Synthesis of 2-methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]pyridin-3-yl}propanoic acid, a dual PPARα/γ agonist

Article abstract of DOI:10.1016/j.tetlet.2009.01.113

Large quantities of an enantiomerically pure novel dual PPARα/γ agonist were required. Three routes were successfully developed to achieve this goal, with the chosen route utilized to deliver 40 g of material.

Full text of DOI:10.1016/j.tetlet.2009.01.113

Tetrahedron Letters 50 (2009) 1765–1767
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Tetrahedron Letters
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Synthesis of 2-methoxy-2-methyl-3-{6-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-
ethoxy]pyridin-3-yl}propanoic acid, a dual PPARa/c agonist
*
Paul S. Humphries , Quyen-Quyen T. Do, David M. Wilhite
Pfizer Global R&D, Department of Medicinal Chemistry, 10614 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Large quantities of an enantiomerically pure novel dual PPARa/c agonist were required. Three routes
were successfully developed to achieve this goal, with the chosen route utilized to deliver 40 g of
material.
Received 16 January 2009
Revised 20 January 2009
Accepted 21 January 2009
Available online 25 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
PPAR
Halopyridine
Buchwald
Pyridine ether
Palladium
Biotransformation
Chiral resolution
Chiral auxiliary
Peroxisome proliferator-activated receptors (PPARs) are phar-
maceutical targets of great importance. Their wide-ranging effects
on key transcriptional pathways for lipid handling, insulin sensitiv-
ity, inflammation, and other functions have led to marketed drugs
and vast clinical and preclinical research efforts.1–4
As part of an ongoing PPAR drug discovery program in our lab-
oratories, we originally synthesized racemic 1 and showed it to be
of further interest to the team.5 Chiral supercritical fluid chroma-
tography (SFC) separation was performed on the racemic material,
and the two enantiomers were isolated in >95% ee.6 It was quickly
established that the majority of the in vitro activity resided in the
first eluting enantiomer 2 (Fig. 1).
30–50 g of material. In order to access 2 on this scale, we decided
to avoid chiral SFC separation of racemic 1. The three successful
strategies that were used are outlined in Figure 2.
For the biotransformation route, racemic ester 6 was submitted
for initial enzyme screening studies, and it was found that both
Bacillus lentus protease and Aspergillus oryzae protease gave >95%
ee after 45–50% conversion. Interestingly, the two proteases selec-
tively produced opposite enantiomers to one another. Slight mod-
ifications were made during the scale-up of this step, including a
switch to protease from bovine pancreas. Ester 9 was subjected
During the progression of 2 through the project’s screening cas-
cade, material was accessed via large-scale chiral SFC separation of
1. The optimized synthetic route to 1 is shown in Scheme 1.7 Alco-
hol 3 was brominated, using a modified procedure from the Impe-
riali group,8 to afford 4. Bromide 4 was then reacted with the
sodium enolate of 5 to form ester 6 in excellent yield. Buchwald
reaction between 6 and alcohol 7 gave ester 8 in good yield.9,10
Intermediate 8 was then hydrolyzed to afford the desired racemic
acid 1 in excellent recovery.
Enantiomerically pure 2 was then required to enter an in vivo
toleration (IVT) study, and we would thus necessitate a further
* Corresponding author. Tel.: +1 860 686 0256; fax: +1 860 715 8624.
E-mail address: phumphri@gmail.com (P.S. Humphries).
Figure 1. Racemic lead 1 and enantiomerically pure 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.113

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P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 1765–1767
Scheme 1. Reagents and conditions: (a) PS–PPh3, NBS, CH2Cl2, rt, 30 min, 87%; (b) NaHMDS, THF, ꢀ50 °C, 90 min, 96%; (c) Pd(OAc)2 (cat.), racemic-2-(di-t-butylphosphino)-
1,10-binaphthyl (cat.), Cs2CO3, PhMe, 115 °C, 16 h, 85%; (d) LiOHꢁH2O, THF, MeOH, H2O, rt, 1 h, 100%.
initial chiral amine screening studies. Initially, only six chiral
amines were utilized and these were chosen from the PPAR patent
literature. The initial conditions used 1 equiv of the chiral amine
stirring in ethyl acetate at ambient temperature, and the best re-
sult was afforded by (ꢀ)-Cinchonidine (60% ee). This salt 13
(Scheme 3) was further recrystallized, which afforded material of
81% ee. The above reactions were then repeated in acetonitrile,
but all gave products 620% ee. Focusing on the (ꢀ)-Cinchonidine
result, we repeated the ethyl acetate and acetonitrile experiments,
but this time using only 0.5 equiv of the chiral amine. The salt
formed from the ethyl acetate trial gave material of 96% ee, which
could be further recrystallized to >99% ee. Salt 13 was neutralized,
and then esterified to afford ester 9. This material was once again
taken through the last two steps to afford the final acid 2 (>98% ee)
by chiral analytical SFC.
For the diastereomeric separation route, our choice of chiral
auxiliary was (R)-phenylglycinol 14, following work by the Astra-
Zeneca PPAR group.11 Racemic acid 1 was successfully reacted with
chiral amino alcohol 14 to afford the pair of diastereomeric amides
15 and 16 (Scheme 4). The two diastereomers were easily separa-
Figure 2. Successful strategies to obtain 2 on large-scale.
ble by flash column chromatography, with the first eluting product
15 being a white solid and the second eluting product 16 a color-
less oil. Diastereomer 15 was then hydrolyzed, using sulfuric acid
in dioxane/water, to afford an optically pure acid that was proven
(by chiral analytical SFC) to be 2.
to the Buchwald reaction followed by hydrolysis, as in the racemic
route, and the product was shown to be 2 (>98% ee) by chiral
analytical SFC (Scheme 2).
For the chiral salt resolution route, racemic ester 6 was hydro-
lyzed to afford acid 10, which was our key intermediate for the
Scheme 2. Reagents and conditions: (a) Protease from bovine pancreas, potassium
phosphate buffer (0.1 M, pH 7.2), MeCN, 30 °C, >98% ee, 44%; (b) Pd(OAc)2 (cat.),
racemic-2-(di-t-butylphosphino)-1,10-binaphthyl (cat.), Cs2CO3, PhMe, 115 °C, 16 h,
81%; (c) LiOHꢁH2O, THF, MeOH, H2O, rt, 1 h, 96%.
Scheme 3. Reagents and conditions: (a) (ꢀ)-Cinchonidine (0.5 equiv), EtOAc, rt,
16 h, 96% ee, 44%; (b) Recrystallization from EtOAc, >99% ee, 91%.

P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 1765–1767
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Acknowledgements
The authors would like to thank Christie Aurigemma and Bill
Farrell for chiral SFC separation, Junhua Tao and Danial Yazbeck
for the Biotransformation work, and finally John Tatlock and Simon
Bailey for stimulating discussions and feedback on this Letter.
References and notes
1. For recent reviews, see: (a) Ram, V. J. Drugs Today 2003, 39, 609; (b) Sternbach,
D. D. Ann. Rep. Med. Chem. 2003, 38, 71; (c) Miller, A. R.; Etgen, G. J. Expert Opin.
Invest. Drugs 2003, 12, 1489; (d) Willson, T. M.; Brown, P. J.; Sternbach, D. D.;
Henke, B. R. J. Med. Chem. 2000, 43, 527.
2. For PPARa, see: (a) van Raalte, D. H.; Li, M.; Pritchard, P. H.; Wasan, K. M.
Pharm. Res. 2004, 21, 1531; (b) Miyachi, H. Expert Opin. Ther. Pat. 2004, 14,
607.
3. For PPARc, see: (a) Henke, B. R. Prog. Med. Chem. 2004, 42, 1; (b) Fajas, L.;
Auwerx, J. In Handbook of Obesity, 2nd ed.; Marcel Dekker: New York, 2004; p
559; (c) Evans, R. M.; Barish, G. D.; Wang, Y.-X. Nat. Med. 2004, 10, 355; (d)
Pershadsingh, H. A. Expert Opin. Invest. Drugs 2004, 13, 215.
4. For PPARd, see: Tan, N. S.; Michalik, L.; Desvergne, B.; Wahli, W. Expert Opin.
Ther. Targets 2004, 8, 39.
5. Humphries, P. S.; Bailey, S.; Almaden, J. V.; Barnum, S. J.; Carlson, T. J.; Christie,
L. C.; Do, Q.-Q. T.; Fraser, J. D.; Hess, M.; Kellum, J.; Kim, Y. H.; McClellan, G. A.;
Ogilvie, K. M.; Simmons, B. H.; Skalitzky, D.; Sun, S.; Wilhite, D.; Zehnder, L. R.
Bioorg. Med. Chem. Lett. 2006, 16, 6120.
Scheme 4. Reagents and conditions: (a) EDC, DMAP, CH2Cl2, rt, 16 h, diastereomer
15 = 44%, diastereomer 16 = 40%.
To obtain enantiomerically pure 2 in crystalline form, an initial
set of 30 recrystallization conditions was performed. All crystals
obtained from this work were the same polymorph, which had
an onset of melting at 104 °C. The large-scale synthesis of 2 was
successfully completed by utilizing the diastereomeric separation
route. The final material was crystallized from acetone/hexanes
to afford crystalline material of suitable purity for the IVT study.
In summary, we have successfully developed three routes to
provide optically pure 2, a molecule with a chiral quaternary stere-
ogenic center. The diastereomeric amide route was chosen and
successfully delivered 30–50 g of crystalline material for a rat IVT
study.
6. All attempts to definitively assign the absolute stereochemistry of 2 have so far
been unsuccessful. The assignments shown in this paper are based not only on
PPAR literature precedent (where all
a-alkoxy propanoic acids show the
eutomer to be (S) and the distomer to be (R)), but also on a closely related
compound whose absolute stereochemistry was assigned from an X-ray crystal
structure (data not disclosed).
7. All new compounds were characterized by full spectroscopic data, yields refer
to chromatographed material with purity >95%.
8. Imperiali, B.; Prins, T. J.; Fisher, S. L. J. Org. Chem. 1993, 58, 1613.
9. Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 10770.
10. Humphries, P. S.; Bailey, S.; Do, Q.-Q. T.; Kellum, J. H.; McClellan, G. A.; Wilhite,
D. M. Tetrahedron Lett. 2006, 47, 5333.
11. WO 99/62872 A1, 1999; Andersson, K. Chem. Abstr. 1999, 132, 22757.