Salicylic Acid → HCID 10171699, compound

Participants

Reaction Conditions

Reaction Steps

To a 100 ml round bottomed flask fitted with argon purge, magnetic stir bar and condenser was added (7-carboxy-heptyl)-methylammonium hydrochloride (3.25 g, 0.0155 mol, 1.0 eq) and dichloromethane (DCM, 50 ml). Chlorotrimethylsilane (3.37 g, 0.0310 mol, 2.0 eq) was added and the resulting mixture was brought to reflux for approximately 2 h. The flask was removed from the heating mantle and placed in an ice water bath. Once the reaction was cooled to 0° C., triethylamine (3.92 g, 0.0388 mol, 2.5 eq) was added and a white vapor formed over the reaction mixture. The reaction was allowed to stir for approximately 10 min at 0° C. In a separate flask, acetylsalicyloyl chloride (ASCC, 3.08 g, 0.0155 mol, 1.0 eq) was dissolved in DCM (20 ml). The ASCC solution was added dropwise to the reaction mixture, the ice bath was removed, and the reaction mixture was allowed to stir and warm to ambient temperature overnight. The DCM was removed under reduced pressure and aqueous 2N NaOH (20 ml) was added to the residue. The aqueous mixture was allowed to stir at ambient temperature for several hours and was then acidified with aqueous 2N HCl. The aqueous mixture became cloudy and a brow oil separated out. The aqueous mixture was extracted with EtOAc (3×100 ml). The combined EtOAc extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The resulting brown oil was further dried under high vacuum to yield a brown solid. HPLC at this point indicated the solid consisted of two components (rt 2.8 min, salicylic acid and rt 4.0 min, desired product). This mixture was stirred in warm water (40-50° C.) to dissolve the salicylic acid. The remaining solid was filtered off, HPLC indicated this is predominantly desired product, crude yield 3.99 g (0.0136 mol, 87.7%). This material was treated in warm water (40-50° C.) and filtered two more times to produce pure 8-[(2-Hydroxy-benzoyl)-methyl-amino]-octanoic acid. (HPLC rt 4.0 min; NMR consistent with desired product; Elemental analysis Theoretical: C=65.31, H=7.82, N=4.76 Found: C=65.32, H=7.72, N=4.73) This application incorporates by reference in its entirety International Publication No. WO 03/072195, which is also attached as an appendix A to this application.

Provenance & Evidence