Sodium Thiosulfate → Dexlansoprazole

Under a nitrogen atmosphere, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (100 g), toluene (500 mL), water (0.23 mL) and diethyl (+)-tartrate (10.6 mL) were mixed. Under a nitrogen atmosphere, titanium (IV) isopropoxide (8.3 mL) was added to the mixture at 50° C. to 60° C., and the mixture was stirred at the same temperature for 30 min. Under a nitrogen atmosphere, diisopropylethylamine (16.3 mL) was added to the obtained mixture at 0° C. to 10° C., cumene hydroperoxide (156.8 mL, content 82%) was added at −10° C. to 10° C., and the mixture was stirred at −10° C. to 10° C. for 4 hr to give a reaction mixture. 25% Aqueous sodium thiosulfate solution (135 g) was added to ½ of the reaction mixture under a nitrogen atmosphere to decompose remaining cumene hydroperoxide. The mixture was concentrated to 230 mL, diisopropyl ether (900 mL) was added to the obtained concentrate at room temperature, and the mixture was stirred at the same temperature to allow crystal precipitation. The crystals were separated and washed successively with diisopropyl ether/n-heptane (1/1) (100 mL) and municipal water (100 mL×2) (pale-yellowish white crystals, 101.6 g). The total amount of the wet crystal was dissolved in acetone (200 mL), and the mixture was stirred for 13 min. To a mixture of acetone (75 mL) and municipal water (375 mL) was added dropwise the acetone solution over 17 min, and municipal water (525 mL) was added dropwise over 15 min. After cooling to 10° C. or below, the mixture was stirred for about 2 hr. The crystals were collected by filtration, washed with cooled acetone/municipal water (1/5, 100 mL), and then with municipal water (100 mL) to give pale-yellowish white crystals (103.2 g) of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole 1.5 hydrate.

1. stirringthe mixture was stirred at −10° C. to 10° C. for 4 hr
2. customto give a reaction mixture
3. concentrationThe mixture was concentrated to 230 mL, diisopropyl ether (900 mL)
4. additionwas added to the obtained
5. concentrationconcentrate at room temperature
6. stirringthe mixture was stirred at the same temperature
7. customcrystal precipitation
8. customThe crystals were separated
9. washwashed successively with diisopropyl ether/n-heptane (1/1) (100 mL) and municipal water (100 mL×2) (pale-yellowish white crystals, 101.6 g)
10. dissolutionThe total amount of the wet crystal was dissolved in acetone (200 mL)
11. stirringthe mixture was stirred for 13 min
12. additionTo a mixture of acetone (75 mL) and municipal water (375 mL)
13. additionwas added dropwise the acetone solution over 17 min
14. additionmunicipal water (525 mL) was added dropwise over 15 min
15. temperatureAfter cooling to 10° C. or below
16. stirringthe mixture was stirred for about 2 hr
17. filtrationThe crystals were collected by filtration
18. washwashed with cooled acetone/municipal water (1/5, 100 mL)

ORD record

ord-9e004b8114b147768babaa983b5ca01c

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08222422B2