4-Methylmorpholine → (R)-1-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile

HRID 1968293Notes

Reaction equation

HRID 1968293 reaction equation
[CH3:1][C:2]([CH3:22])([CH3:21])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([C:10]([CH3:20])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.CN1CCOCC1.CCN=C=[N:34][CH2:35][CH2:36][CH2:37][N:38]([CH3:40])C.Cl.C1C=C2N=NN(O)C2=CC=1.O.Cl.N1CC(C#N)C1>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:22][C:2]([CH3:21])([CH3:1])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([C:10]([CH3:20])=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:38]1[CH2:37][CH:36]([C:35]#[N:34])[CH2:40]1)=[O:6]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 45072465Azetidine-3-carbonitrile hydrochlorideHCID 67223796(R)-3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid

Product 1

HCID 49841216(R)-1-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrileYield 12%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

(R)-3,3-Dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (10 mg, 0.033 mmol), DMAP (6 mg, 0.05 mmol), 4-methylmorpholine (0.015 mL, 0.13 mmol), EDC hydrochloride (10 mg, 0.050 mmol), HOBt hydrate (8 mg, 0.050 mmol) and azetidine-3-carbonitrile hydrochloride (6 mg, 0.050 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred under nitrogen at room temperature for 3 h. The solution was concentrated and purified by preparative HPLC (10-30% AcCN/H2O with 0.035% TFA) to give the title compound (1.4 mg, 12%). 1H NMR (500 MHz, CD3OD) δ 1.18 (s, 9H), 2.35 (d, J=8.8 Hz, 3H) 4.17-4.18 (m, 1H), 4.29-4.31 (m, 2H), 4.52-4.62 (m, 1H), 4.64-4.69 (m, 1H), 5.19-5.23 (m, 2H), 5.45 (s, 1H), 7.83 (d, J=16.1 Hz, 3H), 8.19 (s, 1H). [M+H] calc'd for C20H23N5O2, 366; found, 366

Workup

  1. concentrationThe solution was concentrated
  2. custompurified by preparative HPLC (10-30% AcCN/H2O with 0.035% TFA)

Sources & evidence

ORD record
ord-df7d9a96f49f40ffb8815e329aff912e
Source dataset
uspto-grants-2013_04
Patent number
US08420816B2

Reaction notes

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