Ammonium Chloride → 3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionic acid tert-butyl ester

HRID 1373589Notes

Reaction equation

HRID 1373589 reaction equation
C([Li])CCC.[C:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[CH2:7][CH3:8].[Cl:15][C:16]1[N:21]=[C:20]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([CH:29]=[O:30])=[CH:18][CH:17]=1.[NH4+].[Cl-]>C1COCC1>[C:11]([O:10][C:6](=[O:9])[CH:7]([CH3:8])[CH:29]([C:19]1[C:20]([NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[OH:30])([CH3:14])([CH3:13])[CH3:12]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 88561tert-Butyl propionateHCID 14708120N-(6-chloro-3-formylpyridin-2-yl)-2,2-dimethylpropanamideHCID 178418339Butyllithium

Product 1

HCID 865966783-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A first intermediate compound, 7-Chloro-3-methyl-1H-[1,8]naphthyridin-2-one, was produced as follows: Diisopropyl amine (freshly distilled over sodium, 12.8 mL, 91.4 mmol, 2.2 equiv.) was dissolved in Et2O (40 mL) and cooled to −78° C. Butyl lithium (2.5 M solution in hexane, 37.0 mL, 91.4 mmol, 2.2 equiv.) was added slowly under nitrogen atmosphere. The mixture was stirred for 15 min and t-butyl propionate (13.8 mL, 91.4 mmol, 2.2 equiv.) was added as a solution in dry THF (20 mL). The reaction mixture was stirred for 30 min and N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (10.0 g, 42.0 mmol, 1.0 equiv.) was added as a solution in a minimum amount of dry THF (35 mL). A bright yellow precipitate was formed within 10 min and stirring became difficult. The reaction was allowed to warm up to RT. The reaction mixture turned dark red and was poured into saturated NH4Cl (100 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. 3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2-methyl-propionic acid tert-butyl ester was obtained as a yellow thick syrup which upon drying under high vacuum became a foamy solid (20.0 g, crude). The product was used in the next step without further purification.

Workup

  1. distillationDiisopropyl amine (freshly distilled over sodium, 12.8 mL, 91.4 mmol, 2.2 equiv.)
  2. dissolutionwas dissolved in Et2O (40 mL)
  3. stirringThe reaction mixture was stirred for 30 min
  4. customA bright yellow precipitate was formed within 10 min
  5. stirringstirring
  6. temperatureto warm up to RT
  7. customThe organic layer was separated
  8. extractionthe aqueous layer was extracted with CH2Cl2
  9. dry with materialThe combined organic layers were dried over Na2SO4
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-d58acc777bcf48288c95e968f338d71a
Source dataset
uspto-grants-2007_01
Patent number
US07160888B2

Reaction notes

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