Cesium carbonate → 2-(1-{[2,2-Difluorocyclopropyl]methyl}-2-oxo-1,2-dihydro[1,3]thiazolo[5,4-b]pyridin-5-yl)benzonitrile

HRID 1845903Notes

Reaction equation

HRID 1845903 reaction equation
Cl[C:2]1[N:7]=[C:6]2[S:8][C:9](=[O:17])[N:10]([CH2:11][CH:12]3[CH2:14][C:13]3([F:16])[F:15])[C:5]2=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>CO.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[F:15][C:13]1([F:16])[CH2:14][CH:12]1[CH2:11][N:10]1[C:5]2[C:6](=[N:7][C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:18]#[N:19])=[CH:3][CH:4]=2)[S:8][C:9]1=[O:17]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 312751,4-DioxaneHCID 27346102-Cyanophenylboronic acidHCID 866765045-chloro-1-[(2,2-difluorocyclopropyl)methyl][1,3]thiazolo[5,4-b]pyridin-2(1H)-one

Product 1

HCID 545788942-(1-{[2,2-Difluorocyclopropyl]methyl}-2-oxo-1,2-dihydro[1,3]thiazolo[5,4-b]pyridin-5-yl)benzonitrile

Reagents, catalysts & solvents 3

HCID 2734558Bis(tri-tert-butylphosphine)palladium(0)CatalystHCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

To a microwave vial was added 5-chloro-1-[(2,2-difluorocyclopropyl)methyl][1,3]thiazolo[5,4-b]pyridin-2(1H)-one (1-5) (0.025 g, 0.090 mmol), (2-cyanophenyl)boronic acid (0.020 g, 0.14 mmol), cesium carbonate (0.059 g, 0.18 mmol), bis(tri-tert-butylphosphine) palladium (0.009 g, 0.02 mmol), 1,4-dioxane (1 mL), and water (0.2 mL). The reaction mixture was then heated under microwave irradiation at 100° C. for 10 minutes. The crude reaction mixture was then allowed to cool to room temperature, diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) gave 2-(1-{[2,2-difluorocyclopropyl]methyl}-2-oxo-1,2-dihydro[1,3]thiazolo[5,4-b]pyridin-5-yl)benzonitrile (1-6) as a brown solid. 1H NMR (400 MHz, CD3OD): δ 7.87-7.72 (m, 5H); 7.60-7.54 (m, 1H); 4.25-4.10 (m, 2H); 2.23-2.15 (m, 1H); 1.61-1.54 (m, 1H); 1.38 (m, 1H). HRMS (M+H)+: observed=344.0669, calculated=344.0664.

Workup

  1. customThe crude reaction mixture
  2. temperatureto cool to room temperature
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customPurification of crude
  6. customreaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 10% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water)

Sources & evidence

ORD record
ord-2fbf791bc68b492d9f902075ed6218f1
Source dataset
uspto-grants-2015_02
Patent number
US08952005B2

Reaction notes

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