Thionyl Chloride → N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-(tetrahydro-pyran-4-sulfonyl)-propionamide

HRID 538652Notes

Reaction equation

HRID 538652 reaction equation
C[C:2]([S:7]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)(=[O:9])=[O:8])([CH3:6])[C:3]([OH:5])=O.O=S(Cl)Cl.[NH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])[CH:22]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.N1C=CC=CC=1.O>[C:27]([C:26]([CH3:30])([CH3:29])[C:23]1[CH:22]=[C:21]([NH:20][C:3](=[O:5])[CH:2]([S:7]([CH:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)(=[O:8])=[O:9])[CH3:6])[O:25][N:24]=1)#[N:28]

Participants

8

Reactant 4

HCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 597040272-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid2×HCID 668766082-(5-Aminoisoxazol-3-yl)-2-methylpropanenitrile2×

Product 1

HCID 117650916N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-(tetrahydro-pyran-4-sulfonyl)-propionamideYield 73.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1049PyridineSolventHCID 1140TolueneSolvent3×

Conditions

Temperature
70 °C

Procedure

To 3.43 g (14.6 mmol) 2-Methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionic acid (intermediate 1) in 38 mL toluene and 17 μL pyridine at 90° C. is added 2.60 g (21.8 mmol) SOCl2 dropwise within 20 min and stirring is continued for 2 h at 90° C. The solvent is evaporated under reduced pressure and the residue is coevaporated twice with toluene (16 mL each) to afford the crude acid cloride. To 2.00 g 2-(5-Amino-isoxazol-3-yl)-2-methyl-propionitrile (13.2 mmol, intermediate 7) in 14 mL toluene is added 3.80 mL (21.8 mmol) DIPEA. To this mixture at 60° C. is added dropwise a mixture of the acid chloride in 16 mL toluene within 10 min and stirring is continued overnight at 50° C. After addition of water (24 mL) the mixture is heated to 70° C. for 2 h and then allowed to cool to RT. The precipitate is filtered, washed with water (2×8 mL) and dried at 50° C. to afford 3.43 g of N-[3-(Cyano-dimethyl-methyl)-isoxazol-5-yl]-2-(tetrahydro-pyran-4-sulfonyl)-propionamide.

Workup

  1. customThe solvent is evaporated under reduced pressure
  2. customto afford the crude acid cloride
  3. additionTo this mixture at 60° C. is added dropwise
  4. stirringstirring
  5. waitis continued overnight at 50° C
  6. temperatureto cool to RT
  7. filtrationThe precipitate is filtered
  8. washwashed with water (2×8 mL)
  9. customdried at 50° C.

Sources & evidence

ORD record
ord-d8e849848c934366a53b49a5f025aa87
Source dataset
uspto-grants-2014_10
Patent number
US08865744B1

Reaction notes

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