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

HRID 1968285Notes

Reaction equation

HRID 1968285 reaction equation
[CH3:1][CH:2]([CH3:20])[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]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1.CN1CCOCC1>CN(C=O)C>[CH3:1][CH:2]([CH3:20])[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]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1)=[O:6]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 45072465Azetidine-3-carbonitrile hydrochlorideHCID 67224069(R)-3-Methyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid

Product 1

HCID 49841100(R)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrileYield 28.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R)-3-Methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.29 mmol), HOBt (54 mg, 0.35 mmol) and EDC (84 mg, 0.44 mmol) were combined in DMF (2 mL). Azetidine-3-carbonitrile HCl salt (52 mg, 0.44 mmol) and N-methylmorpholine (130 μL, 1.17 mmol) were added, and the solution was stirred at room temperature for 2 h. Purification by preparative HPLC (10-45% AcCN/water with 0.035% TFA) followed by purification by silica gel chromatography (8% MeOH/DCM) gave the title compound as a white solid (28 mg, 28%). 1H NMR (500 MHz, DMSO-d6) δ 0.90 (dd, J=6.5, 2.0 Hz, 3H), 1.06 (dd, J=6.5, 2.0 Hz, 3H), 2.42-2.51 (m, 1H), 3.61-3.75 (m, 1H), 4.15-4.68 (m, 4H), 4.95-5.21 (m, 3H), 7.09 (t, J=5.0 Hz, 1H), 7.81 (d, J=12.5 Hz, 1H), 8.27 (t, J=5.0 Hz, 1H). [M+H] calc'd for C18H19N5O2, 338; found, 338.

Workup

  1. customPurification by preparative HPLC (10-45% AcCN/water with 0.035% TFA)
  2. customfollowed by purification by silica gel chromatography (8% MeOH/DCM)

Sources & evidence

ORD record
ord-b0fe0585bfe244b593aa7143584c76cf
Source dataset
uspto-grants-2013_04
Patent number
US08420816B2

Reaction notes

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