1-Methoxy-2-propanol → 7-(2-Methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acid

HRID 1188946Notes

Reaction equation

HRID 1188946 reaction equation
[OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7]2.C(P(CCCC)CCCC)CCC.[CH3:39][O:40][CH2:41][CH:42](O)[CH3:43].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH-].[Na+]>O1CCCC1.CO>[CH3:39][O:40][CH2:41][CH:42]([CH3:43])[O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2

Participants

8

Reactant 5

HCID 79001-Methoxy-2-propanolHCID 13831TributylphosphineHCID 14798Sodium HydroxideHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 66897290Methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate

Product 1

HCID 668978497-(2-Methoxy-1-methylethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylic acidYield 52%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

To a solution of methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (2.5 g), tributylphosphine (2.79 g) and 1-methoxypropan-2-ol (1.24 g) in tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (3.48 g) at 60° C. The whole was stirred at 60° C. for 1.5 h and then concentrated in vacuo. Diisopropyl ether was added to the residue and insoluble materials were removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1, volume ratio) and then by basic silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1, volume ratio) to give a colorless oil. A mixture of the oil, 1M aqueous sodium hydroxide solution (15 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 20 h. The mixture was washed with diethyl ether. The organic layer was extracted with 1M aqueous sodium hydroxide solution. The water layers were combined, acidified by 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with hexane to give the title compound (1.50 g, 52%) as colorless crystals. MS 421 (MH+).

Workup

  1. concentrationconcentrated in vacuo
  2. additionDiisopropyl ether was added to the residue and insoluble materials
  3. customwere removed by filtration
  4. concentrationThe filtrate was concentrated in vacuo
  5. customThe residue was purified by silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1, volume ratio)
  6. customby basic silica gel chromatography (ethyl acetate:hexane=1:2 to 2:1, volume ratio) to give a colorless oil
  7. stirringwas stirred at room temperature for 20 h
  8. washThe mixture was washed with diethyl ether
  9. extractionThe organic layer was extracted with 1M aqueous sodium hydroxide solution
  10. extractionextracted with ethyl acetate
  11. washThe organic layer was washed with brine
  12. dry with materialdried (MgSO4)
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. washThe residue was washed with hexane

Sources & evidence

ORD record
ord-6d342f5fa33c4daea06531a5dcfe3007
Source dataset
uspto-grants-2014_03
Patent number
US08673942B2

Reaction notes

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