Uses
3-Cyano-4-isopropoxybenzoic Acid is a useful reagent in the preparation of cyanoaryloxadiazolyl-substituted nitrogen heterocycles as S1P3-sparing agonists of sphingosine phosphate receptors S1P1 and S1P5 for treatment of multiple sclerosis and their pharmacokinetics and side effect profiles. Preparayion and SAR of biaryl oxadiazoles as S1P1 receptor agonists.
Synthesis
Step 4: Synthesis of 3-cyano-4-isopropoxybenzoic acid (86). To a stirred solution of methyl 3-cyano-4-isopropoxybenzoate (7.0 g, 31.5 mmol) in a solvent mixture of ethanol (30 mL) and tetrahydrofuran (30 mL) was added an aqueous 2M sodium hydroxide solution (20 mL, 40 mmol). The reaction mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the mixture was concentrated under vacuum to remove the organic solvent. The residue was diluted with distilled water (100 mL) and acidified with 2N hydrochloric acid to pH < 7. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the organic layers were combined. The organic phase was washed sequentially with distilled water and saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration to remove the desiccant, the filtrate was concentrated to obtain the crude product. The crude product was recrystallized with 10% ether/hexane mixed solvent, the solid was collected by filtration and dried in vacuum to give 3-cyano-4-isopropoxybenzoic acid (86) (6 g, 92% yield) as an off-white solid.
References
[1] Patent: US2010/249071, 2010, A1. Location in patent: Page/Page column 60-61
[2] Patent: WO2017/4608, 2017, A1. Location in patent: Paragraph 0159
[3] Patent: WO2005/107762, 2005, A2. Location in patent: Page/Page column 194-220
[4] Patent: WO2007/56056, 2007, A2. Location in patent: Page/Page column 53
[5] Patent: WO2005/58848, 2005, A1. Location in patent: Page/Page column 47
