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Example 24 Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; bis(L-Proline) cocrystal [0338] This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; L-Proline; L-Proline. RRN 148Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol [0339] (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (6.54 g) and n-heptane (10.2 mL), and stirred for 10 min under argon sparging. The mixture was cooled to -30 C. to -20 C. under nitrogen atmosphere. The solution was added to a suitable cooled addition funnel and was kept ready for addition to the aryl magnesium. [0342] Aryl Magnesium Formation. [0343] A 4-neck 100 mL flask bottle equipped with a thermometer, mechanical stirrer, condenser and addition funnel was purged with nitrogen and was charged with anhydrous THF (7 mL) and <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> (3.73 g, 10 mmol). After stirring and sparging with nitrogen for 30 min at ambient temperature, the mixture was cooled to -60 C. under nitrogen atmosphere. To the solution was added iPrMgCl.LiCl (Aldrich, titrated concentration 12.9% wt/wt, 7.58 g) (0.95 eq. by titration) via a suitable addition funnel at such a rate that the temperature was maintained between -50 C. and -60 C. in 30 min under nitrogen atmosphere. The mixture was stirred for an additional 10 min at -60 to -50 C. The conversion of <strong>[1103738-29-9]1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene</strong> to the aryl magnesium was monitored by quenching an aliquot with saturated ammonium chloride aqueous solution and the aliquot was extracted with ethyl acetate and was analyzed via HPLC-0001. [0344] Aryl Magnesium Coupling to Give an Anomeric Hemiketal. [0345] The cold gluconolactone solution in a cooled (25 C.) addition funnel was added dropwise to the aryl magnesium solution at such a rate as to maintain the temperature between -50 C. and -60 C. for over 40 min. After the addition was completed, the mixture was stirred for 5 h at -50 to -60 C. [0346] The reaction was slowly quenched with nitrogen-sparged (10 min) saturated ammonium chloride aqueous solution (30 g) at -15 C. to 0 C. via an addition funnel over 20 min. The mixture was allowed to warm to 10 to 15 C. over 2.5 h and stirred for over 10 h. The upper organic layer was separated. Deionized water (10 g) was added to the aqueous layer. The aqueous phases were extracted with ethyl acetate (3×15 mL). The organic layers were combined and washed with deionized water (20 mL) and brine (16.7% w/w, 20 g). The ethyl acetate layer was treated with activated charcoal (1.32 g, 30% w/w based on the weight of expected (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol, CX-700 from Zhuxi Co.) for 1 h at 20 C. followed by filtration over filter paper. The organic layer was concentrated at a temperature 35 C. under vacuum (0.01 MPa) until the rate of solvent condensation almost stopped. Methanol (10 mL) was added and the mixture was re-concentrated at 35 C. under vacuum (0.01 MPa) until the rate of solvent condensation almost stopped. |
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