1. 5-Chloro-2-methylbenzoic acid (5.04 g, 29.5 mmol) was dissolved in 100 mL of ethanol in a 250 mL round-bottomed flask fitted with a water condenser. 0.5 mL of concentrated sulfuric acid was added and the solution was heated to reflux. After maintaining reflux for 48 hours, it was cooled to room temperature. Ethanol was removed by distillation under reduced pressure. The resulting oil was dissolved in 300 mL of ether and washed with saturated aqueous sodium bicarbonate (2 x 300 mL). The organic layer was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5.12 g (87% yield) of ethyl 5-chloro-2-methylbenzoate as a clear oil.
2. 5-Chloro-2-methylbenzoic acid ethyl ester (16.60 g, 83.56 mmol) and diethyl-(3-pyridyl)borane (13.52 g, 91.92 mmol) were dissolved in 100 mL of tetrahydrofuran in a 500 mL round-bottomed flask equipped with a magnetic stirrer. Sodium carbonate (26.57 g, 250.69 mmol) and 50 mL of water were added, followed by palladium acetate (0.38 g, 1.67 mmol) and (2'-dicyclohexylphosphoryl-biphenyl-2-yl)-dimethylamine (AmPhos, 0.92 g, 2.51 mmol) and 25 mL of ethanol. The mixture was heated to reflux for 6 h and cooled to room temperature. The mixture was diluted with 600 mL of water and extracted with ether (2 x 300 mL). The organic phases were combined and extracted with 1N HCl (3 x 200 mL). The acidic extracts were combined and made basic with 5N aqueous sodium hydroxide. The basic layer was extracted with ether (3 x 500 mL), the extracts were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 19.57 g (97% yield) of ethyl 5-(3-pyridyl)-2-methylbenzoate as a brown oil.
3. 2.0 g of platinum(II) oxide was added to a 500 mL hydrogenation vessel and purged with nitrogen. A 200 mL solution of ethyl 5-(3-pyridyl)-2-methylbenzoate (19.57 g, 81.10 mmol) in acetic acid was added. The suspension was hydrogenated at 45 psi for 18 hours. The catalyst was filtered through diatomaceous earth and the filter cake was washed with 200 mL acetic acid. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in 500 mL of water and adjusted to alkaline with 5N aqueous sodium hydroxide. The basic layer was extracted with ethyl acetate (2 x 500 mL), the extracts were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was dissolved in 200 mL of hot ethanol. L-(+)-tartaric acid (12.17 g, 81.1 mmol) was added to the ethanol solution and stirred at room temperature for 48 h. A white precipitate was formed and collected by filtration. The white solid was recrystallized from hot 5% H2O/ethanol (300 mL) followed by recrystallization from 350 mL of hot 20% H2O/ethanol to afford 11.25 g (35% yield, 95.8% ee) of (S)-5-(3-piperidinyl)-2-methylbenzoic acid ethyl ester-L-tartrate as a white solid.
4. The mother liquor was combined and concentrated under reduced pressure. The resulting oil was dissolved in 300 mL of water and adjusted to alkaline with 5N aqueous sodium hydroxide. The basic layer was extracted with ethyl acetate (2 x 300 mL), the extracts were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil was dissolved in 200 mL of hot ethanol. D-(-)-tartaric acid (6.82 g, 45.4 mmol) was added to the ethanol solution and stirred at room temperature for 48 h. A white precipitate was formed and collected by filtration. The white solid was recrystallized from hot 5% H2O/ethanol (300 mL) followed by recrystallization from 350 mL of hot 20% H2O/ethanol to give 13.51 g (42% yield, 100% ee) of (R)-5-(3-piperidinyl)-2-methylbenzoic acid ethyl ester-D-tartrate as a white solid.
5. (R)-5-(3-piperidinyl)-2-methylbenzoic acid ethyl ester-D-tartaric acid (2.02 g, 5.08 mmol) was dissolved in 100 mL of ethyl acetate and washed with 100 mL of saturated aqueous NaHCO3 solution. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was dissolved in 10 mL of toluene and 4-trifluoromethylbenzyl imidazole-1-carboxylate (1.37 g, 5.08 mmol) was added. The reaction was stirred at room temperature under nitrogen protection for 72 hours. The reaction was diluted with water (200 mL), acidified with 1N aqueous hydrochloric acid and extracted with ether (2 x 150 mL).
