Phosgene → HCID 66613793, compound

HRID 1911965Notes

Reaction equation

HRID 1911965 reaction equation
[C:1](Cl)(Cl)=[O:2].[CH3:5][NH:6][C:7]1[S:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[N:10][N:11]=1.[CH3:19][S:20][CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1.ClC(Cl)C>[CH3:19][S:20][CH2:21][CH2:22][O:23][C:1](=[O:2])[N:6]([C:7]1[S:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[N:10][N:11]=1)[CH3:5]

Participants

6

Reactant 3

HCID 6371PhosgeneHCID 789252-(Methylthio)ethanolHCID 65644248HCID 65644248, compound

Product 1

HCID 66613793HCID 66613793, compoundYield 108.8%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 63651,1-DichloroethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of phosgene (20%, 0.39 mL, 0.8 mmol) in toluene was pipetted at a dropwise rate into a suspension of methyl-[5-(5-fluoropyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-amine (0.15 g, 0.7 mmol) in dichloroethane (10 mL) at 1° C., stirred for 5 minutes and treated with a solution of 4-N,N-dimethylaminopyridine (0.192 g, 1.6 mmol) in dichloroethane (3 mL). The ice bath was removed after 30 minutes. The reaction mixture was stirred at 23° C. for 90 minutes, refluxed under nitrogen for 14 hours, cooled to 0° C. and reacted with 2-methylthio ethanol (0.033 g, 0.35 mmol). The ice bath was removed after 10 minutes. The reaction mixture was stirred at 23° C. for 1 hour, refluxed for 1 hour, cooled, and diluted with dichloroethane (30 mL). The reaction mixture was washed with dilute hydrochloric acid (0.1 N, 2×20 mL), saturated aqueous NaHCO3 (40 mL), and brine (30 mL), and then dried over MgSO4 and chromatographed on silica to afford the title compound as a white solid (0.125 g, 53%): mp 104-106° C.; 1H NMR (400 MHz, CDCl3) δ 8.90 (br t, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.04 (ddd, J=9.1, 2.5, 1.0 Hz, 1H), 4.52 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 2.87 (t, J=6.8 Hz, 2H), 2.21 (s, 3H); ESIMS m/z 329 ([M+H]+).

Workup

  1. customThe ice bath was removed after 30 minutes
  2. stirringThe reaction mixture was stirred at 23° C. for 90 minutes
  3. temperaturerefluxed under nitrogen for 14 hours
  4. customThe ice bath was removed after 10 minutes
  5. stirringThe reaction mixture was stirred at 23° C. for 1 hour
  6. temperaturerefluxed for 1 hour
  7. temperaturecooled
  8. additiondiluted with dichloroethane (30 mL)
  9. washThe reaction mixture was washed with dilute hydrochloric acid (0.1 N, 2×20 mL), saturated aqueous NaHCO3 (40 mL), and brine (30 mL)
  10. dry with materialdried over MgSO4
  11. customchromatographed on silica

Sources & evidence

ORD record
ord-74b3f7c76ed0476eb51a5d22025fed9d
Source dataset
uspto-grants-2013_12
Patent number
US08604211B2

Reaction notes

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