1-Hydroxybenzotriazole → (E)-N-(benzo[b]thiophen-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide

HRID 1362412Notes

Reaction equation

HRID 1362412 reaction equation
[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH:11][CH3:12])[CH:8]=[CH:9][C:2]1=2.Cl.[O:14]=[C:15]1[NH:24][C:23]2[N:22]=[CH:21][C:20]([CH:25]=[CH:26][C:27]([OH:29])=O)=[CH:19][C:18]=2[CH2:17][CH2:16]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>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][N:11]([CH3:12])[C:27](=[O:29])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[N:22][C:23]4[NH:24][C:15](=[O:14])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:8]=[CH:9][C:2]1=2

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 16640607Benzo[b]thiophene-5-methanamine, N-methyl-HCID 669053063-(7-Oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride

Product 1

HCID 16661128(E)-N-(benzo[b]thiophen-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamideYield 78%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of benzo[b]thiophen-5-yl-N-methylmethanamine (260 mg, 1.47 mmol), 3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-acrylic acid hydrochloride (377 mg, 1.48 mmol), HOBt (200 mg, 1.48 mmol) and DIPEA (1.05 mL, 6.03 mmol) in anhydrous DMF (24 mL) was added EDC hydrochloride (284 mg, 1.48 mmol). The mixture was stirred overnight at 40° C. Water (50 mL) was added and the solution was stirred for 1 h. The reaction mixture was extracted with ethyl acetate (3×80 mL). Combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated to give an orange solid which was purified by column chromatography (silica gel, 5% MeOH/CH2Cl2) to afford (E)-N-(benzo[b]thiophen-5-ylmethyl)-N-methyl-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (430 mg, 78%) as a pink solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.67-10.64 (m, 1H), 8.37-8.33 (m, 1H), 8.08-8.05 (m, 1H), 8.00-7.95 (m, 1H), 7.75-7.71 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.43 (m, 1H), 7.37-7.22 (m, 2H), 4.93-4.73 (m, 2H), 3.12-2.86 (m, 5H), 2.54-2.51 (m, 2H); ESI MS m/z 378 [C21H19N3O2S+H]+.

Workup

  1. stirringthe solution was stirred for 1 h
  2. extractionThe reaction mixture was extracted with ethyl acetate (3×80 mL)
  3. washCombined organic layers were washed with water (50 mL) and brine (50 mL)
  4. concentrationconcentrated
  5. customto give an orange solid which
  6. customwas purified by column chromatography (silica gel, 5% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-e50fbfd6bae14e9fb64b25d194bd0218
Source dataset
uspto-grants-2011_02
Patent number
US07879872B2

Reaction notes

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