An asymmetric synthesis of PPAR-γ agonist navaglitazar from (+)-methyl (2S,3R)-3-(4-methoxyphenyl)glycidate

Article abstract of DOI:10.2533/chimia.2006.580

An asymmetric synthesis of navaglitazar, a peroxisome proliferator activated receptor (PPAR) γ agonist, from commercially available (+)-methyl (2S,3R)-3-(4-methoxyphenyl)glycidate, is described. The new synthesis features high overall yield, low solvent usage, crystalline intermediates and operational simplicity. Schweizerische Chemische Gesellschaft.

Full text of DOI:10.2533/chimia.2006.580

Process chemistry
580
doi:10.2533/chimia.2006.580
chimiA 2006, 60, No. 9
Chimia 60 (2006) 580–583
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
An Asymmetric Synthesis of PPAR-γ
Agonist Navaglitazar from (+)-Methyl
(2S,3R)-3-(4-methoxyphenyl)glycidate
John r. rizzo and tony y. Zhang*
Abstract: An asymmetric synthesis of navaglitazar, a peroxisome proliferator activated receptor (PPAr) γ agonist,
from commercially available (+)-methyl (2s,3r)-3-(4-methoxyphenyl)glycidate, is described. the new synthesis
features high overall yield, low solvent usage, crystalline intermediates and operational simplicity.
Keywords: Asymmetric synthesis · Navaglitazar · Noninsulin dependent diabetes mellitus (NiDDm) ·
Peroxisome Proliferator Activated receptor (PPAr) γ agonist
Introduction
cemic 1, which was in turn prepared by the tion of (+/–)-6 with a wide variety of chiral
bases met with disappointment; however, an
enzymatic hydrolysis with the cross-linked
enzyme crystal (Chiral CLEC-CR) coupled
with the diastereomeric salt formed from
coupling of alkyl bromide 2 with phenol 3
in the racemic form (Scheme 1).
As the program moved along a need
emerged for more material to enable toxi-
Navaglitazar (LY 519818) is a potent per-
oxisome proliferator activated receptor
(PPAR)-γ agonist currently undergoing
Phase II clinical studies for noninsulin de-
pendent diabetes mellitus (NIDDM)[1].
PPAR is a super family of nuclear tran-
scription factors that include steroid, reti-
noid, and thyroid hormone receptors. A
γ-selective agonist is highly sought after
as potential agent to lower plasma glucose
levels without increasing plasma insulin
levels or causing hypoglycemia. Unlike the
traditional agents of the thiazolidinedione
(glitazones) family for the treatment of NI-
DDM, this compound belongs to the dihy-
drocinnamic acid family composed only of
carbon, hydrogen and oxygen atoms.
cological studies with longer duration and (–)-cinchonidine afforded acid 7 in >98%
across several species, and an alternative
to chiral chromatography to access 1 was
developed (Scheme 2). Specifically, aldol
ee. Compound 3 obtained in this fashion
was used to prepare a large amount of 1 in
multi-kg quantities with high enantiomeric
condensation of aldehyde 4 and methyl purity following similar coupling condition
as for the racemate.
methoxyacetate (5) afforded an unstable
Although this enzymatic resolution-
benzylic alcohol, which had to be trapped
in situ with trifluoroacetic anhydride to based approach to 1 enabled fast delivery of
prevent reverse aldol. Hydrogenolysis via high quality material for early phase clinical
heterogeneous palladium catalysis success- development, the throughput of the overall
fully removed the benzyl protecting group sequence left much for improvement. The
as well as the secondary trifluoroacetoxyl operations associated with the establish-
ment of the lone stereocenter within the
molecule were quite complex.
group to afford methyl ester 6. Attempts to
resolve racemic 7 obtained from saponifica-
scheme 1.
Initially, the desired S-enantiomer of the
compound was obtained via chiral prepara-
tive chromatography separation of the ra-
*Correspondence: Dr. t.y. Zhang
eli Lilly and company
chemical Product research and Development Division
Lilly corporate center
indianapolis, iN 46285
UsA
scheme 2.

Process chemistry
581
chimiA 2006, 60, No. 9
Towards addressing these concerns, we interest for diltiazem production, we reckon in ethyl acetate at ambient temperature to
were particularly intrigued by the possibil- that the unwanted enantiomers, namely es- provide methyl p-MeO-2-hydroxydinhy-
ity of utilizing glycidate 8 (2S,3R) as a chi- ters like (2S,3R)-8, can be made useful by drocinnamate (13) as a low melting solid in
serving as a source of chiral building block quantitative yields (Scheme 5).
ral building block for 1 (Scheme 3).
for navaglitazar (1). In this report, we will
describe an efficient and novel asymmetric this point using methyl iodide and sodium
Compound 12 could be methylated at
Glycidate 8, specifically the (2R,3S)-en-
antiomer, has attracted significant attention
hydride in DMF to provide the methyl ether
13 with three chemodifferentiated methoxy
groups. Attempts to selectively demethyl-
ate at the phenol site were not successful.
Boron reagents such as BBr3 and BCl3 were
actually selective at demethylating the alkyl
methyl ether over the phenol methyl ether
and the ester methyl. This reactivity is plau-
sible because boron could associate with
oxygens from both the carbonyl and the
methyl ether to form a five-membered ring
complex, activating the methyl ether selec-
tively. Sulfur-based nucleophilic reagents
such as sodium ethanethiolate cleaved both
ethers non-selectively. Other nucleophiles
such as lithium iodide gave no reaction.
Strong acids such as hydrogen bromide
and hydrogen iodide also demethylated
both sites. In summary, a selective demeth-
ylation reaction in preference for the phenyl
ether was not within reach.
as it constitutes a key starting material for synthesis of 1 from (+)-methyl (2S,3R)-3-
the synthesis of (2S,3S)-diltiazem (11) [2], (4-methoxyphenyl)glycidate 8.
an antihypertensive, anti-anginal vasodila-
tor marketed by Tanabe and several com-
panies across the globe. For obvious com- Results and Discussion
mercial reason the supply of (2R,3S)-8 is
of considerable commercial and academic
Our initial efforts focused on finding an
interest. Disclosed synthetic routes for efficient way of converting (2R,3S)-8 into
(2R,3S)-8 include asymmetric epoxidation compound 3 in order to take advantage of
of p-MeO-cinnamate [3], enantioselective intersecting with the existing route. Estab-
reduction of 2-chloroketoesters [4], kinetic lishing this approach would entail
resolution via enzymatic hydrolysis [5] i) the reduction of the benzylic C–O
or transesterificaion [6], and resolution of
bromo- and iodohydrins [7].
bond,
ii) demethylation of the phenyl ether and
Of particular commercial viability is the iii) methylation of the chiral alcohol to af-
Darzenscondensationreactioncoupledwith
enzymatic hydrolysis to afford (2R,3S)-8,
and (2R,3S)-12 (Scheme 4). Because only
the compound of 2R,3S configuration is of
ford methyl ether.
The reduction of the benzylic epoxide
went uneventfully. Thus (2R,3S)-8 was hy-
drogenated using 5% palladium on carbon
On the other hand the fully deprotected
trihydroxy compound 14 could be obtained
readily. Toward this end, crude alcohol 12
from hydrogenation was hydrolyzed using
sodium hydroxide and ethanol to provide
the sodium salt 13 in quantitative yields.
Demethylation was accomplished using an
aqueous solution of HI at reflux. Although
hydriodic acid is expensive and unstable
as a commercial reagent, we discovered
that an effective source of hydroiodic
acid could be generated conveniently in
situ using sodium iodide and aqueous HCl
(Scheme 6). The reaction is simply con-
ducted in water at reflux. Upon completion
of the reaction, the solution was cooled to
ambient temperature and compound 14, a
well-behaved crystalline compound, pre-
cipitated directly from the reaction as the
free acid. The reaction yields range from
47–79%. The variability of yields was
largely due to the water solubility of 14.
The crude product can be further purified
by a reslurry in MTBE or dissolving in
acetonitrile and filtering off any insoluble
inorganic salts.
scheme 3.
scheme 4.
When the protected ester 3 serves as
the head piece, alkyl bromide 2 has to be
used under carefully controlled conditions
to avoid epimerization of the α-stereocen-
ter under basic conditions. Although com-
pound 14 also bears an α-stereocenter, we
recognize that presence of the two adjacent
ionizable hydroxyl protons would protect
the α-carbon from epimerization via de-
protonation, and hence much harsher cou-
pling conditions could be employed to take
advantage of the less reactive and less ex-
pensive chloride tailpiece.
scheme 5.
scheme 6.

Process chemistry
582
chimiA 2006, 60, No. 9
The fully deprotected headpiece 14 was tions (NaH/MeI/DMF) to install the meth-
then coupled efficiently with the tailpiece yl ether are not acceptable for large scale
under vacuum to provide 123 g of 1 as an
off-white solid.
production and we have been investigating
alternative methods, with some very prom-
ising results. These and others will be re-
ported in connection with the synthesis of
compounds of similar structural motif in
the near future.
15 using aqueous sodium hydroxide and
DMSO at reflux (Scheme 7). The reac-
tion is then cooled to ambient temperature,
MTBE is added and the product precipi-
tates directly from the reaction mixture as
the sodium salt. After drying, 16 is conve-
niently dimethylated using sodium hydride
and methyl iodide in DMF to give 17. The
methyl ester can then be hydrolyzed us-
ing aqueous sodium hydroxide in ethanol
to provide the 1 as the sodium salt. The
sodium salt of the active pharmaceutical
ingredient can be further purified by a re-
crystallization from ethyl acetate if needed.
The enantiomeric excess of 1 was 99.7% (as
determined by chiral HPLC) starting from
(2R,3S)-8, which compares favorably with
that obtained typically from the enzymatic
hydrolysis process (96–98%).
16
To a 250 ml three-neck round bottom
flask was added 14 (10.63 g, 58.35 mmol)
followed by 5N NaOH (29.2 ml, 145.88
mmol). The mixture was stirred at ambient
temperature for 35 min. To the solution was
added 15 (18.39 g, 69.99 mmol) in 30 ml of
DMSO. The resulting solution was heated
to reflux for 3 h. While cooling, 106.3 ml of
water was added and stirred for an addition-
al hour. The solid was filtered and washed
with 106.3 ml of MTBE. The solid was col-
lected and dried under vacuum at 60 °C for
16 h to provide 19.49 g of 16.
Experimental Section
12
(+)-Methyl
(2S,3R)-3-(4-methoxy-
phenyl)glycidate (8, 750 g) was dissolved
in 7.5 l of ethyl acetate and shaken in a Parr
reactor with 375 g of 5% Pd-C (w/w) under
45 psid hydrogen at ambient temperature
for 16 h. The catalyst was filtered and the
filtrate was concentrated under vacuum to
give an oil, which was seeded and allowed
to stand at ambient temperature to give 745
g of 13 as a solid.
17
To a 250 ml flask added was added
16 (15.11 g, 35.10 mmol), followed by
76 ml of dry DMF. The resulting mixture
was stirred for 5 min at room temperature
then cooled in ice-water bath. NaH (1.78
g, 44.50 mmol; 60% in mineral oil) was
added and stirred for 5 min while monitor-
ing H2 evolution. The bath was removed
and stirred for 15 min, and ice-bath was
replaced. Iodomethane (6.56 ml, 105.31
mmol) was added dropwise via an addi-
tion funnel. After being stirred in bath for
1 h, then 3 h at room temperature, the mix-
ture was quenched with 250 ml of water
and extracted with 250 ml of EtOAc. The
EtOAc layer was washed with 3 × 250 ml
water, followed by washing with 250 ml
of brine. The organic phase was dried over
MgSO4, filtered, and concentrated under
vacuum to afford 13.85 g 17 as a yellow
oil.
Conclusions
13
Compound 12 (745 g) was dissolved in
3.725 l of ethyl acetate at ambient tempera-
ture. Sodium hydroxide (3.548 l, 5N) was
added dropwise and stirred for 3 h after
the addition. The ethanol solvent was ex-
changed with 4 l of isopropyl acetate. The
slurry was cooled to 0 °C and filtered. The
filter cake was washed with 2 l of iPrOH
and 4 l of MTBE. The white solid was col-
lected and dried in a vacuum oven at 60 °C
to provide 888.6 g of 13.
We have developed a seven-step asym-
metric synthesis of navaglitazar from the
commerciallyavailable(+)-methyl(2S,3R)-
3-(4-methoxyphenyl)glycidate, which is
essentially a byproduct from diltiazem
production and can be accessed at very low
cost. The process is high yielding, requires
low solvent volumes, features crystalline
intermediates and requires no chromato-
graphic separations (see Experimental Sec-
tion). Conditions employed in the synthesis
are typically acid-base chemistry which is
simple to operate and robust to repeat. The
protective effect of the free carboxylate in
14 allows the use of less reactive chloride
tailpiece 15 in place of bromide 2, without
the risk of epimerizing the α-stereocenter.
Compared with the existing route using
enzyme to resolve (+/-)-6 and (–)-cinchoni-
dine to upgrade, this new process is much
higher in throughput and significantly more
cost effective for accessing the enantiopure
intemediate 14. This new approach provides
a valuable option for preparing 1. We do,
however, recognize that the current condi-
14
Compound 13 (218 g, 1 mol) and sodi-
um iodide (375 g, 2.5 mol) were dissolved
in 1 l of concentrated hydrochloric acid
at ambient temperature. The solution was
heated to reflux for 6 h and then cooled in
an ice-water bath for 2 h. The slurry was
filtered and the filter cake was washed
with 300 ml of cold water. The white solid
was collected and dried in a vacuum oven
at 60°C to provide 178.7 g of crude solid,
which was stirred in 2 l of acetonitrile for 1
h at ambient temperature. The solution was
filtered and the filtrate was concentrated
Navaglitazar Sodium
Compound 17 (13.85 g, 31.77 mmol)
and absolute EtOH (138.5 ml) were added
to a 1 l flask. The solution was stirred with
cooling (ice water bath). A solution of 5N
NaOH (63.5 ml, 317.66 mmol) was added
via addition funnel over 13 min. Stirring
was continued for 1 h at room temperature.
The flask was cooled in ice-water bath with
stirring for an additional hour. The precipi-
tate was filtered, washed with 250 ml of
cold absolute EtOH, and then 1 l of MTBE.
The solid was collected and dried in a vac-
uum oven set at 60 °C overnight to afford
7.92 g of navaglitazar sodium as a white
powder. A portion (7.86 g, 17.68 mmol)
was dissolved in EtOAc (86.5 ml, 11 vol)
and heated to reflux under nitrogen. After
2.5 h, the heat source was removed and the
solution was allowed to cool slowly to room
temperature. Once at room temperature the
solution was stirred for 1 h. The precipitate
was filtered, washed with 300 ml of MTBE,
and dried in vacuo at 60 °C for 16 h, afford-
ing 7.21 g navaglitazar sodium.
scheme 7.

Process chemistry
583
chimiA 2006, 60, No. 9
Navaglitazar (1)
The Na salt of 1 (2.50 g, 5.62 mmol)
was dissolved in 25 ml of deionized water
and was heated to 60 °C. 1N HCl (6.2 ml,
6.19 mmol) was added and the resulting
mixture was stirred for 15 min, heated to
70 °C, and allowed to cool to ambient tem-
perature without agitation. The agitation
was resumed at ambient temperature for 45
min. The solid was filtered, washed with 20
ml of deionized water. Drying in vacuum
oven at 60 °C for 16 h gave 2.23 g of 1 as
a white solid.
Acknowledgement
The authors wish to thank Mr. Jacob R.
Ramecle for technical assistance, and Tanabe
Inc. for a sample of 8.
Received: June 6, 2006
[1] J.A. Martin, D.A. Brooks, L. Prieto, R.
Gonzalez, A. Torrado, I. Rojo, B. Lopez
de Uralde, C. Lamas, R. Ferritto, M. Dolo-
res Martin-Ortega, J. Agejas, F. Parra, J.R.
Rizzo, G.A. Rhodes, R.L. Robey, C.A.Alt,
S.R. Wendel, T.Y. Zhang,A. Reifel-Miller,
C. Montrose-Rafizadeh, J.T. Brozinick, E.
Hawkins, E.A. Misener, D.A. Briere, R.
Ardecky, J.D. Fraser, A.M. Warshawsky,
Bioorg. & Med. Chem. Lett. 2005, 15,
51–55.
[2] J. Elks, C.R. Ganellin, ‘Dictionary of
Drugs’, Chapmann and Hall; London,
1990; p 426.
[3] a) A. Solladie-Cavallo, L. Bouerat, Org.
Lett. 2000, 2, 3531–3534; b) A. Solla-
die-Cavallo, L. Bouerat, L. Jierry, Eur. J.
Org. Chem. 2001, 4557–4560; c) A. Solla-
die-Cavallo, L. Jierry, A. Klein, Comptes
Rendus Chimie 2003, 6, 603–606; d) A.
Solladie-Cavallo, L. Jierry, A. Klein, M.
Schmitt, R. Welter, Tetrahedron: Asymm.
2004, 15, 3891–3898.
[4] T. Shibatani, T. Nishida, H. Matsu-
mae, Tanabe Seiyaku Co., Ltd., Japan,
EP 447938, 1991.
[5] a) T. Shibatani, R. Yoshioka, H. Matsu-
mae, A. Idei, WO 9922014, 1999; b) M.
Furui, H. Higaki, K. Nakamichi, H. Seko,
JP 09037791, 1997.
[6] A. Gentile, C. Giordano, C. Fuganti, L.
Ghirotto, S. Servi, J. Org. Chem. 1992,
57, 6635–7.
[7] N. Anand, M. Kapoor, S. Koul, S.C. Tane-
ja, R.L. Sharma, G.N. Qazi, Tetrahedron:
Asymm. 2004, 15, 3131–3138.