2-Methyltetrahydrofuran → KNI-1317

Temperature

75 °C

MeOH (330 mL) and K2CO3 (66.9 g; 484 mmol) were sequentially added to a 2-methyltetrahydrofuran solution of crude acetic acid 3-{(1S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester (theoretical amount: 405 g; 731 mmol) in a 3-L flask at room temperature. Two and a half hours later, additional K2CO3 (20 g; 144 mmol) was added. Three hours later the reaction mixture was vacuum-filtered on a pad of Celite, using 4:1 2-methyltetrahydrofuran/MeOH (330 mL) for rinsing over the solids and washing the filter cake. The filtrate was transferred to a 6-L separatory funnel, using 4:1 2-methyltetrahydrofuran/MeOH (80 mL) for rinsing. The solution was diluted with i-PrOAc (1.66 L) and was then washed with a solution of NaCl (83.0 g) in H2O (1.60 L). The organic fraction was washed with 0.5 N HCl (1.66 L) and then with a saturated aqueous NaCl solution (400 mL). The resulting organic fraction was transferred to a 4-L Erlenmeyer flask and MgSO4 (120 g) was added. After stirring for 10 min, the mixture was vacuum-filtered directly into a 5-L distillation flask, using 2:1 i-PrOAc/2-methyltetrahydrofuran (600 mL) for rinsing the separatory funnel and Erlenmeyer flask and washing the MgSO4. The 2-methyltetrahydrofuran was displaced by distillation at one atmosphere with the simultaneous addition of i-PrOAc in five portions (a total of 3.60 L was used), while maintaining a minimum pot volume of ˜2.50 L. The resulting crystallizing mixture was cooled to 75° C. and was held at this temperature for 30 min. The suspension was then allowed to slowly cool to room temperature overnight. The suspension was vacuum-filtered, using i-PrOAc (600 mL) for transferring and washing the crystals. After drying in a vacuum oven at 40° C., 204 g (54% from (2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid) of crystalline (4R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide was obtained. This material was recrystallized as described below.

1. filtrationThree hours later the reaction mixture was vacuum-filtered on a pad of Celite
2. washfor rinsing over the solids
3. washwashing the filter cake
4. customThe filtrate was transferred to a 6-L separatory funnel
5. washfor rinsing
6. additionThe solution was diluted with i-PrOAc (1.66 L)
7. washwas then washed with a solution of NaCl (83.0 g) in H2O (1.60 L)
8. washThe organic fraction was washed with 0.5 N HCl (1.66 L)
9. additionwas added
10. filtrationthe mixture was vacuum-filtered directly into a 5-L distillation flask
11. washfor rinsing the separatory funnel and Erlenmeyer flask
12. washwashing the MgSO4
13. distillationThe 2-methyltetrahydrofuran was displaced by distillation at one atmosphere with the simultaneous addition of i-PrOAc in five portions (a total of 3.60 L
14. temperaturewhile maintaining a minimum pot volume of ˜2.50 L
15. customThe resulting crystallizing mixture
16. waitwas held at this temperature for 30 min
17. temperatureto slowly cool to room temperature overnight
18. filtrationThe suspension was vacuum-filtered
19. washwashing the crystals
20. customAfter drying in a vacuum oven at 40° C.

ORD record

ord-9ef142b4405d418babb2ae5b893aa8a0

Source dataset

uspto-grants-2007_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07169932B2