Sodium Dithionite → tert-butyl 3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-1-carboxylate

HRID 1096615Notes

Reaction equation

HRID 1096615 reaction equation
[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([N+:15]([O-])=O)=[CH:5][CH:4]=1.[CH:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:21]3)=[N:15][C:6]2=[CH:5][CH:4]=1

Participants

4

Reactant 3

HCID 24489Sodium DithioniteHCID 42325667tert-Butyl (3R)-3-formylpiperidine-1-carboxylateHCID 667860886-methoxy-N-(3-methoxypropyl)-3-nitropyridin-2-amine

Product 1

HCID 66785067tert-butyl 3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-1-carboxylateYield 76%

Procedure

6-Methoxy-N-(3-methoxypropyl)-3-nitropyridin-2-amine (33B) (1.56 mmol max, crude oil) and (R)-tert-butyl 3-formylpiperidine-1-carboxylate (1.56 mmol, 0.332 g) were added to an oven dried 50 mL round-bottomed flask equipped with a reflux condenser and for stirring under nitrogen. Ethanol (4 mL) and dimethyl sulfoxide (2 mL) were added and the solution was allowed to stir at room temperature for 5 min. Sodium hydrosulfite (4.68 mmol; 0.959 g of 85%) was then added and the resultant mixture was heated to reflux and allowed to stir for 16 hr. The reaction solution was then concentrated in-vacuo, poured into water (100 mL), extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording a brown oil that was further purified by silica gel chromatography (20% CH3CN/CH2Cl2) to afford tert-butyl 3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidine-1-carboxylate (33C) as a clear oil (1.19 mmol, 0.481 g, 76% yield over 2-steps). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s, 9H) 1.54-1.70 (m, 1H) 1.84 (dt, J=13.83, 2.81Hz, 1H) 2.02-2.21 (m, 4H) 2.73-2.88 (m, 1H) 2.96-3.18 (m, 2H) 3.29-3.41 (m, 5H) 3.98 (s, 3H) 4.08-4.44 (m, 4H) 6.65 (d, J=8.59 Hz, 1H) 7.86 (d, J=8.59 Hz, 1H). ESI-MS: m/z 405.5 (M+H)+.

Workup

  1. customdried 50 mL round-bottomed flask
  2. customequipped with a reflux condenser
  3. additionEthanol (4 mL) and dimethyl sulfoxide (2 mL) were added
  4. stirringto stir at room temperature for 5 min
  5. temperatureto reflux
  6. stirringto stir for 16 hr
  7. concentrationThe reaction solution was then concentrated in-vacuo
  8. additionpoured into water (100 mL)
  9. extractionextracted with ethyl acetate
  10. washwashed once with saturated aqueous sodium chloride
  11. customThe organic layer was collected
  12. dry with materialsubsequently dried with anhydrous Na2SO4
  13. filtrationfiltered
  14. customThis filtrate was collected
  15. concentrationconcentrated
  16. customdried in-vacuo
  17. customaffording a brown oil that
  18. customwas further purified by silica gel chromatography (20% CH3CN/CH2Cl2)

Sources & evidence

ORD record
ord-501ffdcbdde643688c9aaf456252f881
Source dataset
uspto-grants-2012_03
Patent number
US08138168B1

Reaction notes

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