1-Isopropylpiperazine → 1-(4-methoxybenzyl)-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one

HRID 509634Notes

Reaction equation

HRID 509634 reaction equation
[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][C:20](=O)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1.[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][CH:20]([N:32]5[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[CH2:30][CH2:31]5)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:23])=[CH:5][CH:4]=1

Participants

7

Reactant 3

HCID 780131-IsopropylpiperazineHCID 5049666Sodium triacetoxyborohydrideHCID 679930121-(4-methoxybenzyl)-7-(3-oxoazetidin-1-yl)-1,5-naphthyridin-2(1H)-one

Product 1

HCID 679930501-(4-methoxybenzyl)-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-oneYield 72.3%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 1-(4-methoxybenzyl)-7-(3-oxoazetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-7) (5.796 g, 17.3 mmol, 1.0 eq) and 1-isopropylpiperazine (4.432 g, 34.6 mmol, 2.0 eq) in DCM (150 mL) and acetic acid (0.5 mL) was heated at reflux temperature for 3 h, then NaBH(OAc)3 (7.33 g, 34.6 mmol, 2.0 eq) was added in portions and the resulting mixture was kept reflux overnight. The reactant mixture was cooled and diluted with H2O (300 mL) and extracted with DCM (4×100 mL). 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 (2-5% MeOH-DCM) to afford the desired product 1-(4-methoxybenzyl)-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-8) (5.6 g, 72.3% yield) as a pale solid. 1H NMR (300 MHz, CDCl3-d6) δ: 7.83 (d, J=7.5 Hz, 1H), 7.78 (s, 1H), 7.15 (d, J=6.9 Hz, 2H), 6.85 (d, J=6.6 Hz, 2H), 6.72 (d, J=7.2 Hz, 1H), 6.37 (s, 1H), 5.40 (s, 2H), 4.02 (m, 2H), 3.78 (m, 5H), 3.67 (m, 1H), 3.51 (m, 1H), 3.42 (m, 1H), 2.97 (m, 1H), 2.80 (m, 4H), 2.55 (m, 2H), 1.17 (d, J=4.8 Hz, 6H); ESI-MS m/z: 448.3 [M+H]+.

Workup

  1. temperaturewas heated
  2. temperatureat reflux temperature for 3 h
  3. temperaturethe resulting mixture was kept reflux overnight
  4. temperatureThe reactant mixture was cooled
  5. extractionextracted with DCM (4×100 mL)
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated in vacuo
  10. customthe residue was purified by flash column chromatography on silica gel (2-5% MeOH-DCM)

Sources & evidence

ORD record
ord-6ac6616f0093419bb991b04c43758e3e
Source dataset
uspto-grants-2015_08
Patent number
US09096590B2

Reaction notes

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