1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-fluoro-5-methylbenzamide

HRID 1670231Notes

Reaction equation

HRID 1670231 reaction equation
[CH:1](N(C(C)C)CC)(C)C.N[C:11]1[N:16]=[CH:15][N:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24]C(NC(=O)CC3C=CC(F)=CC=3)=S)=[CH:20][C:19]=2[F:38])[CH:12]=1.[F:39][C:40]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:41]=1[C:42]([OH:44])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:14][C:15]1[CH:1]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:42](=[O:44])[C:41]3[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:40]=3[F:39])=[CH:20][C:19]=2[F:38])[CH:12]=[CH:11][N:16]=1

Participants

7

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 2428292-Fluoro-5-methylbenzoic acidHCID 115389121-(4-(6-Aminopyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea2×

Product 1

HCID 59852870N-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-2-fluoro-5-methylbenzamideYield 40%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Diisopropylethylamine (0.035 mL, 0.200 mmol, 2.0 eq) was added to a solution of 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 0.022 g, 0.100 mmol, 1.0 eq), 2-fluoro-5-methyl benzoic acid (Aldrich, 0.015 g, 0.100 mmol, 1.0 eq), EDCI (0.021 g, 0.11 mmol, 1.1 eq) and HOBT (0.014 g, 0.100 mmol, 1.0 eq) in DMF (0.700 mL) at room temperature. The reaction mixture was stirred at room temperature for 8 h, quenched with saturated aqueous NaHCO3 solution and extracted with CHCl3 (3×10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30×500 mm, 30-90% aqueous MeOH with 0.1% TFA, 30 minute gradient) and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous NaHCO3 solution and the mixture extracted with CHCl3 (3×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (0.014 g, 40%) as a solid. 1H NMR (CD3OD) δ 7.67-7.80 (m, 2H), 7.36-7.45 (m, 3H), 7.03-7.14 (m, 2H), 6.14-6.16 (m, 1H), 5.89-5.90 (m, 1H), 2.29 (s, 3H); MS (ESI+) m/z 356 (M+H)+; HRMS (ESI+) calcd.: 356.1211. found: 356.1203.

Workup

  1. customquenched with saturated aqueous NaHCO3 solution
  2. extractionextracted with CHCl3 (3×10 mL)
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by reverse phase preparative HPLC (YMC ODS-A S10 30×500 mm, 30-90% aqueous MeOH with 0.1% TFA, 30 minute gradient)
  7. concentrationthe appropriate fractions were concentrated in vacuo
  8. extractionthe mixture extracted with CHCl3 (3×30 mL)
  9. dry with materialThe combined organics were dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-2e55a8b7b5ae4ab59b03eb6741bdfde6
Source dataset
uspto-grants-2011_08
Patent number
US07989477B2

Reaction notes

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