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

HRID 593663Notes

Reaction equation

HRID 593663 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[N:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1([CH:27]=O)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:18]([O:20][C:21]([C:23]1([CH2:27][NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]3[N:9]([CH3:17])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:3]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])[CH3:19]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 12226109Ethyl 1-formylcyclobutanecarboxylateHCID 582155792-(5-amino-pyridin-3-yl)-1-methyl-1H-indole

Product 1

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

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 2-(5-amino-pyridin-3-yl)-1-methyl-1H-indole (Example 100, 0.400 g, 1.756 mmol) and 1-formyl-cyclobutanecarboxylic acid ethyl ester (0.457 g, 2.633 mmol) in dichloromethane (13 mL) is added acetic acid (0.102 g, 1.756 mmol) and the mixture is refluxed. After 2 h, the mixture is cooled with an ice-water bath and sodium triacetoxyborohydride (1.175 g, 5.267 mmol) is added. After 13 h, the mixture is heated to reflux for 1.5 h, cooled to room temperature, diluted with dichloromethane, washed with 1M aqueous NaOH, water and brine. The combined aqueous phase is extracted once with dichloromethane and the combined organic phase is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to give 1-{[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylamino]-methyl}-cyclobutanecarboxylic acid ethyl ester as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3H), 1.99-2.12 (m, 4H), 2.49-2.59 (m, 2H), 3.53 (d, J=5.8 Hz, 2H), 3.78 (s, 3H), 4.12-4.18 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 6.61 (d, J=0.8 Hz, 1H), 7.04 (dd, J=2.8, 1.9 Hz, 1H), 7.15-7.19 (m, 1H), 7.26-7.30 (m, 1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 8.09 (d, J=2.8 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H).

Workup

  1. temperaturethe mixture is refluxed
  2. temperaturethe mixture is cooled with an ice-water bath
  3. waitAfter 13 h
  4. temperaturethe mixture is heated
  5. temperatureto reflux for 1.5 h
  6. washwashed with 1M aqueous NaOH, water and brine
  7. extractionThe combined aqueous phase is extracted once with dichloromethane
  8. dry with materialthe combined organic phase is dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1)

Sources & evidence

ORD record
ord-23da6c2adfa74ce9ace6337f4f0a5ca6
Source dataset
uspto-grants-2016_01
Patent number
US09242963B2

Reaction notes

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