Sulfamic Acid → 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid

HRID 246390

Reaction equation

HRID 246390 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]2[C:13]1[N:14]=[C:15]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=1.S(=O)(=O)([OH:34])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]2[C:13]1[N:14]=[C:15]2[C:21]([C:22]([OH:34])=[O:23])=[CH:20][N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=1

Participants

8

Reactant 4

HCID 5987Sulfamic Acid2×HCID 516951Monobasic potassium phosphate2×HCID 23668197Sodium Chlorite2×HCID 866779772-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde

Product 1

HCID 712798522-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acidYield 52%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent4×HCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
25 °C

Procedure

To a yellow suspension of 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (443 mg, 1.01 mmol) in dioxane (14 mL) and water (4 mL) at 0° C. was added sulfamic acid (590 mg, 6.07 mmol, Eq: 6.00), followed by drop-wise addition of a solution of sodium chlorite (149 mg, 1.32 mmol) and KH2PO4 (1.65 g, 12.1 mmol2.00) in water (4.5 mL) via dropping funnel over 15 min. The ice bath was removed and the light yellow suspension was stirred at 25° C. for 18 h. LCMS indicated reaction about 50% complete, THF (10 mL) added to the yellow suspension then addition at 25° C. of more reagents: sulfamic acid (590 mg, 6.07 mmol, Eq: 6.00) solid, followed by a dropwise addition of a solution of sodium chlorite (149 mg, 1.32 mmol) and KH2PO4 (1.65 g, 12.1 mmo12.00) in 10 mL of water and stirring continued at 25° C. for 4 h. Mixture diluted with water (50 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were dried (MgSO4), added some charcoal heated to reflux, after cooling down to 25° C., filtered over a celite pad and evaporated. Light yellow solid residue was dissolved in dichloromethane/MeOH and dichloromethane evaporated to promote solid formation, solid separated by filtration, rinsed with MeOH and hexanes and dried to give 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (238 mg, 525 μmol, 51.8%). MS (M+H)+=454 (>90% purity); 1H NMR (CDCl3) δ: 9.38 (s, 1H), 8.38 (s, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.3, 2.5 Hz, 1H), 5.79 (s, 2H), 4.21 (s, 3H), 3.99 (s, 3H), 3.60-3.73 (m, 2H), 0.93-1.06 (m, 2H), 0.00 (s, 9H).

Workup

  1. customover 15 min
  2. customThe ice bath was removed
  3. customreaction about 50% complete
  4. additionaddition at 25° C. of more reagents
  5. stirringstirring
  6. waitcontinued at 25° C. for 4 h
  7. extractionextracted with dichloromethane (3×40 mL)
  8. dry with materialThe combined organic layers were dried (MgSO4)
  9. additionadded some charcoal
  10. temperatureheated
  11. temperatureto reflux
  12. temperatureafter cooling down to 25° C.
  13. filtrationfiltered over a celite pad
  14. customevaporated
  15. dissolutionLight yellow solid residue was dissolved in dichloromethane/MeOH
  16. customdichloromethane evaporated
  17. customseparated by filtration
  18. washrinsed with MeOH and hexanes
  19. customdried

Sources & evidence

ORD record
ord-2ea59e60959d41cda516f7b6d1c23c20
Source dataset
uspto-grants-2014_02
Patent number
US08658646B2

Linked notes

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