`
`Contents lists available at SciVerse 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
`
`Review
`Synthetic approaches to the 2010 new drugs
`Kevin K.-C. Liu a, , Subas M. Sakya b,à, Christopher J. O’Donnell b,⇑
`
`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
`
`a b s t r a c t
`
`, Andrew C. Flick b,§, Hong X. Ding c,–
`
`Article history:
`Received 27 October 2011
`Revised 22 December 2011
`Accepted 22 December 2011
`Available online 2 January 2012
`
`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.
`
`Keywords:
`Synthesis
`New drug molecules
`New chemical entities
`Medicine
`Therapeutic agents
`
`Contents
`
`Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155
`1.
`Alogliptin benzoate (NesinaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157
`2.
`Bazedoxifene acetate (ConbrizaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157
`3.
`Cabazitaxel (JevtanaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1157
`4.
`Diquafosol tetrasodium (DiquasÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
`5.
`Eribulin mesylate (HalavenÒ). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1158
`6.
`Fingolimod hydrochloride (GilenyaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1165
`7.
`Iloperidone (FanaptÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
`8.
`Laninamivir octanoate (InavirÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167
`9.
`10. Mifamurtide (MepactÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168
`Peramivir (RapiactaÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168
`11.
`Prucalopride succinate (ResolorÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169
`12.
`Roflumilast (DaxasÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169
`13.
`Romidepsin (IstodaxÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1171
`14.
`Vernakalant hydrochloride (BrinavessÒ or KynapidÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172
`15.
`Vinflunine ditartrate (JavlorÒ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172
`16.
`Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172
`References and notes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1172
`
`⇑ 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.
`
`0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.bmc.2011.12.049
`
`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 ago2–9 and pre-
`sents synthetic methods for molecular entities that were launched
`in various countries during 2010.10 Given that drugs tend to have
`
`APOTEX 1030, pg. 1
`
`
`
`1156
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`O
`
`N
`
`N
`
`O
`
`CN
`
`N
`
`NH2
`•
`
`PhCO2H
`
`HO
`
`N
`
`OH
`
`•
`
`CH3COOH
`
`N
`
`O
`
`I Alogliptin benzoate
`
`II Bazedoxifene acetate
`
`O
`
`N
`
`O
`
`HN
`
`O
`
`HO
`
`OH
`
`O
`
`O
`O
`O
`O
`P
`P
`P
`P
`O
`O
`O
`O− O− O− O−
`•
`4 Na+
`
`O
`
`O
`
`HN
`
`O
`
`N
`
`O
`
`HO
`
`OH
`
`IV Diquafosol tetrasodium
`
`• CH3SO3H
`
`HO
`
`• HCl
`NH2
`OH
`
`O
`
`O O
`
`O
`
`H
`
`O
`
`OH
`O
`
`O
`
`O
`
`O
`
`OH
`
`O
`
`NH
`
`O
`
`O
`
`O
`
`O
`
`O
`
`H
`
`III Cabazitaxel
`
`MeO
`HO
`
`H2N
`
`O
`
`O
`
`O
`
`O
`
`O
`
`O
`
`V Eribulin mesylate
`
`VI Fingolimod hydrochloride
`
`O
`
`O
`
`O
`
`H
`
`O
`
`O
`
`OH
`
`HO
`HN
`
`HN
`O
`
`NH2
`NH
`VIII Laninamivir octanoate
`
`O
`
`O
`
`O
`
`O
`
`F
`
`N
`
`O N
`VII Iloperidone
`
`O
`
`HN
`
`OH
`
`O
`
`O
`
`−
`
`Na+
`
`O O
`
`P
`
`O
`
`NH
`
`O
`
`HN
`
`O
`
`NH2
`
`O
`
`NH
`
`O
`
`HN
`
`O
`
`O
`
`OH
`
`OH
`
`O
`
`(CH2)14CH3
`O
`(CH2)14CH3
`
`• H2O
`
`N
`
`Cl
`
`Cl
`
`O
`
`NH
`
`O
`
`O O
`
`F
`
`F
`
`IX Mifamurtide
`
`HN
`
`O
`
`O
`
`N
`
`O
`
`Cl
`
`NH2
`
`•
`
`CO2H
`
`HO2C
`
`NH
`
`H2N
`HN
`
`O
`
`OH
`
`H
`
`NH
`
`OH
`
`O
`
`X Peramivir
`
`O
`
`O
`
`H3CO
`
`H3CO
`
`NH
`
`O
`
`O
`
`NH
`S
`S
`
`HN
`
`O
`
`HN
`
`O
`
`XI Prucalopride succinate
`
`XII Roflumilast
`
`• 2 C4H6O6
`N
`
`O
`
`O
`O
`
`H
`
`O
`
`O
`
`HH
`
`N
`
`F F
`
`N
`
`O
`
`O
`
`NH
`
`O
`
`OH
`
`N
`
`H
`
`•
`
`HCl
`
`O
`
`XIII Romidepsin
`
`XIV Vernakalant hydrochloride
`
`XV Vinflunine ditartrate
`
`Figure 1. Structures of 15 new drugs marketed in 2010.
`
`APOTEX 1030, pg. 2
`
`
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`1157
`
`structural 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.10 Alogliptin
`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 POCl3 to
`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.10 Clinical 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.24 Cancer 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.24 Clinical 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).23 The
`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).26 10-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
`
`NH2
`
`NC
`
`NH
`
`MeNCO, Et3N
`
`O
`
`NH
`
`DCM, RT
`85%
`
`NC
`
`2
`
`O
`
`N
`
`1
`
`HN
`
`5
`NHBoc
`K2CO3
`
`DMF, 75 °C
`93-96%
`
`EtO2CCH2CO2Et
`NaOEt
`EtOH, ↑↓
`78-85%
`
`O
`
`N
`
`N
`
`O
`
`OH
`
`CN
`
`3
`
`POCl3
`↑↓
`~95%
`
`O
`
`N
`
`O
`
`N
`
`Cl
`
`NC
`4
`
`O
`
`N
`
`NH2
`•
`
`O
`
`OH
`
`O
`
`N
`
`N
`
`NHBoc
`
`PhCOOH
`
`O
`
`N
`
`N
`
`EtOH, 60-70 °C
`
`CN
`I Alogliptin
`
`CN
`
`I Alogliptin benzoate
`
`Scheme 1. Synthesis of alogliptin benzoate (I).
`
`APOTEX 1030, pg. 3
`
`
`
`1158
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`Cl
`
`O
`
`9
`
`N H
`
`•
`Cl
`
`OH
`
`SOCl2, THF
`55 °C to 60 °C
`61%
`
`O
`
`8
`
`Cl
`
`N H
`
`•
`
`OH
`
`Cl
`
`N
`
`•
`7
`HCl
`NaOH, TBAB, H2O
`PhCH3, RT to 90 °C
`61%
`
`OBn
`
`OH
`
`O
`
`N
`•
`HCl
`
`NH
`
`12
`
`N
`
`14
`
`HO
`
`6
`
`BnO
`
`+
`
`Br
`
`H2N
`•
`HCl
`
`O
`
`10
`
`OBn
`
`11
`
`Et3N, DMF, 120 °C, 65%
`
`BnO
`
`BnO
`
`NaH, 9, −5 °C
`
`H2O, PhCH3
`(No yield reported)
`
`N
`
`OBn
`
`N
`
`O
`
`13
`
`HO
`
`1. H2, 10% Pd/C, EtOAc
`45 °C to 50 °C
`2. HCl, 91%
`
`HO
`
`1. NaHCO3 (aq)
`2. CH3COOH, 73%
`
`N
`
`OH
`
`• CH3COOH
`
`N
`
`O
`II Bazedoxifene acetate
`
`Scheme 2. Synthesis of bazedoxifen acetate (II).
`
`and 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.10 Diquafosol 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 P2Y2 receptor
`agonist, which activates P2Y2 receptor on the ocular surface, lead-
`ing to rehydration through activation of the fluid pump mechanism
`of the accessory lacrimal glands on the conjunctival surface.27 The
`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.31 Several synthetic routes for the preparation of eribulin have
`been 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 in
`all cases, this review attempts to highlight what appears to be the
`production-scale route based on patent literature.37,38 Nonetheless,
`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
`
`APOTEX 1030, pg. 4
`
`
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`1159
`
`HO
`10
`
`O OH
`7
`
`MeO
`10
`
`O OSiEt3
`7
`
`HO
`
`13
`
`H
`
`O
`
`O
`
`OH
`O
`
`O
`
`1. Et3SiCl, pyridine, RT, 51%
`2. NaH, MeI, DMF, 76%
`
`Et3SiO
`
`13
`
`H
`
`O
`
`O
`
`OH
`O
`
`O
`
`Et3N(cid:129)3HF, CH2Cl2
`RT, 77%
`
`O
`
`15
`
`O
`
`16
`
`MeO
`10
`
`O OH
`7
`
`MeO
`10
`
`O OMe
`7
`
`O
`
`O
`
`N
`
`CO2H
`
`O
`
`19
`
`HO
`
`13
`
`H
`
`O
`
`O
`
`OH
`O
`
`O
`
`NaH, MeI, DMF
`
`HO
`
`13
`
`0 °C, 74%
`
`OH
`O
`
`O
`
`O
`
`H
`
`O
`
`O
`
`O
`
`O
`
`DCC, DMAP, EtOAc, 76%
`
`17
`
`O
`
`O
`
`MeO
`
`O OMe
`
`O
`
`O O
`
`18
`
`O
`
`O
`
`H
`
`O
`
`O
`
`OH
`
`O
`
`O
`
`O
`
`O
`
`OH
`
`NH
`
`O
`
`O
`
`H
`
`O
`
`OH
`
`O
`
`O
`
`0.1 M HCl, EtOH, 0 °C
`32%
`
`O
`
`Scheme 3. Synthesis of cabazitaxel (III).
`
`III Cabazitaxel
`
`O
`
`N
`
`H
`
`O
`
`O
`
`O
`
`20
`
`O
`
`N
`
`HN
`
`O
`
`O
`
`O
`
`HO
`
`OH
`
`1. Dowex 50Wx4 H+, Bu3NH+
`2. CDI, DMF, 50 °C, 5 h
`3. DEAE Sephadex, NH4HCO3
`4. Dowex 50Wx4 Na+, 25%
`
`O
`
`HN
`
`O
`
`N
`
`O
`
`HO
`
`OH
`
`O
`
`O
`O
`O
`O
`P
`P
`P
`P
`O
`O
`O
`O− O− O− O−
`•
`4 Na+
`
`O
`
`O
`
`N
`
`HN
`
`O
`
`O
`
`HO
`
`OH
`
`O O
`
`P
`
`−
`
`HO
`
`O
`P
`O−
`
`O
`•
`2 Na+
`
`21
`
`IV Diquafosol tetrasodium
`
`Scheme 4. Synthesis of diquafosol tetrasodium (IV).
`
`25 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
`in 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 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 ZnCl2 which 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 conditions 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 tetra-substituted tetrahydrofuran
`The preparation of
`intermediate 24 is described in Scheme 7. D-Glucurono-6,3-lactone
`39 was reacted with acetone and sulfuric acid to give the
`
`APOTEX 1030, pg. 5
`
`
`
`1160
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`MeO
`HO
`
`H2N
`
`O
`
`O
`
`1
`
`O
`27
`
`O
`
`O
`
`O
`
`O
`
`O
`14
`
`O
`
`H
`
`MeO
`
`TBSO
`TBSO
`
`V Eribulin mesylate
`
`SO2Ph
`
`O
`
`O
`
`O
`
`22
`
`O
`
`H
`
`OH
`
`H
`
`H
`
`O
`
`OTBS
`
`H
`
`O
`
`OTBS
`OTBS
`
`I
`
`23
`
`MeO
`
`TBSO
`TBSO
`
`SO2Ph
`
`CHO
`
`O
`
`24
`
`TfO
`MsO
`
`O
`
`25
`
`OPiv
`
`Scheme 5. Synthesis strategy of eribulin mesylate (V).
`
`OH
`
`H
`
`O
`
`OH
`
`O
`
`HO
`
`OH
`
`26
`
`cyclohexanone
`p-TSA, PhCH3
`↑↓, 84%
`
`O
`
`O
`
`OH
`
`O
`
`O
`
`O
`
`27
`
`DIBAL-H
`PhCH3, THF
`−15 °C, 100%
`
`HO
`
`O
`
`OH
`
`O
`
`O
`
`O
`
`28
`
`KOtBu, THF
`Ph3P+CH2OMeCl-
`
`81%
`
`O
`
`O
`
`HO
`
`MeO
`
`O
`
`O
`
`OsO4, NMO
`acetone, H2O
`0 °C to 5 °C, 52%
`
`HO
`
`HO
`
`O
`
`H
`
`O
`
`O
`
`O
`
`O
`
`Ac2O, AcOH
`ZnCl2, 35 °C to 40 °C
`84%
`
`AcO
`
`AcO
`
`OAc
`
`H
`
`O
`
`OAc
`
`O
`
`O
`
`31
`
`29
`
`MeO2C
`
`MeO2C
`
`TMS
`BF3(cid:129)OEt, CH3CN
`0 °C to 5 °C
`
`NaIO4, EtOAc, H2O
`0 °C to 10 °C
`
`MeO2C
`
`30
`
`OAc
`
`H
`
`O
`
`OAc
`
`Triton B(OH)
`THF, MeOAc
`
`38% for 2 steps
`
`MeO2C
`
`Br
`
`TMS
`NiCl2, CrCl2, DMSO
`CH3CN, 0 °C to 15 °C
`65% for 2 steps
`8.3:1 mixture of diastereomers
`
`MeO2C
`
`AcO
`
`O
`
`O
`
`32
`
`O
`
`O
`
`H
`
`H
`
`O
`
`O
`
`H
`
`H
`
`O
`
`34
`
`AcOH, H2O
`90 °C, 71%
`
`MeO2C
`
`OH
`
`OH
`
`H
`
`H
`
`O
`
`H
`
`O
`
`OH
`36
`
`TMS
`
`TBSOTf, 2,6-lutidine
`
`MTBE, 0 °C to RT, 74%
`
`MeO2C
`
`NIS, PhCH3, CH3CN
`TBSCl (cat), 90%
`
`MeO2C
`
`OTBS
`
`H
`
`O
`
`H
`
`OTBS
`OTBS
`
`O
`
`H
`
`38
`
`I
`
`DIBAL-H, PhCH3
`-75 °C, 93%
`
`O
`
`H
`
`Scheme 6. Synthesis of fragment 23 of eribulin mesylate (V).
`
`OH
`
`H
`
`O
`
`OH
`
`O
`
`O
`
`H
`
`H
`
`33
`
`OH
`
`H
`
`O
`
`O
`
`O
`
`O
`
`H
`
`H
`
`O
`
`35
`
`H
`
`H
`
`O
`
`OTBS
`
`H
`
`O
`
`OTBS
`OTBS
`37
`
`OTBS
`
`H
`
`O
`
`H
`
`I
`
`O
`
`H
`
`OTBS
`OTBS
`23
`
`TMS
`
`TMS
`
`APOTEX 1030, pg. 6
`
`
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`1161
`
`corresponding 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 reaction with NaBH(OAc)3, and
`then basic hydrolysis of the benzoate esters using K2CO3 in 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 diastereomers via chromatographic
`methods throughout the synthesis.37 The 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 in Scheme 8 and 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
`
`1. acetone, H2SO4
`2. SO2Cl2, pyridine
`CH3CN, 79% for 2 steps
`3. H2, Pd/C, THF, 75%
`
`OH
`
`O
`
`O
`
`HO
`
`OH
`
`O
`
`H
`39
`
`O
`
`O
`
`O
`
`H
`
`40
`
`O
`
`O
`
`1. DIBAL-H, PhCH3
`-40 °C, 80%
`2. TMSCH2MgCl
`THF, 35 °C, 90%
`
`HO
`
`TMS
`
`HO
`
`O
`
`O
`
`O
`
`41
`
`1. (DHQ)2AQN
`·2H2O
`K2OsO4
`K3Fe(CN)6, K2CO3
`tBuOH, H2O, 92%
`2. BzCl, NMM, DMAP
`PhCH3, 95%, dr = 3:1
`
`BzO
`
`BnO
`
`O
`
`O
`
`O
`42
`
`O
`
`O
`
`1. AllylTMS, TiCl3(OiPr)
`PhCH3, 30 °C, 83%
`2. re-crystallize, 71%
`>99.5% de
`
`BnO
`BzO
`
`O
`
`43
`
`1. DMSO, TCAA
`Et3N, PhCH3, -10 °C
`2. LHMDS, PhSO2Me
`PhCH3, THF, 10 °C to RT
`
`PhO2S
`BnO
`
`O
`
`OBz
`
`45
`
`OBz
`
`1. TMSI, CH3CN, PhCH3, 60 °C
`2. Bu4NCl, NaBH(OAc)3
`DME, PhCH3, 85 °C
`3. K2CO3, MeOH, 50 °C
`4. re-crystallize, nBuOH
`57% over 5 steps
`
`SO2Ph
`
`1. (CH3)2CH(OMe)2
`H2SO4, acetone
`2. NaOtBu, MeI
`THF, 15 °C to RT
`
`MeO
`
`SO2Ph
`
`O
`
`O
`
`O
`
`1. 2 M HCl, MeOH
`
`2. TBSCl, imidazole, DMF
`
`1. KHMDS
`THF, 94%
`2. BnBr, KOtBu
`THF, 95%
`
`BnO
`
`OH
`
`OBz
`
`O
`
`OBz
`
`44
`
`HO
`
`O
`
`OH
`
`46
`
`OH
`
`MeO
`
`SO2Ph
`
`O
`
`OTBS
`
`48
`
`TBSO
`
`1. O3, heptane, -50 °C
`2. Lindlar cat., H2
`3. re-crystallize, heptane
`68% over 5 steps
`
`47
`
`MeO
`
`O
`
`OTBS
`
`24
`
`TBSO
`
`SO2Ph
`
`CHO
`
`Scheme 7. Synthesis of fragment 24 of eribulin mesylate (V).
`
`APOTEX 1030, pg. 7
`
`
`
`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 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 AlMe3 and 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 NaIO4 gave 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 in Scheme 9 below). 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
`
`O
`
`Amberlyst 15
`
`O
`
`OH
`
`H2O, 5 °C
`
`49
`
`50
`
`Br
`
`Br
`
`Sn, HBr, H2O, 35 °C
`45% for 2 steps
`
`Br
`
`OH
`
`51
`
`OH
`
`1. TBDPSCl, imidazole
`DMF, 0 °C to 15 °C
`
`2. SMB Chromatography
`45% for 2 steps
`
`OH
`
`52
`
`TsCl, DMAP
`
`OTs
`
`OTBDPS
`
`CH2Cl2, 78%
`
`Br
`
`OTBDPS
`
`53
`
`Br
`
`O
`
`1. diethylmalonate
`NaOEt, EtOH, 65 °C
`
`O
`
`2. MgCl2, DMF, 125 °C
`71% for 2 steps
`
`O
`
`55
`
`54
`
`MeI, LHMDS, PhCH3
`THF, -78 °C, 68%
`
`O
`
`O
`
`dr = 6:1
`
`56
`
`O
`
`O
`
`H
`
`1. MeNHOMe, AlMe3
`PhCH3, CH2Cl2, 0 °C
`2. TBSCl, imidazole, DMF
`91% for 2 steps
`
`O
`
`O
`
`N
`
`OTBS
`
`57
`
`1. OsO4, NMO, CH2Cl2
`2. NaIO4, THF
`phosphate buffer pH=7, 93%
`
`O
`
`N
`
`1. 53 (from above), (R)-ligand 66
`CrCl2, NiCl2, Et3N, THF
`2. H2N(CH2)2NH2
`
`O
`N
`
`O
`
`TBSO
`
`OH
`OTs
`
`59
`
`OTBDPS
`
`TBSO
`
`O
`
`O
`
`iPrOH, Si2O
`48% for 3 steps
`
`1. MeMgCl, THF
`-20 °C, 88%
`
`2. KHMDS, PhCH3, THF
`Tf2NPh, -78 °C to -20 °C
`
`TBSO
`
`OTf
`
`OTBDPS
`
`O
`
`61
`
`MsO
`
`1. HCl, iPrOH, MeOH, 85%
`2. HPLC separation, 56%
`
`3. PivCl, collidine, DMAP
`CH2Cl2, 0 °C, 85%
`4. MsCl, Et3N, THF, 0 °C, 97%
`
`Scheme 8. First synthesis route of fragment 25 of eribulin mesylate (V).
`
`OTBS
`58
`
`O
`N
`
`60
`
`O
`
`OTBDPS
`
`OTf
`
`25
`
`OPiv
`
`HN
`
`O
`
`NH2
`
`OH
`
`MsCl, pyridine
`DMAP
`
`0 °C to 25 °C
`85%
`
`O
`
`N
`
`NHMs
`
`64 (R, D-valinol)
`65 (S, L-valinol)
`
`66 (R, D-valinol)
`67 (S, L-valinol)
`
`O
`
`O
`
`1. D- or L-valinol
`DMF, 90 °C
`2. LiOH.H2O
`H2O, 60 °C
`65−75% for 2 steps
`
`O
`
`NH
`
`63
`
`O
`
`(Cl3CO)2CO
`THF
`
`OH
`
`NH2
`
`0 °C to 25 °C
`97%
`
`62
`
`Scheme 9. Synthesis of intermediates 66 and 67 of eribulin mesylate (V).
`
`APOTEX 1030, pg. 8
`
`
`
`K. K.-C. Liu et al. / Bioorg. Med. Chem. 20 (2012) 1155–1174
`
`1163
`
`HO2C
`HO
`
`OH
`68
`
`OH
`
`OH
`
`1. cyclohexanone
`H2SO4, 160 °C, 73%
`2. TMSCl, imidazole
`THF
`
`O
`
`H
`
`O
`
`TMSO
`
`O
`
`O
`
`69
`
`1. DIBAL-H, PhCH3, -78 °C
`2. AcOH, H2O, 5 °C
`3. Et3N, DMAP, Ac2O
`re-crystallize
`65% for 3 steps
`
`AcO
`
`AcO
`
`TMS
`
`MeO2C
`
`H
`
`O
`
`H
`
`MeO2C
`
`BF3(cid:129)OEt2, CH3CN
`TFAA, 62%
`
`AcO
`
`O
`
`O
`
`1. NaOMe, MeOH
`
`2. LAH, THF, 0 °C
`
`HO
`
`O
`
`71
`
`H
`
`1. MsCl, Et3N, THF, 10 °C
`2. KCN, EtOH, H2O, 80 °C
`
`NC
`
`O
`
`O H
`
`O
`
`O
`
`1. KHMDS, MeI, PhCH3
`THF, -78 °C
`
`NC
`2. re-crystallize, dr = 34:1
`66% over 5 steps
`
`1. 1 M HCl, AcOH, 72%
`O
`
`2.
`
`AcO
`
`NC
`
`O
`
`73
`
`H
`
`O H
`
`OAc
`
`Br
`
`DBU, PhCH3, 100 °C
`63% for 2 steps
`
`NC
`
`O
`
`H
`
`O
`
`O
`
`70
`
`H
`
`O H
`
`O
`
`O
`
`72
`
`O
`
`H
`
`O H
`
`O
`
`O
`
`74
`
`H
`
`O H
`
`OAc
`
`O
`
`76
`
`O
`(MeO)2P
`CO2Me
`LiCl, iPr2NEt, CH3CN
`
`NC
`
`H
`
`OH
`
`O O
`
`Br
`CH3CN, H2O (cat), 0 °C
`
`1. O3, MeOH, CH2Cl2, -45 °C
`2. NaBH4, -20 °C to 0 °C
`3. K2CO3 (aq)
`4. NaIO4, THF, H2O
`75% for 4 steps
`
`NC
`
`75
`
`H
`
`O
`
`77
`
`1. H2, PtO2, MeOH
`2. Tf 2O, Et3N, CH2Cl2, -78 °C
`3. NaI, DMF
`75% for 4 steps
`
`NC
`
`O
`
`H
`
`O
`
`I
`
`79
`
`1. LiBH4, PhCH3
`THF, 89%
`
`CO2Me
`
`2. Zn, AcOH, MeOH
`0 °C to RT, 90%
`
`1. HCl, iPrOH, MeOH
`then PhCH3, H2O, 60 °C
`
`O
`
`2. TBDPSCl, imidazole
`DMF
`
`O
`
`O
`
`1. (CH3O)NHCH3(cid:129)HCl
`AlMe3, CH2Cl2, 0 °C
`
`OTBDPS
`
`2. TBSCl, imidazole, DMF
`99% crude yieldfor 4 steps
`
`TBSO
`
`O
`
`O
`
`81
`
`Scheme 10. Second synthesis route of fragment 25 of eribulin mesylate (V).
`
`H
`
`O
`
`O
`
`78
`
`OH
`
`OH CN
`
`CO2Me
`
`OH
`
`80
`
`O
`
`O
`N
`
`OTBDPS
`
`82
`
`TfO
`MsO
`
`O
`
`OPiv
`
`25
`
`CrCl2, NiCl2, THF, Et3N
`(S)-ligand 67
`
`MeO
`TBSO
`TBSO
`
`SO2Ph
`
`O
`
`O
`