Sodium Nitrite → HCID 58286959, compound

HRID 1962403Notes

Reaction equation

HRID 1962403 reaction equation
[CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20](F)[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH3:33])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:3][CH2:2]1.N([O-])=[O:35].[Na+]>CN(C)C=O>[CH:1]1([C@H:4]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[C:20]([OH:35])[CH:21]=[CH:22][CH:23]=3)[C:18](=[O:26])[N:17]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:16]=2[CH3:33])=[O:14])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH2:2][CH2:3]1

Participants

4

Reactant 2

HCID 23668193Sodium NitriteHCID 44600701HCID 44600701, compound

Product 1

HCID 58286959HCID 58286959, compoundYield 10.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
220 °C

Procedure

A mixture of 8-fluoro-3-methyl-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid [(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amide (2a, 70.0 mg, 0.157 mmol), sodium nitrite (NaNO2, 77.0 mg, 1.12 mmol) in N,N-dimethylformamide (0.7 mL) was heated under microwave irradiation at 220° C. for 30 min. The obtained dark solution was quenched with 3M aq. HCl (5 ml), stirred for 20 min and partitioned with ethyl acetate (3×5 mL). Each organic solution was washed with 1M HCl (3×2 mL). The combined aq. solution was basified with NaHCO3 (pH=7) and extracted with ethyl acetate. The combined organic extracts were absorbed on 1 g SiO2 and flash chromatographed on 20 g silica gel with gradient heptane-ethyl acetate. The product came out with 75% ethyl acetate and only pure fractions were evaporated to give 7.1 mg of a brown residue, yield 10%. LC-MS (m/z) 444.6 (MH+); tR=1.26. 1H NMR (500 MHz, 70° C., DMSO-d6): 0.48 & 0.59 (two br. s, 2×2H, two CH2 of Cp), 1.27 (br. s, 1H, CH of Cp), 1.91 (br. s, 3H, Me), 4.51 (t, J=8.5 Hz, 1H, CHNH), 6.87 (overlapping d, J=8.1 Hz, 1H), 6.9 (overlapping br. s, 1H), 7.06 (br. T, J=8.3 Hz, 1H), 7.26 (d, J=10.5 Hz, 1H), 7.3 (d, J=7.6 Hz, 1H), 7.40 (q, J=7.2 Hz, 1H), 7.59-7.66 (br. m, 2H), 7.86 (br. m, 1H), 8.58 (s, 1H), 8.72 (s, 1H), 8.93 (br. d, J=7.8 Hz, NHCO), 12.46 (s, 1H, OH).

Workup

  1. customThe obtained dark solution was quenched with 3M aq. HCl (5 ml)
  2. custompartitioned with ethyl acetate (3×5 mL)
  3. washEach organic solution was washed with 1M HCl (3×2 mL)
  4. extractionextracted with ethyl acetate
  5. customThe combined organic extracts were absorbed on 1 g SiO2 and flash
  6. customchromatographed on 20 g silica gel with gradient heptane-ethyl acetate
  7. customwere evaporated

Sources & evidence

ORD record
ord-169e7b0f8aae432b99ed8f175dc9c0eb
Source dataset
uspto-grants-2013_04
Patent number
US08415356B2

Reaction notes

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