A practical enantioselective synthesis of odanacatib, a potent cathepsin K inhibitor, via triflate displacement of an α-Trifluoromethylbenzyl triflate

Article abstract of DOI:10.1021/jo8020314

An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S _N2 triflate displacement of a chiral α-trifluoromethylbenzyl triflate 9a with (S)-γ-fluoroleucine e

Full text of DOI:10.1021/jo8020314

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
paul_oshea@merck.com
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
of 1 in an effort to further explore its pharmacological properties.
Herein, we report our efforts to develop a practical, enantiose-
lective, chromatography-free synthesis of 1 on a multikilogram
scale.
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
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 triflu-
oromethyl 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.
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
† Merck Frosst Centre for Therapeutic Research.
‡ Merck Research Laboratories, Rahway.
(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.
(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.
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(4) Tezuka, K.; Tezuka, Y.; Maejima, A. J. Biol. Chem. 1994, 269, 1106.
10.1021/jo8020314 CCC: $40.75
Published on Web 01/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1605–1610 1605

O’Shea et al.
FIGURE 1. Retrosynthetic analysis.
FIGURE 2. Displacement of activated alcohols.
Results and Discussion
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 heteroaro-
matic14 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-2,2,2-
trifluoroethyl sulfonates. ꢀ-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 alkyl-
trifluoroalkyl triflates under mild conditions using benzoic acid
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 displace-
ment of activated benzylic alcohols is a well-studied transforma-
tion 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.
(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.
1606 J. Org. Chem. Vol. 74, No. 4, 2009

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 correspond-
ing 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 (<10 min) and complete decomposition
of the starting material. Activation of the alcohol 2c (90% ee)
as its corresponding triflate followed by reaction with L-leucine
methyl ester (2 equiv) with K2CO3 in 1,2-dichloroethane (DCE)
at 50 °C did give the desired displacement product; however,
significant erosion of stereochemistry at the benzylic center
(20% ee) was observed. An evaluation of various solvents (iPAc,
CH3CN, THF) and bases (TEA, DIEA) failed to improve the
outcome of this reaction and in most cases led to multiple
byproducts with either decreased conversion and/or nearly
complete erosion of optical purity.
Activation of alcohol 2b with triflic anhydride or triflic
chloride proved problematic, presumably due to competing
thioether sulfonylation and subsequent decomposition. By
comparison, the corresponding mesylate, tosylate, brosylate,
nosylate, and tresylate were readily prepared in high yield and
evaluated directly in the nucleophilic displacement reaction. The
mesylate and tosylate were unreactive toward displacement
under a variety of conditions, with hydrolysis or decomposition
occurring at higher temperatures. Moderate to good conversion
was observed in acetonitrile with K2CO3 at 40-80 °C for the
brosylate (50%), nosylate (80%), and tresylate (82%); however,
in all cases the product obtained was racemic at the benzylic
center.
and 2c, the corresponding mesylate 9aa and tosylate 9ab were
unreactive under a variety of reaction conditions. Therefore, we
investigated more reactive leaving groups. The nosylate-
activated alcohol 9ac afforded hydrolysis product under a variety
of reaction conditions. The corresponding tresylate 9ac afforded
a 42% conversion to the desired compound in a 5:1 diastere-
omeric ratio; however, all attempts to improve the conversion
resulted in lower selectivity and/or decomposition. High conver-
sion was observed with the triflate 9a; however, in the initial
experiments significant erosion of enantiometic excess was
observed at the benzylic center. In an effort to improve on the
stereochemical outcome, a number of reaction parameters were
evaluated. Solvents such as DMSO, DMF, NMP, DMPU, and
toluene were found to be unsuitable due to their reaction with
the triflate. The reaction did proceed in iPAc, CH3CN, PhNO2,
THF, PhCl, CH2Cl2, c-hexane, and n-Bu2O to varying degrees
of success. An evaluation of bases indicated that i-Pr2NEt, Et3N,
2,6-lutidine, K3PO4, and K2CO3 all gave high conversion.
Stability studies on the triflate 9a with chiral HPLC to measure
the ee of unreacted triflate indicated that the loss of ee at the
benzylic center was due to racemization of the triflate as the
reaction progressed. The racemization was promoted by increas-
ing temperature, the use of more polar solvents, and the presence
of soluble triflate salts. Therefore, we were delighted to find
that treatment of triflate 9a with (S)-γ-fluoroleucine ethyl ester
320 and K2CO3 in c-hexane at 70 °C led to high conversion to
the desired product with minimal erosion of ee at the benzylic
center. Thus treatment of 2a (92% ee) with Tf2O in c-hexane
with 2,6-lutidine at 0-10 °C gave the desired triflate 9a in
>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.
We then focused our efforts on the displacement of 1-(4-
bromophenyl)-2′,2′,2′-trifluoroethanol 2a. As in the case of 2b
J. Org. Chem. Vol. 74, No. 4, 2009 1607

O’Shea et al.
Experimental Section
(1R)-1-(4-Bromophenyl)-2,2,2-trifluoroethanol (2a). Cate-
cholborane (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-(4-
bromophenyl)-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,
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 conver-
sion (∼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. Interest-
ingly, 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 <4 °C to prevent formation of the undesired
lactone 15 (Figure 3).
A number of conditions were investigated for the amidation
of acid 12a with cyclopropylaminonitrile 13. Activation of the
acid 12a with oxalyl chloride or thionyl chloride followed by
treatment with amine hydrochloride 13 led to low yields of 1.
Similarly, activation as a mixed anhydride with pivaloyl chloride
did not give useful yields of 1. High conversion and yields were
obtained with a number of peptide coupling agents most notably
phosphonium coupling reagent PyBOP and uronium coupling
reagents TBTU and HATU. Thus, treatment of 12a and 13 with
HATU and DIEA in DMAc at 5 °C led to high conversion to
the desired amide 1. Addition of water directly to the reaction
mixture crystallized 1 in 79% isolated yield with an efficient
rejection of the minor diastereoisomer to give an upgrade in de
from 84% to 98.5%. A final recrystallization from THF/water
provided an additional purity and diastereomeric upgrade
yielding 1 with 97% recovery and >99.5% de.
2945, 2880, 1593, 1492, 1402, 1335, 1247, 1195, 1124, 1096; [R]20
D
-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 Trifluoromethane-
sulfonate (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 <10 °C. The reaction mixture was aged
for 90 min maintaining the temperature at 0-10 °C. Water (5.6 L)
and c-hexane (5.6 L) were added. The aqueous layer was separated
and the organic layer was washed with aqueous 1 N HCl (1 × 5.6
L, 2 × 2.6 L) and water (5.6 L). Following layer separation the
c-hexane was removed under reduced pressure to yield 3.12 kg of
9a in c-hexane, 95% yield, 91.7% ee: 1H NMR (400 MHz, acetone-
d6) δ 7.83-7.79 (m, 2 H), 7.70 (d, 2H, J ) 8.4 Hz), 6.74 (q, 1 H,
J ) 5.9 Hz); 13C (125 MHz, benzene-d6) δ 132.5, 129.4, 126.8,
126.2, 121.6 (q, J ) 280 Hz), 118.6 (q, J ) 323 Hz), 81.9 (q, J )
36 Hz); 19F NMR (377 MHz, acetone-d6) δ -80.3 (s, 3F), -81.7
(d, 3F, J ) 31 Hz); HRMS (ESI) calcd for C9H6BrF6O3S [MH]+
388.0976, found 388.0976; [R]20 -84 (c 1.7, hexanes); HPLC
D
Zorbax SBC18 4.6 mm × 25 cm column; eluants (A) 0.1% aqueous
H3PO4 and (B) acetonitrile; 2 mL/min; gradient A/B 50:0 to 5:95
over 10 min, hold 5 min; λ ) 220 nm; temperature 25 °C;
tR(alcohol) ) 4.0 min, tR(triflate) ) 7.9 min: chiral HPLC Chiralpak
AD 4.6 mm × 25 cm column; eluant hexane 100%; 1 mL/min; λ
) 220 nm; temperature 25 °C; tR((S)-9a) ) 10.4 min, tR((R)-9a)
) 11.6 min, 91.7% ee.
Conclusion
Ethyl N-[(1S)-1-(4-Bromophenyl)-2,2,2-trifluoroethyl]-4-fluoro-
L-leucinate (10a). Potassium carbonate (1.19 kg, 8.59 mol, 1.5
equiv) was added to a mixture of triflate 9a (3.12 kg, 5.7 mol, 1.0
equiv, 91.7% ee), c-hexane (2 L), and amino ester (1.48 kg, 8.02
mol, 1.4 equiv, 96% ee). The mixture was heated to 65-70 °C
and aged for 24 h. The mixture was cooled to 20 °C and c-hexane
(5.6 L) and water (5.6 L) were added, then the mixture stirred for
10 min. The layers were separated; the organic layer was washed
with aqueous 1 N HCl (1 × 5.6 L, 2 × 2.5 L) and water (5 L). The
organic layer was concentrated under reduced pressure to yield 2.6
Odanacatib (MK-0822) 1 was synthesized in six steps and
61% overall yield from commercially available 1-(4-bromophe-
nyl)-2,2,2-trifluoroethanone (5a) without the need for chroma-
tography. 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

A Practical EnantioselectiVe Synthesis of Odanacatib
kg of 10a, 95% yield, 84% de (19F NMR). A sample was purified
MTBE (9 L) was added to the combined aqueous layers. Aqueous
2 N HCl (15.9 L) was added over 15 min until the pH of the
aqueous layer was 2.5. The layers were separated and the brown
emulsion was kept in the MTBE layer. The aqueous layer was
extracted with MTBE (9 L) and the brown emulsion was kept in
the MTBE layer. The combined organic layers were washed with
H2O (9 L) and the brown emulsion was kept in the aqueous layer.
Solka-floc (206 g) and activated carbon Darco KB-B (206 g) were
added to the MTBE layer and the mixture was vigorously stirred
for 1 h at rt. The suspension was then filtered through Solka-Floc
and rinsed with MTBE (2 × 1 L). The brown filtrate was line
concentrated under reduced pressure (30 °C), flushed with iPAc (4
L), and concentrated until a beige solid formed. HPLC analysis
indicated 1.9 kg of acid 12a in 91% yield over two steps, 84% de:
mp 115-117 °C; 1H NMR (500 MHz, CDCl3) δ 8.04 (d, 2H, J )
8.3 Hz), 7.78 (d, 2H, J ) 8.3 Hz), 7.65 (d, 2H, J ) 8.1 Hz), 7.53
(d, 2H, J ) 8.1 Hz), 4.30 (q, 1H, J ) 7.0 Hz), 3.72 (dd, 1H, J )
7.8, 4.3 Hz), 3.12 (s, 3H), 2.20 (ddd, 1 H, J ) 23.3, 15.0, 4.2 Hz),
1.99 (ddd, 1 H, J ) 18.4, 15.1, 8.0 Hz), 1.50 (d, 3H, J ) 21.7 Hz),
1.48 (d, 3H, J ) 21.7 Hz); 13C NMR (125 MHz, CDCl3) δ 177.8,
146.1, 140.7, 140.0, 134.5, 129.7, 128.5, 128.4, 125.6 (q, J ) 282.3
Hz), 95.8 (d, J ) 165.4 Hz), 63.1 (q, J ) 29.2 Hz), 56.9, 45.0,
44.1 (d, J ) 21.9 Hz), 27.6 (d, J ) 24.7 Hz), 27.3 (d, J ) 24.4
Hz); 19F NMR (375 MHz, CDCl3) δ -73.5, -136.9; HRMS (ES)
calcd for C21H24F4NO4S [MH]+ 462.1362, found 462.1362; IR
(NaCl, cm-1) 3337, 3032, 2982, 2930, 1733, 1717, 1652, 1597,
by flash chromatography (5% EtOAc/hexanes) for purposes of
1
characterization: mp 34.5-35.6 °C; H NMR (500 MHz, CDCl3)
δ 7.51 (d, 2H, J ) 8 Hz), 7.26 (d, 2H, J ) 8 Hz), 4.10-3.97 (m,
3H), 3.61 (br s, 1H), 2.13 (br s, 1H), 2.07 (ddd, 1H, J ) 18.5,
14.7, 5 Hz), 1.87 (ddd, 1H, J ) 21, 14, 8 Hz), 1.46 (d, 3H, J ) 17
Hz), 1.42 (d, 3H, J ) 18 Hz), 1.18 (t, 3H, J ) 7 Hz); 13C (100
MHz, CDCl3) δ 174.1, 133.6, 131.8, 130.0, 125.1 (q, J ) 282 Hz),
123.2, 94.7 (d, J ) 156 Hz), 62.7 (q, J ) 27 Hz), 61.1, 57.0 (d, J
) 4 Hz), 44.4 (d, J ) 23 Hz), 27.5 (d, J ) 24 Hz), 26.5 (d, J )
25 Hz), 13.9; 19F (377 MHz, CDCl3) δ -78.5 (d, 3F, J ) 7 Hz),
-140.4 (nonet, 1F, J ) 21 Hz); IR (film, cm-1) 1729, 1490, 1370,
1258, 1158, 1123; [R]20D +37.5 (c 1.9, CHCl3); HPLC Zorbax SB-
C18 4.6 mm × 25 cm column; eluants (A) 0.1% aqueous H3PO4
and (B) acetonitrile; 2 mL/min; gradient A/B 50:50 to 5:95 over
10 min, hold 5 min; λ ) 220 nm; temperature 25 °C; tR(bromo
amine 10a (major diastereoisomer)) ) 5.5 min, tR(bromoamine 10a
(minor diastereoisomer))
C16H20BrF4NO2: C, 46.39; H, 4.87; N, 3.38. Found: C, 46.22; H,
4.61; N, 3.47.
)
5.8 min. Anal. Calcd for
Ethyl 4-Fluoro-N-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-
biphenyl-4-yl]ethyl}-L-leucinate (12). A visually clean 5-necked
50-L round-bottomed flask was charged with crude bromo ester
10a (1.85 kg, 4.46 mol) and THF (9.0 L). With stirring, p-
methylphenylsulfone boronic acid (1.16 kg, 5.79 mol) and tri-o-
tolylphosphine (17.0 g, 0.056 mol) were added. The solution was
degassed with N2 bubbling for 20 min. Pd(OAc)2 (5.01 g, 0.022
mol) was added to the mixture and the solution was aged 20 min.
Degassed 1 M aqueous Na2CO3 (6.7 L, 6.7 mol) was added to the
THF solution. The biphasic mixture was heated to reflux (67 °C)
under N2 atmosphere and maintained at this temperature for 2 h.
The reaction reached 99.8% conversion (by HPLC). The biphasic
mixture was cooled to 35 °C and used directly for the hydrolysis
of the ester. The HPLC assay yield of biaryl 12 was 1.98 kg, 92.7%,
de 85% (by 19F NMR): mp 102.9-103.6 °C; 1H NMR (500 MHz,
acetone-d6) δ 8.03 (d, 2H, J ) 8.4 Hz), 7.94 (d, 2H, J ) 8.4 Hz),
7.79 (2H, d, J ) 8.2 Hz), 7.62 (2H, d, J ) 8.2 Hz), 4.46 (m, 1 H),
3.89 (qd, 2H, J ) 5.9, 2.1 Hz), 3.65 (m, 1 H), 3.16 (s, 3 H), 2.69
(m, 1 H), 2.11-1.93 (m, 2 H), 1.46 (d, 3H, J ) 21.5 Hz), 1.42 (d,
3H, J ) 21.5 Hz), 1.08 (t, 3H, J ) 7.1 Hz); 13C NMR (126 MHz,
acetone-d6) δ 174.2, 145.4, 140.6, 139.9, 135.8, 129.7, 128.3, 128.1,
127.8, 126.2 (q, J ) 282 Hz), 94.9 (d, J ) 166 Hz), 63.0 (q, J )
29 Hz), 60.8, 57.9, 44.4 (d, J ) 24 Hz), 43.9, 27.8 (d, J ) 24 Hz),
26.1 (d, J ) 24 Hz), 13.8; 19F NMR (377 MHz, acetone-d6) δ -78.0
(d, J ) 8 Hz), -138.8 (m, J ) 23 Hz); IR (NaCl cm-1) 3339,
2984, 2933, 1733, 1598, 1482, 1374, 1304, 1262, 1150; HRMS
(ESI) calcd for C23H28F4NO4S [MH]+ 490.1675, found 490.1673;
[R]D20 +47.8 (c 1.0, CH2Cl2); HPLC Zorbax Rx-C8 4.6 mm × 25
cm column; eluants (A) 0.1% aqueous H3PO4 and (B) acetonitrile;
1.8 mL/min; gradient A/B 90:10 to 10:90 over 15 min, hold 5 min;
λ ) 220 nm; temperature 35 °C; tR(bromo amine 10a) ) 9.5 min,
tR(biaryl 12 (minor diastereoisomer)) ) 12.8 min, tR(biaryl 12
(major diastereoisomer)) ) 13 min.
(2S)-4-Fluoro-4-methyl-2-(((1S)-2,2,2-trifluoro-1-(4′-(methyl-
sulfonyl)biphenyl-4-yl))amino)pentanoic Acid (12a). LiOH ·H2O
(935.7 g, 22.3 mol) was added to the crude biphenyl ethyl ester 12
(2.18 kg, 4.46 mol) from the Suzuki reaction. The resulting slurry
was warmed to 35 °C and vigorously stirred for 19 h. The reaction
mixture was cooled to 20 °C and heptane (9 L) and H2O (9 L)
were added. The layers were separated and the black emulsion was
kept in the heptane layer. The organic layer was back-extracted
with H2O (4.5 L) and the black emulsion was kept in the organic
layer. The combined aqueous layers were washed with toluene (9
L) and the black emulsion was kept in the toluene layer. The toluene
layer was back-extracted with H2O (4.5 L) and the black emulsion
was kept in the toluene layer. The combined aqueous layers were
washed with MTBE (9 L) and the black emulsion was kept in the
MTBE layer. The MTBE layer was back-extracted with H2O (4.5
L) and the black emulsion was kept in the MTBE layer. Fresh
1486, 1375, 1303, 1262, 1150; [R]20 + 42.9 (c 1.20, EtOH);
D
conversion, diastereomeric excess and yield were determined by
HPLC Phenomenex Synergy Max RP 4.6 mm × 25 cm column;
eluants (A) 0.1% aqueous H3PO4 and (B) acetonitrile; 1 mL/min;
gradient A/B 40:60 to 15:85 over 20 min; λ ) 265 nm; temperature
30 °C; tR(hydroxy acid 13) ) 3.8 min, tR(biphenyl acid 12a (minor
diastereoisomer)) ) 5.3 min, tR(biphenyl acid 12a (major diaste-
reoisomer)) ) 6.1 min, tR(lactone 14) ) 6.6 min, tR(biphenyl ester
12) ) 9.1 min.
(2S)-N-(1-Cyanocyclopropyl)-4-fluoro-4-methyl-2-({(1S)-2,2,2-
trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentan-
amide (1). To a visually clean 5-necked 50-L round-bottomed flask
equipped with a mechanical stirrer, a thermocouple, a dropping
funnel, and a nitrogen inlet was added biaryl acid 12a (1.87 kg,
4.0 mol) and DMAc (9.3 L). The solution was cooled to 3 °C and
1-aminocyclopropane carbonitrile hydrochloride (576 g, 4.86 mol)
and HATU (1.85 kg, 4.86 mol) were charged to the reactor. The
resulting slurry was stirred for 15 min and DIEA (2.1 L, 12.1 mol)
was added over 1.5 h maintaining the temperature at <10 °C. HPLC
indicated complete reaction at the end of the addition. Water (11.2
L) was added via dropping funnel over 70 min and the slurry that
formed was aged for 1 h at 19-20 °C. The mixture was filtered
and the filter cake was washed successively with a solution of
DMAc:water (9.35 L, 1:1.2), water (18.7 L), 2-propanol (9.3 L),
and MTBE (9.3 L). The batch was dried under vacuum at 35 °C to
yield 1.67 kg of 1, 79% yield, 98.38 area %, 98.5% de by HPLC.
A visually clean 5-necked 50-L round-bottomed flask equipped
with a mechanical stirrer, a thermocouple, a dropping funnel, and
a nitrogen inlet was charged with crude 1 (2.56 kg, 4.87 mol). THF
(30.7 L) was added, then the batch was warmed to 30 °C and stirred
for 1.2 h. Water (20.5 L) was added via dropping funnel. The batch
was cooled to 22 °C and seeded with 1 (500 mg). The batch was
aged for 1 h at 20-22 °C. A seed bed formed and addition of water
(40.9 L) was continued over 1.5 h. The batch was aged at 20 °C
for 12 h. The batch was filtered and washed with water (15 L) and
dried under vacuum at 35 °C to yield 1 as a white solid (2.50 kg,
97% yield, 99.7 area %, 99.9% de by HPLC): mp 223-224 °C; 1H
NMR (CD3OD) δ 8.17 (br s, 1H), 8.05 (d, 2H, J ) 8.5 Hz), 7.96
(d, 2H, J ) 8.5 Hz), 7.80 (d, 2H, J ) 8.0 Hz), 7.64 (d, 2H, J ) 8.0
Hz), 4.43 (m, 1H), 3.55 (ddd, 1H, J ) 5.0, 8.5, 8.0 Hz), 3.18 (s,
3H), 2.84 (br m, 1H), 2.02 (m, 2H), 1.46 (d, 3H, J ) 21.5 Hz),
1.43 (d, 3H, J ) 22.0 Hz), 1.36 (m, 2H), 1.07 (m, 1H), 0.94 (m,
1H); 13C NMR (125 MHz, acetone-d6) δ 175.2, 146.0, 141.2, 140.6,
J. Org. Chem. Vol. 74, No. 4, 2009 1609

O’Shea et al.
136.1, 130.3, 128.9 (q, J ) 282.8 Hz), 128.7, 128.6, 128.4, 120.9,
95.9 (d, J ) 164.3 Hz), 63.5 (q, J ) 30.0 Hz), 59.2 (d, J ) 3.5
Hz), 44.8 (d, J ) 23.1 Hz), 44.3, 27.5 (d, J ) 23.9 Hz), 27.1 (d,
J ) 24.9 Hz), 20.7, 16.5; 19F NMR (CD3OD) δ -73.2, -136.8;
mm × 15 cm column; eluants (A) hexanes, (B) ethanol, and (C)
methanol; 1 mL/min; isocratic A/B/C 80:10:10 for 60 min; λ )
265 nm; temperature 40 °C; tR((S,S)-1) ) 14.5 min, tR((R,S)-1) )
11.9 min, tR((S,R)-1) ) 18.2 min, tR((R,R)-1) ) 25.3 min, >99.5%
(S,S).
IR (cm-1) 3331, 2244, 1687, 1304, 1152; [R]20 + 23.3 (c 0.53,
D
MeOH); HRMS calcd for C25H28F4N3O3S [MH]+ 526.1782; found
526.1781; HPLC Phenomenex Spherisorb 4.6 mm × 25 cm column;
eluants (A) 0.1% aqueous H3PO4 and (B) acetonitrile; 1 mL/min;
gradient A/B 60:40 to 30:70 over 30 min; λ ) 265 nm; temperature
45 °C; tR(1 (major diastereoisomer)) ) 15.8 min, tR(1 (minor
diastereoisomer)) ) 16.4 min; HPLC (chiral) Chiralpak AD 4.6
Supporting Information Available: Copies of 1H, 13C, and
19F NMR spectra for 2a, 9a, 10a, 12, 12a, and 1. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO8020314
1610 J. Org. Chem. Vol. 74, No. 4, 2009