反式-1-苯甲酰基-4-羟基-L-脯氨酸甲酯

反应条件: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester prepared as described in Example 1 Part A(2) (6 g, 24.1 mmole) was dissolved in dichloromethane and cooled to -45° C. under an argon atmosphere. To the above solution diethylaminosulfur trifluoride (5.2 ml, 42 mmole) was added dropwise. The resulting solution was stirred and warmed to -35° C. To the above solution pyridine was added dropwise (9 ml, 116 mmole). The reaction was allowed to stir overnight while warming to room temperature. The solvent was removed in vacuo and the oily residue treated with ethyl acetate and 1N HCl. The mixture was transferred to a separatory funnel, the aqueous layer removed, and the organic layer washed with additional 1N HCl, then water and saturated sodium bicarbonate solution. The organic solution was dried over sodium sulfate, filtered and concentrated to a yellow oil. The crude product was chromatographed on silica gel using 1:1 ethyl acetate:hexane as eluent. Combination and concentration of product containing fractions produced 3.9 gm (64%) of title compound as an oil. warmed to -35° C to stir overnight while warming to room temperature The solvent was removed in vacuo the oily residue treated with ethyl acetate and 1N HCl The mixture was transferred to a separatory funnel the aqueous layer removed the organic layer washed with additional 1N HCl The organic solution was dried over sodium sulfate filtered concentrated to a yellow oil The crude product was chromatographed on silica gel using 1:1 ethyl acetate Combination and concentration of product containing fractions

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 540 Grams (2.84 moles) of technical p-toluenesulfonyl chloride were charged to a 5 liter flask. 1.5 Liters of anhydrous pyridine was added and the flask swirled to dissolve. Gradually, 600 g (2.40 moles) of (trans)-1-benzoyl-4-hydroxy-L-proline methyl ester were added and dissolved by swirling. The clear solution was maintained at room temperature and the conversion followed by TLC. After the starting material completely disappeared, the reaction mixture was transferred to a 12 liter beaker with an efficient agitator. 0.8 Liters of ice water and some tosylate seeds were added. Thick crystal slurry formed in about 10 minutes. Strong agitation was maintained and another 7 liters of an ice-water mixture were added over a period of one hour. The crystals were collected on a filter, the cake pressed down and washed with cold water until the effluent was free of chloride ions and suction applied to the cake until no more liquid emerged. The filtrate was discarded and the product dried to constant weight. to dissolve dissolved Thick crystal slurry formed in about 10 minutes Strong agitation was maintained The crystals were collected on a filter washed with cold water until the effluent the product dried to constant weight

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A 5-liter flask was installed in an oil bath on a magnetic stirrer, provided with a reflux condenser and charged with 3.0 liters of methanol and 750 g (3.2 moles) of (trans)-1-benzoyl-4-hydroxy-L-proline. 19 grams of p-toluenesulfonic acid monohydrate (0.1 moles) were added. The mixture was heated to reflux and the esterification followed by TLC. Refluxing was continued until starting material was no longer detectable. 8 grams (0.1 moles) of sodium acetate was added to neutralize the catalyst acid. The condenser was set for distillation and the mixture concentrated at atmospheric pressure until the pot temperature reached 80° C. The distillate was then discarded. The clear residue was rapidly diluted with 2 liters of warm water. The flask was swirled for quick mixing and to permit the ester to crystallize. The slurry was cooled to room temperature with occasional swirling and maintained at room temperature for at least another hour. The crystals were collected on a filter and the filtrate recycled to aid in the transfer. The cake was pressed down and washed with one liter of cold water. The cake was sucked dry as possible and the product dried via a laboratory fluid bed dryer to constant weight. The combined filtrate was vacuum concentrated from the first crop to a small volume and the resulting slurry cooled to room temperature. A second crop of crystals was collected on a filter and washed with a minimum of cold water. The cake was pressed down and suction applied until no more liquid emerged. The second crop was dried to constant weight. A 5-liter flask was installed in an oil bath on a magnetic stirrer provided with a reflux condenser The mixture was heated to reflux Refluxing The condenser was set for distillation the mixture concentrated at atmospheric pressure until the pot temperature reached 80° C The clear residue was rapidly diluted with 2 liters of warm water for quick mixing to crystallize maintained at room temperature for at least another hour The crystals were collected on a filter washed with one liter of cold water The cake was sucked dry as possible and the product dried via a laboratory fluid bed dryer to constant weight concentrated from the first crop to a small volume the resulting slurry cooled to room temperature A second crop of crystals was collected on a filter washed with a minimum of cold water The second crop was dried to constant weight