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

HRID 1362289
Notes
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Reaction equation

HRID 1362289 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]
ParticipantsProcedureWorkupSources & evidenceReaction notes

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)acrylamide
Yield 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-976b405f1b094e249d7e53f597ee8a48
Source dataset
uspto-grants-2011_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07879872B2

Reaction notes

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