Synthetic approaches to the 2002 new drugs

Mini-Reviews in Medicinal Chemistry, 2004, 4, 207-233 207 1389-5575/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. Synthetic Approaches to the 2002 New Drugs Jin Li* and Kevin K.-C. Liu* Pfizer Global Research and Development, Pfizer Inc., Groton CT 06340, USA Abstract: New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. Therefore, it is important to be acquainted with these new structures as well as their syntheses. To these ends, this review covers the syntheses of 28 NCEs marketed in 2002. Keywords: Synthesis, New Drug, New Chemical Entities, Medicine, Therapeutic Agents. INTRODUCTION Dozens of new drugs are registered and launched every year around the world. Although thousands of drugs have been marketed historically, the structure similarity among some drugs is obvious and even more so for drugs targeting in the same gene family. Furthermore, it has been demonstrated that molecules which share the same or similar chemical template can be further modified for different therapeutic indications against the similar gene family. Therefore, medicinal chemists, being aware of these new drug structures, can strike and adopt ideas for their own innovations. In addition, preparation of these drug molecules has been studied extensively to make it concise due to the cost of goods consideration and to ensure environment- friendliness. Having such robust and reliable synthetic methods in hand to access these core structures will steer synthetic efforts more effectively toward the most promising compounds and help focus the optimization toward other challenging properties such as ADME. In 2002 alone, 33 NCEs including biological drugs, and two diagnostic agents reached the market [1-5]. This review article will focus on the syntheses of the 28 new drugs marketed last year (Figure 1), but excludes new indications for known drugs, new combinations and new formulations. The syntheses of these new drugs were published sporadically in different journals and patents. It is our intention to compile the syntheses of new drugs yearly into an annual review for the readers’ advantage. The synthetic routes cited here represent the most scalable methods according to the best of the authors’ knowledge and appear in alphabetical order by generic name. Adefovir Dipivoxil (HepseraTM) Adefovir dipivoxil (1), discovered by Gilead, became the first nucleoside analogue to gain FDA approval for the treatment of chronic hepatitis B infection [6]. Adefovir works by blocking viral replication [6]. The synthesis [7,8] of adefovir dipivoxil (1) involves a four-step process [9,10] as depicted in Scheme 1. Adenine (29) was condensed with ethylene carbonate (30) in hot DMF to afford intermediate 9- *Address correspondence to these authors at the Pfizer, Groton, CT 06340, USA; Tel: 1-860-7153552; E-mail: jin_li@groton.pfizer.com; kevin_k_liu@groton.pfizer.com (2-hydroxyethyl)-adenine 31 in 83-95% yield. Alkylation of 31 was carried out using diethyl-p-toluenesulfonyloxy- methanephosphonate (32) and sodium t-butoxide in DMF. Phosphonate ester 33 was then cleaved with bromotrimethylsilane to furnish 34 and esterification of the phosphoric acid to append the pivaloyloxymethyl group provided adefovir dipivoxil (1). Amrubicin Hydrochloride (Calsed) This drug is the first anthracycline anticancer antibiotic produced by purely synthetic methods. It was discovered by Sumitomo Pharmaceuticals, and is for the treatment of non- small cell lung cancer and small cell lung cancer [11]. Tetralone 35 was treated with ammonium carbonate and potassium cyanide (Strecker reaction) to give the corresponding aminonitrile intermediate, which was hydrolyzed under basic conditions to afford amino acid 36 in excellent yield [12]. The carboxylic acid in 36 was esterified with HCl in methanol to the corresponding methyl ester, which was treated with D-(-)-mandelic acid in toluene to give optically pure levorotatory ester 37 in 33% yield. Sodium methylsulfinylmethide treatment of 37 followed by reduction with zinc yielded amino ketone 38, which was acylated to give amido ketone 39 in 81 % yield from 37. Compound 39 was converted to tetracyclic amido ketone 40 in one step (90% yield) by heating with phthalic anhydride in the presence of AlCl3-NaCl at 170°C. Ketone 40 was protected as its ketal 41 in order to provide for subsequent regiospecific bromination. Treatment of 41 with 1,3- dibromo-5,5-dimethylhydantoin (DDH) under illumination in refluxing benzene formed oxazine 42 in 89% yield. Hydrolysis of the oxazine ring and deketalization were simultaneously affected by heating 42 with 3N sulfuric acid to give cis-amino alcohol 43 in 82% yield. Modified Arcamone conditions (AgOSO2CF3 in ether/tetramethylurea /DCM) were employed for the stereoselective glycosidation of 43 with 2-deoxy-3,4-di-O-acetyl-D-erythro-pentopyranosyl bromide (44) [13] to give the protected β-glycoside in 86% yield. Basic hydrolysis of the protected coupling product followed by HCl salt formation gave amrubicin hydrochloride (2) in 90% yield. Aripiprazole (AbilifyTM) This atypical antipsychotic agent was originally discovered by Otsuka and was co-developed and co-marketed 208 Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 Li and Liu N H OH O OH O S NH N H O O O Na H O N NC F CO2H CO2H O O O H O O S OO O N S O O O OH O O- O OH O O H O O S OO O N S OH O O O S O O O O O- O OH O H HO O O S OO O N S OH O O- O H O S OO O Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ HO H OH H H S O F F F F F F NH Cl N N OMe O N O N O OH F OH F N N N N NH2 O P O O O O O O O O O O O OH HO OH O OH NH2 HCl Cl Cl N N O N H O O O NH HCl N H O NH F F F F F F H HH H O N N S OO Cl N H NH2 H N O 7 Fulvestrant (12) Gefitinib (13) Adefovir dipivox il (1) Amrubicin hydrochloride (2) Aripiprazole (3) Dexmethylphenidate HCl (4) Dutasteride (5) Ertapenem sodium (6) Escitalopram oxalate (7) Etoricoxib (8) Ezetimibe (9) Fondaparinux sodium (10) Frovatriptan (11) Synthetic Approaches to the 2002 New Drugs Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 209 (Fig. 1). contd..... N F O O H O O H 2N CH 3S O3H Paz ufloxacin me silate (20) Cl O O O O O N O O O OH O OH Pimecrolimus (21) O O N H H N N O O OH O O O O HO S NaO OO N H N O OH HN O HN HN ON OH OH OH H N HO O H2 N O HO O N O O OH OH OH O H2N OH P P OH O OH O OH OH O O O NO2 F F F N N O O O O N NH N N O OH N O S O O N O Na N O F N OH O S N O O O Landiolol (14) Micafungin sodium (15) Neridronate (16) Nitisinone (17) Olmesartan medoxomil (18) Parecoxib sodium (19) Prulifloxacin (22) O 210 Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 Li and Liu (Fig. 1). contd..... N H S O O O O HN O O O Na 4H2O N N OH HO O O N S O O F Ca2+ S O O O N S HO Br OH OH O O Na O N O S H2N OO N NF NN N F F HO Sivelestat sodium hydrate (24)2 Rosuvastatin calcium (23) Treprostinil (26) Valdecoxib (27) Voriconazole (28) Tiotropium bromide (25) Fig. (1). Structures of 28 new drugs marketed in 2002. N N NH N NH2 O O O N N N N NH2 OH N N N N NH2 O P OEt OEt O P OEt EtO OTs O N N N N NH2 O P OH OH O TMSBr Cl O O N N N N NH2 O P O O OO NaOH, DMF CH3 CN, Δ 29 30 120o C 83-95% 31 33 32 NaOBut, DMF 35-48% 34 80-90% TEA, NMP 40% 1 2 Scheme 1. Synthesis of adefovir dipivoxil. by Bristol-Myers Squibb. The compound is a partial agonist at dopamine D2 and 5HT1a and an antagonist at 5-HT2a receptors [14]. It is indicated for the treatment of schizophrenia. Hydroxyl quinolinone 45 was alkylated with 1,4-dibromobutane in the presence of potassium carbonate in DMF to give 46 in 78% yield [15]. Bromide 46 was condensed with 1-(2,3-dichlorophenyl)piperazine [16] (47) in the presence of NaI and TEA to give aripiprazole (3) in 87% yield. Dexmethylphenidate Hydrochloride (FocalinTM) Dexmethylphenidate (4) is the more pharmacologically active d-threo-enantiomer of methylphenidate which was marketed for the treatment of attention deficit/hyperactivity disorder (ADHD) in 1954 [17]. In addition, it has been shown that there are significant metabolic differences between the two enantiomers. This drug was discovered by Cangene and is marketed by Novartis. To date, several methods have been disclosed in the literature for preparing Synthetic Approaches to the 2002 New Drugs Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 211 OCH3 OCH3 O OCH3 OCH3 NH2 CH3 O OH OH NHAc CH3 OO O O Br OAc AcO OH OH N CH3 O O OO O CH3 OCH3 OCH3 NH2 CO2H OH OH NH2 CH3 O O O OO HO OH OH OH NHAc CH3 O O OO OH OH NH2 CH3 O O O OH HCl OCH3 OCH3 NHAc CH3 O O O O OCH3 OCH3 CO2 CH3 NH2 35 1) KCN, (NH4)2CO3, 50% EtOH, Δ, 99% 2) Ba(OH)2 , H2O, Δ, 92% 36 1) HCl, MeOH, 95% 2) D-(-)-mandelic acid toluene, IPA, 33% 37 1) NaH, DMSO, THF 2) Zn, NaOH/H2O, toluene 38 Ac2O, pyridine, toluene 80% from 37 39 AlCl3, NaCl, 170 oC 90% 40 ethylene glycol TsOH, toluene, Δ 88% DDH, benzene, hv Δ, 89% 42 41 3N H2 SO4, Δ 82% 43 44 2) HCl, MeOH, 90%AgOSO2CF3, ether tetramethylurea, CH2 Cl2 86% 1) KOH, CH2Cl2 MeOH, 2 Scheme 2. Synthesis of amrubicin hydrochloride. the d-threo-enantiomer of methylphenidate, most involving with enzymatic resolution [18], or crystallization/ recrystallization methods [19,20]. An asymmetric synthesis [21] route is depicted in Scheme 4. R-Pipecolic acid (48) was reacted with (Boc)2O to afford N-Boc pipecolic acid 49. Treatment of 49 with N,O-dimethylhydroxylamine in DCM provided the Weinreb amide 50 in 93% yield. Reaction of amide 50 with phenyllithium at –23°C in Et2O furnished enantiopure ketone 51 in 73% yield. Ketone 51 was converted to chiral aromatic alkene 5 2 using methylenetriphenylphosphorium ylide in THF at rt. The transformation of olefin 52 to diastereomeric alcohols 53 and 54 was achieved using BH3-THF complex in 89% overall yield. Diastereomerically pure alcohol 53 was subjected to PDC-mediated oxidation in DMF followed by treatment with excess ethereal diazomethane. The resulting N-Boc- methylphenidate was deprotected with 3N methanolic HCl to give dexmethylphenidate (4) as a white solid in 67% yield. 212 Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 Li and Liu N H OHO ClCl N N O N H O N H OBr(CH2)4O ClCl N NH 45 Br(CH2)4Br, K2CO3 DMF, 60oC, 78% 46 47 Nal, TEA CH3CN, 87% 3 Scheme 3. Synthesis of aripiprazole. N H OH O N Boc OH N OH OBoc N Boc N H OMeO N N OBoc O N Boc OH N Boc OH N OBoc (Boc)2O, TEA MeOH, rt, 97% 49 N, O-dimethylhydroxylamine BOP, TEA, DCM, rt , 93% 50 PhLi, Et2O -23oC, 73% 51 methyltriphenylphosphorium bromide KOBut, THF, rt , 93% 52 1) BH3 THF, THF 2) NaOH , H2O2, rt 53 64% 54 25% 1) PDC/DMF 2) CH2N2 3) HCl/MeOH 67% 4 48 53 Scheme 4. Synthesis of dexmethylphenidate. Dutasteride (AvodartTM) This steroid 5α-reductase type 1 and 2 inhibitor was patented by GlaxoSmithKline. It is used for the treatment of symptomatic benign prostatic hyperplasia in men with an enlarged prostate to improve urinary symptoms, reduce the risk of acute urinary retention and BPH-related surgery [22]. Steroidal dutasteride (5) was synthesized from 3-oxo-4- androstene-17β−carboxylic acid (55) [23]. Oxidation of 55 with potassium permanganate, sodium periodate and sodium carbonate in refluxing t-butyl alcohol and water gave seco- steroid 56 which was cyclized with ammonium acetate in acetic acid to give 4-aza-steroid 57 in good yield. Stereo- selective hydrogenation of 57 with H2 over PtO2 in hot acetic acid and in the presence of ammonium acetate yielded saturated azasteroid 58, which was dehydrogenated with DDQ in the presence of bis(trimethylsilyl)trifluoroacetamide (BSTFA) 59 in refluxing dioxane to give 60. Treatment of 60 with thionyl chloride gave the corresponding acyl chloride intermediate, which was then condensed with 2,5- bis(trifluoromethyl)aniline (61) by means of DMAP in heated toluene to give dutasteride (5) in 57% yield from intermediate 60. Ertapenem Sodium (InvanzTM) Ertapenem sodium (6) was introduced in the U.S. and Europe by Merck & Co. as a once daily injectable carbapenum antibiotic drug. Ertapenem (6) is indicated for the treatment of moderate to severe infections in adults caused by susceptible strains of a range of Gram-positive and Gram-negative aerobic and anaerobic bacteria [24]. Following a conventional carbapenem synthetic strategy, ertapenem sodium (6) can be assembled from 4-nitrobenzyl- protected β-methyl carbapenemenolphosphate 71 and 2- aminocarbonylpyrrolidine-4-ylthio-containing side chain 70. Many efficient approaches to 71 have been reported in the literature [25], and this compound is now commercially available on a large scale [26]. The synthesis of 70 is outlined in Scheme 6 [27,28]. Protection of the amino group in trans-4-hydroxy-L -proline (62 ) with diisopropyl phosphite followed by NaClO oxidation gave N-DIPP protected hydroxyl proline 63 in 80% yield. The carboxyl group in 6 3 was activated v i a reaction with diphenylphosphinic chloride (DPPC) in the presence of diisopropylethylamine (DIPEA). This intermediate 64 was directly reacted with methanesulfonyl chloride in the Synthetic Approaches to the 2002 New Drugs Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 213 N H CO2H O H CO2H O NSiMe3 Me3SiO F3C N H CO2H O H HO2C O CO2H F3 C NH2 CF3 N H CO2H O N H O H O H N CF3 CF3 KMnO4, NaIO4, Na 2 CO3 t-BuOH, H2O, 100 oC 58-66% NH4OAc, HOAc 56 55 120oC, 85-95% PtO2 , H2 HOAc, 60o C NH4OAc, 75-85% 57 DDQ, 59 dioxane, 100o C, 70-85% 58 60 1) SOCl2, toluene, pyridine, DMF 61 toluene, DMAP, 100oC, 57% 5 HH HH HH H H H H H H HH H HH H Scheme 5. Synthesis of dutasteride. presence of pyridine to furnish mesylate 65. Mesylate 65 was then quenched with aqueous sodium sulfide yielding 66 instantaneously, which then slowly cyclized to 6 7 . Aminolysis of 67 with m -aminobenzoic acid (68) and subsequent deprotection of the DIPP group with concentrated HCl provided 70 in 90-95% yield in a one-pot process. The coupling reaction between 70 and 71 followed by deprotection of PNB group was completed in one reaction vessel to furnish ertapenem sodium (6) (yield was not disclosed) [28]. Escitalopram Oxalate (Cipralex®) Escitalopram (7) is a selective serotonin reuptake inhibitor (SSRI) and was launched first in Switzerland. It is the more active S-enantiomer of citalopram which is a well- known antidepressant drug that has been on the market for some years [29]. It is for the treatment of major depressive episodes and panic disorder with or without agoraphobia. The synthesis of escitalopram was carried out in several different routes [30-33]. 5-Cyanophthalide (72) was treated with Grignard reagent 73 at 0°C to provide intermediate 75 which was reacted in situ with another Grignard reagent 76 to afford the diol in a one-pot process. Racemic diol 77 was resolved using (+)-p-toluoyltartaric acid to afford desired S isomer 78 in 55% yield. The ring closure reaction was carried out at 0°C using methanesulfonyl chloride in toluene to furnish escitalopram (7) in 60% yield. Etoricoxib (ArcoxiaTM) Merck & Co.’s etoricoxib (8) was launched for the first time in the U.K. last May as a new COX-2 inhibitor. Etoricoxib (8) is indicated for the symptomatic relief of osteoarthritis and rheumatoid arthritis, treatment of acute gouty arthritis, relief of chronic musculoskeletal pain including low back pain, relief of acute pain associated with dental surgery and treatment of primary dysmenorrhea [34]. The synthesis of etoricoxib (8) was explored extensively by the Merck process research group [35]. Key intermediate 85 was synthesized through at least three different routes. In the Horner-Wittig approach, 6-methyl methylnicotinate (79) was converted into Weinreb amide 80 in 95% yield. Amide 80 was then converted to aldehyde 81 via a DIBAL-H mediated reduction. Subsequent treatment of a solution of aldehyde 81 in isopropyl acetate with aniline and diphenyl phosphite provided N,P-acetal 82 in 87% yield. The Horner-Wittig reaction of N,P -acetal 82 with 4-methanesulfonyl- benzaldehyde (83) furnished enamine 84 , which was hydrolyzed to ketosulfone 85. A Grignard approach was also developed in the preparation of ketosulfone 85. Addition of Grignard reagent 86 to Weinreb amide 80 in toluene/THF provided ketosulfide 85 in 80% yield. Tungstate-catalyzed oxidation of ketosulfide 87 using hydrogen peroxide provided ketosulfone 85 in 89% yield by simple filtration. Ketosulfone 85 was prepared through Claisen condensation protocol as well. Thus, reaction of 4-methanesulfonyl phenyl acetic acid (88) with methyl nicotinate 79 under Ivanoff condition, i.e., the magnesium dianion in THF, resulted 58% yield of ketosulfone 85. Treatment of ketosulfone 85 with a three-carbon electrophile, 2-chloro-N , N - dimethylaminotrimethinium hexafluorophos-phate (89) in the presence of potassium t-butoxide at ambient temperature resulted adduct 90. Inverse quench of adduct 90 into a mixture of HOAc /TFA led to the putative intermediate 91. Ring closure of the pyridine ring occurred upon heating at 214 Mini-Reviews in Medicinal Chemistry, 2004, Vol. 4, No. 2 Li and Liu CO2H H2N O S O Cl N H HO COOH H O P O O N HS H N O DIPP CO2 H N MsO O P OO DIPP N HO COOH DIPP O P OiPr OiPr N HO H H O O S OH NH O N H ONa O Cl N HS H N O CO2H H H N MsO O S DIPP P OCl N HO O P OO DIPP N HO H H O O P O OPh OPh O OPNB N DIPP S O 62 1) 2) NaClO 0-5 o C, PH=9 80% 63 2) DIPEA -20oC, DCM 64 one pot process , 90-95% from 63 to 67. Pyridine -20 oC 65 aq. Na2S DIPP = 66 25oC, 2h 67 AcOH, rt 69 HCl conc, rt 70 one pot process, 90-95% from 67 to 70 71 1) Pd/C, NaOH, NEP, TMG 2) H2 6 68 1) _ _ Scheme 6. Synthesis of ertapenem sodium. reflux in the presence of an excess of aqueous ammonium hydroxide to give desired etoricoxib (8) in 97% yield in a one-pot process from 85. Ezetimibe (Zetia) Ezetimibe (9) was approved as the first hypolipidemic drug to act by blocking the absorption of dietary cholesterol. This drug was discovered by Schering-Plough and is co- developed and co-marketed by Merck and Schering-Plough for the treatment of hypercholesterolemia and also two less common forms of hyperlipidemia: homozygous familial hypercholesterolemia and homozygous sitosterolemia [36]. The synthesis of ezetimibe (9) begins with the one-step diastereoselective and practical synthesis [37] of the trans β- lactam from commercially available (S)-3-hydroxy-γ-lactone (92). Lactam 95 was obtained by generation of a dianion of lactone 92 with LDA in THF followed by addition of the imine and N,N’-dimethylpropyleneurea (DMPU) to give predominately adduct 93 (93 :94 = 79:21). However, intermediate 93 and 94 did not cyclize to their respective lactams due to formation of stable lithium aggregates. Addition of lithium chloride/DMF was employed to cyclize the intermediates into trans-lactam 95 as the major product (trans:cis = 95:5) in a one-pot process from 92 in 64% yield. The 95:5 ratio of compound 95 was oxidatively cleaved with NaIO4 to give aldehyde 96. Mukaiyama aldol condensation was a