2,6-Lutidine → HCID 24804763, compound

HRID 2094226Notes

Reaction equation

HRID 2094226 reaction equation
[CH2:1]([O:3][C:4]([C:6](=O)[NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.O=P(Cl)(Cl)Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:39]([C:45]([NH:47][NH2:48])=O)=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=2)(=[O:36])=[O:35])=[CH:30][C:29]=1[C:49]([F:52])([F:51])[F:50]>CC#N>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:39]([C:45]3[N:7]([C:8]4[CH:12]=[CH:11][O:10][N:9]=4)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:48][N:47]=3)=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=2)(=[O:35])=[O:36])=[CH:30][C:29]=1[C:49]([F:50])([F:52])[F:51]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 24813Phosphorus oxychlorideHCID 45496753HCID 45496753, compoundHCID 59216810HCID 59216810, compound

Product 1

HCID 24804763HCID 24804763, compoundYield 20.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

To a vial equipped with a teflon coated septum and a nitrogen inlet were added ethyl(isoxazol-3-ylcarbamoyl)formate (370 mg, 2.0 mmol), MeCN (2 mL) and 2,6-lutidine (0.6 mL, 5.2 mmol). The vial was cooled to 0° C. POCl3 (0.4 mL, 4.3 mmol) was added, and the solution maintained at 0° C. for 30 min. The solution was then warmed to 40° C. for 3 h. After cooling to room temperature, solid 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)-benzenesulfonamide (500 mg, 1.2 mmol) was added, and the reaction heated to 80° C. for 1 h. The volatiles were removed in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added, and the solution heated to 90° C. for 4 h. After cooling to room temperature, the volatiles were removed in vacuo, and the resulting residue purified by flash chromatography on 12 g of silica gel (50→100% gradient of EtOAc in hexanes). The pure fractions were collected, and the solvent removed in vacuo to afford the title compound (139 mg, 20% yield). HPLC retention time=2.96 minutes. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.0, 1H), 8.19 (d, J=2.0, 1H), 8.12 (d, J=2.4, 1H), 7.98 (d, J=2.0, 1H), 7.90 (dd, J=2.4, 8.4, 1H), 7.58 (d, J=8.4, 1H), 6.62 (d, J=2.0, 1H), 4.41 (q, J=7.2, 2H), 1.40 (t, J=7.2, 3H). MS (ES) [M+H]+ expected 577.0. found 577.0.

Workup

  1. temperaturethe solution maintained at 0° C. for 30 min
  2. temperatureThe solution was then warmed to 40° C. for 3 h
  3. temperatureAfter cooling to room temperature
  4. temperaturethe reaction heated to 80° C. for 1 h
  5. customThe volatiles were removed in vacuo
  6. additionEthanol (9 mL) and triethylamine (1 mL) were added
  7. temperaturethe solution heated to 90° C. for 4 h
  8. temperatureAfter cooling to room temperature
  9. customthe volatiles were removed in vacuo
  10. customthe resulting residue purified by flash chromatography on 12 g of silica gel (50→100% gradient of EtOAc in hexanes)
  11. customThe pure fractions were collected
  12. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-9dab7e661edb4786b094a089d9612eb1
Source dataset
uspto-grants-2013_05
Patent number
US08445518B2

Reaction notes

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