4-Methylmorpholine → (R)-4-(1-(3-(difluoromethyl)azetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one

HRID 1968280Notes

Reaction equation

HRID 1968280 reaction equation
[F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[F:45][CH:46]([F:51])[CH:47]1[CH2:50][NH:49][CH2:48]1.CN1CCOCC1>CN(C=O)C>[F:45][CH:46]([F:51])[CH:47]1[CH2:50][N:49]([C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:17])[CH3:18])[CH2:48]1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 552994833-(Difluoromethyl)azetidineHCID 57389932(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid

Product 1

HCID 49841099(R)-4-(1-(3-(difluoromethyl)azetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-oneYield 50.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R)-2-(6-Fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol), HOBt hydrate (9.46 mg, 0.062 mmol), and EDC hydrochloride (14.81 mg, 0.077 mmol) were combined in DMF (2 mL). 3-(Difluoromethyl)azetidine (8.27 mg, 0.077 mmol) and 4-methylmorpholine (0.023 mL, 0.206 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-60% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and lyophilized to afford the title compound as a white solid (9.8 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 0.78 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 2.31-2.39 (m, 1H), 2.99-3.15 (m, 1H), 3.77-4.35 (m, 4H), 4.82-5.11 (m, 3H), 6.10-6.41(m, 1H), 7.98 (d, J=2.5 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 12.39 (s, 1H). [M+H] calc'd for C18H19F3N4O2, 381; found, 381.

Workup

  1. customThe product was purified by preparative HPLC (10-60% AcCN/H2O with 0.035% TFA)
  2. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-bff0b42b19484ebf85b72deef84b7fe1
Source dataset
uspto-grants-2013_04
Patent number
US08420816B2

Reaction notes

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