Process for preparing optically active 2-[6-(hydroxy-methyl)-1,3-dioxan-4-yl] acetic acid derivatives

#The present invention relates to a production process of pharmaceutical intermediates, particularly optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives of value as intermediates of HMG-CoA reductase inhibitors.

#The hitherto-known technology for producing 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives includes the following processes. (1) A process starting with 3-hydroxy-γ-butyrolactone to synthesize a 3,5,6-trihydroxyhexanoic ester derivative via a 3,5-dihydroxyhexanoic ester derivative (JP-A-04-173767). (2) A process starting with 3,4-dihydroxybutyronitrile acetonide to synthesize a 3,5,6-trihydroxyhexanoic ester derivative via a 3,5-dihydroxyhexanoic ester derivative (JP-A-02-262537). (3) A process starting with a 4-chloroacetoacetic acid ester to synthesize a 3,5,6-trihydroxyhexanoic ester derivative through benzyloxylation, reduction, chain extension and like steps. (JP-A-06-65226). (4) A process starting with a 4-chloro-3-hydroxybutyric ester to synthesize a 3,5,6-trihydroxyhexanoic ester derivative through chain extension, reduction and like steps. (U.S. Pat. No. 5,278,313). (5) A process starting with malic acid to synthesize a 3,5,6-trihydroxyhexanoic ester derivative via a 2,4-dihydroxyadipic acid derivative (JP-A-04-69355).

#However, these processes involve ultra-low temperature reactions around −80° C. in some stage or other of the respective production processes (1, 2, 4 and 5) or a high-pressure hydrogenation reaction requiring a pressure of as high as 100 kg/cm2 (3), thus invariably requiring extraordinary reaction equipment. Moreover, expensive starting materials are used in some or other stages, so that none of the processes are efficient enough for industrial-scale production.

#The following examples are intended to illustrate the present invention in further detail without defining the scope of the invention.

#To 21.3 mL (35 mmol) of a solution of n-butyllithium in hexane (1.5 mol/L) was added a solution of diisopropylamine (3.54 g, 35 mmol)-tetrahydrofuran (10 mL) dropwise under stirring at 5° C., and the mixture was stirred under argon for 1 hour to prepare a lithium diisopropylamide solution. After this solution was cooled to −70° C., 4.06 g (35 mmol) of tert-butyl acetate was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. Then, 1 mL of a solution of (S)-β-hydroxy-γ-butyrolactone (1.02 g, 10 mmol) in THF was added dropwise and the whole mixture was stirred at −70° C. for 2 hours, at the end of which time the temperature was increased to −10° C. In a separate vessel, 60 mL of 1N-hydrochloric acid and 60 ml of diethyl ether were stirred to mix and the above reaction mixture was poured therein. The aqueous phase was adjusted to pH 6.5 with 1N-hydrochloric acid and, after standing, the organic layer was separated. The aqueous layer was further extracted with 3 portions of ethyl acetate, 50 mL each, and the organic layers were pooled and dehydrated over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Kieselgel 60, product of 1.56 g of (5S)-5,6-dihydroxy-3-oxohexanoic tert-butyl ester (yellow oil) was obtained. Yield: 71%.

#1H-NMR (CDCl3, 400 MHz/ppm); 1.48 (9H,s), 2.68–2.83 (2H, m)m, 3.05–3.80 (2H, bs), 3.42 (2H, s), 4.02–4.17 (2H, m), 4.40 (1H, m) 13C-NMR (CDCl3, 400 MHz/ppm); 27.8, 45.7, 51.0, 65.6, 68.0, 82.3, 166.4, 203.4 IR (neat); 3425, 3000, 1710, 850 cm−1 [α]D20=−17.25 (c=2.14, MeOH).