Sodium Chloride → [5-Chloro-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester

HRID 1992654Notes

Reaction equation

HRID 1992654 reaction equation
[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:11](N)=[CH:10][N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=1)[CH3:2].N([O-])=O.[Na+].[Na+].[Cl-:26]>Cl.O.CCOC(C)=O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:11]([Cl:26])=[CH:10][N:9]=[C:8]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:7]=1)[CH3:2]

Participants

8

Reactant 3

HCID 5234Sodium ChlorideHCID 23668193Sodium NitriteHCID 66869297[5-Amino-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester

Product 1

HCID 66869353[5-Chloro-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester

Reagents, catalysts & solvents 4

HCID 62652Cuprous chlorideCatalystHCID 313Hydrochloric AcidSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

[5-Amino-2-(4-methyl-piperazin-1-yl)-pyridin-4-yl]-acetic acid ethyl ester (680 mg, 2.44 mmol) is dissolved under an atmosphere of argon in 18% aqueous hydrochloric acid (12 ml). After cooling the solution to 0° C., a solution of sodium nitrite (244 mg, 3.54 mmol) in water (6 ml) is added over 15 minutes, taking care that the internal temperature did not rise above 5° C. After 20 minutes at 0° C., the reaction mixture is added to a −10° C. solution of copper(I) chloride (freshly prepared, 725 mg, 7.33 mmol) in water (1.8 ml). After 15 minutes at −10° C., TLC analysis indicated complete conversion. The reaction mixture is diluted with EtOAc and poured in a saturated aqueous NaCl solution. The organic layer is separated, dried over Na2SO4, and concentrated. The residue is purified by FCC (CH2Cl2/MeOH, gradient from 98:2 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.27 (t, J=7 Hz, 3H), 2.34 (s, 3H), 2.50 (m, 4H), 3.52 (m, 4H), 3.66 (s, 2H), 4.19 (q, J=7 Hz, 2H), 6.59 (s, 1H), 8.11 (s, 1H). ES+−MS: 298.2, 300.1 (Cl) [M+H]+, ES−−MS: 296.2, 298.2 (Cl) [M−H]−.

Workup

  1. customdid not rise above 5° C
  2. customfreshly prepared
  3. waitAfter 15 minutes at −10° C.
  4. customThe organic layer is separated
  5. dry with materialdried over Na2SO4
  6. concentrationconcentrated
  7. customThe residue is purified by FCC (CH2Cl2/MeOH, gradient from 98:2 to 90:10)

Sources & evidence

ORD record
ord-296ec9ef367b4788b29b4d7fa936ff9d
Source dataset
uspto-grants-2010_01
Patent number
US07648989B2

Reaction notes

Loading…