A Practical Enantioselective Synthesis of Odanacatib, a Potent Cathepsin K Inhibitor, via Triflate Displacement of an r-Trifluoromethylbenzyl Triflate Paul D. O’Shea,*,† Cheng-yi Chen,‡ Danny Gauvreau,† Francis Gosselin,† Greg Hughes,† Christian Nadeau,† and Ralph P. Volante‡ Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-DorVal, Que´bec, H9R 4P8, Canada, and Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065
[email protected] ReceiVed September 12, 2008
An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific SN2 triflate displacement of a chiral R-trifluoromethylbenzyl triflate 9a with (S)-γ-fluoroleucine ethyl ester 3 to generate the required R-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.
Introduction Osteoporosis is a disease characterized by excessive bone loss causing skeletal fragility and an increased risk of fracture. One in two women and one in eight men over the age of 50 will have an osteoporotic fracture.1 Cathepsin K is a recently discovered2 member of the papain superfamily of cysteine proteases that is abundantly expressed in osteoclasts, the cells responsible for bone resorption.3 Bone is a living tissue that is remodeled every five to seven years in a dynamic process governed by the balance between bone formation and resorption in which osteoblasts and osteoclasts play a pivotal role. The abundant and selective expression of Cathepsin K in osteoclasts has made it an attractive therapeutic target for the treatment of osteoporosis.4 Odanacatib (MK-0822) 1 has been identified as a potent and selective inhibitor of Cathepsin K.5 We were interested in developing chemistry suitable for preparing kilogram quantities
of 1 in an effort to further explore its pharmacological properties. Herein, we report our efforts to develop a practical, enantioselective, chromatography-free synthesis of 1 on a multikilogram scale. We envisioned three possible routes for the preparation of 1 and the retrosynthetic analysis is outlined in Figure 1. The first route (A) requires an unprecedented nucleophilic displacement of an appropriately activated chiral R-trifluoromethylbenzyl alcohol with an R-amino ester. The second approach (B) relies on the diastereoselective reductive amination of an aryl trifluoromethyl ketone with an amino acid derivative. The third approach (C) requires nucleophilic displacement of an activated chiral R-hydroxy ester6 with a chiral R-trifluoromethylbenzyl amine. Previous reports from our laboratories have described methodologies attesting to the viability of approaches B7 and C8 for the synthesis of 1. Therefore, herein we report our efforts to investigate the nucleophilic displacement approach A for the preparation of 1.
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Merck Frosst Centre for Therapeutic Research. Merck Research Laboratories, Rahway. (1) Lindsay, R.; Meunier, P. J. Osteoporosis Int. 1998, 8, S1. (2) (a) Bossard, M. J.; Tomaszek, T. A.; Thompson, S. K.; Amegadzie, B. Y.; Hanning, C. R.; Jones, C.; Kurdyla, J. T.; McNulty, D. E.; Drake, F. H.; Gowen, M.; Levy, M. A. J. Biol. Chem. 1996, 271, 12517. (b) Bromme, D.; Okamoto, K.; Wang, B. B.; Biroc, S. J. Biol. Chem. 1996, 271, 2126. (3) Cai, J.; Jamieson, C.; Moir, J.; Rankovic, Z. Expert Opin. Ther. Pat. 2005, 15, 33. (4) Tezuka, K.; Tezuka, Y.; Maejima, A. J. Biol. Chem. 1994, 269, 1106. ‡
10.1021/jo8020314 CCC: $40.75 2009 American Chemical Society Published on Web 01/13/2009
(5) Gauthier, J. Y.; Chauret, N.; Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J. P.; Kimmel, D. B.; Lamontagne, S.; Le´ger, S.; LeRiche, T.; Li, C. S.; Masse´, F.; McKay, D. J.; Nicoll-Griffith, D.; Oballa, R. M.; Palmer, J. T.; Percival, D.; Riendeau, D.; Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; The´rien, M.; Truong, V. L.; Venuti, M.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. Bioorg. Med. Chem. Lett. 2008, 18, 923. (6) Effenberger, F.; Burkard, U.; Willfahrt, J. Liebigs Ann. Chem. 1986, 314. (7) Hughes, G.; Devine, P. N.; Naber, J. R.; O’Shea, P. D.; Foster, B. S.; McKay, D. J.; Volante, R. P. Angew. Chem., Int. Ed. 2007, 46, 1839.
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FIGURE 1. Retrosynthetic analysis.
FIGURE 2. Displacement of activated alcohols.
Results and Discussion The introduction of a fluorine in place of a hydrogen in an organic molecule can have a profound effect on its biological properties.9 Recently, the trifluoroethylamine functionality has been proposed as an amide bond surrogate in peptidomimetics.10 As such, the synthesis of chiral fluoroalkyl amines has received considerable attention in the literature and a number of methodologies have been reported.11 The nucleophilic displacement of activated benzylic alcohols is a well-studied transformation in organic chemistry.12 The stereospecific SN2 displacement of activated chiral secondary benzylic alcohols is an attractive strategy for the preparation of optically active substrates.
(8) (a) Nadeau, C.; Gosselin, F.; O’Shea, P. D.; Davies, I. W.; Volante, R. P. Synlett 2006, 291. (b) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.-y.; Volante, R. P. Org. Lett. 2005, 7, 355. (9) (a) Mikami, K.; Itho, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1. (b) Iseki, K. Tetrahedron 1998, 54, 13887. (c) Resnati, G., Soloshonok, V. A., Eds. Tetrahedron Symposia-in-Print No. 58. Fluoroorganic Chemistry: Synthetic Challenges and Biomedical Rewards. Tetrahedron 1996, 52, 1. (d) Fluorine Containing Amino Acids: Synthesis and Properties; Kuhar, V. P., Soloshonok, V. A., Eds.; Wiley: Chichester, UK, 1994. (e) Bravo, P.; Resnati, G. Tetrahedron: Asymmetry 1990, 1, 661. (10) Sani, M.; Volonterio, A.; Zanda, M. ChemMedChem 2007, 2, 1693. (11) (a) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.-y.; Volante, R. P. Org. Lett. 2005, 7, 355, and the references cited therein. (12) For detailed discussion, see: (a) March, J. AdVanced Organic Chemistry, 4th ed.; J. Wiley & Sons: New York, 1992; p 293. (b) Allen, A. D.; Kanagasabapathy, V. M.; Tidwell, T. T. J. Am. Chem. Soc. 1985, 107, 4513. (c) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1383.
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However, despite some reported successes,13 its practical use remains limited due to racemization as a result of competing SN1 and SN2 pathways. Stereospecific displacements have been reported with use of electron-deficient aromatic or heteroaromatic14 substrates where SN1 pathways are disfavored through generation of destabilized carbocation intermediates. Due to the strong electron-withdrawing property of the CF3 group, we were particularly interested in nucleophilic displacements of activated chiral alcohols such as 9, which would provide easy access to the desired functionalized amino esters 10 (Figure 2). A survey of the literature revealed scant reference to displacement reactions of R-trifluoromethyl benzyl substrates. Tidwell and co-workers15 have reported solvolysis studies of 1-aryl-2,2,2trifluoroethyl sulfonates. β-Trifluoromethyltyrosine derivatives have been reported in racemic fashion via displacement of 1-chloro-2,2,2-trifluoroethyl phenols.16 Fuchikami et al. have reported17 clean SN2 displacement of optically active alkyltrifluoroalkyl triflates under mild conditions using benzoic acid (13) (a) Hillier, M. C.; Marcoux, J. F.; Zhao, D.; Grabowski, E. J. J.; McKeown, A. E.; Tillyer, R. D. J. Org. Chem. 2005, 70, 8385. (b) Hillier, M. C.; Desrosiers, J. N.; Marcoux, J. F.; Grabowski, E. J. J. Org. Lett. 2004, 6, 573. (c) Bolshan, Y.; Chen, C. Y.; Chilenski, J.; Gosselin, F.; Mathre, D. J.; O’Shea, P. D.; Roy, A.; Tillyer, R. D. Org. Lett. 2004, 6, 111. (14) (a) Uenishi, J.; Hamada, M.; Aburatani, S.; Matsui, K.; Yonemitsu, O.; Tsukube, H. J. Org. Chem. 2004, 69, 6781. (b) Lim, C.; Kim, S.-H.; Yoh, S.D.; Fujio, M.; Tsuno, Y. Tetrahedron Lett. 1997, 38, 3243. (15) Allen, A. D.; Ambidge, A. I.; Che, C.; Micheal, H.; Muir, R. J.; Tidwell, T. T. J. Am. Chem. Soc. 1983, 105, 2343. (16) Gong, Y.; Kato, K. J. Fluorine Chem. 2003, 121, 141.
A Practical EnantioselectiVe Synthesis of Odanacatib SCHEME 1.
SN2 Displacement Route to 1
as a nucleophile. In addition, the displacement of secondary benzylic mesylates has been reported; however, there are no details describing the stereospecificity of these reactions. Chiral alcohol 2a was accessed in a straightforward manner via oxazaborolidine-catalyzed enantioselective reduction18 of ketone 5a. Thus, treatment of a solution of 5a with 2.5 mol % of n-Bu-OAB and catechol borane gave 2a in 96% isolated yield and 92% ee. To study the effect of the aromatic ring substitution on the activation and subsequent amino ester displacement, biphenyl methylsulfide alcohol 2b and methyl sulfone 2c were also prepared in high yield via Suzuki19 cross coupling with the requisite boronic acids. We began our studies with an investigation of various activating groups using commercially available L-leucine ester as a model amino ester (Figure 2). We first evaluated biaryl sulfone alcohol 2c as a substrate for the SN2 reaction. Activation of alcohol 2c as its corresponding mesylate or tosylate and reaction with 2 equiv of L-leucine methyl ester gave none of the desired product in a variety of solvents at temperatures from 25 to 100 °C. Higher temperatures (150 °C) led to rapid (95% yield with no loss of ee as a c-hexane solution after aqueous workup. Addition of K2CO3 and 3 followed by heating at 65-70 °C for 18-24 h yielded 10a in 95% yield and 84% de (Scheme 1). An evaluation of cross-coupling conditions between bromo ester 10a and boronic acid 11 with Pd(OAc)2 and various ligands Ph3P, (o-tol)3P, (2-furyl)3P, (Cy)2P-biaryl, and (t-Bu)2-biaryl (17) (a) Hagiwara, T.; Tanaka, K.; Fuchikami, T. Tetrahedron Lett. 1996, 37, 8187. (b) Hagiwara, T.; Ishizuka, M.; Fuchikami, T. Nippon Kagaku Kaishi 1998, 11, 750. (18) (a) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611. (b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (19) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (20) (a) Padmakshan, D.; Bennett, S. A.; Otting, G.; Easton, C. J. Synlett 2007, 1083. (b) Truong, V. L.; Gauthier, J. Y.; Boyd, M.; Roy, B.; Scheigetz, J. Synlett 2005, 1279. (c) Limanto, J.; Shafiee, A.; Devine, P. N.; Upadhyay, V.; Desmond, R. A.; Foster, B. R.; Gauthier, D. R.; Reamer, R. A.; Volante, R. P. J. Org. Chem. 2005, 70, 2372.
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Experimental Section
FIGURE 3. Ester hydrolysis impurities.
revealed high conversion and purity with use of (o-tol)3P. Thus treatment of bromide 10a with boronic acid 11 in the presence of Pd(OAc)2 (0.5 mol %), (o-tol)3P (1.25 mol %), and aqueous Na2CO3 in THF at 65 °C for 2 h gave >99% conversion (93% assay yield by HPLC) of the desired biaryl 12 (Scheme 1). Several reagents were investigated for the hydrolysis of the ethyl ester 12. Potassium trimethylsilanolate (TMSOK) in THF at 20 °C afforded good conversion to the desired acid 12a but caused extensive epimerization (∼10%) at the amino ester stereocenter. Lithium hydroperoxide afforded only low conversion (∼20%) even after extended reaction time. NaOH gave the desired acid but generated up to 10% of hydroxyl acid 14 (Figure 3). KOH led to a much slower hydrolysis and caused 1-5% epimerization of the amino ester stereocenter. Interestingly, LiOH gave complete conversion to the desired acid within a few hours at reflux in THF with a lower amount of hydroxy acid 14 and no epimerization was observed with HPLC analysis. We focused our efforts on a one-pot Suzuki coupling/hydrolysis procedure to increase the efficiency of the process. Thus, on completion of the Suzuki reaction powdered LiOH · H2O (5 equiv) was added to the reaction mixture at 20 °C. The saponification was completed after 18 h at 35 °C and following extractive workup, the desired acid 12a was isolated in 91% yield (over two steps) and 84% de (Scheme 1). It was necessary to store the acid at 99.5% de. Conclusion Odanacatib (MK-0822) 1 was synthesized in six steps and 61% overall yield from commercially available 1-(4-bromophenyl)-2,2,2-trifluoroethanone (5a) without the need for chromatography. The key step is a novel triflate displacement of (1R)1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (9a) with (S)-γ-fluoroleucine ethyl ester 3, which provides 10a with minimal loss of ee at the benzylic center. Subsequent Suzuki cross coupling, saponification, and amidation complete the synthesis. 1608 J. Org. Chem. Vol. 74, No. 4, 2009
(1R)-1-(4-Bromophenyl)-2,2,2-trifluoroethanol (2a). Catecholborane (9.49 L, 2.0 M in toluene, 18.97 mol, 1.6 equiv) was cooled to -50 °C. (S)-Butyloxazaborolidine (988 mL, 0.3 M solution in toluene, 0.30 mol, 2.5 mol %) was added over 30 min and the mixture was cooled to -70 °C. A solution of 1-(4bromophenyl)-2,2,2-trifluoroethanone 5a (3.00 kg, 11.86 mol) in toluene (9.0 L) was added to the reaction mixture over 3 h. The reaction mixture was warmed to -55 °C over 2 h, maintained at this temperature for 4 h, then gradually warmed to 15 °C over 14 h. The reaction mixture was cooled to -20 °C then toluene (2 L) was added, followed by aqueous 1 N HCl (30 L) over 10 min. The batch was warmed to 20 °C and the layers were separated. The organic layer was successively washed with aqueous 2 M Na2CO3 (3 × 15 L), aqueous 1 N HCl (15 L), and H2O (2 × 15 L). The batch was concentrated under reduced pressure (35 °C), flushed with toluene (8 L), and kept as a toluene solution. HPLC assay indicated 2.9 kg of trifluoromethyl alcohol 2a in 96% yield, 92.4% ee: mp 55-56 °C; 1H NMR (500 MHz, CDCl3) δ 7.55 (d, 2H, J ) 8.5 Hz), 7.35 (d, 2H, J ) 8.3 Hz), 5.02-4.98 (m, 1H), 2.64 (d, 1H, J ) 4.0 Hz); 13C NMR (125 MHz, CDCl3) δ 133.2, 132.2, 129.5, 124.3 (q, J ) 282.1 Hz), 124.2, 72.6 (q, J ) 32.4 Hz); 19F NMR (375 MHz, CDCl3) δ -78.5; IR (NaCl cm-1) 3374, 3075, 2945, 2880, 1593, 1492, 1402, 1335, 1247, 1195, 1124, 1096; [R]20D -27.5 (c 1.06, EtOH); HPLC Zorbax Rx-C8 4.6 mm × 25 cm column; eluants (A) 0.1% aqueous H3PO4 and (B) acetonitrile; 2 mL/min; gradient A/B 70:30 to 5:95 over 25 min; λ ) 220 mn; temperature 35 °C; tR(ketone) ) 7.4 min, tR(alcohol) ) 9.4 min; SFC (chiral) Chiralcel OJ 4.6 mm × 25 cm column; eluants (A) 2-propanol and (B) CO2; 2 mL/min; gradient A/B 1:99 for 4 min to 20:80 over 12.7 min; λ ) 220 mn; temperature 35 °C; tR((R)2a) ) 10.2 min, tR((S)-2a) ) 10.9 min, 92.4% ee. Anal. Calcd for C8H6BrF3O: C, 37.68; H, 2.37. Found: C, 37.44; H, 2.10. (1R)-1-(4-Bromophenyl)-2,2,2-trifluoroethyl Trifluoromethanesulfonate (9a). A solution of bromo alcohol 2a (2.13 kg, 5.15 mol, 1.0 equiv, 92% ee) and 2,6-lutidine (0.88 kg, 8.24 mol, 1.6 equiv) in c-hexane (5 L) was cooled to -10 °C. Triflic anhydride (2.18 kg, 7.7 mol, 1.5 equiv) was added over ∼30 min at a rate to maintain the temperature
