Example 261: General procedure for the synthesis of benzyl 3-hydroxycyclobutanecarboxylate from benzyl 3-oxocyclobutanecarboxylate:
1. triethylamine (2 mL, 14.04 mmol) and benzyl bromide (1.2 mL, 10.0 mmol) were added to a solution of 3-oxocyclobutane-1-carboxylic acid (1.0 g, 8.77 mmol) in THF (10 mL), and stirred for 2 hours at room temperature. EtOAc (10 mL) was added and the mixture was washed sequentially with water, 1 M hydrochloric acid and brine. The organic layer was dried with sodium sulfate and concentrated in vacuum. The residue was purified by fast column chromatography (FCC) using a gradient elution with a hexane solution of 0-15% EtOAc to give benzyl 3-oxocyclobutane-1-carboxylate (0.938 g, 53%).
2. Benzyl 3-oxocyclobutane-1-carboxylate (0.800 g, 3.92 mmol) was dissolved in a mixture of THF (2.5 mL) and water (2.5 mL), and cooled to 0°C. Sodium borohydride (0.051 g, 1.96 mmol) was added and stirred at room temperature for 1 hour. After vacuum concentration, EtOAc (10 mL) was added, washed sequentially with water and brine, and the organic layer was dried with sodium sulfate and concentrated. The residue was purified by FCC and eluted using a gradient of 0-10% EtOAc in hexane solution to give benzyl 3-hydroxycyclobutane-1-carboxylate (0.715 g, 88%).
3. Benzyl 3-hydroxycyclobutane-1-carboxylate (0.400 g, 1.94 mmol) was dissolved in THF (10 mL) and phenol (0.547 g, 5.83 mmol) and triphenylphosphine (0.662 g, 2.52 mmol) were added. Diethyl azodicarboxylate (0.4 mL, 2.52 mmol) was added slowly and stirred at room temperature for 24 hours. After evaporation, it was extracted with EtOAc (3 x 10 mL) and the organic layer was washed with brine and concentrated. The residue was purified by FCC and eluted using a gradient of 0-15% EtOAc in hexane solution to give benzyl 3-phenoxycyclobutane-1-carboxylate (0.450 g, 82%).
4. Benzyl 3-phenoxycyclobutane-1-carboxylate (0.400 g, 1.42 mmol) was dissolved in EtOH (10 mL) and 10% palladium carbon (0.010 g) was added. The solution was stirred at room temperature under hydrogen atmosphere for 2 hours. The filtrate was filtered and evaporated and the residue was purified by FCC using a gradient elution with hexane solution of 0-10% EtOAc to give 3-phenoxycyclobutane-1-carboxylic acid (0.245 g, 95%).
5. Finally, 2-N-methyl-6-[5-(3-phenoxycyclobutyl)-1,2,4-oxadiazol-3-yl] was prepared from 3-phenoxycyclobutane-1-carboxylic acid (0.190 g, 0.985 mmol) and 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboxamidine (0.150 g, 0.579 mmol) -2-N-phenyl-1,3,5-triazine-2,4-diamine in a manner similar to the preparation of Intermediate 1 (as described in Example 209). The residue was purified by FCC, eluting using a 10% MeOH hexane solution to give a mixture of isomers of benzyl 3-hydroxycyclobutanecarboxylate (0.095 g, 42%).
