ORGN 78 |
Synthesis of a dual PPAR agonist and the formation of a sterically congested alpha-aryloxyisobutyric acid
| Raymond J. Cvetovich1, John Y. L. Chung1, Michael H. Kress1, Joseph S. Amato1, George Zhou2, Louis Matty1, F.R. Tsay3, and Zhen Li1. (1) Process Research, Merck Research Laboratories, RY800-B369 P.O. Box 2000, Rahway, NJ 07065, (2) Analytical Research, Merck Research Laboratories, (3) Merck Research Laboratories |
The alpha-aryloxyisobutyric acid is a motif present in a variety of pharmaceutically active agents, including hypolipidemics, antisicklings, plant-growth substances, and PPAR (peroxisome proliferator-activated receptor) agonists. Dual PPAR alpha/gamma agonist 1, potentially useful for the treatment of type II diabeties and dyslipidemia, is such an alpha-aryloxyisobutyric acid possesing a highly sterically congested ether linkage due to 2,6-di-n-propyl substitution flanking the phenolic oxygen. A practical synthesis of benzisoxazole 7 and its conversion to alpha-aryloxyisobutyric acid 1 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone 8) was developed. The synthesis of benzisoxazole 7 in multi-kilogram scale was accomplished via a 5 step synthesis. Condensation of diethyl ethoxymethylenemalonate with 5-nonanone followed by hydrolysis/decarboxylation produced bis-2,4-propyl-1,3-resorcinol 2 in 85% yield. Treatment of resorcinol 2 with trifluoroacetic anhydride in the presence of a strong acid catalyst produced trifluoroacetophenone 3 (92%) which was converted to oxime 4 (90%) by the action of primary amines, in particular n-butylamine. The preparation of the benzisoxazole ring was achieved through the rearrangements of either O-mesylate 5 or, uniquely, through cyclic sulfite 6 (90%). The Bargellini chloretone reaction of phenols using chloroform/acetone/hydroxide reportedly gives 15-60% yields of alpha-aryloxyisobutyric acids. Optimization of this procedure produced consistent 92-94% isolated yields of highly hindered alpha-aryloxyisobutyric acid 1 on kilogram scale. |
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