Hydride Reduction of a Lactate Ester: Optimisation and Scale-Up

The two-step synthesis of (2S)-2-(tetrahydropyran-2-yloxy)propane-1-ol was selected for fine chemical scale-up. The first step, an acid-catalyzed protection of ethyl (S)(−)-lactate with 3,4-dihydro-2H-pyran, could be performed without solvent. The reaction enthalpy was determined to be −48 kJ/mol ethyl (S)(−)-lactate, ensuring safe scale-up. The crude reaction mixture was used in the second step, the hydride reduction. For the reduction of the protected ester a clear solution of 1 M LiAlH4 in THF was used. The reaction enthalpy was determined to be −313 kJ/mol ethyl (2S)-2-(tetrahydropyran-2-yloxy)propionate, and the work-up was optimised with experimental design techniques. Combination of all experimental and theoretical results resulted in a master recipe for a 10-dm3 scale synthesis of (2S)-2-(tetrahydropyran-2-yloxy)propane-1-ol.