Triethylamine → (R)-(1-(2-(3-(Methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone

HRID 931226Notes

Reaction equation

HRID 931226 reaction equation
Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)(=[O:27])=[O:26].[S].C(N(CC)CC)C>CN(C)C=O.C(#N)C>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([C:31]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:26])=[O:27]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 5362487SulfurHCID 135966023-(Methylsulfonyl)benzaldehydeHCID 89854051(R)-(1-(5,6-Diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride

Product 1

HCID 178504722(R)-(1-(2-(3-(Methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (125 mg, 0.3 mmol) in anhydrous N,N-dimethylformamide (2.5 mL) was added 3-(methylsulfonyl)benzaldehyde (76 mg, 0.4 mmol). The solution was stirred at 80° C. for 1 h. Sulfur was added (25 mg, 0.8 mmol) followed by triethylamine (140 μL, 1.0 mmol). The mixture was stirred at 85° C. for 24 h followed by stirring at room temperature for another 24 h. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (20-100% ethyl acetate in heptanes gradient followed by 0-10% methanol in dichloromethane). The residue was repurified via flash chromatography (0-10% methanol in dichloromethane) to afford a yellow solid that was stirred in acetonitrile (3 mL) at 40° C. for 2.5 h. The solid was filtered, washed with cold acetonitrile and dried under high vacuum at 40° C. to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 1.60-1.74 (m, 1H) 1.77-1.89 (m, 2H) 1.89-2.11 (m, 4H) 2.81 (br s, 1H) 2.97-3.09 (m, 2H) 3.17-3.26 (m, 3H) 3.41-3.52 (m, 2H) 3.52-3.63 (m, 1H) 3.74 (br s, 1H) 4.37 (br s, 1H) 4.64 (d, 1H) 6.91 (br s, 1H) 7.74-7.89 (m, 2H) 8.05 (d, 1H) 8.35 (br s, 1H) 8.65 (br s, 1H).

Workup

  1. stirringThe mixture was stirred at 85° C. for 24 h
  2. stirringby stirring at room temperature for another 24 h
  3. concentrationThe mixture was concentrated under reduced pressure
  4. customthe residue was partitioned between dichloromethane and water
  5. extractionThe aqueous layer was extracted with dichloromethane
  6. dry with materialthe combined extracts were dried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified via flash chromatography (20-100% ethyl acetate in heptanes gradient followed by 0-10% methanol in dichloromethane)
  10. customThe residue was repurified via flash chromatography (0-10% methanol in dichloromethane)
  11. customto afford a yellow solid
  12. filtrationThe solid was filtered
  13. washwashed with cold acetonitrile
  14. customdried under high vacuum at 40° C.

Sources & evidence

ORD record
ord-bf25be75bd7a4af1a9a8524e4ebe41cb
Source dataset
uspto-grants-2016_03
Patent number
US09296745B2

Reaction notes

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