Pyridine → HCID 86269228, compound

HRID 2279013Notes

Reaction equation

HRID 2279013 reaction equation
[C:1](Cl)(Cl)=[O:2].[N:5]1[CH:10]=[CH:9]C=[CH:7][CH:6]=1.[CH3:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[CH:21]=1.CC[N:41]([CH:45](C)C)C(C)C.[OH-:48].[Na+]>C(Cl)Cl>[CH2:6]([N:5]1[CH2:10][CH2:9][N:41]([C:45]([NH:18][C:16]2[CH:15]=[CH:14][C:13]([O:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([C:26]4[CH:27]=[CH:28][C:29]([N:32]5[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]5)=[CH:30][CH:31]=4)[CH:21]=3)=[C:12]([CH3:11])[N:17]=2)=[O:48])[C:1]1=[O:2])[CH3:7]

Participants

7

Reactant 5

HCID 1049PyridineHCID 6371PhosgeneHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 90403180HCID 90403180, compound

Product 1

HCID 86269228HCID 86269228, compoundYield 39%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A 0° C. solution of phosgene (15% in toluene, 1.41 mL, 2.003 mmol) in DCM (5 mL) was treated drop-wise with a solution of Example B18 (61 mg, 0.534 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmed to RT, stirred for 2 h, then concentrated to dryness. The residue was dissolved in DCM (5 mL), cooled to 0° C., treated with a solution of 6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine (0.10 g, 0.266 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (5 mL), warmed to RT and stirred overnight. The mixture was treated with 1N NaOH, extracted with EtOAc (3×) and the combined organics were washed with 1N NaOH, then brine, dried over Na2SO4, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure and the aqueous residue was treated with K2CO3 and extracted with 5:1 DCM/THF (3×). The combined organics were dried over Na2SO4 and concentrated to dryness to afford 3-ethyl-N-(6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (54 mg, 39%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.42 (d, J=5.6 Hz, 1 H), 7.92-7.86 (m, 3 H), 7.62 (d, J=8.9 Hz, 1 H), 7.32 (d, J=2.4 Hz, 1 H), 6.97 (d, J=8.8 Hz, 2 H), 6.63 (dd, J=5.7, 2.3 Hz, 1 H), 3.80 (t, J=8.3 Hz, 2 H), 3.46 (t, J=8.2 Hz, 2 H), 3.26-3.25 (m, 2 H), 3.20 (s, 4 H), 2.43 (s, 4 H), 2.25 (s, 3 H), 2.21 (s, 3 H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 516.3 (M+H+).

Workup

  1. concentrationconcentrated to dryness
  2. dissolutionThe residue was dissolved in DCM (5 mL)
  3. temperaturecooled to 0° C.
  4. temperaturewarmed to RT
  5. stirringstirred overnight
  6. extractionextracted with EtOAc (3×)
  7. washthe combined organics were washed with 1N NaOH
  8. dry with materialbrine, dried over Na2SO4
  9. concentrationconcentrated to dryness
  10. custompurified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA)
  11. customThe organics were removed under reduced pressure
  12. additionthe aqueous residue was treated with K2CO3
  13. extractionextracted with 5:1 DCM/THF (3×)
  14. dry with materialThe combined organics were dried over Na2SO4
  15. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-d8012dd60ce7461780120380d5b2781d
Source dataset
uspto-grants-2015_09
Patent number
US09133183B2

Reaction notes

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