Ammonia → (S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one

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Reaction Steps

11 g of Mg turnings (452 mmol) are placed into a reactor. A solution of 93.2 g 4-bromobiphenyl (400 mmol), dissolved in 380 ml THF is added. Formation of the corresponding Grignard reagent starts after the addition of 5% of the total volume of the above solution and after the addition of a 10 mg I2. The THF solution of the 4-bromobiphenyl is added at such a rate, that the IT can be kept at 50-55° C. (duration of the addition: 1 h). After the addition is complete, the reaction mixture is heated to reflux for 1.5 h. Then the mixture is cooled to rt, and next 800 ml THF are added, followed by 22 g 1,4-dioxane. Then the mixture is cooled in an ice bath and 18.0 g CuCN (200 mmol) are added. The reaction mixture is then cooled to −40° C. and then over 40 minutes a solution of 27 g (100 mmol) toluene-4-sulphonic acid-(S)-5-oxo-pyrrolidin-2-ylmethyl ester in 270 ml THF is added. After complete addition of the tosylate solution, the mixture is heated for 0.5 h to IT 35° C. The reaction mixture is stirred at that temperature overnight. Then, the reaction mixture is cooled to 20° C. and 200 ml 25% NH3 (aq), followed by 900 ml NH4C129% (aq) are added. The phases are separated and the aqueous phase is re-extracted with 250 ml THF. The combined organic phases are washed twice with 200 ml 15% NaCl solution and are concentrated in vacuo to give 74.5 g of crude product. This crude product is purified twice over silica gel (eluent: toluene:methanol 93:7), to yield (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)] Spectroscopic data as in Example 3.

Provenance & Evidence