Production method of (3aS,7aS)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-1,3-dioxo-octahydro-isoindole-3a-carboxylic acid (CAS no: 501085-21-8) contains 3 steps. The synthetic routes are as follows:

A. 1(S),2(S)-Diphenyl-N,N'-bis-[1(R)-phenyl-ethyl]-ethane-1,2-diamine (2). In a 500-mL, three-necked, round-bottomed flask equipped with a N2 inlet, two septa and a magnetic stirring bar is introduced successively CH₂Cl₂ (180 mL) and an aqueous glyoxal solution (9.40 mL, 82.5 mmol, 1.0 equiv) by syringe through one of the septa. One septum is temporarily removed and solid sulfate (40.0 g) is then added portion-wise over 20 min, while the mixture is stirred at room temperature. The resulting suspension is stirred for an additional 10 min, and then (R)-(+)-phenylethylamine (21.0 mL, 20.0 g, 165.0 mmol, 2.0 equiv) is introduced dropwise via syringe over a 5 min period. The resulting mixture is stirred overnight at room temperature. Magnesium sulfate is removed by filtration and rinsed with CH₂Cl₂ (2 × 25 mL). The filtrate is then concentrated by rotary evaporation and then further dried under high vacuum for 1 h to provide crude bis-imine (1) as an orange oil (21.3 g, 98.0%), which is used directly for the next step without further purification. Into a 1-L, three-necked, round-bottomed flask equipped with one low temperature thermometer, one N2 inlet and one septum is introduced crude bis-imine 1 (21.3 g) as a solution in Et₂O (300 mL) by syringe. This solution is cooled to -78 °C (dry ice-acetone bath), and PhMgCl (162 mL, 2.0 M in THF, 325 mmol, 4.0 equiv) is added drop-wise via syringe pump while maintaining the internal temperature between -78 °C and -75 °C over 2 h. The resulting dark brown mixture is allowed to warm to room temperature gradually over 4 h, and stirred for an additional 2 h at room temperature. The mixture is then cooled to 4 °C (ice/water bath), and carefully quenched by the addition of a saturated aqueous NH₄Cl solution (200 mL) after removal of the septum over 30 min. The solid that is formed is dissolved by the addition of de-ionized water (100 mL), and the two phases are separated in a 1-L separatory funnel. The aqueous phase is then further extracted with ethyl acetate (3 × 150 mL). The combined organic phases are washed with brine (50.0 mL), then dried over MgSO₄ (30 g, 5 min) and filtered. The filtrate is concentrated by rotary evaporation and further dried under high vacuum for 1 h. The crude product (33.5 g) is purified by flash column chromatography. Thus, the crude brown solid is dissolved in the minimum amount of CH₂Cl₂ (approximately 10 mL), charged on a column (8 × 16 cm) containing 400 g of silica gel and eluted with Et₂O-petroleum ether (5:95, 2 L, then 10:90, 2 L). After the first apolar impurity (this spot is only evident by UV), the title compound elutes, before a mixture of other isomers. The combined fractions of the major isomer are concentrated by rotary evaporation to provide a slightly yellow solid (16.8 g). This solid is dissolved in boiling petroleum ether (250 mL), with addition of a small amount of CH₂Cl₂ (5 mL) to complete the dissolution. The solvent is allowed to evaporate to 1/5 of the initial volume at room temperature over 2 days, allowing the crystallisation to occur. These crystals are collected by filtration, and rinsed with a small amount (15.0 mL) of cold (0 °C) petroleum ether. Thus, 13.8–14.7 g (40–43%) of pure diamine 2 are obtained.

B. (3aS,7aR)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-hexahydro-isoindole-1,3-dione (3). Into a 250-mL, one-necked, round-bottomed flask, equipped with a septum and a magnetic stirring bar, containing cyclohexane (8.50 g, 55.1 mmol, 1.0 equiv) is added glacial acetic acid (100 mL), followed by 2-(3,4-dimethoxyphenyl)ethylamine (10.1 g, 55.4 mmol, 1.0 equiv) . The septum is removed and the flask is equipped with a Liebig condenser. The reaction is then heated at reflux (oil bath temperature 120 °C) for 13 h. The resulting mixture is allowed to cool to room temperature and poured into a 1-L beaker containing 400 mL of de-ionized water. The aqueous phase is extracted with diethyl ether (5 × 100 mL). The combined organic phases are transferred into a 1-L Erlenmeyer flask, cooled to 4 °C (water/ice bath) and neutralized by the slow addition (30 min) of a saturated aqueous Na₂CO₃ solution (150 mL) under vigorous stirring. After the addition is finished, the two phases are separated and the organic phase is further washed with saturated aqueous Na₂CO₃ (2 × 50 mL). The organic phase is then dried over anhydrous MgSO₄ (20.0 g, 5 min). After removal of the solid by filtration, the organic phase is concentrated by rotary evaporation and further dried under high vacuum for 1 h. The resulting yellow solid is recrystallized from boiling light petroleum ether/ethyl acetate (100 mL:25 mL). Crystallization is allowed to occur at room temperature over 2 h, then at 4 °C overnight. The crystals are collected by filtration and washed with cold (0 °C) petroleum ether (25 mL) to give 14.2 g (81%) of the title compound 3.

C. (3aS,7aS)-2-[2-(3,4-Dimethoxyphenyl)-ethyl]-1,3-dioxo-octahydro-isoindole-3a-carboxylic acid methyl ester (5). Into a 100-mL, two-necked, round-bottomed flask, equipped with one septum and one low temperature thermometer, containing a solution of diamine 2 (8.79 g, 20.9 mmol, 1.1 equiv) in THF (50 mL) cooled to -78 °C (dry ice-acetone bath) is introduced n-BuLi (8.50 mL, 2.5 M in hexanes, 21.3 mmol, 1.1 equiv) dropwise via syringe over 25 min maintaining the internal temperature between -78 °C and -75 °C. The resulting pink solution is allowed to warm to room temperature (23 °C) by removing the cooling bath, and then stirred at this temperature for 30 min. This solution is then cooled to -78 °C and transferred over 2 h via cannula into a 250-mL two-necked, round-bottomed flask equipped with one septum and one low temperature thermometer containing a solution of imide 3 (6.00 g, 18.9 mmol) in THF (80 mL) while maintaining the internal temperature at -78 °C. The resulting mixture is then stirred for 1 h at -78 °C. A solution of methyl cyanoformate (3.00 mL, 37.8 mmol, 2.0 equiv) (Note 23) in THF (10 mL) is then added dropwise via cannula over 15 min. The resulting yellow solution is stirred for 1 h at -78 °C, then the cooling bath is removed, and saturated aqueous NaHCO₃ (80.0 mL) is added slowly, followed by de-ionized water (20 mL). The phases are separated, and the aqueous phase is extracted with ethyl acetate (3 × 50 mL). The combined organic phases are washed with brine (50 mL), then dried over MgSO₄ (20.0 g, 5 min). After removal of the solid by filtration, the filtrate is concentrated by rotary evaporation. The crude solid residue is dissolved in the minimum amount of CH₂Cl₂ (approximately 15 mL), charged on a column (8 × 16 cm) containing 400 g of silica gel and eluted with ethyl acetate-petroleum ether (30:70, 1 L) to afford recovered diamine 2 (8.40 g, 96%), and then with AcOEt-petroleum ether (50:50, 2 L) to afford title compound 5 (6.20 g, 87 %).