Methanesulfonic Acid → Milategrast mesylate

1-[2-(3,3,5,5-Tetramethylcyclohexyl)phenyl]piperazine methanesulfonate (820 mg, 2.07 mmol) was suspended in t-butyl methyl ether (8.2 mL), and a 1N aqueous solution of sodium hydroxide (2.5 mL) was added thereto, followed by stirring at room temperature for 40 minutes. The organic layer was separated and washed twice with water (8 mL), and the solvent was removed under reduced pressure. To the resultant residue were added tetrahydrofuran (6.1 mL), acetic acid (0.116 mL) and cyclopropanecarbaldehyde (0.182 mL) in this order, followed by stirring at room temperature for 20 minutes. To the mixture was added sodium triacetoxyborohydride (606 mg, 2.86 mmol), followed by stirring at room temperature for 1.5 hours. To the reaction mixture were added a 1N aqueous solution of sodium hydroxide (8.1 mL) and t-butyl methyl ether (6.1 mL), followed by stirring at room temperature, and the organic layer was separated. The organic layer was washed twice with water (6 mL), and the solvent was removed under reduced pressure. To the resultant residue was added 4-methyl-2-pentanone (6 mL), followed by heating and stirring at an external temperature of 100° C. Methanesulfonic acid (0.121 mL, 1.86 mmol) was added thereto and dissolved. The mixture was further stirred at an external temperature of 100° C. for 2 minutes, heptane (3 mL) was added, and heating was stopped and stirring was carried out. The mixture was stirred at room temperature for 14 hours and the produced precipitate was collected by filtration under reduced pressure. The precipitate was washed with a mixture of 4-methyl-2-pentanone (3 mL) and heptane (3 mL), and dried under reduced pressure at 40° C. for 2 hour to give 670 mg of the title compound as white crystals (crystal α).

1. customThe organic layer was separated
2. washwashed twice with water (8 mL)
3. customthe solvent was removed under reduced pressure
4. additionTo the resultant residue were added tetrahydrofuran (6.1 mL), acetic acid (0.116 mL) and cyclopropanecarbaldehyde (0.182 mL) in this order
5. stirringby stirring at room temperature for 20 minutes
6. stirringby stirring at room temperature for 1.5 hours
7. stirringby stirring at room temperature
8. customthe organic layer was separated
9. washThe organic layer was washed twice with water (6 mL)
10. customthe solvent was removed under reduced pressure
11. additionTo the resultant residue was added 4-methyl-2-pentanone (6 mL)
12. temperatureby heating
13. stirringstirring at an external temperature of 100° C
14. dissolutiondissolved
15. stirringThe mixture was further stirred at an external temperature of 100° C. for 2 minutes
16. temperatureheating
17. stirringstirring
18. stirringThe mixture was stirred at room temperature for 14 hours
19. filtrationthe produced precipitate was collected by filtration under reduced pressure
20. washThe precipitate was washed with a mixture of 4-methyl-2-pentanone (3 mL) and heptane (3 mL)
21. customdried under reduced pressure at 40° C. for 2 hour

ORD record

ord-97204ac0fce9456684080ef1008b4a0d

Source dataset

uspto-grants-2011_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07910734B2