Dimethylformamide → 5-({3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile

HRID 1774900Notes

Reaction equation

HRID 1774900 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[N:7][CH:6]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1

Participants

6

Reactant 2

HCID 6228DimethylformamideHCID 510006176-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one

Product 1

HCID 510007035-({3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-4-oxo-3,4-dihydrobenzo[h]quinazolin-6-yl}methyl)pyridine-2-carbonitrile

Reagents, catalysts & solvents 3

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (0.100 g, 0.237 mmol) in 1 mL of DMF under an atmosphere of nitrogen was added zinc cyanide (Example 1, 0.084 g, 0.71 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.7 mg, 0.012 mmol). The mixture was heated to 100° C. for 8 h, then at 140° C. for another 15 h. The reaction was cooled to rt, diluted with ethyl acetate, washed 3× with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 413.1603 for [M+H]+ [Calc'd for C24H21N4O3, [M+H]+=413.1608]: 1H NMR (400 MHz, CDCl3) δ 8.96-8.94 (m, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.98 (s, 1H), 7.78-7.75 (m, 1H), 7.64-7.59 (m, 2H), 7.50 (s, 2H), 4.72-4.69 (m, 1H), 4.49 (s, 2H), 4.11-4.05 (m, 2H), 4.04-3.98 (m, 1H), 3.50-3.47 (m, 1H), 3.29-3.20 (m, 2H), 2.17-2.13 (m, 1H), 2.00-1.95 (m, 1H).

Workup

  1. temperatureThe reaction was cooled to rt
  2. washwashed 3× with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified via preparative reverse phase HPLC

Sources & evidence

ORD record
ord-31431853ba404fa3ae471ee4df53e3e0
Source dataset
uspto-grants-2016_02
Patent number
US09260418B2

Reaction notes

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