Hydrochloric Acid → 4-((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyric acid

HRID 2215515Notes

Reaction equation

HRID 2215515 reaction equation
Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16].[OH-].[Li+].Cl>CN(C)C=O.O1CCCC1.CO.O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 14798Sodium HydroxideHCID 126496614-Aminobutyrate ethyl hydrochlorideHCID 21949175Phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate

Product 1

HCID 219493364-((4-(1-Methylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)butyric acidYield 76.9%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

Ethyl 4-aminobutyrate hydrochloride (1.0 g, 6.0 mmol) was suspended in N,N-dimethylformamide (6.7 ml), 5N aqueous solution of sodium hydroxide (1.2 ml, 6.0 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 (700 mg, 1.3 mmol, Production example 5-2) was added thereto and the reaction mixture was stirred at room temperature for 1.2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, ethyl acetate) to yield a pale yellow oil. This oil was dissolved in tetrahydrofuran (6.0 ml) and methanol (3.0 ml); 4N lithium hydroxide (1.1 ml) was added thereto at room temperature; and the reaction mixture was stirred at room temperature for 3.5 hours. Moreover, 1N hydrochloric acid (4.4 ml) and water (2 ml) were added thereto while stirred at room temperature; and this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After the precipitated crystals were suspended in diethyl ether:hexane=1:1, the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (411 mg, 1.0 mmol, 75%) as colorless crystals.

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 1.2 hours
  2. customThe reaction mixture was partitioned between ethyl acetate and water
  3. dry with materialThe organic layer was dried 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 yellow oil
  7. customat room temperature
  8. stirringand the reaction mixture was stirred at room temperature for 3.5 hours
  9. stirringwhile stirred at room temperature
  10. extractionand this was subjected to extraction with ethyl acetate
  11. washwashed with brine
  12. dry with materialdried over anhydrous magnesium sulfate
  13. concentrationconcentrated under reduced pressure
  14. filtrationhexane=1:1, the crystals were filtered off
  15. washwashed with diethyl ether
  16. customdried under aeration

Sources & evidence

ORD record
ord-93467c5414c943568456e005d5500759
Source dataset
uspto-grants-2006_09
Patent number
US07109219B2

Reaction notes

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