Sodium Hydroxide → Despropionyl Ramelteon Hydrochloride

To an aqueous solution of (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine hydrochloride (1979 kg, Net 122 kg, 513 mol) were added toluene (532 L) and 5% aqueous solution of sodium hydroxide (456 L), and stirred. The layers were separated, and to the organic layer were added methanol (155 kg) and [RuCl(benzene)(R)-BINAP]Cl (894 g) under nitrogen atmosphere, followed by stirring at 80° C. for 15 hrs under hydrogen atmosphere (4.9 MPa). The reaction solution was cooled, and water (330 L) and concentrated hydrochloric acid (52.3 kg) were added at below 30° C., followed by stirring for 30 minutes, then the layers were separated. The aqueous layer was washed with toluene (195 L), and pH was adjusted to about 6.0 by adding 5% aqueous solution of NaOH to the aqueous layer. (containing 5.0% of compound III′). 5% Pd—C (50% wet, 9.7 kg) was added thereto, and stirred at 60° C. for 6 hrs under hydrogen atmosphere (4.9 MPa). The reaction mixture was filtered, and the filtrate was adjusted to around pH 6.0 with 5% aqueous solution of NaOH or dilute hydrochloric acid, followed by concentration under reduced pressure. The residue was recrystallized from mixed solution of n-butanol and water to give title compound (88.6 kg, yield 73.0%, compound (III′) is not detected, compound (IV′) is not detected).

1. customThe layers were separated
2. additionto the organic layer were added methanol (155 kg) and [RuCl(benzene)(R)-BINAP]Cl (894 g) under nitrogen atmosphere
3. stirringby stirring at 80° C. for 15 hrs under hydrogen atmosphere (4.9 MPa)
4. temperatureThe reaction solution was cooled
5. additionwater (330 L) and concentrated hydrochloric acid (52.3 kg) were added at below 30° C.
6. stirringby stirring for 30 minutes
7. customthe layers were separated
8. washThe aqueous layer was washed with toluene (195 L), and pH
9. additionby adding 5% aqueous solution of NaOH to the aqueous layer
10. addition(containing 5.0% of compound III′)
11. addition5% Pd—C (50% wet, 9.7 kg) was added
12. stirringstirred at 60° C. for 6 hrs under hydrogen atmosphere (4.9 MPa)
13. filtrationThe reaction mixture was filtered
14. concentrationfollowed by concentration under reduced pressure
15. customThe residue was recrystallized
16. additionfrom mixed solution of n-butanol and water

ORD record

ord-3887e93ad948490c84ec3687396f4f98

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08097737B2