1-(Chloromethyl)piperidin-2-one → 3-(Pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-oxo-piperidin-1-ylmethyl ester

HRID 1376131Notes

Reaction equation

HRID 1376131 reaction equation
[K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29]>C1COCC1>[O:29]=[C:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20]

Participants

4

Reactant 2

HCID 130983721-(Chloromethyl)piperidin-2-oneHCID 690066653-(4-Pyridinylamino)-1h-indole-2-carboxylic acid potassium salt

Product 1

HCID 103167033-(Pyridin-4-ylamino)-1H-indole-2-carboxylic acid 2-oxo-piperidin-1-ylmethyl esterYield 26%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

Heat at 50° C. a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (1.6 g, 5.49 mmol) in anhydrous THF (30 mL) in an oil bath for 20 min. Add a solution of N-(chloromethyl)-2-piperidone (850 mg, 5.76 mmol) in anhydrous THF (5 mL) dropwise. After 30 min, cool the reaction to ambient temperature. Add water (100 mL), and extract with ethyl acetate (3×100 mL). Combine the organic layers, wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 35 gram silicagel cartridge, eluting with 5% methanol in ethyl acetate then 20% methanol in ethyl acetate. Combined product containing fractions and, concentrate to give the title compound as a white solid (520 mg, 26%): MS 365 (M+H), TLC (silica gel, MeOH/EtOAc 25:75) Rf=0.18, 1H NMR (DMSO-d6) δ 11.77 (1H, s), 8.46 (1H, s), 8.08 (2H, d, J=5.7 Hz), 7.50 (3H, m), 7.09 (1H, m), 6.58 (2H, d, J=6 Hz), 5.54 (2H, s), 3.27 (2H, br2), 2.23 (2H, brs), 1.66 (4H, brs). 13C NMR (DMSO-d6) δ 170.00, 160.43, 152.25, 149.44, 135.54, 125.60, 122.96, 121.84, 120.22, 119.87, 118.99, 113.00, 108.59, 70.99, 47.00, 31.99, 22.39, 20.60.

Workup

  1. temperaturecool
  2. customthe reaction to ambient temperature
  3. extractionAdd water (100 mL), and extract with ethyl acetate (3×100 mL)
  4. washCombine the organic layers, wash with NaHCO3 (sat), water, brine
  5. dry with materialdry with MgSO4
  6. concentrationconcentrate
  7. customPurify the residue on an ISCO RediSep 35 gram silicagel cartridge
  8. washeluting with 5% methanol in ethyl acetate
  9. additionCombined product containing fractions
  10. concentrationconcentrate

Sources & evidence

ORD record
ord-c87d3e3c8bd246cab9ea440a18cac7ac
Source dataset
uspto-grants-2007_01
Patent number
US07169925B2

Reaction notes

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