N,N-Dimethylglycine → 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-imidazol-1-yl-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol

HRID 409452Notes

Reaction equation

HRID 409452 reaction equation
[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:29]1[N:34]=[CH:33][C:32](Br)=[CH:31][N:30]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1.[NH:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C([O-])([O-])=O.[K+].[K+].CN(C)CC(O)=O.N.O>[Cu]I.CCOC(C)=O.CS(C)=O>[F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:6][N:7]([C:29]1[N:34]=[CH:33][C:32]([N:45]2[CH:49]=[CH:48][N:47]=[CH:46]2)=[CH:31][N:30]=1)[C@@H:8]1[CH2:12][N:11]([C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[N:14]=2)[C@H:10]([CH2:27][CH3:28])[CH2:9]1

Participants

9

Reactant 5

HCID 673N,N-DimethylglycineHCID 795ImidazoleHCID 11430Potassium CarbonateHCID 12896473Azane;hydrateHCID 596143681-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol

Product 1

HCID 596143311-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-imidazol-1-yl-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-olYield 20.5%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A 15 ml round-bottom tube is charged with 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol (32 mg, 0.044 mmol), imidazole (6 mg, 0.088 mmol), CuI (9 mg, 0.044 mmol), K2CO3 (12 mg, 0.088 mmol), N,N-dimethyl glycine (5 mg, 0.044 mmol) and DMSO (0.5 ml). Then the tube is sealed and heated to 110 degree for 18 hours. After cooling to rt, saturated NH3/H2O, EtOAc is added and then filtered through Celite pad. The solution is extracted with EtOAc and organic layer was dried over MgSO4. Removal of solvent and purification with reverse phase column give 1-(4-{(2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-imidazol-1-yl-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidin-1-yl}-5-chloro-pyrimidin-2-yl)-piperidin-4-ol (6.5 mg, 0.009 mmol, 20%).

Workup

  1. customThen the tube is sealed
  2. temperatureheated to 110 degree for 18 hours
  3. filtrationfiltered through Celite pad
  4. extractionThe solution is extracted with EtOAc and organic layer
  5. dry with materialwas dried over MgSO4
  6. customRemoval of solvent and purification with reverse phase column

Sources & evidence

ORD record
ord-0920eb78d2a24e18b876fb803a13078a
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Reaction notes

Loading…