Phosgene → HCID 59580437, compound

HRID 1803426Notes

Reaction equation

HRID 1803426 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([NH:13][CH3:14])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:15](Cl)(Cl)=[O:16].[CH3:19][S:20][CH2:21][CH2:22][NH2:23]>ClCCCl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([N:13]([CH3:14])[C:15]([NH:23][CH2:22][CH2:21][S:20][CH3:19])=[O:16])=[CH:11][N:12]=2)[CH:5]=[N:6][CH:7]=1

Participants

6

Reactant 3

HCID 6371PhosgeneHCID 87697(2-(Methylthio)ethyl)amineHCID 66645364HCID 66645364, compound

Product 1

HCID 59580437HCID 59580437, compoundYield 81%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalyst2×HCID 111,2-DichloroethaneSolvent

Procedure

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).

Workup

  1. customthe ice bath was removed
  2. waitAfter another 5 min
  3. temperaturethe mixture was heated
  4. temperatureto reflux
  5. customThe reaction was capped
  6. temperatureheated at 80° C. overnight
  7. customThe reaction was quenched upon addition of ethyl acetate and 0.1 N HCl
  8. customThe layers were separated
  9. washthe organic layer was washed separately with saturated aqueous NaHCO3 and brine
  10. dry with materialThe ethyl acetate layer was dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe crude product was purified by silica gel column chromatography (0 to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-633ecc0782ac4ba7be03e85b6df48d13
Source dataset
uspto-grants-2013_01
Patent number
US08350044B2

Reaction notes

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