The synthesis of the C1–C13 aldehyde fragment 23 is described inScheme 6.L-Mannonic acid-lactone 26 was reacted with cyclo-hexanone in p-toluene sulfonic acid p-TSA to give the biscyclo-
Trang 1Synthetic approaches to the 2010 new drugs
Kevin K.-C Liua, , Subas M Sakyab,à, Christopher J O’Donnellb,⇑, Andrew C Flickb,§, Hong X Dingc,– 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 27 October 2011
Revised 22 December 2011
Accepted 22 December 2011
Available online 2 January 2012
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 represents a privileged structure for its bio-logical 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 15 NCEs that were launched anywhere in the world in 2010
Ó 2011 Elsevier Ltd All rights reserved
Contents
1 Introduction 1155
2 Alogliptin benzoate (NesinaÒ) 1157
3 Bazedoxifene acetate (ConbrizaÒ) 1157
4 Cabazitaxel (JevtanaÒ) 1157
5 Diquafosol tetrasodium (DiquasÒ) 1158
6 Eribulin mesylate (HalavenÒ) 1158
7 Fingolimod hydrochloride (GilenyaÒ) 1165
8 Iloperidone (FanaptÒ) 1166
9 Laninamivir octanoate (InavirÒ) 1167
10 Mifamurtide (MepactÒ) 1168
11 Peramivir (RapiactaÒ) 1168
12 Prucalopride succinate (ResolorÒ) 1169
13 Roflumilast (DaxasÒ) 1169
14 Romidepsin (IstodaxÒ) 1171
15 Vernakalant hydrochloride (BrinavessÒor KynapidÒ) 1172
16 Vinflunine ditartrate (JavlorÒ) 1172
Acknowledgment 1172
References and notes 1172
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 physiology or medicine.1
This annual review was inaugurated nine years ago2–9and pre-sents synthetic methods for molecular entities that were launched
in various countries during 2010.10Given that drugs tend to have 0968-0896/$ - see front matter Ó 2011 Elsevier Ltd All rights reserved.
⇑ 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), Hongxia.ding@shenogen.com (H.X Ding).
Tel.: +1 858 622 7391.
à
Tel.: +1 860 715 0425.
§
Tel.: +1 860 715 0228.
– Tel.: +86 10 8277 4069.
Contents lists available atSciVerse ScienceDirect
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 2N N O
CN
NH 2
•
I Alogliptin benzoate
N HO
O N
OH • CH 3 COOH
II Bazedoxifene acetate
O N O
O O
OH OHO
O
O O O
H O O
O
III Cabazitaxel
HN N O
O O
HO OH
OPOPOPOPO
O O O O
O − O− O− O−
O
HO OH N HN O O
IV Diquafosol tetrasodium
•
4 Na +
PhCO2H
NH2 OH
HO
• HCl
VI Fingolimod hydrochloride
O N F
O O
VII Iloperidone
O O
HO
O O OH
O H
HN HN NH
NH2 O
VIII Laninamivir octanoate
H N
H
N OP O O (CH2)14CH3 O
O
OO NH2
O O O
OH
H OH
O −
O
O (CH2)14CH3 O
Na+
• H 2 O
IX Mifamurtide
HN
OH
NHH O
O OH
NH
H 2 N
X Peramivir
O
NH 2
Cl
H O
• CO 2 H
HO 2 C
XI Prucalopride succinate
O
O F F
O N N Cl
Cl
XII Roflumilast
HN H S
O
O
NH O N O
S O O
XIII Romidepsin
N N
O
H H HO O O O O
N
N
F F
O O
• 2 C 4 H6O6
XV Vinflunine ditartrate
O
O O O
MeO
O O O H
H 2 N HO
O
O O
V Eribulin mesylate
• CH 3 SO3H
O
H3CO
H3CO
N OH
HCl
XIV Vernakalant hydrochloride
• H
Figure 1 Structures of 15 new drugs marketed in 2010.
Trang 3structural homology across similar biological targets, it is widely
believed that the knowledge of new chemical entities and their
syntheses will greatly accelerate drug design In 2010, 29 new
products, including new chemical entities, biological drugs, and
diagnostic agents reached the market.10 This review focuses on
the syntheses of 15 new chemical entities that were launched
any-where in the world for the first time in 2010 (Fig 1) and excludes
new indications for previously launched medications, new
combi-nations, new formulations and drugs synthesized via bio-processes
or peptide synthesizers Although the scale of the synthetic routes
were not disclosed in all cases, this review attempts to highlight
the most scalable routes based on the patent or primary literature
and appear in alphabetical order by generic name The syntheses of
new products that were approved for the first time in 2010 but not
launched before year’s end, will be covered in the 2011 review
2 Alogliptin benzoate (NesinaÒ)
Alogliptin benzoate is a dipeptidyl peptidase IV (DPPIV)
inhibi-tor discovered by Takeda Pharmaceuticals and approved in Japan
in 2010 for the treatment of type II diabetes mellitus.10Alogliptin
is an oral drug for once a day dosing to complement diet and
exer-cise Alogliptin is the most selective marketed DPPIV inhibition and
has similar PK and PD properties compared to previous entries.11,12
The discovery, structure–activity relationship of related analogs,
and synthesis of this compound have been recently published.13
The most convenient synthesis for scale-up will be highlighted
from several published routes (Scheme 1).13–16 Commercially
available 2-cycanobenzyl amine 1 was reacted with
methylisocya-nate in DCM at ambient temperature to provide N-methyl urea 2 in
85% yield Reaction of the urea 2 with dimethyl malonate in
reflux-ing ethanol with sodium ethoxide as base gave the cyclized trione
3 in 78–85% yield The trione 3 was then refluxed in neat POCl3to
provide the penultimate chloride crude 4 in 95% yield which was
reacted with Boc-protected diamine 5 in the presence of potassium
carbonate in DMF to furnish alogliptin I in 93–96% yield Treatment
of alogliptin with benzoic acid in ethanol at 60–70 °C followed by
crystallization delivered the desired alogliptin benzoate (I)
3 Bazedoxifene acetate (ConbrizaÒ)
The selective estrogen receptor modulator bazedoxifene acetate
was approved in Spain for the treatment of osteoporosis in
postmenopausal women.10 The drug was discovered by Wyeth
(now Pfizer) and licensed to Almirall.10Clinical trials with
baze-doxifene along with conjugated estrogens demonstrated
signifi-cant improvement in bone mineral density and prevented bone loss in postmenopausal women without osteoporosis It also reduces fracture risks among women with postmenopausal oster-oporosis.10 Among many syntheses reported for this drug,17–22
the most recent process scale synthesis (multi-kg scale) is high-lighted22 and involves the union of azepane ether 9 and indole
12 4-Hydroxybenzyl alcohol (6) was converted in two steps to chloride 9 (Scheme 2) The reaction of 6 with 2-chloroethyl aze-pane hydrochloride (7) in a biphasic mixture of sodium hydroxide and toluene in the presence of tetrabutylammonium bromide (TBAB) gave the desired intermediate alcohol 8 in 61% yield Treat-ment of 8 with thionyl chloride (SOCl2) gave the requisite chloride
9 in 61% yield The reaction of 2-bromopropiophenone (10) with an excess of 4-benzyloxy aniline hydrochloride (11) in the presence of triethylamine (TEA) in N,N-dimethylformamide (DMF) at elevated temperatures resulted in indole 12 in 65% yield Alkylation of 12 with benzylchloride 9 in the presence of sodium hydride (NaH) afforded N-alkylated compound 13 The benzyl ether functional-ities from compound 13 were removed via hydrogenolysis and subsequently subjected to acidic conditions, providing diol 14 as the hydrochloride salt in 91% yield The hydrochloride was then ex-changed for the acetate via free base preparation with 5% sodium bicarbonate or triethylamine, followed by treatment with acetic acid giving bazedoxifene acetate (II) in 73–85% yield
4 Cabazitaxel (JevtanaÒ) Cabazitaxel was developed by Sanofi-Aventis as an intravenous injectable drug for the treatment of hormone-refractory metastatic prostate cancer.23 As a microtubule inhibitor, cabazitaxel differs from docetaxel because it exhibits a much weaker affinity for P-glycoprotein (P-gp), an adenosine triphosphate (ATP)-dependent drug efflux pump.24Cancer cells that express P-gp become resis-tant to taxanes, and the effectiveness of docetaxel can be limited
by its high substrate affinity for P-gp.24Clinical studies confirmed that cabazitaxel retains activity in docetaxel-resistant tumors.23
Common adverse events with cabazitaxel include diarrhea and neutropenia Cabazitaxel in combination with prednisone is an important new treatment option for men with docetaxel-refrac-tory metastatic CRPC (castration-resistant prostate cancer).23The semi-synthesis of cabazitaxel25 started from 10-deacetylbaccatin III (15) which can be prepared from 7-xylosyl-10-deacetylbaccatin natural product mixture according to a literature process proce-dure (Scheme 3).2610-Deacetylbaccatin III was protected with tri-ethylsilyl chloride (TESCl) in pyridine to afford the corresponding 7,13-bis-silyl ether in 51% yield, which was methylated with MeI
HN
NHBoc
DMF, 75 °C
N N O
N O
CN
NHBoc
N N O
CN
NH 2
O
I Alogliptin benzoate 5
I Alogliptin
PhCOOH EtOH, 60-70 °C
NH NH O
NC
N N O
O
CN
N N O
Cl O
NC
1
93-96%
NH2
NC
M eNCO, Et3N
DCM, RT 85%
EtO2CCH2CO2Et NaOEt EtOH, ↑↓
78-85%
2
OH POCl 3
↑↓
~95%
K2CO3
Trang 4and NaH in DMF to give 10-methoxy-7,13-bis silyl ether 16 in 76%
yield After de-silylation of 16 with triethylamine trihydrofluoride
complex at room temperature, triol 17 was obtained in 77% yield
Selective methylation of 17 with MeI and NaH in DMF at 0 °C
pro-vided 7,10-dimethyl ether 18 in 74% yield Compound 18 was
con-densed with commercially available oxazolidinecarboxylic acid 19
in the presence of
dicyclohexylcarbodiimide/dimethylaminopyri-dine (DCC/DMAP) in ethyl acetate at room temperature to generate
ester 20 in 76% yield The oxazolidine moiety of compound 20 was
selectively hydrolyzed under mild acidic conditions to yield the
hy-droxy Boc-amino ester derivative cabazitaxel (III) in 32% yield
5 Diquafosol tetrasodium (DiquasÒ)
Diquafosol tetrasodium was approved in April 2010 as DiquasÒ
ophthalmic solution 3% for the treatment of dry eye syndrome and
launched in Japan by Santen Pharmaceuticals.10Diquafosol
tetra-sodium was originally discovered by Inspire Pharmaceuticals In
2001, it was licensed to Santen for co-development and
commer-cialization in Asian countries, and co-developed in collaboration
with Allergan for the countries outside of Asia In the US,
diquafo-sol tetrasodium was submitted for a New Drug Application (NDA)
as ProlacriaÒ(2% ophthalmic formulation) in June 2003 However,
it is still in Phase III clinical development for dry eye syndrome
Diquafosol tetrasodium, also known as INS-365, is a P2Y2receptor
agonist, which activates P2Y2receptor on the ocular surface,
lead-ing to rehydration through activation of the fluid pump mechanism
of the accessory lacrimal glands on the conjunctival surface.27The
large-scale synthesis route of diquafosol tetrasodium is described
in Scheme 4.28,29 Commercially available uridine 50-diphosphate
disodium salt (21) was transformed into the corresponding
tribu-tylamine salt by ion exchange chromatography on Dowex 50 using
Bu3NH+ phase, and then dimerized by means of CDI in DMF at
50 °C The crude product was purified by Sephadex DEAE column
followed by ion exchange using a Dowex 50W resin in Na+mode The one-pot process provided diquafosol tetrasodium (IV) in 25% yield.29
6 Eribulin mesylate (HalavenÒ) Eribulin is a highly potent cytotoxic agent approved in the US for the treatment of metastatic breast cancer for patients who have received at least two previous chemotherapeutic regimens.30 Erib-ulin was discovered and developed by Eisai and it is currently undergoing clinical evaluation for the treatment of sarcoma (PhIII) and non-small cell lung cancer which shows progression after plat-inum-based chemotherapy and for the treatment of prostate can-cer (PhII) Early stage clinical trials are also underway to evaluate eribulin’s efficacy against a number of additional cancers Eribulin
is a structural analog of the marine natural product halichondrin B Its mechanism of action involves the disruption of mitotic spindle formation and inhibition of tubulin polymerization which results
in the induction of cell cycle blockade in the G2/M phase and apop-tosis.31Several synthetic routes for the preparation of eribulin have been disclosed,32–35each of which utilizes the same strategy de-scribed by Kishi and co-workers for the total synthesis of halichon-drin B.36Although the scales of these routes were not disclosed in all cases, this review attempts to highlight what appears to be the production-scale route based on patent literature.37,38Nonetheless, the synthesis of eribulin represents a significant accomplishment
in the field of total synthesis and brings a novel chemotherapeutic option to cancer patients
The strategy to prepare eribulin mesylate (V) employs a conver-gent synthesis featuring the following: the late stage coupling of sulfone 22 and aldehyde 23 followed by macrocyclization under Nozaki–Hiyami–Kishi coupling conditions, formation of a challeng-ing cyclic ketal, and installation of the primary amine (Scheme 5) Sulfone 22 was further simplified to aldehyde 24 and vinyl triflate
O
Br BnO
H2N
OBn
+
BnO
N
OBn
Et3N, DMF, 120 °C, 65%
9
10
O
Cl
HO
OH
O
OH SOCl 2 , THF
55 °C to 60 °C 61%
N HCl
H2O, PhCH3 (No yield reported)
NaOH, TBAB, H2O PhCH3, RT to 90 °C 61%
N Cl HCl 7
N HCl
NaH, 9,−5 °C
2 HCl, 91%
HCl
1 NaHCO 3 (aq)
2 CH3COOH, 73%
N HO
O N
OH • CH3COOH
II Bazedoxifene acetate
N BnO
O N
OBn
N HO
O N OH
•
• HCl
•
1 H2, 10% Pd/C, EtOAc
45 °C to 50 °C
Scheme 2 Synthesis of bazedoxifen acetate (II).
Trang 525 which were coupled through a Nozaki–Hiyami–Kishi reaction.
The schemes that follow will describe the preparation of fragments
23, 24 and 25 along with how the entire molecule was assembled
The synthesis of the C1–C13 aldehyde fragment 23 is described
inScheme 6.L-Mannonic acid-lactone 26 was reacted with
cyclo-hexanone in p-toluene sulfonic acid (p-TSA) to give the
biscyclo-hexylidene ketal 27 in 84% yield Lactone 27 was reduced with
diisobutylaluminum hydride (DIBAL-H) to give lactol 28 followed
by condensation with the ylide generated from the reaction of
methoxymethylene triphenylphosphorane with potassium
tert-butoxide to give a mixture of E and Z vinyl ethers 29 in 81% yield
Dihydroxylation of the vinyl ether of 29 using catalytic osmium
teteroxide and N-methylmorpholine-N-oxide (NMO) with
concom-itant cyclization produced diol 30 in 52% yield Bis-acetonide 30
was then reacted with acetic anhydride in acetic acid in the
pres-ence of ZnCl2which resulted in selective removal of the pendant
ketal protecting group These conditions also affected peracylation,
giving rise to tetraacetate 31 in 84% yield Condensation of 31 with
methyl 3-(trimethylsilyl)pent-4-enoate in the presence of boron
trifluoride etherate in acetonitrile provided alkene 32
Saponifica-tion condiSaponifica-tions using Triton B(OH) removed the acetate protecting groups within 32 and presumably induced isomerization of the al-kene into conjugation with the terminal ester, triggering an intra-molecular Michael attack of the 2-hydroxyl group, ultimately resulting in the bicylic-bispyranyl diol methyl ester 33 as a crystal-line solid in 38% yield over two steps Oxidative cleavage of the vic-inal diol of 33 with sodium periodate gave aldehyde 34 which was coupled to (2-bromovinyl)trimethylsilane under Nozaki–Hiyami– Kishi conditions to give an 8.3:1 mixture of allyl alcohols 35 in 65% yield over two steps Hydrolysis of the cyclohexylidine ketal
35 with aqueous acetic acid followed by recrystallization gave dia-stereomerically pure triol 36 which was reacted with tert-butyldi-methylsilyl triflate (TBSOTf) to afford the tris-TBS ether 37 in good yield Vinyl silane 37 was treated with NIS and catalytic tert-butyl-dimethylsilyl chloride (TBSCl) to give vinyl iodide 38 in 90% yield Reduction of the ester with DIBAL-H produced the key C1–C14 fragment 23 in 93% yield
The preparation of the tetra-substituted tetrahydrofuran intermediate 24 is described inScheme 7.D-Glucurono-6,3-lactone
39 was reacted with acetone and sulfuric acid to give the
HN N O
O O
OH HO O P O P O
O −
O HO
HN N O
O O
HO OH
OPOPOPO PO
O O O O
O − O− O− O−
O
HO OH
N HN O O
IV Diquafosol tetrasodium
1 Dowex 50Wx4 H + , Bu3NH +
21
O −
2 Na +
•
4 Na +
•
2 CDI, DMF, 50 °C, 5 h
3 DEAE Sephadex, NH4HCO3
4 Dowex 50Wx4 Na+, 25%
Scheme 4 Synthesis of diquafosol tetrasodium (IV).
1 Et3SiCl, pyridine, RT, 51%
15
III Cabazitaxel
HO
O OH
O
HO O OH
H O O
O
16
Et 3 N•3HF, CH 2 Cl 2
17
NaH, MeI, DMF
18
O
O
N CO2H O
O
19
DCC, DMAP, EtOAc, 76%
20
OH
O MeO O OMe
H O O O
O N O O
O
O
O O
OH OHO
O
O O O
H O O
O 32%
RT, 77%
0 °C, 74%
0.1 M HCl, EtOH, 0 °C
2 NaH, MeI, DMF, 76%
7 10
O OH
O MeO O OSiEt3
H O O
O
7 10
13
HO
O OH
O MeO O OH
H O O
O
7 10
O OH
O MeO O OM e
H O O
O
7 10
13
H
O O
Scheme 3 Synthesis of cabazitaxel (III).
Trang 6O O
OTBS OTBS OTBS
H
H
I H
O
H
O O
OTBS OTBS OTBS
H
H
I MeO 2 C
H
O O
OTBS OTBS OTBS
H
H
TMS H
MeO 2 C O
O
OH OH OH
H
H
TMS H
MeO 2 C
O O OH
H
H
TMS H
MeO 2 C
O O O
O O
H
H H
MeO 2 C
O O H
O O OH
H
H H
MeO2C
O O OH AcO
O OAc H
O O
OAc MeO2C
AcO AcO O
OAc H
O O OAc
HO
HO OH
O O O O HO
O O O O
MeO
O
O O
O O H HO O
O O
O O H O O
HOH
HO OH
26
cyclohexanone
p-TSA, PhCH3
↑↓, 84%
DIBAL-H PhCH 3 , THF
−15 °C, 100%
KOtBu, THF
Ph 3 P+CH 2 OMeCl -81%
OsO4, NMO acetone, H 2 O
0 °C to 5 °C, 52%
Ac2O, AcOH ZnCl 2 , 35 °C to 40 °C 84%
MeO 2 C TMS
BF 3 •OEt, CH 3 CN
0 °C to 5 °C
Triton B(OH) THF, MeOAc 38% for 2 steps
NaIO4, EtOAc, H2O
0 °C to 10 °C NiCl 2 , CrCl 2 , DMSO
CH3CN, 0 °C to 15 °C 65% f or 2 steps 8.3:1 mixture of diastereomers
TMS Br
AcOH, H 2 O
90 °C, 71%
TBSOTf, 2,6-lutidine MTBE, 0 °C to RT, 74%
NIS, PhCH 3 , CH 3 CN TBSCl (cat), 90%
DIBAL-H, PhCH3 -75 °C, 93%
O O O
MeO
O O H
H 2 N HO
O
O O
V Eribulin mesylate
O O O
MeO
OTBS
TBSO TBSO
O
O
OTBS OTBS
H H
OH
I H
O
SO 2 Ph
22
23
H
O
MeO TBSO TBSO
CHO
MsO
O
OPiv
25
TfO
24
SO 2 Ph
1
14 27
Scheme 5 Synthesis strategy of eribulin mesylate (V).
Trang 7corresponding acetonide and the 5-hydroxyl group was then
removed by converting it to its corresponding chloride through
reaction with sulfuryl chloride (SO2Cl2) followed by hydrogenolysis
to give lactone 40 in good overall yield Reduction of the lactone
40 with DIBAL-H gave the corresponding lactol which was
con-densed with (trimethylsilyl)methylmagnesium chloride to afford
silane 41 Elimination of the silyl alcohol of 41 was accomplished
under Peterson conditions with potassium hexamethyldisilazide
(KHMDS) to afford the corresponding terminal alkene in 94% yield
The secondary alcohol of this intermediate was alkylated with
ben-zyl bromide to afford ether 42 in 95% yield Asymmetric
dihydroxy-lation of the alkene of 42 under modified Sharpless conditions
using potassium osmate (VI) dehydrate (K2OsO4), potassium
ferricyanide (K3Fe(CN)6) and the (DHQ)2AQN ligand produced the
vicinal diol which was then reacted with benzoyl chloride,
N-methylmorpholine, and DMAP to give di-benzoate 43 in
excel-lent yield as a 3:1 mixture of diastereomeric alcohols Allyl
tri-methylsilane was added to the acetal of 43 using TiCl3(OiPr) as
the Lewis acid to give 44 in 83% yield Re-crystallization of 44 from
isopropanol and n-heptane afforded 44 in >99.5% de in 71% yield
Oxidation of the secondary alcohol of 44 under the modified Swern
conditions generated the corresponding ketone which was
con-densed with the lithium anion of methyl phenyl sulfone to give a
mixture of E and Z vinyl sulfones 45 Debenzylation of 45 using
iod-otrimethylsilane (TMSI) followed by chelation-controlled
reduc-tion of the vinyl sulfone through reacreduc-tion with NaBH(OAc)3, and
then basic hydrolysis of the benzoate esters using K2CO3in MeOH
resulted in triol 46 as a white crystalline solid in 57% yield over the
five steps after re-crystallization The vicinal diol of 46 was pro-tected as the corresponding acetonide through reaction with 2,2-dimethoxypropane and sulfuric acid and this was followed by methyl iodide-mediated methylation of the remaining hydroxyl group to give methyl ether 47 The protecting groups within aceto-nide 47 were then converted to the corresponding bis-tert-butyldi-methylsilyl ether by first acidic removal of the acetonide with aqueous HCl and reaction with TBSCl in the presence of imidazole
to give bis-TBS ether 48 Then, ozonolysis of the olefin of 48 fol-lowed by hydrogenolysis in the presence of Lindlar catalyst affor-ded the key aldehyde intermediate 24 in 68% yield over the previous five steps after re-crystallization from heptane
Two routes to the C14–C26 fragment 25 will be described as both are potentially used to prepare clinical supplies of eribulin The first route features a convergent and relatively efficient syn-thesis of 25, however it is limited by the need to separate enanti-omers and mixture of diastereenanti-omers via chromatographic methods throughout the synthesis.37The second route to 25 is a much lengthier synthesis from a step-counting perspective; how-ever it takes full advantage of the chiral pool of starting materials and requires no chromatographic separations and all of the prod-ucts were carried on as crude oils until they could be isolated as crystalline solids.38
The first route to fragment 25 is described inScheme 8and was initiated by the hydration of 2,3-dihydrofuran (49) using an aque-ous suspension of Amberlyst 15 to generate the intermediate tetra-hydro-2-furanol (50) which was then immediately reacted with 2,3-dibromopropene in the presence of tin and catalytic HBr to
O O O
OH
H HO
OH
1 acetone, H2SO4
2 SO2Cl2, pyridine
CH3CN, 79% for 2 steps
O
O O
H O
O 1 DIBAL-H, PhCH3 -40 °C, 80%
O
HO
O HO
1 KHMDS THF, 94%
O O
O BnO
O O
O BnO BzO BzO
1 (DHQ)2AQN
K2OsO4·2H2O
K3Fe(CN)6, K2CO3
tBuOH, H2 O, 92%
1 AllylTMS, TiCl3(OiPr)
PhCH 3 , 30 °C, 83%
O
BnO OH
1 DMSO, TCAA
Et 3 N, PhCH 3 , -10 °C
O BnO PhO 2 S
O HO
1 TMSI, CH3CN, PhCH3, 60 °C
2 Bu4NCl, NaBH(OAc)3 DME, PhCH 3 , 85 °C
1 (CH 3 ) 2 CH(OMe) 2
H2SO4, acetone
2 NaOtBu, MeI
THF, 15 °C to RT
O
MeO
1 2 M HCl, MeOH
2 TBSCl, imidazole, DM F
O
MeO
1 O3, heptane, -50 °C
2 Lindlar cat., H 2
3 re-crystallize, heptane 68% over 5 steps
O MeO
OTBS TBSO
CHO
SO2Ph
SO2Ph
OBz OBz
OBz OBz
OH
O
OTBS TBSO
2 re-crystallize, 71%
>99.5% de
2 BzCl, NMM, DMAP PhCH3, 95%, dr = 3:1
3 H2, Pd/C, THF, 75% 2 TMSCH2MgCl
THF, 35 °C, 90%
2 BnBr, KOtBu
THF, 95%
2 LHMDS, PhSO2Me PhCH3, THF, 10 °C to RT
3 K 2 CO 3 , MeOH, 50 °C
4 re-crystallize,nBuOH
57% over 5 steps
Trang 8afford diol 51 in 45% for the two steps The primary alcohol of 51
was selectively protected as its tert-butyldiphenylsilyl ether using
TBDPSCl and imidazole and the racemate was then separated using
simulated moving bed (SMB) chromatography to give enantiopure
52 in 45% yield over the two steps The secondary alcohol of 52 was
reacted with p-toluenesulfonyl chloride and DMAP to give tosylate
53 in 78% yield which was used as a coupling partner later in the
synthesis of this fragment The synthesis of the appropriate
cou-pling partner was initiated by condensing diethylmalonate with
(R)-2-(3-butenyl)oxirane (54), followed by decarboxylation to give
lactone 55 in 71% yield for the two step process Methylation of the
lactone with LHMDS and MeI provided 56 in 68% yield as a 6:1
mixture of diastereomers The lactone 56 was reacted with the
alu-minum amide generated by the reaction of AlMe3and
N,O-dim-ethylhydroxylamine to give the corresponding Weinreb amide
which was protected as its tert-butyldimethylsilyl ether upon
reac-tion with TBSCl and imidazole to give 57 in 91% yield over the two
steps Dihydroxylation of the olefin of 57 by reaction with OsO4 and NMO followed by oxidative cleavage with NaIO4gave the de-sired coupling partner aldehyde 58 in 93% yield Aldehyde 58 was coupled with vinyl bromide 53 using an asymmetric Nozaki–Hiy-ami–Kishi reaction using CrCl2, NiCl2, Et3N and chiral ligand 66 (de-scribed inScheme 9below) The reaction mixture was treated with ethylene diamine to remove the heavy metals and give the second-ary alcohol 59 This alcohol was stirred with silica gel in isopropa-nol to affect intramolecular cyclization to give the tetrahydrofuran
60 in 48% yield over the three step process The Weinreb amide of
60 was reacted with methyl magnesium chloride to generate the corresponding methyl ketone which was converted to vinyl triflate
61 upon reaction with KHMDS and Tf2NPh De-silylation of the primary and secondary silyl ethers with methanolic HCl gave the corresponding diol in 85% yield over two steps and the resulting mixture of diastereomers was separated using preparative HPLC
to provide the desired diastereomer in 56% yield The primary
Br
OH OH Amberlyst 15
H2O, 5 °C
Br Br
Sn, HBr, H2O, 35 °C 45% for 2 steps
1 TBDPSCl, imidazole DMF, 0 °C to 15 °C
2 SMB Chromatography 45% for 2 steps
Br
OH OTBDPS
Br
OTs OTBDPS TsCl, DMAP
CH2Cl2, 78%
O
1 diethylmalonate NaOEt, EtOH, 65 °C
2 MgCl 2 , DMF, 125 °C 71% for 2 steps
MeI, LHMDS, PhCH3 THF, -78 °C, 68%
dr = 6:1
O O
1 MeNHOMe, AlM e 3
PhCH3, CH2Cl2, 0 °C
2 TBSCl, imidazole, DMF 91% for 2 steps
O N O
OTBS
1 OsO4, NMO, CH2Cl2
2 NaIO4, THF phosphate buf fer pH=7, 93%
O N O
OTBS
O H
1 53 (from above), (R)-ligand 66
CrCl2, NiCl2, Et3N, THF
2 H 2 N(CH 2 ) 2 NH 2
OTBDPS OTs
N O O TBSO
OH
iPrOH, Si2 O 48% f or 3 steps
N O O TBSO
1 MeMgCl, THF -20 °C, 88%
2 KHMDS, PhCH3, THF
Tf2NPh, -78 °C to -20 °C
TBSO
61
MsO
25
1 HCl,iPrOH, MeOH, 85%
2 HPLC separation, 56%
3 PivCl, collidine, DMAP
CH2Cl2, 0 °C, 85%
4 MsCl, Et 3 N, THF, 0 °C, 97%
OTf OTf
O
OTBDPS
O
OTBDPS
O
OPiv
Scheme 8 First synthesis route of fragment 25 of eribulin mesylate (V).
NHMs N
O MsCl, pyridine DMAP
0 °C to 25 °C 85%
NH 2
N O O
O
O
HN OH
1 D- or L -valinol DMF, 90 °C
NH2 OH
O (Cl 3 CO) 2 CO THF
0 °C to 25 °C 97%
62 63 64 (R,D -valinol)
65 (S,L -valinol)
66 (R,D -valinol)
67 (S,L -valinol)
2 LiOH.H2O
H 2 O, 60 °C
65 −75% for 2 steps
Trang 9OH
OH
HO
HO2C 1 cyclohexanone
H2SO4, 160 °C, 73%
2 TMSCl, imidazole
THF
O
O O H
TMSO
O O H
AcO
AcO
1 DIBAL-H, PhCH 3 , -78 °C
2 AcOH, H2O, 5 °C
3 Et3N, DMAP, Ac2O re-crystallize 65% for 3 steps
M eO 2 C
TMS
BF3•OEt2, CH3CN
TFAA, 62%
O
O O H
AcO
MeO2C H
1 NaOMe, MeOH
2 LAH, THF, 0 °C
O H O H
O O HO
1 MsCl, Et 3 N, THF, 10 °C
2 KCN, EtOH, H2O, 80 °C
O H O H
O O NC
O H O H
O O NC
1 KHMDS, MeI, PhCH3 THF, -78 °C
2 re-crystallize, dr = 34:1 66% over 5 steps
1 1 M HCl, AcOH, 72%
2.
AcO
Br
O
CH 3 CN, H 2 O (cat), 0 °C
O H O H
NC
OAc Br
DBU, PhCH 3 , 100 °C 63% f or 2 steps
O H O H
NC
OAc
1 O3, MeOH, CH2Cl2, -45 °C
2 NaBH4, -20 °C to 0 °C
3 K 2 CO 3 (aq)
4 NaIO4, THF, H2O
75% for 4 steps
O
O
H O H
NC
OH (MeO) 2 P CO 2 Me O
LiCl,iPr2 NEt, CH 3 CN
O O H
NC
OH
CO 2 Me
1 H2, PtO2, M eOH
2 Tf 2 O, Et 3 N, CH 2 Cl 2 , -78 °C
3 NaI, DMF
75% f or 4 steps
O O H
NC
I
CO2Me
1 LiBH 4 , PhCH 3
THF, 89%
2 Zn, AcOH, MeOH
0 °C to RT, 90%
O
OH CN
OH
O
OTBDPS
1 HCl,iPrOH, MeOH
then PhCH 3 , H 2 O, 60 °C
2 TBDPSCl, imidazole
DMF
O O
O
OTBDPS TBSOO N
O
1 (CH 3 O)NHCH 3 •HCl AlMe 3 , CH 2 Cl 2 , 0 °C
2 TBSCl, imidazole, DMF 99% crude yieldfor 4 steps
Scheme 10 Second synthesis route of fragment 25 of eribulin mesylate (V).
O
MeO TBSO TBSO
O
O
OH
22
O
MeO
TBSO
TBSO
MsO
O
OPiv
83
1 KHMDS, THF, -14 °C
2 chromatography 72% for 3 steps
3 DIBAL-H, CH 2 Cl 2
-78 °C, 92%
HO
O
MeO
TBSO
TBSO
O
MsO
O
OPiv
25
TfO
24
CrCl 2 , NiCl 2 , THF, Et 3 N (S)-ligand 67
SO 2 Ph
SO 2 Ph
SO 2 Ph
Trang 10alcohol was protected as its pivalate ester with the use of pivaloyl
chloride, DMAP and collidine; the secondary alcohol was converted
to a mesylate upon treatment with methanesulfonyl chloride
(MsCl) and Et3N to give the C15–C27 fragment 25 in high yield
The preparations of the chiral ligand 66 used in the coupling
reaction inScheme 8along with the chiral ligand 67 utilized later
in the synthesis are described inScheme 9
2-Amino-3-methylben-zoic acid (62) was reacted with triphosgene to give benzoxazine
dione 63 in 97% yield, which then was reacted with eitherD- or
L-valinol in DMF followed by aqueous LiOH to give alcohols 64
and 65, respectively in 65–75% yield for the two steps Reaction
of alcohol 64 or 65 with MsCl in the presence of DMAP effected
for-mation of the dihydrooxazole ring and mesylation of the aniline to give the corresponding (R)-ligand 66 derived fromD-valinol or the (S)-ligand 67 derived fromL-valinol, respectively in high yield
An alternative route to intermediate 25 is described inScheme
10 and although much lengthier than the route described in
Scheme 8, it avoids chromatographic purifications as all of the products are carried on crude until a crystalline intermediate was isolated and purified by re-crystallization Quinic acid (68) was reacted with cyclohexanone in sulfuric acid to generate a pro-tected bicyclic lactone in 73% yield and the resulting tertiary alco-hol was protected as its trimethylsilyl ether 69 Reduction of the lactone 69 was accomplished with DIBAL-H and the resulting lactol
O O O
MeO
PO PO
PO
O
O
PO OP H
H
OH I
1 DMP, CH 2 Cl 2
RT, 90%
2 SmI 2 , MeOH THF, -78 °C, 85%
O
O O
MeO
OTBS
TBSO TBSO
O
O
OTBS OTBS
H H
OH
I H
-75 °C, 84%
84, P = TBS
O O O
MeO
PO PO
PO
O
O
O
PO OP H
H
H
O
I
85, P = TBS
O O O
MeO
TBSO TBSO
TBSO
O
O
O
TBSO
OTBS
OH
H
H NiCl 2 , CrCl 2
Et3N, (S)-ligand 67
CH 3 CN, THF
30 °C to 35 °C, 70%
1 TCAA, DMSO, Et3N PhCH3, -15 °C to 0°C, 91%
2 TBAF, imidazole•HCl, THF
O O O
MeO
HO HO
HO
O
O
O
O OH
O
H H
PPTS, CH2Cl2 79% for 2 steps
87
O O O
MeO
O O H
HO HO
O
O O
88 86
H
H
H
SO2Ph
SO2Ph
OH
O O O
MeO
O O O H
H2N HO
O
O
O
1 Ts 2 O, collidine, pyridine (cat.)
CH2Cl2, -20 °C
2 NH4OH, IPA, RT
3 MeSO3H, aq NH4OH, 15 °C 84% yield for 3 steps
V Eribulin mesylate
• CH 3 SO3H