1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (E)-1'-Methyl-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4'-piperidin]-2(4H)-one

HRID 633961Notes

Reaction equation

HRID 633961 reaction equation
Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:34]([N:37]([CH:40]([CH3:42])C)[CH2:38][CH3:39])(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:34][N:37]1[CH2:38][CH2:39][C:46]2([CH2:47][C:48]3[C:53](=[N:52][CH:51]=[C:50](/[CH:55]=[CH:56]/[C:57](=[O:58])[N:11]4[CH2:12][CH:9]([O:8][CH2:7][C:3]5[S:2][CH:6]=[CH:5][CH:4]=5)[CH2:10]4)[CH:49]=3)[NH:54][C:45]2=[O:44])[CH2:42][CH2:40]1

Participants

9

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 66905305(E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic Acid HydrochlorideHCID 671545443-(2-Thienylmethoxy)azetidine hydrochloride

Product 1

HCID 52950662(E)-1'-Methyl-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1H-spiro[[1,8]naphthyridine-3,4'-piperidin]-2(4H)-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (45.8 mg, 0.22 mmol), EDCI (40.26 mg, 0.21 mmol), HOBt (28.5 mg, 0.21 mmol) and diisopropylethylamine (62 μL, 0.35 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (47.0 mg, 0.14 mmol) in dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (20 ml) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (95:5 to 0:1) as eluent. After precipitation in a mixture dichloromethane/diethylether/pentane, the title product was obtained as a white solid (12 mg, 24%).

Workup

  1. customThe aqueous layer was separated
  2. extractionextracted with ethyl acetate (2×20 mL)
  3. washThe combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL)
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated to dryness
  7. customThe residue was purified by chromatography on silica gel
  8. customAfter precipitation in a mixture dichloromethane/diethylether/pentane

Sources & evidence

ORD record
ord-0b95486177c64022ba4339db4e05ca3c
Source dataset
uspto-grants-2016_04
Patent number
US09321769B2

Reaction notes

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