Sodium hydride → 2-({4-[(4-Acetylpiperazin-1-yl)methyl]-6-methoxypyridin-2-yl}amino)-1,3-thiazole-5-carbonitrile

HRID 1355474Notes

Reaction equation

HRID 1355474 reaction equation
[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][C:20](=O)OC(C)(C)C)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].ClC1[S:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=1>Cl.O1CCOCC1.O.C([O-])(O)=O.[Na+]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][C:20]3[S:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=3)[CH:12]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]

Participants

8

Reactant 3

HCID 24758Sodium hydrideHCID 14852222-Chlorothiazole-5-carbonitrileHCID 18506936tert-Butyl 4-[(4-acetylpiperazin-1-yl)methyl]-6-methoxypyridin-2-ylcarbamate

Product 1

HCID 185068202-({4-[(4-Acetylpiperazin-1-yl)methyl]-6-methoxypyridin-2-yl}amino)-1,3-thiazole-5-carbonitrile

Reagents, catalysts & solvents 4

HCID 313Hydrochloric AcidSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

tert-Butyl 4-[(4-acetylpiperazin-1-yl)methyl]-6-methoxypyridin-2-ylcarbamate (15-4, 310 mg, 0.85 mmole) was taken up in 4 M HCl in dioxane (15 mL) at RT. After 4 hr the mixture was diluted with H2O and neutralized with solid NaHCO3. The resulting mixture was extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in dry THF (5 mL). To this was added NaH (90 mg, 60% dispersion in mineral oil, 2.13 mmole). After gas evolution had ceased 2-chloro-5-cyano-1,3-thiazole (185 mg, 1.28 mmole) was added and the mixture heated to reflux. After 2.5 hr the mixture was cooled to RT and quenched with saturated NH4Cl. The layers were separated and the aqueous layer extracted with CH2Cl2 (4×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-15% EtOH/EtOAc) gave the titled compound as a tan solid. 1H-NMR (500 MHz, d6-DMSO) δ8.26 (s, 1H), 6.70 (s, 1H), 6.43 (s, 1H), 4.04 (s, 3H), 3.47 (s, 2H), 3.43 (m, 4H), 2.38 (m, 2H), 2.31 (m, 2H), 1.98 (s, 3H); MS (ES) (M+H)+373.

Workup

  1. extractionThe resulting mixture was extracted with CH2Cl2 (3×)
  2. dry with materialThe combined organic layers were dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. additionwas added
  6. temperaturethe mixture heated to reflux
  7. customquenched with saturated NH4Cl
  8. customThe layers were separated
  9. extractionthe aqueous layer extracted with CH2Cl2 (4×)
  10. dry with materialThe combined organic layers were dried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-f5221b39af8d489781f92ae426f3acff
Source dataset
uspto-grants-2003_07
Patent number
US06586423B2

Reaction notes

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