 Dolutegravir sodium has been approvedfor treating a broad population of HIV-infected patients, includingadults undergoing their first treatment as well as those who havebeen treated with other integrase transfer strand inhibitingagents.46
The most likely process-scale synthesis of dolutegravir sodium,
as described inScheme 8, began with benzyl protection and lation of pyrone 46 with benzaldehyde, yielding alcohol 47 in 74%
alky-AlCl3, CH2Cl2, 0 °C to rt 69%
18
O TBDPSO OTBDPS
OH O
19
TBDPSCl, imidazole
0 °C, THF, 81%
O TBDPSO OTBDPS
56% for 3 steps
1/2 H2O
O HO HO OH OH
3 n-BuLi, rt
PhOMe, 150 °C 70%
Scheme 3 Synthesis of canagliflozin hydrate (III).
COCl2, THF/toluene, rt
IV Cetilistat
N O O
O
O Cl
Scheme 4 Synthesis of cetilistat (IV).
Trang 8over 2 steps (Scheme 8).57,58Alcohol mesylation and in situ
elim-ination provided the styrenyl olefin 48 in 94% yield, which further
underwent an oxidative cleavage of the olefin to generate 49 by
sequential addition of RuCl3/NaIO4and NaClO2(56% overall yield)
Treatment of pyranone 49 with 3-amino-propane-2-diol (50) in
ethanol at elevated temperatures delivered the corresponding
pyridinone in 83% yield, and this was followed by esterification
and sodium periodate-mediated diol cleavage to furnish
intermediate 51 in 71% overall yield across the two-step
sequence.57,58 l Next, the key ring-forming step in the synthesis
of dolutegravir sodium consisted of cyclization of 51 with
(R)-3-amino-butan-1-ol, a process which relies on substrate control to
provide the desired tricyclic carbamoylpyridone system 52 in high
stereoselectivity (20/1 in favor of the desired isomer).51Previously,
cyclization of systems such as 51 with unsubstituted amino
alco-hols were found to yield a mixture of diastereomeric products,
therefore indicating the pivotal role of the chiral amino alcohol
in influencing stereochemical bias during the overall cyclization
step.51,56In practice, reaction of 51 with (R)-3-amino-butan-1-ol
at 90 °C led to isolation of a single cyclization product 52, after
recrystallization from EtOAc.57,58 From 52, N-bromosuccinimide
(NBS) bromination and subsequent treatment with amine 53 under
palladium-catalyzed amidocarbonylative conditions led to amide
54 in 75% yield over 2 steps Finally, removal of the benzyl group
and subsequent crystallization using sodium hydroxide in water
and ethanol provided dolutegravir sodium (VII) in 99% yield.57,58
9 Efinaconazole (JubliaÒ)Efinaconazole, marketed and developed by ValeantPharmaceuticals International, was first approved for use inCanada in October 2013 under the brand name JubliaÒ for thetreatment of onychomycosis, a fungal infection of the nail.Efinaconazole is believed to work by 14a-demethylase inhibition,which is a key pathway in ergosterol synthesis.59 Inhibition ofergosterol prevents secondary degenerative changes in the nailbed, plate, and surrounding tissue.59 Although several syntheses
of efinaconazole have been reported, none have reported on gram-scale.60–64However, as preparation of the penultimate epox-ide (60) has been described on hundred-kilogram scale in thesynthesis of ravuconazole,65and final production of efinaconazolehas been disclosed on a 24 g scale route, the presumed scale route
kilo-is described inScheme 9.66Commercially available (R)-methyl lactate (55) was first con-verted to THP protected alcohol 57 in 4 steps and 78% yield viamorpholino amide 56 Grignard displacement of the morpholineafforded ketone 58 in 81% yield Next, ketone 58 was epoxidized
by means of the Corey ylide followed by ring-opening of the ide by triazole which had been activated by exposure to sodium t-butoxide Finally, subjection to methanesulfonic acid furnisheddiol 59 in 51% yield as the corresponding mesylate salt Diol 59was then converted to epoxide 60 through the use of mesyl chlo-ride and triethylamine in 78% yield and >99% ee Finally, treatment
epox-N O
N H
O
N
S O
N
O N S
1 DIPEA, CH2Cl2
2 CDI, 10 °C to 25 °C N
S N
91%
N N
O N S
O O
TMSI, EtOH, CH2Cl2
N
I
OEt O O
S
1. O NH
N O
O N
O N S
O N
O N
Trang 9NSN O O NH
NSCl O O DIPEA, CH2Cl2, -10 °C
N
SNO O O
15 °C to 25 °C 91%
N
N Cl Me
LHMDS, THF, 0 °C 72%
H
N
F S
H2N t-Bu
S , DMA
F
CO 2 Me
H FS O O F
F
S N
N N Cl
S O O F
F
S N
N N
NH2
. CH 3 SO 3 H 80% for 2 steps
Scheme 7 Synthesis of dabrafenib mesylate (VI).
Trang 10of epoxide 60 with 4-methylene piperidine–HBr in the presence of
lithium hydroxide afforded efinaconazole (VIII) in 87% yield
10 Elvitegravir (VitekaÒ)
Elvitegravir is a quinolone-containing HIV integrase inhibitor
discovered by Japan Tobacco and licensed to Gilead
Pharmaceuticals for worldwide development with the exception
of Japan.67It was approved in Europe in 2013 for the treatment
of HIV infection in adults having no known mutations associatedwith resistance to the drug.67The drug interferes with HIV replica-tion by preventing the virus from integrating into the DNA ofhuman cells.67,68 In addition to several patent applications thathave been filed for the synthesis of elvitegravir, the discovery
1 BnBr, K2CO3, CH3CN, 80 °C
2 i LHMDS, THF
ii PhCHO, −60 °C O
O OH
O
O OBn Ph OH
O
O OBn OH O
1 MsCl, Et3N, THF, rt
1 RuCl3, NaIO4, CH3CN
O OBn OMe O HO OH
H 2 N OHOH
2 CH 3 I, NaHCO 3 , NMP, rt
3 NaIO4, CH3CN, H2O, AcOH, rt
N N O
OBn O
O
N N O
O H
O F
F
NH2F F
2 53, Pd(PPh3)4, CO(g), DIPEA DMSO, 90 °C, 84%
N N O
OBn O
O H
O F F
1.
O
O OBn Ph
O
O N O OTHP
MgBr F
F THF, 25 °C to 35 °C
OTHP F
F
N N
MsCl, Et 3 N, THF, MTBE, -10 °C 78%, >99% ee
O N
F
N N
LiOH, CH3CN
100 °C 87%
HO N N
N N
1 Me3SOI, NaOt-Bu, THF
Scheme 9 Synthesis of efinaconazole (VIII).
Trang 11synthesis69has also been published.69–80 The process route that
has been reported on kilogram scale is highlighted inScheme 10
None of the synthetic intermediates reportedly were isolated but
instead were carried forward in the sequence Therefore, no yields
were provided in the lead reference.76
Commercial 2,4-dimethoxy-5-bromo benzoic acid (61) wasreacted with 0.5 equiv of butylethylmagnesium to generate thedimagnesium salt in THF, which was then lithiated at 20 °C togive the aryl lithium species The aryl lithium species was thenreacted with the 2-fluoro-3-chloro benzaldehyde (62) to give
O
OH O
67
1 CDI, THF
Cl F OHC
O O
OH O OH Cl
F
1 Et3SiH, TFA
O O
OH O Cl
F
O O
O Cl
F
O Mg 2
OEt O
DMF-DMA toluene, 100 °C
O O
O Cl
F
OEt O N
O O
O Cl
F
OEt O NH
HO
NH2H
toluene, rt
OH
69
BSA, KCl DMF, 100 °C
N O
O Cl
F
OEt O OH
N OH
O OH O O
F F F O
NH
NH2F F F
EtOH, 90 °C 23%
O O
Trang 12alcohol 63 Treatment with triethylsilane in TFA resulted in
removal of the hydroxyl functionality to provide benzoic acid 64
This acid was then reacted with carbonyldiimidazole and
subse-quently magnesium malonate 65 to give ketoester 66 after
workup Next, condensation with DMF–DMA converted ketoester
66 to the vinylogous amide 67, and this material was immediately
subjected to an addition–elimination reaction involving (S)-valinol
(68) in toluene at ambient temperature to provide intermediate 69
Warming the resulting intermediate 69 in the presence of
N,O-bistrimethylsilyl acetamide (BSA) and potassium chloride in DMF
furnished the ring-closed quinolone 70 The ester 70 was
saponi-fied with potassium hydroxide in aqueous isopropanol and then
acidified and crystallized with the use of seed crystals Upon
cooling, the crystalline product elvitegravir (IX) was collected byfiltration
11 GemigliptinL-tartrate hydrate (ZemigloÒ)Gemigliptin is a prolyl-specific dipeptidyl aminopeptidase IV(DPP IV, DPP-4, CD26) inhibitor approved for the treatment of type
2 diabetes mellitus by the Korean Food and Drug Administration in
2012 Gemigliptin was discovered and developed by LG LifeSciences81and is now the sixth DPP-4 inhibitor approved for thetreatment of type 2 diabetes.82At the time this review was pre-pared, there were no publications describing the discovery strategyand preclinical data that led to the advancement of gemigliptin to
O OEt HO
F F
NfSO2Cl, Et3N, CH2Cl2
O OEt NfO
F F
O OEt EtO
F F O
NaBH4, EtOH
Br EtO
F F
O
O OEt
O NH 2
F F
OH
OH O OH O
O NH
F F
87
3 tartaric acid EtOH, H 2 O
Boc
Boc Boc
Boc
Scheme 13 Synthesis of gemigliptin L -tartrate hydrate (X).
Trang 13the clinic Additionally, the synthesis of the drug has only been
described in the patent literature.83–85
The molecule was prepared via a convergent route and the
syn-thesis of the dihydropyridopyrimidine fragment is described in
Scheme 11.85 Commercial N-Boc-3-piperidone (71) was treated
with LHMDS followed by ethyl trifluoroacetate to effect a Claisen
condensation, producing diketone 72 in 81% yield Cyclization of
72 with 2,2,2-trifluoroacetamide (73) gave bis-trifluoromethyl
dihydropyridopyrimidine 74 in 23% yield Removal of the Boc
pro-tecting group efficiently provided amine 75 in 96% yield
The synthesis of the carbon skeleton of the difluoropyridone
fragment 80 is described inScheme 12.841,4-Addition of ethyl
bro-modifluoroacetate (76) to ethyl acrylate (77) in the presence of
copper powder and tetramethylethylenediamine (TMEDA) gavediester 78, which was selectively reduced with sodium borohy-dride (NaBH4) to give alcohol 79 in 90% overall yield for thetwo-step procedure Alcohol 79 was then treated with perfluo-robutanesulfonyl chloride and triethylamine to give activatedalcohol 80 in 75% yield
The completion of the synthesis of gemigliptin is described in
Scheme 13.83,84Boc-L-aspartic acid 4-tert-butyl ester (81) was ted with ammonium bicarbonate and pyridine in the presence ofdi-tert-butyl dicarbonate to give formamide 82 Dehydration of
trea-82 to give nitrile 83 was accomplished through reaction with nuric chloride in 95% overall yield for the two-step sequence.Hydrogenation of 83 in the presence of Pearlman’s catalyst
cya-N OTs
NN
180 °C, 92% N
N
NH2
N N OPh
91
Boc
92
Cs2CO3, KI DMF, ↑↓
32%
N N
NH 2
N N OPh
N Boc
1 4 N HCl, THF, ↑↓
2 30% aq NaOH (pH ~9), rt
N N
NH2
N N OPh
N O
H 2 NCHO
50% for 3 steps
Scheme 14 Synthesis of ibrutinib (XI).
N N O
NH2O
NH NH O
N N
O
NH2
NH2O
HO
O CN
N
HO O
O O
N N O
H
O O
99
DMF, 50 °C 68%
47% for 2 steps
XII Istradefylline
Scheme 15 Synthesis of istradefylline (XII).
Trang 14provided butyl amine 84 Alkylation of 84 with activated alcohol
80 in triethylamine followed by cyclization in acetic acid afforded
difluoropyridone 85 Acidic hydrolysis of the ester proceeded with
concomitant removal of the Boc protecting group, and was
fol-lowed by reprotection of the amine with di-tert-butyl dicarbonate
to give acid 86 in 84% overall yield for the three-step procedure in
>97% ee Coupling of 86 with fragment 75 in the presence of
1-hy-droxybenzotriazole (HOBT) and
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDC) gave amide 87 in 51% yield Removal
of the Boc group with thionyl chloride in ethanol followed by
neu-tralization with aqueous sodium hydroxide and salt formation
withL-tartaric acid provided gemigliptinL-tartrate hydrate (X) in97.5% yield.83
12 Ibrutinib (ImbruvicaÒ)Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase(BTK) which was granted breakthrough status by the U.S Foodand Drug Administration in 2013 for the treatment of mantle celllymphoma (MCL) and in 2014 for chronic lymphocytic leukemia(CLL).86 In preclinical studies involving CLL cells, the drug effec-tively promoted apoptosis, inhibited proliferation, and also
CN O Cl
O O
O
N OH
O
N N O
AlCl3, NHEt2toluene, rt
1 SOCl2, toluene
rt to 50 °C
1 ethanolamine toluene, 83 °C
XIII Levomilnacipran hydrochloride
Scheme 16 Synthesis of levomilnacipranHCl (XIII).
NH2
HN
F 3 C
Br O
HO
Br O
O
1 COCl2, DMF (cat)/CH2Cl2
2 Et 3 N, CF 3 CH 2 NH 2 , 0 °C 71% for 2 steps
N O
I +
65% for 3 steps HO
Scheme 17 Synthesis of lomitapide mesylate (XIV).