Synthesis of SGLT2 Inhibitors by Means of Fukuyama Coupling Reaction.

Disclosed herein is a novel and efficient synthesis of dapagliflozin and canagliflozin, the most advanced sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors), for the treatment of type 2 diabetes mellitus (T2DM). Per Ac-protected thioester was prepared by the treatment of per Ac d-gluconolactone with 1-dodecanethiol and iPrMgCl without affecting labile Ac-protecting groups. Aryl bromide (ArBr) was synthesized through reduction of diaryl ketone to diaryl methane by the TiCl4/NaBH4/DME-MeOH reduction system. Fukuyama coupling of the thioester with aryl zinc reagent prepared from ArBr gave a multifunctional aryl ketone at 40 °C in a high yield where the use of a limited amount of a mixed solvent (7.2 volumes (v), THF:toluene:DMF = 3v/4v/0.2v) was crucial to achieve the higher yield. After cleavage of the THP group, hydroxy ketone obtained was treated with methanesulfonic acid (MSA) in MeOH to give a methoxy-cyclized product in a single step and in a quantitative yield, which was allowed to silane reduction to furnish dapagliflozin in an excellent yield. By following the same procedure, canagliflozin was synthesized. The current synthetic method is featured by high yields, mild reaction conditions, and the use of inexpensive reagents and readily cleavable protecting groups.

New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors.

Synthesis of diarylmethanes, a key building block for SGLT2 inhibitors, has been developed through ketone synthesis by Friedel-Crafts acylation with TiCl4, followed by reduction with TiCl4/NaBH4. The new protocol proceeded more cleanly than the previous methods employing AlCl3 and BF3·OEt2/Et3SiH to provide the diarylmethanes corresponding to canagliflozin, empagliflozin, and luseogliflozin in a highly expedient and affordable manner. In the case of a diarylmethane for the synthesis of dapagliflozin, the reduction step took place by an alternative method using InCl3/Al/BF3·OEt2.

Green Synthesis, Antioxidant, and Plant Growth Regulatory Activities of Novel α-Furfuryl-2-alkylaminophosphonates.

A series of novel α-furfuryl-2-alkylaminophosphonates have been efficiently synthesized from the one-pot three-component classical Kabachnik-Fields reaction in a green chemical approach by addition of an in situ generated dialkylphosphite to Schiff's base of aldehydes and amines by using environmental and eco-friendly silica gel supported iodine as a catalyst by microwave irradiation. The advantage of this protocol is simplicity in experimental procedures and products were resulted in high isolated yields. The synthesized α-furfuryl-2-alkylaminophosphonates were screened to in vitro antioxidant and plant growth regulatory activities and some are found to be potent with antioxidant and plant growth regulatory activities. These in vitro studies have been further supported by ADMET (absorption, distribution, metabolism, excretion, and toxicity), quantitative structure-activity relationship, molecular docking, and bioactivity studies and identified that they were potentially bound to the GLN340 amino acid residue in chain C of 1DNU protein and TYR597 amino acid residue in chain A of 4M7E protein, causing potential exhibition of antioxidant and plant growth regulatory activities. Eventually, title compounds are identified as good blood-brain barrier (BBB)-penetrable compounds and are considered as proficient central nervous system active and neuroprotective antioxidant agents as the neuroprotective property is determined with BBB penetration thresholds.