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Synthesis 2004(12): 1959-1962  
DOI: 10.1055/s-2004-829171
PAPER
© Georg Thieme Verlag Stuttgart · New York

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

Roman D. Davis, Russ N. Fitzgerald*, Jiasheng Guo
GlaxoSmithKline, Chemical Development-Synthetic Chemistry, 5 Moore Drive, Research Triangle Park, NC 27709, USA
Fax: +1(919)3158735; e-Mail: russ.n.fitzgerald@gsk.com;
Further Information

Publication History

Received 11 March 2004
Publication Date:
27 July 2004 (online)

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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.

Key words

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

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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.

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.