2009药物合成

Review Synthetic approaches to the 2009 new drugs Kevin K.-C. Liu a,�, Subas M. Sakya b,�, Christopher J. O’Donnell b,⇑, Andrew C. Flick b,§, Jin Li c,– a Pfizer Inc., La Jolla, CA 92037, USA b Pfizer Inc., Groton, CT 06340, USA c a A R R A A K . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137 . . . . . . . . . . . . nce�) . �) . . . . . . . . . . . . . . . . � methoxylbenzyl; PPA, polyphosphoric acid; (S,S)-DET, (S,S)-(�)-diethyl tartrate; TBAF, t-butyl ammonium fluoride; TBDMSCl, t-butyldimethylsilyl chloride; TEA, triethylamine; TFA, trifluoroacetic acid; TFAA, trifluoroacetic acid anhydride; THF, tetrahydrofuran; THP, tetrahydropyran; TIPS, triisopropyl silyl; TPAP, tetrapropylam- monium perruthenate; TMG, 1,1,3,3-tetramethylguanidine; TMSCl, trimethylsilyl chloride; p-TSA, para-toluene sulfonic acid; Ts-DAEN, N-[(1S,2S)-2-amino-1,2-bis(4- methoxyphenyl)ethyl]-4-methyl-benzenesulfonamide. ⇑ Corresponding author. Tel.: +1 860 715 4118. E-mail addresses: Kevin.k.liu@pfizer.com (K.K.-C. Liu), subas.m.sakya@pfizer.com (S.M. Sakya), christopher.j.odonnell@pfizer.com (C.J. O’Donnell), andrew.flick@pfizer.com (A.C. Flick), jin.li@shenogen.com (J. Li). � Tel.: +1 858 622 7391. � Tel.: +1 860 715 0425. § Tel.: +1 860 715 0228. Bioorganic & Medicinal Chemistry 19 (2011) 1136–1154 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier .com/locate /bmc – Tel.: +86 10 8277 4069. 8. Dronedarone hydrochloride (Multaq ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146 9. Eltrombopag olamine (Promacta�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146 10. Eslicarbazepine acetate (Exelief�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147 11. Febuxostat (Uloric�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147 Abbreviations: AIBN, 2,20-azobisisobutyronitrile; Boc, t-butoxycarbonyl; CBZ, benzyloxycarbonyl; CDI, N,N0-carbonyldiimidazole; CMHP, cumene hydroperoxide; DBN, 1,5-diazabicyclo[4.3.0]on-5-ene; DBTA, dibenzoyl tartaric acid; DCE, dichloroethane; DCM, dichloromethane; DET, diethyl tartrate; DIAD, diisopropyl azodicarboxylate; DIBAL-H, diisobutylaluminum hydride; DIC, N,N0-diisopropylcarbodiimide; DIPEA, diisopropylethylamine; DMAP, 4-dimethylaminopyridine; DMF, N,N-dimethylformamide; DMPU, N,N0-dimethylpropyleneurea; DMSO, methyl sulfoxide; DPPC, diphenylphosphinic chloride; EDCI, N-(3-dimethylaminopropal)-N0-ethylcarbodiimide; HMTA, hexamethylenetetramine; HOBT, 1-hydroxybenzotriazole hydrate; IPA, isopropyl alcohol; IPAC, isopropyl acetate; LDA, lithium diisopropylamide; LIHMDS, lithium bis(trimethylsilyl)amide; MCPBA, meta-chloroperoxybenzoic acid; MEK, methyl ethyl ketone; MS, molecular sieves; NBS, N-bromosuccinimide; NCS, N-chlorosuccinimide; NEP, N-ethylpyrrolidinone; NMM, N-methylmorpholine; NMP, 1-methyl-2-pyrrolidinone; PCC, pyridinium chlorochromate; PDC, pyridinium dichromate; PMB, 4- Contents 1. Introduction . . . . . . . . . . . . . . . . . 2. Armodafinil (Nuvigil�) . . . . . . . . . 3. Asenapine maleate (Saphris�) . . . 4. Besifloxacin hydrochloride (Besiva 5. Dapoxetine hydrochloride (Priligy 6. Degarelix acetate (Firmagon�) . . . 7. Dexlansoprazole (Dexilant�) . . . . 0968-0896/$ - see front matter � 2011 Elsevier Ltd. A doi:10.1016/j.bmc.2010.12.038 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1140 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1142 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1142 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1144 New drug molecules New chemical entities Medicine Therapeutic agents Synthesis Shenogen Pharma Group, Beijing, China r t i c l e i n f o rticle history: eceived 12 November 2010 evised 15 December 2010 ccepted 16 December 2010 vailable online 24 December 2010 eywords: a b s t r a c t New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular rec- ognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009. � 2011 Elsevier Ltd. All rights reserved. ll rights reserved. 12. Indacaterol maleate (Onbrez�). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148 13. Minodronic acid hydrate (Bonoteo� and Recalbon�). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148 14. Nalfurafine hydrochloride (Remitch�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149 15. Pazopanib hydrochloride (Votrient�). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150 16. Plerixafor hydrochloride (Mozobil�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150 17. Pralatrexate (Folotyn�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151 18. Prasugrel (Effient�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151 19. Saxagliptin (Onglyza�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151 20. Tapentadol hydrochloride (Nucynta�) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152 21. Tolvaptan (Samsca�). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153 22. Ulipristal acetate (ellaOne�). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153 References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153 1. Introduction ‘The most fruitful basis for the discovery of a new drug is to start with an old drug.’—Sir James Whyte Black, winner of the 1988 Nobel Prize in physiology and medicine.1 Inaugurated eight years ago, this annual review presents synthetic methods for molecular entities that were launched in various countries for the first time during the past year.2–8 Given that drugs tend to have structural homology across similar biolog- ical targets, it is widely believed that the knowledge of new chem- ical entities and their syntheses will greatly facilitate drug design. In 2009, 51 new products including new chemical entities, biolog- ical drugs, and diagnostic agents reached the market,9 the largest number in the last decade. Twelve additional products were ap- proved for the first time in 2009; however, they were not launched before year’s end and thus the syntheses of those drugs will be covered in 2010s review. This review focuses on the syntheses of II Asenapine maleate S NH2 OO I Armodafinil S N O O OH Cl F NH2N HCl III Besifloxacin hydrochloride O C O N O O NH O NHHN O O O O NHO O NH2 O N Cl H H CO2H CO2H • • K. K.-C. Liu et al. / Bioorg. Med. Chem. 19 (2011) 1136–1154 1137 治疗嗜睡症莫达非尼的单一旋光异构体 N OH2N O O O O HCl VII Dronedarone hydrochlorideVI Dexlansoprazole O NC N S OH O N H N OH OHN N O O 2 NH2CH2CH2OH N HN N • • O S O O O NHN O NMe2 HCl IV Dapoxetine hydrochloride N H H N N HO O CF3 • IX EslicarbVIII Eltrombopag olamine Figure 1. Structures of 21 new H N N H H N N H H N N l OH O NH NH2O O H N CH3CO2H V Degarelix acetate • azepine acetate X Febuxostat drugs marketed in 2009. O H N N N N N NS O OH2N HCl NH NH N HN N NH HN HN 8 HCl N H O HO N H HO2C HO2C XI Indacaterol maleate N N P OH P O OH OH O OH OH H2O XII Minodronic acid hydrate XIII Nalfurafine hydrochloride HCl N OH O N O O • OH • • HO • • 1138 K. K.-C. Liu et al. / Bioorg. Med. Chem. 19 (2011) 1136–1154 OH O O XIV Pazopanib hydrochloride OH 21 new drugs marketed in 2009 (Fig. 1) and excludes new indica- tions for known drugs, new combinations, new formulations and drugs synthesized via bio-processes or peptide synthesizers. The synthetic routes cited herein represent the most scalable methods reported and appear in alphabetical order by generic name. OH OA Ac2O, H2SO4 S NH2 O NH3 (10 equiv) (S,S)-D H2O, E CMHP, DCM, 0 °C 1 2 5 MeOH, RT, –35 °C 75%83% Scheme 1. Synthesis o N N N N N H O NH2 H2N XVI Pralatrexate XVI HO N XIX Tapentadol hydrochloride HCl N Cl HO O XX To • Fig. 1 (cont S XV Plerixafor hydrochloride O 2. Armodafinil (Nuvigil�) Armodafinil, the R-enantiomer of the racemic marketed drug modafinil, was approved in June 2007 for treatment of excessive sleepiness associated with shift work sleep disorder, narcolepsy c S OMe O S NH2 O HS OMe O ET/Ti(OiPr)4 t3N, 55 °C EtOAc, 25 °C O I Armodafinil 0–20 °C 3 4 , 99.5% ee f armodafinil (I). N O F I Prasugrel XVIII Saxagliptin H N O lvaptan H O N H O O O XXI Ulipristal acetate HO O NH2 N NC inued) and obstructive sleep apnea/hypoapnea syndrome (OSAHS).9 The marketing of this drug was started in June 2009 by Cephalon, who discovered and developed the drug. In comparison to modafinil, armodafinil has a long half-life due to its slower metabolism and excretion, resulting in greater exposure of the drug and conse- quently a longer duration of action.10 Since the drug is the enantio- merically pure form of an existing racemic drug, multiple synthetic approaches to the enantiopure drug were utilized to progress the compound.11 To facilitate preparation of the enantiopure drug for Phase 1 studies, a continuous chiral separation method was devel- oped on large scale.12 However, due to the cost of this process, this route was abandoned in favor of a crystallization method.13 While exploring crystallization of various intermediates of the racemic sulfoxide, it was discovered that the acid intermediate formed a eu- tectic mixture. Seeding of this mixture with the desired R-enantio- mer provided the pure, desired enantiomer via an auto-seeded programmed polythermal preferential crystallization (AS3PC) method.14 Again, however, this route was deemed unsuitable for industrial scale because the S-enantiomer was still discarded in the process. Thus, an alternate catalytic oxidation method, based on initialwork fromKaganand co-workers15was developed anduti- lized in the industrial process.16 The resulting synthesis is a four- step sequence that requires only two isolations anddelivers thefinal target in high chemical and chiral purity (Scheme 1). Benzhydrol (1) was added to a mixture of acetic anhydride and catalytic sulfuric acid in DCM at 0 �C to give acetate 2. Crude 2 was reacted with methyl thioglycolate (3) and the reaction mixture was warmed to 20 �C to provide ester4, carried on to the next stepwithout isolation. Ester 4was then subjected to three volumes of ammonia in metha- nol at room temperature (rt) andwarmed to 35 �C. Upon completion l OE t O CO2H Cl O Cl 1. SOCl2, PhCH3, ↑↓ 2. sarcosine methyl ester TEA, DMF, RT, 45% NO CO2Me KOtBu, PhCH3 RT, 71% O Cl N O O PPA, 110 °C, 62% or H3PO4, P2O5 O NO Cl Mg, I2 (cat) MeOH, PhCH3 <40 °C, ~100% 10:11 = 1:4 O NO Cl O NO Cl H H H H+ 6 7 8 9 10 11 1. KOH, EtOH, ↑↓ 2. HCl, PhCH3, RT 3. crystallization O HO2C Cl 12 NHMe • HCl H H NaOAc, PhCH3 ↑↓, 65% from 9 O NO Cl H H 10 1. LiAlH4, AlCl3, THF PhCH3, <15 °C, 100% 2. maleic acid, EtOH, RT 3. re-crystallize O N Cl H H II Asenapine maleate CO2H CO2H • Scheme 2. Synthesis of asenapine maleate (II). K. K.-C. Liu et al. / Bioorg. Med. Chem. 19 (2011) 1136–1154 1139 C F N N N O OH O Cl F F NHN NO2 Cl F F F O O OE Cl F F F O OEt O HC(OEt)3 13 14 17 neat, RT NO2 TEA, CH3CN, RT 16 18 Scheme 3. Synthesis of besiflo N O OH O Cl F N H2N N O OH O Cl F F F O OEt O NH t neat, RT KOH (aq) HCl MeOH 100 °C 15 • HCl NH2 III Besifloxacin hydrochloride xacin hydrochloride (III). of the reaction, themixturewas cooled to25 �Candwaterwas added toprecipitate thedesired amide5, obtainedbyfiltration in83%yield. Amide 5 was then poised for the aforementioned asymmetric oxidation step, and thus dissolved in ethyl acetate and treated with (S,S)-(�)-diethyl tartrate, titanium(IV) isopropoxide, and water and stirred at 55 �C for 50 min. The mixture was then cooled to room temperature (25 �C) and triethylamine and cumene hydroperoxide (CMHP) were added. The reaction mixture was stirred for 1 h and the resulting product precipitated and collected by filtration to provide the armodafinil (I) in 75% yield with 99.5% ee. 3. Asenapine maleate (Saphris�) Asenapine is an atypical antipsychotic approved in the U.S. for acute treatment of schizophrenia in adults and the acute treatment of mania or mixed episodes associated with bipolar I disorder in Cl OH 1-naphthol 50%NaOH (aq) DMF, RT, 90% O OH 1. MsCl, Et3N, DMAP THF, 0 °C; Me2NH, RT 2. HCl, EtOAc, 67% for 2-steps 3. recrystallize from IPA 86%, 99.6% ee O NMe2 • HCl IV Dapoxetine hydrochloride19 20 Scheme 4. Synthesis of dapoxetine hydrochloride (IV). tBuO N H OH O CH3 O 1) DIC, HOBT, DMF DCM, H2N-resin 2) TFA, DCM H2N H N CH3 O 1) Boc-L-proline, DIC HOBT, DMF 3) Boc-L-N6-i-Pr-N6-Z-lysine DIC, HOBT, DMF 2) TFA, DCM 4) TFA, DCM H2N N O NHO O HN resin 1) Boc-L-leucine DIC, HOBT, DMF 2) TFA, DCM H2N O H N N O NHO O HN resin 1) Boc-D-4-(Fmoc-amino)phenyl alanine, DIC, HOBT, DMF 2) piperidine, DMF 3) tBuNCO, DMF 4) TFA, DCM N H O H N N O NHO O HN resin H2N O 1) Boc-L-4-(Fmoc-amino)phenylalanine DIC, HOBT, DMF 2) piperidine, DMF H NHHN O DC 21 22 23 24 3)Cbz Cbz N Cbz N DIC, HOBT, DMF resin 1140 K. K.-C. Liu et al. / Bioorg. Med. Chem. 19 (2011) 1136–1154 NH NHtBuO O O 4) TFA, resinO NHHN O 25 N N H O H N N O NHO O HN H N NH NHtBuO O H2N NH O O 1) Bo DI 2) TF 26 3) Bo DI 4) TF Cbz N Scheme 5. Synthesis of d O M c-L-serine(O-Bzl) C, HOBT, DMF A, DCM c-D-3-pyridyl-alanine C, HOBT, DMF A, DCM egarelix acetate (V). N O O d. C N H O H N H N NH O N H NH O NHHN O O O H2N H N N O OBzl O 27 K. K.-C. Liu et al. / Bioorg. Me adults. Although asenapine potently antagonizes a wide variety of serotonin and dopamine receptors, its pharmacological activity is attributed to its antagonism of the 5-HT2A and D1/D2 receptors.17 Asenapine was discovered and developed by Organon and later co-developed in collaboration with Pfizer. In 2006, however, Pfizer discontinued co-development of asenapine and in 2007 Organon was acquired by Schering-Plough who completed the develop- ment. The drug is now marketed by Merck & Co. after their acquisition of Schering-Plough in 2009. Several synthetic routes for the preparation of asenapine have been disclosed,18,19 and the largest reported process scale route is described in Scheme 2.20–23 5-Chloro-2-phenoxyphenylacetic acid (6) was treated with thionyl chloride to generate the corresponding acid chloride that was subsequently treated with sarcosine methyl ester to give amide 7 in 45% overall yield. Treatment of compound 7 with potassium tert-butoxide in toluene effected a Dieckmann-like N H H N N H H N N H H N N H O O Cl O N O OH O NH O HN O O CH3CO2H V Degarelix acetate NHtBuO N H H N O N H NH O HN O O N H H N N O OBzl O H2N H N O Cl O 28 Scheme 5 (co NH O HN resin 1) Boc-D-4-chlorophenylalanine DIC, HOBT, DMF 2) TFA, DCM 3) Boc-D-2-naphthylalanine DIC, HOBT, DMF 4) TFA, DCMCbz N hem. 19 (2011) 1136–1154 1141 condensation to provide oxo-lactam 8 in 71% yield. An intramolec- ular Friedel–Crafts alkylation-dehydration sequence was then performed by subjecting 8 to polyphosphoric acid, affording unsat- urated lactam 9 in 62% yield. Alternatively, reacting 8 with phos- phoric acid and phosphorous pentoxide would also deliver 9. Reduction of 9 with magnesium in methanol and catalytic iodine gave a 1:4 mixture of the desired trans-lactam 10 to the undesired cis-lactam isomer 11 in quantitative conversion. In the initial route, 10 was separated from 11 via column chromatography and 11 could be epimerized to 10 upon treatment with DBU. After two recycling steps, compound 10was prepared in 32% yield. However, a higher-yielding route that avoided the epimerization of 11 and column chromatography was later developed. The mixture of lactams (10 and 11) were treated with KOH in refluxing ethanol to affect lactam ring-opening. These basic conditions facilitated concomitant epimerization of the corresponding cis-amino acid H N N NH O O NH NH2O O H N O NHO O NH2 O H N N O NHO O HN resin NH NHtBuO NH O 1) Ac2O,DCM 2) HF, anisole, 0 °C 3) CH3CO2H, H2O Cbz N ntinued) product to the trans-amino acid 12, which upon treatment with sodium acetate in refluxing toluene regenerated trans-lactam 10 as a single isomer in 65% yield from 9. Reduction of 10with lithium aluminum hydride followed by maleic acid co-crystallization provided asenapine maleate (II) in 70% yield. 4. Besifloxacin hydrochloride (Besivance�) Besifloxacin is a fourth-generation fluoroquinolone antibiotic which is marketed as besifloxacin hydrochloride. It was originally developed by the Japanese firm SSP Co. Ltd and designated SS734. SSP then licensed U.S. and European rights of SS734 for oph- thalmic use t