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Purification / work up; |
Crude 2h was recrystallized in a 500 ml 3-neck flask by the following procedure. 15 g of 2h was dissolved in 84 ml of NMP and stirred for 10 minutes at 200C. The mixture was heated to 48C, then MeOH (67.5 ml) was added dropwise over 20 minutes using a syringe pump and the mixture seeded with 0.15 g of EPO <DP n="64"/>crude 2h. The mixture was stirred at 480C for 10 minutes, during which time a thin slurry results. Additional MeOH (88.5 ml) was added dropwise using a syringe pump over 90 minutes at 48C. After completed addition, the reactor was cooled to 00C over 5 hours and further stirred at 00C for 1 hour. The suspension was filtered, washed 2 times with MeOH (150 ml each) wherein each wash was stirred for 1 hour at ambient temperature and then pressed dry using nitrogen. The solid was dried at 500C in a house vacuum oven for 5 hours to give 11.7 g of S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate 2h (78% recovery, 99.93% a/a) as a white crystalline solid with consistent 1H NMR (500 MHz, de-DMSO) : 8.90 (br, IH); 8.75 (br, IH); 8.35 (s, IH); 7.75 (t, IH); 7.60 (d, IH); 7.50 (d, IH); 7.41 (s, IH); 7.38 (m, IH); 7.33 (m, IH); 7.25 (t, IH); 7.05 (d, IH); 6.85 (d, IH); 5.15 (m, IH); 4.15 (d, 2H); 3.90 (s, 3H); 3.77 (m, 2H); 3.70 (m, 2H); 2.10 (m, IH); 1.90 (m, IH) ppm. Crude 2h was recrystallized in a 500 ml 3-neck flask by the following procedure. 15 g of 2h was dissolved in 84 ml of NMP and stirred for 10 minutes at 200C. The mixture was heated to 48C, then MeOH (67.5 ml) was added dropwise over 20 minutes using a syringe pump and the mixture seeded with 0.15 g of crude 2h. The mixture was stirred at 48C for 10 minutes, during which time a thin slurry results. Additional MeOH (88.5 ml) was added dropwise using a syringe pump over 90 minutes at 48C. After completed addition, the reactor was cooled to 00C over 5 hours and further stirred at 00C for 1 hour. The suspension was filtered, washed 2 times with MeOH (150 ml each) wherein each wash was stirred for 1 hour at ambient temperature and then pressed dry using nitrogen. The solid was dried at 500C in a house vacuum oven for 5 hours to give 11.7 g of S) -tetrahydrofuran-3-yl 3- (3- (3-methoxy-4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate 2h (78% recovery, 99.93% a/a) as a white crystalline solid with consistent 1H NMR (500 MHz, d6-DMSO) : 8.90 (br, IH); 8.75 (br, IH); 8.35 (s, IH); 7.75 (t, IH); 7.60 (d, IH); 7.50 (d, IH); 7.41 (s, IH); 7.38 (m, IH); 7.33 (m, IH); 7.25 (t, IH); 7.05 (d, IH); 6.85 (d, IH); 5.15 (m, IH); 4.15 (d, 2H); 3.90 (s, 3H); 3.77 (m, 2H); 3.70 (m, 2H); 2.10 (m, IH); 1.90 (m, IH) ppm. |
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In 1,1,1,3',3',3'-hexafluoro-propanol;Purification / work up; |
Example 4 Crystallization Experiments with Compound 1 Table 2 below provides a summary of crystallization experiments carried out on Compound 1 using various solvents and conditions described herein. The resulting Form A1 or amorphous form obtained were dried in vacuo then analyzed by XRPD. |