Phosphoric Acid → HCID 66665085, compound

To a solution of cyclopentyl methanol (22.3 g, 0.22 mol) and triethylamine (33.8 g, 0.33 mol) in tetrahydrofuran was added dropwise methanesulfonyl chloride (29.3 g, 0.26 mol) with keeping the temperature below 15° C. over 50 minutes, and the reaction mixture was stirred at the same condition for 1 hour. To the mixture was added dropwise water (134 g) with keeping the internal temperature below 15° C. over 10 minutes. To the resultant was further added toluene (232 g), and the mixture was extracted. The organic layer was washed with water (134 g), and the solvent was evaporated under reduced pressure to give a crude product of Compound (Ie) (40.0 g), which was used in the next step without further purification. The resulting Compound (Ie) and hydrazine monohydrate (66.9 g, 1.34 mol) were dissolved in ethanol (178 g), and the reaction mixture was stirred at 60° C. to 65° C. (internal temperature) for 7 hours. The mixture was cooled to room temperature, and partitioned between chloroform (674 g) and water (71.5 g). The chloroform layer was washed with water (71.5 mL, ×2) to give a solution of a free base of Compound (IIff) in chloroform (808 g). To the solution (202 g, equivalent to 55 mmol) were added at room temperature 85% phosphoric acid (6.42 g, 60 mmol) and then 2-propanol (30 g), and the solvent was evaporated under reduced pressure. To the concentrated residue was added 2-propanol (36.7 g), and the solvent was evaporated under reduced pressure (×4). To the concentrated residue (24 g) was added 2-propanol to adjust the total weight to 45 g, and the mixture was stirred at 40° C. for 1 hour. The mixture was cooled to 5° C. over 1.5 hours, and then stirred at 5° C. for 1 hour. The precipitate was collected by filtration, washed with a mixed solution of 2-propanol (1.98 g) and n-hexane (3.47 g), and dried under reduced pressure to give Compound (IIff) (9.33 g, 80%) as a white crystalline solid.

1. customthe temperature below 15° C.
2. customover 50 minutes
3. customthe internal temperature below 15° C.
4. customover 10 minutes
5. extractionthe mixture was extracted
6. washThe organic layer was washed with water (134 g)
7. customthe solvent was evaporated under reduced pressure
8. customto give a crude product of Compound (Ie) (40.0 g), which
9. customwas used in the next step without further purification
10. stirringthe reaction mixture was stirred at 60° C. to 65° C. (internal temperature) for 7 hours
11. custompartitioned between chloroform (674 g) and water (71.5 g)
12. washThe chloroform layer was washed with water (71.5 mL, ×2)
13. customto give a solution of a free base of Compound (IIff) in chloroform (808 g)
14. custom2-propanol (30 g), and the solvent was evaporated under reduced pressure
15. additionTo the concentrated residue was added 2-propanol (36.7 g)
16. customthe solvent was evaporated under reduced pressure (×4)
17. additionTo the concentrated residue (24 g) was added 2-propanol
18. stirringthe mixture was stirred at 40° C. for 1 hour
19. temperatureThe mixture was cooled to 5° C. over 1.5 hours
20. stirringstirred at 5° C. for 1 hour
21. filtrationThe precipitate was collected by filtration
22. washwashed with a mixed solution of 2-propanol (1.98 g) and n-hexane (3.47 g)
23. customdried under reduced pressure
24. customto give Compound (IIff) (9.33 g, 80%) as a white crystalline solid

ORD record

ord-5a056026a6864f8b9047c5d7d1d74120

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08809383B2