| 83% |
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide; In dichloromethane; water; at -15 - 5℃; for 1h;Large scale; |
0.02 g of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy free radical), 0.96 g of potassium bromide, 18.6 g of sodium hydrogencarbonate and 50 ml of methylene chloride were placed in a 500 ml flask, Stirred at ~ 5 C.After dissolving 11.64 g (44.71 mmol) of t-butyl 2 - [(4R, 6S) -6-hydroxymethyl-2,2-dimethyl- 1,3-dioxane- 4-yl] acetate in 50 ml of methylene chloride , Added to the above reaction. After cooling the reaction product to -15 C. or lower, 36.6 ml (53.65 mmol, 1.2 equivalent) of a 10.9% (w / w) sodium hypochlorite aqueous solution was added dropwise at once. After the dropwise addition, stirring was carried out at 0 C. for 1 hour, the reaction progress degree was checked by gas chromatography (GC), the reaction product was filtered under reduced pressure, 10% sodium thiosulfate solution (10 w / w% sodium thiosulfate solution) 100 ml was added and the organic layer was separated. 100 ml of a saturated sodium chloride solution was added to the organic layer, and the organic layer was further separated. After adding 150 ml of water to the organic layer and stirring for 10 minutes, the stagnant organic layer was separated, dried over anhydrous magnesium sulfate, filtered, methylene chloride as an organic solvent was distilled under reduced pressure at 40 C. and 3 cmHg for 10 minutes To obtain a concentrated residue 1 as an oil phase (step A).The concentrated residue 1 was adjusted to a pressure of 3 cmHg in a vacuum vacuum dryer and dried for 30 minutes at 80 C. without separately adjusting the humidity to obtain the title compound as pale brown crystals (Step B) . (The XRD graph of the product is shown in Figure 1 and its value is as shown in Figure 2. The DSC value of the product is shown in Figure 3.) Yield of product 83% (8.2kg) |
| 65% |
With sodium hydrogencarbonate; |
The reaction vessel was charged with t-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2,2-dimethyl-1,3-dioxan- 6.7 L), & lt; / RTI & gt;The mixture was cooled to -15 [deg.] C and sodium bicarbonate (NaHCO3, 487 g, 5.8 mol) was added to the mixture.Pay attention to heat generation. Sodium bromide (NaBr, 131g, 1.3mol) is added temporarily and then sodium hypochlorite (NaOCl, 798ml, 1.42mol) is gradually added while maintaining the temperature below -10 C.PIPO-TEMPO (0.001 equivalent, 0.838 g, 0.0013 mol) is dissolved in toluene solvent (300 ml), and the solution is slowly dropped to -5 C. When the reaction was completed, Na2S2O3 (1.5 L) was added thereto, and the mixture was stirred at room temperature for 20 minutes to terminate the reaction,The organic layer is recovered by layer separation. The aqueous layer was further washed twice using a toluene solvent (1 L), and the recovered organic layer was subjected to anhydrous treatment with Na2SO4 and filtered.The obtained organic layer was concentrated under reduced pressure to obtain a solid product, which was then recrystallized with heptaneThe title compound of Formula 2 was obtained as a high purity solid (199 g, yield 65%, very pale yellow solid, GC analysis:> 98%). |
| 54% |
With sodium hypochlorite; TEMPOL; sodium hydrogencarbonate; potassium bromide; In water; ethyl acetate; at -10 - 5℃; for 1h;Inert atmosphere; |
Reference Example 2: tert-Butyl 2-[(4R,6S)-6-formyl-2,2-dimeihyl-1, 3-dioxane-4-yl] acetate [Show Image] To a dispersion of tert-butyl 2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-1,3-dioxane-4-yl] acetate (15 g, 57.6 mmol), sodium hydrogencarbonate (13.6 g, 161.3 mmol), potassium bromide (1.37 g, 11.5 mmol) and 4-hydroxy-2, 2, 6, 6-tetramethylpiperidine-1-oxyl free radical (248 mg, 1.44 mol) in ethyl acetate (150 ml), an aqueous solution of sodium hypochlorite (44.2 g, 16.7wt%, 70.2 mmol) was added under nitrogen stream at -10C carefully dropwise to keep the inner temperature within 5C. After the dropwise addition, the mixture was stirred at 0C for 1 hour and the aqueous layer was separated. The organic layer was further diluted with ethyl acetate (100 ml), and sequentially washed with a 5% sodium thiosulfate aqueous solution (75 ml) and water (40 ml × 2). Then, the organic layer was dried with anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained crude product was purified with silica gel column chromatography (silica gel: 200 g, developing solvent: hexane / ethyl acetate = 2 / 1 by volume) to obtain the title compound (8.0 g, yield: 54%) as white crystals. 1H-NMR (CDCl3): delta1.35(1H, q, J=12.7Hz), 1.45 (9H, s), 1.46 (3H, s), 1.49(3H, s), 1.83(1H, dt, J=2.7Hz, 12.9Hz), 2.35(1H, dd, J=5.9Hz, 15.4Hz), 2.46(1H, dd, J=7.1Hz, 15.4Hz), 4.33(1H, m), 9.58 (1H, s) |
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With sodium hypochlorite; sodium hydrogencarbonate; potassium bromide;4-oxo-2,2,6,6-tetramethylpiperidin-oxyl; In dichloromethane; water; at 0 - 5℃; for 1 - 2h; |
2,2,6,6-tetramethyl piperidinyl oxy free radical (TEMPO) (0.2 g), potassium bromide (9.6 g) and sodium bicarbonate (90 g) were dissolved in methylene chloride (600 ml) and stirred the contents together at 0-5 C. A solution of (4R-cis)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester of Formula III (100 g) in methylene chloride (400 ml) was added to the above solution at 0-5 C. To this solution 10% sodium hypochlorite solution (159 ml) (NaOCl) was added at 0-5 C. Again sodium bicarbonate (96 g) and followed by 10% sodium hypochlorite solution was added to the reaction mass. Reaction mass was maintained for 1-2 hours at 0-5 C. and filtered through perlite. The organic layer was separated and washed with 10% sodium thiosulfate solution (250 ml), then water (250 ml) followed by saturated sodium chloride solution (250 ml). Organic layer was distilled at below 40 C. under reduced pressure to afford the title product. Yield: 95 g. |
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With sodium hypochlorite;2-azatricyclo[3.3.1.13,7]dec-2-yloxidanyl; potassium bromide; In dichloromethane; at -15 - -5℃; |
To the -15C to -5C pre-cooled reaction mixture of AZADO(0.002g), potassium bromide(0.22 g) and methylene chloride(30 ml) added 5 g of tert-butyl 2-((4R,6S)-6- (hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate. Stirred the reaction mixture for 15 minutes at -15C to -5C. 19 ml of sodium hypochlorite solution was added to the reaction mixture at same temperature. Stirred the reaction mixture for 15 minutes. Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution. 20 ml of water was added and separated the both aqueous and organic layers. Washed the organic layer with water followed by brine solution. Distilled off the solvent completely to get the title compound as a solid.Yield: 4.1 grams |
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Example-28Preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate; To the -15 C. to -5 C. pre-cooled reaction mixture of AZADO (0.002 g), potassium bromide (0.22 g) and methylene chloride (30 ml) added 5 g of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate. Stirred the reaction mixture for 15 minutes at -15 C. to -5 C. 19 ml of sodium hypochlorite solution was added to the reaction mixture at same temperature. Stirred the reaction mixture for 15 minutes. Quenched the reaction mixture with 10% aqueous sodium thiosulfate solution. 20 ml of water was added and separated the both aqueous and organic layers. Washed the organic layer with water followed by brine solution. Distilled off the solvent completely to get the title compound as a solid.Yield: 4.1 grams |
| 19.2 g |
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Preparation of Tert-Butyl 3,5-Dideoxy-2,4-O-(1-Methylethylidene)-L-Erythro-Hexuronate tert-Butyl 2,4-dideoxy-3,5-O-(1-methylethylidene)-D-erythro-hexonate (commercially available; 20 g) was added to a pre cooled (0 C. to 5 C.) mixture of 2,2,6,6-tetramethylpiperidine-1-oxyl (0.04 g), potassium bromide (1.92 g), and sodium bicarbonate (18 g) in dichloromethane (120 mL) and stirred at 0 C. to 5 C. for 15 minutes. Aqueous sodium hypochlorite (10%; 40 mL) was added slowly to the resulting mixture and stirred at 0 C. to 5 C. for 30 minutes. Sodium bicarbonate (18 g) was added to the mixture and stirred at 0 C. to 5 C. for 10 minutes, followed by the slow addition of aqueous sodium hypochlorite (10%; 40 ml) in 30 minutes at 0 C. to 5 C. The reaction mixture was stirred at 0 C. to 5 C. for 30 minutes. After completion of the reaction, the reaction mixture was filtered through hyflo bed and washed with dichloromethane (20 mL). The filtrate was washed with aqueous sodium thiosulphate (10%; 100 mL). The organic layer was separated and washed with de-ionized water (100 mL) and finally washed with aqueous solution of sodium chloride (10%; 100 mL). The organic layer was separated and concentrated under vacuum at 40 C. to give tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate. Dry weight: 19.2 g. |
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With [2,2]bipyridinyl; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; copper(l) chloride; In dichloromethane; acetonitrile; at 25 - 40℃; |
A reactor was charged with 1.1 g of copper (I) chloride and 10 mL of acetonitrile. 2-2' Bipyridyl (156 mg) and TEMPO (156 mg) were added to the reactor under oxygen environment at 25C. A solution of (6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)- acetic acid tert-butyl ester 2.6 g in 26 mL DCM was added dropwise over a period of 10 min into it. The reaction mass was stirred at 40C and progress of reaction was monitored on GLC, which shows that 90% conversion for desired product |
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