Water → Tert-butyl 3-[6-chloro-2-(2,2-dimethylpropanamido)pyridin-3-yl]-3-hydroxypropanoate

HRID 1373583Notes

Reaction equation

HRID 1373583 reaction equation
C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH3:12].[Cl:19][C:20]1[N:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:23]([CH:33]=[O:34])=[CH:22][CH:21]=1.O>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:15]([O:14][C:11](=[O:13])[CH2:12][CH:33]([C:23]1[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])=[N:25][C:20]([Cl:19])=[CH:21][CH:22]=1)[OH:34])([CH3:18])([CH3:17])[CH3:16]

Participants

8

Reactant 4

HCID 962WaterHCID 10908tert-Butyl acetateHCID 14708120N-(6-chloro-3-formylpyridin-2-yl)-2,2-dimethylpropanamideHCID 57426343Lithium bis(trimethylsilyl)amide

Product 1

HCID 14708126Tert-butyl 3-[6-chloro-2-(2,2-dimethylpropanamido)pyridin-3-yl]-3-hydroxypropanoateYield 79%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
-78 °C

Procedure

A first intermediate compound, 7-Chloro-1H-[1,8]naphthyridin-2-one, was produced as follows: To a stirred solution of lithium hexamethyldisilazane (26.3 mmol, 1.0 M in THF) in THF (10 mL) at −78° C. is added t-butyl acetate (3.53 mL, 26.3 mmol) dropwise. The mixture is stirred at −78° C. for 30 min and N-(6-chloro-3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (3.00 g, 12.5 mmol) in THF (20 mL) is added dropwise. A yellow precipitate forms and the mixture is stirred at −78° C. for 30 minutes and warmed to room temperature over 3 hours. H2O (10 mL) is added, the mixture stirred for 5 minutes and then diluted with ethyl acetate (20 mL) and brine (10 mL). The organic layer is separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The compound is recrystallized from ethyl acetate and hexanes to yield 3-[6-chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-propionic acid tert-butyl ester (3.52 g, 79%); mp 130–132° C., 1H NMR (400 MHz, CDCl3) δ 8.25 (br s, 1H), 7.76 (d, 1H), 7.16 (d, 1H), 5.05–4.98 (m, 1H), 4.08 (d, 1H), 2.80 (dd, 1H), 2.70 (dd, 1H), 1.41 (s, 9H), 1.36 (s, 9H); MS ES+ 357.03 (M+H)+.

Workup

  1. stirringA yellow precipitate forms and the mixture is stirred at −78° C. for 30 minutes
  2. temperaturewarmed to room temperature over 3 hours
  3. stirringthe mixture stirred for 5 minutes
  4. customThe organic layer is separated
  5. washwashed with brine (20 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under vacuum
  9. customThe compound is recrystallized from ethyl acetate and hexanes

Sources & evidence

ORD record
ord-1a0a82ef850d45df845a756073b48948
Source dataset
uspto-grants-2007_01
Patent number
US07160888B2

Reaction notes

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