1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester → 2-methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one

HRID 593665Notes

Reaction equation

HRID 593665 reaction equation
C([O:3][C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:9][CH2:8][CH2:7]1)=O)C.[CH:28]([Mg]Cl)([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([CH3:30])[C:4]([C:6]1([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]3[N:19]([CH3:27])[C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:17]=2)[CH2:7][CH2:8][CH2:9]1)=[O:3]

Participants

4

Reactant 2

HCID 595346291-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl esterHCID 178418918HCID 178418918, compound

Product 1

HCID 595346582-methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester (Example 213b, 0.45 g, 1.21 mmol) in THF (150 mL) cooled with an ice-water bath is added iPrMgCl (2.0M in THF, 2.43 mL, 4.85 mmol) dropwise. After 45 min, the mixture is quenched with 1M aqueous NaHSO4 (5 mL), washed with saturated aqueous sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:2 to 1:1), followed by purification by RP HPLC on an Xbridge RP18 eluting with a gradient of acetonitrile in 0.1% aqueous NH4OH to give 2-methyl-1-(1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutyl)-propan-1-one.

Workup

  1. customthe mixture is quenched with 1M aqueous NaHSO4 (5 mL)
  2. washwashed with saturated aqueous sodium bicarbonate and brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 3:2 to 1:1)
  7. customfollowed by purification by RP HPLC on an Xbridge
  8. washRP18 eluting with a gradient of acetonitrile in 0.1% aqueous NH4OH

Sources & evidence

ORD record
ord-f3e71448acfc44559f6e5ae6f679a6f1
Source dataset
uspto-grants-2016_01
Patent number
US09242963B2

Reaction notes

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