Sodium Hydroxide → HCID 178488035, compound

Temperature

25 °C

2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (300 g) and 2-mercapto-5-methoxybenzimidazole (245.9 g) were taken in methanol (1050 mL) at 25° C. and sodium hydroxide (135 g) solution in water was added. The reaction mixture was stirred for 45 min and quenched in water (2100 mL). The reaction mixture was acidified with 10% glacial acetic acid (322 mL) and extracted with toluene (1500 mL). The toluene extract was washed with water and partially distilled for azeotropic removal of water. The reaction mixture was cooled to 25° C. and water (2.9 mL), D-(−)-Diethyl tartrate (163.7 g), Titanium isopropoxide (122.9 g) were added. The reaction mixture was heated to 50° C. for 1 hour and cooled to 0° C. Diisopropylethylamine (52.4 g) and cumene hydroperoxide (80%) (257 g) were added and stirred for 20 min at 15° C. The reaction mixture was stirred for 8 hours at 15° C. Sodium thiosulfate (61.7 g) aqueous solution and aqueous sodium hydroxide (257.1 g) solution were added to the reaction mixture. The separated aqueous layer was treated with methylene dichloride (2150 mL) and acidified with glacial acetic acid to adjust the pH of 6.5. The separated organic layer was distilled under vacuum to obtain residue. Methanol (1050 mL) was added to the residue and magnesium methoxide solution (14.14 g) in methanol:methylene dichloride (428:35 mL) was added at 25° C. The reaction mixture was stirred for 9 hours and catalytic amount water (4.3 mL) was added. The reaction mixture was filtered and washed with methanol (300 mL). The filtrate was treated with charcoal and distilled under vacuum to obtain residue. Acetone (50 mL) was added to the residue and stirred for 2 hours at 25° C. The slurry was filtered and washed with acetone/methanol (385:43 mL) and dried to obtain wet-cake (416 g) of esomeprazole magnesium. The wet-cake was dissolved in methanol (1500 mL) and charcoalized. The reaction mixture was filtered and methanol was partially distilled from filtrate to obtain residue with 3 times of methanol. Acetone (3428 mL) was added to the above residue at 25° C. and stirred for 2 hours. The reaction mixture was filtered and wet-cake was washed with acetone/methanol (385:43 mL). The product was dried in fluid bed dryer for 3 hours at 25° C. to obtain 305 g esomeprazole magnesium dihydrate with residual solvents within ICH limits. Water content 6.09% (by KF), X-ray powder diffraction (FIG. 1) and Differential scanning calorimetry (FIG. 2).

1. customquenched in water (2100 mL)
2. extractionextracted with toluene (1500 mL)
3. extractionThe toluene extract
4. washwas washed with water
5. distillationpartially distilled for azeotropic removal of water
6. additionwater (2.9 mL), D-(−)-Diethyl tartrate (163.7 g), Titanium isopropoxide (122.9 g) were added
7. temperatureThe reaction mixture was heated to 50° C. for 1 hour
8. temperaturecooled to 0° C
9. additionDiisopropylethylamine (52.4 g) and cumene hydroperoxide (80%) (257 g) were added
10. stirringstirred for 20 min at 15° C
11. stirringThe reaction mixture was stirred for 8 hours at 15° C
12. additionSodium thiosulfate (61.7 g) aqueous solution and aqueous sodium hydroxide (257.1 g) solution were added to the reaction mixture
13. additionThe separated aqueous layer was treated with methylene dichloride (2150 mL)
14. distillationThe separated organic layer was distilled under vacuum
15. customto obtain residue
16. stirringThe reaction mixture was stirred for 9 hours
17. filtrationThe reaction mixture was filtered
18. washwashed with methanol (300 mL)
19. additionThe filtrate was treated with charcoal
20. distillationdistilled under vacuum
21. customto obtain residue
22. stirringstirred for 2 hours at 25° C
23. filtrationThe slurry was filtered
24. washwashed with acetone/methanol (385:43 mL)
25. customdried

ORD record

ord-b9f2829c9d8247609200c74b44521501

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08962851B2