1,2-Dimethoxyethane → Ramosetron hydrochloride

Temperature

-40 °C

By heating a mixture of 4.05 g of (R)-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid monohydrochloride (99.4% e.e.), 120 ml of dimethoxyethane and 5.47 g of thionyl chloride at 70° C. for 2 hours, (R)-4,5,6,7-tetrahydro-1H-benzimidazole-5-carbonyl chloride was synthesized, and the solvent was evaporated under a reduced pressure. A 80 ml portion of toluene was added to the residue and again evaporated under a reduced pressure, and the residue was mixed with 120 ml of toluene and 5.24 g of 1-methyl-1H-indole and cooled to −40° C. in an atmosphere of nitrogen. A 30 ml portion of 1.0 mol/l toluene solution of ethylaluminum sesquichloride was slowly added to this liquid and stirred at −40° C. for 3 hours, and 10 ml of tetrahydrofuran was added thereto after the stirring. This liquid was slowly dispersed in 160 ml of water cooled at 0° C., and after removing the organic layer, the water layer was washed with 40 ml of toluene and extracted by adding 80 ml of 2-butanone and 50 ml of 20% sodium hydroxide aqueous solution thereto. The water layer was washed with 40 ml of 2-butanone, and the organic layers were combined and washed twice with 20 ml of 10% brine and then with 4 ml of water. A 40 ml portion of ethanol was added to the thus obtained organic layer and evaporated under a reduced pressure, and 40 ml of ethanol was again added to the residue and evaporated under a reduced pressure. A 120 ml portion of a mixed solvent of ethanol and ethyl acetate (1:3) was added to the residue, and this was heated at 70° C. for 1 hour by adding 5 ml ethyl acetate solution of 4 mol/l hydrogen chloride and then slowly cooled to 0° C. The precipitated crystals were filtered, and the crystals were washed with an ethanol-ethyl acetate mixed solvent and then dried in vacuo at 50° C., thereby obtaining 4.98 g of (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 78.8%, 99.5% e.e.). FAB-MS (m/z): 280 [M+H+]

1. temperatureBy heating
2. customthe solvent was evaporated under a reduced pressure
3. additionA 80 ml portion of toluene was added to the residue
4. customagain evaporated under a reduced pressure
5. additionthe residue was mixed with 120 ml of toluene and 5.24 g of 1-methyl-1H-indole
6. additionA 30 ml portion of 1.0 mol/l toluene solution of ethylaluminum sesquichloride was slowly added to this liquid
7. addition10 ml of tetrahydrofuran was added
8. additionThis liquid was slowly dispersed in 160 ml of water
9. temperaturecooled at 0° C.
10. customafter removing the organic layer
11. washthe water layer was washed with 40 ml of toluene
12. extractionextracted
13. additionby adding 80 ml of 2-butanone and 50 ml of 20% sodium hydroxide aqueous solution
14. washThe water layer was washed with 40 ml of 2-butanone
15. washwashed twice with 20 ml of 10% brine
16. additionA 40 ml portion of ethanol was added to the thus obtained organic layer
17. customevaporated under a reduced pressure, and 40 ml of ethanol
18. additionwas again added to the residue
19. customevaporated under a reduced pressure
20. additionA 120 ml portion of a mixed solvent of ethanol and ethyl acetate (1:3) was added to the residue
21. temperaturethis was heated at 70° C. for 1 hour
22. additionby adding 5 ml ethyl acetate solution of 4 mol/l hydrogen chloride
23. temperatureslowly cooled to 0° C
24. filtrationThe precipitated crystals were filtered
25. washthe crystals were washed with an ethanol-ethyl acetate mixed solvent
26. customdried in vacuo at 50° C.

ORD record

ord-ece0e3c677de42008b0ec22e9f029105

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07652052B2