|
With copper(II) sulfate; at 20 - 25℃; for 16.0h;Industry scale;Product distribution / selectivity; |
L-xylose 1 (1000 g, 6.66 moles, 1 eq), acetone (10 L), copper sulfate (1.33 kg, 8.3 moles, 1.25 eq), and Amberlyst0 15 resin (1000g) were combined in a 22 L round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet/outlet. The reaction was stirred under nitrogen at room temperature for 16 hours. TLC (100% ethyl acetate, visualization with phosphomolybdic acid (PMA) ) showed no starting material (Rf-0. 05). 750 g of solid sodium carbonate was added and stirred for 30 minutes. The solution was filtered through Celite0 (diatomite, World Minerals Inc., Santa Barbara, CA) to remove solids. The filtrate was concentrated to an oil under vacuum to yield 1.4 kg of a clear oil. 1H NMR confirmed absence of L-xylose 1. The oil was then dissolved in 7 L of a 4: 1 methanol/water solution. While stirring, 1.4 kg of Amberlyst0 15 resin was added at room temperature. The solution was stirred at room temperature until TLC (100% ethyl acetate, visualization with PMA) showed the absence of di-protected xylose 2 (Rf-0. 75). The solution was filtered and the filtrate was brought to pH 8 with solid sodium bicarbonate (approximately 20 g). The solvent was removed under vacuum at 50% to yield 1160 g of a light oil. The oil was triturated with 10 L of a 3: 2 dichloromethane/ethyl acetate solution and dried over sodium sulfate. The dried solution was then filtered through Celite0 and concentrated under vacuum to yield 1055 g (83%) of 3. 1H NMR and TLC confirmed structure.; Preparation of Acetal 3 A reaction vessel was charged with L-xylose 1 (1.0 wt, 1.0 mol eq) and acetone (7.9 wt, 10.0 vol). The resultant slurry was stirred vigorously and anhydrous copper sulfate (1.33 wt) was added while maintaining the reaction temperature below 25C. Amberlyst0 15 resin (1.00 wt) was then added while maintaining the reaction temperature below 25C. The resulting mixture was stirred vigorously at 20-25C until the reaction to form 2 was deemed complete by 1H NMR (<1 mol % L-xylose 1 remaining, typically about 16 hours). The mixture was then filtered through Celite (X3 and the filtrate transferred via a 1 jim filter to a second vessel. The filter cake was washed with acetone (2 x 1. 58 wt, 2 x 2.0 vol) and the combined filtrates were transferred to a second vessel containing sodium carbonate (0.5 wt). The resulting mixture was stirred vigorously for 30-40 minutes, after which it was verified that the supernatant liquid in water had pH > 7. The mixture was then concentrated by vacuum distillation at up to 30C to ca 5 vol. Industrial methylated spirits (IMS, 2.02 wt, 2.5 vol) was then charged to the vessel and the resulting mixture was concentrated to ca 5 vol under vacuum at 25-30C. A further portion of IMS (2.02 wt, 2.5 vol) was charged to the vessel and the resulting mixture was distilled under vacuum at 25-35C to ca 5 vol. The IMS charge and distillation was repeated once more. 1H NMR was used to verify that the sample contained less than 1 mol % of acetone with respect to ethanol. The mixture was then filtered and the filter cake washed with IMS (1.62 wt, 2.0 vol). The combined filtrate and wash were heated to 25-30C, and a 1.2 M HC1 solution (0.34 vol) was added while maintaining the reaction temperature at 25-30C. The pH at this point was <1. The reaction mixture was stirred until deprotection to form compound 3 was deemed complete by 1H NMR (>94 mol% product 3, typically about 4 hours). The resulting mixture was transferred to a separate vessel, which contained a slurry of sodium bicarbonate (1.0 wt) in IMS (1.61 wt, 2.0 vol), while maintaining the temperature at 20-30C. The resulting mixture was stirred for 30-40 minutes, after which it was verified that the supernatant liquid in water had pH > 7. The mixture was concentrated by vacuum distillation at up to 35C to ca 4 vol. Toluene (4.31 wt, 5.0 vol) was then charged to the vessel, and the resulting mixture was concentrated to ca 4 vol in vacuo at 25-35C. A further portion of toluene (4.31 wt, 5.0 vol) was charged to the vessel, and the vessel contents were concentrated to ca 4 vol total in vacuo at 25- 35C. 1H NMR was used to verify that the sample contained <1 mol% ethanol (IMS) with respect to toluene. Tertiary butyl methyl ether (TBME) (2.96 wt, 4.0 vol) was then charged to the vessel, and 1H NMR analysis was performed to verify that the toluene/TBME molar ratio was 1: 1. The resultant mixture was stirred for 30-40 minutes before being filtered, and the filter cake was washed with TBME (1.48 wt, 2.0 vol). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
