Design and synthesis of 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)- 5-methyloxazol-4-yl]ethoxy}phenyl)propanoic acid: A novel triple-acting PPARα, -γ, and -δ Agonist

Article abstract of DOI:10.1246/cl.2012.406

The design and synthesis of triple-acting PPARα, -γ, and -δ agonist 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]- ethoxy}phenyl)propanoic acid (1a) is described. The compound possesses a potent triple-acting PPARα, -γ, and -δ agonist profile with an EC₅₀ of 0.029, 0.013, and 0.029 μM, respectively. The synthetic route, involving the synthesis of oxazole rings as the key step, starts from commercially available 3-oxopentanoic acid methyl ester and 3- hydroxyacetophenone to afford the target compound 1 with an overall yield of 32%.

Full text of DOI:10.1246/cl.2012.406

doi:10.1246/cl.2012.406
406
Published on the web March 24, 2012
Design and Synthesis of 3-(2-Ethyl-4-{2-[2-(4-fluorophenyl)-
5-methyloxazol-4-yl]ethoxy}phenyl)propanoic Acid:
A Novel Triple-acting PPAR¡, -£, and -¤ Agonist
Qijun Zhang,1 Peng Sun,2 Guojun Zheng,2 Yaping Wang,2 Xiangjing Wang,1 Hegeng Wei,2 and Wensheng Xiang*1
1Department of Biochemical Engineering, Northeast Agricultural University, Harbin 150030, P. R. China
2Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, P. R. China
(Received December 26, 2011; CL-111230; E-mail: xiangwensheng@neau.edu.cn)
The design and synthesis of triple-acting PPAR¡, -£, and -¤
Table 1. Effects of modifying the terminal trifluoromethyl substituent
agonist 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]-
ethoxy}phenyl)propanoic acid (1a) is described. The compound
possesses a potent triple-acting PPAR¡, -£, and -¤ agonist profile
with an EC50 of 0.029, 0.013, and 0.029 ¯M, respectively. The
synthetic route, involving the synthesis of oxazole rings as the key
step, starts from commercially available 3-oxopentanoic acid
methyl ester and 3-hydroxyacetophenone to afford the target
compound 1 with an overall yield of 32%.
O
COOH
N
O
R
EC50/¯Ma
PPAR£
Compound
R
PPAR¡
PPAR¤
Rosiglitazone
Iab
0.001
0.013
0.004
0.025
0.089
6.761
5.248
0.029
0.007
0.003
0.851
6.761
1a
1b
1c
1d
1e
F
0.029
1.175
2.884
5.495
2.630
CH3
NO2
t-Bu
Insulin resistance is a basic etiological factor for type 2
diabetes and is also linked to a wide spectrum of other
pathophysiologic conditions including hypertension, hyperlipide-
mia, atherosclerosis, and obesity which are collectively called
syndrome X or insulin resistance associated disorders (IRAD).1
Peroxisome proliferator-activated receptors (PPARs), attractive
diabetes target proteins, are members of the nuclear hormone
receptor superfamily and function as transcription factors in the
regulation of genes involved in glucose and lipid fatty acid
metabolism and vessel wall function.2,3 To date, three distinct
PPAR subtypes (PPAR¡, PPAR£, and PPAR¤ or PPAR¢) have
been identified in most mammalian species.4
Currently the two drugs rosiglitazone and pioglitazone on the
market are potent ligands of PPAR£ and show efficient insulin
sensitization in type 2 diabetes patients.5 But to effectively target
insulin resistance/hyperglycemia and associated conditions in-
cluding dyslipidemia and hypertension (i.e., the metabolic
syndrome), the concept of simultaneously activating PPAR¡, -£,
and -¤ through a single compound has received considerable
attention over the past few years.6 A number of PPAR pan agonists
have been described in the literature.7-13 However, to the best of
our knowledge there are no triple-acting PPARs drugs on the
market currently. Thus the development of novel and efficacious
triple-acting PPAR¡, -£, and -¤ agonists has extensively clinical
significance. We herein present the design and synthesis of a new
class of triple-acting PPAR¡, -£, and -¤ agonists below.
CHN4
aEC50 value is the molar concentration of the test compound that
causes 50% of the maximal reporter activity. Ia: inactivated.
b
O
COOH
S
N
O
S
N
COOH
O
F3C
GW501516
R
1
1a, R = F
1b, R = CH3
1c, R = NO2
1d, R = t-Bu
1e, R = CHN4
Figure 1. A new class of triple-acting PPAR¡, -£, and -¤ agonists.
OH
OMs
O
O
a
N
O
+
O
N
O
O
O
R
R
3
15
2
O
COOH
b
Because selective PPAR¤ agonist GW501516 has weak
potency on PPAR¡,14,15 we sought to improve selectivity for
PPAR¡ and subsequently optimize potency and selectivity. The
modifications of the GW501516 included the replacement of
thiazolyl by oxazolidinyl and the head group by the biaryl unit.
Further exploring the effects of modifying the terminal trifluoro-
methyl substituent by a range of groups showed that substitution
in this position was largely well tolerated and the potency
correlated well with the lipophilicity of the substituent (Table 1).
Thus we have accomplished a new class of triple-acting PPAR¡,
-£, and -¤ agonists, one of which, 1a, is currently in clinical trials
for the treatment of dyslipidemia (Figure 1).
N
O
R
1
Scheme 1. Reagents and conditions: (a) K2CO3, MeCN, reflux, 1 d,
70-90%; (b) NaOH, EtOH, r.t., overnight, 85-95%.
We envisaged the compound 1 to be efficiently formed via
intermolecular coupling of the key intermediate 2 and 3
(Scheme 1). The phenol derivative 2 was obtained following
the procedures reported by WO054176.16 For compound 3, we
Chem. Lett. 2012, 41, 406-408
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

407
O
O
Br
O
O
a
b
a
b
O
O
O
O
O
O
O
OH
O
O
O
O
N
O
4
5
6
Br
O
NH2
12
13
c
R
R
14
O
N3
O
NH2
OH
OMs
d
O
O
O
c
d
O
N
N
7
10
O
O
O
O
Cl
e
f
R
R
Cl
R
9
3
R
R
O
Scheme 3. Reagents and conditions: (a) Br2, CH2Cl2, 5 °C, overnight,
98%; (b) 90 °C, 18 h, 65-75%; (c) NaBH4, MeOH, CH2Cl2, 0 °C, 80-
95%; (d) MsCl, Et3N, CH2Cl2, 0 °C, 1 h, 95-98%.
O
g
O
HN
O
N
O
O
O
intermediate 14 as the key step can easily form an oxazole-olefin
under low pH conditions. Meanwhile, the HBr produced by
cyclization must be timely removed.
R
11
8
h
The synthesis route for compound 1 is outlined in Scheme 1.
The condensation of phenol 2 with intermediate 3 in acetonitrile
under alkaline conditions was conducted under reflux for 24 h to
generate the ester 15.23 Then saponification of ester 15 with 3 M
NaOH, as a final step, afforded the target compound 1 with an
overall yield of 32%.24-29
OH
OMs
i
N
N
O
O
R
R
In conclusion, compound 1a was designed and synthesized as
a novel triple-acting PPAR¡, -£, and -¤ agonist in high purity and
yield. Moreover, the development of these methods to synthesize
oxazole rings is a very useful protocol for the preparation of other
pharmaceutical drugs including oxazole compounds.
3
9
Scheme 2. Reagents and conditions: (a) benzoyl chloride, pyridine,
CH2Cl2, 1 d, 90%; (b) Br2, ether, 5 °C, 95%; (c) NaN3, H2O, acetone, r.t.,
92%; (d) Pd-C, HCl, H2O, EtOAc, H2, r.t., 12 h, 80-97%; (e) PPh3, 1,4-
dioxane, 75 °C, 3 h, 15-29%; (f) K2CO3, H2O, EtOAc, 0 °C, overnight;
(g) POCl3, toluene, reflux, 3 h, 32-41% in two steps; (h) NaOH, EtOH,
r.t., 2 h, 87-97%; (i) MsCl, Et3N, CH2Cl2, r.t., 1 h, 92-98%.
We are grateful for financial support from the National Key
Project for Basic Research (No. 2010CB1126102) and the
Outstanding Youth Foundation of Heilongjiang Province
(No. JC200706).
tried several synthetic routes. The key step was the formation of
oxazole rings as depicted in Schemes 2 and 3. We first attempted
to prepare intermediate 8 by reacting azide 7 with triphenylphos-
phine and acyl chloride.17,18 Azide 7 was produced from 5-
hydroxy-2-pentanone through protection, bromination, and reac-
tion with NaN3.19 However, the yield of this process was
disappointingly low (less than 20%). Efforts to enhance the
efficiency of this reaction by varying the solvents were unsuc-
cessful. Next, we tried another route employing the reduction of
azide 7 to amide 10 through catalytic hydrogenation over the
Pd/C catalyst. Then the reaction of compound 10 with acyl
chloride gave intermediate 11. Subsequent dehydration of com-
pound 11 with POCl3, produced intermediate 8 with an overall
yield of 32%.18 However, the above procedures failed to generate
large quantity of intermediate 8 and, as a result, they are not
applicable to large-scale synthesis. So we turned to the third route
which was much simpler, safer, and more efficient.
In this route, as shown in Scheme 3, the commercially
available 3-oxopentanoic acid methyl ester (12) was brominated
to give bromo ketone 13.19 Compound 13 was cyclized with acid
amides in the absence of solvent under elevated temperatures to
yield the oxazole intermediate 14.20,21 Subsequently, the oxazole
ester was reduced with NaBH4 in methanol to provide the oxazole
alcohol 9.22 Then, elaboration of the hydroxy moiety with MsCl
under alkaline conditions was adopted to afford the key
intermediate 3 with a yield of 56%.21 In this approach, the
reaction of cyclizing compound 13 with acid amides to prepare
References and Notes
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and compound 3a (2.3 g, 8.26 mmol). The mixture was heated under reflux
for overnight. Then the acetonitrile was evaporated to dryness and the
residues were dissolved in water, extracted in a separatory funnel with
ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to
dryness to give a crude of product 15a (1.7 g, 85%) as a brown oil.
1H NMR (CDCl3, 400 MHz): ¤ 1.20 (t, J = 7.6 Hz, 3H, CH3), 2.35 (s, 3H,
CH3), 2.56 (m, 4H, 2CH2), 2.93 (m, 4H, 2CH2), 3.66 (s, 3H, OCH3), 4.21
(t, J = 6.6 Hz, 2H, OCH2), 6.73 (m, 2H, ArH), 7.06 (m, 3H, ArH), 7.94
(m, 2H, ArH); 13C NMR (CDCl3, 100 MHz): ¤ 10.2, 15.2, 25.7, 26.4, 27.0,
35.5, 51.6, 66.6, 111.7, 114.9, 115.7, 115.9, 124.2, 127.9, 129.7, 130.1,
132.8, 143.3, 145.0, 157.5, 158.6, 162.4, 164.9, 173.5; IR (KBr) ¯max
(cm¹1): 2964, 1735, 1608, 1498, 1259, 1232, 1195, 1155. HR-MS m/z:
calcd for C24H26FNO4Na [M + Na]: 434.1738; found: 434.1746.
12 N. Mahindroo, C.-F. Huang, Y.-H. Peng, C.-C. Wang, C.-C. Liao, T.-W.
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15 W. R. Oliver, Jr., J. L. Shenk, M. R. Snaith, C. S. Russell, K. D. Plunket,
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25 3-(2-Ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]ethoxy}phen-
yl)propanoic acid (1a). To a solution of crude compound 15a (1.2 g,
2.86 mmol) in 15 mL of ethanol was added dropwise 10% solution of
sodium hydroxide (2.3 mL, 5.72 mmol) at room temperature. After stirring
for overnight, dilute hydrochloric acid was added until the pH was
adjusted to 3 to precipitate solid which was filtered to give crude 1a. Then
the rude was recrystallized with ethyl acetate to afford pure product 1a
(1.2 g, 92%) as a white solid. Mp: 148-149 °C; 1H NMR (CDCl3,
400 MHz): ¤ 1.22 (t, J = 7.6 Hz, 3H, CH3), 2.37 (s, 3H, CH3), 2.62 (m,
4H, 2CH2), 2.92 (m, 2H, CH2), 2.97 (t, J = 6.4 Hz, 2H, CH2), 4.22 (t,
J = 6.4 Hz, 2H, OCH2), 6.73 (m, 2H, ArH), 7.10 (m, 1H, ArH), 7.68 (m,
2H, ArH), 7.97 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz): ¤ 10.2, 15.1,
25.7, 26.3, 26.7, 35.4, 66.6, 111.7, 114.9, 115.0, 115.7, 115.9, 124.0,
128.1, 130.0, 132.7, 143.3, 145.1, 157.5, 158.8, 162.5, 165.0, 179.1; IR
(KBr) ¯max (cm¹1): 2962, 1716, 1614, 1315, 1288, 1155, 1105. HR-MS
m/z: calcd for C23H25FNO4 [M + H]: 398.1723; found: 398.1775.
26 3-{2-Ethyl-4-[2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy]phenyl}propa-
noic acid (1b). White solid. Mp: 103-104 °C; 1H NMR (CDCl3, 400
MHz): ¤ 1.19 (t, J = 7.6 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.37 (s, 3H,
CH3), 2.59 (m, 4H, 2CH2), 2.88 (t, J = 7.6 Hz, 2H, CH2), 2.96 (t,
J = 6.4 Hz, 2H, CH2), 4.18 (t, J = 6.4 Hz, 2H, CH2), 6.68 (m, 2H, ArH),
7.03 (d, J = 8.0 Hz, 1H, ArH), 7.23 (d, J = 8.0 Hz, 2H, ArH), 7.85 (d,
J = 7.6 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz): ¤ 10.3, 15.2, 21.5,
25.7, 26.2, 26.9, 35.7, 66.6, 111.6, 114.9, 124.7, 126.0 (2C), 129.4 (2C),
129.7, 130.1, 132.3, 140.2, 143.3, 144.8, 157.4, 159.8, 178.3; IR (KBr)
16 Canada, Emily, Jane, WO Patent 054176, 2005.
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21 Methyl 2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]acetate (14a). Crude
compound 13 (10 g, 48 mmol) was stirred with 4-fluorobenzamide (10 g,
72 mmol) at 90 °C for 18 h under a vacuum of 400 mbar. After cooling to
room temperature, the mixture was treated under argon with 60 mL of
toluene and 30 mL of aqueous sodium bicarbonate solution. Then the
resulting suspension was stirred in ice-water bath for 1 h and the
precipitate benzamide was filtered off with suction. The combined
aqueous phases were extracted in a separatory funnel with 150 mL of
toluene. Thereafter the combined organic phase was washed with water,
dried over anhydrous sodium sulfate, and evaporated to dryness to give
crude 14a following by recrystallization to afford pure product 14a (8.6 g,
70%) as a white solid. Mp: 97-98 °C; 1H NMR (CDCl3, 400 MHz): ¤ 2.34
(s, 3H, CH3), 3.56 (s, 2H, CH2), 3.73 (s, 3H, OCH3), 7.10 (t, J = 8.8 Hz,
2H, ArH), 7.96 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz): ¤ 10.2, 31.9,
52.1, 115.6, 115.8, 123.2, 128.7, 129.3, 145.7, 158.7, 162.5, 164.9, 170.7.
IR (KBr) ¯max (cm¹1): 2958, 1735, 1602, 1496, 1222, 1199, 1172, 1159.
¯
(cm¹1): 2922, 1709, 1603, 1286, 1259, 1087, 1022. HR-MS m/z:
max
calcd for C24H28NO4 [M + H]: 394.1974; found: 394.2040. Elemental
Anal. Calcd for C24H27NO4: C, 73.26; H, 6.92; N, 3.56%. Found: C,
73.21; H, 6.90; N, 3.62%.
27 3-(2-Ethyl-4-{2-[5-methyl-2-(4-nitrophenyl)oxazol-4-yl]ethoxy}phenyl)-
propanoic acid (1c). Yellow solid. Mp: 180-182°C; 1H NMR (DMSO-d6,
400MHz): ¤ 1.20 (t, J = 7.6 Hz, 3H, CH3), 2.42 (s, 3H, CH3), 2.57-2.61
(m, 4H, 2CH2), 2.89 (t, J = 7.6 Hz, 2H, CH2), 2.99 (t, J = 6.4 Hz, 2H,
CH2), 4.21 (t, J = 6.4Hz, 2H, OCH2), 6.67-6.73 (m, 2H, ArH), 7.05 (d,
J = 8.0 Hz, 1H, ArH), 8.13 (d, J = 8.0 Hz, 2H, ArH), 8.29 (d, J = 7.6Hz,
2H, ArH); 13C NMR (DMSO-d6, 100MHz): ¤ 9.8, 15.0, 25.0, 25.5, 26.2,
35.0, 65.7, 111.4, 114.3, 124.1, 126.2, 129.4, 130.2, 132.2, 134.0, 142.7,
146.9, 147.5, 156.4, 156.6, 173.9; IR (KBr) ¯max (cm¹1): 2974, 1711, 1603,
1556, 1386, 1338, 1303, 1145, 1105. HR-MS m/z: calcd for C23H25N2O6
[M + H]: 425.1668; found: 425.1708.
28 3-[4-(2-{2-[4-(tert-Butyl)phenyl]-5-methyloxazol-4-yl}ethoxy)-2-ethyl-
phenyl]propanoic acid (1d). White solid. Mp: 123-124 °C; 1H NMR
(CDCl3, 400 MHz): ¤ 1.17 (t, J = 7.6 Hz, 3H, CH3), 1.27 (s, 9H,
C(CH3)3), 2.35 (s, 3H, CH3), 2.57 (m, 4H, 2CH2), 2.86 (m, 2H, CH2),
2.96 (t, J = 6.4 Hz, 2H, CH2), 4.17 (t, J = 6.4 Hz, 2H, OCH2), 6.67 (m,
2H, ArH), 7.02 (d, J = 4.0 Hz, 1H, ArH), 7.43 (d, J = 4.4 Hz, 2H, ArH),
7.89 (d, J = 4.4 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz): ¤ 10.2,
15.1, 25.6, 26.2, 26.8, 31.1 (3C), 34.8, 35.6, 66.5, 111.5, 114.8, 124.6,
125.6 (2C), 125.7 (2C), 129.6, 130.0, 132.3, 143.2, 144.7, 153.1, 157.3,
159.6, 178.5; IR (KBr) ¯max (cm¹1): 2962, 1711, 1606, 1506, 1292, 1197.
HR-MS m/z: calcd for C27H34NO4 [M + H]: 436.2443; found: 436.2523.
Elemental Anal. Calcd for C27H33NO4: C, 74.45; H, 7.64; N, 3.22%.
Found: C, 74.41; H, 7.63; N, 3.25%.
29 3-[2-Ethyl-4-(2-{5-methyl-2-[4-(1H-tetrazol-5-yl)phenyl]oxazol-4-yl}-
ethoxy)phenyl]propanoic acid (1e). White solid. Mp: 145-146 °C;
1H NMR (CDCl3, 400 MHz): ¤ 1.11 (t, J = 7.6 Hz, 3H, CH3), 2.35 (s, 3H,
CH3), 2.43-2.63 (m, 4H, 2CH2), 2.74 (t, J = 6.4 Hz, 2H, CH2), 2.90 (t,
J = 6.4 Hz, 2H, CH2), 4.17 (t, J = 6.4 Hz, 2H, OCH2), 6.61-6.68 (m, 2H,
ArH), 6.70 (d, J = 2.4 Hz, 1H, ArH), 7.67 (d, J = 8.4 Hz, 2H, ArH), 8.08
(d, J = 8.4 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz): ¤ 9.8, 15.1, 25.0,
25.6, 26.2, 35.0, 65.9, 111.5, 114.4, 126.1, 127.3, 128.7, 129.5, 130.2,
133.2, 142.8, 145.6, 155.6, 156.7, 157.5, 173.8; IR (KBr) ¯max (cm¹1):
3451, 2960, 1712, 1616, 1577, 1499, 1438, 1238. HR-MS m/z: calcd for
HR-MS m/z: calcd for
C13H13FNO3 [M + H]: 250.0874; found:
250.0877.
22 2-[2-(4-Fluorophenyl)-5-methyloxazol-4-yl]ethanol (9a). To a solution
of compound 14a (0.2 g, 0.8 mmol) in 3 mL of methanol and 2 mL of
dichloromethane was added NaBH4 (30.5 mg, 0.8 mmol) three times and
the mixture solution was stirred in an ice bath for 1 h. When 14a was no
longer detected by TLC, solvent was removed followed by recrystalliza-
tion with ethyl acetate to afford pure product 9a (0.168 g, 94%) as a white
solid. Mp: 114-115 °C; 1H NMR (CDCl3, 400 MHz): ¤ 2.32 (s, 3H, CH3),
2.71 (t, J = 5.6 Hz, 2H, CH2), 3.35 (br, 1H, OH), 3.92 (m, 2H, OCH2),
7.11 (t, J = 8.8 Hz, 2H, ArH), 7.95 (m, 2H, ArH); 13C NMR (CDCl3,
100 MHz): ¤ 10.1, 28.2, 61.8, 115.7, 115.9, 123.9, 128.0, 133.9, 144.2,
158.7, 162.5, 165.0. IR (KBr) ¯max (cm¹1): 3279, 2928, 1647, 1500. HR-
MS m/z: calcd for C12H12FNO2Na [M + Na]: 244.0744; found: 244.0748.
23 2-[2-(4-Fluorophenyl)-5-methyloxazol-4-yl]ethyl
methanesulfonate
(3a). To a solution of 9a (2.7 g, 12 mmol) in CH2Cl2 (30 mL) was added
Et3N (3.4 mL, 24 mmol) at 0 °C under argon. The mixture was kept at 0 °C
for 30 min and then MsCl (1.42 mL, 18 mmol) was added dropwise. After
stirring for 1 h at 0 °C and 9a was no longer detected by TLC, ammonium
chloride solution was added. Thereafter, the mixture was washed with
water, dried over anhydrous sodium sulfate, and evaporated to dryness to
1
afford product 3a (3.58 g, 98%) as a white solid. Mp: 90-92 °C; H NMR
(CDCl3, 400 MHz): ¤ 2.32 (s, 3H, CH3), 2.95 (m, 5H, CH2 and SO2CH3),
4.51 (t, J = 6.4 Hz, 2H, OCH2), 7.11 (m, 2H, ArH), 7.93 (m, 2H, ArH);
13C NMR (CDCl3, 100 MHz): ¤ 10.1, 26.2, 37.2, 68.6, 115.8, 116.0,
123.9, 128.0, 131.1, 145.5, 158.9, 162.5, 165.0. IR (KBr) ¯max (cm¹1):
2955, 1635, 1498, 1338. HR-MS m/z: calcd for C13H15FNO4S [M + H]:
300.0661; found: 300.0698.
24 Methyl 3-(2-ethyl-4-{2-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]eth-
oxy}phenyl)propanoate (15a). To a solution of compound 2 (1.5 g,
4.13 mmol) in 15 mL of acetonitrile was added K2CO3 (0.86 g, 6.2 mmol)
C
24H26N5O4 [M + H]: 448.1940; found: 448.1968.
Chem. Lett. 2012, 41, 406-408
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/