Improved Method for the Synthesis of 2-Methyl-2-Aryloxypropanoic Acid Derivatives

Abstract

An improved method for the formation of 2-methyl-2-aryloxypropanoic acid derivatives, an important class of compounds for the potential treatment of type II diabetes, is reported. This method offers several advantages over the existing chemistry for this transformation.

2-methyl-2-aryloxypropanoic acid - PPAR agonist - alkylation - fibric acid

References

1 Willson TM. Brown PJ. Sternbach DD. Henke BR. J. Med. Chem.  2000,  43:  527 

2a Julia M. Bull. Soc. Chim. Fr.  1956,  776 

2b Jones W, Thorp J, and Waring W. inventors; U.S. Patent,  US3262850. 

3a Mieville A. inventors; U.S. Patent,  US4058552. 

3b Gignier J, and Bourrelly J. inventors; Eur. Patent,  EP0002151 A1. 

3c Sornay R. Gurrieri J. Tourne C. Renson FJ. Majoie B. Wulfert E. Arzneim.-Forsch.  1976,  26:  885 

4 Bargellini G. Gazz. Chim. Ital.  1906,  36:  337 

5 Phillips DK. inventors; US Patent,  US3948973. 

6

The alkylation of one of our compounds using conditions reported by Bargellini was monitored by reaction calorimetry with a Metler Toledo RC1 unit. The total heat generated during the addition (1 h addition time) of the 1,1,1-trichloro-2-methyl-2-propanol was measured at 2180 kJ/kg. The average heat output rate for the duration of the addition was measured at 550 W/kg. Based on the reaction calorimetry, an adiabatic temperature rise of 58 °C was calculated.

7

We thank Prof. Barry Trost, Stanford University, for first suggesting this reagent to us.

8 Matsuoka R, and Guo J. inventors; Patent Application,  PCT/US0329484. 

9 Chapman OL. Adam W. Wojtkowski PW. Rodriquez O. Rucktäschel R. J. Am. Chem. Soc.  1972,  94:  1365 

10a Chinn L. Salamon K. J. Med. Chem.  1977,  20:  229 

10b Thomae K. inventors; Patent  DD125199. 

10c York J. Winneroski L. Xu Y. Abstracts of Papers, 226th National Meeting of the American Chemical Society, New York, NY, 2003; American Chemical So321ciety: Washington, DC, 2003; ORGN 117 

10d For examples involving alkoxy nucleophiles see: House H. Prabhu A. Wilkins J. Lee L. J. Org. Chem.  1976,  41:  3067 

11

The alkylation of the compound noted in ref. [6] with 2-bromo-2-methylpropanoic acid was monitored by reaction calorimetry with a Metler Toledo RC1 unit. The total heat generated during the addition (1 h addition time) of the 2-bromo-2-methylpropanoic acid was measured at 669 kJ/kg. The average heat output rate for the duration of the addition was measured at 141 W/kg. Based on the reaction calorimetry, an adiabatic temperature rise of 35 °C was calculated.

12

Aldrich Chemical Co. 2002-2003.

13 Bulteau G. inventors; U. S. Patent,  US3632629. 

14 Gilman H. Wilder G. J. Am. Chem. Soc.  1955,  77:  6644