An Improved Method for the Synthesis of 3-Fluorosalicylic Acid with Application to the Synthesis of 3-(Trifluoromethyl)salicylic Acid

Abstract

An improved method for the synthesis of 3-fluorosalicylic acid is described. A positional protective group strategy allows formylation selectively at the ortho position of 4-bromo-2-fluorophenol. Oxidation of the resulting salicylaldehyde to the salicylic acid, followed by debromination, affords 3-fluorosalicylic acid. The method has also been applied to the synthesis of 3-(trifluoromethyl)salicylic acid.During the course of our work on HIV-1 non-nucleoside reverse transcriptase inhibitors, 1 we sought a reliable method for the preparation of 3-substituted salicylic acids from readily available starting materials.Despite the historical significance of salicylic acid derivatives, relatively few methods exist for the preparation of derivatives substituted in the 3-position. For example, only three references were revealed in a literature search for the preparation of 3-fluorosalicylic acid (4) or 3-fluorosalicylaldehyde. The Reimer-Tiemann reaction of 2-fluorophenol has been used to prepare 3-fluorosalicylaldehyde. 2 This aldehyde has also been prepared by magnesium-assisted ortho formylation of 2-fluorophenol. 3 Both of these methods suffer from low yields of this product. 3-Fluorosalicylic acid (4) has also been prepared in low yield through Kolbe-Schmitt carbonation of 2-fluorophenol. 2,4

The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

“…Alkylation of both phenoxide anions and both carboxylates derived from the substituted diphenylmethane 58 22 with dimethyl sulfate, using potassium carbonate in acetone as the base, afforded intermediate 59, which was then oxidized to the desired benzophenone 54 with chromium trioxide in acetic acid (Scheme 1). As shown in Scheme 2, treatment of 3-(trifluoromethyl)salicylic acid (60) 23 with formaldehyde under acidic conditions afforded the diphenylmethane 61, which was methylated and oxidized to yield the substituted benzophenone 57.…”

Novel Modifications in the Alkenyldiarylmethane (ADAM) Series of Non-Nucleoside Reverse Transcriptase Inhibitors

“…To complete the aromatic halogen series, difluoro ADAM analogues 35 and 36 were planned (Scheme ). The synthesis of these compounds started with 3-fluorosalicylic acid ( 31 ) . This compound was condensed with formaldehyde under acidic conditions in methanol to yield the difluorodisalicylmethane intermediate 32 .…”

“…(3,3′-Dicarboxy-5,5′-difluoro-4,4′-dihydroxydiphenyl)methane (32). 3-Fluorosalicylic acid (31) 27 (748 mg, 4.72 mmol) was taken up in methanol (3.5 mL) and water (0.6 mL). The mixture was cooled to -78 °C and stirred vigorously while concentrated sulfuric acid (8.3 mL) was added dropwise.…”

Novel liquid-crystalline mesogens and main-chain chiral smectic thiol-ene polymers based on trifluoromethylphenyl moieties

“…Because of the incompatibility of some reactions developed in Scheme 1 (route i) with the olefin substituent present in the chiral alcohol, we designed a new synthetic protocol as shown in Scheme 3 (route i). Selective monobromination of commercially available compound 32 gave phenol 33, 20 which was coupled with previously reported (S)-octan-7-ene-2-ol (34) 8 to provide compound 35. However, unexpected olefin migration occurred in the following Suzuki coupling and we isolated an inseparable mixture of the desired compound 36, along with the internal olefin by-product 37 (75 : 25).…”