Ammonium Chloride → 4-[(3-Bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

HRID 2422362Notes

Reaction equation

HRID 2422362 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([Cl:19])=[N:14][CH:15]=[CH:16][C:17]=1[NH2:18].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH:31]=[C:30]([CH2:33]Cl)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH:29]=[C:30]([CH2:33][NH:18][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([Cl:19])[C:12]=2[Br:11])[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 109988611,1-Dimethylethyl 4-(chloromethyl)-3,6-dihydro-1(2H)-pyridinecarboxylateHCID 299193003-Bromo-2-chloropyridin-4-amine

Product 1

HCID 727367364-[(3-Bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl esterYield 70.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Lithium bis(trimethylsilyl)amide (1M solution in THF, 5.1 ml) was added dropwise to a stirred solution of 3-bromo-2-chloro-4-aminopyridine (1.04 g) in tetrahydrofuran (15 ml) at −78° C. under N2. The resulting solution was then stirred at room temperature for 30 min., warmed to 0° C. then cooled again at −78° C. 4-Chloromethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.16 g, prepared according to WO 98/25605) dissolved in a minimum volume of THF was added dropwise then the solution was refluxed for 14 hours. The reaction mixture was cooled to room temperature, poured into diluted aqueous ammonium chloride, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 then CH2Cl2/EtOAc 8:2 cyclohexane:ethyl acetate 8:2) to afford 4-[(3-bromo-2-chloro-pyridin-4-ylamino)-methyl]-3,6-dihydro-2H -pyridine-1-carboxylic acid tert-butyl ester (1.42 g), which was identified by its mass and 1H NMR spectra. MS (ES+) 346/348/350 (MH+-isoprene), 402/404/406 (MH+).

Workup

  1. temperaturewarmed to 0° C.
  2. temperaturethen cooled again at −78° C
  3. additionwas added dropwise
  4. temperaturethe solution was refluxed for 14 hours
  5. temperatureThe reaction mixture was cooled to room temperature
  6. extractionextracted with EtOAc
  7. washThe organic layer was washed with brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel chromatography (CH2Cl2

Sources & evidence

ORD record
ord-ea2865b058b7467b8166b4b37457240a
Source dataset
uspto-grants-2011_06
Patent number
US07960401B2

Reaction notes

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