Phosphorus oxychloride → 2-Chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine

HRID 2199891Notes

Reaction equation

HRID 2199891 reaction equation
[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[C:22]4[C:17]([CH:18]=[CH:19][C:20](=O)[NH:21]4)=[N:16][CH:15]=3)[CH2:11]2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][C:14]([N:12]3[CH2:13][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)[CH2:11]3)=[CH:15][N:16]=2)[N:21]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 679930417-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one

Product 1

HCID 866975552-Chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridineYield 33.7%

Procedure

7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-9) (5.346 g, 16.3 mmol, 1.0 eq) was dissolved in POCl3 (100 mL) and the resulting mixture was stirred at reflux for 30 min. The reaction was complete based on TLC analysis. Then the mixture was cooled to RT and concentrated in vacuo to remove POCl3. The residue was poured into ice water (500 mL) and neutralized with saturated aqueous Na2CO3 solution to adjust the pH value to 8-9 while keeping the temperature below 0° C. The mixture was stirred at RT for 30 min. The residue was extracted with DCM (4×200 mL) and the combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (2-7% MeOH-DCM) to afford the desired product 2-chloro-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridine (C-10) (1.9 g, 33.7% yield). ESI-MS m/z: 346.14 [M+H]+.

Workup

  1. temperatureat reflux for 30 min
  2. concentrationconcentrated in vacuo
  3. customto remove POCl3
  4. additionThe residue was poured into ice water (500 mL)
  5. customthe temperature below 0° C
  6. stirringThe mixture was stirred at RT for 30 min
  7. extractionThe residue was extracted with DCM (4×200 mL)
  8. washthe combined organic layers were washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationThe filtrate was concentrated in vacuo
  12. customthe residue was purified by flash column chromatography on silica gel (2-7% MeOH-DCM)

Sources & evidence

ORD record
ord-7101d34727124458876bbcd74eab50b5
Source dataset
uspto-grants-2016_06
Patent number
US09359352B2

Reaction notes

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