Potassium Carbonate → HCID 66989272, compound

HRID 1917622Notes

Reaction equation

HRID 1917622 reaction equation
[CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[C:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]2)=[O:4].Br[CH2:36][C:37]1[N:42]=[C:41]([N:43]2[C:51](=[O:52])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]2=[O:53])[CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[C:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([O:14][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([N:43]3[C:44](=[O:53])[C:45]4[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:51]3=[O:52])[N:42]=1)[CH:10]=[CH:9]2)=[O:4]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 112323512-(6-Bromomethyl-pyridin-2-YL)-isoindole-1,3-dioneHCID 178500183HCID 178500183, compound

Product 1

HCID 66989272HCID 66989272, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A suspension of methyl 3-[1-(2,2-dimethylpropanoyl)-7-hydroxy-3-(4-methoxybenzoyl)indolizin-2-yl]-2,2-dimethylpropanoate (350 mg, 0.75 mmol), 2-(6-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (286 mg, 0.90 mmol), and potassium carbonate (416 mg, 3.0 mmol) in DMF (4 mL) is stirred for 6 h at 70° C. The mixture is partitioned between CH2Cl2 and brine. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, heptane to 50% EtOAc in heptane) gives methyl 3-[1-(2,2-dimethylpropanoyl)-7-{[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pyridin-2-yl]methoxy}-3-(4-methoxybenzoyl)indolizin-2-yl]-2,2-dimethylpropanoate that is dissolved in EtOH (5 mL) and treated with a 50% aqueous hydrazine (wt/wt) solution (0.75 mL). The mixture is heated at 70° C. for 2 h then cooled to 23° C. and filtered. The volatile components from the filtrate are removed in vacuo. The residue is purified by flash chromatography (SiO2, heptane to 50% EtOAc in heptane) giving methyl 3-{7-[(6-aminopyridin-2-yl)methoxy]-1-(2,2-dimethylpropanoyl)-3-(4-methoxybenzoyl)indolizin-2-yl}-2,2-dimethylpropanoate (342 mg, 78%) that is dissolved in MeOH (2 mL), THF (2 mL), and aqueous 5M sodium hydroxide (1 mL). The solution is heated at 70° C. for 3 h then cooled and acidified with AcOH. The mixture is partitioned between CH2Cl2 and brine then organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give 3-{7-[(6-aminopyridin-2-yl)methoxy]-1-(2,2-dimethylpropanoyl)-3-(4-methoxybenzoyl)indolizin-2-yl}-2,2-dimethylpropanoic acid (310 mg, 98%) that is dissolved in DMF (3 mL). This solution is treated with ammonium carbonate (57 mg, 0.73 mmol), Boc-anhydride (136 mg, 0.62 mmol), and pyridine (0.1 mL, 1.5 mmol) and stirred for 30 min. The mixture is directly purified by reverse phase HPLC to give the title compound (115 mg, 40%).

Workup

  1. customThe mixture is partitioned between CH2Cl2 and brine
  2. customThe organics are collected
  3. dry with materialdried with MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurification of the crude by flash chromatography (SiO2, heptane to 50% EtOAc in heptane)

Sources & evidence

ORD record
ord-c3f25ca3f7814819a58e63d2c0a291c4
Source dataset
uspto-grants-2013_12
Patent number
US08618300B2

Reaction notes

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