Methyl 2-aminopyridine-4-carboxylate → 2-[4-(1-Tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester

HRID 872307Notes

Reaction equation

HRID 872307 reaction equation
[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][N:31]=1>C(O)C>[CH3:39][O:38][C:36]([C:34]1[CH:33]=[CH:32][N:31]2[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[N:29]=[C:30]2[CH:35]=1)=[O:37]

Participants

4

Reactant 2

HCID 236984Methyl 2-aminopyridine-4-carboxylateHCID 86691038tert-Butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate

Product 1

HCID 666656142-[4-(1-Tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl esterYield 47%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A mixture of {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (4.40 g, 9.91 mmol), methyl 2-aminopyridine-4-carboxylate (3.01 g, 19.8 mmol, 2 equiv) and powdered activated 3A sieves (10 g) in ethanol (37 mL) was heated for 4 h at the reflux temperature. The resulting solution was filtered through a pad of Celite with the aid of CH2Cl2. The resulting solution was separated between CH2Cl2 (50 mL) and a saturated aqueous NaHCO3 solution 50 mL). The organic phase was washed with a saturated aqueous NaCl solution, dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% hexane for 1.0 min., gradient to 80% hexane/20% EtOAc over 1.0 min., 80% hexane/20% EtOAc for 2.0 min., gradient to 75% hexane/25% EtOAc over 1.0 min., 75% hexane/25% EtOAc for 2.0 min, gradient to 50% hexane/50% EtOAc over 4.0 min., 50% hexane/50% EtOAc for 5.0 min., gradient to 25% hexane/75% EtOAc over 9.5 min.) to give 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (2.3 g, 47%):

Workup

  1. temperaturewas heated for 4 h at the reflux temperature
  2. filtrationThe resulting solution was filtered through a pad of Celite with the aid of CH2Cl2
  3. customThe resulting solution was separated between CH2Cl2 (50 mL)
  4. washThe organic phase was washed with a saturated aqueous NaCl solution
  5. dry with materialdried (Na2SO4 anh)
  6. concentrationconcentrated under reduced pressure
  7. customThe remaining material was purified
  8. customMPLC (Biotage Isolera; 100 g SNAP cartridge: 100% hexane for 1.0 min., gradient to 80% hexane/20% EtOAc over 1.0 min., 80% hexane/20% EtOAc for 2.0 min., gradient to 75% hexane/25% EtOAc over 1.0 min., 75% hexane/25% EtOAc for 2.0 min, gradient to 50% hexane/50% EtOAc over 4.0 min., 50% hexane/50% EtOAc for 5.0 min., gradient to 25% hexane/75% EtOAc over 9.5 min.)

Sources & evidence

ORD record
ord-da036bc2241b42d9b5662ea8eb3b79c0
Source dataset
uspto-grants-2015_03
Patent number
US08975265B2

Reaction notes

Loading…