An efficient synthesis of a dual PPAR alpha/gamma agonist and the formation of a sterically congested alpha-aryloxyisobutyric acid via a Bargellini reaction.
A practical synthesis of benzisoxazole 1 and its conversion to alpha-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be approximately 5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered alpha-aryloxyisobutyric acids can be made in a single step in high yield.
Cvetovich
Raymond J
RJ
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA. raymond_cvetovich@merck.com
Chung
John Y L
JY
Kress
Michael H
MH
Amato
Joseph S
JS
Matty
Louis
L
Weingarten
M David
MD
Tsay
Fuh-Rong
FR
Li
Zhen
Z
Zhou
George
G
D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry
D002087:Butyrates; D007555:Isoxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; C511261:2-((5,7-dipropyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl)oxy)-2-methylpropanoic acid