Diisopropylethylamine → N-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride salt

HRID 347544Notes

Reaction equation

HRID 347544 reaction equation
[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=O)[C:8]2=[O:16])=[CH:4][CH:3]=1.[ClH:19].Cl.[F:21][C:22]1[CH:23]=[C:24]([NH:49]C(NC(=O)CC2C=CC(F)=CC=2)=S)[CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]2=[C:35]([CH3:48])C(OCCN3CCN(C)CC3)=CN2N=CN=1.C[N:64]([C:66](ON1N=NC2C=CC=CC1=2)=[N+:67]([CH3:69])C)C.[B-](F)(F)(F)F.[CH3:85]CN(C(C)C)C(C)C>CN(C=O)C>[ClH:19].[NH:64]1[C:66]2=[N:67][CH:69]=[CH:85][C:29]([O:28][C:27]3[CH:26]=[CH:25][C:24]([NH:49][C:13]([C:9]4[C:8](=[O:16])[N:7]([CH2:6][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=5)[CH:12]=[CH:11][CH:10]=4)=[O:15])=[CH:23][C:22]=3[F:21])=[C:34]2[CH:35]=[CH:48]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 168966831-(4-Fluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acidHCID 1317262361-(3-Fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4] triazin-4-yloxy)phenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea, bis-hydrochloride salt2×

Product 1

HCID 131726245N-(4-(1H-Pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxamide, hydrochloride saltYield 59%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

A homogeneous solution of 1-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.051 g, 0.21 mmol, 1.0 eq), 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.50 g, 0.21 mmol, 1.0 eq, Compound B of Example 132) and TBTU (0.086 g, 0.23 mmol, 1.1 eq) in DMF (1 mL) was treated with DIPEA (0.11 mL, 0.62 mmol, 3.0 eq) at room temperature. The reaction mixture was stirred for 12 h and quenched with 10% aqueous LiCl (15 mL). The resulting solution was extracted with ethyl acetate (4×40 mL). The combined organic extracts were washed with 10% aqueous LiCl (4×50 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting 0–2.5% MeOH in CHCl3) and the appropriate fractions were isolated and concentrated in vacuo. The free base was dissolved in THF, cooled to 0° C. and the homogeneous solution treated with anhydrous 4 N HCl in dioxane. The reaction mixture was warmed to room temperature, concentrated in vacuo and the residue triturated with diethyl ether. The solid was dried in vacuo to afford the title compound (0.062 g, 59%) as a HCl salt. 1H NMR (DMSO-d6) δ 12.43 (s, 1H), 12.27 (s, 1H), 8.50–8.52 (m, 1H), 8.35–8.37 (m, 1H), 8.25–8.27 (m, 1H), 8.05–8.0 (m, 1H), 7.43–7.55 (m, 5H), 7.20–7.24 (m, 2H), 6.71 (t, 1H, J=6.89 Hz), 6.65 (d, 1H, J=6.03 Hz), 6.43 (s, 1H), 5.32 (s, 2H); HRMS(ESI+): calcd: 473.1425, found: 473.1427.

Workup

  1. customquenched with 10% aqueous LiCl (15 mL)
  2. extractionThe resulting solution was extracted with ethyl acetate (4×40 mL)
  3. washThe combined organic extracts were washed with 10% aqueous LiCl (4×50 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationthe filtrate concentrated in vacuo
  7. customThe residue was purified by flash chromatography (SiO2, eluting 0–2.5% MeOH in CHCl3)
  8. customthe appropriate fractions were isolated
  9. concentrationconcentrated in vacuo
  10. dissolutionThe free base was dissolved in THF
  11. additionthe homogeneous solution treated with anhydrous 4 N HCl in dioxane
  12. temperatureThe reaction mixture was warmed to room temperature
  13. concentrationconcentrated in vacuo
  14. customthe residue triturated with diethyl ether
  15. customThe solid was dried in vacuo

Sources & evidence

ORD record
ord-f6ef18a356fa4c91a3ace8563263be83
Source dataset
uspto-grants-2007_02
Patent number
US07173031B2

Reaction notes

Loading…