Abbreviations: AIBN, 2,2 0 -azobisisobutyronitrile; Boc, t-butoxycarbonyl; CBZ, benzyloxycarbonyl; CDI, N,N 0 -carbonyldiimidazole; CMHP, cumene hydroperoxide; DBN, 1,5-diazabicyclo[4.3.
Trang 1Synthetic approaches to the 2009 new drugs
a
Pfizer Inc., La Jolla, CA 92037, USA
b
Pfizer Inc., Groton, CT 06340, USA
c
Shenogen Pharma Group, Beijing, China
a r t i c l e i n f o
Article history:
Received 12 November 2010
Revised 15 December 2010
Accepted 16 December 2010
Available online 24 December 2010
Keywords:
Synthesis
New drug molecules
New chemical entities
Medicine
Therapeutic agents
a b s t r a c t
New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target These new chemical entities (NCEs) provide insights into molecular rec-ognition and also serve as leads for designing future new drugs This review covers the syntheses of 21 NCEs marketed in 2009
Ó 2011 Elsevier Ltd All rights reserved
Contents
1 Introduction 1137
2 Armodafinil (NuvigilÒ) 1138
3 Asenapine maleate (SaphrisÒ) 1140
4 Besifloxacin hydrochloride (BesivanceÒ) 1142
5 Dapoxetine hydrochloride (PriligyÒ) 1142
6 Degarelix acetate (FirmagonÒ) 1144
7 Dexlansoprazole (DexilantÒ) 1144
8 Dronedarone hydrochloride (MultaqÒ) 1146
9 Eltrombopag olamine (PromactaÒ) 1146
10 Eslicarbazepine acetate (ExeliefÒ) 1147
11 Febuxostat (UloricÒ) 1147
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd All rights reserved.
Abbreviations: AIBN, 2,2 0 -azobisisobutyronitrile; Boc, t-butoxycarbonyl; CBZ, benzyloxycarbonyl; CDI, N,N 0 -carbonyldiimidazole; CMHP, cumene hydroperoxide; DBN, 1,5-diazabicyclo[4.3.0]on-5-ene; DBTA, dibenzoyl tartaric acid; DCE, dichloroethane; DCM, dichloromethane; DET, diethyl tartrate; DIAD, diisopropyl azodicarboxylate; DIBAL-H, diisobutylaluminum hydride; DIC, N,N 0 -diisopropylcarbodiimide; DIPEA, diisopropylethylamine; DMAP, 4-dimethylaminopyridine; DMF, N,N-dimethylformamide; DMPU, N,N 0 -dimethylpropyleneurea; DMSO, methyl sulfoxide; DPPC, diphenylphosphinic chloride; EDCI, N-(3-dimethylaminopropal)-N 0 -ethylcarbodiimide; HMTA, hexamethylenetetramine; HOBT, 1-hydroxybenzotriazole hydrate; IPA, isopropyl alcohol; IPAC, isopropyl acetate; LDA, lithium diisopropylamide; LIHMDS, lithium bis(trimethylsilyl)amide; MCPBA, meta-chloroperoxybenzoic acid; MEK, methyl ethyl ketone; MS, molecular sieves; NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; NEP, N-ethylpyrrolidinone; NMM, N-methylmorpholine; NMP, 1-methyl-2-pyrrolidinone; PCC, pyridinium chlorochromate; PDC, pyridinium dichromate; PMB, 4-methoxylbenzyl; PPA, polyphosphoric acid; (S,S)-DET, (S,S)-()-diethyl tartrate; TBAF, t-butyl ammonium fluoride; TBDMSCl, t-butyldimethylsilyl chloride; TEA, triethylamine; TFA, trifluoroacetic acid; TFAA, trifluoroacetic acid anhydride; THF, tetrahydrofuran; THP, tetrahydropyran; TIPS, triisopropyl silyl; TPAP, tetrapropylam-monium perruthenate; TMG, 1,1,3,3-tetramethylguanidine; TMSCl, trimethylsilyl chloride; p-TSA, para-toluene sulfonic acid; Ts-DAEN, N-[(1S,2S)-2-amino-1,2-bis(4-methoxyphenyl)ethyl]-4-methyl-benzenesulfonamide.
⇑Corresponding author Tel.: +1 860 715 4118.
E-mail addresses: Kevin.k.liu@pfizer.com (K.K.-C Liu), subas.m.sakya@pfizer.com (S.M Sakya), christopher.j.odonnell@pfizer.com (C.J O’Donnell), andrew.flick@pfizer.com
(A.C Flick), jin.li@shenogen.com (J Li).
Tel.: +1 858 622 7391.
à
Tel.: +1 860 715 0425.
§
Tel.: +1 860 715 0228.
– Tel.: +86 10 8277 4069.
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 212 Indacaterol maleate (OnbrezÒ) 1148
13 Minodronic acid hydrate (BonoteoÒand RecalbonÒ) 1148
14 Nalfurafine hydrochloride (RemitchÒ) 1149
15 Pazopanib hydrochloride (VotrientÒ) 1150
16 Plerixafor hydrochloride (MozobilÒ) 1150
17 Pralatrexate (FolotynÒ) 1151
18 Prasugrel (EffientÒ) 1151
19 Saxagliptin (OnglyzaÒ) 1151
20 Tapentadol hydrochloride (NucyntaÒ) 1152
21 Tolvaptan (SamscaÒ) 1153
22 Ulipristal acetate (ellaOneÒ) 1153
Acknowledgments 1153
References and notes 1153
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 physiology and medicine.1
Inaugurated eight years ago, this annual review presents
synthetic methods for molecular entities that were launched in
various countries for the first time during the past year.2–8Given
that drugs tend to have structural homology across similar biolog-ical targets, it is widely believed that the knowledge of new chem-ical entities and their syntheses will greatly facilitate drug design
In 2009, 51 new products including new chemical entities, biolog-ical drugs, and diagnostic agents reached the market,9the largest number in the last decade Twelve additional products were ap-proved for the first time in 2009; however, they were not launched before year’s end and thus the syntheses of those drugs will be covered in 2010s review This review focuses on the syntheses of
II Asenapine maleate
N O
H2N
O O
IX Eslicarbazepine acetate
S
NH2
O O
I Armodafinil
O
O
H S O
VII Dronedarone hydrochloride
O NMe2
HCl
IV Dapoxetine hydrochloride
VI Dexlansoprazole
N
OH
Cl
F N
H2N
HCl
III Besifloxacin hydrochloride
O NC
N S OH O
X Febuxostat
N H N H N H N H N O
O
Cl
O
N
O OH O
NH O
NH HN O O
O
NH
NH2 O
O
O
H N
O
NH2
CH3CO2H
V Degarelix acetate
N
H
OH OH
N N O
O
VIII Eltrombopag olamine
2 NH2CH2CH2OH
N
O
S HN N O
CF3
O
N
Cl
CO2H
CO2H
•
•
•
•
Trang 321 new drugs marketed in 2009 (Fig 1) and excludes new
indica-tions for known drugs, new combinaindica-tions, new formulaindica-tions and
drugs synthesized via bio-processes or peptide synthesizers The
synthetic routes cited herein represent the most scalable methods
reported and appear in alphabetical order by generic name
2 Armodafinil (NuvigilÒ) Armodafinil, the R-enantiomer of the racemic marketed drug modafinil, was approved in June 2007 for treatment of excessive sleepiness associated with shift work sleep disorder, narcolepsy
S OMe O
S
NH2
O
NH2 O
HS OMe O
(S,S)-DET/Ti(OiPr)4
H2O, Et3N, 55 °C CMHP, EtOAc, 25 °C
O
I Armodafinil
3
4
5
MeOH, RT, –35 °C
75%, 99.5% ee 83%
N
N
O
O
O
NH2
H2N
XVI Pralatrexate
N
S O O
F
XVII Prasugrel XVIII Saxagliptin
HO
N
XIX Tapentadol hydrochloride
HCl
N
Cl HO
O
H N O
XX Tolvaptan
H O
N
H
O O O
XXI Ulipristal acetate
H
N
N N S
O
O
H2N
HCl
XIV Pazopanib hydrochloride
NH NH N HN
N NH HN HN
XV Plerixafor hydrochloride
8 HCl
N
HO N
HO2C
HO2C
XI Indacaterol maleate
N N
P OH P O OH OH
OH
H2O
XII Minodronic acid hydrate XIII Nalfurafine hydrochloride
HCl N
OH
O
O
• OH
•
•
HO
•
HO
O
NH2
N NC
OH
O
Fig 1 (continued)
Trang 4and obstructive sleep apnea/hypoapnea syndrome (OSAHS).9The
marketing of this drug was started in June 2009 by Cephalon, who
discovered and developed the drug In comparison to modafinil,
armodafinil has a long half-life due to its slower metabolism and
excretion, resulting in greater exposure of the drug and
conse-quently a longer duration of action.10Since the drug is the
enantio-merically pure form of an existing racemic drug, multiple synthetic
approaches to the enantiopure drug were utilized to progress the
compound.11To facilitate preparation of the enantiopure drug for
Phase 1 studies, a continuous chiral separation method was
devel-oped on large scale.12However, due to the cost of this process, this
route was abandoned in favor of a crystallization method.13While
exploring crystallization of various intermediates of the racemic
sulfoxide, it was discovered that the acid intermediate formed a
eu-tectic mixture Seeding of this mixture with the desired
R-enantio-mer provided the pure, desired enantioR-enantio-mer via an auto-seeded programmed polythermal preferential crystallization (AS3PC) method.14Again, however, this route was deemed unsuitable for industrial scale because the S-enantiomer was still discarded in the process Thus, an alternate catalytic oxidation method, based
on initial work from Kagan and co-workers15was developed and uti-lized in the industrial process.16The resulting synthesis is a four-step sequence that requires only two isolations and delivers the final target in high chemical and chiral purity (Scheme 1) Benzhydrol (1) was added to a mixture of acetic anhydride and catalytic sulfuric acid in DCM at 0 °C to give acetate 2 Crude 2 was reacted with methyl thioglycolate (3) and the reaction mixture was warmed to
20 °C to provide ester 4, carried on to the next step without isolation Ester 4 was then subjected to three volumes of ammonia in metha-nol at room temperature (rt) and warmed to 35 °C Upon completion
N
O OH O
Cl
F N
H2N N
O OH O
Cl
F N
N N
O OH O
Cl F
N
NO2
Cl F F
F
O OEt O
NH Cl
F F
F
O OEt O
OEt Cl
F F
F
O OEt
O HC(OEt)3
HCl MeOH
100 °C
16
17
18 III Besifloxacin hydrochloride
• HCl
NH2 neat, RT
NO2
TEA, CH3CN, RT
O
CO2H Cl
O Cl
1 SOCl2, PhCH3,↑↓
2 sarcosine methyl ester TEA, DMF, RT, 45%
N
RT, 71%
O Cl
N
PPA, 110 °C, 62%
or
H3PO4, P2O5
O
N O Cl
Mg, I2 (cat) MeOH, PhCH3
<40 °C, ~100%
10:11 = 1:4
O
N O Cl
O
N O
Cl
1 KOH, EtOH,↑↓
2 HCl, PhCH3, RT
3 crystallization
O
HO2C Cl
12
NHMe
• HCl
NaOAc, PhCH3
↑↓, 65% from 9
O
N O
Cl
10
1 LiAlH4, AlCl3, THF PhCH3, <15 °C, 100%
2 maleic acid, EtOH, RT
3 re-crystallize
O
N
Cl
II Asenapine maleate
CO2H
CO2H
•
Scheme 2 Synthesis of asenapine maleate (II).
Trang 5of the reaction, the mixture was cooled to 25 °C and water was added
to precipitate the desired amide 5, obtained by filtration in 83% yield
Amide 5 was then poised for the aforementioned asymmetric
oxidation step, and thus dissolved in ethyl acetate and treated with
(S,S)-()-diethyl tartrate, titanium(IV) isopropoxide, and water and
stirred at 55 °C for 50 min The mixture was then cooled to room
temperature (25 °C) and triethylamine and cumene hydroperoxide
(CMHP) were added The reaction mixture was stirred for 1 h and
the resulting product precipitated and collected by filtration to provide the armodafinil (I) in 75% yield with 99.5% ee
3 Asenapine maleate (SaphrisÒ) Asenapine is an atypical antipsychotic approved in the U.S for acute treatment of schizophrenia in adults and the acute treatment
of mania or mixed episodes associated with bipolar I disorder in
Cl
OH 1-naphthol
50%NaOH (aq) DMF, RT, 90%
O
OH 1 MsCl, Et
3N, DMAP THF, 0 °C; Me2NH, RT
2 HCl, EtOAc, 67% for 2-steps
3 recrystallize from IPA 86%, 99.6% ee
O NMe2• HCl
IV Dapoxetine hydrochloride
Scheme 4 Synthesis of dapoxetine hydrochloride (IV).
O CH3
O
1) DIC, HOBT, DMF DCM, H2N-resin 2) TFA, DCM H2N
H
CH3
O
1) Boc-L-proline, DIC HOBT, DMF 3) Boc-L-N6
-i-Pr-N6
-Z-lysine DIC, HOBT, DMF 2) TFA, DCM
4) TFA, DCM
H2N
N
O HN resin
1) Boc-L-leucine DIC, HOBT, DMF 2) TFA, DCM
H2N O
H N N
O HN resin
1) Boc-D-4-(Fmoc-am ino)phenyl alanine, DIC, HOBT, DMF 2) piperidine, DMF
4) TFA, DCM
N O
H N
O HN resin
H2N
NH
NHtBu
O
O
1) Boc-L-4-(Fmoc-amino)phenylalanine DIC, HOBT, DMF
2) piperidine, DMF
OH O
NH HN O O
4) TFA, DCM
N O
H N
O HN resin
H
NH
NHtBu
O
O
H2N
NH O
NH HN O O
O
1) Boc-L-serine(O-Bzl) DIC, HOBT, DMF 2) TFA, DCM
25
26
3)
3) Boc-D-3-pyridyl-alanine DIC, HOBT, DMF 4) TFA, DCM
Cbz N
Cbz
DIC, HOBT, DMF
Cbz N
resin
Trang 6adults Although asenapine potently antagonizes a wide variety of
serotonin and dopamine receptors, its pharmacological activity is
attributed to its antagonism of the 5-HT2Aand D1/D2 receptors.17
Asenapine was discovered and developed by Organon and later
co-developed in collaboration with Pfizer In 2006, however, Pfizer
discontinued co-development of asenapine and in 2007 Organon
was acquired by Schering-Plough who completed the
develop-ment The drug is now marketed by Merck & Co after their
acquisition of Schering-Plough in 2009 Several synthetic routes
for the preparation of asenapine have been disclosed,18,19 and
the largest reported process scale route is described in Scheme
2.20–235-Chloro-2-phenoxyphenylacetic acid (6) was treated with
thionyl chloride to generate the corresponding acid chloride that
was subsequently treated with sarcosine methyl ester to give
amide 7 in 45% overall yield Treatment of compound 7 with
potassium tert-butoxide in toluene effected a Dieckmann-like
condensation to provide oxo-lactam 8 in 71% yield An intramolec-ular Friedel–Crafts alkylation-dehydration sequence was then performed by subjecting 8 to polyphosphoric acid, affording unsat-urated lactam 9 in 62% yield Alternatively, reacting 8 with phos-phoric acid and phosphorous pentoxide would also deliver 9 Reduction of 9 with magnesium in methanol and catalytic iodine gave a 1:4 mixture of the desired trans-lactam 10 to the undesired cis-lactam isomer 11 in quantitative conversion In the initial route,
10 was separated from 11 via column chromatography and 11 could be epimerized to 10 upon treatment with DBU After two recycling steps, compound 10 was prepared in 32% yield However,
a higher-yielding route that avoided the epimerization of 11 and column chromatography was later developed The mixture of lactams (10 and 11) were treated with KOH in refluxing ethanol
to affect lactam ring-opening These basic conditions facilitated concomitant epimerization of the corresponding cis-amino acid
N
H N N
H N N
H N N
H N N O
O
Cl
O
N
O OH O
NH O
NH HN
O O
O
NH
NH2 O
O
O
H
O
NH2
CH3CO2H
V Degarelix acetate
N H O
H N N
O HN resin
H N
NH
NHtBu
O
O N
NH O
NH HN
O O
O
H2N
H N N
O OBzl
O
1) Boc-D-4-chlorophenylalanine DIC, HOBT, DMF
2) TFA, DCM 3) Boc-D-2-naphthylalanine DIC, HOBT, DMF 4) TFA, DCM
N H O
H N
O HN resin
H N
NH
NHtBu
O
O N
H
NH O
NH HN
O O
O
N H
H N N
O OBzl
O
H2N
H N O
Cl
O
1) Ac2O,DCM 2) HF, anisole, 0 °C 3) CH3CO2H, H2O
27
28
Cbz N
Cbz N
Scheme 5 (continued)
Trang 7product to the trans-amino acid 12, which upon treatment with
sodium acetate in refluxing toluene regenerated trans-lactam 10
as a single isomer in 65% yield from 9 Reduction of 10 with lithium
aluminum hydride followed by maleic acid co-crystallization
provided asenapine maleate (II) in 70% yield
4 Besifloxacin hydrochloride (BesivanceÒ)
Besifloxacin is a fourth-generation fluoroquinolone antibiotic
which is marketed as besifloxacin hydrochloride It was originally
developed by the Japanese firm SSP Co Ltd and designated
SS734 SSP then licensed U.S and European rights of SS734 for
oph-thalmic use to InSite Vision, Inc., in 2000, who then developed an
eye drop formulation (ISV-403) and conducted preliminary clinical
trials before selling the product and all rights to Bausch & Lomb in
2003 The eye drop was approved by the United States Food and
Drug Administration (FDA) on May 29, 2009 and marketed under
the trade name Besivance.24aBesifloxacin has been found to inhibit
production of pro-inflammatory cytokines in vitro The synthesis of
besifloxacin commences with commercially available ethyl
3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate (13, Scheme
3 24b Condensation of this ketoester with triethyl orthoformate resulted in a mixture of vinylogous esters 14 Substitution with cyclopropanamine converts 14 to the vinylogous amide 15 as an unreported distribution of cis- and trans-isomers This mixture was treated with base at elevated temperature to give 16 Presumably, the trans-isomer isomerizes to the cis-isomer, which subsequently undergoes an intramolecular nucleophilic aromatic substitution with concomitant saponification to construct quinolone acid 16 Quinolone 16 is then subjected to another nucleophilic substitution involving readily available iminoazepine
17 and the displacement reaction proceeds regioselectively to fur-nish the atomic framework of besifloxacin (18) Acidic methanoly-sis of 18 at elevated temperature gave besiflozacin (III)
5 Dapoxetine hydrochloride (PriligyÒ) Dapoxetine is a selective serotonin re-uptake inhibitor (SSRI) which has been approved in Finland and Sweden for the treatment
of premature ejaculation.25Dapoxetine was discovered and devel-oped by Lilly and was licensed to Alza, a wholly-owned subsidiary
of Johnson & Johnson Several synthetic routes for the preparation
anisoyl chloride SnCl4, DCE, RT
O
O2N
nBu
35
AlCl3 DCE,↑↓
O
O2N
nBu
36
N Cl
37
K2CO3, MEK, RT
O
O2N
nBu
N
38
1 H2(3.4 atm) PtO2, EtOH, RT
2 MsCl, Et3N DCE, RT
O
O H
CO2Me
n-Bu
HNO3, H2SO4
O H
CO2H
n-Bu
O2N
Ac2O,K2CO3 DMF, 130 °C
O2N
nBu
34
O
H
nBu
N
VII Dronedarone hydrochloride 61% from 38
100%
95% from 34
S
N
O
S HN N
(R)-(+)-DET/H2O/Ti(iOPr)4
DIPEA, CMHP, PhCH3
–5–0 °C 80%, 98% ee
N
O
S HN N O
29
N
NO2
S HN N
(R)-(+)-DET/H2O/Ti(iOPr)4
DIPEA, CMHP THF, –5–0 °C 80%, 98% ee
N
NO2
S HN N
O KOH, CF3CH2OH
O
S HN N O
CF3
Dexlansoprazole (VI)
Dexlansoprazole (VI)
Scheme 6 Synthesis of dexlansoprazole (VI).
Trang 8Br
NaNO3, H2SO4, H2O CH3I, K2CO3
acetone, ↑↓, 76%
VIII Eltrombopag olamine
OH Br
NO2
10 °C, 25%
OMe Br
NO2
Pd(PPh3)4, Na2CO3(2 M )
OMe
NO2
CO2H
48% HBr, CH3CO2H
↑↓, 79%
OH
NO2
CO2H H2, Pd/C, 50 psi NaOH (3M), EtOH
RT, 100%
OH
NH2
CO2H
NHNH2
↑↓, 76%
N
H
OH OH
N N O
O
N HN O OH
NH2
CO2H
N HN O
+
1 NaNO2, HCl (1 M) NaHCO3, EtOH, 5 °C, 32%
2 NH2CH2CH2OH, MeOH
RT, 98%
44 43
42
3-carboxyphenyl boronic acid, dioxane,↑↓, 47%
• 2 NH2CH2CH2OH
OEt
Scheme 8 Synthesis of eltrombopag olamine (VIII).
( S)
N O
H2N
O O
IX Eslicarbazapine acetate
N
O
H2N
O
N O
H2N HO
N O
H2N
O O
RuCl2(p-Cymene)2
HCOOH, DMF,↑↓
Et3N, H2O, AcOH
cat DMAP
Ac2O, pyridine DCM,↑↓
90%
cat DMAP
Ac2O, pyridine
RT, 88%
48
49
50
51, H2
EtOAc, RT
O
NH
NH2 O
S O O
P P H H
Rh tBu tBu
[Rh(COD)(RcSp-DuanPhos)]BF4
BF4
51
2 MTBE, 80 °C – RT 95%, 97.8% ee
Scheme 9 Synthesis of eslicarbazepine acetate (IX).
Trang 9of dapoxetine have been disclosed, all on gram scale.26 Based on
the routes and yields, the most likely process route is described
inScheme 4.27Commercially available
(R)-(+)-3-chloro-1-phenyl-1-propanol (19) was reacted with 1-naphthol in the presence of
50% aqueous sodium hydroxide in DMF to give ether 20 in 90%
yield Activation of the secondary alcohol was accomplished
through treatment of 20 with methane sulfonyl chloride and
tri-ethylamine with catalytic DMAP Upon complete conversion to
the corresponding mesylate, dimethylamine was added to the
reaction mixture The addition of hydrochloric acid in ethyl acetate
to the resultant crude product gave dapoxetine hydrochloride (IV)
in 67% yield Purification of this material by re-crystallization from
isopropanol provided IV in 86% yield and in 99.6% ee
6 Degarelix acetate (FirmagonÒ)
Ferring launched degarelix acetate, a gonadotrophin-releasing
hormone (GnRH) antagonist, in 2009 in the U.S for the treatment
of prostate cancer.28 The compound has been approved by the
E.U for the same indication, and in the same year it was launched
in the UK and Germany Degarelix has been developed as a
one-month or three-month sustained-release injectable
formula-tion Compared to other GnRH antagonists, degarelix displays
improved aqueous solubility, longer acting effects and weaker
histamine-releasing properties The synthesis of degarelix acetate
employed iterative peptide coupling and protection/de-protection
sequences in high yields (85–99%), and this sequence is described
inScheme 5.29,30Boc-D-alanine (21) was immobilized via MBHA
resin (Bachem) by reaction with diisopropyl carbodiimide (DIC)
and 1-hydroxybenzotriazole (HOBT) The resulting product was
treated with trifluoroacetic acid (TFA) to remove the N-Boc
protecting group to reveal amine 22 The N-terminus of 22 was
then subjected to sequential coupling and de-protection cycles
with the following protected amino acids: N-Boc-L-proline, N-a
-Boc-N6-isopropyl-N6-carbobenzoxy-L-lysine and N-Boc-L-leucine
to give 23 and 24, respectively The N-terminus of 24 was coupled
with N-a-Boc-D-4-(Fmoc-amino)phenylalanine, followed by
re-moval of the Fmoc group with piperidine in DMF to give the
corresponding free aniline The free aniline resin was then reacted
with t-butyl isocyanate to generate the corresponding t-butyl urea
followed by reaction with TFA to remove the Boc group to give the t-butyl urea amine 25 The N-terminus of 25 was coupled with N-a-Boc-L-4-(Fmoc-amino)phenylalanine, followed by removal of the Fmoc group with piperidine in DMF to generate the corre-sponding free aniline The free aniline was reacted withL -hydroo-rotic acid, followed by reaction with TFA to liberate amine 26 Amine 26 was then coupled with O-benzylated-N-Boc-serine, followed by removal of the Boc group with TFA and reacting the resulting amine with N-a-Boc-D-(3-pyridyl)alanine and subse-quent removal of the Boc group with TFA gave amine 27 Amine
27 was coupled with N-Boc-D-(4-chlorophenyl)alanine, followed
by removal of the Boc group with TFA, and the resulting amine was then coupled with N-Boc-D-(2-naphthyl)alanine, followed by removal of its Boc group with TFA to give 28 Acylation of 28 with acetic anhydride followed by sequential treatment with HF and TFA resulted in cleavage from the resin, removal of the O-benzyl group, and conversion of the t-butyl urea to the corresponding
NH2-urea, resulting in free degarelix Finally, treatment with acetic acid provided degarelix acetate (V)
7 Dexlansoprazole (DexilantÒ) Takeda Pharmaceuticals received approval of dexlansoprazole, a dual release formulation of the (R)-isomer of lansoprazol proton pump inhibitor (PPI) already in the market, from the FDA in January
2009.9Dexlansoprazole is a delayed release capsule for the once-daily, oral treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD), the healing
of erosive esophagitis (EE) and the maintenance of healed EE.31,32
The dual release formulation is designed to provide two separate releases of medication, one at 1–2 h and then another at 4–5 h after treatment, for extended efficacy in the treatment of GERD.33Similar
to the synthesis of the chiral sulfoxide of armodafinil vide supra, the preparation of the chiral sulfoxide of lansoprazole utilized the cat-alytic oxidation method developed by Kagan and co-workers (Scheme 6).15 Two routes have been reported that describe the preparation of dexlansoprazole on large scale The first route developed by Takeda reacts commercially available thioether 29, also used to make lansoprazole, under the Kagan asymmetric oxi-dation conditions34and the alternative route utilizes the cheaper
HO
S
NH2
OEt Br
EtOH,↑↓
HO
N
OEt
HO
N
OEt OHC
HMTA, PPA
O
N
OEt OHC
NH2OH•HCl HCO2Na
O
N
OEt NC
Br
KI, K2CO3, DMF, RT
2 N NaOH THF, H2O
O
N
OH NC
X Febuxostat
52
53
57 56
58
80 °C
HCO2H, ↑↓
Trang 10commercial intermediate nitrosulfide 30 in the analogous
asym-metric oxidation by Kagan (Scheme 6).35Thus, the catalyst complex
consisting of (+)-DET, Ti(OiPr)4and water was formed in the
pres-ence of thioether 29 in toluene at 30–40 °C The reaction mixture
was then cooled to 5 °C and DIPEA and cumene hydroperoxide
(CMHP) were added to give, after aqueous work-up and in situ
crys-tallization from the organic layer, dexlansoprazole (VI) in 98% ee
No yield was given in the patent An alternate, but similar, sequence was also described wherein the nitrosulfide intermediate 30 was subjected to similar oxidative conditions that gave intermediate ni-tro compound 31 in 80% yield and 98% ee Compound 31 was trea-ted with KOH and trifluoroethanol to provide dexlansoprazole (VI)
Cl
O O
O
H
O O
O
H
O O
O Br
N
NH2
Et3N, EtOH, ↑↓
50%
N
N
HCl, DCM
RT, 58%
N
N
H3PO3, PhCH3
↑↓, 53%
N N
P OH P O OH OH
OH
H2O
XII Minodronic acid hydrate
•
LiAlH(Ot-Bu)3
THF, –80 °C, 61%
1 Me3SiCl, Et3N
2 Br2, CCl4, RT 62% for 2 steps
NH2
59
F3C OEt O
61
CF3
O CH3COCl, AlCl3
2-methyl
62
CF3 O O
H2, 10% Pd/C
63
CF3
O Et
1 CH3COCl, AlCl3
iPrOAc, 0 °C
2 H2, 10% Pd/C
64
CF3
O Et
Et
1 NaOH EtOH, 78 °C
2 HCl (g),
iPrOAc, RT
NH2
Et Et
65
N OH
1 AcCl, AlCl3
DCE, 70 °C
2 BnBr, K2CO3
O Bn
O
2 Ac2O, 40 °C
H O Bn
O O
1 Br2, BF3•OEt2
DCM, RT
2 BH3•Me2S, (+)-CBS THF, 81%, 91% ee
H O Bn
OH O
Br
1 K2CO3, acetone
10 °C
2 65, DME, 110 °C
H O R
OH
O
H
Et Et
66
69
70: R = Bn XI: R = H Indacaterol maleate
1 H2, Pd, AcOH
2 maleic acid, EtOH, 70 °C
60
83% from 69
O
O
OH OH
• HCl
•
Scheme 11 Synthesis of indacaterol maleate (XI).