Sodium hydride → (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid (3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amide

HRID 538647Notes

Reaction equation

HRID 538647 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([OH:14])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][C:49]([C:59]1[CH:63]=[C:62]([NH2:64])[O:61][N:60]=1)([CH3:58])[CH2:50][O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1.[H-].[Na+]>CN(C=O)C>[CH3:58][C:49]([C:59]1[CH:63]=[C:62]([NH:64][C:12]([C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:14])[O:61][N:60]=1)([CH3:48])[CH2:50][O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1

Participants

7

Reactant 5

HCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 51980116(S)-1-(Tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acidHCID 592532173-[1,1-Dimethyl-2-(tetrahydropyran-2-yloxy)-ethyl]-isoxazol-5-ylamine2×

Product 1

HCID 67953847(S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid (3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amideYield 20.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To 1.20 g (6.02 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid in DMF (50 mL) are added 3.67 mL (21.1 mmol) diisopropyl-ethyl-amine and 3.44 g (9.03 mmol) of HATU. The solution is stirred at RT for 1 h. In a second flask to 1.45 g (6.02 mmol) of 3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylamine (intermediate 7a) in DMF (25 mL) are added 602 mg sodium hydride (60% dispersion in oil; 15.1 mmol) under cooling by an ice bath. Then this solution is added to the activated acid and stirring is continued for 48 h. The reaction mixture is purified by HPLC-MS to afford 0.51 g of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid (3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amide. Yield: 20%; ESI-MS: 422 [M+H]+; HPLC (Rt): 1.55 min (method C)

Workup

  1. temperatureunder cooling by an ice bath
  2. additionThen this solution is added to the activated acid
  3. stirringstirring
  4. waitis continued for 48 h
  5. customThe reaction mixture is purified by HPLC-MS

Sources & evidence

ORD record
ord-4a4c4f37bdb94c3e9c2c7e58565754ab
Source dataset
uspto-grants-2014_10
Patent number
US08865744B1

Reaction notes

Loading…