Reaction Steps
Under N2, n-butyllithium (56 mL, 2.5 M in hexane, 0.14 mol) is added to the mixture of HMDS (24.2 g, 0.15 mol) in 300 mL dry tetrahydrofuran at −10° C., the resulting mixture is then stirred for 30 min at −10° C. A mixture of (S)-2-Biphenyl-4-ylmethyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3a, R1=t-butoxycarbonyl) (35.1 g, 0.1 mol) in 50 mL dry tetrahydrofuran is added to the reaction mixture at −10° C., after about 30 min, n-butyllithium (40 mL, 2.5 M in hexane, 0.1 mol) is added to the reaction mixture at −10° C., the resulting mixture is then stirred for 30 min at −10° C. benzoyl chloride (15.5 g, 0.11 mol) is added to the reaction mixture at −10° C., after about 1 hour at −10° C., the reaction mixture is diluted with 100 mL saturated aqueous ammonium chloride solution and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Formaldehyde (37% in water, 24.3 g, 0.3 mol), K2CO3 aqueous solution (27.6 g in 100 mL water, 0.2 mol) and tetrabutyl-ammonium-hydroxide solution (40% in water, 1.3 g, 5 mmol) are added to the remaining organic phase, and heated to 50° C., and stirred for 2 hours. Then the reaction mixture is diluted with 100 mL brine and stirred for 15 min, stop stirring, and remove the lower aqueous layer. Lithium hydroxide monohydrate solution (15 g in 100 mL water, 0.36 mol) and tetrabutylammonium bromide (0.32 g, 1 mmol) are added to the remaining organic phase, stirred at r.t. for 2 hours. Then, about 50 g of phosphoric acid 85% is added in order to set the pH to 3.0-4.0. Then 100 mL toluene and 100 mL brine is added. After phase separation and concentrated under vacuo. The residue is dissolved in 200 mL acetonitrile at 80° C., filtered hot (80° C.) to remove inorganic salt and cooled to 0° C., whereas crystallization occurs and standing for 3 hours, crystals are collected by filtration, washed with 50 mL acetonitrile and died under vacuum at 50° C. to afford (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid. 1HNMR (400 MHz, DMSO): 1.27 (s, 9H, (CH3)3), 2.26 (m, 1H, 3-CHH), 2.49 (m, 1H, 3CHH), 2.71 (d, 1H, 5-CH2), 3.85 (m, 1H, 4-CH), 5.60 (s, 1H, C═CHH), 6.05 (s, 1H, C═CHH), 6.65 (d, 1H, NH), 7.20˜7.70 (9H, m, aromatic), 12.34 (s, 1H, COOH). The ratio of intermediate (3S,5S-4, R1=t-butoxycarbonyl, R4=phenyl) to (3R,5S-4, R1=t-butoxycarbonyl, R4=phenyl) is 70:30 as determined by HPLC. Spectroscopic data as Example 35, Method 1.
