General procedure for the synthesis of 5-hydroxy-4-propyl-2(5H)-furanone from n-pentanal and 2-oxoacetic acid (example of an industrial batch): the amounts of all materials were calculated based on the amount of glyoxalic acid in 50% w/w glyoxalate solution.
(0050) Heptane (1285 kg, 1889 L, 4.04 v/v) and morpholine (595 L, 601.3 kg, 6902 mol, 1.09 equiv) were added to the reactor. After the addition of morpholine, the dosing equipment was flushed with heptane (20 L, 0.04 v/v). The mixed solution was stirred at 22-23 °C for 10 min and subsequently cooled to 4.4 °C.
(0051) A 50% aqueous solution of glyoxalate (935 kg, 6318 mol, 1.0 eq.) was slowly added, controlling the rate of addition to keep the reaction temperature below 40 °C. Upon completion of addition, the addition equipment was flushed with heptane (20 L, 0.04 v/v). The reaction mixture was stirred at a temperature range of 30.9 to 23.8 °C for 2 hours. Subsequently, n-pentanal (706 L, 576.8 kg, 6697 mol, 1.06 eq.) was slowly added, again controlling the rate of addition to keep the temperature below 40 °C.
(0052) Upon completion of n-pentanal addition, the addition equipment was flushed with heptane (40 L, 0.08 v/v). The material in the reactor was heated to 40.1-41.7 °C and the reaction was maintained at this temperature for 18 hours and 04 minutes. Upon completion of the reaction, the mixture was cooled to 22.8 °C and aqueous hydrochloric acid (1168 L, 1.73 eq.) was slowly added at this temperature, controlling the rate of addition to maintain the temperature between 23.5-25.0 °C. The reaction was then purged by stirring. After completion of acid addition, the reaction mixture was continued to be stirred for 4 hours.
(0053) The reaction mixture was allowed to stand to separate the organic phase after layering. The aqueous phase was washed three times with heptane (3 x 943 L, 3 x 2 v/v). Diisopropyl ether (1322 kg, 1888 L, 4.04 v/v) was added to the aqueous phase, followed by the addition of solid sodium carbonate (199 kg) in batches until the pH reached 0.4. After standing and stratifying the mixture, the organic phase was separated. The target compound (II) was extracted from the aqueous phase with diisopropyl ether (2 × 530 kg, 2 × 756 L, 2 × 1.6 v/v). All organic phases were combined and washed once with 20% w/w aqueous sodium chloride solution (944.2 kg, 1.6 v/v). Subsequently, the organic layer was dried by azeotropic distillation under vacuum (jacket temperature not exceeding 40 °C) and filtered. Finally, the solution was concentrated under vacuum below 40 °C and filtered by polishing through a 10 μm cartridge filter. Correction for water content (3.7%) and DIPE content (3.8%) based on the total mass of water (934.9 kg) resulted in 864.8 kg of compound (II) (6084 mol, 96.3% yield).
