Réaction #620492

Équation de réaction

2-(methylthio)ethanamine

[2-(5-fluoropyridin-3-yl)-thiazol-5-yl]-methyl-amine

phosgene

→

desired product

Rendement 81.0%

[2-(5-fluoropyridin-3-yl)-thiazol-5-yl]-1-methyl-3-(2-methylsulfanyl-ethyl)urea

Rendement 81.0%

Solvants

DCE

Conditions de réaction

Traitement

1. 1
   Autrethe ice bath was removed
2. 2
   workup.WAITAfter another 5 min
3. 3
   Températurethe mixture was heated
4. 4
   Températureto reflux
5. 5
   AutreThe reaction was capped
6. 6
   Températureheated at 80° C. overnight
7. 7
   AutreThe reaction was quenched upon addition of ethyl acetate and 0.1 N HCl
8. 8
   AutreThe layers were separated
9. 9
   Lavagethe organic layer was washed separately with saturated aqueous NaHCO3 and brine
10. 10
    SéchageThe ethyl acetate layer was dried over MgSO4
11. 11
    Filtrationfiltered
12. 12
    Concentrationconcentrated under reduced pressure
13. 13
    AutreThe crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes)

Mode opératoire

To a solution of [2-(5-fluoropyridin-3-yl)-thiazol-5-yl]-methyl-amine (0.4 g, 1.91 mmol) in DCE (5 mL) at 0° C. was added phosgene (1.3 mL, 2.5 mmol, 20 wt % solution in toluene). After 5 min, DMAP (0.5 g, 4.1 mmol) was added in one portion and the ice bath was removed. After another 5 min, the mixture was heated to reflux and stirred for 20 min. The reaction was cooled to ambient temperature and half of the solution was transferred to a vial and to this was added 2-(methylthio)ethanamine (0.183 g, 2.0 mmol) and DMAP (0.244 g, 2.0 mmol). The reaction was capped and heated at 80° C. overnight. The reaction was quenched upon addition of ethyl acetate and 0.1 N HCl. The layers were separated, and the organic layer was washed separately with saturated aqueous NaHCO3 and brine. The ethyl acetate layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to give the desired product as an off-white solid (0.253 g, 81%): mp 117-119° C.; 1H NMR (300 MHz, CDCl3) δ 8.94 (br s, 1H), 8.50 (d, J=2.7 Hz, 1H), 7.99-7.94 (m, 1H), 7.54 (s, 1H), 5.37 (m, 1H), 3.53 (q, J=11.8, 5.5 Hz, 2H), 3.43 (s, 3H), 2.72 (app t, J=6.6 Hz, 2H), 2.13 (s, 3H); ESIMS m/z 327.1 (M+H); m/z 325.0 (M−1).

Source