Fig 1. Chemical structure formula and three-dimensional structure of 3,4-Dimethylaniline

Benzofuran-6-carboxylic Acid is a reagent in the development of potent LFA-1/ICAM antagonist SAR 118 as an opthalmic solution for treating dry eyes. Preparation of piperidinylpyrimidine derivatives as inhibitors of HIV-1 LTR activation[1,2].

Schizophrenia is a chronic and highly debilitating disease afflicting over three million people in the U.S. This complex disorder is characterized by a constellation of symptoms, including positive (hallucinations, delusions), negative (apathy, withdrawal), and cognitive. Significant advances have been made in therapies for the treatment of the positive and negative symptoms of schizophrenia, but the vast majority of schizophrenic patients (85%) are also reported to suffer from cognitive deficits that remain largely untreated. It is believed that neuronal nicotinic acetylcholine receptors(nAChRs) are involved in a variety of attention and cognitive processes.These calcium-permeable, ligand gated ion channels modulate synaptic transmission in key regions of the central nervous system (CNS) involved in learning and memory, including the hippocampus, thalamus, and cerebral cortex.Among the nAChRs, physiological, pharmacological, and human genetic data suggest a link between the α7 nAChR and cognitive deficits in schizophrenia.

Benzofuran-6-carboxylic acid is an important intermediate for the synthesis of α7 nAChR. Benzofuran-6-carboxylic Acid (162mg,1.0mmol) was combined with (R)-3-aminoquinuclidine dihydrochloride(219 mg, 1.1 mmol), diisopropylethylamine (522 µL,3.0 mmol), and DMF (5 mL), cooled to 0℃,and treated with HATU (380 mg, 1.0 mmol). The mixture was allowed to warm to room temperature and was stirred for 18 h. The mixture was concentrated in vacuo and partitioned between a 1:1 mixture of saturated sodium chloride/concentrated ammonium hydroxide (10mL) and chloroform (30 mL). The aqueous layer was extracted with chloroform. The organics were combined, dried over anhydrous sodium sulfate, and concentrated to an amber oil (530 mg). The crude material was chromatographed over 11 g of slurry-packed silica gel, eluting with 2% ammonium hydroxide/10% methanol/chloroform into 7 mL fractions. Fractions 3-6 were combined and concentrated to a dark-yellow solid (274 mg). The solid was further dried in vacuo. The solid was dissolved in methanol (5 mL), treated with 3 N methanolic hydrochloric acid (1 mL), stirred for 16 h, then concentrated to dryness. The residue was dissolved in methanol(1 mL) and 2-propanol(10 mL) and treated with diethyl ether (∼20mL) until the mixture became turbid. The mixture was stirred for 16 h, filtered under nitrogen, and dried in a vacuum oven at 50℃ to afford 206 mg (67%) of Regioisomeric benzofuran as an off-white solid[3].

References

[1] Zhong, M., et al.: ACS Med. Chem., 3, 203 (2012); 
[2] Fujiwara, N., et al.: Bioorg. Med. Chem., 16, 9804 (2008).
[3] Wishka D G, Walker D P, Yates K M, et al. Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationshi[J]. 2006, 49(14):4425-36.