PAPER
Improved Method for the Synthesis of 2-Methyl-2-Aryloxypropanoic Acid Derivatives
1961
2-(4-Methoxyphenoxy)-2-methylpropanoic Acid (2b)
wash. The 2-methyl-2-aryloxypropanoic acid derivative
is isolated after work-up and crystallization in 72–87%
yield with high purity (>98% AUC).
Beige solid; yield: 1.28 g (75%); Mp 58–59 °C (Lit.2a mp 57 °C).
1H NMR (400 MHz, CDCl3): d = 6.93 (d, J = 8.8 Hz, 2 H, ArH),
6.82 (d, J = 8.8 Hz, 2 H, ArH), 3.78 (s, 3 H, OCH3), 1.54 (s, 6 H,
CH3).
13C NMR (100 MHz, DMSO-d6): d = 175.8, 155.2, 149.4, 121.7,
114.9, 79.5, 55.9, 25.6.
In summary, an alternative method for the synthesis of 2-
methyl-2-aryloxypropanoic acid derivatives using the re-
agent, 2-bromo-2-methylpropanoic acid, was developed.
This method has been successfully applied on multi-kilo-
gram scales and avoids the process safety and quality is-
sues observed in the current methods available.
Anal. Calcd for C11H14O4: C, 62.85; H, 6.71; O, 30.44. Found: C,
62.67; H, 6.68; O, 30.44.
2-(4-Trifluoromethylphenoxy)-2-methylpropanoic Acid (2c)
Colorless Solid; yield: 9.6 g (72%); mp 104–105 °C (Lit.13 95 °C).
Melting points were determined on an Electrothermal IA9100 melt-
ing point apparatus and are uncorrected. 1H NMR spectra were ob-
tained with Varian 300/400 MHz instruments while 13C NMR
spectra were obtained exclusively with a Varian 400 MHz instru-
ment. Elemental analyses were performed by Atlantic Microlabs,
Inc. All reagents and solvents with the exception of 1d were pur-
chased from commercial sources and were used without further pu-
rification. The compound, 1d, was synthesized in-house from
commercial starting materials.
1H NMR (400 MHz, DMSO-d6): d = 13.26 (s, 1 H, CO2H), 7.62 (d,
J = 8.8 Hz, 2 H, ArH), 6.94 (d, J = 8.8 Hz, 2 H, ArH), 1.55 (s, 6 H,
CH3).
13C NMR (100 MHz, DMSO-d6): d = 175.1, 159.1, 127.4, 122.0,
118.4, 79.5, 25.6.
Anal. Calcd for C11H11F3O3: C, 53.23; H, 4.47; O, 19.34. Found: C,
53.09; H, 4.44; O, 19.48.
2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic Acid
2-({4-[2-([4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl]{[4-(trifluo-
romethyl)phenyl]methyl}amino)ethyl]phenyl}oxy)-2-methyl-
propanoic Acid (2d); General Procedure
(Fenofibric Acid) (2e)
Colorless solid; yield: 6.07 g (87%); mp 179–180 °C (Lit.3a mp 185
°C).
A suspension of phenol 1d (1.0 kg, 1.75 mol) and 20–40 mesh
NaOH (0.385 kg, 9.63 mol) in 2-butanone (6 L) was heated to 50 °C
over 0.5 h. The mixture was stirred at 50°C for 1 h. A solution of
BrC(CH3)2CO2H (0.438 kg, 2.63 mol) in 2-butanone (1 L) was add-
ed over 1 h. The resultant suspension was stirred an additional 2.5 h
at 50 °C monitoring by HPLC. After the reaction was deemed com-
plete, H2O (4 L) was added and the bi-phasic solution was cooled to
20 °C. The aqueous layer, containing excess base and small
amounts of methacrylic acid, was separated and discarded. EtOAc
(5 L) was added to the 2-butanone solution followed by 0.5 M HCl
(3.5 L). After discarding the aqueous layer, the organic layer was
washed with H2O (4 L) and reduced to 3 L via distillation under re-
duced pressure. After solvent exchange to iso-octane, the product
was isolated via filtration and dried under vacuum at 55–60 °C to
give 2d as an off-white solid; yield: 809 g (81%); mp 113–114 °C.
1H NMR [400 MHz, (CD3)2CO]: d = 11.29 (br s, 1 H, CO2H), 7.84
(ddd, J = 12.0, 7.6, 2.0 Hz, 1 H, ArH), 7.56 (ddd, J = 8.4, 4.0, 2.0
Hz, 1 H, ArH), 7.70 (d, J = 8.4 Hz, 2 H, ArH), 7.59 (d, J = 8.4 Hz,
2 H, ArH), 7.33 (dt, J = 10.4, 8.4 Hz, 1 H, ArH), 7.19 (d, J = 8.4 Hz,
2 H, ArH), 7.14 (s, 1 H, thiazole-H), 6.86 (d, J = 8.4 Hz, 2 H, ArH),
4.87 (s, 2 H, ArCH2), 3.77 (t, J = 7.2 Hz, 2 H, ArCH2), 3.00 (t, J =
7.2 Hz, 2 H, R2NCH2), 1.54 (s, 6 H, CH3).
1H NMR (400 MHz, CDCl3): d = 7.75 (d, J = 8.4 Hz, 2 H, ArH),
7.71 (d, J = 8.4 Hz, 2 H, ArH), 7.44 (d, J = 8.4 Hz, 2 H, ArH), 6.94
(d, J = 8.4 Hz, 2 H, ArH), 1.70 (s, 6 H, CH3).
13C NMR (100 MHz, DMSO-d6): d = 193.9, 175.1, 160.2, 137.7,
136.9, 132.5, 131.9, 130.0, 129.2, 117.7, 79.5, 25.7.
Anal. Calcd for C17H15ClO4: C, 64.06; H, 4.74; O, 20.08. Found: C,
64.02; H, 4.78; O, 19.95.
2-(2-Chlorophenoxy)-2-methylpropanoic Acid (2f)
Colorless solid; yield: 1.9 g (77%); mp 76–77 °C (Lit.14 72 °C).
1H NMR (400 MHz, CDCl3): d = 7.40 (dd, J = 7.6, 1.6 Hz, 1 H,
ArH), 7.19 (ddd, J = 8.0, 7.6, 1.2 Hz, 1 H, ArH), 7.07 (dd, J = 8.4,
1.2 Hz, 1 H, ArH), 7.04 (ddd, J = 8.4, 8.0, 1.6 Hz, 1 H, ArH), 1.64
(s, 6 H, CH3).
13C NMR (100 MHz, CDCl3): d = 179.0, 150.9, 130.7, 127.7, 127.6,
124.6, 121.7, 81.6, 25.1.
Anal. Calcd for C10H11ClO3: C, 55.96; H, 5.17; O, 22.36. Found: C,
56.03; H, 5.24; O, 22.27.
13C NMR (100 MHz, DMSO-d6): d = 175.8, 169.7, 154.5, 149.1,
148.2, 143.2, 133.1, 132.4, 130.2, 128.7, 128.4, 126.1, 126.0, 123.0,
119.4, 118.4, 118.2, 115.2, 115.0, 103.7, 79.0, 54.0, 32.5, 25.7.
Acknowledgment
We would like to thank Bill Hinkley for obtaining reaction calori-
metry data on the Bargellini reaction and the reaction using 2-bro-
mo-2-methylpropanoic acid.
Anal. Calcd for C29H25F5N2O3S: C, 60.41; H, 4.37; O, 8.32. Found:
C, 60.22; H, 4.40; O, 8.32.
2-(4-Chlorophenoxy)-2-methylpropanoic Acid (Clofibric acid,
References
2a)
Colorless solid; yield: 14.5 g (87%); mp 120–121 °C (Lit.12 mp
119–120 °C).
(1) Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R.
J. Med. Chem. 2000, 43, 527.
(2) (a) Julia, M. Bull. Soc. Chim. Fr. 1956, 776. (b) Jones, W.;
Thorp, J.; Waring, W. U.S. Patent, US3262850, 1966.
(3) (a) Mieville, A. U.S. Patent, US4058552, 1977. (b)Gignier,
J.; Bourrelly, J. Eur. Patent, EP0002151 A1, 1978.
(c) Sornay, R.; Gurrieri, J.; Tourne, C.; Renson, F. J.;
Majoie, B.; Wulfert, E. Arzneim.-Forsch. 1976, 26, 885.
(4) Bargellini, G. Gazz. Chim. Ital. 1906, 36, 337.
(5) Phillips, D. K. US Patent, US3948973, 1976.
1H NMR (300 MHz, DMSO-d6): d = 13.14 (s, 1 H, CO2H), 7.33 (d,
J = 9.0 Hz, 2 H, ArH), 6.85 (d, J = 9.0 Hz, 2 H, ArH), 1.51 (s, 6 H,
CH3).
13C NMR (100 MHz, DMSO-d6): d = 175.4, 154.9, 129.7, 126.1,
120.8, 79.5, 25.6.
Anal. Calcd for C10H11ClO3: C, 55.96; H, 5.17; O, 22.36. Found: C,
55.98; H, 5.21; O, 22.44.
Synthesis 2004, No. 12, 1959–1962 © Thieme Stuttgart · New York