Sodium Nitrite → HCID 178480031, compound

HRID 1056946Notes

Reaction equation

HRID 1056946 reaction equation
[NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[C:11](=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[N:37]([O-])=O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[N:1]=[N:37][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[N:18][NH:17][C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1

Participants

6

Reactant 2

HCID 23668193Sodium NitriteHCID 123212492HCID 123212492, compound

Product 1

HCID 178480031HCID 178480031, compoundYield 20.3%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
20 °C

Procedure

A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (103 mg, 0.200 mmol) in acetic acid (0.40 mL) was treated with water (1.0 mL) followed by sodium nitrite (69.0 mg, 1.00 mmol) and stirred at 20° C. for 30 min. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate (2×) and brine, dried with magnesium sulfate, filtered, and concentrated to give the SEM-protected intermediate which was used without further purification. The crude intermediate was diluted with methylene chloride (4.00 mL) and trifluoroacetic acid (4.00 mL) and stirred at 40° C. for 3 h. The reaction mixture was concentrated, diluted with acetonitrile, adjusted to pH 7 with 1 M NaOH, and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (16 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 14.05 (br s, 1H), 7.86-7.72 (m, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.31-7.22 (m, 1H), 6.85-6.73 (m, 2H), 3.53 (s, 3H); LCMS calculated for C19H13F2N6O2 (M+H)+: m/z=395.1. found: 395.1.

Workup

  1. customThe organic layer was separated
  2. washwashed with saturated sodium bicarbonate (2×) and brine
  3. dry with materialdried with magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give the SEM-protected intermediate which
  7. customwas used without further purification
  8. additionThe crude intermediate was diluted with methylene chloride (4.00 mL) and trifluoroacetic acid (4.00 mL)
  9. stirringstirred at 40° C. for 3 h
  10. concentrationThe reaction mixture was concentrated
  11. additiondiluted with acetonitrile
  12. custompurified via preparative LCMS (XBridge C18 column
  13. washeluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-5f39a63890ee43b1b0758f61701dc691
Source dataset
uspto-grants-2016_07
Patent number
US09399640B2

Reaction notes

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