Ammonium Chloride → 2-(6-tert-Butyl-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-4-iodo-pyridine-3-carbaldehyde

HRID 337313Notes

Reaction equation

HRID 337313 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:28]1[N:35]=[CH:34][CH:33]=[C:32]([I:36])[C:29]=1[CH:30]=[O:31].[NH4+].[Cl-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:28]1[C:29]([CH:30]=[O:31])=[C:32]([I:36])[CH:33]=[CH:34][N:35]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 99923282-Fluoro-4-iodopyridine-3-carbaldehydeHCID 710417426-(tert-butyl)-8-fluoroisoquinolin-1(2H)-one

Product 1

HCID 866769352-(6-tert-Butyl-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-4-iodo-pyridine-3-carbaldehydeYield 75.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
65 °C

Procedure

To a solution of 6-tert-butyl-8-fluoroisoquinolin-1(2H)-one (225 mg, 1.03 mmol, Eq: 1.00) in THF (11.1 ml) was added lithium bis(trimethylsilyl)amide in THF (1 M) (1.13 ml, 1.13 mmol, Eq: 1.1) at room temperature. The reaction mixture was stirred for 20 min. at the same temperature. Then 2-fluoro-4-iodonicotinaldehyde (335 mg, 1.33 mmol, Eq: 1.3) in THF (5 mL) was added. The reaction mixture was heated to 65° C. and stirred for 3 h. Then the reaction was poured into an aqueous-saturated solution of NH4Cl (30 mL) and product was extracted with EtOAc (2×50 mL). The combined organic extracts were dried (Na2SO4) and evaporated under vacuum. Crude was diluted with CH2Cl2 (2 mL) and purified by chromatography (SiO2, Hex:AcOEt, 100% to 70% in 25 min) to afford the desired product (350 mg) as a light yellow powder. LC/MS, m/z 451[M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 9 H) 6.65 (dd, J=7.58, 2.02 Hz, 1 H) 7.21 (dd, J=13.64, 1.77 Hz, 1 H) 7.31 (d, J=1.77 Hz, 1 H) 7.55 (d, J=7.58 Hz, 1 H) 7.91 (d, J=5.05 Hz, 1 H) 8.28 (d, J=5.31 Hz, 1 H) 9.94 (s, 1 H).

Workup

  1. stirringstirred for 3 h
  2. extractionwas extracted with EtOAc (2×50 mL)
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. customevaporated under vacuum
  5. additionCrude was diluted with CH2Cl2 (2 mL)
  6. custompurified by chromatography (SiO2, Hex:AcOEt, 100% to 70% in 25 min)

Sources & evidence

ORD record
ord-c783e622b9834f9a90448e1b242d48bf
Source dataset
uspto-grants-2014_11
Patent number
US08889682B2

Reaction notes

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