Hydrochloric Acid → 3-(3-(4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)propionic acid

HRID 2215507Notes

Reaction equation

HRID 2215507 reaction equation
[OH-:1].[Na+].[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:23]([C:33]([O:35]C4C=CC=CC=4)=O)C(=O)OC4C=CC=CC=4)[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].[OH-:42].[Li+].Cl>CN(C)C=O.O1CCCC1.CO.O>[CH3:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:33](=[O:35])[NH:7][CH2:8][CH2:9][C:10]([OH:42])=[O:1])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 14798Sodium HydroxideHCID 21949175Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate

Product 1

HCID 219492973-(3-(4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)ureido)propionic acidYield 66%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Ethyl 4-aminopropionate hydrochloride (588 mg, 3.8 mmol) was suspended in N,N-dimethylformamide (3.0 ml), and then 5N aqueous solution of sodium hydroxide (0.77 ml, 3.8 mmol) was added, and the reaction mixture was stirred at room temperature. Phenyl N-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)-pyridin-2-yl)-N-(phenoxycarbonyl)carbamate (400 mg, 0.77 mmol, Production example 5-2) was added thereto, and the reaction mixture was stirred at room temperature for 0.75 hours. Water was added to the reaction mixture, and this was subjected to extraction with ethyl acetate-tetrahydrofuran, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate) to yield a pale brown oil. This oil was dissolved in tetrahydrofuran (4.0 ml) and methanol (2.0 ml), 4N aqueous solution of lithium hydroxide (0.77 ml) was added at room temperature, and the reaction mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 1N hydrochloric acid (3.1 ml) was added while stirred at room temperature; and this was subjected to extraction with ethyl acetate-tetrahydrofuran, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A small amount of acetone was added to the obtained amorphous solid, and this solution was diluted with diethyl ether. The crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (200 mg, 0.50 mmol, 66%) as colorless crystals.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 0.75 hours
  2. extractionthis was subjected to extraction with ethyl acetate-tetrahydrofuran
  3. dry with materialdried over anhydrous magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate)
  6. customto yield a pale brown oil
  7. stirringthe reaction mixture was stirred at room temperature for 1.5 hours
  8. stirringwhile stirred at room temperature
  9. extractionand this was subjected to extraction with ethyl acetate-tetrahydrofuran
  10. washwashed with brine
  11. dry with materialdried over anhydrous magnesium sulfate
  12. concentrationconcentrated under reduced pressure
  13. additionA small amount of acetone was added to the obtained amorphous solid
  14. additionthis solution was diluted with diethyl ether
  15. filtrationThe crystals were filtered off
  16. washwashed with diethyl ether
  17. customdried under aeration

Sources & evidence

ORD record
ord-650b16d42ce64292ad7ee2969a645228
Source dataset
uspto-grants-2006_09
Patent number
US07109219B2

Reaction notes

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