Diisopropylethylamine → (E)-N-(2-Ethoxy-3-isopropylbenzyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylamide

HRID 2097035Notes

Reaction equation

HRID 2097035 reaction equation
[CH2:1]([O:3][C:4]1[C:12]([CH:13]([CH3:15])[CH3:14])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6]CN)[CH3:2].[CH:16]([N:19](C(C)C)CC)(C)C.Cl.[O:26]=[C:27]1[NH:36][C:35]2[N:34]=[CH:33][C:32](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:31][C:30]=2[CH2:29][CH2:28]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[C:12]([CH:13]([CH3:14])[CH3:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:19]([CH3:16])[C:39](=[O:41])/[CH:38]=[CH:37]/[C:32]1[CH:33]=[N:34][C:35]2[NH:36][C:27](=[O:26])[CH2:28][CH2:29][C:30]=2[CH:31]=1)[CH3:2]

Participants

8

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 66905305(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic Acid HydrochlorideHCID 66967034(2-Ethoxy-3-isopropylbenzyl)methylamine

Product 1

HCID 16662052(E)-N-(2-Ethoxy-3-isopropylbenzyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylamideYield 52%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A solution of (2-ethoxy-3-isopropylbenzyl)methylamine (0.223 g, 1.07 mmol) and diisopropyl-ethylamine (0.51 mL, 2.94 mmol) in DMF (20 mL) was treated sequentially with (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (0.250 g, 0.981 mmol), 1-hydroxybenzotriazole hydrate (0.144 g, 1.07 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.205 g, 1.07 mmol). After stirring for 18 h, the reaction mixture was diluted with H2O (30 mL). The resulting solids were collected by filtration, and when washed with Et2O (50 mL), unexpectedly dissolved. The filtrate was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×100 mL), dried over Na2SO4, filtered and concentrated to a light orange solid. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 99.5:0.5) gave the title compound (0.20 g, 52%) as a white solid and as a mixture of amide rotamers: 1H NMR (500 MHz, DMSO-d6) δ 10.64-10.61 (m, 1H), 8.37-8.31 (m, 1H), 8.09-7.99 (m, 1H), 7.52-7.49 (m, 1H), 7.28-7.20 (m, 2H), 7.11-7.05 (m, 1H), 6.89-6.86 (m, 1H), 4.81-4.66 (m, 2H), 3.86-3.79 (m, 2H), 3.28-3.25 (m, 1H), 3.11-2.85 (m, 5H), 2.55-2.49 (m, 2H), 1.39-1.35 (m, 3H), 1.19-1.17 (m, 6H); MS (ESI) m/e 408 (M+H)+.

Workup

  1. filtrationThe resulting solids were collected by filtration, and when
  2. washwashed with Et2O (50 mL)
  3. dissolutionunexpectedly dissolved
  4. extractionThe filtrate was extracted with EtOAc (3×50 mL)
  5. washThe combined organics were washed with brine (2×100 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated to a light orange solid
  9. customPurification by column chromatography (silica gel, CH2Cl2/MeOH, 100 to 99.5:0.5)

Sources & evidence

ORD record
ord-00a34fc6594b48258ca959837ad784ae
Source dataset
uspto-grants-2013_05
Patent number
US08450307B2

Reaction notes

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