HOAt → N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide

HRID 1962879

Reaction equation

HRID 1962879 reaction equation
[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:18][CH3:19])[C:15]([OH:17])=O)=[CH:8][CH:7]=2)#[CH:2].ON1C2N=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:52][C:53]([CH3:58])([CH2:56][OH:57])[C:54]#[N:55]>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[C:54]([C:53]([NH:52][C:15](=[O:17])[CH:14]([O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:12]2)[S:18][CH3:19])([CH3:58])[CH2:56][OH:57])#[N:55]

Participants

9

Reactant 4

HCID 181649HOAtHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 144057522-Amino-3-hydroxy-2-methylpropanenitrileHCID 59565474(3-Ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid

Product 1

HCID 59565307N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamideYield 38.8%

Reagents, catalysts & solvents 4

HCID 6342AcetonitrileSolvent2×HCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

To a solution of (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (4.0 g) and triethylamine (6 ml) in dry acetonitrile (50 ml) at room temperature were added successively a 1-hydroxy-7-azabenzotriazole (2.39 g) and O-(1H Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (5.64 g) and a solution of 2-amino-3-hydroxy-2-methyl-propionitrile (1.76 g) in dry acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 18 hrs and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then, dried over sodium sulphate. After filtration and concentration under reduced pressure, the crude residue was dissolved in 50 ml of THF/H2O (1/1) and treated with 260 mg of LiOH monohydrate at room temperature for 1 hr. The crude mixture was extracted (pH=11) thrice with ethyl acetate. The organic layers were combined, washed with water, with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure, the crude residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:4, 0:1) to provide 2.02 g of N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (m.p. 78-80° C.).

Workup

  1. customThe two layers were separated
  2. extractionthe aqueous layer was extracted thrice with ethyl acetate
  3. washwashed once with brine
  4. dry with materialdried over sodium sulphate
  5. filtrationAfter filtration and concentration under reduced pressure
  6. dissolutionthe crude residue was dissolved in 50 ml of THF/H2O (1/1)
  7. additiontreated with 260 mg of LiOH monohydrate at room temperature for 1 hr
  8. extractionThe crude mixture was extracted (pH=11) thrice with ethyl acetate
  9. washwashed with water, with brine
  10. dry with materialdried over sodium sulphate
  11. filtrationAfter filtration and concentration under reduced pressure
  12. customthe crude residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:4, 0:1)

Sources & evidence

ORD record
ord-83e5b67dd8ca41aa977d80063878cfd0
Source dataset
uspto-grants-2013_04
Patent number
US08415272B2

Linked notes

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