1,2-Dimethoxyethane → Ramosetron hydrochloride

Temperature

-25 °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 −25° C. in an atmosphere of nitrogen. A 33 ml portion of 1.8 mol/l toluene solution of diethylaluminum chloride was slowly added to this liquid and stirred at −25° C. for 2 hours, and 8 ml of tetrahydrofuran was added thereto after the stirring. This liquid was slowly dispersed in 100 ml of water which was cooled at 0° C., and then heated to 45° C. After removing the organic layer, the water layer was washed with 40 ml of toluene, and this was 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. The thus obtained organic layer was evaporated under a reduced pressure, 40 ml of ethanol was added to the resulting residue 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 12 hours 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 5.45 g of (−)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride (yield 86.3%, 99.2% 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 33 ml portion of 1.8 mol/l toluene solution of diethylaluminum chloride was slowly added to this liquid
7. addition8 ml of tetrahydrofuran was added
8. additionThis liquid was slowly dispersed in 100 ml of water which
9. temperaturewas cooled at 0° C.
10. temperatureheated to 45° C
11. customAfter removing the organic layer
12. washthe water layer was washed with 40 ml of toluene
13. extractionthis was extracted
14. additionby adding 80 ml of 2-butanone and 50 ml of 20% sodium hydroxide aqueous solution
15. washThe water layer was washed with 40 ml of 2-butanone
16. washwashed twice with 20 ml of 10% brine
17. customThe thus obtained organic layer was evaporated under a reduced pressure, 40 ml of ethanol
18. additionwas added to the resulting residue
19. customevaporated under a reduced pressure, and 40 ml of ethanol
20. additionwas again added to the residue
21. customevaporated under a reduced pressure
22. additionA 120 ml portion of a mixed solvent of ethanol and ethyl acetate (1:3) was added to the residue
23. temperaturethis was heated at 70° C. for 12 hours
24. additionby adding 5 ml ethyl acetate solution of 4 mol/l hydrogen chloride
25. temperatureslowly cooled to 0° C
26. filtrationThe precipitated crystals were filtered
27. washthe crystals were washed with an ethanol-ethyl acetate mixed solvent
28. customdried in vacuo at 50° C.

ORD record

ord-c30928179351455385a77a8e45ec2c1c

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07652052B2