Tetrahydrofuran → 2,2-Dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester

HRID 593539Notes

Reaction equation

HRID 593539 reaction equation
Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(OCC)C.Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 87885Chloromethyl pivalateHCID 3251421Potassium bis(trimethylsilyl)amideHCID 445539625-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride

Product 1

HCID 582155992,2-Dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidCatalystHCID 3283Diethyl EtherSolvent

Conditions

Temperature
0 °C

Procedure

A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of 2,2-dimethyl-propionic acid chloromethyl ester (2.58 mL, 8.95 mmol). The reaction mixture is stirred at room temperature for 3.5 h, then washed with water and extracted with ethyl acetate twice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford an oil, which is taken up in diethyl ether. A few drops of concentrated HCl are added. Evaporation of the solvent and lyophilization give 2,2-dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester as a solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 1.12 (s, 9H), 2.27 (s, 3H), 6.06 (s, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.74 (dd, J=7.8, 5.1 Hz, 1H), 8.01-8.16 (m, 1H), 8.64-8.79 (m, 2H). HRMS (ESI) m/z 357.1121 [(M+H)+ Calcd for C20H22ClN2O2: 357.1127].

Workup

  1. stirringThe reaction mixture is stirred at room temperature for 3.5 h
  2. washwashed with water
  3. extractionextracted with ethyl acetate twice
  4. dry with materialThe organic layer is dried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1)
  7. customto afford an oil, which
  8. customEvaporation of the solvent and lyophilization

Sources & evidence

ORD record
ord-29c330d649034f5999f2034029f91dd4
Source dataset
uspto-grants-2016_01
Patent number
US09242963B2

Reaction notes

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