1-Hydroxybenzotriazole → (E)-N-methyl-N-((1-methyl-1H-indol-4-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

HRID 2097163Notes

Reaction equation

HRID 2097163 reaction equation
[CH3:1][NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:13].Cl.[O:15]=[C:16]1[NH:25][C:24]2[N:23]=[CH:22][C:21]([CH:26]=[CH:27][C:28](O)=[O:29])=[CH:20][C:19]=2[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH3:13])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]1[CH:22]=[N:23][C:24]2[NH:25][C:16](=[O:15])[CH2:17][CH2:18][C:19]=2[CH:20]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57825683N-methyl-1-(1-methyl-1H-indol-4-yl)methanamineHCID 669053063-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride

Product 1

HCID 16661129(E)-N-methyl-N-((1-methyl-1H-indol-4-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamideYield 36%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of N-methyl(1-methyl-1H-indol-4-yl)methanamine (418 mg, 2.40 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (617 mg, 2.42 mmol), HOBt (327 mg, 2.42 mmol) and DIPEA (1.71 mL, 9.82 mmol) in anhydrous DMF (40 mL) was added EDC hydrochloride (460 mg, 2.40 mmol). The mixture was stirred overnight at 40° C. Water (60 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with CH2Cl2 (3×100 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give a red solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-methyl-N-((1-methyl-1H-indol-4-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (320 mg, 36%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.64-10.61 (m, 1H), 8.36-8.32 (m, 1H), 8.07-7.98 (m, 1H), 7.56-7.51 (m, 1H), 7.37-7.23 (m, 3H), 7.19-7.09 (m, 1H), 6.92-6.79 (m, 1H), 6.49-6.48 (m, 1H), 5.05-4.87 (m, 2H), 3.78-3.77 (m, 3H), 3.01-2.82 (m, 5H), 2.54-2.52 (m, 2H); ESI MS m/z 375 [C22H22N4O2+H]+.

Workup

  1. stirringthe solution was stirred for 1 h
  2. extractionThe reaction mixture was extracted with CH2Cl2 (3×100 mL)
  3. washCombined organic layers were washed with water (50 mL) and brine (50 mL)
  4. concentrationconcentrated
  5. customto give a red solid which
  6. customwas purified by column chromatography (silica gel, 5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-0c0daeb1e9634c47996634d182db72c1
Source dataset
uspto-grants-2013_05
Patent number
US08450307B2

Reaction notes

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