Process Development of (1S,2S,5R,6S)- Spiro[bicyclo[3.1.0]hexane-2‘,5‘-dioxo-2,4‘-imidazolidine]-6-carboxylic Acid, (R)-α-Methylbenzenemethanamine Salt (LSN344309)

Process development and a pilot-plant process for the synthesis of 4 and its resolution to obtain (1S,2S,5R,6S)-spiro[bicyclo-[3.1.0]hexane-2',5'-dioxo-2,4'-imidazolidine]-6-carboxylic acid, (R)-alpha-methylbenzenemethanamine salt (5) are described. Starting from the inexpensive raw 2-cyclopenten-1-one and sulfur ylide 1 the racemic bicyclo keto ester 2 was synthesized. Reaction of 2 with potassium cyanide and ammonium carbonate under Bucherer-Berg's reaction conditions affords racemic 3 in 80% yield. Hydrolysis of 3 followed by the resolution with (R)-(+)-alpha-methylbenzylamine gave 4 in excellent yield and purity under optimized conditions. The improvement of the original discovery process to accommodate safety and environmental requirements for scale-up in manufacturing facilities is also discussed.