Triethylamine → N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide

HRID 2218487Notes

Reaction equation

HRID 2218487 reaction equation
[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[F:23].C(N(CC)CC)C>O1CCCC1.[Ni]>[OH:1][CH:2]([CH2:25][OH:26])[CH2:3][O:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]

Participants

5

Reactant 2

HCID 8471TriethylamineHCID 10206158N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide

Product 1

HCID 10269634N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamideYield 31.8%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A solution of N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.260 g, 0.539 mmol) and triethylamine (2.0 mL, 14.3 mmol) in tetrahydrofuran (14 mL) was hydrogenated over Raney Nickel (0.2 g wet) at 50 psig at room temperature for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organics were washed twice with saturated sodium bicarbonate solution, twice with water, collected, dried over sodium sulfate, filtered and concentrated in vacuo. HPLC purification was performed using a YMC 30×100 mm 5u (C18) column in 0-100% acetonitrile (3.0% n-propanol)/100-0% water (3.0% n-propanol) at 30 ml/min. The desired fractions were collected and concentrated. The afforded residue was extracted with ethyl acetate/water. Organic layers were washed with saturated NaCl solution, collected and dried in vacuo to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide as a white solid (0.061 g, 31%): m.p.=113-115° C.; 1NMR (400 MHz; DMSO-d6) δ 11.90 (s, 1H), 8.73 (s, 1H), 7.37 (m, 1H), 7.10-7.19 (m, 2H), 7.02 (t, 1H, J=7.4 Hz), 6.84-6.93 (m, 2H), 4.82 (m, 1H), 4.57-4.58 (m, 1H), 3.86-3.88 (m, 1H), 3.67-3.73 (m, 2H), 3.3 (2H, under HDO); MS(APCI+)=357.1; Anal. calcd/found for C16H15F3N2O4: C, 53.94/53.97; H, 4.24/4.37; N, 7.86/7.83.

Workup

  1. customThe catalyst was removed by filtration
  2. concentrationthe filtrate was concentrated in vacuo
  3. customThe afforded residue was partitioned between ethyl acetate and water
  4. washThe organics were washed twice with saturated sodium bicarbonate solution, twice with water
  5. customcollected
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customHPLC purification
  10. customThe desired fractions were collected
  11. concentrationconcentrated
  12. extractionThe afforded residue was extracted with ethyl acetate/water
  13. washOrganic layers were washed with saturated NaCl solution
  14. customcollected
  15. customdried in vacuo

Sources & evidence

ORD record
ord-04e2aa1089dd463ba7fe188e689b0535
Source dataset
uspto-grants-2008_08
Patent number
US07411001B2

Reaction notes

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