1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → HCID 178495118, compound

Temperature

65.5 °C

Dimethyl sulfoxide (713 mL) is degassed with nitrogen at 25-30° C. for 0.5-1 h under a nitrogen atmosphere. Methyl 2-[4-(5-amino-6-hydroxy-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (35.0 g, 90.0 mmol) and (3S)-3-isothiocyanato-1-methoxy-butane (19.58 g, 0.14 mol) are added and the reaction heated to 63-68° C. The reaction mixture is stirred for 18-24 h at this temperature and then add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.3 g, 100.7 mmol) is added in portions. The reaction mixture is stirred for 2-4 h at 60-65° C. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g, 9.9 mmol) is added if the reaction does not reach complete conversion. The reaction mixture is cooled to 20-30° C. and is filtered over diatomaceous earth. Ethyl acetate (351 mL) and water (350 mL) are added to the filtrate. The layers are separated and the aqueous phase extracted with ethyl acetate (312 mL). The organic layers are combined and washed with water (2×210 mL), and then heptane (626 mL) is added. The solution is stirred for 0.5-1 h and filtered over silica gel, rinsing with a mixture of ethyl acetate (351 mL) and heptane (348 mL). The solution is concentrated under reduced pressure below 45° C. and ethyl acetate (156 mL) is added. Activated carbon (3.5 g) is added and the mixture heated to 60-70° C. with stirring for 0.5-1 h. The mixture is cooled to 20-30° C., filtered, and the filtrate concentrated under reduced pressure below 45° C. Toluene (242 mL) is charged to the resulting residue and the material concentrated under reduced pressure below 45° C. Toluene (40 mL) is added and the mixture heated to 60-70° C. with stirring for 0.5-1 h. The mixture is cooled to 25-30° C., stirred for 2-4 h, and then cooled to 0-5° C. The mixture is stirred at 0-5° C. for 2-4 h and the solids are collected by filtration. The filtercake is washed with toluene (40 mL) and is dried under reduced pressure below 60° C. to give the title compound as an off-white solid (33.0 g, 71%).

1. customDimethyl sulfoxide (713 mL) is degassed with nitrogen at 25-30° C. for 0.5-1 h under a nitrogen atmosphere
2. stirringThe reaction mixture is stirred for 2-4 h at 60-65° C
3. temperatureThe reaction mixture is cooled to 20-30° C.
4. filtrationis filtered over diatomaceous earth
5. additionEthyl acetate (351 mL) and water (350 mL) are added to the filtrate
6. customThe layers are separated
7. extractionthe aqueous phase extracted with ethyl acetate (312 mL)
8. washwashed with water (2×210 mL)
9. additionheptane (626 mL) is added
10. stirringThe solution is stirred for 0.5-1 h
11. filtrationfiltered over silica gel
12. washrinsing with a mixture of ethyl acetate (351 mL) and heptane (348 mL)
13. concentrationThe solution is concentrated under reduced pressure below 45° C. and ethyl acetate (156 mL)
14. additionis added
15. additionActivated carbon (3.5 g) is added
16. temperaturethe mixture heated to 60-70° C.
17. stirringwith stirring for 0.5-1 h
18. temperatureThe mixture is cooled to 20-30° C.
19. filtrationfiltered
20. concentrationthe filtrate concentrated under reduced pressure below 45° C
21. additionToluene (242 mL) is charged to the resulting residue
22. concentrationthe material concentrated under reduced pressure below 45° C
23. additionToluene (40 mL) is added
24. temperaturethe mixture heated to 60-70° C.
25. stirringwith stirring for 0.5-1 h
26. temperatureThe mixture is cooled to 25-30° C.
27. stirringstirred for 2-4 h
28. temperaturecooled to 0-5° C
29. stirringThe mixture is stirred at 0-5° C. for 2-4 h
30. filtrationthe solids are collected by filtration
31. washThe filtercake is washed with toluene (40 mL)
32. customis dried under reduced pressure below 60° C.

ORD record

ord-9999acd0ea91437693974fbb1d65d3cc

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08288548B2