Sodium Bicarbonate → (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbonitrile

HRID 447432Notes

Reaction equation

HRID 447432 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]P(=O)(OCC)OCC)[CH:2]=1.C(O[K])(C)(C)C.[CH:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=2)[NH:26][N:25]=1)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:22]/[C:24]2[C:32]3[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=3)[NH:26][N:25]=2)[CH:2]=1

Participants

7

Reactant 4

HCID 516892Sodium BicarbonateHCID 104626053-(Diethoxyphosphorylmethyl)pyridineHCID 178418922HCID 178418922, compoundHCID 178509486HCID 178509486, compound

Product 1

HCID 66734132(E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbonitrileYield 67%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

Diethyl pyridin-3-ylmethylphosphonate was redissolved in DMF (50 mL), cooled to 0° C. and treated with tBuOK (6.72 g, 60 mmol) portion wise over 3 min; the reaction turned a dark reddish brown. After stirring for 3 min at 0° C., a solution of 3-formyl-1H-indazole-6-carbonitrile (3.42 g, 20 mmol) in DMF (25 mL) was added dropwise by pipette over 5 min. After addition, the resulting mixture was stirred for 1 h at 0° C. before quenching with ice (100 mL). The reaction mixture was cooled to 0° C. and slowly acidified with 2M HCl until pH 5. During this addition, a copious amount of precipitate was formed. After stirring for 2 min at this temperature, sat NaHCO3 was added slowly until pH 8 and the mixture was stirred for an additional 2 min. Water was added until the total volume reached 600 mL. After stirring for 10 min, the resulting precipitate was collected by suction filtration and rinsed thoroughly with water, then dried under high vacuum to give the title compound (3.30 g, 67%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H, NH), 8.89 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 4.42 (d, J=8.4 Hz, 1H), 8.22-8.17 (m, 2H), 7.74 (d, J=16.8 Hz, 1H), 7.59 (d, J=18.0 Hz, 1H, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J=10.0 Hz, 1H, partially overlapping with the doublet at 7.59 ppm), 7.43 (dd, J=8.0 Hz, 5.6 Hz, 1H); MS ESI 247.0 [M+H]+, calcd for [C15H10N4+H]+ 247.1.

Workup

  1. additionAfter addition
  2. stirringthe resulting mixture was stirred for 1 h at 0° C.
  3. custombefore quenching with ice (100 mL)
  4. temperatureThe reaction mixture was cooled to 0° C.
  5. additionDuring this addition
  6. customa copious amount of precipitate was formed
  7. stirringAfter stirring for 2 min at this temperature
  8. additionwas added slowly until pH 8
  9. stirringthe mixture was stirred for an additional 2 min
  10. stirringAfter stirring for 10 min
  11. filtrationthe resulting precipitate was collected by suction filtration
  12. washrinsed thoroughly with water
  13. customdried under high vacuum

Sources & evidence

ORD record
ord-0dbc4f867e284394aa1f4da10497b42b
Source dataset
uspto-grants-2013_07
Patent number
US08481525B2

Reaction notes

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