Cesium carbonate → 2-((6-chloro-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrile

HRID 1057023Notes

Reaction equation

HRID 1057023 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[C:20]([CH:19]=[CH:18][N:17]=2)[C:22]#[N:23])[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 70155242-AminoisonicotinonitrileHCID 841406282,6-Dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridine

Product 1

HCID 725507132-((6-chloro-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)isonicotinonitrileYield 54.5%

Reagents, catalysts & solvents 2

HCID 634876Binap, (A+-)-CatalystHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a 25 mL round-bottomed flask charged with 2,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridine (1.20 g, 5.20 mmol, 1.00 equiv), 2-aminopyridine-4-carbonitrile (620 mg, 5.20 mmol, 1.00 equiv), cesium carbonate (2.40 g, 7.20 mmol, 1.40 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (170 mg, 0.260 mmol, 0.0500 equiv), and tris(dibenzylidineacetone)dipalladium(0) (120 mg 0.130 mmol, 0.0250 equiv) was added 1,4-dioxane (10 mL) under nitrogen atmosphere. The reaction was then heated to 80° C. for 16 h after which the mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water (2×15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (40:60 ethyl acetate/heptane) afforded the desired product as a yellow solid (892 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 10.38 (s, 1H), 8.49 (d, J=5.3 Hz, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.34-7.23 (dd, J=4.0, 2.0 Hz, 1H), 6.98 (d, J=1.1 Hz, 1H), 3.95 (dd, J=11.9, 4.0 Hz, 2H), 3.44 (td, J=11.9, 2.4 Hz, 2H), 2.82 (tt, J=12.0, 3.6 Hz, 1H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H).

Workup

  1. temperaturewas cooled to room temperature
  2. washwashed with water (2×15 mL)
  3. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by flash column chromatography (40:60 ethyl acetate/heptane)

Sources & evidence

ORD record
ord-de3791f7b2ad437087f0a815ce86466d
Source dataset
uspto-grants-2016_07
Patent number
US09399636B2

Reaction notes

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