Hydrochloric Acid → (R)-Solketal

A solution of 1a (4.1 g, 19 mmol) in ethanol (350 ml) was added over 1 h to a stirred solution of NaBH4 (0.72 g, 19 mmol) in ethanol (50 ml). The slightly cloudy solution was then stirred at rt for an additional 4 h, during which the pH of the reaction mixture was made basic by the addition of NaOH followed by the addition of aqueous NaOH (1 N; 50 ml). The mixture obtained was stirred overnight at rt, and the pH was then adjusted precisely to neutral by the dropwise addition of concentrated aqueous HCl under vigorous stirring. The solvents were removed in vacuo adding ethanol several times in order to remove residues of water by azeotropic distillation until a dry, white and powdery solid was obtained, which was mixed with ethyl acetate (200 ml) and cooled to 0° C. Lead tetraacetate (recrystallized from acetic acid; 29.5 g, 0.66 mol) was added in one portion. The resulting brown to yellow slurry was stirred 1-1.5 h at 0° C. and then 1-2 h at rt. After cooling to 0° C. the slurry was filtered through a pad of Celite®. The filtrate was cooled again and the cold, yellow solution was then added over 30 min to a cooled solution of NaBH4 (7.2 g, 19 mmol) in EtOH (150 ml), which turned dark grey upon the addition of the ethyl acetate solution and might need occasional addition of EtOH to aid stirring and minimize foaming. After the addition was completed the grey solution was allowed to warm to rt while stirring for 2-2.5 h, then made basic by adding NaOH followed by aqueous sodium hydroxide (1 N, 100 ml). The mixture obtained was stirred for 30 min at rt, then diethyl ether (100 ml) was added, the layers were separated, and the aqueous layer was extracted with diethyl ether (2×50 ml). The combined organic layers were washed with brine (25 ml), dried (NaSO4) and concentrated under reduced pressure at rt to a volume of about 50 ml. Diethyl ether (100 ml) was added, the aqueous phase was saturated with NaCl, and the layers were separated. The aqueous layer was extracted with diethyl ether (4×50 ml). The combined organic layers were dried (NaSO4) and concentrated. Any residual water was then distilled off by forming an azeotrope with acetone (25, ml) and (R)-glycerol acetonide 1 (1.32 g, 53%) was obtained as a clear liquid. The product was further purified by flash column chromatography (50 g of silica gel; elution with DCM (350 ml) removed impurities; 5% methanol-DCM (500 ml)) to yield (R)-glycerol acetonide 1 (1.26 g, 97%); νmax 3420, 2950, 1380, 1260, 1215, 1160, 1050 cm−1; δH (250 MHz, CDCl3) 3.6-4.4 (m, 5H, CHO), 2.95 (br s, 1H, OH), 1.43 (s, 3H, CH3), 1.38 (s, 3H, CH3); a sample of 184 mg was distilled (24° C. (0.5 torr)) to yield 169 mg of a clear liquid which was dissolved in 1.00 ml of MeOH for measurement of optical rotation: [α]24.8D−10.76 (literature (Jung, M. E.; Shaw, T. E., J. Am. Chem. Soc. 102:6304-6311 (1980)): [α]D+10.7 for opposite enantiomer, [α]D−13.2 for neat sample), [α]578−11.27, [α]546−12.99, and [α]436−23.59.

1. customThe mixture obtained
2. stirringwas stirred overnight at rt
3. customThe solvents were removed in vacuo
4. additionadding ethanol several times in order
5. customto remove residues of water
6. distillationby azeotropic distillation until a dry
7. customwhite and powdery solid was obtained
8. temperaturecooled to 0° C
9. stirringThe resulting brown to yellow slurry was stirred 1-1.5 h at 0° C.
10. custom1-2 h
11. customat rt
12. temperatureAfter cooling to 0° C. the slurry
13. filtrationwas filtered through a pad of Celite®
14. temperatureThe filtrate was cooled again
15. stirringto aid stirring
16. additionAfter the addition
17. temperatureto warm to rt
18. stirringwhile stirring for 2-2.5 h
19. customThe mixture obtained
20. stirringwas stirred for 30 min at rt
21. customthe layers were separated
22. extractionthe aqueous layer was extracted with diethyl ether (2×50 ml)
23. washThe combined organic layers were washed with brine (25 ml)
24. dry with materialdried (NaSO4)
25. concentrationconcentrated under reduced pressure at rt to a volume of about 50 ml
26. additionDiethyl ether (100 ml) was added
27. customthe layers were separated
28. extractionThe aqueous layer was extracted with diethyl ether (4×50 ml)
29. dry with materialThe combined organic layers were dried (NaSO4)
30. concentrationconcentrated
31. distillationAny residual water was then distilled off
32. customby forming an azeotrope with acetone (25, ml)

ORD record

ord-bb173f23b04c469c9ad28cfbead39020

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07465817B2