Sodium hydride → 2-[3-Chloro-4-(4-methyl-5-oxo-[1,4]diazepan-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile

HRID 1355530Notes

Reaction equation

HRID 1355530 reaction equation
[H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[C:8]([CH2:11][N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[CH2:14][CH2:13]2)[CH:7]=[CH:6][N:5]=1.Cl[C:22]1[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=1>C1COCC1>[Cl:10][C:9]1[C:4]([NH:3][C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)=[N:5][CH:6]=[CH:7][C:8]=1[CH2:11][N:12]1[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:20])[CH2:14][CH2:13]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 14852222-Chlorothiazole-5-carbonitrileHCID 185067941-(2-Amino-3-chloro-pyridin-4-ylmethyl)-4-methyl-[1,4]diazepan-5-one

Product 1

HCID 185068612-[3-Chloro-4-(4-methyl-5-oxo-[1,4]diazepan-1-ylmethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

NaH (0.016 g, 0.40 mmol) was stirred in anhydrous THF, 1.5 mL, under N2. 1-(2-Amino-3-chloro-pyridin-4-ylmethyl)-4-methyl-[1,4]diazepan-5-one (0.045 g, 0.17 mmol) was added followed after 10 min by the addition of 2-chloro-thiazole-5-carbonitrile (0.034 g, 0.23 mmol) and the reaction was heated to reflux. After 4 h the reaction was cooled to RT and quenched by the addition of water. The pH was adjusted to 7 with 1M HCl and the mixture was extracted 3× with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC to afford a colorless oil. The residue was azeotroped 3× with MeOH and the resulting residue was dissolved in a minimum of MeOH. The solvent slowly evaporated to afford a white solid which was further dried in vacuo. TFA salt: 1H NMR (CD3OD) δ 8.46 (d, 1H, J=5.1 Hz), 8.12 (s, 1H), 7.34 (d, 1H, J=5.1 Hz), 4.43 (s, 2H), 3.75 (m, 2H), 3.36 (m, 4H), 3.02 (s, 3H), 2.88 (m, 2H). MS [M+H]+=377.2.

Workup

  1. temperaturethe reaction was heated to reflux
  2. customquenched by the addition of water
  3. extractionthe mixture was extracted 3× with EtOAc
  4. dry with materialThe organic extracts were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by preparative reverse phase HPLC
  8. customto afford a colorless oil
  9. customThe residue was azeotroped 3× with MeOH
  10. dissolutionthe resulting residue was dissolved in a minimum of MeOH
  11. customThe solvent slowly evaporated
  12. customto afford a white solid which
  13. customwas further dried in vacuo

Sources & evidence

ORD record
ord-93c8c53f04db4033a1266cee95776581
Source dataset
uspto-grants-2003_07
Patent number
US06586424B2

Reaction notes

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