Thionyl Chloride → 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73738Notes

Reaction equation

HRID 73738 reaction equation
O=S(Cl)Cl.[Cl:5][C:6]1[C:14]([I:15])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[F:16][C:17]([F:27])([F:26])[O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Cl:5][C:6]1[C:14]([I:15])=[CH:13][C:9]([C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=2)=[O:12])=[CH:8][N:7]=1

Participants

8

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 6008484-(Trifluoromethoxy)aniline2×HCID 222714776-Chloro-5-iodonicotinic acid

Product 1

HCID 867025996-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

DMF (0.13 mL) and SOCl2 (0.734 mL, 10.05 mmol) were added to a mixture of 6-chloro-5-iodonicotinic acid (1.00 g, 3.35 mmol) and 4-(trifluoromethoxy)aniline (0.623 mg, 3.52 mmol) in toluene (7 mL) and the RM was stirred at 80° C. for 1 h. The solvent was evaporated off under reduced pressure and under argon the residue was dissolved in THF (7.00 mL) and DIPEA (1.17 mL, 6.7 mmol), cooled to −15° C. treated dropwise with a solution of 4-(trifluoromethoxy)aniline (0.476 mL, 3.52 mmol) in THF (7.00 mL) and stirred at RT for 1 h. The solvent was evaporated off under reduced pressure and the residue treated with aq. 1N HCl (30 mL) and extracted with TBME (100 mL). The combined extracts were washed with sat. aq. Na2CO3 (30 mL) and brine (30 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure until crystallization commenced. The product was triturated with n-heptane, filtered and dried to afford the title compound as an off-white solid. HPLC (Condition 4) tR=6.36 min, UPLC-MS (Condition 3) tR=1.23 min, m/z=441.1 [M−H]−.

Workup

  1. customThe solvent was evaporated off under reduced pressure and under argon the residue
  2. dissolutionwas dissolved in THF (7.00 mL)
  3. stirringstirred at RT for 1 h
  4. customThe solvent was evaporated off under reduced pressure
  5. additionthe residue treated with aq. 1N HCl (30 mL)
  6. extractionextracted with TBME (100 mL)
  7. washThe combined extracts were washed with sat. aq. Na2CO3 (30 mL) and brine (30 mL)
  8. dry with materialdried over Na2SO4
  9. customthe solvent was evaporated off under reduced pressure until crystallization
  10. customThe product was triturated with n-heptane
  11. filtrationfiltered
  12. customdried

Sources & evidence

ORD record
ord-fe09018f89b14514a428d7019f1595a4
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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