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Bioorganic & Medicinal Chemistry 20 (2012) 1155–1174
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier .com/locate /bmc
Review
Synthetic approaches to the 2010 new drugs
Kevin K.-C. Liu a,�, Subas M. Sakya b,�, Christopher J. O’Donnell b,⇑, Andrew C. Flick b,§, Hong X. Ding c,–
a Pfizer Inc., La Jolla, CA 92037, USAb Pfizer Inc., Groton, CT 06340, USAc Shenogen Pharma Group, Beijing, China
a r t i c l e i n f o
Article history:Received 27 October 2011Revised 22 December 2011Accepted 22 December 2011Available online 2 January 2012
Keywords:SynthesisNew drug moleculesNew chemical entitiesMedicineTherapeutic agents
0968-0896/$ - see front matter � 2011 Elsevier Ltd. Adoi:10.1016/j.bmc.2011.12.049
⇑ Corresponding author. Tel.: +1 860 715 4118.E-mail addresses: [email protected] (K.K.-C.
com (S.M. Sakya), [email protected] (pfizer.com (A.C. Flick), [email protected] (
� Tel.: +1 858 622 7391.� Tel.: +1 860 715 0425.§ Tel.: +1 860 715 0228.– Tel.: +86 10 8277 4069.
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 alsoserve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that werelaunched anywhere in the world in 2010.
� 2011 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11552. Alogliptin benzoate (Nesina�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11573. Bazedoxifene acetate (Conbriza�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11574. Cabazitaxel (Jevtana�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11575. Diquafosol tetrasodium (Diquas�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11586. Eribulin mesylate (Halaven�). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11587. Fingolimod hydrochloride (Gilenya�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11658. Iloperidone (Fanapt�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11669. Laninamivir octanoate (Inavir�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167
10. Mifamurtide (Mepact�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116811. Peramivir (Rapiacta�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116812. Prucalopride succinate (Resolor�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116913. Roflumilast (Daxas�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116914. Romidepsin (Istodax�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117115. Vernakalant hydrochloride (Brinavess� or Kynapid�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117216. Vinflunine ditartrate (Javlor�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172
ll rights reserved.
Liu), [email protected]. O’Donnell), [email protected]. Ding).
1. Introduction
‘The most fruitful basis for the discovery of a new drug is to startwith 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 ago2–9 and pre-sents synthetic methods for molecular entities that were launchedin various countries during 2010.10 Given that drugs tend to have
N
N
O
O N
CN
NH2•
I Alogliptin benzoate
N
HO
ON
OH • CH3COOH
II Bazedoxifene acetate
O NH
O
O
O
OH OOH
O
O O O
HOOO
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
NH2OH
HO• HCl
VI Fingolimod hydrochloride
N O
O N
F
OO
VII Iloperidone
O
O
HO
OO
OH
OH
HNHN
NH
NH2O
VIII Laninamivir octanoate
HN
NH
HN
NH
OPO O (CH2)14CH3
O
O
OO NH2
O
O
O
OH
HN
OH
OHO
O−
O
O
(CH2)14CH3
O
Na+
• H2O
IX Mifamurtide
HN
OHNH
H
O
O
OH
NHH2N
X Peramivir
O
NH2Cl
HNO
N O
• CO2H
HO2C
XI Prucalopride succinate
O
O
FF
O
NH
NCl
Cl
XII Roflumilast
HNHN
S
OO
NHONH
O
SO
O
XIII Romidepsin
N
N
OH
HHO
O
O
O
O
N
NH
F F
OO
• 2 C4H6O6
XV Vinflunine ditartrate
O
OOO
MeO
O
OO
H
H2NHO
O
O
O
V Eribulin mesylate
• CH3SO3H
OH3CO
H3CO
N
OH
HCl
XIV Vernakalant hydrochloride
•H
Figure 1. Structures of 15 new drugs marketed in 2010.
1156 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1157
structural homology across similar biological targets, it is widelybelieved that the knowledge of new chemical entities and theirsyntheses will greatly accelerate drug design. In 2010, 29 newproducts, including new chemical entities, biological drugs, anddiagnostic agents reached the market.10 This review focuses onthe syntheses of 15 new chemical entities that were launched any-where in the world for the first time in 2010 (Fig. 1) and excludesnew indications for previously launched medications, new combi-nations, new formulations and drugs synthesized via bio-processesor peptide synthesizers. Although the scale of the synthetic routeswere not disclosed in all cases, this review attempts to highlightthe most scalable routes based on the patent or primary literatureand appear in alphabetical order by generic name. The syntheses ofnew products that were approved for the first time in 2010 but notlaunched before year’s end, will be covered in the 2011 review.
2. Alogliptin benzoate (Nesina�)
Alogliptin benzoate is a dipeptidyl peptidase IV (DPPIV) inhibi-tor discovered by Takeda Pharmaceuticals and approved in Japanin 2010 for the treatment of type II diabetes mellitus.10 Alogliptinis an oral drug for once a day dosing to complement diet and exer-cise. Alogliptin is the most selective marketed DPPIV inhibition andhas 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 highlightedfrom several published routes (Scheme 1).13–16 Commerciallyavailable 2-cycanobenzyl amine 1 was reacted with methylisocya-nate in DCM at ambient temperature to provide N-methyl urea 2 in85% yield. Reaction of the urea 2 with dimethyl malonate in reflux-ing ethanol with sodium ethoxide as base gave the cyclized trione3 in 78–85% yield. The trione 3 was then refluxed in neat POCl3 toprovide the penultimate chloride crude 4 in 95% yield which wasreacted with Boc-protected diamine 5 in the presence of potassiumcarbonate in DMF to furnish alogliptin I in 93–96% yield. Treatmentof alogliptin with benzoic acid in ethanol at 60–70 �C followed bycrystallization delivered the desired alogliptin benzoate (I).
3. Bazedoxifene acetate (Conbriza�)
The selective estrogen receptor modulator bazedoxifene acetatewas approved in Spain for the treatment of osteoporosis inpostmenopausal women.10 The drug was discovered by Wyeth(now Pfizer) and licensed to Almirall.10 Clinical trials with baze-doxifene along with conjugated estrogens demonstrated signifi-
HN
NHBoc
DMF, 75 °C
N
N
O
NO
CN
NHBoc
5
I Alogliptin
PhC
EtOH
NH
NHO
NC
1
93-96%
NH2
NC
MeNCO, Et3N
DCM, RT85%
EtO2CCH2CONaOEt
EtOH, ↑↓78-85%
2
K2CO3
Scheme 1. Synthesis of al
cant improvement in bone mineral density and prevented boneloss in postmenopausal women without osteoporosis. It alsoreduces 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 indole12. 4-Hydroxybenzyl alcohol (6) was converted in two steps tochloride 9 (Scheme 2). The reaction of 6 with 2-chloroethyl aze-pane hydrochloride (7) in a biphasic mixture of sodium hydroxideand 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 chloride9 in 61% yield. The reaction of 2-bromopropiophenone (10) with anexcess of 4-benzyloxy aniline hydrochloride (11) in the presence oftriethylamine (TEA) in N,N-dimethylformamide (DMF) at elevatedtemperatures resulted in indole 12 in 65% yield. Alkylation of 12with 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 andsubsequently subjected to acidic conditions, providing diol 14 asthe hydrochloride salt in 91% yield. The hydrochloride was then ex-changed for the acetate via free base preparation with 5% sodiumbicarbonate or triethylamine, followed by treatment with aceticacid giving bazedoxifene acetate (II) in 73–85% yield.
4. Cabazitaxel (Jevtana�)
Cabazitaxel was developed by Sanofi-Aventis as an intravenousinjectable drug for the treatment of hormone-refractory metastaticprostate cancer.23 As a microtubule inhibitor, cabazitaxel differsfrom docetaxel because it exhibits a much weaker affinity for P-glycoprotein (P-gp), an adenosine triphosphate (ATP)-dependentdrug efflux pump.24 Cancer cells that express P-gp become resis-tant to taxanes, and the effectiveness of docetaxel can be limitedby its high substrate affinity for P-gp.24 Clinical studies confirmedthat cabazitaxel retains activity in docetaxel-resistant tumors.23
Common adverse events with cabazitaxel include diarrhea andneutropenia. Cabazitaxel in combination with prednisone is animportant new treatment option for men with docetaxel-refrac-tory metastatic CRPC (castration-resistant prostate cancer).23 Thesemi-synthesis of cabazitaxel25 started from 10-deacetylbaccatinIII (15) which can be prepared from 7-xylosyl-10-deacetylbaccatinnatural product mixture according to a literature process proce-dure (Scheme 3).26 10-Deacetylbaccatin III was protected with tri-ethylsilyl chloride (TESCl) in pyridine to afford the corresponding7,13-bis-silyl ether in 51% yield, which was methylated with MeI
N
N
O
O N
CN
NH2• OH
O
I Alogliptin benzoate
OOH
, 60-70 °C
N
N
O
O
CN
N
N
O
ClO
NC
2Et
OHPOCl3
↑↓~95%
3 4
ogliptin benzoate (I).
O
BrBnO
H2N
OBn+
BnO
NH
OBnEt3N, DMF, 120 °C, 65%
9
10
O
Cl
11 12
HO
OH
6 8
O
OHSOCl2, THF
55 °C to 60 °C61%
N
HCl
H2O, PhCH3(No yield reported)
NaOH, TBAB, H2OPhCH3, RT to 90 °C61%
NCl
HCl 7N
HCl
NaH, 9, −5 °C
2. HCl, 91%
HCl
1. NaHCO3 (aq)
2. CH3COOH, 73%
13 14
N
HO
ON
OH • CH3COOH
II Bazedoxifene acetate
N
BnO
ON
OBnN
HO
ON
OH
•
• •
•HCl
•
1. H2, 10% Pd/C, EtOAc45 °C to 50 °C
Scheme 2. Synthesis of bazedoxifen acetate (II).
1158 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
and NaH in DMF to give 10-methoxy-7,13-bis silyl ether 16 in 76%yield. After de-silylation of 16 with triethylamine trihydrofluoridecomplex 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 19in the presence of dicyclohexylcarbodiimide/dimethylaminopyri-dine (DCC/DMAP) in ethyl acetate at room temperature to generateester 20 in 76% yield. The oxazolidine moiety of compound 20 wasselectively hydrolyzed under mild acidic conditions to yield the hy-droxy Boc-amino ester derivative cabazitaxel (III) in 32% yield.
5. Diquafosol tetrasodium (Diquas�)
Diquafosol tetrasodium was approved in April 2010 as Diquas�
ophthalmic solution 3% for the treatment of dry eye syndrome andlaunched in Japan by Santen Pharmaceuticals.10 Diquafosol tetra-sodium was originally discovered by Inspire Pharmaceuticals. In2001, it was licensed to Santen for co-development and commer-cialization in Asian countries, and co-developed in collaborationwith Allergan for the countries outside of Asia. In the US, diquafo-sol tetrasodium was submitted for a New Drug Application (NDA)as Prolacria� (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 P2Y2 receptoragonist, which activates P2Y2 receptor on the ocular surface, lead-ing to rehydration through activation of the fluid pump mechanismof the accessory lacrimal glands on the conjunctival surface.27 Thelarge-scale synthesis route of diquafosol tetrasodium is describedin Scheme 4.28,29 Commercially available uridine 50-diphosphatedisodium salt (21) was transformed into the corresponding tribu-tylamine salt by ion exchange chromatography on Dowex 50 usingBu3NH+ phase, and then dimerized by means of CDI in DMF at50 �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 (Halaven�)
Eribulin is a highly potent cytotoxic agent approved in the USfor the treatment of metastatic breast cancer for patients who havereceived at least two previous chemotherapeutic regimens.30 Erib-ulin was discovered and developed by Eisai and it is currentlyundergoing 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 evaluateeribulin’s efficacy against a number of additional cancers. Eribulinis a structural analog of the marine natural product halichondrin B.Its mechanism of action involves the disruption of mitotic spindleformation and inhibition of tubulin polymerization which resultsin the induction of cell cycle blockade in the G2/M phase and apop-tosis.31 Several synthetic routes for the preparation of eribulin havebeen disclosed,32–35 each of which utilizes the same strategy de-scribed by Kishi and co-workers for the total synthesis of halichon-drin B.36 Although the scales of these routes were not disclosed inall cases, this review attempts to highlight what appears to be theproduction-scale route based on patent literature.37,38 Nonetheless,the synthesis of eribulin represents a significant accomplishmentin the field of total synthesis and brings a novel chemotherapeuticoption to cancer patients.
The strategy to prepare eribulin mesylate (V) employs a conver-gent synthesis featuring the following: the late stage coupling ofsulfone 22 and aldehyde 23 followed by macrocyclization underNozaki–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
HN
N
O
OO
OHHO
OP
OP
O
O−
O
HO
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
1. Dowex 50Wx4 H+, Bu3NH+
21
O−
2 Na+•
4 Na+•
2. CDI, DMF, 50 °C, 5 h3. DEAE Sephadex, NH4HCO34. Dowex 50Wx4 Na+, 25%
Scheme 4. Synthesis of diquafosol tetrasodium (IV).
1. Et3SiCl, pyridine, RT, 51%
15
III Cabazitaxel
HO
OOH
O
HO O OH
HOOO
16
Et3N•3HF, CH2Cl2
17
NaH, MeI, DMF
18
O
O
N CO2H
O
O
19
DCC, DMAP, EtOAc, 76%
20
OHO
MeO O OMe
HO
OO
O
N
O
OO
O O NH
O
O
O
OH OOH
O
O O O
HOOO
32%
RT, 77%
0 °C, 74%
0.1 M HCl, EtOH, 0 °C
2. NaH, MeI, DMF, 76%
710
13 Et3SiO
OOH
O
MeO O OSiEt3
HOOO
710
13
HO
OOH
O
MeO O OH
HOOO
710
13 HO
OOH
O
MeO O OMe
HOOO
710
13
H
OO
Scheme 3. Synthesis of cabazitaxel (III).
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1159
25 which were coupled through a Nozaki–Hiyami–Kishi reaction.The schemes that follow will describe the preparation of fragments23, 24 and 25 along with how the entire molecule was assembled.
The synthesis of the C1–C13 aldehyde fragment 23 is describedin Scheme 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 withdiisobutylaluminum hydride (DIBAL-H) to give lactol 28 followedby condensation with the ylide generated from the reaction ofmethoxymethylene 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 osmiumteteroxide and N-methylmorpholine-N-oxide (NMO) with concom-itant cyclization produced diol 30 in 52% yield. Bis-acetonide 30was then reacted with acetic anhydride in acetic acid in the pres-ence of ZnCl2 which resulted in selective removal of the pendantketal protecting group. These conditions also affected peracylation,giving rise to tetraacetate 31 in 84% yield. Condensation of 31 withmethyl 3-(trimethylsilyl)pent-4-enoate in the presence of borontrifluoride etherate in acetonitrile provided alkene 32. Saponifica-
tion conditions using Triton B(OH) removed the acetate protectinggroups 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, ultimatelyresulting 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 wascoupled to (2-bromovinyl)trimethylsilane under Nozaki–Hiyami–Kishi conditions to give an 8.3:1 mixture of allyl alcohols 35 in65% yield over two steps. Hydrolysis of the cyclohexylidine ketal35 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 goodyield. 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–C14fragment 23 in 93% yield.
The preparation of the tetra-substituted tetrahydrofuranintermediate 24 is described in Scheme 7. D-Glucurono-6,3-lactone39 was reacted with acetone and sulfuric acid to give the
O
O
OTBSOTBS
OTBS
H
HI
H
OH
O
O
OTBSOTBS
OTBS
H
HI
MeO2C
H
O
O
OTBSOTBS
OTBS
H
HTMS
H
MeO2CO
O
OHOH
OH
H
HTMS
H
MeO2C
O
OOH
H
HTMS
H
MeO2C
OOO
OO
H
H H
MeO2C
OO
H
O
OOH
H
H H
MeO2C
OO
OH
AcO
OOAc
H
OO
OAcMeO2C
AcO
AcO OOAc
H
OO
OAc
HO
HO OH
OO
OO
HO
OO
OO
MeO
O
O O
OOH
HOO
O O
OOH
OOO OHHOH
HO OH
27 2826
cyclohexanonep-TSA, PhCH3
↑↓, 84%
DIBAL-HPhCH3, THF
−15 °C, 100%
KOtBu, THFPh3P+CH2OMeCl-
81%
29 30 31
OsO4, NMOacetone, H2O
0 °C to 5 °C, 52%
Ac2O, AcOHZnCl2, 35 °C to 40 °C
84%
32 33
MeO2CTMS
BF3•OEt, CH3CN0 °C to 5 °C
Triton B(OH)THF, MeOAc
38% for 2 steps
34 35
NaIO4, EtOAc, H2O
0 °C to 10 °C NiCl2, CrCl2, DMSOCH3CN, 0 °C to 15 °C65% for 2 steps8.3:1 mixture of diastereomers
TMS
Br
36 37
AcOH, H2O
90 °C, 71%
TBSOTf, 2,6-lutidine
MTBE, 0 °C to RT, 74%
38 23
NIS, PhCH3, CH3CN
TBSCl (cat), 90%
DIBAL-H, PhCH3
-75 °C, 93%
Scheme 6. Synthesis of fragment 23 of eribulin mesylate (V).
OOO
MeO
O
OO
H
H2NHO
O
O
O
V Eribulin mesylate
O
OO
MeO
OTBS
TBSOTBSO
O
OOTBS
OTBS
H
H
OH
I
H
O
SO2Ph
22
23
H
O
MeO
TBSOTBSO
CHO
MsO
OOPiv
25
TfO
24
SO2Ph
1
14
27
Scheme 5. Synthesis strategy of eribulin mesylate (V).
1160 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1161
corresponding acetonide and the 5-hydroxyl group was thenremoved by converting it to its corresponding chloride throughreaction with sulfuryl chloride (SO2Cl2) followed by hydrogenolysisto give lactone 40 in good overall yield. Reduction of the lactone40 with DIBAL-H gave the corresponding lactol which was con-densed with (trimethylsilyl)methylmagnesium chloride to affordsilane 41. Elimination of the silyl alcohol of 41 was accomplishedunder 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 conditionsusing potassium osmate (VI) dehydrate (K2OsO4), potassiumferricyanide (K3Fe(CN)6) and the (DHQ)2AQN ligand produced thevicinal 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) asthe Lewis acid to give 44 in 83% yield. Re-crystallization of 44 fromisopropanol and n-heptane afforded 44 in >99.5% de in 71% yield.Oxidation of the secondary alcohol of 44 under the modified Swernconditions generated the corresponding ketone which was con-densed with the lithium anion of methyl phenyl sulfone to give amixture 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 reaction with NaBH(OAc)3, andthen basic hydrolysis of the benzoate esters using K2CO3 in MeOHresulted in triol 46 as a white crystalline solid in 57% yield over the
O
OO
OH
HHO
OH
1. acetone, H2SO42. SO2Cl2, pyridineCH3CN, 79% for 2 steps
O
O
O
H
1. KHMDSTHF, 94%
OO
OBnO
1. (DHQ)2AQNK2OsO4
·2H2OK3Fe(CN)6, K2CO3tBuOH, H2O, 92%
O
BnO OH 1. DMSO, TCAAEt3N, PhCH3, -10 °C
BnOP
O
HO1. (CH3)2CH(OMe)2H2SO4, acetone
2. NaOtBu, MeITHF, 15 °C to RT
Me
O
MeO1. O3, heptane, -50 °C2. Lindlar cat., H2
3. re-crystallize, heptane68% over 5 steps
39 40
42
44
46
48
SO2Ph
SO2Ph
OBzOBz
OOBz
OHOH O
OTBSTBSO
2. BzCl, NMM, DMAPPhCH3, 95%, dr = 3
3. H2, Pd/C, THF, 75%
2. BnBr, KOtBuTHF, 95%
2. LHMDS, PhSO2MePhCH3, THF, 10 °C to RT
Scheme 7. Synthesis of fragment
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 bymethyl iodide-mediated methylation of the remaining hydroxylgroup 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 withaqueous HCl and reaction with TBSCl in the presence of imidazoleto 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 theprevious five steps after re-crystallization from heptane.
Two routes to the C14–C26 fragment 25 will be described asboth 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 diastereomers via chromatographicmethods throughout the synthesis.37 The second route to 25 is amuch lengthier synthesis from a step-counting perspective; how-ever it takes full advantage of the chiral pool of starting materialsand requires no chromatographic separations and all of the prod-ucts were carried on as crude oils until they could be isolated ascrystalline solids.38
The first route to fragment 25 is described in Scheme 8 and wasinitiated 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 with2,3-dibromopropene in the presence of tin and catalytic HBr to
O
O 1. DIBAL-H, PhCH3-40 °C, 80%
O
HOTMS O
OHO
OO
OBnOBzO
BzO
1. AllylTMS, TiCl3(OiPr)PhCH3, 30 °C, 83%
O
hO2S1. TMSI, CH3CN, PhCH3, 60 °C2. Bu4NCl, NaBH(OAc)3DME, PhCH3, 85 °C
O
O
1. 2 M HCl, MeOH
2. TBSCl, imidazole, DMF
O
MeO
OTBSTBSO
41
43
45
47
24
CHO
SO2Ph
SO2Ph
Bz
O
2. re-crystallize, 71%>99.5% de:1
2. TMSCH2MgClTHF, 35 °C, 90%
3. K2CO3, MeOH, 50 °C4. re-crystallize, nBuOH57% over 5 steps
24 of eribulin mesylate (V).
1162 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
afford diol 51 in 45% for the two steps. The primary alcohol of 51was selectively protected as its tert-butyldiphenylsilyl ether usingTBDPSCl and imidazole and the racemate was then separated usingsimulated moving bed (SMB) chromatography to give enantiopure52 in 45% yield over the two steps. The secondary alcohol of 52 wasreacted with p-toluenesulfonyl chloride and DMAP to give tosylate53 in 78% yield which was used as a coupling partner later in thesynthesis 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 givelactone 55 in 71% yield for the two step process. Methylation of thelactone with LHMDS and MeI provided 56 in 68% yield as a 6:1mixture of diastereomers. The lactone 56 was reacted with the alu-minum amide generated by the reaction of AlMe3 and N,O-dim-ethylhydroxylamine to give the corresponding Weinreb amidewhich was protected as its tert-butyldimethylsilyl ether upon reac-tion with TBSCl and imidazole to give 57 in 91% yield over the two
O O OHAmberlyst 15
H2O, 5 °C
BrBr
Sn, HBr, H2O, 35 °C45% for 2 steps
Br
OHOTBDPS
Br
TsCl, DMAP
CH2Cl2, 78%
49 50
52
O OO1. diethylmalonate
NaOEt, EtOH, 65 °C
2. MgCl2, DMF, 125 °C71% for 2 steps
1. MeNHOMe, AlMe3PhCH3, CH2Cl2, 0 °C
2. TBSCl, imidazole, DMF91% for 2 steps
ON
O
OTBS
1.
2.
54 55
57
1. 53 (from above), (R)-ligand 66CrCl2, NiCl2, Et3N, THF
2. H2N(CH2)2NH2OTBD
OTs
NOO
TBSO
OH
59
1. MeMgCl, THF-20 °C, 88%
2. KHMDS, PhCH3, THFTf2NPh, -78 °C to -20 °C
TBSO
61
12
3
4
OTf
OOTBDPS
Scheme 8. First synthesis route of frag
NH
O
O
O1. D- or L-valinolDMF, 90 °C
NH2
OH
O(Cl3CO)2COTHF
0 °C to 25 °C97%
62 63
2. LiOH.H2OH2O, 60 °C
65−75% for 2 ste
Scheme 9. Synthesis of intermediates 6
steps. Dihydroxylation of the olefin of 57 by reaction with OsO4
and NMO followed by oxidative cleavage with NaIO4 gave the de-sired coupling partner aldehyde 58 in 93% yield. Aldehyde 58 wascoupled with vinyl bromide 53 using an asymmetric Nozaki–Hiy-ami–Kishi reaction using CrCl2, NiCl2, Et3N and chiral ligand 66 (de-scribed in Scheme 9 below). The reaction mixture was treated withethylene 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 tetrahydrofuran60 in 48% yield over the three step process. The Weinreb amide of60 was reacted with methyl magnesium chloride to generate thecorresponding methyl ketone which was converted to vinyl triflate61 upon reaction with KHMDS and Tf2NPh. De-silylation of theprimary and secondary silyl ethers with methanolic HCl gave thecorresponding diol in 85% yield over two steps and the resultingmixture of diastereomers was separated using preparative HPLCto provide the desired diastereomer in 56% yield. The primary
Br
OHOH
1. TBDPSCl, imidazoleDMF, 0 °C to 15 °C
2. SMB Chromatography45% for 2 steps
OTsOTBDPS
51
53
MeI, LHMDS, PhCH3THF, -78 °C, 68%
dr = 6:1
OO
OsO4, NMO, CH2Cl2
NaIO4, THFphosphate buf fer pH=7, 93%
ON
O
OTBS
O
H
56
58
PS
iPrOH, Si2O
48% for 3 steps
NOO
TBSO
60
MsO
25
. HCl, iPrOH, MeOH, 85%
. HPLC separation, 56%
. PivCl, collidine, DMAPCH2Cl2, 0 °C, 85%. MsCl, Et3N, THF, 0 °C, 97%
OTf
OOTBDPS
OOPiv
ment 25 of eribulin mesylate (V).
NHMs
N
OMsCl, pyridineDMAP
0 °C to 25 °C85%NH2
O
HNOH
64 (R, D-valinol)65 (S, L-valinol)
66 (R, D-valinol)67 (S, L-valinol)
ps
6 and 67 of eribulin mesylate (V).
OH
OHOH
HO
HO2C 1. cyclohexanoneH2SO4, 160 °C, 73%
2. TMSCl, imidazoleTHF
O
O
O
H
TMSO
O O
O
O
H
AcO
AcO1. DIBAL-H, PhCH3, -78 °C2. AcOH, H2O, 5 °C
3. Et3N, DMAP, Ac2Ore-crystallize65% for 3 steps
MeO2CTMS
BF3•OEt2, CH3CNTFAA, 62%
O
O
O
H
AcO
MeO2CH
1. NaOMe, MeOH
2. LAH, THF, 0 °C
O H
O
H
OO
HO
1. MsCl, Et3N, THF, 10 °C
2. KCN, EtOH, H2O, 80 °C
O H
O
H
OO
NC
O H
O
H
OO
NC
1. KHMDS, MeI, PhCH3THF, -78 °C
2. re-crystallize, dr = 34:166% over 5 steps
1. 1 M HCl, AcOH, 72%
2.AcO
Br
O
CH3CN, H2O (cat), 0 °C
O H
O
H
NCOAc
Br
DBU, PhCH3, 100 °C
63% for 2 steps
O H
O
H
NCOAc
1. O3, MeOH, CH2Cl2, -45 °C2. NaBH4, -20 °C to 0 °C
3. K2CO3 (aq)4. NaIO4, THF, H2O75% for 4 steps
O
O
H
O
H
NCOH
(MeO)2P CO2MeO
LiCl, iPr2NEt, CH3CN
O
O
H
NCOH
CO2Me
1. H2, PtO2, MeOH2. Tf2O, Et3N, CH2Cl2, -78 °C
3. NaI, DMF75% for 4 steps
O
O
H
NCI
CO2Me
1. LiBH4, PhCH3THF, 89%
2. Zn, AcOH, MeOH0 °C to RT, 90%
O
OH CN
OH
68 69 70
71 72
73 74
75 76
77 78
79 80
OOTBDPS
1. HCl, iPrOH, MeOHthen PhCH3, H2O, 60 °C
2. TBDPSCl, imidazoleDMF
OO
OOTBDPS
TBSONOO
1. (CH3O)NHCH3•HClAlMe3, CH2Cl2, 0 °C
2. TBSCl, imidazole, DMF99% crude yieldfor 4 steps
81 82
Scheme 10. Second synthesis route of fragment 25 of eribulin mesylate (V).
O
MeO
TBSOTBSO
O
OOH
22
O
MeO
TBSOTBSO
MsO
OOPiv
83
1. KHMDS, THF, -14 °C2. chromatography72% for 3 steps
3. DIBAL-H, CH2Cl2-78 °C, 92%
HO
O
MeO
TBSOTBSO
O
MsO
OOPiv
25
TfO
24
CrCl2, NiCl2, THF, Et3N
(S)-ligand 67
SO2Ph
SO2PhSO2Ph
Scheme 11. Synthesis of fragment 22 of eribulin mesylate (V).
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1163
1164 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
alcohol was protected as its pivalate ester with the use of pivaloylchloride, DMAP and collidine; the secondary alcohol was convertedto 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 couplingreaction in Scheme 8 along with the chiral ligand 67 utilized laterin the synthesis are described in Scheme 9. 2-Amino-3-methylben-zoic acid (62) was reacted with triphosgene to give benzoxazinedione 63 in 97% yield, which then was reacted with either D- orL-valinol in DMF followed by aqueous LiOH to give alcohols 64and 65, respectively in 65–75% yield for the two steps. Reactionof alcohol 64 or 65 with MsCl in the presence of DMAP effected for-
OOO
MeO
PO
POPO
O
O
PO
OPH
H
OHI
1. DMP, CRT, 90%
2. SmI2, MTHF, -78
O
MeO
TBSOTBSO
O
OOH
H
O
22
84, P = TBS
O
MeO
TBS
TBSOTBSO
O
O
ONiCl2, CrCl2Et3N, (S)-ligand 67
CH3CN, THF30 °C to 35 °C, 70%
OOO
MeO
HO
HOHO
O
O
O
O
OH
O
H
H
PPTS, C
79% for
87
86
H
H
SO2Ph
SO2Ph
OH
O
MeO
H2NHO
O
O
O1. Ts2O, collidine, pyridine (cat.)CH2Cl2, -20 °C
2. NH4OH, IPA, RT3. MeSO3H, aq. NH4OH, 15 °C84% yield for 3 steps
V Eribulin
Scheme 12. Synthesis of e
mation of the dihydrooxazole ring and mesylation of the aniline togive the corresponding (R)-ligand 66 derived from D-valinol or the(S)-ligand 67 derived from L-valinol, respectively in high yield.
An alternative route to intermediate 25 is described in Scheme10 and although much lengthier than the route described inScheme 8, it avoids chromatographic purifications as all of theproducts are carried on crude until a crystalline intermediatewas 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 thelactone 69 was accomplished with DIBAL-H and the resulting lactol
H2Cl2
eOH°C, 85%
O
O
OTBSOTBS
OTBS
H
HI nBuLi, THF
-75 °C, 84%
23
OOO
MeO
PO
POPO
O
O
O
PO
OPH
H
H
OI
85, P = TBS
OO
OTBSO
OTBS
OH
H
H 1. TCAA, DMSO, Et3NPhCH3, -15 °C to 0°C, 91%
2. TBAF, imidazole•HCl, THF
H2Cl2
2 steps
OOO
MeO
O
OO
H
HOHO
O
O
O
88
H
H
H
OO
O
OO
H
mesylate
• CH3SO3H
ribulin mesylate (V).
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1165
was treated with acetic acid to remove the TMS group and theresulting compound was reacted with acetic anhydride, DMAPand Et3N to give bis-acetate 70 in 65% yield for the three steps afterre-crystallization. Methyl 3-(trimethylsilyl)pent-4-enoate wascoupled to the acetylated lactol 70 in the presence of boron tri-fluoride etherate and trifluoroacetic anhydride to give adduct 71in 62% yield. The acetate of 71 was removed upon reaction with so-dium methoxide in methanol and the resulting tertiary alcohol cy-clized on to the isomerized enone alkene to give the fused pyranring. Reduction of the methyl ester with lithium aluminum hydrideprovided pyranyl alcohol 72. Mesylation of the primary alcoholwas followed by displacement with cyanide anion to give nitrile73. The nitrile was methylated upon reaction with KHMDS andMeI and the resulting product was purified by re-crystallizationto provide nitrile 74 in 66% over the previous five steps in a 34:1diastereomeric ratio. Acid hydrolysis of the ketal of 74 liberatedthe corresponding diol in 72% yield and this was reacted with 2-acetoxy-2-methylpropionyl bromide to give bromo acetate 75.Elimination of the bromide was accomplished upon treatmentwith 1,8-diazabicycloundec-7-ene (DBU) to give alkene 76 in 63%yield for two steps. Ozonolysis of the cyclohexene ring followedby reductive work-up with NaBH4 and basic hydrolysis of the ace-tate produced a triol which upon reaction with NaIO4 underwentoxidative cleavage to give cyclic hemiacetal 77 in 75% yield overthe previous four steps. Wittig condensation with carbometh-oxymethylene triphenylphosphorane gave the homologated unsat-urated ester 78. Catalytic hydrogenation of the alkene using PtO2 asthe catalyst was followed by converting the primary alcohol to thecorresponding triflate prior to displacement with sodium iodideresulted in iodide 79 in 75% yield over four steps. The ester of 79was reduced to the corresponding primary alcohol upon reactionwith LiBH4 in 89% yield and the resulting iodoalcohol was treatedwith Zn dust to affect reductive elimination of the iodide anddecomposition of the pyran ring system to give the tetrahydrofu-ran diol 80 in 90% yield. This diol was treated with methanolicHCl to affect an intramolecular Pinner reaction and this was fol-lowed by protection of the primary alcohol as its tert-butyldiphen-ylsilyl ether to give lactone 81. The lactone was reacted with thealuminum amide generated from AlMe3 and N,O-dimethylhydr-oxylamine and the resulting secondary alcohol was protected asits tert-butyldimethylsilyl ether to give Weinreb amide 82 in 99%crude yield over four steps. Compound 82 is the diastereomericallypure version of compound 60 and can be converted to compound25 by the methods described in Scheme 8 absent the requiredHPLC separation of diastereomers.
With the three key fragments completed, the next step was toassemble them and complete the synthesis of eribulin. Aldehyde24 was coupled to vinyl triflate 25 using an asymmetric Nozaki–Hiyami–Kishi reaction using CrCl2, NiCl2, Et3N and chiral ligand67 (Scheme 9) to give alcohol 83 (Scheme 11). Formation of the
( )7
BrCH2COCl, AlCl3,DCM, -15 °C
76%
89 90
( )7
OBr
9
1. Et3SiH, TiCl4, CH2Cl2, RT2. LiAlH4, THF, −5 °C
70% for 2 steps
93
( )7
HN
OH
OHO
6
Scheme 13. Synthesis of fingo
THP ring was accomplished by reaction with KHMDS which al-lowed for displacement of the mesylate with the secondary alcoholand provided the THP containing product in 72% yield for the threesteps. The pivalate ester group was removed with DIBAL-H to givethe western fragment 22 in 92% yield.
The completion of the synthesis of eribulin is illustrated inScheme 12. The lithium anion of sulfone 22 generated upon reac-tion with nBuLi was coupled to aldehyde 23 to give diol 84 in84% yield. Both of the alcohol functional groups of 84 were oxi-dized using a Dess–Martin oxidation in 90% yield and the resultingsulfone was removed via a reductive cleavage upon reaction withSmI2 to give keto-aldehyde 85 in 85% yield. Macrocyclization of85 was accomplished via an asymmetric Nozaki–Hiyami–Kishireaction using CrCl2, NiCl2, Et3N and chiral ligand 67 to give alcohol86 in 70% yield. Modified Swern oxidation of the alcohol providedthe corresponding ketone in 91% yield and this was followed by re-moval of the five silyl ether protecting groups upon reaction withTBAF and subsequent cyclization to provide ketone 87. Compound87 was treated with PPTS to provide the ‘caged’ cyclic ketal 88 in79% over two steps. The vicinal diol of 88 was reacted with Ts2Oin collidine to affect selective tosylation of the primary alcoholand this crude product was reacted with ammonium hydroxideto install the primary amine to give eribulin which was treatedwith methanesulfonic acid in aqueous ammonium hydroxide togive eribulin mesylate (V) in 84% yield over the final three steps.
7. Fingolimod hydrochloride (Gilenya�)
Fingolimod hydrochloride is an immunosuppressive drugdeveloped by Novartis and approved in the US, Europe, and Austra-lia in 2010 for the treatment of multiple sclerosis.39 The structureof fingolimod derives from the naturally-occurring myriocin (ISP-1) metabolite of the fungus I. sinclairii and the aminoalcohol func-tionality within the drug possesses structural similarity to thesphingosine family of natural products.40–42 Although several con-venient preparations of fingolimod (FTY720) have been reported inthe literature,43–62 the route most closely resembling the process-scale approach63 is described in Scheme 13. Friedel–Craftsacylation of commercial toluene derivative 89 with bromoacetylchloride followed by ethoxide-mediated N-acylated aminomalo-nate (91) attack onto the resulting a-bromoketone 90 gave riseto ketoamide 92 in good overall yield. Next, separate hydridereduction protocols were employed to furnish diol 93. Presumably,triethylsilyl hydride reduced the ketone and both ethyl esterswithin 92 to the corresponding diacid, which then underwent lith-ium aluminum hydride treatment to arrive at diol 93. Carefulattention to stoichiometry was required to avoid over reductionof amide 93, which was critical to achieve high-yielding (76%) saltformation of fingolimod HCl (VI) through the use of 6 N ethanolichydrochloric acid.
1, Na (0), EtOH, 0 °C
95%
CO2EtEtO2C
NHAc91
( )7
O HNAc
CO2EtCO2Et
92
N HCl, EtOH, 78 °C
76%
VI Fingolimod hydrochloride
( )7
OH
HONH2 • HCl
limod hydrochloride (VI).
1166 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
8. Iloperidone (Fanapt�)
Acting as an antagonist on serotonin (5-HT2) and dopaminereceptor subtypes, iloperidone is an antipsychotic indicated for
HN
O
OH1. Ac2O, HCOOH0 °C to RT, 76 %
N
O
NH2OH•HCl, KOH, ↑↓
EtOCH2CH2OH/H2O (2:1)
HO
OO
K2CO3, DMF, 81%
K2C
94 95
98
100
VII Iloperidone
2. cat. DMF, SOCl20 °C to RT, 100%
O
NH
O N
F
N
O N
FO
O
Scheme 14. Synthesis o
(MeO)2SO2, NaH
101
HOO OMe
OH
HNOTBDMS
O
OMe
HDMF, 80%
AcO
OO
OMe
OH
HNHN
ONHBoc
NBoc
107
1. Lindlar cat., H2, EtOH, 70%
2. THF, 80%
NN
NBoc
NHBoc
106
NN
NH
NH2
1. Boc2O, DIEA, DMF2. Boc2O, NaH, THF
HO
OO
OCHPh2
OH
HNHN
ONHBoc
NBoc
109
Ph2CN2, THF
85%
1.
CH2Cl2, 70%
2. TFA, CH2C70%
Cl
O
AcO
HO
AcOAcO
OO
H
103
NaN3, Dowex 50W H+, D
70% for 2 steps
105
NO
OO
OO
O
OMe
6
Scheme 15. Synthesis of lani
the treatment of acute schizophrenia in adults. Based on itsin vitro and in vivo binding properties against both serotonin anddopamine receptors, it is expected that iloperidone will showfewer extrapyramidal symptoms than currently marketed
N O
O
F F
Cl
F
F
AlCl3, ↑↓, 32%
BrCl
O3, DMF, RT, 80%
96
97
99
N
O N
FCl
O
f iloperidone (VII).
OO OMe
OH
NOTBDMS
O
OMe
AcO
OO
OMe
OH
HNN3
O
102
104
Ac2O, AcOH, conc H2SO4(10:10:1, v/v)
HO
OO
OH
OH
HNHN
ONHBoc
NBoc
108
NaOH, H2O, 90%
, Et3N
l2
O
O
HO
OO
OH
OH
HNHN
NH
NH2O
VIII Laninamivir octanoate
AcO
HO
MF
namivir octanoate (VIII).
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1167
antipsychotics such as haloperidol and clozapine.64 The originaldiscovery was made by Hoechst-Roussel Pharmaceuticals whopassed the developing rights to Vanda Pharmaceuticals and subse-quently Novartis for marketing in the US and Canada.10 While thisdrug was originally approved in the US in 2009, the marketing wasonly initiated in the US in 2010. Although a number of synthesesare reported in the literature, the process enabled route from akey intermediate 98 is described in Scheme 14.65–72 The key inter-mediate 98 was synthesized from isonipecotic acid (94) in foursteps.65 Formylation of isonipecotic acid (76% yield) followed byconversion of the acid to the acyl chloride gave 95 in 100% yield.Friedel–Crafts acylation of 1,3-difluorobenzene (96) with the acidchloride 95 provided ketone 97 in 32% yield.65,68 Treatment ofketone 97 with hydroxylamine hydrochloride in the presence ofpotassium hydroxide gave the corresponding oxime, which uponrefluxing in 2-ethoxylethanol and water cyclized to piperidinebenzisoxazole 98 with concomitant loss of the N-formyl group.Alkylation of piperidine 98 with 1-chloro-3-bromo propane inDMF in the presence of potassium carbonate provided the chlorideintermediate 99 in 80% yield. Subsequent reaction with phenol 100under basic conditions gave the desired product iloperidone (VII)in 81% yield.71
9. Laninamivir octanoate (Inavir�)
Laninamivir octanote, a prodrug of a potent neuraminidaseinhibitor (LANI), was approved and launched in 2010 in Japan forthe treatment of influenza A and influenza B. This ester prodrugof a potent neuraminidase inhibitor was designed to permeatefrom the lung tissue to the plasma and then hydrolyze at such arate to reveal the active form (laninamivir) as a long-acting thera-peutic agent. Neuraminidase cleaves the glycosidic linkages of neu-raminic acids which are responsible for binding new viruses to
115
Et3N, DMA, RT
HN
NH
O
O
OO NH2
O
O
OH
HN
OH
OH
O
OH
HN
112, DCC, DMF, RT
HN
NH
OPO O (CH2)14CH3
OO
OH
O
O
(CH2)14CH3
O
CbzH2, 10%
111
113
114HN
NH
HN
O
O
OO NH2
O
O
OH
HN
OH
OH
IX
O
H2NOPO O (CH2)14CH3
O
OH
O
O
(CH2)14CH3
O
110
Cbz
Scheme 16. Synthesis o
infected cells, thereby allowing viruses to release and infect othercells. Neuraminidase is essential for the replication of all influenzaviruses. Like other neuraminidase inhibitors, laninamivir octanoateis a sialic acid analogue which is structurally similar to zanamivir,differing only by changing one of the hydroxy groups with amethyl ether substitution on the triol side chain. Laninamivir isadministered via an inhalable formulation (20 mg, dry powder in-haler) and results from clinical trials of the drug have demon-strated that a single inhaled dose is as effective as a 5-day courseof oseltamivir for treatment of influenza.73 The synthesis of lani-namivir octanoate began with the well-documented sugar inter-mediate 101 (Scheme 15).74,75 Alcohol 101 was alkylated withdimethyl sulfate in the presence of NaH in DMF to give methylether 102 in 80% yield.76 Acetonide 102 was then de-protectedand subsequently acylated with Ac2O, AcOH, and H2SO4 (10:10:1,v/v) which resulted in oxazoline formation along with eliminationof the methoxy functionality to furnish a,b-unsaturated ester 103.Exposure of oxazoline 103 to NaN3 in the presence of Dowex 50W/H+ produced the trans-amidoazide 104 in 70% yield over two steps.Azide 104 was then subjected to guanidine formation conditionsutilizing N,N-bis(tertbutoxycarbonyl)-1H-pyrazole-1-carboxyami-dine (106), which was prepared from pyrazole-1-carboxamidine(105) by consecutive protection of the amidine nitrogens, first bytreatment with Boc anhydride and diisopropylethyl amine (DIEA)in DMF, and then subsequent treatment to Boc anhydride in thepresence of NaH in THF to give 107 in 80% yield. The protected gua-nidine 107 was hydrolyzed under basic conditions to give the cor-responding acid 108 in good yield. Acid 108 was esterified withdiphenyl diazomethane in THF to provide 109 in 85% yield.77 Final-ly, the primary alcohol within diol 109 was selectively acylatedwith octanoyl chloride in the presence of TEA, followed by de-pro-tection with TFA in CH2Cl2 to give laninamivir octanote (VIII) in70% yield.
HN
NH
NO
O
OO NH2
O
O
OH
HN
OH
OH
O
116
O
O
OH
O
Pd/C
NH
OPO O (CH2)14CH3
OO
O−
O
O
(CH2)14CH3
O
Na+
• H2O Mifamurtide
DCC, DMF, RT
N
O
OHO
112
H2N NH
OPO O (CH2)14CH3
OO
OH
O
O
(CH2)14CH3
O
114
f mifamurtide (IX).
1168 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
10. Mifamurtide (Mepact�)
Mifamurtide is an anticancer agent for the treatment of osteo-sarcoma, the most common primary malignancy of bone tissuemainly affecting children and adolescents.10 The drug was inventedby Ciba-Geigy (now Novartis) in the early 1980s and the agent wassubsequently licensed to Jenner Biotherapies in the 1990s. IDMPharma bought the rights to the drug from Jenner in April 2003.78
In March 2009, mifamurtide was approved in the 27 European Un-ion member states plus Iceland, Liechtenstein and Norway via acentralized marketing authorization. After the approval, IDM Phar-ma was acquired by Takeda, which began launching mifamurtide,as Mepact�, in February 2010. Mifamurtide, a fully synthetic lipo-philic derivative of muramyl dipeptide (MDP), is muramyl tripep-tide phosphatidylethanolamine (MTP-PE), which is formulated asa liposomal infusion.79 Being a phospholipid, mifamurtide accumu-lates in the lipid bilayer of the liposomes upon infusion. After appli-cation of the liposomal infusion, the drug is cleared from the plasmawithin minutes. However, it is concentrated in lung, liver, spleen,nasopharynx and thyroid, and the terminal half-life is 18 h, whichis longer than the natural substance. Two synthetic routes havebeen reported,80,81 and Scheme 16 describes the more process-amenable route. Commercially available 1,2-dipalmitoyl-sn-glyce-ro-3-phosphoethanolamine (110) was coupled with N-Boc-L-ala-nine (111) by means of N-hydroxysuccinimide (112), DCC in DMFto give amide 113, which was followed by hydrogenolysis of theCBZ group to give the corresponding L-alanyl-phosphoric acid114. Next, commercially available N-acetylmuramoyl-L-alanyl-D-isoglutamine (115) was subjected to hydroxybenzotriazole (HOBT)and DIC in DMF to provide the corresponding succinimide ester 116which was condensed with compound 114 to provide mifamurtide(IX). No yields were provided for these transformations.
11. Peramivir (Rapiacta�)
The second drug added to the influenza treatment armamentar-ium last year was peramivir, a novel neuraminidase inhibitoracting as a transition-state analogue inhibitor of influenza neur-aminidase and thereby preventing new viruses from emerging
HNO
O
Boc
X Peramivir
117
NH
O
1. MeOH, HCl (g), ↑↓
2. L-tartaric acid, Et3N, 85%
H2N•
L-tartaric acid
2. aq. NaOH, RT3. MeOH, HCl (g), RT76% for 3 steps
HN
ONH
H
O
NHH2N
NO
1. Ac2O, PhCH3, 5 °C to RT2. HCl, 0 °C to 5 °C3. NaOH, 0 °C to 10 °C
4. 123, 30% aq. NaOH, pH=8.4, RT82% for 4 steps
118
121
1. 120, PhCH3, Et3N60 °C to 70 °C
Scheme 17. Synthesis
from infected cells. It was first discovered and developed by Bio-Cryst Pharmaceuticals, and Johnson and Johnson licensed the glo-bal marketing and development rights in 1998. However, in early2001, its development was discontinued due to low bioavailabilityof the oral formulation and failure in clinical trials, and all therights were returned to BioCryst. The low bioavailability of oral for-mulation resulted in BioCryst developing an intramuscular andintravenous formulation of peramivir. Fortunately, as part of theUS government’s effort to prepare against the threat of the influ-enza pandemic, peramivir received strong support, including ‘‘FastTrack’’ designation from the FDA and a grant of $180 million fromNIH, which accelerated the development of peramivir. Moreover,BioCryst entered into two agreements with Green Cross Pharma-ceuticals and with Shionogi Pharmaceuticals in 2006–2007, forthe development and marketing peramivir in South Korea and Ja-pan, respectively. In October 2009, the FDA approved the use ofintravenous peramivir for the treatment of 2009 H1N1 hospital-ized patients under the Emergency Use Act (EUA) which expiredon June 23th, 2010. Finally, the intravenous form of peramivir re-ceived approval in Japan in early of 2010 and launched for the firsttime with the commercial name Rapiacta�. Several syntheses ofthis drug have been reported82–84 and the improved route dis-closed in a recent patent is described (Scheme 17).85 Ring openingof commercially available (±)-2-azabicyclo[2.2.1]hept-5-en-3-one(117) with methanolic HCl followed by classical resolution withL-tartaric acid gave the (1S,4R)-methyl ester 118 in 85% yield. Pro-tection of 118 with Boc anhydride and TEA in CH2Cl2 afforded car-bamate 119 in 90% yield. Alkene 119 was then subject to nitronedipolar cycloaddition conditions involving 2-ethyl-N-hydroxybuta-nimidoyl chloride 120 and triethylamine, followed by the basicworkup and then treatment with methanolic HCl, ultimatelyresulting in dihydroisoxazole 121. Interestingly, the nitrone gener-ated from 120 approached alkene 119 from the less hindered faceand proceeded with remarkable regioselectivity to provide azacy-cle 121 in 76% yield for the three step sequence. Treatment of121 with 1.5 equiv lithium aluminum hydride resulted in ruptureof the N–O bond within this system, which afforded the aminoalcohol 122 in 81% yield. It should be noted that neither the Bocgroup or the methyl ester were reduced under these reaction
O
OBoc2O, Et3N, CH2Cl2
90%HN
O
O
Boc
Cl
NOH
H
O
OH
LiAlH4 (1.5 eq)
HNO
O
Boc
OHNH2
NN
H2N NH• HCl
119
120
122
123
81%0 °C to ↑↓
of peramivir (X).
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1169
conditions. Then, a one-pot three step sequence involving acetyla-tion of the amino group, removal of the Boc group, and hydrolysisof the carboxylic ester followed by guanylation with pyrazolecar-boxamidine hydrochloride (123) provided peramivir (X) in 82%yield over the final four steps.
12. Prucalopride succinate (Resolor�)
Prucalopride succinate, a first-in-class dihydrobenzofurancarb-oxamide, is a selective serotonin (5-HT4) receptor agonist.86–94
The drug, marketed under the brand name Resolor�, possessesenterokinetic activity and was developed by the Belgian-basedpharmaceutical firm Movetis. Prucalopride alters colonic motilitypatterns via serotonin 5-HT4 receptor stimulation, triggering thecentral propulsive force for defecation.95–97 The preparation of pru-calopride succinate begins with the commercially available sali-cylic aniline 124 (Scheme 18). Acidic esterification, acetylation ofthe aniline nitrogen atom, and ambient-temperature chlorinationvia sulfuryl chloride (SO2Cl2) converted aminophenol 124 to ace-tamidoester 125 in 83% yield over the course of three steps.98–102
An unique set of conditions involving sodium tosylchloramide(chloramine T) trihydrate and sodium iodide were then employed
N
H2N
O
O
NHAcCl
O O1. TMS-acetylene, PdCl2(PPh3)2CuI, Et3N, p-diox., TMG, SiO2110 °C
O
HO
O OH
NH2
HO1. H2SO4, MeOH, 80 °C2. AcCl, NaHCO3, aq. EtOAc, RT3. SO2Cl2, EtOAc, RT
82% for 3 steps
124
127
129
1. 129, ClCO2Et, Et3N, RT2. EtOH, succinic acid, RT O
NH2Cl
OHN
N
XI Prucalopride
2. H2, 5% Rh/C, RT, acetone73% for 2 steps
Scheme 18. Synthesis of pru
XII Ro
O
O
FFSOCl2, PhCH3, 105 °C, 81%
H2N
NCl
Cl 133
1. 131, K2CO3, acetone, 402. CHClF2, NaOH, TBAB, Ph3. HCl (pH=3~4), H2O, 35 °C
97% for 3 steps
Br
131
OHO
HO
OMe
130
Scheme 19. Synthesis o
to convert 125 to o-phenolic iodide 126, which then underwentsequential Sonogashira/cyclization reaction utilizing TMS-acety-lene with tetramethylguanidine (TMG) in the presence of silicagel to furnish the benzofuran progenitor of 127.103 Hydrogenationof this intermediate benzofuranyl Sonagashira product saturatedthe 2,3-benzofuranyl bond while leaving the chlorine atom intact,ultimately delivering dihydrobenzofuran 127 in excellent yield forthe two step sequence. Base-induced saponification and acetamideremoval gave rise to acid 128. This acid was activated as the corre-sponding mixed anhydride and treated with commercial piperi-dine 129 to construct prucalopride which was stirred at roomtemperature for 24 h in ethanolic succinic acid to provide prucalo-pride succinate (XI). The yield for the formation of the salt was notprovided.
13. Roflumilast (Daxas�)
Roflumilast is a selective, long-acting PDE-4 inhibitor approvedin 2010 for the treatment of inflammatory conditions of the lungssuch as asthma and chronic obstructive pulmonary disorder.104–108
Marketed under the trade name Daxas�, roflumilast was developedby researchers at the University of Liverpool in partnership with
O
NH2Cl
O OH
1. NaOH, H2O, 90 °C2. HCl, H2O, 80 °C
81%
Cl
O O
NHAc
HO
I
NaI, DMFchloramine T trihydrateH2O, HCl, 10 °C
63%Cl
O
NHAc125 126
128
O
succinate
•COOH
HOOC
calopride succinate (XI).
flumilast
NH
O NCl
Cl
OO
O
FF
OH°CCH3, H2O, 35 °C
132
f roflumilast (XII).
134
H2NO
OCH3
1. Fmoc-L-Threonine, BOPDIEA, 95%
135
NH
O
OCH3Me
O
NH
OH
O
NHAllocTrtS
136
NH
O
OCH3Me
O
NHO
NHAllocTrtS
1. PdCl2(PPh3)2, Bu3SnH, HOAc, CH2Cl2
137
NH
O
OCH3
Me
O
NHO
NHTrtS
ONHFmoc
138
NH
O
OCH3Me
O
NHO
NHTrtS
ONH2
2. Et2NH, CH2Cl2, RT3. N-Alloc-S-Trt-D-cysteineEDCI, HOBT, DMF, CH2Cl267% for 2 steps
95% for 2 steps
2. N -Fmoc-D-valine, EDCI, HOBT, DMFCH2Cl2, 83% for 2 steps
OMe
MeO
O
OMe
139
OTBDPS140
OMe
MeO
O
141OTBDPS
NH
Ru
TsN
142
OMe
MeO
OH
143
OTBDPS
1. TBAF, THF, RT
2. TsCl, DMAP, CH2Cl2, RT70% for 2 steps.
OMe
MeO
OH
144
OTs
1. LiBF4, CH3CN, H2O, RT2. NaClO2, NaH2PO4,2-methyl-2-butene, tBuOH
O
HO
OH
145STrt
1. Ts2O, pyridine, 0 °C2. DABCO, CH3CN, RT
2. 140, nBuLi, THF-78 °C to 0 °C, 75%
Et2NH, CH3CN0 °C to RT, quant
1. iPrMgCl, NHMe(OMe)THF, 0 °C, 67%
1. 142 (10 mol%), iPrOH
3. HSCPh3, KOtBu, THF, 0 °C65% for 3 steps
2. Red-Al®, Et2O,0 °C to RT, 58% for 2 steps
1. LiOH, THF, H2O, 0 °C, 73%HN
HN
S
OO
NHONH
O
SO
O
XIII Romidepsin
O
HO
OH
145
STrt
138
NH
O
OCH3
O
NHO
NHTrtS
ONH2
+
BOP, iPr2NEt, CH3CNCH2Cl2, RT, quant
O OH
STrt
NH
O
OCH3
O
NHO
NHTrtS
O NH
HNHN
STrt
OO
NHONH
O
TrtSO
O
146
147
I2, MeOH
RT, 81%2. DIAD, PPh3, TsOH, THF, 0 °C, 24%
Scheme 20. Synthesis of romidepsin (XIII).
1170 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174 1171
Nycomed. Although the dose-limiting side effects of the drug aremild nausea, diarrhea, and weight loss, these symptoms subsidedafter a few weeks of treatment.106 The straightforward preparationof roflumilast begins with commercially available methyl 3,4-dihydroxybenzoate (130) (Scheme 19).109,110 Alkylation of themore reactive 3-hydroxyl group with (bromomethyl)cyclopropane(131) preceded a second alkylation of the remaining p-phenol withchlorodifluoromethane in aqueous sodium hydroxide. Thesephase-transfer conditions saponified the ester within 130 and afteracidic quench, carboxylic acid 132 was ultimately furnished inexcellent yield (97%) over the three step protocol. Activation of132 as the corresponding acyl halide through use of thionyl chlo-ride (SOCl2) and subsequent exposure to commercial aminopyri-dine 133 provided roflumilast (XII) in 81% yield.
14. Romidepsin (Istodax�)
Romidepsin, a histone deacetylase inhibitor, originally devel-oped by Fujisawa (now Astellas Pharma), causes cell cycle arrest,differentiation, and apoptosis in various cancer cells.111 In 2004,the FDA granted fast-track designation for romidepsin as mono-therapy for the treatment of cutaneous T-cell lymphoma (CTCL)in patients who have relapsed following, or become refractoryto, other systemic therapies. The FDA designated romidepsin asan orphan drug and it was approved in 2009 for this indicationand it was commercialized in 2010. In 2007, another fast-trackdesignation was granted for the product as monotherapy ofpreviously treated peripheral T-cell lymphoma. Romidepsin(FR901228) was originally discovered and isolated from the fer-mentation broth of Chromobacterium violaceum No. 968. It wasidentified through efforts in the search for novel agents whichselectively reverse the morphological phenotype of Ras onco-gene-transformed cells since the Ras signaling pathway plays acritical role in cancer development. Therefore, the drug could alsohave multiple molecular targets for its anticancer activity besidesHDAC.112 FR901228 is a bicyclic depsipeptide which is structur-ally unrelated to any known class of cyclic peptides with an unu-sual disulfide bond connecting a thiol and D-cysteine. This drug iscommercially produced by fermentation; however its interestingand novel structure warrants examination of its synthesis within
1. HCl,2. H2 (6EtOHOH3CO
H3CO
N
OBn1. 149, HBF4,CH2Cl2, − 10 °C2. aq. NaOH,CH2Cl2, −10 °C
N
OB1. cyclohexanone, cyclohexanol160 °C
2. Boc2O, Et3N, MeOH, 20 °C3. BnCl, NaOH, DMSO, 40 °C
95% for 3 steps BOCNH
OH
HO2C
OH
H3CO
H3CO
148
Cl3CCN, (n-Bu)3NClKOH, 12 °C, 96%
150 151
154
72% f
H
78% for 2 steps
Scheme 21. Synthesis of vernak
the context of this review.113,114 The synthesis of romidepsindescribed is based on the total synthesis reported by the Wil-liams115 and Simon groups (Scheme 20).116
L-Valine methyl ester(134) was coupled to N-Fmoc-L-threonine in the presence of theBOP reagent in 95% yield. The N-Fmoc protecting group wasremoved with Et2NH and the corresponding free amine wascoupled to N-alloc-(S-triphenylmethyl)-D-cysteine with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and HOBT inDMF and CH2Cl2 to yield the tripeptide 135 in good yield. Thethreonine residue of tripeptide 135 was then subjected to dehy-drating conditions to give alkene 136 in 95% yield. The N-allocprotecting group of the dehydrated tripeptide 136 was removedwith palladium and tin reagents and the corresponding freeamine was subsequently coupled with N-Fmoc-D-valine to givetetrapeptide 137 in 83% yield. After removal of the N-Fmoc pro-tecting group of compound 137 with Et2NH amine 138 was ob-tained in quantitative yield. The acid coupling partner 145 foramine 138 was prepared as follows: methyl 3,3-dimethoxypropi-onate (139) was converted to its corresponding Weinreb amideby standard conditions and reacted with lithium acetylide 140to give propargylic ketone 141 in 75% yield. Noyori’s asymmetricreduction of ketone 141 using ruthenium catalyst 142 gave the(R)-propargylic alcohol in 98% ee. This was followed by Red-Alreduction of the alkyne to selectively yield (E)-alkene 143 in58% yield for the two steps. Liberation of the primary alcoholwith tetrabutylammonium fluoride (TBAF) followed by selectivetosylation gave 144 in 70% yield in two steps. Hydrolysis of thedimethyl acetal of 144 with LiBF4 was followed by a Pinnick oxi-dation to give the corresponding carboxylic acid. The tosylate wasdisplaced with trityl mercaptan in the presence of tert-butyl alco-hol to give allylic alcohol 145 in 65% yield for the three steps.Aminoamide 138 was then coupled to acid 145 using BOP to givepeptide 146 in quantitative yield. The methyl ester of compound146 was hydrolyzed with lithium hydroxide to provide the freecarboxylic acid which underwent macrolactonization under Mits-unobu conditions in the presence of diisopropyl azodicarboxylate(DIAD) and triphenylphosine to give macrocycle 147 in 24% yield.Finally, the disulfide linkage was formed by treating bis-tritylsul-fane 147 with iodine in methanol at room temperature to giveromidepsin (XIII) in 81% yield.
OH3CO
H3CO
N
OH
HClH2O, EtOH, RT0 psi), Pd/C, RT
HON
OBn
XIV Vernakalant hydrochloride
O
H3CO
H3COCCl3
NH
nO1521. CF3CO2H
2. 152, H2O, 80 °C3. (−)-Tartaric acid, EtOAc, 28 °C
72% for 2 steps
149
153
•
or 2 steps
H
H
alant hydrochloride (XIV).
N
N
OH
HHO
O
O
O
O
N
NH
OO
• 2 (C4H6O6)
XV Vinflunine ditartrate
N
N
OH
HHO
O
O
O
O
N
NH
OO
155 (vinorelbine)
FF
1. HF•SbF5, NBS-50 °C, 25%
2. tartaric acid
N
N
OH
HHO
O
O
O
O
N
NH
OO
156
HF•SbF5, CHCl3
-45 °C, 40%N
N
OH
HHO
O
O
O
O
N
NH
OO
157
F F
1. TFA, NBS, CH2Cl2, -45°C2. aq. NaHCO3, AgBF4, THF88% for 2 steps
3. aq. tartaric acid, PhCH3
Scheme 22. Synthesis of vinflunine ditartrate (XV).
1172 K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
15. Vernakalant hydrochloride (Brinavess� or Kynapid�)
Vernakalant is an investigational drug under regulatory reviewfor the acute conversion of atrial fibrillation. The drug was initiallydeveloped by Cardiome Pharma under the trade names Kynapid�
and Brinavess� and its intravenous formulation was further devel-oped by Merck in April 2009.117,118 Like other class III antiarrhyth-mics, vernakalant blocks atrial potassium channels, therebyprolonging repolarization.119–121 It differs from typical class IIIagents by blocking the cardiac transient outward potassium cur-rent, with increased potency as the heart rate increases. It alsoslightly blocks the hERG potassium channel, leading to a prolongedQT interval, which may theoretically increase the risk of ventricu-lar tachycardia.122 The preparation of vernakalant entails the unionof a prolinol derivative 150 with a 3,4-dimethoxyphenethyl alcohol(148) across a cyclohexanyl lynchpin 152 and is described inScheme 21.123–125 Decarboxylation of commercially available(2S,4R)-4-hydroxyprolinol (150) was effected using cyclohexanoland cyclohexanone at elevated temperatures. Subsequent protec-tion of the nitrogen atom and the oxygen atom within this systemresulted in carbamate 151. Acid-mediated removal of the N-pro-tective functionality preceded nucleophilic attack on epoxide 152in hot water, and the ensuing mixture of diastereomers was sepa-rated by classical resolution via the tartrate salt. O-Benzylated ver-nakalant 154 was obtained when enantiomerically pure alcohol153 was subjected to trichloroacetimidate 149 (which arose fromthe corresponding alcohol 148 under modified Williamson condi-tions126). Acidic hydrogenolysis, which the authors report as sepa-rate steps, furnished vernakalant hydrochloride (XIV) in excellentoverall yield.
16. Vinflunine ditartrate (Javlor�)
Vinflunine ditartrate is a second generation difluorinated analogof the naturally-occurring substance vinorelbine and it is approvedfor the treatment of non-small cell lung cancer, metastatic breastcancer and ovarian cancer. Vinflunine, a tubulin polymerizationinhibitor, belongs to the vinca alkaloid class of anti-cancer agents.
Introduction of the difluoro group of vinflunine dramatically im-proved antitumor activity of the parent vinorelbine structure.127
Vinflunine was discovered by Pierre Fabre Laboratories and in2004 was licensed to Bristol-Myers Squibb for development andcommercialization. In 2007, the rights to venflunine were returnedto Pierre Fabre which completed its development. Vinflunine canbe prepared directly from vinorelbine (155) through the use ofsuperacid chemistry (Scheme 22). Reaction of 155 with antimonypentaflouride in hydrofluoric acid and N-bromosuccinimide fol-lowed by treatment with two equivalents of tartaric acid producedvinflunine ditartrate (XV) in 25% yield.128 An alternative synthesisof vinflunine was realized through reaction of vinblastine or 30,40-dihydrovinblastine (156) with antimony pentaflouride and hydro-fluoric acid in chloroform to give the difluoro alkaloid 157 in 40%yield.128,129 Ring contraction was effected by reaction with trifluo-roacetic acid and N-bromosuccinimide followed by aqueous so-dium bicarbonate and silver tetrafluoroborate to give vinfluninein 88% yield. Vinflunine ditartrate (XV) was prepared by treatinga solution of vinflunine in toluene with 2 equiv of tartaric acid.
Acknowledgment
The authors thank Dr. Christopher Butler and Dr. Antonia Ste-pan for their helpful suggestions in preparing this review.
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